Understanding normal brain aging and developing methods to maintain or improve cognition in older adults are major goals of fundamental and translational neuroscience. Here, we show a core feature of cognitive decline - working memory deficits - emerges from disconnected local and long-range circuits instantiated by theta-gamma phase-amplitude codes in temporal cortex and theta phase synchronization across frontotemporal cortex. We developed a noninvasive stimulation procedure for modulating long-range theta interactions in adults aged 60–76 years. After 25 minutes of stimulation, frequency tuned to individual brain network dynamics, we observed a preferential increase in neural synchronization patterns and the return of sender-receiver relationships of information flow within and between frontotemporal regions. The end result was rapid improvement in working memory performance that outlasted a 50-minute post-stimulation period. The results provide insight into the physiological foundations of age-related cognitive impairment and contribute groundwork for future non-pharmacological interventions targeting aspects of cognitive decline.

During the last decade one of the most contentious and heavily studied topics in the attention literature has been the role that working memory representations play in controlling perceptual selection. The hypothesis has been advanced that to have attention select a certain perceptual input from the environment, we only need to represent that item in working memory. Here we summarize the work indicating that the relationship between what representations are maintained in working memory and what perceptual inputs are selected is not so simple. First, it appears that attentional selection is also determined by high-level task goals that mediate the relationship between working memory storage and attentional selection. Second, much of the recent work from our laboratory has focused on the role of long-term memory in controlling attentional selection. We review recent evidence supporting the proposal that working memory representations are critical during the initial configuration of attentional control settings, but that after those settings are established long-term memory representations play an important role in controlling which perceptual inputs are selected by mechanisms of attention.

We can more precisely tune attention to highly rewarding objects than other objects in our environment, but how our brains do this is unknown. After a few trials of searching for the same object, subjects' electrical brain activity indicated that they handed off the memory representations used to control attention from working memory to long-term memory. However, when a large reward was possible, the neural signature of working memory returned as subjects recruited working memory to supplement the cognitive control afforded by the representations accumulated in long-term memory. The amplitude of this neural signature of working memory predicted the magnitude of the subsequent behavioral rewardbased attention effects across tasks and individuals, showing the ubiquity of this cognitive reaction to high-stakes situations.

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 ...

Adaptive human behavior depends on the capacity to adjust cognitive processing after an error. Here we show that transcranial direct current stimulation of medial-frontal cortex provides causal control over the electrophysiological responses of the human brain to errors and feedback. Using one direction of current flow, we eliminated performance-monitoring activity, reduced behavioral adjustments after an error, and slowed learning. By reversing the current flow in the same subjects, we enhanced performance-monitoring activity, increased behavioral adjustments after an error, and sped learning. These beneficial effects fundamentally improved cognition for nearly 5 h after 20 min of noninvasive stimulation. The stimulation selectively influenced the potentials indexing error and feedback processing without changing potentials indexing mechanisms of perceptual or response processing. Our findings demonstrate that the functioning of mechanisms of cognitive control and learning can be up-or down-regulated using noninvasive stimulation of medial-frontal cortex in the human brain.