Brain Imaging and Mental Illness 1

Running Head: BRAIN IMAGING AND MENTAL ILLNESS

The Applications of Brain Imaging to the Diagnosis and Treatment Process of Mental Illnesses
Ellen E. Harrell
Glen Allen High School
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For nearly every medical problem you may encounter in your lifetime, whether it’s

something as common as a broken bone or as serious as cancer, medical imaging will likely be

used to confirm your diagnosis. Yet, if you ever seek medical treatment for the excruciating

effects of a mental illness, medical imaging will likely not be used to verify your illness. For

decades, psychiatrists, medical experts, and other health professionals have been fervently

debating the role of medical imaging in psychiatry. Many are quick to argue that imaging

research has not been developed enough yet to even consider using it in diagnoses, but some

revolutionary psychiatrists, like the famous Dr. Daniel Amen, argue imaging is the only hope to

ever diagnose patients correctly.

The controversy behind medical imaging in psychiatry runs deep; both supporters and

opponents have sound reasoning as to why it should or should not be used. Despite the

controversy behind using imaging, the underlying truth is that imaging is showing prospects in

distinguishing frequently misdiagnosed mental illnesses. The question lies in the feasibility of

applying imaging research to clinical practice. A notable example of the clarification that

imaging provides is in distinguishing bipolar disorder from unipolar depression: two disorders

commonly confused for one another. This paper will review three facets of brain imaging in

order to understand the clinical usefulness of brain imaging. The first is the controversy in using

brain imaging to make psychiatric diagnoses. The second and third are the clarifications imaging

provides in diagnosing patients with bipolar disorder and depression, and the way that imaging

can evaluate the effectiveness of treatment of these two diseases. These reviews ultimately lead

to the conclusion that imaging may ultimately become clinically useful.

Controversy Behind Brain Imaging in Psychiatry

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For decades, psychiatrists have been dreaming of transitioning to an imaging-based

diagnosis process. The theory is that imaging would enable a clear-cut diagnosis: one based off

of brain abnormalities rather than clusters of symptoms. Dr. Daniel Amen, a pioneering

psychiatrist who uses brain imaging to diagnose mental illnesses, is known for his insistence of

using this method. In his TED Talk, “The most important lesson from 83,000 brain scans,” Dr.

Amen argues that doctors cannot truly understand the illness being treated unless they observe

the organ responsible for the symptoms (Amen, 2013). Amen argues this by explaining how

mental illness clearly shows on imaging, the dangers of not using brain imaging, and how his

imaging has been clinically used.

In his own clinics, Dr. Amen uses SPECT brain imaging to diagnose and treat mental

illness. He reviews in his TED Talk how “SPECT...tells us three things about the brain: good

activity, too little, or too much” (Amen, 2013). Following this, he explains that “holes” on the

scans can indicate different disorders: among these, schizophrenia, obsessive compulsive

disorder, depression, and traumatic brain injury (Amen, 2013). Amen acknowledges how using

the traditional diagnostic classifications previously made him feel like “[he] was throwing darts

in the dark…” because of the lack of clarity provided by only using symptom analysis (Amen,

2013). He concludes that “[t]reatment needs to be tailored to individual brains,” and this is only

attainable through brain imaging (Amen, 2013).

While some experts, like Amen, have faith in brain imaging playing a large role in future

diagnoses and treatments, others suggest that Amen and his counterparts should not place all

their hope on imaging. Their reasons for this are threefold. The first reason is that brain imaging

is taking far longer to develop into a clinical tool than originally expected. The second reason
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lies in the uniqueness of each and every brain. The third reason is that many imaging studies tend

to focus too much on some regions of the brain, such as the amygdala.

