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Major depressive disorder (MDD) is a mood disorder of multifactorial origin affecting millions of people worldwide. The alarming estimated rates of prevalence and relapse make it a global public health concern. Moreover, the current setback of available antidepressants in the clinical setting is discouraging. Therefore, efforts to eradicate depression should be directed towards understanding the pathomechanisms involved in the hope of finding cost-effective treatment alternatives. The pathophysiology of MDD comprises the breakdown of different pathways, including the hypothalamus-pituitary-adrenal (HPA) axis, the glutamatergic system, and monoaminergic neurotransmission, affecting cognition and emotional behavior. Inflammatory cytokines have been postulated to be the possible link and culprit in the disruption of these systems. In addition, evidence from different studies suggests that impairment of glial functions appears to be a major contributor as well. Thus, the intricate role between glia, namely microglia and astrocytes, and the central nervous system's (CNSs) immune response is briefly discussed, highlighting the kynurenine pathway as a pivotal player. Moreover, evaluations of different treatment strategies targeting the inflammatory response are considered. The immuno-modulatory properties of vitamin D receptor (VDR) suggest that vitamin D is an attractive and plausible candidate in spite of controversial findings. Further research investigating the role of VDR in mood disorders is warranted.

Perception is not simply based on a hierarchical organization of the brain; it arises from an interplay between inputs from the environment and internal predictions of these inputs. It is an active process which involves an interaction between bottom-up information coming from the senses and feedback connections coming from higher-order cortical areas. In our experiment, we use the hollow-mask illusion to investigate the strength of top-down processes in schizophrenic patients and healthy controls. By using dynamic causal modelling (DCM) on functional magnetic resonance tomography (fMRI) data, we have presented evidence to suggest that patients with schizophrenia are less constrained by top-down processes during perception (Dima, D., Roiser, J.P., Dietrich, D.E., Bonnemann, C., Lanfermann, H., Emrich, H.M., Dillo, W., 2009. Understanding why patients with schizophrenia do not perceive the hollow-mask illusion using dynamic causal modeling. Neuroimage 46, 1180–1186). In this study, we re-address this issue by using DCM on event-related potentials (ERPs) data. Our aim was to validate our previous findings by conducting the same connectivity analysis – DCM – on data obtained from a different neuroimaging method. Our results confirm our initial hypothesis that top-down influences are constrained in schizophrenia, especially in perceptual tasks that require top-down control, like the hollow-mask illusion.

Background Borna disease virus 1 (BoDV-1) is a non-segmented, negative-strand RNA virus that persistently infects mammals including humans. BoDV-1 worldwide occurring strains display highly conserved genomes with overlapping genetic signatures between those of either human or animal origin. BoDV-1 infection may cause behavioral and cognitive disturbances in animals but has also been found in human major depression and obsessive–compulsive disorder (OCD). However, the impact of BoDV-1 on memory functions in OCD is unknown. Method To evaluate the cognitive impact of BoDV-1 in OCD, event-related brain potentials (ERPs) were recorded in a continuous word recognition paradigm in OCD patients ( n  = 16) and in healthy controls ( n  = 12). According to the presence of BoDV-1-specific circulating immune complexes (CIC), they were divided into two groups, namely group H (high) and L (low), n  = 8 each. Typically, ERPs to repeated items are characterized by more positive waveforms beginning approximately 250 ms post-stimulus. This “old/new effect” has been shown to be relevant for memory processing. The early old/new effect (ca. 300–500 ms) with a frontal distribution is proposed to be a neural correlate of familiarity-based recognition. The late old/new effect (post-500 ms) is supposed to reflect memory recollection processes. Results OCD patients were reported to show a normal early old/new effect and a reduced late old/new effect compared to normal controls. In our study, OCD patients with a high virus load (group H) displayed exactly these effects, while patients with a low virus load (group L) did not differ from healthy controls. Conclusion These results confirmed that OCD patients had impaired memory recollection processes compared to the normal controls which may to some extent be related to their BoDV-1 infection.

