Intravenous saline administration in patients with severe acquired brain injury and orthostatic intolerance for tilt-table mobilization.

PRIMARY OBJECTIVE: This study aimed to investigate the effect of intravenous saline administration on orthostatic hypotension (OH) during head up tilt (HUT) and the change in the renin-angiotensin-aldosterone system before and after HUT in patients with severe acquired brain injury (ABI). RESEARCH DESIGN: The study is designed as an observational study. METHODS AND PROCEDURES: Fourteen patients with ABI, low level of consciousness and OH were monitored before, during and after HUT with non-invasive beat-to-beat blood pressure measurement, and transcranial Doppler determination of middle cerebral artery blood flow velocity. Blood samples were collected before and after two HUT sessions separated by 1 hour and saline was administered in between. MAIN OUTCOMES AND RESULTS: Patients' ability to stand upright did not change after saline administration due to OH. The patients showed signs of reduced cerebral autoregulation at both HUT sessions. The patients had a significant lower level of renin and angiotensin II but not aldosterone. CONCLUSIONS: Patients with severe ABI and OH demonstrate no improvement in standing time with reduced plasma renin and angiotensin II after two HUT sessions and 1 hour fluid administration. Research focusing on the ability to retain fluid after bed rest is warranted.

Alterations in the brain's connectome during recovery from severe traumatic brain injury: protocol for a longitudinal prospective study.

INTRODUCTION: Traumatic brain injury (TBI) is considered one of the most pervasive causes of disability in people under the age of 45. TBI often results in disorders of consciousness, and clinical assessment of the state of consciousness in these patients is challenging due to the lack of behavioural responsiveness. Functional neuroimaging offers a means to assess these patients without the need for behavioural signs, indicating that brain connectivity plays a major role in consciousness emergence and maintenance. However, little is known regarding how changes in connectivity during recovery from TBI accompany changes in the level of consciousness. Here, we aim to combine cutting-edge neuroimaging techniques to follow changes in brain connectivity in patients recovering from severe TBI. METHODS AND ANALYSIS: A multimodal, longitudinal assessment of 30 patients in the subacute stage after severe TBI will be made comprising an MRI session combined with electroencephalography (EEG), a positron emission tomography session and a transcranial magnetic stimulation (TMS) combined with EEG (TMS/EEG) session. A group of 20 healthy participants will be included for comparison. Four sessions for patients and two sessions for healthy participants will be planned. Data analysis techniques will focus on whole-brain, both data-driven and hypothesis-driven, connectivity measures that will be specific to the imaging modality. ETHICS AND DISSEMINATION: The project has received ethical approval by the local ethics committee of the Capital Region of Denmark and by the Danish Data Protection. Results will be published as original research articles in peer-reviewed journals and disseminated in international conferences. None of the measurements will have any direct clinical impact on the patients included in the study but may benefit future patients through a better understanding of the mechanisms underlying the recovery process after TBI. TRIAL REGISTRATION NUMBER NCT02424656; PRE-RESULTS.

Impaired Cerebral Autoregulation during Head Up Tilt in Patients with Severe Brain Injury.

Early mobilization is of importance for improving long-term outcome for patients after severe acquired brain injury. A limiting factor for early mobilization by head-up tilt is orthostatic intolerance. The purpose of the present study was to examine cerebral autoregulation in patients with severe acquired brain injury and a low level of consciousness. Fourteen patients with severe acquired brain injury and orthostatic intolerance and fifteen healthy volunteers were enrolled. Blood pressure was evaluated by pulse contour analysis, heart rate and RR-intervals were determined by electrocardiography, middle cerebral artery velocity was evaluated by transcranial Doppler, and near-infrared spectroscopy determined frontal lobe oxygenation in the supine position and during head-up tilt. Cerebral autoregulation was evaluated as the mean flow index calculated as the ratio between middle cerebral artery mean velocity and estimated cerebral perfusion pressure. Patients with acquired brain injury presented an increase in mean flow index during head-up tilt indicating impaired autoregulation (P < 0.001). Spectral analysis of heart rate variability in the frequency domain revealed lower magnitudes of ~0.1 Hz spectral power in patients compared to healthy controls suggesting baroreflex dysfunction. In conclusion, patients with severe acquired brain injury and orthostatic intolerance during head-up tilt have impaired cerebral autoregulation more than one month after brain injury.

Gait training facilitates central drive to ankle dorsiflexors in children with cerebral palsy.

