Neuroimaging of marijuana smokers during inhibitory processing: a pilot investigation

Neuropsychological investigations of substance abusers have reported impairments on tasks mediated by the frontal executive system, including functions associated with behavioral inhibition and decision making. The higher order or executive components which are involved in decision making include selective attention and short term storage of information, inhibition of response to irrelevant information, initiation of response to relevant information, self-monitoring of performance, and changing internal and external contingencies in order to "stay the course" towards the ultimate goal. Given the hypothesized role of frontal systems in decision making and the previous evidence that executive dysfunctions and structural brain changes exist in subjects who use illicit drugs, we applied fMRI and diffusion tensor imaging (DTI) techniques in a pilot investigation of heavy cannabis smokers and matched control subjects while performing a modification of the classic Stroop task. Marijuana smokers demonstrated significantly lower anterior cingulate activity in focal areas of the anterior cingulate cortex and higher midcingulate activity relative to controls, although both groups were able to perform the task within normal limits. Normal controls also demonstrated increased activity within the right dorsolateral prefrontal cortex (DLPFC) during the interference condition, while marijuana smokers demonstrated a more diffuse, bilateral pattern of DLPFC activation. Similarly, although both groups performed the task well, marijuana smokers made more errors of commission than controls during the interference condition, which were associated with different brain regions than control subjects. These findings suggest that marijuana smokers exhibit different patterns of BOLD response and error response during the Stroop interference condition compared to normal controls despite similar task performance. Furthermore, DTI measures in frontal regions, which include the genu and splenium of the corpus callosum and bilateral anterior cingulate white matter regions, showed no between group differences in fractional anisotropy (FA), a measure of directional coherence within white matter fiber tracts, but a notable increase in trace, a measure of overall isotropic diffusivity in marijuana smokers compared to controls. Overall, results from the present study indicate significant differences in the magnitude and pattern of signal intensity change within the anterior cingulate and the DLPFC during the Stroop interference subtest in chronic marijuana smokers compared to normal controls. Furthermore, although chronic marijuana smokers were able to perform the task reasonably well, the functional activation findings suggest they utilize different cortical processes from the control subjects in order to do so. Findings from this study are consistent with the notion that substance abusers demonstrate evidence of altered frontal neural function during the performance of tasks that involve inhibition and performance monitoring, which may affect the ability to make decisions.     

Risky decision making and the anterior cingulate cortex in abstinent drug abusers and nonusers

Risky decision making is a hallmark behavioral phenotype of drug abuse; thus, an understanding of its biological bases may inform efforts to develop therapies for addictive disorders. A neurocognitive task that measures this function (Rogers Decision-Making Task; RDMT) was paired with measures of regional cerebral perfusion to identify brain regions that may underlie deficits in risky decision making in drug abusers. Subjects were abstinent drug abusers (> or =3 months) and healthy controls who underwent positron emission tomography scans with H(2)(15)O. Drug abusers showed greater risk taking and heightened sensitivity to rewards than control subjects. Both drug abusers and controls exhibited significant activations in a widespread network of brain regions, primarily in the frontal cortex, previously implicated in decision-making tasks. The only significant group difference in brain activation, however, was found in the left pregenual anterior cingulate cortex, with drug abusers exhibiting less task-related activation than control subjects. There were no significant correlations between neural activity and task performance within the control group. In the drug abuse group, on the other hand, increased risky choices on the RDMT negatively correlated with activation in the right hippocampus, left anterior cingulate gyrus, left medial orbitofrontal cortex, and left parietal lobule, and positively correlated with activation in the right insula. Drug abuse severity was related positively to right medial orbitofrontal activity. Attenuated activation of the pregenual ACC in the drug abusers relative to the controls during performance on the RDMT may underlie the abusers' tendency to choose risky outcomes.     

Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers

BACKGROUND: Mood disturbances in methamphetamine (MA) abusers likely influence drug use, but the neurobiological bases for these problems are poorly understood. OBJECTIVE: To assess regional brain function and its possible relationships with negative affect in newly abstinent MA abusers. DESIGN: Two groups were compared by measures of mood and cerebral glucose metabolism ([18F]fluorodeoxyglucose positron emission tomography) during performance of a vigilance task. SETTING: Participants were recruited from the general community to a research center. PARTICIPANTS: Seventeen abstaining (4-7 days) MA abusers (6 women) were compared with 18 control subjects (8 women). MAIN OUTCOME MEASURES: Self-reports of depressive symptoms and anxiety were measured, as were global and relative glucose metabolism in the orbitofrontal, cingulate, lateral prefrontal, and insular cortices and the amygdala, striatum, and cerebellum. RESULTS: Abusers of MA provided higher self-ratings of depression and anxiety than control subjects and differed significantly in relative regional glucose metabolism: lower in the anterior cingulate and insula and higher in the lateral orbitofrontal area, middle and posterior cingulate, amygdala, ventral striatum, and cerebellum. In MA abusers, self-reports of depressive symptoms covaried positively with relative glucose metabolism in limbic regions (eg, perigenual anterior cingulate gyrus and amygdala) and ratings of state and trait anxiety covaried negatively with relative activity in the anterior cingulate cortex and left insula. Trait anxiety also covaried negatively with relative activity in the orbitofrontal cortex and positively with amygdala activity. CONCLUSIONS: Abusers of MA have abnormalities in brain regions implicated in mood disorders. Relationships between relative glucose metabolism in limbic and paralimbic regions and self-reports of depression and anxiety in MA abusers suggest that these regions are involved in affective dysregulation and may be an important target of intervention for MA dependence.     

Error processing in current and former cocaine users

Deficits in response inhibition and error processing can result in maladaptive behavior, including failure to use past mistakes to inform present decisions. A specific deficit in inhibiting a prepotent response represents one aspect of impulsivity and is a prominent feature of addictive behaviors in general, including cocaine abuse/dependence. Brain regions implicated in cognitive control exhibit reduced activation in cocaine abusers. The purposes of the present investigation were (1) to identify neural differences associated with error processing in current and former cocaine-dependent individuals compared to healthy controls and (2) to determine whether former, long-term abstinent cocaine users showed similar differences compared with current users. The present study used an fMRI Go/No-Go task to investigate differences in BOLD response to correct rejections and false alarms between current cocaine users (n?=?30), former cocaine users (n?=?29), and healthy controls (n?=?35). Impulsivity trait measures were also assessed and compared with BOLD activity. Nineteen regions of interest previously implicated in errors of disinhibition were queried. There were no group differences in the correct rejections condition, but both current and former users exhibited increased BOLD response relative to controls for false alarms. In current users, the pregenual cingulate gyrus and left angular/supramarginal gyri overactivated. In former users, the right middle frontal/precentral gyri, right inferior parietal lobule, and left angular/supramarginal gyri overactivated. Overall, our results support a hypothesis that neural activity in former users differs more from healthy controls than that of current users due to cognitive compensation that facilitates abstinence.     

Functional magnetic resonance imaging of cocaine craving

OBJECTIVE: Identification of brain activity associated with craving is important for understanding the neurobiology of addiction. METHOD: Brain activity was measured in cocaine addicts and healthy subjects by functional magnetic resonance imaging (fMRI) while the subjects watched videotapes designed to elicit happy feelings, sad feelings, or the desire to use cocaine. The subjects indicated the onset of drug craving or emotional response, allowing comparison of groups before and after such feelings. RESULTS: Robust activation of the anterior cingulate was evident in patients watching cocaine-cue tapes but not in patients watching happy or sad tapes or in healthy subjects under any condition. Anterior cingulate activation preceded the reported onset of craving and was evident in patients who did not report craving. In contrast, patients showed less activation than healthy subjects during the cocaine-cue tapes in areas of the frontal lobes. After the reported onset of craving, cocaine-dependent subjects showed greater activity than healthy subjects in regions that are more active in healthy subjects when they watch sad tapes than when they watch happy tapes, suggesting a physiologic link between cocaine-cue responses and normal dysphoric states. Dynamic aspects of regional brain activations, but not the location of activations, were abnormal in cocaine-dependent subjects watching sad tapes, suggesting more general affective dysregulation. Patients showed low activation of sensory areas during initial viewing of all videotapes, suggesting generalized alteration in neuroresponsiveness. CONCLUSIONS: Cocaine cues lead to abnormally high cingulate and low frontal lobe activation in cocaine addicts. Addicts also show more general abnormalities in affect-related brain activation.     

