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Music's ability to induce feelings of pleasure has been the subject of intense neuroscientific research lately. Prior neuroimaging studies have shown that music-induced pleasure engages cortico-striatal circuits related to the anticipation and receipt of biologically relevant rewards/incentives, but these reports are necessarily correlational. Here, we studied both the causal role of this circuitry and its temporal dynamics by applying transcranial magnetic stimulation (TMS) over the left dorsolateral PFC combined with fMRI in 17 male and female participants. Behaviorally, we found that, in accord with previous findings, excitation of fronto-striatal pathways enhanced subjective reports of music-induced pleasure and motivation, whereas inhibition of the same circuitry led to the reduction of both. fMRI activity patterns indicated that these behavioral changes were driven by bidirectional TMS-induced alteration of fronto-striatal function. Specifically, changes in activity in the NAcc predicted modulation of both hedonic and motivational responses, with a dissociation between pre-experiential versus experiential components of musical reward. In addition, TMS-induced changes in the fMRI functional connectivity between the NAcc and frontal and auditory cortices predicted the degree of modulation of hedonic responses. These results indicate that the engagement of cortico-striatal pathways and the NAcc, in particular, is indispensable to experience rewarding feelings from music. [ABSTRACT FROM AUTHOR]

The externalizing psychopathological dimension is associated with alterations in adolescents' functional brain connectivity. The current study aims to identify the functional correlates of the unique variability in conduct problems within the context of the broad externalizing dimension. The broad externalizing dimension and unique variability in conduct problems were estimated using a bifactor model. Resting-state data were available for a sample of 125 adolescents. Based on multiresolution parcellation of functional brain networks atlas, major resting-state functional brain networks and the connectivity correlates of unique conduct problems and the broad externalizing dimension were established. The broad externalizing dimension was related to connectivity alterations in the ventral attention/salience network, while unique variability in conduct problems dimension was related to connectivity alterations in the cerebellum crusi as well as the mesolimbic network. The current study is a first step toward the identification of functional resting-state network correlates of broad and specific variability in the externalizing dimension. [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]

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]

Abstract: The worldwide increase in obesity has spurred numerous efforts to understand the regulation of eating behaviours and underlying brain mechanisms. These mechanisms can affordably be studied via neurobehavioural measures. Here, we systematically review these efforts, evaluating neurocognitive tests and personality questionnaires based on: (a) consistent relationship with obesity and eating behaviour, and (b) reliability. We also considered the measures’ potential to shed light on the brain mechanisms underlying these individual differences. Sixty-six neurocognitive tasks were examined. Less than 11%, mainly measures of executive functions and food motivation, yielded both replicated and reliable effects. Several different personality questionnaires were consistently related to BMI. However, further analysis found that many of these questionnaires relate closely to Conscientiousness, Extraversion and Neuroticism within the Five-Factor Model of personality. Both neurocognitive tests and personality questionnaires suggest that the critical neural systems related to individual differences in obesity are lateral prefrontal structures underpinning self-control and striatal regions implicated in food motivation. This review can guide selection of the highest yield neurobehavioural measures for future studies. [Copyright &y& Elsevier]

Converging evidence, including observations in patients with Parkinson's disease (PD), suggests that dopamine plays a role in impulsivity. This multi-faceted construct includes considerations of both time and risk; determining how these more specific processes are affected by PD and dopaminergic treatment can inform neurobiological models. We examined the effects of PD and its treatment on temporal discounting and risky decision-making in a cohort of 23 mild-moderate PD patients and 20 healthy participants. Patients completed the Balloon Analogue Risk Task and a temporal discounting paradigm both on and off their usual dopamine replacement therapy. PD patients did not differ from controls in their initial risk-taking on the Balloon Analogue Risk Task, but took progressively more risks across trials when on medication. A subset of patients and controls was tested again, 1.5-3 years later, to explore the effects of disease progression. On follow-up, baseline risk-taking diminished in patients, but the tendency to take increasing risks across trials persisted. Neither disease progression nor its treatment affected the temporal discounting rate. These findings suggest a different neural basis for temporal discounting and risk-taking, and demonstrate that risk-taking can be further decomposed into initial and trial-by-trial effects, with dopamine affecting only the latter. [ABSTRACT FROM AUTHOR]

Sleep disturbances are increasingly recognized as adversely affecting brain health in aging. Our aim was to investigate interrelations between subjective sleep-related symptoms, obesity, cardiometabolic disorders, brain structure and cognitive decline in a population-based aging sample. Data were extracted from the UK Biobank for anthropometric and demographic information, self-reported sleep behaviours, cardiometabolic measures, structural brain magnetic resonance imaging and cognitive test scores. "Sleep-related symptoms" (SRS) were measured using four questionnaire items: loud snoring, daytime sleepiness, likelihood to nap and difficulty getting up in the morning. Associations were tested using a structural equation model (SEM), adjusted for confounders. Further, multiple regression analysis was used to test for direct relationships between SRS and specific cognitive domains. Among 36,468 participants with an average age of 63.6 (SD 7.5) years and 46.7% male, we found that SRS were associated with obesity and several pre-existing cardiometabolic disturbances. In turn, cardiometabolic disorders were associated with increased white matter hyperintensities and cortical thinning, which were related to cognitive dysfunction. SRS were also directly related to several structural brain changes and to cognitive dysfunction. Regression analyses showed that SRS were directly associated with slower reaction times, and lower scores in fluid intelligence, working memory and executive function. Self-reported sleep-related symptoms were associated with cognitive dysfunction directly and through pre-existing cardiometabolic disorders and brain structural alterations. These findings provide evidence that symptoms of sleep disturbances, here defined primarily by hypersomnolence and snoring, are important risk factors or markers for cognitive dysfunction in an aging population. • How sleep-related symptoms lead to cognitive dysfunction is not well understood. • Obesity, cardiometabolic disturbances and structural brain changes may be involved. • These variables had complex interrelationships in a large population sample. • Sleep-related symptoms were associated with poorer cognition directly. • Cardiometabolic and brain structural changes were also important pathways. [ABSTRACT FROM AUTHOR]

