ORIGINAL RESEARCH

published: 13 January 2022

doi: 10.3389/fpsyt.2021.713141

Brain SPECT as an Imaging

Biomarker for Evaluating Effects of
Novel Treatments in Psychiatry–A
Case Series
Steven R. D. Best 1*, Natalie Haustrup 2† and Dan G. Pavel 3‡
1
The Neuroscience Center, Deerfield, IL, United States, 2 Haustrup Scientific Consulting, Cork, Ireland, 3 PathFinder Brain
SPECT, Deerfield, IL, United States

The difficulties of evaluating patients with complex neuropsychiatric conditions and

prescribing appropriate treatments are well known. Imaging complements clinical
assessments and allows a clinician to narrow the differential diagnosis by facilitating
accurate and efficient evaluation. This is particularly relevant to neuropsychiatric
Edited by:
conditions that are often diagnosed using a trial-and error process of exclusion.
Theodore A. Henderson, Single Photon Emission Computed Tomography (SPECT) is a functional brain imaging
The Synaptic Space, Inc. and
procedure that allows practitioners to measure the functional changes of gray matter
Neuro-Luminance, Inc., United States
structures based on regional cerebral blood flow (rCBF). The accurate diagnosis and
Reviewed by:
Daniel Keeser, treatment selection in psychiatry is challenging due to complex cases and frequent
Ludwig Maximilian University of comorbidities. However, such complex neuropsychiatric conditions are increasingly
Munich, Germany
Richard Bruce Bolster,
benefitting from new treatment approaches, in addition to established medications.
University of Winnipeg, Canada Among these are combination transcranial magnetic stimulation with ketamine infusions
*Correspondence: (CTK), hyperbaric oxygen therapy (HBOT) and perispinal administration of etanercept
Steven R. D. Best
(PSE). This article provides readers with six case study examples that demonstrate
[email protected]
how brain SPECT imaging can be used, both as a diagnostic tool, and as a potential
† Present address:
biomarker for monitoring and evaluating novel treatments for patients with complex
Natalie Haustrup,
Eli Lilly and Company, Cork, Ireland neuropsychiatric conditions. Six patients were assessed in our clinic and baseline brain
‡ Posthumously
SPECT imagesTourettes and a long history of alcohol were visually compared with
(1934–2021)
SPECT images collected after periods of treatment with CTK or HBOT followed by
Specialty section: PSE. This retrospective review demonstrates the clinical utility of these novel treatments
This article was submitted to
and describes how SPECT imaging can complement standard diagnostic assessments.
Neuroimaging and Stimulation,
a section of the journal A novel display technique for SPECT images is described and we argue that SPECT
Frontiers in Psychiatry imaging can be used for monitoring biomarker for clinical change.
Received: 21 May 2021
Keywords: SPECT, biomarker, CTK, HBOT, depression, psychiatry, brain, treatment
Accepted: 13 December 2021
Published: 13 January 2022
Citation:
Best SRD, Haustrup N and Pavel DG
INTRODUCTION
(2022) Brain SPECT as an Imaging
Biomarker for Evaluating Effects of
While experienced psychiatrists may be able to diagnose patients with neuropsychiatric
Novel Treatments in Psychiatry–A conditions based on behavioral criteria, functional brain imaging tools can inform the clinician
Case Series. of their underlying neurobiology. Functional brain imaging can therefore provide clinicians
Front. Psychiatry 12:713141. with insightful information that enables them to narrow the differential diagnosis and to
doi: 10.3389/fpsyt.2021.713141 monitor and to evaluate any therapeutic benefit of the treatment (1). Single Photon Emission

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Best et al. Brain SPECT Biomarker Treatment Psychiatry

Computed Tomography (SPECT) is a functional brain imaging precise clinical context, given the extent of comorbidities present
procedure that displays the functional status in the whole gray in many neuropsychiatric conditions.
matter volume. A radiotracer is administered to the patient Previous studies have demonstrated how SPECT can be
and is transported via the bloodstream and is quickly removed utilized to diagnose psychiatric disorders (3, 28, 29) and
through normal kidney excretion. During circulation, some to evaluate established treatments (4, 30–32). The accurate
radiotracer is taken up by the brain tissue with the uptake diagnosis and treatment selection is complicated in psychiatry
of radiotracer dependent on the regional cerebral blood flow by complex cases and frequent comorbidities (2). However,
(rCBF). The detection of the radiotracer uptake across the brain these conditions are increasingly benefitting from new treatment
allows the clinician to identify areas of both underperfusion approaches, including Transcranial Magnetic Stimulation
(hypofunctioning) and of hyperperfusion (hyperfunctioning). (TMS), combinations of TMS with ketamine infusion (CTK)
Brain SPECT also has the functionality to detect the presence of and Hyperbaric Oxygen Therapy (HBOT) with perispinal
comorbidity that can occur due to a variety of causes, including administration of etanercept (PSE) (33–36)]. TMS is a non-
neurodevelopmental problems, traumatic brain injury, neuro- invasive technique for stimulation of the brain that can induce
inflammation, non-convulsive epilepsy, neurotoxic exposure and antidepressant and anti-manic effects, however treatment
nutritional deficiencies all of which contribute to altering the response can be slow (37–39). Ketamine is effective in reducing
blood flow levels in various gray matter structures. depressive symptoms (40) via multiple mechanisms of action,
SPECT generates a three-dimensional (3-D) mapped including modulating signaling that stimulates neurogenesis
representation of the brain that can be presented with color- and neuroplasticity, as well as acting as a tumor necrosis factor
coded intensities proportional to rCBF and correlating with (TNF)-alpha inhibitor resulting in an anti-inflammatory effect
the function in that region. Accurate and reliable visual (41–43). CTK is a patented procedure and studies have indicated
interpretation of brain SPECT relies on optimizing the that CTK is an effective, long-term therapy for patients with
presentation of images using effective display tools and various neuropsychiatric conditions, whereby the coincident
techniques, which are demonstrated herein. Diagnosis can administration of ketamine allowed for higher TMS intensities
also benefit from the complementary information exhibited by than otherwise would be tolerated by patients (33, 44–46).
SPECT images displayed in a variety of formats including slices, Treatment with HBOT followed by PSE has also been identified
surfaces and volumes. The optimal approach to accomplish as a possible treatment for cognitive impairment (35, 36, 47, 48).
accurate and efficient interpretation of brain imaging modalities HBOT is believed to have anti-inflammatory effects by reducing
is debated by researchers and clinicians in the literature (2–7), excess pro-inflammatory cytokine activation, such as TNF-alpha,
with discussions primarily centered on either conventional visual and facilitates improvement by provocation of stem cell activity,
analysis by an experienced investigator and/or quantification which can lessen the neurological impact of brain injuries
techniques including voxel-wise analysis or region of interest (49–51). PSE injections modulate TNF-alpha directly to the
(ROI) approaches (8–12). SPECT image quantification within central nervous system and act to normalize the inflammatory
clinical research typically identifies statistically significant response in stroke, traumatic brain injury, and encephalopathic
differences based on mean group values, which do not always conditions (52). Despite supportive evidence of the clinical
equate to individual differences, which is typically the focus utility of novel treatments, such as CTK and HBOT with
in clinical practice (8). Therefore, the visual interpretation of PSE, further investigation of these combination treatments
individual SPECT images remains a foundational skill within is required.
clinical practice and quantification is considered favorable for This article builds on the current literature and presents a
larger studies for identifying trends (8, 13). retrospective review of a case series including six patients with
However, SPECT imaging is underutilized in clinical practice complex neuropsychiatric presentations. Baseline brain SPECT
despite a growing, evidence-based foundation for its application images were visually compared with SPECT images collected
in numerous indications relevant to psychiatric practice (14– after periods of treatment with three novel treatments of CTK
23). This underutilization is particularly unfortunate as SPECT or HBOT followed by PSE during routine clinical practice. In this
is an easy-to-perform, non-invasive procedure and remains article we also describe a novel SPECT imaging display technique,
among the least expensive neuroimaging tools available (24, present evidence of the clinical utility of CTK and HBOT with
25). The historic underutilization of neuroimaging techniques PSE and we propose that SPECT can be used as an imaging
in psychiatry has also led to the consequential inadequate biomarker for monitoring and evaluating clinical change.
biological understanding of neuropsychiatric conditions (26).
Without such biological understanding it is also difficult to MATERIALS AND METHODS
identify meaningful biomarkers for diagnosis, prognosis or risk,
which is particularly relevant as psychiatric treatments can lead Study Cases
to biological changes (24, 26, 27). In addition, neuropsychiatric Six patients presented to our clinic with disabling
conditions are often diagnosed using a process of exclusion neuropsychiatric conditions of various causes following
and additional information from brain SPECT imaging can extensive unsuccessful periods of treatments. The conditions
complement the information gathered from clinical assessments. and comorbidities differed for each patient (I-VI). Treatments
Given the current underutilization of SPECT, additional work were selected for each patient following the clinical assessment
is required to integrate the brain SPECT information in a more of the patient. The six cases presented herein were purposefully

