The Evolution of Hand Proprioceptive and Motor Impairments in the Sub-Acute Phase After Stroke.

BACKGROUND: Hand proprioception is essential for fine movements and therefore many activities of daily living. Although frequently impaired after stroke, it is unclear how hand proprioception evolves in the sub-acute phase and whether it follows a similar pattern of changes as motor impairments. OBJECTIVE: This work investigates whether there is a corresponding pattern of changes over time in hand proprioception and motor function as comprehensively quantified by a combination of robotic, clinical, and neurophysiological assessments. METHODS: Finger proprioception (position sense) and motor function (force, velocity, range of motion) were evaluated using robotic assessments at baseline (<3 months after stroke) and up to 4 weeks later (discharge). Clinical assessments (among others, Box & Block Test [BBT]) as well as Somatosensory/Motor Evoked Potentials (SSEP/MEP) were additionally performed. RESULTS: Complete datasets from 45 participants post-stroke were obtained. For 42% of all study participants proprioception and motor function had a dissociated pattern of changes (only 1 function considerably improved). This dissociation was either due to the absence of a measurable impairment in 1 modality at baseline, or due to a severe lesion of central somatosensory or motor tracts (absent SSEP/MEP). Better baseline BBT correlated with proprioceptive gains, while proprioceptive impairment at baseline did not correlate with change in BBT. CONCLUSIONS: Proprioception and motor function frequently followed a dissociated pattern of changes in sub-acute stroke. This highlights the importance of monitoring both functions, which could help to further personalize therapies.

The locations of stroke lesions next to the posterior internal capsule may predict the recovery of the related proprioceptive deficits.

Background: Somatosensory deficits after stroke correlate with functional disabilities and impact everyday-life. In particular, the interaction of proprioception and motor dysfunctions affects the recovery. While corticospinal tract (CST) damage is linked to poor motor outcome, much less is known on proprioceptive recovery. Identifying a predictor for such a recovery could help to gain insights in the complex functional recovery processes thereby reshaping rehabilitation strategies. Methods: 50 patients with subacute stroke were tested before and after neurological rehabilitation. Proprioceptive and motor impairments were quantified with three clinical assessments and four hand movement and proprioception measures using a robotic device. Somatosensory evoked potentials (SSEP) to median nerve stimulation and structural imaging data (MRI) were also collected. Voxel-based lesion-symptom mapping (VLSM) along with a region of interest (ROI) analysis were performed for the corticospinal tract (CST) and for cortical areas. Results: Before rehabilitation, the VLSM revealed lesion correlates for all clinical and three robotic measures. The identified voxels were located in the white matter within or near the CST. These regions associated with proprioception were located posterior compared to those associated with motor performance. After rehabilitation the patients showed an improvement of all clinical and three robotic assessments. Improvement in the box and block test was associated with an area in anterior CST. Poor recovery of proprioception was correlated with a high lesion load in fibers towards primary sensorymotor cortex (S1 and M1 tract). Patients with loss of SSEP showed higher lesion loads in these tracts and somewhat poorer recovery of proprioception. The VSLM analysis for SSEP loss revealed a region within and dorsal of internal capsule next to the posterior part of CST, the posterior part of insula and the rolandic operculum. Conclusion: Lesions dorsal to internal capsule next to the posterior CST were associated with proprioceptive deficits and may have predictive value. Higher lesion load was correlated with poorer restoration of proprioceptive function. Furthermore, patients with SSEP loss trended towards poor recovery of proprioception, the corresponding lesions were also located in the same location. These findings suggest that structural imaging of the internal capsule and CST could serve as a recovery predictor of proprioceptive function.

100 years after Liepmann-Lesion correlates of diminished selection and application of familiar versus novel tools.