Obesity is a neurobehavioral disorder that results from a combination of overeating and insufficient physical activity. Finely tuned mechanisms exist to match food intake to caloric expenditure. However, faced with abundant inexpensive and calorie-dense foods, many humans (and perhaps most) have a tendency to consume beyond their caloric needs. The brain controls food intake by sensing internal energy-balance signals and external cues of food availability, and by controlling feeding behavior; it is therefore at the centre of the obesity problem. This article reviews the recent use of functional brain imaging in humans to study the neural control of appetite, and how the neural systems involved may cause vulnerability to overeating in the obesogenic environment. [Copyright &y& Elsevier]

White matter tracts, which play a crucial role in the coordination of information flow between different regions of grey matter, are particularly vulnerable to multiple sclerosis. Many studies have shown that the white matter lesions in multiple sclerosis are associated with focal abnormalities of grey matter, but little is known about the alterations in the coordinated patterns of cortical morphology among regions in the disease. Here, we used cortical thickness measurements from structural magnetic resonance imaging to investigate the relationship between the white matter lesion load and the topological efficiency of structural cortical networks in multiple sclerosis. Network efficiency was defined using a ‘small-world’ network model that quantifies the effectiveness of information transfer within brain networks. In this study, we first classified patients (n = 330) into six subgroups according to their total white matter lesion loads, and identified structural brain networks for each multiple sclerosis group by thresholding the corresponding inter-regional cortical thickness correlation matrix, followed by a network efficiency analysis with graph theoretical approaches. The structural cortical networks in multiple sclerosis demonstrated efficient small-world architecture regardless of the lesion load, an organization that maximizes the information processing at a relatively low wiring cost. However, we found that the overall small-world network efficiency in multiple sclerosis was significantly disrupted in a manner proportional to the extent of total white matter lesions. Moreover, regional efficiency was also significantly decreased in specific brain regions, including the insula and precentral gyrus as well as regions of prefrontal and temporal association cortices. Finally, we showed that the lesions also altered many cortical thickness correlations in the frontal, temporal and parietal lobes. Our results suggest that the white matter lesions in multiple sclerosis might be associated with aberrant neuronal connectivity among widely distributed brain regions, and provide structural (morphological) evidence for the notion of multiple sclerosis as a disconnection syndrome. [ABSTRACT FROM PUBLISHER]

Abstract: Stress plays an important role in drug addiction. It can trigger relapse in abstinent addicts, and both in the everyday world and in the laboratory, a stressor can induce drug craving. Drug cues, such as the sight of drug, can also trigger subjective craving and relapse, and this effect may be amplified by stress. Underpinning this interaction may be the fact that stress and reward-predicting drug cues act on overlapping brain regions. We exposed 15 smokers undergoing functional magnetic resonance imaging to a psychosocial stressor, the Montreal Imaging Stress Task, followed by drug cues consisting of video clips of smokers. In a separate session similar video clips were shown after a non-stress control task. We observed significantly decreased neural activity during stress in the hippocampus, amygdala, bed nucleus of the stria terminalis, hypothalamus and nucleus accumbens. Following stress there was an increased neural response to drug cues in the medial prefrontal cortex, posterior cingulate cortex, dorsomedial thalamus, medial temporal lobe, caudate nucleus, and primary and association visual areas. These regions are thought to be involved in visual attention and in assigning incentive value to cues. Stress-induced limbic deactivation predicted subsequent neural cue-reactivity. We suggest that stress increases the incentive salience of drug cues. [Copyright &y& Elsevier]

Abstract: Patient motion during positron emission tomography scanning can affect the accuracy of the data analysis in two ways: 1) movement occurring during emission data acquisition alters the time activity curves (TACs), measured at a voxel or region of interest (ROI), and hence introduces errors in the parameter estimates derived from kinetic modeling; 2) emission–transmission mismatches introduce errors during attenuation and scatter correction, and hence in the radioactivity distribution estimates for each time frame of the scan. With the aim of designing an algorithm-based frame realignment method, we first conducted investigations that aimed at optimizing the parameters of a coregistration method, such as the choice of the target volume and the similarity criterion. Based on these results we designed a novel frame realignment strategy in a multi-step algorithm using uncorrected reconstructed images, cross-correlation similarity criteria for the determination of inter-frame motion parameters and emission-transmission mismatch for each frame. Features and validation results are reported here based on a multi-subject simulated [11C]raclopride dynamic PET scan database incorporating intra-frame movements of various magnitudes and with various times of occurrence. Performances of the proposed algorithm were evaluated at regional and voxel-based level for binding potential parametric images. [Copyright &y& Elsevier]

In rare instances, patients with Parkinson''s disease (PD) may become addicted to their own medication or develop behavioral addictions such as pathological gambling. This is surprising because PD patients typically have a very low incidence of drug abuse and display a personality type that is the polar opposite of the addictive personality. These rare addictive syndromes, which appear to result from excessive dopaminergic medication use, illustrate the link between dopamine, personality, and addiction. We describe the clinical phenomena and attempt to relate them to current models of learning and addiction. We conclude that persistently elevated dopaminergic stimulation promotes the development and maintenance of addictive behaviors. [Copyright &y& Elsevier]

