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Recent brain imaging has evidenced that parietofrontal networks show alterations after stroke which also relate to motor recovery processes. There is converging evidence for an upregulation of parietofrontal coupling between parietal brain regions and frontal motor cortices. The majority of studies though have included only moderately to mildly affected patients, particularly in the subacute or chronic stage. Whether these network alterations will also be present in severely affected patients and early after stroke and whether such information can improve correlative models to infer motor recovery remains unclear. In this prospective cohort study, 19 severely affected first-ever stroke patients (mean age 74 years, 12 females) were analysed which underwent resting-state functional MRI and clinical testing during the initial week after the event. Clinical evaluation of neurological and motor impairment as well as global disability was repeated after three and six months. Nineteen healthy participants of similar age and gender were also recruited. MRI data were used to calculate functional connectivity values between the ipsilesional primary motor cortex, the ventral premotor cortex, the supplementary motor area and the anterior and caudal intraparietal sulcus of the ipsilesional hemisphere. Linear regression models were estimated to compare parietofrontal functional connectivity between stroke patients and healthy controls and to relate them to motor recovery. The main finding was a significant increase in ipsilesional parietofrontal coupling between anterior intraparietal sulcus and the primary motor cortex in severely affected stroke patients (P, Backhaus et al. used resting-state functional imaging of the ipsilesional parietofrontal network in severely impaired acute stroke patients and reported increased connectivity between anterior intraparietal sulcus and primary motor cortex compared to controls and an association of this connectivity with subsequent persistent disability in the late subacute stage of recovery., Graphical Abstract Graphical Abstract

The aging of the nervous system is a heterogeneous process. It remains a significant challenge to identify relevant markers of pathological and healthy brain aging. A central aspect of aging are decreased sensory acuities, especially because they correlate with the decline in higher cognitive functioning. Sensory and higher cognitive processing relies on information flow between distant brain areas. Aging leads to disintegration of the underlying white matter tracts. While this disintegration is assumed to contribute to higher cognitive decline, data linking structural integrity and sensory function are sparse. The investigation of their interrelation may provide valuable insight into the mechanisms of brain aging. We used a combined behavioral and neuroimaging approach and investigated to what extent changes in microstructural white matter integrity reflect performance declines in tactile pattern recognition with aging. Poor performance in older participants was related to decreased integrity in the anterior corpus callosum. Probabilistic tractography showed that this structure is connected to the prefrontal cortices. Our data point to decreased integrity in the anterior corpus callosum as a marker for advanced brain aging. The correlation between impaired tactile recognition and disintegration in frontal brain networks could provide an explanation why the decrease of sensory function predicts cognitive decline.

BackgroundRheumatoid meningitis (RM) is a rare manifestation of rheumatoid arthritis (RA) and may present with stroke-like episodes. We describe diagnostic findings and the outcome in patients with RM.MethodsWe identified 6 patients with RM in different stages of RA mostly admitted with stroke-like episodes or common features of meningitis. We used MRI, CSF, and histology for in-depth characterization.ResultsWe observed RM in 2 patients without history of RA, 1 patient with early seropositive RA, and 3 patients with late-stage RA. Recurrent stroke-like episodes occurred in 5 of 6 patients; headache and partial status epilepticus was in the foreground in 1 patient. Symptoms were accompanied by constitutional symptoms in all patients. MRI showed leptomeningeal or pachymeningeal fluid-attenuated inversion recovery hyperintensities with contrast enhancement. CSF mostly showed mild pleocytosis but can initially be normal. Anticitrullinated peptide antibodies (ACPA) and rheumatoid factor (RF) were positive in all patients. Histopathology revealed granulomatous inflammation in 2 patients. Response to steroids was prompt and further immunosuppressive treatment prevented recurrence.ConclusionsRM is a rare manifestation of RA and often presents with stroke-like episodes. It is currently not implemented in the workup of aseptic meningitis in national guidelines. Crucial clues for diagnosis included recurrent stroke-like episodes refractory to antiepileptic treatment, headache and constitutional symptoms, meningeal enhancement on MRI, CSF pleocytosis, and positive serology findings for ACPA and RF. Prognosis is favorable with early immunosuppressive treatment.