Foot drop and toe walking are frequent concerns in children with cerebral palsy. The main underlying cause of these problems is early damage and lack of maturation of the corticospinal tract. In the present study we investigated whether 4 weeks of daily treadmill training with an incline may facilitate corticospinal transmission and improve the control of the ankle joint in children with cerebral palsy. Sixteen children with cerebral palsy (Gross Motor Classification System I:6, II:6, III:4) aged 5-14 years old, were recruited for the study. Evaluation of gait ability and intramuscular coherence was made twice before and twice after training with an interval of 1 month. Gait kinematics were recorded by 3D video analysis during treadmill walking with a velocity chosen by the child at the first evaluation. Foot pressure was measured by force sensitive foot soles during treadmill and over ground walking. EMG-EMG coherence was calculated from two separate electrode recordings placed over the tibialis anterior muscle. Training involved 30 min of walking daily on a treadmill with an incline for 30 days. Gait training was accompanied by significant increases in gait speed, incline on the treadmill, the maximal voluntary dorsiflexion torque, the number and amplitude of toe lifts late in the swing phase during gait and the weight exerted on the heel during the early stance phase of the gait cycle. EMG-EMG coherence in the beta and gamma frequency bands recorded from tibialis anterior muscle increased significantly when compared to coherence before training. The largest changes in coherence with training were observed for children <10 years of age. Importantly, in contrast to training-induced EMG increases, the increase in coherence was maintained at the follow-up measurement 1 month after training. Changes in the strength of coherence in the beta and gamma band were positively correlated with improvements in the subjects' ability to lift the toes in the swing phase. These data show that daily intensive gait training increases beta and gamma oscillatory drive to ankle dorsiflexor motor neurons and that it improves toe lift and heel strike in children with cerebral palsy. We propose that intensive gait training may produce plastic changes in the corticospinal tract, which are responsible for improvements in gait function.

Failure of normal development of central drive to ankle dorsiflexors relates to gait deficits in children with cerebral palsy.

Neurophysiological markers of the central control of gait in children with cerebral palsy (CP) are used to assess developmental response to therapy. We measured the central common drive to a leg muscle in children with CP. We recorded electromyograms (EMGs) from the tibialis anterior (TA) muscle of 40 children with hemiplegic CP and 42 typically developing age-matched controls during static dorsiflexion of the ankle and during the swing phase of treadmill walking. The common drive to TA motoneurons was identified through time- and frequency-domain cross-correlation methods. In control subjects, the common drive consists of frequencies between 1 and 60 Hz with peaks at beta (15-25 Hz) and gamma (30-45 Hz) frequencies known to be caused by activity within sensorimotor cortex networks: this drive to motoneurons strengthens during childhood. Similar to this drive in control subjects, this drive to the least affected TA in the CP children tended to strengthen with age, although compared with that in the control subjects, it was slightly weaker. For CP subjects of all ages, the most affected TA muscle common drive was markedly reduced compared with that of their least affected muscle as well as that of controls. These differences between the least and most affected TA muscles were unrelated to differences in the magnitude of EMG in the two muscles but positively correlated with ankle dorsiflexion velocity and joint angle during gait. Time- and frequency-domain analysis of ongoing EMG recruited during behaviorally relevant lower limb tasks provides a noninvasive and important measure of the central drive to motoneurons in subjects with CP.

The effect of baclofen and diazepam on motor skill acquisition in healthy subjects.

Antispastic medication is often used in the clinic together with physiotherapy. However, some of the antispastic drugs, e.g., baclofen and diazepam, may influence the plastic mechanisms that are necessary for motor learning and hence efficient physiotherapy. In the present study, we consequently investigated the influence of baclofen and diazepam on acquisition of a visuomotor skill. The study was designed as a semi-randomized, double-blinded, placebo-controlled, crossover study in 16 healthy human subjects. The motor skill task required the subjects to match a given force trajectory by increasing or decreasing ankle dorsiflexor torque. Subjects trained for a total of 30 min. Transcranial magnetic stimulation of the primary motor cortex leg area was applied to elicit motor evoked potentials in the anterior tibial muscle (TA). Coupling between populations of TA motor units was calculated in the frequency (coherence) domain during isometric dorsiflexion. Subjects receiving placebo showed statistically significant improvement in motor performance (q = 34.1, P = 0.014) accompanied by a statistically significant reduction in intramuscular coherence. Subjects receiving baclofen and diazepam conversely showed no progression in motor performance (P > 0.05), and the training was not accompanied by a decrease in intramuscular coherence. TA motor evoked potentials had significantly lower threshold following the training in the placebo group, whereas this was not the case in the treatment groups. These data indicate that diazepam and baclofen interfere with the acquisition of a motor skill by disrupting some of the neuroplastic changes that are involved in improved motor performance. This suggests that antispastic treatment should be used with caution in subjects receiving concomitant physiotherapy.

Interference in ballistic motor learning: specificity and role of sensory error signals.

