Multi-focal Stimulation of the Cortico-cerebellar Loop During the Acquisition of a Novel Hand Motor Skill in Chronic Stroke Survivors.

Impairment of hand motor function is a frequent consequence after a stroke and strongly determines the ability to regain a self-determined life. An influential research strategy for improving motor deficits is the combined application of behavioral training and non-invasive brain stimulation of the motor cortex (M1). However, a convincing clinical translation of the present stimulation strategies has not been achieved yet. One alternative and innovative approach is to target the functionally relevant brain network-based architecture, e.g., the dynamic interactions within the cortico-cerebellar system during learning. Here, we tested a sequential multifocal stimulation strategy targeting the cortico-cerebellar loop. Anodal transcranial direct current stimulation (tDCS) was applied simultaneously to a hand-based motor training in N = 11 chronic stroke survivors during four training sessions on two consecutive days. The tested conditions were: sequential multifocal (M1-cerebellum (CB)-M1-CB) vs. monofocal control stimulation (M1-sham-M1-sham). Additionally, skill retention was assessed 1 and 10 days after the training phase. Paired-pulse transcranial magnetic stimulation data were recorded to characterize stimulation response determining features. The application of CB-tDCS boosted motor behavior in the early training phase in comparison to the control condition. No faciliatory effects on the late training phase or skill retention were detected. Stimulation response variability was related to the magnitude of baseline motor ability and short intracortical inhibition (SICI). The present findings suggest a learning phase-specific role of the cerebellar cortex during the acquisition of a motor skill in stroke and that personalized stimulation strategies encompassing several nodes of the underlying brain network should be considered.

Targeting the frontoparietal network using bifocal transcranial alternating current stimulation during a motor sequence learning task in healthy older adults.

BACKGROUND: Healthy older adults show a decrease in motor performance and motor learning capacity as well as in working memory (WM) performance. WM has been suggested to be involved in motor learning processes, such as sequence learning. Correlational evidence has shown the involvement of the frontoparietal network (FPN), a network underlying WM processes, in motor sequence learning. However, causal evidence is currently lacking. Non-invasive brain stimulation (NIBS) studies have focused so far predominantly on motor-related areas to enhance motor sequence learning while areas associated with more cognitive aspects of motor learning have not yet been addressed. HYPOTHESIS: In this study, we aim to provide causal evidence for the involvement of WM processes and the underlying FPN in the successful performance of a motor sequence learning task by using theta transcranial alternating current stimulation (tACS) targeting the FPN during a motor sequence learning task. METHODS: In a cohort of 20 healthy older adults, we applied bifocal tACS in the theta range to the FPN during a sequence learning task. With the use of a double-blind, cross-over design, we tested the efficacy of active compared to sham stimulation. Two versions of the motor task were used: one with high and one with low WM load, to explore the efficacy of stimulation on tasks differing in WM demand. Additionally, the effects of stimulation on WM performance were addressed using an N-back task. The tACS frequency was personalized by means of EEG measuring the individual theta peak frequency during the N-back task. RESULTS: The application of personalized theta tACS to the FPN improved performance during the motor sequence learning task with high WM load (p < .001), but not with low WM load. Active stimulation significantly improved both speed (p < .001), and accuracy (p = .03) during the task with high WM load. In addition, the stimulation paradigm improved performance on the N-back task for the 2-back task (p = .013), but not for 1-back and 3-back. CONCLUSION: The performance during a motor sequence learning task can be enhanced by means of personalized bifocal theta tACS to the FPN when WM load is high, indicating that the efficacy of this stimulation paradigm is dependent on the cognitive demand during the learning task. These data provide further causal evidence for the critical involvement of WM processes and the FPN during the execution of a motor sequence learning task in healthy older. These findings open new exciting possibilities to counteract the age-related decline in motor performance, learning capacity and WM performance.

Precision Spectroscopy of Negative-Ion Resonances in Ultralong-Range Rydberg Molecules.

The level structure of negative ions near the electron detachment limit dictates the low-energy scattering of an electron with the parent neutral atom. We demonstrate that a single ultracold atom bound inside a Rydberg orbit forming an ultralong-range Rydberg molecule provides an atomic-scale system that is highly sensitive to electron-neutral scattering and thus allows for detailed insights into the underlying near-threshold anion states. Our measurements reveal the so-far unobserved fine structure of the ^{3}P_{J} triplet of Rb^{-} and allows us to extract parameters of the associated p-wave scattering resonances that deviate from previous theoretical estimates. Moreover, we observe a novel alignment mechanism for Rydberg molecules mediated by spin-orbit coupling in the negative ion.

