Erroneously Disgusted: fMRI Study Supports Disgust-Related Neural Reuse in Obsessive-Compulsive Disorder (OCD)

Objective: fMRI scans of patients with obsessive-compulsive disorder (OCD) consistently show a hyperactivity of the insular cortex, a region responsible for disgust-processing, when confronted with symptom-triggering stimuli. This asks for an investigation of the role of disgust and the insula in OCD patients.Methods: Seventeen inpatients with OCD and 17 healthy controls (HC) underwent fMRI scanning. Whole-brain contrasts were calculated for “Disgust vs. Neutral” for both groups, plus an analysis of variance (ANOVA) to assess the interaction between group and condition. Additionally, the emotional dimensions of valence and arousal, along with the ability to cope, were assessed by picture ratings.Results: The picture ratings confirmed the patients’ heightened sensitivity to disgust with higher values for arousal and inability to cope, but not for valence. fMRI scans revealed no hyperactivity of the insula in patients compared to controls for the condition “Disgust vs. Neutral,” indicating no basic hypersensitivity to disgusting stimuli. Increased activity in the precuneus in controls for this condition might correspond to the downregulation of arousal.Conclusions: The absent differences in neural activity of the insula in patients compared to controls for the disgust-condition, but heightened activity for symptom-provoking conditions, suggests that the illness is due to an erroneous recruitment of the insula cortex for OCD-stimuli. The finding is interpreted within the framework of the neural reuse hypothesis

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA‐Epilepsy study

Objective: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross‐sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 healthy controls across 22 sites from the global ENIGMA‐Epilepsy working group. Methods: A state‐of‐the‐art deep learning‐based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in (1) all epilepsies, (2) temporal lobe epilepsy with hippocampal sclerosis (TLE‐HS), (3) nonlesional temporal lobe epilepsy, (4) genetic generalized epilepsy, and (5) extratemporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness. Results: Across all epilepsies, reduced total cerebellar volume was observed (d = .42). Maximum volume loss was observed in the corpus medullare (dmax = .49) and posterior lobe gray matter regions, including bilateral lobules VIIB (dmax = .47), crus I/II (dmax = .39), VIIIA (dmax = .45), and VIIIB (dmax = .40). Earlier age at seizure onset ( η ρ max 2 $$\eta {\mathit{\mathsf{\rho}}}_{\mathsf{max}}^{\mathsf{2}}$$ = .05) and longer epilepsy duration ( η ρ max 2 $$\eta {\mathit{\mathsf{\rho}}}_{\mathsf{max}}^{\mathsf{2}}$$ = .06) correlated with reduced volume in these regions. Findings were most pronounced in TLE‐HS and ETLE, with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls. Significance: We provide robust evidence of deep cerebellar and posterior lobe subregional gray matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in nonmotor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellar subregional damage into neurobiological models of epilepsy

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Influence of co-dosed lipids from biota extracts on the availability of chemicals in in vitro cell-based bioassays

Extraction of chemicals from biota leads to co-extraction of lipids. When dosing such extracts into in vitro bioassays, co-dosed lipids act as an additional phase that can reduce the bioavailability of the chemicals and the apparent sensitivity of the assay. Equilibrium partitioning between medium, cells, and co-dosed lipids was described with an existing equilibrium partitioning model for cell-based bioassays extended by an additional lipid phase. We experimentally investigated the influence of co-dosed lipids on the effects elicited by four test chemicals of different hydrophobicity in two bioassays, indicative of the aryl hydrocarbon receptor and oxidative stress response (AREc32). The partitioning model explained the effect of the test chemicals in the presence of spiked triolein within a factor of 0.33-5.83 between the measured and predicted effect concentration (EC). We applied the model to marine mammal blubber extracted with silicone. Extracts dosed in the AREc32 bioassay showed a linear increase of apparent EC with increasing lipid fraction. The partitioning model was used to interpret the role of the co-extracted lipid. A quantitative lipid correction of bioassay results in the presence of co-dosed lipids was possible for known compounds and defined mixtures, while we could only estimate a range for mixtures of unknown chemicals

Erroneously Disgusted : fMRI Study Supports Disgust-Related Neural Reuse in Obsessive-Compulsive Disorder (OCD)

