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Post by Former NIMH Director Thomas Insel: Mental Illness Defined as Disruption in Neural Circuits

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Light beams connecting neurons.

Pulses of blue and yellow light precisely turn neurons on-and-off using genetically-targeted probes that take advantage of light-sensitive genes borrowed from primitive life-forms. Artist’s rendering.

Source: Karl Deisseroth, M.D., Ph.D., Stanford University

It has become an NIMH mantra to describe mental disorders as brain disorders. What does this mean? Is it accurate to group schizophrenia, depression, and ADHD together with Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease? Is a neurologic approach to mental disorders helpful or does this focus on the brain lead to less attention to the mind?

First, mental disorders appear to be disorders of brain circuits, in contrast to classical neurological disorders in which focal lesions are apparent. By analogy, heart disease can involve arrhythmias or infarction (death) of heart muscle. Both can be fatal, but the arrhythmia may not have a demonstrable lesion. In past decades, there was little hope of finding abnormal brain circuitry beyond the coarse approach of an EEG, which revealed little detail about regional cortical function. With the advent of imaging techniques like PET, fMRI, MEG, and high resolution EEG, we can map the broad range of cortical function with high spatial and temporal resolution. For the first time, we can study the mind via the brain. Mapping patterns of cortical activity reveals mechanisms of mental function that are just not apparent by observing behavior.

Has brain imaging been useful for understanding mental disorders? While we are still in the early days of using these powerful technologies, a recent survey of the literature reveals some excellent examples of how studying the brain forces us to “re-think” mental disorders. For instance, studies of brain development demonstrate delays in cortical maturation in children with attention deficit hyperactivity disorder. How curious that this disorder, which is defined by cognitive (attention) and behavioral (hyperactivity) symptoms, increasingly appears to be a disorder of cortical development. Viewing ADHD as a brain disorder raises new, important questions: What causes delayed maturation? What treatments might accelerate cortical development?

A brain disorder approach also may transform the way we diagnose mental disorders. The NIMH Research Domain Criteria (R-DoC) project is involved in re-thinking diagnosis based on understanding the underlying brain changes. As an example, what we now call “major depressive disorder” probably represents many unique syndromes, responding to different interventions. Neuroimaging is beginning to yield biomarkers, that is, patterns that predict response to treatment or possibly reflect changes in physiology prior to changes in behavior or mood. And studies with deep brain stimulation addressing depression as a “brain arrhythmia” are demonstrating how changing the activity of specific circuits leads to remission of otherwise treatment refractory depressive episodes.

An important implication of this new approach is that abnormal behavior and cognition (e.g. mood, attention) may be late and convergent outcomes of altered brain development. This is a familiar lesson from neurodegenerative disorders: the symptoms of Alzheimer’s, Parkinson’s, and Huntington’s diseases emerge years after changes in the brain. Could the same be true of these circuit disorders that appear early in life? If so, could imaging allow earlier detection and preemption of the behavioral and cognitive changes – from the social isolation of autism to the psychosis of schizophrenia? This preemptive approach, which has transformed outcomes in heart disease and cancer, could also transform psychiatry, by focusing on prevention for those at risk rather than the partial amelioration of symptoms late in the process.

But we need to recognize the range of unknowns that remain. In truth, we still do not know how to define a circuit. Where does a circuit begin or end? How do the patterns of “activity” on imaging scans actually translate to what is happening in the brain? What is the direction of information flow? In fact, the metaphor of a circuit in the sense of flow of electricity may be woefully inadequate for describing how mental activity emerges from neuronal activity in the brain. Hence the need for continuing research into fundamental neuroscience. The advent of new tools, such as optogenetics, which uses light for precise manipulation of cells in awake, behaving animals will take us a long way towards understanding the characteristics of a neuronal circuit.

While the neuroscience discoveries are coming fast and furious, one thing we can say already is that earlier notions of mental disorders as chemical imbalances or as social constructs are beginning to look antiquated. Much of what we are learning about the neural basis of mental illness is not yet ready for the clinic, but there can be little doubt that clinical neuroscience will soon be helping people with mental disorders to recover.