100 years ago, Liepmann highlighted the role of left ventro-dorsal lesions for impairments in conceptual (rather ventral) and motor (more dorsal) related aspects of apraxia. Many studies thereafter attributed to an extended left fronto-temporo-parietal network. Yet, to date there are only few studies that looked at apraxic performance in the selection and application of familiar versus novel tools. In the current study we applied modern voxel-based lesion-symptom mapping (VLSM) to analyze neural correlates of impaired selection and application of familiar versus novel tools. 58 left (LBD) and 51 right brain damaged (RBD) stroke patients participated in the Novel Tools Test (NTT) and the Familiar Tools Test (FTT) of the Diagnostic Instrument for Limb Apraxia (DILA-S). We further assessed performance in control tasks, namely semantic knowledge (BOSU), visuo-spatial working memory (Corsi Block Tapping) and meaningless imitation of gestures (IML). Impaired tool use was most pronounced after LBD. Our VLSM results in the LBD group suggested that selection- versus application-related aspects of praxis and semantics of familiar versus novel tool use can be behaviorally and neuro-anatomically differentiated. For impairments in familiar tool tasks, the major focus of lesion maps was rather ventral while deficiencies in novel tool tasks went along with rather dorsal lesions. Affected selection processes were linked to rather anterior lesions, while impacted application processes went along with rather posterior lesion maps. In our study, particular tool selection processes were rather specific for familiar versus novel tools. Foci for lesion overlaps of experimental and control tasks were noticed ventrally for semantic knowledge and FTT, in fronto-parietal regions for working memory and NTT, and ventro-dorsally for imitation of meaningless gestures and the application of NTT and FTT. We visualized our current interpretation within a neuroanatomical model for apraxia of tool use.

Increased Amygdala Activity Associated With Cognitive Reappraisal Strategy in Functional Neurologic Disorder.

Cognitive reappraisal is an emotion regulation strategy to reduce the impact of affective stimuli. This regulation could be incomplete in patients with functional neurologic disorder (FND) resulting in an overflowing emotional stimulation perpetuating symptoms in FND patients. Here we employed functional MRI to study cognitive reappraisal in FND. A total of 24 FND patients and 24 healthy controls employed cognitive reappraisal while seeing emotional visual stimuli in the scanner. The Symptom Checklist-90-R (SCL-90-R) was used to evaluate concomitant psychopathologies of the patients. During cognitive reappraisal of negative IAPS images FND patients show an increased activation of the right amygdala compared to normal controls. We found no evidence of downregulation in the amygdala during reappraisal neither in the patients nor in the control group. The valence and arousal ratings of the IAPS images were similar across groups. However, a subgroup of patients showed a significant higher account of extreme low ratings for arousal for negative images. These low ratings correlated inversely with the item "anxiety" of the SCL-90-R. The increased activation of the amygdala during cognitive reappraisal suggests altered processing of emotional stimuli in this region in FND patients.

Behavioral and neurophysiological effects of an intensified robot-assisted therapy in subacute stroke: a case control study.

BACKGROUND: Physical training is able to induce changes at neurophysiological and behavioral level associated with performance changes for the trained movements. The current study explores the effects of an additional intense robot-assisted upper extremity training on functional outcome and motor excitability in subacute stroke patients. METHODS: Thirty moderately to severely affected patients < 3 months after stroke received a conventional inpatient rehabilitation. Based on a case-control principle 15 patients were assigned to receive additional 45 min of robot-assisted therapy (Armeo®Spring) 5 times per week (n = 15, intervention group, IG). The Fugl-Meyer Assessment for the Upper Extremity (FMA-UE) was chosen as primary outcome parameter. Patients were tested before and after a 3-week treatment period as well as after a follow-up period of 2 weeks. Using transcranial magnetic stimulation motor evoked potentials (MEPs) and cortical silent periods were recorded from the deltoid muscle on both sides before and after the intervention period to study effects at neurophysiological level. Statistical analysis was performed with non-parametric tests. Correlation analysis was done with Spearman´s rank correlation co-efficient. RESULTS: Both groups showed a significant improvement in FMA-UE from pre to post (IG: + 10.6 points, control group (CG): + 7.3 points) and from post to follow-up (IG: + 3.9 points, CG: + 3.3 points) without a significant difference between them. However, at neurophysiological level post-intervention MEP amplitudes were significantly larger in the IG but not in the CG. The observed MEP amplitudes changes were positively correlated with FMA-UE changes and with the total amount of robot-assisted therapy. CONCLUSION: The additional robot-assisted therapy induced stronger excitability increases in the intervention group. However, this effect did not transduce to motor performance improvements at behavioral level. Trial registration The trial was registered in German Clinical Trials Register. CLINICAL TRIAL REGISTRATION NUMBER: DRKS00015083. Registration date: September 4th, 2018. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00015083 . Registration was done retrospectively.

Cortical, subcortical and spinal neural correlates of slackline training-induced balance performance improvements.

Humans develop posture and balance control during childhood. Interestingly, adults can also learn to master new complex balance tasks, but the underlying neural mechanisms are not fully understood yet. Here, we combined broad scale brain connectivity fMRI at rest and spinal excitability measurements during movement. Six weeks of slackline training improved the capability to walk on a slackline which was paralleled by functional connectivity changes in brain regions associated with posture and balance control and by task-specific changes of spinal excitability. Importantly, the performance of trainees was not better than control participants in a different, untrained balance task. In conclusion, slackline training induced large-scale neuroplasticity which solely transferred into highly task specific performance improvements.

