New variant of necklace fibres display peculiar lysosomal structures and mitophagy.

Here, we describe a new variant of necklace fibres with specific myopathological features that have not been described thus far. They were observed in two patients, from two independent families with identical DNM2 (dynamin 2) mutation (c.1106 G > A (p.Arg369Gln)), displaying mildly heterogeneous clinical phenotypes. The variant is characterized by lysosomal inclusions, arranged in a necklace pattern, containing homogenous material, devoid of myonuclei. The so-called necklace region has a certain characteristic distance to the sarcolemma. Electron microscopy, including three dimensional reconstructions of serial section images highlights their ultrastructural properties and relation to neighbouring organelles. This new pattern is compared to the previously reported patterns in muscle biopsies containing necklace fibres associated with MTM1- and DNM2-mutations.

Long-Lasting Enhancement of Visual Perception with Repetitive Noninvasive Transcranial Direct Current Stimulation.

Understanding processes performed by an intact visual cortex as the basis for developing methods that enhance or restore visual perception is of great interest to both researchers and medical practitioners. Here, we explore whether contrast sensitivity, a main function of the primary visual cortex (V1), can be improved in healthy subjects by repetitive, noninvasive anodal transcranial direct current stimulation (tDCS). Contrast perception was measured via threshold perimetry directly before and after intervention (tDCS or sham stimulation) on each day over 5 consecutive days (24 subjects, double-blind study). tDCS improved contrast sensitivity from the second day onwards, with significant effects lasting 24 h. After the last stimulation on day 5, the anodal group showed a significantly greater improvement in contrast perception than the sham group (23 vs. 5%). We found significant long-term effects in only the central 2-4° of the visual field 4 weeks after the last stimulation. We suspect a combination of two factors contributes to these lasting effects. First, the V1 area that represents the central retina was located closer to the polarization electrode, resulting in higher current density. Second, the central visual field is represented by a larger cortical area relative to the peripheral visual field (cortical magnification). This is the first study showing that tDCS over V1 enhances contrast perception in healthy subjects for several weeks. This study contributes to the investigation of the causal relationship between the external modulation of neuronal membrane potential and behavior (in our case, visual perception). Because the vast majority of human studies only show temporary effects after single tDCS sessions targeting the visual system, our study underpins the potential for lasting effects of repetitive tDCS-induced modulation of neuronal excitability.

Multiple, Successful Pregnancies in Pompe Disease.

Pompe disease is an autosomal recessive lysosomal storage disease characterized in adult patients by slowly progressive limb-girdle muscle weakness and respiratory insufficiency. Data on pregnancy in women with Pompe disease, intrauterine development of the fetus and parturition are rare. Here we describe a twin pregnancy followed by a second pregnancy in a 38-year-old female patient with Pompe disease. We report the impact of pregnancy on muscle and respiratory functions as well as the neurological and endocrine systems and discuss the medical consequences for anaesthetic management at parturition.

Dissociable spatial and non-spatial attentional deficits after circumscribed thalamic stroke.

Thalamic nuclei act as sensory, motor and cognitive relays between multiple subcortical areas and the cerebral cortex. They play a crucial role in cognitive functions such as executive functioning, memory and attention. In the acute period after thalamic stroke attentional deficits are common. The precise functional relevance of specific nuclei or vascular sub regions of the thalamus for attentional sub functions is still unclear. The theory of visual attention (TVA) allows the measurement of four independent attentional parameters (visual short term memory storage capacity (VSTM), visual perceptual processing speed, selective control and spatial weighting). We combined parameter-based assessment based on TVA with lesion symptom mapping in standard stereotactic space in sixteen patients (mean age 41.2 ± 11.0 SD, 6 females), with focal thalamic lesions in the medial (N = 9), lateral (N = 5), anterior (N = 1) or posterior (N = 1) vascular territories of the thalamus. Compared with an age-matched control group of 52 subjects (mean age 40.1 ± 6.4, 35 females), the patients with thalamic lesions were, on the group level, mildly impaired in visual processing speed and VSTM. Patients with lateral thalamic lesions showed a deficit in processing speed while all other TVA parameters were within the normal range. Medial thalamic lesions can be associated with a spatial bias and extinction of targets either in the ipsilesional or the contralesional field. A posterior case with a thalamic lesion of the pulvinar replicated a finding of Habekost and Rostrup (2006), demonstrating a spatial bias to the ipsilesional field, as suggested by the neural theory of visual attention (NTVA) (Bundesen, Habekost, & Kyllingsbæk, 2011). A case with an anterior-medial thalamic lesion showed reduced selective attentional control. We conclude that lesions in distinct vascular sub regions of the thalamus are associated with distinct attentional syndromes (medial = spatial bias, lateral = processing speed).

