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The glutamate and γ-aminobutyric acid neuroreceptor subtypes mGluR

Currently, the metabotropic glutamate receptor 5 (mGluR5) is the subject of several lines of research in the context of neurology and is of high interest as a target for positron-emission tomography (PET). Here, we assessed the feasibility of using [11C]ABP688, a specific antagonist radiotracer for an allosteric site on the mGluR5, to evaluate changes in glutamatergic neurotransmission through a mismatch-negativity (MMN) task as a part of a simultaneous and synchronized multimodal PET/MR-EEG study. We analyzed the effect of MMN by comparing the changes in nondisplaceable binding potential (BPND) prior to (baseline) and during the task in 17 healthy subjects by applying a bolus/infusion protocol. Anatomical and functional regions were analyzed. A small change in BPND was observed in anatomical regions (posterior cingulate cortex and thalamus) and in a functional network (precuneus) after the start of the task. The effect size was quantified using Kendall’s W value and was 0.3. The motor cortex was used as a control region for the task and did not show any significant BPND changes. There was a significant ΔBPND between acquisition conditions. On average, the reductions in binding across the regions were - 8.6 ± 3.2% in anatomical and - 6.4 ± 0.5% in the functional network (p ≤ 0.001). Correlations between ΔBPND and EEG latency for both anatomical (p = 0.008) and functional (p = 0.022) regions were found. Exploratory analyses suggest that the MMN task played a role in the glutamatergic neurotransmission, and mGluR5 may be indirectly modulated by these changes.

Background Traumatic experiences tend to be preserved in altered biomarker profiles. These profiles can be traced back from cross-sectional data regarding the age of exposure. Consequently, the change across developmental stages, e.g. from childhood to adulthood, can also be reconstructed. This study introduces a backtrace procedure that is illustrated using white blood cell (WBC) counts in full / partial post-traumatic stress disorder (PTSD). The procedure was applied separately on men's and women's data to provide a replication of the analysis based on different subsamples. Methods The analysis was carried out with data from the CoLaus|PsyCoLaus study (N = 5111, 2370 men and 2741 women, age range 35-88 years). It was restricted to traumatic experiences that occurred until the age of 35, i.e., the lower age limit of the sample. The WBC counts from up to two assessments were standardized, pooled and assigned to the reported age of trauma exposure. This resulted in age series for each marker, whereas the reference values were based on subjects who did not experience any trauma exposure. The backtrace procedure ascertained the peaks and troughs of the age series and determined the best-fitting critical age range surrounding each peak or trough based on the best p-value from simple t-tests. Results In CoLaus|PsyCoLaus, 750 participants reported trauma exposure until the age of 35, and 86 (out of 329 ) men and 187 (out of 421) women thereof were coded with a full or partial PTSD. Full / partial PTSD after trauma exposure in childhood was characterized by increased WBC counts (lymphocytes, eosinophils – in women also neutrophils). This pattern was partly retained during adolescence, in men due to eosinophils counts and in women due to lymphocyte counts. For exposure in young adulthood, the deviations were in the negative direction – in men with decreased basophils, in women with decreased lymphocytes and monocytes. Conclusions Summarizing, the backtrace approach revealed WBC profiles in PTSD that were specific to particular developmental age stages. The strongest persistent upregulation of the immune system related to trauma exposure was traceable to childhood / early adolescence both in men and in women. Further research will show which biomarkers are similarly suitable for backtracing as WBC counts. As in PTSD, the backtrace approach could also be applied to identifying persistent biomarker profiles in other mental disorders, as well as autoimmune and other chronic diseases.

