Mesocorticolimbic function in cocaine polydrug users: A multimodal study of drug cue reactivity and cognitive regulation.

Addictions are thought to be fostered by the emergence of poorly regulated mesocorticolimbic responses to drug-related cues. The development and persistence of these responses might be promoted by altered glutamate transmission, including changes to type 5 metabotropic glutamate receptors (mGluR5s). Unknown, however, is when these changes arise and whether the mGluR5 and mesocorticolimbic alterations are related. To investigate, non-dependent cocaine polydrug users and cocaine-naïve healthy controls underwent a positron emission tomography scan (15 cocaine users and 14 healthy controls) with [11 C]ABP688, and a functional magnetic resonance imaging scan (15/group) while watching videos depicting activities with and without cocaine use. For some drug videos, participants were instructed to use a cognitive strategy to lower craving. Both groups exhibited drug cue-induced mesocorticolimbic activations and these were larger in the cocaine polydrug users than healthy controls during the session's second half. During the cognitive regulation trials, the cocaine users' corticostriatal responses were reduced. [11 C]ABP688 binding was unaltered in cocaine users, relative to healthy controls, but post hoc analyses found reductions in those with 75 or more lifetime cocaine use sessions. Finally, among cocaine users (n = 12), individual differences in prefrontal [11 C]ABP688 binding were associated with midbrain and limbic region activations during the regulation trials. Together, these preliminary findings raise the possibility that (i) recreational polydrug cocaine users show biased brain processes towards cocaine-related cues and (ii) repeated cocaine use can lower cortical mGluR5 levels, diminishing the ability to regulate drug cue responses. These alterations might promote susceptibility to addiction and identify early intervention targets.

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex.

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.

Relationship between impulsivity, uncontrolled eating and body mass index: a hierarchical model.

BACKGROUND: Impulsivity increases the risk for obesity and weight gain. However, the precise role of impulsivity in the aetiology of overeating behavior and obesity is currently unknown. Here we examined the relationships between personality-related measures of impulsivity, Uncontrolled Eating, body mass index (BMI), and longitudinal weight changes. In addition, we analyzed the associations between general impulsivity domains and cortical thickness to elucidate brain vulnerability factors related to weight gain. METHODS: Students (N = 2318) in their first year of university-a risky period for weight gain-completed questionnaire measures of impulsivity and eating behavior at the beginning of the school year. We also collected their weight at the end of the term (N = 1177). Impulsivity was divided into three factors: stress reactivity, reward sensitivity and lack of self-control. Using structural equation models, we tested a hierarchical relationship, in which impulsivity traits were associated with Uncontrolled Eating, which in turn predicted BMI and weight change. Seventy-one participants underwent T1-weighted MRI to investigate the correlation between impulsivity and cortical thickness. RESULTS: Impulsivity traits showed positive correlations with Uncontrolled Eating. Higher scores in Uncontrolled Eating were in turn associated with higher BMI. None of the impulsivity-related measurements nor Uncontrolled Eating were correlated with longitudinal weight gain. Higher stress sensitivity was associated with increased cortical thickness in the superior temporal gyrus. Lack of self-control was positively associated with increased thickness in the superior medial frontal gyrus. Finally, higher reward sensitivity was associated with lower thickness in the inferior frontal gyrus. CONCLUSION: The present study provides a comprehensive characterization of the relationships between different facets of impulsivity and obesity. We show that differences in impulsivity domains might be associated with BMI via Uncontrolled Eating. Our results might inform future clinical strategies aimed at fostering self-control abilities to prevent and/or treat unhealthy weight gain.

A Prospective Study of the Prevalence of Parkinsonism in Patients With Liver Cirrhosis.

Acquired hepatocerebral degeneration refers to a neurological syndrome consisting of various movement disorders and cognitive impairment in advanced liver cirrhosis or portosystemic shunt. Neurological signs and symptoms may be attributed to the accumulation of toxic substances in the brain. The most common neurological presentation of this is parkinsonism. Our prospective study aimed to investigate the prevalence of parkinsonism in patients with cirrhosis who were evaluated for liver transplant and to identify any correlation between findings on brain magnetic resonance imaging (MRI) and severity of parkinsonism. Of the 120 enrolled participants with liver cirrhosis, 62 (52%) exhibited signs of parkinsonism and all had MRI basal ganglia hyperintensity. Eighteen patients from this group were transplanted and showed statistically significant improvements in their Unified Parkinson's Disease Rating Scale (UPDRS) scores. Conclusion: The data suggest the reversibility of the neurological impairment seen in cirrhosis, and therefore the effectiveness of transplantation in improving parkinsonian symptoms. There was no correlation between severity of MRI findings and clinical motor UPDRS part III. Laboratory findings showed no correlation among the abnormal levels, MRI brain signal abnormality, or UPDRS scores.

