Search

Cross-sectional neuroimaging studies show that bipolar disorder is associated with structural brain abnormalities, predominantly observed in prefrontal and temporal cortex, cingulate gyrus, and subcortical regions. However, longitudinal studies are needed to elucidate whether these abnormalities presage disease onset or are consequences of disease processes, and to identify potential contributing factors. Here, we narratively review and summarize longitudinal structural magnetic resonance imaging studies that relate imaging outcomes to manic episodes. First, we conclude that longitudinal brain imaging studies suggest an association of bipolar disorder with aberrant brain changes, including both deviant decreases and increases in morphometric measures. Second, we conclude that manic episodes have been related to accelerated cortical volume and thickness decreases, with the most consistent findings occurring in prefrontal brain areas. Importantly, evidence also suggests that in contrast to healthy controls, who in general show age-related cortical decline, brain metrics remain stable or increase during euthymic periods in bipolar disorder patients, potentially reflecting structural recovering mechanisms. The findings stress the importance of preventing manic episodes. We further propose a model of prefrontal cortical trajectories in relation to the occurrence of manic episodes. Finally, we discuss potential mechanisms at play, remaining limitations, and future directions.

Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI (Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.

Genetic and hormonal factors have been suggested to influence human sexual orientation. Previous studied proposed brain differences related to sexual orientation and that these follow cross-sex shifted patterns. However, the neurobiological correlates of sexual orientation and how genetic factors relate to brain structural variation remains largely unexplored. Using the largest neuroimaging-genetics dataset available on same-sex sexual behavior (SSB) (n = 18,645), we employed a data-driven multivariate classification algorithm (PLS) on magnetic resonance imaging data from two imaging modalities to extract brain covariance patterns related to sex. Through analyses of latent variables, we tested for SSB-related cross-sex shifts in such patterns. Using genotype data, polygenic scores reflecting the genetic predisposition for SSB were computed and tested for associations with neuroimaging outcomes. Patterns important for classifying between males and females were less pronounced in non-heterosexuals. Predominantly in non-heterosexual females, multivariate brain patterns as represented by latent variables were shifted toward the opposite sex. Complementary univariate analyses revealed region specific SSB-related differences in both males and females. Polygenic scores for SSB were associated with volume of lateral occipital and temporo-occipital cortices. The present large-scale study demonstrates multivariate neuroanatomical correlates of SSB, and tentatively suggests that genetic factors related to SSB may contribute to structural variation in certain brain structures. These findings support a neurobiological basis to the differences in human sexuality.

BackgroundMajor depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and whether this process is associated with clinical characteristics in a large multi-center international dataset.MethodsWe performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 depressed males, and 1,326 female controls and 2,044 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronological age was calculated to indicate brain predicted age difference (brain-PAD).FindingsOn average, MDD patients showed a higher brain-PAD of +0.90 (SE 0.21) years (Cohen’s d=0.12, 95% CI 0.06-0.17) compared to controls. Relative to controls, first-episode and currently depressed patients showed higher brain-PAD (+1.2 [0.3] years), and the largest effect was observed in those with late-onset depression (+1.7 [0.7] years). In addition, higher brain-PAD was associated with higher self-reported depressive symptomatology (b=0.05, p=0.004).InterpretationThis highly powered collaborative effort showed subtle patterns of abnormal structural brain aging in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the predictive value of these brain-PAD estimates.FundingThis work was supported, in part, by NIH grants U54 EB020403 and R01 MH116147.

Background Bipolar disorder (BD) is a highly heritable psychiatric disorder characterized by episodes of manic and depressed mood states and associated with cortical brain abnormalities. Although the course of BD is often progressive, longitudinal brain imaging studies are scarce. It remains unknown whether brain abnormalities are static traits of BD or result from pathological changes over time. Moreover, the genetic effect on implicated brain regions remains unknown. Methods Patients with BD and healthy control (HC) subjects underwent structural magnetic resonance imaging at baseline (123 patients, 83 HC subjects) and after 6 years (90 patients, 61 HC subjects). Cortical thickness maps were generated using FreeSurfer. Using linear mixed effects models, we compared longitudinal changes in cortical thickness between patients with BD and HC subjects across the whole brain. We related our findings to genetic risk for BD and tested for effects of demographic and clinical variables. Results Patients showed abnormal cortical thinning of temporal cortices and thickness increases in visual/somatosensory brain areas. Thickness increases were related to genetic risk and lithium use. Patients who experienced hypomanic or manic episodes between time points showed abnormal thinning in inferior frontal cortices. Cortical changes did not differ between diagnostic BD subtypes I and II. Conclusions In the largest longitudinal BD study to date, we detected abnormal cortical changes with high anatomical resolution. We delineated regional effects of clinical symptoms, genetic factors, and medication that may explain progressive brain changes in BD. Our study yields important insights into disease mechanisms and suggests that neuroprogression plays a role in BD.

