Prefrontal Inhibitory Control Research Articles

Heart rate variability covaries with amygdala functional connectivity during voluntary emotion regulation

The Neurovisceral Integration Model posits that shared neural networks support the effective regulation of emotions and heart rate, with heart rate variability (HRV) serving as an objective, peripheral index of prefrontal inhibitory control. Prior neuroimaging studies have predominantly examined both HRV and associated neural functional connectivity at rest, as opposed to contexts that require active emotion regulation. The present study sought to extend upon previous resting-state functional connectivity findings, examining task-related HRV and corresponding amygdala functional connectivity during a cognitive reappraisal task. Seventy adults (52 older and 18 younger adults, 18–84 years, 51% male) received instructions to cognitively reappraise negative affective images during functional MRI scanning. HRV measures were derived from a finger pulse signal throughout the scan. During the task, younger adults exhibited a significant inverse association between HRV and amygdala-medial prefrontal cortex (mPFC) functional connectivity, in which higher task-related HRV was correlated with weaker amygdala-mPFC coupling, whereas older adults displayed a slight positive, albeit non-significant correlation. Furthermore, voxelwise whole-brain functional connectivity analyses showed that higher task-based HRV was linked to weaker right amygdala-posterior cingulate cortex connectivity across older and younger adults, and in older adults, higher task-related HRV correlated positively with stronger right amygdala-right ventrolateral prefrontal cortex connectivity. Collectively, these findings highlight the importance of assessing HRV and neural functional connectivity during active regulatory contexts to further identify neural concomitants of HRV and adaptive emotion regulation.

Effects of motor pacing on frontal-hemodynamic responses during continuous upper-limb and whole-body movements.

Advances in timing research advocate for the existence of two timing mechanisms (automatic vs. controlled) that are related to the level of cognitive control intervening for motor behavior regulation. In the present study, we used the functional near-infrared spectroscopy (fNIRS) cutting-edge technique to examine the hypothesis that prefrontal inhibitory control is needed to perform slow motor activities. Participants were asked to perform a sensorimotor-synchronization task at various paces (i.e., slow, close-to-spontaneous, fast). We contrasted upper-limb circle drawing to a more naturalistic behavior that required whole-body movements (i.e., steady-state walking). Results indicated that whole-body movements led to greater brain oxygenation over the motor regions when compared with upper-limb activities. The effect of motor pace was found in the walking task only, with more bilateral orbitofrontal and left dorsolateral activation at slow versus fast pace. Exploratory analyses revealed a positive correlation between the activation of the orbitofrontal and motor areas for the close-to-spontaneous pace in both tasks. Overall, results support the key role of prefrontal cognitive control in the production of slow whole-body movements. In addition, our findings confirm that upper-limb (laboratory-based) tasks might not be representative of those engaged during everyday-life motor behaviors. The fNIRS technique may be a valuable tool to decipher the neurocognitive mechanisms underlying naturalistic, adaptive motor behaviors.

Sex- and exposure age-dependent effects of adolescent stress on ventral tegmental area dopamine system and its afferent regulators.

Adolescent stress is a risk factor for schizophrenia. Emerging evidence suggests that age-dependent sensitive windows for childhood trauma are associated more strongly with adult psychosis, but the neurobiological basis and potential sex differences are unknown.Using in vivo electrophysiology and immunohistology in rats, we systematically compared the effects of two age-defined adolescent stress paradigms, prepubertal (postnatal day [PD] 21-30; PreP-S) and postpubertal (PD41-50; PostP-S) foot-shock and restraint combined stress, on ventral tegmental area (VTA) dopaminergic activity, pyramidal neuron activity in the ventral hippocampus (vHipp) and the basolateral amygdala (BLA), corticoamygdalar functional inhibitory control, and vHipp and BLA parvalbumin interneuron (PVI) impairments. These endpoints were selected based on their well-documented roles in the pathophysiology of psychosis.Overall, we found distinct sex- and exposure age-dependent stress vulnerability. Specifically, while males were selectively vulnerable to PreP-S-induced adult VTA dopamine neuron and vHipp hyperactivities, females were selectively vulnerable to PostP-S. These male selective PreP-S effects were correlated with stress-induced aberrant persistent BLA hyperactivity, dysfunctional prefrontal inhibitory control of BLA neurons, and vHipp/BLA PVI impairments. In contrast, female PostP-S only produced vHipp PVI impairments in adults, with the BLA structure and functions largely unaffected.Our results indicated distinct adolescent-sensitive periods during which stress can sex-dependently confer maximal risks to corticolimbic systems to drive dopamine hyperactivity, which provide critical insights into the neurobiological basis for sex-biased stress-related psychopathologies emphasizing but not limited to schizophrenia. Furthermore, our work also provides a framework for future translational research on age-sensitive targeted interventions.

