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Abstract Functional electrical stimulation (FES) can support functional restoration of a paretic limb post-stroke. Hebbian plasticity depends on temporally coinciding pre- and post-synaptic activity. A tight temporal relationship between motor cortical (MC) activity associated with attempted movement and FES-generated visuo-proprioceptive feedback is hypothesized to enhance motor recovery. Using a brain–computer interface (BCI) to classify MC spectral power in electroencephalographic (EEG) signals to trigger FES-delivery with detection of movement attempts improved motor outcomes in chronic stroke patients. We hypothesized that heightened neural plasticity earlier post-stroke would further enhance corticomuscular functional connectivity and motor recovery. We compared subcortical non-dominant hemisphere stroke patients in BCI-FES and Random-FES (FES temporally independent of MC movement attempt detection) groups. The primary outcome measure was the Fugl-Meyer Assessment, Upper Extremity (FMA-UE). We recorded high-density EEG and transcranial magnetic stimulation-induced motor evoked potentials before and after treatment. The BCI group showed greater: FMA-UE improvement; motor evoked potential amplitude; beta oscillatory power and long-range temporal correlation reduction over contralateral MC; and corticomuscular coherence with contralateral MC. These changes are consistent with enhanced post-stroke motor improvement when movement is synchronized with MC activity reflecting attempted movement.

Electrocorticographic recordings in 10 patients show that stimulus response and repetition suppression are temporally, spatially, and spectrally distinct.

BackgroundCerebral microbleeds (MBs) are a hallmark of cerebral small vessel disease (CSVD) and can be found on T2*-weighted sequences on MRI. Quantitative susceptibility mapping (QSM) is a postprocessing method that also enables MBs identification and furthermore allows to differentiate them from calcifications.AimsWe explored the implications of using QSM at submillimeter resolution for MBs detection in CSVD.MethodsBoth 3 and 7 Tesla (T) MRI were performed in elderly participants without MBs and patients with CSVD. MBs were quantified on T2*-weighted imaging and QSM. Differences in the number of MBs were assessed, and subjects were classified in CSVD subgroups or controls both on 3T T2*-weighted imaging and 7T QSM.Results48 participants [mean age (SD) 70.9 (8.8) years, 48% females] were included: 31 were healthy controls, 6 probable cerebral amyloid angiopathy (CAA), 9 mixed CSVD, and 2 were hypertensive arteriopathy [HA] patients. After accounting for the higher number of MBs detected at 7T QSM (Median = Mdn; Mdn7T−QSM = 2.5; Mdn3T−T2 = 0; z = 4.90; p < 0.001) and false positive MBs (6.1% calcifications), most healthy controls (80.6%) demonstrated at least one MB and more MBs were discovered in the CSVD group.ConclusionsOur observations suggest that QSM at submillimeter resolution improves the detection of MBs in the elderly human brain. A higher prevalence of MBs than so far known in healthy elderly was revealed.

Abstract The brain is universally regarded as a system for processing information. If so, any behavioral or cognitive dysfunction should lend itself to depiction in terms of information processing deficiencies. Information is characterized by recursive, hierarchical complexity. The brain accommodates this complexity by a hierarchy of large/slow and small/fast spatiotemporal loops of activity. Thus, successful information processing hinges upon tightly regulating the spatiotemporal makeup of activity, to optimally match the underlying multiscale delay structure of such hierarchical networks. Reduced capacity for information processing will then be expressed as deviance from this requisite multiscale character of spatiotemporal activity. This deviance is captured by a general family of multiscale criticality measures (MsCr). MsCr measures reflect the behavior of conventional criticality measures (such as the branching parameter) across temporal scale. We applied MsCr to MEG and EEG data in several telling degraded information processing scenarios. Consistently with our previous modeling work, MsCr measures systematically varied with information processing capacity: MsCr fingerprints showed deviance in the four states of compromised information processing examined in this study, disorders of consciousness, mild cognitive impairment, schizophrenia and even during pre-ictal activity. MsCr measures might thus be able to serve as general gauges of information processing capacity and, therefore, as normative measures of brain health.

Multiparameter mapping (MPM) is a quantitative MRI protocol that is promising for studying microstructural brain changes in vivo with high specificity. Reliability values are an important prior knowledge for efficient study design and facilitating replicable findings in development, aging and neuroplasticity research. To explore longitudinal reliability of MPM we acquired the protocol in 31 healthy young subjects twice over a rescan interval of 4 weeks. We assessed the within-subject coefficient of variation (WCV), the between-subject coefficient of variation (BCV), and the intraclass correlation coefficient (ICC). Using these metrics, we investigated the reliability of (semi-) quantitative magnetization transfer saturation (MTsat), proton density (PD), transversal relaxation (R2*) and longitudinal relaxation (R1). To increase relevance for explorative studies in development and training-induced plasticity, we assess reliability both on local voxel- as well as ROI-level. Finally, we disentangle contributions and interplay of within- and between-subject variability to ICC and assess the optimal degree of spatial smoothing applied to the data. We reveal evidence that voxelwise ICC reliability of MPMs is moderate to good with median values in cortex (subcortical GM): MT: 0.789 (0.447) PD: 0.553 (0.264) R1: 0.555 (0.369) R2*: 0.624 (0.477). The Gaussian smoothing kernel of 2 to 4 mm FWHM resulted in optimal reproducibility. We discuss these findings in the context of longitudinal intervention studies and the application to research designs in neuroimaging field.

Background: One key mechanism thought to underlie speech processing is the alignment of cortical brain rhythms to the acoustic input, a mechanism termed entrainment. Recent work showed that transcranial electrical stimulation (tES) in speech relevant frequencies or adapted to the speech envelope can in fact enhance speech processing. However, it is unclear whether an oscillatory tES is necessary, or if transients in the stimulation (e.g., peaks in the tES signal) at relevant times are sufficient. Objective: In this study we used a novel pulsed-tES-protocol and tested behaviorally if a transiently pulsed - instead of a persistently oscillating - tES signal, can improve speech processing. Methods: While subjects listened to spoken sentences embedded in noise, brief electric direct current pulses aligned to speech transients (syllable onsets) were applied to auditory cortex regions to modulate comprehension. Additionally, we modulated the temporal delay between tES-pulses and speech transients to test for periodic modulations of behavior, indicative of entrainment by tES. Results: Speech comprehension was improved when tES-pulses were applied with a delay of 100 ms in respect to the speech transients. Contradictory to previous reports we find no periodic modulation of behavior. However, we find indications that periodic modulations can be spurious results of sampling behavioral data too coarsely. Conclusions: Subject’s speech comprehension benefits from pulsed-tES, yet behavior is not modulated periodically. Thus, pulsed-tES can aid cortical entrainment to speech input, which is especially relevant in a noisy environment. Yet, pulsed-tES does not seem to entrain brain oscillations by itself.

Abstract Background Dyspnea is frequent in amyotrophic lateral sclerosis (ALS) and one of the most bothersome symptoms. The recently developed Dyspnea-ALS-Scale (DALS-15) is a disease-specific patient-reported outcome to detect and quantify dyspnea. Objectives To analyze in a case-based approach the diagnostic and clinical implications and the benefit of the DALS-15 for individual patients in daily clinical routine. Methods Dyspnea was assessed by the 15-item comprising DALS-15 in two patients with ALS. Spirometry was performed and blood gases were analyzed. Results were evaluated in the clinical context of the respective patients. Results In one patient the presence of dyspnea detected by the DALS-15 indicated noninvasive ventilation (NIV) although forced vital capacity (FVC) and blood gas analysis were well preserved. After NIV implementation, the DALS-15 was helpful to determine the patient’s need for medication, the timing of NIV titration and the adaptation of NIV sessions. In another patient, who was anarthric and no longer able to perform spirometry due to severe bulbar impairment, the DALS-15 allowed a standardized assessment of dyspnea-related distress independently of bulbar dysfunction. Conclusion The DALS-15 provides a deeper insight into the respiratory status of individual patients. It helps to diagnose respiratory impairment in patients in whom NIV should be considered although FVC and blood gas results do not reveal indication for NIV. It is also valuable for the guidance of patients in later stages of respiratory impairment when NIV is already implemented, and in patients with severe bulbar dysfunction. The DALS-15 can improve specific symptom management and coordination of care and therefore has the potential to optimize individual treatment in ALS patients with dyspnea.

