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Purpose Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. Method A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). Results Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. Discussion This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

The application of Deep Learning (DL) for medical diagnosis is often hampered by two problems. First, the amount of training data may be scarce, as it is limited by the number of patients who have acquired the condition to be diagnosed. Second, the training data may be corrupted by various types of noise. Here, we study the problem of brain tumor detection from magnetic resonance spectroscopy (MRS) data, where both types of problems are prominent. To overcome these challenges, we propose a new method for training a deep neural network that distills particularly representative training examples and augments the training data by mixing these samples from one class with those from the same and other classes to create additional training samples. We demonstrate that this technique substantially improves performance, allowing our method to reach human-expert-level accuracy with just a few thousand training examples. Interestingly, the network learns to rely on features of the data that are usually ignored by human experts, suggesting new directions for future research., Submitted to IEEE Transactions on Neural Networks and Learning Systems

European journal of nuclear medicine and molecular imaging 48(6), 1956-1965 (2020). doi:10.1007/s00259-020-05114-0, Published by Springer-Verl., Heidelberg [u.a.]

Abnormal gamma-band oscillations (GBO) have been frequently associated with the pathophysiology of schizophrenia. GBO are modulated by glutamate, a neurotransmitter, which is continuously discussed to shape the complex symptom spectrum in schizophrenia. The current study examined the effects of ketamine, a glutamate N-methyl-d-aspartate receptor (NMDAR) antagonist, on the auditory-evoked gamma-band response (aeGBR) and psychopathological outcomes in healthy volunteers to investigate neuronal mechanisms of psychotic behavior. In a placebo-controlled, randomized crossover design, the aeGBR power, phase-locking factor (PLF) during a choice reaction task, the Positive and Negative Syndrome Scale (PANSS) and the Altered State of Consciousness (5D-ASC) Rating Scale were assessed in 25 healthy subjects. Ketamine was applied in a subanaesthetic dose. Low-resolution brain electromagnetic tomography was used for EEG source localization. Significant reductions of the aeGBR power and PLF were identified under ketamine administration compared to placebo (p

Background Structural magnetic resonance imaging (MRI) is routinely performed in patients with mild cognitive impairment (MCI), but diagnostic accuracy to detect early cerebral atrophy is limited. Objective To validate the visual entorhinal cortex atrophy (ERICA) rating scale regarding diagnosis, biomarker status, neuropsychological profile, and dementia risk in MCI. Methods The ERICA score was retrospectively assessed regarding its discrimination of MCI (n = 80) from subjective cognitive decline and Alzheimer's disease (AD) dementia (n = 60, respectively), its prediction of conversion to dementia (median follow-up 28 months) and amyloid/tau biomarker status, and its association with neuropsychological tests. Results The ERICA score achieved 97% positive predictive value (PPV) for the presence of MCI. Discrimination between MCI and AD dementia (area under the curve: 0.71) was comparable to volumetry, and superior to the medial temporal lobe atrophy (MTA) score (p = 0.006). The PPV of the ERICA score for conversion to dementia was 83%, equivalent to tau status. It achieved 90% PPV for conversion when combined with tau, and 100% negative predictive value with verbal recall. While no measure predicted the predominantly positive amyloid status, the ERICA score was at least comparable to volumetry, and superior to the MTA score in predicting tau positivity (92% PPV for phospho-tau). The ERICA score was associated with verbal learning and memory, and, unlike the MTA score, also with AD-specific deficits in cued verbal recall. Conclusion The ERICA score is a simple and valuable tool to exploit structural MRI for diagnosis and prognosis in MCI and is non-inferior to volumetry.