Local glutamate in cingulate cortex subregions differentially correlates with affective network activations during face perception

The cingulate cortex is involved in emotion recognition/perception and regulation. Rostral and caudal subregions belong to different brain networks with distinct roles in affective perception. Despite recent accounts of the relevance of cingulate cortex glutamate (Glu) on blood‐oxygen‐level‐dependent (BOLD) responses, the specificity of the subregional Glu levels during emotional tasks remains unclear. Seventy‐two healthy participants (age = 27.33 ± 6.67, 32 women) performed an affective face‐matching task and underwent magnetic resonance spectroscopy (MRS) at 7 Tesla. Correlations between the BOLD response during emotion perception and Glu concentration in the pregenual anterior cingulate cortex (pgACC) and anterior midcingulate cortex (aMCC) were compared on a whole‐brain level. Post hoc specificity of the association with an affect was assessed. Lower Glu in the pgACC correlated with stronger activation differences between negative and positive faces in the left inferior and superior frontal gyrus (L IFG and L SFG). In contrast, lower Glu in the aMCC correlated with BOLD contrasts in the posterior cingulate cortex (PCC). Furthermore, negative face detection was associated with prolonged response time (RT). Our results demonstrate a subregion‐specific involvement of cingulate cortex Glu in interindividual differences during viewing of affective facial expressions. Glu levels in the pgACC were correlated with frontal area brain activations, whereas Glu in the salience network component aMCC modulated responses in the PCC–precuneus. We show that region‐specific metabolite mapping enables specific activation of different BOLD signals in the brain underlying emotional perception.     

EEG of chronic marijuana users during abstinence: relationship to years of marijuana use, cerebral blood flow and thyroid function.

OBJECTIVE: Marijuana abuse is associated with neurological changes including increases in frontal EEG alpha during abstinence. Research is needed to assess to what extent these EEG patterns are indicative of cerebral perfusion deficits. METHODS: We recorded the resting eyes closed EEG of 75 abstinent marijuana users and 33 control subjects. Fifty-six marijuana users used marijuana for less than eight years and 19 used for eight years or more. The EEG evaluation occurred within 72h of admission to an inpatient unit. Fifty-nine marijuana users remained abstinent for a month and were tested twice. Supplemental psychological and physiological data were also collected. RESULTS: Log alpha2 and beta2 power at posterior sites were significantly lower for the marijuana abusers that used eight years or more than the other marijuana abusers and the control subjects. These EEG changes continued for the month of abstinence. The marijuana users who used marijuana for more than eight years, also, had lower heart rates and thyroid function (T4) compared to the other marijuana users and the control subjects. CONCLUSIONS: Chronic marijuana use was also associated with reduced EEG power in alpha and beta bands at posterior sites. These reductions in EEG power appear to be related to cerebral perfusion deficits and/or thyroid function in marijuana abusers. SIGNIFICANCE: Our results suggest EEG, cerebral blood flow velocity, cardiovascular and thyroid function alterations in marijuana abuser with an extended period of use. These alterations reflect under arousal in these systems.     

Gender-specific vulnerability for rCBF abnormalities among cocaine abusers

Fifty abstinent cocaine-dependent patients and 20 healthy controls were evaluated with 99mTc-HMPAO SPECT to examine gender differences in perfusion. Group contrasts with statistical parametric mapping revealed male and female patients exhibited not only different regions, but different types of perfusion abnormality, including decreased perfusion in the anterior cingulate/frontal regions among cocaine-dependent men, and increased perfusion in the posterior cingulate of cocaine-dependent women. The findings suggested that cocaine-dependent men have perfusion deficits previously associated with cocaine withdrawal and impaired response inhibition, whereas, cocaine-dependent women demonstrated perfusion abnormalities consistent with heightened stress responsivity and worse treatment outcome. The possibility of different neural mechanisms underlying relapse in men and women, and the implications for utilizing specialized treatments are discussed.     

Perfusion abnormalities and decision making in cocaine dependence.