Abstract Background Central drop foot is a common problem in patients with stroke or multiple sclerosis (MS). For decades, it has been treated with orthotic devices, keeping the ankle in a fixed position. It has been shown recently that semi-implantable functional electrical stimulation (siFES) of the peroneal nerve can lead to a greater gait velocity increase than orthotic devices immediately after being switched on. Little is known, however, about long-term outcomes over 12 months, and the relationship between quality of life (QoL) and gait speed using siFES has never been reported applying a validated tool. We provide here a report of short (3 months) and long-term (12 months) outcomes for gait speed and QoL. Methods Forty-five consecutive patients (91% chronic stroke, 9% MS) with central drop foot received siFES (Actigait®). A 10 m walking test was carried out on day 1 of stimulation (T1), in stimulation ON and OFF conditions, and repeated after 3 (T2) and 12 (T3) months. A 36-item Short Form questionnaire was applied at all three time points. Results We found a main effect of stimulation on both maximum (p

Abstract Background Prepulse inhibition (PPI) of the acoustic startle response, a measurement of sensorimotor gaiting, is modulated by monoaminergic, presumably dopaminergic neurotransmission. Disturbances of the dopaminergic system can cause deficient PPI as found in neuropsychiatric diseases. A target specific influence of deep brain stimulation (DBS) on PPI has been shown in animal models of neuropsychiatric disorders. In the present study, three patients with early dementia of Alzheimer type underwent DBS of the median forebrain bundle (MFB) in a compassionate use program to maintain cognitive abilities. This provided us the unique possibility to investigate the effects of different stimulation conditions of DBS of the MFB on PPI in humans. Results Separate analysis of each patient consistently showed a frequency dependent pattern with a DBS-induced increase of PPI at 60 Hz and unchanged PPI at 20 or 130 Hz, as compared to sham stimulation. Conclusions Our data demonstrate that electrical stimulation of the MFB modulates PPI in a frequency-dependent manner. PPI measurement could serve as a potential marker for optimization of DBS settings independent of the patient or the examiner.

Regaining communication abilities in patients who are unable to speak or move is one of the main goals in decoding brain waves for brain-computer interface (BCI) control. Many BCI approaches designed for communication rely on attention to visual stimuli, commonly applying an oddball paradigm, and require both eye movements and adequate visual acuity. These abilities may, however, be absent in patients who depend on BCI communication. We have therefore developed a response-based communication BCI, which is independent of gaze shifts but utilizes covert shifts of attention to the left or right visual field. We recorded the electroencephalogram (EEG) from 29 channels and coregistered the vertical and horizontal electrooculogram. Data-driven decoding of small attention-based differences between the hemispheres, also known as N2pc, was performed using 14 posterior channels, which are expected to reflect correlates of visual spatial attention. Eighteen healthy participants responded to 120 statements by covertly directing attention to one of two colored symbols (green and red crosses for “yes” and “no,” respectively), presented in the user’s left and right visual field, respectively, while maintaining central gaze fixation. On average across participants, 88.5% (std: 7.8%) of responses were correctly decoded online. In order to investigate the potential influence of stimulus features on accuracy, we presented the symbols with different visual angles, by altering symbol size and eccentricity. The offline analysis revealed that stimulus features have a minimal impact on the controllability of the BCI. Hence, we show with our novel approach that spatial attention to a colored symbol is a robust method with which to control a BCI, which has the potential to support severely paralyzed people with impaired eye movements and low visual acuity in communicating with their environment.

Unique to humans is the ability to report subjective awareness of a broad repertoire of external and internal events. Even when asked to focus on external information, the human’s mind repeatedly wanders to task-unrelated thoughts, which limits reading comprehension or the ability to withhold automated manual responses. This led to the attentional decoupling account of mind wandering (MW). However, manual responses are not an ideal parameter to study attentional decoupling, given that during MW, the online adjustment of manual motor responses is impaired. Hence, whether early attentional mechanisms are indeed downregulated during MW or only motor responses being slowed is not clear. In contrast to manual motor responses, eye movements are considered a sensitive proxy of attentional shifts. Using a simple target detection task, we asked subjects to indicate whether a target was presented within a visual search display by pressing a button while we recorded eye movements and unpredictably asked the subjects to rate their actual level of MW. Generally, manual reaction times increased with MW, both in target absent and present trials. But importantly, even in trials with MW, subjects detected earlier a presented than an absent target. The decoupling account would predict more fixations of the target before pressing the button during MW. However, our results did not corroborate this assumption. Most importantly, subject’s time to direct gaze at the target was equally fast in trials with and without MW. Our results corroborate our hypothesis that during MW early, bottom–up driven attentional processes are not decoupled but selectively manual motor responses are slowed.

Introduction: The initial disease stages of hypertensive arteriopathy (HA) and cerebral amyloid angiopathy (CAA), the two main forms of sporadic human cerebral small vessel diseases (CSVD), are too subtle to be detectable on clinical routine imaging. Small vessel disease (SVD) is a systemic condition, affecting not only the brain, but also other organs. The retina appears as an ideal marker for the early detection of incipient CSVD. We therefore investigated the retinal microvasculature of the spontaneously hypertensive stroke-prone rat (SHRSP), an animal model of sporadic CSVD.Materials and Methods: The brains and retinas of 26 male SHRSP (18–44 weeks) were examined histologically and immunohistochemically for the presence of HA phenomena (erythrocyte thrombi, small perivascular bleeds) and amyloid angiopathy (AA).Results: CAA and AA in the retina showed a significant correlation with age (CAA: rho = 0.55, p = 0.005; AA: rho = 0.89, p < 0.001). The number of erythrocyte thrombi in the brain correlated with the severity of retinal erythrocyte thrombi (rho = 0.46, p = 0.023), while the occurrence of CAA correlated with the appearance of AA in the retina (rho = 0.51, p = 0.012). Retinal SVD markers predicted CSVD markers with good sensitivity.Conclusions: These results indicate that SVD also occurs in the retinal microvasculature of SHRSP and the prediction of cerebral erythrocyte thrombi and CAA might be possible using retinal biomarkers. This underlines the important role of the investigation of the retina in the early diagnosis of CSVD.

Brain function requires the flexible coordination of billions of neurons across multiple scales. This could be achieved by scale-free, critical dynamics balanced at the edge of order and disorder. Criticality has been demonstrated in several, often reduced neurophysiological model systems. In the intact human brain criticality has yet been only verified for the resting state. A more direct link between the concept of criticality and oscillatory brain physiology, which is strongly related to cognition, is yet missing. In the present study we therefore carried out a frequency-specific analysis of criticality in the MEG, recorded while subjects were in a defined cognitive state through mindfulness meditation. In a two-step approach we assessed whether the macroscopic neural avalanche dynamics is scale-free by evaluating the goodness of a power-law fits of cascade size and duration distributions of MEG deflections in different frequency bands. In a second step we determined the closeness of the power-law exponents to a critical value of -1.5. Power-law fitting was evaluated by permutation testing, fitting of alternative distributions, and cascade shape analysis. Criticality was verified by defined relationships of exponents of cascade size and duration distributions. Behavioral relevance of criticality was tested by correlation of indices of criticality with individual scores of the Mindful Attention Awareness Scale. We found that relevant scale-free near-critical dynamics originated only from broad-band high-frequency (> 100 Hz) MEG activity, which has been associated with action potential firing, and therefore links criticality on the macroscopic level of MEG to critical spike avalanches on a microscopic level. Whereas a scale-free dynamics was found under mindfulness meditation and rest, avalanche dynamics shifted towards a critical point during meditation by reduction of neural noise. Together with our finding that during mindfulness meditation avalanches show differences in topography relative to rest, our results show that self-regulated attention as required during meditation can serve as a control parameter of criticality in scale-free brain dynamics.

