Why Should We Care About Functional Neuroanatomy?

Abstract

The primary goal of this chapter is to address the relevance of functional neuroanatomy and its critical importance to clinical, school, and counseling psychology. The chapter begins with a general overview of the functional neuroanatomy of the brain and progresses into the value of having an understanding of developmental neuroanatomy in order to provide optimal treatment when working with individuals. The importance of understanding the past, present, and future of psychology is highlighted through a review of the history of the field of neuropsychology. Contributions to the field from prominent neuropsychologists are discussed, including the advancement of the evaluation process, development of neuropsychological assessments, and the introduction of clinical training programs. Different technologies that are helpful in the current analysis of neuroanatomy are briefly introduced along with discussions of an overview of corresponding developmental neuropsychological interventions. The relevance of understanding the various cultural factors that play into behavior and enduring a multicultural approach to assessment and interventions are explained. A synopsis of the benefits of future chapters in functional neuroanatomy and intervention will be provided to assist the clinical, school, and counseling psychologist in understanding its importance in providing appropriate care to individuals with varying and specific cognitive, behavioral, and emotional issues related to the brain.

FormalPara Learning Objectives

• 1. To understand why functional neuroanatomy developed.

• 2. To understand how functional neuroanatomy developed.

• 3. To understand the practical and clinical uses of functional neuroanatomy in addressing and prioritizing an individual’s problem set, needs, and subsequent interventions.

• 4. To explain how to use a multicultural approach to functional neuroanatomy to help guide treatment from assessment to intervention.

• 5. To understand the implications and future directions of functional neuroanatomy.

Overview

The purpose of this chapter is to provide the history and background of functional neuroanatomy and its critical role in working with the biological basis of behavior of individuals in clinical, counseling, and school settings. This chapter will address the importance of examining the client or student from a multicultural perspective. It will identify the areas of growth and implications of clinical practice within the psychological fields. Finally, it will address the future of functional neuroanatomy after decades of expansion and research in practice, in an attempt to give the reader a better understanding of where we are with functional neuroanatomy and the biological basis of behavior.

Functional Neuroanatomy and the Biological Basis of Behavior

School, clinical, and counseling psychologists are essentially experts in helping others with emotional regulation and changing behaviors that may be intrusive to their life at school, in the workplace, at home, or in the community. As a psychologist or counselor, people come to us to understand why they or a loved one are engaging in inappropriate behaviors, or why they are not performing up to standards in school or the work place, and what can be done to help them. It is important to understand the underlying biological bases of an individual’s behavior in order to create a more personalized and accurate treatment plan or educational plan. As stated in Chap. 2, various parts of the brain are associated with emotion. In this chapter, there will be more focus on the circuitry of the brain and its connection to behavior. One way to think of the circuitry of the brain is to compare it to wires that connect different parts of machinery. While the individual parts of the brain are generally used for specific functions, the neurological circuitry is what connects those different parts. Complications in these circuits can cause clinical implications which school, clinical, and counseling psychologists commonly encounter when working with their clients. Through understanding networking and connections of the various areas of the brain, mental health professionals can better support their clients through evidence-based interventions and psychoeducation. See Tables 3.1 and 3.2 for more specific information about brain lobes, structures, and their functions.

Table 3.1 Brain lobes and hemisphere functions, notes, and structures

Table 3.2 Brain structures, functions, and location/damage notes

When a student or client is brought to the attention of the practitioner, it is often because they are engaging in some sort of negative behavior. For example, a teacher may come to a school psychologist describing a student who is impulsive and never stays in her seat, or a student who never pays attention and is constantly daydreaming. One may jump to thinking that the child has attention-deficit/hyperactivity disorder (ADHD) and an exhausted parent or teacher may want to move quickly toward medication. Practitioners who understand the biological basis of behavior will know to dig deeper. While prescribing medication may not be within the realm of some psychologists, having this understanding will strengthen the skill of case conceptualization and aid those involved on the decision as to whether medication is necessary, and if this is a child with ADHD or not. Given the brief description of the child, a psychologist may begin to think of frontal lobe circuitry and possible implications in the anterior cingulate, orbitofrontal, dorsolateral, and ventrolateral cortexes. All of these areas are involved with various functions, such as self-regulation of behavior, decision making, planning, monitoring, focusing and sustaining attention, motivation, self-awareness, and self-restraint (Torregrossa, Quinn, & Taylor, 2008). A disconnection or miscommunication between these areas with the rest of the brain may look like inattention or hyperactivity (Torregrossa et al., 2008). However, these areas are also involved with functions, such as judgment of another’s feelings, self-regulation of behavior, emotional processing, anticipation, use of feedback, response inhibition, and emotional regulation. If the child looks like she is never paying attention, maybe she is hypervigilant. If she has poor concentration, it may not be due to ADHD, but instead she may have experienced a traumatic event which has negatively impacted her ability to sustain attention. Understanding the biological and physical differences of these complications is significant for identifying and implementing appropriate supports.

