c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

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Journal homepage: www.elsevier.com/locate/cortex

Special Issue "Luria’s legacy in the era of cognitive neuroscience": Review

Updating functional brain units: Insights far

beyond Luria

~ a-Casanova a,b,c,*, Gonzalo Sa

Jordi Pen  nchez-Benavides d and
Jorge Sigg-Alonso e
a
Integrative Pharmacology and Systems Neuroscience Research Group, Neuroscience Program, Hospital del Mar
Medical Research Institute, Barcelona, Spain
b
Department of Psychiatry and Legal Medicine, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain
c
 , Barcelona, Spain
Test Barcelona Services, Teia
d
Barcelonabeta Brain Research Center (BBRC), Fundacio Pasqual Maragall, Barcelona, Spain
e
Department of Behavioral and Cognitive Neurobiology, Institute of Neurobiology, National Autonomous University
of Mexico (UNAM), Queretaro, Mexico

article info abstract

Article history: This paper reviews Luria's model of the three functional units of the brain. To meet this
Received 28 September 2023 objective, several issues were reviewed: the theory of functional systems and the contri-
Revised 15 January 2024 butions of phylogenesis and embryogenesis to the brain's functional organization. This
Accepted 15 February 2024 review revealed several facts. In the first place, the relationship/integration of basic ho-
Published online 29 February 2024 meostatic needs with complex forms of behavior. Secondly, the multi-scale hierarchical
and distributed organization of the brain and interactions between cells and systems.
Keywords: Thirdly, the phylogenetic role of exaptation, especially in basal ganglia and cerebellum
AR Luria expansion. Finally, the tripartite embryogenetic organization of the brain: rhinic, limbic/
Cognitive neuroscience paralimbic, and supralimbic zones. Obviously, these principles of brain organization are in
Systems neuroscience contradiction with attempts to establish separate functional brain units.
Neuronal networks The proposed new model is made up of two large integrated complexes: a primordial-
Exaptation limbic complex (Luria's Unit I) and a telencephalic-cortical complex (Luria's Units II and III).
Behavior As a result, five functional units were delineated: Unit I. Primordial or preferential (brainstem),
Neuropsychology for life-support, behavioral modulation, and waking regulation; Unit II. Limbic and para-
limbic systems, for emotions and hedonic evaluation (danger and relevance detection and
contribution to reward/motivational processing) and the creation of cognitive maps
(contextual memory, navigation, and generativity [imagination]); Unit III. Telencephalic-
cortical, for sensorimotor and cognitive processing (gnosis, praxis, language, calculation,
etc.), semantic and episodic (contextual) memory processing, and multimodal conscious
agency; Unit IV. Basal ganglia systems, for behavior selection and reinforcement (reward-
oriented behavior); Unit V. Cerebellar systems, for the prediction/anticipation (orthometric
supervision) of the outcome of an action.
The proposed brain units are nothing more than abstractions within the brain's
simultaneous and distributed physiological processes. As function transcends anatomy,
the model necessarily involves transition and overlap between structures. Beyond the

 , Barcelona, Catalonia, Spain.

* Corresponding author. Test Barcelona Services, Tarragona 25, 08329 Teia
E-mail address: [email protected] (J. Pen ~ a-Casanova).
https://doi.org/10.1016/j.cortex.2024.02.004
0010-9452/© 2024 Elsevier Ltd. All rights reserved.
20 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

classic approaches, this review includes information on recent systemic perspectives on

functional brain organization. The limitations of this review are discussed.
© 2024 Elsevier Ltd. All rights reserved.

(functional systems and phylogenesis), (2) to propose and

1. Introduction discuss a new advanced model of brain functional units.

Aleksandr Romanovich Luria (1902e1977) was one of the

eminent figures who contributed to the foundation of neuro- 2. Review of two basic issues
psychology. Luria's neuropsychology is the comprehensive
and creative synthesis of the neuroscientific and clinical This section deals with two basic issues related to Luria's
knowledge of his time. His theoretical concepts and specific neuropsychology that will help the development process for
contributions to all fields of neuropsychology are recognized an updated functional model of the brain: the theory of
by the world's scientific community (Akhutina, Glozman, functional systems, and phylogenetic and embryogenetic ap-
Moskovich, & Robbins, 2004; Cole, 1978; Mecacci, 2005; Pen ~ a- proaches, including the concept of exaptation.
Casanova, 1989). One of the characteristics of Luria's neuro-
psychology is the unitary view of the human brain and mind 2.1. The theory of functional systems
(Mecacci, 2005).
A conceptual model of brainebehavior relationships con- Functional systems (Anokhin, 1935; Bertalanffy, 1949, 1968;
stitutes one of the foundations of clinical neuropsychology, Ukhtomsky, 1950) represent a view opposed to reflexes, as
especially in the process of systematic and accurate inter- reflexes are based on linear (stimulus-response) information
pretation of neuropsychological assessment data (Cimino, processing from receptors to effectors. The basic principle of
2000). Concerning the organization of the brain, Luria (1973c) functional systems is the physiological self-organizing non-
considered “the existence of solid anatomical and functional linear relationship between a multitude of distributed local
grounds for distinguishing three main functional units of the systems to establish a holistic system or integrated unit
brain whose participation is necessary for any type of mental (Bertalanffy, 1968; Luria, 1973a, 1973c). Consequently, the
activity” (p. 43). He noted that “they can be described as a unit goals of functional systems are not specific actions in
for regulating tone or waking, a unit for obtaining, processing, themselves but the adaptive results of these actions. From
and storing information coming from the outside world, and a this view, the key function of the brain is not to build
unit for programming, regulating, and verifying mental ac- knowledge about the world but to act in a changing envi-
tivity” (p. 43). Luria also recognized that “it would be a mistake ronment to maintain life (Cisek, 2021; Leopold & Averbeck,
to imagine that each of these units can carry out a certain 2022).
form of activity completely independently” (p. 99). In this field, and for the objective of this paper, it is
In Luria's time, the approach to brain function was typi- particularly important to recognize two types of functional
cally corticocentric. The so-called “corticocentric myopia” systems (FS), and their differentiated contribution to the ho-
(Parvizi, 2009) was a kind of leitmotif in classical neuroscience meostasis and survival of the individual (Luria, 1973c). This
and neuropsychology. The development, especially in the last differentiation (see below) agrees with the current concepts
decade, of new clinical, anatomical, and physiological that recognize the difference between basic “physiological
knowledge implies a serious challenge to classic concepts and control”, which operates via feedback loops within the body,
Luria's specific contributions (see Prigatano, 2003 [on dogma in and “behavioral control”, which extends toward the external
neuropsychology]). Currently, the study of brainebehavior environment (Cisek, 2007, 2021).
relationships must be improved by reviewing the classic Functional systems type I (basic physiological control). This
basic assumptions (Westlin et al., 2023). In addition, the con- type of functional system provides homeostasis at the
tributions of systems biology and systems physiology, neu- expense of internal (already available) resources of the body
roconnectivity (see Bigler, 2016; Bigler & Maxwell, 2011; (Luria, 1973c). Homeostasis (Cannon, 1932) constitutes a state
Bullmore & Sporns, 2009; Catani & Thiebaut de Schotten, of internal physical and chemical equilibrium that maintains
2012; Hart, Ypma, Romero-Garcia, Price, & Suckling, 2016), life (Bernard, 1866). Such equilibrium includes a series of
and precision medicine in neurology and psychiatry (see variables, including body temperature, heart rate, fluid bal-
Crary, 2023; Hampel et al., 2023; Hu, Xin, Hu, Zhang, & Wang, ance, hunger, and libido (Cannon, 1932).
2017; Pascoal et al., 2021) imply a radical change in the tradi- All these functions depend on primitive evolutionary sys-
tional paradigm of neuropsychology. tems located primarily in the brainstem and in Yakovlev's
Therefore, the need to upgrade Luria's brain units is critical telencephalic rhinic zone, intimately bound to the hypothal-
and necessary in the context of current knowledge. In this amus (Yakovlev, 1948). Signals from internal states generate
process, we have highlighted a series of criticisms that can outputs that activate the solution of basic homeostatic needs
help update Luria's model (see Pen ~ a-Casanova, 1989, 2007, (Luria, 1973c; Cisek, 2021; Leopold & Averbeck, 2022). Thus,
~
2018; Pena-Casanova & Sigg-Alonso, 2019, 2020). even in a situation of sleep, biologically interoceptive relevant
The objectives of this paper are twofold: (1) to review two information (e.g., cold or bladder distention) can promote
basic issues for the development of a functional brain model wakening and adequate behaviors (Seeley & Sturm, 2007). The
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 21

topic of hormones and behavior (behavioral endocrinology) is connectivity architecture of the brain (Van den Heuvel, Mandl,
an important part of this area (see below). Kahn, & Hulshoff Pol, 2009).
Functional systems type II (behavioral control). This type of Functional webs (for a functional model see Pulvermüller,
“complex” functional system (CFS) supports homeostasis 2002) dramatically show that cortico-cortical interrelation-
thanks to the generation of mental content and the execution ships transcend the anatomical model (Yeo et al., 2011). In
of different types of behavior (Anokhin, 1935; Luria, 1973c). addition, the cortical components of these networks have
After Luria, CFSs “are organized into complex behavioral vertical connections with the basal ganglia and the cere-
systems, as a result of whose action the appropriate needs are bellum, defining a global integrated functional system
satisfied and the necessary balance of the internal economy of (Coppola et al., 2022; Milardi et al., 2019). For more informa-
the organism is restored” (Luria, 1973c, p. 53). In this sense, tion, see section 3.3.
homeostatic needs are all satisfied behaviorally (Cabanac, Neuroarchitecture does not respect the limits of mental
2010). It is concluded that basic biological needs are inte- terms such as perception, action, emotion, praxis, memory, or
grated anatomically and functionally with “higher” cognitive language, and these terms are epistemically very limited
functions (Luria, 1973b). In fact, direct and indirect motiva- (Pernu, 2017). From the complex systems perspective, three
tional connections are articulated between the hypothalamus principles of brain organization have been described: 1)
and the telencephalon (Leopold & Averbeck, 2022). Motivation massive combinatorial anatomical connectivity; 2) highly
and action systems in the brain need to link and interact in distributed functional coordination; and 3) network/circuits as
different timescales (from immediate [e.g., escape from a functional units (Pessoa, 2022). These ideas imply the need to
danger situation] to long scale [e.g., plan and maintain an dissolve boundaries within the brain and lead to the concept
academic project]), (Courtemanche & Cammalleri, 2019). of the entangled brain (Pessoa, 2022). Obviously, these prin-
Beyond strict biological needs (primum vivere), CFSs are the ciples of brain organization are in contradiction with the at-
foundation of sophisticated forms of socio-cultural behaviors tempts to establish separate functional brain units.
(Ardila, 2018; Leontiev, 1959; Luria, 1974; Vygotsky, 1960, 1965). Finally, from the network science perspective, the bases of
For an update of Vygotsky's and Luria's ideas on sociocultural behavior considered in terms of serial perceptual, cognitive,
structures in individual psychological function, including the and motor processing are far from physiological reality (Cisek
neurobiology of ideology, see Wexler (2006). & Kalaska, 2010). As an alternative, a model of “interactive
behavior as simultaneous processes that specify potential
2.1.1. Network science and connectional neuroanatomy motor actions and select between them” (interactive para-
Vygotsky (1965) already raised the problem of distributed digm) has been proposed (Cisek & Kalaska, 2010, p. 269).
localization of psychological functions, recognizing the
assumption of the existence of “complex dynamic systems 2.1.1.1. A NOTE OF CAUTION ON FUNCTIONAL NEUROIMAGING AND THE
which have to be considered that result of integration of NEED FOR CONVERGING KNOWLEDGE. Given that many authors have
elementary functions” (p. 382). Thus, distributed systems drawn attention to the limitations and poor scientific value of
necessarily imply binding systems between local centers certain functional neuroimaging studies (Cohen, 1996; Nichols
(Luria, 1973c; Shepherd, 1994). In fact, the brain shows a & Newsome, 1999; Otzenberger, Gounot, Marrer, Namer, &
multi-scale hierarchical organization (Shepherd, 1994, 2004) Metz-Lutz, 2005; Raichle, 2003; Ross, 2010; Uttal, 2001) it is
with complex nested elements that finally subserve important to recognize consistent, widely accepted, and
conscious states, cognition, and behavior (Dehaene & convergent studies with other research methodologies, espe-
Naccache, 2001, chap. 1; Hilgetag & Goulas, 2020; Lawn cially with traditional, lesion-based, approaches.
et al., 2023). The contributions of network science (Baraba  si It is important to highlight that classical neuropsychology
et al., 2023; Medaglia, Lynall, & Bassett, 2015) are crucial to is based eminently on focal vascular lesions and local trau-
our current understanding of how human brain function matic injuries. Currently, in the case of neurodegenerative
arises from the interactions of cells and systems, at the diseases, the determination of functional localization is usu-
micro-, meso- and macro-scale (Sporns, 2011, 2016). This ally based on “regression analysis where impairment magni-
multi-scale distributed organization leads to the concept of tude in a given domain is correlated with the magnitude of
emergent property, defined as “a property of a system which atrophy of hypometabolism” (Mesulam, 2023, p. 21).
is not possessed by any of its constituent parts in isolation”
(Rose, 2006, p. 20). 2.2. Phylogenesis, embryogenesis, and the functional
Non-invasive neuroimaging methods, including positron organization of the brain
emission tomography (PET) (Martin, Powers, & Raichle, 1987;
Raichle, 2011), functional magnetic resonance imaging The human brain is a product of evolution (Cisek, 2021; Kaas,
(fMRI) (Kwong et al., 1992; Ogawa et al., 1992), and specific 2008, 2013; Kaas, Qi, & Stepniewska, 2022). It is important to
methods to study the brain's connectivity (see Rahimi, remember the role of selection in evolving systems (Wong
Jackson, Farahibozorg, & Hauk, 2023) are extremely valuable et al., 2023), and that “assembly theory” explains and quan-
for the study of cortical networks. Beyond the cytoarchitec- tifies selection and evolution (Sharma et al., 2023). Even fac-
tonic and topologic organization of the cerebral cortex, tors such as evolutionary connectomics (Karten, 2015) or the
connectional neuroanatomy acquires a fundamental role in evolution of neuromodulators (Castrillon et al., 2023) have an
the study of brain physiology and pathology (Catani & important role in understanding brain organization.
Thiebaut de Schotten, 2012). Notably, functionally connected As a final result, the anatomical and functional organiza-
resting-state networks reflect the underlying structural tion of the brain is shaped by its history (Cisek & Hayden,
22 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

2021). This fact, as commented, offers a great opportunity to and the cerebellar hemispheres will be one of the results of
understand the fundamental principles of the brain's struc- their development (Bear, Connors, & Paradiso, 2016; Lecours &
ture and function. However, beyond the most biological as- Simard, 1998; Yakovlev, 1948). In this part of the brain, the
pects, the evolution of culture and humanities has a crucial right and the left parts grow identically, with no laterality ef-
role in humans (Leerssen, 2021). fects on the body (Yakovlev, 1948).
In the five-vesicle phase of development (five weeks of
2.2.1. Phylogenesis and exaptation gestation), three main divisions appear: (1) rhombencephalon
Exaptation is a process by which an old core phylogenetic unit (myelencephalon [medulla oblongata], and metencephalon
has been co-opted for multiple functions (Gould & Vrba, 1982). [pons and cerebellum]); (2) mesencephalon (midbrain); and (3)
Specifically, a series of studies show that basal ganglia cir- prosencephalon. The prosencephalon is further divided into
cuitry is present in the phylogenetically oldest vertebrates (4) the diencephalon (hypothalamus, thalamus, and epi-
(Cisek, 2021; Stephenson-Jones, Samuelsson, Ericsson, thalamus) and (5) the telencephalon (cerebral hemispheres:
Robertson, & Grillner, 2011). This type of circuitry has most cortex, subcortical white matter, basal ganglia, and basal
likely been conserved as a mechanism for action selection forebrain nuclei).
used by all vertebrates (Grillner & Robertson, 2016; The current prosomeric model of brain organization places
Stephenson-Jones et al., 2011). Thus, phylogenetically, the hypothalamus and telencephalon in the same segmental
emotional/affective, and cognitive regulations are considered place (neuromere) of the neural tube (Puelles & Rubenstein,
extensions and refinements of the motor control system 2015). Structures found in the same segment are considered
(Stephenson-Jones et al., 2011). Consequently, for the basal more likely to retain their interrelationship through phyloge-
ganglia, motor functions, emotion, and cognition constitute netic evolution (Leopold & Averbeck, 2022). This model clearly
similar parallel processes (Koziol & Budding, 2009; shows the inextricable connection between the most basic
Stephenson-Jones et al., 2011). functions linked to homeostasis and cognition.
The evolution of the brain also exhibits a parallel growth of From the embryogenetic process, Yakovlev (1948) proposed
the cortex, mostly frontal and inferior parietal lobes (Cisek, a tripartite anatomic and behavioral organization of the cor-
2021), the caudate nucleus, and the lateral hemispheres and tex: entopallium, mesopallium, and ectopallium, arranged in
dentate nucleus of the cerebellum (Parvizi, 2009). This devel- concentric rings. The entopallium is intimately bound to the
opment generates, by exaptation, two parallel vertically rostral end of the brainstem, the hypothalamus.
organized cortical-subcortical-cortical series of loops: the Each of the pallial layers constitutes a different telence-
basal ganglia systems and the cerebellar systems (Coppola phalic division, respectively: telencephalon impar, telenceph-
et al., 2022; Milardi et al., 2019). alon semipar, and telencephalon totopar. The boundary
A detailed phylogenetic characterization of the evolved between telencephalon semipar and telencephalon totopar is
vertebrate brain shows that its architecture displays an gradual (Lautin, 2002). A transitional cortex (mesocortex) in-
enormous amount of communication of signals. This archi- tercalates between the allocortex and the isocortex (Mesulam,
tecture supports an important degree of computational flexi- 2000; Pandya, Seltzer, Petrides, & Cipolloni, 2015; Yakovlev,
bility that “enables animals to cope successfully with complex 1948). Interestingly for the purpose of his paper, Yakovlev
and ever-changing environments” (Pessoa, Medina, & Desfilis, (1948) related each of the “three brains” to a different type of
2021, p. 1). Considering the extreme complexity and variability cytoarchitectonic, connections, and motility. It is also impor-
of the environment, genetic instructions are, in principle, not tant to comment that Yakovlev's (1948) distinctions overlap
sufficient to specify neural connections with sufficient adap- with the classification of the cortical areas of the human brain
tive precision (Cisek & Kalaska, 2010). In addition, self- according to Mesulam (Mesulam, 2000, p. 8 [Figure 1e6]).
organization (Singer, 1986) or self-tuition processes (Leopold The telencephalon impar (median zone, rhinic) includes the
& Averbeck, 2022) are needed that allow the optimization of septum, paraolfactory areas (subcallosal area of Broca), ol-
genetically predetermined connectivity systems using factory bulbs (paleocortex), and hippocampi (archicortex).
ecological experiences. Therefore, developmental neuronal These structures roughly correspond to the areas described by
activity becomes a critical factor in the development of the Mesulam (2000) as “corticoid þ allocortex” (limbic areas). The
functional architecture of the forebrain (Singer, 1986). rhinic brain is devoted to endokinesis or cell-bound movement,
These considerations also lead to the embodied perspec- related to visceral motility (e.g., peristalsis). At this point, we
tive. This viewpoint holds that cognitive processes are deeply should note that endokinesis is already related to pre-
rooted in the body's continuous sensorimotor interactions telencephalic structures.
(task-relevant inputs and outputs) with the world The telencephalon semipar (limbic zone, paramedian), in-
(Pulvermüller, 2013; Wilson, 2002). cludes the cingulate gyrus, isthmus of the cingulate, para-
hippocampal gyrus, limen insulae, and insula (Yakovlev, 1948).
2.2.2. Embryogenesis and the behavioral architecture of the These structures roughly correspond to the areas described by
brain Mesulam (2000) as “paralimbic areas”, the paralimbic belt.
For the delineation of a functional model of the brain, it is very After Lautin (2002), the semipar brain is isomorphic to Broca's
important to understand the central nervous system structure lobe (gyrus fornicatus, olfactory lobe).
through its development. On the fifth day of gestation, the After Yakovlev (1948), the mode of projection of this para-
rostral end of the neural tube resembles a median holosphere median brain is ambilateral and is related to ereismokinesis or
with two primordia distributed symmetrically. These body-bound movement, dedicated to the expression of emotions
primordia represent the subcortical structures of the brain, (e.g., pain, mimicry, swearing).
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 23

It is important to remember that the cerebral cortex has a anterior cortices, respectively, were unified into a single Unit
dual origin: two tendencies or lines of increasing complexity (new Unit III, the entire cortex). Finally, considering exap-
from the allocortex to the isocortex (Abbie, 1940; Dart, 1934; tation (Gould & Vrba, 1982; Stephenson-Jones et al., 2011) and
Sanides, 1969). These tendencies, which originate from the the vertical organization of the brain (Edelman & Tononi, 2000;
limbic primordia (olfactory paleocortex and hippocampal Koziol & Budding, 2009; Parvizi, 2009), two functional units
archicortex), will define the anatomical, cytoarchitectonic, were added: basal ganglia systems (new Unit IV), and cere-
and functional characteristics of the supralimbic networks bellar systems (new Unit V). In subsequent sections, the
(Cummings & Mega, 2003). These two tendencies generate the anatomical structures and functions of each new unit will be
paralimbic ring as follows: discussed.
The olfactocentric trend (olfactory paleocortex, closely asso-
ciated with the amygdala) provides the temporal pole, insula, 3.1. Unit I: preferential or primordial systems
and posterior orbitofrontal cortex. The hippocampocentric trend
(hippocampus and the indusium griseum [archicortex]), con- This unit consists of the medial and most primitive phyloge-
stitutes the primordia for the parahippocampal (“rhinal”) netic regions of the brain: the brainstem (medulla, pons, and
cortices (entorhinal, prorhinal, perirhinal, presubiculum, and midbrain), its related structures, and Yakovlev's telenceph-
parasubiculum), the retrosplenial area, the cingulate gyrus, alon impar. This part of the brain closely resembles that of fish
the subcallosal regions (paraolfactory zone), and the posterior and reptiles (Crosby, 1917). As previously commented, the
parahippocampal mesocortex (Pandya et al., 2015). These telencephalon impar includes the septum, paraolfactory
trends are important in the design of a functional brain model areas, olfactory bulbs, and hippocampi (Lautin, 2002;
since they allow the recognition of differentiated groups of Yakovlev, 1948). The main brainstem structures that consti-
structures (olfactocentric and hippocampocentric) and their tute this unit are the following: 1) cranial nerve nuclei and
related functions. related structures (associated with eye movements, [e.g.,
Telencephalon totopar (supralimbic zone). This telence- convergence center] and hearing); 2) long tracts (motor and
phalic part is the result of the ontogenetic development of the somatosensory pathways); 3) cerebellar circuitry (cerebellar
primordia of the frontal, parietal, temporal, and occipital lobes peduncles, pontine nuclei, red nucleus [parvocellular], central
(Yakovlev, 1948). These structures correspond to the homo- tegmental tract, inferior olivary nucleus); 4) Reticular forma-
typic isocortex (high-order [heteromodal] association areas, tion systems and related structures (Blumenfeld, 2010).
and modality-specific [unimodal] association areas) and the Specifically, the reticular formation systems and related
idiotypic cortex (primary sensory and motor areas), according structures include 1) systems with widespread projection, and
to Mesulam's classification (Mesulam, 2000). The totopar specific ascending neuromodulatory systems (noradrenergic,
telencephalon has a mode of contralateral projection and is dopaminergic, serotonergic, cholinergic, histaminergic, and
related to telokinesis or object-bound voluntary movement (e.g., others [see below]); 2) nuclei involved in sleep regulation; 3)
tool use). pain neuromodulatory systems (periaqueductal gray, rostral
Note that to conceptually schematize the vertical organi- ventral medulla); and 4) brainstem motor and autonomic
zation of the brain, the cerebral cortices are frequently control nuclei: posture and locomotion (reticular formation,
simplified into three broad groups of areas: limbic, associative, vestibular nuclei, superior colliculi, red nucleus, substantia
and sensorimotor (see below, sections 3.4.2 and 3.5.1). nigra, pedunculopontine tegmental nucleus); breathing
The distinctions made by Yakovlev (1948) are com- (cough, hiccup, sneeze, shiver, swallow: nausea and vomit-
plemented and improved by current conceptions of survival ing); autonomic control, including blood pressure and heart
and motor and behavioral control systems (Cisek, 2007, 2021; rate; sphincter control (including the pontine micturition
Cisek & Kalaska, 2010; Leopold & Averbeck, 2022; Grillner & El center).
Manira, 2020; Kaas, 2008). As mentioned, the prosomeric In summary, the brainstem and related structures regulate
framework modifies not only the topological view of the many of the most basic bodily functions necessary for sur-
telencephalon but also its interconnections with the hypo- vival, including the regulation of immunity (Pavlov, Chavan, &
thalamus (Leopold & Averbeck, 2022). Tracey, 2018; Schiller, Ben-Shaanan, & Rolls, 2021; Tracey,
2007; Udit, Blake, & Chiu, 2022). Furthermore, as will be seen
below, reticular systems will act in an interrelated manner in
3. Far beyond Luria: a model of two large the activation and modulation of a multitude of complex
integrated complexes and five functional units forms of behavior.