It was expected that brain imaging technology would have enabled faster diagnoses by

today. Despite this expectation, in 2005, researchers had still not yet come to a consensus about a

tool that could be used for mental illness evaluations (Carey, 2005). By this point, nearly three

decades had already passed since brain imaging began to take off. The 1990’s were dubbed the

“Decade of the Brain” by scientists who hoped brain scans would “turn on the lights in what had

been a locked black box” in this era (Carey, 2005). By 2005, researchers were collectively

publishing nearly 500 imaging studies each year, showing that the research had gained speed

(Carey, 2005). Despite these rampant publications, there still were not enough clinical findings

that could be easily translated into clinical practice. Even though this quantity of studies had

been published, there were not enough replications of findings and across the board conclusions

to apply any medical imaging to clinical diagnoses of mental health issues.

In fact, the more imaging studies that were conducted, the more obstacles were

discovered. One of these can be shown through a finding regarding normal, clinically

insignificant brain differences. Initially, it was thought that schizophrenia could be identified by

a loss of brain volume; studies demonstrated that those with schizophrenia can “lose 5 to 10

percent of overall brain volume” over ten years (Carey, 2005). However, the finding that brain

volume varies from person to person by “at least ten percent” completely uproots the potential

use of brain volume to diagnose schizophrenia (Carey, 2005). Unless a clear before and after

image was taken, it cannot be determined how much brain volume someone with Schizophrenia

has lost. It is also unlikely that a patient who later developed Schizophrenia would ever take an

image of their brain prior to their rapid brain volume loss, as they likely would not have had any
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clinical need for such a scan. Regular brain differences, like variations in brain volume, threaten

the prospects of brain imaging as a diagnostic tool, as there is difficulty in distinguishing regular

brain differences from the abnormalities that cause mental illness.

Other analyses and studies have supported this skepticism. While there are high hopes for

neuroimaging in mental illness diagnoses, there are problems associated with imaging itself that

make the process more difficult. In the meta-analysis “Addressing Reverse Interference in

Psychiatric Neuroimaging: Meta-analyses of Task Related Brain Activation in Common Mental

Disorders,” different regions of the brain were mapped in 537 fMRI studies (Sprooten et al.,

2017). These studies were of patients with a wide variety of disorders: “schizophrenia, bipolar

disorder, major depressive disorder, anxiety disorders, and obsessive compulsive disorder

(Sprooten et al., 2017). After looking at 21,427 patients, researchers found specific regions of the

brain and these areas’ levels of activation to be associated with different mental disorders

(Sprooten et al., 2017). These regions include the nucleus accumbens, the anterior insula, the

posterior parahippocampal gyrus, among many other regions (Sprooten et al., 2017). The

findings of this meta-analysis do support using brain imaging to study mental disorders, and

ultimately they would contribute to the clinical use of imaging to diagnose mental illness. The

meta-analysis proves distinctly that different mental disorders have distinct neural differences.

However, this same meta-analysis also points out another important obstacle: brain

imaging studies tend to focus on some areas of the brain more than others, which results in the

over-attribution of disorders to certain areas of the brain. The study emphasizes that different

types of imaging studies, such as region-of-interest studies (ROI studies), “[over-represent]... the

amygdala and the caudate nucleus,” two regions of the brain mental illness is commonly

associated with (Sprooten, et al., 2017). This over-representation did not occur in “whole-brain
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studies” (Sprooten, et al., 2017). In these whole-brain studies, two regions primarily, the

thalamus and parahippocampal gyrus, were shown to be likely involved in mental illness but are

less commonly studied in region-of-interest studies. Many researchers tend to focus their

research on one specific area of the brain responsible for fear and anger: the amygdala. The

widespread attribution of mental illness to the amygdala and the research that supports the

relationship between the amygdala and mental illness has stifled the research of other brain

regions (Sprooten et al., 2017).This finding signifies that mental illness research needs to analyze

more than just particular biomarkers in the brain; it must analyze the whole, not just the sum of

its parts.

