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 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

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 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 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.

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-pituitaryadrenal (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.

Neurobiological aspects of synaesthesia are discussed from the perspective of the broader philosophical topic of “syn-aisthesis” and the basic fundamentals of a neuropsychological understanding of perceptual inter-modal integration. Herein, the predominance of conceptualization processes in regard to top-down functions of the brain appears as a prerequisite for perception. Functional Magnet Resonance Imaging (fMRI) data of synaesthetes compared to controls are discussed, providing evidence for the theory that prefrontal and parietal conceptualization processes by themselves exert transmodal functions and thus contain properties of “binding”. A partial hyperactivity of such processes in synaesthesia may thus be a causal factor of this condition.

The group of schizophrenia disorders affects approximately 1% of the population and has both genetic and environmental etiologies. Sufferers report various behavioral abnormalities including hallucinations and delusions (positive symptoms), reduced joy and amotivation (negative symptoms), plus inattention and poor learning (cognitive deficits). Despite the heterogeneous symptoms experienced, most patients smoke. The self-medication hypothesis posits that patients smoke to alleviate symptoms, consistent with evidence for nicotine-induced enhancement of cognition. While nicotine acts on multiple nicotinic acetylcholine receptors (nAChRs), the primary target of research is often the homomeric α7 nAChR. Given genetic linkages between schizophrenia and this receptor, its association with P50 sensory gating deficits, and its reduced expression in post-mortem brains, many have attempted to develop α7 nAChR ligands for treating schizophrenia. Recent evidence that ligands can be orthosteric agonists or positive allosteric modulators (PAMs) has revitalized the hope for treatment discovery. Herein, we present evidence regarding: (1) pathophysiological alterations of α7 nAChRs that might occur in patients; (2) mechanistic evidence for the normal action of α7 nAChRs; (3) preclinical studies using α7 nAChR orthosteric agonists and type I/II PAMs; and (4) where successful translational testing has occurred for particular compounds, detailing what is still required. We report that the accumulating evidence is positive, but that greater work is required using positron emission tomography to understand current alterations in α7 nAChR expression and their relationship to symptoms. Finally, cross-species behavioral tasks should be used more regularly to determine the predictive efficacy of treatments.

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.

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.

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.

The Binocular Depth Inversion Test (BDIT) measures a common illusion of visual perception whereby implausible objects are seen as normal, e.g., a hollow face is perceived as a normal, convex face. Such inversion is frequent, especially for objects with a high degree of familiarity. Under normal conditions, cognitive factors apparently override the binocular disparity cues of stereopsis. This internal mechanism of censorship of perception, which balances top-down and bottom-up processes of perception to come to a cognitive coherence, which is congruent to previous experience and concepts, appears to be disturbed in (pro-)psychotic states. The BDIT has been shown to be a sensitive measure of impaired higher visual processing and conceptual cognition common to conditions including schizophrenia, cannabinoid-intoxication, and sleep deprivation but not depression. In this pilot study, we tested the performance of patients with anxiety disorders (ICD-10 F40 and F41) compared to matched controls using the BDIT paradigm. Anxiety patients scored significantly higher on the BDIT than controls, in a range comparable to propsychotic conditions. The findings suggest that anxiety patients could have abnormalities in central perceptual processing, top-down processing (conceptual cognition), and reality testing similar to (pro-)psychotic conditions. Implications of these findings are discussed in relation to therapeutic interventions with anxiety disorders.

It is known from clinical studies that some patients attempt to cope with the symptoms of post‐traumatic stress disorder (PTSD) by using recreational drugs. This review presents a case report of a 19‐year‐old male patient with a spectrum of severe PTSD symptoms, such as intense flashbacks, panic attacks, and self‐mutilation, who discovered that some of his major symptoms were dramatically reduced by smoking cannabis resin. The major part of this review is concerned with the clinical and preclinical neurobiological evidence in order to offer a potential explanation of these effects on symptom reduction in PTSD. This review shows that recent studies provided supporting evidence that PTSD patients may be able to cope with their symptoms by using cannabis products. Cannabis may dampen the strength or emotional impact of traumatic memories through synergistic mechanisms that might make it easier for people with PTSD to rest or sleep and to feel less anxious and less involved with flashback memories. The presence of endocannabinoid signalling systems within stress‐sensitive nuclei of the hypothalamus, as well as upstream limbic structures (amygdala), point to the significance of this system for the regulation of neuroendocrine and behavioural responses to stress. Evidence is increasingly accumulating that cannabinoids might play a role in fear extinction and antidepressive effects. It is concluded that further studies are warranted in order to evaluate the therapeutic potential of cannabinoids in PTSD. Copyright © 2012 John Wiley & Sons, Ltd.

Despite some principal similarities, there is no systematic comparison between the different types of synesthesia (genuine, acquired and drug-induced). This comprehensive review compares the three principal types of synesthesia and focuses on their phenomenological features and their relation to different etiological models. Implications of this comparison for the validity of the different etiological models are discussed. Comparison of the three forms of synesthesia show many more differences than similarities. This is in contrast to their representation in the literature, where they are discussed in many respects as being virtually similar. Noteworthy is the much broader spectrum and intensity with the typical drug-induced synesthesias compared to genuine and acquired synesthesias. A major implication of the phenomenological comparison in regard to the etiological models is that genuine and acquired synesthesias point to morphological substrates, while drug-induced synesthesia appears to be based on functional changes of brain activity.