Brain imaging has recently evidenced that the structural state of distinct reciprocal cortico-cerebellar fiber tracts, the dentato-thalamo-cortical tract (DTCT), and the cortico-ponto-cerebellar tract (CPCeT), significantly influences residual motor output in chronic stroke patients, independent from the level of damage to the corticospinal tract (CST). Whether such structural information might also directly relate to measures of cortical excitability is an open question. Eighteen chronic stroke patients with supratentorial ischemic lesions and 17 healthy controls underwent transcranial magnetic stimulation to assess recruitment curves of motor evoked potentials of both hemispheres. Diffusion-weighted imaging and probabilistic tractography were applied to reconstruct reciprocal cortico-cerebellar motor tracts between the primary motor cortex and the cerebellum. Tract-related microstructure was estimated by means of fractional anisotropy, and linear regression modeling was used to relate it to cortical excitability. The main finding was a significant association between cortical excitability and the structural integrity of the DTCT, the main cerebellar outflow tract, independent from the level of damage to the CST. A comparable relationship was neither detectable for the CPCeT nor for the healthy controls. This finding contributes to a mechanistic understanding of the putative supportive role of the cerebellum for residual motor output by facilitating cortical excitability after stroke.

Sleep has previously been claimed to be essential for the continued learning processes of declarative information as well as procedural learning. This study was conducted to examine the importance of sleep, especially the effects of midday naps, on motor sequence and visuomotor adaptation learning. Thirty-five (27 females) healthy, young adults aged between 18 and 30years of age participated in the current study. Addressing potential differences in explicit sequence and motor adaptation learning participants were asked to learn both, a nine-element explicit sequence and a motor adaptation task, in a crossover fashion on two consecutive days. Both tasks were performed with their non-dominant left hand. Prior to learning, each participant was randomized to one of three interventions; (1) power nap: 10-20min sleep, (2) long nap: 50-80min sleep or (3) a 45-min wake-condition. Performance of the motor learning task took place prior to and after a midday rest period, as well as after a night of sleep. Both sleep conditions were dominated by Stage N2 sleep with embedded sleep spindles, which have been described to be associated with enhancement of motor performance. Significant performance changes were observed in both tasks across all interventions (sleep and wake) confirming that learning took place. In the present setup, the magnitude of motor learning was not sleep-dependent in young adults - no differences between the intervention groups (short nap, long nap, no nap) could be found. The effect of the following night of sleep was not influenced by the previous midday rest or sleep period. This finding may be related to the selectiveness of the human brain enhancing especially memory being thought of as important in the future. Previous findings on motor learning enhancing effects of sleep, especially of daytime sleep, are challenged.

Background and Purpose— Tractography by diffusion tensor imaging has extended our knowledge on the contribution of damage to different pathways to residual motor function after stroke. Integrity of the corticospinal tract (CST), for example, has been identified to characterize and predict its course. Yet there is only scarce data that allow a judgment on the impact of extrapyramidal pathways between the basal ganglia on motor function poststroke. We aimed at studying their association with performance in fine motor skills after stroke. Methods— We performed probabilistic tractography and reconstructed nigro-pallidal tracts connecting substantia nigra and globus pallidus, as well as the CST in 26 healthy subjects. Resulting tracts were registered to the individual images of 20 patients 3 months after stroke, and their microstructural integrity was measured by fractional anisotropy. Clinical examination of the patients’ gross (grip force) and fine (nine-hole peg test) motor skills was performed 1 year after stroke. For assessment of factors influencing nine-hole peg test, we used a multivariate model. Results— Nigro-pallidal tracts were traceable in all participants, had no overlap to the CST and passed the nucleus subthalamicus. In stroke patients, nigro-pallidal tracts ipsilateral to the stroke lesion showed a significantly reduced fractional anisotropy (ratio, 0.96±0.02; P =0.021). One year after stroke, nine-hole peg test values were significantly slower for the affected hand, while grip force was comparable between both hands. Reduced integrity of the nigro-pallidal tracts was associated with worse performance in the nine-hole peg test ( P =0.040), as was reduced integrity of the CST ( P P Conclusions— Nigro-pallidal tracts with containing connections of the nucleus subthalamicus represent a relevant part of the extrapyramidal system and specifically contribute to residual fine motor skills after stroke beyond the well-known contribution of the CST. They may deliver supportive information for prediction of motor recovery after stroke.

