Jacob G. McPherson

Evidence for Increased Activation of Persistent Inward Currents in Individuals With Chronic Hemiparetic Stroke

Despite the prevalence of hyperactive stretch reflexes in the paretic limbs of individuals with chronic hemiparetic stroke, the fundamental pathophysiological mechanisms responsible for their expression remain poorly understood. This study tests whether the manifestation of hyperactive stretch reflexes following stroke is related to the development of persistent inward currents (PICs) leading to hyperexcitability of motoneurons innervating the paretic limbs. Because repetitive volleys of 1a afferent feedback can elicit PICs, this investigation assessed motoneuronal excitability by evoking the tonic vibration reflex (TVR) of the biceps muscle in 10 awake individuals with chronic hemiparetic stroke and measuring the joint torque and electromyographic (EMG) responses of the upper limbs. Elbow joint torque and the EMG activity of biceps, brachioradialis, and the long and lateral heads of triceps brachii were recorded during 8 s of 112-Hz biceps vibration (evoking the TVR) and for 5 s after cessation of stimulation. Repeated-measures ANOVA tests revealed significantly (P <or= 0.05) greater increases in elbow flexion torque and EMG activity in the paretic as compared with the nonparetic limbs, both during and up to 5 s following biceps vibration. The finding of these augmentations exclusively in the paretic limb suggests that contralesional motoneurons may become hyperexcitable and readily invoke PICs following stroke. An enhanced tendency to evoke PICs may be due to an increased subthreshold depolarization of motoneurons, an increased monoaminergic input from the brain stem, or both.

Targeted, activity-dependent spinal stimulation produces long-lasting motor recovery in chronic cervical spinal cord injury

Significance This study describes a new strategy for enhancing motor recovery after neurological injury. Using a recurrent neural–computer interface, we attempt to facilitate and direct functionally relevant activity-dependent neural plasticity, the mechanism thought to underlie the benefits of use-dependent physical therapy. We show that this approach can lead to meaningful functional gains that last for weeks after discontinuation of stimulation, a finding that is both unique and highly clinically relevant. Our results suggest that we have leveraged the nervous system’s intrinsic capacity for reorganization and repair to drive true neurological rehabilitation rather than enhancing performance through reanimation or replacement of function. This approach could also be adapted to other impairments, such as locomotion, bowel, bladder or sexual dysfunction, and pain. Use-dependent movement therapies can lead to partial recovery of motor function after neurological injury. We attempted to improve recovery by developing a neuroprosthetic intervention that enhances movement therapy by directing spike timing-dependent plasticity in spared motor pathways. Using a recurrent neural–computer interface in rats with a cervical contusion of the spinal cord, we synchronized intraspinal microstimulation below the injury with the arrival of functionally related volitional motor commands signaled by muscle activity in the impaired forelimb. Stimulation was delivered during physical retraining of a forelimb behavior and throughout the day for 3 mo. Rats receiving this targeted, activity-dependent spinal stimulation (TADSS) exhibited markedly enhanced recovery compared with animals receiving targeted but open-loop spinal stimulation and rats receiving physical retraining alone. On a forelimb reach and grasp task, TADSS animals recovered 63% of their preinjury ability, more than two times the performance level achieved by the other therapy groups. Therapeutic gains were maintained for 3 additional wk without stimulation. The results suggest that activity-dependent spinal stimulation can induce neural plasticity that improves behavioral recovery after spinal cord injury.

Dual energy X-ray absorptiometry of the knee in spinal cord injury: methodology and correlation with quantitative computed tomography

Study Design:Comparison of diagnostic tests; methodological validation.Objectives:Primary: to investigate the precision and reliability of a knee bone mineral density (BMD) assessment protocol that uses an existing dual energy X-ray absorptiometry (DXA) forearm acquisition algorithm in individuals with spinal cord injury (SCI). Secondary: to correlate DXA-based knee areal BMD with volumetric BMD assessments derived from quantitative computed tomography (QCT).Setting:Academic medical center, Chicago, IL, USA.Methods:Participants: a convenience sample of 12 individuals with acute SCI recruited for an observational study of bone loss and 34 individuals with chronic SCI who were screened for a longitudinal study evaluating interventions to increase BMD. Main outcome measures: root-mean-square standard deviation (RMS-SD) and intra/inter-rater reliability of areal BMD acquired at three knee regions using an existing DXA forearm acquisition algorithm; correlation of DXA-based areal BMD with QCT-derived volumetric BMD.Results:The RMS-SD of areal BMD at the distal femoral epiphysis, distal femoral metaphysis and proximal tibial epiphysis averaged 0.021, 0.012 and 0.016 g cm−2, respectively, in acute SCI and 0.018, 0.02 and 0.016 g cm−2 in chronic SCI. All estimates of intra/inter-rater reliability exceeded 97% and DXA-based areal BMD was significantly correlated with QCT-derived volumetric BMD at all knee regions analyzed.Conclusions:Existing DXA forearm acquisition algorithms are sufficiently precise and reliable for short-term assessments of knee BMD in individuals with SCI. Future work is necessary to quantify the reliability of this approach in longitudinal investigations and to determine its ability to predict fractures and recovery potential.Sponsorship:This work was funded by the Department of Defense, grant number DOD W81XWH-10-1-0951, with partial support from Merck & Co, Inc.

