Connectomics and the
brain in relation to
Psychiatry
Presented by Dr Meghna Himani
Under the guidance of Dr Parth Singh Meena,
Professor, Department Of Psychiatry,
JLN medical College Ajmer
Table of contents
01 02 03
Introduction History of human Useful Tools and
brain mapping Concepts
04 05 06
Connectomics in Psychiatric Limitations
brain disorders disorders and
connectomics
Table of contents
07 08
Future Directions References
The brain is structured so that each neuron is
connected to thousands of other neurons, and
so to understand what a single neuron is doing,
ideally you study it within the context of the
rest of the neural network.
- Wei-Chung Allen Lee
( Associate professor of neurology, Harvard
Medical School )
Introduction
Connectome
● The entire set of complex connections that make up the human brain.
● The connectome is structurally connected by white matter between the
cortex and subcortical structures ( the gray matter), and these
connections act as wires to transfer information between functional areas
of the brain.
Connectomics
● It is the study of the connections in the nervous system and is
conceptualized as the mapping of the organization and the complete
interactions of all neural elements in the brain.
● It explores both structural and functional connections between neurons.
History of human
brain mapping
● 1909 - German neurologist, Korbinian Brodmann, detailed a brain
parcellation based on anatomical and cellular structure of the brain’s
surface.
● His model divided the human brain into around 47 parts, each with a
supposed functional role.
● Brodmann did this by examining the cellular properties of the cerebral
cortex, attempting to define boundaries where cellular structure
changed
Limitations
● Studied only the gray matter of the brain, and not the white matter
that wired it together
● It does not say much about how different areas of the brain
interact
● The physically observable differences between regions did not
necessarily correlate with the functions they performed.
“Just as a world map alone cannot
explain the complex inter relationships
and interactions between countries and
cultures, the Brodmann map does little
to help us understand complex brain
function and disorders.”
The Human Connectome Project
● It was a five-year project to digitally map the structural and functional neural
connections in the human brain.
● Collectively over a thousand subjects each underwent detailed studies of their
brain using advanced, MRI-based techniques.
● The result was a new brain map, the HCP Parcellation, or Atlas, that defined
discrete brain areas based on their functional roles and how they were both
functionally and structurally connected.
● This included 83 areas from previous studies and 97 that
were previously unknown, totaling 180 in each hemisphere.
● Rather than looking at anatomical structure alone, the HCP
atlas segments the brain based on cortical architecture,
function, functional connectivity, and/or topography.
● This marked a major turning point in consolidating a
community and framework for computational brain mapping.
Useful Tools
and Concepts
Diffusion-weighted magnetic resonance imaging
(DWI MRI)
● MRI methods provide a macroscopic view of the connectome, i.e., they show
extrinsic pathways between regions that traverse white matter.
● These constitute only a small fraction (~10%) of the total number of neuronal
connections and the others are intrinsic, (intra‐cortical).
Building connectomes using diffusion MRI: why, how and but
Stamatios N. Sotiropouloscorresponding author 1 , 2 and Andrew Zalesky 3
● Connectome mapping is divided into two tasks
○ Node delineation - Nodes represent spatially
distinct cortical and subcortical gray matter
regions.
○ Edge mapping - edges represent the white
matter fiber bundles that interconnect pairs of
regions.
Functional Magnetic Resonance Imaging
● It is used to establish functional connectivity between brain areas, i.e.,
when spatially separated brain areas show activity together for a certain
task.
● Blood oxygenation level-dependent (BOLD) - fMRI is based on the
hypothesis that blood oxygenation level increases around a neuron when it
is activated and this signal is picked up by the MRI machine.
● Voxel based measurements - Voxels
are to 3D images what pixels are to 2D
images. The mathematical processing
of the intensity or quantity of signals in
these voxels helps pick up connections
which are spatially apart and
temporally sparse.
Parcellation
● Brain is divided into smaller functional units with the help of
markers.
● Division can be done based on :-
○ Local properties - cytoarchitecture, receptor density, myelin.
○ Global properties - resting state connectivity and structural
covariance.
Statistical inference
● Time series data Is collected by doing hundreds of scans in one setting.
● Differences in the means of signals and their intensitues are evaluated to
find and remove artifacts
● Preprocessing Of data is done to make it readable
● Then higher order statistical analysis is done to find out how signals are
correlated to each other
● This analysis reduces the brain into meaningful components or clusters.
Graph theory metrics
● Each node represents an area and an edge attached to it
represents the connection.
● These are represented in a correlation matrix which charts the
overall strengths of each node to another.
● Retaining the strongest connections through statistical measures
gives a chart of the functional connection between brain regions.