Sex differences in [11C]ABP688 binding: a positron emission tomography study of mGlu5 receptors.

PURPOSE: The purpose of this study was to assess, in a large sample of healthy young adults, sex differences in the binding potential of [11C]ABP688, a positron emission tomography (PET) tracer selective for the metabotropic glutamate type 5 (mGlu5) receptor. METHODS: High resolution [11C]ABP688 PET scans were acquired in 74 healthy volunteers (25 male, 49 female, mean age 20 ± 3.0). Mean binding potential (BPND = fND * (Bavail / KD)) values were calculated in the prefrontal cortex, striatum, and limbic regions using the simplified reference tissue model with cerebellar grey matter as the reference region. RESULTS: [11C]ABP688 BPND was significantly higher in men compared to women in the prefrontal cortex (p < 0.01), striatum (p < 0.001), and hippocampus (p < 0.05). Whole-brain BPND was 17% higher in men. BPND was not related to menstrual phase in women. CONCLUSIONS: Binding availability of mGlu5 receptors as measured by PET [11C]ABP688 is higher in healthy men than women. This likely represents a source of variability in [11C]ABP688 studies and could have relevance for sex differences in cognitive-behavioral functions and neuropsychiatric disorders.

Effect of (Z)-isomer content on [11C]ABP688 binding potential in humans.

PURPOSE: To determine how the low-affinity (Z)-isomer of the radiotracer [11C]ABP688 affects binding potential values in vivo in humans. METHODS: High-resolution [11C]ABP688 PET scans were acquired on 74 healthy volunteers (25 male, 49 female, mean age 20 ± 3.0). The relative contents of (E)- and (Z)-isomers were determined prior to injection using analytical high-performance liquid chromatography [rt(E) = 10 min, rt(Z) = 8.5 min]. Mean binding potential [BPND = fND * (Bavail/KD)] values were calculated in the striatum, limbic regions, and prefrontal cortex using the simplified reference tissue model with cerebellar grey matter as reference. RESULTS: Mean ± SD (E)-isomer content in [11C]ABP688 production was 92 ± 3.8% (range 78-97%). Percent (E)-isomer was positively correlated with BPND in the striatum (ρ = 0.28, p = 0.015) and limbic regions (ρ = 0.25, p = 0.036). In multiple regression analysis, sex (ß = 0.39, p = 0.001) and (E)-isomer content (ß = 0.23, p = 0.040) were significant predictors of BPND. CONCLUSIONS: Even modest levels of (Z)-[11C]ABP688 can reduce estimates of tracer binding in vivo. Future studies should use production methods that enrich levels of (E)-[11C]ABP688, report tracer isomer ratios, and account for this factor in their analyses.

Neurocognitive and Hormonal Correlates of Voluntary Weight Loss in Humans.

Insufficient responses to hypocaloric diets have been attributed to hormonal adaptations that override self-control of food intake. We tested this hypothesis by measuring circulating energy-balance hormones and brain functional magnetic resonance imaging reactivity to food cues in 24 overweight/obese participants before, and 1 and 3 months after starting a calorie restriction diet. Increased activity and functional connectivity in prefrontal regions at month 1 correlated with weight loss at months 1 and 3. Weight loss was also correlated with increased plasma ghrelin and decreased leptin, and these changes were associated with food cue reactivity in reward-related brain regions. However, the reduction in leptin did not counteract weight loss; indeed, it was correlated with further weight loss at month 3. Activation in prefrontal regions associated with self-control could contribute to successful weight loss and maintenance. This work supports the role of higher-level cognitive brain function in body-weight regulation in humans.

A prospective study of benign fasciculation syndrome and anxiety.

