Anne Marije Kaag

Reduced Frontal Brain Volume in Non-Treatment-Seeking Cocaine-Dependent Individuals: Exploring the Role of Impulsivity, Depression, and Smoking

In cocaine-dependent patients, gray matter (GM) volume reductions have been observed in the frontal lobes that are associated with the duration of cocaine use. Studies are mostly restricted to treatment-seekers and studies in non-treatment-seeking cocaine abusers are sparse. Here, we assessed GM volume differences between 30 non-treatment-seeking cocaine-dependent individuals and 33 non-drug using controls using voxel-based morphometry. Additionally, within the group of non-treatment-seeking cocaine-dependent individuals, we explored the role of frequently co-occurring features such as trait impulsivity (Barratt Impulsivity Scale, BIS), smoking, and depressive symptoms (Beck Depression Inventory), as well as the role of cocaine use duration, on frontal GM volume. Smaller GM volumes in non-treatment-seeking cocaine-dependent individuals were observed in the left middle frontal gyrus. Moreover, within the group of cocaine users, trait impulsivity was associated with reduced GM volume in the right orbitofrontal cortex, the left precentral gyrus, and the right superior frontal gyrus, whereas no effect of smoking severity, depressive symptoms, or duration of cocaine use was observed on regional GM volumes. Our data show an important association between trait impulsivity and frontal GM volumes in cocaine-dependent individuals. In contrast to previous studies with treatment-seeking cocaine-dependent patients, no significant effects of smoking severity, depressive symptoms, or duration of cocaine use on frontal GM volume were observed. Reduced frontal GM volumes in non-treatment-seeking cocaine-dependent subjects are associated with trait impulsivity and are not associated with co-occurring nicotine dependence or depression.

Relationship between trait impulsivity and cortical volume, thickness and surface area in male cocaine users and non-drug using controls

BACKGROUND Trait impulsivity is commonly associated with cocaine dependence. The few studies that have investigated the relation between trait impulsivity and cortical morphometry, have shown a distinct relation between impulsivity and cortical volume (CV) of temporal, frontal and insula cortex. As CV is the function of cortical surface area (SA) and cortical thickness (CT) impulsivity may be differently associated to SA than to CT. METHOD Fifty-three cocaine users (CU) and thirty-five controls (HC) (males aged 18-55 years) completed the Barrat impulsiveness scale and a structural scan was made on a 3T MRI scanner. CV, SA and CT were measured using Freesurfer. Multivariate analysis was used to test for group differences and group by impulsivity interaction effects in CV, SA and ST across nine regions of interest in the temporal, frontal and insular cortices. Possible confounding effects of drug- and alcohol exposure were explored. RESULTS Compared to HC, CU had a smaller SA of the superior temporal cortex but a larger SA of the insula. There were divergent relations between trait impulsivity and SA of the superior temporal cortex and insula (positive in HC, negative in CU) and CT of the anterior cingulate cortex (negative in HC, positive in CU). Within CU, there was a negative association between monthly cocaine use and CT of the insula and superior temporal cortex. DISCUSSION The distinct relation between trait impulsivity and cortical morphometry in CU and HC might underlie inefficient control over behavior resulting in maladaptive impulsive behaviour such as cocaine abuse.

White matter alterations in cocaine users are negatively related to the number of additionally (ab)used substances

Diffusion tensor imaging studies have provided evidence for white matter (WM) alterations in cocaine users. While polysubstance use is a widespread phenomenon among cocaine users, its role in WM alterations in cocaine users is currently unknown. This study examined the relation between the number of substances that are used(cocaine, alcohol and marijuana) and WM alterations in 67 male non‐drug users and 67 male regular cocaine users, who were classified into five groups based on the number of used substances. Diffusion‐weighted images were acquired on a 3.0 T magnetic resonance imaging scanner. Using tract‐based spatial statistics we demonstrated that there was a negative relation between the number of used substances and fractional anisotropy, a global measure of WM integrity. Also, we demonstrated a positive relation between the number of used substance and radial diffusivity within the prefrontal lobe, suggesting an increase in demyelination with the number of used substances. We did not find a dose‐effect between the level of substance use and WM alterations. The results of the current study may reflect the presence of a pre‐existing vulnerability to polysubstance use resulting from prefrontal WM abnormalities and related impaired cognitive control although WM alterations because of polysubstance use cannot be fully excluded. This study is an important first step in understanding the problems related to polysubstance use among cocaine users.

