Hyperexcitability of brain stem pathways in cerebral palsy.

Individuals with cerebral palsy (CP) experience impairments in the control of head and neck movements, suggesting dysfunction in brain stem circuitry. To examine if brain stem circuitry is altered in CP, we compared reflexes evoked in the sternocleidomastoid (SCM) muscle by trigeminal nerve stimulation in adults with CP and in age/sex-matched controls. Increasing the intensity of trigeminal nerve stimulation produced progressive increases in the long-latency suppression of ongoing SCM electromyography in controls. In contrast, participants with CP showed progressively increased facilitation around the same reflex window, suggesting heightened excitability of brain stem pathways. We also examined if there was altered activation of cortico-brain stem pathways in response to prenatal injury of the brain. Motor-evoked potentials (MEPs) in the SCM that were conditioned by a prior trigeminal afferent stimulation were more facilitated in CP compared with controls, especially in ipsilateral MEPs that are likely mediated by corticoreticulospinal pathways. In some participants with CP, but not in controls, a combined trigeminal nerve and cortical stimulation near threshold intensities produced large, long-lasting responses in both the SCM and biceps brachii muscles. We propose that the enhanced excitatory responses evoked from trigeminal and cortical inputs in CP are produced by heightened excitability of brain stem circuits, resulting in the augmented activation of reticulospinal pathways. Enhanced activation of reticulospinal pathways in response to early injury of the corticospinal tract may provide a compensated activation of the spinal cord or, alternatively, contribute to impairments in the precise control of head and neck functions. NEW & NOTEWORTHY This is the first study to show that in adults with spastic cerebral palsy, activation of brain stem circuits by cortical and/or trigeminal afferents produces excitatory responses in anterior neck muscles compared with inhibitory responses in age/sex-matched controls. This may reflect a more excitable reticulospinal tract in response to early brain injury to provide a compensated activation of postural muscles. On the other hand, a hyperexcitable brain stem may contribute to impairments in the precise control of head and neck functions.

Spinal inhibition and motor function in adults with spastic cerebral palsy.

KEY POINTS: Abnormal activation of motoneurons in the spinal cord by sensory pathways is thought to contribute to impaired movement control and spasticity in individuals with cerebral palsy. Here we use single motor unit recordings to show how individual motoneurons in the spinal cord respond to sensory inputs in a group of participants with cerebral palsy having different degrees of motor dysfunction. In participants who had problems walking independently and required assistive devices such as wheelchairs, sensory pathways only excited motoneurons in the spinal cord. In contrast, in participants with cerebral palsy who walked independently for long distances, sensory inputs both inhibited and excited motoneurons in the spinal cord, similar to what we found in uninjured control participants. These findings demonstrate that in individuals with severe cerebral palsy, inhibitory control of motoneurons from sensory pathways is reduced and may contribute to motor dysfunction and spasticity. ABSTRACT: Reduced inhibition of spinal motoneurons by sensory pathways may contribute to heightened reflex activity, spasticity and impaired motor function in individuals with cerebral palsy (CP). To measure if the activation of inhibitory post-synaptic potentials (IPSPs) by sensory inputs is reduced in CP, the tonic discharge rate of single motor units from the soleus muscle was plotted time-locked to the occurrence of a sensory stimulation to produce peri-stimulus frequencygrams (PSFs). Stimulation to the medial arch of the foot was used to activate cutaneomuscular afferents in 17 adults with bilateral spastic CP and 15 neurologically intact (NI) peers. Evidence of IPSP activation from the PSF profiles, namely a marked pause or reduction in motor unit firing rates at the onset of the cutaneomuscular reflex, was found in all NI participants but in only half of participants with CP. In the other half of the participants with CP, stimulation of cutaneomuscular afferents produced a PSF profile indicative of a pure excitatory post-synaptic potential, with firing rates increasing above the mean pre-stimulus rate for 300 ms or more. The amplitude of motoneuron inhibition during the period of IPSP activation, as measured from the surface EMG, was less in participants with poor motor function as evaluated with the Gross Motor Functional Classification System (r = 0.72, P < 0.001) and the Functional Mobility Scale (r = -0.82, P < 0.001). These findings demonstrate that in individuals with CP, reduced activation of motoneuron IPSPs by sensory inputs is associated with reduced motor function and may contribute to enhanced reflexes and spasticity in CP.

