Body System Effects of a Multi-Modal Training Program Targeting Chronic, Motor Complete Thoracic Spinal Cord Injury.

The safety and efficacy of pharmacological and cellular transplantation strategies are currently being evaluated in people with spinal cord injury (SCI). In studies of people with chronic SCIs, it is thought that functional recovery will be best achieved when drug or cell therapies are combined with rehabilitation protocols. However, any functional recovery attributed to the therapy may be confounded by the conditioned state of the body and by training-induced effects on neuroplasticity. For this reason, we sought to investigate the effects of a multi-modal training program on several body systems. The training program included body-weight-supported treadmill training for locomotion, circuit resistance training for upper body conditioning, functional electrical stimulation for activation of sublesional muscles, and wheelchair skills training for overall mobility. Eight participants with chronic, thoracic-level, motor-complete SCI completed the 12-week training program. After 12 weeks, upper extremity muscular strength improved significantly for all participants, and some participants experienced improvements in function, which may be explained by increased strength. Neurological function did not change. Changes in pain and spasticity were highly variable between participants. This is the first demonstration of the effect of this combination of four training modalities. However, balancing participant and study-site burden with capturing meaningful outcome measures is also an important consideration.

Characterization of Involuntary Contractions after Spinal Cord Injury Reveals Associations between Physiological and Self-Reported Measures of Spasticity.

Correlations between physiological, clinical and self-reported assessments of spasticity are often weak. Our aims were to quantify functional, self-reported and physiological indices of spasticity in individuals with thoracic spinal cord injury (SCI; 3 women, 9 men; 19-52 years), and to compare the strength and direction of associations between these measures. The functional measure we introduced involved recording involuntary electromyographic activity during a transfer from wheelchair to bed which is a daily task necessary for function. High soleus (SL) and tibialis anterior (TA) F-wave/M-wave area ratios were the only physiological measures that distinguished injured participants from the uninjured (6 women, 13 men, 19-67 years). Hyporeflexia (decreased SL H/M ratio) was unexpectedly present in older participants after injury. During transfers, the duration and intensity of involuntary electromyographic activity varied across muscles and participants, but coactivity was common. Wide inter-participant variability was seen for self-reported spasm frequency, severity, pain and interference with function, as well as tone (resistance to imposed joint movement). Our recordings of involuntary electromyographic activity during transfers provided evidence of significant associations between physiological and self-reported measures of spasticity. Reduced low frequency H-reflex depression in SL and high F-wave/M-wave area ratios in TA, physiological indicators of reduced inhibition and greater motoneuron excitability, respectively, were associated with long duration SL and biceps femoris (BF) electromyographic activity during transfers. In turn, participants reported high spasm frequency when transfers involved short duration TA EMG, decreased co-activation between SL and TA, as well as between rectus femoris (RF) vs. BF. Thus, the duration of muscle activity and/or the time of agonist-antagonist muscle coactivity may be used by injured individuals to count spasms. Intense electromyographic activity and high tone related closely (possibly from joint stabilization), while intense electromyographic activity in one muscle of an agonist-antagonist pair (especially in TA vs. SL, and RF vs. BF) likely induced joint movement and was associated with severe spasms. These data support the idea that individuals with SCI describe their spasticity by both the duration and intensity of involuntary agonist-antagonist muscle coactivity during everyday tasks.

Activation of the dorsal periaqueductal gray in the rat induces Fos-like immunoreactivity in select non-cholinergic mesopontine neurons.

Autonomic responses evoked from the dorsal periaqueductal gray (dPAG) have been reported to be mediated in part by acetylcholine release in the medulla. To identify the possible origin of cholinergic neurons activated by dPAG stimulation, the pattern of Fos-like immunoreactivity (FLI) in the mesopontine cholinergic cell groups was examined in three groups of urethane anesthetized rats. Relative to surgery (n=6) and blood pressure control groups (n=6), chemical disinhibition of the dPAG (n=10) induced a significant increase in FLI in the lateral dorsal tegmental nucleus (LDTg) but not the pedunculopontine tegmental nucleus. LDTg neurons stained for choline acetyltransferase immunoreactivity however did not co-label for FLI. Other pontomesencephalic regions outside of the dPAG demonstrating a significant increase in FLI relative to controls included the lateral and ventrolateral columns of the PAG, the cuneiform nucleus, dorsal raphe, and the microcellular tegmental nucleus. These findings suggest that acetylcholine release in during dPAG stimulation does not originate from mesopontine neurons.