Mapping the hemodynamic response in human subjects to a dopaminergic challenge with dextroamphetamine using ASL-based pharmacological MRI

Pharmacological magnetic resonance imaging (phMRI) maps the neurovascular response to a pharmacological challenge and is increasingly used to assess neurotransmitter systems. Here we investigated the hemodynamic response to a dopaminergic (DAergic) challenge with dextroamphetamine (dAMPH) in humans using arterial spin labeling (ASL) based phMRI. Twelve healthy male subjects aged 21.0years (±1.5) were included. We used a pseudo-continuous ASL sequence (40min) to quantify cerebral blood flow (CBF) and started dAMPH infusion (0.3mg/kg) after 10min. On another day, we measured baseline dopamine D2/3 receptor availability with [(123)I]IBZM single photon emission computed tomography (SPECT). Baseline measures on mood and impulsivity and subjective behavioral responses to dAMPH were obtained. CBF response was corrected for cardiovascular effects using an occipital cortex mask for internal reference. Corrected CBF (sCBF) was analyzed using ROI-based and voxel-based analysis, in addition to independent component analysis (ICA). CBF data was correlated to D2/3 receptor availability and behavioral measures. Subjects reported experiencing euphoria following dAMPH administration. In the striatum sCBF significantly increased, as demonstrated by all three analysis methods. Voxel-based analysis and ICA also showed increased sCBF in the thalamus, anterior cingulate and cerebellum. Decreased sCBF was observed in several cortical areas, the posterior cingulated and paracingulate cortex. Apart from one ICA component, no correlations were found with sCBF changes and D2/3 receptor availability and behavioral measures. Our observations are in line with literature and provide further evidence that ASL-based phMRI with dAMPH is a promising technique to assess DAergic function in human subjects.

Dopaminergic dysfunction in abstinent dexamphetamine users: Results from a pharmacological fMRI study using a reward anticipation task and a methylphenidate challenge

BACKGROUND Dopamine (DA) is involved in systems governing motor actions, motivational processes and cognitive functions. Preclinical studies have shown that even relatively low doses of d-amphetamine (dAMPH) (equivalent to doses used in clinical Practice) can lead to DA neurotoxicity in rodents and non-human primates (Ricaurte et al., 2005). METHODS Therefore, we investigated the DAergic function in eight male recreational users of dAMPH and eight male healthy controls using functional magnetic resonance imaging (fMRI). We compared brain activation between both groups during a monetary incentive delay task (Knutson et al., 2001) with and without an oral methylphenidate (MPH) challenge. All subjects were abstinent for at least 2 weeks during the baseline scan. The second scan was performed on the same day 1.5 h after receiving an oral dose of 35 mg MPH (approximately 0.5 mg/kg) when peak MPH binding was assumed. RESULTS When anticipating reward, dAMPH users showed lower striatal activation in comparison to control subjects. In addition, MPH induced a reduction in the striatal activation during reward anticipation in healthy controls, whereas no such effect was observed in dAMPH users. CONCLUSION The combination of these findings provides further evidence for frontostriatal DAergic dysfunction in recreational dAMPH users and is consistent with preclinical data suggesting neurotoxic effects of chronic dAMPH use. The findings of this explorative study could have important implications for humans in need for treatment with dAMPH, such as patients suffering from ADHD and therefore this study needs replication in a larger sample.

Dysfunctional amygdala activation and connectivity with the prefrontal cortex in current cocaine users

Stimulant use is associated with increased anxiety and a single administration of dexamphetamine increases amygdala activation to biologically salient stimuli in healthy individuals. Here, we investigate how current cocaine use affects amygdala activity and amygdala connectivity with the prefrontal cortex in response to biologically salient stimuli in an emotional face matching task (EFMT).

The effect of N-acetylcysteine on brain glutamate and gamma-aminobutyric acid concentrations and on smoking cessation : A randomized, double-blind, placebo-controlled trial

Using data form a 14-day double-blind trial with 48 smokers randomized to either N-acetylcysteine (2400 mg) or placebo, we tested the effect of N-acetylcysteine on glutamate and gamma-aminobutyric acid concentrations in the dorsal anterior cingulate cortex and on smoking cessation. Smoking related behaviors and neurotransmitter concentrations in the dorsal anterior cingulate cortex were assessed before and after treatment. Forty-seven non-smoking males served as baseline controls. Smokers showed higher baseline glutamate but similar gamma-aminobutyric acid concentrations than non-smokers. There were no treatment effects on dorsal anterior cingulate cortex neurotransmitter concentrations, smoking cessation, craving, or withdrawal symptoms. These results confirm glutamate disbalance in smokers, but not efficacy of N-acetylcysteine.