Abstract The present study investigated the neural correlates associated with gait improvements triggered by an active prosthesis in patients with drop-foot following stroke during the chronic stage. Eleven patients took part in the study. MEG recordings in conjunction with somatosensory stimulation of the left and right hand as well as gait analyses were performed shortly before or after prosthesis implantation surgery and 3–4 months later. Plastic changes of the sensorimotor cortex of the ipsi- and contralesional hemisphere were revealed. Gait analysis indicated that all patients improved their gait with the active prosthesis. Patients with larger plastic changes within the lesioned hemisphere maintained their improved gait performance even when the prosthesis was turned off. Patients with larger contralesional changes also improved their gait with the active prosthesis. However, their gait measures decreased when the prosthesis was turned off. The current data provide the neural basis of gait improvement triggered by an active prosthesis and has important implications with respect to the choice of the type of active prosthesis (implantable vs removable) and to the selection procedure of the patients (length of testing period).

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor symptoms following dopaminergic depletion in the substantia nigra. Besides motor impairments, however, several non-motor detriments can have the potential to considerably impact subjectively perceived quality of life in patients. Particularly emotion recognition of facial expressions has been shown to be affected in PD, and especially the perception of negative emotions like fear, anger, or disgust is impaired. While emotion processing generally refers to automatic implicit as well as conscious explicit processing, the focus of most previous studies in PD was on explicit recognition of emotions only, while largely ignoring implicit processing deficits. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is widely accepted as a therapeutic measure in the treatment of PD and has been shown to advantageously influence motor problems. Among various concomitant non-motor effects of STN-DBS, modulation of facial emotion recognition under subthalamic stimulation has been investigated in previous studies with rather heterogeneous results. Although there seems to be a consensus regarding the processing of disgust, which significantly deteriorates under STN stimulation, findings concerning emotions like fear or happiness report heterogeneous data and seem to depend on various experimental settings and measurements. In the present review, we summarized previous investigations focusing on STN-DBS influence on recognition of facial emotional expressions in patients suffering from PD. In a first step, we provide a synopsis of disturbances and problems in facial emotion processing observed in patients with PD. Second, we present findings of STN-DBS influence on facial emotion recognition and especially highlight different impacts of stimulation on implicit and explicit emotional processing.

Cognitive control is characterized by selective attention to relevant stimuli while irrelevant, distracting stimuli are inhibited. While the classical color-word Stroop task was implemented to investigate the processes of cognitive control, a variant of it—the face-word Stroop task—allows for directly investigating processes of emotional conflict control. It is thought that the prefrontal cortex (PFC) is especially involved in processes of cognitive control, while the rostral cingulate is mainly associated with the resolution of emotional conflict. In recent years, the role of the dorsolateral PFC (DLPFC) during the performance of the classical Stroop was investigated by means of transcranial direct current stimulation (tDCS) with divergent results. However, investigations to the causal role of the DLPFC during emotional conflict processing are rare. For this purpose, we used a combined high-definition tDCS (HD-tDCS)/electroencephalogram (EEG) setting to investigate the impact of anodal stimulation of the left DLPFC on behavioral and electrophysiological responses during an emotional face-word Stroop task. In two separate sessions, participants (n = 18) received either sham or anodal HD-tdc stimulation while responding to the emotional expression of the face and ignoring the word. Our results show that anodal stimulation of the left DLPFC increases the behavioral interference effect, that is, the already decelerated reaction times (RTs) to incongruent trials further increase while RTs to congruent trials remain largely unaffected. Furthermore, the stimulation modulates brain response to emotional facial expressions during the face-word Stroop generally—independent of the valence of the emotional expression and the congruency of the combined face-word presentation, the N170 decreases during anodal stimulation. These results reveal that the left DLPFC has a causal role in emotional conflict processing during a face-word Stroop.

Transcutaneous vagus nerve stimulation (tVNS) is widely used for clinical applications, but its mechanism of action is poorly understood. One candidate pathway that might mediate the effects of tVNS is an increase in GABAergic neurotransmission. In this study, we investigated the effect of tVNS on visual bistable perception, which is highly coupled to GABA. Participants were 34 healthy young subjects. We used a static (Necker cube) and a dynamic (structure from motion) bistable perception task. Each subject underwent tVNS as well as sham (placebo) stimulation for ∼45 min. We analyze effects of tVNS on percept durations by means of Bayesian multilevel regression. We find no evidence for a modulation of bistable perception dynamics through tVNS in either task, but the analyses do not ultimately confirm the null hypothesis either. We discuss different possible implications of our finding and propose that GABAergic effects of tVNS should be further investigated using more direct measures of GABA concentration, and, more generally, that a better understanding of the mechanisms of action of vagus nerve stimulation is needed. Finally, we discuss limitations of our study design, data analysis, and conclusions.

In its early stages multiple system atrophy (MSA), a neurodegenerative movement disorder, can be difficult to differentiate from idiopathic Parkinson's disease (PD), and emphasis has been put on identifying premotor symptoms to allow for its early identification. The occurrence of vegetative symptoms in addition to motor impairment, such as orthostatic hypotension and neurogenic bladder dysfunction, enable the clinical diagnosis in the advanced stages of the disease. Usually with further disease progression, laryngeal abnormalities become clinically evident and can manifest in laryngeal stridor due to impaired vocal fold motion, such as vocal fold abduction restriction, mostly referred to as vocal fold paresis, or paradoxical vocal fold adduction during inspiration. While the pathogenesis of laryngeal stridor is discussed controversially, its occurrence is clearly associated with reduced life expectancy. Before the clinical manifestation of laryngeal dysfunction however, abnormal vocal fold motion can already be seen in patients that might not yet fulfill the diagnostic criteria of MSA. In this article we summarize the current literature on pharyngolaryngeal findings in MSA and report preliminary findings from a pilot study investigating eight consecutive MSA patients. Patients showed varying speech abnormalities. Only 2/8 patients exhibited laryngeal stridor. However, during FEES, all patients presented with irregular arytenoid cartilages movements and vocal fold abduction restriction. 3/8 showed vocal fold fixation and 1/8 paradoxical vocal fold motion. All patients presented with oropharyngeal dysphagia, 5/8 with penetration or aspiration events. We suggest that specific abnormal vocal fold motion can help identifying MSA patients and may allow for delimiting this disorder from idiopathic PD. These findings therefore may serve as a novel clinical biomarker for MSA. Based on the available data and our preliminary clinical experience we developed a standardized easy-to-implement task-protocol to be performed during flexible endoscopic evaluation of swallowing (FEES) for detection of MSA-related pharyngolaryngeal movement disorders. Furthermore, we initiated a prospective study to evaluate the diagnostic utility of this protocol.