Acquisition and reacquisition of skills is a main pillar of functional recovery after stroke. Nighttime sleep has a positive influence on motor learning in healthy individuals, whereas the effect of daytime sleep on neuro-rehabilitative training and relearning of the trained skills is often neglected. The aim of this study was to investigate the relationship between daytime sleep (napping) and the ability to learn a new visuomotor task in chronic stroke patients. The main hypothesis was that sleep enhances motor memory consolidation after training resulting in better motor performance after a period of daytime sleep. Thirty stroke survivors completed the study. They were randomized to one of three different conditions (i) wakeful resting, (ii) short nap (10-20 min), or (iii) long nap (50-80 min). All individuals trained the task with the contralesional, stroke-impaired hand, behavioral evaluation was performed after the break time (wake, nap), and 24 h later. Patients demonstrated a significant task-related behavioral improvement throughout the training. In contrast to the main hypothesis, there was no evidence for sleep-dependent motor consolidation early after the initial, diurnal break, or after an additional full night of sleep. In a secondary analysis, the performance changes of stroke survivors were compared with those of a group of healthy older adults who performed the identical task within the same experimental setup with their non-dominant hand. Performance levels were comparable between both cohorts at all time points. Stroke-related difficulties in motor control did not impact on the degree of performance improvement through training and daytime sleep did not impact on the behavioral gains in the two groups. In summary, the current study indicates that one-time daytime sleep after motor training does not influence behavioral gains.

Objective To compare the effect of simultaneous deep brain stimulation of the subthalamic nucleus and substantia nigra pars reticulata (STN+SNr-DBS) to conventional subthalamic stimulation (STN-DBS) on sleep quality in Parkinson's disease (PD) patients. Methods The study was a single-center, randomized, double-blind, cross-over clinical trial to compare the effect of STN-DBS vs. combined STN+SNr-DBS on subjective measures of sleep quality. Fifteen PD patients (2 female, age 62.5 ± 6.7 years) suffering from moderate idiopathic PD (disease duration: 12.0 ± 5.0 years, Hoehn & Yahr stage: 2.2 ± 0.4 in the MED-ON & STN-DBS-ON condition, Hoehn & Yahr stage: 2.6 ± 0.8 in the MED-OFF condition preoperatively) participated in the study. Sleep quality was evaluated in both stimulation conditions using the PDSS-2 score as a self-rating questionnaire covering several aspects of sleep disturbances. Results PD patients showed mild-moderate sleep disturbances (STN-DBS: PDSS-2 score 17.0 ± 11.0; STN+SNr-DBS: 14.7 ± 9.5) with slight but not significant differences between both stimulation conditions. Considering the different subitems of the PDSS-2, combined STN+SNr stimulation was superior to conventional STN stimulation in improving restless legs symptoms (RLS) at night (STN-DBS = 1.9 ± 2.7 STN+SNr-DBS = 1.0 ± 1.8; W = −2.06, p = 0.039) and immobility at night (STN-DBS = 1.5 ± 1.4 STN+SNr-DBS = 0.6 ± 0.8; W = −2.041, p = 0.041). Conclusion This study demonstrates the safety of STN+SNr-DBS compared to conventional STN-DBS on sleep in general with potential beneficial input on RLS symptoms and akinesia at night.

Background and Purpose: The immediate decrease of the apparent diffusion coefficient (ADC) is the main characteristic change of water diffusion in acute ischemic stroke. There is only limited information on the time course of diffusion parameters in different tissue compartments of cerebral ischemia. Materials and Methods: In a longitudinal study, we examined 21 patients with acute ischemic stroke by diffusion tensor imaging within 5 h after symptom onset, 3 h later, 2 days, and 1 month after symptom onset. Acute diffusion lesion and the fluid-attenuated inversion recovery (FLAIR) after 2 days were used as volumes of interest to define persistent core, lesion growth, and reversible acute diffusion lesion. For all diffusion parameters ratios between the stroke lesion VOIs and the mirror VOIs were calculated for each time point. ADC ratio, fractional anisotropy ratios, and eigenvalues ratios were measured in these volumes of interest and in contralateral mirror regions at each time points. Results: In the persistent core, ADC ratio (0.772) and all eigenvalues ratios were reduced on admission up to 1 day after stroke and increased after 1 month (ADC ratio 1.067). Within the region of infarct growth time course of diffusion parameter changes was similar, but delayed. In the brain area with reversible diffusion lesion, a partial normalization of diffusion parameters over the time was observed, while after 1 month diffusion parameters did not show the signature of healthy brain tissue. There were significantly different trends for all parameters over time between the three tissue compartments. Conclusion: Diffusion tensor imaging displays characteristic changes of water diffusion in different tissue compartments over time in acute ischemic stroke. Even regions with reversible diffusion lesion show diffusion signatures of persisting tissue alterations.