Considering recent advances in neuroscience, our previous 3.1.1. Neuromodulatory systems

articles on Luria's model, and the concepts reviewed in the A summary of the main neuromodulatory systems with their
previous section, a new functional brain model is tentatively primary location, anatomic target, and main physiological/
proposed. functional role, is presented below (see Bohlen & Halbach,
The new model is made up of two large integrated com- 2008; Ettinger, 2023).
plexes: a primordial-limbic complex (Luria's Unit I) and a Norepinephrine (NE) [noradrenaline, NA]. NE is produced
telencephalic complex (Luria's Units II and III). The model is mainly in the pons (locus coeruleus [LC]) and some small,
characterized by the following components: Luria's Unit I was related nuclei. Three pathways exit the LC: 1) Descendent
divided into two units: brainstem (new Unit I), and limbic pathway to the spinal cord; 2) Ascendent dorsal pathway to
systems (new Unit II). Luria's Units II and III, the posterior and the hippocampus, cerebellum, and forebrain; 3) Ascendent
24 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

ventral pathway to the hypothalamus, midbrain, and Dopaminergic signaling pathways are crucial to the
extended amygdala (central medial amygdala, sublenticular maintenance of physiological processes and an unbalanced
substantia innominata, and the bed nucleus of the stria ter- activity may lead to dysfunctions related to some neurode-
minalis). This specific pathway arises from a series of small generative diseases of the nervous system, such as Parkin-
nuclei in the lateral medulla oblongata and pons (Moore & son's, Huntington's, schizophrenia, Attention Deficit and
Bloom, 1979). Hyperactivity Disorder (ADHD), and addiction (Klein et al.,
NE is involved with arousal, vigilance, alertness, mood 2019; Lester et al., 2010).
elevation, and on focus of attention on salient stimuli. It is also Serotonin (5-hydroxytryptamine, 5-HT). This neuro-
associated with reward dependency (Menza, Golbe, Cody, & modulator is produced in the midbrain and pons, the raphe
Forman, 1993). It is released in response to stress (Dunn, nuclei. Descendent pathways project into the spinal cord.
Swiergiel, & Palamarchouk, 2004). NE inhibits the sponta- Ascendant pathways project to all regions of the brain,
neous resting activity of the cortical neurons and these neu- including the cerebellum. However, most serotonin is found
rons become more sensitive to specific sensory inputs (Segal & outside the central nervous system (Berger, Gray, & Roth, 2009,
Bloom, 1976). p. 356).
There is an intense relationship between dopaminergic The serotonergic system is complex, with 15 known types
systems and noradrenergic neurons in the brain, especially of receptors. Class 1 serotonin receptors are inhibitory, while
referring to the modulation of the LC-epinephrine system in class 2 receptors are excitatory. All 15 serotonin receptors are
dopamine transmission (Zhu, 2018). expressed outside as well as within the brain.
Dopamine (DA). Dopamine is a neurotransmitter, synthe- Many of the effects of serotonergic projections are estab-
sized in both the central nervous system and the periphery. lished through the modulation of dopaminergic and
The dopaminergic systems play important roles in neuro- GABAergic neurons (Yan, Zheng & Yan, 2004). The behavioral,
modulation, such as motor control, motivation, incentive- cognitive, and emotional processes modulated by serotonin
motivated behavior, reward, cognitive function, maternal, include “mood, perception, reward, anger, aggression, appe-
and reproductive behaviors (Klein et al., 2019; Lester, Rogers, & tite, memory, sexuality, and attention, among others. Indeed,
Blaha, 2010). it is difficult to find a human behavior that is not regulated by
Dopaminergic modulatory systems are mainly located in serotonin” (Berger et al., 2009, p. 356).
the substantia nigra pars compacta (SNc), the ventral A unified theory of brain serotonin function has been
tegmental area (VTA), and surrounding areas (Haber, Fudge, & proposed (Carhart-Harris & Nutt, 2017). This is a bipartite
McFarland, 2000). Three projection systems arise from these model based on the view that serotonergic transmission en-
formations. hances two distinct adaptive responses to adversity, mediated
The mesostriatal (nigrostriatal) pathway arises mainly from in large part by its two most prevalent brain receptors: 5-HT1A
the SNc and projects to the caudate and putamen (striatum). and 5-HT2A. The authors propose that passive coping (i.e.,
DA release in these structures facilitates motor function. tolerating a source of stress) is mediated by postsynaptic 5-
The mesolimbic pathway arises mainly from the VTA and HT1AR receptors, characterized by stress moderation (the
projects to limbic formations, such as the amygdala, cingulate brain's default mode for adversity). Conversely, active coping
gyrus, nucleus accumbens septi, and medial temporal cortex. (i.e., actively addressing a source of stress) is mediated by 5-
DA activity in the nucleus accumbens septi generates a sense HT2AR receptors, characterized by enhanced plasticity
of reward; in the amygdala, it activates the processing of (defined as the capacity for change). This theory also considers
threatening stimuli; and in the hippocampus, it facilitates that the 5-HT1AR pathway is enhanced by conventional 5-HT-
memory processing (Bergman et al., 2014; Rocchetti et al., reuptake-blocking antidepressants, whereas the 5-HT2AR
2015). pathway is enhanced by 5-HT2AR-agonist psychedelics
The mesocortical pathway arises mostly from the VTA and (Carhart-Harris & Nutt, 2017).
projects to the entire cortex, predominantly to the prefrontal Acetylcholine (ACh). Cholinergic projection neurons are
cortex (Bonci & Jones, 2007). The release of mesocortical DA found in two major areas of the brain: the basal forebrain and
facilitates normal cortical activity (especially dorsolateral the mesopontine tegmentum. In the basal forebrain, cholin-
prefrontal activities) and working memory. ergic neurons are in the nucleus basalis of Meynert (NBM) [in
There are five G protein-coupled DA receptors: D1 and D5 the substantia innominata], medial septal nucleus, and bed
(D1-like family), D2, D3, and D4 (D2-like family). These receptors nucleus of the stria terminalis (BNST); additional ACh neurons
mediate all the physiological functions of DA, ranging from are in the diagonal band of Broca and the preoptic nucleus of
voluntary movement and reward to hormonal regulation and the hypothalamus (Ananth, Rajebhosale, Kim, Talmage, &
hypertension (Beaulieu & Gainetdinov, 2011). D1 receptors Role, 2023; Mesulam, Mufson, Levey, & Wainer, 1983). In the
predominate in the cortex. D2 receptors are concentrated in the mesopontine tegmentum, ACh neurons are located in the
striatum, nucleus accumbens septi, and olfactory tubercle, but pedunculopontine nucleus and laterodorsal tegmental nu-
are also found in the cortex in limited numbers. These re- cleus (He, Li, Deng, & Zuo, 2023). In the brain, ACh functions as
ceptors are also found on dopaminergic cell soma where they a neurotransmitter and a neuromodulator.
act as autoreceptors. D3 receptors are found in the nucleus Central cholinergic systems are involved in arousal,
accumbens septi and olfactory tubercle and are fewer in attention, motivation, reward, learning, memory, and plas-
number. D4 receptors are sparsely located in the frontal cortex, ticity (Deiana, Platt, & Riedel, 2011; Drever, Riedel, & Platt,
midbrain, and amygdala. D5 receptors are found in the hip- 2011; Van der Zee, Platt, & Riedel, 2011). ACh also promotes
pocampus and hypothalamus (Beaulieu & Gainetdinov, 2011). REM sleep (Platt & Riedel, 2011).
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 25

There are two main types of ACh receptors: nicotinic (fast- serotonergic and dopaminergic, and between the cholinergic
acting ionotropic) and muscarinic (slow-acting G protein- and dopaminergic systems. Furthermore, the anatomical and
coupled receptors). Nicotinic receptor subtypes are a and b. functional differentiation of three major dopaminergic path-
Five muscarinic receptor subtypes, M1eM5, are known to exist ways with specific roles in the organization of limbic, associa-
(Abrams et al., 2006). The NBM acts on M1 receptors within the tive and sensorimotor functions is very significant (see below).
neocortex (predominantly frontal and parietal lobes). The
medial septal nucleus innervates the hippocampus and parts 3.1.2. From reticular systems to receptomics: an integrated
of the cerebral cortex at M1 receptors. The mesopontine view
tegmentum mainly activates M1 receptors in the brainstem, The core region of the brainstem was named the “reticular
deep cerebellar nuclei, pontine nuclei, LC, and the inferior formation” due to the presence of fibers affording the
olive. It also projects to the basal ganglia, thalamus, basal appearance of a web (“reticulum”). This label was established
forebrain, and tectum (Woolf, Eckenstein, & Butcher, 1984; at a time when histological techniques could not recognize the
Woolf & Butcher, 1985, 1986, 1989 [rat brain]; Oda & Nakanishi, nuclear heterogeneity of this region. The classic view of the
2000 [human brain]). The cerebellar cholinergic system be- reticular formation (Moruzzi & Magoun, 1995 [1949]) has been
longs to the third type of afferent nerve fiber system (after the substantially modified in recent decades (Parvizi & Damasio,
climbing and mossy fibers) and has important modulatory 2001). These are several of the main updates:
effects on cerebellar circuits and cerebellar-mediated func-
tions (Zhang, Zhou, & Yuan, 2016). (1) The reticular formation is not made up of a web of
In addition, ACh is an important internal transmitter in neurons but rather a series of nuclei with structural
striatum interneurons (Oda & Nakanishi, 2000). In humans, (anatomical) and functional differences. For this reason,
non-human primates, and rodents, these interneurons it was suggested that the term “reticular formation”
respond to salient environmental stimuli with responses that may be misleading (Brodal, 1959; Olszewski, 1954).
are temporally aligned with the responses of dopaminergic (2) The heterogeneous series of nuclei of the reticular for-
neurons of the substantia nigra (Goldberg & Reynolds, 2011; mation can modulate cortical activity via pathways
Matityahu et al., 2023; Morris, Arkadir, Nevet, Vaadia, & other than the traditional intralaminar nuclei of the
Bergman, 2004; Tan & Bullock, 2008). It cannot be denied that thalamus. Most of these projection systems originate in
excitatory and inhibitory amino acid-based neurotransmitters the rostral brainstem reticular formation (pontome-
(e.g., glutamate, and gamma-aminobutyric acid [GABA]) play a sencephalic); however, other projecting systems are
fundamental role in modulating the activity of midbrain DA found in the hypothalamus, thalamus, and basal fore-
neurons, however, recent studies suggest that cholinergic brain (Parvizi & Damasio, 2001). Some of these systems
transmission may also be very important (Lester et al., 2010; are diffuse, projecting to large regions of the brain. In
Mena-Segovia, Winn, & Bolam, 2008). Ascending cholinergic contrast, in other cases, individual neurons have specific
projections from the pedunculopontine and laterodorsal projections that allow a focalized control of specific
tegmental nuclei target dopaminergic neurons in the sub- targets (Blumenfeld, 2010). Projection systems are
stantia nigra compacta and ventral tegmental area following a crucial for maintaining an alert conscious state, regu-
topographical gradient. In a close interaction with glutamate lating attention, the sleepewake cycle, memory,
and GABA, cholinergic projections activate nicotinic and emotional status, and super-learning (Breton-
muscarinic receptors within the substantia nigra and VTA, to Provencher, Drummond, & Sur, 2021; Caligiore, Arbib,
influence DA transmission in the ventral/dorsal striatum and Miall, & Baldassare, 2019).
prefrontal cortex (Lester et al., 2010; Mena-Segovia et al., 2008). (3) Different ascending pathways from the reticular for-
Brainstem cholinergic neurons are thus in a position to criti- mation use diverse neurotransmitters, thus the under-
cally influence the activity of DA neurons in the midbrain and lying molecular mechanisms are distinct. The effect of
thereby have an important role in the expression of diverse activating a single modulatory system (i.e., transmitter/
forms of behavior (Mena-Segovia et al., 2008). receptor) influences the brain's function across a given
Histamine (H). Histamine-releasing cells are found in the anatomical distribution (Parvizi & Damasio, 2001). The
tuberomammillary nucleus located within the posterior third concept of a “cortical receptome” was recently intro-
of the hypothalamus; this nucleus is a part of the tuber ciner- duced to study “the distribution and densities of
eum. Axons are sent to the cerebral cortex, hippocampus, expression of different modulatory receptor types
neostriatum, nucleus accumbens septi, amygdala, and other across the brain's anatomical connectivity matrix”
nuclei of the hypothalamus (Yanai & Tashiro, 2007). H is (Jancke, Herlitze, Kringelbach, & Deco, 2022, p. 1). The
involved in arousal, alertness, the sleepewake cycle, appetite term “chemo-receptomics” encapsulates a similar
control (energy homeostasis), learning, and memory (Yanai & concept (Zerbi et al., 2019).
Tashiro, 2007). Antihistamines that cross the bloodebrain (4) Modulation of the cortex by reticular systems is much
barrier affect arousal. Histamine also plays a significant role more complex than the simple desynchronization of its
in the transmission of vestibular information that can produce electrophysiological rhythms (Parvizi & Damasio, 2001).
nausea and vomiting (Clark, Boutros, & Mendez, 2018). There Local synchronization patterns embedded within global
are four histamine receptors (see Parsons & Ganellin, 2006). desynchronization are generated. In addition, the non-
The preceding paragraphs highlight the great interdepen- specific projections from the thalamus are of great sig-
dence of the neurotransmitter systems reviewed, especially nificance for generating a thalamocortical reverberance
between the dopaminergic and noradrenergic, between the (Llinas, Ribary, Contreras, & Pedroarena, 1998).
26 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

These are important contributions that can be used to In summary, the following structures are included within
establish unified theories of brain function beyond anatomical Unit II (see Kamali et al., 2023; Mesulam, 2000): 1) the hypo-
structural hierarchies because they link micro-scale infor- thalamus (for a review see Lechan and Toni, 2016); 2) the
mation to systems-level dynamics (Lawn et al., 2023). Thus, as limbic parts of the cortex (corticoid [septal region, substantia
stated in the previous section, response to a threat dramati- innominata, amygdaloid complex], and allocortical forma-
cally increases the release of norepinephrine from the LC, tions [hippocampal complex and piriform or primary olfactory
which increases global brain connectivity, primarily within areas]); 3) the paralimbic cortex (orbitofrontal cortex, insula,
the salience network (Zerbi et al., 2019). The interrelationship temporal pole, parahippocampal cortices, and the cingulate
between neurotransmitter systems has already been high- cortex); 4) the limbic striatum (olfactory tubercle and nucleus
lighted in the preceding section. accumbens septi), limbic pallidum, ventral tegmental area of
In this conceptual context, the specific functional compu- Tsai, and habenula; 5) the limbic and paralimbic thalamic
tational characteristics and the interplay between the three nuclei (anterior dorsal, anterior ventral, laterodorsal, medi-
basic learning processes (unsupervised, reinforcement, and odorsal, medial pulvinar, and other midline nuclei).
supervised) are influenced by the ascending neuromodulatory The primary limbic functions can be summarized into five
systems (Doya, 2002; Poldrack & Rodriguez, 2004), forming a groups (Mesulam, 2000): 1) perception of smell, taste and pain;
highly integrated system “combining different learning 2) the processing of affiliative behaviors related to social group
mechanisms into an effective super-learning process support- cohesion (Nelson, 2011); 3) the bidirectional linking of emotion
ing the acquisition of flexible motor behavior” (Caligiore et al., and drives (e.g., cold, hunger, libido) to extra-personal events
2019, p. 19). and subjective mental content; 4) the bidirectional linking of
mental content with autonomic, endocrine, and immunolog-
3.1.3. Unit I and biological survival ical states (Udit et al., 2022); 5) the binding of distributed in-
As stated above, several structures of Unit I are mostly involved formation related to recent events and experiences in a way
in basic bodily functions necessary for biological survival and that supports context/episodic memory, and imagination
behavior. This unit is named “preferential or primordial” (Comrie, Frank, & Kay, 2022). These functions are extended and
because it has a functional priority due to its main participation shared with related behavioral capacities (Whalen & Phelps,
in life-supporting processes (Pen ~ a-Casanova, 2018). 2009). In this sense, it is clear that the core of emotional
The machinery of homeostasis has been designed to experience is closely related to ancient phylogenetic brain
“protect the integrity of living organisms” (Damasio, 2009, p. systems underpinning consciousness in the upper brainstem
212). In fact, “values” attributed to objects and activities have and related structures (Turnbull & Salas, 2021). A posteriori, a
some relation, direct or indirect, to the maintenance of living series of complex cognitive processes have emerged to help
organisms within a homeostatic range (Cisek, 2021). Biological animals “manage these basic emotional states, in the context
“values” are intimately related to primitive systems of reward/ of environmental and social constraints (e.g., attaching
motivation and emotions. Phylogenetically, the primordial emotional valence to future events, suppressing or amplifying
(Unit I) and limbic systems (Unit II) are strongly inter- emotions, or using emotions to frame decisions)” (Turnbull &
connected with homeostatic regulation systems (Luria, 1973b, Salas, 2021, p. 9). This topic will be discussed below.
1973c; Mesulam, 2000). The hypothalamus plays a role in the The influence of the hypothalamus regarding the control of
physiological interconnection with the amygdala, hippocam- complex behaviors is expressed via three predominant path-
pus, and autonomic systems (Hariri, 2015). The salience ways (Risold, Thompson, & Swanson, 1997; Leopold &
network (see below) will play an essential role in the motiva- Averbeck, 2022): 1) projections to subpallial structures,
tional and reward evaluation of objects. The anatomy and including the bed nucleus of the stria terminalis (BNST) and
physiology of brainstem systems, and especially reticular septum, which interact with the amygdala and hippocampus,
systems, clearly show that the brain functions as a whole: the respectively; 2) projections to relay thalamic nuclei to the
cited “entangled brain” (Pessoa, 2022). telencephalon (paraventricular, anterior thalamic and
reuniens nuclei); 3) direct projections to the telencephalon,
3.2. Unit II: limbic and paralimbic systems including its pallial structures. It is therefore considered that,
in addition to control over the motor circuits via descending
Although Luria (1973b) analyzed the functional role of the projections (Swanson, 2000), the hypothalamus directly in-
allocortex and commented on the significance of the Klüver- tervenes in the expression of the behavior generated in the
Bucy and Bekhterev-Korsakoff syndromes, he did not differ- telencephalon (Leopold & Averbeck, 2022).
entiate a limbic unit. It is worth commenting that this unit had Paralimbic cortices have intensive links with limbic and
been previously proposed (Jubert, 1983; Te llez & Sa  nchez, heteromodal areas (Mora  n, Mufson, & Mesulam, 1987;
2016). Schmahmann & Pandya, 2006). These structures are special-
Beyond Yakovlev's (1948) telencephalic divisions, the unit ized in behaviors that integrate information from the internal
proposed here is based on current structural, physiological, environment (interoception) with stimuli from the external
and neurobehavioral data that characterize the revised and environment (Lledo, 2022).
expanded limbic systems (Kamali et al., 2023; Catani, In a revised model of the limbic system, three distinct but
Dell'acqua, & Thiebaut de Schotten, 2013). Critical to the partially overlapping networks were identified (Catani,
model, limbic structures are the parts of the brain that have Dell'acqua, et al., 2013): 1) the hippocampal-diencephalic and
the most intense mutual links with the hypothalamus parahippocampal-retrosplenial network devoted to memory
(Mesulam et al., 1983). and spatial orientation; 2) the temporo-amygdala-
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 27

