Clinical phenotypes and classification algorithm for complex regional pain syndrome

ObjectiveWe pursued the hypothesis that complex regional pain syndrome (CRPS) signs observed by neurologic examination display a structure allowing for alignment of patients to particular phenotype clusters.MethodsClinical examination data were obtained from 3 independent samples of 444, 391, and 202 patients with CRPS. The structure among CRPS signs was analyzed in sample 1 and validated with sample 2 using hierarchical clustering. For patients with CRPS in sample 3, an individual phenotype score was submitted to k-means clustering. Pain characteristics, quantitative sensory testing, and psychological data were tested in this sample as descriptors for phenotypes.ResultsA 2-cluster structure emerged in sample 1 and was replicated in sample 2. Cluster 1 comprised minor injury eliciting CRPS, motor signs, allodynia, and glove/stocking-like sensory deficits, resembling a CRPS phenotype most likely reflecting a CNS pathophysiology (the central phenotype). Cluster 2, which consisted of edema, skin color changes, skin temperature changes, sweating, and trophic changes, probably represents peripheral inflammation, the peripheral phenotype. In sample 3, individual phenotype scores were calculated as the sum of the mean values of signs from each cluster, where signs from cluster 1 were coded with 1 and from cluster 2 with −1. A k-means algorithm separated groups with 78, 36, and 88 members resembling the peripheral, central, and mixed phenotypes, respectively. The central phenotype was characterized by cold hyperalgesia at the affected limb.ConclusionsStatistically determined CRPS phenotypes may reflect major pathophysiologic mechanisms of peripheral inflammation and central reorganization.

Effects of repeated walking in a perturbing environment: a 4-day locomotor learning study

Previous studies have shown that when subjects repeatedly walk in a perturbing environment, initial movement error becomes smaller, suggesting that retention of the adapted locomotor program occurred (learning). It has been proposed that the newly learned locomotor program may be stored separately from the baseline program. However, how locomotor performance evolves with repeated sessions of walking with the perturbation is not yet known. To address this question, 10 healthy subjects walked on a treadmill on 4 consecutive days. Each day, locomotor performance was measured using kinematics and surface electromyography (EMGs), before, during, and after exposure to a perturbation, produced by an elastic tubing that pulled the foot forward and up during swing, inducing a foot velocity error in the first strides. Initial movement error decreased significantly between days 1 and 2 and then remained stable. Associated changes in medial hamstring EMG activity stabilized only on day 3, however. Aftereffects were present after perturbation removal, suggesting that daily adaptation involved central command recalibration of the baseline program. Aftereffects gradually decreased across days but were still visible on day 4. Separation between the newly learned and baseline programs may take longer than suggested by the daily improvement in initial performance in the perturbing environment or may never be complete. These results therefore suggest that reaching optimal performance in a perturbing environment should not be used as the main indicator of a completed learning process, as central reorganization of the motor commands continues days after initial performance has stabilized.

Study of Cutaneous Reflex Compensation During Locomotion After Nerve Section in the Cat

In the cat, section of all cutaneous nerves of the hindfeet except the tibial (Tib) nerve supplying the plantar surface results in a long-lasting decrease in the intensity of Tib stimulation needed for a threshold response in flexor muscles and an increase in the amplitude of the phase-dependent responses recorded in various muscles during locomotion. Stimulating through chronically implanted nerve cuffs ensured a stable stimulation over time. The increase in reflex amplitude was well above the small increase in the amplitude of the locomotor bursts themselves that results from the denervation. Short latency responses (P1) were seen in flexor muscles, especially at the knee (semitendinosus) and ankle (tibialis anterior and extensor digitorum longus), with stimuli applied in the swing phase and also to a lesser degree in the later part of the cycle. Longer latency responses (P2) were increased in hip, knee, and ankle flexors, as well as in a contralateral extensor (vastus lateralis) when applied in late stance. Responses evoked from stimulating the proximal end of sectioned nerves were not larger than before neurectomy. This suggests that the increased responsiveness to Tib stimulation is not simply caused by an increase in motoneuron excitability, because this would have resulted in a nonspecific increase of responses to stimulation of any nerve. It is concluded that the adult locomotor system is capable of central reorganization to enhance specific remaining cutaneous reflex pathways after a partial cutaneous denervation of the paw.

