A randomized controlled study to evaluate the efficacy of noninvasive limb cover for chronic phantom limb pain among veteran amputees.

OBJECTIVE: To assess the efficacy of a noninvasive limb cover for treating chronic phantom limb pain (PLP). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Outpatient clinic. PARTICIPANTS: We randomly assigned 57 subjects to 2 groups: true noninvasive limb cover (n=30) and sham noninvasive limb cover (n=27). Inclusion criteria included age of 18 years or greater, upper or lower extremity amputation with healed residual limb, and 3 or more episodes of PLP during the previous 6 weeks. INTERVENTIONS: Subjects received 2 true or sham noninvasive limb covers to be worn over the prosthesis and residual limbs 24 hours a day for 12 weeks. MAIN OUTCOME MEASURES: Primary outcome measure was the numerical pain rating scale of PLP level (0-10). Secondary outcomes included overall pain level (0-10), PLP frequency per week, and the Veterans RAND 12-Item Health Survey (VR-12). We collected data at baseline and at 6- and 12-week follow-up visits. RESULTS: Demographic and clinical characteristics were not significantly different between groups. The true noninvasive limb cover group reported nonsignificant reductions in PLP from 5.9±1.9 at baseline to 3.9±1.7 at the 12-week follow-up. The sham noninvasive limb cover group also had nonsignificant reducations in PLP from 6.5±1.8 to 4.2±2.3. PLP did not differ significantly between the 2 groups at 6 weeks (mean difference, 0.8; 95% confidence interval [CI], -1.4 to 3) or at 12 weeks (mean difference, 0.2; 95% CI, -1.9 to 2.3). Similarly, overall pain level, PLP episodes per week, and VR-12 physical and mental health component scores did not differ between the 2 groups at 6 and 12 weeks. CONCLUSIONS: A true noninvasive limb cover did not significantly decrease PLP levels or the frequency of PLP episodes per week, overall bodily pain levels, or VR-12 physical and mental health component scores compared with a sham noninvasive limb cover in our veteran amputee sample.

Modulation of cardiovascular excitatory responses in rats by transcutaneous magnetic stimulation: role of the spinal cord.

This study investigated the efficacy of magnetic stimulation on the reflex cardiovascular responses induced by gastric distension in anesthetized rats and compared these responses to those influenced by electroacupuncture (EA). Unilateral magnetic stimulation (30% intensity, 2 Hz) at the Jianshi-Neiguan acupoints (pericardial meridian, P 5-6) overlying the median nerve on the forelimb for 24 min significantly decreased the reflex pressor response by 32%. This effect was noticeable by 20 min of magnetic stimulation and continued for 24 min. Median nerve denervation abolished the inhibitory effect of magnetic stimulation, indicating the importance of somatic afferent input. Unilateral EA (0.3-0.5 mA, 2 Hz) at P 5-6 using similar durations of stimulation similarly inhibited the response (35%). The inhibitory effects of EA occurred earlier and were marginally longer (20 min) than magnetic stimulation. Magnetic stimulation at Guangming-Xuanzhong acupoints (gallbladder meridian, GB 37-39) overlying the superficial peroneal nerve on the hindlimb did not attenuate the reflex. Intravenous naloxone immediately after termination of magnetic stimulation reversed inhibition of the cardiovascular reflex, suggesting involvement of the opioid system. Also, intrathecal injection of delta- and kappa-opioid receptors antagonists, ICI174,864 (n=7) and nor-binaltorphimine (n=6) immediately after termination of magnetic stimulation reversed inhibition of the cardiovascular reflex. In contrast, the mu-opioid antagonist CTOP (n=7) failed to alter the cardiovascular reflex. The endogenous neurotransmitters for delta- and kappa-opioid receptors, enkephalins and dynorphin but not beta-endorphin, therefore appear to play significant roles in the spinal cord in mediating magnetic stimulation-induced modulation of cardiovascular reflex responses.