BACKGROUND: Previous studies have shown that cocaine abusers have cerebral perfusion deficits that may diminish cognitive functioning. This study examined whether cocaine-dependent patients have perfusion abnormalities associated with poor decision-making ability as measured by the Iowa Gambling Task (IGT). METHODS: Seventeen abstinent cocaine-dependent patients were administered the IGT after completion of resting 99mTc-HMPAO single-photon emission computed tomography (SPECT). RESULTS: Better IGT performance was negatively correlated with perfusion within the anterior cingulate gyrus, middle frontal gyrus, medial frontal gyrus, and superior frontal gyrus. The time to complete card selections was positively correlated with the severity of impairment. CONCLUSIONS: Resting hyperperfusion in brain regions previously implicated in decision making and response inhibition was associated with worse IGT scores. Impaired performance was related to a greater amount of time taken for card selections, suggesting that reduced ability was due to cognitive factors other than an impulsive response pattern.     

Prefrontal hypoactivation during cognitive control in early abstinent methamphetamine-dependent subjects

Individuals who abuse methamphetamine (MA) perform at levels below those of healthy controls on tests that require cognitive control. As cognitive control deficits may influence the success of treatment for addiction, we sought to help clarify the neural correlates of this deficit. MA-dependent (n = 10, abstinent 4–7 days) and control subjects (n = 18) performed a color-word Stroop task, which requires cognitive control, during functional MRI (fMRI). The task included a condition in which participants were required to respond to one stimulus dimension while ignoring another conflicting dimension, and another condition without conflict. We compared the groups on performance and neural activation in the two conditions. MA-dependent subjects made more errors and responded more slowly than controls. Controlling for response times in the incongruent condition, voxel-wise mixed effects analyses (whole-brain corrected) demonstrated that MA-dependent subjects had less activation than control subjects in the right inferior frontal gyrus, supplementary motor cortex/anterior cingulate gyrus and the anterior insular cortex during the incongruent condition only. MA-dependent subjects did not exhibit greater activation in any brain region in either of the Stroop conditions. These preliminary findings suggest that hypofunction in cortical areas that are important for executive function underlies cognitive control deficits associated with MA dependence.     

Prefrontal cortical dysfunction in abstinent cocaine abusers

The anterior cingulate cortex (ACC) and lateral prefrontal (LPFC) cortex are brain regions important to executive cognitive functions (ECF). We determined ACC and LPFC function in 23-day abstinent cocaine abusers using positron emission tomography (PET H(2)(15)O) during performance of a modified version of the Stroop Task. Cocaine abusers showed less activation than non-drug-using comparison subjects in the left ACC and the right LPFC and greater activation in the right ACC. Average amount of cocaine used per week was negatively correlated with activity in the rostral ACC and right LPFC. Disruption of ECF in substance abusers could interfere with attempts to stop drug use and undermine treatment. Since impairment in ECF may be a common feature of various neuropsychiatric disorders, these findings have applicability beyond the neurobiology of addiction.     

Differential impact of heavy cannabis use on sensory gating in schizophrenic patients and otherwise healthy controls

Cannabis abuse may precipitate the onset of schizophrenia and a dysfunction of the endocannabinoid system may be involved in the pathology of schizophrenia. Nevertheless, only few studies have addressed the neurobiological consequences of cannabis abuse for the development and course of schizophrenia. We measured the long-term effect of chronic cannabis abuse on the inhibitory function of the brain by the auditory P50 sensory gating in schizophrenic (n=15) and otherwise healthy chronic cannabis abusers (i.e. cannabis controls; n=11) and compared it to that of schizophrenic patients (n=12) and healthy controls (n=18) without cannabis or other drug abuse. All study subjects had to be abstinent from cannabis for at least 28 days. The main finding of our study was a P50 sensory gating deficit in cannabis controls that was correlated with the number of years with daily consumption (r=0.81; p=0.003). In contrast, we found no differences in P50 sensory gating between schizophrenic cannabis-abusers and non-abusers or healthy controls and no correlation with the number of years with daily consumption in those groups. To our knowledge this is the first study comparing the influence of chronic cannabis abuse in schizophrenic and otherwise healthy abusers on the inhibitory function of the brain. Our data provide some evidence that chronic cannabis abuse may affect sensory cortical circuits even after prolonged abstinence and they point to a possible differential effect in schizophrenic and otherwise healthy users.     