The ACT-4D: A novel rehabilitation robot for the quantification of upper limb motor impairments following brain injury

Rehabilitation robots and other controlled diagnostic devices are useful tools to objectively quantify debilitating, post-stroke impairments. The goal of this paper is to describe the design of the ACT-4D rehabilitation robot which can quantify arm impairments during functional movement. The robot can instantly switch between a compliant mode that minimizes impedance of voluntary movement, and a stiff mode that applies controlled position/speed perturbations to the elbow (up to 75 Nm or 450 deg/s at 4500 deg/s2). It has a limited range of movement of the shoulder and elbow, which is further reduced when a damper is needed to enhance the positional stiffness of the base robot. In recent experiments, the ACT-4D has been used successfully for the quantification of elbow impairments.

The relationship between the flexion synergy and stretch reflexes in individuals with chronic hemiparetic stroke

This study utilized a novel robotic device, the ACT-4D, to investigate the relationship between the flexion synergy and stretch reflexes in individuals with chronic hemiparetic stroke. Because the flexion synergy influences the amount of elbow flexor muscle activation present in the paretic limb during tasks requiring shoulder abduction loading, it was hypothesized that stretch reflexes may be modulated by expression of this abnormal muscle coactivation pattern. To test this hypothesis, the ACT-4D was used to enable 10 individuals with chronic hemiparetic stroke to generate varying amounts of shoulder abduction torque while concurrently receiving elbow extension position perturbations. It was found that increased expression of the flexion synergy led to greater reflex amplitudes as well as lower reflex velocity thresholds. The physiological basis of the flexion synergy is briefly discussed, as are the implications of the flexion synergy and stretch reflexes for purposeful movement.

Potential associations between chronic whiplash and incomplete spinal cord injury

Study Design:This research utilized a cross-sectional design with control group inclusion.Objectives:Preliminary evidence suggests that a portion of the patient population with chronic whiplash may have sustained spinal cord damage. Our hypothesis is that in some cases of chronic whiplash-associated disorders (WAD), observed muscle weakness in the legs will be associated with local signs of a partial spinal cord injury of the cervical spine.Setting:University based laboratory in Chicago, IL, USA.Methods:Five participants with chronic WAD were compared with five gender/age/height/weight/body mass index (BMI) control participants. For a secondary investigation, the chronic WAD group was compared with five unmatched participants with motor incomplete spinal cord injury (iSCI). Spinal cord motor tract integrity was assessed using magnetization transfer imaging. Muscle fat infiltration (MFI) was quantified using fat/water separation magnetic resonance imaging. Central volitional muscle activation of the plantarflexors was assessed using a burst superimposition technique.Results:We found reduced spinal cord motor tract integrity, increased MFI of the neck and lower extremity muscles and significantly impaired voluntary plantarflexor muscle activation in five participants with chronic WAD. The lower extremity structural changes and volitional weakness in chronic WAD were comparable to participants with iSCI.Conclusion:The results support the position that a subset of the chronic whiplash population may have sustained partial damage to the spinal cord.Sponsorship:NIH R01HD079076-01A1, NIH T32 HD057845 and the Foundation for Physical Therapy Promotion of Doctoral Studies program.

Progressive recruitment of contralesional cortico-reticulospinal pathways drives motor impairment post stroke

Activation of the shoulder abductor muscles in the arm opposite a unilateral brain injury causes involuntary increases in elbow, wrist and finger flexion in the same arm, a phenomenon referred to as the flexion synergy. It has been proposed that flexion synergy expression is related to reduced output from ipsilesional motor cortex and corticospinal pathways. In this human subjects study, we provide evidence that the magnitude of flexion synergy expression is instead related to a progressive, task‐dependent recruitment of contralesional cortex. We also provide evidence that recruitment of contralesional cortex may induce excessive activation of ipsilateral reticulospinal descending motor pathways that cannot produce discrete movements, leading to flexion synergy expression. We interpret these findings as an adaptive strategy that preserves low‐level motor control at the cost of fine motor control.

