Reward processing in schizophrenia and its relation to Mu opioid receptor availability and negative symptoms: A [11C]-carfentanil PET and fMRI study.

BACKGROUND: Reward processing deficits are a core feature of schizophrenia and are thought to underlie negative symptoms. Pre-clinical evidence suggests that opioid neurotransmission is linked to reward processing. However, the contribution of Mu Opioid Receptor (MOR) signalling to the reward processing abnormalities in schizophrenia is unknown. Here, we examined the association between MOR availability and the neural processes underlying reward anticipation in patients with schizophrenia using multimodal neuroimaging. METHOD: 37 subjects (18 with Schizophrenia with moderate severity negative symptoms and 19 age and sex-matched healthy controls) underwent a functional MRI scan while performing the Monetary Incentive Delay (MID) task to measure the neural response to reward anticipation. Participants also had a [11C]-carfentanil PET scan to measure MOR availability. RESULTS: Reward anticipation was associated with increased neural activation in a widespread network of brain regions including the striatum. Patients with schizophrenia had both significantly lower MOR availability in the striatum as well as striatal hypoactivation during reward anticipation. However, there was no association between MOR availability and striatal neural activity during reward anticipation in either patient or controls (Pearson's Correlation, controls df = 17, r = 0.321, p = 0.18, patients df = 16, r = 0.295, p = 0.24). There was no association between anticipation-related neural activation and negative symptoms (r = -0.120, p = 0.14) or anhedonia severity (social r = -0.365, p = 0.14 physical r = -0.120, p = 0.63). CONCLUSIONS: Our data suggest reduced MOR availability in schizophrenia might not underlie striatal hypoactivation during reward anticipation in patients with established illness. Therefore, other mechanisms, such as dopamine dysfunction, warrant further investigation as treatment targets for this aspect of the disorder.

Contribution of the µ-opioid receptor system to affective disorders in temporal lobe epilepsy: A bidirectional relationship?

OBJECTIVE: Affective disorders are frequent comorbidities of temporal lobe epilepsy (TLE). The endogenous opioid system has been implicated in both epilepsy and affective disorders, and may play a significant role in their bidirectional relationship. In this cross-sectional study, we investigated the association between µ-opioid receptor binding and affective disorders in patients with TLE. METHODS: Nine patients with TLE and depression/anxiety underwent 11 C-carfentanil positron emission tomography (CFN PET) and neuropsychiatric assessment, including the Hospital Anxiety and Depression Scale and the Positive and Negative Affect Schedule. The normalized CFN PET scans were compared with those of 26 age-matched healthy controls. Correlation analyses with affective symptoms were performed by region of interest-based analysis focusing on the limbic circuit and orbitofrontal cortex. RESULTS: We observed widely reduced CFN binding potential (BP) in bilateral frontal lobes and striata in patients with TLE compared to healthy controls. In the TLE group, more severe anxiety and negative affect were associated with decreased CFN BP in the posterior cingulate gyrus. SIGNIFICANCE: In patients with TLE, interictally reduced binding in the opioid system was associated with higher levels of anxiety and negative affect. We speculate that seizure-related agonist-driven desensitization and downregulation of opioid receptors could be a potential underlying pathomechanism.

Astrogliosis in aging and Parkinson's disease dementia: a new clinical study with 11C-BU99008 PET.

