Targeting Frontal Gamma Activity with Neurofeedback to Improve Working Memory in Schizophrenia

Optimal working memory (WM), the mental ability to internally maintain and manipulate task-relevant information, requires coordinated activity of dorsal-lateral prefrontal cortical (DLPFC) neurons. More specifically, during delay periods of tasks with WM features, DLPFC microcircuits generate persistent, stimulus-specific higher-frequency (e.g., gamma) activity. This activity largely depends on recurrent connections between parvalbumin positive inhibitory interneurons and pyramidal neurons in more superficial DLPFC layers. Due to the size and organization of pyramidal neurons (especially apical dendrites), local field potentials generated by DLPFC microcircuits are strong enough to pass outside the skull and can be detected using electroencephalography (EEG). Since patients with schizophrenia (SCZ) exhibit both DLPFC and WM abnormalities, EEG markers of DLPFC microcircuit activity during WM may serve as effective biomarkers or treatment targets. In this review, we summarize converging evidence from primate and human studies for a critical role of DLPFC microcircuit activity during WM and in the pathophysiology of SCZ. We also present a meta-analysis of studies available in PubMed specifically comparing frontal gamma activity between participants with SCZ and healthy controls, to determine whether frontal gamma activity may be a valid biomarker or treatment target for patients with SCZ. We summarize the complex cognitive and neurophysiologic processes contributing to neural oscillations during tasks with WM features, and how such complexity has stalled the development of neurophysiologic biomarkers and treatment targets. Finally, we summarize promising results from early reports using neuromodulation to target DLPFC neural activity and improve cognitive function in participants with SCZ, including a study from our team demonstrating that gamma-EEG neurofeedback increases frontal gamma power and WM performance in participants with SCZ. From the evidence discussed in this review, we believe the emerging field of neuromodulation, which includes extrinsic (electrical or magnetic stimulation) and intrinsic (EEG neurofeedback) modalities, will, in the coming decade, provide promising treatment options targeting specific neurophysiologic properties of specific brain areas to improve cognitive and behavioral health for patients with SCZ.