Methylphenidate as a treatment option for substance use disorder: a transdiagnostic perspective.

A transition in viewing mental disorders from conditions defined as a set of unique characteristics to one of the quantitative variations on a collection of dimensions allows overlap between disorders. The overlap can be utilized to extend to treatment approaches. Here, we consider the overlap between attention-deficit/hyperactivity disorder and substance use disorder to probe the suitability to use methylphenidate as a treatment for substance use disorder. Both disorders are characterized by maladaptive goal-directed behavior, impaired cognitive control, hyperactive phasic dopaminergic neurotransmission in the striatum, prefrontal hypoactivation, and reduced frontal cortex gray matter volume/density. In addition, methylphenidate has been shown to improve cognitive control and normalize associated brain activation in substance use disorder patients and clinical trials have found methylphenidate to improve clinical outcomes. Despite the theoretical basis and promising, but preliminary, outcomes, many questions remain unanswered. Most prominent is whether all patients who are addicted to different substances may equally profit from methylphenidate treatment.

White matter and neurochemical mechanisms underlying age-related differences in motor processing speed.

Aging is associated with changes in the central nervous system and leads to reduced life quality. Here, we investigated the age-related differences in the CNS underlying motor performance deficits using magnetic resonance spectroscopy and diffusion MRI. MRS measured N-acetyl aspartate (NAA), choline (Cho), and creatine (Cr) concentrations in the sensorimotor and occipital cortex, whereas dMRI quantified apparent fiber density (FD) in the same voxels to evaluate white matter microstructural organization. We found that aging was associated with increased reaction time and reduced FD and NAA concentration in the sensorimotor voxel. Both FD and NAA mediated the association between age and reaction time. The NAA concentration was found to mediate the association between age and FD in the sensorimotor voxel. We propose that the age-related decrease in NAA concentration may result in reduced axonal fiber density in the sensorimotor cortex which may ultimately account for the response slowness of older participants.

Cannabis Use and Neuroadaptation: A Call for Δ 9 -Tetrahydrocannabinol Challenge Studies.

Currently, the assessment of the neurobehavioral consequences of repeated cannabis use is restricted to studies in which brain function of chronic cannabis users is compared to that of non-cannabis using controls. The assumption of such studies is that changes in brain function of chronic users are caused by repeated and prolonged exposure to acute cannabis intoxication. However, differences in brain function between chronic cannabis users and non-users might also arise from confounding factors such as polydrug use, alcohol use, withdrawal, economic status, or lifestyle conditions. We propose a methodology that highlights the relevance of acute Δ9-tetrahydrocannabinol (THC) dosing studies for a direct assessment of neuroadaptations in chronic cannabis users. The approach includes quantification of neurochemical, receptor, and functional brain network changes in response to an acute cannabis challenge, as well as stratification of cannabis using groups ranging from occasional to cannabis-dependent individuals. The methodology allows for an evaluation of THC induced neuroadaptive and neurocognitive changes across cannabis use history, that can inform neurobiological models on reward driven, compulsive cannabis use.

Volume and Connectivity Differences in Brain Networks Associated with Cognitive Constructs of Binge Eating.

Bulimia nervosa (BN) and binge eating disorder (BED) are characterized by episodes of eating large amounts of food while experiencing a loss of control. Recent studies suggest that the underlying causes of BN/BED consist of a complex system of environmental cues, atypical processing of food stimuli, altered behavioral responding, and structural/functional brain differences compared with healthy controls (HC). In this narrative review, we provide an integrative account of the brain networks associated with the three cognitive constructs most integral to BN and BED, namely increased reward sensitivity, decreased cognitive control, and altered negative affect and stress responding. We show altered activity in BED/BN within several brain networks, specifically in the striatum, insula, prefrontal cortex (PFC) and orbitofrontal cortex (OFC), and cingulate gyrus. Numerous key nodes in these networks also differ in volume and connectivity compared with HC. We provide suggestions for how this integration may guide future research into these brain networks and cognitive constructs.