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Best et al. Brain SPECT Biomarker Treatment Psychiatry

selected as they demonstrate the usefulness of brain SPECT SPECT Imaging and Visual Analysis
imaging in evaluating patients with neuropsychiatric conditions Brain SPECT was carried out before (baseline) and after
and to monitor their response to treatment. An overview of treatment for each patient. A triple head gamma SPECT
the patients, their diagnosis and treatment are presented in camera (Picker Prism 3000XP), equipped with low-energy,
Table 1 with more thorough details of patient histories, selected ultra-high resolution (LEUHR) fan beam collimators was
treatments and outcomes presented in the Results section. All used to detect the uptake levels of the radiotracer, 99mTc-
subjects consented to the use of their data and information for D, L-hexamethylene-propylene amine oxime (HMPAO),
the research purposes described herein. which is correlated with rCBF and metabolic activity.
Reconstructions of multiparametric display were performed on
the Picker Odyssey computer using filtered back projection
Novel Treatment Options
and Chang attenuation correction (54). Once the final
SPECT imaging was used to identify the extent and severity of
distribution is established post-injection and without
hypoperfused areas, which complemented the standard clinical
significant change for 2–3 h, the visualization of the whole
assessment data collected. Treatment decisions were based on
gray matter volume can be completed via a 3-D mapping of
the full baseline assessment and patients were either treated
perfusion levels. Visual analysis was performed by an expert
with CTK or HBOT followed by PSE. The CTK procedure
nuclear medicine physician with over 30 years of experience
has been described in detail previously (9). Patients who
in SPECT.
present at our clinic with TRD are treated with CTK before,
In the absence of a qualified biomarker (27, 55), this study
or instead of, electroconvulsive therapy (ECT) or TMS or
evaluates SPECT as an imaging biomarker based on the US
ketamine administered independently, based on evidence that
Food and Drug Administration (FDA) monitoring biomarker
CTK offers benefits over these established treatments for patients
definition (56). Monitoring biomarkers are analyzed at different
with TRD (33, 46). In brief, four patients treated with CTK
time points to monitor the status of a disease or medical
received TMS (30 min) and 5 min after the commencement of
condition, and as a marker of the response to an intervention
TMS, intravenous infusions of the NMDA-receptor inhibitor,
(56). In this review, the monitoring biomarker corresponds to the
ketamine, began (20 min). The TMS (1 Hz) was applied
increase in brain perfusion detected with optimized displays of
continuously for 30 min at a power output setting equivalent
SPECT images before and after treatment. For each patient, the
to 130% of motor threshold (MT). A biomarker-dependent
baseline SPECT images were compared with the post-treatment
dosing strategy was applied, whereby ketamine was gradually
SPECT images to assess the functional improvements across
titrated in small increments until the patient entered a mildly
different areas of the brain.
cataleptic state. Catalepsy refers to the neuromuscular condition
The increased perfusion was detected using a purposefully
characterized by muscular rigidity and fixity of posture regardless
designed, discrete color scale (DGP40%) as a semi-quantitative
of external stimuli, as well as markedly decreased sensitivity to
tool that assessed relative perfusion across different displays. The
pain. Titrations began at 20 mg, with an average dosage range
distribution of the radiotracer within the brain was visualized
of 0.4–2.3 mg/kg (full range from 0.2 to 4.7 mg/kg). Once
in several ways during this study: Firstly, slicing, whereby
the patient began to stiffen or posture, the ketamine infusions
processing was based on reconstruction, filtering, reorientation
could be discontinued. Following the completion of the ketamine
and attenuation correction and led to three orthogonal cuts
infusion, the TMS would continue for a further 5 min, after which
(sagittal, coronal and transaxial) supplemented by a fourth
the CTK procedure was complete. Frequency of treatment is
axial display obtained along the temporal axis. Secondly, 3-
dependent on patient responsiveness (typically 10–30 sessions).
D stereotactic surface projections were obtained with the
Two patients who presented to this clinic with treatment
Neurostat software (57). Stereotactic surface projection is a
refractory illness in the context of traumatic brain injury (TBI)
technique used for the analysis of SPECT images to extract
or mild TBI (mTBI) were treated with HBOT followed by PSE.
functional areas projected onto the brain surface for the
Previous experiences of treating patients have indicated that
visual representation of brain perfusion. The discrete DGP40%
the benefits of HBOT and PSE injection may be cumulative
color scale was applied to the orthogonal slice displays and
(53). HBOT treatments were administered daily in a multi-place
the surface projection images to facilitate visualization of the
chamber for 60 min at a depth of 1.75 atmosphere absolute
level of perfusion. The maximum perfusion in the image
(ATA). After the first ten HBOT treatments, one 25 mg PSE
was scaled to 100%, with each color band corresponding
injection was administered approximately once weekly and the
to a different level of perfusion, as measured in steps of
number of further HBOT sessions and PSE injections was
approximately 3%. The threshold is set at 40% to suppress
tailored to the patient. The method of perispinal administration
background noise.
of etanercept was used under license from the patent holder,
Finally, thresholded volumetric displays were used to create
TACT IP, LLC1 .
a surface that represents voxels of a constant value and are
therefore also termed iso-surface images. The region of the
1 The method of perispinal administration of etanercept utilized was used under brain with the highest uptake of radiotracer was used as the
license from the patent holder, TACT IP, LLC, Boca Raton, FL, USA. TACT IP LLC
claim methods of use of etanercept for the treatment of neurological disorders,
reference value (the cerebellum in the majority of cases) and
including, but not limited to, US patents 6419944, 6537549, 6982089, 7214658, a 67% threshold value (relative to the reference value) was
7629311, 8119127, 8236306, and 8349323. applied to generate 3-D iso-surface images with “holes” in

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Best et al. Brain SPECT Biomarker Treatment Psychiatry

TABLE 1 | Characteristics of patients with complex neuropsychiatric conditions (n = 6) with selected treatment.