Parabrachial neurons mediate dorsal periaqueductal gray evoked respiratory responses in the rat.

The neural substrates mediating autonomic components of the behavioral defense response reside in the periaqueductal gray (PAG). The cardiovascular components of the defense response evoked from the dorsal PAG (DPAG) have been well described and are dependent, in part, on the integrity of neurons in the region of the parabrachial nucleus as well as the rostral ventrolateral medulla. Descending pathways mediating the ventilatory response associated with activation of DPAG neurons are unknown. The present study was undertaken to test the hypothesis that parabrachial area neurons are also involved in mediating the respiratory response to DPAG stimulation. In urethane-anesthetized, spontaneously breathing rats, electrical stimulation of the DPAG significantly increased respiratory rate, arterial pressure, and heart rate. Changes in respiratory frequency were associated with significant decreases in inspiratory and expiratory durations. After bilateral inhibition of neurons in the lateral parabrachial nucleus (LPBN) region with 5 mM muscimol (n = 6), DPAG-evoked increases in respiration and heart rate were attenuated by 90 +/- 6 and 72 +/- 13%, respectively. The pressor response evoked by DPAG stimulation, however, was attenuated by only 57 +/- 6%. Bilateral blockade of glutamate receptors with 20 mM kynurenic acid (n = 6) in the LPBN also markedly attenuated DPAG-evoked increases in respiration and heart rate (65 +/- 15 and 53 +/- 9% reduction, respectively) but only modestly changed the DPAG-evoked pressor response (34 +/- 16% reduction). These results demonstrate that LPBN neurons play a significant role in the DPAG-mediated respiratory component of behavioral defense responses. This finding supports previous work demonstrating that the dorsolateral pons plays a significant role in mediating most physiological adjustments associated with activation of the DPAG.

Increased c-Fos expression in select lateral parabrachial subnuclei following chemical versus electrical stimulation of the dorsal periaqueductal gray in rats.

The parabrachial nucleus (PBN) is located in the rostral dorsolateral pons and has been identified as a critical relay for cardiovascular responses (sympathoexcitation and baroreflex attenuation) evoked by the dorsal periaqueductal gray (PAG). We examined the pattern of c-Fos protein immunoreactivity throughout the rostral-caudal extent of the PBN in four groups of anesthetized male Sprague-Dawley rats to identify the specific PBN regions activated by dorsal PAG stimulation. Both electrical stimulation and chemical (0.3 mM bicuculline methobromide) activation of the dorsal PAG elicited a selective increase in Fos-like immunoreactivity (FLI) in the superior lateral and central lateral subnuclei of the rostral lateral PBN (LPBN) relative to surgery and blood pressure control groups. In the middle LPBN chemical stimulation of the dorsal PAG selectively increased FLI in the central lateral subnucleus while electrical stimulation increased FLI in the Kolliker-Fuse area only. Finally, in the caudal LPBN only electrical stimulation of the dorsal PAG induced significant changes in FLI above control. Significant changes in FLI in the medial PBN were not observed under any experimental conditions. These results confirm neuroanatomical data demonstrating that neurons in superior lateral and central lateral subnuclei of the rostral and middle LPBN are the primary targets of the dorsal PAG. Our results also demonstrate that this descending projection to the central lateral and superior lateral subnuclei of the LPBN is in part excitatory. Finally, our results raise the possibility that neurons in the central lateral subnucleus of the middle and rostral LPBN are integrally involved in descending modulation of sympathetic drive associated with dorsal PAG activation.