Neural and behavioral effects of perceptual load on auditory selective attention

Healthy adults performed an auditory version of the flanker task under low versus high perceptual load while behavioral and electrophysiological measures were recorded. Participants experienced less attentional interference under low load than high load, whether analyses were performed between tasks (Garner interference; found in accuracy and RT), between stimuli (flanker congruity; found in accuracy), or between sequences (Gratton effect; found in accuracy). Analysis of event-related potentials to the distractor (flanker), which was physically identical across load conditions, revealed load modulation of tasks effects in the P1 component (peak amplitude and latency), an early perceptual component peaking approximately 75 ms after distractor onset. As in behavioral performance, ERP analyses showed that auditory attentional disruption in P1 was significantly smaller under low perceptual load. Dipole source analysis suggested activation of prefrontal inhibitory control during low load and default mode network during high load. The results are in keeping with the predictions of tectonic theory (Melara & Algom, 2003), but inconsistent with expectations derived from perceptual load theory (Lavie, 1995).

Age-related modulations of alpha and gamma brain activities underlying anticipation and distraction.

Attention operates through top-down (TD) and bottom-up (BU) mechanisms. Recently, it has been shown that slow (alpha) frequencies index facilitatory and suppressive mechanisms of TD attention and faster (gamma) frequencies signal BU attentional capture. Ageing is characterized by increased behavioral distractibility, resulting from either a reduced efficiency of TD attention or an enhanced triggering of BU attention. However, only few studies have investigated the impact of ageing upon the oscillatory activities involved in TD and BU attention. MEG data were collected from 14 elderly and 14 matched young healthy human participants while performing the Competitive Attention Task. Elderly participants displayed (1) exacerbated behavioral distractibility, (2) altered TD suppressive mechanisms, indexed by a reduced alpha synchronization in task-irrelevant regions, (3) less prominent alpha peak-frequency differences between cortical regions, (4) a similar BU system activation indexed by gamma activity, and (5) a reduced activation of lateral prefrontal inhibitory control regions. These results show that the ageing-related increased distractibility is of TD origin.

Efficacy of Inhibitory Control in Antisaccade Task and the Polymorphisms of DRD2 Dopamine Receptor Gene in Schizophrenic Patients

The purpose of this pilot study was to investigate the association of five polymorphic loci of the DRD2 gene (rs1799732, rs1800497, rs6277, rs6275, and rs2242592) with antisaccade task performance in male cohorts of schizophrenic patients (n = 33) and healthy subjects (n = 30). The antisaccade error rate was analyzed as related to prefrontal inhibitory control. In patients, the increased percent of errors was associated with minor alleles of polymorphisms rs6277 (C), rs6275 (T), and rs2242592 (G), which are supposedly related to the risk of schizophrenia. At the same time, it was found that a decreased error rate in healthy subjects is associated with the C/C variant of rs6277; no association was observed between polymorphisms rs6275 and rs2242592 and task performance.

