Cortisol decreases activation in extinction related brain areas resulting in an impaired recall of context-dependent extinction memory.

Conditioned responding gradually stops during successful extinction learning. The renewal effect is defined as the recovery of a extinguished conditioned response when the context of extinction is different from acquisition. The stress hormone cortisol is known to have an influence on extinction memory and associative learning. Different effects of cortisol on behaviour and brain activity have been observed with respect to stress timing, duration, and intensity. However, the influence of cortisol prior to the initial encoding of stimulus-outcome associations on extinction learning, renewal and its behavioural and neurobiological correlates is still largely unknown. In our study, 60 human participants received 20 mg cortisol or placebo and then learned, extinguished, and recalled the associations between food stimuli presented in distinct contexts and different outcomes in three subsequent task phases. Learning performance during acquisition and extinction phases was equally good for both treatment groups. In the cortisol group, significantly more participants showed renewal compared to placebo. In the subgroup of participants with renewal, cortisol treated participants showed significantly better extinction learning performance compared to placebo. Participants showing renewal had in general difficulties with recalling extinction memory, but in contrast to placebo, the cortisol group exhibited a context-dependent impairment of extinction memory recall. Imaging analyses revealed that cortisol decreased activation in the hippocampus during acquisition. The cortisol group also showed reduced dorsolateral prefrontal cortex activation when extinction learning took place in a different context, but enhanced activation in inferior frontal gyrus during extinction learning without context change. During recall, cortisol decreased ventromedial prefrontal cortex activation. Taken together, our findings illustrate cortisol as a potent modulator of extinction learning and recall of extinction memory which also promotes renewal.

Quantitative muscle magnetic resonance imaging depicts microstructural abnormalities but no signs of inflammation or dystrophy in post-COVID-19 condition.

BACKGROUND AND PURPOSE: Post-COVID-19 condition (PCC) has high impact on quality of life, with myalgia and fatigue affecting at least 25% of PCC patients. This case-control study aims to noninvasively assess muscular alterations via quantitative muscle magnetic resonance imaging (MRI) as possible mechanisms for ongoing musculoskeletal complaints and premature exhaustion in PCC. METHODS: Quantitative muscle MRI was performed on a 3 Tesla MRI scanner of the whole legs in PCC patients compared to age- and sex-matched healthy controls, including a Dixon sequence to determine muscle fat fraction (FF), a multi-echo spin-echo sequence for quantitative water mapping reflecting putative edema, and a diffusion-weighted spin-echo echo-planar imaging sequence to assess microstructural alterations. Clinical examination, nerve conduction studies, and serum creatine kinase were performed in all patients. Quantitative muscle MRI results were correlated to the results of the 6-min walk test and standardized questionnaires assessing quality of life, fatigue, and depression. RESULTS: Twenty PCC patients (female: n = 15, age = 48.8 ± 10.1 years, symptoms duration = 13.4 ± 4.2 months, body mass index [BMI] = 28.8 ± 4.7 kg/m2 ) were compared to 20 healthy controls (female: n = 15, age = 48.1 ± 11.1 years, BMI = 22.9 ± 2.2 kg/m2 ). Neither FF nor T2 revealed signs of muscle degeneration or inflammation in either study groups. Diffusion tensor imaging (DTI) revealed reduced mean, axial, and radial diffusivity in the PCC group. CONCLUSIONS: Quantitative muscle MRI did not depict any signs of ongoing inflammation or dystrophic process in the skeletal muscles in PCC patients. However, differences observed in muscle DTI depict microstructural abnormalities, which may reflect potentially reversible fiber hypotrophy due to deconditioning. Further longitudinal and interventional studies should prove this hypothesis.

Robustness and stability of volume-based tractography in a multicenter setting.

