Graham W. Redgrave

Impaired cortico-striatal functional connectivity in prodromal Huntington's Disease

Huntingtons Disease (HD) is a neurodegenerative disease caused by a CAG triplet-repeat expansion-mutation in the Huntingtin gene. Subjects at risk for HD can be identified by genetic testing in the prodromal phase. Structural changes of basal-ganglia nuclei such as the caudate nucleus are well-replicated findings observable early in prodromal-HD subjects and may be preceded by distinct functional alterations of cortico-striatal circuits. This study aims to assess functional integrity of the motor system as a cortico-striatal circuit with particular clinical relevance in HD. Ten subjects in the prodromal phase of HD and ten matched controls were administered blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at rest (3T). Functional connectivity was measured as synchrony of BOLD activity between the caudate nucleus and thirteen cortical brain regions (seeds). Basal-ganglia volumes were assessed as established markers of disease progression in prodromal-HD. Linear regression analysis was performed to test for a relationship between structural changes and group differences in functional connectivity. Prodromal-HD subjects showed reduced BOLD synchrony between two seeds in the premotor cortex (BA6) and the caudate nucleus. While similar effect sizes could be observed for reduced basal-ganglia volumes and differences in functional connectivity, coefficients of determination indicate a moderate relationship between functional connectivity and striatal atrophy. Our data show reduced cortico-striatal functional connectivity at rest in prodromal-HD and suggest a relation to early structural brain changes. Additional longitudinal studies are necessary to elucidate the temporal relationship between functional alterations and earliest structural brain changes in prodromal-HD.

Brain Metabolite Alterations and Cognitive Dysfunction in Early Huntington's Disease

Huntingtons disease (HD) is a neurodegenerative disorder characterized by early cognitive decline that progresses at later stages to dementia and severe movement disorder. HD is caused by a cytosine–adenine–guanine triplet‐repeat expansion mutation in the Huntingtin gene, allowing early diagnosis by genetic testing. This study aimed to identify the relationship of N‐acetylaspartate and other brain metabolites to cognitive function in HD‐mutation carriers by using high‐field‐strength magnetic resonance spectroscopy (MRS) at 7 Tesla. Twelve individuals with the HD mutation in premanifest or early‐stage disease versus 12 healthy controls underwent 1H magnetic resonance spectroscopy (7.2 mL voxel in the posterior cingulate cortex) at 7 Tesla, and also T1‐weighted structural magnetic resonance imaging. All participants received standardized tests of cognitive functioning including the Montreal Cognitive Assessment and standardized quantified neurological examination within an hour before scanning. Individuals with the HD mutation had significantly lower posterior cingulate cortex N‐acetylaspartate (−9.6%, P = .02) and glutamate (−10.1%, P = .02) levels than did controls. In contrast, in this small group, measures of brain morphology including striatal and ventricle volumes did not differ significantly. Linear regression with Montreal Cognitive Assessment scores revealed significant correlations with N‐acetylaspartate (r2 = 0.50, P = .01) and glutamate (NAA) (r2 = 0.64, P = .002) in HD subjects. Our data suggest a relationship between reduced N‐acetylaspartate and glutamate levels in the posterior cingulate cortex with cognitive decline in the early stages of HD. N‐acetylaspartate and glutamate magnetic resonance spectroscopy signals of the posterior cingulate cortex region may serve as potential biomarkers of disease progression or treatment outcome in HD and other neurodegenerative disorders with early cognitive dysfunction, when structural brain changes are still minor.

Differential brain activation in anorexia nervosa to Fat and Thin words during a Stroop task.

We measured brain activation in six anorexia nervosa patients and six healthy controls performing a novel emotional Stroop task using Fat, Thin, and Neutral words, and words made of XXXXs. Reaction times increased in the patient group in Thin and Fat conditions. In the Thin–XXXX contrast, patients showed greater activation than controls at the junction of left insula, frontal and temporal lobes and in left middle and medial frontal gyri. In the Fat–XXXX contrast, controls showed greater activation in left dorsolateral prefrontal cortex and right parietal areas. Mechanisms underlying attentional bias in anorexia nervosa likely differ under conditions of positive and negative valence. This paradigm is a promising tool to examine neural mediation of emotional response in anorexia nervosa.