Objective Pedophilic disorder (PD) is characterized bypersistent, intense sexual attraction to prepubertal children that the individual has acted on, or causes marked distress or interpersonal difficulty. Although prior research suggests that PD has neurodevelopmental underpinnings, the evidence remains sparse. To aid the understanding of etiology and treatment development, we quantified neurobiological and clinical correlates of PD. Method We compared 55 self‐referred, help‐seeking, non‐forensic male patients with DSM‐5 PD with 57 age‐matched, healthy male controls (HC) on clinical, neuropsychological, and structural brain imaging measures (cortical thickness and surface area, subcortical and white matter volumes). Structural brain measures were related to markers for aberrant neurodevelopment including IQ, and the 2nd to 4th digit ratio (2D:4D). Results PD was associated with psychiatric disorder comorbidity and ADHD and autism spectrum disorder symptoms. PD patients had lower total IQ than HC. PD individuals exhibited cortical surface area abnormalities in regions belonging to the brain's default mode network and showed abnormal volume of white matter underlying those regions. PD subjects had smaller hippocampi and nuclei accumbens than HC. Findings were not related to history of child‐related sexual offending. IQ correlated negatively with global expression of PD‐related brain features and 2D:4D correlated with surface area in PD. Conclusions In the largest single‐center study to date, we delineate psychiatric comorbidity, neurobiological and cognitive correlates of PD. Our morphometric findings, their associations with markers of aberrant neurodevelopment, and psychiatric comorbidities suggest that neurodevelopmental mechanisms are involved in PD. The findings may need consideration in future development of clinical management of PD patients.

Placebo responses in the treatment of erectile dysfunction (ED) are poorly described in the literature to date.To quantify the association of placebo with ED outcomes among men enrolled in placebo-controlled, phosphodiesterase 5 inhibitor (PDE5I) trials.For this systematic review and meta-analysis, a database search was conducted to identify double-blind, placebo-controlled studies using PDE5Is for the treatment of ED published from January 1, 1998, to December 31, 2018, within MEDLINE, Embase, Cochrane Library, and Web of Science. Only articles published in the English language were included.Double-blind, placebo-controlled randomized clinical trials of PDE5Is for ED were included. Studies were excluded if they did not provide distribution measures for statistical analysis. Study selection review assessments were conducted by 2 independent investigators. A total of 2215 studies were identified from the database search, and after review, 63 studies that included 12 564 men were analyzed.Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed in abstracting data and assessing validity. Data were extracted from published reports by 2 independent reviewers. Quality assessment was performed using the Jadad scale. Data were pooled using a random-effects model.The main outcome was improvement in the erectile function domain of the International Index of Erectile Function questionnaire in the placebo arm of the included studies. Effect size was reported as bias-corrected standardized mean difference (Hedges g). The hypothesis was formulated before data extraction.A total of 63 studies that included 12 564 men (mean [SD] age, 55 [7] years; age range, 36-68 years) were included. Erectile function was significantly improved among participants in the placebo arm, with a small to moderate effect size (Hedges g [SE], 0.35 [0.03]; P .001). Placebo effect size was larger among participants with ED associated with posttraumatic stress disorder (Hedges g [SE], 0.78 [0.32]; P = .02) compared with the overall analysis. No significant difference was found between placebo and PDE5Is for ED after prostate surgery or radiotherapy (Hedges g [SE], 0.30 [0.17]; P = .08).In this study, placebo was associated with improvement of ED, especially among men with ED-related posttraumatic stress disorder. No difference was found between placebo and PDE5I among men treated for ED after prostate surgery.

Neuroimaging of opiate-dependent individuals indicates both altered brain structure and function. Magnetic resonance-based arterial spin labeling has been used to measure noninvasively cerebral blood flow (i.e. perfusion) in alcohol, tobacco and stimulant dependence; only one arterial spin labeling paper in opiate-dependent individuals demonstrated frontal and parietal perfusion deficits. Additional research on regional brain perfusion in opiate dependence and its relationship to cognition and self-regulation (impulsivity, risk taking and decision making) may inform treatment approaches for opiate-dependent individuals. Continuous arterial spin labeling magnetic resonance imaging at 4 T and neuropsychological measures assessed absolute brain perfusion levels, cognition and self-regulation in 18 cigarette smoking opiate-dependent individuals (sODI) stable on buprenorphine maintenance therapy. The sODI were compared with 20 abstinent smoking alcohol-dependent individuals (a substance-dependent control group), 35 smoking controls and 29 nonsmoking controls. sODI had lower perfusion in several cortical and subcortical regions including regions within the brain reward/executive oversight system compared with smoking alcohol-dependent individuals and nonsmoking controls. Perfusion was increased in anterior cingulate cortex and globus pallidus of sODI. Compared with all other groups, sODI had greater age-related declines in perfusion in most brain reward/executive oversight system and some other regions. In sODI, lower regional perfusion related to greater substance use, higher impulsivity and weaker visuospatial skills. Overall, sODI showed cortical and subcortical hypoperfusion and hyperperfusion. Relating to neuropsychological performance and substance use quantities, the frontal perfusion alterations are clinically relevant and constitute potential targets for pharmacological and cognitive-based therapeutic interventions to improve treatment outcome in opiate dependence.