Dopaminergic and noradrenergic modulation of stress-induced alterations in brain activation associated with goal-directed behaviour.

BACKGROUND: Acute stress is thought to reduce goal-directed behaviour, an effect purportedly associated with stress-induced release of catecholamines. In contrast, experimentally increased systemic catecholamine levels have been shown to increase goal-directed behaviour. Whether experimentally increased catecholamine function can modulate stress-induced reductions in goal-directed behaviour and its neural substrates, is currently unknown. AIM: To assess whether and how experimentally induced increases in dopamine and noradrenaline contribute to the acute stress effects on goal-directed behaviour and associated brain activation. METHODS: One hundred participants underwent a stress induction protocol (Maastricht acute stress test; MAST) or a control procedure and received methylphenidate (MPH) (40 mg, oral) or placebo according to a 2 × 2 between-subjects design. In a well-established instrumental learning paradigm, participants learnt stimulus-response-outcome associations, after which rewards were selectively devalued. Participants' brain activation and associated goal-directed behaviour were assessed in a magnetic resonance imaging scanner at peak cortisol/MPH concentrations. RESULTS: The MAST and MPH increased physiological measures of stress (salivary cortisol and blood pressure), but only MAST increased subjective measures of stress. MPH modulated stress effects on activation of brain areas associated with goal-directed behaviour, including insula, putamen, amygdala, medial prefrontal cortex, frontal pole and orbitofrontal cortex. However, MPH did not modulate the tendency of stress to induce a reduction in goal-directed behaviour. CONCLUSION: Our neuroimaging data suggest that MPH-induced increases in dopamine and noradrenaline reverse stress-induced changes in key brain regions associated with goal-directed behaviour, while behavioural effects were absent. These effects may be relevant for preventing stress-induced maladaptive behaviour like in addiction or binge eating disorder.

Balancing Between Goal-Directed and Habitual Responding Following Acute Stress.

Instrumental learning is regulated by two memory systems: a relatively rigid but efficient habit system and a flexible but resource-demanding goal-directed system. Previous work has demonstrated that exposure to acute stress may shift the balance between these systems toward the habitual system. In the current study, we used a 2-day outcome devaluation paradigm with a 75% reward contingency rate and altered food reward categories to replicate and extend our previous findings. Participants learned neutral stimulus-response-reward associations on the first day. On the second day, rewards were devalued by eating to satiety. Subsequently, acute stress was induced in half of the participants using the Maastricht Acute Stress Test, while the other half engaged in a nonstressful control task. Finally, relative goal-directed versus habitual behavior was evaluated in a slips-of-action phase, where more slips-of-action indicate a shift toward the habitual system. Results showed that participants successfully acquired the stimulus-response-reward associations, that devaluation was effective, and that stressed participants displayed significant increases in cortisol and blood pressure. Stress led participants to commit more slips-of-action compared with nonstressed controls. The current study extends previous work, showing that the employed paradigm and outcome devaluation procedure are boundary conditions to the stress-induced shift in instrumental responding.

A proof-of-principle study of the effect of combined haloperidol and levodopa administration on working memory-related brain activation in humans.

OBJECTIVE: Cognitive deficits including impaired working memory are a hallmark feature of schizophrenia. Dopamine D1 receptor modulated changes in prefrontal cortex function play a potentially important role in the pathology underlying such deficits. However, pharmacological interventions that selectively engage the D1 receptor are severely restricted for research in humans. The present study is a proof-of-principle for enhancing cognitive performance and associated brain activation via indirect D1 stimulation, operationalised by combining the nonselective dopamine agonist L-dopa with the D2-antagonist haloperidol. METHODS: Fourteen healthy volunteers received placebo or combined carbidopa (25 mg)/L-dopa (100 mg) plus haloperidol (2 mg) orally on two separate occasions according to a within-subjects crossover design. Drug-induced differences in brain activity were assessed during an N-back working memory task in a 3T magnetic resonance imaging environment. RESULTS: Drug treatment was associated with greater functional connectivity between the dorsolateral prefrontal cortex and areas within the salience network during all N-back trials. Drug treatment was also associated with reduced activation, most prominently in the occipital/temporal brain areas during 2-back performance. CONCLUSIONS: This preliminary study provides initial evidence for combined L-dopa/haloperidol modulation in cognition-related brain areas and networks, which is relevant for the treatment of cognitive impairments in mental illness.

