BA11 FKBP5 expression levels correlate with dendritic spine density in postmortem PTSD and controls

AbstractGenetic variants of the immunophilin FKBP5 have been implicated in susceptibility to post-traumatic stress disorder (PTSD) and other stress-related disorders. We examined the relationship between mushroom, stubby, thin and filopodial spine densities measured with Golgi staining and FKBP5 gene expression in the medial orbitofrontal cortex (BA11) in individuals diagnosed with PTSD and normal controls (n = 8/8). ANCOVA revealed PTSD cases had a significantly elevated density of stubby spines (29%, P < 0.037) and a trend for a reduction in mushroom spine density (25%, p < 0.082). Levels of FKBP5 mRNA were marginally elevated in the PTSD cases (z = 1.94, p = 0.053) and levels correlated inversely with mushroom (Spearman's rho = −0.83, p < 0.001) and overall spine density (rho = −0.75, p < 0.002) and directly with stubby spine density (rho = 0.55, p < 0.027). These data suggest that FKBP5 may participate in a cellular pathway modulating neuronal spine density changes in the brain, and that this pathway may be dysregulated in PTSD

Status and promise of particle interferometry in heavy-ion collisions

After five years of running at RHIC, and on the eve of the LHC heavy-ion program, we highlight the status of femtoscopic measurements. We emphasize the role interferometry plays in addressing fundamental questions about the state of matter created in such collisions, and present an enumerated list of measurements, analyses and calculations that are needed to advance the field in the coming years

Cerebral activations related to ballistic, stepwise interrupted and gradually modulated movements in parkinson patients

Patients with Parkinson's disease (PD) experience impaired initiation and inhibition of movements such as difficulty to start/stop walking. At single-joint level this is accompanied by reduced inhibition of antagonist muscle activity. While normal basal ganglia (BG) contributions to motor control include selecting appropriate muscles by inhibiting others, it is unclear how PD-related changes in BG function cause impaired movement initiation and inhibition at single-joint level. To further elucidate these changes we studied 4 right-hand movement tasks with fMRI, by dissociating activations related to abrupt movement initiation, inhibition and gradual movement modulation. Initiation and inhibition were inferred from ballistic and stepwise interrupted movement, respectively, while smooth wrist circumduction enabled the assessment of gradually modulated movement. Task-related activations were compared between PD patients (N = 12) and healthy subjects (N = 18). In healthy subjects, movement initiation was characterized by antero-ventral striatum, substantia nigra (SN) and premotor activations while inhibition was dominated by subthalamic nucleus (STN) and pallidal activations, in line with the known role of these areas in simple movement. Gradual movement mainly involved antero-dorsal putamen and pallidum. Compared to healthy subjects, patients showed reduced striatal/SN and increased pallidal activation for initiation, whereas for inhibition STN activation was reduced and striatal-thalamo-cortical activation increased. For gradual movement patients showed reduced pallidal and increased thalamo-cortical activation. We conclude that PD-related changes during movement initiation fit the (rather static) model of alterations in direct and indirect BG pathways. Reduced STN activation and regional cortical increased activation in PD during inhibition and gradual movement modulation are better explained by a dynamic model that also takes into account enhanced responsiveness to external stimuli in this disease and the effects of hyper-fluctuating cortical inputs to the striatum and STN in particular

Correlations between Diffusion Tensor Imaging (DTI) and Magnetic Resonance Spectroscopy (1H MRS) in schizophrenic patients and normal controls

<p>Abstract</p> <p>Background</p> <p>Evidence suggests that white matter integrity may play an underlying pathophysiological role in schizophrenia. N-acetylaspartate (NAA), as measured by Magnetic Resonance Spectroscopy (MRS), is a neuronal marker and is decreased in white matter lesions and regions of axonal loss. It has also been found to be reduced in the prefrontal and temporal regions in patients with schizophrenia. Diffusion Tensor Imaging (DTI) allows one to measure the orientations of axonal tracts as well as the coherence of axonal bundles. DTI is thus sensitive to demyelination and other structural abnormalities. DTI has also shown abnormalities in these regions.</p> <p>Methods</p> <p>MRS and DTI were obtained on 42 healthy subjects and 40 subjects with schizophrenia. The data was analyzed using regions of interests in the Dorso-Lateral Prefrontal white matter, Medial Temporal white matter and Occipital white matter using both imaging modalities.</p> <p>Results</p> <p>NAA was significantly reduced in the patient population in the Medial Temporal regions. DTI anisotropy indices were also reduced in the same Medial Temporal regions. NAA and DTI-anisotropy indices were also correlated in the left medial temporal region.</p> <p>Conclusion</p> <p>Our results implicate defects in the medial temporal white matter in patients with schizophrenia. Moreover, MRS and DTI are complementary modalities for the study of white matter disruptions in patients with schizophrenia.</p