Background Pathophysiological evidence suggests an involvement of fronto-striatal circuits in Tourette syndrome (TS). To identify TS related abnormalities in gray and white matter we used optimized voxel-based morphometry (VBM) and magnetization transfer imaging (MTI) which are more sensitive to tissue alterations than conventional MRI and provide a quantitative measure of macrostructural integrity. Methods Volumetric high-resolution anatomical T1-weighted MRI and MTI were acquired in 19 adult, unmedicated male TS patients without co-morbidities and 20 age- and sex-matched controls on a 1.5 Tesla neuro-optimized GE scanner. Images were pre-processed and analyzed using an optimized version of VBM in SPM2. Results Using VBM, TS patients showed significant decreases in gray matter volumes in prefrontal areas, the anterior cingulate gyrus, sensorimotor areas, left caudate nucleus and left postcentral gyrus. Decreases in white matter volumes were detected in the right inferior frontal gyrus, the left superior frontal gyrus and the anterior corpus callosum. Increases were found in the left middle frontal gyrus and left sensorimotor areas. In MTI, white matter reductions were seen in the right medial frontal gyrus, the inferior frontal gyrus bilaterally and the right cingulate gyrus. Tic severity was negatively correlated with orbitofrontal structures, the right cingulate gyrus and parts of the parietal-temporal-occipital association cortex bilaterally. Conclusion Our MRI in vivo neuropathological findings using two sensitive and unbiased techniques support the hypothesis that alterations in frontostriatal circuitries underlie TS pathology. We suggest that anomalous frontal lobe association and projection fiber bundles cause disinhibition of the cingulate gyrus and abnormal basal ganglia function.

Background Whether Borna disease virus (BDV-1) is a human pathogen remained controversial until recent encephalitis cases showed BDV-1 infection could even be deadly. This called to mind previous evidence for an infectious contribution of BDV-1 to mental disorders. Pilot open trials suggested that BDV-1 infected depressed patients benefitted from antiviral therapy with a licensed drug (amantadine) which also tested sensitive in vitro. Here, we designed a double-blind placebo-controlled randomized clinical trial (RCT) which cross-linked depression and BDV-1 infection, addressing both the antidepressant and antiviral efficacy of amantadine. Methods The interventional phase II RCT (two 7-weeks-treatment periods and a 12-months follow-up) at the Hannover Medical School (MHH), Germany, assigned currently depressed BDV-1 infected patients with either major depression (MD; N  = 23) or bipolar disorder (BD; N  = 13) to amantadine sulphate (PK-Merz®; twice 100 mg orally daily) or placebo treatment, and contrariwise, respectively. Clinical changes were assessed every 2–3 weeks by the 21-item Hamilton rating scale for depression (HAMD) (total, single, and combined scores). BDV-1 activity was determined accordingly in blood plasma by enzyme immune assays for antigens (PAG), antibodies (AB) and circulating immune complexes (CIC). Results Primary outcomes (≥25% HAMD reduction, week 7) were 81.3% amantadine vs. 35.3% placebo responder ( p  = 0.003), a large clinical effect size (ES; Cohen’s d) of 1.046, and excellent drug tolerance. Amantadine was safe reducing suicidal behaviour in the first 2 weeks. Pre-treatment maximum infection levels were predictive of clinical improvement (AB, p  = 0.001; PAG, p  = 0.026; HAMD week 7). Respective PAG and CIC levels correlated with AB reduction ( p  = 0,001 and p  = 0.034, respectively). Follow-up benefits (12 months) correlated with dropped cumulative infection measures over time ( p  < 0.001). In vitro, amantadine concentrations as low as 2.4–10 ng/mL (50% infection-inhibitory dose) prevented infection with human BDV Hu-H1, while closely related memantine failed up to 100,000-fold higher concentration (200 μg/mL). Conclusions Our findings indicate profound antidepressant efficacy of safe oral amantadine treatment, paralleling antiviral effects at various infection levels. This not only supports the paradigm of a link of BDV-1 infection and depression. It provides a novel possibly practice-changing low cost mental health care perspective for depressed BDV-1-infected patients addressing global needs. Trial registration The trial was retrospectively registered in the German Clinical Trials Registry on 04th of March 2015. The trial ID is DRKS00007649; https://www.drks.de/drks_web/setLocale_EN.do

Synesthesia entails a special kind of sensory perception, where stimulation in one sensory modality leads to an internally generated perceptual experience of another, not stimulated sensory modality. This phenomenon can be viewed as an abnormal multisensory integration process as here the synesthetic percept is aberrantly fused with the stimulated modality. Indeed, recent synesthesia research has focused on multimodal processing even outside of the specific synesthesia-inducing context and has revealed changed multimodal integration, thus suggesting perceptual alterations at a global level. Here, we focused on audio-visual processing in synesthesia using a semantic classification task in combination with visually or auditory-visually presented animated and in animated objects in an audio-visual congruent and incongruent manner. Fourteen subjects with auditory-visual and/or grapheme-color synesthesia and 14 control subjects participated in the experiment. During presentation of the stimuli, event-related potentials were recorded from 32 electrodes. The analysis of reaction times and error rates revealed no group differences with best performance for audio-visually congruent stimulation indicating the well-known multimodal facilitation effect. We found enhanced amplitude of the N1 component over occipital electrode sites for synesthetes compared to controls. The differences occurred irrespective of the experimental condition and therefore suggest a global influence on early sensory processing in synesthetes.

