No abstract

Executive control and flexible adjustment of behavior following errors are essential to adaptive functioning. Loss of adaptive control may be a biomarker of a wide range of neuropsychiatric disorders, particularly in the schizophrenia spectrum. Here, we provide support for the view that oscillatory activity in the frontal cortex underlies adaptive adjustments in cognitive processing following errors. Compared with healthy subjects, patients with schizophrenia exhibited low frequency oscillations with abnormal temporal structure and an absence of synchrony over medialfrontal and lateral-prefrontal cortex following errors. To demonstrate that these abnormal oscillations were the origin of the impaired adaptive control in patients with schizophrenia, we applied noninvasive dc electrical stimulation over the medial-frontal cortex. This noninvasive stimulation descrambled the phase of the low-frequency neural oscillations that synchronize activity across cortical regions. Following stimulation, the behavioral index of adaptive control was improved such that patients were indistinguishable from healthy control subjects. These results provide unique causal evidence for theories of executive control and cortical dysconnectivity in schizophrenia.oscillations | neural synchrony | adaptive control | schizophrenia | transcranial direct current stimulation N etworks involving frontal cortex allow us to adapt our actions to dynamic environments and adjust information processing following errors (1). This adaptive control is a hallmark of healthy goal-directed behavior, but it is dysfunctional in a variety of psychiatric and neurological disorders (2-4). In particular, the adaptive-control deficits that are a central feature of schizophrenia are highly predictive of poor functioning in daily life (5). In the laboratory, a canonical signature of adaptive control is the magnitude of posterror slowing of reaction time (RT), in which healthy subjects respond more slowly after making an error (6, 7). Patients with schizophrenia show an impaired ability to slow down their responses after errors (4, 8-13, but also 14, 15), providing a laboratory index that captures the rigid, perseverative, and maladaptive behavior that is characteristic of the disorder (8, 16).Adaptive control in the healthy brain is hypothesized to depend partly on the low-frequency EEG oscillations measured over medial-frontal cortex. The low-frequency oscillations are thought to reflect coordinated activity across the diverse set of brain areas recruited to perform a task (1,(17)(18)(19)(20)(21)(22). In addition, medial-frontal theta (4-8 Hz) oscillations appear to signal the need for adaptive control across a variety of tasks and situations. Situations that call for adaptive control include stimulus novelty, response conflict, negative feedback, and behavioral errors, with all of these situations sharing a common medial-frontal spectral signature in the theta band (21). However, the functional significance of medial-frontal theta may be much broader than simply ...

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.

Dendritic filopodia select synaptic partner axons by interviewing the cell surface of potential targets, but how filopodia decipher the complex pattern of adhesive and repulsive molecular cues to find appropriate contacts is unknown. Here, we demonstrate in cortical neurons that a single cue is sufficient for dendritic filopodia to reject or select specific axonal contacts for elaboration as synaptic sites. Super-resolution and live-cell imaging reveals that EphB2 is located in the tips of filopodia and at nascent synaptic sites. Surprisingly, a genetically encoded indicator of EphB kinase activity, unbiased classification, and a photoactivatable EphB2 reveal that simple differences in the kinetics of EphB kinase signaling at the tips of filopodia mediate the choice between retraction and synaptogenesis. This may enable individual filopodia to choose targets based on differences in the activation rate of a single tyrosine kinase, greatly simplifying the process of partner selection and suggesting a general principle.