Misdiagnosis of Bipolar Disorder

Even though the current progress made by imaging research may fall short of the hope

placed upon it, our limited knowledge of imaging may still compete with the flawed current

system of diagnosis. The Diagnostic and Statistical Manual of Mental Disorders 5th Edition, or

DSM-V, uses a symptom based, question-and-answer reliant method. To understand how deeply

these flaws affect patients, this paper will focus on the misdiagnosis of bipolar disorder and the

overdiagnosis of unipolar depression. By focusing only on these disorders, it is easy to see how

the flaws of the DSM-V criteria ripple into broader consequences. In regards to bipolar disorder

specifically, the DSM-V fails to accurately diagnose the disorder because of its overly restrictive

criteria and its limited ability to distinguish it from unipolar depression.

The Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV),

which preceded the currently used Diagnostic and Statistical Manual of Mental Disorders 5th

Edition (DSM-IV), was particularly restrictive in its diagnostic criteria, preventing many patients

to get the proper diagnosis. This can be broken into two problems regarding the Diagnostic and
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Statistical Manuals of Mental Disorders: one being the length requirements for hypomanic states

and the other being the limited improvement of the DSM’s from version to version. In diagnosing

bipolar II disorder, a specific type of bipolar disorder, patients are required to have a hypomanic

state that lasts four or more days, when in reality, experts believe hypomanic states to last 1 to 3

days (Singh & Rajput, 2006). Mental disorders tend to present subjectively from patient to

patient, often varying in classifications like length requirements. This complicates the use of

length requirements in diagnosis: how can a doctor diagnose disorders in patients when

symptoms present themselves differently in different patients, and their symptoms overlap with

other disorders’ symptoms so much?

Despite being more up-to-date than the DSM-VI, the DSM-V still failed to broaden its

diagnostic criteria enough. It includes the problematic 4 day long manic state requirement of the

DSM-IV, but has included a slightly broader, new specifier: “mixed features” (Culpepper, 2014).

This specifier only broadened the bipolar disorder diagnostic requirements ever so slightly. It

allows characteristics of manic states, such as “significant energy, impulsivity, and irritability” to

be experienced simultaneously with depressive symptoms under the bipolar disorder diagnostic

criteria (Culpepper, 2014). Nonetheless, even with these broader requirements, bipolar disorder

is not so clear-cut that each person’s symptoms will show in the same way, even under these

classifications.

Unfortunately, bipolar disorder and major depressive disorder tend to get confused quite

often. Many patients with bipolar disorder are often misdiagnosed with depression because they

first seek treatment for their depressive episodes, rather than both their depressive and mania

episodes (Singh & Rajput, 2006). It does not help that the symptoms between bipolar disorder

and major depressive disorder overlap, leading to nearly “40% of bipolar disorder patients”
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getting initially diagnosed with unipolar depression (Singh & Rajput, 2006). Unsurprisingly,

experts are finding that depression tends to be overdiagnosed across the board. Of all individuals

over the age of twelve in America, eleven percent were taking anti-depressant medications in

2008 (Abrams, 2013). A study conducted by Johns Hopkins Bloomberg School of Public

Health’s Ramin Mojtabai determined that “over 60 percent of adults who were diagnosed with

depression did not meet the official criteria for the disorder upon reevaluation” (Abrams, 2013).

These statistics show that doctors overly attribute depressive symptoms to unipolar depression,

despite their symptoms not clearly aligning with depression. An imaging based diagnostic

process based off of specific brain abnormalities signifying depression may help prevent this, as

doctors would not have to use unclear symptom presentations as diagnostic criteria.

Seeing these flaws in the diagnostic process, it is unsurprising that bipolar disorder is one

of the most frequently misdiagnosed mental disorders; an overwhelming “69% of patients...are

misdiagnosed initially” (Singh & Rajput, 2006). Patients are rarely correctly diagnosed even

years after (Singh & Rajput, 2006). Dr. Tanvir Singh and Dr. Muhammad Rajput’s review of

“Misdiagnosis of Bipolar Disorder” revealed that one out of three patients remained

misdiagnosed for ten years or more (Singh & Rajput, 2006). Even more troubling is the fact that

these patients are misdiagnosed with unipolar depression, and the most common medication for

treating unipolar depression selective serotonin reuptake inhibitors, or SSRIs (NAMI, 2017).