Relative contributions of eyelid and eye-retraction motor systems to reflex and classically conditioned blink responses in the rabbit

Early compensatory mechanisms between eyelid and eye-retraction motor systems following selective nerve and/or muscle lesions were studied in behaving rabbits. Reflex and conditioned eyelid responses were recorded in 1) controls and following 2) facial nerve section, 3) retractor bulbi muscle removal, and 4) facial nerve section and retractor bulbi muscle removal. Animals were classically conditioned with a delay paradigm by using a tone (350 ms, 600 Hz, 90 dB) as conditioned stimulus, followed 250 ms later by an air puff (100 ms, 3 kg/cm2) as unconditioned stimulus. Conditioned eyelid responses generated in the absence of the facial motor system (i.e., by the almost sole action of the retractor bulbi motor system) presented a wavy profile, due to the succession of eye-retraction movements. Learned eyelid responses generated in the absence of the eye-retraction motor system (i.e., by the almost exclusive action of the facial motor system) were similar to those of controls, but were reduced in amplitude and peak velocity. Finally, the isolated action of the extraocular recti muscle produced very small eyelid movements during both reflex and learned eyelid responses. Although each of these motor systems could act independently of the others, the motor result of their joint action did not coincide with the simple addition of their separate actions. Both facial and eye-retraction motor systems appear to be necessary for normal eyelid closure during blinking in rabbits. Central reorganization to compensate for loss of either of these systems may explain why the response of each system in isolation cannot be added linearly to obtain normal blink response magnitudes and profiles.

Recovery of arterial pressure control after partial baroreceptor denervation in awake rabbits

We examined recovery of control of heart rate (HR) and total peripheral resistance (TPR) by arterial baroreceptors after bilateral carotid sinus and aortic denervation or unilateral carotid sinus and aortic denervation in conscious rabbits. In one group of animals, HR responses to changes in mean arterial pressure (MAP) after injection of nitroglycerin or phenylephrine were measured in control studies and at 2, 5, 10, and 15 days after partial baroreceptor denervation. All denervation procedures increased MAP and HR at 2 and 5 days after denervation. Reflex sensitivity decreased to 57–67% of control on day 2 after denervation. HR responses recovered by day 10 after bilateral aortic or carotid sinus denervation; however, recovery following unilateral denervation was less complete. In a second group of animals, studied after implantation of aortic flowmeters, TPR changes following reduction in cardiac output by inferior vena caval occlusion were 49% of control responses on day 2 after denervation and returned close to control level on day 5. Controls of HR and TPR recovered substantially and were not significantly different from control 10 days after partial denervation. Recovery apparently occurred through the remaining arterial baroreceptors, possibly due to central reorganization of reflex pathways.

Reorganization of the receptive fields of spinocervical tract neurons following denervation of a single digit in the cat

The effect of acute and chronic section of the digital nerves of a single toe on the organization of low-threshold, mechanoreceptive fields of lumbosacral spinocervical tract (SCT) neurons has been studied in adult cats anesthetized with chloralose. The immediate effect of sectioning the digital nerves of a single toe is to produce a patch of dorsal horn in the medial region of the ipsilateral lumbosacral cord in which SCT neurons lack any peripheral receptive field when gentle hair movement or light touch of glabrous skin are used as stimuli. Other SCT neurons in the region may lose only part of their receptive fields. Between 30 and 70 days later most of the affected SCT neurons have established receptive fields. These are mainly on somatotopically inappropriate areas of skin medially and laterally adjacent to the denervated region. A small proportion of SCT neurons form discontinuous receptive fields. The relative somatotopic organization within the affected region remains unchanged. As there is no sign of regeneration of the sectioned nerves the new receptive fields must result from a central reorganization of excitatory inputs to SCT neurons. It is concluded that chronic peripheral nerve section affects the anatomical and physiological mechanisms underlying the formation of light touch receptive fields of dorsal horn neurons in the lumbosacral cord of the adult cat, but that the resulting reorganization of receptive fields is spatially restricted.