Muscle diffusion tensor imaging (mDTI)-based tractography is a promising tool with which to detect subclinical changes in muscle injuries and to evaluate pathophysiology in neuromuscular diseases. Classic region of interest (ROI)-based tractography is very time-consuming and requires an examiner with extensive experience. (Semi)automatic approaches such as volume-based tractography (VBT) can diminish this problem but its robustness and stability are unknown. The aim of the current study was to assess the performance of VBT in a multicenter setting and to evaluate semiautomatic segmentation approaches in the analysis of VBT-derived data in terms of the comparability of the outcome measures. Five traveling volunteers underwent 3-T mDTI of seven calf muscles of both legs at six different MR sites. Tract properties and diffusion metrics were calculated using VBT. Within-subject coefficients of variance (wsCVs) and intraclass correlation coefficients (ICCs) were calculated to assess the multicenter reproducibility of tract properties such as tract density (TD), mean tract length, volume and tract propagation angle, and diffusion metrics such as fractional anisotropy, mean diffusivity, axial diffusivity (λ1 ) and radial diffusivity in traveling subjects. Furthermore, 50 individual datasets from five different centers (10 datasets per center) were pooled to assess the feasibility of VBT with manual and semiautomatic segmentation. To assess the differences of tract properties and diffusion metrics between segmentation approaches an ANOVA was performed, and ICC and Bland-Altman plots were analyzed. wsCVs and ICCs showed good reproducibility of the tract properties TD and volume, as well as diffusion metrics. ANOVA showed no significant differences between manual and semiautomatic approaches. ICCs were excellent (≥ 0.992) and Bland-Altman analysis did not reveal any systemic bias between the methods. Tract properties and diffusion metrics derived from VBT showed good comparability among centers. Semiautomatic approaches revealed excellent agreement with gold standard of manual segmentation. These findings suggest that pooling data from different centers to construct a reference database for tractography results is feasible using semiautomatic segmentation approaches.

NMDA receptor-mediated processing in inferior frontal gyrus facilitates acquisition and extinction learning and strengthens renewal.

While the renewal effect of extinction is considered to be invoked by attention to context during the extinction phase, there is also evidence that processing during initial learning (acquisition) may be important for later renewal. A noradrenergic agonist and a dopaminergic antagonist, administered before acquisition, did not affect renewal, however, the effects of NMDAergic neurotransmission in this regard are as yet unknown. In a previous study, administration of a single dose of the NMDA agonist d-cycloserine (DCS) before extinction learning facilitated extinction in the context of acquisition (AAA), but had no effect upon renewal. In the present fMRI study, DCS was administered prior to the initial acquisition of a predictive learning task, in order to investigate whether NMDA receptor (NMDAR) stimulation at this timepoint will modulate overall learning as well as the level of renewal, while increasing activation in the extinction- and renewal-relevant brain regions of inferior frontal gyrus (iFG) and hippocampus (HC). DCS facilitated acquisition, as well as extinction learning in the context of acquisition (AAA), and raised the level of ABA renewal. While BOLD activation during acquisition did not differ between treatment groups, activation in bilateral iFG showed a double dissociation during processing of AAA extinction trials, with DCS-mediated higher activation in right iFG and deactivation in left iFG. In contrast, placebo showed higher activation in left iFG and deactivation in right iFG. During the test (recall) phase, left iFG and right anterior hippocampus activation was increased in DCS participants who showed renewal, with activation in this region correlating with the ABA renewal level. The results demonstrate that NMDA receptor stimulation can facilitate both initial learning and extinction of associations, and in this way has an impact upon the resultant level of renewal. In particular NMDAergic processing in iFG appears relevant for the facilitation of AAA extinction and ABA recall in the test phase.

Somatosensory dysfunction in patients with posttraumatic headache: A systematic review.

OBJECTIVES: Aim of the review is to summarize the knowledge about the sensory function and pain modulatory systems in posttraumatic headache and discuss its possible role in patients with posttraumatic headache. BACKGROUND: Posttraumatic headache is the most common complication after traumatic brain injury, and significantly impacts patients' quality of life. Even though it has a high prevalence, its origin and pathophysiology are poorly understood. Thereby, the existing treatment options are insufficient. Identifying its mechanisms can be an important step forward to develop target-based personalized treatment. METHODS: We searched the PubMed database for studies examining pain modulation and/or quantitative sensory testing in individuals with headache after brain injury. RESULTS: The studies showed heterogenous alterations in sensory profiles (especially in heat and pressure pain perception) compared to healthy controls and headache-free traumatic brain injury-patients. Furthermore, pain inhibition capacity was found to be diminished in subjects with posttraumatic headache. CONCLUSIONS: Due to the small number of heterogenous studies a distinct sensory pattern for patients with posttraumatic headache could not be identified. Further research is needed to clarify the underlying mechanisms and biomarkers for prediction of development and persistence of posttraumatic headache.