These medications exacerbate bipolar disorder tremendously, as a patient with rapid cycling

bipolar experience “268% more total mood episodes/year, and 293%...more depressive

episodes/year” when on SSRIs. These percentages are unacceptable, seeing that bipolar disorder

is already one of the most lethal disorders with a suicide rate 20 times that of the general

population (Singh & Rajput, 2006). Treating it as depression can worsen it tremendously,
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meaning that the “40% of patients” who are diagnosed with depression initially might actually be

aggravating their condition when they seek medical help (Singh & Rajput, 2006).

Regardless of whether or not imaging is the answer, the diagnosis process for mental

illness needs to be reevaluated. A continuation of the current system, relying on the flawed

DSM-V, allows for the continuation of these horrendously common misdiagnoses and

mistreatments, allowing vulnerable individuals to remain at risk for far longer than they should.

Biomarkers of Bipolar Disorder and Depression

Where the DSM-IV criteria is failing to distinguish bipolar disorder and unipolar

depression, neuroimaging is showing promise. Researchers believe that if they can identify

different biomarkers, or visible abnormalities, in brain imaging associated with different mental

disorders, they may be able to make diagnoses off of these biomarkers in the future. While these

studies are in their earliest stages, studies aiming to identify different biomarkers would be

extremely useful, especially in regards to diagnosing bipolar disorder. Current research shows

that bipolar disorder may be able to be distinguished from unipolar depression on imaging

(Keener & Phillips, 2009). These markers could be findings in MRI, positron emission

tomography (PET), and diffusion tensor imaging (DTI) studies (Keener & Phillips, 2009). If

such markers were found, they would allow individuals who are at risk for bipolar disorder to be

diagnosed early prior to the illnesses’ onset, which would allow them to be distinguished more

easily from patients with unipolar depression (Keener & Phillips, 2009).

Certain studies have found specific biomarkers that may be able to show bipolar

disorder. In Dr. Matthew Keener and Dr. Mary Phillips’s “Neuroimaging in Bipolar Disorder: A

Critical Review of Findings,” it was found that adults with bipolar disorder have enlarged

amygdalae (Keener & Phillips, 2009). This differs with the finding that adolescents with bipolar
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disorder have smaller amygdalae (Keener & Phillips, 2009). It also must be noted that these

studies specifically focused on bipolar I disorder, and studies on bipolar II disorder are lagging

behind (Keener & Phillips, 2009). The study concludes that neuroimaging is useful in identifying

the endophenotypic markers associated with bipolar disorder, and that future studies should

focus on neural systems associated with emotional regulation (Keener & Phillips, 2009).

While these endophenotypic markers can be found in bipolar disorder, research is also

developing biomarkers with depression. As in a publication by Drysdale et al., depression “is not

a unitary disease…” (Drysdale, et al., 2017). This disorder has been found to have four distinct

types (Drysdale, et al., 2017). According to this article, depression can be identified by its

pathways in the limbic system and in the frontostriatal circuits; in each different type of

depression, there is dysfunction (Drysdale, et al., 2017). Although symptoms overlap among the

four types, these different types have different pathways in the brain that serve as biomarkers

(Drysdale, et al., 2017). In these studies, it was found that “[c]lustering patients...enabled the

development of diagnostic classifiers (biomarkers) with high sensitivity and specificity…”

meaning that depression can be identified in this manner statistically (Drysdale, et al., 2017). If

this is the case, depression can more easily be differentiated from other disorders based off of the

way it presents itself in imaging. This would, perhaps, lead to better diagnoses.