Motor recovery following stroke is believed to necessitate alteration in functional connectivity between cortex and muscle. Cortico-muscular coherence has been proposed as a potential biomarker for post-stroke motor deficits, enabling a quantification of recovery, as well as potentially indicating the regions of cortex involved in recovery of function. We recorded simultaneous EEG and EMG during wrist extension from healthy participants and patients following ischaemic stroke, evaluating function at three time points post-stroke. EEG–EMG coherence increased over time, as wrist mobility recovered clinically, and by the final evaluation, coherence was higher in the patient group than in the healthy controls. Moreover, the cortical distribution differed between the groups, with coherence involving larger and more bilaterally scattered areas of cortex in the patients than in the healthy participants. The findings suggest that EEG–EMG coherence has the potential to serve as a biomarker for motor recovery and to provide information about the cortical regions that should be targeted in rehabilitation therapies based on real-time EEG.

The data presented here comprise clinical, neuropsychological, and intrathalamic electrophysiological data from 7 patients with pharmacoresistant focal epilepsy and are related to the article “Pre-stimulus thalamic theta power predicts human memory formation” C.M. Sweeney-Reed, T. Zaehle, J. Voges, F.C. Schmitt, L. Buentjen, K. Kopitzki, et al. (2016) [1]. The patients participated in a memory paradigm after receiving electrodes implanted in the DMTN due to the surgical approach taken in electrode insertion for deep brain stimulation of the anterior thalamic nucleus. Epilepsy duration and pre-operative neuropsychological tests provide an indication of the profile of patients receiving intrathalamic electrode implantation and the memory capabilities in such a patient group. The electrophysiological data were recorded from the right DMTN preceding stimulus presentation during intentional memory encoding. The patients viewed a series of photographic scenes, which they judged as indoors or outdoors. The 900 ms epochs prior to stimulus presentation were labeled as preceding successful or unsuccessful subsequent memory formation according to a subsequent memory test for the items. The difference between theta power preceding successful versus unsuccessful subsequent memory formation is shown against time for each patient individually. Keywords: Memory encoding, Dorsomedial thalamic nucleus, Pre-stimulus theta

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that affects upper and lower motor neurons. Observational and intervention studies can be tracked using clinical measures such as the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) but for a complete understanding of disease progression, objective in vivo biomarkers of both central and peripheral motor pathway pathology are highly desirable. The aim of this study was to determine the utility of structural and diffusion imaging as central nervous system biomarkers compared to the standard clinical measure, ALSFRS-R, to track longitudinal evolution using three time-point measurements. N = 34 patients with ALS were scanned and clinically assessed three times at a mean of three month time intervals. The MRI biomarkers were structural T1-weighted volumes for cortical thickness measurement as well as deep grey matter volumetry, voxel-based morphometry and diffusion tensor imaging (DTI). Cortical thickness focused specifically on the precentral gyrus while quantitative DTI biomarkers focused on the corticospinal tracts. The evolution of imaging biomarkers and ALSFRS-R scores over time were analysed using a mixed effects model that accounted for the scanning interval as a fixed effect variable, and, the initial measurements and time from onset as random variables. The mixed effects model showed a significant decrease in the ALSFRS-R score, (p 0.5). In addition, deep grey matter volumetry and voxel-based morphometry also identified no significant changes. Furthermore, the availability of three time points was able to indicate that there was a linear progression in both clinical and fractional anisotropy measures adding to the validity of these results. The results indicate that DTI is clearly a superior imaging marker compared to atrophy for tracking the evolution of the disease and can act as a central nervous biomarker in longitudinal studies. It remains, however, less sensitive than the ALSFRS-R score for monitoring decline over time.

Purpose: Aim of the present study was to investigate potential impairment of non-motor areas in amyotrophic lateral sclerosis (ALS) using near-infrared spectroscopy (NIRS) and diffusion tensor imaging (DTI). In particular, we evaluated whether homotopic resting-state functional connectivity (rs-FC) of non-motor associated cortical areas correlates with clinical parameters and disease-specific degeneration of the corpus callosum (CC) in ALS. Material and methods: Interhemispheric homotopic rs-FC was assessed in 31 patients and 30 healthy controls (HCs) for 8 cortical sites, from prefrontal to occipital cortex, using NIRS. DTI was performed in a subgroup of 21 patients. All patients were evaluated for cognitive dysfunction in the executive, memory, and visuospatial domains. Results: ALS patients displayed an altered spatial pattern of correlation between homotopic rs-FC values when compared to HCs (p = 0.000013). In patients without executive dysfunction a strong correlation existed between the rate of motor decline and homotopic rs-FC of the anterior temporal lobes (ATLs) (ρ = −0.85, p = 0.0004). Furthermore, antero-temporal homotopic rs-FC correlated with fractional anisotropy in the central corpus callosum (CC), corticospinal tracts (CSTs), and forceps minor as determined by DTI (p

Background: Diagnosis of immune-mediated neuropathies and their differentiation from amyotrophic lateral sclerosis (ALS) can be challenging, especially at early disease stages. Accurate diagnosis is, however, important due to the different prognosis and available treatment options. We present one patient with a left-sided dorsal flexor paresis and initial suspicion of ALS and another with multifocal sensory deficits. In both, peripheral nerve imaging was the key for diagnosis. Methods: We performed high-resolution nerve ultrasound (HRUS) and 7T or 3T magnetic resonance neurography (MRN). Results: In both patients, HRUS revealed mild to severe, segmental or inhomogeneous, nerve enlargement at multiple sites, as well as an area increase of isolated fascicles. MRN depicted T2 hyperintense nerves with additional contrast-enhancement. Discussion: Peripheral nerve imaging was compatible with the respective diagnosis of an immune-mediated neuropathy, i.e., multifocal motor neuropathy (MMN) in patient 1 and multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) in patient 2. Peripheral nerve imaging, especially HRUS, should play an important role in the diagnostic work-up for immune-mediated neuropathies and their differentiation from ALS.

Calcium imaging in freely behaving rodents using head-mounted miniature microscopes is currently becoming an increasingly popular technique in neuroscience. Due to the large amounts of complex data that the technique produces, user friendly software is needed for quick and efficient processing. Here, we present a new tool for analyzing calcium imaging data from head-mounted microscopes together with simultaneously acquired behavioral data: CAVE (Calcium ActiVity Explorer). CAVE bundles a unique set of algorithms specifically tailored to the analysis of single-photon imaging data from awake behaving animals including efficient motion correction and automatic ROI selection with manual audit and refinement. For behavioral analysis, CAVE can automatically track animal position and orientation. Individual behavioral epochs and external events can then be analyzed in correlation to calcium imaging and tracking data. Our program is written in MATLAB, the source code is open source and particularly focuses on providing a streamlined workflow for novice users while also retaining detailed configuration options for advanced users. We evaluate the performance of CAVE by investigating neural activity in hippocampus and somatosensory cortex. The fast analysis provided by CAVE allowed us to track activity in a large set of animals over the course of several months during exploration behavior, detailing the properties of onset and offset of observable activity and the visible cells per imaging location.

