Margaret J. Chandler

Modulation of intrinsic cardiac neurons by spinal cord stimulation : implications for its therapeutic use in angina pectoris

OBJECTIVE Electrical stimulation of the dorsal aspect of the upper thoracic spinal cord is used increasingly to treat patients with severe angina pectoris refractory to conventional therapeutic strategies. Clinical studies show that spinal cord stimulation (SCS) is a safe adjunct therapy for cardiac patients, producing anti-anginal as well as anti-ischemic effects. However, little information is yet available about the underlying mechanisms involved. METHODS In order to determine its mechanism of action, the effects of SCS on the final common integrator of cardiac function, the intrinsic cardiac nervous system, was studied during basal states as well as during transient (2 min) myocardial ischemia. Activity generated by intrinsic cardiac neurons was recorded in 9 anesthetized dogs in the absence and presence of myocardial ischemia before, during and after stimulating the dorsal T1-T2 segments of the spinal cord at 66 and 90% of motor threshold using epidural bipolar electrodes (50 Hz; 0.2 ms; parameters within the therapeutic range used in humans). RESULTS The SCS suppressed activity generated by intrinsic cardiac neurons. No concomitant change in monitored cardiovascular indices was detected. Neuronal activity increased during transient ventricular ischemia (46%), as well as during the early reperfusion period (68% compared to control). Despite that, activity was suppressed during both states by SCS. CONCLUSIONS SCS modifies the capacity of intrinsic cardiac neurons to generate activity. SCS also acts to suppress the excitatory effects that local myocardial ischemia exerts on such neurons. Since no significant changes in monitored cardiovascular indices were observed during SCS, it is concluded that modulation of the intrinsic cardiac nervous system might contribute to the therapeutic effects of SCS in patients with angina pectoris.

An unanesthetized-gerbil model of cerebral ischemia-induced behavioral changes

A surgical procedure has been developed to study the effects of cerebral ischemia in the unanesthetized Mongolian gerbil. The methodology is based upon the surgical isolation and instrumentation of both common carotid arteries. A loop of dental floss is placed around each carotid artery and passed through double lumen catheter material; this allows for later occlusion of the carotid arteries and their release in unanesthetized subjects. Functional changes following transient carotid artery occlusion are readily demonstrated by the occurrence of altered spontaneous locomotor activity at various times postischemia. This model should be useful in the evaluation of potential therapeutic agents in the treatment of cerebral ischemia.

Viscerosomatic convergence onto feline spinal neurons from esophagus, heart and somatic fields: effects of inflammation

&NA; One objective of this study was to examine a mechanism for the inability of patients to distinguish esophageal pain from cardiac pain. Patients with esophageal disease and angina pectoris often perceive pain as originating from the same somatic fields. Another objective was to compare the effect of esophageal distension between animals with a non‐inflamed or with an inflamed esophagus. For this study in anesthetized cats, we recorded extracellular action potentials from T2–T7 spinal neurons that responded to intraluminal distension of an untreated or a turpentine‐inflamed distal esophagus. Threshold distension volumes were compared between these 2 groups of animals. Neurons also were examined for effects of intracardiac bradykinin injection and somatic stimuli. Results showed that spinal neurons responded to a smaller threshold distension volume when cells in animals with an inflamed distal esophagus were compared to cells in animals with a non‐inflamed distal esophagus. Spinal neurons that received input from the distal esophagus also received convergent input from the heart and somatic fields. Our data supported the hypotheses thatreferred pain from the distal esophagus resulted from activation of the same spinal neurons by visceral and somatic input,pain originating from the distal esophagus and heart might be difficult to distinguish because of viscerosomatic and viscerovisceral convergence onto the same spinal neurons, andan inflamed distal esophagus might be more sensitive to distension than a non‐inflamed esophagus.

