Robert Hester

Executive Dysfunction in Cocaine Addiction: Evidence for Discordant Frontal, Cingulate, and Cerebellar Activity

Using a GO-NOGO response inhibition task in which working memory (WM) demands can be varied, we demonstrate that the compromised abilities of cocaine users to exert control over strong prepotent urges are associated with reduced activity in anterior cingulate and right prefrontal cortices, two regions thought to be critical for implementing cognitive control. Furthermore, unlike drug-naive controls, and opposite to the anterior cingulate pattern, cocaine users showed an over-reliance on the left cerebellum, a compensatory pattern previously seen in alcohol addiction. The results indicate that cocaine users find it difficult to inhibit their own actions, particularly when WM demands, which have been shown previously to increase during cue-induced craving for the drug, are increased. The results reveal a neuroanatomical basis for this dysexecutive component to addiction, supporting the suggested importance cognitive functions may play in prolonging abuse or predisposing users toward relapse.

The functional neuroanatomical correlates of response variability: evidence from a response inhibition task

Intra-individual performance variability may be an important index of the efficiency with which executive control processes are implemented, Lesion studies suggest that damage to the frontal lobes is accompanied by an increase in such variability. Here we sought for the first time to investigate how the functional neuroanatomy of executive control is modulated by performance variability in healthy subjects by using an event-related functional magnetic resonance imaging (ER-fMRI) design and a Go/No-go response inhibition paradigm. Behavioural results revealed that individual differences in Go response time variability were a strong predictor of inhibitory success and that differences in mean Go response time could not account for this effect. Task-related brain activation was positively correlated with intra-individual variability within a distributed inhibitory network consisting of bilateral middle frontal areas and right inferior parietal and thalamic regions. Both the behavioural and fMRI data are consistent with the interpretation that those subjects with relatively higher intra-individual variability activate inhibitory regions to a greater extent, perhaps reflecting a greater requirement for top-down executive control in this group, a finding that may be relevant to disorders of executive/attentional control.

Neural mechanisms involved in error processing: A comparison of errors made with and without awareness

The ability to detect an error in ones own performance and then to improve ongoing performance based on this error processing is critical for effective behaviour. In our event-related fMRI experiment, we show that explicit awareness of a response inhibition commission error and subsequent post-error behaviour were associated with bilateral prefrontal and parietal brain activation. Activity in the anterior cingulate region, typically associated with error detection, was equivalent for both errors subjects were aware of and those they were not aware of making. While anterior cingulate activation has repeatedly been associated with error-related processing, these results suggest that, in isolation, it is not sufficient for conscious awareness of errors or post-error adaptation of response strategies. Instead, it appears, irrespective of awareness, to detect information about stimuli/responses that requires interpretation in other brain regions for strategic implementation of post-error adjustments of behaviour.

Individual differences in the functional neuroanatomy of inhibitory control

We combined the data of five event-related fMRI studies of response inhibition. The re-analysis (n = 71) revealed response inhibition to be accomplished by a largely right hemisphere network of prefrontal, parietal, subcortical and midline regions, with converging evidence pointing to the particular importance of the right frontal operculum. Functional differences were observed between the sexes with greater activity in females in many of these cortical regions. Despite the relatively narrow age range (18-46), cortical activity, on the whole, tended to increase with age, echoing a pattern of functional recruitment often observed in the elderly. More absent minded subjects showed greater activity in fronto-parietal areas, while speed of Go trial responses produced a varied pattern of activation differences in more posterior and subcortical areas. Although response inhibition produces robust activation in a discrete network of brain regions, these results reveal that individual differences impact on the relative contribution made by the nodes of this network.

Impaired Error Awareness and Anterior Cingulate Cortex Hypoactivity in Chronic Cannabis Users

Drug abuse and other psychiatric conditions (eg, schizophrenia) have been associated with a diminished neural response to errors, particularly in the anterior cingulate cortex (ACC) thought critical to error processing. A diminished capacity for detecting errors has been linked to clinical symptoms including the loss of insight, delusions, and perseverative behavior. A total of 16 active chronic cannabis users and 16 control participants were administered a Go/No-go response inhibition task during event-related fMRI data collection. The task provides measures of inhibitory control and error awareness. Cannabis users’ inhibitory control performance was equivalent to that of the control group, but the former showed a significant deficit in awareness of commission errors. Cannabis users showed a diminished capacity for monitoring their behavior that was associated with hypoactivity in the ACC and right insula. In addition, increased levels of hypoactivity in both the ACC and right insula regions were significantly correlated with error-awareness rates in the cannabis group (but not controls). These difficulties are consistent with earlier reports of hypoactivity in the neural systems underlying cognitive control and the monitoring of interoceptive awareness in chronic drug users, and highlight the potential relationship between cognitive dysfunction and behavioral deficits that have the potential to contribute to the maintenance of drug abuse.