Small world network
● The brain tries to be energy efficient by
giving importance to certain areas (nodes)
and their connections (edges).
● The brain tries to cluster high functioning
areas (hubs) and reduce distance between
edges to increase network efficiency.
Intrinsic Networks
● Brain is always in active state, even at rest.
● If we analyze the signals at rest, we get to know the basic functional
structure of brain. These fundamental network processes are called
lntrinsic Connectivity Networks (ICNs).
● 3 networks that form the basic ICN are -
○ Default mode network - baseline activity of the brain, integrating
self referential mental processes. Includes posterior cingulate
cortex, medial prefrontal cortex and medial temporal lobe.
○ Central executive network - activated during cognitively
demanding tasks, like rule based problem solving, working
memory and goal directed decision making. Includes dorsolateral
prefrontal cortex and posterior parietal cortex.
○ Salience network - the change of brain state from DMN to CEN.
Includes the dorsal anterior cingulate cortex and frontoinsular
cortex.
● Other networks - Auditory network (AN), Language network (LN),
Visual network (VN), Precuneus network (PN), Sensorimotor network
(SN).
This image shows the location of a
subject's Language network
Pathoconnectomics
● It is the mapping of abnormal brain networks . It acts as a framework for the
study of brain dysfunction in psychiatry.
● It also informs us regarding how information is and will be processed in an
abnormal setting.
● Integration and segregation seems to be dysfunctional in most psychiatric
disorders.
● Pathoconnectomics may help us understand and
diagnose psychiatric disorders and furthur
treatments
● This can also help us understand various
phenomena like consciousness, attention ,
impulsity, aggression, low mood, suspiciousness,
anhedonia and delusions.
Connectomics in
brain disorders
Maladaptive responses and pathological spread
1. Diaschisis -
● Temporary interruption of function in regions that are remote from an
injured site. It has recently been extended to include alterations of
functional connectivity between areas that may not even be directly
linked to the lesioned area.
● Studies of patients who have suffered stroke suggest that the severity of
behavioural impairment that follows focal neural damage often correlates
with the extent of activation and connectivity changes in regions remote
from the injured site.
● These associations between behaviour and altered network functional
connectivity occur even if anatomical connectivity between damaged and
undamaged regions is intact. This finding suggests that a ‘functional
deafferentation’ of remote sites may be sufficient to impair behaviour.
2. Transneuronal degeneration -
● It is a structural deterioration of areas remote from the initial insult.
● The form of degeneration can vary, and encompasses changes such as:
neuronal shrinkage; reductions in dendrite and synapse number;
alterations of axonal myelin content and fibre number; and neuronal
death.
● Pathology in any single area can disrupt interactions with other
regions, causing irregular firing and metabolic stress in the connected
site.
● Degeneration of remote regions may also result from diminished
excitatory input or a loss of trophic support from damaged presynaptic
neurons.
● It is also possible for focal pathology to disinhibit activity and cause cell
death or damage in remote sites owing to excess neuronal stimulation.
● Fast axonal transport is another contributor to transneuronal
degeneration, and has been implicated in the pathogenesis of several
neurodevelopmental and neurodegenerative disorders.
3. Dedifferentiation -
● It is the diffuse, non-specific recruitment of brain regions to perform a
task and is thought to result from a break-down of usually specialized
and segregated neural activity.
Adaptive responses to neural insult
1. Compensation -
● Increases in activity or functional connectivity following a pathological
insult that preserve behavioural output are commonly attributed to
neural compensation.
● The extent of focal neural damage and the severity of behavioural
impairment correlate with greater compensatory recruitment,
functional reorganization and altered functional connectivity of remote
areas.
2. Degeneracy and reserve
● Degeneracy is the capacity of structurally distinct elements of a system
to carry out the same function; in other words, it describes the ability
of distinct neuronal systems to make overlapping contributions to the
same output, offering both functional adaptability and robustness to
damage.
● Degeneracy provides a neural network basis for cognitive reserve —
the ability to flexibly engage alternative cognitive or compensatory
strategies to deal with a behavioural impairment caused by neural
insult.
Maladaptive responses to insult — such as
diaschisis and dedifferentiation should occur more
frequently and should be more widespread
following damage to topologically central regions
than after damage to regions with a more
peripheral role in the network.
Psychiatric disorders
and connectomics
Schizophrenia
● Reduced whole-brain structural and functional
connectivity.
● Decreased or aberrant local integration and
segregation mainly in prefrontal, pericentral, superior
parietal, Temporo occipital, thalamic and striatal
areas.