Background: Targeting the N-methyl-d-aspartate receptor (NMDAR) is a major translational approach for treating negative symptoms of schizophrenia. Ketamine comprehensively produces schizophrenia-like symptoms, such as positive, cognitive and negative symptoms in healthy volunteers. The amplitude of the mismatch negativity (MMN) is known to be significantly reduced not only in patients with schizophrenia, but also in healthy controls receiving ketamine. Accordingly, it was the aim of the present study to investigate whether changes of MMN amplitudes during ketamine administration are associated with the emergence of schizophrenia-like negative symptoms in healthy volunteers. Methods: We examined the impact of ketamine during an MMN paradigm with 64-channel electroencephalography (EEG) and assessed the psychopathological status using the Positive and Negative Syndrome Scale (PANSS) in healthy male volunteers using a single-blind, randomized, placebo-controlled crossover design. Low-resolution brain electromagnetic tomography was used for source localization. Results: Twenty-four men were included in our analysis. Significant reductions of MMN amplitudes and an increase in all PANSS scores were identified under the ketamine condition. Smaller MMN amplitudes were specifically associated with more pronounced negative symptoms. Source analysis of MMN generators indicated a significantly reduced current source density (CSD) under the ketamine condition in the primary auditory cortex, the posterior cingulate and the middle frontal gyrus. Limitations: The sample included only men within a tight age range of 20–32 years. Conclusion: The MMN might represent a biomarker for negative symptoms in schizophrenia related to an insufficient NMDAR system and could be used to identify patients with schizophrenia with negative symptoms due to NMDAR dysfunction.

Ciguatera fish poisoning (CFP) is the most common seafood toxin poisoning worldwide, caused by the consumption of reef fish contaminated with ciguatoxin (CTX).1 The neurotoxin is produced by specific microalgae termed dinoflagellates in shallow (sub-) tropical waters and from there transmitted through the food chain. CFP is characterized by variable gastrointestinal, cardiac, and neurologic symptoms, the latter typically comprising sensory disturbances such as hypoesthesia and paresthesia, cold allodynia, and myalgia. Headache, vertigo, ataxia, impaired consciousness, and cognitive problems are other facultative symptoms. Diagnosis of CFP is usually based on clinical grounds and exclusion. Despite the CNS being a major target of the toxin, only a few studies reported abnormal MRI findings so far.

Auditory verbal hallucinations (AVH) are a common positive symptom of schizophrenia. Excitatory-to-inhibitory (E/I) imbalance related to disturbed N-methyl-D-aspartate receptor (NMDAR) functioning has been suggested as a possible mechanism underlying altered connectivity and AVH in schizophrenia. The current study examined the effects of ketamine, a NMDAR antagonist, on glutamate-related mechanisms underlying interhemispheric gamma-band connectivity, conscious auditory perception during dichotic listening (DL), and the emergence of auditory verbal distortions and hallucinations (AVD/AVH) in healthy volunteers. In a single-blind, pseudo-randomized, placebo-controlled crossover design, nineteen male, right-handed volunteers were measured using 64 channel electroencephalography (EEG). Psychopathology was assessed with the PANSS interview and the 5D-ASC questionnaire, including a subscale to detect auditory alterations with regard to AVD/AVH (AUA-AVD/AVH). Interhemispheric connectivity analysis was performed using eLORETA source estimation and lagged phase synchronization (LPS) in the gamma-band range (30-100 Hz). Ketamine induced positive symptoms such as hallucinations in a subgroup of healthy subjects. In addition, interhemispheric gamma-band connectivity was found to be altered under ketamine compared to placebo, and subjects with AUA-AVD/AVH under ketamine showed significantly higher interhemispheric gamma-band connectivity than subjects without AUA-AVD/AVH. These findings demonstrate a relationship between NMDAR functioning, interhemispheric connectivity in the gamma-band frequency range between bilateral auditory cortices and the emergence of AVD/AVH in healthy subjects. The result is in accordance with the interhemispheric miscommunication hypothesis of AVH and argues for a possible role of glutamate in AVH in schizophrenia.

