Myopathy as a cause of Long COVID fatigue: Evidence from quantitative and single fiber EMG and muscle histopathology.

OBJECTIVE: To describe neurophysiological abnormalities in Long COVID and correlate quantitative electromyography (qEMG) and single fiber EMG (sfEMG) results to clinical scores and histopathology. METHODS: 84 patients with non-improving musculoskeletal Long COVID symptoms were examined with qEMG and sfEMG. Muscle biopsies were taken in a subgroup. RESULTS: Mean motor unit potential (MUP) duration was decreased in ≥ 1 muscles in 52 % of the patients. Mean jitter was increased in 17 % of the patients in tibialis anterior and 25 % in extensor digitorum communis. Increased jitter was seen with or without myopathic qEMG. Low quality of life score correlated with higher jitter values but not with qEMG measures. In addition to our previously published mitochondrial changes, inflammation, and capillary injury, we show now in muscle biopsies damage of terminal nerves and motor endplate with abundant basal lamina material. At the endplate, axons were present but no vesicle containing terminals. The post-synaptic cleft in areas appeared atrophic with short clefts and coarse crests. CONCLUSIONS: Myopathic changes are common in Long COVID. sfEMG abnormality is less common but may correlate with clinical scores. sfEMG changes may be due to motor endplate pathology. SIGNIFICANCE: These findings may indicate a muscle pathophysiology behind fatigue in Long COVID.

Frequency drift in MR spectroscopy at 3T.

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.

Effect of repetitive transcranial magnetic stimulation on altered perception of One's own face.

BACKGROUND: Chronic orofacial pain (COP) patients often perceive the painful face area as "swollen" without clinical signs; such self-reported illusions of the face are termed perceptual distortion (PD). The pathophysiological mechanisms underlying PD remain elusive. OBJECTIVE: To test the neuromodulatory effect of repetitive transcranial magnetic stimulation (rTMS) on PD in healthy individuals, to gain insight into the cortical mechanisms underlying PD. METHODS: PD was induced experimentally by injections of local anesthetic (LA) around the infraorbital nerve and measured as perceived size changes of the affected area. Participants were randomly allocated to inhibitory rTMS (n = 26) or sham rTMS (n = 26) group. The participants rated PD at baseline, 6 min after LA, immediately, 20 and 40 min after rTMS. The rTMS (inhibitory and sham) was applied to face (lip) representation area of primary somatosensory cortex (SI) as an intervention at 10 min after the LA, when the magnitude of PD is large. As inhibitory rTMS, continuous theta-burst stimulation paradigm (50 Hz) for 40s was employed to inhibit cortical activity. RESULTS: We demonstrated a significant decrease in the magnitude of PD immediately and 20 min after the application of inhibitory rTMS compared with sham rTMS (P < 0.006). In two control experiments, we also showed that peripheral muscle stimulation and stimulation of a cortical region other than the lip representation area had no effect on the magnitude of the PD. CONCLUSIONS: Inhibitory rTMS applied to a somatotopical-relevant cortical region modulates PD of the face in healthy individuals and could potentially have therapeutic implications for COP patients.

Magnetic resonance (MR) spectroscopic measurement of γ-aminobutyric acid (GABA) in major depression before and after electroconvulsive therapy.

OBJECTIVE: Prior studies suggest that a dysregulation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) is involved in the pathophysiology of major depression. We aimed to elucidate changes in cortical GABA content in relation to depression and electroconvulsive therapy (ECT) using magnetic resonance spectroscopy (MRS). METHODS: In total, 11 patients with major depression or depressive episode of bipolar disorder (mean pre-ECT Ham-17 of 26) and 11 healthy subjects were recruited. GABA was quantified using short-TE MRS in prefrontal and occipital cortex. Other neurometabolites such as glutathione (GSH), N-acetylaspartate (NAA) and glutamate (Glu) were secondary outcome measures. RESULTS: No significant differences in GABA/Cr levels were observed between patients at baseline and healthy subjects in prefrontal cortex, t(20)=0.089, p=0.93 or occipital cortex t(21)=0.37, p=0.72. All patients improved on Ham-17 (mean post-ECT Ham-17 of 9). No significant difference was found in GABA, Glu, glutamine, choline or GSH between pre- and post-ECT values. However, we observed a significant decrease in NAA levels following ECT t(22)=3.89, p=0.0038, and a significant correlation between the NAA decline and the number of ECT sessions p=0.035. CONCLUSIONS: Our study does not support prior studies arguing for GABA as a key factor in the treatment effect of ECT on major depression. The reduction in NAA levels following ECT could be due to neuronal loss or a transient dysfunction in prefrontal cortex. As no long-term follow-up scan was performed, it is unknown whether NAA levels will normalise over time.

