Kicking the habit: The neural basis of ingrained behaviors in cocaine addiction

Cocaine addiction is a complex and multifaceted process encompassing a number of forms of behavioral plasticity. The process of acquiring and consuming drugs can be sufficiently risky and complicated that the casual drug user may choose not to act on every motivation to use drugs. The repetition of drug seeking and taking, however, often results in the gradual development of drug craving and compulsive drug seeking associated with addiction. Moreover, the complex sets of behaviors associated with drug addiction can become ingrained to such an extent that, when activated by drug-associated stimuli or exposure to the drug itself, the processes underlying drug seeking and taking are automatically engaged and very difficult to suppress. Here, we examine the hypothesis that aspects of cocaine seeking and taking become ingrained with repetition, thereby contributing to continued drug use despite a conscious desire to abstain. We also review emerging evidence indicating that neuronal circuits including the dorsolateral striatum play a particularly important role in the habitual aspects of drug seeking and taking.     

Kicking the habit: The neural basis of ingrained behaviors in cocaine addiction

Cocaine addiction is a complex and multifaceted process encompassing a number of forms of behavioral plasticity. The process of acquiring and consuming drugs can be sufficiently risky and complicated that the casual drug user may choose not to act on every motivation to use drugs. The repetition of drug seeking and taking, however, often results in the gradual development of drug craving and compulsive drug seeking associated with addiction. Moreover, the complex sets of behaviors associated with drug addiction can become ingrained to such an extent that, when activated by drug-associated stimuli or exposure to the drug itself, the processes underlying drug seeking and taking are automatically engaged and very difficult to suppress. Here, we examine the hypothesis that aspects of cocaine seeking and taking become ingrained with repetition, thereby contributing to continued drug use despite a conscious desire to abstain. We also review emerging evidence indicating that neuronal circuits including the dorsolateral striatum play a particularly important role in the habitual aspects of drug seeking and taking.     

A neuropsychological assessment of frontal cognitive functions in Prader–Willi syndrome

Background Prader–Willi syndrome (PWS) is associated with a characteristic behavioural phenotype whose main features are, alongside compulsive hyperphagia, deficits in social behaviour: social withdrawal, temper tantrums, perseverative speech and behaviour, mental rigidity, stereotyped behaviour, impulsiveness, etc. Similar symptoms may also be found in autistic spectrum disorders and lesional pathologies of the frontal lobe. In both cases, such symptoms have been related to dysfunctions in frontal cognitive processes such as attention, working memory and executive functions. This study uses standardized neuropsychological instruments to analyse the degree to which these processes are affected in PWS. Methods The sample comprised 16 individuals with a genetically confirmed PWS diagnosis. Subjects’ IQ (Wechsler Adult Intelligence Scale), academic level, laterality and body mass index (BMI) were calculated. Attention, memory and executive functions were analysed using standard, widely employed neuropsychological tests. We compared the results of the sample group with the general population. Correlation analyses were carried out with IQ, academic level and BMI. Results In all the neuropsychological measures focusing on attention, executive functions and visuoperceptual organization, the study sample scored significantly lower than the normative reference population. The scores of the tests used for measuring immediate memory were also significantly lower when trials required sequential processing, although not when they required simultaneous processing. In the memorization of a list of words, subjects showed an initial deficit which disappeared with repetition, enabling them to obtain scores similar to the reference population. No significant correlations were found with BMI, and a higher IQ or academic level did not improve scores in the majority of tests. Conclusions The study shows a deficit in elementary frontal cognitive processes in PWS patients. This deficit may be involved in the social behaviour disorders that characterize such patients, as described in other development or frontal syndrome pathologies. However, we cannot affirm that the deficits found are specific to PWS; they could also occur in other causes of intellectual disability. Although in the study sample IQ did not correlate with frontal deficits, further research is needed to establish whether the neuropsychological alterations described form part of a cognitive phenotype for PWS. We believe that our understanding of the social behaviours typical of PWS may be improved by taking into consideration the cognitive functioning models of the prefrontal lobe, particularly those applied to pervasive developmental disorders.     