Frontoparietal attentional network activation differs between smokers and nonsmokers during affective cognition

Smoking withdrawal-induced disruption of affect and cognition is associated with dysregulated prefrontal brain function, although little is known regarding the neural foci of smoker–nonsmoker differences during affective cognition. Thus, the current study used functional magnetic resonance imaging (fMRI) to identify smoker–nonsmoker differences in affective cognition. Thirty-four healthy volunteers (17 smokers, 17 nonsmokers) underwent fMRI during an affective Stroop task (aST). The aST includes emotional cue-reactivity trials, and response selection trials that contain either neutral or negative emotional distractors. Smokers had less activation during negative cue-reactivity trials in regions subserving emotional awareness (i.e., posterior cingulate), inhibitory control (i.e., inferior frontal gyrus) and conflict resolution (i.e., anterior cingulate); during response-selection trials with negative emotional distractors, smokers had greater activation in a frontoparietal attentional network (i.e., middle frontal and supramarginal gyri). Exploratory analyses revealed that task accuracy was positively correlated with anterior cingulate cortex and inferior frontal gyrus response on fMRI. These findings suggests that chronic nicotine use may reduce inhibitory control and conflict resolution of emotional distraction, and result in recruiting additional attentional resources during emotional interference on cognition.     

Effects of psychotic state and task demand on prefrontal function in schizophrenia: an fMRI study of overt verbal fluency

OBJECTIVE: Impaired prefrontal cortical function is regarded as a central feature of schizophrenia. Although many neuroimaging studies have found evidence of abnormal prefrontal activation when patients with schizophrenia perform cognitive tasks, the extent to which this abnormality depends on the presence of active psychotic symptoms and on the demands of the task is unclear. The authors tested the hypothesis that prefrontal functional abnormalities in schizophrenia would be more evident in patients with active psychosis than in patients who were in remission and would become more apparent in the face of increasing task demands. METHOD: The authors used functional magnetic resonance imaging (fMRI) to examine prefrontal cortical activity during a paced letter verbal fluency task in three groups of subjects: acutely psychotic patients with schizophrenia, schizophrenia patients in remission, and healthy volunteers. Online subject performance was measured by utilizing a clustered fMRI acquisition sequence that allowed overt verbal responses to be made in the relative absence of scanner noise. RESULTS: Patients with schizophrenia showed less activation than the healthy comparison subjects in the anterior cingulate and the inferior frontal and right middle frontal cortices, independent of psychotic state and task demand. Acutely psychotic patients showed less activation than the healthy comparison subjects, but these differences were less marked than the differences between the patients in remission and the healthy comparison subjects. Acutely psychotic patients had less activation than the comparison subjects in the anterior cingulate but no significant difference in lateral prefrontal activation. Increasing task demand led to greater anterior cingulate and middle frontal activation in patients with active psychosis than in patients in remission. CONCLUSIONS: Schizophrenia is associated with impaired prefrontal function, but its manifestation depends on the severity of psychotic symptoms and the level of task difficulty.     

Neural correlates of the classic color and emotional stroop in women with abuse-related posttraumatic stress disorder.

BACKGROUND: The anterior cingulate and medial prefrontal cortex play an important role in the inhibition of responses, as measured by the Stroop task, as well as in emotional regulation. Dysfunction of the anterior cingulate/medial prefrontal cortex has been implicated in posttraumatic stress disorder (PTSD). The purpose of this study was to use the Stroop task as a probe of anterior cingulate function in PTSD. METHODS: Women with early childhood sexual abuse-related PTSD (n = 12) and women with abuse but without PTSD (n = 9) underwent positron emission tomographic measurement of cerebral blood flow during exposure to control, color Stroop, and emotional Stroop conditions. RESULTS: Women with abuse with PTSD (but not abused non-PTSD women) had a relative decrease in anterior cingulate blood flow during exposure to the emotional (but not color) classic Stroop task. During the color Stroop there were also relatively greater increases in blood flow in non-PTSD compared with PTSD women in right visual association cortex, cuneus, and right inferior parietal lobule. CONCLUSIONS: These findings add further evidence for dysfunction of a network of brain regions, including anterior cingulate and visual and parietal cortex, in abuse-related PTSD.     

