Dr. Alik Widge: Finding and Treating Brain Circuits to Restore Mental Flexibility

Rising Star Awardee Dr. Alik Widge proposes to identify precisely the brain circuits that govern the inflexibility of thinking common among patients with brain illnesses, and to test whether neurostimulation of these circuits could improve mental flexibility.

As brain health science advances, it becomes clearer that the boundaries between diagnoses are quite fluid. Some symptoms, such as mental rigidity, which can manifest for patients as difficulty adapting to new ways of thinking, are shared across a range of illnesses. For example, without effective treatment, people with major depressive disorder (MDD) may find it challenging to try to interpret experiences positively, people with obsessive-compulsive disorder (OCD) or post-traumatic stress might experience intrusive thought patterns repeatedly, and people with schizophrenia might not be able to see past their delusions. As growing evidence supports the theory that such cross-diagnostic symptom patterns share common mechanisms based in specific neural circuits, scientists are beginning to investigate how to identify and target these circuits, to develop treatments to assist the recovery of folks across the affliction spectrum.

Alik S. Widge, M.D., Ph.D., Assistant Professor of Psychiatry at Massachusetts General Hospital & Harvard Medical School, has won the 2017 One Mind / Janssen Rising Star Translational Research Award in Honor of the late Jeffrey S. Nye, M.D, Ph.D. for his brilliant proposal to

  1. pinpoint which brain circuit(s), when impaired, most strongly generate mental rigidity, and
  2. test whether stimulating these circuit(s) might restore mental flexibility.

Deep brain stimulation (DBS) is an experimental treatment for severe MDD and OCD, among other conditions. DBS involves surgically implanting a “pacemaker”-like electrode in a precise location in a patient’s brain, to deliver mild, rhythmic pulses of electricity to targeted neural circuits—in many cases, this procedure produces rapid reductions in symptoms, but if the precision of the targeting can improve, DBS may remedy these conditions more consistently.

Now, Dr. Widge’s team aims to refine the precision of such neurostimulation techniques for safer, more effective treatments. Dr. Widge’s lab’s previous discoveries suggest that DBS might improve cognitive flexibility by stimulating the function of specific neural circuits leading to the prefrontal cortex, the brain region involved in problem-solving and decision-making. When patients with DBS implants for MDD or OCD performed a challenging task with rapidly-changing demands, they performed better when receiving active DBS neurostimulation. Also, with DBS on, electrical signals in the test patients’ prefrontal cortex changed in ways that are associated with healthier brain function. Although this form of DBS stimulates a variety of neural circuits at once, Dr. Widge’s team has hypothesized that the improvement they observed arose from the stimulation of just one or a few of these circuits.

To test this hypothesis, Dr. Widge’s team will combine DBS with optogenetics, a technique which will enable them to use light to selectively inhibit these circuits in turn in rat models. If inhibiting any of these circuits alone negates the benefits of DBS in their rat experiments, Widge’s team will know that those circuits are involved in mental flexibility. By then selectively stimulating only those circuits, Widge can verify the efficacy of such stimulation to enhance flexibility in a rodent model.

If all goes as hypothesized, Widge may soon be able to apply this evidence to test stimulating the analogous circuit(s) in the human brain to optimally strengthen patients’ mental flexibility. It seems likely that even non-invasive methods such as transcranial magnetic stimulation or transcranial direct current stimulation might in the near term be precise enough to also improve flexibility, without the need for surgery.

By potentially empowering patients with a variety of diagnoses to think with greater agility, creativity, and adaptability, Dr. Widge and his team are working toward a profound contribution to the wellbeing of millions. We at One Mind Institute are proud to accelerate the research of this protean scientist, and grateful for the support of this award’s sponsor, Janssen Research & Development, LLC.

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