Patient Age Sex Diagnosis Treatment

I 62 F Treatment-resistant depression (TRD) as well as grief and the effects of prolonged polypharmacy CTK
II 34 F Regulatory disorder of childhood, post-head injury epilepsy, reflex sympathetic dystrophy (RSD) HBOT and PSE
III 54 M Childhood-onset Tourettes, long history of alcohol abuse, severe depression, fatigue and sleep apnea CTK
IV 55 F Major depressive disorder (MDD), panic/agoraphobia, chronic back pain, frequent headaches CTK
V 77 M Dementia with major cognitive deficits and aphasia HBOT and PSE
VI 43 M Bipolar II, lifelong symptoms of depression, anxiety, impulsive behavior and family stressors CTK

the image corresponding to areas of the cortex with lower her daily life: enthusiastic, rational, planning for future, taking
perfusion. Since the images are continuous, the threshold value charge of her financial and family situation and a renewed
of 67% was selected as it accentuated corresponding areas religious sentiment.
in the color images, focused attention on hypoperfused areas
and allowed for a better estimation of extent and severity. A
threshold of 67% was applied to the iso-surface images shown Patient II: HBOT and PSE Treatments
herein. In addition to the 67% threshold, which depicts areas of A 34-year-old female presented with lifelong symptoms of
hypoperfusion, thresholds of 85 and 90% were also used to create regulatory disorder of childhood, two concussions, post-head
iso-surface images that visualized the size and location of areas of injury epilepsy, and reflex sympathetic dystrophy (RSD). These
hyperperfusion. The application of multiple thresholds allowed ultimately led to marked suffering and extreme disability in
the visualization of hypo- and hyper-perfusion areas across activities of daily living. For almost 2 years the patient spent
the brain. The clarity, complementarity and user-friendliness of each day in a basement with dark glasses and protective hearing
these displays enabled a reliable visual evaluation before and equipment due to intense photophobia and misophonia. Prior to
after treatment. visiting our clinic, the patient’s medication history included over
30 types.
RESULTS Baseline brain SPECT images for Patient II, shown in
the top line of Figure 2, indicated extensive, diffuse bilateral
Patient I: CTK Treatment hypoperfusion of the frontal (more accentuated on the left),
A 62-year-old female presented at the clinic on the verge temporal and orbitofrontal lobes and extended into the
of suicide. The patient had worked as a nurse prior and frontoparietal and parietal vertex areas. Additionally, there was
following episodes of alcohol abuse. The patient had a bilateral hypoperfusion of the occipital lobes and hypoperfusion
history of multiple medication trials and polypharmacy, of the anterior cingulate in the dorsal aspect. The patient had
physical pain and prolonged family stressors (sickness and robust perfusion of the thalamus and basal ganglia. There was
eventual death of husband) and intense grief. The patient also marked hyperperfusion in the cerebellar vermis.
was classified as treatment-non-responsive following multiple HBOT was selected for patient II on account of multiple head
treatment failures, which were intended to address her injuries and a developmental history of a regulatory disorder.
suffering. The patient’s formal diagnoses were treatment- Following 40 HBOT treatments, brain SPECT images (Figure 2
resistant depression (TRD) as well as grief and the effects of middle line) indicated increased perfusion in most areas of the
prolonged polypharmacy. cortex and in some subcortical structures.
Baseline brain SPECT images for Patient I, shown in the At a later stage, PSE injections were started as another line
top line of Figure 1, indicated a marked and very extensive of intervention. PSE clinical injections were given at weekly
bilateral hypoperfusion involving all lobes at baseline, and most intervals. Following 4 PSE injections, SPECT was performed and
accentuated on the right side. The more extensive hypoperfusion images shown in the bottom line of Figure 2 indicated major
were located in the lateral frontal, frontoparietal and superior improvements (increased perfusion) in all lobes and subcortical
parietal areas. There was marked hypoperfusion in the dorsal areas. Specifically, the images showed increased perfusion in
aspect of the anterior cingulate. In the subcortical area, there the orbito-frontal and apico-mesial temporal areas, bilaterally,
was slight bilateral striatum hyperperfusion and robust perfusion and in the putamen bilaterally and in the mid thalamus.
of the thalamus. The patient was then treated with a total In addition, there was marked hyperperfusion in the mid
of 30 CTK sessions. SPECT images were subsequently taken posterior/inferior occipital area and, several areas of moderate
following 5 months of CTK treatment (58 sessions) and cortical hyperperfusion in the lateral posterior aspect of both
are displayed in the bottom line of Figure 1. These images temporal lobes, as well as in the posterior cingulate/precuneus
indicated a markedly improved perfusion across all cortical area. Significantly, these improvements were mirrored in
and subcortical structures. These improvements corresponded the patient’s cognition and ability to engage in daily acts
with dramatic clinical improvement leading to major changes in of living.

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Best et al. Brain SPECT Biomarker Treatment Psychiatry

FIGURE 1 | Brain SPECT images from Patient I. Top line images relate to brain SPECT images at baseline. Bottom line images are taken following 5 months of CTK
treatment. The six images on each row (from left to right) include four stereotactic surface projections of the left lateral (LLAT), vertex, underside and right lateral
(RLAT), one iso-surface image of the vertex and one axial slice. Color-coded intensity indicates hyperfunctioning areas (blue hues) and hypofunctioning areas (white
and black surrounded by white). Images are presented as described in the Methods.

FIGURE 2 | Brain SPECT images for Patient II. Top line relates to brain SPECT images at baseline, indicating extensive areas of hypofunctioning in all lobes. Middle
line shows SPECT images post-HBOT treatment. Bottom line of SPECT images collected post-PSE treatment. In each row (from left to right) one temporal axial
image, two orthogonal slices (sagittal and axial), one iso-surface image of the vertex and two stereotactic surface projections of the left lateral (LLAT) and underside.

