Kinetic analysis of the metabotropic glutamate subtype 5 tracer [18F]FPEB in bolus and bolus-plus-constant-infusion studies in humans

[¹⁸F]FPEB is a positron emission tomography tracer which, in preclinical studies, has shown high specificity and selectivity toward the metabotropic glutamate receptor 5 (mGluR5). It possesses the potential to be used in human studies to evaluate mGluR5 function in a range of neuropsychiatric disorders, such as anxiety and Fragile X syndrome. To define optimal scan methodology, healthy human subjects were scanned for 6 hours following either a bolus injection (n=5) or bolus-plus-constant-infusion (n=5) of [¹⁸F]FPEB. Arterial blood samples were collected and parent fraction measured by high-performance liquid chromatography (HPLC) to determine the metabolite-corrected plasma input function. Time activity curves were extracted from 13 regions and fitted by various models to estimate V_T and BP_ND. [¹⁸F]FPEB was well fitted by the two-tissue compartment model, MA1 (t*=30), and MRTM (using cerebellum white matter as a reference). Highest V_T values were observed in the anterior cingulate and caudate, and lowest V_T values were observed in the cerebellum and pallidum. For kinetic modeling studies, V_T and BP_ND were estimated from bolus or bolus-plus-constant-infusion scans as short as 90 minutes. Bolus-plus-constant-infusion of [¹⁸F]FPEB reduced intersubject variability in V_T and allowed equilibrium analysis to be completed with a 30-minute scan, acquired 90–120 minutes after the start of injection.     

Estrogen‐related receptor β deletion modulates whole‐body energy balance via estrogen‐related receptor γ and attenuates neuropeptide Y gene expression

Estrogen‐related receptors (ERRs) α, β and γ are orphan nuclear hormone receptors with no known ligands. Little is known concerning the role of ERRβ in energy homeostasis, as complete ERRβ‐null mice die mid‐gestation. We generated two viable conditional ERRβ‐null mouse models to address its metabolic function. Whole‐body deletion of ERRβ in Sox2‐Cre:ERRβ^lox/lox mice resulted in major alterations in body composition, metabolic rate, meal patterns and voluntary physical activity levels. Nestin‐Cre:ERRβ^lox/lox mice exhibited decreased expression of ERRβ in hindbrain neurons, the predominant site of expression, decreased neuropeptide Y (NPY) gene expression in the hindbrain, increased lean body mass, insulin sensitivity, increased energy expenditure, decreased satiety and decreased time between meals. In the absence of ERRβ, increased ERRγ signaling decreased satiety and the duration of time between meals, similar to meal patterns observed for both the Sox2‐Cre:ERRβ^lox/lox and Nestin‐Cre:ERRβ^lox/lox strains of mice. Central and/or peripheral ERRγ signaling may modulate these phenotypes by decreasing NPY gene expression. Overall, the relative expression ratio between ERRβ and ERRγ may be important in modulating ingestive behavior, specifically satiety, gene expression, as well as whole‐body energy balance.     

Levetiracetam-loaded biodegradable polymer implants in the tetanus toxin model of temporal lobe epilepsy in rats

Approximately one-third of people with epilepsy receive insufficient benefit from currently available anticonvulsant medication, and some evidence suggests that this may be due to a lack of effective penetration into brain parenchyma. The current study investigated the ability of biodegradable polymer implants loaded with levetiracetam to ameliorate seizures following implantation above the motor cortex in the tetanus toxin model of temporal lobe epilepsy in rats. The implants led to significantly shorter seizures and a trend towards fewer seizures for up to 1 week. The results of this study indicate that drug-eluting polymer implants represent a promising evolving treatment option for intractable epilepsy. Future research is warranted to investigate issues of device longevity and implantation site.     

The reinforcing effect of exercise in anorexia nervosa: Clinical correlates and relationship to outcome

ABSTRACT

The purpose of the current study was to examine the relative reinforcing effect of exercise compared to a non-monetary alternative reinforcer (leisure activity), and to money, before and after weight restoration in an inpatient population with anorexia nervosa (AN). Sixty-two inpatients with AN completed a progressive ratio (PR) task to earn exercise, leisure activities, or cash at low weight and after weight restoration. Measures of pathology and motivation to exercise were completed and post-treatment discharge weights were collected. Patients worked harder for exercise at low weight than after weight restoration (df = 46, t = 5.50, p < .001). PR task performance was weakly associated with a measure of commitment to exercise (low weight: r = 0.31, weight restored: r = 0.36, p < .05), but not with other clinical measures or follow-up weights. Contrary to prior suggestions, measurement of the reinforcing value of exercise among individuals with AN via a PR task does not appear valuable in assessing clinical severity or outcome. Other, simpler, self-report measures of commitment to exercise may have greater value in assessing these outcomes.     