Small gray matter volume in orbitofrontal cortex in Prader‐Willi syndrome: A voxel‐based MRI study

Prader‐Willi syndrome (PWS) is a genetically determined neurodevelopmental disorder presenting with behavioral symptoms including hyperphagia, disinhibition, and compulsive behavior. The behavioral problems in individuals with PWS are strikingly similar to those in patients with frontal pathologies, particularly those affecting the orbitofrontal cortex (OFC). However, neuroanatomical abnormalities in the frontal lobe have not been established in PWS. The aim of this study was to look, using volumetric analysis, for morphological changes in the frontal lobe, especially the OFC, of the brains of individuals with PWS. Twelve adults with PWS and 13 age‐ and gender‐matched control subjects participated in structural magnetic resonance imaging (MRI) scans. The whole‐brain images were segmented and normalized to a standard stereotactic space. Regional gray matter volumes were compared between the PWS group and the control group using voxel‐based morphometry. The PWS subjects showed small gray‐matter volume in several regions, including the OFC, caudate nucleus, inferior temporal gyrus, precentral gyrus, supplementary motor area, postcentral gyrus, and cerebellum. The small gray‐matter volume in the OFC remained significant in a separate analysis that included total gray matter volume as a covariate. These preliminary findings suggest that the neurobehavioral symptoms in individuals with PWS are related to structural brain abnormalities in these areas. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.     

Pharmacological intervention for cognitive deficits and aggression in frontal lobe injury

We present a case that promotes early intervention and pharmacological treatment for the neuropsychiatric sequelae (frontal lobe syndrome, including cognitive impairment and aggressive behavior) associated with traumatic brain injury (TBI) and delirium. The patient, who sustained significant systemic complications related to his trauma, was previously diagnosed with alcohol and drug dependence and antisocial personality disorder. These antecedent conditions and prolonged systemic complications likely played a complicating role in his course of recovery.     

Brain activities associated with gaming urge of online gaming addiction

The aim of this study was to identify the neural substrates of online gaming addiction through evaluation of the brain areas associated with the cue-induced gaming urge. Ten participants with online gaming addiction and 10 control subjects without online gaming addiction were tested. They were presented with gaming pictures and the paired mosaic pictures while undergoing functional magnetic resonance imaging (fMRI) scanning. The contrast in blood-oxygen-level dependent (BOLD) signals when viewing gaming pictures and when viewing mosaic pictures was calculated with the SPM2 software to evaluate the brain activations. Right orbitofrontal cortex, right nucleus accumbens, bilateral anterior cingulate and medial frontal cortex, right dorsolateral prefrontal cortex, and right caudate nucleus were activated in the addicted group in contrast to the control group. The activation of the region-of-interest (ROI) defined by the above brain areas was positively correlated with self-reported gaming urge and recalling of gaming experience provoked by the WOW pictures. The results demonstrate that the neural substrate of cue-induced gaming urge/craving in online gaming addiction is similar to that of the cue-induced craving in substance dependence. The above-mentioned brain regions have been reported to contribute to the craving in substance dependence, and here we show that the same areas were involved in online gaming urge/craving. Thus, the results suggest that the gaming urge/craving in online gaming addiction and craving in substance dependence might share the same neurobiological mechanism.     

Regional cerebral blood flow and abnormal eating behavior in Prader–Willi syndrome

Background: Prader–Willi syndrome (PWS) is a genetically determined neurodevelopmental disorder and is generally regarded as a genetic model of obesity. Individuals with PWS exhibit behavioral symptoms including temper tantrums, rigid thinking, and compulsive behavior. The most striking feature of PWS is abnormal eating behavior, including hyperphagia, intense preoccupation with food, and incessant food seeking. To explore brain regions associated with the behavioral symptoms of PWS, we investigated differences in resting-state regional cerebral blood flow (rCBF) between individuals with PWS and healthy controls. Correlation analyses were also performed to examine the relationship between rCBF and altered eating behavior in PWS individuals. Methods: Twelve adults with PWS and 13 age- and gender-matched controls underwent resting-state single photon emission computerized tomography (SPECT) with N-isopropyl-p-[¹²³I] iodoamphetamine (IMP). The rCBF data were analyzed on a voxel-by-voxel basis using SPM5 software. Results: The results demonstrated that compared with controls, individuals with PWS had significantly lower rCBF in the right thalamus, left insular cortex, bilateral lingual gyrus, and bilateral cerebellum. They had significantly higher rCBF in the right inferior frontal gyrus, left middle/inferior frontal gyrus (anterior and posterior clusters), and bilateral angular gyrus. Additionally, rCBF in the left insula, which was significantly lower in PWS individuals, was negatively correlated with the eating behavior severity score. Conclusions: These results suggest that specific brain regions, particularly the left insula, may be partly responsible for the behavioral symptoms in PWS.     

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.     