Transcranial electrical stimulation (TES) has been considered a promising tool for improving working memory (WM) performance. Recent studies have demonstrated modulation of networks underpinning WM processing through application of transcranial alternating current (TACS) as well as direct current (TDCS) stimulation. Differences between study designs have limited direct comparison of the efficacy of these approaches, however. Here we directly compared the effects of theta TACS (6 Hz) and anodal TDCS on WM, applying TACS to the frontal-parietal loop and TDCS to the dorsolateral prefrontal cortex (DLPFC). WM was evaluated using a visual 2-back WM task. A within-subject, crossover design was applied (N = 30) in three separate sessions. TACS, TDCS, and sham stimulation were administered in a counterbalanced order, and the WM task was performed before, during, and after stimulation. Neither reaction times for hits (RT-hit) nor accuracy differed according to stimulation type with this study design. A marked practice effect was noted, however, with improvement in RT-hit irrespective of stimulation type, which peaked at the end of the second session. Pre-stimulation RT-hits in session three returned to the level observed pre-stimulation in session two, irrespective of stimulation type. The participants who received sham stimulation in session one and had therefore improved their performance due to practice alone, had thus reached a plateau by session two, enabling us to pool RT-hits from sessions two and three for these participants. The pooling allowed implementation of a within-subject crossover study design, with a direct comparison of the effects of TACS and TDCS in a subgroup of participants (N = 10), each of whom received both stimulation types, in a counterbalanced order, with pre-stimulation performance the same for both sessions. TACS resulted in a greater improvement in RT-hits than TDCS (F(2,18) = 4.31 p = 0.03). Our findings suggest that future work optimizing the application of TACS has the potential to facilitate WM performance.

Progranulin (PGRN), Total-Tau (t-tau), and Neurofilament light chain (NfL) are well known biomarkers of neurodegeneration. The objective of the present study was to investigate whether these parameters represent also biomarkers in autoimmune-mediated Encephalitis (AE) and may give us insights into the pathomechanisms of AE. We retrospectively examined the concentration of PGRN in the cerebrospinal fluid (CSF) and serum of 38 patients suffering from AE in acute phase and/or under treatment. This AE cohort comprises patients with autoantibodies against: NMDAR (n = 18 patients), Caspr2 (n = 8), Lgi-1 (n = 10), GABAB(R) (n = 1), and AMPAR (n = 1). Additionally, the concentrations of NfL (n = 25) and t-tau (n = 13) in CSF were measured when possible. Follow up data including MRI were available in 13 patients. Several age-matched cohorts with neurological diseases besides neuroinflammation or neurodegeneration served as control groups. We observed that PGRN was significantly elevated in the CSF of patients with NMDAR-AE in the acute phase, but normalized at follow up under treatment (p < 0.01). In the CSF of other patients with AE PGRN was in the range of the CSF levels of control groups. T-tau was highly elevated in the CSF of patients with temporal FLAIR-signal in the MRI and in patients developing a hippocampal sclerosis. NfL was exceptionally high initially in Patients with AE with a paraneoplastic or parainfectious cause and also normalized under treatment. The normalizations of all biomarkers were mirrored in an improvement on the modified Rankin scale. The data suggest that the concentration of PGRN in CSF might be a biomarker for acute NMDAR-AE. Pathological high t-tau levels may indicate a risk for hippocampal sclerosis. The biomarker properties of NfL remain unclear since the levels decrease under treatment, but it could not predict severity of disease in this small cohort. According to our results, we recommend to measure in clinical practice PGRN and t-tau in the CSF of patients with AE.

A well-accepted model of episodic memory involves the processing of spatial and non-spatial information by segregated pathways and their association within the hippocampus. However, these pathways project to distinct proximodistal levels of the hippocampus. Moreover, spatial and non-spatial subnetworks segregated along this axis have been recently described using memory tasks with either a spatial or a non-spatial salient dimension. Here, we tested whether the concept of segregated subnetworks and the traditional model are reconcilable by studying whether activity within CA1 and CA3 remains segregated when both dimensions are salient, as is the case for episodes. Simultaneously, we investigated whether temporal or spatial information bound to objects recruits similar subnetworks as items or locations per se, respectively. To do so, we studied the correlations between brain activity and spatial and/or temporal discrimination ratios in proximal and distal CA1 and CA3 by detecting Arc RNA in mice. We report a robust proximodistal segregation in CA1 for temporal information processing and in both CA1 and CA3 for spatial information processing. Our results suggest that the traditional model of episodic memory and the concept of segregated networks are reconcilable, to a large extent and put forward distal CA1 as a possible "home" location for time cells.

In brain-computer interface (BCI) applications the detection of neural processing as revealed by event-related potentials (ERPs) is a frequently used approach to regain communication for people unable to interact through any peripheral muscle control. However, the commonly used electroencephalography (EEG) provides signals of low signal-to-noise ratio, making the systems slow and inaccurate. As an alternative noninvasive recording technique, the magnetoencephalography (MEG) could provide more advantageous electrophysiological signals due to a higher number of sensors and the magnetic fields not being influenced by volume conduction. We investigated whether MEG provides higher accuracy in detecting event-related fields (ERFs) compared to detecting ERPs in simultaneously recorded EEG, both evoked by a covert attention task, and whether a combination of the modalities is advantageous. In our approach, a detection algorithm based on spatial filtering is used to identify ERP/ERF components in a data-driven manner. We found that MEG achieves higher decoding accuracy (DA) compared to EEG and that the combination of both further improves the performance significantly. However, MEG data showed poor performance in cross-subject classification, indicating that the algorithm's ability for transfer learning across subjects is better in EEG. Here we show that BCI control by covert attention is feasible with EEG and MEG using a data-driven spatial filter approach with a clear advantage of the MEG regarding DA but with a better transfer learning in EEG.

Cross-frequency coupling (CFC) between slow and fast brain rhythms, in the form of phase–amplitude coupling (PAC), is proposed to enable the coordination of neural oscillatory activity required for cognitive processing. PAC has been identified in the neocortex and mesial temporal regions, varying according to the cognitive task being performed and also at rest. PAC has also been observed in the anterior thalamic nucleus (ATN) during memory processing. The thalamus is active during the resting state and has been proposed to be involved in switching between task-free cognitive states such as rest, in which attention is internally-focused, and externally-focused cognitive states, in which an individual engages with environmental stimuli. It is unknown whether PAC is an ongoing phenomenon during the resting state in the ATN, which is modulated during different cognitive states, or whether it only arises during the performance of specific tasks. We analyzed electrophysiological recordings of ATN activity during rest from seven patients who received thalamic electrodes implanted for treatment of pharmacoresistant focal epilepsy. PAC was identified between theta (4–6 Hz) phase and high frequency band (80–150 Hz) amplitude during rest in all seven patients, which diminished during engagement in tasks involving an external focus of attention. The findings are consistent with the proposal that theta–gamma coupling in the ATN is an ongoing phenomenon, which is modulated by task performance.

Neural oscillations in the gamma range are the dominant rhythmic activation pattern in the human auditory cortex. These gamma oscillations are functionally relevant for the processing of rapidly changing acoustic information in both speech and non-speech sounds. Accordingly, there is a tight link between the temporal resolution ability of the auditory system and inherent neural gamma oscillations. Transcranial random noise stimulation (tRNS) has been demonstrated to specifically increase gamma oscillation in the human auditory cortex. However, neither the physiological mechanisms of tRNS nor the behavioral consequences of this intervention are completely understood. In the present study we stimulated the human auditory cortex bilaterally with tRNS while EEG was continuously measured. Modulations in the participants’ temporal and spectral resolution ability were investigated by means of a gap detection task and a pitch discrimination task. Compared to sham, auditory tRNS increased the detection rate for near-threshold stimuli in the temporal domain only, while no such effect was present for the discrimination of spectral features. Behavioral findings were paralleled by reduced peak latencies of the P50 and N1 component of the auditory event-related potentials (ERP) indicating an impact on early sensory processing. The facilitating effect of tRNS was limited to the processing of near-threshold stimuli while stimuli clearly below and above the individual perception threshold were not affected by tRNS. This non-linear relationship between the signal-to-noise level of the presented stimuli and the effect of stimulation further qualifies stochastic resonance (SR) as the underlying mechanism of tRNS on auditory processing. Our results demonstrate a tRNS related improvement in acoustic perception of time critical auditory information and, thus, provide further indices that auditory tRNS can amplify the resonance frequency of the auditory system.