Trading Accuracy for Speed in Selective Attention Tasks during Sleep Deprivation

Selective attention is a critical cognitive function in tasks that require careful monitoring of visual information. An increasing amount of night work on jobs that meet such requirements motivates the study of the effects of sleep deprivation (SD) on selective attention. Monitoring tasks in occupational settings can be operationalized for study in the laboratory by visual search tasks, in which the subject has to identify rare target items among distractor items. Visual search under SD leads to a decrease of overall response speed and accuracy. However, an increase of response speed per item with increasing number of items was also found under SD. This might indicate an unfavorable speed‐accuracy trade‐off: decision speed per item increases, while accuracy decreases in turn. Eye gaze tracking may provide additional indications for the duration of individual decisions during the search process.We recorded gaze behavior during two standard visual search tasks to explore if SD leads to faster and sloppier decisions per item (shorter fixation durations). Visual search performance (response time and sensitivity d′) in the conjunction (CST) and spatial configuration (SST) search task and the associated gaze behavior were tested in two groups of subjects. While sleep deprived participants (N=24, age: 25 ± 5 SD; 12 women) were kept awake during a 24 hour period, participants of a control group (N=24, age: 26 ± 4 SD; 10 women) were allowed to sleep (TIB: 8 hours).We found an increase of response time under SD compared to the control group (CST: p = 0.019, MSD= 128 ms ± 220 SD, MC= 1 ms ± 169 SD; SST: p < 0.001, MSD= 65 ms ± 755 SD, MC=− 45 ms ± 604 SD) and a decrease in sensitivity d′ (CST: p = 0.03, MSD= −0.14 ± 0.65 SD, MC= 0.01 ± 0.58 SD; SST: p < 0.001, MSD=−0.43 ± 0.82 SD, MC= 0.10 ± 0.64 SD). For gaze behavior, we found indications of a cognitive slowing in slower saccade velocities for the SD group compared to the control group (CST: p < 0.001, MSD= −38.8 °/s ± 42.4 SD, MC= −5.1 °/s ± 33.8 SD; SST: p < 0.001, MSD= −29.0 °/s ± 32.4 SD, MC= −2.8 °/s ± 23.7 SD) but not in terms of longer fixation durations. On the contrary, fixation durations decreased in the SD group relative to the control group (CST: p = 0.018, MSD= −16.1 ms ± 30.3 SD, MC= −6.2 ms ± 25.1 SD; SST: p = 0.008, MSD= −11.0 ms ± 23.4 SD, MC= −2.2 ms ± 19.7 SD). Moreover, the change in fixation duration was positively correlated with the change in task accuracy (CST: ρ = 0.29, p = 0.048; SST: ρ = 0.33, p = 0.022), suggesting that subjects that showed the strongest decrease in fixation duration exhibited also the strongest decrease in search accuracy. Further analysis showed that the general decrease of fixation duration was mainly associated with a steep increase of the frequency of very brief fixation durations, so called ‘express fixations' with durations shorter than 120 ms.The decrease in fixation duration under SD is further evidence for a shifted speed‐accuracy trade‐off as indicated by earlier search studies. SD seemingly leads to an increase of decision speed at the cost of reduced accuracy. Consequently, SD not only results in overall cognitive slowing but also in an impairment of adequate resource allocation in selective attention, potentially due to the absence of prefrontal inhibitory control.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Brain-heart interaction in perseverative cognition.

The move from the concept of homeostasis to that of allostasis has led reactivity stress research to widen the object of its investigation: from the brief physiological response that occurs when one is facing a stressor to what happens when one is anticipating or recovering from a stressor. A paradigmatic example is represented by perseverative cognition, during which human beings react "as if" they were constantly facing a concrete stressor. The core idea behind this review is that the cognitive inflexibility that characterizes perseverative cognition is reflected in both our body (by increased autonomic nervous system rigidity assessed by heart rate variability; HRV) and our brain (by reduced prefrontal-amygdala functional connectivity). This is a review of studies conducted in different settings (laboratory, daily life), populations (healthy, major depression, generalized anxiety), location (United States, Europe), and age groups (children, adults) that consistently replicated the association between autonomic, subjective, and behavioral measures of cognitive inflexibility during perseverative cognition. Moreover, compelling neuroimaging data suggest that HRV reduction from pre- to post-induction of perseverative cognition is associated with both structural and functional brain abnormalities reflecting impaired prefrontal inhibitory control over subcortical structures (e.g., diminished prefrontal-amygdala functional connectivity). The integration of neuroscience techniques with clinical autonomic research has advanced our understanding of the neurobiology of brain-heart interaction during perseverative cognition, potentially yielding to more effective treatment packages. This is clinically relevant if one considers that perseverative cognition is a pervasive transdiagnostic factor that carries prognostic risk for both psychological and somatic health.

Establishing a Right Frontal Beta Signature for Stopping Action in Scalp EEG: Implications for Testing Inhibitory Control in Other Task Contexts.