orbitofrontal network for the integration of autonomic 3.2.1.3. HIPPOCAMPUS AND HIPPOCAMPAL FORMATION. The hippo-
(“visceral”) sensation and emotion with semantic memory campal formation (dentate gyrus, hippocampus, and sub-
and behavior (see the section on the saliency network); 3) the iculum) receives information from the entorhinal cortex,
default-mode network associated with autobiographical which has reciprocal connections with the sensory associa-
memories and introspective self-directed thinking. This tion areas (Andersen, Morris, Amaral, Bliss, & O'Keefe, 2007;
network probably plays an important role in imagination Hannula & Duff, 2017; Lisman, 2007). James Papez (1937, 1995)
processes (see below). The described networks, as expected, proposed a circuit composed of the following serial structures:
share cortical and subcortical nodes (Catani, Dell'acqua, et al., hippocampal formation (subiculum) e mammillary bodies
2013). (via the fornix) e anterior thalamic nucleus (via the mam-
millothalamic tract) e cingulate gyrus e presubiculum, ento-
3.2.1. Limbic and paralimbic structures: functional aspects rhinal cortex e hippocampus (via the perforant and alvear
In this section, only the functional aspects of the main limbic pathways). This circuit was considered an integrated system
and paralimbic structures will be briefly discussed. For a of cortical and subcortical structures related to emotions
global update on limbic circuits see Kamali et al. (2023). (Papez, 1937, 1995).
The Papez serial circuit remains an influential concept,
3.2.1.1. MAIN BASAL FOREBRAIN-RELATED STRUCTURES. The septal initially for emotion, however, in recent decades, also for
area (SA [septal nuclei]), diagonal band of Broca [DBB], sub- memory, spatial navigation, and imagination (Comrie et al.,
stantia innominata (nucleus basalis of Meynert [NBM], and 2022). Currently, it has been argued that the Papez circuit is
BNST) constitute a core part of the basal forebrain. anatomically naı̈ve as well as outmoded (Aggleton, Nelson, &
The SA is part of the reward system (Devinsky & D'Esposito, O'Mara, 2022; Rolls, 2015). Over the past years, neuroimaging
2004). The NBM, the largest nucleus of cholinergic neurons in studies revealed additional limbic connectivity that in-
the brain, may modulate neocortex function, including limbic corporates multiple circuits to the limbic network (Catani,
areas, with widespread projections (Liu, Chang, Pearce, & Dell'acqua, et al., 2013; Kamali et al., 2023).
Gentleman, 2015). The DBB may have a role in the direct In addition to memory, the hippocampus is also related to
connectivity between the septal nuclei and the hippocampal/ imagination. The capacity to imagine constitutes a biological
amygdala complex (Nolte, 2009). The BNST is a group of nuclei function that is crucial to human cognition. Imagination ex-
located ventral to the septum. Most of the projections reach- periences include “recollections, predictions, simulations,
ing the hypothalamus are from the BNST. Like the hypothal- counterfactuals, fantasies, suppositions, and mind-wander-
amus and septal nuclei, the BNST has narrow connections ing” (Comrie et al., 2022, p. 1). This fundamental ability is
with the prefrontal cortex, amygdala, hippocampus, thal- referred to as generativity (Comrie et al., 2022); these forms of
amus, basal ganglia, and brainstem nuclei/ventral tegmental generativity are relevant to a wide range of cognitive domains,
area (Haines, 2007; Mesulam et al., 1983). The stria terminalis such as memory, planning, learning, and inference, and, in
links the BNST to the amygdala (Hofmann & Straube, 2021). By pathology, are related to hallucinations and confabulations. It
means of connections, the BNST may participate in many is worth mentioning that imagination was traditionally a
limbic circuits that involve both the hypothalamus and septal specific topic of philosophy and psychopathology (Phillips &
nuclei (Kamali et al., 2023). The cited connections are Morley, 2003).
considered an example of the hypothalamic influence on Thanks to the revised model of Catani, Dell'acqua, et al.,
telencephalic motivational circuits, probably influencing and (2013), the concepts of salience and multiple domain net-
generating the expression of exploratory behaviors related to works, and the concept of hippocampal generativity (Comrie
pallial structures, such as the hippocampus and the amygdala et al., 2022), it is possible to reconcile models suggesting that
(Leopold & Averbeck, 2022; Costa, Mitz, & Averbeck, 2019). the hippocampus plays a role in episodic memory, whereas
The habenula is a highly ancient brain structure across others claim a specific role in the generation of spatial and
vertebrates and has been traditionally overlooked in func- cognitive maps, which encode all dimensions of experience in
tional brain models. Initially, its function was considered to be the service of memory (Schiller et al., 2015). Reconciliation can
related to the control of the nearby pineal gland, the “seal of be accomplished from the compatible conception of a cogni-
the soul” after Descartes (1677) (Namboodiri, Rodriguez- tive map as organizing experience and behavior across all
Romaguera, & Stuber, 2016). The habenula is a strategic domains of cognition (Tolman, 1948). These network func-
node in the information flow between fronto-limbic brain tional patterns reflect behavior guided through multidimen-
areas to brainstem nuclei (Ables, Park, & Iban ~ ez-Tallon, 2023). sional (spatial, temporal, and associational) cognitive maps
It plays a central role in regulating motivational, emotional, (Ekstrom & Ranganath, 2018; Schiller et al., 2015).
and cognitive behaviors (Hikosaka, 2010).
3.2.1.4. AMYGDALA AND RELATED STRUCTURES. The amygdala has
3.2.1.2. OLFACTORY (PIRIFORM) PRIMARY CORTEX AND RELATED STRUC- classically been considered a part of the limbic system, with
TURES. The piriform cortex (PiC) receives information from the particularly relevant connectivity to the hypothalamus and
olfactory bulb and is bilaterally connected to the hippocam- brainstem. Anatomical studies of the last decades have shown
pus. The PiC relates to practically all the mesocortical and that the amygdala has a wide-ranging network of connections
limbic areas. The olfactory sense plays a key role in territorial, (Amaral, 1986; LeDoux & Schiller, 2009) and that it has un-
sexual, and feeding behaviors (Mesulam, 2000). For a review of dergone an evolutionary reorganization. The “amygdaloid
central olfactory structures and olfaction and its pleasures see complex” is made up of a group of 13, heavily interconnected
Cleland and Linster (2019), and Gottfried (2010). nuclei, and cortical regions (Freese & Amaral, 2009). The
28 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

amygdala receives sensory information from all modalities. 3.2.1.5. INSULA. The insula was initially associated with
The human is most densely influenced by the ventral pathway visceral sensation; however, it is currently also considered
(“what”), and this information ends in the lateral nucleus. The part of the systems that mediate emotions, awareness, exec-
amygdala also receives one of its most substantial cortical utive functions, and related behaviors (Craig, 2010). Specif-
connections from the insula (Van Hoesen, 1981). Information ically, the anterior insula has been linked to several seemingly
arriving at the lateral nucleus is computed (“evaluated”) to unrelated processes such as sensory, affective, and higher-
determine whether a specific stimulus has a potential danger. order cognition, body and emotional awareness, pain, sense
This kind of evaluation can also happen via other sensory of self, self-recognition and motivation, singing and music
modalities. For example, one can detect an insect visually and recognition, uncertainty, empathy and risky decisions, visual
through the sound it makes (Devinsky & D'Esposito, 2004). consciousness, time perception, and integration of internal
Interestingly, visual, and auditory inputs are topographically interoceptive and external sensory signals (see review in
segregated within the lateral nucleus, and this fact probably Schimmelpfennig, Topczewski, Zajkowski, & Jankowiak-
allows for a more rapid response to a unimodal danger stim- Siuda, 2023). In fact, the insula integrates interoceptive and
ulus (Freese & Amaral, 2009). It is important to note that the exteroceptive information to compute and generate subjec-
“evaluative” nucleus does not project massively to the effector tive emotional states (Allen et al., 2016; Uddin, Kinnison,
nucleus (the central nucleus) since the basal nucleus is Pessoa, & Anderson, 2014); it forms part of the salience
interposed. Interestingly, the main source of inputs to the network (see below).
basal nucleus is the orbitofrontal cortex (Van Hoesen, 1981). Functionally, the insula is divided into three zones with
These connections would inform the context in which the differentiated connections (Clark et al., 2018): 1) the dorsal
stimulus appears and would potentially act as a “coincidence anterior insular zone is functionally related to the dorsolateral
detector” (Freese & Amaral, 2009). Thus, following the prefrontal cortex, supplementary motor cortex, and anterior
example of the cited authors, a snake can evoke a fear midcingulate cortex. This zone is associated with speech,
response if it is encountered along a walk in the forest but calculation, working memory, and decision-making (Vogt,
should not elicit the same response if it is observed behind a 2009); 2) the ventral anterior insular zone is functionally
thick glass at the zoo. related to the orbitofrontal cortex and anterior cingulate cor-
Once the amygdala “has evaluated” a potential danger, it tex (Rolls & Grabenhorst, 2008). This zone is associated with
can generate a whole-body response. The amygdala, as a hub, visceral sensations such as fear, sadness, happiness, and
outputs to the hypothalamus (hypothalamicepituitarye anger; and 3) the posterior insular zone is functionally related
adrenal axis activation), brainstem (sympathetic arousal), to medial and lateral somatosensory areas. This zone is
substantia innominata (alertness), insula (interoception, pain) associated with interoceptive and exteroceptive stimuli,
hippocampal formation (contextual memory), and prefrontal including vision and audition (Clark et al., 2018). A recent
cortex [PFC] (attention, and cognition) (Whalen & Phelps, study shows that subjective states induced by intracranial
2009). The PFC regulates the function of the amygdala (inhi- electrical stimulation match the cytoarchitectonic organiza-
bition) (Hariri, 2015). In summary, the amygdala is considered tion of the human insula (Duong et al., 2023).
an evolved system for danger and relevance detection (Freese It is important to highlight the fact that Von Economo
& Amaral, 2009; Sander, Grafman, & Zalla, 2003). It acts as an neurons (spindle cells) are bipolar pyramidal cells that are
emotional hub and contributes to reward/motivation pro- only found in the anterior cingulate cortex, the anterior
cessing. Physiologically, emotions cannot be separated from insula, and, to a much lesser extent, in the dorsolateral pre-
the autonomic (endokinesis) or limbic motor systems (ereis- frontal cortex (Banovac, Sedmak, Judas, & Petanjek, 2021). Von
mokinesis). The amygdala is an important part of the saliency Economo neurons play an important role in the links between
network (see below). In fact, the temporopolar region belongs the cingulate cortex, anterior insula, and other areas of the
to the amygdalocentric sphere of the limbic system that in- brain. They are related to various neuropsychological phe-
cludes the insula, posterior orbitofrontal cortex, the anterior nomena such as salience detection, emotional expression,
cingulate, and the paraolfactory gyrus (Mesulam & Mufson, self-control, social bonding, focused attention, and the fast
1982). assessment of complex circumstances (Allman et al., 2011;
Urbach-Wiethe is an extremely rare disease characterized Cauda et al., 2013; Schimmelpfennig et al., 2023). Von Econ-
by bilateral calcification of the anterior medial temporal lobe, omo neurons form a network of frontoparietal functional
especially the amygdala, yet sparing the hippocampus. This connectivity that comprises four sub-networks relating to
disease allows us to analyze the role of the amygdala in saliency detection, sensory-motor network, anterior default
cognitive function. Patients show no evidence of Pavlovian mode network, and dorsal attentional network (Cauda et al.,
conditioning to fear but do retain memory of events associ- 2013).
ated with the conditioning. An impairment in the recognition
of fearful facial expressions is also observed, however, not a 3.2.1.6. ORBITO-FRONTAL CORTEX. The orbitofrontal cortex re-
failure in the recognition of the identity of the faces ceives links from the temporal association cortex, amygdala,
(Markowitsch et al., 1994; Siebert, Markowitsch, & Bartel, and hypothalamus. It also receives information from the vi-
2003). A recent review of Urbach-Wiethe patients with baso- sual system, taste, olfaction, and somatosensory cortices. The
lateral amygdala lesions shows that they are broadly consis- insula and the amygdala are similarly strongly connected to
tent with rodent models of selective lesions in the same region the orbitofrontal cortex (Rudebeck, Mitz, Chacko, & Murray,
(Koen et al., 2016). 2013). All these connections make the orbitofrontal cortex a
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 29

privileged place for the integration of emotional processes and involved in emotion, motivation, decision-making, and
the acquisition of appropriate behaviors based on rewards and social cognition (Piguet & Hodges, 2013).
reinforcements (Stalnaker, Cooch, & Schoenbaum, 2015). In 2. Dissolution of face and object recognition (associative visual ob-
addition to this integrative function, the orbitofrontal cortex ject agnosia). Patients present the characteristics of asso-
participates in response inhibition reactions thanks to its ciative visual agnosia, including prosopagnosia.
connections with motor cortices (Rolls & Grabenhorst, 2008). Progressive visual prosopagnosia has been reported in
The function of the orbitofrontal cortex is closely linked to the cases of atrophy of the TPR, fusiform gyrus, amygdala, and
anterior striatal (limbic) systems (see below). hippocampus (Mesulam, 2023)
3. Dissolution of word comprehension and object naming (semantic
3.2.1.7. TEMPORAL POLE (TEMPOROPOLAR REGIONS).
The temporal variant of primary progressive aphasia). In these cases, a
pole (planum polare) constitutes the rostral limit of the peri- combination of severe anomia in conversational speech,
rhinal cortex. This cortex is closely linked to the amygdala, word comprehension impairment, and surface dysgraphia
orbitofrontal cortex, insula, and hypothalamus. It receives the or dyslexia in writing or reading appears (Mendez & Nasir,
end of the auditory and visual “what” streams and is heavily 2023).
linked to the prefrontal cortex by the uncinate fasciculus 4. Combined dissolution of word comprehension and object recog-
(Catani & Thiebaut de Schotten, 2012; Schmahmann & nition (semantic dementia). Semantic dementia (semantic
Pandya, 2006). Lesions of the ‘temporal poles’ in the monkey variant of primary progressive aphasia) is characterized by
produce Klüver-Bucy syndrome (Klüver & Bucy, 1939), but asymmetrical atrophy of the anterior temporal pole and
complete Klüver-Bucy syndrome is rarely seen in humans anterior fusiform gyrus (Landin-Romero, Tan, Hodges, &
(Yilmazer-Hanke, O'Louglin, & McDermott, 2016). Kumfor, 2016). Patients show a progressive and relatively
The temporal poles participate with the temporoparietal circumscribed loss of “semantic knowledge”, which is
junction and frontal lobes in the neural networks that un- characterized by the combination of word comprehension
derlie the concept of the “social brain” and the “theory of deficits, fluent aphasia, and a particularly severe anomia
mind”, the capacity to make inferences about others' mental (Mesulam et al., 2009). This clinical picture opens a path
states (Stuss, Gallup, & Alexander, 2001; Clark et al., 2018; toward the study of the brain network of naming,
Poulin-Dubois, 2020) (see Table 4 below). lexicalesemantic relationships, and semantic cognition
As proposed by Mesulam (2023), the term “temporopolar (Lambon Ralph, Jefferies, Patterson, & Rogers, 2017;
region” (TPR), rather than ‘temporal pole’ or ‘anterior tem- Migliaccio et al., 2016).
poral pole’, refers to the 2e3 cm of the cerebrum that ex- 5. Combined dissolution of word comprehension and conduct.
tends from the limen insulae to the anterior tip of the These cases are characterized by semantic aphasia with
temporal lobe. Accordingly, the principal components of behavioral dysfunction. Lesions predominate in the left
TPR include the temporopolar cap (Brodmann area [BA] 38), hemisphere or are symmetrical (Mesulam, 2023).
anterior parts of the superior temporal, middle temporal, 6. Combined dissolution of word comprehension, object recognition,
inferior temporal and fusiform gyri and perirhinal, peri- and conduct. It is characterized by progressive semantic
amygdaloid and pyriform cortices. The medial tempor- aphasia, with associative agnosia, and behavioral
opolar region belongs to the amygdalocentric component of dysfunction (Mesulam, 2023). In fact, it is like pattern 4,
the limbic system and is responsible for integrating where behavioral disorders are added.
exteroceptive information with interoceptive states under-
lying social contacts (Allen et al., 2016; Mesulam, 2023;
Uddin et al., 2014). 3.2.1.8. PARAHIPPOCAMPAL GYRUS. The parahippocampal gyrus
After Mesulam (2023), the functional neuroanatomy of the includes the parahippocampal, entorhinal, and perirhinal
TPR presents three axes: (1) an anterograde horizontal axis cortices (Amaral & Lavenex, 2007, chap. 3). The para-
from unimodal to heteromodal and paralimbic cortex; (2) a hippocampal cortex receives important projections from the
radial axis where visual (ventral), auditory (dorsal), and par- association areas through the dorsal visual stream (“where”
alimbic (medial) zones encircle the temporopolar cortex and pathway) and from the parietal region related to visuospatial
display hemispheric asymmetry; and (3) a vertical depth-of- information. The parahippocampal cortex supports scene
processing for the associative elaboration of words (audi- perception but not the details of individual objects (Stevens,
tory), objects (visual), and interoceptive (multimodal) states. Khan, Wig, & Schacter, 2012).
This functional matrix supports “the transformation of object The perirhinal cortex receives input mainly from the
and word representations from unimodal percepts to multi- ventral visual stream (“what” pathway) and its major projec-
modal concepts” (Mesulam, 2023, p. 20). tion is to the entorhinal cortex (Whitter, Wouterlood, Naber, &
Temporopolar syndromes show at least the following six van Haeften, 2000). The entorhinal cortex constitutes the
patterns (Mesulam, 2023). gateway to the hippocampus, where “what” and “where” in-
puts converge (Lisman, 2007).
1. Dissolution of comportment (behavioral variant of fronto-
temporal dementia). This syndrome can be associated with 3.2.1.9. CINGULATE CORTEX. The cingulate cortex is considered a
bilateral or right-side temporopolar atrophy (Mesulam, supracallosal extension of the hippocampale
2023). Clinically characterized by progressive changes in parahippocampal regions (Mesulam, 2000). The cingulum
personality and interpersonal conduct. Atrophy reflects bundle is found below the cingulate cortices and is made up of
the progressive disintegration of the neural circuits fibers that arise from or terminate in the cingulate cortex. It
30 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

also contains fibers that link the parahippocampal and pre- 3.3. Unit III: cortical systems
frontal cortices (Clark et al., 2018). The main limbic connec-
tions of the cingulate cortex come from the amygdala and the In Luria's (1973c) model, the cortex was divided into two units:
hippocampus. The hippocampal links reach the posterior parts unit for obtaining, processing, and storing information coming from
of the cingulate whereas the amygdala connections are the outside world (lateral postcentral regions of the neocortex
directed mainly to its anterior parts. See Vogt (2009) for a on the convex surface of the hemispheres, Unit II); and unit for
comprehensive review of the cingulate cortex. The cingulate programming, regulating, and verifying mental activity (precentral
cortices are involved in heterogeneous functions including anterior regions of the hemispheres, Unit III). Luria's (1973c)
visceral function, pain perception, emotion, motivation, division of the neocortex into two units (postcentral II and
attention, memory, and learning (Clairis & Lopez-Persem, precentral) has some practical interest, however, current
2023; Mesulam, 2000). neuroscientific knowledge shows that this dichotomy is a
The anatomical and functional complexity of the cingulate naive oversimplification. This fact is obvious when consid-
cortex (Vogt, 2009) can be simplified into four divisions: ering novel ideas on the structural and functional hodological
visceral/emotional effector, cognitive effector, skeletomotor, organization of the brain (see Catani & Thiebaut de Schotten,
and sensory processing regions (Cummings & Mega, 2003). 2012).
The visceral region overlaps with the orbitofrontal paralimbic The proposed Unit III includes all cortices, related thalamic
region. See anatomical and functional details in Tables 1 systems, and the intracortical connectome as described by
and 2. Catani and Thiebaut de Schotten (2012). This unit partially
The anterior cingulate cortex constitutes the upper struc- overlaps with the cortical regions of Units I and II. Due to its
ture of the “emotional brain” and forms part of the salience dimensions and its importance in cognition, the supralimbic
network (see below). It participates in affective, autonomic, cortex has a major role in this unit. Telokinesis (Yakovlev,
cognitive, social, and motor behavior. It forms part of the 1948) is the main form of motility related to the supralimbic
network that initiates goal-directed behaviors (Devinsky & cortices.
D'Esposito, 2004). The visceral/emotional division mainly The claustrum. To be more exhaustive, a special subcor-
connects with the amygdala, periaqueductal gray, and auto- tical telencephalic structure has been included in this unit:
nomic brain stem motor nuclei (Devinsky, Morrell, & Vogt, the claustrum. The claustrum consists of two main divisions:
1995). The cognitive effector division participates in the se- the dorsal (insular) claustrum, placed medial to the insular
lection of motor behavioral responses and responses to cortices, and the ventral (piriform) claustrum, placed medial
noxious stimuli (Devinsky & D'Esposito, 2004). Finally, the to the piriform cortex (Druga, 2014). This structure is
skeletomotor division receives limbic input and connects with composed of spiny glutamatergic projection neurons that
motor primary areas (M1), the supplementary motor area, and predominantly target the cortex (Madden et al., 2022). The
the basal ganglia. It sends out corticospinal fibers (Morecraft & claustrum integrates cortico-cortical links and has been
Van Hoesen, 1998; Devinsky & D'Esposito, 2004). Se. recognized as a central node for consciousness (Yin,
Terhune, Symthies, & Meck, 2016). Recent reviews have
3.2.2. A brief note on a frequently neglected topic in brain synthesized claustrum functions in a novel functional model,
models: behavioral endocrinology the “network instantiation in cognitive control” (NICC). This
Hormones are released from endocrine glands into the blood, new model proposes that “frontal cortices direct the claus-
where they may travel to act on target structures. While trum to flexibly instantiate cortical networks to subserve
neural messages are fast (millisecond ranges) and directed via cognitive control” (Madden et al., 2022, p. 1133). Animal
specific pathways, hormones can operate over greater dis- studies show that anterior cingulate cortex input to the
tances and within much longer time ranges. In addition, claustrum is required for top-down action control (White
hormonal function lies outside of voluntary control (Nelson, et al., 2018). For more information see Mathur (2014), Binks,
2011). A given hormone can only directly influence cells that Watson, and Puelles (2019), and Torgerson and Van Horn
have specific receptors for that specific hormone (specific (2014).
target cells). Hormones coordinate the physiology and Local areas. A cytoarchitectonic analysis of the cerebral
behavior of individuals thanks to the regulation and control of cortex shows that the cerebral hemispheres can be subdivided
bodily functions. They can mediate processes such as growth, into multiple hierarchically distributed local areas (local pro-
sex differences, aggression, parental behaviors, reproduction, cessors) based on neuronal architecture (cell types, number of
or metabolism. Hormones that influence behavior include layers, and canonical microcircuits). As previously mentioned,
testosterone, estradiol, progesterone, cortisol, oxytocin, five large cortical types can be recognized: limbic, paralimbic,
vasopressin, prolactin, and leptin. This brief note is important association (unimodal and heteromodal), and primary
to highlight factors that are generally not contemplated in sensory-motor areas (Mesulam, 2000). See Units IV and V
functional brain models. The reader will find detailed infor- below.
mation in neuroscience treatises (e.g., Kandel, Koester, Mack, Unit III highlights the role of distributed local cortical
& Siegelbaum, 2021; Poeppel, Magoun, & Gazzaniga, 2020) and specialized processors (areas) in the context of the global
biological psychiatry manuals (e.g., Charney & Nestler, 2017). function of the brain. Local cortical areas and their connec-
The topic “muscleegutebrain axis” is also part of this section tions play their specific role within the context of complex
(see Burtscher, Millet, Place, Kayser, & Zanou, 2021; Cutuli, networks (distributed functional webs), as initially described
Decandia, Giacovazzo, & Coccurello, 2023; Lu et al., 2023). by Luria (1973c) and recently updated in a hodotopic
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 31