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Best et al. Brain SPECT Biomarker Treatment Psychiatry

Patient III: CTK Treatment his lifestyle completely at this stage. SPECT imaging completed
A 54-year-old male emergency-room (ER) nurse presented with 14 months later, as shown in the bottom line of Figures 3 and 4,
childhood-onset Tourettes and a long history of alcohol abuse, indicated further significant improvements. There were extensive
severe depression, fatigue and sleep apnea. areas of relative increase in blood flow in the lateral aspect of the
Baseline brain SPECT images for Patient III, shown in left hemisphere and bilateral vertex area, along with significantly
the top line of Figures 3 and 4, indicated extensive bilateral improved perfusion in the orbitofrontal and apico-mesial
hypoperfusion with this most accentuated in the left frontal lobe. temporal areas. Additionally, there was increased perfusion in
Additionally, there was localized hypoperfusion in the occipital the left striatum and in the cerebellum. These apparently minor
and frontal poles. On the right side, there were multiple localized improvements correlated with significant clinical improvements
and confluent areas of hypoperfusion that were more accentuated with the patient having resumed working (part-time job), had
in part of the frontal lobe extending to the superior aspect of significantly changed lifestyle with a stable marriage.
the parietal lobe including the vertex. Marked hypoperfusion was
also evidenced in the right striatum and right ventral striatum,
and the thalamus had an asymmetric appearance with localized
Patient IV: CTK Treatment
A 55-year-old female presented with major depressive disorder
areas of marked hypoperfusion in the posterior aspect. There was
(MDD), panic/agoraphobia, chronic back pain and frequent
moderate hyperperfusion in the anterior and posterior cingulate.
headaches. The neurological exam did not indicate focal
CTK treatment was selected and SPECT imaging was
neurological dysfunction of the central nervous system.
completed 5 months after the first CTK treatment (middle line
Intermittently, she had been treated with varied pharmacologic
of Figures 3 and 4). SPECT indicated several improvements,
interventions and psychotherapy for 24 years, before presenting
including in the area of severe frontal hypoperfusion at baseline.
to this clinic. During that time, the patient’s symptoms did not
Subsequently the patient continued with medication, accepted
respond to Wellbutrin, Lexapro, Abilify, Viibryd, Paxil, Nardil,
continuous positive airway pressure (CPAP) treatment, and
Vicodin, nor conventional psychotherapy.
changed his lifestyle. Nonetheless, he was still unable to change
Baseline brain SPECT images of Patient IV, shown in the
top line of Figure 5, indicated extensive bilateral hypoperfusion
in the frontal lobes (most accentuated on the left side),
including the dorsolateral prefrontal regions and in the parietal
vertex bilaterally. Not discernible in the images provided is
the hypoperfusion in both orbitofrontal areas and in the
mesial aspect of the right temporal lobe. There was moderate
hyperperfusion of the thalamus and marked hyperperfusion in
the mid posterior, inferior aspect of the occipital lobes.
The patient was treated with 30 CTK sessions and SPECT
images shown in the bottom line of Figure 5 were taken 14
months thereafter. Patient IV also received small amounts of
anti-panic medicine that was used judiciously. The SPECT
images indicated major bilateral perfusion improvement in the
frontal conexities, fronto-parietal and anterior cingulate areas as
well as bilateral increase in the basal ganglia. Not discernible
in the images provided is the significant improvement of
the orbitofrontal areas. There was also significantly increased
perfusion in the thalamus and bilaterally in the striatum.
Following treatment, the patient reported markedly improved
symptoms: major decrease of depression, anxiety and back pain
and greatly increased levels of life satisfaction. At the two-year
follow-up, the patient had been practically free of suffering.

Patient V: HBOT and PSE Treatment

A 77-year-old male presented with onset of dementia induced
by general anesthesia with major cognitive, physical and
emotional impairments. Immediately post knee-replacement
surgery the patient began to show dramatic cognitive,
FIGURE 3 | Brain SPECT iso-surface images for Patient III. Top line relates to physical, and emotional impairment as compared with
brain SPECT images at baseline. Middle line shows SPECT images 5 months his pre-surgical state; these symptoms were still present
after the first CTK treatment. Bottom line shows SPECT images 14 months when the patient arrived at our clinic 4 years post-surgery.
following CTK treatment. In each row (from left to right) three iso-surface
images of the left lateral (LLAT), vertex and right lateral (RLAT).
Diagnoses of dementia with major cognitive deficits and aphasia
was established.

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Best et al. Brain SPECT Biomarker Treatment Psychiatry

FIGURE 4 | Brain SPECT stereotactic surface projections for Patient III. Top line relates to brain SPECT images at baseline. Middle line shows SPECT images 5
months after the first CTK treatment. Bottom line shows SPECT images 14 months following CTK treatment. In each row (from left to right) six stereotactic surface
projections of LLAT, RLAT, Vertex, Underside, right mod sagittal, and left mid sagittal.

FIGURE 5 | Brain SPECT images for Patient IV. Top line relates to brain SPECT images at baseline. Bottom line shows SPECT images 14 months following 30
sessions of CTK treatment. In each row (from left to right) two stereotactic surface projections of the left lateral (LLAT) and vertex, one iso-surface image of the vertex,
one sagittal slice and two axial slices.

Baseline brain SPECT images of Patient V, shown in the top Involvement extended to parts of the dorsolateral prefrontal
line of Figure 6, indicated extensive hemispheric hypoperfusion (DLPF) cortex. There was also significant hypo-perfusion in the
and multiple localized hypoperfusion in the left hemisphere. temporal lobes (more pronounced on the left) and to a lesser

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Best et al. Brain SPECT Biomarker Treatment Psychiatry

