Background: Our previous work described the neural processes of motor response inhibition during a stop signal task (SST). Employing the race model, we computed the stop signal reaction time (SSRT) to index individuals' ability in inhibitory control. The pre-supplementary motor area (preSMA), which shows greater activity in individuals with short as compared to those with long SSRT, plays a role in mediating response inhibition. In contrast, the right inferior prefrontal cortex (rIFC) showed greater activity during stop success as compared to stop error. Here we further pursued this functional differentiation of preSMA and rIFC on the basis of an intra-subject approach.

Prior research points to the importance of psychostimulants in improving self-control. However, the neural substrates underlying such improvement remain unclear. Here, in a pharmacological functional MRI study of the stop signal task, we show that methylphenidate (as compared with placebo) robustly decreased stop signal reaction time (SSRT), an index of improved control, in cocaine-dependent patients (a population in which inhibitory control is impaired). Methylphenidate-induced decreases in SSRT were positively correlated with inhibition-related activation of left middle frontal cortex (MFC) and negatively with activation of the ventromedial prefrontal cortex (vmPFC) in whole brain linear regressions. Inhibition-related MFC but not vmPFC activation distinguished individuals with short and long SSRT in 36 demographically matched healthy individuals, whereas vmPFC but not MFC activation, along with improvement in SSRT, was correlated with a previously implicated biomarker of methylphenidate response (systolic blood pressure). These results implicate a specific neural (i.e., vmPFC) mechanism whereby stimulants improve inhibitory control. Altered ventromedial prefrontal activation and increased blood pressure may represent useful CNS and peripheral biomarkers in individualized treatment with methylphenidate for patients with cocaine dependence.D eficits in cognitive control have been implicated in the pathophysiology of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and cocaine dependence (1-5), and a wide literature supports the utility of stimulants, including methylphenidate, in improving cognitive control (6-9, see ref. 10 for review). For example, studies have shown that stimulants alter cerebral activation and influence cognitive functions, including improving inhibitory control, in healthy individuals (11-21). Similarly, Overtoom et al. (22) reported that methylphenidate improved stopping performance and restored the electrophysiological potential of stopping in a stop signal task, whereas it did not affect go trial reaction time, in adult patients with ADHD. Although neuroimaging studies have examined the effects of stimulants on regional brain activation and connectivity, the neural substrates underlying stimulant-mediated improvements in inhibitory control remain unclear. A more complete understanding of the neural mechanisms whereby stimulants improve cognitive control will be critically important, not only for an improved understanding of its biological basis but also for understanding the pathophysiology and treatment of conditions associated with its impairment. Using a stop signal task, we (and others) have demonstrated that patients with cocaine (and other stimulant) misuse display impaired inhibitory control and prefrontal activation during a stop signal task (5, 23-27). Whereas prior research has examined stimulants in clinical trials of therapeutic efficacy (28-33) and neuroimaging studies of regional brain activation and connectivity in cocaine user...

Background There is a growing recognition that individuals at clinical high risk need intervention for functional impairments, along with emerging psychosis, as the majority of clinical high risk (CHR) individuals show persistent deficits in social and role functioning regardless of transition to psychosis. Recent studies have demonstrated reduced reading ability as a potential cause of functional disability in schizophrenia, related to underlying deficits in generation of mismatch negativity (MMN). The present study extends these findings to subjects at CHR. Methods The sample consisted of 34 CHR individuals and 33 healthy comparisons subjects (CNTLs) from the Recognition and Prevention (RAP) Program at the Zucker Hillside Hospital in New York. At baseline, reading measures were collected, along with MMN to pitch, duration, and intensity deviants, and measures of neurocognition, and social and role (academic/work) functioning. Results CHR subjects showed impairments in reading ability, neurocognition, and MMN generation, relative to CNTLs. Lower-amplitude MMN responses were correlated with worse reading ability, slower processing speed, and poorer social and role functioning. However, when entered into a simultaneous regression, only reduced responses to deviance in sound duration and volume predicted poor social and role functioning, respectively. Conclusions Deficits in reading ability exist even prior to illness onset in schizophrenia and may represent a decline in performance from prior abilities. As in schizophrenia, deficits are related to impaired MMN generation, suggesting specific contributions of sensory-level impairment to neurocognitive processes related to social and role function.