Abstract: Research on dopamine (DA) transmission has emphasized the importance of increased phasic DA cell firing in the presence of unpredictable rewards. Using [11C]raclopride PET, we previously reported that DA transmission was both suppressed and enhanced in different regions of the striatum during an unpredictable reward task [Zald, D.H., Boileau, I., El Dearedy, W., Gunn, R., McGlone, F., Dichter, G.S. et al. (2004). Dopamine transmission in the human striatum during monetary reward tasks. J. Neurosci. 24, 4105–4112]. However, it was unclear if reductions in DA release during this task reflected a response to the high proportion of nonrewarding trials, and whether the behavioral demands of the task influenced the observed response. To test these issues, we presented 10 healthy subjects with an automated (passive) roulette wheel game in which the amount of reward and its timing were unpredictable and the rewarding trials greatly outnumbered the nonrewarding ones. As in the previous study, DA transmission in the putamen was significantly suppressed relative to a predictable control condition. A similar suppression occurred when subjects were presented with temporally unpredictable novel pictures and sounds. At present, models of DA functioning during reward do not account for this suppression, but given that it has been observed in two different studies using different reward paradigms, this phenomenon warrants attention. Neither the unpredictable reward nor the novelty conditions produced consistent increases in striatal DA transmission. These data suggest that active behavioral engagement may be necessary to observe robust statewise increases in DA release in the striatum. [Copyright &y& Elsevier]

Studies in laboratory rodents suggest that previously neutral stimuli repeatedly paired with the administration of drugs of abuse can acquire the ability to increase striatal dopamine release. This conditioned neurochemical response is believed to prompt drug seeking in animals and has been hypothesized to contribute to drug craving and relapse in substance abusers. In the present study, we used positron emission tomography and [11C]raclopride to investigate whether amphetamine-predictive stimuli can elicit striatal dopamine release in humans. Nine healthy male volunteers received a capsule containing amphetamine tablets (0.3 mg/kg) on three separate occasions approximately every other day (mean ± SD, 2.25 ± 1.13 d apart) in the same environment (scanner suite). At least 2 weeks later, the amphetamine was switched to a placebo of identical appearance and given in the same environmental context. [11C]Raclopride binding to dopamine D2/3 receptors was assessed after exposure to the first amphetamine-containing pill, after placebo administration, and during a control (no pill) scan. Relative to the control scan, amphetamine administration decreased [11C]raclopride binding potential by 22% in the ventral striatum and 11% in the putamen. Placebo also decreased [11C]raclopride binding potential in the ventral striatum and did so with the same amplitude as amphetamine (23%). These results suggest that cues associated with amphetamine increase dopamine transmission, providing evidence that this system is involved in reward prediction in humans. [ABSTRACT FROM AUTHOR]

Abstract: Multiple sclerosis (MS) is thought to predominantly affect white matter (WM). Recently, however, loss of cortical gray matter has also been described. Little is known about the cause of cortical atrophy in MS, whether it occurs early in the disease course, and whether it affects all cortical regions equally or if there is a preferential pattern of focal cortical atrophy. An automated method was used to compute the thickness at every vertex of the cortical surface of the brains of 425 early relapsing–remitting MS patients. We correlated cortical thickness with the WM lesion load and the Expanded Disability Status Scale score. Mean cortical thickness correlated with WM lesion load and disability. The correlations of cortical thickness with total lesion load and disability were most significant in cingulate gyrus, insula, and associative cortical regions. Conversely, primary sensory, visual, and motor areas showed a less significant relationship. The highest amount of atrophy per lesion volume or disability scale unit was in the anterior cingulate cortex. This study confirms the relation between cortical atrophy, WM lesion load, and disability in MS, and suggests that cortical atrophy occurs even in MS patients with only mild disability. Most interestingly, we show a specific regional pattern of focal atrophy in MS that is distinctively different from the one in normal aging. The predilection of the atrophic process for areas that are heavily inter-connected with other brain regions suggests that interruption of WM tracts by MS plaques contributes, at least in part, to the development of cortical atrophy. [Copyright &y& Elsevier]

Mesolimbic dopamine is thought to play a role in the processing of rewards. However, animal studies also demonstrate dopamine release in response to aversive stressful stimuli. Also, in animal studies, disruptions of the mother-infant relationship have been shown to have long-lasting effects on the mesolimbic dopamine system and the hypothalamic-pituitary adrenal axis. We therefore investigated dopamine release in response to stress in human subjects, considering the relationship to early life parental care. We screened 120 healthy young college students for parental care in early life using a combination of telephone interviews and questionnaires. Five students from the top end and five students from the bottom end of the parental care distribution were then invited for a positron emission tomography study using [11C]raclopride and a psychosocial stress task. The psychosocial stressor caused a significant release of dopamine in the ventral striatum as indicated by a reduction in [11C]raclopride binding potential in the stress versus resting condition in subjects reporting low parental care. Moreover, the magnitude of the salivary cortisol response to stress was significantly correlated with the reduction in [11C C]raclopride binding in the ventral striatum (r = 0.78), consistent with a facilitating effect of cortisol on dopamine neuron firing. These data suggest that aversive stressful events can be associated with mesolimbic dopamine release in humans, and that the method presented here may be useful to study the effects of early life events on neurobiological stress systems. [ABSTRACT FROM AUTHOR]