GABA levels and measures of intracortical and interhemispheric excitability in healthy young and older adults: an MRS-TMS study.

Edited magnetic resonance spectroscopy (MRS) and transcranial magnetic stimulation (TMS) have often been used to study the integrity of the GABAergic neurotransmission system in healthy aging. To investigate whether the measurement outcomes obtained with these 2 techniques are associated with each other in older human adults, gamma-aminobutyric acid (GABA) levels in the left sensorimotor cortex were assessed with edited MRS in 28 older (63-74 years) and 28 young adults (19-34 years). TMS at rest was then used to measure intracortical inhibition (short-interval intracortical inhibition/long-interval intracortical inhibition), intracortical facilitation, interhemispheric inhibition from left to right primary motor cortex (M1) and recruitment curves of left and right M1. Our observations showed that short-interval intracortical inhibition and long-interval intracortical inhibition in the left M1 were reduced in older adults, while GABA levels did not significantly differ between age groups. Furthermore, MRS-assessed GABA within left sensorimotor cortex was not correlated with TMS-assessed cortical excitability or inhibition. These observations suggest that healthy aging gives rise to altered inhibition at the postsynaptic receptor level, which does not seem to be associated with MRS-assessed GABA+ levels.

Cerebellar gray matter explains bimanual coordination performance in children and older adults.

The cerebellum appears to undergo late maturation in children and early decline at older age. Whether these age-related changes affect bimanual coordination performance remains unclear at best. Here, we identified the ages at which bimanual coordination performance stops improving and starts declining. In an independent cohort, we defined brain regions of interest involved in bimanual coordination using functional magnetic resonance imaging. We used these regions of interest to investigate the extent to which the gray matter of cerebellar and other brain regions explains bimanual coordination performance from 10- to 80-year-olds. Results showed that bimanual coordination performance starts declining from the age of 40 years. In participants aged 10-20 years, cerebellar lobule VI was the only significant brain predictor of bimanual coordination performance. In participants aged 60-80 years, this cerebellar region, together with the primary sensorimotor cortex, formed a group of strongest predictors. These results from 2 independent samples (10-20 and 60-80 years) suggest that cerebellar lobule VI is critical for the development and preservation of bimanual coordination skills in children and older adults, respectively. In addition, post hoc analyses suggested that the primary motor cortex mediated the adverse effect of age on bimanual coordination performance in older adults.

Anatomy of Subcortical Structures Predicts Age-Related Differences in Skill Acquisition.

Skill acquisition capabilities vary substantially from one individual to another. Volumetric brain studies have demonstrated that global volume of several subcortical structures predicts variations in learning outcome in young adults (YA) and older adults (OA). In this study, for the first time, we utilized shape analysis, which offers a more sensitive detection of subregional brain anatomical deformations, to investigate whether subregional anatomy of subcortical structures is associated with training-induced performance improvement on a bimanual task in YA and OA, and whether this association is age-dependent. Compared with YA, OA showed poorer performance, greater performance improvement, and smaller global volume and compressed subregional shape in subcortical structures. In OA, global volume of the right nucleus accumbens and subregional shape of the right thalamus, caudate, putamen and nucleus accumbens were positively correlated with acquisition of difficult (non-preferred) but not easy (preferred) task conditions. In YA, global volume and subregional shape of the right hippocampus were negatively correlated with performance improvement in both the easy and difficult conditions. We argue that pre-existing neuroanatomical measures of subcortical structures involved in motor learning differentially predict skill acquisition potential in YA and OA.

Individual differences in brainstem and basal ganglia structure predict postural control and balance loss in young and older adults.