Contains fulltext : 191289.pdf (Publisher’s version ) (Open Access) Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 x 10(-21)), left fusiform gyrus (d=-0.288; P=8.25 x 10(-21)) and left rostral middle frontal cortex (d=-0.276; P=2.99 x 10(-19)). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Both non-emotional symptoms, such as inattention, and symptoms of emotional instability (EI) are partially co-varying and normally distributed in the general population. Attention Deficit Hyperactivity Disorder (ADHD), which is associated with both inattention and emotional instability, has been related to lower reward anticipation activation in the ventral striatum. However, it is not known whether non-emotional dysregulation, such as inattention, or EI—or both—are associated with this effect. We hypothesized that altered reward processing relates specifically to EI. To test this, 29 healthy participants were recruited to this functional MRI study (n = 15 females). Reward processing was studied using a modified version of the Monetary Incentive Delay (MID) task. Brown Attention-Deficit Disorder Scales questionnaire was used to assess EI and inattention symptoms on a trait level. We observed less ventral striatal activation during reward anticipation related to the EI trait in females, also when controlling for the inattention trait, but not in the whole sample or males only. Our study suggests the existence of sex differences in the relationship between reward processing and EI/inattention traits.

BACKGROUND: The CACNA1C gene encodes the 1C subunit of L-type voltage-gated calcium channels and has been associated with several psychiatric syndromes — including bipolar disorder — in many genome-wide association studies. Experimental and clinical studies have reported changes with respect to behaviour and biomarkers in risk allele carriers, corroborating the essential role of the CACNA1C gene in neurons, during development and in the mature brain. However, the association of this gene with regional cortical thickness has not been evaluated in patients with bipolar disorder. METHODS: Using magnetic resonance imaging, we measured the average cortical thickness of 68 brain regions in 87 patients genotyped for the single-nucleotide polymorphism rs1006737 in CACNA1C. RESULTS: We found associations with the mean thickness of several cortical areas: the left lateral orbitofrontal and rostral anterior cingulate cortices, as well as other parts of the frontal and parietal cortices. Limitations: This cross-sectional cohort study could not fully differentiate correlation from causation. CONCLUSION: The CACNA1C polymorphism rs1006737 is associated with the mean thickness of cortical brain areas that have been shown to be altered in bipolar disorder.

BackgroundThe concept of cognitive reserve (CR) hypothesizes that intellectually stimulating activities provide resilience against brain pathology/disease. Whereas brain abnormalities and cognitive impairment are frequently reported in bipolar disorder (BD), it is unknown whether the impact of brain alterations can be lessened by higher CR in BD.MethodWe tested if higher CR would reduce the influence of total volumes of deep white matter hypointensities (WMH), ventricular cerebrospinal fluid (CSF), and prefrontal cortex on memory, executive, and attention/speed functions in patients with BD (n = 75). Linear regression models with interaction terms for CR and brain volumes were applied to directly test if CR reduces the influence of brain pathology on cognitive domains.ResultsCR reduced the influence of total volumes of deep WMH (β = −0.38, Q = 0.003) and ventricular CSF (β = −41, Q = 006) on executive functions.ConclusionsThe interactions between CR and total volumes of deep WMH/ventricular CSF appear to account for executive functioning in BD. The results suggest that the concept of CR is applicable in BD. Higher reserve capacity in BD alters the relationship between brain pathology and clinical presentation.

Obesity/overweight is reported to affect MR-measured brain tissue volume and white matter (WM) signal intensity. This study investigated possible effects of fat on these measures, using pig fat on three participants at a 4T magnet. Grey matter volumes in the presence of fat were lower than baseline measures. Total WM volumes in the presence of fat were higher than baseline measures. WM hypo-intensities on T1-weighted images were higher in the presence of fat than baseline measures. Therefore physical effects of head fat of obese/overweight individual may at least, partly contribute to the association of obesity/overweight with MR structural measures.