Inhibitory control and emotional stress regulation: neuroimaging evidence for frontal-limbic dysfunction in psycho-stimulant addiction

This review focuses on neuroimaging studies that examined stress processing and regulation and cognitive inhibitory control in patients with psycho-stimulant addiction. We provide an overview of these studies, summarizing converging evidence and discrepancies as they occur in the literature. We also adopt an analytic perspective and dissect these psychological processes into their sub-components, to identify the neural pathways specific to each component process and those that are more specifically involved in psycho-stimulant addiction. To this aim we refer frequently to studies conducted in healthy individuals. Despite the separate treatment of stress/affect regulation, stress-related craving or compulsive drug seeking, and inhibitory control, neural underpinnings of these processes overlap significantly. In particular, the ventromedial prefrontal regions including the anterior cingulate cortex, amygdala and the striatum are implicated in psychostimulant dependence. Our overarching thesis is that prefrontal activity ensures intact emotional stress regulation and inhibitory control. Altered prefrontal activity along with heightened striatal responses to addicted drug and drug-related salient stimuli perpetuates habitual drug seeking. Further studies that examine the functional relationships of these neural systems will likely provide the key to understanding the mechanisms underlying compulsive drug use behaviors in psycho-stimulant dependence.     

Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli

OBJECTIVE: Cocaine-related cues have been hypothesized to perpetuate drug abuse by inducing a craving response that prompts drug-seeking behavior. However, the mechanisms, underlying neuroanatomy, and specificity of this neuroanatomy are not yet fully understood. METHOD: To address these issues, experienced cocaine users (N=17) and comparison subjects (N=14) underwent functional magnetic resonance imaging while viewing three separate films that portrayed 1 ) individuals smoking crack cocaine, 2) outdoor nature scenes, and 3) explicit sexual content. Candidate craving sites were identified as those that showed significant activation in the cocaine users when viewing the cocaine film. These sites were then required to show significantly greater activation when contrasted with comparison subjects viewing the cocaine film (population specificity) and cocaine users viewing the nature film (content specificity). RESULTS: Brain regions that satisfied these criteria were largely left lateralized and included the frontal lobe (medial and middle frontal gyri, bilateral inferior frontal gyrus), parietal lobe (bilateral inferior parietal lobule), insula, and limbic lobe (anterior and posterior cingulate gyrus). Of the 13 regions identified as putative craving sites, just three (anterior cingulate, right inferior parietal lobule, and the caudate/lateral dorsal nucleus) showed significantly greater activation during the cocaine film than during the sex film in the cocaine users, which suggests that cocaine cues activated similar neuroanatomical substrates as naturally evocative stimuli in the cocaine users. Finally, contrary to the effects of the cocaine film, cocaine users showed a smaller response than the comparison subjects to the sex film. CONCLUSIONS: These data suggest that cocaine craving is not associated with a dedicated and unique neuroanatomical circuitry; instead, unique to the cocaine user is the ability of learned, drug-related cues to produce brain activation comparable to that seen with nondrug evocative stimuli in healthy comparison subjects.     

Circadian Rhythms and Substance Abuse: Chronobiological Considerations for the Treatment of Addiction

Reward-related learning, including that associated with drugs of abuse, is largely mediated by the dopaminergic mesolimbic pathway. Mesolimbic neurophysiology and motivated behavior, in turn, are modulated by the circadian timing system which generates ～24-h rhythms in cellular activity. Both drug taking and seeking and mesolimbic dopaminergic neurotransmission can vary widely over the day. Moreover, circadian clock genes are expressed in ventral tegmental area dopaminergic cells and in mesolimbic target regions where they can directly modulate reward-related neurophysiology and behavior. There also exists a reciprocal influence between drug taking and circadian timing as the administration of drugs of abuse can alter behavioral rhythms and circadian clock gene expression in mesocorticolimbic structures. These interactions suggest that manipulations of the circadian timing system may have some utility in the treatment of substance abuse disorders. Here, the literature on bidirectional interactions between the circadian timing system and drug taking is briefly reviewed, and potential chronotherapeutic considerations for the treatment of addiction are discussed.     

