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Biomarker-driven Deep Brain Stimulation May Be Possible in Psychiatry

Key findings

  • Deep brain stimulation (DBS) improved performance on a cognitive control task and increased electroencephalography theta oscillations in the prefrontal cortex in 14 patients with major depressive disorder or obsessive-compulsive disorder
  • Theta change in the prefrontal cortex correlated significantly with clinical response to DBS, suggesting the possibility of a physiologically informed approach to psychiatric DBS
  • In the future, DBS parameters might be titrated directly to the change in the theta biomarker, rather than relying on patient reports

Early studies of deep brain stimulation (DBS) in major depressive disorder (MDD) and obsessive-compulsive disorder (OCD) were extremely encouraging, but the results of controlled clinical trials have been ambiguous.

In a previous study, published in Frontiers in NeuroscienceDarin D. Dougherty, MD, director of the Division of Neurotherapeutics at Massachusetts General Hospital, suggested that these trials might reflect a limited understanding of the mechanism of action of DBS, not lack of efficacy. Some patients who did not respond may not have received an adequate dose, or they may not have had a circuit deficit that was appropriate for DBS.

Little is known about target circuits for DBS, but one brain region, the ventral internal capsule/ventral striatum (VCVS), has passed blinded trials of DBS for MDD and OCD. A commonality of those two disorders is impaired cognitive control—the inability to flexibly adjust one's mental responses in the face of changing environmental demands.

Brain structures involved in cognitive control include the medial prefrontal cortex (mPFC), dorsal anterior cingulate and lateral PFC, and the circuits that connect those structures to striatum pass through the VCVS DBS target.

Dr. Dougherty and colleagues have determined that the effect of VCVS DBS is driven in part by enhancement of PFC-driven cognitive control. In Nature Communications, they conceptualize an improved approach to DBS for psychiatric disorders.

VCVS DBS and Cognitive Control

The researchers studied 12 patients with MDD and two with OCD who had VCVS DBS implants. The patients were asked to perform a variant of the Multi-Source Interference Task (MSIT) with their usual stimulation either on or off as they underwent electroencephalography (EEG). The MSIT included emotional distractors to increase cognitive load.

Cognitive conflict (interference), emotional distraction and DBS "on" status all influenced response time on the MSIT. Cognitive conflict slowed response time, whereas DBS improved it.

Cognitive Control and PFC Theta Oscillations

During cognitive conflict tasks such as the MSIT, increased low-frequency EEG oscillations have been found to be particularly common in the theta (4- to 8-Hz) band and within the mPFC. The research team reasoned that if DBS does enhance cognitive control, the enhancement should be reflected in more powerful PFC theta oscillations.

They found that the cognitive effort required for the MSIT increased the power of theta oscillations throughout the PFC, particularly the ventrolateral PFC. DBS "on" status potentiated the increase. Moreover, the DBS effect was specific to the theta band with few changes in other frequencies.

Biomarker of Response to DBS

Further research showed that conflict-evoked PFC theta was a biomarker of response to DBS. By themselves, on/off changes in response time did not correlate with subjects' response to DBS. However, theta change in the ventrolateral PFC did correlate significantly in both MDD and OCD.

A Better Approach to Psychiatric DBS?

The correlation between theta modulation and clinical outcomes suggests the possibility of using a physiologically informed approach to psychiatric DBS. Currently, clinicians adjust the amount of stimulation based on the patient's report of immediate mood changes. But unlike the symptoms of, say, Parkinson's disease, psychiatric symptoms do not change reliably within hours. The procedure for adjusting DBS stimulation usually becomes frustrating for both patients and clinicians.

In the future, stimulation parameters such as intensity and location could be titrated to the change in the theta biomarker, rather than relying on patient report. For instance, patients might continuously perform tasks requiring cognitive control with continuous monitoring of trial-to-trial induced oscillations. Stimulation parameters could then be adjusted manually by a programming clinician or under computer control.

Considering the prevalence of cognitive control deficits in other psychiatric illnesses, these results might have broad clinical applications. Next-generation hardware is already capable of self-titrating DBS to achieve a particular electrophysiologic response, and the Mass General authors have described early examples of its use in a study published in Experimental Neurology. They have also demonstrated a strategy for altering brain oscillations in order to treat neuropsychiatric disease in PLOS ONE and showed in the Journal of Neural Engineering that when patients have implanted electrodes for seizure monitoring, they can track these same cognitive conflict states in real time by monitoring patients' electrical brain activity.

Learn more about the Division of Neurotherapeutics

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Jordan W. Smoller, MD, ScD, is the director of the Psychiatric and Neurodevelopmental Genetics Unit and is the associate chief for research in the Department of Psychiatry at Mass General. In this video, he discusses his research efforts to leverage large-scale data sets that are now available from a variety of sources, including neuroscience, genomics, electronic health records, to improve the ability to diagnose, detect and treat psychiatric disorders and serious complications of those disorders.