Translational Psychiatry 11(1), 60 (2021). doi:10.1038/s41398-020-01160-2, Published by Nature Publishing Group, London

The symbiosis of neuronal activities and glucose energy metabolism is reflected in the generation of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) signals. However, their association with the balance between neuronal excitation and inhibition (E/I-B), which is closely related to the activities of glutamate and GABA (γ -aminobutyric acid) and the receptor availability (RA) of GABAA and mGluR5, remains unexplored. This study investigates these associations during the resting state (RS) condition using simultaneously recorded PET/MR/EEG (trimodal) data. Glucose metabolism and neuroreceptor binding availability (non-displaceable binding potential (BPND)) of GABAA and mGluR5 were found to be significantly higher and closely linked within core resting-state networks (RSNs). The neuronal generators of EEG microstates and the fMRI measures were most tightly associated with the BPND of GABAA relative to mGluR5 BPND and the glucose metabolism, emphasising a predominance of inhibitory processes within in the core RSNs at rest.

Simultaneous PET/MR/EEG (Positron Emission Tomography – Magnetic Resonance – Electroencephalography), a new tool for the investigation of neuronal networks in the human brain, is presented here within the framework of the European Union Project TRIMAGE. The trimodal, cost-effective PET/MR/EEG imaging tool makes use of cutting edge technology both in PET and in MR fields. A novel type of magnet (1.5T, non-cryogenic) has been built together with a PET scanner that makes use of the most advanced photodetectors (i.e., SiPM matrices), scintillators matrices (LYSO) and digital electronics. The combined PET/MR/EEG system is dedicated to brain imaging and has an inner diameter of 260 mm and an axial Field-of-View of 160 mm.It enables the acquisition and assessment of molecular metabolic information with high spatial and temporal resolution in a given brain simultaneously. The dopaminergic system and the glutamatergic system in schizophrenic patients are investigated via PET, the same physiological/pathophysiological conditions with regard to functional connectivity, via fMRI, and its electrophysiological signature via EEG. In addition to basic neuroscience questions addressing neurovascular-metabolic coupling, this new methodology lays the foundation for individual physiological and pathological fingerprints for a wide research field addressing healthy aging, gender effects, plasticity and different psychiatric and neurological diseases.The preliminary performances of two components of the imaging tool (PET and MR) are discussed. Initial results of the search of possible candidates for suitable schizophrenia biomarkers are also presented as obtained with PET/MR systems available to the collaboration.

Gamma-aminobutyric acid (GABA) and glutamate are believed to have inhibitory and exhibitory neuromodulatory effects that regulate the brain's response to sensory perception. Furthermore, frequency-specific synchronization of neuronal excitability within the gamma band (30-80 Hz) is attributable to a homeostatic balance between excitation and inhibition. However, our understanding of the physiological mechanism underlying gamma rhythms is based on animal models. Investigations of the relationship between GABA concentrations, glutamate concentrations, and gamma band activity in humans were mostly restricted to the visual cortex and are conflicting. Here, we performed a multimodal imaging study combining magnetic resonance spectroscopy (MRS) with electroencephalography (EEG) in the auditory cortex. In 14 healthy subjects, we investigated the impact of individual differences in GABA and glutamate concentration on gamma band response (GBR) following auditory stimulus presentation. We explored the effects of bulk GABA on the GBR across frequency (30-200 Hz) and time (-200 to 600 ms) and found no significant relationship. Furthermore, no correlations were found between gamma peak frequency or power measures and metabolite concentrations (GABA, glutamate, and GABA/glutamate ratio). These findings suggest that, according to MRS measurements, and given the auditory stimuli used in this study, GABA and glutamate concentrations are unlikely to play a significant role in the inhibitory and excitatory drive in the generation of gamma band activity in the auditory cortex. Hum Brain Mapp 38:3975-3987, 2017. © 2017 Wiley Periodicals, Inc.

Neue Berufsbilder des Hausarztes und der Advanced Practice Nurse betreuen Pa­tienten im Tandem und bieten veranderte Betreuungsformen an. Patientenkonferenzen zu diesen Themen unterstutzen das gemeinsame Lernen und zeigen den Kompetenzenshift zwischen den Berufsbildern in der interprofessionellen Grundversorgung.