Many studies have examined the rapid stopping of action as a proxy of human self-control. Several methods have shown that a critical focus for stopping is the right inferior frontal cortex. Moreover, electrocorticography studies have shown beta band power increases in the right inferior frontal cortex and in the BG for successful versus failed stop trials, before the time of stopping elapses, perhaps underpinning a prefrontal-BG network for inhibitory control. Here, we tested whether the same signature might be visible in scalp electroencephalography (EEG)-which would open important avenues for using this signature in studies of the recruitment and timing of prefrontal inhibitory control. We used independent component analysis and time-frequency approaches to analyze EEG from three different cohorts of healthy young volunteers (48 participants in total) performing versions of the standard stop signal task. We identified a spectral power increase in the band 13-20 Hz that occurs after the stop signal, but before the time of stopping elapses, with a right frontal topography in the EEG. This right frontal beta band increase was significantly larger for successful compared with failed stops in two of the three studies. We also tested the hypothesis that unexpected events recruit the same frontal system for stopping. Indeed, we show that the stopping-related right-lateralized frontal beta signature was also active after unexpected events (and we accordingly provide data and scripts for the method). These results validate a right frontal beta signature in the EEG as a temporally precise and functionally significant neural marker of the response inhibition process.

Right inferior frontal cortex activity correlates with tolcapone responsivity in problem and pathological gamblers.

Failures of self-regulation in problem and pathological gambling (PPG) are thought to emerge from failures of top-down control, reflected neurophysiologically in a reduced capacity of prefrontal cortex to influence activity within subcortical structures. In patients with addictions, these impairments have been argued to alter evaluation of reward within dopaminergic neuromodulatory systems. Previously we demonstrated that augmenting dopamine tone in frontal cortex via use of tolcapone, an inhibitor of the dopamine-degrading enzyme catechol-O-methyltransferase (COMT), reduced delay discounting, a measure of impulsivity, in healthy subjects. To evaluate this potentially translational approach to augmenting prefrontal inhibitory control, here we hypothesized that increasing cortical dopamine tone would reduce delay discounting in PPG subjects in proportion to its ability to augment top-down control. To causally test this hypothesis, we administered the COMT inhibitor tolcapone in a randomized, double-blind, placebo-controlled, within-subject study of 17 PPG subjects who performed a delay discounting task while functional MRI images were obtained. In this subject population, we found that greater BOLD activity during the placebo condition within the right inferior frontal cortex (RIFC), a region thought to be important for inhibitory control, correlated with greater declines in impulsivity on tolcapone versus placebo. Intriguingly, connectivity between RIFC and the right striatum, and not the level of activity within RIFC itself, increased on tolcapone versus placebo. Together, these findings support the hypothesis that tolcapone-mediated increases in top-down control may reduce impulsivity in PPG subjects, a finding with potential translational relevance for gambling disorders, and for behavioral addictions in general.

In vitro cellular and mitochondrial toxicity of tolcapone and related nitrocatechols

Failures of self-regulation in problem and pathological gambling (PPG) are thought to emerge from failures of top-down control, reflected neurophysiologically in a reduced capacity of prefrontal cortex to influence activity within subcortical structures. In patients with addictions, these impairments have been argued to alter evaluation of reward within dopaminergic neuromodulatory systems. Previously we demonstrated that augmenting dopamine tone in frontal cortex via use of tolcapone, an inhibitor of the dopamine-degrading enzyme catechol-O-methyltransferase (COMT), reduced delay discounting, a measure of impulsivity, in healthy subjects. To evaluate this potentially translational approach to augmenting prefrontal inhibitory control, here we hypothesized that increasing cortical dopamine tone would reduce delay discounting in PPG subjects in proportion to its ability to augment top-down control. To causally test this hypothesis, we administered the COMT inhibitor tolcapone in a randomized, double-blind, placebo-controlled, within-subject study of 17 PPG subjects who performed a delay discounting task while functional MRI images were obtained. In this subject population, we found that greater BOLD activity during the placebo condition within the right inferior frontal cortex (RIFC), a region thought to be important for inhibitory control, correlated with greater declines in impulsivity on tolcapone versus placebo. Intriguingly, connectivity between RIFC and the right striatum, and not the level of activity within RIFC itself, increased on tolcapone versus placebo. Together, these findings support the hypothesis that tolcapone-mediated increases in top-down control may reduce impulsivity in PPG subjects, a finding with potential translational relevance for gambling disorders, and for behavioral addictions in general.