Decreased GABA levels in the symptomatic hemisphere in patients with transient ischemic attack.

Transient ischemic attack (TIA) is an ischemic episode of neurologic dysfunction characterized by a spontaneous clinical resolution of symptoms within 24 hours. Mechanisms of this remarkable recovery are not yet well understood. In patients with permanent brain injury caused by a stroke cortical levels of γ-Aminobutyric acid (GABA) are decreased. In this study, we aimed to investigate, whether similar alterations of cortical GABA are also present in patients with TIA. Ten first-time TIA patients with temporary unilateral motor symptoms from upper limb and 10 control subjects underwent Magnetic Resonance Spectroscopy (MRS) with SPECIAL technique. GABA:creatine (GABA:CR) ratios were measured in the hand area of the primary motor cortex in both hemispheres. GABA:CR ratios were significantly lower in the symptomatic hemisphere of TIA patients when compared with healthy subjects. Whether reduced GABA is induced directly by transient ischemia or is a secondary compensatory mechanism, which facilitate re-establishment of normal function remains to be elucidated. Further research investigating our findings in larger samples will aid in understanding of the clinical significance of GABA alterations in TIA patients. GABA MRS may provide vital information about mechanisms involved in recovery after transient ischemia, which may have crucial importance for development of new neuroprotective strategies in stroke.

Diffusion MRI findings in patients with extensive and minimal post-concussion symptoms after mTBI and healthy controls: a cross sectional study.

PRIMARY OBJECTIVES: We hypothesized that the microstructure of the corpus callosum, thalamus and hippocampus, as measured with diffusion and Mean of the Kurtosis Tensor (MKT) MRI, differs between healthy subjects and patients with extensive and minimal post-concussion symptoms (PCS) and that MKT measures correlate with PCS severity and self-reported cognitive symptoms. RESEARCH DESIGN: A cross-sectional study comparing patients with extensive PCS and patients with minimal PCS 2-5 months after mild traumatic brain injury (mTBI) with each other and with an external healthy control group. METHODS AND PROCEDURES: Diffusion MRI was obtained in 25 patients with extensive PCS and in 25 patients with minimal PCS as measured by the Rivermead Post-concussion Symptoms Questionnaire. The patients were matched on age, sex and time since accident. Data from an external healthy control group (n = 27) was included. MAIN OUTCOME AND RESULTS: There was no difference in MKT between the two groups with mTBI and no correlation between MKT and PCS. There was no difference between the three groups in other diffusion measures. CONCLUSIONS: Our results did not point to microstructural changes in the corpus callosum, thalamus and hippocampus in relation to PCS after mTBI.

Human Occipital and Parietal GABA Selectively Influence Visual Perception of Orientation and Size.

GABA is the primary inhibitory neurotransmitter in human brain. The level of GABA varies substantially across individuals, and this variability is associated with interindividual differences in visual perception. However, it remains unclear whether the association between GABA level and visual perception reflects a general influence of visual inhibition or whether the GABA levels of different cortical regions selectively influence perception of different visual features. To address this, we studied how the GABA levels of parietal and occipital cortices related to interindividual differences in size, orientation, and brightness perception. We used visual contextual illusion as a perceptual assay since the illusion dissociates perceptual content from stimulus content and the magnitude of the illusion reflects the effect of visual inhibition. Across individuals, we observed selective correlations between the level of GABA and the magnitude of contextual illusion. Specifically, parietal GABA level correlated with size illusion magnitude but not with orientation or brightness illusion magnitude; in contrast, occipital GABA level correlated with orientation illusion magnitude but not with size or brightness illusion magnitude. Our findings reveal a region- and feature-dependent influence of GABA level on human visual perception. Parietal and occipital cortices contain, respectively, topographic maps of size and orientation preference in which neural responses to stimulus sizes and stimulus orientations are modulated by intraregional lateral connections. We propose that these lateral connections may underlie the selective influence of GABA on visual perception.SIGNIFICANCE STATEMENT GABA, the primary inhibitory neurotransmitter in human visual system, varies substantially across individuals. This interindividual variability in GABA level is linked to interindividual differences in many aspects of visual perception. However, the widespread influence of GABA raises the question of whether interindividual variability in GABA reflects an overall variability in visual inhibition and has a general influence on visual perception or whether the GABA levels of different cortical regions have selective influence on perception of different visual features. Here we report a region- and feature-dependent influence of GABA level on human visual perception. Our findings suggest that GABA level of a cortical region selectively influences perception of visual features that are topographically mapped in this region through intraregional lateral connections.