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD);\ud however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical\ud heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with\ud BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered\ud individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean\ud fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and\ud meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD\ud compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R2 = 0.041, Pcorr < 0.001) and\ud cingulum (right: R2 = 0.041, left: R2 = 0.040, Pcorr < 0.001). Lithium medication, later onset and short disease duration were related to\ud higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities\ud in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD.\ud These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Objective Frontal cortical abnormalities and executive function impairment co-occur in bipolar disorder. Recent studies have shown that bipolar subtypes differ in the degree of structural and functional impairments. The relationships between cognitive performance and cortical integrity have not been clarified and might differ across patients with bipolar disorder type I, II, and healthy subjects. Method Using a vertex-wise whole-brain analysis, we investigated how cortical integrity, as measured by cortical thickness, correlates with executive performance in patients with bipolar disorder type I, II, and controls (N = 160). Results We found focal associations between executive function and cortical thickness in the medial prefrontal cortex in bipolar II patients and controls, but not in bipolar I disorder. In bipolar II patients, we observed additional correlations in lateral prefrontal and occipital regions. Conclusions Our findings suggest that bipolar disorder patients show altered structure-function relationships, and importantly that those relationships may differ between bipolar subtypes. The findings are line with studies suggesting subtype-specific neurobiological and cognitive profiles. This study contributes to a better understanding of brain structure-function relationships in bipolar disorder and gives important insights into the neuropathophysiology of diagnostic subtypes.

© 2014 Elsevier Inc. Alcohol-dependent individuals (ALC) have smaller hippocampi and poorer neurocognition than healthy controls. Results from studies on the association between alcohol consumption and hippocampal volume have been mixed, suggesting that comorbid or premorbid factors (i.e., those present prior to the initiation of alcohol dependence) determine hippocampal volume in ALC. We aimed to characterize the effects of select comorbid (i.e., cigarette smoking) and premorbid factors (brain-derived neurotrophic factor [BDNF] genotype [Val66Met rs6265]) on hippocampal volume in an ALC cohort followed longitudinally into extended abstinence. One hundred twenty-one adult ALC in treatment (76 smokers, 45 non-smokers) and 35 non-smoking light-drinking controls underwent quantitative magnetic resonance imaging, BDNF genotyping, and neurocognitive assessments. Representative subgroups were studied at 1 week, 1 month, and at an average of 7 months of abstinence. ALC had smaller hippocampi than healthy controls at all time points. Hippocampal volume at 1 month of abstinence correlated with lower visuospatial function. Smoking status did not influence hippocampal volume or hippocampal volume recovery during abstinence. However, only BDNF Val homozygotes tended to have hippocampal volume increases over 7 months of abstinence, and Val homozygotes had significantly larger hippocampi than Met carriers at 7 months of abstinence. These findings suggest that BDNF genotype, but not smoking status or measures of drinking severity, regulate functionally relevant hippocampal volume recovery in abstinent ALC. Future studies aimed at exploring genetic determinants of brain morphometry in ALC may need to evaluate individuals during extended abstinence after the acute environmental effects of chronic alcohol consumption have waned.

Recent MRS studies have indicated that a higher body mass index (BMI) is associated with lower brain metabolite levels. Generally, individuals with higher BMIs have more body fat deposits than individuals with normal BMIs. This single-voxel spectroscopy (SVS) study investigated possible effects of fat on MR-measured metabolite signal areas, which may at least partly explain the observed associations of BMI with MR-measured brain metabolite levels in vivo. SVS data were acquired at 4 T from a phantom containing N-acetylaspartate, glutamate and creatine, as well as from three healthy male adults. Back fat obtained from pig was used to assess the effects of fat on metabolite signals. With the same voxel size and placement, the phantom was first scanned without fat (baseline), and then with 0.7-cm- and 1.4-cm-thick fat layers placed on it. Each participant was also scanned first without fat and then with two 0.7-cm fat layers, one placed beneath the occiput and the other on the forehead. Two spectra were acquired per participant from the anterior cingulate and the parieto-occipital cortices. The metabolite resonance and corresponding water peak areas were then fitted and metabolite to water signal ratios were used for analyses. In both phantom and in vivo experiments, the metabolite-to-water ratios decreased in the presence of fat relative to baseline metabolite-to-water ratios. The reduced metabolite signals in the presence of fat reported here are reminiscent of the negative correlations observed between BMI and MR-measured metabolite levels. These apparent physical effects of fat have potentially far-reaching consequences for the accuracy of MR measurements of brain metabolite levels and their interpretation, particularly when large fat stores exist around the skull, such as in individuals with higher BMI.