Differential Impairments Underlying Decision Making in Anorexia Nervosa and Bulimia Nervosa: A Cognitive Modeling Analysis

OBJECTIVE This study examined the underlying processes of decision-making impairments in individuals with anorexia nervosa (AN) and bulimia nervosa (BN). We deconstructed their performance on the widely used decision task, the Iowa Gambling Task (IGT) into cognitive, motivational, and response processes using cognitive modeling analysis. We hypothesized that IGT performance would be characterized by impaired memory functions and heightened punishment sensitivity in AN, and by elevated sensitivity to reward as opposed to punishment in BN. METHOD We analyzed trial-by-trial data of IGT obtained from 224 individuals: 94 individuals with AN, 63 with BN, and 67 healthy comparison individuals (HC). The prospect valence learning model was used to assess cognitive, motivational, and response processes underlying IGT performance. RESULTS Individuals with AN showed marginally impaired IGT performance compared to HC. Their performance was characterized by impairments in memory functions. Individuals with BN showed significantly impaired IGT performance compared to HC. They showed greater relative sensitivity to gains as opposed to losses than HC. Memory functions in AN were positively correlated with body mass index. DISCUSSION This study identified differential impairments underlying IGT performance in AN and BN. Findings suggest that impaired decision making in AN might involve impaired memory functions. Impaired decision making in BN might involve altered reward and punishment sensitivity.

Refeeding and weight restoration outcomes in anorexia nervosa: Challenging current guidelines

OBJECTIVE Cohort study from February 2003 through May 2011 to determine weight restoration and refeeding complication outcomes for patients with anorexia nervosa (AN) treated in an integrated inpatient-partial hospital eating disorder program designed to produce rapid weight gain and weight restoration in the majority. METHOD Consecutive admissions (females and males, adolescents and adults; N = 361 patients, 461 admissions) at least 1.8 kg below target weight with AN or subthreshold variants were included. Main outcome measures were rates of hypophosphatemia, transfer to medicine, or death; rates of weight gain and percent achieving weight restoration. RESULTS Hypophosphatemia was present in 7.9% of cases at admission and in 18.5% at some point during treatment. Hypophosphatemia was mild to moderate. Lower admission body mass index (BMI), but not rate of weight gain, predicted hypophosphatemia [OR = 0.65; p < .00001 (95% CI 0.57-0.76)]. Five patients (1.1%) were transferred to medicine or surgery, none because of refeeding. There were no deaths. Mean inpatient weight gain was 1.98 kg/week; mean partial hospital weight gain was 1.36 kg/week. By program discharge, 71.8% of adults reached a BMI of 19, 58.5% a BMI of 20. For adolescents, 80.4% came within 2 kg of their target weight; 76.1% came within 1 kg. DISCUSSION Refeeding patients with AN using a hospital-based, behavioral protocol may be accomplished safely and more rapidly than generally recognized, weight restoring most patients by discharge. Helpful elements may include the programs integrated, step-down structure; multidisciplinary team approach emphasizing group therapy to effect behavior change; and close medical monitoring for those with BMI < 15.

Alcohol misuse by women

Alcohol misuse among women is an important and growing problem. There is epidemiological and metabolic evidence that risk factors for and consequences of alcohol misuse are significantly different for women than for men. Understanding these differences is imperative if effective preventative and treatment interventions are to be undertaken. This article reviews the epidemiology of alcohol misuse by women, effects of alcohol misuse on women, fetuses, and relationships, and assessment and treatment strategies. We then suggest directions for future research in this field.

Dietary conditions and highly palatable food access alter rat cannabinoid receptor expression and binding density.

Endogenous cannabinoid signaling, mediated predominately by CB1 receptor activation, is involved in food intake control and body weight regulation. Despite advances in determining the role of the CB1 receptor in obesity, its involvement in the driven nature of eating pathologies has received little attention. The present study examined CB1 receptor alterations as a consequence of dietary-induced binge eating in female Sprague Dawley rats. Four control groups were used to control for calorie restriction and highly palatable food variables characterizing this behavioral model. All groups were kept on their respective feeding schedules for 6-weeks and were given a uniform 33% calorie restriction (~22 h food deprivation) prior to sacrifice. Our findings indicate that regional CB1 mRNA and density were influenced by dietary conditions, but were not specific to the dietary-induced binge eating paradigm used. An increase of approximately 50% (compared with naive controls) in CB1 receptor mRNA levels in the nucleus of the solitary tract as measured by in situ hybridization was found in animals receiving continuous access to a highly palatable food (i.e., vegetable shortening with 10% sucrose). This group also had a significant increase in body weight and adiposity. An approximate 20% reduction in CB1 mRNA was observed in the cingulate cortex (areas 1 and 2) in animals exposed to an intermittent schedule of feeding, compared with groups that had ad libitum feeding schedules (i.e., continuous access and naive controls). Receptor density as measured by [(3)H]CP55,940 autoradiography, was reduced by approximately 30% in the nucleus accumbens shell region in groups receiving repeated access to the highly palatable food. Taken together, these findings indicate that dietary conditions can differentially influence CB1 receptors in forebrain and hindbrain regions.

A systematic review of approaches to refeeding in patients with anorexia nervosa.