framework (ffytche & Catani, 2005). As previously remarked, 3.3.1. Clinicaleanatomical focal syndromes after Luria and
microcircuits constitute the interface between neurons and beyond: a critical topic in neuropsychology, neuropsychometry,
the global functional integration at the brain-scale level and neuroimaging
(Changeux & Michel, 2006; Grillner & Graybiel, 2006). Thanks Restricted cortical lesions give rise to classic cerebral/cortical
to the connection pathways, local brain processes build the focal syndromes (see the classic works of Ajuriaguerra &
basis of synthetic mental activities, and it is possible to Hecaen, 1949; Luria, 1973a, 1973c; He caen & Albert, 1978). In
properly analyze cortical and cortico-subcortical focal syn- Luria's approach, the assessment aim was the “qualification of
dromes (e.g., aphasia, apraxia, and agnosia). the deficit” resulting from a local cortical lesion. In other
Functional webs are defined by mutual links within a words: to define the Grundst€orung [basic disorder] of Goldstein
distributed functional web, that is, between neurons in (Luria, 1964, 1970, 1976, 1977; Goldstein, 1925). Consequently,
widespread areas including the primary areas (for a review “syndromic analysis” was considered the core of neuropsy-
on cell assemblies see Palm, Knoblauch, Hauser, & Schüz, chological assessment and opposed to psychometric ap-
2014). All these distributed areas would serve as binding proaches (Luria & Majovski, 1977). See below for a discussion
sites (Pulvermüller, 2002, 2013). The cerebral cortex is the on this topic.
basis for a set of associative memories allowing for the The basic disorder. Luria's objective was to define the brain
merging of information from different modalities (Fuster, locations related to a “basic disorder” investigated through
1999). Merging information is driven by correlations of specific neuropsychological tests. Thus, the systematic study
spatiotemporal patterns of neuronal activities such that of “cases of impaired phonemic hearing as a result of lesions
participating neurons are bound into strongly connected of different areas of the left hemisphere” (Luria, 1970, p. 118),
webs (Pulvermüller, 2002). The process of web activation has gave rise to a figure reproduced in many of his works (Fig. 1,
been called ignition (Braitenberg, 1978; Palm, 1981, 1982). The left). After Luria, this figure shows “that disturbances of pho-
dynamics of a functional network are therefore characterized nemic hearing were seen only in cases where the lesions
by a full ignition of the network by a strong sensory stimulus, involved the posterior part of the temporal lobe or adjacent
or, by the stimulation of cortical neurons outside the func- areas” (Luria, 1970, p. 118). To demonstrate the existence of an
tional web (Pulvermüller, 2002). Obviously, this cortical- “impairment of discriminative phonemic audition” (p. 115),
internal activation of a web involves not only cortical pro- Luria used the ability to discriminate “disjunctive phonemes”,
cesses themselves, but also thalamic, cerebellar, and which differ from each other by several distinctive features
subcortical modulatory afferents. The concept of cortical in- (“b” and “r”), and the ability to differentiate “oppositional” or
ternal stimulus agrees with Goldberg's (2018) idea of “inter- “correlative” phonemes, which differ from one another by
nally generated inputs” that characterizes the Default Mode only a single feature (“b” and “p”).
Network (see below), and with the idea of the activation of From the systematic study of hundreds of patients, Luria
networks “representing certain knowledge in long-term came to define the series of “basic disorders” that characterize
store”. According to Goldberg's hypothesis, activations in his neuropsychological approach, beyond language distur-
cerebral cortices could involve a “frontal resonance” (for bances. In fact, Luria built qualitative neuropsychology,
more information see Goldberg, 2018, ch. 4). following the classic approach (see Christensen, 1974): speci-
The surface anatomy of the cerebral hemispheres, ficities and dichotomies between impaired and preserved
including the cytoarchitectonic areas, has been the basis for tasks.
the study of cortical function and the development of neuro- The other side of the basic disorder. When the performance of
psychology (see Catani & Thiebaut de Schotten, 2012). A a sample of unselected aphasics is studied, a bimodal distri-
detailed review of local cortical processors (functional anat- bution of scores is clearly observed (subjects accumulate at
omy) and local brain syndromes is beyond the scope of this the extremes of the possible scores). This fact represents
paper, nevertheless, a synopsis is presented in Tables 1e4, another view of the dissociation between “impaired” versus
based on Luria (1973a), Ellis and Young (1997), Mesulam (2000), “preserved” tasks/functions. Fig. 1 (right) shows the distribu-
Feinberg and Farah (2003), Heilman and Valenstein (2003), tion of word repetition scores of 100 unselected consecutive
Rapp (2001), Stuss and Knight (2002), Devinsky and D'Esposito aphasics, excluding the most severe cases. The test consists of
(2004), Rizzo and Eslinger (2004), Alom and Pen ~ a-Casanova the repetition of ten words of different lengths and fre-
(2007), Miller and Cummings (2007), Morgan and Ricker quencies from the Barcelona Neuropsychological Test Battery
(2008), Blumenfeld (2010), Catani and Thiebaut de Schotten (Pen~ a-Casanova, 2019). One point is awarded for each correct
~ a-Casanova
(2012), Godefroy (2013), Clark et al. (2018), and Pen item. As seen in Fig. 1, the distribution of the scores is clearly
(2019). bimodal in the case of aphasia patients. These types of disso-
These tables show the ordered and hierarchical functional ciations are the basis for the diagnosis of classic clinical forms
structure of the cerebral cortex and its associated syndromes. of aphasia (e.g., Devinsky & D'Esposito, 2004, Ch. 6). In fact,
Precisely this ordered structure receives inputs from the Luria's figure shows the impaired segment (low scores and
subcortical systems, which in the case of the basal ganglia and localization) of the bimodal distribution of scores in unse-
cerebellum have been roughly divided into limbic, associative, lected cases of aphasia.
and sensorimotor systems. In addition, updated topics such as In contrast, all normal subjects obtain the maximum score
the dorsal and ventral pathways, the precuneus, the intra- in repetition (ceiling effect). Consequently, this type of vari-
parietal sulcus, or the paralimbic cortex of the temporopolar able was described as “species-wide capacity” (Lezak,
region are included. Howieson, Bigler, & Tranel, 2012), and classified as “Lurian”
32 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

Table 1 e Frontal lobes: functional anatomy (local processors) and main clinical symptoms/syndromes related (simplified).

Primary motor cortex

Areas: BA 4 (somatotopic motor homunculus of effector-specific areas)a,b interrupted by the SCAN (somato-cognitive action network (inter-effector
areas)c
Input: Premotor cortex (M2, BA 6, posterior BA 8), cingulate motor area (M3, BA 23c, BA 24c), primary somatosensory and somatosensory
association cortices, thalamus (ventral anterior [basal ganglia], and ventral lateral [cerebellum])d
Output: corticospinal tract and cranial nerve nuclei, basal ganglia, reticular formation (RF), and red nucleus (RN).
Notes: (1) pyramidal tract composition: fibers from M1, (30%), PMC, SMA, somesthetic parietal cortex. (2) M1 areas have no callosal connections
between the R and L hemispheres.e (3) L dominance for routinized skilled movements.
Function: execution of precise isolated movements of highly specialized parts of the body (fingers, toes, tongue, and larynx)c
Clinical symptoms/syndromes:
 Paresis or paralysis of contralateral body musculature (maximal in distal muscles, fine movements).
 Hypertonia (spasticity)

Motor association cortex (M2): lateral premotor cortex (LPC), supplementary motor complex (SMC), frontal eye field (FEF), and supplementary
eye fields (SEF)

Lateral premotor cortex (LPC)

Areas: BA 6
Input: superior parietal cortex (sensory guidance)
Output: M1 [axial and proximal limb musculature], reticular formation [reticulospinal tract]
Function: (1) Initiation and organization of actions (guiding reaching and hand grasping [external cues]); (2) motor learning (motor sequences); (3)
Store of elementary motor acts (motor schemata); (4) involved in initial stages of working memoryf,g
Clinical symptoms/syndromes:
 Paresis þ spasticity, maximal in proximal muscles, (contralateral R, L)
 Grasp reflex and related symptoms (R, L)
 Motor impersistence (R) (also prefrontal lesions)d,f
 Slow movements and disturbance of their kinetic sequential structure with perseverations (premotor þ prefrontal lesions) (L)
 Luria's kinetic apraxia (“dynamic” or “premotor apraxia”)h: impaired reproduction of rhythms, or shift from motor patterns
 Multimodal ideomotor apraxia (impaired pantomime upon verbal command, no difficulty in handling object or showing the actual object) (L)d,g
 Visual (optic) apraxia (interruption of visual projections to LPC and SMA)d,f,g
 Tactile (or palpatory) apraxia (interruption of somatosensory projections to LPC and SMA)g
 Buccofacial apraxia (L). Apraxia of speech (L)
 Callosal apraxia (unilateral left apraxia) (L) (callosal disconnection of right hemisphere praxis areas)

Supplementary motor complex: supplementary motor area (SMA) and pre-SMA

Input: (1) primary somesthetic area, superior parietal lobule, prefrontal and anterior cingulate cortices; (2) thalamus (ventral anterior and
ventral lateral nuclei [basal ganglia and cerebellum])f
Output: (1) premotor and primary motor areas; (2) basal ganglia, red nucleus, and spinal cord; (2) posterior inferior frontal gyrus (frontal aslant
tract [FAT])i

Supplementary motor area (SMA)

Function: planning of spontaneous self-initiated movements based on internal cues; sequences of movementsf
Clinical symptoms/syndromes
 Electrical stimulation and spontaneous seizures: speech arrest and vocalizations (cries, grunts, and palilalia)
 Grasp reflex and related symptoms (R, L)
 Impairment of rapid alternating movements: Luria's kinetic apraxia
 Global akinesia or bradykinesia (contralaterally more prominent)
 Akinetic mutism and persistent deficits in motor initiation, (B)
 Muteness (L, R). Subacutely and contralaterally: spontaneous motor and emotional facial expression are impaired.
 Alien hand syndrome [SMA þ anterior cingulate þ prefrontal cortices lesion]: reflex grasping, groping, and compulsive manipulations (L)d
 Transcortical motor aphasia (L) þ crural contralateral weakness
 Transient impairment of motor initiation

Pre-Supplementary motor area (pre-SMA)

Areas: Transition from the agranular SMA to the granular prefrontal areasf,g
Function: initiation of movement (more complex motor acts than the SMA)d,f

Frontal eye field and supplementary eye fields (SEF)

Areas: BA8; SEF is an extension of the SMA; a functional complex constituted by SEF, DLPC, and ACCd,f,g
Input: parietal and temporal cortices.
Output: superior colliculus, caudate nucleus, paramedian pontine RF, midbrain (rostral interstitial nucleus of the medial longitudinal
fasciculus)d,f,g
Function: motor component of the visual attention system
Clinical symptoms/syndromes:
 Stimulation or seizures: contralateral conjugate eye deviation and elements of attentive reactions (mydriasis and head rotation)
 Impairment of voluntary eye movements (“looking”): tonic deviation of the eyes to the side of the lesion
 Oculomotor impersistence
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 33

Table 1 e (continued )
Broca's territory

Areas: BA 44, posterior BA 45, and adjacent areas (ventrolateral prefrontal cortex)
Input: (1) supplementary motor complex (via FATi); (2) Wernicke's territory posterior third of BA 22 (superior temporal gyrus, T1), BA 39e40
(parietal inferior lobe) via the arcuate fasciculus (direct and indirect pathways)j,k,l (dorsal pathway); (3) temporopolar region (uncinate
fasciculus) and inferior temporal gyrus (T3, BA 37) (ventral pathway)j,k
Output: facial region of M1
Function: functional gate enabling the phonetic translation to be executed by the motor areas (prearticulatory encoding)l,m
Clinical symptoms/syndromes
 Direct stimulation (L): speech arrest, impaired fluency, and subtle impairment of comprehensiond
 Dysarthria (L)
 Broca's aphasia, chronic severe persistent form (L). Lesions: Brodmann's areas (BAs), 44, 45, 9, 46, 47; white matter and BG (head of the caudate
and putamen); sensorimotor areas for face and larynxd
- “Reduction” (non-fluent speech): phonemic disintegration (anarthria), anomia, and agrammatismn
- Mild supralexical comprehension deficit (sensory agrammatism); Alexia and agraphia
- Right Hemiplegia þ left hand apraxia (callosal apraxia)o
 Broca's area aphasia (L): dysarthria and resolving aphasia. Lesions restricted to Broca's area
- Mutism followed by mild aphasiad,p
 Stuttering (FAT participation)i
 Loss of emotional intonation and singing; aprosodia, expressive amusia (R)d,o

Prefrontal association cortex

Dorsolateral prefrontal cortex (DLPC)

Areas: BA 46, 9, 10 (components of the associative control network [frontoparietal or central executive], in connection with the SN and the
MDN)d,f
Function: higher-order (“executive”) control of behavior
Clinical symptoms/syndromes: higher control-“executive” syndrome
 Deficits in attention (includes perceptual [attentional selection], maintenance, and inhibitory processes)e,f,q (B)
 Poor performance in working memory tests (B)q
 Impaired capacity to generate solutions to novelties (B); Concrete thought (B)d,f,q
 Deficits in planning and organization (inflexibility, perseverations): inability to set goalsd,f,q
 Retrieval deficit disorder (B)
 Depression or pseudodepressive symptoms. Apathy
 Dynamic aphasia (L). Atypical transcortical motor aphasia

Orbitofrontal cortex prefrontal cortex (OFPF)

Areas: BA 12 (medial), BA 11 (lateral)
Function: inhibition, impulse control, social judgement. Self-regulation (limbicebehavioral interaction)
Clinical symptoms/syndromes: disinhibited, impulse control syndrome (pseudopsychopathic syndrome)
 Affective and social changes with impairment of social behaviord,f,q (lacking proper social skills) (B)
 Interpersonal disinhibition, impulsive decision making, hyperactivity, irritability; commission of minor crimes (e.g., shoplifting)d (B)
 Emotional lability, euphoria or dysphoria, and increased aggressivenessd,f,q (B)
 Unconcern over responsibilities and failure to appreciate the consequences of one's actions. Poor social judgment. (B)
 Careless actions: inappropriate laugh with silly and childish behavior; excessive joviality and tendency to joke and frivolity (moria, “stupidity”
[Jastrowitz]; Witzelsucht, “addiction to jokes” [Oppenheim])r (B)
 Lack of empathy for others. Impaired “Theory of mind” (capacity to make inferences about others' mental states)f (R, B)
 Anxiety and obsessive-compulsive symptomsd (B)
 Increased appetite and weight gaind (B)
 Environmental dependency syndrome: imitation and utilization behaviors,t (B)

Medial prefrontal cortex (MPFC), and anterior cingulate cortex (ACC)

Areas: BA 32 (rostral part [heteromodal], caudal part [paralimbic]); BA 24 (anterior cingulate [paralimbic cortex])
Function; motivation, initiative, emotional responsiveness
Clinical symptoms/syndromes: apathetic amotivational syndromeq
 Abuliau
 Akinetic mutism (extreme form of impairment)d
 Apathy (lack of goal-directed activity and motivation) and its dimensionsv,w
- Diminished initiative: less spontaneous and/or active than usual self (e.g., conversation, work-related or social activities)
- Diminished interest: less enthusiastic about usual initiatives (e.g., events, friends, and family, maintaining or completing tasks)
- Diminished emotional expression/responsiveness; less empathyx

(continued on next page)

34 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

Table 1 e (continued )
Right frontal lobe lesions (general disorders)d
 Left-sided extinction and neglect
 Akinesia (reduced gestural expression)
 Blunted or labile effect; depression
 Disinhibition
 Impairment of sustained attention; motor impersistence
 Affective dysprosodia
 Reduplication syndromes (e.g., Capgras syndrome)d
 Alien hand sign
Bilateral prefrontal lesionsd,h (þ white matter connections þ anterior cingulate)
 Apathetic-akinetic-abulic syndromef (frontal massive cortical and white matter lesions þ ACC damage)
 Abulia or catatonia
 Pseudodepression
 Higher-control cognitive syndrome symptoms: e.g., concrete thought, impaired working memory, perseverations
 Disinhibited, impulse control syndrome symptoms: e.g., loss of social skills
 Confabulation. Delusionsd
 Disprosodyd
 Incontinence

Paralimbic frontal-associated cortex

Areas: subgenual anterior cingulate cortex (sACC) (BA 25), pregenual anterior cingulate cortex (pACC) (BA 24 and 32), anterior midcingulate
cortex (aMCC), and posterior midcingulate cortex (pMCC)f,g,y,z
 Premotor division areas (aMCC and pMCC): M3; BA 23c, 24c
 Cognition division areas (aMCC): BA 24 caudal, and BA 32 caudal
 Affect division areas (sACC and pACC): BA 25, BA 33, and rostral BA 24
Input and output: CMC, and prefrontal and limbic cortices (reciprocally)
Function: process of the motivational content of internal and external stimuli and regulation of context-dependent actions
 See medial prefrontal cortex (MPFC), and anterior cingulate cortex (ACC): apathetic amotivational syndrome.

Note. B, bilateral; L, left hemisphere; R, right hemisphere.

References.
a
Penfield and Booldrey (1937).
b
Penfield and Rasmussen (1950).
c
Gordon et al. (2023).
d
Devinsky and D'Esposito (2004).
e
Karol and Pandya (1971).
f
Clark et al. (2018).
g
Mesulam (2000).
h
Luria (1973c).
i
Dick et al. (2019).
j
Catani and Thiebaut de Schotten (2012).
k
Friederici (2012, 2017).
l
Ferpozzi et al. (2018).
m
Cerri et al. (2015).
n
; Lecours and Lhermitte (1979).
o
Alom and Pen ~ a-Casanova (2007).
p
Pen~ a-Casanova (2019).
q
Koziol and Budding (2009).
r
Garcı́a and Pen ~ a-Casanova (2022).
s
Lhermitte (1986).
t
Lhermitte, Pillon, and Seradu (1986).
u
Siegel et al. (2014).
v
Cummings and Miller (2007).
w
Miller et al. (2021).
x
Stuss et al. (2001).
y
Kaufer (2007).
z
Vogt (2009, 2016).
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 35

Table 2 e Parietal lobes: functional anatomy (local processors) and main clinical symptoms/syndromes related (simplified).

Primary somatosensory cortex (S1)

Areas: BA 3a, 3b, 1, and 2 (sensory homunculus [somatotopic map]).

Input: projections from the ventral posteromedial (VPM) and ventral posterolateral (VPL) nuclei of the thalamusa,b
Output: parietal lobe somatosensory association areas
Function: initial cortical contralateral processing of somesthetic input (light touch, vibration, proprioception, superficial pain, temperature, and
two-point discriminationa,b,c
Clinical symptoms/syndromes:
 Verger-Dejerine syndrome (S1 syndrome)d

Somatosensory association areas and secondary somatosensory cortex (SII) (Superior parietal lobule, SPL)

Areas: Superior parietal lobule (SPL), BA 5, and BA 7 (in the lateral aspect). BA 7 in the medial aspect (precuneus); Parietal operculum: contains SII
(secondary somatosensory cortex) that receives input from both sides of the body; Posterior insula includes the vestibular area.a,b
Input: primary somatosensory cortex, occipital lobe, temporal lobe, insula.
Output: reciprocal connections with the pulvinar, the ACC, the lateral thalamic nuclei; brainstem and spinal cord, red nucleus, basal ganglia,
superior colliculus, pontine tegmentum; frontal lobes; commissural projections
Function: (1) integration of touch, proprioception, vision, audition, and vestibular information; (2) participation in the Dorsal Attention Network
(DAN), “where” (R dominance)b
Clinical symptoms/syndromes:
 Impaired body schema; (BA 5, BA, 7)
 Haptic hallucinations; (S1, BA 5)
 Phantom limb; (R, L, contralateral)
 Loss of pain perception (SII); (R, L, contralateral)
 Painful dysesthesias (pseudothalamic Dejerine-Roussy syndrome) (þ insula and parietal operculum lesions), (R, L, contralateral)
 Pain asymbolia; (R)
 Central vestibular syndrome (posterior insula); (R)

Precuneus (medial aspect of the SPL, BA 7) (heteromodal parietal cortex)

Input: lateral parietal (SPL, IPL, IPS), frontal (PMA/SMA, DL, and VM prefrontal), posterior cingulate, retrosplenial cortex (precuneus, medial
temporal lobe, hippocampus), precuneus (dorsal thalamus, pulvinar), brainstem (pretectal area, superior colliculus, reticular formation),
frontal eye fields.
Function: the precuneus is a major node of the Default Mode Network (DMN), and posterior cingulate cortex (PCC).
Clinical symptoms/syndromes:
 Consciousness impairments (active in DMN)
 Body movements in space (active in pointing, reaching, and saccades; act imagination [R]; attending to a target)
 Episodic memory retrieval defects (active in retrieval of episodic/contextual memory; integration of past information [self and the external
world])
 Self-awareness and social behavior impairments (active in action attributed to another [R], agency, self-related tasks [þPCC], theory of mind,
and empathy)

Cortex of the intraparietal sulcus (IPS) (heteromodal parietal cortex)

Areas: lateral (L) (saccade region); medial (M) (reach region); anterior (A) (grasp region); ventral (V) (navigation area), posterior (P) (3D analysis)
Function: multimodal integrative area (attention, salience/threat-related stimuli, attention to location; connectivity with the amygdala)b
Clinical symptoms/syndromes:
 Ba lint syndrome (B)
 Contribution to hemineglect and extinction (P) (R)
 Image mental rotation disorders (V) (R)
 Optic ataxia (M, A) (R, L)
 Disorders of eye movements; attentional disorders (L) (R, L, B)

(continued on next page)

36 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

Table 2 e (continued )
Inferior parietal lobule (IPL)

Areas: supramarginal gyrus (BA 40, gyrus supramarginalis [GS]), and angular gyrus (BA 39, gyrus angularis [GA])a,b,c
Function: multimodal association area related to praxis, language, visuomotor processing, and spatial attention processing. Dorsal pathway
(spatial orientation, “where” and “how”)
Clinical symptoms/syndromes:
Left hemisphere lesionsa,d,e,f
 Tactile agnosia (BA 40, also BA 39, or SII)a,c
 Tactile anomia (tactile aphasia) (L)g
 Tactile apraxia (objects cannot be handled without visual information)
 Pure agraphesthesia (somesthetic alexia) (tactile-verbal lexical disconnection)
 Anomic aphasia (parietal type) (L)d
 Semantic aphasia (Luria's): semantic and logic-grammatical relationshipse (L)
 Transcortical sensory aphasia (TSA) or Wernicke type II (Lecours & Lhermitte)f,h (TSA of parietal type) þ (echolalia), (L)
 Alexia with agraphia (Wernicke's type III aphasia [Lecours & Lhermitte])f (L)
 Pure agraphia (apraxic and/or psycholinguistic), (Gerstmann syndrome component, GSc)d (L gyrus angularis [GA])
 Acalculia (GSc)
 Gerstmann syndrome: finger agnosia (principal GSc), righteleft disorientation, agraphia, and acalculia. (L GA þ SPL)
 Constructional apraxia (L type).
 Ideomotor apraxia (damage of spatiotemporal representations of skilled movement): deficit in execution, imitation, or recognition of gestures
(learned purposeful acts)c
 Ideational apraxia (extensive lesions)
 Dressing apraxia (L type)
 Conscious contralateral hemiasomatognosia (L or B)
 Autotopagnosia (L or B)
 Aprosodia
Right hemisphere lesionsa,b,c
 Mental rotation processing impairment: presemantic apperceptive agnosiai (R).
 Contralesional hemispatial neglect and left extinction.
 Anton-Babinski syndrome: neglect, anosognosia, and hemiasomatognosia; Anosodiaphoria.
 Psychotic and affective disturbances
 Visuospatial disorders: spatial alexia, spatial agraphia, spatial acalculia
 Hemispatial imagination defects
 Constructional apraxia (R type)
 Dressing apraxia (R type)
 Conscious contralateral hemiasomatognosia
 Pain asymbolia (also B) (þ lesions in SII)
Bilateral lesions
 Ba lint syndrome: Occipital parietal region (B): Ba
 lint's syndrome (oculomotor apraxia, optic ataxia, object-centered neglect [dorsal
simultagnosia]). (Ba lint syndrome) þ (visual disorientation) ¼ Holmes' syndrome

Parietal paralimbic cortex

Areas: posterior cingulate cortex (PCC) (BA 23 and 31) subdivided into dorsal (dPCC) and ventral (vPCC) regions, and the retrosplenial cingulate
cortex (RSC). The posteromedial cortex (PMC) consists of the PPC, RSC, and precuneus.
Functions: The PMC is part of the DMN and is coupled with the sACC; the dPCC receives multisensory information from the parietal lobe,
including the dorsal visual pathway “where”; The vPCC receives inputs from the ventral visual stream “what”, The RCC strongly participates
in familiar scenes processinga,c

INSULA

Areas and functions: Anterior insular cortex (AIC), and posterior insular cortex (PIC)c,j
- AIC: constitutes a sensory multimodal exteroceptive association area. A dorsal part (dAIC) is connected with the anterior midcingulate
“cognitive” cortex, dorsolateral prefrontal cortex, and supplementary motor area. A ventral part (vAIC) is connected with the anterior
“emotional” cingulate cortex, and the orbitofrontal cortexa,b,j
 The AIC forms pat of the salience network (SN) þ (ventrolateral prefrontal cortex, and the anterior congulate cortex)
 Activation of SN results in attention to the salient stimuli; internal or external, and suppression of DMN.
- PIC: constitutes an “interoceptive awareness” and “alarm” center for abnormal visceral sensations.b It is functionally connected with the medial
and lateral somatosensory areas, including the intraparietal sulcus.a,b
Clinical symptoms/syndromes:
 dAIC: associated with disorders of speech, mathematics, working memory, value, variance, reward skewness, risk prediction, and decision
makingc
 vAIC: associated with symptoms of fear, sadness, happiness, and anger. Anxiety. Depression
 PIC: associated with interoceptive and exteroceptive stimuli impairments, including audition and vision.
- Absence of feelings of agency (self attribution).