Alcohol Effects on Stress Pathways: Impact on Craving and Relapse Risk.

A significant amount of neurobiological research regarding the development of alcohol use disorders (AUDs) has focused on alcohol-related activation and long-term alterations in the mesocortical dopaminergic reward pathways. However, alcohol does not only interact with brain reward systems. Many of its acute and chronic effects may be related to allostatic adaptations in hypothalamic and extrahypothalamic stress regulation pathways. For example, acute binge intoxication is associated with hypothalamically driven increases in blood cortisol, norepinephrine, and sex steroid metabolite levels. This may contribute to the development of mesocortical sensitization to alcohol. Furthermore, chronic alcohol exposure is associated with systemic dysregulation of the hypothalamic pituitary adrenal axis, sympathetic adrenal medullary system, and sex steroid systems. This dysregulation appears to manifest as neuroendocrine tolerance. In this review, we first summarize the literature suggesting that alcohol-induced alterations in these hypothalamic systems influence craving and contribute to the development of AUDs. We note that for women, the effects of alcohol on these neuroendocrine stress regulation systems may be influenced by the rhythmic variations of hormones and steroids across the menstrual cycle. Second, we discuss how changes in these systems may indicate progression of AUDs and increased risk of relapse in both sexes. Specifically, neuroendocrine tolerance may contribute to mesocortical sensitization, which in turn may lead to decreased prefrontal inhibitory control of the dopaminergic reward and hypothalamic stress systems. Thus, pharmacological strategies that counteract alcohol-associated changes in hypothalamic and extrahypothalamic stress regulation pathways may slow the development and progression of AUDs.

Cold Face Test-Induced Increases in Heart Rate Variability Are Abolished by Engagement in a Social Cognition Task

Abstract. The vagus nerve is a major constituent in the bidirectional relationship between the heart and the prefrontal cortex. This study investigated the role of the vagus in social cognition using the cold face test (facial cooling) to stimulate the vagus nerve and increase prefrontal inhibitory control. Heart Rate Variability (HRV) was measured to index parasympathetic outflow while social cognition ability was tested using the Reading the Mind in the Eyes Test (RMET). Healthy males (n = 25) completed the RMET under two conditions: with and without facial cooling. Results indicated that although facial cooling increased HRV at rest, there was no improvement in the RMET during the facial cooling condition. Interestingly, completing the RMET with facial cooling abolished this increase in HRV, suggesting interference along the vagal reflex arc. These results are consistent with the involvement of a common cortico-subcortical circuit in autonomic and cognitive processes, important for emotion recognition.

Prefrontal functional connectivity measured with near-infrared spectroscopy during smoking cue exposure.

Cue reactivity (CR) is an important concept for relapse in substance use disorders (SUD). Although cue exposure (CE) therapy is discussed as relapse prevention, current approaches still need improvement considering its efficacy. From a neurobiological perspective, CR is related to an over-activation in sensitized subcortical structures, their projections to motivationally relevant cortical structures (e.g. orbitofrontal cortex, OFC) and deficient prefrontal inhibitory control. Therefore, we analyzed prefrontal cortical activation and its relation to craving during smoking CE. We focused on the OFC-as a projection area of sensitized subcortical structures-due its importance in the processing of reinforcement value and the dorsolateral prefrontal cortex (dlPFC) based on its importance for behavioral inhibition. Functional near-infrared spectroscopy (fNIRS) was used to assess hemodynamics in prefrontal regions during smoking CE in 24 subjects (n = 12 occasional smokers, n = 12 controls). Subjective craving intensity (minimum craving as marker of baseline inhibition, range as marker of inhibition time course) was additionally assessed. Craving ratings indicated that CR was elicited solely in smokers, not controls. Those subjective ratings correlated with hemodynamic activity in OFC (craving range) and dlPFC (minimum craving). OFC activation was found earlier throughout the CE in smokers compared to controls. Connectivity (seed-based correlation) between OFC and dlPFC was increased in smokers. fNIRS can capture prefrontal hemodynamic activity involved in CR elicited during CE and is therefore a promising method to investigate CR and its implications for relapse prevention in SUD.

