Effect of baseline cannabis use and working‐memory network function on changes in cannabis use in heavy cannabis users: A prospective fMRI study

Theoretical models of addiction suggest that a substance use disorder represents an imbalance between hypersensitive motivational processes and deficient regulatory executive functions. Working‐memory (a central executive function) may be a powerful predictor of the course of drug use and drug‐related problems. Goal of the current functional magnetic resonance imaging study was to assess the predictive power of working‐memory network function for future cannabis use and cannabis‐related problem severity in heavy cannabis users. Tensor independent component analysis was used to investigate differences in working‐memory network function between 32 heavy cannabis users and 41 nonusing controls during an N‐back working‐memory task. In addition, associations were examined between working‐memory network function and cannabis use and problem severity at baseline and at 6‐month follow‐up. Behavioral performance and working‐memory network function did not significantly differ between heavy cannabis users and controls. However, among heavy cannabis users, individual differences in working‐memory network response had an independent effect on change in weekly cannabis use 6 months later (ΔR² = 0.11, P = 0.006, f² = 0.37) beyond baseline cannabis use (ΔR² = 0.41) and a behavioral measure of approach bias (ΔR² = 0.18): a stronger network response during the N‐back task was related to an increase in weekly cannabis use. These findings imply that heavy cannabis users requiring greater effort to accurately complete an N‐back working‐memory task have a higher probability of escalating cannabis use. Working‐memory network function may be a biomarker for the prediction of course and treatment outcome in cannabis users. Hum Brain Mapp 35:2470–2482, 2014. © 2013 Wiley Periodicals, Inc .     

Psychophysiological responses to drug-associated stimuli in chronic heavy cannabis use

Due to learning processes originally neutral stimuli become drug-associated and can activate an implicit drug memory, which leads to a conditioned arousing 'drug-seeking' state. This condition is accompanied by specific psychophysiological responses. The goal of the present study was the analysis of changes in cortical and peripheral reactivity to cannabis as well as alcohol-associated pictures compared with emotionally significant drug-unrelated and neutral pictures in long-term heavy cannabis users. Participants were 15 chronic heavy cannabis users and 15 healthy controls. Verbal reports as well as event-related potentials of the electroencephalogram and skin conductance responses were assessed in a cue-reactivity paradigm to determine the psychophysiological effects caused by drug-related visual stimulus material. The evaluation of self-reported craving and emotional processing showed that cannabis stimuli were perceived as more arousing and pleasant and elicited significantly more cannabis craving in cannabis users than in healthy controls. Cannabis users also demonstrated higher cannabis stimulus-induced arousal, as indicated by significantly increased skin conductance and a larger late positivity of the visual event-related brain potential. These findings support the assumption that drug-associated stimuli acquire increased incentive salience in addiction history and induce conditioned physiological patterns, which lead to craving and potentially to drug intake. The potency of visual drug-associated cues to capture attention and to activate drug-specific memory traces and accompanying physiological symptoms embedded in a cycle of abstinence and relapse – even in a 'so-called' soft drug – was assessed for the first time.     

Dynamic neural responses to cue-reactivity paradigms in heroin-dependent users: an fMRI study

Neuroimaging methods have been employed to study cue-reactivity-induced neural correlates in the human brain. However, very few studies have focused on characterizing the dynamic neural responses to the factorial interactions between the cues and the subjects. Fifteen right-handed heroin-dependent subjects and 12 age-matched nondrug using subjects participated in this study. Cue-reactivity paradigms were employed, while changes in blood oxygenation level-dependent (BOLD) signals were acquired by functional MRI (fMRI). The fMRI datasets were analyzed with AFNI software and repeated two-way ANOVA was employed for factorial analyses. Neural correlates of factorial interactions between cue-factor and subject-factor were identified in the regions of the ventral tegmental area (VTA), the left and right amygdala, the left and right fusiform cortex, and the precuneus in the mesocorticolimbic system, and in the superior frontal, dorsal lateral prefrontal, and orbitofrontal cortices in the prefrontal cortex system. The neural response patterns in the prefrontal systems are dynamic: decreased response to neutral-cues and increased response to heroin-cues. Further, heroin-cue-induced neural responses within the subregions in the PFC system are significantly intercorrelated. In conclusion, the cue-reactivity paradigms significantly activated the dynamic neural activations in the prefrontal system. It is suggested that the dynamic response patterns in the PFC system characterize the impaired brain control functions in heroin-dependent subjects.     