While hypercholesterolemia plays a causative role for the development of ischemic stroke in large vessels, its significance for cerebral small vessel disease (CSVD) remains unclear. We thus aimed to understand the detailed relationship between hypercholesterolemia and CSVD using the well described Ldlr-/- mouse model.We used Ldlr-/- mice (n = 16) and wild-type (WT) mice (n = 15) at the age of 6 and 12 months. Ldlr-/- mice develop high plasma cholesterol levels following a high fat diet. We analyzed cerebral capillaries and arterioles for intravascular erythrocyte accumulations, thrombotic vessel occlusions, blood-brain barrier (BBB) dysfunction and microbleeds.We found a significant increase in the number of erythrocyte stases in 6 months old Ldlr-/- mice compared to all other groups (P < 0.05). Ldlr-/- animals aged 12 months showed the highest number of thrombotic occlusions while in WT animals hardly any occlusions could be observed (P < 0.001). Compared to WT mice, Ldlr-/- mice did not display significant gray matter BBB breakdown. Microhemorrhages were observed in one Ldlr-/- mouse that was 6 months old. Results did not differ when considering subcortical and cortical regions.In Ldlr-/- mice, hypercholesterolemia is related to a thrombotic CSVD phenotype, which is different from hypertension-related CSVD that associates with a hemorrhagic CSVD phenotype. Our data demonstrate a relationship between hypercholesterolemia and the development of CSVD. Ldlr-/- mice appear to be an adequate animal model for research into CSVD.

Previous studies have shown that in amyotrophic lateral sclerosis (ALS) multiple motor and extra-motor regions display structural and functional alterations. However, their temporal dynamics during disease-progression are unknown. To address this question we employed a longitudinal design assessing motor- and novelty-related brain activity in two fMRI sessions separated by a 3-month interval. In each session, patients and controls executed a Go/NoGo-task, in which additional presentation of novel stimuli served to elicit hippocampal activity. We observed a decline in the patients' movement-related activity during the 3-month interval. Importantly, in comparison to controls, the patients' motor activations were higher during the initial measurement. Thus, the relative decrease seems to reflect a breakdown of compensatory mechanisms due to progressive neural loss within the motor-system. In contrast, the patients' novelty-evoked hippocampal activity increased across 3 months, most likely reflecting the build-up of compensatory processes typically observed at the beginning of lesions. Consistent with a stage-dependent emergence of hippocampal and motor-system lesions, we observed a positive correlation between the ALSFRS-R or MRC-Megascores and the decline in motor activity, but a negative one with the hippocampal activation-increase. Finally, to determine whether the observed functional changes co-occur with structural alterations, we performed voxel-based volumetric analyses on magnetization transfer images in a separate patient cohort studied cross-sectionally at another scanning site. Therein, we observed a close overlap between the structural changes in this cohort, and the functional alterations in the other. Thus, our results provide important insights into the temporal dynamics of functional alterations during disease-progression, and provide support for an anatomical relationship between functional and structural cerebral changes in ALS.

Cognitive fatigue is one of the most frequent symptoms in multiple sclerosis (MS), associated with significant impairment in daily functioning and quality of life. Despite its clinical significance, progress in understanding and treating fatigue is still limited. This limitation is already caused by an inconsistent and heterogeneous terminology and assessment of fatigue. In this review, we integrate previous literature on fatigue and propose a unified schema aiming to clarify the fatigue taxonomy. With special focus on cognitive fatigue, we survey the significance of objective behavioral and electrophysiological fatigue parameters and discuss the controversial literature on the relationship between subjective and objective fatigue assessment. As MS-related cognitive fatigue drastically affects quality of life, the development of efficient therapeutic approaches for overcoming cognitive fatigue is of high clinical relevance. In this regard, the reliable and valid assessment of the individual fatigue level by objective parameters is essential for systematic treatment evaluation and optimization. Transcranial electrical stimulation (tES) may offer a unique opportunity to manipulate maladaptive neural activity underlying MS fatigue. Therefore, we discuss evidence for the therapeutic potential of tES on cognitive fatigue in people with MS.

Instrumental learning and decision-making rely on two parallel systems: a goal-directed and a habitual system. In the past decade, several paradigms have been developed to study these systems in animals and humans by means of e.g. overtraining, devaluation procedures and sequential decision-making. These different paradigms are thought to measure the same constructs, but cross-validation has rarely been investigated. In this study we compared two widely used paradigms that assess aspects of goal-directed and habitual behavior. We correlated parameters from a two-step sequential decision-making task that assesses model-based and model-free learning with a slips-of-action paradigm that assesses the ability to suppress cue-triggered, learnt responses when the outcome has been devalued and is therefore no longer desirable. Model-based control during the two-step task showed a very moderately positive correlation with goal-directed devaluation sensitivity, whereas model-free control did not. Interestingly, parameter estimates of model-based and goal-directed behavior in the two tasks were positively correlated with higher-order cognitive measures (e.g. visual short-term memory). These cognitive measures seemed to (at least partly) mediate the association between model-based control during sequential decision-making and goal-directed behavior after instructed devaluation. This study provides moderate support for a common framework to describe the propensity towards goal-directed behavior as measured with two frequently used tasks. However, we have to caution that the amount of shared variance between the goal-directed and model-based system in both tasks was rather low, suggesting that each task does also pick up distinct aspects of goal-directed behavior. Further investigation of the commonalities and differences between the model-free and habit systems as measured with these, and other, tasks is needed. Also, a follow-up cross-validation on the neural systems driving these constructs across different paradigms would promote the definition and operationalization of measures of instrumental learning and decision-making in humans.

The parapontine nucleus of the thalamus (PPN) is a neuromodulatory midbrain structure with widespread connectivity to cortical and subcortical motor structures, as well as the spinal cord. The PPN also projects to the thalamus, including visual relay nuclei like the LGN and the pulvinar. Moreover, there is intense connectivity with sensory structures of the tegmentum in particular with the superior colliculus (SC). Given the existence and abundance of projections to visual sensory structures, it is likely that activity in the PPN has some modulatory influence on visual sensory selection. Here we address this possibility by measuring the visual discrimination performance (luminance contrast thresholds) in a group of patients with Parkinson's Disease (PD) treated with deep-brain stimulation (DBS) of the PPN to control gait and postural motor deficits. In each patient we measured the luminance-contrast threshold of being able to discriminate an orientation-target (Gabor-grating) as a function of stimulation frequency (high 60Hz, low 8/10, no stimulation). Thresholds were determined using a standard staircase-protocol that is based on parameter estimation by sequential testing (PEST). We observed that under low frequency stimulation thresholds increased relative to no and high frequency stimulation in five out of six patients, suggesting that DBS of the PPN has a frequency-dependent impact on visual selection processes at a rather elementary perceptual level.

Clinically, Alzheimer’s disease (AD) is by far the most common cause of dementia. Criteria for the diagnosis of dementia with Lewy bodies (DLB) are highly specific but not at all sensitive, which is reflected by the higher number of DLB cases detected histopathologically at autopsy. Imaging of dopamine transporter with FP-CIT SPECT is one possibility to increase sensitivity. Pathological confirmation was also included in the revised consensus criteria for the diagnosis of DLB. However, in the absence of parkinsonism, one of the core features, a clinical diagnosis of AD is more likely. The role of FP-CIT SPECT in DLB diagnosis remains to be clarified. Based on our 3 case reports and a review of the literature, the utility of this imaging method in the differential diagnosis of AD and DLB is highlighted.