With the current increase in awareness of how toxic stress and adverse events during childhood can impact brain development, we look at the communication between the limbic system and the prefrontal cortex; however, several areas of the brain are activated when responding to stressful situations. Two major parts of the limbic system are the amygdala and hippocampus. Together these areas create and store memories and produce emotional responses. Research in neuroimaging has shown that the amygdala and hippocampus are altered in children who experience toxic stress and adverse events (De Bellis & Zisk, 2014; Souza-Queiroz et al., 2016). This type of alteration leads to a disruption in communication between the limbic system and the prefrontal cortex, which can then lead to the fight, flight, or freeze reaction instead of processing through appropriate decision making and problem solving (De Bellis & Zisk, 2014). Thus, experiencing neglect or chronic stressors during childhood increases the risk of significant problems with cognitive, affective, behavioral, physiological, relational, and self-attributional functioning (Kinniburgh et al., 2005; Perry & Hambrick, 2008). Psychoeducation can help individuals to understand their emotional and behavioral responses and work toward healthy emotional regulation. It can also aid parents and educators to promote and create predictable, consistent, and nurturing environments that lead to healthy brain development.

During childhood and adolescence, healthy environments that are stimulating and allow for opportunities of creativity and critical thinking can lead to positive neural growth (Cozolino, 2013; De Bellis & Zisk, 2014). Cozolino (2013) explains how social experiences affect brain function and development and argues as to why this is closely related to how humans learn throughout their lifetime. With his book, The Social Neuroscience of Education, Cozolino (2013) explains the brain-body connection and highlights the benefits of centering education on building secure and healthy attachments and how it impacts learning. Many of the behavioral aspects in his book, which are focused on teachers and the field of education, can be generalized and applied to other fields. For example, teacher burnout is explained as a hit to self-esteem and emotional well-being which leads to lowered job satisfaction and poor performance. In other words, when humans feel a decreased sense of self-worth, an emotional response to environmental factors, their behavior reflects that (i.e., career change or poor job performance). As Albert Bandura (1997) once stated, “The work we do determines whether a substantial part of our lives is repetitively boring, burdensome, and distressing, or lastingly challenging and self-fulfilling” (p. 422).

Functional neuroanatomy has provided researchers and clinicians with a greater understanding of how the brain is connected to behavior. With this understanding, health service psychologists can evaluate more comprehensively and create and implement additional sound and sustainable interventions and supports for those with whom they work. This information is invaluable when considering how to psychologically approach situations, no matter the complexity. Functional neuroanatomy has provided psychological practitioners with the knowledge base to provide support at individual, family, small group, and system-wide levels, while, at the same time, it has increased awareness and reliability in differential diagnosis.

History of Functional Neuroanatomy

The American Psychological Association (APA) promotes psychology programs to include history of psychology in the curriculum. It is important to study the history of functional neuroanatomy in order understand where we have been, how we have gotten to where we are currently, and where we are going in the future of the field of psychology. Having a deeper understanding of how the field has developed also allows for a more in-depth understanding and sound practice of one’s theoretical orientation. The American Psychological Association (APA) also requires graduate programs to include history in the curriculum of the program (APA, 2006). The study of neuroanatomy dates back to pre-World War II with psychologists, such as Broca and Wernicke, who studied localization of brain functions (Hebben, Milberg, & Kaufman, 2010). After the war, major contributions were made to the field of clinical neuropsychology due to the large number of soldiers experiencing symptoms of post-traumatic stress disorder (PTSD), then viewed as “shell shock” or “soldier’s heart,” and traumatic brain injuries (Substance Abuse and Mental Health Services Administration, 2014). Researchers and clinicians thus began working toward a deeper understanding of the brain and its connection to emotional, behavioral, and physical responses.