Timing of spatial priming within the fronto-parietal attention network: A TMS study.

The posterior parietal cortex (PPC) and the dorsolateral prefrontal cortex (DLPFC) are known to be part of a cortical network involved in visual spatial attention. Top-down control can modulate processing at target and distractor positions over a sequence of trials, leading to positive priming at prior target positions and negative priming at prior distractor positions. In order to elucidate the exact time course of this top-down mechanism we here propose a transcranial magnetic stimulation (TMS) protocol. Single-pulses were applied over the right PPC, the right DLPFC or over the vertex (sham stimulation) at five time intervals (50, 100, 150, 200, 250 ms) after onset of a probe display during a spatial negative priming paradigm. Both suppression of the negative priming effect at a previous distractor position and enhancement of positive priming at a previous target position was found if a TMS pulse was applied 100 ms after the probe display onset either over the right DLPFC or the right PPC. We suggest that top-down mechanisms within the right fronto-parietal attention network are compromised during TMS interference in this time window.

TMS over the right precuneus reduces the bilateral field advantage in visual short term memory capacity.

BACKGROUND: Several studies have demonstrated a bilateral field advantage (BFA) in early visual attentional processing, that is, enhanced visual processing when stimuli are spread across both visual hemifields. The results are reminiscent of a hemispheric resource model of parallel visual attentional processing, suggesting more attentional resources on an early level of visual processing for bilateral displays [e.g. Sereno AB, Kosslyn SM. Discrimination within and between hemifields: a new constraint on theories of attention. Neuropsychologia 1991;29(7):659-75.]. Several studies have shown that the BFA extends beyond early stages of visual attentional processing, demonstrating that visual short term memory (VSTM) capacity is higher when stimuli are distributed bilaterally rather than unilaterally. OBJECTIVE/HYPOTHESIS: Here we examine whether hemisphere-specific resources are also evident on later stages of visual attentional processing. METHODS: Based on the Theory of Visual Attention (TVA) [Bundesen C. A theory of visual attention. Psychol Rev 1990;97(4):523-47.] we used a whole report paradigm that allows investigating visual attention capacity variability in unilateral and bilateral displays during navigated repetitive transcranial magnetic stimulation (rTMS) of the precuneus region. RESULTS: A robust BFA in VSTM storage capacity was apparent after rTMS over the left precuneus and in the control condition without rTMS. In contrast, the BFA diminished with rTMS over the right precuneus. CONCLUSION: This finding indicates that the right precuneus plays a causal role in VSTM capacity, particularly in bilateral visual displays.

Mechanisms and neuronal networks involved in reactive and proactive cognitive control of interference in working memory.

Cognitive control can be reactive or proactive in nature. Reactive control mechanisms, which support the resolution of interference, start after its onset. Conversely, proactive control involves the anticipation and prevention of interference prior to its occurrence. The interrelation of both types of cognitive control is currently under debate: Are they mediated by different neuronal networks? Or are there neuronal structures that have the potential to act in a proactive as well as in a reactive manner? This review illustrates the way in which integrating knowledge gathered from behavioral studies, functional imaging, and human electroencephalography proves useful in answering these questions. We focus on studies that investigate interference resolution at the level of working memory representations. In summary, different mechanisms are instrumental in supporting reactive and proactive control. Distinct neuronal networks are involved, though some brain regions, especially pre-SMA, possess functions that are relevant to both control modes. Therefore, activation of these brain areas could be observed in reactive, as well as proactive control, but at different times during information processing.

Neurological and neuropsychological characteristics of occipital, occipito-temporal and occipito-parietal infarction.