Sex differences in COMT polymorphism effects on prefrontal inhibitory control in adolescence.

Catecholamine-0-methyl-transferase (COMT) gene variation effects on prefrontal blood oxygenation-level-dependent (BOLD) activation are robust; however, despite observations that COMT is estrogenically catabolized, sex differences in its prefrontal repercussions remain unclear. Here, in a large sample of healthy adolescents stratified by sex and Val(158)Met genotype (n=1133), we examine BOLD responses during performance of the stop-signal task in right-hemispheric prefrontal regions fundamental to inhibitory control. A significant sex-by-genotype interaction was observed in pre-SMA during successful-inhibition trials and in both pre-SMA and inferior frontal cortex during failed-inhibition trials with Val homozygotes displaying elevated activation compared with other genotypes in males but not in females. BOLD activation in the same regions significantly mediated the relationship between COMT genotype and inhibitory proficiency as indexed by stop-signal reaction time in males alone. These sexually dimorphic effects of COMT on inhibitory brain activation have important implications for our understanding of the contrasting patterns of prefrontally governed psychopathology observed in males and females.

Self-rated social-emotional perception and its neurophysiologic and cardiac correlates while viewing a film showing the suffering of other people

Using electroencephalographic (EEG) and cardiac measures, the study examined relevant mechanisms that may explain individual differences in self-rated emotion perception (i.e., the propensity of perceiving the emotional states of other persons in everyday life). Healthy women (n = 122) were confronted with film scenes showing the suffering of other people. Functional coupling between prefrontal and posterior cortices, measured by EEG coherences, more strongly decreased in individuals higher on emotion perception. This finding suggests that the propensity to loosen prefrontal inhibitory control on posterior cortical areas involved in basic processes of emotion perception is associated with higher susceptibility to social-emotional information and, therefore, with higher scores on self-rated emotion perception. In addition, higher self-rated perception of other persons' emotions was related to more pronounced cardiac responses to the observation of horrifying events occurring to people in the film which indicate enhanced attention and heightened perceptual processing

Elevated Antisaccade Error Rate as an Intermediate Phenotype for Psychosis Across Diagnostic Categories

Elevated antisaccade error rate, reflecting problems with inhibitory behavioral control, is a promising intermediate phenotype for schizophrenia. Here, we consider whether it marks liability across psychotic disorders via common or different neurophysiological mechanisms and whether it represents a neurocognitive risk indicator apart from the generalized cognitive deficit. Schizophrenia (n = 267), schizoaffective (n = 150), and psychotic bipolar (n = 202) probands, their first-degree relatives (ns = 304, 193, 242, respectively), and healthy controls (n = 244), participating in the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium, performed antisaccade and prosaccade tasks and completed a neuropsychological battery. Antisaccade error rate was elevated in proband groups with greatest deficit observed in schizophrenia and was unrelated to symptoms and antipsychotic treatment. Increased error rate was also observed among relatives, even those without history of psychosis or psychosis spectrum personality traits. Relatives' deficits were similar across proband diagnoses. Error rate was familial and remained elevated in proband and relative groups after accounting for generalized cognitive impairment. Speed of attentional shifting, indexed by prosaccade latency, was similarly influenced in all groups by manipulations that freed vs increasingly engaged attention systems and was inversely associated with antisaccade error rate in all but schizophrenia probands. These findings indicate that elevated antisaccade error rate represents an intermediate phenotype for psychosis across diagnostic categories, and that it tracks risk beyond that attributable to the generalized cognitive deficit. The greater severity of antisaccade impairment in schizophrenia and its independence from attention shifting processes suggest more severe and specific prefrontal inhibitory control deficits in this disorder.