Neural correlates of effort-dependent and effort-independent cognitive fatigue components in patients with multiple sclerosis.

BACKGROUND: Among patients with multiple sclerosis (MS), fatigue is the most commonly reported symptom. It can be subdivided into an effort-dependent (fatigability) and an effort-independent component (trait-fatigue). OBJECTIVE: The objective was to disentangle activity changes associated with effort-independent "trait-fatigue" from those associated with effort-dependent fatigability in MS patients. METHODS: This study employed behavioral measures and functional magnetic imaging to investigate neural changes in MS patients associated with fatigue. A total of 40 MS patients and 22 age-matched healthy controls performed in a fatigue-inducing N-back task. Effort-independent fatigue was assessed using the Fatigue Scale of Motor and Cognition (FSMC) questionnaire. RESULTS: Effort-independent fatigue was observed to be reflected by activity increases in fronto-striatal-subcortical networks primarily involved in the maintenance of homeostatic processes and in motor and cognitive control. Effort-dependent fatigue (fatigability) leads to activity decreases in attention-related cortical and subcortical networks. CONCLUSION: These results indicate that effort-independent (fatigue) and effort-dependent fatigue (fatigability) in MS patients have functionally related but fundamentally different neural correlates. Fatigue in MS as a general phenomenon is reflected by complex interactions of activity increases in control networks (effort-independent component) and activity reductions in executive networks (effort-dependent component) of brain areas.

Symptom-specific amygdala hyperactivity modulates motor control network in conversion disorder.

Initial historical accounts as well as recent data suggest that emotion processing is dysfunctional in conversion disorder patients and that this alteration may be the pathomechanistic neurocognitive basis for symptoms in conversion disorder. However, to date evidence of direct interaction of altered negative emotion processing with motor control networks in conversion disorder is still lacking. To specifically study the neural correlates of emotion processing interacting with motor networks we used a task combining emotional and sensorimotor stimuli both separately as well as simultaneously during functional magnetic resonance imaging in a well characterized group of 13 conversion disorder patients with functional hemiparesis and 19 demographically matched healthy controls. We performed voxelwise statistical parametrical mapping for a priori regions of interest within emotion processing and motor control networks. Psychophysiological interaction (PPI) was used to test altered functional connectivity of emotion and motor control networks. Only during simultaneous emotional stimulation and passive movement of the affected hand patients displayed left amygdala hyperactivity. PPI revealed increased functional connectivity in patients between the left amygdala and the (pre-)supplemental motor area and the subthalamic nucleus, key regions within the motor control network. These findings suggest a novel mechanistic direct link between dysregulated emotion processing and motor control circuitry in conversion disorder.

Functional networks of motor inhibition in conversion disorder patients and feigning subjects.

The neural correlates of motor inhibition leading to paresis in conversion disorder are not well known. The key question is whether they are different of those of normal subjects feigning the symptoms. Thirteen conversion disorder patients with hemiparesis and twelve healthy controls were investigated using functional magnetic resonance tomography under conditions of passive motor stimulation of the paretic/feigned paretic and the non-paretic hand. Healthy controls were also investigated in a non-feigning condition. During passive movement of the affected right hand conversion disorder patients exhibited activations in the bilateral triangular part of the inferior frontal gyri (IFG), with a left side dominance compared to controls in non-feigning condition. Feigning controls revealed for the same condition a weak unilateral activation in the right triangular part of IFG and an activity decrease in frontal midline areas, which couldn't be observed in patients. The results suggest that motor inhibition in conversion disorder patients is mediated by the IFG that was also involved in inhibition processes in normal subjects. The activity pattern in feigning controls resembled that of conversion disorder patients but with a clear difference in the medial prefrontal cortex. Healthy controls showed decreased activity in this region during feigning compared to non-feigning conditions suggesting a reduced sense of self-agency during feigning. Remarkably, no activity differences could be observed in medial prefrontal cortex for patients vs healthy controls in feigning or non-feigning conditions suggesting self-agency related activity in patients to be in between those of non-feigning and feigning healthy subjects.

Neural correlates of training-induced improvements of calculation skills in patients with brain lesions.