Some of the most notable clinicians and researchers include, but are not limited to, Ward Halstead, Ralph Reitan, Alexander Luria, and Edith Kaplan. Halstead and Reitan created the assessment Halstead-Reitan Neuropsychological Test Battery (HRNTB), which has been updated several times and is still used in adult clinical neuropsychology today (Horton & Reynolds, 2015). The original core subtests of the HRNTB were created by Halstead and then updated by Reitan, who was his mentee. The development of both the original battery and the updated subtests were significant milestones in the field of neuropsychology. Reitan’s contributions to the HRNTB allowed for assessment and treatment of individuals who suffered from brain damage and established that performances were related to the brain rather than related to behavior. Because of his research and practice, the role of clinical neuropsychologists in the healthcare system was recognized and welcomed for the first time. Horton and Reynolds (2015) argue, “every clinical neuropsychologist working today owes a debt to Reitan’s contributions.”

Alexander Luria (1902–1977) is another neuropsychologist who is well known for his significant contributions to contemporary neuropsychology through his findings on the function and organization of the brain (Hazin & Tarcísio da Rocha Falcão, 2014). Luria has contributed to the field in various ways, including the theory of extracortical organization of higher mental functions (Kotik-Friedgut, 2006). This theory laid the foundation for consideration of cross-cultural differences of brain development and structure. Thus, it is now well accepted today that social, cultural, and historical factors all play a vital role in neural development and must be considered throughout the evaluation process. Luria established that an evaluation should include both qualitative and quantitative measures.

Additionally, psychologist Edith Kaplan has contributed to the field of neuropsychology in many domains, most notable through her focus on apraxia, aphasia, and developmental issues (Oscar-Berman & Fein, 2013). Kaplan also developed a predoctoral and postdoctoral clinical neuropsychological internship-training program during her time as the director of Clinical Neuropsychological Services at the Boston VA Medical Center (1976–1987). Along with Luria, Kaplan added to the assessment domain by emphasizing the importance of qualitative data collection and analysis alongside of quantitative data. Kaplan and colleagues developed the Boston Process Approach (later called the Boston Hypothesis Testing Approach) which laid emphasis on the importance of how an individual arrives at an answer and initiated the concept of “testing the limits” (Miller, 2013).

Nearly all domains of the psychology field have changed and developed over the last several decades, including evaluation procedures and assessment tools. Much of the development in these areas is due to the research that has been dedicated to functional neuroanatomy. Because of the work of the previously mentioned individuals, and so many more, functional neuroanatomy has played a significant role in the progress of the fields of adult clinical neuropsychology, pediatric neuropsychology, and school neuropsychology. Miller (2013) addresses the work of Rourke (1982) who researched the history of clinical neuropsychology and described three stages in which the field went through: (1) the single test approach, (2) the test battery/lesion specification stage, and (3) the functional profile stage. The single test approach is described as a stage wherein researchers were utilizing a single measure to determine if a patient had brain damage (Miller, 2013). Psychologists were concerned, at the time, with overall brain functioning versus assessment of diverse domains of functioning. The test battery/lesion specification stage was a time in history when clinicians moved away from the single test approach and began to utilize several test batteries to measure a number of cognitive processes in order to discover neuropsychological dysfunction in patients (Miller, 2013). Much of the credit for the progress made during this stage is given to the previously mentioned psychologists, Ward Halstead, Ralph Reitan, Alexander Luria, and Edith Kaplan. Finally, the functional profile stage is noted as the time when neuroimaging techniques began to tie into assessment procedures for cognitive functioning. The developments made during this stage lead to a more comprehensive approach to neuropsychological assessment.

The study of functional neuroanatomy has evolved over time from a very narrow view of functioning and assessment, to a greater understanding of the brain-body connection and how it relates to emotion and behavior. Today, rather than approaching an evaluation to determine whether there is a presence of brain dysfunction or not, comprehensive assessments are often conducted to look more so at patterns of strengths and weaknesses.