Optimal arrangement of magnetic coils for functional magnetic stimulation of the inspiratory muscles in dogs.

In an attempt to maximize inspiratory pressure and volume, the optimal position of a single or of dual magnetic coils during functional magnetic stimulation (FMS) of the inspiratory muscles was evaluated in twenty-three dogs. Unilateral phrenic magnetic stimulation (UPMS) or bilateral phrenic magnetic stimulation (BPMS), posterior cervical magnetic stimulation (PCMS), anterior cervical magnetic stimulation (ACMS) as well as a combination of PCMS and ACMS were performed. Trans-diaphragmatic pressure (Pdi), flow, and lung volume changes with an open airway were measured. Transdiaphragmatic pressure was also measured with an occluded airway. Changes in inspiratory parameters during FMS were compared with 1) electrical stimulation of surgically exposed bilateral phrenic nerves (BPES) and 2) ventral root electrical stimulation at C5-C7 (VRES C5-C7). Relative to the Pdi generated by BPES of 36.3 +/- 4.5 cm H2O (Mean +/- SEM), occluded Pdi(s) produced by UPMS, BPMS, PCMS, ACMS, and a combined PCMS + ACMS were 51.7%, 61.5%, 22.4%, 100.3%, and 104.5% of the maximal Pdi, respectively. Pdi(s) produced by UPMS, BPMS, PCMS, ACMS, and combined ACMS + PCMS were 38.0%, 45.2%, 16.5%, 73.8%, and 76.8%, respectively, of the Pdi induced by VRES (C5-C7) (48.0 +/- 3.9 cm H2O). The maximal Pdi(s) generated during ACMS and combined PCMS + ACMS were higher than the maximal Pdi(s) generated during UPMS, BPMS, or PCMS (p < 0.05). ACMS alone induced 129.8% of the inspiratory flow (73.0 +/- 9.4 L/ min) and 77.5% of the volume (626 +/- 556 ml) induced by BPES. ACMS and combined PCMS + ACMS produce a greater inspiratory pressure than UPMS, BPMS or PCMS. ACMS can be used to generate sufficient inspiratory pressure, flow, and volume for activation of the inspiratory muscles.

Motor recovery and anatomical evidence of axonal regrowth in spinal cord-repaired adult rats.

Behavioral assessments of hindlimb motor recovery and anatomical assessments of extended axons of long spinal tracts were conducted in adult rats following complete spinal cord transection. Rats were randomly divided into 3 groups: 1) sham control group (laminectomy only; n = 12); 2) transection-only group, spinal cord transection at T8 (n = 20); and 3) experimental treatment group, spinal cord transection at T8, with peripheral nerve grafts (PNG) and application of acidic fibroblast growth factor (aFGF) (n = 14). The locomotor behavior and stepping of all rats were analyzed over a 6-month survival time using the Basso, Beattie, Bresnahan (BBB) open field locomotor test and the contact placing test. Immunohistochemistry for serotonin (5-HT), anterograde tracing with biotinylated dextran amine (BDA), and retrograde tracing with fluoro-gold were used to evaluate the presence of axons below the damage site following treatment. When compared with the transection-only group, the nerve graft with the aFGF group showed 1) significant improvement in hindlimb locomotion and stepping, 2) the presence of 5-HT-labeled axons below the lesion site at lumbar cord level (these were interpreted as regenerated axons from the raphe nuclei), 3) the presence of anterograde BDA labeling of corticospinal tract axons at the graft site and below, and 4) fluoro-gold retrograde labeling of neuron populations in motor cortex and in red nucleus, reticulospinal nuclei, raphe nuclei, and vestibular nuclei. We conclude that peripheral nerve grafts and aFGF treatments facilitate the regrowth of the spinal axons and improve hindlimb function in a T-8 spinal cord-transected rat model.

Peripheral nerve grafts and aFGF restore partial hindlimb function in adult paraplegic rats.