extent in the orbitofrontal areas. To address these cognitive, To further display the utility of SPECT as an evaluative
physical, and emotional impairments, a treatment plan was biomarker, Figure 8 displays iso-surface images clearly indicating
prepared including a 40-session course of HBOT and PSE the increased perfusion following CTK treatment in almost all
injections. After the first 10 HBOT treatments, the patient was previously hypoperfused areas.
administered 25 mg PSE injections approximately once weekly
for 5 months.
At 5 months post-treatment with HBOT and PSE, SPECT DISCUSSION
images shown in the bottom line of Figure 6 showed an overall
similar appearance to baseline. However, there were localized This article describes a novel display technique for SPECT
increases in perfusion, as marked by the green arrows, in images and provides readers with six case study examples that
parts of the anterior aspect of the prefrontal cortex (including demonstrate how brain SPECT imaging can be used, both as
in the ventro-mesial aspect), right superior parietal, right a complementary diagnostic tool, and as a potential biomarker
lateral occipital, superior aspect of the left fronto-parietal area, for monitoring and evaluating novel treatments for patients with
posterior cingulate-precuneus and apico-mesial aspect of the complex neuropsychiatric conditions. Developing and applying
right temporal. In addition, there was a significant increase in the clinical tools, such as SPECT imaging, can provide the clinician
striatum bilaterally. with complementary insights into the underlying neurobiology
Despite the follow-up SPECT remaining abnormal, the to standard clinical assessments. However, as SPECT imaging
improved perfusion in small areas, specifically the mesial continues to be underutilized in clinical practice, more practical
temporal lobe, prefrontal cortex, ventro-mesial frontal, posterior evidence, guidance and studies such as this one are required to
cingulate, precuneus and dorsal parietal are known to be key demonstrate how SPECT can be utilized to evaluate the patient
in contributing to memory, cognition and behavior. Indeed, and to inform the clinician.
initiating after the first PSE injection, the patient began showing In this retrospective review, six patients presented with
progressive clinical improvements in cognitive and physical complex neuropsychiatric conditions and comorbidities
function. A follow-up visit 16 months after the end of treatment following extensive unsuccessful periods of different treatments.
showed that the same level of clinical improvement had While experienced psychiatrists may be able to diagnose patients
been maintained. with neuropsychiatric conditions based on behavioral criteria,
functional brain imaging tools can inform the clinician of their
Patient VI: CTK Treatment underlying neurobiology. Additionally, the examination of
A 43-year-old male presented with bipolar II, lifelong symptoms different functional areas of the brain using SPECT imaging
of depression, anxiety, impulsive behavior and family stressors. may provide insights into the patients’ status that may not
Specifically, the patient reported struggling with intense identifiable during clinical assessment. Particularly, in cases of
depressed mood, substantial life stress, including a divorce in diagnostic dilemma, such as those presented herein, SPECT
progress, and the inability to hold a job due to the impairment images were used to identify areas of hypo- and hyper-perfusion
and distress associated with his symptoms. He had received to complement the initial clinical assessment. In the cases
psychopharmacological and psychotherapeutic treatment for the presented herein, the improved perfusion identified in the
previous 6 years, but without improvement. post-treatment SPECT images, whether extensive or localized,
Baseline brain SPECT images of Patient VI, shown in were mirrored by particular clinical improvements. Therefore,
the top line of Figure 7, indicated hypoperfusion in multiple it is fundamental for the clinician to understand how clinical
hemispheric areas, most pronounced in the frontal lobes, anterior improvements manifest in the patients’ underlying neurobiology.
cingulate, orbitofrontal and apico-mesial areas of the temporal This case series effectively demonstrates the importance for the
lobes. Hyperperfusion was indicated in the right putamen and in clinician to combine clinical assessments evaluating presenting
parts of the posterior cingulate and right cerebellum and vermis. behaviors and symptoms, with the underlying neurobiology
This combination of hypoperfused areas is commonly associated attainable using SPECT imaging. Furthermore, building a
with dysfunctions related to memory, executive function, social database that correlates SPECT images with clinical assessments
interaction and impulse control and the hyperperfused areas has the potential to develop more targeted treatments and to
are often associated with anxiety and depression (58, 59). Based establish effective biomarkers.
on the initial assessment, CTK treatment was selected, and the In these complex cases, high-quality SPECT images provided
patient received a total of 24 sessions over 5 months. valuable insights into the underlying neurobiological status
SPECT was performed 5½ months after the first CTK of patients allowing the clinician to narrow the differential
treatment and images are displayed in the bottom line of diagnosis. A high-quality brain SPECT will provide detailed
Figure 6. Images indicated significantly improved relative information about the location, magnitude, and extent of areas
perfusion in almost all previously under-perfused areas. of hyper- and/or hypoperfusion(s). The clinical efficacy of
Previously hyperperfused areas were either unchanged or brain SPECT for the monitoring of patients with multiple
increasingly hyperperfused. The patient also reported substantial co-morbidities and treatment-resistant conditions, is greatly
improvements in symptoms related to functioning and enhanced by a standardized, comprehensive display of the results.
psychometric assessments showed substantial decreases in This includes a user-friendly, color, multi-parametric set of 2D
symptoms related to both depression and mania. and 3D images. Consistency is also critically important, not

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Best et al. Brain SPECT Biomarker Treatment Psychiatry

FIGURE 6 | Brain SPECT images for Patient V. Top line relates to brain SPECT images at baseline. Bottom line shows SPECT images 5 months post-treatment with
HBOT and PSE. Green arrows indicate areas of increased perfusion. In each row (from left to right) one axial slice and one temporal slice, three stereotactic surface
projections of the right lateral (RLAT), left lateral (LLAT) and right sagittal and one iso-surface image of the underside.

FIGURE 7 | Brain SPECT images for Patient VI. Top line relates to brain SPECT images at baseline. Bottom line shows SPECT images 5.5 months following 24
sessions of CTK treatment. In each row (from left to right) one temporal slice, one sagittal slice and one axial slice and three stereotactic surface projections of the
underside, right lateral (RLAT) and left lateral (LLAT).

only in the execution of the procedure itself but also in the of the presentation of images using effective display tools and
processing and display of the images. Whilst quantification of techniques. In the clinical cases presented, we have demonstrated
SPECT images may facilitate readers with limited experience to that the optimization of images using a novel set of display tools
interpret SPECT scans and aid in the identification of trends facilitated the visual interpretation of SPECT imaging data by
(60, 61), it is imperative to also recognize any limitations of such expert clinicians, without the need for quantification or statistical
quantitative analysis of imaging techniques, particularly within analysis. A more detailed description of this display will be
clinical practice and during the assessment of individual cases (8). published shortly (62).
The visual assessment of SPECT images pertaining to individual In the absence of a qualified biomarker (27, 55), this study
cases remains a foundational skill within clinical practice, the evaluates SPECT as an imaging biomarker based on the US
accuracy and reliability of which relies on the optimization Food and Drug Administration (FDA) monitoring biomarker

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Best et al. Brain SPECT Biomarker Treatment Psychiatry

FIGURE 8 | Iso-surface SPECT images for Patient VI. Top line relates to brain SPECT images at baseline and bottom line are brain SPECT images 14 months after
CTK treatment began. In each row (from left to right) are iso-surface images of the anterior, posterior left lateral (LLAT), vertex, underside and right lateral (RLAT).

definition (56). A monitoring biomarker is defined as “a relative perfusion in previously hypoperfused areas, which
biomarker measured repeatedly for assessing status of a disease correlated to the clinical improvements noted for each patient.
or medical condition or for evidence of exposure to (or effect These cases thereby provide further evidence of the clinical
of) a medical product or an environmental agent” (56). In this utility of these novel treatments for patients with complex
review, the monitoring biomarker corresponds to the increase neuropsychiatric conditions.
in brain perfusion detected with optimized displays of SPECT Despite the growing, evidence-based foundation for the
images before and after treatment. Following treatment, all application of SPECT in numerous indications relevant to
patients demonstrated improvements measured via periodic psychiatric practice, there is a need for clinicians to utilize
clinical evaluations and in some cases neuropsychological this powerful tool and contribute to our understanding of the
testing and detailed observations from family members. These neurobiology relating to different neuropsychiatric conditions
clinical improvements were also apparent from the increased and comorbidities. Greater biological understanding will result
perfusion evident in the brain SPECT images collected post- in the identification of meaningful biomarkers for diagnosis,
treatment compared with those collected at baseline. Whilst prognosis or risk and can further aid the clinician in their
clinical improvements following treatment may be discernible evaluation of a patient before and after treatments. There
during standard clinical assessment, SPECT was used as a is a particular value in sharing methodologies and results
monitoring biomarker to indicate the underlying neurobiological regarding the implementation of SPECT in routine practice in
response of each individual to the treatment intervention. clinical settings. This retrospective review demonstrated that
In this case series, SPECT images indicated the specific brain SPECT imaging could represent a potential imaging
areas of improved brain perfusion that resulted following biomarker since syndrome status was correlated with changes
treatment and provided additional context to the clinical in the perfusion pattern detected. Given the display modalities
improvements identified. Therefore, the SPECT images provided used, the relative perfusion assessment with SPECT imaging
insights into the functioning status of the patient in addition before and after treatment has acted as a monitoring biomarker
to monitoring symptoms during clinical assessment. These that indicated the therapeutic benefit of the novel types of
follow-up scans thereby informed how these novel treatments treatments used in this case-series. Furthermore, SPECT images
affected the underlying neurobiology of each individual and have provided additional information that explains the functional
how perfusion improvements in specific areas correlated to changes that gave rise to the observed clinical improvements.
clinical improvements. This understanding of the topographic functional status is
The application of SPECT imaging as a monitoring biomarker important if we are to further progress to personalized targeted
also further contributes to the understanding and the growing treatments and the development of effective biomarkers.
literature that describes the clinical utility of these novel This article has some limitations. First, these cases represent
treatments for patients with neuropsychiatric conditions. In assessments carried out during routine clinical practice and not
this case series, intervention with novel treatments of CTK as part of a pre-planned study, therefore there is a small number
or HBOT and PSE resulted in marked improvements in of cases presented without a normalized reference cohort and

