Neural population dynamics reveal that motor-targeted intraspinal microstimulation preferentially depresses nociceptive transmission in spinal cord injury-related neuropathic pain.

The purpose of this study is to determine whether intraspinal microstimulation (ISMS) intended to enhance voluntary motor output after spinal cord injury (SCI) modulates neural population-level spinal responsiveness to nociceptive sensory feedback. The study was conducted in vivo in three cohorts of rats: neurologically intact, chronic SCI without behavioral signs of neuropathic pain, and chronic SCI with SCI-related neuropathic pain (SCI-NP). Nociceptive sensory feedback was induced by application of graded mechanical pressure to the plantar surface of the hindpaw before, during, and after periods of sub-motor threshold ISMS delivered within the motor pools of the L5 spinal segment. Neural population-level responsiveness to nociceptive feedback was recorded throughout the dorso-ventral extent of the L5 spinal segment using dense multi-channel microelectrode arrays. Whereas motor-targeted ISMS reduced nociceptive transmission across electrodes in neurologically intact animals both during and following stimulation, it was not associated with altered nociceptive transmission in rats with SCI that lacked behavioral signs of neuropathic pain. Surprisingly, nociceptive transmission was reduced both during and following motor-targeted ISMS in rats with SCI-NP, and to an extent comparable to that of neurologically intact animals. The mechanisms underlying the differential anti-nociceptive effects of motor-targeted ISMS are unclear, although they may be related to differences in the intrinsic active membrane properties of spinal neurons across the cohorts. Nevertheless, the results of this study support the notion that it may be possible to purposefully engineer spinal stimulation-based therapies that afford multi-modal rehabilitation benefits, and specifically that it may be possible to do so for the individuals most in need - i.e., those with SCI-related movement impairments and SCI-NP.

Motor-targeted spinal stimulation promotes concurrent rebalancing of pathologic nociceptive transmission in chronic spinal cord injury.

Electrical stimulation of spinal networks below a spinal cord injury (SCI) is a promising approach to restore functions compromised by inadequate excitatory neural drive. The most translationally successful examples are paradigms intended to increase neural transmission in weakened yet spared motor pathways and spinal motor networks rendered dormant after being severed from their inputs by lesion. Less well understood is whether spinal stimulation is also capable of reducing neural transmission in pathways made pathologically overactive by SCI. Debilitating spasms, spasticity, and neuropathic pain are all common manifestations of hyperexcitable spinal responses to sensory feedback. But whereas spasms and spasticity can often be managed pharmacologically, SCI-related neuropathic pain is notoriously medically refractory. Interestingly, however, spinal stimulation is a clinically available option for ameliorating neuropathic pain arising from etiologies other than SCI, and it has traditionally been assumed to modulate sensorimotor networks overlapping with those engaged by spinal stimulation for motor rehabilitation. Thus, we reasoned that spinal stimulation intended to increase transmission in motor pathways may simultaneously reduce transmission in spinal pain pathways. Using a well-validated pre-clinical model of SCI that results in severe bilateral motor impairments and SCI-related neuropathic pain, we show that the responsiveness of neurons integral to the development and persistence of the neuropathic pain state can be enduringly reduced by motor-targeted spinal stimulation while preserving spinal responses to non-pain-related sensory feedback. These results suggest that spinal stimulation paradigms could be intentionally designed to afford multi-modal therapeutic benefits, directly addressing the diverse, intersectional rehabilitation goals of people living with SCI.

Spinal stimulation for motor rehabilitation immediately modulates nociceptive transmission.

Objective. Spinal cord injury (SCI) often results in debilitating movement impairments and neuropathic pain. Electrical stimulation of spinal neurons holds considerable promise both for enhancing neural transmission in weakened motor pathways and for reducing neural transmission in overactive nociceptive pathways. However, spinal stimulation paradigms currently under development for individuals living with SCI continue overwhelmingly to be developed in the context of motor rehabilitation alone. The objective of this study is to test the hypothesis that motor-targeted spinal stimulation simultaneously modulates spinal nociceptive transmission.Approach. We characterized the neuromodulatory actions of motor-targeted intraspinal microstimulation (ISMS) on the firing dynamics of large populations of discrete nociceptive specific and wide dynamic range (WDR) neurons. Neurons were accessed via dense microelectrode arrays implantedin vivointo lumbar enlargement of rats. Nociceptive and non-nociceptive cutaneous transmission was induced before, during, and after ISMS by mechanically probing the L5 dermatome.Main results. Our primary findings are that (a) sub-motor threshold ISMS delivered to spinal motor pools immediately modulates concurrent nociceptive transmission; (b) the magnitude of anti-nociceptive effects increases with longer durations of ISMS, including robust carryover effects; (c) the majority of all identified nociceptive-specific and WDR neurons exhibit firing rate reductions after only 10 min of ISMS; and (d) ISMS does not increase spinal responsiveness to non-nociceptive cutaneous transmission. These results lead to the conclusion that ISMS parameterized to enhance motor output results in an overall net decrease n spinal nociceptive transmission.Significance. These results suggest that ISMS may hold translational potential for neuropathic pain-related applications and that it may be uniquely suited to delivering multi-modal therapeutic benefits for individuals living with SCI.

