Medial–Frontal Stimulation Enhances Learning in Schizophrenia by Restoring Prediction Error Signaling

Abstract

Posterror learning, associated with medial-frontal cortical recruitment in healthy subjects, is compromised in neuropsychiatric disorders. Here we report novel evidence for the mechanisms underlying learning dysfunctions in schizophrenia. We show that, by noninvasively passing direct current through human medial-frontal cortex, we could enhance the event-related potential related to learning from mistakes (i.e., the error-related negativity), a putative index of prediction error signaling in the brain. Following this causal manipulation of brain activity, the patients learned a new task at a rate that was indistinguishable from healthy individuals. Moreover, the severity of delusions interacted with the efficacy of the stimulation to improve learning. Our results demonstrate a causal link between disrupted prediction error signaling and inefficient learning in schizophrenia. These findings also demonstrate the feasibility of nonpharmacological interventions to address cognitive deficits in neuropsychiatric disorders.

Error-related brain activity in youth and young adults before and after treatment for generalized or social anxiety disorder

“…Interestingly, though standard treatments do not appear to reduce the magnitude of the ERN, recent studies indicated that manipulating the allocation of attentional resources reduced the ERN in OCD (Klawohn et al, 2016), and that attention bias modification reduced the ERN in healthy adults (Nelson et al, 2015). In addition, there is evidence that transcranial direct-current stimulation (tDCS) can modulate the ERN in patients with schizophrenia (Reinhart et al, 2015). Thus, one intriguing possibility for examination in future research is that supplementing established anxiety treatments with attention training or tDCS may impact the ERN and improve long-term outcomes.…”

Disruption and rescue of interareal theta phase coupling and adaptive behavior

“…The learning improvements after inphase stimulation were so dramatic that subjects appeared to immediately reach peak levels of performance, no longer requiring explicit feedback to perform the task at high proficiency ( Fig. 2A, blue lines, blocks [5][6][7][8][9][10][11][12]. This observation was supported by stimulation × feedback interactions for error magnitude [F (1, 29) = 4.527; P = 0.042] and response variability [F (1, 29) = 5.368; P = 0.028] during the poststimulation period.…”

“…Impaired adaptive control is observed in many neurological and neuropsychiatric disorders such as schizophrenia, autism, Alzheimer's disease, attention-deficit/hyperactivity disorder, obsessivecompulsive disorder, Parkinson's disease, and epilepsy (3)(4)(5)(6)(7)(8)(9). Thus, it is not surprising that efforts to improve adaptive control have long characterized the fields of psychology and neuroscience.…”

Electrophysiology as a theoretical and methodological hub for the neural sciences

“…Fortuitously, frontal midline theta and related ERP features appear to be viable neural mechanisms (Section 3.1), endophenotypes (Kang et al, ; Zlojutro et al, ), diagnostic tools (Figure c), and predictors of treatment response (Burkhouse et al, ; Gorka et al, ) for patient groups defined by frontal dysfunction. These signatures can be up‐ and downregulated with pharmacology (Jocham & Ullsperger, ) and transcranical electric current (Reinhart & Woodman, ; Reinhart, Zhu, Park, & Woodman, ), demonstrating causal control over this signal and downstream effects on network instantiation and behavior in humans.…”