Rita Z. Goldstein

Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications

The loss of control over drug intake that occurs in addiction was initially believed to result from disruption of subcortical reward circuits. However, imaging studies in addictive behaviours have identified a key involvement of the prefrontal cortex (PFC) both through its regulation of limbic reward regions and its involvement in higher-order executive function (for example, self-control, salience attribution and awareness). This Review focuses on functional neuroimaging studies conducted in the past decade that have expanded our understanding of the involvement of the PFC in drug addiction. Disruption of the PFC in addiction underlies not only compulsive drug taking but also accounts for the disadvantageous behaviours that are associated with addiction and the erosion of free will.

Role of Dopamine, the Frontal Cortex and Memory Circuits in Drug Addiction: Insight from Imaging Studies

Drug addiction is characterized by a set of recurring processes (intoxication, withdrawal, craving) that lead to the relapsing nature of the disorder. We have used positron emission tomography to investigate in humans the role of dopamine (DA) and the brain circuits it regulates in these processes. We have shown that increases in DA are associated with the subjective reports of drug reinforcement corroborating the relevance of drug-induced DA increases in the rewarding effects of drugs in humans. During withdrawal we have shown in drug abusers significant reductions in DA D2 receptors and in DA release. We postulate that this hypodopaminergic state would result in a decreased sensitivity to natural reinforcers perpetuating the use of the drug as a means to compensate for this deficit and contributing to the anhedonia and dysphoria seen during withdrawal. Because the D2 reductions are associated with decreased activity in the anterior cingulate gyrus and in the orbitofrontal cortex we postulate that this is one of the mechanisms by which DA disruption leads to compulsive drug administration and the lack of control over drug intake in the drug-addicted individual. This is supported by studies showing that during craving these frontal regions become hyperactive in proportion to the intensity of the craving. Craving is also associated with activation of memory circuits including the amygdala (implicated in conditioned learning), hippocampus (implicated in declarative learning), and dorsal striatum (implicated in habit learning) all of which receive DA innervation. We therefore postulate that dopamine contributes to addiction by disrupting the frontal cortical circuits that regulate motivation, drive, and self-control and by memory circuits that increase the motivational salience of the drug and drug-associated stimuli.

Severity of neuropsychological impairment in cocaine and alcohol addiction: association with metabolism in the prefrontal cortex.

We used exploratory and confirmatory statistical approaches to study the severity of neuropsychological (NP) impairment in 42 crack/cocaine addicted subjects and in 112 comparison subjects (40 alcoholics and 72 controls). Twenty neuropsychological test indices most reliably defining predetermined cognitive domains were submitted to exploratory factor analysis. A four-dimensional model of neurocognitive function was derived: Verbal Knowledge, Visual Memory, Verbal Memory, and Attention/Executive functioning accounted for 63% of the variance. We then examined this models association with resting glucose metabolism in the brain reward circuit measured with 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography. Results revealed that (1) cocaine addicted individuals had a generalized mild level of neurocognitive impairment (<1 S.D. below control mean); and (2) controlling for age and education, relative metabolism in the dorsolateral prefrontal cortex significantly predicted the Visual Memory and Verbal Memory factors and relative metabolism in the anterior cingulate gyrus significantly predicted the Attention/Executive factor. Nevertheless, it remains to be determined whether metabolic changes in these regions are associated with addiction. Our results also suggest that compared to cocaine, alcohol has a more detrimental effect on Attention/Executive functioning, as assessed with traditional NP measures. We conclude that relative to other psychopathological disorders (such as schizophrenia), the severity of neuropsychological impairment in cocaine addiction is modest, albeit not indicative of the absence of neurocognitive dysfunction. The impact of such small differences in performance on quality of life, and possibly on craving and relapse, may be substantial. Tasks that simulate real-life decision-making or that target specific putative cognitive-behavioral or motivational-emotional mechanisms might offer greater sensitivity in characterizing the changes that accompany addiction to drugs. Obtaining valid estimates of alcohol use in cocaine addicted subjects is essential in characterizing neurocognitive functioning in individuals addicted to drugs.

Inverse association between BMI and prefrontal metabolic activity in healthy adults.