Functional Neuroanatomy and Multicultural Issues

As our world becomes increasingly more diverse, practitioners, researchers, and scholars must all address the broadening of our growing multicultural society and continue to be informed of all of the diverse populations and cultures that make up the world’s population. In the United States alone, our population is expected to grow more slowly in future decades than it did in the previous century. However, the total population of over 330 million at the time of publication of this textbook is projected to reach the 400 million threshold in 2051 and 417 million in 2060. In addition, around the time the 2020 Census was conducted, more than half of the nation’s children were part of a minority race or ethnic group. This proportion is expected to continue to grow so that by 2060, just 36 percent of all children (people under age 18) will be single-race non-Hispanic White, compared with 52 percent today the U.S. population as a whole is expected to follow a similar trend, becoming majority-minority in 2044. The minority population is projected to rise to 56 percent of the total in 2060, compared with 38 percent in 2014 (United States Census Bureau, 2015). When examining functional neuroanatomy in practice, clinicians must understand the importance of the various multicultural factors and variables of the client in front of them. As the populations become more majority-minority in the next few decades, the biological basis of behavior as seen from the multicultural perspective will also diversify. Human beings are not a homogenous species and the diverse cultures that make up society are factors that can affect the utility of functional neuroanatomy from assessment to intervention.

Pediatric clinical neuropsychology is a subspecialty within the field of clinical neuropsychology that is concerned with the study and understanding of brain-behavior relationships in children and adolescents with known or suspected brain neurodevelopmental disorder, disease, injury, learning disability, or other acquired or congenital disorder affecting brain function and development. As a subspecialty, it has more access to the use of functional neuroanatomy in as many pediatric clinical neuropsychologists work in hospitals, clinics, or specialized practices that have access to equipment, such as a functional MRI (fMRI) and brain scanning technology. However, school and counseling psychologists can also vastly benefit from the use of functional neuroanatomy, but currently do not have the access to the same technology.

What remains a constant is that all of these subspecialties within the field of psychology work with the regular population of individuals from every socioeconomic, ethnic, sociocultural of all genders, beliefs, and walks of life. Therefore, psychologists must take a strong stance on looking at the diverse multicultural components that make up an individual and impact their presentation from a functional neuroanatomy sense. For example, the brain of an individual who experienced early childhood trauma in the form of abuse or neglect may look and present vastly different in an fMRI versus the brain of a regular functioning individual. Therefore, sociocultural components and factors must be taken into effect when examining and assessing individuals with the assistance of functional neuroanatomy.

So, what does a brain scan discover in an individual who reportedly experiences any kind of trauma? First, it is essential to provide a general overview of what a brain scan is in practice. For the purposes of clinical practice, brain scans that identify functional neuroanatomy come from brain scan technology that covers a diverse group of methods for imaging the brain. In psychiatric clinical practice, brain scans are mostly used to rule out visible brain lesions that may be causing psychiatric symptoms. In the schools and counseling psychology, brain scan technology can be used on a consult basis with the professionals who conduct the studies. In research, psychologists use brain scan technology to learn about the pathologies of the brain in mental illness. A common method is magnetic resonance imaging (MRI) which allows clinicians to look at the changes in the volume and structure of different areas of the brain, and integrity of the pathways connecting them.

Then there is functional MRI (fMRI) which examines blood flow in different areas and regions of the brain as a measure of their dynamic function, mostly in response to a task or event, such as thinking about a traumatic event or viewing of a short video that produces stress and raises cortical levels in the brain. Practitioners use brain circuitry to look at how people can be proactive by teaching clients to learn fear and safety, for example. Researchers who want to use functional neuroanatomy through a multicultural lens may also want to add variables in the research that address socioeconomic status, cultural norms, and any array of methodology that addresses the diversity of the subjects. At the current stage of the technology and research, psychiatrists, psychologists, and neuroscientists only use these methods for researching the brain changes in mental illness, and not for making diagnoses. In order to make broader conclusions about the data, practitioners and researchers must combine data from people with a mental illness to determine how, on average, different areas of their brain may differ in volume or function from others. This is further confounded when adding varying degrees of what makes up a groups’ multicultural profile and the makeup and constellation of that group can be very complex. To summarize, brain imaging has been a very useful tool in understanding the aberrations in structure and function of a brain with PTSD, but it does not diagnose the condition.