Adrenergic receptors modulate motoneuron excitability, sensory synaptic transmission and muscle spasms after chronic spinal cord injury.

The brain stem provides most of the noradrenaline (NA) present in the spinal cord, which functions to both increase spinal motoneuron excitability and inhibit sensory afferent transmission to motoneurons (excitatory postsynaptic potentials; EPSPs). NA increases motoneuron excitability by facilitating calcium-mediated persistent inward currents (Ca PICs) that are crucial for sustained motoneuron firing. Spinal cord transection eliminates most NA and accordingly causes an immediate loss of PICs and emergence of exaggerated EPSPs. However, with time PICs recover, and thus the exaggerated EPSPs can then readily trigger these PICs, which in turn produce muscle spasms. Here we examined the contribution of adrenergic receptors to spasms in chronic spinal rats. Selective activation of the α(1A) adrenergic receptor with the agonists methoxamine or A61603 facilitated Ca PIC and spasm activity, recorded both in vivo and in vitro. In contrast, the α(2) receptor agonists clonidine and UK14303 did not facilitate Ca PICs, but did decrease the EPSPs that trigger spasms. Moreover, in the absence of agonists, spasms recorded in vivo were inhibited by the α(1) receptor antagonists WB4010, prazosin, and REC15/2739, and increased by the α(2) receptor antagonist RX821001, suggesting that both adrenergic receptors were endogenously active. In contrast, spasm activity recorded in the isolated in vitro cord was inhibited only by the α(1) antagonists that block constitutive receptor activity (activity in the absence of NA; inverse agonists, WB4010 and prazosin) and not by the neutral antagonist REC15/2739, which only blocks conventional NA-mediated receptor activity. RX821001 had no effect in vitro even though it is an α(2) receptor inverse agonist. Our results suggest that after chronic spinal cord injury Ca PICs and spasms are facilitated, in part, by constitutive activity in α(1) adrenergic receptors. Additionally, peripherally derived NA (or similar ligand) activates both α(1) and α(2) adrenergic receptors, controlling PICs and EPSPs, respectively.

Jaw tremor as a physiological biomarker of bruxism.

OBJECTIVE: To determine if sleep bruxism is associated with abnormal physiological tremor of the jaw during a visually-guided bite force control task. METHODS: Healthy participants and patients with sleep bruxism were given visual feedback of their bite force and asked to trace triangular target trajectories (duration=20s, peak force <35% maximum voluntary force). Bite force control was quantified in terms of the power spectra of force fluctuations, masseter EMG activity, and force-to-EMG coherence. RESULTS: Patients had greater jaw force tremor at ∼8 Hz relative to controls, along with increased masseter EMG activity and force-to-EMG coherence in the same frequency range. Patients also showed lower force-to-EMG coherence at low frequencies (<3 Hz), but greater coherence at high frequencies (20-40 Hz). Finally, patients had greater 6-10 Hz force tremor during periods of descending vs. ascending force, while controls showed no difference in tremor with respect to force dynamics. CONCLUSION: Patients with bruxism have abnormal jaw tremor when engaged in a visually-guided bite force task. SIGNIFICANCE: Measurement of jaw tremor may aid in the detection/evaluation of bruxism. In light of previous literature, our results also suggest that bruxism is marked by abnormal or mishandled peripheral feedback from the teeth.

Self-sustained firing of human motor units.