Obesity has been associated with a higher risk for impaired cognitive function, which most likely reflects associated medical complications (i.e., cerebrovascular pathology). However, there is also evidence that in healthy individuals excess weight may adversely affect cognition (executive function, attention, and memory). Here, we measured regional brain glucose metabolism (using positron emission tomography (PET) and 2‐deoxy‐2[18F]fluoro‐d‐glucose (FDG)) to assess the relationship between BMI and brain metabolism (marker of brain function) in 21 healthy controls (BMI range 19–37 kg/m2) studied during baseline (no stimulation) and during cognitive stimulation (numerical calculations). Statistical parametric mapping (SPM) revealed a significant negative correlation between BMI and metabolic activity in prefrontal cortex (Brodmann areas 8, 9, 10, 11, 44) and cingulate gyrus (Brodmann area 32) but not in other regions. Moreover, baseline metabolism in these prefrontal regions was positively associated with performance on tests of memory (California Verbal Learning Test) and executive function (Stroop Interference and Symbol Digit Modality tests). In contrast, the regional brain changes during cognitive stimulation were not associated with BMI nor with neuropsychological performance. The observed association between higher BMI and lower baseline prefrontal metabolism may underlie the impaired performance reported in healthy obese individuals on some cognitive tests of executive function. On the other hand, the lack of an association between BMI and brain metabolic activation during cognitive stimulation indicates that BMI does not influence brain glucose utilization during cognitive performance. These results further highlight the urgency to institute public health interventions to prevent obesity.

Role of the anterior cingulate and medial orbitofrontal cortex in processing drug cues in cocaine addiction

Our goal in the current report was to design a new functional magnetic resonance imaging (fMRI) task to probe the role of the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC) in processing of salient symptom-related cues during the simultaneous performance of an unrelated task in drug-addicted persons. We used a novel fMRI color-word drug Stroop task in 14 individuals with cocaine use disorders; subjects had to press for color of drug vs. matched neutral words. Although there were no accuracy or speed differences between the drug and neutral conditions in the current sample of subjects, drug words were more negatively valenced than the matched neutral words. Further, consistent with prior reports in individuals with other psychopathologies using different Stroop fMRI paradigms, our more classical color-word Stroop design revealed bilateral activations in the caudal-dorsal anterior cingulate cortex (cdACC) and hypoactivations in the rostro-ventral anterior cingulate cortex/medial orbitofrontal cortex (rACC/mOFC). A trend for larger rACC/mOFC hypoactivations to the drug than neutral words did not survive whole-brain corrections. Nevertheless, correlation analyses indicated that (1) the more the cdACC drug-related activation, the more negative the valence attributed to the drug words (r=-0.86, P<0.0001) but not neutral words; and (2) the more the rACC/mOFC hypoactivation to drug minus neutral words, the more the errors committed specifically to the drug minus neutral words (r=0.85, P<0.0001). Taken together, results suggest that this newly developed drug Stroop fMRI task may be a sensitive biobehavioral assay of the functions recruited for the regulation of responses to salient symptom-related stimuli in drug-addicted individuals.

Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway

Attention-deficit hyperactivity disorder (ADHD) is typically characterized as a disorder of inattention and hyperactivity/impulsivity but there is increasing evidence of deficits in motivation. Using positron emission tomography (PET), we showed decreased function in the brain dopamine reward pathway in adults with ADHD, which, we hypothesized, could underlie the motivation deficits in this disorder. To evaluate this hypothesis, we performed secondary analyses to assess the correlation between the PET measures of dopamine D2/D3 receptor and dopamine transporter availability (obtained with [11C]raclopride and [11C]cocaine, respectively) in the dopamine reward pathway (midbrain and nucleus accumbens) and a surrogate measure of trait motivation (assessed using the Achievement scale on the Multidimensional Personality Questionnaire or MPQ) in 45 ADHD participants and 41 controls. The Achievement scale was lower in ADHD participants than in controls (11±5 vs 14±3, P<0.001) and was significantly correlated with D2/D3 receptors (accumbens: r=0.39, P<0.008; midbrain: r=0.41, P<0.005) and transporters (accumbens: r=0.35, P<0.02) in ADHD participants, but not in controls. ADHD participants also had lower values in the Constraint factor and higher values in the Negative Emotionality factor of the MPQ but did not differ in the Positive Emotionality factor—and none of these were correlated with the dopamine measures. In ADHD participants, scores in the Achievement scale were also negatively correlated with symptoms of inattention (CAARS A, E and SWAN I). These findings provide evidence that disruption of the dopamine reward pathway is associated with motivation deficits in ADHD adults, which may contribute to attention deficits and supports the use of therapeutic interventions to enhance motivation in ADHD.