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Best et al. Brain SPECT Biomarker Treatment Psychiatry

physicians were not blinded to the clinical context, however this DATA AVAILABILITY STATEMENT
does reflect a practical clinical routine.
Overall, this collection of these case studies further The datasets presented in this article are not readily available
substantiates the clinical relevance of brain SPECT imaging because HIPAA-protected data. Requests to access the datasets
in psychiatry and neuropsychiatry. This review demonstrates should be directed to [email protected].
that SPECT imaging can be a valuable tool in cases of diagnostic
dilemma and can complement standard assessment techniques ETHICS STATEMENT
and diagnostic tools. In our study, six patients with complex
neuropsychiatric conditions and comorbidities were successfully Ethical review and approval was not required for the study on
treated, which contributes to the growing literature indicating human participants in accordance with the local legislation and
the clinical utility of the novel therapies of CTK and HBOT institutional requirements. The patients/participants provided
with PSE (33, 47). The positive outcomes for these patients their written informed consent to participate in this study.
were facilitated by the detailed initial evaluation of patients Written informed consent was obtained from the individual(s)
that included baseline SPECT imaging that complemented for the publication of any potentially identifiable images or data
the standard clinical assessment. The repetitious clinical included in this article.
approach, the novel display technique and positive treatment
outcomes in these six cases has also demonstrated how AUTHOR CONTRIBUTIONS
image optimization and visual analysis of SPECT images
can be utilized during clinical assessments of individual SB provided the CTK, HBOT and PSE treatments, as well
cases. Finally, we demonstrated how SPECT images recorded as integrated the psychiatric and SPECT data. NH co-wrote
before and after treatment provided valuable insights into the the article and contributed to the discussion of the results.
improved neurobiological status of these patients in response to DP performed the SPECT imaging, as well as analyzed and
intervention. Therefore, we argue that perfusion assessed with interpreted the SPECT data. Please note that DP sadly passed
SPECT images before and after treatment can be used as an away during the finalization of this manuscript, however all other
imaging biomarker for monitoring, evaluating and explaining authors read and approved the final manuscript.
clinical change.
ACKNOWLEDGMENTS
AUTHOR’S NOTE
This article would not have been possible without the pioneering
Proper execution of a brain SPECT scan is an art and requires work of DP, who sadly passed away during the finalization of this
great attention to detail in order to obtain high quality images, manuscript. This paper is dedicated to his memory. The authors
such as the ones presented here. For specific information would also like to acknowledge Simon DeBruin of Good Lion
regarding imaging and processing protocols, please contact the Imaging for the image processing that resulted in the impressive
authors directly. and clear images displayed herein.

REFERENCES 7. Nishimiya M, Matsuda H, Imabayashi E, Kuji I, Sato N. Comparison of

SPM and NEUROSTAT in voxelwise statistical analysis of brain SPECT
1. Henderson T, van Lierop M, McLean M, Uszler JM, Thornton J, Siow and MRI at the early stage of Alzheimer’s disease. Ann Nucl Med. (2008)
Y, Functional neuroimaging in psychiatry-aiding in diagnosis and guiding 22:921–7. doi: 10.1007/s12149-008-0211-7
treatment. what the american psychiatric association does not know. Front 8. Catafau AM. Brain SPECT in Clinical Practice. Part I: Perfusion. J Nucl Med.
Psychiatry. (2020) 11:276. doi: 10.3389/fpsyt.2020.0027 (2001) 42:259–71.
2. Taber KH, Hurley RA, Yudofsky SC. Diagnosis and treatment 9. Coburn KL, Lauterbach EC, Boutros NN, Black KJ, Arciniegas DB, Coffey
of neuropsychiatric disorders. Annu Rev Med. (2010) 61:121– CE. (2006). The value of quantitative electroencephalography in clinical
33. doi: 10.1146/annurev.med.051408.105018 psychiatry: a report by the committee on research of the American
3. Richieri R, Boyer L, Faget-Agius C, Farisse J, Mundler O, Lançon neuropsychiatric association. J Neuropsychiatry Clin Neurosci. (2006) 18:460–
C, et al. (2015). Determinants of brain SPECT perfusion and 500. doi: 10.1176/jnp.2006.18.4.460
connectivity in treatment-resistant depression. Psychiatry Res. (2014) 10. Evans JR, Budzynski TH, Budzynski HK, Abarbanel A. Introduction to
231:134–40. doi: 10.1016/j.pscychresns.2014.11.013 Quantitative EEG and Neurofeedback: Advanced Theory and Applications.
4. Escobar R, Rios A, Montoya ID, Lopera F, Ramos D, Carvajal C, et al. USA: Academic Press (2009).
Clinical and cerebral blood flow changes in catatonic patients treated with 11. Hoffman DA, Lubar JF, Thatcher RW, Sterman MB, Rosenfeld PJ, Striefel
ECT. J Psychosom Res. (2000) 49:423–9. doi: 10.1016/S0022-3999(00)00 S, et al. Limitations of the American Academy of Neurology and American
190-2 Clinical Neurophysiology Society Paper on QEEG. J Neuropsychiatry Clin
5. Ito H, Kawashima R, Awata S, Ono S, Sato K, Goto R, et al. Hypoperfusion in Neurosci. (1999) 11:401–7. doi: 10.1176/jnp.11.3.401
the limbic system and prefrontal cortex in depression: SPECT with anatomic 12. Hughes JR, John ER. Conventional and Quantitative Electroencephalography
standardization technique. J Nucl Med. (1996) 37:410–4 in Psychiatry. J Neuropsychiatry Clin Neurosci. (1999) 11:190–
6. Dougherty DD, Rauch SL. Brain correlates of antidepressant treatment 208. doi: 10.1176/jnp.11.2.190
outcome from neuroimaging studies in depression. Psychiatr Clin North Am. 13. Huang C, Eidelberg D, Habeck C, Moeller J, Svensson L, Tarabula
(2006) 30:91–103. doi: 10.1016/j.psc.2006.12.007 T, et al. (2007). Imaging markers of mild cognitive impairment:

