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1.  Overweight is not associated with cortical thickness alterations in children 
Introduction: Several studies report an association between body mass index (BMI) and cortical thickness in adults. Some studies demonstrate diffuse cortical thinning in obesity, while others report effects in areas that are associated with self-regulation, such as lateral prefrontal cortex.
Methods: This study used multilevel modeling of data from the NIH Pediatric MRI Data Repository, a mixed longitudinal and cross-sectional database, to examine the relationship between cortical thickness and body weight in children. Cortical thickness was computed at 81,942 vertices of 716 MRI scans from 378 children aged between 4 and 18 years. Body mass index Z score for age was computed for each participant. We performed vertex-wise statistical analysis of the relationship between cortical thickness and BMI, accounting for age and gender. In addition, cortical thickness was extracted from regions of interest in prefrontal cortex and insula.
Results: No significant association between cortical thickness and BMI was found, either by statistical parametric mapping or by region of interest analysis. Results remained negative when the analysis was restricted to children aged 12–18.
Conclusions: The correlation between BMI and cortical thickness was not found in this large pediatric sample. The association between BMI and cortical thinning develops after adolescence. This has implications for the nature of the relationship between brain anatomy and weight gain.
doi:10.3389/fnins.2015.00024
PMCID: PMC4316697
obesity; cortical thickness; cortical development; MRI; adolescence; childhood; gray matter; body mass index
2.  Cocaine Cue-Induced Dopamine Release in Amygdala and Hippocampus: A High-Resolution PET [18F]Fallypride Study in Cocaine Dependent Participants 
Neuropsychopharmacology  2013;38(9):1780-1788.
Drug-related cues are potent triggers for relapse in people with cocaine dependence. Dopamine (DA) release within a limbic network of striatum, amygdala and hippocampus has been implicated in animal studies, but in humans it has only been possible to measure effects in the striatum. The objective here was to measure drug cue-induced DA release in the amygdala and hippocampus using high-resolution PET with [18F]fallypride. Twelve cocaine-dependent volunteers (mean age: 39.6±8.0 years; years of cocaine use: 15.9±7.4) underwent two [18F]fallypride high-resolution research tomography–PET scans, one with exposure to neutral cues and one with cocaine cues. [18F]Fallypride non-displaceable-binding potential (BPND) values were derived for five regions of interest (ROI; amygdala, hippocampus, ventral limbic striatum, associative striatum, and sensorimotor striatum). Subjective responses to the cues were measured with visual analog scales and grouped using principal component analysis. Drug cue exposure significantly decreased BPND values in all five ROI in subjects who had a high-, but not low-, craving response (limbic striatum: p=0.019, associative striatum: p=0.008, sensorimotor striatum: p=0.004, amygdala: p=0.040, and right hippocampus: p=0.025). Individual differences in the cue-induced craving response predicted the magnitude of [18F]fallypride responses within the striatum (ventral limbic: r=0.581, p=0.048; associative: r=0.589, p=0.044; sensorimotor: r=0.675, p=0.016). To our knowledge this study provides the first evidence of drug cue-induced DA release in the amygdala and hippocampus in humans. The preferential induction of DA release among high-craving responders suggests that these aspects of the limbic reward network might contribute to drug-seeking behavior.
doi:10.1038/npp.2013.77
PMCID: PMC3717549  PMID: 23546387
Addiction & Substance Abuse; amygdale; craving; Dopamine; hippocampus; Imaging; Clinical or Preclinical; Psychiatry & Behavioral Sciences; reward; striatum; addiction; craving; reward; striatum; limbic; conditioning
3.  Neurobehavioural correlates of body mass index and eating behaviours in adults: A systematic review 
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.
doi:10.1016/j.neubiorev.2012.11.008
PMCID: PMC4017079  PMID: 23261403
Obesity; impulsivity; BMI; neuropsychology; executive functions; food motivation; Five-Factor Model; Big Five; personality; self-control; sensitivity to reward; reliability
4.  The role of dopamine in risk taking: a specific look at Parkinson’s disease and gambling 
An influential model suggests that dopamine signals the difference between predicted and experienced reward. In this way, dopamine can act as a learning signal that can shape behaviors to maximize rewards and avoid punishments. Dopamine is also thought to invigorate reward seeking behavior. Loss of dopamine signaling is the major abnormality in Parkinson’s disease. Dopamine agonists have been implicated in the occurrence of impulse control disorders in Parkinson’s disease patients, the most common being pathological gambling, compulsive sexual behavior, and compulsive buying. Recently, a number of functional imaging studies investigating impulse control disorders in Parkinson’s disease have been published. Here we review this literature, and attempt to place it within a decision-making framework in which potential gains and losses are evaluated to arrive at optimum choices. We also provide a hypothetical but still incomplete model on the effect of dopamine agonist treatment on these value and risk assessments. Two of the main brain structures thought to be involved in computing aspects of reward and loss are the ventral striatum (VStr) and the insula, both dopamine projection sites. Both structures are consistently implicated in functional brain imaging studies of pathological gambling in Parkinson’s disease.