Acute phenylalanine/tyrosine depletion (APTD) has been proposed as a new method to decrease catecholamine neurotransmission safely, rapidly, and transiently. Validation studies in animals are encouraging, but direct evidence in human brain is lacking. In the present study, we tested the hypothesis that APTD would reduce stimulated dopamine (DA) release, as assessed by positron emission tomography (PET) and changes in [11C]raclopride binding potential (BP), a measure of DA D2/D3 receptor availability. Eight healthy men received two PET scans, both following d-amphetamine, 0.3 mg/kg, p.o., an oral dose known to decrease [11C]raclopride BP in ventral striatum. On the morning before each scan, subjects ingested, in counter-balanced order, an amino-acid mixture deficient in the catecholamine precursors, phenylalanine, and tyrosine, or a nutritionally balanced mixture. Brain parametric images were generated by calculating [11C]raclopride BP at each voxel. BP values were extracted from the t-map (threshold: t=4.2, equivalent to p<0.05, Bonferroni corrected) and a priori identified regions of interest from each individual's coregistered magnetic resonance images. Both receptor parametric mapping and region of interest analyses indicated that [11C]raclopride binding was significantly different on the two test days in the ventral striatum (peak t=6.31; x=-25, y=-8, and z=0.1). In the t-map defined cluster, [11C]raclopride BP values were 11.8 ± 11.9% higher during the APTD session (p<0.05). The reduction in d-amphetamine-induced DA release exhibited a linear association with the reduction in plasma tyrosine levels (r = -0.82, p < 0.05). Together, the results provide the first direct evidence that APTD decreases stimulated DA release in human brain. APTD may be a suitable new tool for human neuropsychopharmacology research. [ABSTRACT FROM AUTHOR]

Theoretical work suggests that obesity is related to enhanced incentive salience of food cues. However, evidence from both behavioral and neuroimaging studies on the topic is mixed. In this work, we review the literature on cue reactivity in obesity and perform a preregistered meta-analysis of studies investigating effects of obesity on brain responses to passive food pictures viewing. Further, we examine whether age influences brain responses to food cues in obesity. In the meta-analysis, we included 13 studies of children and adults that investigated group differences (obese vs lean) in responses to food vs non-food pictures viewing. While we found no significant differences in the overall meta-analysis, we show that age significantly influences brain response differences to food cues in the left insula and the left fusiform gyrus. In the left insula, obese vs lean brain differences in response to food cues decreased with age, while in the left fusiform gyrus the pattern was opposite. Our results suggest that there is little evidence for obesity-related differences in responses to food cues and that such differences might be mediated by additional factors that are often not considered. [ABSTRACT FROM AUTHOR]

We report a case of metastatic castration-resistant prostate cancer, who received prior treatment with docetaxel and was then given cabazitaxel as salvage therapy. The patient was monitored by prostate-specific antigen doubling time and prostate-specific antigen absolute value. The prostate-specific antigen doubling time was found to be a good response predictor in the patient. [ABSTRACT FROM AUTHOR]

The article discusses a 2022 study on the correlation of socioeconomic status (SES) with brain anatomy. Topics covered include regional correlates' parsing into genetic and environmental factors, the strong genetic effects in the prefrontal cortex and insula, and the influential environmental effects in the cerebellum and lateral temporal. Also noted is the complex interplay of these factors as they influence the SES-brain relation.

The article presents a study which explores the human brain anatomy reflects separable genetic and environmental components of socioeconomic status. It mentions that socioeconomic status (SES) correlates with brain structure, a relation of interest given the long-observed relations of SES to cognitive abilities and health.

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.

Associations between brain and obesity are bidirectional: changes in brain structure and function underpin over-eating, while chronic adiposity leads to brain atrophy. Investigating brain-obesity interactions across the lifespan can help better understand these relationships. This study explores the interaction between obesity and cortical morphometry in children, young adults, adults, and older adults. We also investigate the genetic, neurochemical, and cognitive correlates of the brain-obesity associations. Our findings reveal a pattern of lower cortical thickness in fronto-temporal brain regions associated with obesity across all age cohorts and varying age-dependent patterns in the remaining brain regions. In adults and older adults, obesity correlates with neurochemical changes and expression of inflammatory and mitochondrial genes. In children and older adults, adiposity is associated with modifications in brain regions involved in emotional and attentional processes. Thus, obesity might originate from cognitive changes during early adolescence, leading to neurodegeneration in later life through mitochondrial and inflammatory mechanisms. This study reveals that obesity-related brain changes evolve across the lifespan and involve mitochondrial and inflammatory genes, as well as neurochemical and cognitive alterations. [ABSTRACT FROM AUTHOR]

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]

One of the most exciting recent hypotheses in neurology is that most neurodegenerative diseases are caused by the neuron to neuron propagation of prion-like misfolded proteins. In Parkinson disease, the theory initially emerged from postmortem studies demonstrating a caudal-rostral progression of pathology from lower brainstem to neocortex. Later, animal studies showed that the hallmark protein of PD, α-synuclein, exhibited all the characteristics of a prion. Here, we describe our work using human neuroimaging to test the theory that PD pathology advances via a propagating process along the connectome. We found that the pattern and progression of brain atrophy follow neuronal connectivity, correlate with clinical features, and identify an epicenter in the brainstem. [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]