The role of astrogliosis in the pathology of brain aging and neurodegenerative diseases has recently drawn great attention. Imidazoline-2 binding sites represent a possible target to map the distribution of reactive astrocytes. In this study, we use 11C-BU99008, an imidazoline-2 binding sites-specific PET radioligand, to image reactive astrocytes in vivo in healthy controls and patients with established Parkinson's disease dementia. Eighteen healthy controls (age: 45-78 years) and six patients with Parkinson's disease dementia (age: 64-77 years) had one 11C-BU99008 PET-CT scan with arterial input function. All subjects underwent one 3 T MRI brain scan to facilitate the analysis of the PET data and to capture individual cerebral atrophy. Regional 11C-BU99008 volumes of distribution were calculated for each subject by the two-tissue compartmental modelling. Positive correlations between 11C-BU99008 volumes of distribution values and age were found for all tested regions across the brain within healthy controls (P < 0.05); furthermore, multiple regression indicated that aging affects 11C-BU99008 volumes of distribution values in a region-specific manner. Independent samples t-test indicated that there was no significant group difference in 11C-BU99008 volumes of distribution values between Parkinson's disease dementia (n = 6; mean age = 71.97 ± 4.66 years) and older healthy controls (n = 9; mean age = 71.90 ± 5.51 years). Our data set shows that astrogliosis is common with aging in a region-specific manner. However, in this set-up, 11C-BU99008 PET cannot differentiate patients with Parkinson's disease dementia from healthy controls of similar age.

Implications of Large-Effect Loci for Conservation: A Review and Case Study with Pacific Salmon.

The increasing feasibility of assembling large genomic datasets for non-model species presents both opportunities and challenges for applied conservation and management. A popular theme in recent studies is the search for large-effect loci that explain substantial portions of phenotypic variance for a key trait(s). If such loci can be linked to adaptations, 2 important questions arise: 1) Should information from these loci be used to reconfigure conservation units (CUs), even if this conflicts with overall patterns of genetic differentiation? 2) How should this information be used in viability assessments of populations and larger CUs? In this review, we address these questions in the context of recent studies of Chinook salmon and steelhead (anadromous form of rainbow trout) that show strong associations between adult migration timing and specific alleles in one small genomic region. Based on the polygenic paradigm (most traits are controlled by many genes of small effect) and genetic data available at the time showing that early-migrating populations are most closely related to nearby late-migrating populations, adult migration differences in Pacific salmon and steelhead were considered to reflect diversity within CUs rather than separate CUs. Recent data, however, suggest that specific alleles are required for early migration, and that these alleles are lost in populations where conditions do not support early-migrating phenotypes. Contrasting determinations under the US Endangered Species Act and the State of California's equivalent legislation illustrate the complexities of incorporating genomics data into CU configuration decisions. Regardless how CUs are defined, viability assessments should consider that 1) early-migrating phenotypes experience disproportionate risks across large geographic areas, so it becomes important to identify early-migrating populations that can serve as reliable sources for these valuable genetic resources; and 2) genetic architecture, especially the existence of large-effect loci, can affect evolutionary potential and adaptability.

Relationship between astrocyte reactivity, using novel 11C-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals.

Post mortem neuropathology suggests that astrocyte reactivity may play a significant role in neurodegeneration in Alzheimer's disease. We explored this in vivo using multimodal PET and MRI imaging. Twenty subjects (11 older, cognitively impaired patients and 9 age-matched healthy controls) underwent brain scanning using the novel reactive astrocyte PET tracer 11C-BU99008, 18F-FDG and 18F-florbetaben PET, and T1-weighted MRI. Differences between cognitively impaired patients and healthy controls in regional and voxel-wise levels of astrocyte reactivity, glucose metabolism, grey matter volume and amyloid load were explored, and their relationship to each other was assessed using Biological Parametric Mapping (BPM). Amyloid beta (Aß)-positive patients showed greater 11C-BU99008 uptake compared to controls, except in the temporal lobe, whilst further increased 11C-BU99008 uptake was observed in Mild Cognitive Impairment subjects compared to those with Alzheimer's disease in the frontal, temporal and cingulate cortices. BPM correlations revealed that regions which showed reduced 11C-BU99008 uptake in Aß-positive patients compared to controls, such as the temporal lobe, also showed reduced 18F-FDG uptake and grey matter volume, although the correlations with 18F-FDG uptake were not replicated in the ROI analysis. BPM analysis also revealed a regionally-dynamic relationship between astrocyte reactivity and amyloid uptake: increased amyloid load in cortical association areas of the temporal lobe and cingulate cortices was associated with reduced 11C-BU99008 uptake, whilst increased amyloid uptake in primary motor and sensory areas (in which amyloid deposition occurs later) was associated with increased 11C-BU99008 uptake. These novel observations add to the hypothesis that while astrocyte reactivity may be triggered by early Aß-deposition, sustained pro-inflammatory astrocyte reactivity with greater amyloid deposition may lead to astrocyte dystrophy and amyloid-associated neuropathology such as grey matter atrophy and glucose hypometabolism, although the evidence for glucose hypometabolism here is less strong.

