Remote Activation of the Ventral Midbrain by Transcranial Direct Current Stimulation of Prefrontal Cortex: Amelioration of Impaired Learning in Schizophrenia

Lay Summary

Non-invasive brain stimulation may help schizophrenia patients learn from positive outcomes

Researchers will undertake Phase I of a planned two-phase study to ultimately determine whether a non-invasive brain stimulation technique helps schizophrenia patients learn from positive rewards and reduce the “negative” symptoms that characterize this disease.

Schizophrenia is characterized by “positive” states that are manifested by patients’ hallucinations and delusions, and by “negative” states in which patients lack emotion, motivation, and an ability to experience pleasure. These negative symptoms are thought to arise because patients have difficulty learning to repeat actions that are most likely to yield rewarding outcomes. What produces this learning disability?

Scientists suspect that it occurs because neurons deep in the brain’s center (midbrain) don’t produce enough of the excitatory neurotransmitter “dopamine” to successfully send communication signals. If that is the case, midbrain neurons cannot send sufficient signals that reinforce learning from rewarding situations to the part of the brain (prefrontal cortex) that regulates complex cognitive, emotional and behavioral functions. Since the prefrontal cortex lies near the scull at the front of the brain, though, the investigators suspected that it would be possible to non-invasively strengthen signaling between the prefrontal cortex and midbrain using transcranial direct current stimulation (tDCT).

They hypothesize that: 1) tDCS will strengthen reward-based signals from the midbrain to the prefrontal cortex and correct positive reinforcement learning disabilities in schizophrenia patients with negative symptoms; and 2) patients with more enhanced connectivity following stimulation will exhibit greater gains in learning from positive reinforcement.

This hypothesis is based on results of preliminary studies using tDCS in healthy volunteers. After placing electrodes on the scalp over the prefrontal cortex, investigators were able to use tDCS to remotely activate participants’ midbrain. Participants showed improved reward-based behavior on experimental learning-based decision tests.

Investigators now will test the feasibility of using tDCS in a small number of schizophrenia patients with negative symptoms to see if this non-invasive brain stimulation technique similarly improves brain signaling and associated improvements in learning from positive reinforcement. Patients will be assessed on reward-learning tests before and after tDCS stimulation. Additionally, investigators will obtain preliminary information on how tDCS may influence functional connectivity between the prefrontal cortex and midbrain in these patients by using fMRI imaging while patients perform the pre-post tDCS decision tests.

Phase I is designed to demonstrate initial evidence of feasibility of using the tDCS technique in patients, and to determine the extent of signaling changes and associated reward-learning improvement. These findings will help to determine how many patients and healthy volunteers are needed for a Phase II study to provide preliminary evidence of effectiveness.

Significance: If non-invasive tDCS brain stimulation shows efficacy in decreasing negative symptoms of schizophrenia by improving reward-based learning, it would be a major therapeutic advance in helping patients to function in everyday life.

Abstract

Remote activation of the ventral midbrain by transcranial direct current stimulation of prefrontal cortex: amelioration of impaired learning in schizophrenia, Phase I

Schizophrenic patients in a ‘positive’ state exhibit the symptoms of hallucinations and delusions while those in a ‘negative’ state exhibit a flat effect and general depression. Previous studies have shown that patients experiencing the negative symptoms of schizophrenia exhibit specific deficits in learning reward contingencies from positive reinforcement. It is postulated that this deficiency is due to an undervaluation of appetitive rewards caused by dysregulated dopaminergic signaling emerging from the midbrain. Difficulty in learning to repeat actions most likely to yield rewarding outcomes has been suggested as an account that could explain the negative symptoms manifested in the daily life of schizophrenic patients. While these negative symptoms are very common, they are notoriously irresponsive to pharmacological intervention. We recently developed an innovative brain stimulation technique that utilizes noninvasive transcranial direct current stimulation (tDCS) of the prefrontal cortex to remotely stimulate the interconnected ventral midbrain and induce changes in behavioral preference. The purpose of this proposal is to examine if our tDCS paradigm can be used to influence the ventral midbrain of schizophrenia patients in a negative state, and thus ameliorate their deficiencies in reinforcement learning from positive feedback. To this end our team will take a highly interdisciplinary approach, integrating ideas from computational reinforcement learning, noninvasive brain stimulation, and functional magnetic resonance imaging to reach across the disciplines of biomedical engineering and psychiatry. Our proposal holds great promise for understanding the neural mechanisms governing reinforcement learning in schizophrenia, while also furthering our development of an intervention that could be used to improve general deficiencies in learning.