The impact of large structural brain changes in chronic stroke patients on the electric field caused by transcranial brain stimulation.

Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) are two types of non-invasive transcranial brain stimulation (TBS). They are useful tools for stroke research and may be potential adjunct therapies for functional recovery. However, stroke often causes large cerebral lesions, which are commonly accompanied by a secondary enlargement of the ventricles and atrophy. These structural alterations substantially change the conductivity distribution inside the head, which may have potentially important consequences for both brain stimulation methods. We therefore aimed to characterize the impact of these changes on the spatial distribution of the electric field generated by both TBS methods. In addition to confirming the safety of TBS in the presence of large stroke-related structural changes, our aim was to clarify whether targeted stimulation is still possible. Realistic head models containing large cortical and subcortical stroke lesions in the right parietal cortex were created using MR images of two patients. For TMS, the electric field of a double coil was simulated using the finite-element method. Systematic variations of the coil position relative to the lesion were tested. For TDCS, the finite-element method was used to simulate a standard approach with two electrode pads, and the position of one electrode was systematically varied. For both TMS and TDCS, the lesion caused electric field "hot spots" in the cortex. However, these maxima were not substantially stronger than those seen in a healthy control. The electric field pattern induced by TMS was not substantially changed by the lesions. However, the average field strength generated by TDCS was substantially decreased. This effect occurred for both head models and even when both electrodes were distant to the lesion, caused by increased current shunting through the lesion and enlarged ventricles. Judging from the similar peak field strengths compared to the healthy control, both TBS methods are safe in patients with large brain lesions (in practice, however, additional factors such as potentially lowered thresholds for seizure-induction have to be considered). Focused stimulation by TMS seems to be possible, but standard tDCS protocols appear to be less efficient than they are in healthy subjects, strongly suggesting that tDCS studies in this population might benefit from individualized treatment planning based on realistic field calculations.

Microstructural changes in the thalamus after mild traumatic brain injury: A longitudinal diffusion and mean kurtosis tensor MRI study.

PRIMARY OBJECTIVE: The primary aim of this study was to assess microstructural changes in the thalamus, hippocampus and corpus callosum with a fast mean kurtosis tensor (MKT) technique, in the acute and sub-acute phase after mTBI. It was hypothesized that MKT would differ between baseline and follow-up in patients. The secondary aim was to relate diffusion measures to symptoms of mTBI. RESEARCH DESIGN: A longitudinal case-control study. METHODS AND PROCEDURES: Twenty-seven patients with mTBI and 27 age- and gender-matched healthy controls were enrolled in the study. Patients were scanned within 2 weeks and 3 months after mTBI, while the controls were scanned once. MAIN OUTCOMES AND RESULTS: MKT decreased significantly (p = 0.02) from baseline to follow-up in the thalamus in patients. Compared to healthy subjects, thalamic MKT values were significantly larger in patients at baseline (p = 0.048). Secondary analysis revealed a significant decrease (p = 0.01) in fractional anisotropy in the splenium of corpus callosum from baseline to follow-up. CONCLUSIONS: The current study indicates microstructural changes in the thalamus and corpus callosum from within 14 days to 3 months after mTBI and suggests MKT as a potential biomarker after mTBI.

Transcranial Direct Current Stimulation Potentiates Improvements in Functional Ability in Patients With Chronic Stroke Receiving Constraint-Induced Movement Therapy.

BACKGROUND AND PURPOSE: Transcranial direct current stimulation may enhance effect of rehabilitation in patients with chronic stroke. The objective was to evaluate the efficacy of anodal transcranial direct current stimulation combined with constraint-induced movement therapy of the paretic upper limb. METHODS: A total of 44 patients with stroke were randomly allocated to receive 2 weeks of constraint-induced movement therapy with either anodal or sham transcranial direct current stimulation. The primary outcome measure, Wolf Motor Function Test, was assessed at baseline and after the intervention by blinded investigators. RESULTS: Both groups improved significantly on all Wolf Motor Function Test scores. Group comparison showed improvement on Wolf Motor Function Test in the anodal group compared with the sham group. CONCLUSIONS: Anodal transcranial direct current stimulation combined with constraint-induced movement therapy resulted in improvement of functional ability of the paretic upper limb compared with constraint-induced movement therapy alone. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01983319.