Motoneurons of invertebrates and vertebrates can continue to fire repetitively after being activated by a brief, excitatory synaptic input (self-sustained firing). This firing behavior is due to the activation of intrinsic, voltage-gated currents which produce sustained regenerative depolarizations (plateau potentials) of the cell. Examination of these intrinsic cellular properties has been performed in reduced animal preparations and it is unknown if such self-sustained firing occurs in motoneurons of the intact human. In this paper, we present evidence of this in the human by using a technique of dual motor unit recordings. Subjects were instructed to maintain a constant dorsiflexion effort, and the common synaptic input (e.g. descending drive) onto the tibialis anterior (TA) motoneuron pool was monitored by recording the firing frequency of a low threshold 'control' unit. Once the firing rate of the control unit was constant, vibration of the TA tendon recruited a second 'test' unit which continued to fire after the vibration (i.e. synaptic input) was removed, even though the firing rate of the control unit (and thus, the common drive) remained the same or decreased. Self-sustained firing of motoneurons such as this may reduce the need for prolonged synaptic input when constant muscle activation is required (e.g. for postural tone).

Reduced functional recovery by delaying motor training after spinal cord injury.

The purpose of this study was to examine if a delay in rehabilitative motor training after spinal cord injury affects functional motor recovery. We studied a skilled motor task in which rats traversed a raised horizontal ladder and we quantified errors in accurate stepping, i.e., foot slips between rungs. After lesions to the dorsal quadrant of the thoracic (T8) spinal cord that aimed to unilaterally sever the corticospinal and rubrospinal tracts, rats were re-trained to walk across the ladder, either immediately after injury or after a 3-mo delay. Before training, the error rate in accurate stepping of the affected hindlimb was similar in the immediately (69.4 +/- 5.3%) and delay (62.7 +/- 4.1%; means +/- SE)-trained animals (not significantly different), suggesting that accurate stepping did not improve spontaneously if rats were not exposed to the ladder. After a 3-wk course of training (30 runs across the ladder per day, 5 day/wk), improvements in accurate stepping performance were greater if training was implemented immediately after injury. On average, immediately trained animals improved stepping performance by 61.5 +/- 28.2%, whereas the delay trained group improved by only 34.9 +/- 28.8% (significantly different). The degree of damage to the corticospinal and rubrospinal tracts was very similar in the two groups of animals, indicating that differences in lesion size did not contribute to the differences in performance improvement. Animals with large lesions to the corticospinal and rubrospinal tracts (>70%) displayed poor recovery from training (especially for delay-trained animals), suggesting that these two pathways were important in mediating improvements in accurate stepping. In addition, recovery of stepping-like reflexes appeared not to contribute to the recovery of accurate stepping given that the time course of reflex recovery was not related to the time course of recovery of accurate stepping. We conclude that training of a skilled motor task that relies on descending control is more beneficial when initiated immediately after a partial spinal cord injury.

Spastic long-lasting reflexes in the awake rat after sacral spinal cord injury.

Following chronic sacral spinal cord transection in rats the affected tail muscles exhibit marked spasticity, with characteristic long-lasting tail spasms evoked by mild stimulation. The purpose of the present paper was to characterize the long-lasting reflex seen in tail muscles in response to electrical stimulation of the tail nerves in the awake spastic rat, including its development with time and relation to spasticity. Before and after sacral spinal transection, surface electrodes were placed on the tail for electrical stimulation of the caudal nerve trunk (mixed nerve) and for recording EMG from segmental tail muscles. In normal and acute spinal rats caudal nerve trunk stimulation evoked little or no EMG reflex. By 2 wk after injury, the same stimulation evoked long-lasting reflexes that were 1) very low threshold, 2) evoked from rest without prior EMG activity, 3) of polysynaptic latency with >6 ms central delay, 4) about 2 s long, and 5) enhanced by repeated stimulation (windup). These reflexes produced powerful whole tail contractions (spasms) and developed gradually over the weeks after the injury (< or =52 wk tested), in close parallel to the development of spasticity. Pure low-threshold cutaneous stimulation, from electrical stimulation of the tip of the tail, also evoked long-lasting spastic reflexes, not seen in acute spinal or normal rats. In acute spinal rats a strong C-fiber stimulation of the tip of the tail (20 x T) could evoke a weak EMG response lasting about 1 s. Interestingly, when this C-fiber stimulation was used as a conditioning stimulation to depolarize the motoneuron pool in acute spinal rats, a subsequent low-threshold stimulation of the caudal nerve trunk evoked a 300-500 ms long reflex, similar to the onset of the long-lasting reflex in chronic spinal rats. A similar conditioned reflex was not seen in normal rats. Thus there is an unusually long low-threshold polysynaptic input to the motoneurons (pEPSP) that is normally inhibited by descending control. This pEPSP is released from inhibition immediately after injury but does not produce a long-lasting reflex because of a lack of motoneuron excitability. With chronic injury the motoneuron excitability is increased markedly, and the pEPSP then triggers sustained motoneuron discharges associated with long-lasting reflexes and muscle spasms.

