Early functional connectivity alterations in contralesional motor networks influence outcome after severe stroke: a preliminary analysis.

Connectivity studies have significantly extended the knowledge on motor network alterations after stroke. Compared to interhemispheric or ipsilesional networks, changes in the contralesional hemisphere are poorly understood. Data obtained in the acute stage after stroke and in severely impaired patients are remarkably limited. This exploratory, preliminary study aimed to investigate early functional connectivity changes of the contralesional parieto-frontal motor network and their relevance for the functional outcome after severe motor stroke. Resting-state functional imaging data were acquired in 19 patients within the first 2 weeks after severe stroke. Nineteen healthy participants served as a control group. Functional connectivity was calculated from five key motor areas of the parieto-frontal network on the contralesional hemisphere as seed regions and compared between the groups. Connections exhibiting stroke-related alterations were correlated with clinical follow-up data obtained after 3-6 months. The main finding was an increase in coupling strength between the contralesional supplementary motor area and the sensorimotor cortex. This increase was linked to persistent clinical deficits at follow-up. Thus, an upregulation in contralesional motor network connectivity might be an early pattern in severely impaired stroke patients. It might carry relevant information regarding the outcome which adds to the current concepts of brain network alterations and recovery processes after severe stroke.

Structural cerebellar reserve positively influences outcome after severe stroke.

The concept of brain reserve capacity positively influencing the process of recovery after stroke has been continuously developed in recent years. Global measures of brain health have been linked with a favourable outcome. Numerous studies have evidenced that the cerebellum is involved in recovery after stroke. However, it remains an open question whether characteristics of cerebellar anatomy, quantified directly after stroke, might have an impact on subsequent outcome after stroke. Thirty-nine first-ever ischaemic non-cerebellar stroke patients underwent MRI brain imaging early after stroke and longitudinal clinical follow-up. Structural images were used for volumetric analyses of distinct cerebellar regions. Ordinal logistic regression analyses were conducted to associate cerebellar volumes with functional outcome 3-6 months after stroke, operationalized by the modified Rankin Scale. Larger volumes of cerebellar lobules IV, VI, and VIIIB were positively correlated with favourable outcome, independent of the severity of initial impairment, age, and lesion volume (P < 0.01). The total cerebellar volume did not exhibit a significant structure-outcome association. The present study reveals that pre-stroke anatomy of distinct cerebellar lobules involved in motor and cognitive functioning might be linked to outcome after acute non-cerebellar stroke, thereby promoting the emerging concepts of structural brain reserve for recovery processes after stroke.

Brain network topology early after stroke relates to recovery.

Analyses of alterations of brain networks have gained an increasing interest in stroke rehabilitation research. Compared with functional networks derived from resting-state analyses, there is limited knowledge of how structural network topology might undergo changes after stroke and, more importantly, if structural network information obtained early after stroke could enhance recovery models to infer later outcomes. The present work re-analysed cross-sectional structural imaging data, obtained within the first 2 weeks, of 45 acute stroke patients (22 females, 24 right-sided strokes, age 68 ± 13 years). Whole-brain tractography was performed to reconstruct structural connectomes and graph-theoretical analyses were employed to quantify global network organization with a focus on parameters of network integration and modular processing. Graph measures were compared between stroke patients and 34 healthy controls (15 females, aged 69 ± 10 years) and they were integrated with four clinical scores of the late subacute stage, covering neurological symptom burden (National Institutes of Health Stroke Scale), global disability (modified Rankin Scale), activity-related disability (Barthel Index) and motor functions (Upper-Extremity Score of the Fugl-Meyer Assessment). The analyses were employed across the complete cohort and, based on clustering analysis, separately within subgroups stratified in mild to moderate (n = 21) and severe (n = 24) initial deficits. The main findings were (i) a significant reduction of network's global efficiency, specifically in patients with severe deficits compared with controls (P = 0.010) and (ii) a significant negative correlation of network efficiency with the extent of persistent functional deficits at follow-up after 3-6 months (P ≤ 0.032). Specifically, regression models revealed that this measure was capable to increase the explained variance in future deficits by 18% for the modified Rankin Scale, up to 24% for National Institutes of Health Stroke Scale, and 16% for Barthel Index when compared with models including the initial deficits and the lesion volume. Patients with mild to moderate deficits did not exhibit a similar impact of network efficiency on outcome inference. Clustering coefficient and modularity, measures of segregation and modular processing, did not exhibit comparable structure-outcome relationships, neither in severely nor in mildly affected patients. This study provides empirical evidence that structural network efficiency as a graph-theoretical marker of large-scale network topology, quantified early after stroke, relates to recovery. Notably, this contribution was only evident in severely but not mildly affected stroke patients. This suggests that the initial clinical deficit might shape the dependency of recovery on global network topology after stroke.

Cortical thickness of contralesional cortices positively relates to future outcome after severe stroke.

