Search

Stimulant drug‐paired cues can acquire the ability to activate mesocorticolimbic pathways and lead to new bouts of drug use. Studies in laboratory animals suggest that these effects are augmented by progressively greater drug use histories, impulsive personality traits, and acute drug ingestion. As a preliminary test of these hypotheses in humans, we exposed cocaine users (n = 14) and healthy volunteers (n = 10) to cocaine‐related videos during two functional magnetic resonance imaging (fMRI) sessions, once following acute administration of placebo and once following d‐amphetamine (0.3 mg/kg, p.o.). Across sessions, cocaine users showed larger cocaine cue‐induced responses than healthy controls in the associative striatum and midbrain. Among the cocaine users, larger drug cue‐induced responses during the placebo session were correlated with higher Barratt Impulsiveness Scale (BIS‐11) nonplanning scores (associative striatum) and greater lifetime use of stimulant drugs (limbic, associative, and sensorimotor striatum). The administration of d‐amphetamine did not augment the cue‐induced activations, but, in cocaine users, drug cue‐induced striatal activations were more widespread following prolonged cocaine cue exposure. Together, these effects of past and present drug use might aggravate the risk for stimulant drug use problems. [ABSTRACT FROM AUTHOR]

Brain asymmetry reflects left‐right hemispheric differentiation, which is a quantitative brain phenotype that develops with age and can vary with psychiatric diagnoses. Previous studies have shown that substance dependence is associated with altered brain structure and function. However, it is unknown whether structural brain asymmetries are different in individuals with substance dependence compared with nondependent participants. Here, a mega‐analysis was performed using a collection of 22 structural brain MRI datasets from the ENIGMA Addiction Working Group. Structural asymmetries of cortical and subcortical regions were compared between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis (n = 1,796) and nondependent participants (n = 996). Substance‐general and substance‐specific effects on structural asymmetry were examined using separate models. We found that substance dependence was significantly associated with differences in volume asymmetry of the nucleus accumbens (NAcc; less rightward; Cohen's d = 0.15). This effect was driven by differences from controls in individuals with alcohol dependence (less rightward; Cohen's d = 0.10) and nicotine dependence (less rightward; Cohen's d = 0.11). These findings suggest that disrupted structural asymmetry in the NAcc may be a characteristic of substance dependence. [ABSTRACT FROM AUTHOR]

Background: Although the typical inheritance of spastic paraplegia 7 is recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant hereditary spastic paraplegia (HSP). Objectives: We aimed to conduct an exome‐wide genetic analysis on a large Canadian cohort of HSP patients and controls to examine the association of SPG7 and HSP. Methods: We analyzed 585 HSP patients from 372 families and 1175 controls, including 580 unrelated individuals. Whole‐exome sequencing was performed on 400 HSP patients (291 index cases) and all 1175 controls. Results: The frequency of heterozygous pathogenic/likely pathogenic SPG7 variants (4.8%) among unrelated HSP patients was higher than among unrelated controls (1.7%; OR 2.88, 95% CI 1.24–6.66, P = 0.009). The heterozygous SPG7 p.(Ala510Val) variant was found in 3.7% of index patients versus 0.85% in unrelated controls (OR 4.42, 95% CI 1.49–13.07, P = 0.005). Similar results were obtained after including only genetically‐undiagnosed patients. We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, compared to zero in controls (OR 19.58, 95% CI 1.05–365.13, P = 0.0031), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7‐interacting genes (CACNA1A, AFG3L2, and MORC2). Of these, there is especially compelling evidence for epistasis between SPG7 and AFG3L2. The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function. Conclusions: Our results provide evidence for complex inheritance in SPG7‐associated HSP, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objective: Isolated (or idiopathic) rapid eye movement sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Biomarkers are lacking to predict conversion to a dementia or a motor-first phenotype. Here, we aimed at identifying a brain-clinical signature that predicts dementia in iRBD.Methods: A brain-clinical signature was identified in 48 patients with polysomnography-confirmed iRBD using partial least squares between brain deformation and 27 clinical variables. The resulting variable was applied to 78 patients with iRBD followed longitudinally to predict conversion to a synucleinopathy, specifically DLB. The deformation scores from patients with iRBD were compared with 207 patients with PD, DLB, or prodromal DLB to assess if scores were higher in DLB compared to PD.Results: One latent variable explained 31% of the brain-clinical covariance in iRBD, combining cortical and subcortical deformation and subarachnoid/ventricular expansion to cognitive and motor variables. The deformation score of this signature predicted conversion to a synucleinopathy in iRBD (p = 0.036, odds ratio [OR] = 2.249; 95% confidence interval [CI] = 1.053-4.803), specifically to DLB (OR = 4.754; 95% CI = 1.283-17.618, p = 0.020) and not PD (p = 0.286). Patients with iRBD who developed dementia had scores similar to clinical and prodromal patients with DLB but higher scores compared with patients with PD. The deformation score also predicted cognitive performance over 1, 2, and 4 years in patients with PD.Interpretation: We identified a brain-clinical signature that predicts conversion in iRBD to more severe/dementing forms of synucleinopathy. This pattern may serve as a new biomarker to optimize patient care, target risk reduction strategies, and administer neuroprotective trials. ANN NEUROL 2021;89:341-357. [ABSTRACT FROM AUTHOR]