Note. B, bilateral; L, left hemisphere; R, right hemisphere.

References.
a
Devinsky and D'Esposito (2004).
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 37

b
Clark et al. (2018).
c
Mesulam (2000).
d
Pen~ a-Casanova (2019).
e
Luria (1973c).
f
Lecours and Lhermitte (1979).
g
Endo, Makishita, Yanagisawa, and Sugishita (1996).
h
Ardila (2020).
i
Turnbull and McCarthy (1996).
j
Ogar and Gorno Tempini (2007).

Table 3 e Occipital lobes: functional anatomy (local processors) and main clinical symptoms/syndromes related (simplified).

Primary visual cortex (striate cortex)

Areas: BA 17 (V1). Retinotopic-spatial organization.

Input: lateral geniculate body (geniculostriate radiation)a,b,c
Output: peristriate cortex
Function: initial cortical processing of visual inputa,b,c
- Visual field deficits (retinotopic deficit patterns)
- Partial local lesions: (1) scotoma in the contralateral visual field (þ anosognosia possible); (2) seizures: simple visual hallucinations
- Partial lesions (superior or inferior): contralateral homonymous quadrantanopia (inferior or superior respectively)
- Contralateral homonymous hemianopia (macular area spared) (þ anosognosia possible)
Clinical symptoms/syndromes:
 Cortical blindness (massive bilateral lesions)
- Anton's syndrome (cortical blindness þ anosognosia)
- Dide and Bocatzo syndrome (bilateral medial occipitotemporal lesions): visual field defects, topographic disorientation, anterograde and
retrograde amnesia, and alexia (some authors include visual anosognosia)d
 Residual capacity: blindsight (ability to reach toward visual stimuli subserved by retinocollicular projections)

Visual association cortex (extrastriate visual cortex)

Areas: BA18 (V2, peristriate cortex) and BA19. Including beyond the occipital lobe parts of the fusiform, inferior temporal, and middle temporal
gyri (BA37, 20, 21).
Input: V1 (and reciprocal connections with other structures) (see output)
Output: (1) multiple parallel systems arise from V1 and V2 that project to different specialized peristriate areas: V3 to V8; (2) Further visuofugal
flow divides into the ventral (“what”) and dorsal (“where”, and “how”) pathways.
Function: form, motion, color, spatial orientation, and depth (stereopsis) processing
Ventral pathway: (colors, faces, objects, and movement) þ (adjacent geniculocalcarine radiation)
Clinical symptoms/syndromes:
 Palinopsia (visual perseveration) (R)
 Contralateral hemiachromatopsia (L, R); complete achromatopsia (B). Color area (V8) impaired
 Color anomia (color-verbal lexical disconnection) (L)
 Apperceptive prosopagnosia (defect in the visuospatial perception)
 Associative prosopagnosiae (B, L, R) (fusiform face area)
 Prosopanomia (face-verbal lexical disconnection) (L)
 Apperceptive visual agnosia
 Shape agnosiaf (L)
 Associative visual object agnosia (usually lesion extension to fusiform and lingual gyri) (L inferior, B inferior)
 Visual object-verbal lexical disconnection: optic aphasia (L)
 Visual object-praxis system disconnection: optic apraxia (L)
 Impairment of visual imagination (þ loss of visual dreaming: Charcot-Wilbrand syndrome) (L)g
 Lesion of visuoamygdaloid pathways: visual hypoemotionality (L)
 Akinetopsia (B) Movement area (V5):
 Body form and body action agnosia (L) Extrastriate body area:
 Pure alexia (L) Visual word form recognition area
- Occipito-splenial form (lesion extends to the splenium of the corpus callosum) (þ/ right hemianopia)
- Subangular form (subangular connections affected) (þ/ right hemianopia)
 Ventral Simultagnosia (space processing)
 Combined syndromes: Pure alexia þ color anomia þ right homonymous hemianopia (Potzl syndrome), (L)
Dorsal pathway
 Balint's syndrome (see parietal lobe)

(continued on next page)

38 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

Table 3 e (continued )
Related clinical disorders

 Charles Bonnet syndrome: visual hallucinations following loss of vision

Note. B, bilateral; L, left hemisphere; R, right hemisphere.

References.
a
Mesulam (2000).
b
Devinsky and D'Esposito (2004).
c
Clark et al. (2018).
d
Lazzarino De Lorenzo, Ffytche, Di Camillo, and Buiatti (2014).
e
Volfart et al. (2023).
f
Ptak and Lazeyras (2019).
g
Pen~ a-Casanova, Roig-Rovira, Bermudez, & Tolosa-Sarro (1985).

Table 4 e Temporal lobes: functional anatomy (local processors) and main clinical symptoms/syndromes related
(simplified).

Primary auditory cortex (A1)

Areas: BA 41 (A1) (Heschls's gyrus). Tonotopic organization (no strictly contralateral representation as in M1 and S1)
Input: medial geniculate body
Output: auditory unimodal association areas
Function: initial cortical processing of auditory input (pure tones)a
Clinical symptoms/syndromes:
 Electrical stimulation: unformed auditory sensations
 Subclinical auditory impairments (unilateral R, L)
 Cortical deafness (B)a,b,c,d,e

Auditory unimodal association cortex

Areas: BA 42, BA 22 (BA 22 is part of Wernicke's territory)

Input: primary auditory cortex
Output: two (ventral and dorsal) auditory streams arise in the posterior superior temporal sulcus. The ventral auditory stream (“what”)
terminates in the inferior frontal gyrus. The dorsal auditory stream (“where”, and “how”) terminates in the inferior parietal lobe (indirect
pathway), inferior frontal gyrus, premotor cortex, and dorsolateral prefrontal cortexb,c
Function: higher order processing of auditory inputa,b,c,d
Clinical symptoms/syndromes:
 Auditory hallucinations and illusions (posterior superior temporal gyrus). These symptoms may arise from injury to all parts of the peripheral
and central auditory pathways.
 Electrical stimulation and partial seizures: complex auditory hallucinations, including voices and music (also produced by stimulation in
limbic areas)
 Cortical deafness (B)
 Generalized auditory agnosiaf (L, R, B)
 Pure word deafness (pure verbal auditory agnosia), apperceptive and associative forms (B or L and callosal disconnection from R)
 Auditory agnosia for environmental sounds, apperceptive and associative forms
 Phonagnosia (L)

Temporal heteromodal association cortex and wernike's area

 Agnosias (faces, forms, objects, and words). See occipital lobe (ventral stream): prosopagnosia, shape and object agnosia, pure alexiac
 Wernicke's aphasia (Wernicke's type I aphasia [Lecours & Lhermitte]), (L)
- Logorrhea, anosognosia; acoustic-phonological and semantic control deficitsg
- Mood alterations; anger, paranoia, indifference (sensory-limbic disruption)
 Transcortical sensory aphasia (temporal type: Wernicke's type II aphasia [Lecours & Lhermitte]), (L)
 Conduction aphasia (þ parietal lobe lesions þ subcortical lesions [arcuate fasciculus]), (L)
 Sensory amusia (R, L)
 Sensory aprosodia (R)

Temporoparietal junction (TPJ) and the “social brain” (SB)

Areas: posterior superior temporal sulcus, parts of the superior and middle temporal gyri, and inferior parietal lobe
Function: multisensory, body-associated processor, including self-awareness and theory of mind. It forms part of the “social brain” (SB). The
anatomical/functional parts of the “social brain” include the superior temporal sulcus, temporoparietal junction, anterior insula, temporal
pole, subgenual cingulate cortex, orbitofrontal cortex, and ventromedial prefrontal cortexb

Medial temporal limbic cortices (temporopolar cortices)

Areas: BA 38
Input: auditory and visual ventral streams “what”, primary olfactory cortex, nucleus basalis, hippocampus, and amygdalaa,b,c
Output: amygdala, OFC, insula, hypothalamus
Function: sensory-limbic interactions (medial, dorsal, and ventral parts); transmodal center for visual processing (faces, pictures, words); a hub
for personal semantic memories
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 39

Table 4 e (continued )
Clinical symptoms/syndromes:
 Klüver-Bucy syndrome (B): (1) visual agnosia; (2) hyperorality (tendency to examine objects orally), occasionally associated to hyperphagia
and obesity; (3) hypermetamorphosis (a significant tendency to react to visual stimuli); (4) placidity (loss of aggressive and fearful responses);
and (5) hypersexuality. In humans: incomplete forms.
 Isolated Klüver-Bucy syndrome symptoms as hyper-hyposexuality, inappropriate sexual gestures, placidity, hyperorality
- Related condition: Urbach-Wiethe disease (loss of fear reactions)
 Hyper-hyposexuality
 Emotional disorders
 Increased or decreased aggression
 Mania (R basal)
 Hallucinations or illusions
 Theory-of-mind and social behavior impairments
 Neurodegenerative syndromes of the temporopolar regionh
- Behavioral variant of frontotemporal dementia (dissolution of comportment); (R >>> L)
- Associative visual object agnosia (face and object recognition). Affected areas: TPR þ fusiform gyrus, amygdala, and hippocampus (R  L)
- Semantic variant of primary progressive aphasia (word comprehension and object naming defects), (L >>> R).
- Semantic dementia (word comprehension and object recognition); (L  R) (þ anterior fusiform gyrus)
- Semantic aphasia þ behavioral dysfunction; (L  R)
- Semantic dementia þ behavioral dysfunction; (L  R)

B, bilateral; L, left hemisphere; R, right hemisphere.

References.
a
Devinsky and D'Esposito (2004).
b
Clark et al. (2018).
c
Mesulam (2000).
d
Pen~ a-Casanova (2019).
e
Luria (1973c).
f
Miceli and Caccia (2023).
g
Robson et al. (2012).
h
Mesulam (2023).

Fig. 1 e Left. The bar chart indicates the brain location (below) in which disturbances of phonemic hearing are observed (Luria,
1970, p. 118). Right. Bar chart of the distribution of word repetition scores (10 items), in an unselected sample of aphasia
patients (n ¼ 100). A bimodal distribution is observed (“normal” vs “impaired” task). The capacity of the patients has been
classified into the following categories: N, normal; L1: mild 1; L-Q, limit-questionable (an acceptable isolated error); L2, mild 2;
M1, moderate 1; M2, moderate 2; G1 (gravis), severe 1; G2, severe 2 (maximum impairment, zero score). See text for details.
40 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

or “pathognomonic” (Koziol & Budding, 2009), in normal sub- In fact, a good neuropsychological assessment requires
jects. In fact, this is a “qualitative” variable in normal subjects. both qualitative and quantitative approaches. Qualitative
Given the bimodality of the observed distribution of test versus quantitative neuropsychology is a false dichotomy
scores in aphasia patients, it does not make sense to reconvert (Pen~ a-Casanova, 2021).
scores into a Gaussian distribution, and much less consider The psychometric-ordinal method (categorical grading of pa-
that, for example, repetition consists of a unitary task. It thology). To overcome the “dichotomous jump” of ceiling
should be noted that, in the first edition of the Boston Diag- variables in normal subjects, a psychometric-ordinal method
nostic Aphasia Examination (Goodglass & Kaplan, 1972), the was developed. The solution is based on the bimodal distri-
scores of aphasic subjects were referenced as if their distri- bution of aphasic scores (Pen ~ a-Casanova, 2019; Pen ~ a-
bution were Gaussian. This error was corrected in the Casanova et al., 2021). As commented, bimodality reflects
following edition, in which the statistical reference was the scores observed on dichotomous axes that allow aphasic
established in percentiles (Goodglass, Kaplan & Barresi, 2021). syndromes to be roughly classified: verbal expression,
Qualitative versus quantitative neuropsychology. Tradition- comprehension, repetition, and naming (Devinsky &
ally, a dichotomy is established between qualitative and D'Esposito, 2004). Thus, considering the data on word repeti-
quantitative (psychometric) evaluations. Luria's qualitative tion (as shown in Fig. 1, right), and for a variable with a range
assessment is frequently opposed to “Western” psychometric of 0e10, a graded series of categories of impairment inspired
approaches (Akhutina & Melikyan, 2012; Caroli & Mecacci, by Leyton, Ballard, Piguet, and Hodges (2014) were defined.
2020; Luria & Majovski, 1977; Mikadze, 2011). These categories were the following: the maximum possible
This issue depends mainly on the type of variable consid- score (10) defines normality [N] (expected ceiling score in
ered (Pen ~ a-Casanova, Go  mez, & Die guez-Vide, 2021). Vari- normal subjects). L1/LQ (score 9) defines a mild 1 [levis] or L-Q,
ables can be roughly dichotomous, or qualitative, as in the borderline [questionable] defect; L2 (score 8-7), defines a mild
case explained above (repetition of words), or they can have a 1 category, M1 (score 6), represents a moderate 1 category; M2
“Gaussian” distribution, perfect or not (e.g., scores from the (score 5), moderate 2 category. The G (severe [gravis]) cate-
Boston Naming Test). These scores are mainly expressed as gories are defined by a score below 50% of correct items [4-0].
means, deviations, percentiles, or scaled scores. Without a To differentiate the zero score, G (gravis), this category was
quantitative approach, it is impossible to manage scores that divided into G1 (4-1 scores), and G2 (zero score). For more in-
show a Gaussian distribution in normal subjects. Some tests formation, see Pen ~ a-Casanova et al. (2021). Thanks to the
necessarily require a psychometric approach, especially when psychometric-ordinal categorization method, and with
scores, in normal subjects, depend on factors such as age and normative data from normal subjects, the graphic profiles of
schooling. Without scores, it is impossible to determine the all aphasic syndromes are perfectly defined (Pen ~ a-Casanova,
degree of deficit and its evolution over time. In the case of Dieguez-Vide, Sigg, & Conesa, 2019). This method avoids the
clinical trials, the quantitative approach is obviously required. problems of quantification of symptoms of Luria's school
However, furthermore, beyond the specific (quantitative) (Glozman, 1999a, 1999b, 2002). Glozman's method allows the
score obtained, neuropsychology imperatively requires a assignment of scores (0 - .5 - 1 - 1.5 - 2 - 3) to types of symptoms
qualitative analysis of the response process and result. This graded by severity, based on a descriptive qualitative category.
need is made evident through the “Boston process approach to This means that the variables become “ordinal” since quali-
neuropsychological assessment” (Ashendorf, Swenson, & tative categories are graded by a theoretical (not empirical)
Libon, 2013; Werner, 1937). On the other hand, the ipsative severity scale (see Glozman, 2006).
analysis of quantitative scores may lead to qualitative diag- Heterogeneity of aphasia syndromes and limitations of a single
nostic clinical profiles (Fig. 2). In language assessment, for basic disorder. Luria's classification of aphasic disorders re-
example, in addition to scores, symptoms (semiology) must be flects his study paradigm: each form of aphasia is related to a
described and classified (e.g., different types of paraphasia). single “basic disorder” (see Akhutina, 2016). In reality, we

Fig. 2 e Profile of aphasia (only repetition tests are shown). Test results follow the ordinal psychometric criteria shown in
Fig. 1 and are succinctly explained in the text. The columns, from right to left, successively show the name of the test, the
possible score range, the patient's score, the psychometric category of severity of the disorder, and, finally, the graphic
profile of the results (Test Barcelona Workstation automated profile sccreenshot). The variable “Repetition: sentences-
whole” reflects the score of the number of sentences (as a unit), correctly repeated. The last variable “Repetition: sentences-
words” (0e65) reflects the repetition of the same sentences according to the total number of words correctly repeated.
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 41

must recognize that the “basic disorder approach” is not corresponds to the arcuate fasciculus. The indirect path runs
without problems since a specific syndrome can be the result laterally and is composed of two segments (posterior and
of the combination of several “basic disorders” (Pen ~ a- anterior). The posterior segment connects Wernicke's terri-
Casanova et al., 2021). tory with the inferior parietal cortex; the anterior segment
Explaining forms of aphasia through a single “basic disor- connects the inferior parietal cortices with Broca's territory.
der” has serious difficulties since, in many clinical scenarios, The so-called “cognitive neuropsychology” with its func-
very different symptoms appear. For example, in Broca's tional models, aims to overcome the limitations of traditional
aphasia, it is possible to observe different degrees of speech clinical neuropsychology (Ellis & Young, 1997; Mapou &
reduction, phonetic disintegration, anomia, and agramma- Spector, 1995), and, specifically, of the neuropsychology of
tism (Lecours & Lhermitte, 1979). These symptoms, which can language (see Coltheart, Sartori, & Job, 1987; Kay, Lesser, &
be dissociated, are hardly explained by a single “basic disor- Coltheart, 1992). The interaction of cognitive models with
der”. Furthermore, the limited value of broad concepts such as clinical and anatomical observations can significantly pro-
“repetition disorder” should be highlighted, given the diversity mote progress in the understanding of brain function.
of materials (e.g., syllables, pairs of syllables, pseudowords, Valdois, Ryalls, and Lecours (1989) proposed a critical
words, phrases of different length and structure) and psy- analysis of the clinical forms of aphasia recognized by Luria.
cholinguistic variables (e.g., frequency, imaginability, or These authors demonstrated the manner in which the main
grammatical category) involved. In these cases, ipsative forms and factors of aphasia described by Luria coincide with
analysis (intra-task/test dissociations) and observed semi- those characterized in other widely recognized classifications.
ology allow diagnoses that would not otherwise be possible. For example, as commented, after Luria (1970), acoustic-
This is the case of “phonologic” aphasia, which shows a main agnosic aphasia (sensory aphasia) results from an impair-
impairment in the repetition of pseudowords (McCarthy & ment of the auditory analyzer (“phonemic hearing”). Never-
Warrington, 1984) or “deep” aphasia, which is mainly char- theless, Luria also contemplated the disorder to be secondary
acterized by sematic paraphasia in repetition (Michel & to a certain loss of the “phonematic structure of words”. This
Andreewsky, 1983). latter hypothesis goes far beyond the initially postulated
The problem of a “single basic disorder” (Luria, 1977), and impairment of phonemic hearing (Valdois et al., 1989). Luria's
even “broad concepts”, such as “repetition disorder” (Lacey, conception has been criticized by several authors as some of
Skipper-Kallal, Xing, Fama, & Turkeltaub, 2017), can be illus- Wernicke's aphasics performed correctly in discrimination
trated by the repetition profile of a particular form of con- tasks (Blumstein, Baker, & Goodglass, 1977). Although the
duction aphasia (phonologic dysecophemia). This is a 45-year- phonemic hearing hypothesis cannot be discarded a priori
old patient (PMDC) with a high level of education, who was (Valdois et al., 1989), recent studies demonstrate that Wer-
diagnosed with a parietal (posterior insular) glioma. The nicke's aphasia reflects a combination of acoustic-
neuropsychological assessment (Fig. 2) only showed a signif- phonological and semantic control deficits (Robson, Sage, &
icant (severe) impairment in the repetition of minimal pairs Lambon Ralph, 2012).
(4/10) and pseudowords (4/10), with discrete and moderate In summary, Luria's syndromic and topographic analysis of
errors, respectively, in the repetition of syllables and syllable aphasia is partially obsolete given the advances in neurosci-
pairs. The phenomenon of lexicalization was observed. ence. For example, the previously commented recognition of
Repetition of words and phrases was strictly normal. Reading, double (dorsal and ventral) acoustic temporal streams
including absolutely pseudoword reading and pointing, was (Friederici, 2011; Hamilton, Oganian, Hall, & Chang, 2021;
also normal. Oral expression and comprehension were strictly Hickok & Poeppel, 2004), advances in the knowledge of the
normal. In contrast, pseudoword dictation was significantly representation of semantics, and semantic cognition in the
impaired (4/10, severe). Word dictation and written naming brain (see Lambon Ralph et al., 2017; Pulvermüller, 2002, 2013),
were normal. new connectomic knowledge such as the frontal aslant tract
This case shows several facts of special theoretical and (FAT) (Thiebaut de Schotten, Dell'Acqua, Valabregue, & Catani,
practical interest. First, an ipsative dissociation is observed in 2012; Catani et al., 2012; Catani, Mesulam, et al., 2013; Dick,
repetition (McCarthy & Warrington, 1984; Ellis & Young, 1997, Garic, Graziano, & Tremblay, 2019), and studies on the role
Ch. 6), with a preservation of the repetition of semantic ma- of the thalamus (Radanovic & Almeida, 2021; Fritsch, Rangus,
terial (words and phrases) versus asemantic material & Nolte, 2022) and basal ganglia (Radanovic & Almeida, 2021)
(phonologic dysechophemia [Lecours & Nespoulous, 1988]). in language. Consequently, current knowledge goes far
Note that minimal pairs imply an acoustic-discriminative beyond the classic Wernicke-Lichtheim (Lichtheim, 1885)
capacity that affords them a special status. Secondly, a func- model of aphasia.
tional clinical dissociation is established between the ventral The frontal aslant tract. This fascicle constitutes the struc-
(semantics/speech comprehension) and dorsal acoustic tural connection between the inferior frontal and medial su-
(phonologic/auditory-motor integration) pathways. See perior frontal gyrus (Martino & De Lucas, 2014). This
Hickok and Poeppel (2004) and Friederici (2011). Thirdly, this connection was proposed to represent a central pathway for
case highlights the functional interaction between dorsal and two functional circuits: speech and executive function/
ventral streams (Fridriksson et al., 2018) and the need for its inhibitory control that rely on overlapping mechanisms (Dick
specific study in cases of aphasia. Finally, it should be noted et al., 2019).
that the dorsal pathway is made up of a direct and an indirect The left inferior frontal gyrus (FIG) and the supplementary
component (Catani & Thiebaut de Schotten, 2012, Ch. 7). The and presupplementary motor areas (SMA/PreSMA) are
direct pathway (long segment) runs medially, and considered to be related to speech and language processes,
42 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

