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Tobias Kalisch,1,2,* Jan-Christoph Kattenstroth,2,* Rebecca Kowalewski,2 Martin Tegenthoff,1 Hubert R Dinse21Department of Neurology, BG-Kliniken Bergmannsheil, Ruhr-University Bochum, Bochum, Germany; 2Neural Plasticity Lab, Institute for Neuroinformatics, Ruhr-University Bochum, Bochum, Germany*These authors contributed equally to this workAbstract: Age-related changes in lower limb joint position sense and their contributions to postural stability are well documented. In contrast, only a few studies have investigated the effect of age on proprioceptive hand function. Here, we introduce a novel test for measuring joint position sense in the fingers of the human hand. In a concurrent matching task, subjects had to detect volume differences between polystyrene balls grasped with their dominant (seven test stimuli: 126–505 cm3) and their nondominant hand (three reference stimuli: 210, 294, and 505 cm3). A total of 21 comparisons were performed to assess the number of errors, the weight of errors (ie, the volume difference between test and reference stimuli), and the direction of errors (ie, over- or underestimation of test stimulus). The test was applied to 45 healthy subjects aged 21 to 79 years. Our results revealed that all variables changed significantly with age, with the number of errors showing the strongest increase. We also assessed tactile acuity (two-point discrimination thresholds) and sensorimotor performance (pegboard performance) in a subset of subjects, but these scores did not correlate with joint position sense performance, indicating that the test reveals specific information about joint position sense that is not captured with pure sensory or motor tests. The average test–retest reliability assessed on 3 consecutive days was 0.8 (Cronbach's alpha). Our results demonstrate that this novel test reveals age-related decline in joint position sense acuity that is independent from sensorimotor performance.Keywords: aging, hand functions, joint position sense

Abstract Background The aim of this study was to examine the relationship between chronic neuropathic pain after incomplete peripheral nerve lesion, chronic nociceptive pain due to osteoarthritis, and the excitability of the motor cortex assessed by transcranial magnetic stimulation (TMS). Hence in 26 patients with neuropathic pain resulting from an isolated incomplete lesion of the median or ulnar nerve (neuralgia), 20 patients with painful osteoarthritis of the hand, and 14 healthy control subjects, the excitability of the motor cortex was tested using paired-pulse TMS to assess intracortical inhibition and facilitation. These excitability parameters were compared between groups, and the relationship between excitability parameters and clinical parameters was examined. Results We found a significant reduction of intracortical inhibition in the hemisphere contralateral to the lesioned nerve in the neuralgia patients. Intracortical inhibition in the ipsilateral hemisphere of neuralgia patients and in both hemispheres of osteoarthritis patients did not significantly differ from the control group. Disinhibition was significantly more pronounced in neuralgia patients with moderate/severe pain intensity than in patients with mild pain intensity, whereas the relative compound motor action potential as a parameter of nerve injury severity did not correlate with the amount of disinhibition. Conclusions Our results suggest a close relationship between motor cortex inhibition and chronic neuropathic pain in the neuralgia patients, which is independent from nerve injury severity. The lack of cortical disinhibition in patients with painful osteoarthritis points at differences in the pathophysiological processes of different chronic pain conditions with respect to the involvement of different brain circuitry.

Abstract Background Repeated execution of a tactile task enhances task performance. In the present study we sought to improve tactile performance with unattended activation-based learning processes (i.e., focused stimulation of dermal receptors evoking neural coactivation (CA)). Previous studies show that the application of CA to a single finger reduced the stationary two-point discrimination threshold and significantly increased tactile acuity. These changes were accompanied by an expansion of the cortical finger representation in primary somatosensory cortex (SI). Here we investigated the effect of different types of multifinger CA on the tactile performance of each finger of the right hand. Results Synchronous and asynchronous CA was applied to all fingers of a subject's dominant hand. We evaluated changes in absolute touch thresholds, static two-point discrimination thresholds, and mislocalization of tactile stimuli to the fingertips. After synchronous CA, tactile acuity improved (i.e., discrimination thresholds decreased) and the frequency of mislocalization of tactile stimuli changed from directly neighboring fingers to more distant fingers. On the other hand, asynchronous CA did not significant improve tactile acuity. In fact, there was evidence of impaired tactile acuity. Multifinger CA with synchronous or asynchronous stimulation did not significantly alter absolute touch thresholds. Conclusion Our results demonstrate that it is possible to extend tactile CA to all fingers of a hand. The observed changes in mislocalization of tactile stimuli after synchronous CA indicate changes in the topography of the cortical hand representation. Although single-finger CA has been shown to improve tactile acuity, asynchronous CA of all fingers of the hand had the opposite effect, suggesting the need for synchrony in multifinger CA for improving tactile acuity.