Striatal alcohol cue‐reactivity is stronger in male than female problem drinkers

Despite apparent sex differences in the development and treatment of alcohol use disorder, relatively little is known about the underlying neural mechanisms. In this study, we therefore investigated neural cue‐reactivity in a sample of male (n = 28) and female (n = 27) problem drinkers (matched on age and alcohol use severity) with an average alcohol use disorder identification test score of 12 which is indicative of a likely alcohol use disorder. Neural cue‐reactivity data were extracted from four regions of interest: the ventral and dorsal striatum and the ventral and dorsal anterior cingulate cortex, with a significance level set at p < 0.05. While the cue‐reactivity paradigm induced similar levels of self‐reported craving in men and women, visual alcohol cues induced significantly stronger striatal activation in men compared to drinkers. While sex differences in ventral striatal cue‐reactivity were partly explained by sex differences in alcohol intake, cannabis use, negative affect and anxiety, this was not the case for sex differences in dorsal striatal cue‐reactivity. These results suggest that alcohol cues are differentially processed by men and women and that the neurobiological mechanisms behind cue‐reactivity differ between the sexes. Consequently, paradigms using alcohol‐related pictures may not be optimal to induce cue‐reactivity in female drinkers and may not be optimal to measure neurobiological markers of alcohol use severity and relapse. Future alcohol cue‐reactivity studies should, in addition to including both men and women, include different types of cues (e.g., stressors and imagery in addition to pictures) to assess sex differences in alcohol cue‐reactivity.     

Alterations of the salience network in obesity: A resting‐state fMRI study

Obesity is a major health problem in modern societies. It has been related to abnormal functional organization of brain networks believed to process homeostatic (internal) and/or salience (external) information. This study used resting‐state functional magnetic resonance imaging analysis to delineate possible functional changes in brain networks related to obesity. A group of 18 healthy adult participants with obesity were compared with a group of 16 lean participants while performing a resting‐state task, with the data being evaluated by independent component analysis. Participants also completed a neuropsychological assessment. Results showed that the functional connectivity strength of the putamen nucleus in the salience network was increased in the obese group. We speculate that this abnormal activation may contribute to overeating through an imbalance between autonomic processing and reward processing of food stimuli. A correlation was also observed in obesity between activation of the putamen nucleus in the salience network and mental slowness, which is consistent with the notion that basal ganglia circuits modulate rapid processing of information. Hum Brain Mapp 34:2786–2797, 2013. © 2012 Wiley Periodicals, Inc.     

The MATCH cohort study in the Netherlands: rationale,objectives, methods and baseline characteristics of patients with (long‐term) common mental disorders

Research in the last decades shows that common mental disorders may be long‐term and severely disabling, resulting in severe mental illness (SMI). The percentage of Dutch SMI‐patients with common mental disorders receiving mental health services is estimated at 65–70%. However, it is unclear which patients in fact become SMI‐patients. We need to know more about the possible course of common mental disorders, understand the origins of chronicity in more detail, and have more insight in related care processes and care use of patients with common mental disorders. The MATCH cohort study is a four‐year multicentre naturalistic cohort study, with yearly assessments in primary, secondary, and tertiary services in three large Dutch mental health services. Socio‐demographics, mental disorders, course and severity of psychopathology, physiological health indicators, neurocognitive functioning, past and present life events, health care use and contact with mental health services, social functioning and quality of life, and recovery and well‐being are assessed. Baseline findings of 283 participating individuals and their key clinicians are described. The sample appears to appropriately represent the distribution of individuals across diagnostic categories in services, and level of care (outpatient, day treatment, inpatient) in the Netherlands and other developed nations. Copyright © 2016 John Wiley & Sons, Ltd.     