Variability of amino acid digestibility of lupin and pea grains in caecectomised laying hens.

1. The objective of this study was to investigate the variations in amino acid (AA) digestibility of lupin and pea grains in caecectomised laying hens. The relationship between AA digestibility and chemical constituents of the grains was determined. 2. Twelve variants of lupins and peas were each added to a basal diet at a concentration of 300 g/kg, at the expense of maize starch. The lupin and pea variants were separately investigated in two subsequent trials. Each trial consisted of two 7 × 7 Latin squares, each comprising the basal diet and six diets with lupins or peas. 3. Fourteen caecectomised laying hens (LSL-classic) were individually housed in metabolism cages and 120 g/d of experimental diets were provided for eight days. During the last four days, excreta were collected quantitatively and feed intake was recorded. A regression approach was used to determine the AA digestibility of the lupin and pea variants. 4. Amino acid digestibility of the lupins and peas was high, although significant differences in AA digestibility among the lupins and peas were detected. The digestibility of lysine was in the range of 0.87-0.91 and 0.87-0.93 for lupins and peas, respectively. The digestibility of methionine in lupins and peas varied between 0.80-0.88 and 0.72-0.90. Variations in AA digestibility in peas were more pronounced than in lupins. 5. Significant correlations between chemical constituents of lupins, such as alkaloids, and AA digestibility were detected in some cases, without a consistent pattern. In peas, tannin concentration and the insoluble protein fraction were negatively correlated with digestibility of some AAs, but only when one colour flower variant was considered. Trypsin inhibitor activity in peas was negatively correlated with AA digestibility, particularly for the white flower variants.

Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines.

Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode-skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to-baseline intensities of 1-2mA and during tACS at higher peak-to-peak intensities above 2mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low-intensity 'conventional' TES defined as <4mA, up to 60min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3-13A/m2 that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in Göttingen, Germany, on September 6-7, 2016 and were refined thereafter by email correspondence.

[The importance of neuronal networks for motor rehabilitation after a stroke]. / Bedeutung neuronaler Netzwerke für die motorische Rehabilitation nach einem Schlaganfall.

Every year in Europe 1.5 million patients suffer a new stroke. Despite the further developments in acute therapy with nationwide stroke units, thrombolysis, thrombectomy and post-acute neurorehabilitation, only a small proportion of patients recover to a satisfactory degree allowing them to return to their normal social and professional life. This makes stroke the main cause of long-term disability with a corresponding impact on patient lives, socioeconomics and the healthcare system. Thus, the concepts of neurorehabilitation have to be extended to enhance the effects of rehabilitative treatment strategies. To achieve this, an understanding of the prediction of the course of recovery, the mechanisms underlying functional recovery and factors influencing recovery have to be enhanced for the development towards patient-tailored precision medicine approaches. A central point towards this is the understanding of stroke as a disease, which not only influences the damaged area but also the associated network. This is crucial for the understanding of the stroke-induced deficits, for prediction of recovery and options for interventional treatment strategies, which can target different areas in this network (e.g. primary motor cortex and secondary motor regions) based on individual factors of the patient. The present article discusses the importance of network alterations for motor neurorehabilitation after a stroke and which novel options, concepts and consequences could arise from this for neurorehabilitation.

Inactivation of the putative ubiquitin-E3 ligase PDLIM2 in classical Hodgkin and anaplastic large cell lymphoma.

Apart from its unique histopathological appearance with rare tumor cells embedded in an inflammatory background of bystander cells, classical Hodgkin lymphoma (cHL) is characterized by an unusual activation of a broad range of signaling pathways involved in cellular activation. This includes constitutive high-level activity of nuclear factor-κB (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), activator protein-1 (AP-1) and interferon regulatory factor (IRF) transcription factors (TFs) that are physiologically only transiently activated. Here, we demonstrate that inactivation of the putative ubiquitin E3-ligase PDLIM2 contributes to this TF activation. PDLIM2 expression is lost at the mRNA and protein levels in the majority of cHL cell lines and Hodgkin and Reed-Sternberg (HRS) cells of nearly all cHL primary samples. This loss is associated with PDLIM2 genomic alterations, promoter methylation and altered splicing. Reconstitution of PDLIM2 in HRS cell lines inhibits proliferation, blocks NF-κB transcriptional activity and contributes to cHL-specific gene expression. In non-Hodgkin B-cell lines, small interfering RNA-mediated PDLIM2 knockdown results in superactivation of TFs NF-κB and AP-1 following phorbol 12-myristate 13-acetate (PMA) stimulation. Furthermore, expression of PDLIM2 is lost in anaplastic large cell lymphoma (ALCL) that shares key biological aspects with cHL. We conclude that inactivation of PDLIM2 is a recurrent finding in cHL and ALCL, promotes activation of inflammatory signaling pathways and thereby contributes to their pathogenesis.