Patients suffering from schizophrenia are less susceptible to various visual illusions. For example, healthy participants perceive a hollow mask as a normal face, presumably due to the strength of constraining top-down influences, while patients with schizophrenia do not (Schneider, U., Leweke, F.M., Sternemann, U., Weber, M.M., Emrich, H.M., 1996. Visual 3D illusion: a systems-theoretical approach to psychosis. Eur. Arch. Psychiatry Clin. Neurosci. 246, 256–260; Scheider, U., Borsutzky, M., Seifert, J., Leweke, F.M., Huber, T.J., Rollnik J.D., Emrich, H.M., 2002. Reduced binocular depth inversion in schizophrenic patients. Schizophrenia Research 53, 101–108.; Emrich, H.M., Leweke, F.M., Schneider, U., 1997. Towards a cannabinoid hypothesis of schizophrenia: cognitive impairments due to a dysregulation of the endogenous cannabinoid system. Pharmacol. Biochem. Behav. 56, 803–807). However the neural mechanisms underpinning this effect remain poorly understood. We used functional magnetic resonance imaging to investigate the hollow-mask illusion in schizophrenic patients and healthy controls. The primary aim of this study was to use measures of effective connectivity arising from dynamic causal modelling (DCM) to explain differences in both the perception of the hollow-mask illusion and associated differences in neural responses between patients with schizophrenia and controls, which we hypothesised would be associated with difference in the influences of top-down and bottom-up processes between the groups. Consistent with this explanation, we identified differences between the two groups in effective connectivity. In particular, there was a strengthening of bottom-up processes, and weakening of top-down ones, during the presentation of ‘hollow’ faces for the patients. In contrast, the controls exhibited a strengthening of top-down processes when perceiving the same stimuli. These findings suggest that schizophrenic patients rely on stimulus-driven processing and are less able to employ conceptually-driven top-down strategies during perception, where incoming sensory data are constrained with reference to a generative model that entails stored information from past experience.

There is increasing evidence from case reports that synesthesia is more common in individuals with autism spectrum conditions (ASC). Further, genes related to synesthesia have also been found to be linked to ASC and, similar to synaesthetes, individuals with ASC show altered brain connectivity and unusual brain activation during sensory processing. However, up to now a systematic investigation of whether synesthesia is more common in ASC patients is missing. The aim of the current pilot study was to test this hypothesis by investigating a group of patients diagnosed with Asperger Syndrome (AS) using questionnaires and standard consistency tests in order to classify them as grapheme-color synaesthetes. The results indicate that there are indeed many more grapheme-color synaesthetes among AS patients. This finding is discussed in relation to different theories regarding the development of synesthesia as well as altered sensory processing in autism.

Highlighting the association between schizophrenia and Cannabis sativa and the endogenous cannabinoid receptor system, respectively, two opposite aspects are of major relevance. On the one hand, cannabis is the most widely used illegal drug. There is substantial evidence that cannabis has to be classified as an independent risk factor for psychosis that may lead to a worse outcome of the disease. This risk seems to be increased in genetically predisposed people and may depend on the amount of cannabis used. On the other hand, during the last few years, an endogenous cannabinoid receptor system (including two known cannabinoid [CB 1 and CB 2 ] receptors and five endogenous ligands) has been discovered. There are several lines of evidence suggesting that, at least in a subgroup of patients, alterations in the endocannabinoid system may contribute to the pathogenesis of schizophrenia (e.g., increased density of CB 1 receptor binding and increased levels of cerebrospinal fluid endocannabinoid anandamide). Accordingly, beside the 'dopamine hypothesis' of schizophrenia, a 'cannabinoid hypothesis' has been suggested. Interestingly, there is a complex interaction between the dopaminergic and the endocannabinoid receptor system. Thus, agents that interact with the cannabinoid receptor system, such as the nonpsychoactive cannabidiol, might be beneficial in the treatment of psychosis.

Attention-deficit/hyperactivity disorder (ADHD) is increasingly diagnosed in adults. In this study we address the question whether there are impairments in recognition memory. In the present study 13 adults diagnosed with ADHD according to DSM-IV and 13 healthy controls were examined with respect to event-related potentials (ERPs) in a visual continuous word recognition paradigm to gain information about recognition memory effects in these patients. The amplitude of one attention-related ERP component, the N1, was significantly increased for the ADHD adults compared with the healthy controls in the occipital electrodes. The ERPs for the second presentation were significantly more positive than the ERPs for the first presentation. This effect did not significantly differ between groups. Neuronal activity related to an early attentional mechanism appears to be enhanced in ADHD patients. Concerning the early or the late part of the old/new effect ADHD patients show no difference which suggests that there are no differences with respect to recollection and familiarity-based recognition processes.