Craving for cannabis in patients with psychotic disorder,their non‐affected siblings and healthy controls: psychometric analysis of the obsessive compulsive drug use scale

Cannabis use is more common in individuals with non‐affective psychotic disorder and their siblings compared to healthy controls. As cannabis use is associated with a greater risk to develop psychotic disorder and an adverse outcome in those who already developed psychosis, it is important to know the role of craving in continued cannabis use and relapse in these vulnerable subjects. Therefore, we examined the validity of the Obsessive Compulsive Drug Use Scale for cannabis (OCDUS‐CAN) in patients with non‐affective psychotic disorder, their siblings, and healthy controls who all used cannabis in the past year. Simultaneous component analysis (SCA) was used to determine component weights that optimally explained the (co)variance of the OCDUS‐CAN variables in these different populations simultaneously. A three‐component SCA solution explained 74.2 % of the total variance, and consisted of well‐interpretable subscales that could be best described as craving/urge, resistance, and impact. Reliability of the subscales was good. The three subscales significantly discriminated between frequent and infrequent cannabis users. Patients scored higher on the craving/urge and impact scale than siblings and controls, which could be related to primary and secondary symptoms of their disorder. The OCDUS‐CAN is well suitable for people with or without vulnerability for psychotic disorder. Copyright © 2012 John Wiley & Sons, Ltd.     

Increased self‐focus in major depressive disorder is related to neural abnormalities in subcortical‐cortical midline structures

Patients with major depressive disorder (MDD) often show a tendency to strongly introspect and reflect upon their self, which has been described as increased self‐focus. Although subcortical‐cortical midline structures have been associated with reflection and introspection of oneself in healthy subjects, the neural correlates of the abnormally increased attribution of negative emotions to oneself, i.e. negative self‐attribution, as hallmark of the increased self‐focus in MDD remain unclear. The aim of the study was, therefore, to investigate the neural correlates during judgment of self‐relatedness of positive and negative emotional stimuli thereby testing for emotional self‐attribution. Using fMRI, we investigated 27 acute MDD patients and compared them with 25 healthy subjects employing a paradigm that focused on judgment of self‐relatedness when compared with mere perception of the very same emotional stimuli. Behaviourally, patients with MDD showed significantly higher degrees of self‐relatedness of specifically negative emotional stimuli when compared with healthy subjects. Neurally, patients with MDD showed significantly lower signal intensities in various subcortical and cortical midline regions like the dorsomedial prefrontal cortex (DMPFC), supragenual anterior cingulate cortex, precuneus, ventral striatum (VS), and the dorsomedial thalamus (DMT). Signal changes in the DMPFC correlated with depression severity and hopelessness whereas those in the VS and the DMT were related to judgment of self‐relatedness of negative emotional stimuli. In conclusion, we present first evidence that the abnormally increased negative self‐attribution as hallmark of the increased self‐focus in MDD might be mediated by altered neural activity in subcortical‐cortical midline structures. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.     

Serotonergic modulation of neuronal responses to behavioural inhibition and reinforcing stimuli: an fMRI study in healthy volunteers

Serotonin (5-HT) has been implicated in the aetiology of a number of psychiatric conditions, including depression, anxiety and antisocial personality disorder. The development of these disorders may arise from alterations in underlying motivational and cognitive processes such as emotional recognition, reinforcement processing and central inhibitory control. This study aimed to localize where in the brain 5-HT modulates neuropsychological processes relevant to putative 5-HT disorders, using functional magnetic resonance imaging. We examined the effect of the antidepressant mirtazapine on brain activations associated with behavioural inhibition and reinforcement processing in healthy subjects. Forty-five men were randomly allocated to receiving mirtazapine or placebo in a double-blind fashion. A Go/No-Go, Reward/No-Reward and Loss/No-loss task were performed during functional magnetic resonance imaging using a 1.5 Tesla Philips Gyroscan scanner. Blood oxygenation level dependent (BOLD) responses were analysed using SPM2. Task activations were largely consistent with previous findings. Mirtazapine modulated brain activations in the Go/No-Go and Reward/No-Reward task. During behavioural inhibition, enhanced activations were observed in the right orbitofrontal cortex (BA47). Increased activations in bilateral parietal cortex were found during the Reward task while no significant interaction was observed in the Loss task. Our results support the suggestion of an important role of serotonin in modulating basic processes involved in psychiatric disorders. Combining drug challenge with fMRI (pharmacoMRI; pMRI) is a promising tool for investigating these processes in healthy as well as patient groups.     