The effect of sleep on motor learning in the aging and stroke population - a systematic review.

There is extensive evidence for positive effects of sleep on motor learning in young individuals; however, the effects of sleep on motor learning in people with stroke and in healthy older individuals are not well understood. The aim of this systematic review was to quantify the association between sleep and procedural memory performance - a marker for motor learning - in healthy older people and people with stroke. After searches in PubMed, Medline and Embase fourteen studies, including 44 subjects after stroke and 339 healthy older participants were included. Overall, sleep was found to enhance motor performance in people after stroke in comparison to an equivalent time of wakefulness. In addition, although evidence is limited, sleep only enhanced motor performance in people after stroke and not in age-matched healthy older adults. In older adults the effect of a sleep intervention did - in general - not differ from equivalent periods of wakefulness. Tasks with whole hand or whole body movements could show significant changes. The results suggest a delayed retention effect after longer breaks including sleep, hinting towards a changed learning strategy as a result of aging. Current evidence for sleep dependent learning in people after stroke is promising, however sparse.

The control of complex finger movements by directional information flow between mesial frontocentral areas and the primary motor cortex.

Complex movements require the interplay of local activation and interareal communication of sensorimotor brain regions. This is reflected in a decrease of task-related spectral power over the sensorimotor cortices and an increase in functional connectivity predominantly in the upper alpha band in the electroencephalogram (EEG). In the present study, directionality of information flow was investigated using EEG recordings to gain better understanding about the network architecture underlying the performance of complex sequential finger movements. This was assessed by means of Granger causality-derived directed transfer function (DTF). As DTF measures the influence one signal exerts on another based on a time lag between them, it allows implications to be drawn on causal relationships. To reveal causal connections between brain regions that are specifically modulated by task complexity, we contrasted the performance of right-handed sequential finger movements of different complexities (simple, scale, complex) that were either pre-learned (memorized) or novel instructed. A complexity-dependent increase in information flow from mesial frontocentral to the left motor cortex and, less pronounced, also to the right motor cortex specifically in the upper alpha range was found. Effective coupling during sequences of high complexity was larger for memorized sequences compared with novel sequences (P = 0.0037). These findings further support the role of mesial frontocentral areas in directing the primary motor cortex in the process of orchestrating complex movements and in particular learned sequences.

[Combination of TMS and MRT to understand neurological diseases]. / Kombination von TMS und MRT zum Verständnis neurologischer Erkrankungen.

Modern neuroimaging techniques, such as structural and functional magnetic resonance imaging (MRI) and non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS) are increasingly used in the neuroscientific research of neurological disorders, such as stroke, tinnitus and movement disorders. These methods offer a non-invasive approach and especially in combination, not only the opportunity to add to the pathophysiological understanding of these disorders but also to provide information about the functional recovery and the natural course of the disease in a predictive way. Based on such knowledge therapeutic approaches can be adapted in a patient-tailored fashion to achieve the best therapeutic effects. Furthermore, these methods might provide additional non-invasive information for neurosurgical interventions reducing perioperative interventional risks.In the present article these aspects will be discussed with a focus on the combination of MRI and TMS especially addressed for the topic of recovery from stroke.

[Transcranial brain stimulation after stroke]. / Transkranielle Hirnstimulation nach Schlaganfall.

Stroke is the leading cause of disability in adults. In Germany an estimated 1.5 million stroke survivors have to cope with persisting sensorimotor or cognitive deficits and effective therapies are scarce. The idea of using non-invasive brain stimulation to treat neuropsychiatric diseases was already born more than 2,000 years ago (Scribonius largus, 43-48 AD). However, only the development of modern non-invasive brain stimulation methods, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) has made it possible to evaluate these ideas. The therapeutic value of these non-invasive brain stimulation methods is currently under study for several neuropsychiatric diseases, mostly in a proof-of-principle fashion. In this article the focus will be on non-invasive brain stimulation to enhance functional regeneration after stroke.