The neural correlates of cue-induced craving in cocaine-dependent women

OBJECTIVE: Drug use reminders are associated with localized changes in brain activity related to intense drug wanting or craving in cocaine-dependent men. While cocaine dependence is prevalent and disabling in women, and certain clinically relevant sex differences exist, there is an absence of knowledge related to the neural correlates of cocaine craving in cocaine-dependent women. METHOD: The differential neural response to imagery depicting cocaine use and neutral imagery was defined by using [15O]H2O positron emission tomography (PET) imaging in eight cocaine-dependent women. Results were compared with a matched group of eight cocaine-dependent men. RESULTS: Cocaine-related imagery was associated with relative increases in cocaine craving and increases in regional cerebral blood flow in the superior temporal gyrus, dorsal anterior and posterior cingulate cortex, nucleus accumbens area, and the central sulcus. Compared with the results of an identical PET study in matched cocaine-dependent men, conditioned cocaine craving in women was associated with less activation of the amygdala, insula, orbitofrontal cortex, and ventral cingulate cortex and greater activation of the central sulcus and widely distributed frontal cortical areas. CONCLUSIONS: These findings suggest the presence of sex differences in the functional anatomy of cue-induced cocaine craving associated with drug dependence. Such differences may reflect sex differences in conditioned associations to cocaine use, in affective and other corollaries of cocaine craving, or in their volitional regulation and may underlie apparent sex differences in the effects of cocaine abstinence and the expectations of treatment outcome. Some support for the need for sex-specific strategies for treatment of cocaine dependence is also furnished by the findings of this study.     

Dopamine, corticostriatal connectivity, and intertemporal choice

Value-based decisions optimize behavioral outcomes. Because delayed rewards are discounted, an increased tendency to choose smaller, immediate rewards can lead to suboptimal choice. Steep discounting of delayed rewards (impulsivity) characterizes subjects with frontal lobe damage and behavioral disorders including substance abuse. Correspondingly, animal studies and indirect evidence in humans suggest that lower dopamine in the frontal cortex contributes to steeper discounting by impairing corticostriatal function. To test this hypothesis directly, we performed a randomized, double-blind, counterbalanced, placebo-controlled study in which we administered the brain penetrant catechol-O-methyltransferase inhibitor tolcapone or placebo to healthy subjects performing a delay discounting task. Tolcapone significantly increased choice of delayed monetary rewards, and this tolcapone-induced increase covaried with increased BOLD activity in the left ventral putamen and anterior insula. Tolcapone also changed corticostriatal connectivity: specifically, by inducing a decrease in the coherence between ventral putamen and pregenual cingulate cortex. These results indicate that raising cortical dopamine levels attenuates impulsive choice by changing corticostriatal function.     

Cerebral metabolic dysfunction and impaired vigilance in recently abstinent methamphetamine abusers.

BACKGROUND: Methamphetamine (MA) abusers have cognitive deficits, abnormal metabolic activity and structural deficits in limbic and paralimbic cortices, and reduced hippocampal volume. The links between cognitive impairment and these cerebral abnormalities are not established. METHODS: We assessed cerebral glucose metabolism with [F-18]fluorodeoxyglucose positron emission tomography in 17 abstinent (4 to 7 days) methamphetamine users and 16 control subjects performing an auditory vigilance task and obtained structural magnetic resonance brain scans. Regional brain radioactivity served as a marker for relative glucose metabolism. Error rates on the task were related to regional radioactivity and hippocampal morphology. RESULTS: Methamphetamine users had higher error rates than control subjects on the vigilance task. The groups showed different relationships between error rates and relative activity in the anterior and middle cingulate gyrus and the insula. Whereas the MA user group showed negative correlations involving these regions, the control group showed positive correlations involving the cingulate cortex. Across groups, hippocampal metabolic and structural measures were negatively correlated with error rates. CONCLUSIONS: Dysfunction in the cingulate and insular cortices of recently abstinent MA abusers contribute to impaired vigilance and other cognitive functions requiring sustained attention. Hippocampal integrity predicts task performance in methamphetamine users as well as control subjects.