Individual associations of adolescent alcohol use disorder versus cannabis use disorder symptoms in neural prediction error signaling and the response to novelty

Two of the most commonly used illegal substances by adolescents are alcohol and cannabis. Alcohol use disorder (AUD) and cannabis use disorder (CUD) are associated with poorer decision-making in adolescents. In adolescents, level of AUD symptomatology has been negatively associated with striatal reward responsivity. However, little work has explored the relationship with striatal reward prediction error (RPE) representation and the extent to which any augmentation of RPE by novel stimuli is impacted. One-hundred fifty-one adolescents participated in the Novelty Task while undergoing functional magnetic resonance imaging (fMRI). In this task, participants learn to choose novel or non-novel stimuli to gain monetary reward. Level of AUD symptomatology was negatively associated with both optimal decision-making and BOLD response modulation by RPE within striatum and regions of prefrontal cortex. The neural alterations in RPE representation were particularly pronounced when participants were exploring novel stimuli. Level of CUD symptomatology moderated the relationship between novelty propensity and RPE representation within inferior parietal lobule and dorsomedial prefrontal cortex. These data expand on an emerging literature investigating individual associations of AUD symptomatology levels versus CUD symptomatology levels and RPE representation during reinforcement processing and provide insight on the role of neuro-computational processes underlying reinforcement learning/decision-making in adolescents.     

Adjunctive rufinamide in Lennox‐Gastaut syndrome: a long‐term,open‐label extension study

Kluger G, Glauser T, Krauss G, Seeruthun R, Perdomo C, Arroyo S. Adjunctive rufinamide in Lennox‐Gastaut syndrome: a long‐term, open‐label extension study.
Acta Neurol Scand: 122: 202–208.
© 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Objective – This open‐label extension evaluated the long‐term efficacy and tolerability of rufinamide in patients with Lennox‐Gastaut syndrome (LGS) who had previously completed a 12‐week double‐blind study. Materials and methods – In total, 124 patients (aged 4–37 years), receiving 1–3 concomitant antiepileptic drugs, were treated with rufinamide ～25–60 mg/kg/day. Efficacy was assessed by seizure frequency; tolerability by adverse events (AEs) and laboratory tests. Results – Overall, patients were treated with rufinamide for a median (range) of 432 (10–1149) days. Reductions in seizure frequency were observed throughout the study; during the last 12 months of treatment, 41.0% and 47.9% of patients had ≥50% reduction in total and tonic–atonic seizure frequency, respectively. The most common AEs were vomiting (30.6%) and pyrexia (25.8%). Conclusions – In this open‐label extension, rufinamide appeared to be an effective long‐term adjunctive therapy for the treatment of LGS‐associated seizures in children and young adults.     

Stimulating neural plasticity with real‐time fMRI neurofeedback in Huntington's disease: A proof of concept study

Novel methods that stimulate neuroplasticity are increasingly being studied to treat neurological and psychiatric conditions. We sought to determine whether real‐time fMRI neurofeedback training is feasible in Huntington's disease (HD), and assess any factors that contribute to its effectiveness. In this proof‐of‐concept study, we used this technique to train 10 patients with HD to volitionally regulate the activity of their supplementary motor area (SMA). We collected detailed behavioral and neuroimaging data before and after training to examine changes of brain function and structure, and cognitive and motor performance. We found that patients overall learned to increase activity of the target region during training with variable effects on cognitive and motor behavior. Improved cognitive and motor performance after training predicted increases in pre‐SMA grey matter volume, fMRI activity in the left putamen, and increased SMA–left putamen functional connectivity. Although we did not directly target the putamen and corticostriatal connectivity during neurofeedback training, our results suggest that training the SMA can lead to regulation of associated networks with beneficial effects in behavior. We conclude that neurofeedback training can induce plasticity in patients with Huntington's disease despite the presence of neurodegeneration, and the effects of training a single region may engage other regions and circuits implicated in disease pathology.