Improved estimates for the role of grey matter volume and GABA in bistable perception.

Across a century or more, ambiguous stimuli have been studied scientifically because they provide a method for studying the internal mechanisms of the brain while ensuring an unchanging external stimulus. In recent years, several studies have reported correlations between perceptual dynamics during bistable perception and particular brain characteristics such as the grey matter volume of areas in the superior parietal lobule (SPL) and the relative GABA concentration in the occipital lobe. Here, we attempt to replicate previous results using similar paradigms to those used in the studies first reporting the correlations. Using the original findings as priors for Bayesian analyses, we found strong support for the correlation between structure-from-motion percept duration and anterior SPL grey matter volume. Correlations between percept duration and other parietal areas as well as occipital GABA, however, were not directly replicated or appeared less strong than previous studies suggested. Inspection of the posterior distributions (current "best guess" based on new data given old data as prior) revealed that several original findings may reflect true relationships although no direct evidence was found in support of them in the current sample. Additionally, we found that multiple regression models based on grey matter volume at 2-3 parietal locations (but not including GABA) were the best predictors of percept duration, explaining approximately 35% of the inter-individual variance. Taken together, our results provide new estimates of correlation strengths, generally increasing confidence in the role of the aSPL while decreasing confidence in some of the other relationships.

Automatic thalamus and hippocampus segmentation from MP2RAGE: comparison of publicly available methods and implications for DTI quantification.

PURPOSE: In both structural and functional MRI, there is a need for accurate and reliable automatic segmentation of brain regions. Inconsistent segmentation reduces sensitivity and may bias results in clinical studies. The current study compares the performance of publicly available segmentation tools and their impact on diffusion quantification, emphasizing the importance of using recently developed segmentation algorithms and imaging techniques. METHODS: Four publicly available, automatic segmentation methods (volBrain, FSL, FreeSurfer and SPM) are compared to manual segmentation of the thalamus and hippocampus imaged with a recently proposed T1-weighted MRI sequence (MP2RAGE). We evaluate morphometric accuracy on 22 healthy subjects and impact on diffusivity measurements obtained from aligned diffusion-weighted images on a subset of 10 subjects. RESULTS: Compared to manual segmentation, the highest Dice similarity index of the thalamus is obtained with volBrain using a local library ([Formula: see text], [Formula: see text]) followed by volBrain using an external library ([Formula: see text], [Formula: see text]), FSL ([Formula: see text], [Formula: see text]), FreeSurfer ([Formula: see text], [Formula: see text]) and SPM ([Formula: see text], [Formula: see text]). The same order is found for hippocampus with volBrain local ([Formula: see text], [Formula: see text]), volBrain external ([Formula: see text], [Formula: see text]), FSL ([Formula: see text], [Formula: see text]), FreeSurfer ([Formula: see text], [Formula: see text]) and SPM ([Formula: see text], [Formula: see text]). For diffusivity measurements, volBrain provides values closest to those obtained from manual segmentations. volBrain is the only method where FA values do not differ significantly from manual segmentation of the thalamus. CONCLUSIONS: Overall we find that volBrain is superior in thalamus and hippocampus segmentation compared to FSL, FreeSurfer and SPM. Furthermore, the choice of segmentation technique and training library affects quantitative results from diffusivity measures in thalamus and hippocampus.

Perfusion and pH MRI in familial hemiplegic migraine with prolonged aura.

INTRODUCTION: To investigate tissue flow disturbance and hypoxia during migraine aura, we studied a case of familial hemiplegic migraine (FHM) using novel magnetic resonance imaging (MRI) techniques. CASE RESULTS: A 44-year-old male was admitted with suspected stroke because of confusion and aphasia. Initial gadolinium-based perfusion MRI showed a decrease in cerebral blood flow and an increase in capillary flow disturbances within the left hemisphere. Later during the prolonged aura phase, chemical exchange saturation transfer MRI indicated a drop in pH in the affected area. The patient was diagnosed with an R908Q mutation in the ATP1A2 gene causing FHM type 2. DISCUSSION: During prolonged aura in FHM, MRI shows reduced CBF, capillary flow disturbances and a possible pH drop that could indicate tissue hypoxia.