The beneficial effects of placebo treatments on fear and anxiety (placebo anxiolysis) are well known from clinical practice, and there is strong evidence indicating a contribution of treatment expectations to the efficacy of anxiolytic drugs. Although clinically highly relevant, the neural mechanisms underlying placebo anxiolysis are poorly understood. In two studies in humans, we tested whether the administration of an inactive treatment along with verbal suggestions of anxiolysis can attenuate experimentally induced states of phasic fear and/or sustained anxiety. Phasic fear is the response to a well defined threat and includes attentional focusing on the source of threat and concomitant phasic increases of autonomic arousal, whereas in sustained states of anxiety potential and unclear danger requires vigilant scanning of the environment and elevated tonic arousal levels. Our placebo manipulation consistently reduced vigilance measured in terms of undifferentiated reactivity to salient cues (indexed by subjective ratings, skin conductance responses and EEG event-related potentials) and tonic arousal [indexed by cue-unrelated skin conductance levels and enhanced EEG alpha (8–12 Hz) activity], indicating a downregulation of sustained anxiety rather than phasic fear. We also observed a placebo-dependent sustained increase of frontal midline EEG theta (4–7 Hz) power and frontoposterior theta coupling, suggesting the recruitment of frontally based cognitive control functions. Our results thus support the crucial role of treatment expectations in placebo anxiolysis and provide insight into the underlying neural mechanisms.

Our understanding of the neural correlates of auditory-verbal-hallucinations (AVH) has substantially increased during the last few years, but is far from sufficient. One current hypothesis, the interhemispheric miscommunication theory, is based on findings from fMRI, DTI and EEG, but there is only limited evidence so far concerning underlying functional coupling mechanisms. Here we report a 64-channel EEG study using lagged phase synchronization analysis and eLORETA source estimation to examine the functional connectivity between bilateral auditory cortices in the gamma-band in 26 schizophrenia patients (13 with and 13 without AVH) and 26 matched healthy controls (HC) while performing a dichotic listening task. We found a significantly reduced right-ear-advantage (REA) in AVH but not in non-AVH patients compared to HC. The major finding was significantly stronger gamma-band connectivity between bilateral auditory cortices during conscious perception of left (versus right) ear syllables in patients with AVH compared to HC and patients without AVH. A significant positive correlation was found between this connectivity alteration and the AVH symptom score in schizophrenia patients. These findings provide further support for the interhemispheric miscommunication hypothesis of AVH pathophysiology by indicating that aberrant gamma-band coupling between auditory cortices is related to the emergence of AVH in schizophrenia.

Background: Schizophrenia has long been suggested to represent a disorder with prominent neural dysconnectivity. Gamma-band oscillations are highly relevant in this context, due both to their proposed involvement in neuronal synchronization and to their association with neurotransmitter systems relevant for schizophrenia. Several task-related studies have confirmed reduced power and synchronization of gamma-band oscillations in schizophrenia, but it has been suggested that these findings might not apply to the resting state. The present study aimed to investigate resting-state gamma-band connectivity in patients with schizophrenia. Methods: Sixty-four channel resting-state electroencephalography (eyes closed) was recorded in 22 patients with first-episode schizophrenia and 22 healthy controls matched for age and gender. Orthogonalized power envelope correlation was used as a measure of connectivity across 80 cortical regions at 40 Hz. Mean connectivity at each region was compared across groups using the nonparametric randomization approach. Additionally, the network-based statistic was applied to identify affected networks in patients. Results: Patients displayed increased mean functional gamma-band connectivity compared to controls in the left rolandic operculum. Network-based analyses indicated increased connectivity in patients within a strongly lateralized network consisting mainly of left inferior frontal/orbitofrontal, lateral and medial temporal, and inferior parietal areas. Within this network, gamma-band connectivity was higher in patients with low positive and disorganization symptom levels. Conclusions: The present study provides a link between resting-state gamma-band connectivity and the core symptoms of schizophrenia. The observed findings are different than those reported by task-related studies, suggesting that resting-state studies might reveal new aspects in the pathophysiology of schizophrenia.