Spontaneous Multimodal Neural Transmission Suggests That Adult Spinal Networks Maintain an Intrinsic State of Readiness to Execute Sensorimotor Behaviors.

Spontaneous action potential discharge (spAP) is both ubiquitous and functionally relevant during neural development. spAP remains a prominent feature of supraspinal networks in maturity, even during unconsciousness. Evidence suggests that spAP persists in mature spinal networks during wakefulness, and one function of spAP in this context could be maintenance of a "ready state" to execute behaviors. The extent to which spAP persists in mature spinal networks during unconsciousness remains unclear, and its function(s), if any, are likewise unresolved. Here, we attempt to reconcile some of the questions and contradictions that emerge from the disintegrated picture of adult spinal spAP currently available. We recorded simultaneously from large populations of spinal interneurons in vivo in male rats, characterizing the spatial distribution of spAP in the lumbar enlargement and identifying subgroups of spontaneously active neurons. We find (1) concurrent spAP throughout the dorsoventral extent of the gray matter, with a diverse yet strikingly consistent mixture of neuron types across laminae; (2) the proportion of neurons exhibiting spAP in deeper, sensorimotor integrative regions is comparable to that in more superficial, sensory-dominant regions; (3) firing rate, but not spike train variability, varies systematically with region; and (4) spAP includes multimodal neural transmission consistent with executing a spinally-mediated behavior. These findings suggest that adult spAP may continue to support a state of readiness to execute sensorimotor behaviors even during unconsciousness. Such functionality has implications for our understanding of how perception is translated into action, of experience-dependent modification of behavior, and (mal)adaptative responses to injury or disease.SIGNIFICANCE STATEMENT Neurons often discharge action potentials (APs) seemingly spontaneously, that is, in the absence of ongoing behaviors or overt stimuli. This phenomenon is particularly evident during neural development, where spontaneous AP discharge (spAP) is ubiquitous in the central nervous system and is crucial to establishing connectivity among functionally related groups of neurons. The function(s) of spAP in adult spinal networks, if any, have remained enigmatic, especially during unconsciousness. Here, we report evidence that one such function could be to support an intrinsic state of readiness to execute sensorimotor behaviors. This finding has implications for our understanding of how perception is translated into action, of experience-dependent modification of behavior, and (mal)adaptative responses to injury or disease.

Biomechanical parameters of the elbow stretch reflex in chronic hemiparetic stroke.

We sought to determine the relative velocity sensitivity of stretch reflex threshold angle and reflex stiffness during stretches of the paretic elbow joint in individuals with chronic hemiparetic stroke, and to provide guidelines to streamline spasticity assessments. We applied ramp-and-hold elbow extension perturbations ranging from 15 to 150°/s over the full range of motion in 13 individuals with hemiparesis. After accounting for the effects of passive mechanical resistance, we modeled velocity-dependent reflex threshold angle and torque-angle slope to determine their correlation with overall resistance to movement. Reflex stiffness exhibited substantially greater velocity sensitivity than threshold angle, accounting for ~ 74% (vs. ~ 15%) of the overall velocity-dependent increases in movement resistance. Reflex stiffness is a sensitive descriptor of the overall velocity-dependence of movement resistance in spasticity. Clinical spasticity assessments can be streamlined using torque-angle slope, a measure of reflex stiffness, as their primary outcome measure, particularly at stretch velocities greater than 100°/s.

Short- and long-term reproducibility of diffusion-weighted magnetic resonance imaging of lower extremity musculature in asymptomatic individuals and a comparison to individuals with spinal cord injury.

BACKGROUND: Diffusion-weighted magnetic resonance imaging (DW-MRI) of skeletal muscle has the potential to be a sensitive diagnostic and/or prognostic tool in complex, enigmatic neuromusculoskeletal conditions such as spinal cord injury and whiplash associated disorder. However, the reliability and reproducibility of clinically accessible DW-MRI parameters in skeletal muscle remains incompletely characterized - even in individuals without neuromusculoskeletal injury - and these parameters have yet to be characterized for many clinical populations. Here, we provide normative measures of the apparent diffusion coefficient (ADC) in healthy muscles of the lower limb; assess the rater-based reliability and short- and long-term reproducibility of the ADC in the same muscles; and quantify ADC of these muscles in individuals with motor incomplete spinal cord injury. METHODS: Twenty individuals without neuromusculoskeletal injury and 14 individuals with motor incomplete spinal cord injury (SCI) participated in this investigation. We acquired bilateral diffusion-weighted MRI of the lower limb musculature in all participants at 3 T using a multi-shot echo-planar imaging sequence with b-values of 0, 100, 300 and 500 s/mm2 and diffusion-probing gradients applied in 3 orthogonal directions. Outcome measures included: (1) average ADC in the lateral and medial gastrocnemius, tibialis anterior, and soleus of individuals without neurological or musculoskeletal injury; (2) intra- and inter-rater reliability, as well as short and long-term reproducibility of the ADC; and (3) estimation of average muscle ADC in individuals with SCI. RESULTS: Intra- and inter-rater reliability of the ADC averaged 0.89 and 0.79, respectively, across muscles. Least significant change, a measure of temporal reproducibility, was 4.50 and 11.98% for short (same day) and long (9-month) inter-scan intervals, respectively. Average ADC was significantly elevated across muscles in individuals with SCI compared to individuals without neurological or musculoskeletal injury (1.655 vs. 1.615 mm2/s, respectively). CONCLUSIONS: These findings provide a foundation for future studies that track longitudinal changes in skeletal muscle ADC of the lower extremity and/or investigate the mechanisms underlying ADC changes in cases of known or suspected pathology.