Astrocyte reactivity with late-onset cognitive impairment assessed in vivo using 11C-BU99008 PET and its relationship with amyloid load.

11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer's disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. The 8 amyloid (Aß)-positive CI subjects had higher 11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between 11C-BU99008 and 18F-florbetaben. Autoradiography using 3H-BU99008 with post-mortem Alzheimer's brains confirmed through visual assessment that increased 3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer's disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aß load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.

Acute acetate administration increases endogenous opioid levels in the human brain: A [11C]carfentanil molecular imaging study.

INTRODUCTION: A recent study has shown that acetate administration leads to a fourfold increase in the transcription of proopiomelanocortin (POMC) mRNA in the hypothalamus. POMC is cleaved to peptides, including ß-endorphin, an endogenous opioid (EO) agonist that binds preferentially to the µ-opioid receptor (MOR). We hypothesised that an acetate challenge would increase the levels of EO in the human brain. We have previously demonstrated that increased EO release in the human brain can be detected using positron emission tomography (PET) with the selective MOR radioligand [11C]carfentanil. We used this approach to evaluate the effects of an acute acetate challenge on EO levels in the brain of healthy human volunteers. METHODS: Seven volunteers each completed a baseline [11C]carfentanil PET scan followed by an administration of sodium acetate before a second [11C]carfentanil PET scan. Dynamic PET data were acquired over 90 minutes, and corrected for attenuation, scatter and subject motion. Regional [11C] carfentanil BPND values were then calculated using the simplified reference tissue model (with the occipital grey matter as the reference region). Change in regional EO concentration was evaluated as the change in [11C]carfentanil BPND following acetate administration. RESULTS: Following sodium acetate administration, 2.5-6.5% reductions in [11C]carfentanil regional BPND were seen, with statistical significance reached in the cerebellum, temporal lobe, orbitofrontal cortex, striatum and thalamus. CONCLUSIONS: We have demonstrated that an acute acetate challenge has the potential to increase EO release in the human brain, providing a plausible mechanism of the central effects of acetate on appetite in humans.

GABA-A receptor differences in schizophrenia: a positron emission tomography study using [11C]Ro154513.

A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABAARs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABAARs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABAARs are altered in vivo or related to symptoms. We investigated α5-GABAARs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [11C]Ro15-4513 PET imaging in a cross-sectional, case-control study design. Thirty-one schizophrenia patients (n = 10 antipsychotic free) and twenty-nine matched healthy controls underwent a [11C]Ro15-4513 PET scan and MRI. The α5 subtype GABA-A receptor availability was indexed using [11C]Ro15-4513 PET imaging. Dynamic PET data were analyzed using the two-tissue compartment model with an arterial plasma input function and total volume of distribution (VT) as the outcome measure. Symptom severity was assessed using the PANSS scale. There was significantly lower [11C]Ro15-4513 VT in the hippocampus of antipsychotic-free patients, but not in medicated patients (p = 0.64), relative to healthy controls (p < 0.05; effect size = 1.4). There was also a significant positive correlation between [11C]Ro15-4513 VT and total PANSS score in antipsychotic-free patients (r = 0.72; p = 0.044). The results suggest that antipsychotic-free patients with schizophrenia have lower α5-GABAARs levels in the hippocampus, consistent with the hypothesis that GABA hypofunction underlies the pathophysiology of the disorder.

Genetic Associations in Four Decades of Multienvironment Trials Reveal Agronomic Trait Evolution in Common Bean.

