Reality-Based Brain and Behavior Models


Brain disorders? Precisely

Mental disorders represent a public health challenge of staggering proportions. In the most recent Global Burden of Disease study, mental and substance abuse disorders constitute the leading source of years lost to disability from all medical causes… Could a “precision medicine” approach find traction here?

Precision medicine—a more targeted approach to disease—is already becoming a reality in cancer, where molecular diagnosis is leading to better defined, individualized treatments with improved outcomes. Precision medicine is also the basis for planning large-cohort studies, using genomics and phenotyping (physiological and behavioral characteristics) to improve diagnostics and therapeutics across medicine. The idea is to integrate clinical data with other patient information to uncover disease subtypes and improve the accuracy with which patients are categorized and treated.

Diagnosis in psychiatry, in contrast to most of medicine, remains restricted to subjective symptoms and observable signs…But recently psychiatry has undergone a tectonic shift as the intellectual foundation of the discipline begins to incorporate the concepts of modern biology, especially contemporary cognitive, affective, and social neuroscience. As these rapidly evolving sciences yield new insights into the neural basis of normal and abnormal behavior, syndromes once considered exclusively as “mental” are being reconsidered as “brain” disorders—or, to be more precise, as syndromes of disrupted neural, cognitive, and behavioral systems.

But before research on the convergence of biology and behavior can deliver on the promise of precision medicine for mental disorders, the field must address the imprecise concepts that constrain both research and practice. Labels … invite continual recapitulation of the fruitless “mind-body” and “nature-nurture” debates that have impeded a deep understanding of psychopathology.

…the brain is organized around tightly regulated circuits that subserve perception, motivation, cognition, emotion, and social behavior. Thus, it is imperative to include measures of both brain and behavior to understand the various aspects of dysfunction associated with disorders. Shifting from the language of “mental disorders” to “brain disorders” or “neural circuit disorders” may seem premature, but recognizing the need to incorporate more than subjective reports or observable behavior in our diagnosis of these illnesses is long overdue.

This Research Domain Criteria (RDoC) initiative…was actually to rethink research on psychopathology by building a framework beyond symptoms. Symptoms would be an important starting point, but the framework would include a focus on systems or dimensions that had both cognitive and biological validity. Genomic variants and brain circuit–level differences are evident in studies of people with psychopathology, but the findings cross current diagnostic boundaries rather than validating them… RDoC asks researchers to shift from designing research projects narrowly built around current diagnostic categories to dimensions or systems, … which are supported by a deep cognitive and neural science and can be the basis for objective measures of psychopathology.

Deconstructed, Parsed, and Diagnosed.

An early promising result from this project has emerged from studies that deconstruct current diagnostic groups to identify subgroups that have biological validity, and predict treatment response. For instance:

  • imaging and neurophysiology have demonstrated three subtypes of attention deficit hyperactivity disorder with quite different responses to stimulant medication
  • Preliminary reports from studies using cognitive testing, imaging, and/or genomic panels are finding biologically meaningful subgroups of psychotic or mood disorders. Notably, these biologically defined subgroups do not map neatly onto clusters of symptoms.

RDoC domains, but not symptom-based diagnosis, predicted length of hospital stay or hospital readmission

Just as the precision medicine approach for cancer can alter our approach to diagnosing mental disorders, psychiatry can leverage important therapeutic insights from cancer and other studies of chronic diseases. For complex, chronic disorders, from diabetes to hypertension, the search for a magic bullet is giving way to combinatorial or convergent solutions.


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