GABA levels are decreased after stroke and GABA changes during rehabilitation correlate with motor improvement.

BACKGROUND AND OBJECTIVE: γ-Aminobutyric acid (GABA) is the dominant inhibitory neurotransmitter in the brain and is important in motor learning. We aimed to measure GABA content in primary motor cortex poststroke (using GABA-edited magnetic resonance spectroscopy [MRS]) and in relation to motor recovery during 2 weeks of constraint-induced movement therapy (CIMT). METHODS: Twenty-one patients (3-12 months poststroke) and 20 healthy subjects were recruited. Magnetic resonance imaging structural T1 and GABA-edited MRS were performed at baseline and after CIMT, and once in healthy subjects. GABA:creatine (GABA:Cr) ratio was measured by GABA-edited MRS. Motor function was measured using Wolf Motor Function Test (WMFT). RESULTS: Baseline comparison between stroke patients (n = 19) and healthy subjects showed a significantly lower GABA:Cr ratio in stroke patients (P < .001) even after correcting for gray matter content in the voxel (P < .01) and when expressing GABA relative to N-acetylaspartic acid (NAA; P = .03). After 2 weeks of CIMT patients improved significantly on WMFT, but no consistent change across the group was observed for the GABA:Cr ratio (n = 17). However, the extent of improvement on WMFT correlated significantly with the magnitude of GABA:Cr changes (P < .01), with decreases in GABA:Cr ratio being associated with better improvements in motor function. CONCLUSIONS: In patients 3 to 12 months poststroke, GABA levels are lower in the primary motor cortex than in healthy subjects. The observed association between GABA and recovery warrants further studies on the potential use of GABA MRS as a biomarker in poststroke recovery.

Long-term reproducibility of GABA magnetic resonance spectroscopy.

Recent findings suggest that cortical gamma aminobutyric acid (GABA) levels may provide a surrogate marker for a number of psychiatric and neurological conditions, as well as behavioural traits. However, the natural variability of GABA levels in the human brain over long periods of time (>8 days) has not yet been studied. The purpose of this work was to investigate the long-term variability of GABA concentrations in the human occipital cortex. Nineteen healthy male participants were recruited and underwent two sessions of magnetic resonance spectroscopy (MRS) to determine occipital GABA levels with an average between-session interval of 7 months. We assessed between-session variability, as well as the correlation between session 1 and session 2 GABA measurements. The mean coefficient of variation between sessions was 4.3% (bootstrap 95% confidence interval: 2.5, 6.4), which is comparable to reported GABA variability measurements over much shorter time intervals (<8 days). A significant positive correlation was observed between session 1 and session 2 GABA measurements (r=0.53, p=0.014), and the intra-class correlation coefficient was calculated to be 0.52 which was also statistically significant (p=0.012). These findings establish experimentally that GABA concentrations in the occipital cortex, as measured by MRS, are relatively stable over periods as long as 7 months. The findings have significant implications for the internal validity of longitudinal studies of GABA levels in the human brain, and they lend foundational support to studies relating GABA levels to behavioural traits in healthy individuals.

Occipital GABA correlates with cognitive failures in daily life.

The brain has limited capacity, and so selective attention enhances relevant incoming information while suppressing irrelevant information. This process is not always successful, and the frequency of such cognitive failures varies to a large extent between individuals. Here we hypothesised that individual differences in cognitive failures might be reflected in inhibitory processing in the sensory cortex. To test this hypothesis, we measured GABA in human visual cortex using MR spectroscopy and found a negative correlation between occipital GABA (GABA+/Cr ratio) and cognitive failures as measured by an established cognitive failures questionnaire (CFQ). For a second site in parietal cortex, no correlation between CFQ score and GABA+/Cr ratio was found, thus establishing the regional specificity of the link between occipital GABA and cognitive failures. We further found that grey matter volume in the left superior parietal lobule (SPL) correlated with cognitive failures independently from the impact of occipital GABA and together, occipital GABA and SPL grey matter volume statistically explained around 50% of the individual variability in daily cognitive failures. We speculate that the amount of GABA in sensory areas may reflect the potential capacity to selectively suppress irrelevant information already at the sensory level, or alternatively that GABA influences the specificity of neural representations in visual cortex thus improving the effectiveness of successful attentional modulation.