Previously we reported electrophysiological evidence for a role for the anterior thalamic nucleus (ATN) in human memory formation (Sweeney-Reed et al., 2014). Theta-gamma cross-frequency coupling (CFC) predicted successful memory formation, with the involvement of gamma oscillations suggesting memory-relevant local processing in the ATN. The importance of the theta frequency range in memory processing is well-established, and phase alignment of oscillations is considered to be necessary for synaptic plasticity. We hypothesized that theta phase alignment in the ATN would be necessary for memory encoding. Further analysis of the electrophysiological data reveal that phase alignment in the theta rhythm was greater during successful compared with unsuccessful encoding, and that this alignment was correlated with the CFC. These findings support an active processing role for the ATN during memory formation.

The functional role of the alpha-rhythm which dominates the human electroencephalogram (EEG) is unclear. It has been related to visual processing, attentional selection and object coherence, respectively. Here we tested the interaction of alpha oscillations of the human brain with visual search tasks that differed in their attentional demands (pre-attentive vs. attentive) and also in the necessity to establish object coherence (conjunction vs. single feature). Between pre- and post-assessment elderly subjects received 20 min/d of repetitive transcranial alternating current stimulation (tACS) over the occipital cortex adjusted to their individual alpha frequency over five consecutive days. Compared to sham the entrained alpha oscillations led to a selective, set size independent improvement in the conjunction search task performance but not in the easy or in the hard feature search task. These findings suggest that cortical alpha oscillations play a specific role in establishing object coherence through suppression of distracting objects.

Attitude to morality, reflecting cultural norms and values, is considered unique to human social behavior. Resulting moral behavior in a social environment is controlled by a widespread neural network including the dorsolateral prefrontal cortex (DLPFC), which plays an important role in decision making. In the present study we investigate the influence of neurophysiological modulation of DLPFC reactivity by means of transcranial direct current stimulation (tDCS) on moral reasoning. For that purpose we administered anodal, cathodal, and sham stimulation of the left DLPFC while subjects judged the appropriateness of hard moral personal dilemmas. In contrast to sham and cathodal stimulation, anodal stimulation induced a shift in judgment of personal moral dilemmas towards more non-utilitarian actions. Our results demonstrate that alterations of left DLPFC activity can change moral judgments and, in consequence, provide a causal link between left DLPFC activity and moral reasoning. Most important, the observed shift towards non-utilitarian actions suggests that moral decision making is not a permanent individual trait but can be manipulated; consequently individuals with boundless, uncontrollable, and maladaptive moral behavior, such as found in psychopathy, might benefit from neuromodulation-based approaches.

The anterior thalamic nucleus (ATN) is thought to play an important role in a brain network involving the hippocampus and neocortex, which enables human memories to be formed. However, its small size and location deep within the brain have impeded direct investigation in humans with non-invasive techniques. Here we provide direct evidence for a functional role for the ATN in memory formation from rare simultaneous human intrathalamic and scalp electroencephalogram (EEG) recordings from eight volunteering patients receiving intrathalamic electrodes implanted for the treatment of epilepsy, demonstrating real-time communication between neocortex and ATN during successful memory encoding. Neocortical-ATN theta oscillatory phase synchrony of local field potentials and neocortical-theta-to-ATN-gamma cross-frequency coupling during presentation of complex photographic scenes predicted later memory for the scenes, demonstrating a key role for the ATN in human memory encoding.

Improving performance in motor skill acquisition is proposed to be supported by tuning of neural networks. To address this issue we investigated changes of phase-amplitude cross-frequency coupling (paCFC) in neuronal networks during motor performance improvement. We recorded intracranially from subdural electrodes (electrocorticogram; ECoG) from 6 patients who learned 3 distinct motor tasks requiring coordination of finger movements with an external cue (serial response task, auditory motor coordination task, go/no-go). Performance improved in all subjects and all tasks during the first block and plateaued in subsequent blocks. Performance improvement was paralled by increasing neural changes in the trial-to-trial paCFC between theta ([Formula: see text]; 4-8 Hz) phase and high gamma (HG; 80-180 Hz) amplitude. Electrodes showing this covariation pattern (Pearson's r ranging up to .45) were located contralateral to the limb performing the task and were observed predominantly in motor brain regions. We observed stable paCFC when task performance asymptoted. Our results indicate that motor performance improvement is accompanied by adjustments in the dynamics and topology of neuronal network interactions in the [Formula: see text] and HG range. The location of the involved electrodes suggests that oscillatory dynamics in motor cortices support performance improvement with practice.

Recent studies have shown that the feeling of body ownership can be fooled by simple visuo-tactile manipulations. Perceptual illusions have been reported in which participants sense phantom touch seen on a rubber hand (rubber hand illusion). While previous studies used homologous limbs for those experiments, we here examined an illusion where people feel phantom touch on a left rubber hand when they see it brushed simultaneously with brushes applied to their right hand. Thus, we investigated a referral of touch from the right to the left hand (across the body midline). Since it is known from animal studies that tactile illusions may alter early sensory processing, we expected a modulation of the primary somatosensory cortex (SI) corresponding to this illusion. Neuromagnetic source imaging of the functional topographic organization in SI showed a shift in left SI, associated with the strength of the referral of touch. Hence, we argue that SI seems to be closely associated with this perceptual illusion. The results suggest that the transfer of tactile information across the body midline could be mediated by neurons with bilateral tactile receptive fields (most likely BA2).

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease which affects the motor system but also other frontal brain regions. In this study we investigated changes in functional neuronal networks including posterior brain regions that are not directly affected by the neurodegenerative process. To this end, we analyzed the contralateral delay activity (CDA), an ERP component considered an online marker of memory storage in posterior cortex, while 23 ALS patients and their controls performed a delayed-matching-to-sample working memory (WM) task. The task required encoding of stimuli in the cued hemifield whilst ignoring stimuli in the other hemifield. Despite their unimpaired behavioral performance patients displayed several changes in the neuronal markers of the memory processes. Their CDA amplitude was smaller; it showed less load-dependent modulation and lacked the reduction observed when controls performed the same task three months later. The smaller CDA in the patients could be attributed to more ipsilateral cortical activity which may indicate that ALS patients unnecessarily processed the irrelevant stimuli as well. The latter is presumably related to deterioration of the frontal cortex in the patient group which was indicated by slight deficits in tests of their executive functions that increased over time. The frontal pathology presumably affected their top-down control of memory storage in remote regions in the posterior brain. In sum, the present results demonstrate functional changes in neuronal networks, i.e. neuroplasticity, in ALS that go well beyond the known structural changes. They also show that at least in WM tasks, in which strategic top-down control demands are relatively low, the frontal deficit can be compensated for by intact low level processes in posterior brain regions.

In the philosophical theory of communicative action, rationality refers to interpersonal communication rather than to a knowing subject. Thus, a social view of rationality is suggested. The theory differentiates between two kinds of rationality, the emancipative communicative and the strategic or instrumental reasoning. Using experimental designs in an fMRI setting, recent studies explored similar questions of reasoning in the social world and linked them with a neural network including prefrontal and parietal brain regions. Here, we employed an fMRI approach to highlight brain areas associated with strategic and communicative reasoning according to the theory of communicative action. Participants were asked to assess different social scenarios with respect to communicative or strategic rationality. We found a network of brain areas including temporal pole, precuneus, and STS more activated when participants performed communicative reasoning compared with strategic thinking and a control condition. These brain regions have been previously linked to moral sensitivity. In contrast, strategic rationality compared with communicative reasoning and control was associated with less activation in areas known to be related to moral sensitivity, emotional processing, and language control. The results suggest that strategic reasoning is associated with reduced social and emotional cognitions and may use different language related networks. Thus, the results demonstrate experimental support for the assumptions of the theory of communicative action.