Abstract Background Training of a repetitive synchronised movement of two limb muscles leads to short-term plastic changes in the primary motor cortex, which can be assessed by transcranial magnetic stimulation (TMS) mapping. We used this paradigm to study the effect of memantine, a NDMA antagonist, on short-term motor cortex plasticity in 20 healthy human subjects, and we were especially interested in possible differential effects of different treatment regimens. In a randomised double-blinded cross over study design we therefore administered placebo or memantine either as a single dosage or as an ascending dosage over 8 days. Before and after one hour of motor training, which consisted of a repetitive co-contraction of the abductor pollicis brevis (APB) and the deltoid muscle, we assessed the motor output map of the APB muscle by TMS under the different conditions. Results We found a significant medial shift of the APB motor output map after training in the placebo condition, indicating training-induced short-term plastic changes in the motor cortex. A single dosage of memantine had no significant effect on this training-induced plasticity, whereas memantine administered in an ascending dosage over 8 days was able to block the cortical effect of the motor training. The memantine serum levels after 8 days were markedly higher than the serum levels after a single dosage of memantine, but there was no individual correlation between the shift of the motor output map and the memantine serum level. Besides, repeated administration of a low memantine dosage also led to an effective blockade of training-induced cortical plasticity in spite of serum levels comparable to those reached after single dose administration, suggesting that the repeated administration was more important for the blocking effect than the memantine serum levels. Conclusion We conclude that the NMDA-antagonist memantine is able to block training-induced motor cortex plasticity when administered over 8 days, but not after administration of a single dose. This differential effect might be mainly due to the prolonged action of memantine at the NMDA receptor. These findings must be considered if clinical studies are designed, which aim at evaluating the potency of memantine to prevent "maladaptive" plasticity, e.g. after limb amputation.

Learning new categories is fundamental to cognition, occurring in daily life through various sensory modalities. However, it is not well known how acquiring new categories can modulate the brain networks. Resting-state functional connectivity is an effective method for detecting short-term brain alterations induced by various modality-based learning experiences. Using fMRI, our study investigated the intricate link between novel category learning and brain network reorganization. Eighty-four adults participated in an object categorization experiment utilizing visual (n = 41, with 20 females and a mean age of 23.91 ± 3.11 years) or tactile (n = 43, with 21 females and a mean age of 24.57 ± 2.58 years) modalities. Resting-state networks (RSNs) were identified using independent component analysis across the group of participants, and their correlation with individual differences in object category learning across modalities was examined using dual regression. Our results reveal an increased functional connectivity of the frontoparietal network with the left superior frontal gyrus in visual category learning task and with the right superior occipital gyrus and the left middle temporal gyrus after tactile category learning. Moreover, the somatomotor network demonstrated an increased functional connectivity with the left parahippocampus exclusively after tactile category learning. These findings illuminate the neural mechanisms of novel category learning, emphasizing distinct brain networks' roles in diverse modalities. The dynamic nature of RSNs emphasizes the ongoing adaptability of the brain, which is essential for efficient novel object category learning. This research provides valuable insights into the dynamic interplay between sensory learning, brain plasticity, and network reorganization, advancing our understanding of cognitive processes across different modalities., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Healthcare and social workers had an increased occupational risk of contracting SARS-CoV-2 during the pandemic. Some developed long-lasting symptoms known as post-COVID syndrome (PCS). To assess the consequences of COVID-19 for individuals insured by the German Social Accident Insurance, the BG hospitals (Berufsgenossenschaftliche Kliniken: clinics for occupational accident insurance) established an interdisciplinary diagnostic programme. Data collected during routine clinical practice are transmitted to a multicenter post-COVID registry to enhance knowledge of the long-term consequences related to COVID-19 and to optimize diagnostics, treatment, and rehabilitation. The design of the post-COVID registry, along with a description of the study population, is detailed in this paper., Methods: The registry includes patients with an occupational disease or accident. Depending on the severity and complexity of the symptoms, patients received an outpatient post-COVID examination or an inpatient post-COVID check (PCC). The collected data comprise demographics, occupational and social history, disease progression, pre-existing conditions, utilization of health services, persistent symptoms, and psychosocial and neuropsychological assessments. Further investigations are carried out in response to symptoms and needs, using clinical assessment, instrumental and imaging techniques, as well as questionnaires. In addition, serum and cerebrospinal fluid samples are preserved for biomarker analysis., Results: By September 2024, 1,957 patients from six BG hospitals were included. An interim analysis of 1,150 cases shows that patients are predominantly female (77%) and the average age is 51 years (standard deviation [SD] 10.5). Around 43% worked in nursing at the time of infection. In 63% of cases, an inpatient post-COVID check was carried out. About 20% were hospitalized during acute COVID-19 infection, with an average stay of 14.6 days (SD 18.4). More than half were still unable to work at the time of examination, with no significant differences between hospitalized and non-hospitalized patients. Common pre-existing conditions included heart disease (48%), allergies (45%), and lung disease (33%). PCS symptoms mainly consisted of reduced physical capacity (95%), concentration difficulties (79%), and shortness of breath (69%). 81% had previously received outpatient and/or inpatient rehabilitation., Conclusion: The outpatient and the inpatient PCC are essential in managing the recovery process for patients with PCS. Data analysis will provide insights into the need for medical care and rehabilitation. In addition, longitudinal analyses will be used to track the progress of the post-COVID registry over time and monitor the effectiveness of the recommended measures., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2024 Schwenkreis et al.)