Introduction: Alterations in dopamine signaling play a key role in reinforcement learning and nicotine addiction, but the relationship between these two processes has not been well characterized. We investigated this relationship in young adult smokers using a combination of behavioral and computational measures of reinforcement learning.Methods: We asked moderately dependent smokers to engage in a reinforcement learning task three times: smoking as usual, smoking abstinence, and cigarette consumption. Participants' trial-to-trial training choices were modeled using a reinforcement learning model that calculates separate learning rates associated with positive and negative prediction errors.Results: We found that learning from positive prediction error signals is reduced during smoking abstinence and enhanced following cigarette consumption. By contrast, learning from negative prediction error signals was enhanced during smoking abstinence and reduced following cigarette consumption. Finally, when tested with novel pairs of stimuli, participants were relatively better at selecting the positive feedback predicting stimuli than avoiding the negative feedback predicting stimuli during the smoking as usual session, a pattern that reversed following cigarette consumption.Conclusions: These findings provide a specific computational account of altered reinforcement learning induced by smoking state (abstinence and consumption) and may represent a unique target for treatment of nicotine addiction.Implications: This study illustrates the potential of computational psychiatry for understanding reinforcement learning deficits associated with substance use disorders in general and nicotine addiction in particular. We found that learning from positive prediction error signals is reduced during smoking abstinence and enhanced following cigarette consumption. By contrast, learning from negative prediction error signals was enhanced during smoking abstinence and reduced following cigarette consumption. By highlighting important computational differences between three states of smoking, these findings hold out promise for integrating experimental, computational, and theoretical analyses of decision-making function together with research on addiction-related disorders. [ABSTRACT FROM AUTHOR]

Objectives The purpose of this trial is to (1) determine the best exercise modality to improve sleep quality and sleep architecture in people with Parkinson disease (PD); (2) investigate whether exercise-induced improvements in sleep mediate enhancements in motor and cognitive function as well as other non-motor symptoms of PD; and (3) explore if changes in systemic inflammation after exercise mediate improvements in sleep. Methods This is a multi-site, superiority, single-blinded randomized controlled trial. One hundred fifty persons with PD and sleep problems will be recruited and randomly allocated into 4 intervention arms. Participants will be allocated into 12 weeks of either cardiovascular training, resistance training, multimodal training, or a waiting list control intervention. Assessments will be conducted at baseline, immediately after each intervention, and 8 weeks after each intervention by blinded assessors. Objective sleep quality and sleep architecture will be measured with polysomnography and electroencephalography. Motor and cognitive function will be assessed with the Unified PD Rating Scale and the Scale for Outcomes in PD-Cognition, respectively. Subjective sleep quality, fatigue, psychosocial functioning, and quality of life will be assessed with questionnaires. The concentration of inflammatory biomarkers in blood serum will be assessed with enzyme-linked immunosorbent assays. Impact This study will investigate the effect of different types of exercise on sleep quality and architecture in PD, exploring interactions between changes in sleep quality and architecture with motor and cognitive function and other non-motor symptoms of the disease as well as mechanistic interactions between systemic inflammation and sleep. The results will provide important practical information to guide physical therapists and other rehabilitation professionals in the selection of exercise and the design of more personalized exercise–based treatments aimed at optimizing sleep, motor, and cognitive function in people with PD. [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]

Knutson et al. performed functional MRI on individuals while the subjects were deciding whether or not to purchase various items. Their results, reported in this issue of Neuron, support the theory that the decision to purchase involves the integration of emotional signals related to the anticipation of both obtaining the desired product and suffering the financial loss of paying for it. [Copyright &y& Elsevier]

Background: The ability to encode and consolidate motor memories is essential for persons with Parkinson's disease (PD), who usually experience a progressive loss of motor function. Deficits in memory encoding, usually expressed as poorer rates of skill improvement during motor practice, have been reported in these patients. Whether motor memory consolidation (i.e., motor skill retention) is also impaired is unknown. Objective: To determine whether motor memory consolidation is impaired in PD compared to neurologically intact individuals. Methods: We conducted a pre-registered systematic review (PROSPERO: CRD42020222433) following PRISMA guidelines that included 46 studies. Results: Meta-analyses revealed that persons with PD have deficits in retaining motor skills (SMD = –0.17; 95% CI = –0.32, –0.02; p = 0.0225). However, these deficits are task-specific, affecting sensory motor (SMD = –0.31; 95% CI –0.47, –0.15; p = 0.0002) and visuomotor adaptation (SMD = –1.55; 95% CI = –2.32, –0.79; p = 0.0001) tasks, but not sequential fine motor (SMD = 0.17; 95% CI = –0.05, 0.39; p = 0.1292) and gross motor tasks (SMD = 0.04; 95% CI = –0.25, 0.33; p = 0.7771). Importantly, deficits became non-significant when augmented feedback during practice was provided, and additional motor practice sessions reduced deficits in sensory motor tasks. Meta-regression analyses confirmed that deficits were independent of performance during encoding, as well as disease duration and severity. Conclusion: Our results align with the neurodegenerative models of PD progression and motor learning frameworks and emphasize the importance of developing targeted interventions to enhance motor memory consolidation in PD. [ABSTRACT FROM AUTHOR]

The role of dopaminergic system in decision-making is well documented, and evidence suggests that it could play a significant role in response selection processes. The N-40 is a fronto-central event-related potential, generated by the supplementary motor areas (SMAs) and a physiological index of response selection processes. The aim of the present study was to determine whether infraclinical effects of dopamine depletion on response selection processes could be evidenced via alterations of the N-40. We obtained a dopamine depletion in healthy volunteers with the acute phenylalanine and tyrosine depletion (APTD) method which consists in decreasing the availability of dopamine precursors. Subjects realized a Simon task in the APTD condition and in the control condition. When the stimulus was presented on the same side as the required response, the stimulus-response association was congruent and when the stimulus was presented on the opposite side of the required response, the stimulus-response association was incongruent. The N-40 was smaller for congruent associations than for incongruent associations. Moreover, the N-40 was sensitive to the level of dopaminergic activity with a decrease in APTD condition compared to control condition. This modulation of the N-40 by dopaminergic level could not be explained by a global decrease of cerebral electrogenesis, since negativities and positivities indexing the recruitment of the primary motor cortex (anatomically adjacent to the SMA) were unaffected by APTD. The specific sensitivity of N-40 to ATPD supports the model of Keeler et al. (Neuroscience 282:156-175, 2014) according to which the dopaminergic system is involved in response selection. [ABSTRACT FROM AUTHOR]