Responses of neurons in ventroposterolateral nucleus of primate thalamus to urinary bladder distension

The purpose of this study was to examine effects of a noxious visceral stimulus, urinary bladder distension (UBD), on cells in the ventroposterolateral (VPL) nucleus of anesthetized monkeys. We hypothesized that processing of visceral information in the VPL nucleus of the thalamus is similar to spinothalamic tract (STT) organization of visceral afferent input. Urinary bladder distension excites sacral and upper-lumbar STT cells that have somatic input from proximal somatic fields; whereas, thoracic STT cells are inhibited by UBD. Extracellular action potentials of 67 neurons were recorded in VPL nucleus. Urinary bladder distension excited 22 cells, inhibited 9 cells, and did not affect activity of 36 cells. Seventeen of 22 cells excited by UBD also received convergent somatic input from noxious squeeze of the hip, groin, or perineal regions. No cells activated only by innocuous somatic stimuli were excited by UBD. Five of 9 cells inhibited by UBD had upper-body somatic fields. There was a significant tendency for VPL neurons excited by UBD to have proximal lower-body somatic fields that were excited by noxious stimulation of skin and underlying muscle (P less than 0.001). Antidromic activation of 4 thalamic neurons affected by UBD showed that visceral input stimulated by UBD reached the primary somatosensory (SI) cortex.

Low intensity spinal cord stimulation may induce cutaneous vasodilation via CGRP release

This study examined whether spinal cord stimulation (SCS) at intensities below motor threshold (MT) produces cutaneous vasodilation through sympathetic inhibition and/or antidromic activation of sensory fibers. SCS was applied to anesthetized rats with stimulus parameters used clinically, i.e. 50 Hz, 0.2 ms and stimulus intensities at 30, 60 or 90% of MT. SCS-induced vasodilation was not attenuated by hexamethonium, an autonomic ganglion blocking agent, but was abolished by CGRP-(8-37), an antagonist of the calcitonin gene-related peptide (CGRP) receptor. We concluded that SCS-induced vasodilation under the conditions of this study was mediated by peripheral release of CGRP via antidromic activation of sensory fibers.

Effects of vagal afferent stimulation on cervical spinothalamic tract neurons in monkeys

&NA; The purpose of this study was to determine if electrical stimulation of vagal afferents inhibited activity of primate spinothalamic tract (STT) neurons located in cervical segments of the spinal cord. Previous studies show vagal inhibition of STT neurons in more caudal segments of the cord, which receive visceral spinal inputs and somatic inputs from proximal body regions. We hypothesized that activation of vagal afferents would inhibit cervical STT neurons that were excited by cardiopulmonary sympathetic afferents and not inhibit those cells inhibited or unaffected by this visceral input. Because visceral pain is referred to proximal somatic fields, we also hypothesized that STT neurons with excitatory somatic fields confined to distal areas would not be inhibited by vagal stimulation. In 42 cervical STT neurons, we found no difference in effects of vagal stimulation between cells excited or not excited by stimulation of cardiopulmonary sympathetic afferents. Responses to vagal stimulation also were the same for cervical STT cells with proximal or distal somatic fields. Furthermore, there was no difference in the inhibitory effects of vagal stimulation in cervical as compared to thoracic STT neurons. We concluded that vagal afferent stimulation causes a general inhibitory effect at all levels of the spinal cord on neurons which transmit nociceptive information.

Propriospinal neurons in the C1-C2 spinal segments project to the L5-S1 segments of the rat spinal cord

Physiological studies indicate that neurons in the upper cervical spinal cord have descending projections to the lumbosacral spinal cord and mediate inhibition of dorsal horn neurons activated from afferent input. In the present study, retrograde tracing techniques were used to examine the distribution of propriospinal neurons in C1-C2 spinal segments that project to lumbosacral spinal segments. Fluorogold or horseradish peroxidase were injected unilaterally or bilaterally into the L5-S1 spinal segments. After 2-4 days, rats were perfused with fixative and C1-C2 spinal segments were processed for retrograde labeling. Numerous neurons were found in the C1-C2 segments. In unilaterally and bilaterally injected rats, retrogradely labeled neurons were located on both the ipsilateral and contralateral sides. Retrogradely labeled neurons were located in the following locations: lateral cervical and spinal nuclei, nucleus proprius, ventral horn and the central gray region (area X). These studies demonstrate a descending projection from C1-C2 segments to the lower lumbar and sacral spinal cord. We hypothesize that many of these C1-C2 propriospinal neurons are important in modulating responses of spinal neurons at lower segmental levels to various peripheral stimuli.