Why Functional Neuroanatomy Is Critical to Professional Psychological Practice

Functional Neuroanatomy is not only critical to the professional practice of psychology, but it has become essential for professionals to utilize it to optimize their assessment, treatment, progress monitoring, and interventions for the client or patient. The 1990s was declared the “Decade of the Brain” in the United States and is now nearly three decades old (Goldstein, 1994). Although there have been great strides taken since then to explore and understand the brain better, there is still a lot of work to be done. Perhaps, the biggest push is in the area of brain scan technology. Although this chapter does not discuss the various technologies that exist, it will address why technology plays a role in why functional neuroanatomy is critical to professional psychological practice. See Chap. 5, (Noggle & Davis, 2021) for comprehensive coverage on neuroimaging.

Using technology to determine the functional neuroanatomy and clinical treatment planning for individuals go hand-in-hand. The data collected from brain scans is only as good as the technology that creates the images needed to examine the brain. However, it is important to note that technology, such as the MRI can only detect changes in blood flow without using a radioactive tracer. When a particular site in the brain is more active, blood flows to that area (Schooler et al., 2018). This blood brings oxygen to the brain cells that are working harder and, subsequently, thought to be working more efficiently. By tracking variations in blood flow, functional MRI can detect activity in the brain as it happens (Filippi, 2015).

So how is this critical to professional psychological practice? The bottom line is that if a client is seen for a severe condition of depression, anxiety, or even psychosis, brain technology can now utilize real-time data in the form of images to detect whether different parts of the brain are being utilized or maybe even neglected as the absence of active blood flow also predicts potential hypotheses for the practitioner.

Scientists have started to discover which areas of the brain are involved in different mental health conditions, such as depression, anxiety, and post-traumatic stress disorder (PTSD; Akiki et al., 2017); more clear data has been collected as to which areas of the brain are involved. For example, PTSD appears to be heavily involved with activity in the amygdala, which is, subsequently, involved in processing fear as well as lowered activity in parts of the frontal lobes (Zotev et al., 2018). This is essential to psychological practice because, with this data and analysis, we can now proceed to better confirmation of diagnoses and, subsequently, better and more accurate treatment plans.

Some technologies, like Positron Emission Tomography (PET) imaging and functional MRI (fMRI), measure the activity of the brain either at rest or while a person performs specific tasks (Filippi, 2015). Other technologies, such as the already discussed MRI, measure the brain’s structure and the corresponding size and shape of its various components. All of these technologies play a massive role in how strong a hypothesis can be made leading to better outcomes due to stronger decisions on diagnoses and treatment.

Given the scientific and technological advantages we have to guide treatment based on functional neuroanatomy, we must remember that there is variation in brain activity among people with the same diagnosis. Ultimately, brain scans can be useful and supplemental to better outcomes through confirmation of diagnosis and treatment based on empirical data. However, caution should be taken in considering this a perfect science at this time.

Functional Neuroanatomy and Its Relationship to the Future

Research has indicated very specific reviews and critiques of cross-linguistic brain imaging studies of conditions, such as developmental dyslexia (Lallier et al., 2017). Inquiries arise as to the predictions that should be tested in future brain imaging studies of typical and atypical reading in order to refine the current neurobiological understanding of developmental dyslexia. This is only one example of where functional neuroanatomy can go in the future in terms of identifying, understanding, and treating complex mental health and disabling conditions. Watson, Kirkcaldie, and Paxinos (2010) posed that the future of functional neuroanatomy needs to be considered with caution so that the future generation of scientists that we are training are more optimistic and open-minded by realizing the limitation of the scientific tools in the past, present, and future. They emphasized that they become more motivated to look forward for proper application of the future technologies in discovering the etiologies and treatments of the Central Nervous System (CNS) disorders. Ultimately, we need to increase the amount of research in the areas of functional neuroanatomy to obtain larger sample sizes of individuals with specific mental illnesses and their symptomatology. Watson et al. posed that we must not rely on the scientific tools alone, but, in addition, on stronger clinical judgment based on the best diagnostic and treatment measures we can obtain.

A number of functional neuroanatomy studies have been conducted on Tourette syndrome (Stern et al., 2000), anxiety (Etkin, 2009), and bipolar disorder (Strakowski et al., 2005; Cerullo et al., 2009). The future of functional neuroanatomical studies look to include other psychiatric disorders and a host of research on emotional regulation, working memory, and specific learning disabilities.