Multienvironment trials (METs) are widely used to assess the performance of promising crop germplasm. Though seldom designed to elucidate genetic mechanisms, MET data sets are often much larger than could be duplicated for genetic research and, given proper interpretation, may offer valuable insights into the genetics of adaptation across time and space. The Cooperative Dry Bean Nursery (CDBN) is a MET for common bean (Phaseolus vulgaris) grown for > 70 years in the United States and Canada, consisting of 20-50 entries each year at 10-20 locations. The CDBN provides a rich source of phenotypic data across entries, years, and locations that is amenable to genetic analysis. To study stable genetic effects segregating in this MET, we conducted genome-wide association studies (GWAS) using best linear unbiased predictions derived across years and locations for 21 CDBN phenotypes and genotypic data (1.2 million SNPs) for 327 CDBN genotypes. The value of this approach was confirmed by the discovery of three candidate genes and genomic regions previously identified in balanced GWAS. Multivariate adaptive shrinkage (mash) analysis, which increased our power to detect significant correlated effects, found significant effects for all phenotypes. Mash found two large genomic regions with effects on multiple phenotypes, supporting a hypothesis of pleiotropic or linked effects that were likely selected on in pursuit of a crop ideotype. Overall, our results demonstrate that statistical genomics approaches can be used on MET phenotypic data to discover significant genetic effects and to define genomic regions associated with crop improvement.

Reduced mu opioid receptor availability in schizophrenia revealed with [11C]-carfentanil positron emission tomographic Imaging.

Negative symptoms, such as amotivation and anhedonia, are a major cause of functional impairment in schizophrenia. There are currently no licensed treatments for negative symptoms, highlighting the need to understand the molecular mechanisms underlying them. Mu-opioid receptors (MOR) in the striatum play a key role in hedonic processing and reward function and are reduced post-mortem in schizophrenia. However, it is unknown if mu-opioid receptor availability is altered in-vivo or related to negative symptoms in schizophrenia. Using [11 C]-carfentanil positron emission tomography (PET) scans in 19 schizophrenia patients and 20 age-matched healthy controls, here we show a significantly lower MOR availability in patients with schizophrenia in the striatum (Cohen's d = 0.7), and the hedonic network. In addition, we report a marked global increase in inter-regional covariance of MOR availability in schizophrenia, largely due to increased cortical-subcortical covariance.

Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson's disease: an in vivo11C-BU99008 PET study.

Astroglia are multifunctional cells that regulate neuroinflammation and maintain homeostasis within the brain. Astroglial α-synuclein-positive cytoplasmic accumulations have been shown post-mortem in patients with Parkinson's disease and therefore astroglia may play an important role in the initiation and progression of Parkinson's disease. Imidazoline 2 binding sites are expressed on activated astroglia in the cortex, hippocampus, basal ganglia and brainstem; therefore, by measuring imidazoline 2 binding site levels we can indirectly evaluate astrogliosis in patients with Parkinson's disease. Here, we aimed to evaluate the role of astroglia activation in vivo in patients with Parkinson's disease using 11C-BU99008 PET, a novel radioligand with high specificity and selectivity for imidazoline 2 binding sites. Twenty-two patients with Parkinson's disease and 14 healthy control subjects underwent 3 T MRI and a 120-min 11C-BU99008 PET scan with volume of distribution (VT) estimated using a two-tissue compartmental model with a metabolite corrected arterial plasma input function. Parkinson's disease patients were stratified into early (n = 8) and moderate/advanced (n = 14) groups according to disease stage. In early Parkinson's disease, increased 11C-BU99008 VT uptake was observed in frontal (P = 0.022), temporal (P = 0.02), parietal (P = 0.026) and occipital (P = 0.047) cortical regions compared with healthy controls. The greatest 11C-BU99008 VT increase in patients with early Parkinson's disease was observed in the brainstem (52%; P = 0.018). In patients with moderate/advanced Parkinson's disease, loss of 11C-BU99008 VT was observed across frontal (P = 0.002), temporal (P < 0.001), parietal (P = 0.039), occipital (P = 0.024), and insula (P < 0.001) cortices; and in the subcortical regions of caudate (P < 0.001), putamen (P < 0.001) and thalamus (P < 0.001); and in the brainstem (P = 0.018) compared with healthy controls. In patients with Parkinson's disease, loss of 11C-BU99008 VT in cortical regions, striatum, thalamus and brainstem correlated with longer disease duration (P < 0.05) and higher disease burden scores, measured with Movement Disorder Society Unified Parkinson's Disease Rating Scale (P < 0.05). In the subgroup of patients with moderate/advanced Parkinson's disease, loss of 11C-BU99008 VT in the frontal (r = 0.79; P = 0.001), temporal (r = 0.74; P = 0.002) and parietal (r = 0.89; P < 0.001) cortex correlated with global cognitive impairment. This study demonstrates in vivo the role of astroglia in the initiation and progression of Parkinson's disease. Reactive astroglia observed early in Parkinson's disease could reflect a neuroprotective compensatory mechanisms and pro-inflammatory upregulation in response to α-synuclein accumulation. However, as the disease progresses and significant neurodegeneration occurs, astroglia lose their reactive function and such loss in the cortex has clinical relevance in the development of cognitive impairment.