It remains unclear which specific brain regions are the most critical for human postural control and balance, and whether they mediate the effect of age. Here, associations between postural performance and corticosubcortical brain regions were examined in young and older adults using multiple structural imaging and linear mixed models. Results showed that of the regions involved in posture, the brainstem was the strongest predictor of postural control and balance: lower brainstem volume predicted larger center of pressure deviation and higher odds of balance loss. Analyses of white and gray matter in the brainstem showed that the pedunculopontine nucleus area appeared to be critical for postural control in both young and older adults. In addition, the brainstem mediated the effect of age on postural control, underscoring the brainstem's fundamental role in aging. Conversely, lower basal ganglia volume predicted better postural performance, suggesting an association between greater neural resources in the basal ganglia and greater movement vigor, resulting in exaggerated postural adjustments. Finally, results showed that practice, shorter height and heavier weight (i.e., higher body mass index), higher total physical activity, and larger ankle active (but not passive) range of motion were predictive of more stable posture, irrespective of age.

Cortical grey matter content is associated with both age and bimanual performance, but is not observed to mediate age-related behavioural decline.

Declines in both cortical grey matter and bimanual coordination performance are evident in healthy ageing. However, the relationship between ageing, bimanual performance, and grey matter loss remains unclear, particularly across the whole adult lifespan. Therefore, participants (N = 93, range 20-80 years) performed a complex Bimanual Tracking Task, and structural brain images were obtained using magnetic resonance imaging. Analyses revealed that age correlated negatively with task performance. Voxel-based morphometry analysis revealed that age was associated with grey matter declines in task-relevant cortical areas and that grey matter in these areas was negatively associated with task performance. However, no evidence for a mediating effect of grey matter in age-related bimanual performance decline was observed. We propose a new hypothesis that functional compensation may account for the observed absence of mediation, which is in line with the observed pattern of increased inter-individual variance in performance with age.

Nucleus accumbens and caudate atrophy predicts longer action selection times in young and old adults.

There is a convergence in the literature toward a critical role for the basal ganglia in action selection. However, which substructures within the basal ganglia fulfill this role is still unclear. Here we used shape analyses of structural magnetic resonance imaging data to determine the extent to which basal ganglia structures predict performance in easy and complex multilimb reaction-time tasks in young and old adults. Results revealed that inward deformation (i.e., local atrophy) of the nucleus accumbens and caudate were predictive of longer action selection times in complex conditions, but not in easy conditions. Additionally, when assessing the relation between behavioral performance and the shape of the left nucleus accumbens in the two age groups separately, we found a significant performance-structure association in old, but not young adults. This result suggests that the relevance of the nucleus accumbens for the process of action selection increases with age. Hum Brain Mapp 37:4629-4639, 2016. © 2016 Wiley Periodicals, Inc.

Alterations in brain white matter contributing to age-related slowing of task switching performance: The role of radial diffusivity and magnetization transfer ratio.

Successfully switching between tasks is critical in many daily activities. Age-related slowing of this switching behavior has been documented extensively, but the underlying neural mechanisms remain unclear. Here, we investigated the contribution of brain white matter changes associated with myelin alterations to age-related slowing of switching performance. Diffusion tensor imaging derived radial diffusivity (RD) and magnetization transfer imaging derived magnetization transfer ratio (MTR) were selected as myelin sensitive measures. These metrics were studied in relation to mixing cost (i.e., the increase in reaction time during task blocks that require task switching) on a local-global switching task in young (n = 24) and older (n = 22) adults. Results showed that higher age was associated with widespread increases in RD and decreases in MTR, indicative of white matter deterioration, possibly due to demyelination. Older adults also showed a higher mixing cost, implying slowing of switching performance. Finally, mediation analyses demonstrated that decreases in MTR of the bilateral superior corona radiata contributed to the observed slowing of switching performance with increasing age. These findings provide evidence for a role of cortico-subcortical white matter changes in task switching performance deterioration with healthy aging. Hum Brain Mapp 37:4084-4098, 2016. © 2016 Wiley Periodicals, Inc.

Whole-brain grey matter density predicts balance stability irrespective of age and protects older adults from falling.