Background: Alcohol use disorders are related to neurocognitive abnormalities during early abstinence in those seeking treatment for alcohol dependence (ALC). Considerable evidence indicates that chronic cigarette smoking is associated with multiple neurocognitive deficiencies. However, very little is known about the effects of chronic smoking on neurocognitive recovery during early abstinence from alcohol. We evaluated whether cigarette smoking interferes with cognitive improvement during early abstinence from alcohol, a period thought important for maintaining long-term sobriety. Methods: Neurocognitive functions previously shown to be adversely affected by both alcohol use disorders and chronic cigarette smoking were evaluated. We assessed 35 smoking ALC (sALC) and 34 nonsmoking ALC (nsALC) at approximately 1 and 5 weeks of monitored abstinence. Results: Although neither group was clinically impaired, both cross-sectional and longitudinal deficiencies were observed in sALC versus nsALC in processing speed, working memory, and auditory-verbal learning and memory. Lifetime alcohol consumption, medical, and psychiatric comorbidities did not predict neurocognitive performance or improvement across assessments. Within sALC, greater drinking and smoking severities were synergistically (more than additively) related to less improvement on visuospatial learning and memory. Former smoking status in the nsALC-mediated group differences in auditory-verbal delayed recall. Conclusions: Chronic cigarette smoking appears to negatively impact neurocognition during early abstinence from alcohol. Although the cognitive deficiencies observed in this cohort were not in a clinical range of impairment, they should be considered to enhance treatment efficacy. Our findings lend support to integrating smoking cessation as well as the individual assessment of cognition into early ALC treatment. Additionally, there is a need to elucidate the effects of current and former smoking status in future reports of neurocognition. © 2013 by the Research Society on Alcoholism.

Objective: Proton magnetic resonance spectroscopy (1H MRS) in opiate dependence showed abnormalities in neuronal viability and glutamate concentration in the anterior cingulate cortex (ACC). Metabolite levels in dorsolateral prefrontal cortex (DLPFC) or orbitofrontal cortex (OFC) and their neuropsychological correlates have not been investigated in opiate dependence. Methods: Single-volume proton MRS at 4 Tesla and neuropsychological testing were conducted in 21 opiatedependent individuals (OD) on buprenorphine maintenance therapy. Results were compared to 28 controls (CON) and 35 alcohol-dependent individuals (ALC), commonly investigated treatment-seekers providing context for OD evaluation. Metabolite concentrations were measured from ACC, DLPFC, OFC and parieto-occipital cortical (POC) regions. Results: Compared to CON, OD had lower concentrations of N-acetylaspartate (NAA), glutamate (Glu), creatine +phosphocreatine (Cr) and myo-Inositol (mI) in the DLPFC and lower NAA, Cr, and mI in the ACC. OD, ALC, and CON were equivalent on metabolite levels in the POC and γ-aminobutyric acid (GABA) concentration did not differ between groups in any region. In OD, prefrontal metabolite deficits in ACC Glu as well as DLPFC NAA and choline containing metabolites (Cho) correlated with poorer working memory, executive and visuospatial functioning; metabolite deficits in DLPFC Glu and ACC GABA and Cr correlated with substance use measures. In the OFC of OD, Glu and choline-containing metabolites were elevated and lower Cr concentration related to higher nonplanning impulsivity. Compared to 3 week abstinent ALC, OD had significant DLPFC metabolite deficits. Conclusion: The anterior frontal metabolite profile of OD differed significantly from that of CON and ALC. The frontal lobe metabolite abnormalities in OD and their neuropsychological correlates may play a role in treatment outcome and could be explored as specific targets for improved OD treatment.

Chronic alcohol-use disorders (AUDs) have been shown to interact with normal age-related volume loss to exacerbate brain atrophy with increasing age. However, chronic cigarette smoking, a highly co-morbid condition in AUD and its influence on age-related brain atrophy have not been evaluated. We performed 1.5 T quantitative magnetic resonance imaging in non-smoking controls [non-smoking light drinking controls (nsCONs); n = 54], smoking light drinking controls (sCONs, n = 34), and one-week abstinent, treatment-seeking alcohol-dependent (ALC) non-smokers (nsALCs, n = 35) and smokers (sALCs, n = 43), to evaluate the independent and interactive effects of alcohol dependence and chronic smoking on regional cortical and subcortical brain volumes, emphasizing the brain reward/executive oversight system (BREOS). The nsCONs and sALCs showed greater age-related volume losses than the nsALCs in the dorsal prefrontal cortex (DPFC), total cortical BREOS, superior parietal lobule and putamen. The nsALCs and sALCs demonstrated smaller volumes than the nsCONs in most cortical region of interests (ROIs). The sCONs had smaller volumes than the nsCONs in the DPFC, insula, inferior parietal lobule, temporal pole/parahippocampal region and all global cortical measures. The nsALCs and sALCs had smaller volumes than the sCONs in the DPFC, superior temporal gyrus, inferior and superior parietal lobules, precuneus and all global cortical measures. Volume differences between the nsALCs and sALCs were observed only in the putamen. Alcohol consumption measures were not related to volumes in any ROI for ALC; smoking severity measures were related to corpus callosum volume in the sCONs and sALCs. The findings indicate that consideration of smoking status is necessary for a better understanding of the factors contributing to regional brain atrophy in AUD.