● Abnormal hub organization - A less hub-dominated configuration
has been observed in functional and structural schizophrenia
connectomes, specifically, reduced regional centrality in hubs
including the frontal association, parietal, limbic, and paralimbic
brain areas based on structural studies, and the frontal, temporal,
parietal, limbic, and occipital areas based on functional studies.
● Default mode network (DMN) is disturbed.
● These abnormalities change throughout the illness and after
treatment.
ADHD
● Altered connectivity mainly located in the dorsal
attention, sensorimotor, default mode network
(DMN), and subcortical regions.
● Different changes in connectivity pattern accounted
for the two primary symptoms of ADHD:
○ decreased connectivity in prefrontal-dominant
circuitry correlated to behavioral scores of
inattention
○ increased connectivity in orbitofrontal-striatal
circuitry were correlated with and
hyperactivity/impulsivity
● Inattention ADHD subgroup exhibits unique atypical
patterns in the dorsal lateral prefrontal cortex and
the cerebellum and combined ADHD group exhibited
unique patterns in the midline components of the
DMN.
● Reductions in both global integration and local
clustering in both structural and functional
connectomes
● ADHD children exhibited a lag in the maturation of
functional connections both within and between
subnetworks.
Autism Spectrum Disorder
● Hypoconnectivity in the so-called “social network” encompassing
the default mode, attention and executive networks and
hyperconnectivity in limbic regions.
● Structural analysis also showed disrupted long-range
“socioemotional” circuits.
● Some models describe the ASD brain connectome
as dominated by reduced long-range connections
and excessive short-range fibers.
● Reduced global efficiency was found only in Broca’s
area in these ASD infants.
● Both functional and structural hubs are disturbed in
ASD, indicating dysfunction in global integration
Bipolar disorder
● Reduced gray matter seen in prefrontal and
anterior cingulate cortex
● Dysfunctional networks for emotion regulation,
changes in Amygdala and Hippocampus
● Abberent activation of the frontolimbic circuitry.
Depression
● Structural abnormalities in the medial prefrontal
cortex, amygdala, anterior cingulate gyrus and
hippocampus, abnormal connectivity at prefrontal-
amygdalar- pallidostriatal- mediothalamic mood
regulating circuit.
● Imbalance between network activation responsible
for attentional tasks and self reflective tasks.
Limitations
● It is challenging to adequately power neuroimaging studies to detect brain-
behavior relationships. Many early-stage studies may have used inadequate
sample sizes, leading to false positive findings.
● Present results across modalities were discrepant in many aspects, and it is
difficult to determine whether these discrepancies reflect additional
biological information or limitations of the analysis or imaging methods.
● DWI does not give the axon structure as it is in real but shows various
indices such as fractional anisotropy, mean diffusivity and axial diffusivity
which are thought to represent the axonal structure.
● Feasibility issues are present in functional MRI.
● Resting state measurement and analysis is not optimally standardized,
repeated scans and measures are essential.
Future
Directions
Neuromodulation
● Clinicians may use brain connectivity to better target
neuromodulation techniques such as transcranial magnetic
stimulation (TMS) or deep brain stimulation (DBS).
● In this context, the goal is not to determine whether a
particular connectivity value is abnormal – instead, an MRI
is used to localize a target based on its connectivity to brain
regions that are most relevant to a patient’s condition.
● These regions would be chosen based on the results
of a comprehensive psychiatric evaluation, not based
on connectivity alterations.
● For instance, DBS sites intersecting a specific white
matter tract are more effective for OCD, while TMS
sites connected to the subgenual cingulate cortex
are more effective for major depression.
Personalized treatment
● Unlike biomarker development, connectivity-based
localization has often yielded similar treatment targets
across different studies.
● Using appropriate methods, one can even use
connectivity to identify brain stimulation targets that
show high test-retest reliability at the individual level,
potentially enabling personalized treatment targeting
Treatment targeting
● Treatment targets can be localized even if
the disorder is not well-defined. A
common circuit appears to be connected
to neuromodulation targets that improve
or worsen depression, even when
depression is secondary to a neurological
disorder.
References
● Connectomics and the brain in relation to psychiatry, Swarna Buddha Nayok,
Vanteemar S Sreeraj, Ganesan Venkatasubramanian.
● Connectomics in psychiatric research: advances and applications by Miao Cao,
Zhijiang Wang, Yong He
● The connectomics of brain disorders by Alex Fornito, Andrew Zalesky and Michael
Breakspear
● What is Connectomics? By Michael Sughrue, MD Neurosurgery
● A New Field of Neuroscience Aims to Map Connections in the Brain by Catherine
caruso
Thank you