including the understanding of sign speech and gestures. stereotactic surgical procedures. In many cases, the lesions
There is sufficient data to relate the FAT to speech initiation, affect several nuclei and there are manifestations of perile-
verbal fluency, and stuttering (Dick et al., 2019). Neuroimaging sional edema. These facts make it extremely difficult to
studies show that the left FIG is related to lexical and establish specific clinicopathological relationships.
phonological selection and retrieval. For its part, the preSMA/ The majority of patients show mild symptoms in the area
SMA regions are more related to selection and execution in of lexical-semantic abilities, although different clinical pat-
both speech and non-speech areas (Dick et al., 2019). terns can be observed. Depending on the location, two major
The transient incidence of FoixeChavanyeMarie syn- syndromes can be differentiated based on lexical-semantic
drome after FAT resection is significant. This syndrome in- defects and the preservation of repetition and reading aloud,
volves paralysis of voluntary facial, lingual, pharyngeal, and and relatively impaired comprehension: in the case of pulvi-
masticatory movements, in the presence of preservation of nar lesion, language is fluent, with anomia (oral and written),
reflex and automatic movements of the same muscles semantic paraphasia and perseverations (Crosson, 2021;
(Martino, de Lucas, Iba n
~ ez-Pla
 garo, Valle-Folgueral, & Fritsch et al., 2022); In the case of lesions of the “anterior
Vazquez-Barquero, 2012). Furthermore, damage to the pre- nuclei”, a reduction in verbal fluency, anomia, and overall
SMA/SMA gives rise to motor and speech deficits character- higher severity are observed (Fritsch et al., 2022).
ized by akinesia and transcortical motor aphasia (Ardila & In the theoretical field, a recurrent circuit model has been
Lopez, 1984; Freedman, Alexander, & Naeser, 1984). proposed that describes how cortico-thalamo-cortical and
The current data suggest that interactions between the cortico-cortical circuitry supports word retrieval, auditory
right IFG and preSMS/SMA could be particularly important in verbal comprehension, and other language functions (see
inhibitory control. This function would be carried out with the Crosson, 2021).
participation of a cortico-basal ganglia-thalamic-cerebellar Subcortical non-thalamic aphasias. There are two main
circuit (Aron, 2007; Aron, Robbins, & Poldrack, 2014; Bohland, problems in the study of non-thalamic subcortical aphasias.
Bullock, & Guenther, 2010; Dick et al., 2019). First, the difficulty in finding isolated lesions affecting a single
Semantics. In Luria's model, semantics is related to its structure due to its complex anatomical characteristics and
second functional unit, specifically in its tertiary regions (the vascularization. Second, the basal ganglia form part of inter-
“posterior associative center”) of the left hemisphere (Luria, connected circuits that constitute networks with reciprocal
1973c). Current knowledge has greatly expanded the brain inhibition and stimulation, so injury to one structure can give
areas related to semantics and semantic cognition (Gardner rise to multiple effects in related structures (Radanovic &
et al., 2012; Lambon Ralph, Sage, & Roberts, 2000). After Mansur, 2017). Despite this complexity, some consistent data
Gardner et al. (2012, p. 778), semantic cognition involves “the are observed: in about one-third of patients, no language
retrieval of information about the meaning of words, pictures, impairment is found, regardless of the injury site, and naming
sounds, and objects and the application of this knowledge to a defects occur in almost half of the patients. Comprehension
specific task or context”. and repetition deficits also appear in nearly one-third of the
Neuroimaging studies show that semantic selective areas patients (Radanovic & Almeida, 2021; Radanovic & Mansur
are relatively symmetric across the two cerebral hemispheres 2017).
and that the semantic system is organized into intricate pat- Lesions involving the head of the caudate and anterior
terns that seem to be consistent across individuals (Huth, de capsule cause language disorders accompanied by hemi-
Heer, Griffiths, Theunissen, & Gallant, 2016). Clinicopatho- paresis. Aphasia arising from left caudate lesions may result
logical studies show that object naming and word compre- from adjacent white matter lesions (see Devinsky &
hension are mainly dependent on the temporopolar region D'Esposito, 2004).
(usually left); in contrast, behavioral control and non-verbal The role of the basal ganglia in language has been dis-
recognition show a more bilateral representation with a cussed by various authors, highlighting Crosson's (2021)
rightward bias (Mesulam, 2023). model on cortico-thalamo-cortical recurrent circuits, and the
Subcortical aphasias. The great complexity of subcortical aforementioned model in which the aslant fasciculus is
circuits has led to the differentiation of subcortical aphasias included.
into two groups: “thalamic” and “non-thalamic”. The second
group includes aphasias caused by lesions in the basal ganglia 3.3.1.1. COGNITIVE GRADIENTS. To adequately capture the
and subcortical white matter pathways (Radanovic & Almeida, congruence between anatomical and functional neocortical
2021). It is worth highlighting the initial working model pro- metrics, the concept of a cognitive gradient was introduced.
posed by Crosson (1985) on subcortical functions in language. After Goldberg (1989), “a cognitive gradient is a continuous
Thalamic aphasias. Thalamic aphasia is a rare disorder distribution of related functions along an axis defined at its
resulting from focal lesions of the thalamus. The role of the extremes by a pair of sensory projection or motor areas” (p.
thalamus in language is considered to be related to its partic- 11). This concept is expressed clinically in the case of diseases
ipation in certain cortico-strio-thalamic and cortico-thalamo- that spread from a certain cortical region, thus expressing a
cortical circuits (Fritsch et al., 2022). Thalamic focal lesions topographic evolution with a coherent expected symptom-
that consistently generate language disturbances are located atology. Goldberg's gradiental approach is based on Luria's
in the pulvinar/lateral posterior nucleus and the anterior/ first two laws regarding the work structure of individual
ventral anterior thalamus (Radanovic & Almeida, 2021). cortical regions (see below).
Regarding etiologies, ischemic or hemorrhagic strokes Neuroimaging studies also show spatial and functional
stand out, as well as tumors, infections, or injuries caused by gradients anchored by, at one extreme, regions serving
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 43

primary sensory/motor functions and, at the other extreme, Contextual connectivity constitutes a framework for un-
transmodal regions that, in humans, are known as the derstanding the intrinsic dynamic architecture of large-scale
default-mode network (DMN) (Margulies et al., 2016; Raichle functional brain networks (Ciric, Nomi, Uddin, & Satpute,
et al., 2001). The DMN regions are equidistant from primary 2017), with the emergence of canonical functional networks
sensory/motor landmarks (see below). (Xie, Cai, Damasceno, Nagarajan, & Raj, 2021) and high-order
functional hubs in the human brain (Santos et al., 2023).
3.3.2. Clinico-anatomical correlation update: the hodotopic Using resting-state functional connectivity, seven coarse
framework functional networks have been described in the human brain:
In contrast to classic neuropsychology focused on the cortex, a visual, sensorimotor, dorsal attention, ventral attention,
hodotopic framework for clinicaleanatomical correlation has limbic, frontoparietal, and default networks (Yeo et al., 2011).
been proposed (ffytche & Catani, 2005). According to this ter- These networks have been complemented and expanded with
minology, a topological mechanism (from the Greek new contributions such as the salience network (Menon,
topos ¼ place) refers to the loss of a specialized local function. 2015), and the multiple-demand network (Camilleri et al.,
In contrast, a hodological mechanism (from the Greek 2018; Duncan, 2010).
hodos ¼ path, street, road) refers to dysfunction related to Given the theoretical and practical importance of these
connecting pathways. networks, they will be briefly described. A priori, we want to
This advanced framework consists of specialized cortical highlight that the networks described below, as will be com-
areas and white matter connections, including short U-sha- mented, are compatible with traditional and updated
ped association fibers, to form a functional territory, and anatomical and functional systems of the brain. This
longer association tracts. The framework, beyond classic compatibility updates classic studies on local brain lesions and
cortical deficits and subcortical disconnections, includes the the different endophenotypes of neurodegenerative diseases.
concepts of cortical hyperfunction and white matter hyper- However, the systemic approach has serious limitations if the
connectivity. According to Catani and Thiebaut de Schotten vertical organization of the brain is not considered (see below).
(2012, p. 61), “a topological mechanism refers generally to a
dysfunction of the cortex irrespective of whether the 3.3.3.1. VISUAL NETWORK (VN). The VN consists of primary
dysfunction is one of deficit, hyperfunction, or a combination (retinotopic) and associative visual areas (higher-order visual
of the two”. In contrast, “a hodological mechanism refers processing) that give rise to dorsal and ventral attention net-
generally to dysfunction related to connecting pathways, works. These networks are related to the traditional local
irrespective of whether the dysfunction is one of disconnec- pathology of the occipital lobes and their anatomical conflu-
tion, hyperconnection, or a combination of the two” (Catani & ences with the parietal (dorsal) and temporal (ventral) lobes.
Thiebaut de Schotten, 2012, p. 62). This framework is Attention is not a unitary process that selects which sensory
compatible with the functional structure of psychiatric dis- input is preferentially processed (Asplund, Todd, Snyder, &
orders that will be discussed later. Marois, 2010). It can be engaged by salient or unexpected
events (stimulus-driven) or it can be maintained under
3.3.3. Functional cortical networks: systemic perspectives voluntary control (goal-directed). These two forms of atten-
Although Luria's neuropsychology is based on distributed tion are implemented by largely distinct ventral and dorsal
complex functional systems (Luria, 1973a, 1973c), technolog- networks, respectively (Corbetta & Shulman, 2002).
ical advances have made it possible to recognize a new
functional dimension of the brain: the systemic perspective. 3.3.3.2. DORSAL ATTENTION NETWORK (DAN). The DAN encom-
The systemic view of the functional organization of the brain passes left/right posterior intraparietal sulci, dorsolateral
describes cognitive functions as the result of interdependent prefrontal cortex, and frontal eye fields (Asplund et al., 2010).
dynamic systems of processes that do not have strict spatial Additionally, the cerebral dorsal attention network shows
boundaries (Kennedy, Van Essen, & Christen, 2016; Park & strong and selective connectivity with a set of cerebellar cir-
Friston, 2013; Sporns, 2016). cuits, including the VIIb/VIIIa lobe (Brissenden & Somers,
The adult human connectome shows a hierarchical con- 2019). Specifically, these circuits have characteristic proper-
nectivity (Smith et al., 2019), with centralized and distributed ties of the dorsal attentional pathway: task-specific activation,
cognitive task processing (Amico, Arenas, & Gon ~ i, 2019; working memory load-dependent responses, and the repre-
Grillner & Graybiel, 2006). Within the sensory and motor sentation of visuospatial location (Brissenden & Somers, 2019).
cortices, functional connectivity shows topographic hierar- The dorsal attention network is related to the integration of
chical representations across adjacent areas. In contrast, the visuospatial relations, the location of objects, visuomanual
association cortex is made up of networks of widely distrib- monitoring, and attentional shifting (where?). This kind of
uted and densely interconnected areas without a rigid hier- attention is deployed during tasks requiring strategic volun-
archical organization (Yeo et al., 2011). Large-scale networks tary goal-directed control (Corbetta & Shulman, 2002). This
may function as partially isolated modules, and many asso- network subsequently accesses the processing of the use of
ciation areas belong to at least two networks. As examples of the objects (how?).
interaction, the precuneus, lateral temporal cortex, medial Drawing tasks (graphical constructional praxis) are mainly
prefrontal cortex, and posterior parietal cortex participate in related to DAN (Bai, Liu, & Guan, 2021).
multiple networks that together comprise the subsystem of
the default mode network (Yeo, Krienen, Chee, & Buckner, 3.3.3.3. VENTRAL ATTENTION NETWORK (VAN). This network is
2014). related to the identification of objects (what?), their
44 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

corresponding salience, and their motivational and reward concepts” (Mesulam, 2023). Neurodegenerative diseases
“value”. This network encompasses the lateral and inferior affecting the temporopolar region show a hemispheric func-
frontal/prefrontal cortex and the temporoparietal junction tional asymmetry that is reflected in the six clinical patterns
(TPJ). VAN supports stimulus-driven attention: automatic described by Mesulam (see above).
reorienting attention to unexpected visual stimuli (Asplunt Furthermore, the SN serves as a dynamic “switch” between
et al., 2010; Corbetta & Shulman, 2002). In fact, this network the DMN and frontoparietal network (FPN), in line with
expands within the concept of the salience network, which in salience and cognitive demand (Chen et al., 2013;
turn relates to the limbic network (see below). Schimmelpfennig et al., 2023). In fact, the interaction between
the DMN (self-referential) and FPN (attentional control to-
3.3.3.4. SENSORIMOTOR NETWORK (SMN). The sensorimotor wards external tasks) is expressed in the form of anti-
network outputs motor activities related to different sensory correlation. The SN would determine the dynamic change of
inputs, and activities programmed by other systems. In the the anticorrelation between the DMN and FPN
context of this review, the SMN is, in part, assimilated to (Schimmelpfennig et al., 2023).
stimulus-response tasks (see below, sensorimotor network in It is important to note that the concept of “salience” is used
the context of basal ganglia function). The structure and in different ways, such as sensory prominence, exceptionality,
functional organization of the primary motor cortex (M1) has or novelty. In Goldberg's (2018) view, a distinction can be made
been the subject of recent updates (Gordon et al., 2023). between “salience determined by the individual as internal
salience and salience imposed by the experimenter as external
3.3.3.5. CINGULO-OPERCULAR NETWORK (CON) AND SOMATO-COGNITIVE salience” (p. 73). Without denying the importance of the eval-
ACTION NETWORK (SCAN). Recent studies show that two behav- uation of relevant external stimuli, the epistemic introduction
ioral control systems are intercalated in the precentral pri- of the concept of internal salience (agent-centered) constitutes
mary motor cortex (M1) (Gordon et al., 2023). One consists of a relevant contribution given that the DMN is activated in “self-
classic effector-specific circuits (Penfield & Booldrey, 1937; referential” situations (Schimmelpfennig et al., 2023).
Penfield & Rasmussen, 1950) for precise isolated movements Dysfunctions involving SN activity are linked to a broad
of highly specialized parts of the body (fingers, toes, and spectrum of deficits and dysfunctional behavioral patterns in
tongue), needed for activities such as language or praxis. A a variety of clinical disorders. SN hyperactivity has been
second system, SCAN, interrupts the classic homunculus. associated with clinical disorders such as depression,
These inter-effector areas show strong functional links to insomnia, or narcissism. Conversely, SN hypoactivity has
each other, as well as to CON, which is crucial for action, been related to chronic pain, anxiety, schizophrenia, epi-
physiological control, arousal, errors, and pain (Dosenbach lepsy, autism, and bipolar disorder (Schimmelpfennig et al.,
et al., 2006; Neta et al., 2015; Pool & Ransohoff, 1949; Wager 2023).
et al., 2013; Wall & Davis, 1951). SCAN integrates motor and
autonomic body control, and action planning (higher-level 3.3.3.7. FRONTOPARIETAL NETWORK. This network, also called the
executive control). SCAN includes specific regions of M1, central executive network, or associative control network, encom-
supplementary motor area, thalamus (mainly centromedian passes the dorsolateral prefrontal cortex (DLPFC) and poste-
and ventral intermediate), posterior putamen, and motor rior parietal cortex (PPC). FPN is crucial in goal-directed tasks
cerebellum. This network is functionally connected to the that require flexibility to solve new situations (Marek, Nico, &
dorsal anterior cingulate cortex (voluntary movements), pa- Dosenbach, 2018). The FPN plays a very important role in
rietal regions (movement intentions), and insular regions cognitive control, however, this function is carried out thanks
(somatosensory, pain, and interoceptive visceral information) to a set of anatomically separate networks that includes the
(Gordon et al., 2023). frontoparietal, salience and cingulo-opercular networks
(Marek et al., 2018). Mirror neurons, originally described in the
3.3.3.6. LIMBIC (LN) AND SALIENCE NETWORKS (SN). Although there monkey premotor area, are embedded in the frontoparietal
is no unanimity, the LN includes the cortical and subcortical network for action execution and observation (Cerri et al.,
structures described in Unit II. Limbic connections have been 2015).
defined using cortico-cortical evoked potential techniques Lesion and neuroimaging studies have identified a rostral-
(Enatsu et al., 2015). This study revealed that various limbic to-caudal functional gradient in the lateral frontal cortex,
structures are intimately connected in reverberating circuits corresponding to complex or abstract (higher-order) to simple
and are linked to ipsilateral and contralateral regions. or concrete (lower-order) cognitive control. Human functional
The revised model (Catani, Dell'acqua, et al., 2013) of the connectivity investigations show that frontal areas are bidi-
limbic system has already been discussed in the section on rectionally connected with parietal and temporal areas,
Unit II. Here, it is important to highlight the participation of LN forming parallel association networks. Furthermore, these
in the SN and the default network. parallel networks have similar order-specific corticostriatal
As already mentioned, the SN constitutes an expanded connectivity, which agrees with a striatal gating model of hi-
vision of the VAN and the LN. Experimental anatomical erarchical rule use (Choi, Drayna, & Badre, 2018). As com-
studies in macaques and neuroimaging studies show that the mented, a causal relationship between the activity of FPN and
temporopolar region sits at the confluence of the auditory, DMN has been demonstrated, such that activation in FPN re-
visual, and limbic streams of processing at the downstream gions (dorsomedial prefrontal cortex) inhibits activation in
pole of the “what” pathway (Mesulam, 2023). As commented, DMN components (medial prefrontal cortex) (Chen et al.,
the temporopolar region is crucial in processing “multimodal 2013). Dysfunctions involving FPN activity are linked to
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 45

many diseases, including schizophrenia, depression, and 3.3.3.10.

anxiety (Marek et al., 2018). OTHER SPECIFIC COGNITIVE NETWORKS. Several neurocognitive net-
works dedicated to distinct cognitive functions have been
3.3.3.8. MULTIPLE DEMAND NETWORK (MDN). The MDN includes described, such as language networks, drawing task networks,
the lateral inferior prefrontal cortex, anterior insula/frontal or calculation and arithmetic pathways. This approach leads
operculum, dorsal anterior cingulate/pre-supplementary to an atomization that is, in fact, a reality within large func-
motor area, a small area in the anterior frontal cortex, and tional brain systems.
the intraparietal sulcus (Duncan, 2010). Later studies proposed Concerning language, recent contributions emphasize
an extended MDN, including the bilateral pre-supplementary processing in “dorsal” and “ventral” pathways, mediating
area/Middle anterior cingulate cortex (Camilleri et al., 2018). phonological and semantic processing, respectively
This network is involved in a series of tasks with multiple (Cannestra et al., 2000; Hickok & Poeppel, 2004; Catani, Jones,
cognitive demands, including novelty, perceptual difficulty, & ffytche, 2005; Friederici, 2011; Chang Raygor & Berger,
response conflict, and different memory modalities. The 2015). Perisylvian pathways show lateralized heterogeneous
function of the MDN extends and overlaps with the FPN. In asymmetries (Catani et al., 2007).
MDN, the role of the intraparietal sulcus (IPS) stands out. The Regarding drawing tasks, a network centered on the pos-
anterior IPS cortex is mainly related to sensorimotor pro- terior parietal cortex and dorsal stream has been highlighted
cessing, whereas the posterior IPS cortex processes visual (Bai et al., 2021; Makuuchi, Kaminaga, & Sugishita, 2003;
information. Each zone of the IPS acts in response to more Raimo, Santangelo, & Trojano, 2021). Concerning calculation
than one sensory modality, a fact that makes it a multimodal and arithmetic, the participation of the intraparietal sulcus
integration zone. Together, the IPS cortices participate in eye stands out. This cortical zone is considered a central amodal
movements (parietal saccade region), “planning” and representation of quantity. The involvement of the precentral
executing visually guided reaching movements of the hand and inferior prefrontal cortices is also observed (Dehaene,
and upper limb (parietal reach region), reaching for and Molko, Cohen, & Wilson, 2004).
manipulating objects (parietal grasp region), coding of self and In the context of a general theory on the adaptive function
object motion and coordination of eye and head movements of the brain, it is pertinent to highlight the importance of the
(parietal navigation area), and monitoring the visual 3D neural networks that constitute the so-called “social brain”.
characteristics of objects (parietal 3D analysis). For more in- The network related to this adaptive function includes the
formation, see Clark et al. (2018). superior temporal sulcus, temporoparietal junction, anterior
New cytoarchitectural (Op5-Op7 areas) and functional de- insula, temporal pole, subgenual cingulate cortex, orbito-
tails of the human frontal operculum have recently been frontal cortex, and ventromedial prefrontal cortex.
demonstrated. The study showed that Op6 was active in music
cognition, whereas the right Op5 was involved in chewing/ 3.3.4. Large-scale brain networks: psychopathology and
swallowing and sexual processing (Unger et al., 2023). cognitive control deficits
The large-scale network offers new paradigms for investi-
3.3.3.9. DEFAULT MODE NETWORK. This network consists of gating cognitive and psychopathological dysfunctions in
bilateral and symmetrical cortical areas, in the medial and neurological and psychiatric disorders (Menon, 2011). The
lateral parietal, medial prefrontal, and medial and lateral “triple model” that unifies psychopathology, consists of the
temporal cortices (Raichle, 2011, 2015). The “default” network DMN, FPN, and SN (Menon, 2011; Schimmelpfennig et al.,
is sometimes referred to as “task-negative”, which is really a 2023; Shaw, McKinnon, Heisz, & Becker, 2021). These net-
misnomer since the brain is engaged in internally selected works, which are often called canonical (Ciric et al., 2017) or
and directed tasks (Goldberg, 2018). The DMN is best under- “core” (Menon, 2011), play a role in almost all cognitive func-
stood as a multiple interacting subsystem (Van den Heuvel tions (Schimmelpfennig et al., 2023) and psychopathological
et al., 2009) that plays a crucial role in the “distribution” of states. Deficits in access, engagement, and disengagement of
information while performing active tasks in normal cogni- these networks are shown to play an important role in dis-
tion and disease (Anticevic et al., 2012). orders such as schizophrenia, anxiety, depression, dementia,
The DMN is activated when the mind is engaged in inter- and autism (Menon, 2011).
nally focused tasks, including “thinking”, autobiographical Cognitive deficits are also a common characteristic of
memory retrieval, envisioning the future, imagination, psychiatric disorders. Diverse studies demonstrated a com-
conceiving the perspectives of others, and mind wandering mon pattern of cognitive disturbance across major psychiatric
(Buckner, Andrews-Hanna, & Schacter, 2008; Van den Heuvel disorders. This kind of disturbance parallels the MDN
et al., 2009). The medial temporal lobe subsystem provides observed in intact cognition and interfaces with the SN
information from prior experiences (memories and associa- (McTeague et al., 2017). The systemic perspective in the study
tions); the medial prefrontal subsystem (with the parietal lobe of brain symptoms has generated the concept of spatiotem-
subsystem) facilitates the flexible use of the information poral psychopathology, which proposes that the brain and
during the generation of relevant mental simulations. These symptoms share an underlying spatial and temporal organi-
two subsystems converge on nodes of integration including zation as their common currency (Northoff, 2022).
the posterior cingulate cortex (Buckner et al., 2008). The role of
DMN in cognition probably arises from its position as a trans- 3.3.5. The thalamus in the context of Unit III: a brief note
modal region that is unrelated to immediate sensory inputs The mammalian brain has been conceptualized as a thalamic-
(Margulies et al., 2016). cortical system (Sherman & Guillery, 2006). Thalamic-cortical
46 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