Objectives. Gamma-band oscillations (e.g., the early auditory evoked gamma-band response, aeGBR) have been suggested to mediate cognitive and perceptual processes by driving the synchronization of local neuronal populations. Reduced aeGBR is a consistent finding in patients with schizophrenia and high-risk subjects, and has been proposed to represent an endophenotype for the illness. However, it is still unclear whether this reduction represents a deficit in sensory or cognitive processes, or a combination of the two. The present study investigated this question by manipulating the difficulty of an auditory reaction task in patients with first-episode schizophrenia and healthy controls. Methods. A 64-channel EEG was recorded in 23 patients with first-episode schizophrenia and 22 healthy controls during two conditions of an auditory reaction task: an easy condition that merely required low-level vigilance, and a difficult condition that placed significant demands on attention and working memory. Results. In contrast to healthy controls, patients failed to increase aeGBR power and phase-locking in the difficult condition. In patients, aeGBR power and phase-locking indices were associated with working memory deficits. Conclusions. The observed results confirm the applicability of aeGBR disturbances as a stable endophenotype of schizophrenia, and suggest a cognitive, rather than sensory, deficit at their origin.

Background: High frequency oscillations in the gamma range are known to be involved in early stages of auditory information processing in terms of synchronization of brain regions, e.g., in cognitive functions. It has been shown using EEG source localisation, as well as simultaneously recorded EEG-fMRI, that the auditory evoked gamma-band response (aeGBR) is modulated by attention. In addition to auditory cortex activity a dorsal anterior cingulate cortex (dACC) generator could be involved. In the present study we investigated aeGBR magnetic fields using magnetoencephalography (MEG). We aimed to localize the aeGBR sources and its connectivity features in relation to mental effort. Methods: We investigated the aeGBR magnetic fields in 13 healthy participants using a 275-channel CTF-MEG system. The experimental paradigms were two auditory choice reaction tasks with different difficulties and demands for mental effort. We performed source localization with eLORETA and calculated the aeGBR lagged phase synchronization between bilateral auditory cortices and frontal midline structures. Results: The eLORETA analysis revealed sources of the aeGBR within bilateral auditory cortices and in frontal midline structures of the brain including the dACC. Compared to the control condition the dACC source activity was found to be significantly stronger during the performance of the cognitively demanding task. Moreover, this task involved a significantly stronger functional connectivity between auditory cortices and dACC. Conclusion: In accordance with previous EEG and EEG-fMRI investigations, our study confirms an aeGBR generator in the dACC by means of MEG and suggests its involvement in the effortful processing of auditory stimuli.

Background Disturbed functional connectivity is assumed to underlie neurocognitive deficits in patients with schizophrenia. As neurocognitive deficits are already present in the high-risk state, identification of the neural networks involved in this core feature of schizophrenia is essential to our understanding of the disorder. Resting-state studies enable such investigations, while at the same time avoiding the known confounder of impaired task performance in patients. The aim of the present study was to investigate EEG resting-state connectivity in high-risk individuals (HR) compared to first episode patients with schizophrenia (SZ) and to healthy controls (HC), and its association with cognitive deficits. Methods 64-channel resting-state EEG recordings (eyes closed) were obtained for 28 HR, 19 stable SZ, and 23 HC, matched for age, education, and parental education. The imaginary coherence-based multivariate interaction measure (MIM) was used as a measure of connectivity across 80 cortical regions and six frequency bands. Mean connectivity at each region was compared across groups using the non-parametric randomization approach. Additionally, the network-based statistic was applied to identify affected networks in patients. Results SZ displayed increased theta-band resting-state MIM connectivity across midline, sensorimotor, orbitofrontal regions and the left temporoparietal junction. HR displayed intermediate theta-band connectivity patterns that did not differ from either SZ or HC. Mean theta-band connectivity within the above network partially mediated verbal memory deficits in SZ and HR. Conclusions Aberrant theta-band connectivity may represent a trait characteristic of schizophrenia associated with neurocognitive deficits. As such, it might constitute a promising target for novel treatment applications.