Neuropsychological deficits after occipital infarction are most often described in case studies and only a small sample of studies has attempted to exactly correlate the anatomical localization of lesions with associated neuropsychological symptoms. The present study investigated a large number of patients (N = 128) in order to provide an overview of neurological and neuropsychological deficits after occipital, occipito-temporal and occipito-parietal infarction. A particular approach of the study was to define exact anatomical correlates of neuropsychological dysfunction by using voxel-based lesion-symptom mapping (VLSM) in 61 patients. In addition to a visual field defect and phosphenes, patients often reported anomia, difficulties in reading and memory deficits. Visual disorders, such as achromatopsia, akinetopsia or prosopagnosia, were rarely reported by the patients. Memory and visual disorders were diagnosed efficiently using simple clinical screening tests, such as the Rey-Osterrieth Complex Figure Test for immediate recall, the Demtect and the Lang Stereo Test. Visual field defects, reading disorders and the perception of phosphenes were associated primarily with lesions of the calcarine sulcus. Anomia and memory deficits were related to lesions of the occipital inferior gyrus, the lingual gyrus and hippocampus, as well as to lesions of principal white matter tracts.

Evolution of premotor cortical excitability after cathodal inhibition of the primary motor cortex: a sham-controlled serial navigated TMS study.

BACKGROUND: Premotor cortical regions (PMC) play an important role in the orchestration of motor function, yet their role in compensatory mechanisms in a disturbed motor system is largely unclear. Previous studies are consistent in describing pronounced anatomical and functional connectivity between the PMC and the primary motor cortex (M1). Lesion studies consistently show compensatory adaptive changes in PMC neural activity following an M1 lesion. Non-invasive brain modification of PMC neural activity has shown compensatory neurophysiological aftereffects in M1. These studies have contributed to our understanding of how M1 responds to changes in PMC neural activity. Yet, the way in which the PMC responds to artificial inhibition of M1 neural activity is unclear. Here we investigate the neurophysiological consequences in the PMC and the behavioral consequences for motor performance of stimulation mediated M1 inhibition by cathodal transcranial direct current stimulation (tDCS). PURPOSE: The primary goal was to determine how electrophysiological measures of PMC excitability change in order to compensate for inhibited M1 neural excitability and attenuated motor performance. HYPOTHESIS: Cathodal inhibition of M1 excitability leads to a compensatory increase of ipsilateral PMC excitability. METHODS: We enrolled 16 healthy participants in this randomized, double-blind, sham-controlled, crossover design study. All participants underwent navigated transcranial magnetic stimulation (nTMS) to identify PMC and M1 corticospinal projections as well as to evaluate electrophysiological measures of cortical, intracortical and interhemispheric excitability. Cortical M1 excitability was inhibited using cathodal tDCS. Finger-tapping speeds were used to examine motor function. RESULTS: Cathodal tDCS successfully reduced M1 excitability and motor performance speed. PMC excitability was increased for longer and was the only significant predictor of motor performance. CONCLUSION: The PMC compensates for attenuated M1 excitability and contributes to motor performance maintenance.

Immune-mediated necrotizing myopathy is characterized by a specific Th1-M1 polarized immune profile.

Immune-mediated necrotizing myopathy (IMNM) is considered one of the idiopathic inflammatory myopathies, comprising dermatomyositis, polymyositis, and inclusion body myositis. The heterogeneous group of necrotizing myopathies shows a varying amount of necrotic muscle fibers, myophagocytosis, and a sparse inflammatory infiltrate. The underlying immune response in necrotizing myopathy has not yet been addressed in detail. Affected muscle tissue, obtained from 16 patients with IMNM, was analyzed compared with eight non-IMNM (nIMNM) tissues. Inflammatory cells were characterized by IHC, and immune mediators were assessed by quantitative real-time PCR. We demonstrate that immune- and non-immune-mediated disease can be distinguished by a specific immune profile with significantly more prominent major histocompatibility complex class I expression and complement deposition and a conspicuous inflammatory infiltrate. In addition, patients with IMNM exhibit a strong type 1 helper T cell (T1)/classically activated macrophage M1 response, with detection of elevated interferon-γ, tumor necrosis factor-α, IL-12, and STAT1 levels in the muscle tissue, which may serve as biomarkers and aid in diagnostic decisions. Furthermore, B cells and high expression of the chemoattractant CXCL13 were identified in a subgroup of patients with defined autoantibodies. Taken together, we propose a diagnostic armamentarium that allows for clear differentiation between IMNM and nIMNM. In addition, we have characterized a Th1-driven, M1-mediated immune response in most of the autoimmune necrotizing myopathies, which may guide therapeutic options in the future.