Corrective responses to loss of ground support during walking. I. Intact cats.

1. In the cat step cycle the electromyographic (EMG) activity in ankle extensor muscles commences approximately 70 ms before foot contact. There is a sharp peak between 10 and 25 ms after contact and the EMG then declines for the remainder of the stance phase. It has been posited that the abrupt transition in EMG after contact is the consequence of reflexes elicited by the large barrage of afferent input that signals foot touchdown. However, it is also possible that the basic profile might be generated within the CNS, with little modification by afferent input. 2. These ideas were tested in 11 normal cats. We compared EMG responses and hindlimb kinematics in steps with normal ground support and steps in which an actuator-controlled trap door unexpectedly opened, withdrawing ground support just before foot contact. 3. In the absence of ground support the transition in EMG activity was still present. The averaged EMG pattern was similar for at least 30 ms after the foot passed through the plane of the floor. We conclude that the basic extensor activation profile in this part of the cycle is generated centrally and is not substantially altered by afferent input. 4. Between 35 and 200 ms after contact the stance phase was aborted and the foot was lifted smartly out of the hole. This reaction varied both in latency and kinematic detail, suggesting a fairly complex corrective response.(ABSTRACT TRUNCATED AT 250 WORDS)

Corrective responses to loss of ground support during walking. II. Comparison of intact and chronic spinal cats.

1. The preceding study described a corrective response in cats when one hind leg steps into a hole. In this investigation we examine the extent to which this behavior is organized at the spinal level by comparing the responses elicited in intact and chronic spinal cats. 2. Adult cats were trained to step bipedally with their hind legs on a treadmill. After training, the responses to stepping into a hole cut in the treadmill belt were monitored with a video recorder and by recording electromyograms from muscles in both hind legs. The responses to stepping into the hole were also recorded in chronic spinal cats that had recovered the ability to step with their hind legs a few weeks after spinalization. 3. The behavioral responses in the two groups of animals differed in two respects. First, the latency of the onset of the flexion movement to remove the foot from the hole was shorter in intact animals (70-150 ms in intact vs. 130-350 ms in spinal animals). Second, the flexion movement in the intact animals was stronger. The exaggerated flexion movement in intact animals lifted the paw well clear of the hole and allowed support to be regained on the treadmill belt. The weaker flexion movement in spinal animals was usually insufficient to lift the paw completely from the hole. 4. Differences in the motor patterns recorded from flexor muscles during the corrective response in intact and spinal animals correspond with the differences in the kinematics. First, the onset of flexor activity after the foot entered the hole was delayed by approximately 100 ms in spinal animals relative to intact animals. Second, in intact animals the magnitudes of flexor bursts were increased relative to the flexor bursts associated with the swing phase during stepping, whereas in spinal animals flexor bursts during the corrective response resembled those occurring during swing. 5. Similarities in the duration and the timing of bursts in different flexor muscles in intact and spinal animals during the corrective response and during swing indicated that the corrective response involves activation of the spinal system that normally produces swing phase flexor activity. We conclude that activation of this system is facilitated by input from supraspinal structures during the corrective response in intact animals. 6. In all intact animals and three of five spinal animals, support of the hindquarters when the foot entered the hole was maintained by the contralateral leg.(ABSTRACT TRUNCATED AT 400 WORDS)