Neuroscience Research for Psychiatry: The Brain and Behavior Link

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The latter part of the 20th century saw the psychiatric research community striving for their work to be accepted as quantitative and scientific. Since the birth of psychodynamic psychotherapy at the turn of the century, the field has struggled to move away from untested theories about the causes of mental illness toward an empirically validated scientific discipline. This struggle was epitomized elegantly in Paul Meehl’s classic “Why I Do Not Attend Case Conferences,” which spells out reasons why he felt psychiatric and psychodynamic case conferences at the time were not adequately rigorous (eg, “reward everything-gold and garbage alike”).¹

Candace Pert, a psychoneuroimmunologist who helped discover the opiate receptor-the cellular binding site for endorphins in the brain-and whose research into brain biochemistry contributed to a new understanding of relations between the mind and body, said that she was pleased that psychology was “finally becoming scientific.”² An often-cited quote from her book, Molecules of Emotion, illustrates her perspective: “Most psychologists treat the mind as disembodied, a phenomenon with little or no connection to the physical body . . . But the body and mind are not separate, and we cannot treat one without the other.”³

A move to the hard sciences

The advent of modern clinical neuroscience techniques over the past 3 decades-including non-invasive brain imaging and brain stimulation-along with a concerted effort by the psychiatric academic community, has firmly placed academic psychiatry within the so-called “hard sciences.” Indeed, coursework in research methods, empirically supported treatments, and neuroscience are standard in most, if not all, psychiatric research programs in this country. The result has been a new generation of psychiatric researchers who routinely investigate mental illnesses with modern clinical neuroscience tools.

Perhaps inevitably, one result of this shift is that a segment of the field has expressed that the pendulum has swung too far. To be clear, the transition of the field toward more quantitative and rigorous methods is met with near-universal applause. However, the ever-increasing reliance on measures of physiology has left some researchers pondering whether the field has drifted from its roots. This shift in priorities toward neuroscience-based research is no more evident than in the funding priorities of the National Institute of Mental Health (NIMH), which has a current budget of over $1.4 billion.

Although it is difficult to quantify precisely how much of NIMH’s funding supports brain-based research, understanding the biological basis of mental disorders is a high priority for NIMH. The research includes describing the molecules, cells, and neural circuits associated with complex behaviors and disorders as well as identifying the genomic factors associated with mental illnesses. Other federal funding agencies that support psychiatric research, including the National Institute on Drug Abuse and the National Institute on Child Health and Development, also emphasize research into the biological basis of mental illness.

Concerns

The backlash against this prioritization includes various arguments: that a focus on biological processes does not allow for free will and human agency, that a “neurocentric” view of the mind obscures the factors that shape our behavior and identities and risks undermining selfhood and personal responsibility, and that explaining the mind will always be a personal vision, not a scientific fact.^4-6

In “There’s Such a Thing as Too Much Neuroscience,” New York Times Op-Ed contributor Dr. John C. Markowitz, a professor of clinical psychiatry at Columbia University and a research psychiatrist at the New York State Psychiatric Institute, argued that diverting much of the NIMH budget away from clinical studies and into neuroscience research does little to help patients who are suffering from psychiatric illnesses.⁷ He highlights the shift in emphasis from DSM toward “research domain criteria” (RDoC). Rather than focusing on DSM diagnoses, RDoC focuses on unitary constructs related to mental disorders. He recognizes that RDoC emphasizes understanding these clinically relevant constructs at various levels of analysis, including genes, molecules, cells, brain circuits, physiology, and behavior. However, he laments that the fruits of such multi-level approaches will likely not be borne for a decade or more, and hopes that the newly appointed director of the NIMH, Dr. Joshua Gordon, will prioritize clinical studies to “re-establish that balance” between neuroscience and clinical research.

Any psychiatric researcher undoubtedly feels solidarity with Dr. Markowitz’s yearning for better treatments that will help patients today rather than in decades and for clinically oriented research that will hasten the development of new therapies. Indeed, it was clinically oriented research that yielded the state-of-the-art first-line psychotherapies for many psychiatric conditions, including the current gold-standard cognitive-behavioral therapies for depression and anxiety.

Dr. Thomas Insel, former director of the NIMH, stressed in his January 2013 TED Talk that other fields of medicine-including oncology, infectious diseases, and cardiology-have made remarkable progress developing treatments for previously incurable diseases using biological approaches. Sadly, this stands in sharp contrast to psychiatry, where the prevalence of most disorders has remained remarkably flat since reliable data were first available in the 1950s. In fact, the prevalence estimates of some disorders, such as autism, have increased, and the World Health Organization recently reported that psychiatric disorders currently account for 30% of disability from all medical causes worldwide. Clearly, the field must do more to decrease the suffering of patients with psychiatric illnesses.

A shift in research priorities

The RDoC represents a paradigm shift in how research into psychiatric conditions is conceptualized. A hurdle presented by DSM is that its use of polythetic criterion sets is a barrier against the development of novel treatments. For example, according to DSM, a diagnosis of major depression is contingent on a patient having at least 5 of 9 depressive symptoms. This results in a diagnostic system in which 2 patients may have vastly different symptom constellations yet be classified with the same disorder. This introduces a high degree of heterogeneity into each disorder, and it is thus not surprising that a given antidepressant treatment, for example, is effective for only about 25% to 50% of patients with major depression.⁸

A consequence of relying on DSM for clinical research is that many psychiatric treatments are minimally effective for many patients, and most patients must endure a painful process of trial-and-error over months or even years to find an effective treatment. The use of RDoC hopes to overcome this barrier by focusing on unitary constructs to minimize the heterogeneity in how patient symptoms are classified.