OBJECTIVE Given the importance of weight restoration for recovery in patients with anorexia nervosa (AN), we examined approaches to refeeding in adolescents and adults across treatment settings. METHODS Systematic review of PubMed, PsycINFO, Scopus, and Clinical Trials databases (1960-2015) using terms refeeding, weight restoration, hypophosphatemia, anorexia nervosa, anorexia, and anorexic. RESULTS Of 948 screened abstracts, 27 met these inclusion criteria: participants had AN; reproducible refeeding approach; weight gain, hypophosphatemia or cognitive/behavioral outcomes. Twenty-six studies (96%) were observational/prospective or retrospective and performed in hospital. Twelve studies published since 2010 examined approaches starting with higher calories than currently recommended (≥1400 kcal/d). The evidence supports 8 conclusions: 1) In mildly and moderately malnourished patients, lower calorie refeeding is too conservative; 2) Both meal-based approaches or combined nasogastric+meals can administer higher calories; 3) Higher calorie refeeding has not been associated with increased risk for the refeeding syndrome under close medical monitoring with electrolyte correction; 4) In severely malnourished inpatients, there is insufficient evidence to change the current standard of care; 5) Parenteral nutrition is not recommended; 6) Nutrient compositions within recommended ranges are appropriate; 7) More research is needed in non-hospital settings; 8) The long-term impact of different approaches is unknown; DISCUSSION Findings support higher calorie approaches to refeeding in mildly and moderately malnourished patients under close medical monitoring, however the safety, long-term outcomes, and feasibility outside of hospital have not been established. Further research is also needed on refeeding approaches in severely malnourished patients, methods of delivery, nutrient compositions and treatment settings.

Depressive symptoms in prodromal Huntington's Disease correlate with Stroop-interference related functional connectivity in the ventromedial prefrontal cortex

Huntingtons Disease (HD) is a neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) triplet repeat-expansion in the Huntingtin (HTT) gene. Diagnosis of HD is classically defined by the presence of motor symptoms; however, cognitive and depressive symptoms frequently precede motor manifestations, and may occur early in the prodromal phase. There are sparse data so far on functional brain correlates of depressive symptoms in prodromal HD. A Stroop color-naming test was administered to 32 subjects in the prodromal phase of HD and 52 expansion-negative controls while performing functional magnetic resonance imaging at 3Tesla. Networks of functional connectivity were identified using group independent component analysis, followed by an analysis of functional network interactions. A contrast of temporal regression-based beta-weights was calculated as a reflection of Stroop-interference related activity and correlated with Center for Epidemiologic Studies Depression (CES-D) scores. For secondary analysis, patients were stratified into two subgroups by median split of CAG repeat-length. Stroop performance was independent of HTT mutation-carrier status and CES-D score. Stroop-interference-related activity of the ventromedial prefrontal cortex-node of the default-mode network, calculated by temporal-regression beta-weights, was more highly correlated with depressive symptoms in subjects in the prodromal phase of HD than in controls, differing significantly. The strength of this correlation and its difference from controls increased when a subgroup of patients with longer CAG repeat lengths was analyzed. These findings suggest that depressive symptoms in prodromal HD subjects may reflect altered functional brain network activity in the context of early HD-related brain alterations.

Prefrontal executive function associated coupling relates to Huntington's disease stage

Huntingtons disease (HD) is a neurodegenerative disease caused by cytosine-adenine-guanine (CAG)-repeat expansion in the huntingtin (HTT) gene. Early changes that may precede clinical manifestation of movement disorder include executive dysfunction. The aim of this study was to identify functional network correlates of impaired higher cognitive functioning in relation to HD stage. Blood-oxygenation-level-dependent (BOLD) functional-magnetic resonance imaging (fMRI) and structural-MRI were performed in 53 subjects with the HD-mutation (41 prodromals, 12 early affected) and 52 controls. Disease stage was estimated for each subject with HD-mutation based on age, length of the CAG-repeat expansion mutation and also putaminal atrophy. The Tower of London test was administered with three levels of complexity during fMRI as a challenge of executive function. Functional brain networks of interest were identified based on cortical gray matter voxel-clusters with significantly enhanced task-related functional coupling to the medial prefrontal cortex (MPFC) area. While prodromal HD-subjects showed similar performance levels as controls, multivariate analysis of task-related functional coupling to the MPFC identified reduced connectivity in prodromal and early manifest HD-subjects for a cluster including mainly parts of the left premotor area. Secondary testing indicated a significant moderator effect for task complexity on group differences and on the degree of correlation to measures of HD stage. Our data suggest that impaired premotor-MPFC coupling reflects HD stage related dysfunction of cognitive systems involved in executive function and may be present in prodromal HD-subjects that are still cognitively normal. Additional longitudinal studies may reveal temporal relationships between impaired task-related premotor-MPFC coupling and other brain changes in HD.