Prevalence and determinants of pain in chronic inflammatory demyelinating polyneuropathy: Results from the German INHIBIT registry.

BACKGROUND AND PURPOSE: Pain, fatigue and depression in chronic inflammatory demyelinating polyneuropathy (CIDP) are often underestimated, as the focus lies on sensorimotor dysfunction and gait instability. The aim of this study was to investigate their prevalence, characteristics and contribution to disability in a prospective cohort of 84 patients with CIDP. METHODS: Pain, fatigue, depression and quality of life were measured using the Pain Detect Questionnaire, Krupp's Fatigue Severity Scale, Beck Depression Inventory II and the German Short-Form 36 Health Survey. Sensorimotor deficits and disability were assessed using the Inflammatory Neuropathy Cause and Treatment overall disability score, the Rasch-built Overall Disability Scale, the Medical Research Council sum score and the Inflammatory Neuropathy Cause and Treatment sensory sum score. The interrelation between the five factors was assessed using analysis of variance and linear regression analysis. RESULTS: Pain was reported in 62%, mostly of moderate and severe intensity, whereas pain characteristics indicated neuropathic pain (NP) in 29%. Sensory dysfunction was stronger in NP patients compared to pain-free patients (p = 0.001). Pain of any type, especially NP, was associated with more pronounced fatigue symptoms (p = 0.010). Depressive symptoms were more frequent in patients with pain compared to the pain-free patients (61% vs. 33%, p = 0.02) and were more severe and frequent in NP than in non-NP patients (p = 0.005). Patients with pain had a worse physical quality of life than pain-free patients (p = 0.001). CONCLUSION: Pain, depression and fatigue are relevant disability factors in CIDP affecting quality of life. Sensory dysfunction is associated with NP. Therefore, evaluation of CIDP-related disability should include pain and sensory function for adequate monitoring of therapeutic interventions.

The DA-antagonist Tiapride affects context-related extinction learning in a predictive learning task, but not initial forming of associations, or renewal.

Renewal describes the recovery of an extinguished response if the contexts of extinction and recall differ, highlighting the context dependency of extinction. Studies demonstrated dopaminergic (DA) signalling to be important for context-related extinction learning with and without a fear component. In a previous study in humans, administration of the dopamine D2/D3 antagonist tiapride prior to extinction impaired extinction learning in a novel, but not a familiar context, without affecting renewal. In a further study, context processing during initial acquisition of associations was shown to be related to renewal. In this human fMRI study we investigated the potential role of DA signalling during this initial conditioning for the learning process and for renewal. While tiapride, administered prior to the start of learning, did not affect initial acquisition and renewal, extinction learning in a novel context was impaired, associated with reduced BOLD activation in vmPFC, left iFG and ACC - regions mediating response inhibition and selection from competing options using contextual information. Thus, different timepoints of administration of tiapride (before initial conditioning or extinction) had largely similar effects upon extinction and renewal. In addition, retrieval of previously acquired associations was impaired, pointing towards weaker association forming during acquisition. Conceivably, effects of the DA blockade are associated with the challenge present in the respective task rather than the administration timepoint: the cognitive flexibility required for forming a new inhibitory association that includes a novel element clearly requires DA processing, while initial forming of associations, or of inhibitory associations without a new element, apparently rely less on the proper function of the DA system.

Incidence, Time Course and Influence on Quality of Life of Intensive Care Unit-Acquired Weakness Symptoms in Long-Term Intensive Care Survivors.