Mechanisms of sustained cutaneous vasodilation induced by spinal cord stimulation

This study was performed to investigate whether spinal cord stimulation (SCS) at intensities below motor threshold prolongs cutaneous vasodilation and whether sustained vasodilation by SCS is mediated through sympathetic inhibition and/or antidromic activation of sensory fibers. SCS was applied to the dorsal surface of the L2-L3 spinal cord of anesthesized rats with stimulus parameters used clinically (i.e., 50 Hz, 0.2 ms duration, and stimulus intensity at 30%, 60%, or 90% of motor threshold). Peripheral vasodilation induced by 5-min SCS was not attenuated by hexamethonium, an autonomic ganglion-blocking agent, but was abolished by dorsal rhizotomy. SCS at < or = 60% of motor threshold increased cutaneous blood flow to the level similar to that obtained at 90% of motor threshold, but the vasodilation did not last for 5 min. SCS-induced vasodilation at 90% of motor threshold persisted for the entire stimulation period up to 30 min, and the vasodilation was not attenuated by hexamethonium. It is concluded that sustained vasodilation, which is induced by SCS at only 90% of motor threshold, in this study was mediated via antidromic activation of sensory fibers.

Role of primary afferents in spinal cord stimulation-induced vasodilation: characterization of fiber types

Selected patients with peripheral vascular disease can be treated with spinal cord stimulation (SCS) to improve blood flow in the limbs. However, the mechanisms producing these effects remain unclear. The present study was designed to investigate if SCS produces cutaneous vasodilation via antidromic activation of the unmyelinated C-fibers and/or the small myelinated fibers. SCS was applied to anesthetized rats with a ball electrode at the L2-L3 spinal level. In Protocol 1, effects of capsaicin were examined. Blood flow changes in the hindpaw induced by SCS were measured in the footpad with laser Doppler flowmeters. Topical application of capsaicin (1%) on the tibial nerve did not affect SCS-induced vasodilation at 30 and 60% of motor threshold (MT). However, the duration of vasodilation induced by SCS at 90% MT and at 10 times MT was significantly reduced after capsaicin application on the tibial nerve. In Protocol 2, antidromic compound action potentials (CAPs) of the tibial nerve were recorded in response to SCS. CAPs of the large and the small myelinated afferent fibers were observed in response to SCS at all intensities. However, even with SCS at ten times MT, CAPs of C-fibers could not be detected in the tibial nerve. In Protocol 3, antidromic CAPs of the dorsal root were measured in response to SCS. Antidromic CAPs of C-fibers in dorsal roots were evoked by SCS at >or=90% of MT. It is concluded that SCS-induced vasodilation at <or=60% of MT may be mediated via only the myelinated fibers, whereas vasodilation at >or=90% of MT may also involve antidromic activation of some unmyelinated C-fibers.

Thoracic visceral inputs use upper cervical segments to inhibit lumbar spinal neurons in rats

We tested the hypothesis that cardiopulmonary sympathetic afferent (CPSA) input entering upper thoracic spinal segments relays in the cervical spinal cord to inhibit activity of lumbar spinothalamic tract (SST) cells and dorsal horn (DH) cells. Two sequential spinal transections in the same animal were made, one at rostral C1 and one at C4-C6 segments, to determine neuronal pathways involved in the inhibition. We concluded that inhibitory effects induced by CPSA and somatic stimulation might be mediated by propriospinal mechanisms located in upper cervical segments. Vagal inhibition required supraspinal pathways.