Kerstin Irlbacher

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).

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.

An initial transient-state and reliable measures of corticospinal excitability in TMS studies

OBJECTIVE The objective of this study was to determine if an initial transient state influences the acquisition of reliable estimates of corticospinal excitability in transcranial magnetic stimulation (TMS) studies. Whereas muscle evoked potential (MEP) amplitudes are an important index of cortical excitability, these are severely limited by sweep-to-sweep variability. Interesting in this context is the experimental observation that the first MEP amplitudes might be much larger than subsequent responses [Brasil-Neto JP, Cohen LG, Hallet M. Central fatigue as revealed by postexercise decrement of motor evoked potentials. Muscle Nerve 1994;17:713-9]. This led to the hypothesis that an initial transient-state of increased excitability affects MEP amplitude derived estimates of corticospinal excitability. METHODS To address this issue we acquired repeated measures of single pulse MEP amplitudes over the primary motor cortex with and without navigated brain stimulation (NBS) and with various TMS-coils. Importantly, NBS allows for the sweep-to-sweep differentiation of physical and physiological variability. RESULTS We found a significant decline in estimates of corticospinal excitability and a transition from log-Normal to Normal distributed state, after which reliable measures (British Standards Institute) could be acquired. CONCLUSIONS We argue that an initial transient state of physiological origin influences measures of corticospinal excitability. SIGNIFICANCE This has important implications for investigations of cortical excitability. For example, it could reduce variability over studies and within small group comparisons.

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.

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.

Long-term effects of serial anodal tDCS on motion perception in subjects with occipital stroke measured in the unaffected visual hemifield

Transcranial direct current stimulation (tDCS) is a novel neuromodulatory tool that has seen early transition to clinical trials, although the high variability of these findings necessitates further studies in clinically relevant populations. The majority of evidence into effects of repeated tDCS is based on research in the human motor system, but it is unclear whether the long-term effects of serial tDCS are motor-specific or transferable to other brain areas. This study aimed to examine whether serial anodal tDCS over the visual cortex can exogenously induce long-term neuroplastic changes in the visual cortex. However, when the visual cortex is affected by a cortical lesion, up-regulated endogenous neuroplastic adaptation processes may alter the susceptibility to tDCS. To this end, motion perception was investigated in the unaffected hemifield of subjects with unilateral visual cortex lesions. Twelve subjects with occipital ischemic lesions participated in a within-subject, sham-controlled, double-blind study. MRI-registered sham or anodal tDCS (1.5 mA, 20 min) was applied on five consecutive days over the visual cortex. Motion perception was tested before and after stimulation sessions and at 14- and 28-day follow-up. After a 16-day interval an identical study block with the other stimulation condition (anodal or sham tDCS) followed. Serial anodal tDCS over the visual cortex resulted in an improvement in motion perception, a function attributed to MT/V5. This effect was still measurable at 14- and 28-day follow-up measurements. Thus, this may represent evidence for long-term tDCS-induced plasticity and has implications for the design of studies examining the time course of tDCS effects in both the visual and motor systems.

Transcranial magnetic and electrical stimulation compared: Does TES activate intracortical neuronal circuits?

OBJECTIVE To determine whether, and under which conditions, transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS) can activate similar neuronal structures of the human motor cortex, as indicated by electromyographic recordings. METHODS Focal TMS was performed on three subjects inducing a postero-anterior directed current (p-a), TES with postero-anteriorly (p-a) and latero-medially (l-m) oriented electrodes. We analyzed the onset latencies and amplitudes (single-pulse) and intracortical inhibition and excitation (paired-pulse). RESULTS TMS p-a and TES p-a produced muscle responses with the same onset latency, while TES l-m led to 1.4-1.9 ms shorter latencies. Paired-pulse TMS p-a and TES p-a induced inhibition at short inter-stimulus intervals (ISI) (maximum: 2-3 ms) and facilitation at longer ISIs (maximum: 10 ms). No inhibition but a strong facilitation was obtained from paired-pulse TES l-m (ISIs 1-5 ms). CONCLUSIONS Our findings support the hypothesis, that current direction is the most relevant factor in determining the mode of activation for both TMS and TES: TMS p-a and TES p-a are likely to activate the corticospinal neurons indirectly. In contrast, TES l-m may preferentially activate the corticospinal fibres directly, distant of the neuronal body. SIGNIFICANCE TES is a suitable tool to induce intracortical inhibition and excitation.

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.

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.

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).