PURPOSE: The loss of calculation skills due to brain lesions leads to a major reduction in the quality of life and is often associated with difficulties of returning to work and a normal life. Very little is known about the neural mechanisms underlying performance improvement due to calculation training during rehabilitation. The current study investigates the neural basis of training-induced changes in patients with acalculia following ischemic stroke or traumatic brain lesions. METHODS: Functional hemodynamic responses (fMRI) were recorded in seven patients during calculation and perceptual tasks both before and after acalculia training. RESULTS: Despite the heterogeneity of brain lesions associated with acalculia in our patient sample, a common pattern of training-induced changes emerged. Performance improvements were associated with widespread deactivations in the prefrontal cortex. These deactivations were calculation-specific and only observed in patients exhibiting a considerable improvement after training. CONCLUSION: These findings suggest that the training-induced changes in our patients rely on an increase of frontal processing efficiency.

Action imagery combined with action observation activates more corticomotor regions than action observation alone.

BACKGROUND AND PURPOSE: Both action observation (AO) and action imagery have been proposed as therapeutic options for stroke rehabilitation. Currently, it is not clear to what extent their underlying neuronal mechanisms differ from each other and whether one of these therapeutic options might be preferable for this purpose. METHODS: Twenty-six neurologically healthy subjects were investigated using functional magnetic resonance imaging during AO alone and during AO with additional action imagery of video clips showing simple, object-related hand actions. RESULTS: The blood oxygenation level dependent (BOLD) signal induced by AO increased in a bihemispheric, symmetrical network of areas including the occipital, superior, and inferior parietal cortex, dorsal and ventral premotor regions, and the prefrontal cortex. The addition of imagery to the AO elicited additional activation in both cerebellar hemispheres, caudate nucleus, ventral and dorsal premotor cortex, inferior parietal cortex, and the supplementary motor area. DISCUSSION AND CONCLUSION: These data reveal more profound activations of the motor system during AO in conjunction with imagery than during AO alone. These results may have important implications for neurorehabilitation and motor learning.

Neural correlates of somatosensory processing in patients with neglect.

PURPOSE: Recent evidence from neuroimaging studies using visual tasks suggests that the right superior parietal cortex plays a pivotal role for the recovery of neglect. Importantly, neglect-related deficits are not limited to the visual system and have a rather multimodal nature. We employed somatosensory stimulation in patients with neglect in order to analyze activity changes in networks that are presumably associated with this condition. METHODS: Eleven chronic neglect patients with right hemispherical stroke were investigated with a fMRI paradigm in which the affected and unaffected hand were passively moved. RESULTS: Brain activation was correlated with the performance in clinical neglect tests. Significant positive correlations with brain activation were found for the lesion duration, the performance in bells and letter cancellation tests and the line bisection test. These activated areas formed a distributed pattern in the right superior parietal cortex. CONCLUSIONS: The results suggest a shared representation of visual and somatosensory networks in the right superior parietal cortex in patients with right hemispherical strokes and neglect. The spatial pattern of activity in the superior parietal cortex points out to a different representation of changes related to lesion duration and neglect.

Neural correlates of hysterical blindness.

The neural mechanisms underlying conversion disorders such as hysterical blindness are at present unknown. Typically, patients are diagnosed through exclusion of neurological disease and the absence of pathologic neurophysiological diagnostic findings. Here, we investigate the neural basis of this disorder by combining electrophysiological (event-related potentials) and hemodynamic measures (functional magnet resonance tomography) in a patient with hysterical blindness before and after successful treatment. Importantly, the blindness was limited to the left upper and right lower visual quadrant offering the possibility to use the other 2 sighted quadrants as controls. While the functional magnetic resonance imaging activations were normal for visual stimulation electrophysiological indices of visual processing were modulated in a specific manner. Before treatment, the amplitude of the N1 event-related potentials component had smaller amplitudes for stimuli presented in the blind quadrants of the visual field. Following successful treatment the N1 component elicited by stimuli presented in formerly blind quadrants had a normal distribution without any amplitude differences between the 4 quadrants. The current findings point out that dissociative disorders such as hysterical blindness may have neurophysiological correlates. Furthermore, the observed neurophysiological pattern suggests an involvement of attentional mechanisms in the neural basis hysterical blindness.

Motor excitability during movement imagination and movement observation in psychogenic lower limb paresis.