An aforementioned criticism was that regular variations among brains may be

misinterpreted as abnormalities when looking at scans. However, other studies affirm that

imaging can be clinically useful from patient to patient, regardless of normal differences among

their brains. In a study conducted by Anjali Sankar, it was found that neuroimaging can be used

across different ethnic groups to verify the existence of depression. The study confirmed that

“structural neuroanatomy combining white and grey matter distinguished patients…” (Sankar,
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2016). These differences in white and grey matter were all evident in the frontal, parietal,

occipital, and cerebellar structures (Sankar, 2016). These regions all contributed to accurately

classifying patients with depression in this study, showing that imaging does have diagnostic

prospects. These prospects, as verified by this study, are not limited to certain ethnic groups; the

abnormalities exist across people with bipolar from all different ethnicities.

Treatment Based On Neuroimaging

On top of the prospects imaging has for diagnosing mental illness, imaging can also

verify whether or not a medication is working for an individual. Successful treatment can be

verified by medical imaging for both bipolar disorder and unipolar depression.

One study in particular showed that imaging can reveal the effects of medication on

individuals with bipolar disorder. When individuals with bipolar disorder are medicated, their

subcortical limbic structures are less activated (Keener & Phillips, 2009). The studies indicating

this also suggest that these neural paths are also improved in bipolar individuals as a result of

medicating (Keener & Phillips, 2009). This shows that individuals with bipolar disorder alter

their brains when they are medicating, and using imaging to verify these alterations may assist in

showing the effectiveness of treatment.

In one notable study conducted by Chen Chi-Hua, it was discovered that the use of

Selective Serotonin Reuptake Inhibitors, or SSRIs, resulted in different changes in the brain

itself. When these changes occurred, different symptom changes occured (Chen-hua, 2007). The

study measured the brain structure and function of depressed individuals before they took twenty

milligrams of fluoxetine, or Prozac, every day (Chen-hua, 2007). The study measured the change

in both the symptoms and their severity throughout the study (Chen-hua, 2007). Ultimately, it

was found that as a result of taking fluoxetine, patients anterior cingulate cortices were modified
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(Chen-hua, 2007). The study concluded that the pre-treatment activity of the anterior cingulate

cortex can indicate how well an individual with depression will respond to treatment (Chen-hua,

2007).

Conclusion

Seeing the flaws in the current diagnosis process in context with the emerging results of

neuroimaging, it can be determined that neuroimaging should likely play a role in the future of

mental illness diagnoses. The problems of the Diagnostic and Statistical Manuals of Mental

Disorders linger from version to version, and the subjectivity of their diagnostic criteria will

likely never provide the clarity needed. While there are many obstacles and unanswered

questions about the role of imaging, evolving our technology and knowledge will at least answer

many of our questions about mental disorders and the effectiveness of treatments. Whether the

widespread use of imaging will be clinically possible in the near future or ever is undetermined,

but the prospects of imaging do seem strong considering the clarity it provides on bipolar

disorder and depression.

Because misdiagnoses are rampant, it is known that the DSM methods are flawed. It is

also known that there are flaws in medical imaging, but these flaws can be overcome with more

research and more time. Neuroimaging has clarified the biological markers of many mental

disorders, including bipolar disorder and depression. By viewing and analyzing these

biomarkers, perhaps diagnoses will be made possible by simple observation rather than complex

symptom linkage and analysis. Treatment has also been made more understandable based off of

imaging. By analyzing the way that the brain changes throughout a treatment cycle, alongside the

changes in symptoms, those with mental disorders can more effectively be treated based off of

their pretreatment imaging.

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The questions of when and how of course lingers, but imaging should ultimately take on

a bigger role in psychiatry. In this moment, experts need to focus on consolidating the research,

as clinical findings need to be replicated before putting them into practice. More meta-analyses

need to take place, and they need to be applied to clinical practice once verified, as Dr. Daniel

Amen has gradually begun doing. Most importantly, research must begin to be compared and

ultimately applied to practice, so that doctors can begin to understand their patients’ situations in

a timely manner. The DSM’s will only get so much better from version to version. It is of the

utmost importance that doctors reevaluate their own evaluation processes, rather than continue to

“[throw] darts in the dark” (Amen, 2013).

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