Functional and structural imaging studies have demonstrated the involvement of the brain in balance control. Nevertheless, how decisive grey matter density and white matter microstructural organisation are in predicting balance stability, and especially when linked to the effects of ageing, remains unclear. Standing balance was tested on a platform moving at different frequencies and amplitudes in 30 young and 30 older adults, with eyes open and with eyes closed. Centre of pressure variance was used as an indicator of balance instability. The mean density of grey matter and mean white matter microstructural organisation were measured using voxel-based morphometry and diffusion tensor imaging, respectively. Mixed-effects models were built to analyse the extent to which age, grey matter density, and white matter microstructural organisation predicted balance instability. Results showed that both grey matter density and age independently predicted balance instability. These predictions were reinforced when the level of difficulty of the conditions increased. Furthermore, grey matter predicted balance instability beyond age and at least as consistently as age across conditions. In other words, for balance stability, the level of whole-brain grey matter density is at least as decisive as being young or old. Finally, brain grey matter appeared to be protective against falls in older adults as age increased the probability of losing balance in older adults with low, but not moderate or high grey matter density. No such results were observed for white matter microstructural organisation, thereby reinforcing the specificity of our grey matter findings.

Subcortical volumetric changes across the adult lifespan: subregional thalamic atrophy accounts for age-related sensorimotor performance declines.

Even though declines in sensorimotor performance during healthy aging have been documented extensively, its underlying neural mechanisms remain unclear. Here, we explored whether age-related subcortical atrophy plays a role in sensorimotor performance declines, and particularly during bimanual manipulative performance (Purdue Pegboard Test). The thalamus, putamen, caudate and pallidum of 91 participants across the adult lifespan (ages 20-79 years) were automatically segmented. In addition to studying age-related changes in the global volume of each subcortical structure, local deformations within these structures, indicative of subregional volume changes, were assessed by means of recently developed shape analyses. Results showed widespread age-related global and subregional atrophy, as well as some notable subregional expansion. Even though global atrophy failed to explain the observed performance declines with aging, shape analyses indicated that atrophy in left and right thalamic subregions, specifically subserving connectivity with the premotor, primary motor and somatosensory cortical areas, mediated the relation between aging and performance decline. It is concluded that subregional volume assessment by means of shape analyses offers a sensitive tool with high anatomical resolution in the search for specific age-related associations between brain structure and behavior.

Antihistamine induced blood oxygenation level dependent response changes related to visual processes during sensori-motor performance.

The histaminergic involvement in selective processes underlying its role in human sensori-motor performance is largely unknown. Recently, selective effects of central H1-inverse agonism on sensory visual processes were observed in electrophysiological--but not behavioral data; a discrepancy suggested to result from speeded response-choice related processes. This study attempts to establish the effects on visual processes and identify putative compensatory mechanisms related to increased visual and response-choice task demands by assessing H1-inverse agonism induced changes in blood oxygenation level dependent (BOLD) response. Twelve participants received oral doses of dexchlorpheniramine 4 mg, lorazepam 1 mg, and placebo in a three-way crossover designed study. Brain activity was assessed for choice reaction time task performance in a 3 T magnetic resonance scanner 2 h after drug administration. Participants responded with their left or right hand and index or middle finger as indicated by the laterality of stimulus presentation and identity of the stimulus, respectively. Stimuli were intact or visually degraded and responses were compatible or incompatible with the laterality of stimulus presentation. Both dexchlorpheniramine and lorazepam affected the BOLD response in the occipital cortex indicating affected visual information processing. Dexchlorpheniramine decreased BOLD response in the dorsal precuneus and left precentral gyrus as part of a motor network, which however might not be interpreted as a compensatory mechanism, but may be the upstream consequence of impaired visual processing.

The role of P-glycoprotein in CNS antihistamine effects.