There are 3 prevalent misconceptions about RDoC. First, the emphasis of RDoC on understanding neurobiological systems at multiple levels has led many to erroneously believe that because RDoC is “pro-neuroscience” it must be “anti-behavior.” Indeed, Dr. Markowitz suggests that a research proposal that focuses on a symptom is rarely funded by the NIMH compared with research on a “neurosignature,” a brain-based biomarker of disease etiology. It is critical to realize that RDoC stresses understanding a clinical phenomenon, such as anxiety, at multiple levels, from cells to brain circuits to behavior. RDoC does not under-value behavior; rather it stresses that behavior must be understood within the context of other relevant units of analysis. Behavior has not been jettisoned. In fact, it has been elevated to an equal footing with understanding complex molecular processes and brain systems.

Second, there is the mistaken belief that NIMH no longer values clinical trials. This is not the case: the NIMH has invested heavily in new clinical trials to speed the development of novel psychiatric treatments, including behavioral therapies, medications, and device-based techniques such as magnetic brain stimulation. What has changed, however, is that NIMH-funded clinical trials must now include measures that explain how a treatment works by assessing so-called “mechanistic targets.” These targets may be neuroscience-based (brain scans, for example), but may also be behavioral (appraisals of images of sad faces, for example). In other words, this new approach to clinical trials is not “anti-behavior” but is instead “pro-mechanism,” and such mechanisms may certainly incorporate behavioral measurements. This emphasis will help the field learn how and why certain treatments work to inform the development of new interventions.

Finally, there is the belief that the NIMH does not value psychosocial intervention research but instead favors device- or medication-based interventions. In fact, in December 2016, the NIMH released a specific request for applications to develop psychosocial therapeutics and preventive interventions for mental disorders, which represents a significant investment of research dollars specifically for psychosocial treatment development.⁹

Conclusion

RDoC reflects what psychiatric research has taught us over the past 2 decades: psychiatric disorders are, in fact, brain disorders. These illnesses, without a doubt, have their roots in how the brain develops and functions. That does not imply that behavior is not relevant or that talk therapies are ineffective. Indeed, some of the most effective psychiatric interventions are cognitive and behavioral treatments that influence thinking and behavior patterns.

In the current era of brain imaging technologies that have begun to make substantial progress delineating brain systems implicated in psychiatric illnesses, to deny the brain bases of these illnesses is no longer tenable. Moreover, brain and behavior are inexorably linked and dynamically influence each other. This interaction between the brain and behavior implies that comprehensive progress cannot be made to relieve the suffering of patients without systematically addressing the brain basis of such conditions. To develop treatments for heart disease, we must study the heart, and likewise to develop treatments for brain disorders, we must study the brain (including its downstream output, behavior).

Although modern neuroscience research is still relatively young, breakthroughs have emerged that will likely yield new therapeutic approaches for the treatment of psychiatric disorders.^10-12 We must invest in neuroscience-based research to develop innovative psychosocial and pharmacologic treatments that provide symptom relief by targeting relevant brain systems. Although it will be painful to wait for these treatments to arrive, we must continue to prioritize such efforts if we hope to have the success stories in psychiatry that have been achieved in other fields of medicine.

Disclosures:

Dr. Dichter is Associate Professor, Department of Psychiatry and Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC.

References:

1. Meehl PE. Why I do not attend case conferences. In: Meehl PE, ed. Psychodiagnosis: Selected Papers. Minneapolis, MN: University of Minnesota Press; 1973:225-302.

2. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science. 1973;179:1011-1014.

3. Pert CB. Molecules of Emotion: The Science Behind Mind-Body Medicine. New York: Simon & Schuster; 1999.

4. Morse S. Determinism and the death of folk psychology: two challenges to responsibility from neuroscience. Minn J Law Sci Technol. 2008;9:1-36.

5. Satel S, Lilienfeld SO. Brainwashed: The Seductive Appeal of Mindless Neuroscience. New York: Basic Books; 2013.

6. Burton RA. A Skeptic’s Guide to the Mind: What Neuroscience Can and Cannot Tell Us About Ourselves. New York: St. Martin’s Griffin; 2014.

7. Markowitz JC. There’s such a thing as too much neuroscience. New York Times. October 14, 2016. https://www.nytimes.com/2016/10/15/opinion/theres-such-a-thing-as-too-much-neuroscience.html?_r=0. Accessed June 12, 2017.

8. Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci. 2006;7:137-151.

9. Department of Health and Human Services. https://grants.nih.gov/grants/guide/rfa-files/RFA-MH-17-604.html. Accessed June 12, 2017.

10. Felipe RM, Ferrao YA. Transcranial magnetic stimulation for treatment of major depression during pregnancy: a review. Trends Psychiatry Psychother. 2016;38:190-197.

11. Philpot BD, Thompson CE, Franco L, Williams CA. Angelman syndrome: advancing the research frontier of neurodevelopmental disorders. J Neurodev Disord. 2011;3:50-56.

12. Walsh E, Carl H, Eisenlohr-Moul T, et al. Attenuation of frontostriatal connectivity during reward processing predicts response to psychotherapy in major depressive disorder. Neuropsychopharmacol. 2017;42:831-843.