Background and purpose Cerebral ischemia leads to a rapid decrease of the apparent diffusion coefficient. For fractional anisotropy both increase and decrease have been reported in acute ischemic stroke. Aim of this study was to characterize early water diffusion changes in a homogenous group of acute stroke patients and to clarify the issue of early fractional anisotropy changes and their relation to time from symptom onset. Methods MRI data of patients with acute ischemic stroke examined by diffusion tensor imaging within 8h after symptom were analyzed. We calculated fractional anisotropy, eigenvalues and the isotropic and anisotropic components of the diffusion tensor. The values were calculated as ratios between the ischemic lesion and a mirror region in the unaffected side and correlated with clinical parameters. Results We included 63 patients: 49% female, mean age 69 ± 14 years, median NIHSS on admission 9 (IQR 4–14). For the whole sample, mean fractional anisotropy was increased (ratio: 1.083 ± 0.168), while all other diffusion parameters were decreased. Both the isotropic and anisotropic component of the diffusion tensor were decreased with a more pronounced decrease of the isotropic component (ratios: isotropic = 0.730 ± 0.106, anisotropic = 0.788 ± 0.127; p

Mirror neuron system (MNS) dysfunctions might underlie deficits in autism spectrum disorders (ASD). Diffusion tensor imaging based probabilistic tractography was conducted in 15 adult ASD patients and 13 matched, healthy controls. Fractional anisotropy (FA) was quantified to assess group differences in tract-related white matter microstructure of both the classical MNS route (mediating "emulation") and the alternative temporo-frontal route (mediating "mimicry"). Multiple linear regression was used to investigate structure-function relationships between MNS connections and ASD symptom severity. There were no significant group differences in tract-related FA indicating an intact classical MNS in ASD. Direct temporo-frontal connections could not be reconstructed challengeing the concept of multiple routes for imitation. Tract-related FA of right-hemispheric parieto-frontal connections was negatively related to autism symptom severity.

Herpes simplex virus-1 encephalitis (HSVE) is the most common cause of fatal sporadic encephalitis worldwide. Recently, post-HSVE relapses due to autoimmune encephalitis with NMDA receptor antibodies and other synaptic autoantibodies have been reported in up to 27% of patients within 1–2 months after HSVE.1,2 We report an unusual case of a patient with refractory status epilepticus due to HSVE with antibodies against GABAA receptors (GABAAR).

Background and objective The extent to which deep brain stimulation (DBS) can improve quality of life may be perceived as a permanent trade-off between neurological improvements and complications of therapy, comorbidities, and disease progression. Patients and methods We retrospectively investigated 123 consecutive and non-preselected patients. Indications for DBS surgery were Parkinson's disease (82), dystonia (18), tremor of different etiology (21), Huntington's disease (1) and Gilles de la Tourette syndrome (1). AEs were defined as any untoward clinical occurrence, sign or patient complaint or unintended disease if related or unrelated to the surgical procedures, implanted devices or ongoing DBS therapy. Results Over a mean/median follow-up period of 4.7 years (578 patient-years) 433 AEs were recorded in 106 of 123 patients (86.2%). There was no mortality or persistent morbidity from the surgical procedure. All serious adverse events (SAEs) that occurred within 4 weeks of surgery were reversible. Neurological AEs (193 in 85 patients) and psychiatric AEs (78 in 48 patients) were documented most frequently. AEs in 4 patients (suicide under GPI stimulation, weight gain >20 kg, impairment of gait and speech, cognitive decline >2 years following surgery) were severe or worse, at least possibly related to DBS and non reversible. In PD 23.1% of the STN-stimulated patients experienced non-reversible (or unknown reversibility) AEs that were at least possibly related to DBS in the form of impaired speech or gait, depression, weight gain, cognitive disturbances or urinary incontinence (severity was mild or moderate in 15 of 18 patients). Age and Hoehn&Yahr stage of STN-simulated PD patients, but not preoperative motor impairment or response to levodopa, showed a weak correlation (r = 0.24 and 0.22, respectively) with the number of AEs. Conclusions DBS-related AEs that were severe or worse and non-reversible were only observed in PD (4 of 82 patients; 4.9%), but not in other diseases. PD patients exhibited a significant risk for non-severe AEs most of which also represented preexisting and progressive axial and non-motor symptoms of PD. Mild gait and/or speech disturbances were rather frequent complaints under VIM stimulation. GPI stimulation for dystonia could be applied with negligible DBS-related side effects.