Risk taking,sensation seeking and personality as related to changes in substance use from adolescence to young adulthood

IntroductionThis study examined changes in substance use from adolescence to young adulthood as related to adolescents’ risk taking, sensation seeking, antisocial activities, and personality traits.MethodsChilean youth (N = 890, 52% female) were studied in adolescence (14.5 and 16.2 years) and young adulthood (M age 21.3 years). Risk taking was assessed via a laboratory-based performance task (Balloon Analogue Risk Task), and self-administered questionnaires assessed sensation seeking, antisocial behaviors, personality and substance use.ResultsFrequent involvement in sensation seeking and antisocial activities were associated with increased odds of continued marijuana use from adolescence to young adulthood and of illicit substance use at young adulthood. High risk taking was associated with a reduced likelihood of discontinuing marijuana use at young adulthood, and high agreeableness and conscientiousness were associated with reduced likelihood of new onset marijuana use and illicit substance use at young adulthood.ConclusionsResults highlight specific risk-taking tendencies and personality characteristics that relate to initiating, continuing, or discontinuing substance use at entry into adulthood. Sensation seeking and involvement in antisocial activities were the two foremost risk factors for continued use, which is a forecaster of drug dependence. Findings suggest potential prevention and intervention targets for abstaining from or discontinuing substance use as youth transition to adulthood.     

Risperidone decreases craving and relapses in individuals with schizophrenia and cocaine dependence.

OBJECTIVE: To examine the efficacy of atypical neuroleptics for decreasing craving and drug relapses during protracted withdrawal in individuals dually diagnosed with schizophrenia and cocaine dependence. METHOD: We conducted a 6-week, open-label pilot study comparing risperidone with typical neuroleptics in a sample of withdrawn cocaine-dependent schizophrenia patients. RESULTS: Preliminary results suggest that individuals treated with risperidone had significantly less cue-elicited craving and substance abuse relapses at study completion. Further, they showed a trend toward a greater reduction in negative and global symptoms of schizophrenia. CONCLUSION: Atypical neuroleptics may help reduce craving and relapses in this population. Future research should include more rigorous double-blind placebo-controlled studies with this class of medications.     

Potential benefits of quetiapine in the treatment of substance dependence disorders

OBJECTIVE: Some antipsychotic medications prescribed for the treatment of psychoses, mood disorders or post-traumatic stress disorder in patients with coexisting substance dependence disorders (SDD) have reduced substance dependence. We studied the potential benefits of quetiapine in the treatment of SDD. METHODS: We conducted a retrospective chart review of data for 9 patients who were admitted to a 28-day residential rehabilitation program designed for individuals with SDD during a 3-month period from January 2003 through March 2003 and treated with quetiapine for nonpsychotic anxiety. These patients also met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria for alcohol, cocaine and/or methamphetamine dependence and substance-induced anxiety disorder. The patients were assessed using the Hamilton-D Rating Scale for Depression (Ham-D), a 10-point Likert scale to measure alcohol or drug cravings, and random Breathalyzer and urine drug screens. RESULTS: Quetiapine was generally well tolerated. Only 1 of the 9 patients stopped taking the medication because of increased anxiety. Other patients reported improvement in sleep and anxiety. The mean decrease in Ham-D score at discharge for the responders was 18.5 (p < 0.005). The biggest decreases on the Ham-D occurred on the subscales of insomnia, agitation, somatic anxiety, psychologic anxiety, hypochondriasis and obsessional symptoms. The mean decrease in the Likert 10-point craving scale was 5.9 for the responders (p < 0.005). These patients' periodic Breathalyzer and urine test results suggested that they remained abstinent from alcohol and other drug use. CONCLUSION: Quetiapine was beneficial in the treatment of SDD in patients with nonpsychotic anxiety.     

Lateralization of the frontal lobe functions elicited by a cognitive bias task is a fundamental process. Lesion study

Cognitive neuroscience researchers have hypothesized that context-dependent and context-independent response selection is associated with the left and right frontal lobe, respectively, in right-handed adult males. Patients with left frontal lobe lesions show context-independent reasoning in a cognitive bias task (CBT), while those with right frontal lesions show context-dependent reasoning. Young children show more context-independent responses in a modified CBT (mCBT), while adolescents and adults show more context-dependent responses. We investigated the cognitive bias of right-handed children with unilateral frontal lobe lesions/epileptic foci to explore the plasticity of lateralization in the frontal lobes. The study included eight children with left frontal lobe lesions/epileptic foci (LLF) and four children with right frontal lobe lesions/epileptic foci (RLF). Twenty-three right-handed age-matched males served as controls. A computer presented version of the original card-choice task that was simplified and modified for children was used (mCBT). Simple visual stimuli differed dichotomously in shape, color, number, and shading. A target object presented alone was followed by two choices from which subjects made selection based on preference. Considering all four characteristics, the degree of similarity between the target and the subjects' choice was scored for 30 trials. A high score indicated a context-dependent response selection bias and a low score indicated a context-independent bias. The RLF subjects had a higher converted score (mean: 26.8+/-2.2), while LLF subjects showed a lower converted score (mean: 7.75+/-6.3). There were highly significant differences between LLF subjects and the other groups (P<0.001 vs. controls or RLF subjects). No significant correlations were observed between the converted scores and the age at onset, time since insult, or IQ in either LLF or RLF subjects. These findings suggest that the lateralization of frontal lobe function elicited by mCBT is fundamental and independent of language lateralization, rather than secondary to it. Furthermore, these findings also indicate that the timetable for the development of lateralized frontal lobe functions depends upon biologic factors.     