Parkinson's disease varies widely in clinical manifestations, course of progression and biomarker profiles from person to person. Identification of distinct Parkinson's disease subtypes is of great priority to illuminate underlying pathophysiology, predict progression and develop more efficient personalized care approaches. There is currently no clear way to define and divide subtypes in Parkinson's disease. Using data from the Parkinson's Progression Markers Initiative, we aimed to identify distinct subgroups via cluster analysis of a comprehensive dataset at baseline (i.e. cross-sectionally) consisting of clinical characteristics, neuroimaging, biospecimen and genetic information, then to develop criteria to assign patients to a Parkinson's disease subtype. Four hundred and twenty-one individuals with de novo early Parkinson's disease were included from this prospective longitudinal multicentre cohort. Hierarchical cluster analysis was performed using data on demographic and genetic information, motor symptoms and signs, neuropsychological testing and other non-motor manifestations. The key classifiers in cluster analysis were a motor summary score and three non-motor features (cognitive impairment, rapid eye movement sleep behaviour disorder and dysautonomia). We then defined three distinct subtypes of Parkinson's disease patients: 223 patients were classified as 'mild motor-predominant' (defined as composite motor and all three non-motor scores below the 75th percentile), 52 as 'diffuse malignant' (composite motor score plus either ≥1/3 non-motor score >75th percentile, or all three non-motor scores >75th percentile) and 146 as 'intermediate'. On biomarkers, people with diffuse malignant Parkinson's disease had the lowest level of cerebrospinal fluid amyloid-β (329.0 ± 96.7 pg/ml, P = 0.006) and amyloid-β/total-tau ratio (8.2 ± 3.0, P = 0.032). Data from deformation-based magnetic resonance imaging morphometry demonstrated a Parkinson's disease-specific brain network had more atrophy in the diffuse malignant subtype, with the mild motor-predominant subtype having the least atrophy. Although disease duration at initial visit and follow-up time were similar between subtypes, patients with diffuse malignant Parkinson's disease progressed faster in overall prognosis (global composite outcome), with greater decline in cognition and in dopamine functional neuroimaging after an average of 2.7 years. In conclusion, we introduce new clinical criteria for subtyping Parkinson's disease based on a comprehensive list of clinical manifestations and biomarkers. This clinical subtyping can now be applied to individual patients for use in clinical practice using baseline clinical information. Even though all participants had a recent diagnosis of Parkinson's disease, patients with the diffuse malignant subtype already demonstrated a more profound dopaminergic deficit, increased atrophy in Parkinson's disease brain networks, a more Alzheimer's disease-like cerebrospinal fluid profile and faster progression of motor and cognitive deficits. [ABSTRACT FROM AUTHOR]

The differential susceptibility model states that a given genetic variant is associated with an increased risk of pathology in negative environments but greater than average resilience in enriched ones. While this theory was first implemented in psychiatric-genetic research, it may also help us to unravel the complex ways that genes and environments interact to influence feeding behavior and obesity. We reviewed evidence on gene vs. environment interactions that influence obesity development, aiming to support the applicability of the differential susceptibility model for this condition, and propose that various environmental “layers” relevant for human development should be considered when bearing the differential susceptibility model in mind. Mother-child relationship, socioeconomic status and individual’s response are important modifiers of BMI and food intake when interacting with gene variants, “for better and for worse”. While only a few studies to date have investigated obesity outcomes using this approach, we propose that the differential susceptibility hypothesis is in fact highly applicable to the study of genetic and environmental influences on feeding behavior and obesity risk. [ABSTRACT FROM AUTHOR]

Background: Onset of alcohol use by 14 relative to 21 years of age strongly predicts elevated risk for severe alcohol use problems, with 27% versus 4% of individuals exhibiting alcohol dependence within 10 years of onset. What remains unclear is whether this early alcohol use (i) is a marker for later problems, reflected as a pre-existing developmental predisposition, (ii) causes global neural atrophy or (iii) specifically disturbs neuro-maturational processes implicated in addiction, such as executive functions or reward processing. Since our group has demonstrated that a novel intervention program targeting personality traits associated with adolescent alcohol use can prevent the uptake of drinking and binge drinking by 40 to 60%, a crucial question is whether prevention of early onset alcohol misuse will protect adolescent neurodevelopment and which domains of neurodevelopment can be protected. Methods: A subsample of 120 youth at high risk for substance misuse and 30 low-risk youth will be recruited from the Co-Venture trial (Montreal, Canada) to take part in this 5-year follow-up neuroimaging study. The Co-Venture trial is a community-based cluster-randomised trial evaluating the effectiveness of school-based personality-targeted interventions on substance use and cognitive outcomes involving approximately 3800 Grade 7 youths. Half of the 120 high-risk participants will have received the preventative intervention program. Cognitive tasks and structural and functional neuroimaging scans will be conducted at baseline, and at 24- and 48-month follow-up. Two functional paradigms will be used: the Stop-Signal Task to measure motor inhibitory control and a modified version of the Monetary Incentive Delay Task to evaluate reward processing. Discussion: The expected results should help identify biological vulnerability factors, and quantify the consequences of early alcohol abuse as well as the benefits of early intervention using brain metrics. [ABSTRACT FROM AUTHOR]