Synesthesia is a condition in which stimulation in one processing stream (e.g., letters or music) leads to perception in an unstimulated processing stream (e.g., colors). Behavioral differences in mutisensory processing have been shown for multimodal illusions, but the differences in neural processing are still unclear. In the present study, we examined uni- and multimodal processing in 14 people with synesthesia and 13 controls using EEG recordings and a simple detection task. Stimuli were either presented acoustically, visually or multimodaly (simultaneous visual and auditory stimulation). In the multimodal condition, auditory and visual stimuli were either matching or mismatching (e.g., a lion either roaring or ringing). The subjects had to press a button as soon as something was presented visually or acoustically. Results: ERPs revealed occipital group differences in the negative amplitude between 100 and 200 ms after stimulus presentation. Relative to controls, synesthetes showed an increased negative component peaking around 150 ms. This group difference is found in all visual conditions. Unimodal acoustical stimulation leads to increased negative amplitude in synesthetes in the same time window over parietal and visual electrodes. Overall this shows that processing in the occipital lobe is different in synesthetes independent of the stimulated modality. In addition, differences in the negative amplitude between processing of incongruent and congruent multimodal stimuli could be detected in the same time window between synesthetes and controls over left frontal sites. This shows that also multimodal integration processes are different in synesthetes.

In synaesthesia certain external stimuli (e.g., music) trigger automatically internally generated sensations (e.g., colour). Results of behavioural investigations indicate that multisensory processing works differently in synaesthetes. However, the reasons for these differences and the underlying neural correlates remain unclear. The aim of the current study was to investigate if synaesthetes show differences in electrophysiological components of multimodal processing. Further we wanted to test synaesthetes for an enhanced distractor filtering ability in multimodal situations. Therefore, line drawings of animals and objects were presented to participants, either with congruent (typical sound for presented picture, e.g., picture of bird together with chirp), incongruent (picture of bird together with gun shot) or without simultaneous auditory stimulation. 14 synaesthetes (auditory–visual and grapheme-colour synaesthetes) and 13 controls participated in the study. We found differences in the event-related potentials between synaesthetes and controls, indicating an altered multisensory processing of bimodal stimuli in synaesthetes in competition situations. These differences were especially found over frontal brain sites. An interaction effect between group (synaesthetes vs. controls) and stimulation (unimodal visual vs. congruent multimodal) could not be detected. Therefore we conclude that multisensory processing works in general similar in synaesthetes and controls and that only specifically integration processes in multisensory competition situations are altered in synaesthetes.

It has been suggested that synaesthesia is the result of a hyper-sensitive multimodal binding-mechanism. To address the question whether multi-modal integration is altered in synaesthetes in general, grapheme-colour and auditory-visual synaesthetes were studied using the double-flash illusion. This illusion is induced by a single light flash presented together with multiple beep sounds, which is then perceived as multiple flashes. By varying the separation of auditory and visual stimuli, the hypothesis of a widened temporal window of audio-visual integration in synaesthetes was tested. As hypothesised, the results show differences between synaesthetes and controls concerning multisensory integration, but surprisingly other than expected synaesthetes perceive a reduced number of illusions and have a smaller time-window of audio-visual integration compared to controls. This indicates that they do not have a hyper-sensitive binding mechanism. On the contrary, synaesthetes seem to integrate even less than controls between vision and audition.

Recent research suggests synesthesia as a result of a hypersensitive multimodal binding mechanism. To address the question whether multimodal integration is altered in synesthetes in general, grapheme-colour and auditory-visual synesthetes were investigated using speech-related stimulation in two behavioural experiments. First, we used the McGurk illusion to test the strength and number of illusory perceptions in synesthesia. In a second step, we analysed the gain in speech perception coming from seen articulatory movements under acoustically noisy conditions. We used disyllabic nouns as stimulation and varied signal-to-noise ratio of the auditory stream presented concurrently to a matching video of the speaker. We hypothesized that if synesthesia is due to a general hyperbinding mechanism this group of subjects should be more susceptible to McGurk illusions and profit more from the visual information during audiovisual speech perception. The results indicate that there are differences between synesthetes and controls concerning multisensory integration--but in the opposite direction as hypothesized. Synesthetes showed a reduced number of illusions and had a reduced gain in comprehension by viewing matching articulatory movements in comparison to control subjects. Our results indicate that rather than having a hypersensitive binding mechanism, synesthetes show weaker integration of vision and audition.

OBJECTIVE:Attention-deficit/hyperactivity disorder (ADHD) is increasingly diagnosed in adults. In this study we address the question whether there are impairments in recognition memory.METHODS: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.RESULTS: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.CONCLUSION: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.

Color percept induction in synaesthetes by hearing words was previously shown to involve activation of visual and specifically color processing cortex areas. While this provides a rationale for the origin of the anomalous color percept the question of mechanism of this crossmodal activation remains unclear. We pursued this question with fMRI in color hearing synaesthetes by exposing subjects to words and tones. Brain activations in word condition accompanied by highly reliable color percepts were compared with activations in tone condition with only occasional color percepts and both contrasted to activations in normal subjects under the same stimulus conditions. This revealed that already the tone condition similar to the word condition caused abnormally high activations in various cortical areas even though synaesthetic percepts were more rare. Such tone activations were significantly larger than in normal subjects in visual areas of the right occipital lobe, the fusiform gyrus, and the left middle temporal gyrus and in auditory areas of the left superior temporal gyrus. These auditory areas showed strong word and tone activation alike and not the typically lower tone than word activation in normal subjects. Taken together these results are interpreted in favour of the disinhibited feedback hypothesis as the neurophysiological basis of genuine synaesthesia.