INTRODUCTION: Benign fasciculations are common. Despite the favorable prognosis of benign fasciculation syndrome (BFS), patients are often anxious about their symptoms. In this study, we prospectively followed 35 patients with BFS over a 24-month period. METHODS: We conducted serial questionnaires to assess anxiety, associated symptoms, and duration. RESULTS: 71.4% of patients were men, and 34.4% were employed in the medical field. Most reported anxiety, but only 14% were anxious as measured by the Zung self-rating anxiety scale. Fasciculations were most common in the calves and persisted in 93% of patients. Anxiety levels did not change over time. Associated symptoms (subjective weakness, sensory symptoms, and cramps) were common and resolved to varying degrees. No patients developed motor neuron disease. DISCUSSION: BFS is a benign disorder that usually persists over time. Commonly associated symptoms include subjective weakness, sensory symptoms, and cramps. BFS is usually not associated with pathologic anxiety. Muscle Nerve 58:852-854, 2018.

CoQ10 in progressive supranuclear palsy: A randomized, placebo-controlled, double-blind trial.

OBJECTIVE: An investigator-initiated, multicenter, randomized, placebo-controlled, double-blind clinical trial to determine whether coenzyme Q10 (CoQ10) is safe, well tolerated, and effective in slowing functional decline in progressive supranuclear palsy (PSP). METHODS: Sixty-one participants received CoQ10 (2,400 mg/d) or placebo for up to 12 months. Progressive Supranuclear Palsy Rating Scale (PSPRS), Unified Parkinson's Disease Rating Scale, activities of daily living, Mini-Mental State Examination, the 39-item Parkinson's Disease Questionnaire, and 36-item Short Form Health Survey were monitored at baseline and months 3, 6, 9, and 12. The safety profile of CoQ10 was determined by adverse events, vital signs, and clinical laboratory values. Primary outcome measures were changes in PSPRS and Unified Parkinson's Disease Rating Scale scores from baseline to month 12. RESULTS: CoQ10 was well tolerated. No statistically significant differences were noted between CoQ10 and placebo groups in primary or secondary outcome measures. A nonsignificant difference toward slower clinical decline in the CoQ10 group was observed in total PSPRS among those participants who completed the trial. Before the final study visit at 12 months, 41% of participants withdrew because of travel distance, lack of perceived benefit, comorbidities, or caregiver issues. CONCLUSIONS: High doses of CoQ10 did not significantly improve PSP symptoms or disease progression. The high withdrawal rate emphasizes the difficulty of conducting clinical trials in patients with PSP. CLINICALTRIALSGOV IDENTIFIER: NCT00382824. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CoQ10 does not significantly slow functional decline in PSP. The study lacks the precision to exclude a moderate benefit of CoQ10.

Ocular myasthenia gravis in a senior population: diagnosis, therapy, and prognosis.

The objectives of this study were (I) to explore the prognosis of ocular myasthenia gravis (OMG) in patients with onset at age 70 years and above (i.e. senior persons); (2) to identify predictors of secondary generalization in this age group; and 3) to address the effects of immunotherapy on this population of patients. We performed a retrospective analysis of 39 patients with myasthenia gravis who presented with only ocular signs and symptoms after age 70 years. Generalized myasthenia gravis (GMG) developed in 12 OMG patients (31%). None of the GMG patients required ventilator assistance or a feeding tube. Of the 12 ocular patients progressing to GMG, only one (8%) received immunotherapy prior to generalization. Of those OMG patients who did not progress to GMG, 52% received immunomodulatory therapy. Our senior OMG patients had a prognosis comparable with those of the published data for younger individuals. Although the presence of increased acetylceholine receptor antibody titers and occasionally abnormal repetitive nerve stimulation were useful tools to diagnose OMG, no test was predictive of later generalization. Senior onset OMG patients who received immunotherapy less frequently developed GMG than those not so treated.

Inappropriate surgeries resulting from misdiagnosis of early amyotrophic lateral sclerosis.

Initial symptoms of amyotrophic lateral sclerosis (ALS) may mimic radiculopathy, myelopathy, mononeuropathy, or arthropathy. A retrospective review of 260 consecutive patients with ALS evaluated between 1996 and 2004 revealed that 55 (21%) had had surgery within the 5 years prior to ALS diagnosis. Thirty-four of these 55 (61%) had surgery for symptoms and signs that retrospectively were attributable to early manifestations of ALS. Misdiagnosis of early ALS may lead to unnecessary surgeries with their attendant potential complications.