Genome-wide methylomic analysis of monozygotic twins discordant for adolescent depression

BACKGROUND Adolescent depression is a common neuropsychiatric disorder that often continues into adulthood and is associated with a wide range of poor outcomes including suicide. Although numerous studies have looked at genetic markers associated with depression, the role of epigenetic variation remains relatively unexplored. METHODS Monozygotic (MZ) twins were selected from an adolescent twin study designed to investigate the interplay of genetic and environmental factors in the development of emotional and behavioral difficulties. There were 18 pairs of MZ twins identified in which one member scored consistently higher (group mean within the clinically significant range) on self-rated depression than the other. We assessed genome-wide patterns of DNA methylation in twin buccal cell DNA using the Infinium HumanMethylation450 BeadChip from Illumina. Quality control and data preprocessing was undertaken using the wateRmelon package. Differentially methylated probes (DMPs) were identified using an analysis strategy taking into account both the significance and the magnitude of DNA methylation differences. The top differentially methylated DMP was successfully validated by bisulfite-pyrosequencing, and identified DMPs were tested in postmortem brain samples obtained from patients with major depressive disorder (n = 14) and matched control subjects (n = 15). RESULTS Two reproducible depression-associated DMPs were identified, including the top-ranked DMP that was located within STK32C, which encodes a serine/threonine kinase, of unknown function. CONCLUSIONS Our data indicate that DNA methylation differences are apparent in MZ twins discordant for adolescent depression and that some of the disease-associated variation observed in buccal cell DNA is mirrored in adult brain tissue obtained from individuals with clinical depression

Independent Component Analysis of the Effect of L-dopa on fMRI of Language Processing

L-dopa, which is a precursor for dopamine, acts to amplify strong signals, and dampen weak signals as suggested by previous studies. The effect of L-dopa has been demonstrated in language studies, suggesting restriction of the semantic network. In this study, we aimed to examine the effect of L-dopa on language processing with fMRI using Independent Component Analysis (ICA). Two types of language tasks (phonological and semantic categorization tasks) were tested under two drug conditions (placebo and L-dopa) in 16 healthy subjects. Probabilistic ICA (PICA), part of FSL, was implemented to generate Independent Components (IC) for each subject for the four conditions and the ICs were classified into task-relevant source groups by a correlation threshold criterion. Our key findings include: (i) The highly task-relevant brain regions including the Left Inferior Frontal Gyrus (LIFG), Left Fusiform Gyrus (LFUS), Left Parietal lobe (LPAR) and Superior Temporal Gyrus (STG) were activated with both L-dopa and placebo for both tasks, and (ii) as compared to placebo, L-dopa was associated with increased activity in posterior regions, including the superior temporal area (BA 22), and decreased activity in the thalamus (pulvinar) and inferior frontal gyrus (BA 11/47) for both tasks. These results raise the possibility that L-dopa may exert an indirect effect on posterior regions mediated by the thalamus (pulvinar)

Glucocorticoid Receptor 1B and 1C mRNA Transcript Alterations in Schizophrenia and Bipolar Disorder, and Their Possible Regulation by GR Gene Variants

Abnormal patterns of HPA axis activation, under basal conditions and in response to stress, are found in individuals with schizophrenia and bipolar disorder. Altered glucocorticoid receptor (GR) mRNA and protein expression in the dorsolateral prefrontal cortex (DLPFC) in psychiatric illness have also been reported, but the cause of these abnormalities is not known. We quantified expression of GR mRNA transcript variants which employ different 5′ promoters, in 35 schizophrenia cases, 31 bipolar disorder cases and 34 controls. We also explored whether sequence variation within the NR3C1 (GR) gene is related to GR mRNA variant expression. Total GR mRNA was decreased in the DLPFC in schizophrenia cases relative to controls (15.1%, p<0.0005) and also relative to bipolar disorder cases (8.9%, p<0.05). GR-1B mRNA was decreased in schizophrenia cases relative to controls (20.2%, p<0.05), while GR-1C mRNA was decreased in both schizophrenia and bipolar disorder cases relative to controls (16.1% and 17.2% respectively, both p<0.005). A dose-dependent effect of rs10052957 genotype on GR-1B mRNA expression was observed, where CC homozygotes displayed 18.4% lower expression than TC heterozygotes (p<0.05), and 31.8% lower expression than TT homozygotes (p<0.005). Similarly, a relationship between rs6190 (R23K) genotype and GR-1C expression was seen, with 24.8% lower expression in GG homozygotes than GA heterozygotes (p<0.01). We also observed an effect of rs41423247 (Bcl1) SNP on expression of 67 kDa GRα isoform, the most abundant GRα isoform in the DLPFC. These findings suggest possible roles for the GR-1B and GR-1C promoter regions in mediating GR gene expression changes in psychotic illness, and highlight the potential importance of sequence variation within the NR3C1 gene in modulating GR mRNA expression in the DLPFC