RATIONALE: P-glycoprotein (P-gp) is a drug efflux pump expressed, amongst others, on the luminal surface of the cerebral endothelial cells forming the blood-brain barrier. Studies in rodents have demonstrated that antihistamines that are substrates of the P-gp transporter display no or minor central nervous system (CNS) effects as compared to antihistamines that are not P-gp transporter substrates. OBJECTIVES: The present study explored whether P-gp contributes in similar ways to the occurrence of sedative effects of antihistamines in humans. METHODS: An fMRI study was conducted according to a double-blind, randomized, placebo-controlled, cross-over design in 13 healthy volunteers. Participants received cetirizine 15 mg (an antihistamine), verapamil 120 mg (a P-gp blocker), a combination of cetirizine + verapamil, and a placebo. Brain activity was assessed while conducting the attention network test (ANT) in a 3T magnetic resonance scanner. The ANT measures three independent attention domains: i.e., alerting, orienting, and executive attention. It was expected that the combined treatment of cetirizine with verapamil would prevent efflux of cetirizine from the CNS, thus increasing attentional impairment, as compared to cetirizine administered alone. RESULTS: The present study provides evidence that the P-gp transporter is involved in central antihistamine effects in humans. Participants were less alert during the combined treatment of cetirizine and verapamil as indicated by longer reaction times and decreased blood oxygen level-dependent response in the right superior temporal gyrus. CONCLUSION: It is concluded that the affinity for the P-gp transporter may contribute to the lower incidence of CNS side effects of certain antihistamines.

Cognitive, psychomotor and actual driving performance in healthy volunteers after immediate and extended release formulations of alprazolam 1 mg.

RATIONALE: Alprazolam extended-release (XR) is approved for the treatment of panic disorder. This sustained formulation is absorbed in a delayed manner and is therefore expected to produce fewer and less severe side effects than its immediate release equivalent (alprazolam IR). The effect of alprazolam XR on potentially dangerous daily activities, such as driving a car, is expected to be less as compared to alprazolam IR. OBJECTIVES: The present study was designed to compare the effects of alprazolam XR (1 mg) and alprazolam IR (1 mg) on actual driving ability and cognitive function. METHOD: Eighteen healthy volunteers (aged 20-45 years) participated in a double-blind, placebo-controlled, three-way crossover study. At 4 h post-dose, subjects performed a standardized driving test on a primary highway in normal traffic. Cognitive and psychomotor tests were assessed 1, 2.5, and 5.5 h post-dose. Memory functioning was measured only 1 h after administration. RESULTS: Both formulations severely impaired driving performance between 4 and 5 h after administration. The magnitude of impairment in the driving test observed with alprazolam XR was about half that observed with alprazolam IR. Laboratory test results were in line with the driving data. CONCLUSIONS: The acute impairing effects of alprazolam XR 1 mg on driving and psychomotor functions were generally less, as compared to its immediate-release equivalent, but still of sufficient magnitude to increase the risk of becoming involved in traffic accidents.

High-potency marijuana impairs executive function and inhibitory motor control.

Human performance studies have usually relied on low-potency marijuana (4% THC) for determining THC-induced impairment. The present study was designed to assess the effects of high-potency marijuana (13% THC) on human performance. In all, 20 recreational users of marijuana participated in a double-blind, placebo controlled, three way cross-over study. The treatments consisted of single doses of 0, 250, and 500 microg/kg THC. Performance tests were conducted at regular intervals between 15 min and 6 h postsmoking and included measures of motor control (Critical tracking task), executive function (Tower of London) motor impulsivity (Stop signal task), and risk taking (Iowa gambling task). THC significantly impaired performance in the Critical tracking task and decreased the number of correct decisions in the Tower of London task. In addition, THC significantly increased stop reaction time and the proportions of commission and omission errors in the Stop signal task. THC-induced impairments lasted up to 6 h postsmoking as indicated by the absence of a THC x Time after smoking interaction. Effect sizes for performance impairments produced by THC 250 microg/kg were relatively low but generally increased by a factor of two in case of THC 500 microg/kg. These data suggest that high potency marijuana consistently impairs executive function and motor control. Use of higher doses of THC in controlled studies may offer a reliable indication of THC induced impairment as compared to lower doses of THC that have traditionally been used in performance studies.