Ambulatory function in motor incomplete spinal cord injury: a magnetic resonance imaging study of spinal cord edema and lower extremity muscle morphometry

Study design:This research utilized a cross-sectional design.Objectives:Spinal cord edema length has been measured with T2-weighted sagittal MRI to predict motor recovery following spinal cord injury. The purpose of our study was to establish the correlational value of axial spinal cord edema using T2-weighted MRI. We hypothesized a direct relationship between the size of damage on axial MRI and walking ability, motor function and distal muscle changes seen in motor incomplete spinal cord injury (iSCI).Setting:University-based laboratory in Chicago, IL, USA.Methods:Fourteen participants with iSCI took part in the study. Spinal cord axial damage ratios were assessed using axial T2-weighted MRI. Walking ability was investigated using the 6-min walk test and daily stride counts. Maximum plantarflexion torque was quantified using isometric dynomometry. Muscle fat infiltration (MFI) and relative muscle cross-sectional area (rmCSA) were quantified using fat/water separation magnetic resonance imaging.Results:Damage ratios were negatively correlated with distance walked in 6 min, average daily strides and maximum plantarflexion torque, and a negative linear trend was found between damage ratios and lower leg rmCSA. While damage ratios were not significantly correlated with MFI, we found significantly higher MFI in the wheelchair user participant group compared to community walkers.Conclusions:Damage ratios may be useful in prognosis of motor recovery in spinal cord injury. The results warrant a large multi-site research study to investigate the value of high-resolution axial T2-weighted imaging to predict walking recovery following motor incomplete spinal cord injury.

Modification of Spastic Stretch Reflexes at the Elbow by Flexion Synergy Expression in Individuals With Chronic Hemiparetic Stroke

OBJECTIVE To systematically characterize the effect of flexion synergy expression on the manifestation of elbow flexor stretch reflexes poststroke, and to relate these findings to elbow flexor stretch reflexes in individuals without neurologic injury. DESIGN Controlled cohort study. SETTING Academic medical center. PARTICIPANTS Participants (N=20) included individuals with chronic hemiparetic stroke (n=10) and a convenience sample of individuals without neurologic or musculoskeletal injury (n=10). INTERVENTIONS Participants with stroke were interfaced with a robotic device that precisely manipulated flexion synergy expression (by regulating shoulder abduction loading) while delivering controlled elbow extension perturbations over a wide range of velocities. This device was also used to elicit elbow flexor stretch reflexes during volitional elbow flexor activation, both in the cohort of individuals with stroke and in a control cohort. In both cases, the amplitude of volitional elbow flexor preactivation was matched to that generated involuntarily during flexion synergy expression. MAIN OUTCOME MEASURES The amplitude of short- and long-latency stretch reflexes in the biceps brachii, assessed by electromyography, and expressed as a function of background muscle activation and stretch velocity. RESULTS Increased shoulder abduction loading potentiated elbow flexor stretch reflexes via flexion synergy expression in the paretic arm. Compared with stretch reflexes in individuals without neurologic injury, paretic reflexes were larger at rest but were approximately equal to control muscles at matched levels of preactivation. CONCLUSIONS Because flexion synergy expression modifies stretch reflexes in involved muscles, interventions that reduce flexion synergy expression may confer the added benefit of reducing spasticity during functional use of the arm.

Neuromodulatory Inputs to Motoneurons Contribute to the Loss of Independent Joint Control in Chronic Moderate to Severe Hemiparetic Stroke

In chronic hemiparetic stroke, increased shoulder abductor activity causes involuntary increases in elbow, wrist, and finger flexor activation, an abnormal muscle coactivation pattern known as the flexion synergy. Recent evidence suggests that flexion synergy expression may reflect recruitment of contralesional cortico-reticulospinal motor pathways following damage to the ipsilesional corticospinal tract. However, because reticulospinal motor pathways produce relatively weak post-synaptic potentials in motoneurons, it is unknown how preferential use of these pathways could lead to robust muscle activation. Here, we hypothesize that the descending neuromodulatory component of the ponto-medullary reticular formation, which uses the monoaminergic neurotransmitters norepinephrine and serotonin, serves as a gain control mechanism to facilitate motoneuron responses to reticulospinal motor commands. Thus, inhibition of the neuromodulatory component would reduce flexion synergy expression by disfacilitating spinal motoneurons. To test this hypothesis, we conducted a pre-clinical study utilizing two targeted neuropharmacological probes and inert placebo in a cohort of 16 individuals with chronic hemiparetic stroke. Test compounds included Tizanidine (TIZ), a noradrenergic α2 agonist and imidazoline ligand selected for its ability to reduce descending noradrenergic drive, and Isradipine, a dihyropyridine calcium-channel antagonist selected for its ability to post-synaptically mitigate a portion of the excitatory effects of monoamines on motoneurons. We used a previously validated robotic measure to quantify flexion synergy expression. We found that Tizanidine significantly reduced expression of the flexion synergy. A predominantly spinal action for this effect is unlikely because Tizanidine is an agonist acting on a baseline of spinal noradrenergic drive that is likely to be pathologically enhanced post-stroke due to increased reliance on cortico-reticulospinal motor pathways. Although spinal actions of TIZ cannot be excluded, particularly from Group II pathways, our finding is consistent with a supraspinal action of Tizanidine to reduce descending noradrenergic drive and disfacilitate motoneurons. The effects of Isradipine were not different from placebo, likely related to poor central bioavailability. These results support the hypothesis that the descending monoaminergic component of the ponto-medullary reticular formation plays a key role in flexion synergy expression in chronic hemiparetic stroke. These results may provide the basis for new therapeutic strategies to complement physical rehabilitation.