doi:10.3389/fnbeh.2014.00196
PMCID: PMC4038955  PMID: 24910600
impulse control disorders; impulsivity; reward; loss aversion; insula; ventral striatum
6.  White Matter Abnormalities and Structural Hippocampal Disconnections in Amnestic Mild Cognitive Impairment and Alzheimer’s Disease 
PLoS ONE  2013;8(9):e74776.
The purpose of this project was to evaluate white matter degeneration and its impact on hippocampal structural connectivity in patients with amnestic mild cognitive impairment, non-amnestic mild cognitive impairment and Alzheimer’s disease. We estimated white matter fractional anisotropy, mean diffusivity and hippocampal structural connectivity in two independent cohorts. The ADNI cohort included 108 subjects [25 cognitively normal, 21 amnestic mild cognitive impairment, 47 non-amnestic mild cognitive impairment and 15 Alzheimer’s disease]. A second cohort included 34 subjects [15 cognitively normal and 19 amnestic mild cognitive impairment] recruited in Montreal. All subjects underwent clinical and neuropsychological assessment in addition to diffusion and T1 MRI. Individual fractional anisotropy and mean diffusivity maps were generated using FSL-DTIfit. In addition, hippocampal structural connectivity maps expressing the probability of connectivity between the hippocampus and cortex were generated using a pipeline based on FSL-probtrackX. Voxel-based group comparison statistics of fractional anisotropy, mean diffusivity and hippocampal structural connectivity were estimated using Tract-Based Spatial Statistics. The proportion of abnormal to total white matter volume was estimated using the total volume of the white matter skeleton. We found that in both cohorts, amnestic mild cognitive impairment patients had 27-29% white matter volume showing higher mean diffusivity but no significant fractional anisotropy abnormalities. No fractional anisotropy or mean diffusivity differences were observed between non-amnestic mild cognitive impairment patients and cognitively normal subjects. Alzheimer’s disease patients had 66.3% of normalized white matter volume with increased mean diffusivity and 54.3% of the white matter had reduced fractional anisotropy. Reduced structural connectivity was found in the hippocampal connections to temporal, inferior parietal, posterior cingulate and frontal regions only in the Alzheimer’s group. The severity of white matter degeneration appears to be higher in advanced clinical stages, supporting the construct that these abnormalities are part of the pathophysiological processes of Alzheimer’s disease.
doi:10.1371/journal.pone.0074776
PMCID: PMC3785512  PMID: 24086371
7.  A model of food reward learning with dynamic reward exposure 
The process of conditioning via reward learning is highly relevant to the study of food choice and obesity. Learning is itself shaped by environmental exposure, with the potential for such exposures to vary substantially across individuals and across place and time. In this paper, we use computational techniques to extend a well-validated standard model of reward learning, introducing both substantial heterogeneity and dynamic reward exposures. We then apply the extended model to a food choice context. The model produces a variety of individual behaviors and population-level patterns which are not evident from the traditional formulation, but which offer potential insights for understanding food reward learning and obesity. These include a “lock-in” effect, through which early exposure can strongly shape later reward valuation. We discuss potential implications of our results for the study and prevention of obesity, for the reward learning field, and for future experimental and computational work.
doi:10.3389/fncom.2012.00082
PMCID: PMC3468814  PMID: 23087640
reward learning; computational modeling; temporal difference learning; food choice
8.  Impaired small-world efficiency in structural cortical networks in multiple sclerosis associated with white matter lesion load 
Brain  2009;132(12):3366-3379.
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.
doi:10.1093/brain/awp089
PMCID: PMC2792366  PMID: 19439423
cortical thickness; connectivity; MRI; multiple sclerosis; small-world networks
9.  Perceived early-life maternal care and the cortisol response to repeated psychosocial stress 
Background
In the past decade, a body of animal and human research has revealed a profound influence of early-life experiences, ranging from variations in parenting behaviour to severe adversity, on hypothalamic–pituitary–adrenal axis regulation in adulthood. In our own previous studies, we have shown how variations in early-life parental care influence the development of the hippocampus and modify the cortisol awakening response.