Clinical impairment in premanifest and early Huntington's disease is associated with regionally specific atrophy

TRACK‐HD is a multicentre longitudinal observational study investigating the use of clinical assessments and 3‐Tesla magnetic resonance imaging as potential biomarkers for future therapeutic trials in Huntington's disease (HD). The cross‐sectional data from this large well‐characterized dataset provide the opportunity to improve our knowledge of how the underlying neuropathology of HD may contribute to the clinical manifestations of the disease across the spectrum of premanifest (PreHD) and early HD. Two hundred and thirty nine gene‐positive subjects (120 PreHD and 119 early HD) from the TRACK‐HD study were included. Using voxel‐based morphometry (VBM), grey and white matter volumes were correlated with performance in four domains: quantitative motor (tongue force, metronome tapping, and gait); oculomotor [anti‐saccade error rate (ASE)]; cognition (negative emotion recognition, spot the change and the University of Pennsylvania smell identification test) and neuropsychiatric measures (apathy, affect and irritability). After adjusting for estimated disease severity, regionally specific associations between structural loss and task performance were found (familywise error corrected, P < 0.05); impairment in tongue force, metronome tapping and ASE were all associated with striatal loss. Additionally, tongue force deficits and ASE were associated with volume reduction in the occipital lobe. Impaired recognition of negative emotions was associated with volumetric reductions in the precuneus and cuneus. Our study reveals specific associations between atrophy and decline in a range of clinical modalities, demonstrating the utility of VBM correlation analysis for investigating these relationships in HD. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

The moderating effects of intellectual development on core symptoms of autism and PDD-NOS in toddlers and infants

Little research has been conducted on whether deficits in developmental functioning affect the range of core symptoms for autism spectrum disorders (ASD). This study represents a first attempt to determine whether developmental level has an effect on the expression of ASD symptoms in infants and toddlers. Eight hundred and fifty-three infants were evaluated with respect to the nature and extent of their ASD symptoms and developmental functioning. Young children with autism displayed a higher number of symptoms than those with PDD-NOS on all three domains of impairment (social, communication, repetitive behaviors). As expected, children without an ASD evinced far fewer symptoms than both these groups. Developmental level was not found to be a moderator for expression of ASD symptoms for the entire sample, or individual diagnostic groups. Higher developmental level was associated with lower severity of evinced ASD symptoms in the sample.     

Early psychotherapy process and cluster B and C personality pathology: similarities and differences in interactions with symptomatic and interpersonal distress

Abstract

In a prior study (Kolden & Klein, 1996), the authors found that the relationships between global personality pathology and early psychotherapy change processes (as defined by the Generic Model of Psychotherapy) were moderated by the extent of the patient's acute symptomatic and interpersonal distress. In the current study, the authors reanalyzed the same data to examine similarities and differences between personality disorder Clusters B (dramatic, emotional, or erratic) and C (anxious or fearful) in therapy process. In general, we found that more distressed patients reported greater defensiveness. There were no significant interactions between symptomatic distress and personality pathology in the prediction of any of the process variables. However, interpersonal distress moderated relationships between Clusters B and C and some therapy processes. Patients high in Cluster B felt more open and involved in the session when they were less distressed by their interpersonal problems at the start of therapy. In contrast, openness and insight were impeded among patients high in Cluster C when they were less distressed interpersonally. Therapists generally used more direct interventions and exploration of past experiences when working with patients higher in Cluster C pathology. However, therapists used direct interventions more specifically when patients with more severe Cluster B pathology were also higher in interpersonal distress. The discussion considers implications for the facilitation of productive early therapy process in patients suffering from Cluster B or C personality pathology.     

Spatial MEG Laterality maps for language: Clinical applications in epilepsy

Functional imaging is increasingly being used to provide a noninvasive alternative to intracarotid sodium amobarbitol testing (i.e., the Wada test). Although magnetoencephalography (MEG) has shown significant potential in this regard, the resultant output is often reduced to a simplified estimate of laterality. Such estimates belie the richness of functional imaging data and consequently limit the potential value. We present a novel approach that utilizes MEG data to compute “complex laterality vectors” and consequently “laterality maps” for a given function. Language function was examined in healthy controls and in people with epilepsy. When compared with traditional laterality index (LI) approaches, the resultant maps provided critical information about the magnitude and spatial characteristics of lateralized function. Specifically, it was possible to more clearly define low LI scores resulting from strong bilateral activation, high LI scores resulting from weak unilateral activation, and most importantly, the spatial distribution of lateralized activation. We argue that the laterality concept is better presented with the inherent spatial sensitivity of activation maps, rather than being collapsed into a one‐dimensional index. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.