Background: Excess weight in adulthood leads to health complications such as diabetes, hypertension, or dyslipidemia. Recently, excess weight has also been related to brain atrophy and cognitive decline. Reports show that obesity is linked with Alzheimer's disease (AD)-related changes, such as cerebrovascular damage or amyloid-β accumulation. However, to date no research has conducted a direct comparison between brain atrophy patterns in AD and obesity. Objective: Here, we compared patterns of brain atrophy and amyloid-β/tau protein accumulation in obesity and AD using a sample of over 1,300 individuals from four groups: AD patients, healthy controls, obese otherwise healthy individuals, and lean individuals. Methods: We age- and sex-matched all groups to the AD-patients group and created cortical thickness maps of AD and obesity. This was done by comparing AD patients with healthy controls, and obese individuals with lean individuals. We then compared the AD and obesity maps using correlation analyses and permutation-based tests that account for spatial autocorrelation. Similarly, we compared obesity brain maps with amyloid-β and tau protein maps from other studies. Results: Obesity maps were highly correlated with AD maps but were not correlated with amyloid-β/tau protein maps. This effect was not accounted for by the presence of obesity in the AD group. Conclusion: Our research confirms that obesity-related grey matter atrophy resembles that of AD. Excess weight management could lead to improved health outcomes, slow down cognitive decline in aging, and lower the risk for AD. [ABSTRACT FROM AUTHOR]

Essential tremor (ET) is the most prevalent movement disorder with poorly understood etiology. Some neuroimaging studies report cerebellar involvement whereas others do not. This discrepancy may stem from underpowered studies, differences in statistical modeling or variation in magnetic resonance imaging (MRI) acquisition and processing. To resolve this, we investigated the cerebellar structural differences using a local advanced ET dataset augmented by matched controls from PPMI and ADNI. We tested the hypothesis of cerebellar involvement using three neuroimaging biomarkers: VBM, gray/white matter volumetry and lobular volumetry. Furthermore, we assessed the impacts of statistical models and segmentation pipelines on results. Results indicate that the detected cerebellar structural changes vary with methodology. Significant reduction of right cerebellar gray matter and increase of the left cerebellar white matter were the only two biomarkers consistently identified by multiple methods. Results also show substantial volumetric overestimation from SUIT-based segmentation—partially explaining previous literature discrepancies. This study suggests that current estimation of cerebellar involvement in ET may be overemphasized in MRI studies and highlights the importance of methods sensitivity analysis on results interpretation. ET datasets with large sample size and replication studies are required to improve our understanding of regional specificity of cerebellum involvement in ET. Protocol registration: The stage 1 protocol for this Registered Report was accepted in principle on 21 March 2022. The protocol, as accepted by the journal, can be found at: https://doi.org/10.6084/m9.figshare.19697776. [ABSTRACT FROM AUTHOR]

Connections among brain regions allow pathological perturbations to spread from a single source region to multiple regions. Patterns of neurodegeneration in multiple diseases, including behavioural variant of frontotemporal dementia (bvFTD), resemble the large-scale functional systems, but how bvFTD-related atrophy patterns relate to structural network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture. Regional atrophy patterns were estimated in both genetic bvFTD (75 patients, 247 controls) and sporadic bvFTD (70 patients, 123 controls). First, we identified distributed atrophy patterns in bvFTD, mainly targeting areas associated with the limbic intrinsic network and insular cytoarchitectonic class. Regional atrophy was significantly correlated with atrophy of structurally- and functionally-connected neighbours, demonstrating that network structure shapes atrophy patterns. The anterior insula was identified as the predominant group epicentre of brain atrophy using data-driven and simulation-based methods, with some secondary regions in frontal ventromedial and antero-medial temporal areas. We found that FTD-related genes, namely C9orf72 and TARDBP , confer local transcriptomic vulnerability to the disease, modulating the propagation of pathology through the connectome. Collectively, our results demonstrate that atrophy patterns in sporadic and genetic bvFTD are jointly shaped by global connectome architecture and local transcriptomic vulnerability, providing an explanation as to how heterogenous pathological entities can lead to the same clinical syndrome. [ABSTRACT FROM AUTHOR]

Obesity and hypothalamic inflammation are causally related. It is unclear whether this neuroinflammation precedes or results from obesity. Animal studies show that an increase in food intake can lead to hypothalamic inflammation, but hypothalamic inflammation can create a feedback loop that further increases food intake. Internal and external factors mediate patterns of food intake and how it can affect the hypothalamus. Measures of water diffusivity in magnetic resonance imaging of the brain such as fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD) are associated with grey matter inflammation. Here, we investigated how those measures are associated with obesity-related variables in groups of young and older adults. We found relationships between decreased diffusivity and obesity markers in young adults. In older adults, obesity and comorbidities were also related to significant changes in diffusivity. Here, diffusivity was strongly associated with body mass index (BMI) and blood levels of C-reactive protein (CRP) in multiple subcortical regions, rather than only the hypothalamus. Our results suggest that diffusivity measures can be used to investigate obesity-associated changes in the brain that can potentially reflect neuroinflammation. The connection seen between subcortical inflammation and obesity opens the conversation on preventative interventions needed to reduce the effects of obesity at all stages in life. [ABSTRACT FROM AUTHOR]