The purpose of this study was to evaluate the degree of functional recovery in adult rats with completely transected spinal cord following experimental treatment regimens that include implantation of peripheral nerve segments and local application of acidic fibroblast growth factor (aFGF). Rats were randomly divided to five groups: (1) spinal cord transection, (2) spinal cord transection and aFGF treatment, (3) spinal cord transection and peripheral nerve grafts, (4) spinal cord transection, aFGF treatment, and peripheral nerve grafts, and (5) sham control (laminectomy only). The locomotor behavior of all rats was analyzed by the Basso, Beattie and Bresnahan (BBB) open field locomotor test over the six months survival time. Immunohistochemisty for neurofilament protein, and somatosensory (SSEP) and motor evoked potentials (MEP) were used to evaluate axon growth across the damage site following the different treatments. The results show four principal findings: (1) Only the combination of peripheral nerve grafts and aFGF treatment improved hindlimb locomotor function after spinal cord transection. (2) The SSEP and MEP demonstrated electrophysiological evidence of both sensory and motor information crossing the damaged site, but only in the combined nerve grafts and aFGF treatment rats. (3) Immunostaining demonstrated neurofilament positive axons extending through the graft area and into distal end of spinal cord, but only in the group with combined nerve grafts and aFGF treatment. (4) Retransection of group 4 rats eliminated the behavioral recovery, MEP, and SSEP responses, indicating that the improvement of hindlimb locomotor activity came from supraspinal control. These results demonstrate the ability of the repair strategy combining peripheral nerve grafts and aFGF treatment to facilitate the regeneration of spinal ascending and descending tracts and also recovery of motor behavior following spinal cord injury.

High intensity magnetic stimulation over the lumbosacral spine evokes antinociception in rats.

OBJECTIVES: High intensity magnetic stimulation (MS) applied over the skin can painlessly depolarize superficial and deep nerves and we aimed to evaluate the effectiveness of MS of spinal nerves in evoking a potent analgesic response. METHODS: The MS was administered to adult male Sprague-Dawley rats using a Cadwell MES-10 high-speed magnetic stimulator. A Peltier device and von Frey fibers were used to determine heat and mechanical nociceptive responses of the rats. RESULTS: A brief (5 min) course of MS over the rat's lumbosacral spine produced a long-lasting (30-40 min) and robust (80-90% maximum possible effect) hindpaw antinociceptive effect to both mechanical and heat stimuli. Spinal cord transected rats had intact hindpaw nociceptive withdrawal responses, but transection eliminated MS evoked antinociception, indicating a critical extrasegmental component in the mechanism of MS antinociceptive action. The opiate receptor antagonist naloxone (5 mg/kg, i.p.) completely blocked MS evoked antinociception, demonstrating an opioidergic mechanism for MS antinociception. The alpha(2) adrenoceptor antagonist atipamezole (5 mg/kg, i.p.) slightly reduced the MS antinociceptive response to heat and had no effect on MS antinociception for mechanical stimuli. CONCLUSIONS: These data indicate that MS can evoke a robust, long-lasting antinociceptive effect, which requires an intact supraspinal pathway and is opioidergic mediated.

Improvement of gait patterns in step-trained, complete spinal cord-transected rats treated with a peripheral nerve graft and acidic fibroblast growth factor.