Filial imprinting, a crucial ethological paradigm, provides insights into the neurobiology of early learning and its long-term impact on behaviour. To date, invasive techniques like autoradiography or lesions have been used to study it, limiting the exploration of whole brain networks. Recent advances in fMRI for avian brains now open new windows to explore bird's brain functions at the network level. We developed an fMRI technique for awake, newly hatched chicks, capturing BOLD signal changes during imprinting experiments. While early memory acquisition phases are understood, long-term storage and retrieval remain unclear. Our findings identified potential long-term storage of imprinting memories across a neural network, including the hippocampal formation, the medial striatum, the arcopallium, and the prefrontal-like nidopallium caudolaterale. This paradigm opens up new avenues for exploring the broader landscape of learning and memory in neonatal vertebrates, enhancing our understanding of behaviour and brain networks., (© 2024. The Author(s).)

Posttraumatic headache (PTH) is common following traumatic brain injury and impacts quality of life. We investigated descending pain modulation as one possible mechanism for PTH and correlated it to clinical measures. Pain-related evoked potentials (PREP) were recorded in 26 PTH-patients and 20 controls after electrical stimulation at the right hand and forehead with concentric surface electrodes. Conditioned pain modulation (CPM) was assessed using painful cutaneous electric stimulation (PCES) on the right hand as test stimulus and immersion of the left hand into 10 °C-cold water bath as conditioning stimulus based on changes in pain intensity and in amplitudes of PCES-evoked potentials. All participants completed questionnaires assessing depression, anxiety, and pain catastrophising. PTH-patients reported significantly higher pain ratings during PREP-recording in both areas despite similar stimulus intensity at pain threshold. N1P1-amplitudes during PREP and CPM-assessment were lower in patients in both areas, but statistically significant only on the hand. Both, PREP-N1-latencies and CPM-effects (based on the N1P1-amplitudes and pain ratings) were similar in both groups. Patients showed significantly higher ratings for anxiety and depression, which did not correlate with the CPM-effect. Our results indicate generalized hyperalgesia for electrical stimuli in both hand and face in PTH. The lacking correlation between pain ratings and EEG parameters indicates different mechanisms of pain perception and nociception., (© 2024. The Author(s).)

Cognitive functions, such as learning and memory processes, depend on effective communication between brain regions which is facilitated by white matter tracts (WMT). We investigated the microstructural properties and the contribution of WMT to extinction learning and memory in a predictive learning task. Forty-two healthy participants completed an extinction learning paradigm without a fear component. We examined differences in microstructural properties using diffusion tensor imaging to identify underlying neural connectivity and structural correlates of extinction learning and their potential implications for the renewal effect. Participants with good acquisition performance exhibited higher fractional anisotropy (FA) in WMT including the bilateral inferior longitudinal fasciculus (ILF) and the right temporal part of the cingulum (CNG). This indicates enhanced connectivity and communication between brain regions relevant to learning and memory resulting in better learning performance. Our results suggest that successful acquisition and extinction performance were linked to enhanced structural connectivity. Lower radial diffusivity (RD) in the right ILF and right temporal part of the CNG was observed for participants with good acquisition learning performance. This observation suggests that learning difficulties associated with increased RD may potentially be due to less myelinated axons in relevant WMT. Also, participants with good acquisition performance were more likely to show a renewal effect. The results point towards a potential role of structural integrity in extinction-relevant WMT for acquisition and extinction., (© 2024. The Author(s).)