Background and objective To determine rates of adverse events (AEs) related to deep brain stimulation (DBS) surgery or implanted devices from a large series from a single institution. Sound comparisons with the literature require the definition of unambiguous categories, since there is no consensus on the reporting of such AEs. Patients and methods 123 consecutive patients (median age 63 yrs; female 45.5%) treated with DBS in the subthalamic nucleus (78 patients), ventrolateral thalamus (24), internal pallidum (20), and centre median-parafascicular nucleus (1) were analyzed retrospectively. Both mean and median follow-up time was 4.7 years (578 patient-years). AEs were assessed according to three unambiguous categories: (i) hemorrhages including other intracranial complications because these might lead to neurological deficits or death, (ii) infections and similar AEs necessitating the explantation of hardware components as this results in the interruption of DBS therapy, and (iii) lead revisions for various reasons since this involves an additional intracranial procedure. For a systematic review of the literature AE rates were calculated based on primary data presented in 103 publications. Heterogeneity between studies was assessed with the I2 statistic and analyzed further by a random effects meta-regression. Publication bias was analyzed with funnel plots. Results Surgery- or hardware-related AEs (23) affected 18 of 123 patients (14.6%) and resolved without permanent sequelae in all instances. In 2 patients (1.6%), small hemorrhages in the striatum were associated with transient neurological deficits. In 4 patients (3.3%; 0.7% per patient-year) impulse generators were removed due to infection. In 2 patients electrodes were revised (1.6%; 0.3% per patient-year). There was no lead migration or surgical revision because of lead misplacement. Age was not statistically significant different (p>0.05) between patients affected by AEs or not. AE rates did not decline over time and similar incidences were found among all patients (423) implanted with DBS systems at our institution until December 2016. A systematic literature review revealed that exact AE rates could not be determined from many studies, which could not be attributed to study designs. Average rates for intracranial complications were 3.8% among studies (per-study analysis) and 3.4% for pooled analysis of patients from different studies (per-patient analysis). Annual hardware removal rates were 3.6 and 2.4% for per-study and per-patient analysis, respectively, and lead revision rates were 4.1 and 2.6%, respectively. There was significant heterogeneity between studies (I2 ranged between 77% and 91% for the three categories; p< 0.0001). For hardware removal heterogeneity (I2 = 87.4%) was reduced by taking study size (p< 0.0001) and publication year (p< 0.01) into account, although a significant degree of heterogeneity remained (I2 = 80.0%; p< 0.0001). Based on comparisons with health care-related databases there appears to be publication bias with lower rates for hardware-related AEs in published patient cohorts. Conclusions The proposed categories are suited for an unequivocal assessment of AEs even in a retrospective manner and useful for benchmarking. AE rates in the present cohorts from our institution compare favorable with the literature.

Background Naps as well as a night of sleep were found to improve motor learning in young individuals ( Doyon et al., 2009 ). The capacity of older adults to learn and stabilize motor memory traces (consolidation) during over-night sleep is limited ( Pan and Rickard, 2015; Backhaus et al., 2015 ). However a small number of studies suggested sleep-dependent consolidation in healthy older adults, immediately after sleep ( Gudberg et al., 2015; Al-Sharman and Siengsukon, 2014 ) or after a delayed period ( Tucker et al., 2011; Korman et al., 2015 ). Research question Can midday naps enhance motor learning in older adults? Methods We evaluated the performance changes of a sample of thirty-three healthy older adults (60–82 years) by implementing a napping paradigm in a motor learning setup (sequence learning and motor adaption). The participants were randomly assigned to one of three groups; short nap group (a forty-five minutes nap opportunity, 10–20 min sleep), long nap group (ninety minutes nap opportunity, 50–80 min sleep) or a forty-five minutes period of wakefulness. Three learning sessions on two consecutive days were compared for both tasks with the repeated measures mixed model approach. Results All older adults were able to improve their task performance in both tasks throughout all sessions. For sequence learning no differences between the nap groups could be found following the midday nap, nor after an extended period of consolidation, i.e. the following day. Similarly no significant differences between the groups could be found directly after the midday break when performing the motor adaptation task. However during the final block of the last session nappers performed significantly better ( p = 0.023) than those adults staying awake. Conclusion Although midday naps may have a great recuperative value ( Tamaki et al., 1999; Campbell et al., 2011 ), these effects could not be projected on motor learning and subsequent motor performance directly after napping. Based on the current results we conclude that short daytime naps do not enhance the effects of motor learning and consolidation. Thus, deficits in consolidation apparent in older adults are not dependent of the duration of sleep but rather of the process of consolidation during sleep, which seems to be impaired in older adults. This work was supported by the Stiftung der Deutschen Wirtschaft providing a PhD Scholarship to W.B. W.B and F.C.H. hold a research grant from the Werner-Otto-Foundation (9/87).