The effects of peripheral nerve grafts (PNG) and acidic fibroblast growth factor (alpha FGF) combined with step training on the locomotor performance of complete spinal cord-transected (ST, T8) adult rats were studied. Rats were assigned randomly to five groups (N=10 per group): sham control (laminectomy only), ST only, ST-step-trained, repaired (ST with PNG and alpha FGF treatment), or repaired-step-trained. Step-trained rats were stepped bipedally on a treadmill 20 min/day, 5 days/week for 6 months. Bipolar intramuscular EMG electrodes were implanted in the soleus and tibialis anterior (TA) muscles of ST-step-trained (n=3) and repaired-step-trained (n=2) rats. Gait analysis was conducted at 3 and 6 months after surgery. Stepping analysis was completed on the best continuous 10-s period of stepping performed in a 2-min trial. Significantly better stepping (number of steps, stance duration, swing duration, maximum step length, and maximum step height) was observed in the repaired and repaired-step-trained than in the ST and ST-step-trained rats. Mean EMG amplitudes in both the soleus and TA were significantly higher and the patterns of activation of flexors and extensors more reciprocal in the repaired-step-trained than ST-step-trained rats. 5-HT fibers were present in the lumbar area of repaired but not ST rats. Thus, PNG plus alpha FGF treatment resulted in a clear improvement in locomotor performance with or without step training. Furthermore, the number of 5-HT fibers observed below the lesion was related directly to stepping performance. These observations indicate that the improved stepping performance in Repaired rats may be due to newly formed supraspinal control via regeneration.

Stimulation of the expiratory muscles using microstimulators.

Respiratory complications constitute a major cause of morbidity and mortality in patients with spinal cord injury. These complications arise in part due to the loss of supraspinal control over the expiratory muscles and the resultant difficulties in clearing airway secretions effectively. The purpose of the present study is to evaluate the efficacy of lower thoracic spinal nerve stimulation using wireless microstimulators in activating the expiratory muscles. Studies were performed on nine anesthetized dogs. A thoracic laminectomy was performed on each dog,and was followed by spinal cord transection at T2. A total of 16 microstimulators (supplied by the Alfred Mann Foundation, Santa Clarita, CA) were inserted percutaneously into the bilateral intercostal nerves approximately 1 to approximately 3 cm distal to the neuroforamen from T7 to L1 in each dog. The stimulation parameters were: frequency of 20 Hz, pulse width of 200 micros, and stimulation burst of 2 s. The stimulation intensities were 3.78, 5.4, 8.1, and 10.8 mA. The pressure-generating capacity of the expiratory muscles was evaluated by the change in airway pressure (Paw) at functional residual capacity, which was produced by the microstimulators during airway occlusion. As a general trend, the expiratory pressure generated using the microstimulators increased with increasing intensity and the number of spinal nerves recruited. The maximal expiratory pressures generated from one, two, three, four, five, six, seven, and eight pairs of spinal nerves were 8.4 +/- 0.8, 12.2 +/- 1.0, 14.6 +/- 1.4, 17.8 +/- 1.8, 23.0 +/- 1.8, 27.7 +/- 2.2, 35.2 +/- 2.7, and 40.4 +/- 2.9 cmH2O, respectively. Bilateral stimulation of seven (from T8 to L1) and eight spinal nerve levels (from T7 to L1) produced the highest changes in(Paw). Stimulation of six or less spinal nerve levels resulted in significantly lower (Paw). We conclude: 1) lower thoracic spinal nerve stimulation near the neuroforamen using microstimulators produces significant expiratory pressure, 2) percutaneous placement of the microstimulators near the neuroforamen is effective in producing expiratory pressure, and 3) percutaneous placement of the microstimulators for restoring cough may potentially be used as a relatively noninvasive clinical tool for patients with spinal cord injury, or other neurological or respiratory disorders. Further studies will be needed.

Re-growth of catecholaminergic fibers and protection of cholinergic spinal cord neurons in spinal repaired rats.