Motivation theories of obesity suggest that one of the brain mechanisms underlying pathological eating and weight gain is the dysregulation of dopaminergic circuits. Although these dysregulations likely occur at the microscopic level, studies on grey matter volume report macroscopic differences associated with obesity. One region suggested to play a key role in the pathophysiology of obesity is the nucleus accumbens (NAcc). We performed a meta‐analysis of findings regarding NAcc volume and overweight/obesity. We additionally examined whether grey matter volume in the NAcc and other mesolimbic areas depends on the longitudinal trajectory of obesity, using the UK Biobank dataset. To this end, we analysed the data using a latent growth model, which identifies whether a certain variable of interest (eg, NAcc volume) is related to another variable's (body mass index [BMI]) initial values or longitudinal trajectories. Our meta‐analysis showed that, overall, NAcc volume is positively related to BMI. However, further analyses revealed that the relationship between NAcc volume and BMI is dependent on age. For younger individuals, such a relationship is positive, whereas, for older adults, it is negative. This was corroborated by our analysis in the UK Biobank dataset, which includes older adults, where we found that a higher BMI was associated with a lower NAcc and thalamus volume. Overall, the present study suggests that increased NAcc volume at a young age might be a vulnerability factor for obesity, whereas, at an older age, decreased NAcc volume with increased BMI might be an effect of prolonged influences of neuroinflammation on the brain. [ABSTRACT FROM AUTHOR]

Dysregulated neural mechanisms in reward and somatosensory circuits result in an increased appetitive drive for and reduced inhibitory control of eating, which in turn causes obesity. Despite many studies investigating the brain mechanisms of obesity, the role of macroscale whole‐brain functional connectivity remains poorly understood. Here, we identified a neuroimaging‐based functional connectivity pattern associated with obesity phenotypes by using functional connectivity analysis combined with machine learning in a large‐scale (n ~ 2,400) dataset spanning four independent cohorts. We found that brain regions containing the reward circuit positively associated with obesity phenotypes, while brain regions for sensory processing showed negative associations. Our study introduces a novel perspective for understanding how the whole‐brain functional connectivity correlates with obesity phenotypes. Furthermore, we demonstrated the generalizability of our findings by correlating the functional connectivity pattern with obesity phenotypes in three independent datasets containing subjects of multiple ages and ethnicities. Our findings suggest that obesity phenotypes can be understood in terms of macroscale whole‐brain functional connectivity and have important implications for the obesity neuroimaging community. [ABSTRACT FROM AUTHOR]

While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures. [ABSTRACT FROM AUTHOR]

Background: Patients with Parkinson's disease (PD) present with a broad spectrum of nonmotor features including autonomic disorders. More severe autonomic dysfunction in PD is associated with increased cognitive deficits. The presence of cerebral small‐vessel disease, measured by T2‐weighted magnetic resonance imaging white matter hyperintensity (WMH) burden, is also observed in patients with PD with faster cognitive decline. Objective: To investigate whether baseline orthostatic hypotension and autonomic dysfunction in early‐stage PD affect later cognitive decline via mediation through cerebral small‐vessel disease. Methods: De novo PD patients (N = 365) and age‐matched controls (N = 174) with baseline T2‐weighted/ fluid‐attenuated inversion recovery scans were selected from the Parkinson's Progression Markers Initiative. WMHs were automatically segmented. Mediation analysis was used to assess whether WMH load mediates the effect of orthostatic hypotension and autonomic dysfunction (measured by Scales for Outcomes in Parkinson's Disease–Autonomic) on future cognitive decline (measured by Montreal Cognitive Assessment) in an average of 4 years of follow‐up. Results: Mediation analysis supported the existence of a full mediation of WMHs on the effect of diastolic orthostatic hypotension in patients with PD and future cognitive decline (average causal mediation effect: ab = −0.032, 95% confidence interval = −0.064 to −0.01, P = 0.01). There was also a partial mediation for overall autonomic dysfunction (ab = −0.027, 95% confidence interval = −0.054 to 0.00, P = 0.02). Conclusions: WMHs fully mediate the effect of diastolic orthostatic hypotension and partially mediate the effect of autonomic dysregulation on future cognitive decline in patients with PD. Our findings support the hypothesis that autonomic dysfunction in early clinical stages predisposes the brain to WMHs through dysregulation of the blood flow in the small vessels. This in turn increases the risk of future cognitive impairment in early PD. [ABSTRACT FROM AUTHOR]