Introduction: Renewal of extinguished responses is associated with higher activity in specific extinction-relevant brain regions, i.e., hippocampus (HC), inferior frontal gyrus (IFG), and ventromedial PFC (vmPFC). HC is involved in processing of context information, while IFG and vmPFC use such context information for selecting and deciding among competing response options. However, it is as yet unknown to what extent trials with changed versus unchanged outcome, or extinction trials that evoke renewal (i.e., extinction context differs from acquisition and test context: ABA trials) and trials that do not (i.e., same context in all phases: AAA trials) are represented differentially in extinction-relevant brain regions., Methods: In this study, we applied representational similarity analysis (RSA) to determine differences in neural representations of these trial types and their relationship to extinction error rates and renewal level., Results: Overall, individuals with renewal (REN) and those without (NoREN) did not differ significantly in their discrimination levels between ABA and AAA extinction trials, with the exception of right posterior HC, where REN exhibited more pronounced context-related discrimination. In addition, higher dissimilarity of representations in bilateral posterior HC, as well as in several IFG regions, during extinction learning was linked to lower ABA renewal rates. Both REN and NoREN benefitted from prediction error feedback from ABA extinction errors for context- and outcome-related discrimination of trials in IFG, vmPFC, and HC, but only the NoREN group also benefitted from error feedback from AAA extinction errors., Discussion: Thus, while in both groups the presence of a novel context supported formation of distinct representations, only in NoREN the expectancy violation of the surprising change of outcome alone had a similar effect. In addition, only in NoREN context-related discrimination was linked to error feedback in vmPFC. In summary, the findings show that context- and outcome-related discrimination of trials in HC, vmPFC, and IFG is linked to extinction learning errors, regardless of renewal propensity, and at the same time point towards differential context processing strategies in REN and NoREN. Moreover, better discrimination of context-related trials during extinction learning promotes less renewal during extinction recall, suggesting that renewal may be related to suboptimal context-related trial discrimination., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lissek and Tegenthoff.)

Contextual information is essential for learning and memory processes and plays a crucial role during the recall of extinction memory, and in the renewal effect, which is the context-dependent recovery of an extinguished response. The dopaminergic system is known to be involved in regulating attentional processes by shifting attention to novel and salient contextual cues. Higher dopamine levels are associated with a better recall of previously learned stimulus-outcome associations and enhanced encoding, as well as retrieval of contextual information which promotes renewal. In this fMRI study, we aimed to investigate the impact of processing contextual information and the influence of dopaminergic D2-like receptor activation on attention to contextual information during a predictive learning task as well as upon extinction learning, memory performance, and activity of extinction-related brain areas. A single oral dose of 1.25 mg bromocriptine or an identical-looking placebo was administered to the participants. We modified a predictive learning task that in previous studies reliably evoked a renewal effect, by increasing the complexity of contextual information. We analysed fixations and dwell on contextual cues by use of eye-tracking and correlated these with behavioural performance and BOLD activation of extinction-related brain areas. Our results indicate that the group with dopaminergic D2-like receptor stimulation had higher attention to task-relevant contextual information and greater/lower BOLD activation of brain regions associated with cognitive control during extinction learning and recall. Moreover, renewal responses were almost completely absent. Since this behavioural effect was observed for both treatment groups, we assume that this was due to the complexity of the altered task design., (© 2023. The Author(s).)

It has already been described that transcutaneous spinal direct current stimulation (tsDCS) can selectively influence nociceptive evoked potentials. This study is the first aiming to prove an influence of tsDCS on pain-related evoked potentials (PREP) using concentric surface electrodes (CE), whose nociceptive specificity is still under discussion. 28 healthy subjects participated in this sham-controlled, double-blind cross-over study. All subjects underwent one session of anodal and one session of sham low-thoracic tsDCS. Before and after the intervention, PREP using CE, PREP-induced pain perception and somatosensory evoked potentials (SEP) were assessed on the right upper and lower limb. We found a decrease in PREP amplitude at the lower limb after sham stimulation, but not after anodal tsDCS, while SEP remained unchanged under all studied conditions. There was no difference between the effects of anodal tsDCS and sham stimulation on the studied parameters assessed at the upper limb. PREP-induced pain of the upper and lower limb increased after anodal tsDCS. The ability of influencing PREP using a CE at the spinal level in contrast to SEP suggests that PREP using CE follows the spinothalamic pathway and supports the assumption that it is specifically nociceptive. However, while mainly inhibitory effects on nociceptive stimuli have already been described, our results rather suggest that anodal tsDCS has a sensitizing effect. This may indicate that the mechanisms underlying the elicitation of PREP with CE are not the same as for the other nociceptive evoked potentials. The effects on the processing of different types of painful stimuli should be directly compared in future studies., (© 2023. The Author(s).)