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.

Altered Neuromodulatory Drive May Contribute to Exaggerated Tonic Vibration Reflexes in Chronic Hemiparetic Stroke.

Exaggerated stretch-sensitive reflexes are a common finding in elbow flexors of the contralesional arm in chronic hemiparetic stroke, particularly when muscles are not voluntarily activated prior to stretch. Previous investigations have suggested that this exaggeration could arise either from an abnormal tonic ionotropic drive to motoneuron pools innervating the paretic limbs, which could bring additional motor units near firing threshold, or from an increased influence of descending monoaminergic neuromodulatory pathways, which could depolarize motoneurons and amplify their responses to synaptic inputs. However, previous investigations have been unable to differentiate between these explanations, leaving the source(s) of this excitability increase unclear. Here, we used tonic vibration reflexes (TVRs) during voluntary muscle contractions of increasing magnitude to infer the sources of spinal motor excitability in individuals with chronic hemiparetic stroke. We show that when the paretic and non-paretic elbow flexors are preactivated to the same percentage of maximum prior to vibration, TVRs remain significantly elevated in the paretic arm. We also show that the rate of vibration-induced torque development increases as a function of increasing preactivation in the paretic limb, even though the amplitude of vibration-induced torque remains conspicuously unchanged as preactivation increases. It is highly unlikely that these findings could be explained by a source that is either purely ionotropic or purely neuromodulatory, because matching preactivation should control for the effects of a potential ionotropic drive (and lead to comparable tonic vibration reflex responses between limbs), while a purely monoaminergic mechanism would increase reflex magnitude as a function of preactivation. Thus, our results suggest that increased excitability of motor pools innervating the paretic limb post-stroke is likely to arise from both ionotropic and neuromodulatory mechanisms.

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

KEY POINTS: 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. ABSTRACT: A hallmark of hemiparetic stroke is the loss of fine motor control in the contralesional arm and hand and the constraint to a grouped movement pattern known as the flexion synergy. In the flexion synergy, increasing shoulder abductor activation drives progressive, involuntary increases in elbow, wrist and finger flexion. The neural mechanisms underlying this phenomenon remain unclear. Here, across 25 adults with moderate to severe hemiparesis following chronic stroke and 18 adults without neurological injury, we test the overall hypothesis that two inter-related mechanisms are necessary for flexion synergy expression: increased task-dependent activation of the intact, contralesional cortex and recruitment of contralesional motor pathways via ipsilateral reticulospinal projections. First, we imaged brain activation in real time during reaching motions progressively constrained by flexion synergy expression. Using this approach, we found that cortical activity indeed shifts towards the contralesional hemisphere in direct proportion to the degree of shoulder abduction loading in the contralesional arm. We then leveraged the post-stroke reemergence of a developmental brainstem reflex to show that anatomically diffuse reticulospinal motor pathways are active during synergy expression. We interpret this progressive recruitment of contralesional cortico-reticulospinal pathways as an adaptive strategy that preserves low-level motor control at the cost of fine motor control.

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.

MRI measures of fat infiltration in the lower extremities following motor incomplete spinal cord injury: reliability and potential implications for muscle activation.

Muscle fat infiltration (MFI) is an expected consequence of incomplete spinal cord injury (iSCI). The MFI magnitude may have clinical value in determining functional recovery. However, there is a lack of understanding of how MFI relates to the volitional muscle activity in people with motor incomplete spinal cord injury (iSCI). Five iSCI and 5 uninjured age-matched control subjects participated in the study. In this preliminary study, we established the reliability of MFI quantification of select lower extremity muscles across different raters. Secondly, we assessed the magnitude and distribution of MFI in the lower legs of iSCI and uninjured control participants. Thirdly, we explored the relationship between MFI in the plantar flexor muscles and the ability to volitionally activate these muscles. High levels of inter-rater reliability were observed. The iSCI group had significantly elevated and a vastly different MFI distribution in the lower leg muscles compared to healthy controls. MFI was negatively correlated with volitional activation in iSCI. Our preliminary results sanction the importance of lower extremity MFI quantification as a potential measure in determining the functional outcomes in iSCI, and the subsequent pathological sequelae.

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

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.

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.

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/s(2)). 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.

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