Summary: Obesity has inconsistent associations with broad personality domains, possibly because the links pertain to only some facets of these domains. Collating published and unpublished studies (N = 14 848), we meta‐analysed the associations between body mass index (BMI) and Five‐Factor Model personality domains as well as 30 Five‐Factor Model personality facets. At the domain level, BMI had a positive association with Neuroticism and a negative association with Conscientiousness domains. At the facet level, we found associations between BMI and 15 facets from all five personality domains, with only some Neuroticism and Conscientiousness facets among them. Certain personality‐BMI associations were moderated by sample properties, such as proportions of women or participants with obesity; these moderation effects were replicated in the individual‐level analysis. Finally, facet‐based personality "risk" scores accounted for 2.3% of variance in BMI in a separate sample of individuals (N = 3569), 409% more than domain‐based scores. Taken together, personality‐BMI associations are facet specific, and delineating them may help to explain obesity‐related behaviours and inform intervention designs. Preprint and data are available at https://psyarxiv.com/z35vn/. [ABSTRACT FROM AUTHOR]

Many eating‐related psychological constructs have been proposed to explain obesity and overeating. However, these constructs, including food addiction, disinhibition, hedonic hunger, emotional eating, binge eating and the like all have similar definitions, emphasizing loss of control over intake. As questionnaires measuring the constructs correlate strongly (r > 0.5) with each other, we propose that these constructs should be reconsidered to be part of a single broad phenotype: uncontrolled eating. Such an approach enables reviewing and meta‐analysing evidence obtained with each individual questionnaire. Here, we describe robust associations between uncontrolled eating, body mass index (BMI), food intake, personality traits and brain systems. Reviewing cross‐sectional and longitudinal data, we show that uncontrolled eating is phenotypically and genetically intertwined with BMI and food intake. We also review evidence on how three psychological constructs are linked with uncontrolled eating: lower cognitive control, higher negative affect and a curvilinear association with reward sensitivity. Uncontrolled eating mediates all three constructs' associations with BMI and food intake. Finally, we review and meta‐analyse brain systems possibly subserving uncontrolled eating: namely, (i) the dopamine mesolimbic circuit associated with reward sensitivity, (ii) frontal cognitive networks sustaining dietary self‐control and (iii) the hypothalamus‐pituitary‐adrenal axis, amygdala and hippocampus supporting stress reactivity. While there are limits to the explanatory and predictive power of the uncontrolled eating phenotype, we conclude that treating different eating‐related constructs as a single concept, uncontrolled eating, enables drawing robust conclusions on the relationship between food intake and BMI, psychological variables and brain structure and function. [ABSTRACT FROM AUTHOR]

Objective: Recently identified mutations of the axon guidance molecule receptor gene, DCC, present an opportunity to investigate, in living human brain, mechanisms affecting neural connectivity and the basis of mirror movements, involuntary contralateral responses that mirror voluntary unilateral actions. We hypothesized that haploinsufficient DCC+/- mutation carriers with mirror movements would exhibit decreased DCC mRNA expression, a functional ipsilateral corticospinal tract, greater "mirroring" motor representations, and reduced interhemispheric inhibition. DCC+/- mutation carriers without mirror movements might exhibit some of these features.Methods: The participants (n = 52) included 13 DCC+/- mutation carriers with mirror movements, 7 DCC+/- mutation carriers without mirror movements, 13 relatives without the mutation or mirror movements, and 19 unrelated healthy volunteers. The multimodal approach comprised quantitative real time polymerase chain reaction, transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI) under resting and task conditions, and measures of white matter integrity.Results: Mirror movements were associated with reduced DCC mRNA expression, increased ipsilateral TMS-induced motor evoked potentials, increased fMRI responses in the mirroring M1 and cerebellum, and markedly reduced interhemispheric inhibition. The DCC+/- mutation, irrespective of mirror movements, was associated with reduced functional connectivity and white matter integrity.Interpretation: Diverse connectivity abnormalities were identified in mutation carriers with and without mirror movements, but corticospinal effects and decreased peripheral DCC mRNA appeared driven by the mirror movement phenotype. ANN NEUROL 2019;85:433-442. [ABSTRACT FROM AUTHOR]