Conclusions

As mentioned, the study and practice of functional neuroanatomy is not perfect and we have many more opportunities to improve the accessibility of what researchers and practitioners are looking to find. Most notably, functional neuroanatomy could use a tremendous boost in funding for researchers to build lasting outcomes that are specific to the field. Also, the number of individuals who have a diagnosed mental illness and who are willing to be a part of research must be willing to participate in larger participant pools for research fidelity and validity.

With all the improvements and changes in technology, it remains to be seen, but the future of functional neuroanatomy will likely follow suit with much exciting research and trials conducted with larger numbers of participants. As long as there are practitioners and researchers interested and looking to advance the research in cooperation and collaboration of better outcomes for more diverse and multicultural populations, there will be a better and more substantial set of research agendas willing to advance the field of functional neuroanatomy.

Discussion Questions

• 1. Why is it important to understand the history of neuroanatomy? When might knowledge of historical events and developments in the field come into play?

• 2. What are the practical and clinical uses of functional neuroanatomy in addressing and prioritizing an individual’s problem set, needs, and subsequent interventions?

• 3. Thinking of Luria’s theory of extra-cortical organization of higher mental functions, how might one’s culture impact the development of cognitive functioning? Why is it important to consider cultural, social, and historical accounts when assessing children and adults?

• 4. How have Halstead/Reitan and Luria historically influenced the area of understanding functional neuroanatomy?

• 5. What are the implications and future directions of functional neuroanatomy?

• 6. How does using a multicultural approach to functional neuroanatomy help guide treatment from assessment to intervention?

EPPP Sample Questions

• 1. One of the major parts of the brain that stores memories is the:

  • (a) Anterior cingulate

  • (b) Hippocampus

  • (c) Parietal lobe

  • (d) Cerebellum

• 2. Two main functions of the prefrontal cortex are:

  • (a) Language and movement

  • (b) Vision and memory

  • (c) Planning and decision making

  • (d) Speech and balance

• 3. The Boston Process Approach was developed by:

  • (a) Luria

  • (b) Kaplan

  • (c) Halstead

  • (d) Reitan

• 4. The principle of extracortical organization of higher mental functions paved the way for:

  • (a) Examining “shell shock” after World War II

  • (b) Consideration of cross-cultural differences of brain structure and function

  • (c) The creation of the Halstead-Reitan Neuropsychological Test Battery (HRNTB)

  • (d) The concept of “testing the limits”

• 5. Early childhood toxic stress may cause an adolescent to have a “fight, flight, or freeze” response to an adverse stimuli. When looking at an fMRI of this adolescent in comparison to a same aged youth who did not experience early childhood toxic stress, you may notice:

  • (a) More activity in the occipital lobe of the child who experienced toxic stress

  • (b) Less activity around the amygdala of the child who experienced toxic stress

  • (c) Less activity in the frontal lobe of the child who experienced toxic stress

  • (d) Less blood flow near the hippocampus of the child who experienced toxic stressAnswers: B, C, B, B, C

Proactive Readings

Transcending the Past

• Etkin, A. (2009). Functional neuroanatomy of anxiety: A neural circuit perspective. In Behavioral neurobiology of anxiety and its treatment (pp. 251–277). Springer.

• Goldstein, M. (1994). Decade of the brain. An agenda for the nineties. Western Journal of Medicine, 161(3), 239.

Excelling in the Present

• Hebben, N., Milberg, W., & Kaufman, A. (2010). Essentials of neuropsychological assessment (2nd Ed.) Wiley.

• Hazin, I., & Tarcísio da Rocha Falcão, J. (2014). Luria’s neuropsychology in the 21st century: Contributions, advancements, and challenges. Psychology & Neuroscience, 7(4), 433–434. https://doi.org/10.3922/j.psns.2014.4.01

• Watson, C., Kirkcaldie, M., & Paxinos, G. (2010). The brain: An introduction to functional neuroanatomy. Academic Press.

Transforming the Future

• De Bellis, M. D., & Zisk, A. (2014). The biological effects of childhood trauma. Child and Adolescent Psychiatric Clinics, 23(2), 185–222.

• Souza-Queiroz, J., Boisgontier, J., Etain, B., Poupon, C., Duclap, D., D’Albis, M.,... Houenou, J. (2016). Childhood trauma and the limbic network: A multimodal MRI study in patients with bipolar disorder and controls. Journal of Affective Disorders, 200, 159–164. doi:https://doi.org/10.1016/j.jad.2016.04.038