Excitability changes in the visual cortex quantified with signal detection analysis.

PURPOSE: TDCS can increase excitability in the visual cortex. It is a matter of current debate if tDCS can improve visual performance. Promising parameters to measure detection sensitivity may be those of the signal detection theory ( = SDT), as it allows differentiating between response bias and detection sensitivity changes. The measure of detection sensitivity can be used to predict actual performance under a wide variety of different response criteria. METHODS: Here we test if the SDT can quantify tDCS-induced effects in a visual contrast discrimination task in healthy subjects. RESULTS: Anodal stimulation of the visual cortex improved performance, as calculated by detection sensitivity for stimuli presented in the center of the visual field. More peripheral locations in the visual field were unaffected by anodal stimulation. Cathodal stimulation and sham stimulation of the visual cortex had no consistent effect on detection sensitivity. The response bias was not affected by any type of stimulation. CONCLUSIONS: Neuroplastic changes in the visual cortex induced by anodal tDCS can be measured by SDT, suggesting SDT could prospectively be a useful approach for monitoring restorative tDCS-effects on visual function in patients with central visual deficits.

Transcranial direct current stimulation affects visual perception measured by threshold perimetry.

In this study, we aimed to characterize the effect of anodal and cathodal direct current stimulation (tDCS) on contrast sensitivity inside the central 10 degrees of the visual field in healthy subjects. Distinct eccentricities were investigated separately, since at the cortical level, more central regions of the visual field are represented closer to the occipital pole, i.e. closer to the polarizing electrodes, than are the more peripheral regions. Using a double-blind and sham-controlled within-subject design, we measured the effect of stimulation and potential learning effect separately across testing days. Anodal stimulation of the visual cortex compared to sham stimulation yielded a significant increase in contrast sensitivity within 8° of the visual field. A significant increase in contrast sensitivity between the conditions "pre" and "post" anodal stimulation was only obtained for the central positions at eccentricities smaller than 2°. Cathodal stimulation of the visual cortex did not affect contrast sensitivity at either eccentricity. Perceptual learning across testing days was only observed for threshold perimetry before stimulation. Measuring contrast sensitivity changes after tDCS with a standard clinical tool such as threshold perimetry may provide an interesting perspective in assessing therapeutic effects of tDCS in ophthalmological or neurological defects (e.g. with foveal sparing vs. foveal splitting).

A case of pathological excitability located with navigated-TMS: presurgical evaluation of focal neocortical epilepsy.

PURPOSE: The quality of presurgical evaluation in focal extratemporal epilepsy surgery is highly dependent on precise structural and functional identification of the epileptic focus. Navigated transcranial magnetic stimulation (nTMS) is a tool that combines the spatial information of high-resolution magnetic resonance imaging (MRI) with the functionality of non-invasive cortical stimulation. The non-invasive character of nTMS suggests that it could be a promising tool for presurgical evaluation of cortical excitability. METHODS: Presurgical nTMS evaluation was performed on an 8-year-old boy with left-sided intractable focal epilepsy, somatosensory auras and epilepsia partialis continua. In line with standardized procedures, motor evoked potentials were sought in both hemispheres over perirolandic cortex during simultaneous belly-tendon surface recordings of the first dorsal interosseus muscles. RESULTS: One singular motor-evoked potential (MEP) could be elicited in the unaffected hemisphere. In contrast, in the affected hemisphere MEPs could be elicited over a large area of the cortex even after the stimulation strength was reduced by at least 44%. Latency stratification in the affected hemisphere differentiated a motor from a sensory region of interest. Stimulation over the sensory region induced a sensory aura. The sensory site was concordant with a previous transient diffusion restriction found in an MRI two years prior to nTMS. CONCLUSIONS: NTMS can locate pathological excitability with high spatial precision. Future studies should compare nTMS with direct cortex stimulation, as well as the combination of nTMS with electroencephalography (EEG) in a larger patient-collective.

In-frame deletion in the seventh immunoglobulin-like repeat of filamin C in a family with myofibrillar myopathy.