Objective: The prevalence of obesity has created a plethora of questionnaires characterizing psychological aspects of eating behavior, such as reward-related eating (RRE). The Reward-based Eating Drive questionnaires (RED-9, RED-13) broadly and deeply assess the RRE construct. However, large-sample research designs require shorter questionnaires that capture RRE quickly and precisely. This study sought to develop a brief, reliable, and valid version of the RED questionnaire.Methods: All-subset correlation was used to find a subset that maximally associated with the full RED-13 in two separate samples. Results were validated in a third independent sample. Internal consistency, test-retest reliability, and ability to explain variance in external outcomes were also assessed.Results: A five-item questionnaire (RED-X5) correlated strongly with RED-13 in the independent sample (r = 0.95). RED-X5 demonstrated high internal consistency (omega total ≥ 0.80) and 6-month test-retest reliability (r = 0.72). RED-X5 accurately reproduced known associations between RED-13 and BMI, diabetes status, and craving for sweet and savory foods. As a novel finding, RED questionnaires predicted laboratory intake of chips.Conclusions: RED-X5 is a short, reliable, and valid measure of the RRE construct and can be readily implemented in large-sample research designs in which questionnaire space is limited. [ABSTRACT FROM AUTHOR]

Optimal performance depends in part on the ability to inhibit the automatic processing of irrelevant information and also on the adjusting the level of control from one trial to the next. In this study, we investigated the spatio–temporal neural correlates of cognitive control using simultaneous functional magnetic resonance imaging and electroencephalography, while 22 participants (10 women) performed a numerical Stroop task. We investigated the spatial and temporal dynamic of the conflict adaptation effects (i.e., reduced interference on items that follow an incongruent stimulus compared to after a congruent stimulus). Joint independent component analysis linked the N200 component to activation of anterior cingulate cortex (ACC) and the conflict slow potential to widespread activations within the fronto–parietal executive control network. Connectivity analyses with psychophysiological interactions and dynamic causal modeling demonstrated coordinated engagement of the cognitive control network after the processing of an incongruent item, and this was correlated with better behavioral performance. Our results combined high spatial and temporal resolution to propose the following network of conflict adaptation effect and specify the time course of activation within this model: first, the anterior insula and inferior frontal gyrus are activated when incongruence is detected. These regions then signal the need for higher control to the ACC, which in turn activates the fronto–parietal executive control network to improve the performance on the next trial. [ABSTRACT FROM AUTHOR]

Background The neurobiology of risk for alcohol use disorders ( AUDs) remains poorly understood. Individual differences in vulnerability, though, have been indicated by subjective responses to alcohol ingestion and personality traits. Methods To investigate the relationship between these features and striatal dopamine (DA) responses to alcohol, we studied 26 healthy young social drinkers (21.3 ± 3.0 years old; 10.7 ± 8.8 drinks/wk) at varying risk for alcoholism. Each participant received 2 positron emission tomography [11C]raclopride scans after administration of either placebo or oral alcohol (1 ml/kg body weight of 94% alcohol, 0.75 g/kg) in a randomized and counterbalanced design. Results Subjects with high-risk subjective responses to alcohol had more family members with AUDs, greater alcohol use problems, and, in response to the alcohol challenge, significant decreases in [11C]raclopride binding indicative of increased extracellular DA. In contrast, low-risk subjects exhibited increases in [11C]raclopride binding in response to alcohol. The results were similar when risk groups were based on personality traits, although statistically less robust. Conclusions Changes in striatal DA in response to alcohol ingestion may be a neurobiological marker of vulnerability to AUDs. [ABSTRACT FROM AUTHOR]