BACKGROUND: An increasing body of evidence has demonstrated that in contrast to the classic understanding the primary somatosensory cortex (SI) reflects merely seen touch (in the absence of any real touch on the own body). Based on these results it has been discussed that SI may play a role in understanding touch seen on other bodies. In order to further examine this understanding of observed touch, the current study aimed to test if mirror-like responses in SI are affected by the perspective of the seen touch. Thus, we presented touch on a hand and close to the hand either in first-person-perspective or in third-person-perspective. PRINCIPAL FINDINGS: Results of functional magnetic resonance imaging (fMRI) revealed stronger vicarious brain responses in SI/BA2 for touch seen in first-person-perspective. Surprisingly, the third-person viewpoint revealed activation in SI both when subjects viewed a hand being stimulated as well as when the space close to the hand was being touched. CONCLUSIONS/SIGNIFICANCE: Based on these results we conclude that vicarious somatosensory responses in SI/BA2 are affected by the viewpoint of the seen hand. Furthermore, we argue that mirror-like responses in SI do not only reflect seen touch, but also the peripersonal space surrounding this body (in third-person-perspective). We discuss these findings with recent studies on mirror responses for action observation in peripersonal space.

ATP-binding cassette (ABC) transporters are essential regulators of organismic homeostasis, and are particularly important in protecting the body from potentially harmful exogenous substances. Recently, an increasing number of in vitro observations have indicated a functional role of ABC transporters in the differentiation and maintenance of stem cells. Therefore, we sought to determine brain-related phenotypic changes in animals lacking the expression of distinct ABC transporters (ABCB1, ABCG2 or ABCC1).Analyzing adult neurogenesis in ABC transporter-deficient animals in vivo and neuronal stem/progenitor cells in vitro resulted in complex findings. In vivo, the differentiation of neuronal progenitors was hindered in ABC transporter-deficient mice (ABCB1(0/0)) as evidenced by lowered numbers of doublecortin(+) (-36%) and calretinin(+) (-37%) cells. In vitro, we confirmed that this finding is not connected to the functional loss of single neural stem/progenitor cells (NSPCs). Furthermore, assessment of activity, exploratory behavior, and anxiety levels revealed behavioral alterations in ABCB1(0/0) and ABCC1(0/0) mice, whereas ABCG2(0/0) mice were mostly unaffected.Our data show that single ABC transporter-deficiency does not necessarily impair neuronal progenitor homeostasis on the single NSPC level, as suggested by previous studies. However, loss of distinct ABC transporters impacts global brain homeostasis with far ranging consequences, leading to impaired neurogenic functions in vivo and even to distinct behavioral phenotypes. In addition to the known role of ABC transporters in proteopathies such as Parkinson's disease and Alzheimer's disease, our data highlight the importance of understanding the general function of ABC transporters for the brain's homeostasis and the regeneration potential.

The influence of bilateral deep brain stimulation (DBS) of the nucleus nucleus (NAcc) on the processing of reward in a gambling paradigm was investigated using H(2)[(15)O]-PET (positron emission tomography) in a 38-year-old man treated for severe alcohol addiction. Behavioral data analysis revealed a less risky, more careful choice behavior under active DBS compared to DBS switched off. PET showed win- and loss-related activations in the paracingulate cortex, temporal poles, precuneus and hippocampus under active DBS, brain areas that have been implicated in action monitoring and behavioral control. Except for the temporal pole these activations were not seen when DBS was deactivated. These findings suggest that DBS of the NAcc may act partially by improving behavioral control.

INTRODUCTION: Human cerebral small vessel disease (CSVD) has been hypothesized to be an age-dependent disease accompanied by similar vascular changes in other organs. SHRSP feature numerous vascular risk factors and may be a valid model of some aspects of human CSVD. Here we compare renal histopathological changes with the brain pathology of spontaneously hypertensive stroke-prone rats (SHRSP). MATERIAL AND METHODS: We histologically investigated the brains and kidneys of 61 SHRSP at different stages of age (12 to 44 weeks). The brain pathology (aggregated erythrocytes in capillaries and arterioles, microbleeds, microthromboses) and the kidney pathology (aggregated erythrocytes within peritubular capillaries, tubular protein cylinders, glomerulosclerosis) were quantified separately. The prediction of the brain pathology by the kidney pathology was assessed by creating ROC-curves integrating the degree of kidney pathology and age of SHRSP. RESULTS: Both, brain and kidney pathology, show an age-dependency and proceed in definite stages whereas an aggregation of erythrocytes in capillaries and arterioles, we parsimoniously interpreted as stases, represent the initial finding in both organs. Thus, early renal tubulointerstitial damage characterized by rather few intravasal erythrocyte aggregations and tubular protein cylinders predicts the initial step of SHRSPs' cerebral vascular pathology marked by accumulated erythrocytes. The combined increase of intravasal erythrocyte aggregations and protein cylinders accompanied by glomerulosclerosis and thrombotic renal microangiopathy in kidneys of older SHRSP predicts the final stages of SHRSPs' cerebrovascular lesions marked by microbleeds and thrombotic infarcts. CONCLUSION: Our results illustrate a close association between structural brain and kidney pathology and support the concept of small vessel disease to be an age-dependent systemic pathology. Further, an improved joined nephrologic and neurologic diagnostic may help to identify patients with CSVD at an early stage.

Serotonin (5-hydroxytryptamine, 5-HT) is an important neuromodulator in learning and memory processes. A functional genetic polymorphism of the 5-HT 2a receptor (5-HTR2a His452Tyr), which leads to blunted intracellular signaling, has previously been associated with explicit memory performance in several independent cohorts, but the underlying neural mechanisms are thus far unclear. The human hippocampus plays a critical role in memory, particularly in the detection and encoding of novel information. Here we investigated the relationship of 5-HTR2a His452Tyr and hippocampal novelty processing in 41 young, healthy subjects using functional magnetic resonance imaging (fMRI). Participants performed a novelty/familiarity task with complex scene stimuli, which was followed by a delayed recognition memory test 24 hours later. Compared to His homozygotes, Tyr carriers exhibited a diminished hippocampal response to novel stimuli and a higher tendency to judge novel stimuli as familiar during delayed recognition. Across the cohort, the false alarm rate during delayed recognition correlated negatively with the hippocampal novelty response. Our results suggest that previously reported effects of 5-HTR2a on explicit memory performance may, at least in part, be mediated by alterations of hippocampal novelty processing.

The superior colliculus (SC) has been shown to play a crucial role in the initiation and coordination of eye- and head-movements. The knowledge about the function of this structure is mainly based on single-unit recordings in animals with relatively few neuroimaging studies investigating eye-movement related brain activity in humans.The present study employed high-field (7 Tesla) functional magnetic resonance imaging (fMRI) to investigate SC responses during endogenously cued saccades in humans. In response to centrally presented instructional cues, subjects either performed saccades away from (centrifugal) or towards (centripetal) the center of straight gaze or maintained fixation at the center position. Compared to central fixation, the execution of saccades elicited hemodynamic activity within a network of cortical and subcortical areas that included the SC, lateral geniculate nucleus (LGN), occipital cortex, striatum, and the pulvinar.Activity in the SC was enhanced contralateral to the direction of the saccade (i.e., greater activity in the right as compared to left SC during leftward saccades and vice versa) during both centrifugal and centripetal saccades, thereby demonstrating that the contralateral predominance for saccade execution that has been shown to exist in animals is also present in the human SC. In addition, centrifugal saccades elicited greater activity in the SC than did centripetal saccades, while also being accompanied by an enhanced deactivation within the prefrontal default-mode network. This pattern of brain activity might reflect the reduced processing effort required to move the eyes toward as compared to away from the center of straight gaze, a position that might serve as a spatial baseline in which the retinotopic and craniotopic reference frames are aligned.