In patients presenting with low back pain (LBP), once specific causes are excluded (fracture, infection, inflammatory arthritis, cancer, cauda equina and radiculopathy) many clinicians pose a diagnosis of non-specific LBP. Accordingly, current management of non-specific LBP is generic. There is a need for a classification of non-specific LBP that is both data- and evidence-based assessing multi-dimensional pain-related factors in a large sample size. The "PRedictive Evidence Driven Intelligent Classification Tool for Low Back Pain" (PREDICT-LBP) project is a prospective cross-sectional study which will compare 300 women and men with non-specific LBP (aged 18-55 years) with 100 matched referents without a history of LBP. Participants will be recruited from the general public and local medical facilities. Data will be collected on spinal tissue (intervertebral disc composition and morphology, vertebral fat fraction and paraspinal muscle size and composition via magnetic resonance imaging [MRI]), central nervous system adaptation (pain thresholds, temporal summation of pain, brain resting state functional connectivity, structural connectivity and regional volumes via MRI), psychosocial factors (e.g. depression, anxiety) and other musculoskeletal pain symptoms. Dimensionality reduction, cluster validation and fuzzy c-means clustering methods, classification models, and relevant sensitivity analyses, will classify non-specific LBP patients into sub-groups. This project represents a first personalised diagnostic approach to non-specific LBP, with potential for widespread uptake in clinical practice. This project will provide evidence to support clinical trials assessing specific treatments approaches for potential subgroups of patients with non-specific LBP. The classification tool may lead to better patient outcomes and reduction in economic costs., Competing Interests: DLB, ST, MT, LS, SeS, HJW, MA, GT, KE, BF, JVO, CTM, PJO, SB, RD, SK declare no conflicts of interest. BB: declares no conflicts of interest relevant to the current work, but has previously received research support, consultancy fees and/or honoraria from AbbVie, Amgen, Biogen, GE/Lunar, Janssen, Galapagos, Gilead, Medimaps, MSD, Sanofi Genzyme, Theramex, UCB. TS: declares prior consulting fees from Johnson & Johnson, Amgen, Kaia Health Software, SpineArt, Implantcast and speaking and travel arrangements from Johnson & Johnson, ICOTEC, Nuvasive, Ulrichmedical, Silony, Amgen, Kaia Health Software. EE-K has received fees from painCert GmbH, Casquar GmbH and Omega Pharma GmbH, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Belavy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The balance of excitation and inhibition plays a key role in plasticity and learning. A frequently used, reliable approach to assess intracortical inhibition relies on measuring paired-pulse behavior. Moreover, recent developments of magnetic resonance spectroscopy allows measuring GABA and glutamate concentrations. We give an overview about approaches employed to obtain information about excitatory states in human participants and discuss their putative relation. We summarize paired-pulse techniques and basic findings characterizing paired-pulse suppression in somatosensory (SI) and (VI) visual areas. Paired-pulse suppression describes the effect of paired sensory stimulation at short interstimulus intervals where the cortical response to the second stimulus is significantly suppressed. Simultaneous assessments of paired-pulse suppression in SI and VI indicated that cortical excitability is not a global phenomenon, but instead reflects the properties of local sensory processing. We review studies using non-invasive brain stimulation and perceptual learning experiments that assessed both perceptual changes and accompanying changes of cortical excitability in parallel. Independent of the nature of the excitation/inhibition marker used these data imply a close relationship between altered excitability and altered performance. These results suggest a framework where increased or decreased excitability is linked with improved or impaired perceptual performance. Recent findings have expanded the potential role of cortical excitability by demonstrating that inhibition markers such as GABA concentrations, paired-pulse suppression or alpha power predict to a substantial degree subsequent perceptual learning outcome. This opens the door for a targeted intervention where subsequent plasticity and learning processes are enhanced by altering prior baseline states of excitability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dinse, Höffken and Tegenthoff.)

Perception is subject to ongoing alterations by learning and top-down influences. Although abundant studies have shown modulation of perception by attention, motivation, content and context, there is an unresolved controversy whether these examples provide true evidence that perception is penetrable by cognition. Here we show that tactile perception assessed as spatial discrimination can be instantaneously and systematically altered merely by the semantic content during hypnotic suggestions. To study neurophysiological correlates, we recorded EEG and SEPs. We found that the suggestion "your index finger becomes bigger" led to improved tactile discrimination, while the suggestion "your index finger becomes smaller" led to impaired discrimination. A hypnosis without semantic suggestions had no effect but caused a reduction of phase-locking synchronization of the beta frequency band between medial frontal cortex and the finger representation in somatosensory cortex. Late SEP components (P80-N140 complex) implicated in attentional processes were altered by the semantic contents, but processing of afferent inputs in SI remained unaltered. These data provide evidence that the psychophysically observed modifiability of tactile perception by semantic contents is not simply due to altered perception-based judgments, but instead is a consequence of modified perceptual processes which change the perceptual experience., (© 2023. The Author(s).)