Humans are capable of learning numerous motor skills, but newly acquired skills may be abolished by subsequent learning. Here we ask what factors determine whether interference occurs in motor learning. We speculated that interference requires competing processes of synaptic plasticity in overlapping circuits and predicted specificity. To test this, subjects learned a ballistic motor task. Interference was observed following subsequent learning of an accuracy-tracking task, but only if the competing task involved the same muscles and movement direction. Interference was not observed from a non-learning task suggesting that interference requires competing learning. Subsequent learning of the competing task 4 h after initial learning did not cause interference suggesting disruption of early motor memory consolidation as one possible mechanism underlying interference. Repeated transcranial magnetic stimulation (rTMS) of corticospinal motor output at intensities below movement threshold did not cause interference, whereas suprathreshold rTMS evoking motor responses and (re)afferent activation did. Finally, the experiments revealed that suprathreshold repetitive electrical stimulation of the agonist (but not antagonist) peripheral nerve caused interference. The present study is, to our knowledge, the first to demonstrate that peripheral nerve stimulation may cause interference. The finding underscores the importance of sensory feedback as error signals in motor learning. We conclude that interference requires competing plasticity in overlapping circuits. Interference is remarkably specific for circuits involved in a specific movement and it may relate to sensory error signals.

Childhood development of common drive to a human leg muscle during ankle dorsiflexion and gait.

Corticospinal drive has been shown to contribute significantly to the control of walking in adult human subjects. It is unknown to what extent functional change in this drive is important for maturation of gait in children. In adults, populations of motor units within a muscle show synchronized discharges during walking with pronounced coherence in the 15-50 Hz frequency band. This coherence has been shown to depend on cortical drive. Here, we investigated how this coherence changes with development. Forty-four healthy children aged 4-15 years participated in the study. Electromyographic activity (EMG) was recorded from pairs of electrodes placed over the right tibialis anterior (TA) muscle during static dorsiflexion and during walking on a treadmill (speed from 1.8 to 4.8 km h(-1)). A significant increase of coherence with increasing age was found in the 30-45 Hz frequency band (gamma) during walking and during static ankle dorsiflexion. A significant correlation with age was also found in the 15-25 Hz frequency band (beta) during static foot dorsiflexion. χ(2) analysis of differences of coherence between different age groups of children (4-6, 7-9, 10-12 and 13-15 years of age) revealed a significantly lower coherence in the gamma band for recordings during walking in children aged 4-6 years as compared to older children. Recordings during static dorsiflexion revealed significant differences in both the beta and gamma bands for children in the 4-6 and 7-9 years age groups as compared to the older age groups. A significant age-related decrease in step-to-step variability of toe position during the swing phase of walking was observed. This reduction in the step-to-step variability of gait was correlated with increased gamma band coherence during walking. We argue that this may reflect an increased ability to precisely control the ankle joint position with age, which may be contingent on maturation of corticospinal control of the foot dorsiflexor muscles.

Cortical involvement in anticipatory postural reactions in man.

All movements are accompanied by postural reactions which ensure that the balance of the body is maintained. It has not been resolved that to what extent the primary motor cortex and corticospinal tract are involved in the control of these reactions. Here, we investigated the contribution of the corticospinal tract to the activation of the soleus (SOL) muscle in standing human subjects (n=10) in relation to voluntary heel raise, anticipatory postural activation of the soleus muscle when the subject pulled a handle and to reflex activation of the soleus muscle when the subject was suddenly pulled forward by an external perturbation. SOL motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) increased significantly in relation to rest -75 ms prior to the onset of EMG in the heel-raise and handle-pull tasks. The short-latency facilitation of the soleus H-reflex evoked by TMS increased similarly, suggesting that the increased MEP size prior to movement was caused at least partly by increased excitability of corticospinal tract cells with monosynaptic projections to SOL motoneurones. Changes in spinal motoneuronal excitability could be ruled out since there was no significant increase of the SOL H-reflex until immediately prior to EMG onset for any of the tasks. Tibialis anterior MEPs were unaltered prior to the onset of SOL EMG activity in the handle-pull task, suggesting that the MEP facilitation was specific for the SOL muscle. No significant increase of the MEPs was observed prior to EMG onset for the external perturbation. These data suggest that the primary motor cortex is involved in activating the SOL muscle as part of an anticipatory postural reaction.

Premotor cortex modulates somatosensory cortex during voluntary movements without proprioceptive feedback.

Movement perception relies on sensory feedback, but the involvement of efference copies remains unclear. We investigated movements without proprioceptive feedback using ischemic nerve block during fMRI in healthy humans, and found preserved activation of the primary somatosensory cortex. This activation was associated with increased interaction with premotor cortex during voluntary movements, which demonstrates that perception of movements relies in part on predictions of sensory consequences of voluntary movements that are mediated by the premotor cortex.