Double electron electron resonance (DEER) spectroscopy has been established as a valuable method to determine distances between spin labels bound to protein molecules. Caused by selective excitation of molecular orientations DEER primary data also depend on the mutual orientation of the spin labels. For a doubly spin labeled variant of the cytoskeletal protein vinculin tail strong orientation selection can be observed already at X-band frequencies, which allows us to reduce the problem to the relative orientation of two molecular axes and the spin–spin axis parameterized by three angles. A full grid search of parameter space reveals that the DEER experiment introduces parameter-space symmetry higher than the symmetry of the spin Hamiltonian. Thus, the number of equivalent parameter sets is twice as large as expected and the relative orientation of the two spin labels is ambiguous. Except for this inherent ambiguity the most probable relative orientation of the two spin labels can be determined with good confidence and moderate uncertainty by global fitting of a set of five DEER experiments at different offsets between pump and observer frequency. The experiment provides restraints on the angles between the z axis of the nitroxide molecular frame and the spin–spin vector and on the dihedral between the two z axes. When using the same type of label at both sites, assignment of the angle restraints is ambiguous and the sign of the dihedral restraint is also ambiguous.

The cytoskeletal adaptor protein vinculin plays an important role in the control of cell adhesion and migration, linking the actin cytoskeleton to adhesion receptor complexes in cell adhesion sites. The conformation of the vinculin tail dimer, which is crucial for protein function, was analyzed using site-directed spin labeling in electron paramagnetic resonance spectroscopy. Interspin distances for a set of six singly and four doubly spin-labeled mutants of the tail domain of vinculin were determined and used as constraints for modeling of the vinculin tail dimer. A comparison of the results obtained by molecular dynamic simulations and a rotamer library approach reveals that the crystal structure of the vinculin tail monomer is essentially preserved in aqueous solution. The orientation of monomers within the dimer observed previously by x-ray crystallography agrees with the solution electron paramagnetic resonance data. Furthermore, the distance between positions 1033 is shown to increase by >3 nm upon interaction of the vinculin tail domain with F-actin.

BackgroundNonheterosexual individuals have higher risk of psychiatric morbidity. Together with growing evidence for sexual orientation‐related brain differences, this raises the concern that sexual orientation may be an important factor to control for in neuroimaging studies of neuropsychiatric disorders.MethodsWe studied sexual orientation in adult psychiatric patients with bipolar disorder (BD) or ADHD in a large clinical cohort (N = 154). We compared cortical brain structure in exclusively heterosexual women (HEW, n = 29) with that of nonexclusively heterosexual women (nHEW, n = 37) using surface‐based reconstruction techniques provided by FreeSurfer.ResultsThe prevalence of nonheterosexual sexual orientation was tentatively higher than reported in general population samples. Consistent with previously reported cross‐sex shifted brain patterns among homosexual individuals, nHEW patients showed significantly larger cortical volumes than HEW in medial occipital brain regions.ConclusionWe found evidence for a sex‐reversed difference in cortical volume among nonheterosexual female patients, which provides insights into the neurobiology of sexual orientation, and may provide the first clues toward a better neurobiological understanding of the association between sexual orientation and mental health. We also suggest that sexual orientation is an important factor to consider in future neuroimaging studies of populations with certain mental health disorders.

Starting from readily available five-membered cyclic nitrones, paramagnetic analogues of palmitic and hexadec-2 E-enoic acids are described with a range of pyrrolidine ring orientations. Herein we report the synthesis of 3,4-disubstituted lipophilic pyrroline nitroxides through a palladium-catalyzed cross-coupling reaction. Lipophilic phosphonium salt and SH-specific labels (methanethiosulfonates and isoselenuronium salts) with allylic and propargylic terminal groups are also described.

Higher numbers of manic episodes in bipolar patients has, in cross-sectional studies, been associated with less grey matter volume in prefrontal brain areas. Longitudinal studies are needed to determine if manic episodes set off progressive cortical changes, or if the association is better explained by premorbid brain conditions that increase risk for mania. We followed patients with bipolar disorder type 1 for 6 years. Structural brain magnetic resonance imaging scans were performed at baseline and follow-up. We compared patients who had at least one manic episode between baseline and follow-up (Mania group, n = 13) with those who had no manic episodes (No-Mania group, n = 18). We used measures of cortical volume, thickness, and area to assess grey matter changes between baseline and follow-up. We found significantly decreased frontal cortical volume (dorsolateral prefrontal and inferior frontal cortex) in the Mania group, but no volume changes in the No-Mania group. Our results indicate that volume decrease in frontal brain regions can be attributed to the incidence of manic episodes.