IEEE transactions on radiation and plasma medical sciences : ITRPFI 3(3), 377-385 (2019). doi:10.1109/TRPMS.2018.2886525, Published by IEEE, New York, NY

Stigma limits life opportunities of persons with mental illness. Self-stigma, the internalization of negative stereotypes, undermines empowerment and could hinder recovery. Here we examined self-stigma's effect on recovery among 222 disability pensioners with mental illness over 2 years, controlling for age, gender, symptoms and recovery at baseline measured by the Recovery Assessment Scale. More self-stigma at baseline was associated with a significant decrease in recovery after 1 year (not significant after 2 years). An increase of self-stigma from baseline to follow-up predicted less recovery 1 and 2 years later. Interventions that reduce self-stigma could therefore improve recovery.

Loudness dependence of auditory evoked potentials (LDAEP) is a widely used EEG-based biomarker for central serotonergic activity. Serotonin has been shown to be associated with different psychiatric disorders such as depression and schizophrenia. Despite its clinical significance, the underlying neurochemical mechanism of this promising marker is not fully understood, and further research is needed to improve its validity. Other neurotransmitters might have a significant impact on this measure. Thus, we assessed the inhibitory action through individual GABA/H20 concentrations and GABA/glutamate ratios by means of magnetic resonance spectroscopy at 3T in healthy subjects. The measurements were assessed in the primary auditory cortex to investigate the association with the LDAEP, whose generators are mainly in the primary auditory cortex. For the first time, this study examines the link between GABAergic neurotransmission and LDAEP, and the data preliminary show that GABA may not contribute to the generation of EEG-based LDAEP.

In den letzten zwei Jahrzehnten hat die Ausbreitung der biologischen Psychiatrie stark zugenommen. Mit der Moglichkeit, das Gehirn mit modernen technischen Methoden zu erforschen, schien es, als ob die sozialen Einflussfaktoren bei der Entwicklung psychischer Krankheiten ihre Bedeutung verlieren wurden. Tatsachlich scheint dies jedoch nicht gerechtfertigt zu sein. Es ist notwendig, diese Trennung zu uberwinden, indem soziale Faktoren bei der Entwicklung psychischer Erkrankungen in einen konzeptuellen Rahmen eingebunden werden, der gleichzeitig auch die Ergebnisse der aktuellen neurobiologischen Forschung berucksichtigt. Das Ziel dieser Ubersichtsarbeit ist es, den aktuellen Stand der sozialpsychiatrischen Forschung zusammenzufassen und die Perspektive der biologischen Grundlagen und deren Stichhaltigkeit in Bezug auf die soziale Dimension der Psychiatrie am Beispiel schizophrener Storungen hervorzuheben. Der Beitrag zeigt Chancen auf fur einen biosozialen Ansatz in der Sozialpsychiatrie und gibt einen Uberblick uber die aktuelle Literatur. Es gibt eine Fulle neurobiologischer Forschungsansatze, die eng mit sozialpsychiatrischen Themen wie der sozialen Kognition verbunden sind. Sozialpsychiatrie und biologische Psychiatrie sollten nicht langer als diametral entgegengesetzte Subdisziplinen verstanden werden. Vielmehr mussen die Chancen, die aus einer Synthese entstehen konnen, in Forschung und Klinik genutzt werden.