Desipramine facilitation of cocaine abstinence in an adolescent.

An adolescent who was simultaneously dependent on cocaine and treated for attention-deficit hyperactivity disorder (ADHD) with dexedrine developed symptoms of severe depression followed by suicidal behavior. The patient was treated for cocaine craving, depression, and ADHD with desipramine on an inpatient adolescent unit for substance abusers with comorbid psychiatric disorder. The Minnesota Cocaine Craving Scale was used to monitor the cocaine craving. Issues about the strategies for the treatment of cocaine craving and the stimulant treatment/abuse dilemma are discussed with a special emphasis on comorbidity in adolescent substance abusers. Suicidal behavior related to cocaine abuse and craving and the application of the cocaine abstinence three phase model to an inpatient setting are illuminated.     

Cannabis cue-elicited craving and the reward neurocircuitry

Cue-elicited craving or the intense desire to consume a substance following exposure to a conditioned drug cue is one of the primary behavioral symptoms of substance use disorders (SUDs). While the concept of cue-elicited craving is well characterized in alcohol and other substances of abuse, only recently has it been described in cannabis. A review of the extant literature has established that cue-elicited craving is a powerful reinforcer that contributes to drug-seeking for cannabis. Further, emergent research has begun to identify the neurobiological systems and neural mechanisms associated with this behavior. What research shows is that while theories of THC's effects on the dopaminergic-reward system remain divergent, cannabis cues elicit neural activation in the brain's reward network.     

Desipramine facilitation of initial cocaine abstinence

We conducted a double-blind, random assignment, six-week comparison of desipramine hydrochloride (n = 24), lithium carbonate (n = 24), and placebo (n = 24) treatments for cocaine dependence. Subjects were 72 outpatient cocaine abusers who met DSM-III-R dependence criteria for cocaine but not for other substance abuse. Subjects in each treatment group were similar in history of cocaine and other substance abuse, cocaine craving, sociodemographics, and other psychiatric comorbidity. Desipramine, compared with both other treatments, substantially decreased cocaine use. Lithium treatment outcome did not differ from that of placebo. Desipramine-treated subjects attained contiguous periods of abstinence substantially more frequently than subjects receiving lithium or placebo. Fifty-nine percent of the desipramine-treated subjects were abstinent for at least three to four consecutive weeks during the six-week study period, compared with 17% for placebo and 25% for lithium. Cocaine craving reductions were also substantially greater in the desipramine-treated subjects. Establishment of initial abstinence is the first stage in recovery from cocaine dependence. Our findings indicate that desipramine is an effective general treatment, for this first treatment stage, in actively cocaine-dependent outpatients.     

Frontal lobe hematoma associated with transcortical motor aphasia: case report]

An 81-year-old woman with left medial frontal lobe hematoma, which involved the supplementary motor area, is reported. She was right-handed and was initially mute for several hours after the onset. On admission, she exhibited mild paresis of the right lower extremity. Her spontaneous speech was sparse and not fluent, but her articulation and auditory comprehension were normal and repetition was good. She exhibited excellent performance in the confrontation naming task, but showed difficulty in recalling words from a given category during the word fluency task. On the basis of these clinical features, she was diagnosed as having transcortical motor aphasia. Our case may corroborate previous findings that the left medial frontal lobe is important in word fluency but not in confrontation naming.     

Varieties of perseveration

We propose a new taxonomy for perseveration consisting of three categories which are distinctive at the levels of clinical features, process, and neuroanatomy. Stuck-in-set perseveration, the inappripriate maintenance of a current category or framework, involves an underlying process deficit in executive functioning and is related neuroanatomically to frontal lobe damage. Recurrent perseveration, the unintentional repetition of a previous response to a subsequent stimulus, involves an abnormal post-facilitation of memory traces and is related neuroanatomically to posterior left hemisphere damage. Continuous perseveration is the inappropriate prolongation or repetition of a behavior without interruption. It involves a deficit in motor output and is most common in patients with damage to the basal ganglia.