Imaging studies have evidenced that contralesional cortices are involved in recovery after motor stroke. Cortical thickness (CT) analysis has proven its potential to capture the changes of cortical anatomy, which have been related to recovery and treatment gains under therapy. An open question is whether CT obtained in the acute phase after stroke might inform correlational models to explain outcome variability. Data of 38 severely impaired (median NIH Stroke Scale 9, interquartile range: 6-13) acute stroke patients of 2 independent cohorts were reanalyzed. Structural imaging data were processed via the FreeSurfer pipeline to quantify regional CT of the contralesional hemisphere. Ordinal logistic regression models were fit to relate CT to modified Rankin Scale as an established measure of global disability after 3-6 months, adjusted for the initial deficit, lesion volume, and age. The data show that CT of contralesional cortices, such as the precentral gyrus, the superior frontal sulcus, and temporal and cingulate cortices, positively relates to the outcome after stroke. This work shows that the baseline cortical anatomy of selected contralesional cortices can explain the outcome variability after severe stroke, which further contributes to the concept of structural brain reserve with respect to contralesional cortices to promote recovery.

Reduced frontal white matter microstructure in healthy older adults with low tactile recognition performance.

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.

Predictive Value of Upper Extremity Outcome Measures After Stroke-A Systematic Review and Metaregression Analysis.

A better understanding of motor recovery after stroke requires large-scale, longitudinal trials applying suitable assessments. Currently, there is an abundance of upper limb assessments used to quantify recovery. How well various assessments can describe upper limb function change over 1 year remains uncertain. A uniform and feasible standard would be beneficial to increase future studies' comparability on stroke recovery. This review describes which assessments are common in large-scale, longitudinal stroke trials and how these quantify the change in upper limb function from stroke onset up to 1 year. A systematic search for well-powered stroke studies identified upper limb assessments classifying motor recovery during the initial year after a stroke. A metaregression investigated the association between assessments and motor recovery within 1 year after stroke. Scores from nine common assessments and 4,433 patients were combined and transformed into a standardized recovery score. A mixed-effects model on recovery scores over time confirmed significant differences between assessments (P < 0.001), with improvement following the weeks after stroke present when measuring recovery using the Action Research Arm Test (ß = 0.013), Box and Block test (ß = 0.011), Fugl-Meyer Assessment (ß = 0.007), or grip force test (ß = 0.023). A last-observation-carried-forward analysis also highlighted the peg test (ß = 0.017) and Rivermead Assessment (ß = 0.011) as additional, valuable long-term outcome measures. Recovery patterns and, thus, trial outcomes are dependent on the assessment implemented. Future research should include multiple common assessments and continue data collection for a full year after stroke to facilitate the consensus process on assessments measuring upper limb recovery.

Early parietofrontal network upregulation relates to future persistent deficits after severe stroke-a prospective cohort study.

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 < 0.003). This upregulation significantly contributed to correlative models explaining variability in subsequent neurological and global disability as quantified by National Institute of Health Stroke Scale and modified Rankin Scale, respectively. Patients with increased parietofrontal coupling in the acute stage showed higher levels of persistent deficits in the late subacute stage of recovery (P < 0.05). This study provides novel insights that parietofrontal networks of the ipsilesional hemisphere undergo neuroplastic alteration already very early after severe motor stroke. The association between early parietofrontal upregulation and future levels of persistent functional deficits and dependence from help in daily living might be useful in models to enhance clinical neurorehabilitative decision making.

The Influence of Cortico-Cerebellar Structural Connectivity on Cortical Excitability in Chronic Stroke.

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.

Can Daytime Napping Assist the Process of Skills Acquisition 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.

Motor Performance Is not Enhanced by Daytime Naps in Older Adults.

The impact of sleep on motor learning in the aging brain was investigated using an experimental diurnal nap setup. As the brain ages several components of learning as well as motor performance change. In addition, aging is also related to sleep architectural changes. This combination of slowed learning processes and impaired sleep behavior raises the question of whether sleep can enhance learning and specifically performance of procedural tasks in healthy, older adults. Previous research was able to show sleep-dependent consolidation overnight for numerous tasks in young adults. Some of these study findings can also be replicated for older adults. This study aims to clarify whether sleep-dependent consolidation can also be found during shorter periods of diurnal sleep. The impact of midday naps on motor consolidation was analyzed by comparing procedural learning using a sequence and a motor adaptation task, in a crossover fashion in healthy, non-sleep deprived, older adults randomly subjected to wake (45 min), short nap (10-20 min sleep) or long nap (50-70 min sleep) conditions. Older adults exhibited learning gains, these were not found to be sleep-dependent in either task. The results suggest that daytime naps do not have an impact on performance and motor learning in an aging population.

Daytime sleep has no effect on the time course of motor sequence and visuomotor adaptation learning.

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.

Differential effects of BDNF val(66)met in repetitive associative learning paradigms.

In healthy young subjects, the brain derived neurotropic factor (BDNF) val(66)met polymorphism negatively affects behavioural outcome in short-term motor cortex or hippocampus-based learning paradigms. In repetitive training paradigms over several days this effect can be overcome, in tests involving other brain areas even positive effects were found. To further specify the role of this polymorphism in cognitive processes, we used an associative vocabulary learning paradigm over four consecutive days and tested 38 young healthy subjects and 29 healthy elderly subjects. As a control paradigm, we designed a nonverbal haptic Braille letter-learning paradigm based on the same principles. Behavioural outcome was then associated with the BDNF-genotype. In the vocabulary learning task, met carrier (met/val and met/met) benefitted more from the repetitive training than val/val subjects. This was paralleled by a higher reduction of delayed answers during the course of the study, an effect that was also present in the haptic paradigm. However, in a group of healthy elderly subjects, no similar tendency was found. We conclude that the BDNF val(66)met polymorphism alters highly circumscribed answer behaviours in young healthy subjects. This might partly explain the high variability of previously published results.