The extent of re-growth of catecholaminergic fibers, the survival of cholinergic neurons and the degree of autonomic dysreflexia were assessed in complete spinal cord-transected adult rats that received a repair treatment of peripheral nerve grafts and acidic fibroblast growth factor (aFGF). The rats were randomly divided into three groups: (1) sham control group (laminectomy only); (2) spinal cord transection at T8 (transected group); and (3) spinal cord transection at T8, followed by aFGF treatment and peripheral nerve graft (repaired group). The spinal cords and brains of all rats were collected at 6 months post-surgery. Immunohistochemistry for tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH), and fluoro-gold (FG) retrograde tracing were used to evaluate axon growth across the damage site, and immunocytochemistry for choline acetyl transferase (ChAT) was used to evaluate cholinergic neuronal cell survival following the injury and treatment. When comparing with the transected group, the repaired group showed: (1) lower elevation of mean arterial pressure during colorectal distension; (2) retrogradely labeled neurons in the hypothalamus, zona incerta, subcoeruleus nuclei and rostral ventrolateral medulla following application of FG below the repair site; (3) the presence of TH- and DBH-labeled axons below the lesion site; (4) higher numbers of ChAT-positive neurons in ventral horn and intermediolateral column near the lesion site. We conclude that peripheral nerve graft and aFGF treatments facilitate the re-growth of catecholaminergic fibers, also protect sympathetic preganglionic neurons and spinal motor neurons, and reduce autonomic dysfunction in a T-8 spinal cord-transected rat model.

Functional magnetic ventilation in dogs.

OBJECTIVE: To investigate the efficacy of the magnetic stimulation of inspiratory muscles as an alternative to mechanical ventilation and functional electric stimulation. DESIGN: A prospective before-after trial. SETTING: Functional magnetic stimulation laboratory in a Veterans Administration health care system. ANIMALS: Six male mongrel dogs, each weighing between 25 and 35 kg. INTERVENTIONS: Commercially available magnetic stimulators with a round magnetic coil were used. The center of the magnetic coil was placed posteriorly over the C5-7 vertebrae of the spinal cord transected dogs. Magnetic stimulation parameters were set at 80% intensity, 20 Hz, and a 1.2-second on and 3.8-second off pulse train. MAIN OUTCOME MEASURES: The major outcomes were changes in tidal volume (VT), tracheal pressure (Ptr), and arterial partial pressure of carbon dioxide (PaCO2) and oxygen sustained by magnetic stimulation over time. RESULTS: The average Vt and Ptr produced during functional magnetic ventilation (FMV) were.47+/-.07 L and -4.7+/-.51 cmH2O, respectively. Blood gas data showed that PaCO2 increased from a baseline of 33 to 75 mmHg, whereas pH decreased from 7.33 to 6.99 at the end of the 1-hour FMV period. CONCLUSIONS: FMV was achieved for 2 hours in dogs with C2 spinal cord transection. Additional refinements in magnetic stimulation are needed to improve ventilation in animals.

Functional magnetic stimulation facilitates gastric emptying.

OBJECTIVE: To evaluate the effect of functional magnetic stimulation (FMS) on gastric emptying in able-bodied and spinal cord injury (SCI) subjects. DESIGN: A prospective, nonrandomized clinical experiment. SETTING: SCI and disorder center in a Veterans Affairs medical facility. PARTICIPANTS: Five healthy, able-bodied subjects and 4 subjects with SCI. INTERVENTION: A commercially available magnetic stimulator was used; a round magnetic coil was placed along the T9 spinous process. The intensity of the magnetic stimulation was 60%, with a frequency of 20 Hz, and a burst length of 2 seconds for the gastric emptying protocol. Man Outcome Measures: Rate of gastric emptying and time required to reach gastric emptying half-time (GE(t1/2)) with and without FMS. Data fit into linear regression curve. RESULTS: Accelerated gastric emptying was achieved in both able-bodied and SCI subjects. The mean +/- standard error of mean of the GE(t1/2) at baseline and with FMS was 36+/-2.9 minutes and 33+/-3.1 minutes, respectively, for able-bodied subjects, and 84+/-11.1 minutes and 59+/-12.7 minutes, respectively, for SCI subjects. CONCLUSION: Gastric emptying was enhanced by FMS in able-bodied subjects and was greatly enhanced in SCI subjects. FMS can be a useful noninvasive therapeutic tool to facilitate gastric emptying in humans.