BACKGROUND: Cigarette smoking is associated with metabolite abnormalities in anterior brain regions, but it is unclear if these abnormalities are apparent in other regions. Additionally, relationships between regional brain metabolite levels and measures of decision making, risk taking, and impulsivity in smokers and nonsmokers have not been investigated. METHODS: In young to middle-aged (predominately male) nonsmokers (n 5 30) and smokers (n 5 35), Nacetylaspartate (NAA), choline-containing compounds, creatine-containing compounds (Cr), myo-inositol (mI), and glutamate (Glu) levels in the anterior cingulate cortex and right dorsolateral prefrontal cortex (DLPFC) were compared via 4-tesla proton single volume magnetic resonance spectroscopy. Groups also were compared on NAA, cholinecontaining compounds, Cr, and mI concentrations in the gray matter and white matter of the four cerebral lobes and subcortical nuclei/regions with 1.5-tesla proton magnetic resonance spectroscopy. Associations of regional metabolite levels with neurocognitive, decision-making, risk-taking, and self-reported impulsivity measures were examined. RESULTS: Smokers showed lower DLPFC NAA, Cr, mI and Glu concentrations and lower lenticular nuclei NAA level; smokers also demonstrated greater age-related decreases of DLPFC NAA and anterior cingulate cortex and DLPFC Glu levels. Smokers exhibited poorer decision making and greater impulsivity. Across the sample, higher NAA and Glu in the DLPFC and NAA concentrations in multiple lobar gray matter and white matter regions and subcortical nuclei were associated with better neurocognition and lower impulsivity. CONCLUSIONS: This study provides additional novel evidence that chronic smoking in young and middle-aged individuals is associated with significant age-related neurobiological abnormalities in anterior frontal regions implicated in the development and maintenance of addictive disorders.

a b s t r a c t Background: Over 50% of individuals with alcohol use disorders (AUD) also use other substances; brain structural abnormalities observed in alcohol dependent individuals may not be entirely related to alcohol consumption. This MRI study assessed differences in brain regional tissue volumes between short-term abstinent alcohol dependent individuals without (ALC) and with current substance use dependence (polysubstance users, PSU). Methods: Nineteen, one-month-abstinent PSU and 40 ALC as well as 27 light-drinkers (LD) were studied on a 1.5 T MR system. Whole brain T1-weighted images were segmented automatically into regional gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) volumes. MANOVA assessed group differ- ences of intracranial volume-normalized tissue volumes of the frontal, parietal, occipital, and temporal lobes and regional subcortical GM volumes. The volumetric measures were correlated with neurocogni- tive measures to assess their functional relevance. Results: Despite similar lifetime drinking and smoking histories, PSU had significantly larger normalized WM volumes than ALC in all lobes. PSU also had larger frontal and parietal WM volumes than LD, but smaller temporal GM volumes and smaller lenticular and thalamic nuclei than LD. ALC had smaller frontal, parietal, and temporal GM, thalamic GM and cerebellar volumes than LD. ALC had more sulcal CSF volumes than both PSU and LD. Conclusion: One-month-abstinent ALC and PSU exhibited different patterns of gross brain structural abnormalities. The larger lobar WM volumes in PSU in the absence of widespread GM volume loss con- trast with widespread GM atrophy in ALC. These structural differences may demand different treatment approaches to mitigate specific functionally relevant brain abnormalities.

The conformational dynamics of the histidine ABC transporter HisQMP2 from Salmonella enterica serovar Typhimurium, reconstituted into liposomes, is studied by site-directed spin labeling and double electron–electron resonance spectroscopy in the absence of nucleotides, in the ATP-bound, and in the post-hydrolysis state. The results show that the inter-dimer distances as measured between the Q-loops of HisP2 in the intact transporter resemble those determined for the maltose transporter in all three states of the hydrolysis cycle. Only in the presence of liganded HisJ the closed conformation of the nucleotide binding sites is achieved revealing the transmembrane communication of the presence of substrate. Two conformational states can be distinguished for the periplasmic moiety of HisQMP2 as detected by differences in distributions of interspin distances between positions 86 and 96 or 104 and 197. The observed conformational changes are correlated to proposed open, semi-open and closed conformations of the nucleotide binding domains HisP2. Our results are in line with a rearrangement of transmembrane helices 4 and 4′ of HisQM during the closed to the semi-open transition of HisP2 driven by the reorientation of the coupled helices 3a and 3b to occur upon hydrolysis.