Prefrontal-subcortical dissociations underlying inhibitory control revealed by event-related fMRI

Using event‐related fMRI, this study investigated the neural dynamics of response inhibition under fluctuating task demands. Fourteen participants performed a GO/NOGO task requiring inhibition of a prepotent motor response to NOGO events that occurred as part of either a Fast or Slow presentation stream of GO stimuli. We compared functional activations associated with correct withholds (Stops) required during the Fast presentation stream of stimuli to Stops required during the Slow presentation stream. A predominantly right hemispheric network was activated across conditions, consistent with previous studies. Furthermore, a functional dissociation of activations between conditions was observed. Slow Stops elicited additional activation in anterior dorsal and polar prefrontal cortex and left inferior parietal cortex. Fast Stops showed additional activation in a network that included right dorsolateral prefrontal cortex, insula and dorsal striatum. These results are discussed in terms of our understanding of the impact of preparation on the distributed network underlying response inhibition and the contribution of subcortical areas, such as the basal ganglia, to executive control processes.

The role of cognitive control in cocaine dependence.

While hedonic and reward-related processes are central to drug use and dependence, this article focuses on the contribution that cognitive processes may make to addiction. In particular, attention is drawn to those processes involved in exercising control over behavior as drug dependence is characterized by risky, impulsive behavior. Functional neuroimaging implicates prefrontal deficits in cocaine dependence with an emerging picture of cocaine users having attentional biases towards drug-related stimuli, poor performance in laboratory tests of inhibitory control, and compromised monitoring and evaluation of their behavior. Combined, these deficits may contribute to the continuation of use in dependent individuals and may qualify as important targets for therapeutic interventions.

Working memory and executive function: The influence of content and load on the control of attention

In a series of three experiments, increasing working memory (WM) load was demonstrated to reduce the executive control of attention, measured via task-switching and inhibitory control paradigms. Uniquely, our paradigms allowed comparison of the ability to exert executive control when the stimulus was either part of the currently rehearsed memory set or an unrelated distractor item. The results demonstrated a content-specific effect—insofar as switching attention away from, or exerting inhibitory control over, items currently held in WM was especially difficult—compounded by increasing WM load. This finding supports the attentional control theory that active maintenance of competing task goals is critical to executive function and WM capacity; however, it also suggests that the increased salience provided to the contents of WM through active rehearsal exerts a content-specific influence on attentional control. These findings are discussed in relation to cue-induced ruminations, where active rehearsal of evocative information (e.g., negative thoughts in depression or drug-related thoughts in addiction) in WM typically results from environmental cuing. The present study has demonstrated that when information currently maintained in WM is reencountered, it is harder to exert executive control over it. The difficulty with suppressing the processing of these stimuli presumably reinforces the maintenance of these items in WM, due to the greater level of attention they are afforded, and may help to explain how the cue-induced craving/rumination cycle is perpetuated.

Increased ventral striatal BOLD activity during non-drug reward anticipation in cannabis users.

Despite an increased understanding of the pharmacology and long-term cognitive effects of cannabis in humans, there has been no research to date examining its chronic effects upon reward processing in the brain. Motivational theories regarding long-term drug use posit contrasting predictions with respect to how drug users are likely to process non-drug incentives. The reward deficiency syndrome (RDS) of addiction posits that there are deficits in dopamine (DA) motivational circuitry for non-drug rewards, such that only drugs of abuse are capable of normalizing DA in the ventral striatum (VS). Alternatively, the opponent process theory (OPT) holds that in individuals prone to drug use, there exists some form of mesolimbic hyperactivity, in which there is a bias towards reward-centred behaviour concomitant with impulsivity. The current study examined BOLD responses during reward and loss anticipation and their outcome deliveries in 14 chronic cannabis users and 14 drug-naive controls during a monetary incentive delay (MID) task. Despite no significant behavioural differences between the two groups, cannabis users had significantly more right VS BOLD activity during reward anticipation. Correlation analyses demonstrated that this right VS BOLD response was significantly correlated with life-time use and reported life-time cannabis joints consumed. No correlations between cannabis abstinence and BOLD responses were observed. We also observed a number of group differences following outcome deliveries, most notably hypoactivity in the left insula cortex in response to loss and loss avoidance outcome notifications in the cannabis group. These results may suggest hypersensitivity during instrumental response anticipation for non-drug rewards and a hyposensitivity to loss outcomes in chronic cannabis users; the implications of which are discussed with respect to the potentially sensitizing effects of cannabis for other rewards.

Predicting Success: Patterns of Cortical Activation and Deactivation Prior to Response Inhibition

The present study investigated the relationships between attention and other preparatory processes prior to a response inhibition task and the processes involved in the inhibition itself. To achieve this, a mixed fMRI design was employed to identify the functional areas activated during both inhibition decision events and the block of trials following a visual cue introduced 2 to 7 sec prior (cue period). Preparing for successful performance produced increases in activation for both the cue period and the inhibition itself in the frontoparietal cortical network. Furthermore, preparation produced activation decreases in midline areas (insula and medial prefrontal) argued to be responsible for monitoring internal emotional states, and these cue period deactivations alone predicted subsequent success or failure. The results suggest that when cues are provided to signify the imminent requirement for behavioral control, successful performance results from a coordinated pattern of preparatory activation in task-relevant areas and deactivation of task-irrelevant ones.