PURPOSE: Intensive care unit-acquired weakness (ICUAW) can manifest as muscle weakness or neuropathy-like symptoms, with diagnosis remaining a challenge. Uncertainties surround the long-term cause and sequelae. Therefore, the purpose was to assess incidence, time course and long-term influence on quality of life (QoL) of symptoms in ICU survivors. METHODS: After ethical approval and registration (www.drks.de: DRKS00011593), in a single-center cohort study all patients admitted to the ICU in 2007-2017 in a German university hospital were screened. Out of 1,860 patients (≥7d ICU care including ventilation support for ≥72 h, at least 6mo-10y after ICU) 636 were deceased, 912 survivors were contacted. RESULTS: 149 former patients (age: 63.5 ± 13.1y; males: 73%; duration in ICU: 20.8 ± 15.7d; duration of ventilation: 16.5 ± 13.7 h; time post-ICU: 4.4 ± 2.7y, 5-10y: 43%) consented to be interviewed concerning occurrence, duration, recovery and consequences of ICUAW-associated muscle weakness or neuropathy-like symptoms after ICU. In 75% at least 1 persistent or previous symmetrical symptom was reported (myopathy-like muscle weakness: 43%; neuropathy-like symptoms: 13%; both: 44%) and rated as incidence of ICUAW. However, only 18% of participants had received an ICUAW diagnosis by their physicians, although 62% had persistent symptoms up to 10y after ICU (5-10y: 46%). Only 37% of participants reported a complete recovery of symptoms, significantly associated with an initially low number of symptoms after ICU (p < 0.0001), myopathy-like symptoms (p = 0.024), and younger age at the time of ICU admission (55.7 ± 13.1 vs. 62.6 ± 10.6y, p < 0.001). ICUAW still impaired the QoL at the time of the interview in 74% of affected survivors, with 30% reporting severe impairment. CONCLUSION: ICUAW symptoms were disturbingly common in the majority of long-term survivors, indicating that symptoms persist up to 10y and frequently impair QoL. However, only a small number of patients had been diagnosed with ICUAW. Trial registry: Deutsches Register Klinischer Studien (DRKS), https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011593, registration number: DRKS00011593.

Cerebellar-hippocampal processing in passive perception of visuospatial change: An ego- and allocentric axis?

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.

Chaperones in sporadic inclusion body myositis-Validation of proteomic data.

INTRODUCTION: Sporadic inclusion body myositis (sIBM) is characterized by myopathological features including rimmed vacuoles (RVs) and proteins associated with protein aggregation, autophagy, and inflammation. Previous proteomic studies of RV areas revealed an overrepresentation of several chaperones and subunits of the T-complex protein 1 (TCP-1), which is involved in prevention of protein aggregation. METHODS: To validate our proteomic findings, immunofluorescence analyses of selected chaperones and quantitative Western blot analysis of TCP-1 proteins were performed in five sIBM patients and five healthy controls. RESULTS: Immunofluorescence studies confirmed increased immunoreactivity for VCP, UNC45B, GRP-75, αB-crystallin, LAMP-2, Rab-7a, and TCP-1α and TCP-θ in RVs. Quantitative Western blot analysis revealed a significantly higher level of TCP-1 in sIBM muscle tissue when compared with healthy controls. DISCUSSION: Our study findings validate new insights in protein quality control and degradation processes that seem to be relevant in sIBM. These data provide an important basis for future functional and therapeutic studies.

Diffusion tensor imaging reveals changes in non-fat infiltrated muscles in late onset Pompe disease.

MRI is a helpful tool for monitoring disease progression in late-onset Pompe disease (LOPD). Our study aimed to evaluate if muscle diffusion tensor imaging (mDTI) shows alterations in muscles of LOPD patients with <10% fat-fraction. We evaluated 6 thigh and 7 calf muscles (both legs) of 18 LOPD and 29 healthy controls (HC) with muscle diffusion tensor imaging (mDTI), T1w, and mDixonquant sequences in a 3T MRI scanner. The quantitative mDTI-values axial diffusivity (λ1 ), mean diffusivity (MD), radial diffusivity (RD), and fractional anisotropy (FA) as well as fat-fraction were analyzed. 6-Minute Walk Test (6-MWT) data were correlated to diffusion metrics. We found that mDTI showed significant differences between LOPD and HC in diffusion parameters (P < .05). Thigh muscles with <10% fat-fraction showed significant differences in MD, RD, and λ1-3 . MD positively correlated with 6-MWT (P = .06). To conclude, mDTI reveals diffusion restrictions in muscles of LOPD with and without fat-infiltration and reflects structural changes prior to fatty degeneration.