A high working memory load prior to memory retrieval reduces craving in non-treatment seeking problem drinkers

BackgroundReconsolidation-based interventions have been suggested to be a promising treatment strategy for substance use disorders. In this study, we aimed to investigate the effectiveness of a working memory intervention to interfere with the reconsolidation of alcohol-related memories in a sample of non-treatment seeking heavy drinkers.MethodsParticipants were randomized to one of the two conditions that underwent a 3-day intervention: in the experimental condition, a 30-min working memory training was performed immediately after a 15-min memory retrieval session (i.e., within the memory reconsolidation time-window), whereas in the control condition, the working memory training was performed prior to a memory retrieval session.ResultsIn contrast to our original hypothesis, a high working memory load after memory retrieval did not interfere with the reconsolidation of those memories while a high working memory load prior to memory retrieval (the original control condition) strongly reduced retrieval-induced craving and craving for alcohol at follow-up.ConclusionWhereas the neurocognitive mechanism behind this effect needs to be further investigated, the current findings suggest that, if replicated, working memory training prior to addiction-related memory retrieval has the potential to become an effective (adjunctive) intervention in the treatment of substance use disorders.

Prefrontal Glx and GABA concentrations and impulsivity in cigarette smokers and smoking polysubstance users

Glutamate and GABA play an important role in substance dependence. However, it remains unclear whether this holds true for different substance use disorders and how this is related to risk-related traits such as impulsivity. We, therefore, compared Glx (as a proxy measure for glutamate) and GABA concentrations in the dorsal anterior cingulate cortex (dACC) of 48 male cigarette smokers, 61 male smoking polysubstance users, and 90 male healthy controls, and investigated the relationship with self-reported impulsivity and substance use. Glx and GABA concentrations were measured using proton Magnetic Resonance Spectroscopy. Impulsivity, smoking, alcohol and cocaine use severity and cannabis use were measured using self-report instruments. Results indicate a trend towards group differences in Glx. Post-hoc analyses showed a difference between smokers and healthy controls (p=0.04) and a trend towards higher concentrations in smoking polysubstance users and healthy controls (p=0.09), but no differences between smokers and smoking polysubstance users. dACC GABA concentrations were not significantly different between groups. Smoking polysubstance users were more impulsive than smokers, and both groups were more impulsive than controls. No significant associations were observed between dACC neurotransmitter concentrations and impulsivity and level and severity of smoking, alcohol or cocaine use or the presence of cannabis use. The results indicate that differences in dACC Glx are unrelated to type and level of substance use. No final conclusion can be drawn on the lack of GABA differences due to assessment difficulties. The relationship between dACC neurotransmitter concentrations and cognitive impairments other than self-reported impulsivity should be further investigated.

Aversive Counterconditioning Attenuates Reward Signaling in the Ventral Striatum

Appetitive conditioning refers to the process of learning cue-reward associations and is mediated by the mesocorticolimbic system. Appetitive conditioned responses are difficult to extinguish, especially for highly salient reward such as food and drugs. We investigate whether aversive counterconditioning can alter reward reinstatement in the ventral striatum in healthy volunteers using functional magnetic resonance imaging (fMRI). In the initial conditioning phase, two different stimuli were reinforced with a monetary reward. In the subsequent counterconditioning phase, one of these stimuli was paired with an aversive shock to the wrist. In the following extinction phase, none of the stimuli were reinforced. In the final reinstatement phase, reward was reinstated by informing the participants that the monetary gain could be doubled. Our fMRI data revealed that reward signaling in the ventral striatum and ventral tegmental area following reinstatement was smaller for the stimulus that was counterconditioned with an electrical shock, compared to the non-counterconditioned stimulus. A functional connectivity analysis showed that aversive counterconditioning strengthened striatal connectivity with the hippocampus and insula. These results suggest that reward signaling in the ventral striatum can be attenuated through aversive counterconditioning, possibly by concurrent retrieval of the aversive association through enhanced connectivity with hippocampus and insula.