projections relay nearly all incoming information to the cortex Podell, 1995). The prefrontal cortex, as part of the FPN, also
as well as mediating cortico-cortical relationships (Hwang, works following this binomial principle of cognitive selection
Bertolero, Liu, & D'Esposito, 2017; Parvizi, 2009; Sherman & (Podell, Lovell, Zimmerman, & Goldberg, 1995). Left prefrontal
Guillery, 2006). The thalamus is engaged in tasks requiring decision-making (veridical decision-making) is based on in-
multiple cognitive functions; most thalamic subdivisions ternal representations and identification of the correct
show network properties that can integrate multimodal in- response, which is intrinsic to the external situation (context-
formation across diverse functional networks (Dehghani & dependent) and is actor-independent. Right prefrontal cortex
Wimmer, 2019; Hwang et al., 2017). Thus, the thalamus acts decision-making (adaptive decision-making) is actor-centered
as a gateway to mental representations (Wolff & Vann, 2019). and is guided by the actor's priorities (it is context-
Pulvino-cortical feedforward and feedback pathways partici- independent, or invariant), and involves exploratory pro-
pate in cognitive computations (Jaramillo, Mejias, & Wang, cessing of novel situations (Aihara, Aoyagi, Goldberg, &
2019), and the nucleus reuniens sits at the nexus of a hippo- Nakazawa, 2003; Aoyagi, Aihara, Goldberg, & Nakazawa,
campus and medial prefrontal cortex circuit enabling memory 2005). As commented by Koziol (2014, p. 28) “this highlights
and behavior (Dolleman-van der Well et al., 2019). the role of the right frontotemporal network in processing
As commented, a cortico (IFG and preSMA/SMA)-basal cognitive novelty, in task orientation, and the generation of
ganglia-thalamic-cerebellar circuit participates in speech novel problem-solving strategies”. Furthermore, the novelty-
and language processes (left hemisphere), and inhibitory routinization principle is openly related to the functional or-
control (right hemisphere). Furthermore, cortico-thalamo- ganization of the basal ganglia: associative networks (nov-
cortical and cortico-cortical circuitry are considered to sup- elties) versus sensorimotor networks (habits/routines).
port word retrieval, auditory verbal comprehension, and other Automatic acts (routines) alternate with episodes of cognitive
language functions (see Crosson, 2021). controlled behavior (Hikosaka & Isoda, 2010; Koziol & Budding,
2009).
3.3.6. The hemispheric lateralization of functions beyond Language and praxis are specialized forms of lateralized
Luria routinization in the left hemisphere. In fact, “rules” for the
Luria distinguished “three basic laws governing the work functioning of language are invariable (Ullman, 2004, 2006;
structure of the individual cortical regions” (Luria, 1973a, p. 74) Ullman & Pierpont, 2005), just like the “motor patterns” that
composing Units II (postcentral cortices) and III (precentral characterize gestures. All these automated activities are based
cortices): 1) law of the hierarchical structure of the cortical on habit/skill-related corticostriatal systems, allowing fast
zones (primary, secondary, and tertiary cortical zones); 2) law adaptive advantages (Hikosaka, Yamamoto, Yasuda, & Kim,
of the diminishing specificity of the hierarchical cortical zones 2013).
(from maximal modal and somatotopic specificity to supra- The syndromes of the temporopolar region show different
modal symbolic processing); 3) Law of the progressive later- degrees of hemispheric lateralization: the behavioral syn-
alization of functions. Concerning the third law, he wrote: “the drome is predominantly right, associative visual agnosia also
functions of the secondary and tertiary zones of the left presents a predominantly right atrophy, while semantic
(dominant) hemisphere start to differ radically from functions aphasia syndrome shows a predominantly left atrophy.
of the secondary and tertiary zones of the right (non-domi- Hybrid syndromes reflect combined impairments associated
nant) hemisphere (…). The left (dominant) hemisphere (in with bilateral atrophies (Mesulam, 2023).
right-handers) begins to play an essential role not only in the
cerebral organization of speech but also in the organization of 3.3.6.1. RIGHT HEMISPHERE SYNDROMES. Classic clinical studies
all higher forms of cognitive activity connected with speech” show a clear differentiation between right and left hemi-
(Luria, 1973c, p. 78). spheric focal lesions (Ajuriaguerra & He  caen, 1949; Luria,
The classic verbalenonverbal dichotomy of the left versus 1973a, 1973c; Hecaen & Albert, 1978). This fact is obvious in
right hemisphere in humans ignores exaptation and phylo- the case of cerebral vascular lesions (for an updated review,
genetic continuity. In contrast to this verbalenon-verbal di- see Godefroy, 2013). Right hemisphere-dominant functions
chotomy, MacNeilage, Rogers, and Vallortigara (2009) include emotions, body schema, visuospatial abilities, sensory
proposed the principle of novelty-routinization. According to and motor attention, and aspects of social function (see
this principle, the left hemisphere specializes in learning, Devinsky & D'Esposito, 2004, chap. 3). Below are some brief
controlling, and executing well-established behavior patterns comments on emortin, attention, and arousal and neglect.
(routines) in familiar situations (Koziol, 2014). The right Emotion, attention, and Arousal. While both cerebral hemi-
hemisphere is related to the detection and response to un- spheres contribute to most psychological functions, neuro-
expected stimuli (novelties). This principle is compatible with psychological evidence supports an overall right hemisphere
a dynamic view of brain physiology and the changing func- dominance for emotion, attention, and arousal (Hartikainen,
tional neuroanatomy of behavior control (Kim & Hikosaka, 2021). Stimuli that provoke emotional reactions, especially
2015). Despite asymmetries in cognitive and emotional pro- those that may represent a threat, tend to be prioritized in
cessing, the two hemispheres work in a complementary and attentional resource competition. These types of stimuli are
integrative manner (Corballis, 2017). prioritized by right-lateralized ventral attention networks
The neuroanatomical and functional foundations of the (Downar, Crawley, Mikulis, & Davis, 2000; Corbetta &
novelty-routinization principle were systematically reviewed Shulman, 2002).
and studied by Goldberg et al. (Goldberg & Costa, 1981; Emotion regulation involves a diverse set of cognitive
Goldberg, Harner, Lovell, Podell, & Riggio, 1994; Goldberg & control systems to manage elementary emotional
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 47

experiences. These control systems are widely distributed and 2014) and content (awareness of the environment and the
suggest hemispheric asymmetry related to the lateralization self) (Huang, Mashour, & Hudetz, 2023; Laureys, 2005).
of the basic cognitive processes on which they rely upon Consciousness, defined as a “first-person subjective phe-
(Turnbull & Salas, 2021). Aspects such as experience/genera- nomenon” (Schurger & Graziano, 2022, p. 1) or as “an
tion, perception/expression, memory, and emotion regulation individual-specific stream of experiences” (Coppola et al.,
operate simultaneously, constituting a broad and complex 2022, p. 1) is one of the unsolved questions of neuroscience
functional system. Consequently, the functional model of today (Northoff & Zilio, 2022); it is considered the “hard
emotions must combine both laterality and hierarchy (up- question” in neuroscience and philosophy. For reviews see
down). Brain functional asymmetry is important only in Churchland (1989, 1990), Chalmers (1996, 2013), Searle (1997),
certain facets of emotion since certain functional aspects are Dehaene (2001), Bennett and Hacker (2003),Rose (2006),
eminently subcortical (Turnbull & Salas, 2021). Pockett, Banks, and Gallagher (2006), Beakley and Ludlow
Neglect. The syndrome of spatial neglect is commonly (2006), and Dennett (2018).
associated with (predominantly) right brain lesions (Bernard, Due to their relevance to the model, some types of neural
Leme e, Ter Minassian, & Menei, 2018; Leme  e, Bernard, Ter activities, considered to reliably correlate with consciousness,
Minassian, & Menei, 2018; Moore, Hearne, Demeyere, & will be briefly discussed here (see Baars, Held, & Kozma, 2021;
Mattingley, 2023). Neglect is a clinically and anatomically Coppola et al., 2022; Duman et al., 2022; Huang et al., 2023;
heterogeneous syndrome (Moore, Milosevich, Mattingley, & Miller, Clark, & Schlicht, 2022; Northoff & Zilio, 2022; Schurger
Demeyere, 2023). Patients do not react or respond to objects & Graziano, 2022; Signa, Chella, & Gentile, 2021).
or persons located in the contralesional side space. Various neural theories of consciousness have been pro-
In this syndrome, a spontaneous bias of the eyes and head posed, nonetheless, despite their differences, these theories
along the horizontal dimension of space has been observed, as mainly focus on changes in stimulus-related activity that are
in patients with unilateral vestibular dysfunction. Interest- related to conscious content (Northoff & Zilio, 2022). Conse-
ingly, both spatial neglect and vestibular processing at the quently, it has been questioned whether the theories of con-
cortical level show a right hemispheric dominance. Clinical sciousness are explanatory or simply descriptive (Schurger &
and experimental studies show that the superior temporal Graziano, 2022).
cortex, insula, and temporo-parietal junction constitute Global Workspace Theory (GWT) (Baars, 1988) has become
important parts of the multisensory (vestibular) system as a leading approach in neuroscientific studies of the brain and
well as being affected in spatial neglect (Karnath & Dieterich, consciousness. The brain-based variety of GWT is called
2006). It is argued that these structures “are not strictly Global Workspace Dynamics (Baars, Franklin, & Ramsoy, 2013;
vestibular but rather have a multimodal function representing Baars & Held, 2019). This name arises because the cortex is
a significant site for the neural transformation of converging viewed as a unified oscillatory machine (Steriade, 1999),
vestibular, auditory, neck proprioceptive, and visual input thanks to which functional temporo-spatial relationships that
into higher-order spatial representations” (Karnath & underpin consciousness are established (Northoff & Zilio,
Dieterich, 2006, p. 293). 2022). For an alternative approach see Shallice and Cooper
(2011).
3.3.7. Cortical memory and learning: a brief note on Based on this review, the following simplified aspects of
unsupervised learning consciousness can be highlighted:
Memory is a functional property of cortical systems (Fuster, The first aspect is functional anatomy. As a starting point for
1999), which provides a great adaptive capacity. Cortical the study of consciousness, the anatomical characteristics of
learning and memory are characterized as “unsupervised” the brain should be considered. Brain connections determine
(Doya, 1999). Unsupervised learning implies a concise repre- the brain's functional activity (Thiebaut de Schotten & Forkel,
sentation of sensory state, context, and action. This kind of 2022), and the functional geometry of the cortex encodes di-
learning entails finding the appropriate modular and distrib- mensions of consciousness (Huang et al., 2023).
uted architecture of a given task and is guided by the statis- The second aspect concerns interactions and complexity.
tical properties of the input signal itself (Doya, 2000a). This Behavior, cognition, and consciousness emerge through
process is regulated by ascending neuromodulatory inputs cortical and subcortical area interactions (Thiebaut de
(Doya, 2000b) and constructed thanks to a synaptic framework Schotten & Forkel, 2022). This implies the complex integra-
that is the basis of the persistence of memory engrams (Rao- tion between local and distant structures based on densely
, Smit, & van den Oever, 2021). Brain-wide
Ruiz, Visser, Mitric connected networks, including the cortex, cerebellum, and
mapping reveals that engrams for a single memory are subcortex; complexity is considered the corollary of the
distributed across multiple brain regions (Roy et al., 2022). A stream of consciousness (Coppola et al., 2022).
model for memory systems based on processing modes other In this global functional framework of connectivity, the
than consciousness (Henke, 2010), shows that unsupervised “predictive processing” theory does not assume sensory
neocortical memories are episodic (contextual) and semantic. stimuli to be propagated up to higher cortical levels (Miller
et al., 2022). Instead “predictive processing” postulates a top-
3.3.8. Consciousness and complexity: some notes on the down approach, in which the brain acts as a “hypothesis
“hard question” beyond Luria tester” regarding the final causes of the input. Depending on
Consciousness, as a multidimensional phenomenon, has the estimated precision of the predictions (“error signals”),
been defined by two different dimensions: wakefulness (level “the brain model of the world is either amended and its cur-
of consciousness) (Di Perri, Stender, Laureys, & Gosseries, rent hypotheses are changed to accommodate the mismatch
48 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

(…), or the hypotheses are kept fixed and lead to resampling of their relation to emotion-related brain regions, including the
the sensory states according to the current model” (Miller medial prefrontal cortex (Friedman et al., 2015). Some BG
et al., 2022, p. 798). This quote tries to highlight the great disorders are associated with imbalances in the striatal
flexibility, adaptability, and learning capacity of conscious, striosome and matrix compartments (Crittenden & Graybiel,
and non-conscious experience. 2011).
The third aspect is global temporo-spatial relationships and
dynamics. Consciousness can be understood as the functional 3.4.1. BG systems: divisions
result of temporo-spatial propagation of information in the Beyond the divisions of BG established from the three dopa-
relevant brain structures (Northoff & Zilio, 2022; Revach & minergic pathways described above, the corticostriatal sys-
Salti, 2022). tems can be conceptualized into three macro parallel
It is important to emphasize that the study of the neural divisions: limbic (emotional), associative (cognitive), and
substrates of consciousness and self-awareness is funda- sensorimotor (Yin & Knowlton, 2006). These three networks
mental in a neuropsychological model. Traditional classical are related to motivation/value, thought (problem-solving),
neuropsychology has tended to deal with the sub-personal and movement (habits/skills), respectively. Fig. 3 details the
domain, addressing capacities such as gnosis, language, and fundamental cortico-striatal circuits beyond the tripartite
memory. Until recently, little emphasis has been placed on conceptual scheme (limbic, associative, and sensorimotor). Its
the personal level (first-person perspective), and the role of functions and anatomical components and its cortico-cortical
self-awareness in behavior (Gusnard, 2006). After the first- relationships are highlighted.
person perspective, the social second-person perspective is
consequently emphasized. Self-awareness is considered 3.4.1.1. LIMBIC NETWORK (LN). This old phylogenetic network
typically associated with an “evaluation of the agent's includes the orbital and ventral PFC, the limbic (ventral)
behavior” (Gusnard, 2006, p. 43) and the “experience of striatum (nucleus accumbens septi and olfactory tubercle),
ownership of this intentional behavior” (Gusnard, 2006, p. 42). the ventral pallidum (substantia innominata/NBM), and the
mediodorsal thalamus (Ikemoto, 2007; Yin & Knowlton, 2006).
3.4. Unit IV: basal ganglia systems These circuits form a core part of the limbic system (Mesulam,
2000), playing an important role in the SN.
This unit includes the striatalecortical systems, whose output LN is associated with situations of stimulus-outcome (S-O),
is added to the thalamocortical pathways. The basal ganglia as in the case of emotions and conditioned learning (the
(BG) comprise a group of subcortical structures distributed stimulus generates the outcome). The ventral striatum is
within the telencephalon, diencephalon, and mesencephalon. considered a motivation-action gate (Hariri, 2015) and forms
It also includes the pedunculopontine (pedunculotegmental) part of the SN; however, BG integrate motivation and action
nucleus, a midbrain-pontine nucleus, and parts of the basal across their circuits. The striosomes (one of two comple-
forebrain (Clark et al., 2018). BG integrate information from mentary compartments within the striatum [called matrix])
widespread cortical areas and project their outputs back to the could strongly contribute to this merger (Courtemanche &
cerebral cortex (Alexander & Crutcher, 1990; Kemp & Powell, Cammalleri, 2019).
1970). Patients with Parkinson's disease and other conditions
The canonical cerebral BG loops (cortex e striatum e potentially treated with dopamine agonists (e.g., pramipexole
thalamus e cortex [CSTC]), are the essential organizing units and ropinirole), as well as patients treated for psychotic dis-
in the mammalian brain (Funk et al., 2023). BG perform a orders, are groups with an increased risk of developing
process of selective disinhibition of the thalamus (Doya, 2002; gambling disorder (GD). The biological basis of GD involves the
Stephenson-Jones et al., 2011). See Blumenfeld (2010), reward and reinforcement system, based mainly on meso-
Cummings and Mega (2003), Koziol and Budding (2009), Funk limbic and mesocortical dopamine projections, with the nu-
et al. (2023), and Graybiel and Matsushima (2023) for detailed cleus accumbens being a crucial area for developing
information on the circuits of the basal ganglia, including addictions to substances and behaviors (Wolfschlag &
direct, indirect, hyperdirect, and striosomal pathways. Håkansson, 2023). Since reward-related learning is mediated
Midbrain dopaminergic systems modulate the activity of by dopaminergic systems, it can be modified by dopaminergic
BG circuits (Milardi et al., 2019). These dopaminergic neurons medications, possibly leading to increased gambling behavior
are sensitive to rewards and, as a rule, encode reward pre- and decreased impulse control.
diction errors; increases in reward value activate them, and
decreases inhibit them (Schultz, 1998). In fact, corticostriatal 3.4.1.2. ASSOCIATIVE NETWORK. This network is composed of the
systems constitute a system of motor and behavioral selection prefrontal, parietal, and temporal associative cortices, asso-
(Seger, 2006) and reinforcement (Cox & Witten, 2019; Henke, ciative striatum (caudate/dorsomedial striatum), associative
2010; Simonyan, 2019). The BG are implicated in gating and pallidus, and mediodorsal/ventral thalamus (Yin & Knowlton,
selecting programs that are processed by the cortex. 2006). It is associated with novelty and executive actions.
Basal ganglia circuits process limbic, associative, and Novelty implies action-outcome (A-O) contingencies. Suc-
sensorimotor signals in largely separated but interacting cessful problem-solving requires determining a synthesis of
networks (Funk et al., 2023). These loops pass through paired environmental information, afferent synthesis (Anokhin,
striatal compartments, striosomes and matrix, segregated 1935; Luria, 1973a, 1973c), and searching for the individual
pools of spiny projection neurons (Graybiel & Matsushima, operations (stimulus-response [S-R]), which will be used to
2023). The anatomical connections of striosomes indicate obtain the necessary results (Koziol & Budding, 2009). This
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 49

Fig. 3 e Fundamental cortico-striatal circuits in approximate anteroposterior anatomical distribution (from left to right). The
main functions of each circuit appear in the top row. Boxes with dashed lines highlight the anterior and posterior
associative areas that form the frontoparietal network. The anteroposterior interaction is indicated with arrows. The bottom
row represents the functional interactions and the topographical change in motor skill learning (Kim & Hikosaka, 2015):
from executive control to automation (motivation was added). Acc, nucleus accumbens septi; DL, dorsolateral; Gpi, globus
pallidus pars interna; MD, mediodorsal; OT, olfactory tubercle; SMA, supplementary motor area; post & inf, posterior and
inferior; SNpr, substantia nigra pars reticulata; VA, ventral anterior; VL, ventral lateral. Sources: Blumenfeld (2010);
Cummings and Mega (2003); Yin and Knowlton (2006); Devinsky and D'Esposito (2004); Seger (2008); and Koziol and Budding
(2009).

kind of executive cognition (higher-order control) requires 2006). Obviously, it includes, in a broad sense, the sensory
keeping informative units active for relatively short periods components corresponding to the contextual (external and
(working memory). This online information is necessary while internal) situation. This network is associated with situations
the task is running. This functional situation also requires of S-R and habit/skill formation (Koziol & Budding, 2009; Saint-
attentional components and the inhibition of irrelevant Cyr, Ungerleider, & Desimone, 1990). The stimulus (internal or
automatic responses (Luria, 1973c). Higher-order control and external) triggers the appropriate adaptive response (Doya,
problem-solving situations “can be understood as breaking a 2000a).
problem situation down into stimulus-based characteristics” During development, and in the case of learning processes,
(Koziol & Budding, 2009, p. 15). We have cited this sentence a dynamic change in cerebral anatomical location occurs: the
because the concept included is of paramount importance. In associative-executive system (Goal-A-O) is replaced by the
the neuropsychological analysis of arithmetic problems, Luria sensorimotor systems (S-R/habit) (see below).
(1973c) clearly explained this concept: the “executive” (asso- In terms of Kim and Hikosaka (2015) “action skills” (habits)
ciative) need to “reason” (find) the arithmetic operations are motor sequences that have been automated and catego-
applicable to “solve” the problem (the novelty). Calculation rized and carry a meaning or an established manipulative
represents the application of the knowledge of “arithmetic result. For this reason, habits are considered automatic
tables” and the “rules” of arithmetic operations (routinized knowledge structures in goal-directed behavior (Aarts &
knowledge, “stimulus-based characteristics”). Furthermore, Dijksterhuis, 2000). Thus, “praxic” tasks (propositional motor
Luria introduced the concept of “verification” as the last stage acts/skilled movements), as they were introduced (see He caen
of the “executive” process (Luria, 1973c). Obviously, in the & Albert, 1978), are built through this automation system.
mental resolution of arithmetic problems, working memory
plays an essential role, especially in complex problems with 3.4.2. Basal ganglia learning: a brief note on reinforcement
intermediate arithmetic operations. learning and other related forms of learning
BG learning is based on the “evaluation” of the current situa-
3.4.1.3. SENSORIMOTOR NETWORK. This network includes the tion by prediction of reward (Schultz, Apicella, Scarnati, &
sensorimotor cortices, sensorimotor striatum (putamen/ Ljungberg, 1992). This learning implies the “selection of
dorsolateral striatum), and ventral thalamus (Yin & Knowlton, appropriate action by the evaluation of candidate actions”
50 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

(Doya, 2000a, p. 736). Reinforcement learning is guided by the “behavioral final common path” introduced by McFarland
reward signal encoded in the dopaminergic input from the and Sibly (1975), underlines that many different motiva-
substantia nigra and the tegmental ventral area (Apicella, tions converge as a single means of expression. Selection
Scarnati, Ljungberg, & Schultz, 1992; Schultz, 1998). For these takes place at multiple levels, differentiating between BG and
reasons, it has been proposed that the BG essentially consti- cortical levels depending on the type of movement/action to
tute a “reward-oriented behavior” system (Kim & Hikosaka, be performed (Cisek, 2021). It was recently proposed that the
2015). To fulfill this function, BG contain parallel circuits to entire prefrontal cortex is essentially a hierarchically orga-
process two phases of goal-directed behavior: finding valuable nized premotor structure (Fine & Hayden, 2022). According to
objects and manipulating these objects (Kim & Hikosaka, this view, the prefrontal cortex is considered the mirror
2015). This system of “reward-oriented behavior” is related reverse complement of sensory systems and focuses on
to survival, hedonicity, and the aforementioned “behavioral computations that lead to action (Fine & Hayden, 2022). This
final common path” of McFarland and Sibly (1975). Learning approach, like others (Cisek & Kalaska, 2021; Fuster, 2015;
an action skill means a transition between voluntary behavior Koziol, 2014), clearly blurs the role of a single central exec-
(related to a novelty) and automatic behavior (routine/habit). utive function.
This process involves a transfer of function from the asso- Pleasure and reward might be the common currency
ciative (association cortex e rostral BG loops [caudate head]) postulated by McFarland and Sibly (Cabanac, 2010). The na-
and sensorimotor circuits (sensorimotor cortex e caudal BG ture and function of pleasure must form an essential part of
loops [caudate tail]) (Kim & Hikosaka, 2015). This phenomenon functional brain models (Cabanac, 2010; Frijda, 2010;
is expressed in Fig. 3, where the circuit related to motivation Kringelbach, 2010). Pleasure is crucial in vital processes and is
has been added. Furthermore, as in category learning (Seger, closely related to emotional and reward brain processes. Brain
2006, 2008), the role of the posterior cortices is highlighted regions involved in human hedonic processing include
(Kim & Hikosaka, 2015; Koziol & Budding, 2009; Yin & cortical areas (e.g., orbitofrontal, cingulate, insula), as well as
Knowlton, 2016). subcortical structures, such as the VTA in the brainstem, the
Beyond action skills, BG are related to sequence learning, periventricular and periaqueductal gray, the ventral striatum/
which might be considered a form of instrumental condi- pallidum, the amygdala, and the hypothalamus (Kringelbach,
tioning; categorization learning including probabilistic 2010). This set of structures is related to the ventral attentional
learning and rule-based explicit category learning; and posi- and salience networks (see Menon, 2015).
tive and negative reinforcement learning including experien- The reasoning about automatic (sensorimotor) and asso-
tial learning (Koziol & Budding, 2009). ciative systems (higher-order control, action-outcome),
without leaving aside limbic systems, is fully applicable to
3.4.3. The cortico-basal ganglia-cerebellar network the neuropsychology of social cognition, including social
The model of BG systems based on direct, indirect (Albin, intuition (Koziol & Budding, 2009), non-verbal communica-
Young, & Penney, 1989), hyperdirect, and striosomal path- tion, empathy (Engen & Singer, 2013), theory of mind (Byom &
ways (Brimblecombe & Cragg, 2017; Milardi et al., 2019) has Mutlu, 2013; Poulin-Dubois, 2020), punishment (Jean-Richard-
been challenged in the light of new tract-tracing information Dit-Bressel, Killcross, & McNally, 2018; Wu, Luan & Raihani,
(Milardi et al., 2019; Nelson & Kreitzer, 2014). Recent studies 2022), or costly punishment (Mieth, Buchner, & Bell, 2021).
have identified a direct connection between the cortex and The cerebellum also plays a crucial role in social cognition
external and internal segments of the globus pallidus (Milardi (Van Overwalle et al., 2020).
et al., 2019; Quartarone et al., 2020). In addition, the sub-
thalamic nucleus (STN), traditionally considered one of the 3.5. Unit V: cerebellar systems
most relevant structures of the indirect pathway, also receives
direct input from the cerebral cortex (Nambu et al., 2000). In This unit includes the cerebellar systems subdivided accord-
summary, the most recent studies show that BG directly ing to their anatomical connectivity. In fact, these sub-
integrate signals from widespread cortical areas and that they divisions agree with those established in the case of the BG:
are part of a network that also includes the cerebellum. limbic, associative, and sensorimotor. The organization of the
Globally, the cerebral cortex, BG, and cerebellum form an in- human cerebellum, estimated by intrinsic functional con-
tegrated and segregated network acting on multiple motor, nectivity, shows that the extent of cerebellum connections is
cognitive, and affective functions (Bostan & Strick, 2018; proportional to the extent of the network in the cerebrum,
Milardi et al., 2019). with a few exceptions including the visual primary area,
which is not represented in the cerebellum (Buckner, Krienen,
3.4.4. Values and priorities: the behavioral final common Castellanos, Diaz, & Yeo, 2011).
path In recent years, a series of investigations have shown that
In vital biological needs, at every moment, animals behav- cerebellar functions go beyond vestibular and motor control,
iorally satisfy their primordial urgent motivations. In this including the cognitive, autonomic, emotional, and social
way, brain systems “must rank on a priority scale all moti- realms (Leggio & Olivito, 2018; Schmahmann, 2019;
vations simultaneously present according to their urgency” Schmahmann, Guell, Stoodley, & Hako, 2019). The cerebellum
(Cabanac, 2010, p. 117); to achieve this ordered classification is important for information processing, thanks to the special
(ranking) the brain must “compute and select” among characteristics of its canonical circuits, its immense compu-
competing motives based on a common currency (McFarland tational possibilities, and its connectivity with specific areas
& Sibly, 1975). This selection, which represents the of the nervous system (Grimaldi & Manto, 2012).
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 51