Frontiers in Psychiatry | www.frontiersin.org 11 January 2022 | Volume 12 | Article 713141

Best et al. Brain SPECT Biomarker Treatment Psychiatry

Multivariate analysis of CBF SPECT. Neurobiol Aging. (2006) 32. Raji CA, Tarzwell R, Pavel D, Schneider H, Uszler M, Thornton, et al.
28:1062–9. doi: 10.1016/j.neurobiolaging.2006.05.017 Clinical utility of SPECT neuroimaging in the diagnosis and treatment
14. Amen DG, Trujillo M, Newberg A, Willeumier K, Tarzwell R, Wu of traumatic brain injury: a systematic review. PLoS ONE. (2014)
JC, et al. Brain SPECT imaging in complex psychiatric cases: an 9:e91088. doi: 10.1371/journal.pone.0091088
evidence-based, underutilized tool. Open Neuroimaging J. (2011) 5:40– 33. Best SRD, Pavel DG, Haustrup N. Combination therapy with transcranial
8. doi: 10.2174/1874440001105010040 magnetic stimulation and ketamine for treatment-resistant depression:
15. Amen DG, Raji CA, Willeumier K, Taylor D, Tarzwell R, Newberg A, et al. a long-term retrospective review of clinical use. Heliyon. (2019)
Functional neuroimaging distinguishes posttraumatic stress disorder from 5:e02187. doi: 10.1016/j.heliyon.2019.e02187
traumatic brain injury in focused and large community datasets. PLoS ONE. 34. Griffiths C, O’Neill-Kerr A, de Vai R, Sore T, da Silva K. Ketamine infusion
(2015) 10:e0129659. doi: 10.1371/journal.pone.0129659 (KI) in treatment resistant depression (TRD): retrospective clinical data
16. Cohen PF, Tarzwell R, Numerow L, Siow, Y-H, Uszler JM, et al. CANM analysis. Open J Depress. (2019) 8:59–70. doi: 10.4236/ojd.2019.83007
Guidelines For Brain Perfusion Single Photon Emission Computed Tomography 35. Marcinkowska AB, Mankowska ND, Kot J, Winklewski PJ. Impact of
(SPECT). Canadian Association of Nuclear Medicine (2021). Available online hyperbaric oxygen therapy on cognitive functions: a systematic review.
at: https://canm-acmn.ca/guidelines (accessed October 22, 2021) Neuropsychol Rev. (2021). doi: 10.1007/s11065-021-09500-9. [Epub ahead
17. Estudillo-Guerra MA, Pacheco-Barrios K, Cardenas-Rojas A, Adame- of print].
Ocampo G, Camprodon JA, Morales-Quezada L. Brain perfusion during 36. Tobinick E. Perispinal etanercept: a new therapeutic paradigm in neurology.
manic episode and at 6-month follow-up period in bipolar disorder Expert Rev Neurother. (2010) 10:985–1002. doi: 10.1586/ern.10.52
patients: Correlation with cognitive functions. Brain Behav. (2020) 37. Fitzgerald PB, Hoy KE, Elliot D, McQueen SRN, Wambeek LE,
10:e01615. doi: 10.1002/brb3.1615 Daskalakis ZJ. Accelerated repetitive transcranial magnetic stimulation
18. Henderson T, Cohen P, van Lierop M, Thornton J, McClean M, Uszler J, in the treatment of depression. Neuropsychopharmacology. (2018)
et al. A reckoning to keep doing what we are already doing with PET 43:1565–72. doi: 10.1038/s41386-018-0009-9
and SPECT functional neuroimaging. Am J Psychiatry. (2020) 177:637– 38. O’Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z,
8. doi: 10.1176/appi.ajp.2020.19080801 et al. Efficacy and safety of transcranial magnetic stimulation in the acute
19. Henderson T, van Lierop M, McLean M, Uszler JM, Thornton J, Siow Y, et al. treatment of major depression: a multisite randomized controlled trial. Biol
Functional Neuroimaging in Psychiatry—Aiding in diagnosis and guiding Psychiatry. (2007) 1:1208–16. doi: 10.1016/j.biopsych.2007.01.018
treatment. What the American Psychiatric Association does not know. Front 39. Perera T, George MS, Grammer G, Janicak PG, Pascual-Leone A, Wirecki TS.
Psychiatry. (2020) 11:276. doi: 10.3389/fpsyt.2020.00276 The clinical TMS society consensus review and treatment recommendations
20. Raji CA, Willeumier K, Taylor DT. Functional neuroimaging for TMS therapy for major depressive disorder. Brain Stimul. (2016) 9:336–
with default mode network regions distinguishes PTSD from TBI 46. doi: 10.1016/j.brs.2016.03.010
in a military veteran population. Brain Imaging Behav. (2015) 40. Singh JB, Fedgchin M, Daly E, Xi L, Melman C, Bruecker D, et al. Intravenous
9:527–34. doi: 10.1007/s11682-015-9385-5 esketamine in adult treatment-resistant depression: a double-blind, double-
21. Pavel DG, Best SRD. Brain SPECT as Imaging Biomarker for Evaluating randomization, placebo-controlled study. Biol Psychiatry. (2016) 80:424–
Effects of Novel Treatments in Psychiatry. J Nucl Med. (2017) 31. doi: 10.1016/j.biopsych.2015.10.018
58(supplement 1):1298. 41. Xie Z- M, Wang X-M, Xu N, Wang J, Pan W, Tang XH, et al. Alterations in
22. Walker Z, Moreno E, Thomas A, Inglis F, Tabet N, Rainer M, et al. Clinical the inflammatory cytokines and brain-derived neurotrophic factor contribute
usefulness of dopamine transporter SPECT imaging with 123I-FP-CIT in to depression-like phenotype after spared nerve injury: improvement by
patients with possible dementia with Lewy bodies: Randomised study. Br J ketamine. Sci Rep. (2017) 7:3124. doi: 10.1038/s41598-017-03590-3
Psychiatry. (2018) 206:145–52. doi: 10.1192/bjp.bp.114.148643 42. Martin JL, Finsterwald C. Cooperation between BDNF and glutamate in the
23. Yeo JM, Lim X, Khan ZP. Systematic review of the diagnostic utility of SPECT regulation of synaptic transmission and neuronal development. Commun
imaging in dementia. Eur Arch Psychiatry Clin Neurosci. (2013) 263:539– Integr Biol. (2011) 4:14–6. doi: 10.4161/cib.13761
52. doi: 10.1007/s00406-013-0426-z 43. Zanos P. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry.
24. Guinane J, Ng BL. Clinical utility of MRI and SPECT in the diagnosis of (2018) 23:801–11. doi: 10.1038/mp.2017.255
cognitive impairment referred to memory clinic. Int Psychogeriatr. (2018) 44. Best SRD. Treatment of Thalamocortical Dysrhythmia. World Intellectual
30:611–7. doi: 10.1017/S1041610217001624 Property Organization Patent No. WO2014081948A1. International Bureau,
25. Henderson TA. The diagnosis and evaluation of dementia and mild cognitive Virginia: Commission for patents (2014).
impairment with emphasis on SPECT perfusion neuroimaging. CNS Spectr. 45. Best SRD. Treatment of thalamocortical dysrhythmia U.S. Patent No.
(2012) 17:176–206. doi: 10.1017/S1092852912000636 US8974365B2. Washington DC: Patent US, and Trademark Office (2015).
26. Milham MP, Craddock RC, Klein A. Clinically useful brain imaging for 46. Best SRD. Combined ketamine and transcranial magnetic stimulation
neuropsychiatry: How can we get there? Depress Anxiety. (2017) 34:578– for treatment resistant depression in the context of chronic
87. doi: 10.1002/da.22627 OCD: a case report. Neuropsychiatric Electrophysiology. (2015)
27. Abi-Dargham A, Horga G. The search for imaging biomarkers in psychiatric 1:2. doi: 10.1186/s40810-015-0003-y
disorders. Nat Med. (2016) 22:1248–55. doi: 10.1038/nm.4190 47. Best SRD. Treatment of post-anesthesia dementia with perispinal etanercept
28. Camargo EE. Brain SPECT in neurology and psychiatry. J Nucl Med. injection and hyperbaric oxygen therapy: a case report. J Med Case Rep. (2017)
(2001) 42:611–23. 11. doi: 10.1186/s13256-017-1259-6
29. Li J, Yang Y, Zhu Y, Zhou L, Han Y, Yin T, et al. Towards characterizing 48. Tobinick E, Rodriguez-Romanacce H, Levine A, Ignatowski TA. Immediate
the regional cerebral perfusion in evaluating the severity of major neurological recovery following perispinal etanercept years after brain injury.
depression disorder with SPECT/CT. BMC Psychiatry. (2018) Clin Drug Investig. (2014) 34:361–6. doi: 10.1007/s40261-014-0186-1
18:70. doi: 10.1186/s12888-018-1654-6 49. Gonzales-Portillo B, Lippert T, Nguyen H, Lee JY. Hyperbaric oxygen therapy:
30. Karada,g F, Kalkan Oguzhanoglu N, Yüksel D, Kiraç S,Cura Ç, Özdel A new look on treating stroke and traumatic brain injury. Brain circulation.
O, et al. The comparison of pre- and post-treatment 99mTc HMPAO (2019) 5:101–5. doi: 10.4103/bc.bc_31_19
brain SPECT images in patients with obsessive-compulsive disorder. 50. Golden Z, Golden CJ, Neubauer RA. Improving neuropsychological function
Psychiatry Res. (2013) 213:169–177. doi: 10.1016/j.pscychresns.2012. after chronic brain injury with hyperbaric oxygen. Disabil Rehabil. (2006)
07.005 28:1379–86. doi: 10.1080/09638280600638364
31. Mottaghy FM, Keller CE, Gangitano M, Ly J, Thall M, Parker JA, et al. 51. Huang L, Obenaus A. Hyperbaric oxygen therapy for traumatic brain injury.
Correlation of cerebral blood flow and treatment effects of repetitive Med Gas Res. (2011) 1:21. doi: 10.1186/2045-9912-1-21
transcranial magnetic stimulation in depressed patients. Psychiatry Res. (2002) 52. Tobinick, E. Perispinal etanercept advances as a neurotherapeutic. Expert Rev
115:1–14. doi: 10.1016/S0925-4927(02)00032-X Neurother. 18:453–455. doi: 10.1080/14737175.2018.1468253