Female pelvic pain: a case report of mucocele of the appendix.

OBJECTIVE: To describe a rare case of mucocele of the appendix that simulated a cystic image by pelvic ultrasound (US). CASE: A patient with pelvic pain for two months and cystic image on the right ovary by US. After laparoscopy, the image showed a mucocele of the appendix. The patient underwent right colectomy. CONCLUSION: Mucocele may be a cause of pelvic pain and may simulate a cystic image on the right adnexa.

My urge, my tic - a missing link between urges and tic inhibition.

Abstract Despite the fact that premonitory urges precede most tics in patients with Gilles de la Tourette syndrome (GTS), the voluntariness of tic elicitation and its suppressibility as a response to these urges still remains unclear. Moreover, there are no systematic studies examining the association between urge intensity and the ability to suppress tics. As shown by behavioral, neurophysiological, and imaging data, sensorimotor networks in GTS exhibit altered patterns of organization modulated through interactions with frontomesial networks of volitional inhibition.

Altered modulation of intracortical excitability during movement preparation in Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome is a neuropsychiatric disorder in which cortical disinhibition has been proposed as a pathophysiological mechanism involved in the generation of tics. Tics are typically reduced during task performance and concentration. How this task-dependent reduction of motor symptoms is represented in the brain is not yet understood. The aim of the current research was to study motorcortical excitability at rest and during the preparation of a simple motor task. Transcranial magnetic stimulation was used to examine corticospinal excitability, short-interval intracortical inhibition and intracortical facilitation in a group of 11 patients with Gilles de la Tourette syndrome and age-matched healthy controls. Parameters of cortical excitability were evaluated at rest and at six points in time during the preparation of a simple finger movement. Patients with Gilles de la Tourette syndrome displayed significantly reduced short-interval intracortical inhibition at rest, while no differences were apparent for unconditioned motor evoked potential or intracortical facilitation. During the premovement phase, significant differences between groups were seen for single pulse motor evoked potential amplitudes and short-interval intracortical inhibition. Short-interval intracortical inhibition was reduced in the early phase of movement preparation (similar to rest) followed by a transition towards more inhibition. Subsequently modulation of short-interval intracortical inhibition was comparable to controls, while corticospinal recruitment was reduced in later phases of movement preparation. The present data support the hypothesis of motorcortical disinhibition in Gilles de la Tourette syndrome at rest. During performance of a motor task, patients start from an abnormally disinhibited level of short-interval intracortical inhibition early during movement preparation with subsequent modulation of inhibitory activity similar to healthy controls. We hypothesize that while at rest, abnormal subcortical inputs from aberrant striato-thalamic afferents target the motor cortex, during motor performance, motor cortical excitability most likely underlies top-down control from higher motor areas and prefrontal cortex, which override these abnormal subcortical inputs to guarantee adequate behavioural performance.

Virtual reality simulator for the training of lumbar punctures.

OBJECTIVES: Lumbar puncture (LP) is performed by inserting a needle into the spinal canal to extract cerebrospinal fluid for diagnostic purposes. A virtual reality (VR) lumbar puncture simulator based on real patient data has been developed and evaluated. METHODS: A haptic device with six degrees of freedom is used to steer the virtual needle and to generate feedback forces that resist needle insertion and rotation. An extended haptic volume-rendering approach is applied to calculate forces. This approach combines information from segmented data and original CT data which contributes density information in unsegmented image structures. The system has been evaluated in a pilot study with medical students. Participants of two groups, a training and a control group, completed different first training protocols. User performance has been recorded during a second training session to measure the training effect. Furthermore user acceptance has been evaluated in a questionnaire using a 6-point Likert scale with eight items. RESULTS: Forty-two medical students in two groups evaluated the system. Trained users performed better than less trained users (an average of 39% successfully completed virtual LPs compared to 30%). Findings of the questionnaire show that the simulator is very well accepted. E.g. the users agree that training with such a simulator is useful (Likert grade of 1.5 +/- 0.7 with 1 = "strongly agree" and 6 = "strongly disagree"). CONCLUSIONS: Results show that the VR LP simulator gives a realistic haptic and visual impression of the needle insertion and enables new insights into the anatomy of the lumbar region. It offers a new way for increasing skills of students and young residents before applying an LP in patients.