HintergrundIn den letzten zwei Jahrzehnten hat die Ausbreitung der biologischen Psychiatrie stark zugenommen. Mit der Möglichkeit, das Gehirn mit modernen technischen Methoden zu erforschen, schien es, als ob die sozialen Einflussfaktoren bei der Entwicklung psychischer Krankheiten ihre Bedeutung verlieren würden. Tatsächlich scheint dies jedoch nicht gerechtfertigt zu sein. Es ist notwendig, diese Trennung zu überwinden, indem soziale Faktoren bei der Entwicklung psychischer Erkrankungen in einen konzeptuellen Rahmen eingebunden werden, der gleichzeitig auch die Ergebnisse der aktuellen neurobiologischen Forschung berücksichtigt.Ziele und MethodenDas Ziel dieser Übersichtsarbeit ist es, den aktuellen Stand der sozialpsychiatrischen Forschung zusammenzufassen und die Perspektive der biologischen Grundlagen und deren Stichhaltigkeit in Bezug auf die soziale Dimension der Psychiatrie am Beispiel schizophrener Störungen hervorzuheben. Der Beitrag zeigt Chancen auf für einen biosozialen Ansatz in der Sozialpsychiatrie und gibt einen Überblick über die aktuelle Literatur.Ergebnisse und DiskussionEs gibt eine Fülle neurobiologischer Forschungsansätze, die eng mit sozialpsychiatrischen Themen wie der sozialen Kognition verbunden sind. Sozialpsychiatrie und biologische Psychiatrie sollten nicht länger als diametral entgegengesetzte Subdisziplinen verstanden werden. Vielmehr müssen die Chancen, die aus einer Synthese entstehen können, in Forschung und Klinik genutzt werden.

Erworben im Rahmen der Schweizer Nationallizenzen (http://www.nationallizenzen.ch), Mounting evidence supports the notion that personality is crucial in the aetiopathology of common mental disorders, but studies that allow for aetiological conclusions are lacking. The aim of the present study was thus to provide a test of the predisposition model. We analysed data from the Zurich Cohort Study, a 30-year longitudinal epidemiological community study of an adult cohort (n = 591) from 1979 to 2008. Personality was assessed in 1988 with an established personality questionnaire, and psychopathology through seven semi-structured interviews between 1979 and 2008. On the basis of personality assessment from 1988, used as predictor of subsequent psychopathology (1993-2008), while adjusting for sex and prior mental disorders (1979–1988), neuroticism related significantly with future major depression episodes [odds ratio (OR) = 1.41], anxiety disorders (OR = 1.32) and depression treatment use (OR = 1.41). When participants with a past 10-year history (i.e. 1979-1988) of either major depression, anxiety disorder or depression treatment use were excluded, neuroticism in 1988 still significantly predicted first incidence (i.e. 1993-2008) of major depression episodes (OR = 1.53) and depression treatment use (OR = 1.84). The present study provides compelling evidence that the personality trait of neuroticism constitutes an independent risk factor for subsequent major depression episodes and use of respective professional treatments, which serves as a proxy for particularly severe and impairing depression episodes. We therefore advocate that personality traits could provide clinically useful prognostic information when considered carefully.

Gamma‐aminobutyric acid (GABA) and glutamate are believed to have inhibitory and exhibitory neuromodulatory effects that regulate the brain's response to sensory perception. Furthermore, frequency‐specific synchronization of neuronal excitability within the gamma band (30–80 Hz) is attributable to a homeostatic balance between excitation and inhibition. However, our understanding of the physiological mechanism underlying gamma rhythms is based on animal models. Investigations of the relationship between GABA concentrations, glutamate concentrations, and gamma band activity in humans were mostly restricted to the visual cortex and are conflicting. Here, we performed a multimodal imaging study combining magnetic resonance spectroscopy (MRS) with electroencephalography (EEG) in the auditory cortex. In 14 healthy subjects, we investigated the impact of individual differences in GABA and glutamate concentration on gamma band response (GBR) following auditory stimulus presentation. We explored the effects of bulk GABA on the GBR across frequency (30–200 Hz) and time (−200 to 600 ms) and found no significant relationship. Furthermore, no correlations were found between gamma peak frequency or power measures and metabolite concentrations (GABA, glutamate, and GABA/glutamate ratio). These findings suggest that, according to MRS measurements, and given the auditory stimuli used in this study, GABA and glutamate concentrations are unlikely to play a significant role in the inhibitory and excitatory drive in the generation of gamma band activity in the auditory cortex. Hum Brain Mapp 38:3975–3987, 2017. © 2017 Wiley Periodicals, Inc.