Myofibrillar myopathies (MFMs) are an expanding and increasingly recognized group of neuromuscular disorders caused by mutations in DES, CRYAB, MYOT, and ZASP. The latest gene to be associated with MFM was FLNC; a p.W2710X mutation in the 24th immunoglobulin-like repeat of filamin C was shown to be the cause of a distinct type of MFM in several German families. We studied an International cohort of 46 patients from 39 families with clinically and myopathologically confirmed MFM, in which DES, CRYAB, MYOT, and ZASP mutations have been excluded. In patients from an unrelated family a 12-nucleotide deletion (c.2997_3008del) in FLNC resulting in a predicted in-frame four-residue deletion (p.Val930_Thr933del) in the seventh repeat of filamin C was identified. Both affected family members, mother and daughter, but not unrelated control individuals, carried the p.Val930_Thr933del mutation. The mutation is transcribed and, based on myopathological features and immunoblot analysis, it leads to an accumulation of dysfunctional filamin C in the myocytes. The study results suggest that the novel p.Val930_Thr933del mutation in filamin C is the cause of MFM but also indicate that filamin C mutations are a comparatively rare cause of MFM.

Electrophysiological evidence for cognitive control during conflict processing in visual spatial attention.

Event-related potentials were measured to investigate the role of visual spatial attention mechanisms in conflict processing. We suggested that a more difficult target selection leads to stronger attentional top-down control, thereby reducing the effects of arising conflicts. This hypothesis was tested by varying the selection difficulty in a location negative priming (NP) paradigm. The difficult task resulted in prolonged responses as compared to the easy task. A behavioral NP effect was only evident in the easy task. Psychophysiologically the easy task was associated with reduced parietal N1, enhanced frontocentral N2 and N2pc components and a prolonged P3 latency for the conflict as compared to the control condition. The N2pc effect was also obvious in the difficult task. Additionally frontocentral N2 amplitudes increased and latencies of N2pc and P3 were delayed compared to the easy task. The differences at frontocentral and parietal electrodes are consistent with previous studies ascribing activity in the prefrontal and parietal cortex as the source of top-down attentional control. Thus, we propose that stronger cognitive control is involved in the difficult task, resulting in a reduced behavioral NP conflict.

Transcranial cortex stimulation and fMRI: electrophysiological correlates of dual-pulse BOLD signal modulation.

UNLABELLED: Are the local hemodynamic changes in BOLD-fMRI correlated to increased or decreased neuronal activity or both? We combined transcranial electrical cortex stimulation (TES) with simultaneous fMRI and electromyographic (EMG) recording to study the influence of inhibitory and excitatory neuronal activity on the concomitant BOLD signal change. Unilateral or bilateral TES was applied with a postero-anterior orientation. This activates pyramidal cells transsynaptically and allows for the induction of cortical inhibition and excitation of the pyramidal cell, respectively. In this project interhemispheric inhibition (IHI) served as an in vivo model to investigate electrophysiologically well defined inhibitory and excitatory effects. METHODOLOGY: Included event-related fMRI, which triggered TES; online recording of the EMG response monitored the inhibitory and excitatory influences on discharging corticospinal neurons. RESULTS: Revealed that a single suprathreshold stimulus induced a positive BOLD response both in the ipsilateral as well as in the contralateral primary motor cortex (M1). The contralateral co-activation of the homotopic M1 should be a functional correlate of transcallosal connections. If a contralateral conditioning stimulus preceded the test stimulus by 10 ms (IHI), the subsequent ipsilateral BOLD signal was significantly reduced. We find that cortical inhibitory processes are accompanied by attenuation of the local neurovascular signal.

Executive control over response priming and conflict: a transcranial magnetic stimulation study.