Diffusion tensor imaging of the human thigh: consideration of DTI-based fiber tracking stop criteria.

OBJECTIVES: To consider the tract-based analysis of DTI parameters in human muscle by assessing different fiber tracking stop criteria settings on diffusion parameters. MATERIALS AND METHODS: 30 healthy volunteers underwent a 3 T MRI. Diffusion-weighted images were acquired to perform DTI and fiber tracking analysis for six thigh muscles. Whole thigh muscles were evaluated by fiber tractography using different fiber tracking stop parameters [FA (0.01-0.15) to (0.4-0.99); angle 10°-30°, step size 0.75 mm, 1.5 mm, 3 mm]. Diffusion and tractography-derived parameters per stop criterion were compared using a repeated measure ANOVA including Bonferroni-corrected post hoc tests. RESULTS: We found significant differences in all examined diffusion parameters between different stop criteria (main effect p < 0.001). We showed different influence of tracking parameters on diffusion parameters in examined muscles (main effect p ≤ 0.001). CONCLUSIONS: Statistically significant differences in fiber tracking results using different stop criteria were shown. Fiber tracking stop criteria do have an important influence on study results and should be considered in the development of study protocols and comparison of studies. We recommend a FA minimum of 0.10 and a step size lower than voxel size, e.g., a half with a constant ratio between step size and angle of 10°/mm.

Pain Perception, Brain Connectivity, and Neurochemistry in Healthy, Capsaicin-Sensitive Subjects.

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.

The effects of dopaminergic D2-like receptor stimulation upon behavioral and neural correlates of renewal depend on individual context processing propensities.

Renewal is defined as the recovery of an extinguished response when the contexts of extinction and recall differ. Prominent hippocampal activity during context-related extinction can predict renewal. Dopaminergic antagonism during extinction learning impaired extinction and reduced hippocampal activation, without affecting renewal. However, to what extent dopaminergic stimulation during extinction influences hippocampal processing and renewal is as yet unknown. In this fMRI study, we investigated the effects of the dopamine D2-like agonist bromocriptine upon renewal in an associative learning task, in hippocampus and ventromedial PFC. We observed significant differences between bromocriptine (BROMO) and placebo (PLAC) treatments in the subgroups showing (REN) and lacking (NoREN) renewal: the renewal level of BROMO REN was significantly higher, and associated with more prominent hippocampal activation during extinction and recall, compared to PLAC REN and BROMO NoREN. Results suggest that an interaction between D2like-agonist-induced enhancement of hippocampal activity and a pre-existing tendency favoring context processing contributed to the higher renewal levels. In contrast, ventromedial prefrontal activation was unchanged, indicating that increased hippocampal context processing and not prefrontal response selection constituted the central driving force behind the high renewal levels. The findings demonstrate that hippocampal dopamine is important for encoding and providing of context information, and thus crucially involved in the renewal effect.

Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis.