Brain monoamine oxidase A activity predicts trait aggression

The genetic deletion of monoamine oxidase A (MAO A), an enzyme that breaks down the monoamine neurotransmitters norepinephrine, serotonin, and dopamine, produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, Mendelian Inheritance in Men database number 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidence linking the low MAOA genotype and violent behavior but only through interaction with severe environmental stressors during childhood. Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression. Brain MAO A activity was measured in vivo in healthy nonsmoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the multidimensional personality questionnaire (MPQ). Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression (but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions, the higher the self-reported aggression (in both MAOA genotype groups) contributing to more than one-third of the variability. Because trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression.

Anterior cingulate cortex hypoactivations to an emotionally salient task in cocaine addiction

Anterior cingulate cortex (ACC) hypoactivations during cognitive processing characterize drug addicted individuals as compared with healthy controls. However, impaired behavioral performance or task disengagement may be crucial factors. We hypothesized that ACC hypoactivations would be documented in groups matched for performance on an emotionally salient task. Seventeen individuals with current cocaine use disorders (CUD) and 17 demographically matched healthy controls underwent functional magnetic resonance imaging during performance of a rewarded drug cue-reactivity task previously shown to engage the ACC. Despite lack of group differences in objective or subjective task-related performance, CUD showed more ACC hypoactivations throughout this emotionally salient task. Nevertheless, intensity of emotional salience contributed to results: (i) CUD with the largest rostroventral ACC [Brodmann Area (BA) 10, 11, implicated in default brain function] hypoactivations to the most salient task condition (drug words during the highest available monetary reward), had the least task-induced cocaine craving; (ii) CUD with the largest caudal-dorsal ACC (BA 32) hypoactivations especially to the least salient task condition (neutral words with no reward) had the most frequent current cocaine use; and (iii) responses to the most salient task condition in both these ACC major subdivisions were positively intercorrelated in the controls only. In conclusion, ACC hypoactivations in drug users cannot be attributed to task difficulty or disengagement. Nevertheless, emotional salience modulates ACC responses in proportion to drug use severity. Interventions to strengthen ACC reactivity or interconnectivity may be beneficial in enhancing top-down monitoring and emotion regulation as a strategy to reduce impulsive and compulsive behavior in addiction.

Addiction changes orbitofrontal gyrus function: involvement in response inhibition.

We used the Stroop task as a measure of the ability to inhibit a prepotent response tendency and examined its association with relative glucose metabolism in selected prefrontal brain regions in cocaine addicts, alcoholics, and controls (17 per group). Results revealed that for the substance abusers, higher orbitofrontal gyrus (OFG) activation was associated with lower conflict (higher score;r = 0.32, p < 0.05). For the controls, higher OFG activation was associated with higher conflict (lower score;r = −0.42, p < 0.05). Thus, at baseline, increased relative activation of the OFG is associated with worse performance in controls and better performance in substance abusers on the Stroop task, suggesting reversal of the role of the OFG as a function of addiction.

The Neuropsychology of Cocaine Addiction: Recent Cocaine Use Masks Impairment

Individuals with current cocaine use disorders (CUD) form a heterogeneous group, making sensitive neuropsychological (NP) comparisons with healthy individuals difficult. The current study examined the effects on NP functioning of four factors that commonly vary among CUD: urine status for cocaine (positive vs negative on study day), cigarette smoking, alcohol consumption, and dysphoria. Sixty-four cocaine abusers were matched to healthy comparison subjects on gender and race; the groups also did not differ in measures of general intellectual functioning. All subjects were administered an extensive NP battery measuring attention, executive function, memory, facial and emotion recognition, and motor function. Compared with healthy control subjects, CUD exhibited performance deficits on tasks of attention, executive function, and verbal memory (within one standard deviation of controls). Although CUD with positive urine status, who had higher frequency and more recent cocaine use, reported greater symptoms of dysphoria, these cognitive deficits were most pronounced in the CUD with negative urine status. Cigarette smoking, frequency of alcohol consumption, and dysphoria did not alter these results. The current findings replicate a previously reported statistically significant, but relatively mild NP impairment in CUD as compared with matched healthy control individuals and further suggest that frequent/recent cocaine may mask underlying cognitive (but not mood) disturbances. These results call for development of pharmacological agents targeted to enhance cognition, without negatively impacting mood in individuals addicted to cocaine.