Confirmatory Efficacy Trial to Confirm the Effects of Gamma EEG-neurofeedback on Working Memory in Schizophrenia

About This Grant

Schizophrenia is a heterogeneous, debilitating mental disorder with an extraordinarily large personal and socioeconomic impact. Although the disorder may first be recognized due to positive symptoms such as hallucinations and delusions, it is the negative symptoms and cognitive deficits, especially working memory, that account for functional disability. Antipsychotic medications, at best, have a small effect on cognition and functioning. Thus, in a disorder where cognitive deficits are a core feature driving disability, the need for non- pharmacologic cognition enhancing treatments to improve real world outcomes is more relevant than ever. Recent insights into the central role of neural oscillations in the frontal cortex, a key component in a neural circuit that supports working memory, provides a pathway for novel treatment development. Frontal activation during memory tasks is characterized by increased synchronous high frequency oscillations (30-45 Hz gamma waves) on EEG at frontal sites. This phenomenon of frontal gamma synchrony is directly correlated with performance on working memory tasks in healthy adults and is impaired in individuals with schizophrenia. Thus, we developed a neuromodulation intervention using gamma EEG neurofeedback (EEG-NFB) to increase synchronous activation of frontal gamma waves in an effort to improve neural processing in the frontal cortex and working memory. NFB provides real-time brain information feedback in the form of a visual or auditory metaphor so that the individual can modify their own brain activity. We conducted two preliminary clinical trials, an open trial, proof-of-concept study (R61), followed by a double-blind, placebo/sham-controlled, preliminary randomized clinical trial (RCT) to estimate the effect size of neurofeedback treatment on gamma response, working memory, and functioning in individuals with schizophrenia (R33). In the open trial R61 (n=31), individuals with schizophrenia showed significant improvements in both frontal gamma oscillations and working memory, as well as improvements in other cognitive domains, and improvement in working memory was correlated with greater training-related gamma responses. In the RCT (N=64), these significant improvements in working memory and gamma responses were replicated relative to a sham control, and improvements in working memory were again correlated with training-related gamma responses. Importantly, we also found significant improvement in functioning. An additional key finding was that EEG-NFB effects were heterogenous, just like the clinical disorder, in that, some participants responded very well, whereas others did not, thereby highlighting the need to identify which patients are more likely to benefit. Thus, we propose to conduct a larger confirmatory double-blind, placebo-controlled RCT of gamma EEG-NFB in individuals living with schizophrenia (N=104) with working memory and functioning as co-primary endpoints to confirm treatment efficacy and determine mediators and moderators of treatment response.