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

108

Active cocaine abusers have a diminished neural response to errors, particularly in the anterior cingulate cortex thought critical to error processing. The inability to detect, or adjust performance following errors has been linked to clinical symptoms including the loss of insight and perseverative behavior. We investigated the cognitive implications of this diminished error-related activity, using response inhibition tasks that required error awareness and performance adaptation. Twenty-one active cocaine users (six female subjects, mean age ¼ 40.3) and 22 non-drug using adults (six female subjects, mean ¼ 39.9) participated. The results indicated that cocaine users consistently demonstrated poorer inhibitory control, a deficit accompanied by reduced awareness of errors. Adaptation of post-error reaction times did not differ between groups, although a different measure of adaptive behavior: exerting inhibitory control on the trial immediately after failing to inhibit, was significantly poorer in the cocaine using sample. In summary, cocaine users demonstrated a diminished capacity for monitoring their behavior, but were able to perform post-error adjustment to processes not already suffering an underlying deficit. These difficulties are consistent with previous reports of cocaine-related hypoactivity in the neural system underlying cognitive control, and highlight the potential for cognitive dysfunction to manifest as behavioral deficits that likely contribute to the maintenance of drug dependence.

Section: Inhibitory Controlsupporting

confidence: 84%

Post-Error Behavior in Active Cocaine Users: Poor Awareness of Errors in the Presence of Intact Performance Adjustments

Hester

Simões‐Franklin

Garavan

2007

108

“…Thus, extended access to cocaine self-administration induced long-lasting impairments of working memory under high cognitive demand and high-incentive conditions that can be predicted by the increase in cocaine intake. The cognitive dysfunctions observed in LgA rats under a high, but not low, incentive condition, and in humans with cocaine addiction (Hester and Garavan, 2004), may result from an imbalance between a hypoactive cognitive system that controls decision-making under a high cognitive demand situation and an overactive incentive salience system (Bechara, 2005). The working memory impairment in this task also may be explained by an increase of perseveration or compulsion, a prominent feature of prefrontal cortex lesions (Brush et al, 1961;Mishkin, 1964;Pribram, 1961).…”

Section: Discussionmentioning

confidence: 99%

Extended Access to Cocaine Self-Administration Produces Long-Lasting Prefrontal Cortex-Dependent Working Memory Impairments

George

Mandyam

Wee

et al. 2007

154

127

Humans with drug addiction exhibit compulsive drug-seeking associated with impairment of prefrontal cortex cognitive function. Whether prefrontal cortex dysfunction is a consequence of chronic drug exposure, or mediates the transition from drug use to drug dependence, is unknown. The current study investigates whether a history of escalated vs controlled cocaine intake is associated with specific working memory impairments, and long-lasting alterations of the dorsomedial prefrontal cortex and orbitofrontal cortex in rats. Working memory was assessed in rats with a history of extended (6 h per session) or limited (1 h per session) access to cocaine (0.5 mg/kg per injection), 3-17 days after the last self-administration session, using a delayed nonmatching-to-sample task. The density of neurons, oligodendrocytes, and astrocytes was quantified in the dorsomedial prefrontal cortex and orbitofrontal prefrontal cortex 2 months after the last self-administration session. Working memory impairments were observed after a history of chronic and escalated cocaine intake, but not after repeated limited access to cocaine. Moreover, working memory impairments were correlated with a decreased density of neurons and oligodendrocytes but not astrocytes in the dorsomedial prefrontal cortex, and with a decreased density of oligodendrocytes in the orbitofrontal cortex. Considering the role of the prefrontal cortex in goal-directed behavior, the prefrontal cortex dysfunctions observed here may exacerbate the loss of control associated with increased drug use and facilitate the progression to drug addiction.

“…The fronto-cerebellar interplay seems to be dynamic in nature and normally is dominated by frontal structures (Smith and Jonides, 1997;Gould et al, 2003), with cerebellar structures playing a supporting role. However, in addiction disorders, in which the frontal lobes are known to be compromised (Goldstein and Volkow, 2002), cerebellar (and vermis) activity appears to increase to support several tasks involving frontal lobe function including monetary reward response (Martin-Soelch et al, 2001), response inhibition (Hester and Garavan, 2004), and working memory (Desmond et al, 2003). Vermis activation also occurs during reward tasks in Parkinson's and in attention deficit hyperactivity disorder patients, but not in comparison subjects (Ernst et al, 2003;Goerendt et al, 2004;Kunig et al, 2000).…”

Section: Cerebellar Connectivity To Dopamine Circuitrymentioning

confidence: 99%

Cerebellar Vermis Involvement in Cocaine-Related Behaviors

Anderson

Maas

Frederick

et al. 2005

Although the cerebellum is increasingly being viewed as a brain area involved in cognition, it typically is excluded from circuitry considered to mediate stimulant-associated behaviors since it is low in dopamine. Yet, the primate cerebellar vermis (lobules II-III and VIII-IX) has been reported to contain axonal dopamine transporter immunoreactivity (DAT-IR). We hypothesized that DAT-IR-containing vermis areas would be activated in cocaine abusers by cocaine-related cues and, in healthy humans, would accumulate DAT-selective ligands. We used BOLD fMRI to determine whether cocaine-related cues activated DAT-IR-enriched vermis regions in cocaine abusers and positron emission tomography imaging of healthy humans to determine whether the DAT-selective ligand [ 11 C]altropane accumulated in those vermis regions. Cocaine-related cues selectively induced BOLD activation in lobules II-III and VIII-IX in cocaine users, and, at early time points after ligand administration, we found appreciable [ 11 C]altropane accumulation in lobules VIII-IX, possibly indicating DAT presence in this region. These data suggest that parts of cerebellar vermis mediate cocaine's persisting and acute effects. In light of prior findings illustrating vermis connections to midbrain dopamine cell body regions, established roles for the vermis as a locus of sensorimotor integration and motor planning, and findings of increased vermis activation in substance abusers during reward-related and other cognitive tasks, we propose that the vermis be considered one of the structures involved in cocaine-and other incentive-related behaviors.