Objective: fMRI scans of patients with obsessive-compulsive disorder (OCD) consistently show a hyperactivity of the insular cortex, a region responsible for disgust-processing, when confronted with symptom-triggering stimuli. This asks for an investigation of the role of disgust and the insula in OCD patients. Methods: Seventeen inpatients with OCD and 17 healthy controls (HC) underwent fMRI scanning. Whole-brain contrasts were calculated for “Disgust vs. Neutral” for both groups, plus an analysis of variance (ANOVA) to assess the interaction between group and condition. Additionally, the emotional dimensions of valence and arousal, along with the ability to cope, were assessed by picture ratings. Results: The picture ratings confirmed the patients heightened sensitivity to disgust with higher values for arousal and inability to cope, but not for valence. fMRI scans revealed no hyperactivity of the insula in patients compared to controls for the condition “Disgust vs. Neutral,” indicating no basic hypersensitivity to disgusting stimuli. Increased activity in the precuneus in controls for this condition might correspond to the downregulation of arousal. Conclusions: The absent differences in neural activity of the insula in patients compared to controls for the disgust-condition, but heightened activity for symptom-provoking conditions, suggests that the illness is due to an erroneous recruitment of the insula cortex for OCD-stimuli. The finding is interpreted within the framework of the neural reuse hypothesis.(VLID)376886

Pathologically reduced neural flexibility recovers during psychotherapy of OCD patients

International audienceFlexibility is a key feature of psychological health, allowing the individual to dynamically adapt to changing environmental demands, which is impaired in many psychiatric disorders like obsessive-compulsive disorder (OCD). Adequately responding to varying demands requires the brain to switch between different patterns of neural activity, which are represented by different brain network configurations (functional connectivity patterns). Here, we operationalize neural flexibility as the dissimilarity between consecutive connectivity matrices of brain regions (jump length). In total, 132 fMRI scans were obtained from 17 patients that were scanned four to five times during inpatient psychotherapy, and from 17 controls that were scanned at comparable time intervals. Significant negative correlations were found between the jump lengths and the symptom severity scores of OCD, depression, anxiety, and stress, suggesting that high symptom severity corresponds to inflexible brain functioning. Further analyses revealed that impaired reconfiguration (pattern stability) of the brain seems to be more related to general psychiatric impairment rather than to specific symptoms, e.g., of OCD or depression. Importantly, the group × time interaction of a repeated measures ANOVA was significant, as well as the post-hoc paired t-tests of the patients (first vs. last scan). The results suggest that psychotherapy is able to significantly increase the neural flexibility of patients. We conclude that psychiatric symptoms like anxiety, stress, depression, and OCD are associated with an impaired adaptivity of the brain. In general, our results add to the growing evidence that dynamic functional connectivity captures meaningful properties of brain functioning

Interleukin-6 Gene Expression Changes after a 4-Week Intake of a Multispecies Probiotic in Major Depressive Disorder—Preliminary Results of the PROVIT Study

Major depressive disorder (MDD) is a prevalent disease, in which one third of sufferers do not respond to antidepressants. Probiotics have the potential to be well-tolerated and cost-efficient treatment options. However, the molecular pathways of their effects are not fully elucidated yet. Based on previous literature, we assume that probiotics can positively influence inflammatory mechanisms. We aimed at analyzing the effects of probiotics on gene expression of inflammation genes as part of the randomized, placebo-controlled, multispecies probiotics PROVIT study in Graz, Austria. Fasting blood of 61 inpatients with MDD was collected before and after four weeks of probiotic intake or placebo. We analyzed the effects on gene expression of tumor necrosis factor (TNF), nuclear factor kappa B subunit 1 (NFKB1) and interleukin-6 (IL-6). In IL-6 we found no significant main effects for group (F(1,44) = 1.33, p = ns) nor time (F(1,44) = 0.00, p = ns), but interaction was significant (F(1,44) = 5.67, p &lt; 0.05). The intervention group showed decreasing IL-6 gene expression levels while the placebo group showed increasing gene expression levels of IL-6. Probiotics could be a useful additional treatment in MDD, due to their anti-inflammatory effects. Results of the current study are promising, but further studies are required to investigate the beneficial effects of probiotic interventions in depressed individuals