While the role of synchronized oscillatory activity in the gamma-band frequency range for conscious perception is well established in the visual domain, there is limited evidence concerning neurophysiological mechanisms in conscious auditory perception. In the current study, we addressed this issue with 64-channel EEG and a dichotic listening (DL) task in twenty-five healthy participants. The typical finding of DL is a more frequent conscious perception of the speech syllable presented to the right ear (RE), which is attributed to the supremacy of the contralateral pathways running from the RE to the speech-dominant left hemisphere. In contrast, the left ear (LE) input initially accesses the right hemisphere and needs additional transfer via interhemispheric pathways before it is processed in the left hemisphere. Using lagged phase synchronization (LPS) analysis and eLORETA source estimation we examined the functional connectivity between right and left primary and secondary auditory cortices in the main frequency bands (delta, theta, alpha, beta, gamma) during RE/LE-reports. Interhemispheric LPS between right and left primary and secondary auditory cortices was specifically increased in the gamma-band range, when participants consciously perceived the syllable presented to the LE. Our results suggest that synchronous gamma oscillations are involved in interhemispheric transfer of auditory information.

Introduction Resting-state EEG microstates are thought to reflect the momentary local states and interactions of distributed neural networks in the brain. Several changes in resting-state EEG microstates have been described in acutely ill patients with schizophrenia, but it is not known whether these represent trait or state abnormalities. The present study aimed to investigate this issue by assessing EEG microstate characteristics in high-risk individuals (HR) and clinically stable first-episode patients with schizophrenia (SZ) with low symptom levels, compared to each other and healthy controls (HC). Method Participants were 18 HR, 18 SZ, and 22 HC subjects. 64-channel resting-state EEG recordings were used for microstate analyses. Microstates were clustered into four classes (A–D) according to their topography. Temporal parameters and topographies of microstates were compared among groups. Results Microstate class A displayed higher coverage and occurrence in HR than SZ and HC, while microstate class B covered significantly more time in SZ compared to both HR and HC. Microstate class B displayed an aberrant spatial configuration in SZ, and to a lesser extent also in HR, compared to HC, with patients exhibiting significantly higher activity in the vicinity of the left posterior cingulate. Discussion Microstate abnormalities observed in HR were similar to those previously reported in acutely ill patients with schizophrenia. Moreover, there was evidence that HR and SZ might share specific disturbances in brain functional connectivity. These findings raise the possibility that certain abnormalities in resting-state EEG microstates might be associated with an increased risk for psychosis.

Objectives. Abnormalities of oscillatory gamma activity are supposed to reflect a core pathophysiological mechanism underlying cognitive disturbances in schizophrenia. The auditory evoked gamma-band response (aeGBR) is known to be reduced across all stages of the disease. The present study aimed to elucidate alterations of an aeGBR-specific network mediated by gamma oscillations in the high-risk state of psychosis (HRP) by means of functional magnetic resonance imaging (fMRI) informed by electroencephalography (EEG). Methods. EEG and fMRI were simultaneously recorded from 27 HRP individuals and 26 healthy controls (HC) during performance of a cognitively demanding auditory reaction task. We used single trial coupling of the aeGBR with the corresponding blood oxygen level depending response (EEG-informed fMRI). Results. A gamma-band–specific network was significantly lower active in HRP subjects compared with HC (random effects analysis, P < .01, Bonferroni-corrected for multiple comparisons) accompanied by a worse task performance. This network involved the bilateral auditory cortices, the thalamus and frontal brain regions including the anterior cingulate cortex, as well as the bilateral dorsolateral prefrontal cortex. Conclusions. For the first time we report a reduced activation of an aeGBR-specific network in HRP subjects brought forward by EEG-informed fMRI. Because the HRP reflects the clinical risk for conversion to psychotic disorders including schizophrenia and the aeGBR has repeatedly been shown to be altered in patients with schizophrenia the results of our study point towards a potential applicability of aeGBR disturbances as a marker for the prediction of transition of HRP subjects to schizophrenia.