Daytime sleepiness affects prefrontal regulation of food intake

The recent epidemic of obesity corresponds closely with the decline in the average number of hours of sleep obtained nightly. While growing research suggests that sleep loss may affect hormonal and other physiological systems related to food intake, no studies have yet explored the role that sleepiness may play in reducing prefrontal inhibitory control over food intake. Because evidence suggests that women may be more prone to obesity and eating disorders, as well as more likely to suffer from sleep problems, we examined the relation between general daytime sleepiness, brain responses to food stimuli, and self-reported overeating separately for men and women. Thirty-eight healthy adults (16 women; 22 men) aged 18 to 45 underwent functional magnetic resonance imaging (fMRI) while viewing pictures of high- and low-calorie foods. Subjects completed the Epworth Sleepiness Scale (ESS) and provided a rating to the query "how often do you eat more than you intend to." Contrast images comparing brain activation derived from the high- versus low-calorie conditions were correlated voxel-wise with scores from the ESS in a second-level regression model, the output of which was used to predict self-reported overeating. As hypothesized, daytime sleepiness correlated with reduced activation in the ventromedial prefrontal cortex during perception of high- versus low-calorie food images. Moreover, activation within this cluster predicted overeating, but only for women. Findings suggest that normal fluctuations in sleepiness may be sufficient to affect brain regions important for regulating food intake, but that these effects may differ between men and women.

Periadolescent exposure to the NMDA receptor antagonist MK-801 impairs the functional maturation of local GABAergic circuits in the adult prefrontal cortex.

A developmental disruption of prefrontal cortical inhibitory circuits is thought to contribute to the adolescent onset of cognitive deficits observed in schizophrenia. However, the developmental mechanisms underlying such a disruption remain elusive. The goal of this study is to examine how repeated exposure to the NMDA receptor antagonist dizocilpine maleate (MK-801) during periadolescence [from postnatal day 35 (P35) to P40] impacts the normative development of local prefrontal network response in rats. In vivo electrophysiological analyses revealed that MK-801 administration during periadolescence elicits an enduring disinhibited prefrontal local field potential (LFP) response to ventral hippocampal stimulation at 20 Hz (beta) and 40 Hz (gamma) in adulthood (P65-P85). Such a disinhibition was not observed when MK-801 was given during adulthood, indicating that the periadolescent transition is indeed a sensitive period for the functional maturation of prefrontal inhibitory control. Accordingly, the pattern of prefrontal LFP disinhibition induced by periadolescent MK-801 treatment resembles that observed in the normal P30-P40 prefrontal cortex (PFC). Additional pharmacological manipulations revealed that these developmentally immature prefrontal responses can be mimicked by single microinfusion of the GABA(A) receptor antagonist picrotoxin into the normal adult PFC. Importantly, acute administration of the GABA(A)-positive allosteric modulator Indiplon into the PFC reversed the prefrontal disinhibitory state induced by periadolescent MK-801 to normal levels. Together, these results indicate a critical role of NMDA receptors in regulating the periadolescent maturation of GABAergic networks in the PFC and that pharmacologically induced augmentation of local GABA(A)-receptor-mediated transmission is sufficient to overcome the disinhibitory prefrontal state associated with the periadolescent MK-801 exposure.

Discriminative Inhibitory Control of Cocaine Seeking Involves the Prelimbic Prefrontal Cortex

Recent neuroimaging studies have shown that people with cocaine addiction retain some degree of control over drug craving that correlates with neural activity in the lateral prefrontal cortex (PFC). Here, we report similar findings in a rat model of inhibitory control of cocaine seeking. Rats actively responding for cocaine were trained to stop responding when presented with a discriminative stimulus that signaled lack of reinforcement. Rats were then tested for inhibitory control of cocaine seeking in novel behavioral contexts and in circumstances when cocaine seeking is particularly intense (e.g., following drug priming). The role of neuronal activity in different subregions of the PFC was assessed using local pharmacologic inactivation and c-Fos immunohistochemistry. Rats progressively acquired the ability to stop cocaine seeking, even during drug intoxication and after a long history of cocaine self-administration. Inhibitory control of cocaine seeking was flexible, sufficiently strong to block cocaine-primed reinstatement, and selectively depended on increased neuronal activity within the prelimbic PFC, which is considered the rodent functional homolog of the human lateral PFC. Parallel evidence in both animal models and humans indicate that recruitment of prefrontal inhibitory control of drug seeking is still functional after prolonged cocaine use. Preclinical investigation of the mechanisms underlying this capacity may contribute to designing new behavioral and/or pharmacologic strategies to promote its use for the prevention of relapse in addiction.