Interestingly, an original case report from Luria's labora- 3.5.2. The universal cerebellar transform: orthometria
tory drew attention to cognitive deficits resulting from a Unlike the cerebral cortex, the cerebellar cortex presents
cerebellar tumor (Kutsemilova, Luria, & Homskaja, 1964). This histological homogeneity (a single type of canonical circuit)
case report highlighted “pseudo-frontal” symptoms and (Shepherd, 2004). This fact implies that it only performs one
cerebellar contributions to cognition (Budisavljevic & (constant) operation, which is termed the universal cerebellar
Rammani, 2012). transform (UCT) (Schmahmann, 2004, 2019; Schmahmann
et al., 2019). Thus, the same operation will be applied to
3.5.1. Divisions of the cerebellar circuits motor, vestibular, associative (cognitive), and limbic/para-
A classic subdivision of the cerebellum and its networks is limbic activities (emotional and autonomic). Following the
based on phylogenetic development: archicerebellum, paleo- idea of the UCT, “the cerebellum maintains behavior around
cerebellum, and neocerebellum (Brodal, 1992). The divisions homeostatic baseline automatically, without conscious
of the cerebellar system are presented below, following the awareness, informed by implicit learning, and performed ac-
same terminology used in Units II and IV. cording to the context” (Schmahmann, 2019, p. 62). Emerging
data on the histology and function of the cerebellum have
3.5.1.1. LIMBIC/PARALIMBIC NETWORK. The limbic cerebellum revealed a great diversity of neuronal types, synaptic con-
(“emotional cerebellum”) is formed by the posterior vermis. nections, regional specializations, and plasticity mechanisms,
The output from the limbic cerebellum is directed to the among other peculiarities. All the new information challenges
reticular nuclei, hypothalamus, and paralimbic structures the notion of a homogeneous cerebellar circuit function (Hull
(Grimaldi & Manto, 2012; Turner et al., 2007). Damage to this & Regehr, 2022). Recent evidence suggests the involvement of
system is associated with neuropsychiatric syndromes, with the cerebellum in forms of reinforcement learning for some
symptoms of emotional dysmetria. behaviors (Hull & Regehr, 2022).
The cerebellum functions as a “predictor or anticipator”: it
3.5.1.2. ASSOCIATIVE NETWORK. The associative (“cognitive”) informs the cerebral cortex about the predicted outcome of an
cerebellum consists of the lateral parts of the cerebellar action (Koziol et al., 2014) and can be defined as a supervised
hemispheres (neocerebellum). The cerebellar hemispheres learning system (Doya, 2000a; Yamazaki & Lennon, 2019). The
receive the main input from the cerebral cortex (cerebrocer- cerebellum is also related to classic conditioning (Freeman,
ebellum). The related canonical cortico-cerebellar circuit is 2015; Henke, 2010), procedural learning, working memory,
the following: cortex e pons e cerebellar cortex/dentate nu- expertise, creativity, and giftedness (Koziol & Budding, 2009).
cleus e red nucleus e thalamus e cortex (Ito, 2006). Damage to The concept of “motor dysmetria” observed in cases of
this part of the cerebellum gives rise to cognitive cerebellar cerebellar motor lesions applies to cognition and emotion
syndromes, with manifestations of cognitive dysmetria. (Schmahmann, 2004). Consequently, it is possible to recognize
Damage to this part of the cerebellum gives rise to cognitive that the cerebellum has a main predictive “orthometric”
cerebellar syndromes, with manifestations of cognitive dys- physiological function (Pen ~ a-Casanova, 2018). Orthometria (or
metria (Koziol et al., 2014; Schmahmann, 2004). eumetria), as opposed to dysmetria, involves the regulation
and improvement of quality, efficiency, fluidity, intensity,
3.5.1.3. SENSORIMOTOR NETWORK. The sensorimotor cerebellum softness, and, finally, the adaptability of motor, cognitive,
is assimilated to the motor (paleocerebellum) and vestibular behavioral, and emotional acts (Pen ~ a-Casanova, 2018). In
functions (archicerebellum). The spinocerebellum consists of other words, orthometria implies the adequate graduation of
the medial part of the cerebellar hemispheres (output via the the quality of the strength of an impulse to match the final
interpositus nucleus [globose þ emboliform nuclei]) and the need.
anterior and posterior parts of the vermis (output via the
fastigial nucleus) (Brodal, 1992). This part of the cerebellum 3.5.3. Cerebellar syndromes: new insights
receives afferents from the spinal cord; damage to these Studies of cases with cerebellar lesions allow us to recognize
structures gives rise to cerebellar motor syndrome, with the the topography and nature of three generic cerebellar syn-
typical dysmetria. The vestibulocerebellum consists of the small dromes: limbic/emotional, associative/cognitive, and senso-
flocculonodular lobe. This part of the cerebellum receives af- rimotor (motor/vestibular) (Pen ~ a-Casanova, 2018; Pen ~ a-
ferents primarily from the vestibular system; damage here Casanova & Sigg-Alonso, 2020; Schmahmann, 2019).
causes cerebellar vestibular syndrome, affecting balance and The “cerebellar cognitive affective syndrome” is the diag-
eye movements (Blumenfeld, 2010). nostic term applied to cognitive, emotional, and behavioral
In summary, like BG, the cerebellar systems participate in symptoms that appear in patients with cerebellum involve-
motor/vestibular, limbic, and associative activities (Habas, ment (Koziol et al., 2014; Schmahmann, 2004). Within this
Manto, & Cabaraux, 2019). As previously commented, the ac- context, the vermal region has been referred to as the “limbic
tivity of the cerebellar systems is performed in parallel with cerebellum”, and focal involvement in this area has been
BG (Milardi et al., 2019). Recent studies highlighted that cere- related to disturbances in emotional responsiveness, person-
bellar anatomical connections take place through a specific ality, as well as psychotic and behavioral disturbances (Koziol
subnucleus of the thalamus, the “cerebellar thalamus” (Habas & Budding, 2009; Koziol et al., 2014; Schmahmann, 2004).
et al., 2019). The role of these connections should not be The limbic cerebellum acts on the reticular nuclei (effects
considered as a passive relay of information (Habas et al., on the arousal system), the hypothalamus via the superior
2019). cerebellar peduncle (autonomic functions), and the cingulate
52 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9

and other limbic structures (emotions and emotional experi- the vertical organization of the brain interacts with horizontal
ence) (Grimaldi & Manto, 2012; Turner et al., 2007). During processing. For example, local cortical processing is related to
social/emotional processing, cerebellar activity displays a the intra-cortical (horizontal) connectome and, in turn, to
specific mentalizing/theory of mind functionality, which is thalamic, hippocampal, striatal, and cerebellar vertical orga-
strongly connected to corresponding networks in the cere- nization (Catani & Thiebaut de Schotten, 2012; Edelman &
brum. The phylogenetically recent lobules, such as VI and VII, Tononi, 2000; Koziol, 2014; Koziol & Budding, 2009; Koziol,
within the posterolateral cerebellar hemisphere, have been Budding, & Chidekel, 2013). Consequently, the principles of
involved in social cognition (Leggio & Olivito, 2018). parallel vertical organization of the brain (Yakovlev vs
As in the motor area, clinical symptoms of cognitive and MacLean) were considered.
emotional dysmetria can be expressed in the form of hyper- Current knowledge shows that it is unrealistic to establish
metria or hypometria (Schmahmann, Weilburg, & Sherman, strictly separate functional units (Pessoa, 2022; Uddin et al.,
2007). Thus, for example, in emotional control, hypermetria 2014). For this reason, the proposed model necessarily im-
would be expressed as impulsivity, disinhibition, or agitation. plies transition and overlapping between certain structures
Conversely, hypometria would be expressed as anhedonia, and the recognition of large integrated complexes. The pro-
sadness, dysphoria, or depression (Schmahmann et al., 2007). posed brain units are nothing more than abstractions within
Recent studies reported relationships between cerebellar the hierarchical multilevel simultaneous and distributed
development, behavior, and complex brain disorders physiological processes of the brain (Dehaene & Naccache,
(Sathyanesan et al., 2019). 2001, chap. 1; Hilgetag & Goulas, 2020; Lawn et al., 2023;
Shepherd, 1994, 2004; Sporns, 2011, 2016).
Thus, our model is based on the explicit differentiation of
4. Synthesis, discussion, and limitations two large functional complexes: a basic primordialelimbic
complex (brainstem and limbic systems) and an overlapped
Luria's contribution to the three main functional units was an telencephalic complex (Fig. 3). Table 5 and Fig. 4 summarize
important conceptual advance in neuropsychology. As high- the units described in this paper, including structures, types of
lighted in the introduction section, Luria made his proposals in related motility, simplified descriptive functions (as Luria did),
a specific historical context. Scientific and technological ad- and divisions.
vances, mainly in the last decade, imply a serious challenge to Regarding Unit I, it is axiomatic that the “primordial” need
Luria's contributions to the functional organization of the of living beings is to maintain life via the homeostatic stability
brain. The same challenges apply to several classic contribu- of their internal environment (Bernard, 1866; Cannon, 1932).
tions such as Wernicke-Lichtheim's aphasia model (Lichtheim, This primordial homeostatic need is related to endokinesis
1885), the reticular formation (Moruzzi & Magoun, 1995 [1949]), (Yakovlev, 1948). In homeostatic processes, the hypothalamus
the triune brain (MacLean, 1949, 1970), or the serial circuit of (Lechan and Toni, 2016) and autonomic systems play a
Papez (1937). Even traditional conceptions such as the verbal- fundamental role (Cannon, 1932). Ultimately, however, all
enon-verbal dichotomy of the cerebral hemispheres are in a homeostatic needs are behaviorally satisfied (Anokhin, 1935;
dramatic crisis (see MacNeilage et al., 2009). Cabanac, 2010; Luria, 1973b). As mentioned, the prosomeric
Updating Luria's functional brain model requires looking model directly and indirectly intertwines hypothalamic
back over 75 years of research (!). Although the task is difficult function with telencephalic/cortical activity.
and filled with obstacles, trying to define a new functional In addition to the “non-specific” reticular function in the
model of the brain is an important goal. Advances in this field arousal/waking state (Luria, 1973c), the recognition of cortical
necessarily imply improvements in neuropsychological modulatory systems located in the brainstem and other
assessment and its interpretation (Koziol, Beljan, Bree, structures implies a remarkable advance in the understanding
Mather, & Barker, 2016; Koziol & Budding, 2009). This review, of brain function. In this area, the concepts of “cortical
and the proposed model, involve the main aspects briefly receptome” (Jancke et al., 2022) and “chemo connectomics”
synthesized and discussed below. (Zerbi et al., 2019) have been highlighted. These contributions
Luria's (1973c) basic concepts regarding complex functional link micro-scale information with systems-level dynamics
systems remain today, however, vastly more complex and (Lawn et al., 2023). The function of this unit is mainly sum-
with many more components. A differentiation was made marized as life support, behavioral modulation, and waking
between functional systems related to physiological and regulation.
behavioral control, respectively (Luria, 1973c), nevertheless, Unit II (limbic systems) brings new dimensions to the
recent studies show that this dichotomy is becoming blurred primitive functions of Unit I. The structure of the limbic and
(Cisek, 2021; Leopold & Averbeck, 2022; Puelles & Rubenstein, paralimbic systems is very complex with a wide range of
2015). Thus, the neuromeric framework of phylogenetic evo- network connections (Amaral, 1986; Andersen et al., 2007;
lution reorganizes traditional anatomical levels and shows Enatsu et al., 2015; Kamali et al., 2023) and their function is
that the hypothalamus and telencephalon are in the same neither unitary nor simple (Catani, Dell'acqua, et al., 2013;
prosomere. This fact is of capital importance since it shows Mesulam, 2000; Rolls, 2015). It is functionally remarkable that
that physiological control has a clear continuity with behav- limbic structures are the parts of the brain with the most
ioral control. intense mutual connections with the hypothalamus
The phylogenetic phenomenon of exaptation (Gould & (Mesulam et al., 1983). This indicates the integrated relation-
Vrba, 1982; Stephenson-Jones et al., 2011) is also crucial to ship of Units I and II, and their connection, direct or indirect,
understanding many aspects of brain function. Furthermore, with supralimbic structures (Leopold & Averbeck, 2022).
 c o r t e x 1 7 4 ( 2 0 2 4 ) 1 9 e6 9 53

Table 5 e Simplified model of two integrated functional complexes and five brain units.

Integrated preferential-limbic functional complex (Luria's Unit I)

Structures included: brainstem þ limbic systems
- Unit I (brainstem þ impar [rhinic] telencephalon)
 Principal related motility: endokinesis (cell-bound movement, visceral motility)
 Main descriptive functions: life support, behavioral modulation/activation, and waking regulation
- Unit II (semipar [limbic/paralimbic] telencephalon)
 Principal related motility: ereismokinesis (body-bound movement, expression of emotions)
 Main descriptive functions: (1) Emotion þ hedonic evaluation (danger and relevance detection) and contribution to reward/motivational
processing; (2) creation of cognitive maps (contextual memory, navigation, and generativity [imagination])
 Divisions: olfactocentric, amygdalocentric, hippocampocentric

Integrated telencephalic functional complex (Luria's Units II [postcentral cortex] and III [precentral cortex])

Structures included: cortex & associative cortical tracts & thalamic pathways þ basal ganglia þ cerebellum
Principal related motility [supralimbic]: telokinesis (object-bound voluntary movement)
- Unit III (cortex). [unsupervised learning]
 Main descriptive functions: (1) limbic, sensorimotor, and associative/cognitive processing [praxis, language, gnosis, calculation, arithmetic
…]; (2) semantic and contextual (episodic) memory processing; (3) multimodal conscious agency (“the conscious agent”).
 Vertical networks (divisions): limbic/paralimbic, associative/cognitive, and sensorimotor
 Systemic perspective networks*: visual, dorsal attention, ventral attention, sensorimotor, cingulo-opercular, somato-cognitive action,
limbic, salience, frontoparietal [central executive], multiple demands, and default mode. Other (specific cognitive): language, drawing,
calculation …
- Unit IV (basal ganglia). [reinforcement learning]
 Main descriptive functions: selection and reinforcement, reward-oriented behavior (“the selector”)
 Vertical networks (divisions): limbic/paralimbic, associative, and sensorimotor
- Unit V (cerebellum) [supervised learning, conditioning]
 Main descriptive functions: prediction/anticipation (supervision) of the outcome of an action (“the orthometrician”)
 Vertical networks (divisions): limbic/paralimbic, associative, and sensorimotor

Fig. 4 e Simplified diagram of a five-unit brain functional model. Units I, II, and III appear on the left. Units IV and V appear
on the right, to highlight their anatomical and functional relationship with unit III (integrated telencephalic complex [Luria's
units II and III]). Units I and II constitute the integrated preferential-limbic functional complex (Luria's unit I). “Extrapersonal
space” and “internal milieu” are the two extremes of the cortical areas of the human brain (Mesulam, 2000), represented in
units II (limbic areas [corticoid þ allocortex]) and III. Due to the exaptation processes, the limbic striatum is part of unit II
and unit III. 5-HT, serotonin [5-hydroxytryptamine]; ACh, acetylcholine; DA, dopamine; Fr, fasciculus retroreflexus; NA,
noradrenaline [norepinephrine]; Hb, habenula; OC, olfactory cortex; PAG, periaqueductal gray; PN, pontine nuclei; Sm, Stria
medullaris; ST, striosomes.
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The amygdala is considered a system for danger and rele- 2013; Hikosaka & Isoda, 2010; Schultz, 1998). The summa-
vance detection (Freese & Amaral, 2009) and contributes to rized function of Unit IV is selection and reinforcement
reward/motivation processing. The amygdala acts as a hub (reward-oriented behavior).
that can generate a whole-body autonomic and cognitive Unit V (cerebellar systems) adds a particular aspect of
adaptive response (Whalen & Phelps, 2009). On the other automation to brain systems. Although this idea has recently
hand, hippocampal and limbic networks promote a broad been challenged (Hull & Regehr, 2022), it is considered that,
range of domains of cognitive maps and organize specific due to its histological homogeneity, the cerebellum only per-
episodes (experiences) within the relevant situational map forms a single operation, the UCT (Schmahmann, 2004, 2019;
(context) (Schiller et al., 2015; Tolman, 1948). In addition, the Schmahmann et al., 2019). Consequently, this type of uncon-
hippocampus has also been linked to the capacity for imagi- scious operation applies to the limbic, motor, and associative
nation (Comrie et al., 2022). systems. As dysmetria (motor, cognitive, emotional) is
From a systemic perspective, it is important to highlight observed in cases of cerebellar lesions (Manto, 2009), the
the differentiation of three limbic networks (Catani, physiological counterpart can be called “orthometria” (Pen ~ a-
Dell'acqua, et al., 2013): one centered in the hippocampus, Casanova, 2018). The function of Unit V can be mainly sum-
another in the amygdala, and another related to the DMN. marized as prediction/anticipation (supervision) of the
This differentiation expands the conceptualization of limbic outcome of an action. As comented, the cerebellum is also
systems and relates it to the ventral attention network and the related “to expertise, creativity, and giftedness” (Koziol &
salience network (Menon, 2015). Consequently, links are Budding, 2009, p. 145).
established with psychopathology, neuropsychiatry, and To update the neuropsychological clinical approach, the
cognitive control deficits (Menon, 2011; Schimmelpfennig concepts of cognitive gradients (Goldberg, 1989), hodotopic
et al., 2023; Shaw et al., 2021). framework (ffytche & Catani, 2005), and hemispheric lateral-
In summary, Unit II is mainly related to hedonic evaluation ization of functions (MacNeilage et al., 2009) were reviewed.
(danger and relevance detection and contribution to reward/ Beyond the more classic approaches, this review provides
motivational processing) and the creation of cognitive maps information on recent systemic perspectives (Kennedy et al.,
(contextual memory, navigation, and generativity 2016; Park & Friston, 2013; Sporns, 2016). Thus, we have
[imagination]). briefly dealt with topics such as the SN, DMN, MDN, and FPN.
Cortical systems (Unit III), together with BG systems (Unit This systemic perspective demonstrates once again that
IV) and cerebellar circuits (Unit V) form an integrated complex functions transcend anatomy (Pessoa, 2022), just as neuro-
mainly based on phylogenetic exaptation phenomena (Gould architecture does not respect the limits of mental terms such
& Vrba, 1982; Parvizi, 2009; Stephenson-Jones et al., 2011). as perception, memory, or language (Pernu, 2017). Systemic
This functional complex combines horizontal (cortical local approaches are of interest, however, it should not be forgotten
processors) with mainly thalamic, striatal, and cerebellar that cortical function depends on subcortical afferents, espe-
vertical processing (Koziol & Budding, 2009). This combination cially the basal ganglia, cerebellum, and modulatory systems
agrees with the hodotopic framework of clinico-anatomical of the brainstem (Koziol & Budding, 2009). In addition, the role
correlations (ffytche & Catani, 2005). We have updated and of basal ganglia is crucial in the clinical expression of psy-
summarized the cortical functional anatomy highlighting the chiatric disorders (Macpherson & Hikida, 2019).
specific hierarchical, and parallel role of local areas. The cur- Although very briefly, the topic of the biological bases of
rent vision presents obvious differences from Luria's time. consciousness has been discussed. This topic is not central to
This unit is related to semantic and episodic (contextual) this review; however, it should form part of functional models
memories based on unsupervised learning (Doya, 2000a; of the brain, beyond the wakefulness (level of consciousness)
Henke, 2010). It is also characterized by associative global discussed by Luria (1974).
processing of temporo-spatial propagation of brain informa- This paper has several limitations due to the complexity,
tion leading to consciousness (Ciric et al., 2017; Northoff & diversity, and depth of the topics included. The social neuro-
Zilio, 2022; Revach & Salti, 2022; Thiebaut de Schotten & science topics have not been discussed in detail, nonetheless,
Forkel, 2022). From the perspective of the parallel architec- it is true that they are nothing more than an extension of the
ture described here, there is no single central executive general bases described in the paper (see Koziol & Budding,
module that guides decisions (Cisek & Kalaska, 2010; Koziol, 2009).
2014; Fine & Hayden, 2022). This review attempts to go beyond the extraordinary
In summary, the function of Unit III is mainly the following: teachings of A. R. Luria, recognizing the immense progress
cognitive processing, semantic and contextual (episodic) that his contribution represented. At this time, when new
memory processing, and multimodal conscious agency. contributions appear rapidly, some of our proposals will likely
Unit IV (BG systems) provides a particular dimension to have to be modified. We are experiencing an exciting process
brain function: to essentially constitute a “reward-oriented of transformation from classical neuropsychology to systems
behavior” mechanism (Hikosaka & Isoda, 2010). Their net- and precision neuropsychology.
works can be conceptualized in three macro parallel vertical
divisions (Yin & Knowlton, 2006): limbic/emotional (motiva-
tion/value), associative (thought, problem-solving), and Submission declaration
sensorimotor (habits/skills). The BG perform reinforcement
learning thanks to the reward signal encoded in the dopami- This contribution constitutes the development of previous
nergic systems of Unit I (Apicella et al., 1992; Hikosaka et al., personal papers cited in the reference section.