Purpose: Heating of gradient coils and passive shim components is a common cause of instability in the B 0 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., Competing Interests: Declaration of Competing Interest Jack J. Miller would like to acknowledge the support of a Novo Nordisk Research Fellowship run in conjunction with the University of Oxford. Francisco Reyes-Madrigal has served as a speaker for Janssen (Johnson & Johnson) and AstraZeneca. Marc Thioux and Pim van Dijk were supported by The Netherlands Organization for Health Research and Development (ZonMW) and the Dorhout Mees Foundation. All other authors have no conflict of interest to declare., (Copyright © 2021. Published by Elsevier Inc.)

Although we use our visual and tactile sensory systems interchangeably for object recognition on a daily basis, little is known about the mechanism underlying this ability. This study examined how 3D shape features of objects form two congruent and interchangeable visual and tactile perceptual spaces in healthy male and female participants. Since active exploration plays an important role in shape processing, a virtual reality environment was used to visually explore 3D objects called digital embryos without using the tactile sense. In addition, during the tactile procedure, blindfolded participants actively palpated a 3D-printed version of the same objects with both hands. We first demonstrated that the visual and tactile perceptual spaces were highly similar. We then extracted a series of 3D shape features to investigate how visual and tactile exploration can lead to the correct identification of the relationships between objects. The results indicate that both modalities share the same shape features to form highly similar veridical spaces. This finding suggests that visual and tactile systems might apply similar cognitive processes to sensory inputs that enable humans to rely merely on one modality in the absence of another to recognize surrounding objects., (Copyright © 2021 Tabrik et al.)

The assessment of disease activity is fundamental in the management of chronic inflammatory demyelinating polyneuropathy (CIDP). Previous studies with small patient numbers found an increase of corneal immune cell infiltrates as a potential marker of inflammation in patients with CIDP. However, its clinical relevance remained unclear. The present study aimed to determine whether the amount of corneal inflammatory cells (CIC) measured by corneal confocal microscopy (CCM) detects disease activity in CIDP. CIC were measured in 142 CCM-investigations of 97 CIDP-patients. Data on clinical disease activity, disability (INCAT-ODSS) and need for therapy escalation at the timepoint of CCM, 3 and 6 months later were analyzed depending CIC-count. Pathological spontaneous activity during electromyography was examined as another possible biomarker for disease activity in comparison to CIC-count. An increased CIC-count at baseline was found in patients with clinical disease activity and disability progression in the following 3-6 months. An increase to more than 25 CIC/mm 2 had a sensitivity of 0.73 and a specificity of 0.71 to detect clinical disease activity and a sensitivity of 0.77 and a specificity of 0.64 to detect disability progression (increasing INCAT-ODSS) in the following 6 months. An increase to more than 50 CIC/mm 2 had a sensitivity of about 0.51 and a specificity of 0.91 to detect clinical disease activity and a sensitivity of 0.53 and a specificity of 0.80 to detect disability progression. CIC count is a non-invasive biomarker for the detection of disease activity in the following 6 months in CIDP., (© 2021. The Author(s).)

Objectives: Since 2000/2001, no large-scale prospective studies addressing traumatic brain injury (TBI) epidemiology in Germany have been published. Our aim was to look for a possible shift in TBI epidemiology described in other European countries, to look for possible changes in TBI management and to identify predictors of 1-year outcome especially in patients with mild TBI., Design: Observational cohort study., Setting: All patients suffering from a TBI of any degree between 1 October 2014 and 30 September 2015, and who arrived in one of the seven participating BG hospitals within 24 hours after trauma, were included., Participants: In total, 3514 patients were included., Outcome Measures: Initial care, acute hospital care and rehabilitation were documented using standardised documentation forms. A standardised telephone interview was conducted 3 and 12 months after TBI in order to obtain information on outcome., Results: Peaks were identified in males in the early 20s and mid-50s, and in both sexes in the late 70s, with 25% of all patients aged 75 or older. A fall was the most frequent cause of TBI, followed by traffic accidents (especially bicyclists). The number of head CT scans increased, and the number of conventional X-rays of the skull decreased compared with 2000/2001. Besides, more patients were offered rehabilitation than before. Though most TBI were classified as mild, one-third of the patients participating in the telephone interview after 12 months still reported troubles attributed to TBI. Negative predictors in mild TBI were female gender, intracranial bleeding and Glasgow Coma Scale (GCS) 13/14., Conclusion: The observed epidemiologic shift in TBI (ie, elderly patients, more falls, more bicyclists) calls for targeted preventive measures. The heterogeneity behind the diagnosis 'mild TBI' emphasises the need for defining subgroups not only based on GCS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The levels of the gonadal hormones estradiol and progesterone vary throughout the menstrual cycle thereby affecting cognition, emotion, mood, and social behaviour. However, how these hormones modulate the balance of neural excitation and inhibition, which crucially regulate processing and plasticity, is not fully understood. We here used paired-pulse stimulation to investigate in healthy humans the action of low and high estradiol and progesterone on intracortical inhibition in somatosensory (SI) and visual cortex (V1). We found that paired-pulse suppression in both SI and VI depended on estradiol. During high estradiol levels, paired-pulse suppression was significantly reduced. No comparable effects were found for progesterone, presumably due to a confounding effect of estradiol. Also, no hormone level-depending effects were observed for single-pulse evoked SEPs (somatosensory evoked potentials) and VEPs (visual evoked potentials) indicating a specific hormonal action on intracortical processing. The results demonstrate that estradiol globally modulates the balance of excitation and inhibition of SI and VI cortex.