Frontiers in Psychiatry | www.frontiersin.org 12 January 2022 | Volume 12 | Article 713141

Best et al. Brain SPECT Biomarker Treatment Psychiatry

53. Tobinick EL. Use and methods of use of etanercept and other TNF J Neural Transm Suppl. (2016) 123:1309–18. doi: 10.1007/s00702-016-
binding biologics to improve human cognitive function. United States 1586-6
Patent No. US20060009450A1. Washington, DC: Patent US, and Trademark 62. McLean M, Henderson TA, Pavel DG, Cohen P. Increase asymmetric
Office (2006). perfusion of the cerebral cortices and thalamus indicates individuals at risk
54. Chang LT. A method for attenuation correction in radionuclide computed for bipolar disorder: a family Cohort SPECT neuroimaging study. Front
tomography. IEEE Transactions on Nuclear Science. (1978) 25:638– Psychiatry. (2021).
43. doi: 10.1109/TNS.1978.4329385
55. Botteron K, Carter C, Castellanos FX, Dickstein DP, Drevets W, Kim KL, Conflict of Interest: NH has since become an employee of Eli Lilly and Company.
et al. Consensus Report of the APA Work Group on Neuroimaging Markers of SB holds multiple patents claiming methods of use of CTK for treatment of
Psychiatric Disorders. Am. Psychiatr Assoc (Ed.), Arlington, VA, USA (2012). neurological disorders.
56. FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, other
Tools). Monitoring Biomarker. Food and Drug Administration (US) and The remaining author declares that the research was conducted in the absence of
National Institutes of Health (US) (2016). Availabble online at: https://www. any commercial or financial relationships that could be construed as a potential
ncbi.nlm.nih.gov/books/NBK402282 (accessed January 25, 2021). conflict of interest.
57. Minoshima S, Koeppe RA, Frey KA, K.ã DE. Anatomic standardization:
linear scaling and nonlinear warping of functional brain images. J Nucl Med. The handling editor TH declared a past co-authorship/collaboration with
(1994) 35:1528–37 one of the authors DP.
58. Pliszka SR, Glahn DC, Semrud-Clikeman M, Franklin C, Perez
III, Xiong R, et al. Neuroimaging of inhibitory control areas in Publisher’s Note: All claims expressed in this article are solely those of the authors
children with attention deficit hyperactivity disorder who were and do not necessarily represent those of their affiliated organizations, or those of
treatment naive or in long-term treatment. Am J Psychiatry. (2006)
the publisher, the editors and the reviewers. Any product that may be evaluated in
163:1052–1060. doi: 10.1176/ajp.2006.163.6.1052
this article, or claim that may be made by its manufacturer, is not guaranteed or
59. Sheehan W, Thurber S. Review of two years of experiences with SPECT
among psychiatric patients in a rural hospital setting. J Psychiatr Pract. (2008) endorsed by the publisher.
14:318–23. doi: 10.1097/01.pra.0000336760.88178.e5
60. Booij J, Dubroff J, Pryma D, Yu J, Agarwal R, Lakhani P, et al. Diagnostic Copyright © 2022 Best, Haustrup and Pavel. This is an open-access article distributed
performance of the visual reading of 123 I-Ioflupane SPECT images with or under the terms of the Creative Commons Attribution License (CC BY). The use,
without quantification in patients with movement disorders or dementia. J distribution or reproduction in other forums is permitted, provided the original
Nucl Med. (2017) 58:1821–6. doi: 10.2967/jnumed.116.189266 author(s) and the copyright owner(s) are credited and that the original publication
61. Mäkinen E, Joutsa J, Johansson J, Mäki M, Seppänen M, Kaasinen V. Visual in this journal is cited, in accordance with accepted academic practice. No use,
versus automated analysis of [I-123] FP-CIT SPECT scans in parkinsonism. distribution or reproduction is permitted which does not comply with these terms.

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