Aims: The aim of the study was to explore neurometabolic and associated cognitive characteristics of patients with polysubstance use (PSU) in comparison with patients with predominant alcohol use using proton magnetic resonance spectroscopy. Methods: Brain metabolite concentrations were examined in lobar and subcortical brain regions of three age-matched groups: 1-monthabstinent alcohol-dependent PSU, 1-month-abstinent individuals dependent on alcohol alone (ALC) and light drinking controls (CON). Neuropsychological testing assessed cognitive function. Results: While CON and ALC had similar metabolite levels, persistent metabolic abnormalities ( primarily higher myo-inositol) were present in temporal gray matter, cerebellar vermis and lenticular nuclei of PSU. Moreover, lower cortical gray matter concentration of the neuronal marker N-acetylaspartate within PSU correlated with higher cocaine (but not alcohol) use quantities and with a reduced cognitive processing speed. Conclusions: These metabolite group differences reflect cellular/astroglial injury and/or dysfunction in alcohol-dependent PSU. Associations of other metabolite concentrations with neurocognitive performance suggest their functional relevance. The metabolic alterations in PSU may represent polydrug abuse biomarkers and/or potential targets for pharmacological and behavioral PSU-specific treatment. © The Author 2013. Medical Council on Alcohol and Oxford University Press. All rights reserved.

Background: Although comorbid substance misuse is common in alcohol dependence, and polysubstance abusers (PSU) represent the largest group of individuals seeking treatment for drug abuse today, we know little about potential brain abnormalities in this population. Brain magnetic resonance spectroscopy studies of mono-substance use disorders (e.g., alcohol or cocaine) reveal abnormal levels of cortical metabolites (reflecting neuronal integrity, cell membrane turnover/synthesis, cellular bioenergetics, gliosis) and altered concentrations of glutamate and γ-aminobutyric acid (GABA). The concurrent misuse of several substances may have unique and different effects on brain biology and function compared to any mono-substance misuse. Methods: High field brain magnetic resonance spectroscopy at 4. T and neurocognitive testing were performed at one month of abstinence in 40 alcohol dependent individuals (ALC), 28 alcohol dependent PSU and 16 drug-free controls. Absolute metabolite concentrations were calculated in anterior cingulate (ACC), parieto-occipital (POC) and dorso-lateral prefrontal cortices (DLPFC). Results: Compared to ALC, PSU demonstrated significant metabolic abnormalities in the DLPFC and strong trends to lower GABA in the ACC. Metabolite levels in ALC and light drinking controls were statistically equivalent. Within PSU, lower DLPFC GABA levels are related to greater cocaine consumption. Several cortical metabolite concentrations were associated with cognitive performance. Conclusions: While metabolite concentrations in ALC at one month of abstinence were largely normal, PSU showed persistent and functionally significant metabolic abnormalities, primarily in the DLPFC. Our results point to specific metabolic deficits as biomarkers in polysubstance misuse and as targets for pharmacological and behavioral PSU-specific treatment. © 2012 Elsevier Ireland Ltd.

Recent MRS studies have indicated that a higher body mass index (BMI) is associated with lower brain metabolite levels. Generally, individuals with higher BMIs have more body fat deposits than individuals with normal BMIs. This single-voxel spectroscopy (SVS) study investigated possible effects of fat on MR-measured metabolite signal areas, which may at least partly explain the observed associations of BMI with MR-measured brain metabolite levels in vivo. SVS data were acquired at 4 T from a phantom containing N-acetylaspartate, glutamate and creatine, as well as from three healthy male adults. Back fat obtained from pig was used to assess the effects of fat on metabolite signals. With the same voxel size and placement, the phantom was first scanned without fat (baseline), and then with 0.7-cm- and 1.4-cm-thick fat layers placed on it. Each participant was also scanned first without fat and then with two 0.7-cm fat layers, one placed beneath the occiput and the other on the forehead. Two spectra were acquired per participant from the anterior cingulate and the parieto-occipital cortices. The metabolite resonance and corresponding water peak areas were then fitted and metabolite to water signal ratios were used for analyses. In both phantom and in vivo experiments, the metabolite-to-water ratios decreased in the presence of fat relative to baseline metabolite-to-water ratios. The reduced metabolite signals in the presence of fat reported here are reminiscent of the negative correlations observed between BMI and MR-measured metabolite levels. These apparent physical effects of fat have potentially far-reaching consequences for the accuracy of MR measurements of brain metabolite levels and their interpretation, particularly when large fat stores exist around the skull, such as in individuals with higher BMI.