Dam trout: Genetic variability in Oncorhynchus mykiss above and below barriers in three Columbia River systems prior to restoring migrational access.

Restoration of access to lost habitat for threatened and endangered fishes above currently impassable dams represents a major undertaking. Biological monitoring is critical to understand the dynamics and success of anadromous recolonization as, in the case of Oncorhynchus mykiss, anadromous steelhead populations are reconnected with their conspecific resident rainbow trout counterparts. We evaluate three river systems in the Lower Columbia River basin: the White Salmon, Sandy, and Lewis rivers that are in the process of removing and/or providing passage around existing human-made barriers in O. mykiss riverine habitat. In these instances, now isolated resident rainbow trout populations will be exposed to competition and/or genetic introgression with steelhead and vice versa. Our genetic analyses of 2,158 fish using 13 DNA microsatellite (mSAT) loci indicated that within each basin anadromous O. mykiss were genetically distinct from and significantly more diverse than their resident above-dam trout counterparts. Above long-standing natural impassable barriers, each of these watersheds also harbors unique rainbow trout gene pools with reduced levels of genetic diversity. Despite frequent releases of non-native steelhead and rainbow trout in each river, hatchery releases do not appear to have had a significant genetic effect on the population structure of O. mykiss in any of these watersheds. Simulation results suggest there is a high likelihood of identifying anadromous x resident individuals in the Lewis and White Salmon rivers, and slightly less so in the Sandy River. These genetic data are a prerequisite for informed monitoring, managing, and conserving the different life history forms during upstream recolonization when sympatry of life history forms of O. mykiss is restored.

Evaluation of 11C-BU99008, a PET Ligand for the Imidazoline2 Binding Site in Human Brain.

The imidazoline2 binding site (I2BS) is thought to be expressed in glia and implicated in the regulation of glial fibrillary acidic protein. A PET ligand for this target would be important for the investigation of neurodegenerative and neuroinflammatory diseases. 11C-BU99008 has previously been identified as a putative PET radioligand. Here, we present the first in vivo characterization of this PET radioligand in humans and assess its test-retest reproducibility. Methods: Fourteen healthy male volunteers underwent dynamic PET imaging with 11C-BU99008 and arterial sampling. Six subjects were used in a test-retest assessment, and 8 were used in a pharmacologic evaluation, undergoing a second or third heterologous competition scan with the mixed I2BS/α2-adrenoceptor drug idazoxan (n = 8; 20, 40, 60, and 80 mg) and the mixed irreversible monoamine oxidase type A/B inhibitor isocarboxazid (n = 4; 50 mg). Regional time-activity data were generated from arterial plasma input functions corrected for metabolites using the most appropriate model to derive the outcome measure VT (regional distribution volume). All image processing and kinetic analyses were performed in MIAKAT. Results: Brain uptake of 11C-BU99008 was good, with reversible kinetics and a heterogeneous distribution consistent with known I2BS expression. Model selection criteria indicated that the 2-tissue-compartment model was preferred. VT estimates were high in the striatum (105 ± 21 mL⋅cm-3), medium in the cingulate cortex (62 ± 10 mL⋅cm-3), and low in the cerebellum (41 ± 7 mL⋅cm-3). Test-retest reliability was reasonable. The uptake was dose-dependently reduced throughout the brain by pretreatment with idazoxan, with an average block across all regions of about 60% (VT, ∼30 mL⋅cm-3) at the highest dose (80 mg). The median effective dose for idazoxan was 28 mg. Uptake was not blocked by pretreatment with the monoamine oxidase inhibitor isocarboxazid. Conclusion:11C-BU99008 in human PET studies demonstrates good brain delivery, reversible kinetics, heterogeneous distribution, specific binding signal consistent with I2BS distribution, and good test-retest reliability.