ABSTRACT Background: In laboratory animals, environmental stressors markedly activate the mesocortical dopamine system. The present study tested whether this occurs in humans. Methods: The effects of a laboratory psychological stressor (Montreal Imaging Stress Task, MIST) on mesocortical dopamine release in healthy young adults (11 males, mean age ± SD, 20.6 ± 2.4 years) was measured using positron emission tomography and [18F]fallypride. Each subject was scanned in two separate days in counterbalanced order: one with the MIST and one with the control task. Binding potential (BPND) maps of the whole brain were calculated for each scan, using a simplified reference tissue compartmental model. Then BPND was compared between subjects. Heart rate, galvanic skin response, and salivary cortisol level were measured during the scans. Results: The psychological stressor significantly decreased [18F]fallypride binding values in the dorsal part of the medial prefrontal cortex (dmPFC), corresponding to the rostal part of the cingulate motor zone. The greater the stress-induced decrease in [18F]fallypride binding in the dmPFC, the greater the stress-induced increases in heart rate. Conclusions: The present study provides evidence of stress-induced dopamine release in the mPFC in humans, in vivo. Synapse 67:821-830, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Fibromyalgia is characterized by chronic widespread pain and bodily tenderness and is often accompanied by affective disturbances. Accumulating evidence indicates that fibromyalgia may involve a dysfunction of modulatory systems in the brain. While brain dopamine is best known for its role in pleasure, motivation and motor control, recent evidence suggests that it is also involved in pain modulation. Because dopamine is implicated in both pain modulation and affective processing, we hypothesized that fibromyalgia may involve a disturbance of dopaminergic neurotransmission. Fibromyalgia patients and matched healthy control subjects were subjected to deep muscle pain produced by injection of hypertonic saline into the anterior tibialis muscle. In order to determine the endogenous release of dopamine in response to painful stimulation, we used positron emission tomography to examine binding of [11C]-raclopride (D2/D3 ligand) in the brain during injection of painful hypertonic saline and nonpainful normal saline. Fibromyalgia patients experienced the hypertonic saline as more painful than healthy control subjects. Control subjects released dopamine in the basal ganglia during the painful stimulation, whereas fibromyalgia patients did not. In control subjects, the amount of dopamine release correlated with the amount of perceived pain but in fibromyalgia patients no such correlation was observed. These findings provide the first direct evidence that fibromyalgia patients have an abnormal dopamine response to pain. The disrupted dopaminergic reactivity in fibromyalgia patients could be a critical factor underlying the widespread pain and discomfort in fibromyalgia and suggests that the therapeutic effects of dopaminergic treatments for this intractable disorder should be explored. [ABSTRACT FROM AUTHOR]

Acute and chronic behavioral effects of subthalamic stimulation (STN-DBS) for Parkinson's disease (PD) are reported in the literature. As the technique is relatively new, few systematic studies on the behavioral effects in long-term treated patients are available. To further study the putative effects of STN-DBS on mood and emotional processing, 15 consecutive PD patients under STN-DBS for at least 1 year, were tested ON and OFF stimulation while on or off medication, with instruments sensitive to short-term changes in mood and in emotional discrimination. After acute changes in experimental conditions, mood core dimensions (depression, elation, anxiety) and emotion discrimination processing remained remarkably stable, in the face of significant motor changes. Acute stimulator challenge in long-term STN-DBS-treated PD patients does not appear to provoke clinically relevant mood effects. © 2007 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Positron emission tomography and [11C]raclopride were used to assess the dopaminergic response to cigarette smoking in ten smokers. Nicotine-deprived smokers were scanned twice on separate days. In one condition, participants smoked their usual brand of cigarettes while in the scanner and in the other condition they remained nicotine abstinent. On each day, subjects monitored the hedonic properties of their experience as well as their levels of craving. Initial analyses revealed no significant differences between the conditions in [11C]raclopride binding potential (BP) in the caudate, putamen, or ventral striatum. Because previous research suggested that drug-induced dopamine transmission is related to levels of craving and/or hedonic drug effects, the relationship between these variables and [11C]raclopride BP was examined. Craving levels were reduced by smoking but were not systematically related to BP change. However, the hedonic response to smoking was correlated with BP reduction in the caudate ( P < 0.001) and posterior putamen ( P < 0.05) but not in the ventral striatum. Post hoc analyses revealed that only five of the ten smokers reported mood-elevating effects in response to the smoking procedure. In these subjects, smoking was associated with decreased [11C]raclopride BP in the caudate. On the other hand, among subjects that reported a diminished mood response to smoking there was an increase in BP in the caudate and putamen. These results suggest that pleasurable drug experiences are associated with increased dopamine transmission in the dorsal striatum while unpleasant experiences may be related to decreased dopamine release in this region. Synapse 54:65-71, 2004. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The author comments on the article "Compulsive use of dopamine replacement therapy: a model for stimulant drug addiction?" by P. Ambermoon and colleagues in the 2012 issue. The author argues on the suggestion of the article to label addiction the use of levodopa by patients with Parkinson's disease (PD). He states that PD patients also exhibit pathological gambling, compulsive shopping or hypersexuality which are signs of drug addiction due to excessive stimulation of the D2 receptor.