OBJECTIVE: Sporadic inclusion body myositis (sIBM) pathogenesis is unknown; however, rimmed vacuoles (RVs) are a constant feature. We propose to identify proteins that accumulate within RVs. METHODS: RVs and intact myofibers were laser microdissected from skeletal muscle of 18 sIBM patients and analyzed by a sensitive mass spectrometry approach using label-free spectral count-based relative protein quantification. Whole exome sequencing was performed on 62 sIBM patients. Immunofluorescence was performed on patient and mouse skeletal muscle. RESULTS: A total of 213 proteins were enriched by >1.5 -fold in RVs compared to controls and included proteins previously reported to accumulate in sIBM tissue or when mutated cause myopathies with RVs. Proteins associated with protein folding and autophagy were the largest group represented. One autophagic adaptor protein not previously identified in sIBM was FYCO1. Rare missense coding FYCO1 variants were present in 11.3% of sIBM patients compared with 2.6% of controls (p = 0.003). FYCO1 colocalized at RVs with autophagic proteins such as MAP1LC3 and SQSTM1 in sIBM and other RV myopathies. One FYCO1 variant protein had reduced colocalization with MAP1LC3 when expressed in mouse muscle. INTERPRETATION: This study used an unbiased proteomic approach to identify RV proteins in sIBM that included a novel protein involved in sIBM pathogenesis. FYCO1 accumulates at RVs, and rare missense variants in FYCO1 are overrepresented in sIBM patients. These FYCO1 variants may impair autophagic function, leading to RV formation in sIBM patient muscle. FYCO1 functionally connects autophagic and endocytic pathways, supporting the hypothesis that impaired endolysosomal degradation underlies the pathogenesis of sIBM. Ann Neurol 2017;81:227-239.

Daily repetitive sensory stimulation of the paretic hand for the treatment of sensorimotor deficits in patients with subacute stroke: RESET, a randomized, sham-controlled trial.

BACKGROUND: Repetitive sensory stimulation (RSS) adapts the timing of stimulation protocols used in cellular studies to induce synaptic plasticity. In healthy subjects, RSS leads to widespread sensorimotor cortical reorganization paralleled by improved sensorimotor behavior. Here, we investigated whether RSS reduces sensorimotor upper limb impairment in patients with subacute stroke more effectively than conventional therapy. METHODS: A single-blinded sham-controlled clinical trial assessed the effectiveness of RSS in treating sensorimotor deficits of the upper limbs. Patients with subacute unilateral ischemic stroke were randomly assigned to receive standard therapy in combination with RSS or with sham RSS. Patients were masked to treatment allocation. RSS consisted of intermittent 20 Hz electrical stimulation applied on the affected hand for 45 min/day, 5 days per week, for 2 weeks, and was transmitted using custom-made stimulation-gloves with built-in electrodes contacting each fingertip separately. Before and after the intervention, we assessed light-touch and tactile discrimination, proprioception, dexterity, grip force, and subtasks of the Jebsen Taylor hand-function test for the non-affected and the affected hand. Data from these quantitative tests were combined into a total performance index serving as primary outcome measure. In addition, tolerability and side effects of RSS intervention were recorded. RESULTS: Seventy one eligible patients were enrolled and randomly assigned to receive RSS treatment (n = 35) or sham RSS (n = 36). Data of 25 patients were not completed because they were transferred to another hospital, resulting in n = 23 for each group. Before treatment, sensorimotor performance between groups was balanced (p = 0.237). After 2 weeks of the intervention, patients in the group receiving standard therapy with RSS showed significantly better restored sensorimotor function than the control group (standardized mean difference 0.57; 95% CI -0.013-1.16; p = 0.027) RSS treatment was superior in all domains tested. Repetitive sensory stimulation was well tolerated and accepted, and no adverse events were observed. CONCLUSIONS: Rehabilitation including RSS enhanced sensorimotor recovery more effectively than standard therapy alone. Rehabilitation outcome between the effects of RSS and standard therapy was largest for sensory and motor improvement; however, the results for proprioception and everyday tasks were encouraging warranting further studies in more severe patients. TRIAL REGISTRATION: The trial was retrospectively registered January 31, 2012 under DRKS00003515 ( https://www.drks.de/drks_web/navigate.do;jsessionid=AEE2585CCB82A22A2B285470B37C47C8?navigationId=results ).

Big GABA: Edited MR spectroscopy at 24 research sites.