Cerebral blood flow predicts differential neurotransmitter activity.

Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans.

Evidence for GABA-A receptor dysregulation in gambling disorder: correlation with impulsivity.

As a behavioural addiction, gambling disorder (GD) provides an opportunity to characterize addictive processes without the potentially confounding effects of chronic excessive drug and alcohol exposure. Impulsivity is an established precursor to such addictive behaviours, and GD is associated with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity. This study therefore investigated GABAA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [11 C]Ro15-4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. We found significantly higher [11 C]Ro15-4513 total distribution volume (VT ) in the right hippocampus in the GD group compared with HV. We found higher levels of the 'Negative Urgency' construct of impulsivity in GD, and these were positively associated with higher [11 C]Ro15-4513 VT in the amygdala in the GD group; no such significant correlations were evident in the HV group. These results contrast with reduced binding of GABAergic PET ligands described previously in alcohol and opiate addiction and add to growing evidence for distinctions in the neuropharmacology between substance and behavioural addictions. These results provide the first characterization of GABAA receptors in GD with [11 C]Ro15-4513 PET and show greater α5 receptor availability and positive correlations with trait impulsivity. This GABAergic dysregulation is potential target for treatment.

Quantification of [11C]Ro15-4513 GABAAα5 specific binding and regional selectivity in humans.

[11C]Ro15-4513 has been introduced as a positron emission tomography radioligand to image the GABAAα5 receptor subtype thought to be important in learning, memory and addiction. However, the in vivo selectivity of the ligand remains unknown and a full assessment of different analysis approaches has yet to be performed. Using human heterologous competition data, with [11C]Ro15-4513 and the highly selective GABAAα5 selective negative allosteric modulator Basmisanil (RG1662), we quantify the GABAAα5 selectivity of [11C]Ro15-4513, assess the validity of reference tissues and evaluate the performance of four different kinetic analysis methods. The results show that [11C]Ro15-4513 has high but not complete selectivity for GABAAα5, with α5 representing around 60-70% of the specific binding in α5 rich regions. Competition data indicate that the cerebellum and pons are essentially devoid of α5 signal and might be used as reference regions under certain conditions. Off-target non-selective binding to other GABAA subtypes means that the choice of analysis method and the interpretation of outcome measures must be considered carefully. We discuss the merits of two tissue compartmental model analyses to derive both VT and VS, band-pass spectral analysis for estimation of [Formula: see text] and the simplified reference tissue model for estimation of [Formula: see text].

Significant reductions in human visual gamma frequency by the gaba reuptake inhibitor tiagabine revealed by robust peak frequency estimation.

The frequency of visual gamma oscillations is determined by both the neuronal excitation-inhibition balance and the time constants of GABAergic processes. The gamma peak frequency has been linked to sensory processing, cognitive function, cortical structure, and may have a genetic contribution. To disentangle the intricate relationship among these factors, accurate and reliable estimates of peak frequency are required. Here, a bootstrapping approach that provides estimates of peak frequency reliability, thereby increasing the robustness of the inferences made on this parameter was developed. The method using both simulated data and real data from two previous pharmacological MEG studies of visual gamma with alcohol and tiagabine was validated. In particular, the study by Muthukumaraswamy et al. [] (Neuropsychopharmacology 38(6):1105-1112), in which GABAergic enhancement by tiagabine had previously demonstrated a null effect on visual gamma oscillations, contrasting with strong evidence from both animal models and very recent human studies was re-evaluated. After improved peak frequency estimation and additional exclusion of unreliably measured data, it was found that the GABA reuptake inhibitor tiagabine did produce, as predicted, a marked decrease in visual gamma oscillation frequency. This result demonstrates the potential impact of objective approaches to data quality control, and provides additional translational evidence for the mechanisms of GABAergic transmission generating gamma oscillations in humans. Hum Brain Mapp 37:3882-3896, 2016. © 2016 Wiley Periodicals, Inc.