Predicting behavioural response to TDCS in chronic motor stroke.

Transcranial direct current stimulation (TDCS) of primary motor cortex (M1) can transiently improve paretic hand function in chronic stroke. However, responses are variable so there is incentive to try to improve efficacy and or to predict response in individual patients. Both excitatory (Anodal) stimulation of ipsilesional M1 and inhibitory (Cathodal) stimulation of contralesional M1 can speed simple reaction time. Here we tested whether combining these two effects simultaneously, by using a bilateral M1-M1 electrode montage, would improve efficacy. We tested the physiological efficacy of Bilateral, Anodal or Cathodal TDCS in changing motor evoked potentials (MEPs) in the healthy brain and their behavioural efficacy in changing reaction times with the paretic hand in chronic stroke. In addition, we aimed to identify clinical or neurochemical predictors of patients' behavioural response to TDCS. There were three main findings: 1) unlike Anodal and Cathodal TDCS, Bilateral M1-M1 TDCS (1 mA, 20 min) had no significant effect on MEPs in the healthy brain or on reaction time with the paretic hand in chronic stroke patients; 2) GABA levels in ipsilesional M1 predicted patients' behavioural gains from Anodal TDCS; and 3) although patients were in the chronic phase, time since stroke (and its combination with Fugl-Meyer score) was a positive predictor of behavioural gain from Cathodal TDCS. These findings indicate the superiority of Anodal or Cathodal over Bilateral TDCS in changing motor cortico-spinal excitability in the healthy brain and in speeding reaction time in chronic stroke. The identified clinical and neurochemical markers of behavioural response should help to inform the optimization of TDCS delivery and to predict patient outcome variability in future TDCS intervention studies in chronic motor stroke.

Cognitive status does not predict motor gain from post stroke constraint-induced movement therapy.

BACKGROUND: Constraint-Induced Movement Therapy (CIMT) is an evidence-based rehabilitation intervention for stroke. Several factors influence the motor gain from CIMT, including age and level of impairment. However, it is currently unknown to what extent cognitive status affects motor gain during CIMT. OBJECTIVE: The aim of this study was to investigate whether cognitive and emotional status affects motor improvement during two weeks of CIMT and retention of the gain at three months follow-up. METHODS: Twenty stroke patients (3-12 months post stroke) completed two weeks of CIMT. Motor performance was measured using the Wolf Motor Function Test (WMFT). Cognitive and emotional status was measured with a comprehensive neuropsychological test battery and a questionnaire on emotional status. All measures were performed at baseline, after two weeks of training, and at three months follow-up. RESULTS: We found no significant correlation between cognitive or emotional measures at baseline and improvement in motor performance post training. Also, cognitive and emotional status did not correlate with motor retention at three months follow-up. CONCLUSIONS: We found no evidence to support that cognitive performance in stroke patients can predict motor gain from CIMT.

The role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage.

The mortality after aneurysmal subarachnoid hemorrhage (SAH) is 50%, and most survivors suffer severe functional and cognitive deficits. Half of SAH patients deteriorate 5 to 14 days after the initial bleeding, so-called delayed cerebral ischemia (DCI). Although often attributed to vasospasms, DCI may develop in the absence of angiographic vasospasms, and therapeutic reversal of angiographic vasospasms fails to improve patient outcome. The etiology of chronic neurodegenerative changes after SAH remains poorly understood. Brain oxygenation depends on both cerebral blood flow (CBF) and its microscopic distribution, the so-called capillary transit time heterogeneity (CTH). In theory, increased CTH can therefore lead to tissue hypoxia in the absence of severe CBF reductions, whereas reductions in CBF, paradoxically, improve brain oxygenation if CTH is critically elevated. We review potential sources of elevated CTH after SAH. Pericyte constrictions in relation to the initial ischemic episode and subsequent oxidative stress, nitric oxide depletion during the pericapillary clearance of oxyhemoglobin, vasogenic edema, leukocytosis, and astrocytic endfeet swelling are identified as potential sources of elevated CTH, and hence of metabolic derangement, after SAH. Irreversible changes in capillary morphology and function are predicted to contribute to long-term relative tissue hypoxia, inflammation, and neurodegeneration. We discuss diagnostic and therapeutic implications of these predictions.