It is increasingly recognized that multiple psychiatric conditions are underpinned by shared neural pathways, affecting similar brain systems. Here, we carried out a multiscale neural contextualization of shared alterations of cortical morphology across six major psychiatric conditions (autism spectrum disorder, attention deficit/hyperactivity disorder, major depression disorder, obsessive-compulsive disorder, bipolar disorder, and schizophrenia). Our framework cross-referenced shared morphological anomalies with respect to cortical myeloarchitecture and cytoarchitecture, as well as connectome and neurotransmitter organization. Pooling disease-related effects on MRI-based cortical thickness measures across six ENIGMA working groups, including a total of 28,546 participants (12,876 patients and 15,670 controls), we identified a cortex-wide dimension of morphological changes that described a sensory-fugal pattern, with paralimbic regions showing the most consistent alterations across conditions. The shared disease dimension was closely related to cortical gradients of microstructure as well as neurotransmitter axes, specifically cortex-wide variations in serotonin and dopamine. Multiple sensitivity analyses confirmed robustness with respect to slight variations in analytical choices. Our findings embed shared effects of common psychiatric conditions on brain structure in multiple scales of brain organization, and may provide insights into neural mechanisms of transdiagnostic vulnerability. Individuals across six major psychiatric conditions from the ENIGMA consortium reveals a shared morphological effect, following a sensory-fugal axis, which is related to microstructural gradient and neurotransmitter axes. [ABSTRACT FROM AUTHOR]

Negative symptoms in the psychosis continuum are linked to impairments in reward processing and cognitive function. Processes at the interface of reward processing and cognition and their relation to negative symptoms remain little studied, despite evidence suggestive of integration in mechanisms and neural circuitry. Here, we investigated brain activation during reward-dependent modulation of working memory (WM) and their relationship to negative symptoms in subclinical and early stages of the psychosis continuum. We included 27 persons with high schizotypal personality traits and 23 patients with first episode psychosis as well as 27 healthy controls. Participants underwent functional magnetic resonance imaging while performing an established 2-back WM task with two reward levels (5 CHF vs. no reward), which allowed us to assess common reward-cognition regions through whole-brain conjunction analyses and to investigate relations with clinical scores of negative symptoms. As expected for behavior, reward facilitated performance while cognitive load diminished it. At the neural level, the conjunction of high reward and high cognitive load contrasts across the psychosis continuum showed increased hemodynamic activity in the thalamus and the cerebellar vermis. During high cognitive load, more severe apathy but not diminished expression in the psychosis continuum was associated with reduced activity in right lateral orbitofrontal cortex, midbrain, posterior vermal cerebellum, caudate and lateral parietal cortex. Our results suggest that hypoactivity in the cerebellar vermis and the cortical-striatal-midbrain-circuitry in the psychosis continuum relates to apathy possibly via impaired flexible cognitive resource allocation for effective goal pursuit. [ABSTRACT FROM AUTHOR]

The factors that affect food choices are critical to understanding obesity. In the present study, healthy participants were shown pictures of foods to determine the impact of caloric content on food choice. Brain activity was then measured while participants bid for a chance to purchase and eat one item. True caloric density, but not individual estimates of calorie content, predicted how much participants were willing to pay for each item. Caloric density also correlated with the neural response to food pictures in the ventromedial prefrontal cortex, a brain area that encodes the value of stimuli and predicts immediate consumption. That same region exhibited functional connectivity with an appetitive brain network, and this connectivity was modulated by willingness to pay. Despite the fact that participants were poor at explicitly judging caloric content, their willingness to pay and brain activity both correlated with actual caloric density. This suggests that the reward value of a familiar food is dependent on implicit knowledge of its caloric content. [ABSTRACT FROM PUBLISHER]

Parkinson's disease is a progressive neurodegenerative disorder characterized by the intracellular accumulation of insoluble alpha-synuclein aggregates into Lewy bodies and neurites. Increasing evidence indicates that Parkinson's disease progression results from the spread of pathologic alpha-synuclein through neuronal networks. However, the exact mechanisms underlying the propagation of abnormal proteins in the brain are only partially understood. The objective of this study was first to describe the long-term spatiotemporal distributions of Lewy-related pathology in mice injected with alpha-synuclein preformed fibrils and then to recreate these patterns using a computational model that simulates in silico the spread of pathologic alpha-synuclein. In this study, 87 2-3-month-old non-transgenic mice were injected with alpha-synuclein preformed fibrils to generate a comprehensive post-mortem dataset representing the long-term spatiotemporal distributions of hyperphosphorylated alpha-synuclein, an established marker of Lewy pathology, across the 426 regions of the Allen Mouse Brain Atlas. The mice were injected into either the caudoputamen, nucleus accumbens or hippocampus, and followed over 24 months with pathologic alpha-synuclein quantified at seven intermediate time points. The pathologic patterns observed at each time point in this high-resolution dataset were then compared to those generated using a Susceptible-Infected-Removed (SIR) computational model, an agent-based model that simulates the spread of pathologic alpha-synuclein for every brain region taking simultaneously into account the effect of regional brain connectivity and Snca gene expression. Our histopathological findings showed that differentially targeted seeding of pathological alpha-synuclein resulted in unique propagation patterns over 24 months and that most brain regions were permissive to pathology. We found that the SIR model recreated the observed distributions of pathology over 24 months for each injection site. Null models showed that both Snca gene expression and connectivity had a significant influence on model fit. In sum, our study demonstrates that the combination of normal alpha-synuclein concentration and brain connectomics contributes to making brain regions more vulnerable to the pathological process, providing support for a prion-like spread of pathologic alpha-synuclein. We propose that this rich dataset and the related computational model will help test new hypotheses regarding mechanisms that may alter the spread of pathologic alpha-synuclein in the brain. [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]