Transcutaneous spinal direct current stimulation (tsDCS) is a safe and convenient method of neuromodulation. It has been proven to alter sensory processing at cervicomedullary level by amplitude changes of the P30 response of tibial nerve somatosensory evoked potentials (TN SEPs). With knowledge that tsDCS affects cortical circuits, we hypothesized that tsDCS may also affect intracortical excitability of the somatosensory cortex assessed by paired stimulation suppression (PSS). Fourteen healthy men were included in this prospective, single-blinded, placebo-controlled crossover study. Single (SS) and paired stimulation (PS) TN SEPs were recorded over the scalp before, immediately as well as 30 and 60 min after applying 15 min of tsDCS over the twelfth thoracic vertebra. Each volunteer underwent three independent and randomized sessions of either cathodal, anodal or sham stimulation. tsDCS showed no effect on peak-to-peak amplitudes or latencies of cortical P40-N50 response after SS. Furthermore, tsDCS failed to induce significant changes on amplitude ratios of PSS, thus showing no impact on intracortical excitability of the somatosensory cortex in healthy subjects. Further research is required to reveal the different mechanisms and to strengthen clinical use of this promising technique.

Background: Diagnosis of functional movement disorders and specifically functional tremor (FT) (representing 50% of them) remains demanding. Additionally, due to heterogeneity of the disorders, structured concepts and guidelines for diagnosis and therapy are difficult to establish. Ascertaining the state of knowledge to derive instructions for operating procedures is the aim of this review., Main Text: Based on a standardized systematic literature research using the term "psychogenic tremor" in the MEDLINE database dating back ten years, 76 studies were evaluated. Conventional features of FT are variability of frequency and amplitude. Further, response to distraction by motor and cognitive tasks is a key diagnostic feature in differentiation between organic and functional origin. A variety of electrophysiological tests have been evaluated including surface electromyography and accelerometry to establish laboratory-supported criteria for diagnosing tremor. Also, finger tapping tests have been used to identify FT, showing positive potential as supplementary evidence.Imaging studies in general are mostly underpowered and imaging cannot be used on an individual basis. Therapeutic studies in FT often have a diagnostic component. Cognitive behavioral therapy should be the preferred psychological treatment independent of additional psychiatric symptoms. Other psychotherapeutic methods show lack of evidence concerning FT. Relaxation techniques and physiotherapy are an important additional feature, especially in children and adolescents. In regard to drug therapy, randomized and blinded trials are not available. A significant decrease in rating scales could be detected after active, not sham repetitive transcranial magnetic stimulation with a long-lasting effect. Also root magnetic stimulation seems to be effective. The clinical feature of tremor entrainment in FT can be used in combination with biofeedback as so-called tremor retrainment, using self-modulation of frequency and severity, to bring the movements under volitional control., Conclusion: Diagnosis and treatment of FT is challenging and should include a combination of intensive clinical examination and targeted addition of standardized testing, especially electrophysiological methods. Often therapeutic effects have a diagnostic component. A multimodal strategy, considering psychological factors as a potential origin as well as maintaining effects seems to be most effective., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Most of the occupational exposure limits (OELs) are based on local irritants. However, exposure to much lower concentrations of irritant substances can also lead to health complaints from workers. Exposure to irritants is often accompanied by strong unpleasant odors, and strong odors might have distracting effects and hence pose a safety risk. The findings obtained in human exposure studies with chemically sensitive, stressed, or anxious persons suggest that their ability to direct attention away from the odorous exposure and to focus on a cognitive task is reduced. In addition, after repeated odor exposure, these persons show signs of sensitization, i.e., difficulties in ignoring or getting used to the exposure. The question arises as to whether certain health conditions are accompanied by a change in sensitivity to odors and irritants, so that these persons are potentially more distracted by odors and irritants and therefore more challenged in working memory tasks than nonsusceptible persons. In our study, susceptible persons with sensory airway hyperreactivity ("capsaicin-sensitive") respond more strongly to mechanical skin stimuli than controls and show altered network connectivity. Capsaicin-sensitive subjects have a lower pain threshold and thus are more sensitive to mechanical skin stimuli. The intrinsic functional connectivity of their saliency network is higher, and the lower the GABAergic tone of the thalamus, the higher their pain sensitivity to mechanical stimuli. It seems that the increased communication between resting-state networks promotes a stronger perception of the sensory input signal. The results can be used to inform about actual risks (i.e., attention diversion and increased risk of accidents) and "pseudo" risks such as odor perception without a negative impact on one's well-being. This way, uncertainties that still prevail in the health assessment of odorous and sensory irritating chemicals could be reduced., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 Stefanie Heba et al.)