Blunted Endogenous Opioid Release Following an Oral Amphetamine Challenge in Pathological Gamblers.

Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [(11)C]carfentanil PET with an oral amphetamine challenge. Fourteen PG and 15 healthy volunteers (HV) underwent two [(11)C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [(11)C]carfentanil binding between baseline and post-amphetamine scans (ΔBPND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [(11)C]carfentanil BPND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BPND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may have an important role in the pathophysiology of addictions.

Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: a study in healthy volunteers.

A range of medications target different aspects of the GABA system; understanding their effects is important to inform further drug development. Effects on the waking EEG comparing these mechanisms have not been reported; in this study we compare the effects on resting MEG spectra of the benzodiazepine receptor agonist zolpidem, the delta sub-unit selective agonist gaboxadol (also known as THIP) and the GABA reuptake inhibitor tiagabine. These were two randomised, single-blind, placebo-controlled, crossover studies in healthy volunteers, one using zolpidem 10 mg, gaboxadol 15 mg and placebo, and the other tiagabine 15 mg and placebo. Whole head MEG recordings and individual MEG spectra were divided into frequency bands. Baseline spectra were subtracted from each post-intervention spectra and then differences between intervention and placebo compared. After zolpidem there were significant increases in beta frequencies and reduction in alpha frequency power; after gaboxadol and tiagabine there were significant increases in power at all frequencies up to beta. Enhancement of tonic inhibition via extrasynaptic receptors by gaboxadol gives rise to a very different MEG signature from the synaptic action of zolpidem. Tiagabine theoretically can affect both types of receptor; from these MEG results it is likely that the latter is the more prominent effect here.

Acute increases in synaptic GABA detectable in the living human brain: a [¹¹C]Ro15-4513 PET study.

The inhibitory γ-aminobutyric acid (GABA) neurotransmitter system is associated with the regulation of normal cognitive functions and dysregulation has been reported in a number of neuropsychiatric disorders including anxiety disorders, schizophrenia and addictions. Investigating the role of GABA in both health and disease has been constrained by difficulties in measuring acute changes in synaptic GABA using neurochemical imaging. The aim of this study was to investigate whether acute increases in synaptic GABA are detectable in the living human brain using the inverse agonist GABA-benzodiazepine receptor (GABA-BZR) positron emission tomography (PET) tracer, [(11)C]Ro15-4513. We examined the effect of 15 mg oral tiagabine, which increases synaptic GABA by inhibiting the GAT1 GABA uptake transporter, on [(11)C]Ro15-4513 binding in 12 male participants using a paired, double blind, placebo-controlled protocol. Spectral analysis was used to examine synaptic α1 and extrasynaptic α5 GABA-BZR subtype availability in brain regions with high levels of [(11)C]Ro15-4513 binding. We also examined the test-retest reliability of α1 and a5-specific [(11)C]Ro15-4513 binding in a separate cohort of 4 participants using the same spectral analysis protocol. Tiagabine administration produced significant reductions in hippocampal, parahippocampal, amygdala and anterior cingulate synaptic α1 [(11)C]Ro15-4513 binding, and a trend significance reduction in the nucleus accumbens. These reductions were greater than test-retest reliability, indicating that they are not the result of chance observations. Our results suggest that acute increases in endogenous synaptic GABA are detectable in the living human brain using [(11)C]Ro15-4513 PET. These findings have potentially major implications for the investigation of GABA function in brain disorders and in the development of new treatments targeting this neurotransmitter system.