BACKGROUND: Patients with a psychogenic paresis have difficulties performing voluntary movements. Typically, diagnostic interventions are normal. We tested whether patients with a psychogenic lower limb paresis exhibit abnormal motor excitability during motor imagery or movement observation. METHODS: Transcranial magnetic stimulation (TMS) with single and paired pulses was used to explore motor excitability at rest, during imagination of ankle dorsiflexions and during watching another person perform ankle dorsiflexions. Results obtained in ten patients with a flaccid psychogenic leg paresis were compared with a healthy age-matched control group. In addition, results of two patients with a psychogenic fixed dystonia of the leg are presented. RESULTS: During rest, motor excitability evaluated by motor thresholds, size of motor-evoked potentials (MEP) by single pulse TMS, intracortical inhibition and intracortical facilitation tested by paired-pulse TMS were similar in patients and healthy subjects. MEPs recorded in five patients during movement observation were also comparable across the two groups. During motor imagery, patient MEPs were significantly smaller than in the control group and smaller than during rest, indicating an inhibition. CONCLUSION: In patients with motor conversion disorder, the imagination of own body movements induces a reduction of corticospinal motor excitability whereas it induces an excitability increase in healthy subjects. This discrepancy might be the electrophysiological substrate of the inability to move voluntarily. Watching another person perform movements induces a normal excitability increase, indicating a crucial role of the perspective and suggesting that focusing the patient's attention on a different person might become a therapeutic approach.

Age-independent activation in areas of the mirror neuron system during action observation and action imagery. A fMRI study.

PURPOSE: Recent studies have found age-related BOLD signal changes in several areas of the human brain. We investigated whether such changes also occur in brain areas involved in the processing of motor action observation and imagery. METHODS: Functional magnetic resonance imaging with an experimental paradigm in which motor acts had to be observed and/or imagined from a first person perspective was performed in twenty-six subjects. RESULTS: In line with previous work action observation and imagery induced BOLD signal increases in similar areas, predominantly in the premotor and parietal cortex. In contrast to young subjects the elderly displayed a stronger activity in most activated brain areas indicative of compensatory activity for the age-related decline of neural structures. Importantly, activity in the ventrolateral premotor cortex and inferior parietal cortex, seminal areas of the mirror neuron system, did not exhibit activity changes as a function of age. CONCLUSION: These findings suggest that activity within the mirror neuron system is not age dependent and provide a neural basis for therapeutical interventions and novel rehabilitation treatments such as video therapy.

Abnormal motor excitability in patients with psychogenic paresis. A TMS study.

BACKGROUND: Patients with motor conversion disorders present an inability to execute movements voluntarily, although central and peripheral motor pathways are normal. We speculated that this phenomenon could be due to an abnormal loss of excitatory drive on central motor areas. METHODS: The effect of motor imagery on motor excitability was tested in a group of eight patients with a functional (psychogenic) hemiparesis and in an age-matched control group (n=8) by using transcranial magnetic stimulation (TMS). TMS pulses were applied at rest and while subjects imagined a tonic index finger adduction. Amplitudes of motor evoked potentials (MEP) recorded from the first dorsal interosseous muscle were used as an indicator of motor excitability. RESULTS: Motor thresholds and MEP amplitudes at rest were almost identical in the patient group and the control group. During motor imagery, MEP amplitudes increased by 200% in healthy subjects. In the patient group, motor imagery of the "paretic" index finger was associated with a mean MEP amplitude decrease of 37% compared with the MEP size at rest. Motor imagery of the unaffected index finger increased MEPs by 63% which was significantly different both from results in the control group and the "paretic" side. CONCLUSIONS: We suggest that the paradoxical decrease of motor excitability during motor imagery is the electrophysiological correlate of a disturbed voluntary control in motor conversion disorder. The results further indicate that this abnormality is not restricted to the clinically affected body part.

Electrophysiological correlates of motor conversion disorder.

In patients with a functional (psychogenic) paresis, motor conduction tests are, by definition, normal. We investigated whether these patients exhibit an abnormal motor excitability. Four female patients with a functional paresis of the left upper extremity were studied using transcranial magnetic stimulation (TMS). We investigated motor thresholds, intracortical inhibition and intracortical facilitation at rest. Corticospinal excitability was evaluated by single pulse TMS during rest and during imagination of tonic index finger adductions. Data obtained from the affected first dorsal interosseous muscle were compared with the unaffected hand and with a healthy age-matched control group. Three patients demonstrated a flaccid paresis, one patient had a psychogenic dystonia. Motor thresholds, short interval intracortical inhibition and intracortical facilitation recorded from the affected side were normal. In healthy subjects, movement imagination produced an increase of corticospinal excitability. In the patients, motor imagery with the affected index finger resulted in a decrease of corticospinal excitability compared to rest, being significantly different from the unaffected side and from the control group. We suggest that suppression of corticospinal excitability during movement imagination is an electrophysiological correlate of the patients' inability to move voluntarily and provides some insight into the pathophysiology of this disorder.