Methods
In the present study, we investigated the influence of early-life maternal care on cortisol, heart rate and subjective psychological responses to the repeated administration of a psychosocial laboratory stressor in a population of 63 healthy young adults. Low, medium and high early-life maternal care groups were identified using the Parental Bonding Instrument.
Results
Controlling for the effect of sex, we found an inverted u-shaped relation between increasing levels of maternal care and cortisol stress responsivity. Specifically, overall and stress-induced cortisol levels went from below normal in the low maternal care, to normal in the medium care, back to below normal in the high maternal care groups. We found no group differences with respect to heart rate and subjective psychological stress measures. Whereas low and high maternal care groups exhibited similarly low endocrine stress responses, their psychological profiles were opposed with increased levels of depression and anxiety and decreased self-esteem in the low care group.
Limitations
Sex was unequally distributed among maternal care groups, whereby the number of men with low maternal care was too small to allow introducing sex as a second between-group variable.
Conclusion
We discuss the potential significance of this dissociation between endocrine and psychological parameters with respect to stress vulnerability and resistance for each maternal care group.
doi:10.1503/jpn.100022
PMCID: PMC2964367  PMID: 20964960
10.  An acute psychosocial stress enhances the neural response to smoking cues 
Brain research  2009;1293:40-48.
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.
doi:10.1016/j.brainres.2009.07.048
PMCID: PMC2754394  PMID: 19632211
fMRI; stress; nicotine; tobacco; hippocampus; amygdala; nucleus accumbens
11.  Dopamine neurons implanted into people with Parkinson’s disease survive without pathology for 14 years 
Nature medicine  2008;14(5):507-509.
Postmortem analysis of five subjects with Parkinson’s disease9–14 years after transplantation of fetal midbrain cell suspensions revealed surviving grafts that included dopamine and serotonin neurons without pathology. These findings are important for the understanding of the etiopathogenesis of midbrain dopamine neuron degeneration and future use of cell replacement therapies.
doi:10.1038/nm1752
PMCID: PMC2656682  PMID: 18391961
12.  Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson’s disease 
Brain : a journal of neurology  2005;128(Pt 7):1498-1510.
We report the first post-mortem analysis of two patients with Parkinson’s disease who received fetal midbrain transplants as a cell suspension in the striatum, and in one case also in the substantia nigra. These patients had a favourable clinical evolution and positive 18F-fluorodopa PET scans and did not develop motor complications. The surviving transplanted dopamine neurons were positively identified with phenotypic markers of normal control human substantia nigra (n = 3), such as tyrosine hydroxylase, G-protein-coupled inward rectifying current potassium channel type 2 (Girk2) and calbindin. The grafts restored the cell type that provides specific dopaminergic innervation to the most affected striatal regions in the parkinsonian brain. Such transplants were able to densely reinnervate the host putamen with new dopamine fibres. The patients received only 6 months of standard immune suppression, yet by post-mortem analysis 3–4 years after surgery the transplants appeared only mildly immunogenic to the host brain, by analysis of microglial CD45 and CD68 markers. This study demonstrates that, using these methods, dopamine neuronal replacement cell therapy can be beneficial for patients with advanced disease, and that changing technical approaches could have a favourable impact on efficacy and adverse events following neural transplantation.
doi:10.1093/brain/awh510
PMCID: PMC2610438  PMID: 15872020
transplantation; dopamine neuron; Parkinson’s disease
13.  Defective Fas expression exacerbates neurotoxicity in a model of Parkinson's disease 
Fas (CD95), a member of the tumor necrosis factor-receptor superfamily, has been studied extensively as a death-inducing receptor in the immune system. However, Fas is also widely expressed in a number of other tissues, including in neurons. Here, we report that defects in the Fas/Fas ligand system unexpectedly render mice highly susceptible to neural degeneration in a model of Parkinson's disease. We found that Fas-deficient lymphoproliferative mice develop a dramatic phenotype resembling clinical Parkinson's disease, characterized by extensive nigrostriatal degeneration accompanied by tremor, hypokinesia, and loss of motor coordination, when treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose that causes no neural degeneration or behavioral impairment in WT mice. Mice with generalized lymphoproliferative disease, which express a mutated Fas ligand, display an intermediate phenotype between that of lymphoproliferative and WT mice. Moreover, Fas engagement directly protects neuronal cells from MPTP/1-methyl-4-phenylpyridinium ion toxicity in vitro. Our data show that decreased Fas expression renders dopaminergic neurons highly susceptible to degeneration in response to a Parkinson-causing neurotoxin. These findings constitute the first evidence for a neuroprotective role for Fas in vivo.
doi:10.1084/jem.20050163
PMCID: PMC2212882  PMID: 16129703

Results 1-13 (13)