In the present study repetitive transcranial magnetic stimulation (rTMS) was utilised to interrupt neural activity in selected cortical areas at several different time periods while participants performed a stimulus-response correspondence (SRC) task. Responses are usually faster and less error-prone when stimulus (S) and response (R) features correspond than when they do not. Dual-route models of response preparation account for such SRC effects by postulating an indirect route performing S-R selection and a parallel direct route where S features prime their corresponding responses. SRC effects have recently been shown to depend on the preceding trial type, that is, SRC effects are largely reduced when preceded by a non-corresponding trial as compared to a preceding corresponding trial. Present results show that this context dependency of the SRC effect was hindered when rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) 500-300 ms before the onset of the next trial. Moreover, the SRC effect was reduced overall when applying rTMS volleys to the right posterior parietal cortex (PPC) for 200 ms with the onset of the visual stimulus. We conclude that the left DLPFC is involved in the context-dependent control of response conflicts, whereas the right PPC serves early visuomotor transformations and is, therefore, related to direct route priming.

Influence of ipsilateral transcranial magnetic stimulation on the triphasic EMG pattern accompanying fast ballistic movements in humans.

Fast ballistic flexion movements of the wrist are produced by a triphasic pattern of electromyographic (EMG) activity in flexor and extensor muscle. Whereas it is generally accepted that the primary motor cortex generates the first agonist burst (AG1), its contribution to the following antagonist burst (ANT) and second agonist burst (AG2) is unresolved. We applied single pulses of suprathreshold transcranial magnetic stimulation (TMS) at different times to the motor cortex ipsilateral to wrist flexion. This produced interhemispheric inhibition of the opposite motor cortex and a silent period in the ballistic EMG pattern that started about 30 ms after the stimulus and lasted for a further 30 ms. If the silence was timed to start within the first 30 ms of AG1, then timing of the subsequent ANT and AG2 bursts was delayed. However, if the silence began later, then the timing of the ANT burst was not changed. A similar effect on the onset latency of the AG2 was seen if the silence began in the first part of the ANT burst. The results are compatible with a model in which the triphasic pattern is not triggered as a single entity. Instead we suggest that each burst has its own trigger that occurs about 30-40 ms after the start of AG1 (or ANT). If AG1 (or ANT) is interrupted within this time period then this trigger, and hence later bursts, are delayed. If the interruption occurs after 30-40 ms it has no effect on the onset of later bursts since they have already been triggered.

Comparison of motor effects following subcortical electrical stimulation through electrodes in the globus pallidus internus and cortical transcranial magnetic stimulation.

Current concepts of transcranial magnetic stimulation (TMS) over the primary motor cortex are still under debate as to whether inhibitory motor effects are exclusively of cortical origin. To further elucidate a potential subcortical influence on motor effects, we combined TMS and unilateral subcortical electrical stimulation (SES) of the corticospinal tract. SES was performed through implanted depth electrodes in eight patients treated with deep brain stimulation (DBS) for severe dystonia. Chronaxie, conduction velocity (CV) of the stimulated fibres and poststimulus time histograms of single motor unit recordings were calculated to provide evidence of an activation of large diameter myelinated fibres by SES. Excitatory and inhibitory motor effects recorded bilaterally from the first dorsal interosseus muscle were measured after SES and focal TMS of the motor cortex. This allowed us to compare motor effects of subcortical (direct) and cortical (mainly indirect) activation of corticospinal neurons. SES activated a fast conducting monosynaptic pathway to the alpha motoneuron. Motor responses elicited by SES had significantly shorter onset latency and shorter duration of the contralateral silent period compared to TMS induced motor effects. Spinal excitability as assessed by H-reflex was significantly reduced during the silent period after SES. No ipsilateral motor effects could be elicited by SES while TMS was followed by an ipsilateral inhibition. The results suggest that SES activated the corticospinal neurons at the level of the internal capsule. Comparison of SES and TMS induced motor effects reveals that the first part of the TMS induced contralateral silent period should be of spinal origin while its later part is due to cortical inhibitory mechanisms. Furthermore, the present results suggest that the ipsilateral inhibition is predominantly mediated via transcallosal pathways.

In vivo study indicating loss of intracortical inhibition in tumor-associated epilepsy.

Transcranial magnetic stimulation was performed in 2 patients with focal motor seizures in the right hand caused by a circumscribed tumor process affecting the left precentral gyrus. In both cases, paired-pulse transcranial magnetic stimulation showed a loss of intracortical inhibition for interstimulus intervals of 2 to 4msec that was replaced by an enormous facilitation in the lesioned hand motor cortex. The uniform impairment of inhibitory mechanisms in epileptogenic tumors with different histologies suggests a common, nonspecific cause of tumor-related epileptogenesis.