Gene Expression Analysis Implicates a Death Receptor Pathway in Schizophrenia Pathology

An increase in apoptotic events may underlie neuropathology in schizophrenia. By data-mining approaches, we identified significant expression changes in death receptor signaling pathways in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia, particularly implicating the Tumor Necrosis Factor Superfamily member 6 (FAS) receptor and the Tumor Necrosis Factor [ligand] Superfamily member 13 (TNFSF13) in schizophrenia. We sought to confirm and replicate in an independent tissue collection the noted mRNA changes with quantitative real-time RT-PCR. To test for regional and diagnostic specificity, tissue from orbital frontal cortex (OFC) was examined and a bipolar disorder group included. In schizophrenia, we confirmed and replicated significantly increased expression of TNFSF13 mRNA in the DLPFC. Also, a significantly larger proportion of subjects in the schizophrenia group had elevated FAS receptor expression in the DLPFC relative to unaffected controls. These changes were not observed in the bipolar disorder group. In the OFC, there were no significant differences in TNFSF13 or FAS receptor mRNA expression. Decreases in BH3 interacting domain death agonist (BID) mRNA transcript levels were found in the schizophrenia and bipolar disorder groups affecting both the DLPFC and the OFC. We tested if TNFSF13 mRNA expression correlated with neuronal mRNAs in the DLPFC, and found significant negative correlations with interneuron markers, parvalbumin and somatostatin, and a positive correlation with PPP1R9B (spinophilin), but not DLG4 (PSD-95). The expression of TNFSF13 mRNA in DLPFC correlated negatively with tissue pH, but decreasing pH in cultured cells did not cause increased TNFSF13 mRNA nor did exogenous TNFSF13 decrease pH. We concluded that increased TNFSF13 expression may be one of several cell-death cytokine abnormalities that contribute to the observed brain pathology in schizophrenia, and while increased TNFSF13 may be associated with lower brain pH, the change is not necessarily causally related to brain pH

Biases in the Explore-Exploit Tradeoff in Addictions: The Role of Avoidance of Uncertainty.

We focus on exploratory decisions across disorders of compulsivity, a potential dimensional construct for the classification of mental disorders. Behaviors associated with the pathological use of alcohol or food, in alcohol use disorders (AUD) or binge-eating disorder (BED), suggest a disturbance in explore-exploit decision-making, whereby strategic exploratory decisions in an attempt to improve long-term outcomes may diminish in favor of more repetitive or exploitatory choices. We compare exploration vs exploitation across disorders of natural (obesity with and without BED) and drug rewards (AUD). We separately acquired resting state functional MRI data using a novel multi-echo planar imaging sequence and independent components analysis from healthy individuals to assess the neural correlates underlying exploration. Participants with AUD showed reduced exploratory behavior across gain and loss environments, leading to lower-yielding exploitatory choices. Obese subjects with and without BED did not differ from healthy volunteers but when compared with each other or to AUD subjects, BED had enhanced exploratory behaviors particularly in the loss domain. All subject groups had decreased exploration or greater uncertainty avoidance to losses compared with rewards. More exploratory decisions in the context of reward were associated with frontal polar and ventral striatal connectivity. For losses, exploration was associated with frontal polar and precuneus connectivity. We further implicate the relevance and dimensionality of constructs of compulsivity across disorders of both natural and drug rewards.The study was funded by the Wellcome Trust Fellowship grant for VV (093705/Z/10/Z) and Cambridge NIHR Biomedical Research Centre. VV and NAH are Wellcome Trust (WT) intermediate Clinical Fellows. LSM is in receipt of an MRC studentship. The BCNI is supported by a WT and MRC grant. MF is funded by NIMH and NSF grants and is consultant for Hoffman LaRoche pharmaceuticals. The remaining authors declare no competing financial interests.This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/npp.2015.20

Cortical and cerebellar activation induced by reflexive and voluntary saccades

Reflexive saccades are driven by visual stimulation whereas voluntary saccades require volitional control. Behavioral and lesional studies suggest that there are two separate mechanisms involved in the generation of these two types of saccades. This study investigated differences in cerebral and cerebellar activation between reflexive and self-paced voluntary saccadic eye movements using functional magnetic resonance imaging. In two experiments (whole brain and cerebellum) using the same paradigm, differences in brain activations induced by reflexive and self-paced voluntary saccades were assessed. Direct comparison of the activation patterns showed that the frontal eye fields, parietal eye field, the motion-sensitive area (MT/V5), the precuneus (V6), and the angular and the cingulate gyri were more activated in reflexive saccades than in voluntary saccades. No significant difference in activation was found in the cerebellum. Our results suggest that the alleged separate mechanisms for saccadic control of reflexive and self-paced voluntary are mainly observed in cerebral rather than cerebellar areas