Deficient intracortical inhibition (SICI) during movement preparation after chronic stroke.

BACKGROUND: In healthy subjects, preparation to move is accompanied by motor cortical disinhibition. Poor control of intracortical inhibitory function in the primary motor cortex (M1) might contribute to persistent abnormal motor behavior in the paretic hand after chronic stroke. METHODS: Here, we studied GABAergic short intracortical inhibition (SICI) in the ipsilesional M1 in well-recovered chronic stroke patients (n = 14; 63.8 +/- 3.0 years) engaged in preparation to move the impaired hand in a reaction time paradigm. RESULTS: The main finding was an abnormal persistence of SICI in the ipsilesional M1 during movement preparation that was absent in age-matched controls (n = 14). Additionally, resting SICI was reduced in the patient group relative to controls. CONCLUSIONS: Our findings document a deficit of dynamic premovement modulation of intracortical inhibition in the ipsilesional primary motor cortex of patients with chronic stroke. This abnormality might contribute to deficits in motor control of the paretic hand, presenting a possible target for correction in the framework of developing novel therapeutic interventions after chronic stroke.

Spontaneous locally restricted EEG alpha activity determines cortical excitability in the motor cortex.

There is growing interest in the functional meaning of rhythmical brain activity. For oscillatory brain activity around 10 Hz in the human electroencephalogram (EEG) it is discussed whether it is associated with the level of cortical excitation. However, it is not clear whether the relation between 10 Hz EEG oscillatory activity and cortical excitability is a global, locally very unspecific phenomenon or whether focal 10 Hz oscillations in the human brain are a highly specific correlate of the cortical excitation level. To determine this open question, multichannel EEG was combined with transcranial magnetic stimulation (TMS) applied to the primary motor cortex in this study. The present data showed that a motor evoked potential was elicited more easily when alpha power immediately preceding the magnetic pulse was low, and vice versa. Interestingly, this effect was only found for very local EEG alpha activity at sites overlying the cortical motor areas to which the TMS pulses were applied. This was verified using source localization in 3D space. These data provide evidence that the magnitude of motor cortical excitability is determined by the amount of topographically specific alpha oscillations in the sensorimotor cortex.

Memory formation in the motor cortex ipsilateral to a training hand.

Cortical reorganization within the primary motor cortex (M1) contralateral to a practicing hand has been extensively investigated. The extent to which the ipsilateral M1 participates in these plastic changes is not known. Here, we evaluated the influence of unilateral hand practice on the organization of the M1 ipsilateral and contralateral to the practicing hand in healthy human subjects. Index finger movements elicited by single-pulse transcranial magnetic stimulation (TMS) delivered to each M1 were evaluated before and after practice of unilateral voluntary index finger abduction motions. Practice increased the proportion and acceleration of TMS-evoked movements in the trained direction and the amplitude of motor-evoked potentials (MEPs) in the abduction agonist first dorsal interosseous (FDI) muscle in the practicing hand and decreased the proportion and acceleration of TMS-evoked abduction movements and MEP amplitudes in the abduction agonist FDI in the opposite resting hand. Our findings indicate that unilateral hand practice specifically weakened the representation of the practiced movement in the ipsilateral M1 to an extent proportional to the strengthening effect in the contralateral M1, a result that varied with the practicing hand's position. These results suggest a more prominent involvement of interacting bilateral motor networks in motor memory formation and probably acquisition of unimanual motor skills than previously thought.

Dissociation of sustained attention from central executive functions: local activity and interregional connectivity in the theta range.

Human brain oscillatory activity was analysed in the electroencephalographic theta frequency range (4-7 Hz) while subjects executed complex sequential finger movements with varying task difficulty and memory load. Local frontal-midline theta activity was associated with the general level of cognitive demand, with the highest amplitudes in the most demanding condition. Using low-resolution electromagnetic tomography analysis (LORETA), this theta activity was localized in the anterior cingulate gyrus including the cingulate motor area. These results suggest that local theta activity in the anterior cingulate gyrus represents correlates of an attentional system that allocate cognitive resources. In addition, interregional connectivity in the theta frequency range was modulated by memory-related executive functions independently of task difficulty. Connectivity analyses revealed a more distributed long-range network including frontal and parietal cortices during execution of novel compared with well-trained finger movement sequences. Thus, these results are compatible with a model in which theta long-range coupling indicates integration of sensory information into executive control components of complex motor behaviour.