Different paradigms can assess the effect of conditioned pain modulation (CPM). The aim of the present study was to compare heat pain, as an often used test stimulus (TS), to painful cutaneous electrical stimulation (PCES), having the advantage of the additional recording of PCES-related evoked potentials. In 28 healthy subjects we applied heat and PCES at the dominant hand as test stimulus (TS) to compare the CPM-effect elicited by hand immersion into cold water (10 °C) as conditioning stimulus (CS). Subjects rated the pain intensity of TS at baseline, during and 5 min after CS application and additionally of CS, on a numerical rating scale (NRS) (0-100). The 'early' (during CS-before CS) and 'late' (after CS-before CS) CPM-effects were analyzed. Parallel to the PCES, the related evoked potentials were recorded via Cz to evaluate any changes in PCES-amplitudes. CS reduced significantly the pain intensity of both PCES and heat pain as TS. On a group level, the CPM-effect did not differ significantly between both paradigms. Both early and late CPM-effect based on PCES correlated significantly with the CS pain intensity ( r = -0.630 and -0.503, respectively), whereas using heat pain the correlation was not significant. We found a significant reduction of PCES-amplitudes during CS, but this did not correlate with the PCES-induced pain intensity. Correlation with the CS painfulness ( r = -0.464) did not achieve the significance level after Bonferroni correction. The extent of the CPM effects was similar in both testing paradigms at group level, despite intraindividual differences. Future studies should further elicit the exact mechanisms explaining the modality of these specific differences.

Animal-fMRI is a powerful method to understand neural mechanisms of cognition, but it remains a major challenge to scan actively participating small animals under low-stress conditions. Here, we present an event-related functional MRI platform in awake pigeons using single-shot RARE fMRI to investigate the neural fundaments for visually-guided decision making. We established a head-fixated Go/NoGo paradigm, which the animals quickly learned under low-stress conditions. The animals were motivated by water reward and behavior was assessed by logging mandibulations during the fMRI experiment with close to zero motion artifacts over hundreds of repeats. To achieve optimal results, we characterized the species-specific hemodynamic response function. As a proof-of-principle, we run a color discrimination task and discovered differential neural networks for Go-, NoGo-, and response execution-phases. Our findings open the door to visualize the neural fundaments of perceptual and cognitive functions in birds-a vertebrate class of which some clades are cognitively on par with primates.

We report the case of a 27-year-old patient with subacute anti-neurofascin-155 neuropathy with bifacial palsy, who showed excellent response to rituximab. We provide longitudinal data of established clinical scores, nerve conduction studies, antibody titers, and novel imaging methods (nerve ultrasonography and corneal confocal microscopy). Clinical and electrophysiological improvement followed the reduction of serum antibody titer and correlated with a reduction of corneal inflammatory cellular infiltrates whereas the increase in the cross-sectional area of the peripheral nerves remained 12 months after first manifestation. Our findings suggest that novel techniques provide useful follow-up parameters in paranodopathies., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

In addition to its role in visuospatial navigation and the generation of spatial representations, in recent years, the hippocampus has been proposed to support perceptual processes. This is especially the case where high-resolution details, in the form of fine-grained relationships between features such as angles between components of a visual scene, are involved. An unresolved question is how, in the visual domain, perspective-changes are differentiated from allocentric changes to these perceived feature relationships, both of which may be argued to involve the hippocampus. We conducted functional magnetic resonance imaging of the brain response (corroborated through separate event-related potential source-localization) in a passive visuospatial oddball-paradigm to examine to what extent the hippocampus and other brain regions process changes in perspective, or configuration of abstract, three-dimensional structures. We observed activation of the left superior parietal cortex during perspective shifts, and right anterior hippocampus in configuration-changes. Strikingly, we also found the cerebellum to differentiate between the two, in a way that appeared tightly coupled to hippocampal processing. These results point toward a relationship between the cerebellum and the hippocampus that occurs during perception of changes in visuospatial information that has previously only been reported with regard to visuospatial navigation., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)