An important aim in schizophrenia research is to optimize the prediction of psychosis and to improve strategies for early intervention. The objectives of this study were to explore neurocognitive performance in individuals at risk for psychosis and to optimize predictions through a combination of neurocognitive and psychopathological variables. Information on clinical outcomes after 24 months was available from 118 subjects who had completed an extensive assessment at baseline. Subjects who had converted to psychosis were compared with subjects who had not. Multivariate Cox regression analyses were used to determine which baseline measure best predicted a conversion to psychosis. The premorbid IQ and the neurocognitive domains of processing speed, learning/memory, working memory and verbal fluency significantly discriminated between converters and non-converters. When entered into multivariate regression analyses, the combination of PANSS positive/negative symptom severity and IQ best predicted the clinical outcomes. Our results confirm previous evidence suggesting moderate premorbid cognitive deficits in individuals developing full-blown psychosis. Overall, clinical symptoms appeared to be a more sensitive predictor than cognitive performance. Nevertheless, the two might serve as complementary predictors when assessing the risk for psychosis.

IntroductionThe aim of the FP7-European funded project TRIMAGE is to create a trimodal, cost-effective imaging tool consisting of PET/MR/EEG to enable effective early diagnosis of schizophrenia.ObjectiveIn the scope of this project we are interested in the multimodal assessment of response inhibition. The loudness dependence of auditory evoked potential (LDAEP) is a suitable biomarker of inhibitory action in signal processing. Variations in response inhibition can have great impact on different aspects of life. Individuals with reduced capability of inhibitory control have a tendency to impulsive behavior. Studies showed that they have stronger LDAEP values. Patients with schizophrenia may exhibit alterations in the responsiveness to sensory stimuli. Thus, a reduced LDAEP was found in these patients. However, these deviances differed in clinical features of the disorder. Therefore, we would like to further elucidate the relationship between multimodal neuroimaging methods and dimensions of symptoms, observable behavior, personality traits and general psychopathological dysfunction.MethodsA sample of 20 healthy controls and 20 patients with manifest schizophrenia will be examined with the LDAEP paradigm in a trimodal approach with customary imaging tools. PET measurements with the radiotracer [11C]-flumazenil will be used to assess the binding potentials of GABA-A receptors. MRS will provide data about GABA concentrations. Simultaneously recorded EEG-fMRI data will permit new insight in the relationship between LDAEP and impulsivity.DiscussionThe project will use alternative approaches to psychiatric classification. Response inhibition in sensory processing will be investigated from different angles (biochemical, neurophysiological, and neuroanatomical) and combined with psychological characteristic values.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Besides the influence of dopaminergic neurotransmission on negative symptoms in schizophrenia, there is evidence that alterations of serotonin (5-HT) system functioning also play a crucial role in the pathophysiology of these disabling symptoms. From post mortem and genetic studies on patients with negative symptoms a 5-HT dysfunction is documented. In addition atypical neuroleptics and some antidepressants improve negative symptoms via serotonergic action. So far no research has been done to directly clarify the association between the serotonergic functioning and the extent of negative symptoms. Therefore, we examined the status of brain 5-HT level in negative symptoms in schizophrenia by means of the loudness dependence of auditory evoked potentials (LDAEP). The LDAEP provides a well established and non-invasive in vivo marker of the central 5-HT activity. We investigated 13 patients with schizophrenia with predominant negative symptoms treated with atypical neuroleptics and 13 healthy age and gender matched controls with a 32-channel EEG. The LDAEP of the N1/P2 component was evaluated by dipole source analysis and single electrode estimation at Cz. Psychopathological parameters, nicotine use and medication were assessed to control for additional influencing factors. Schizophrenic patients showed significantly higher LDAEP in both hemispheres than controls. Furthermore, the LDAEP in the right hemisphere in patients was related to higher scores in scales assessing negative symptoms. A relationship with positive symptoms was not found. These data might suggest a diminished central serotonergic neurotransmission in patients with predominant negative symptoms.