Magnetic resonance spectroscopy (MRS) is the only biomedical imaging method that can noninvasively detect endogenous signals from the neurotransmitter γ-aminobutyric acid (GABA) in the human brain. Its increasing popularity has been aided by improvements in scanner hardware and acquisition methodology, as well as by broader access to pulse sequences that can selectively detect GABA, in particular J-difference spectral editing sequences. Nevertheless, implementations of GABA-edited MRS remain diverse across research sites, making comparisons between studies challenging. This large-scale multi-vendor, multi-site study seeks to better understand the factors that impact measurement outcomes of GABA-edited MRS. An international consortium of 24 research sites was formed. Data from 272 healthy adults were acquired on scanners from the three major MRI vendors and analyzed using the Gannet processing pipeline. MRS data were acquired in the medial parietal lobe with standard GABA+ and macromolecule- (MM-) suppressed GABA editing. The coefficient of variation across the entire cohort was 12% for GABA+ measurements and 28% for MM-suppressed GABA measurements. A multilevel analysis revealed that most of the variance (72%) in the GABA+ data was accounted for by differences between participants within-site, while site-level differences accounted for comparatively more variance (20%) than vendor-level differences (8%). For MM-suppressed GABA data, the variance was distributed equally between site- (50%) and participant-level (50%) differences. The findings show that GABA+ measurements exhibit strong agreement when implemented with a standard protocol. There is, however, increased variability for MM-suppressed GABA measurements that is attributed in part to differences in site-to-site data acquisition. This study's protocol establishes a framework for future methodological standardization of GABA-edited MRS, while the results provide valuable benchmarks for the MRS community.

d-Cycloserine facilitates extinction learning and enhances extinction-related brain activation.

Extinction learning is modulated by N-methyl d-aspartate receptors (NMDAR) particularly in prefrontal and hippocampal brain regions. The use of of NMDA agonists in exposure therapy of anxiety disorders has been investigated in various patient groups. Behavioral results showed beneficial effects of pre-learning administration of the partial NMDAR agonist d-Cycloserine (DCS) on therapy success. However, the impact of DCS upon non-fear-related contextual extinction, and associated recruitment of extinction-relevant brain regions is as yet unknown. In the present fMRI study, healthy human participants performed a context-related associative learning and extinction task. A single dose of DCS, administered prior to extinction learning, enhanced extinction learning performance in an identical context, and increased activation in prefrontal, temporal as well as hippocampal/insular regions, compared to placebo controls. In contrast, DCS did not affect extinction learning in a novel context, nor the renewal effect, which describes the recovery of an extinguished response if the context of extinction differs from the context of recall. Our findings demonstrate a specific involvement of prefrontal and hippocampal NMDAR in the modification of established stimulus-outcome associations in identical contexts and thus their role in behavioral flexibility, underlining their potential for enhancing AAA extinction learning.

Diffusion tensor imaging of the human calf: Variation of inter- and intramuscle-specific diffusion parameters.

PURPOSE: To investigate to what extent inter- and intramuscular variations of diffusion parameters of human calf muscles can be explained by age, gender, muscle location, and body mass index (BMI) in a specific age group (20-35 years). MATERIALS AND METHODS: Whole calf muscles of 18 healthy volunteers were evaluated. Magnetic resonance imaging (MRI) was performed using a 3T scanner and a 16-channel Torso XL coil. Diffusion-weighted images were acquired to perform fiber tractography and diffusion tensor imaging (DTI) analysis for each muscle of both legs. Fiber tractography was used to separate seven lower leg muscles. Associations between DTI parameters and confounds were evaluated. All muscles were additionally separated in seven identical segments along the z-axis to evaluate intramuscular differences in diffusion parameters. RESULTS: Fractional anisotropy (FA) and mean diffusivity (MD) were obtained for each muscle with low standard deviations (SDs) (SDFA : 0.01-0.02; SDMD : 0.07-0.14(10-3 )). We found significant differences in FA values of the tibialis anterior muscle (AT) and extensor digitorum longus (EDL) muscles between men and women for whole muscle FA (two-sample t-tests; AT: P = 0.0014; EDL: P = 0.0004). We showed significant intramuscular differences in diffusion parameters between adjacent segments in most calf muscles (P < 0.001). Whereas muscle insertions showed higher (SD 0.03-0.06) than muscle bellies (SD 0.01-0.03), no relationships between FA or MD with age or BMI were found. CONCLUSION: Inter- and intramuscular variations in diffusion parameters of the calf were shown, which are not related to age or BMI in this age group. Differences between muscle belly and insertion should be considered when interpreting datasets not including whole muscles. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1137-1148.