Neurons with spontaneous high-frequency discharges in the central nervous system and chronic pain.

Neurons with high-frequency discharge (hyperactive neuron) were recorded in the thalamus of chronic pain patients. We created a chronic pain rat model, and recorded the discharge of high-frequency neurons by using a microelectrode in the thalamic area. The character of these high-frequency discharge neurons was assessed. Deep brain stimulation (DBS) was done in 9 patients, and motor cortical stimulation (MCS) in 2. Prior to implantation of the stimulation electrodes, extracellular unitary activity was recorded and local microstimulation was done by the same microelectrode. From the ventrocaudal (Vc) nucleus of the chronic pain patients, hyperactive neurons were recorded. There were three types of discharge patterns in interval histograms. Some hyperactive neurons showed firing suppression for a short time period by intravenous administration of phenytoin and calcium antagonist (Nicardipine). In animal experiments, unilateral dorsal root sectioning from C5 to Th1 were made in male Wistar rats according to the method of Lombard et al. (1979). A few months after the operation, hyperactive neurons were recorded from the thalamic nuclei and lemniscus medialis. The firing patterns and distribution of hyperactive neurons were very similar to those of humans. Sensorimotor cortical electrical stimulation showed a reduction of firing in the hyperactive neurons. Iontophoretical application of glutamate yielded an increase in firing. In contrast, GABA and NMDA antagonist MK-801 revealed remarkable firing suppression. These results suggest that hyperactive neurons may correlate with the glutamatergic, especially NMDA and GABAergic receptor or fibers.

Kinaesthetic neurons in thalamus of humans with and without tremor.

Increased afferent input may alter receptive field sizes, properties and somatotopographic representation in the cortex. Changes in the motor thalamus may also occur as a result of altered afferent input. Such plasticity has been implicated in both sensory and movement disorders. Using tremor as a model of augmented afferent input to kinaesthetic/deep neurons representing the shaking limbs, we studied the representation and properties of these neurons in human thalamus in patients with resting tremor (RestTr) from Parkinson's disease, patients with action- or posture-induced tremor (ActionTr), and patients without tremor (NoTr). Data were collected during stereotactic thalamotomy or insertion of deep brain stimulators for relief of pain or movement disorder. Using microelectrode recording, 58 kinaesthetic neurons responding to wrist and/or elbow movement were studied by mapping the receptive field, carefully isolating each joint during testing. There were no significant differences in the proportions of single and multijoint responsive neurons in the different patient groups (RestTr, ActionTr and NoTr). The borders between tactile-cutaneous, deep-kinaesthetic and voluntary cell representations in the thalamus were mapped in 74 patients and compared between the different tremor groups. A significant difference in kinaesthetic representation was found: both the RestTr and ActionTr groups had a significantly greater kinaesthetic representation than the NoTr patients. There was an expansion of kinaesthetic representation in patients with chronic increased afferent drive from tremor, without alteration in RF size. No decrease in tactile representation was found, suggesting that the increase in kinaesthetic representation does not occur at the expense of tactile representation. These data suggest that plasticity can occur at the thalamic level in humans and may contribute to the pathogenesis of tremor.

Spinal cord stimulation for nonspecific limb pain versus neuropathic pain and spontaneous versus evoked pain.

OBJECTIVE: To compare the outcome of spinal cord stimulation (SCS) in patients with nonspecific limb pain versus patients with neuropathic pain syndromes and in patients with spontaneous versus evoked pain. METHODS: A retrospective review of 122 patients accepted for treatment with SCS between January 1990 and December 1998 was conducted. All patients first underwent a trial of SCS with a monopolar epidural electrode. Seventy-four patients had a successful trial and underwent permanent implantation of the monopolar electrode used for the trial (19 patients), or a quadripolar electrode (53 patients), or a Resume quadripolar electrode via laminotomy (2 patients). RESULTS: Of the 74 patients, 60.7% underwent implantation of a permanent device and were followed for an average of 3.9 years (range, 0.3-9 yr). Early failure (within 1 yr) occurred in 20.3% of patients, and late failure (after 1 yr) occurred in 33.8% of patients. Overall, 45.9% of patients were still receiving SCS at latest follow-up. Successful SCS (>50% reduction in pain for 1 yr) occurred in 83.3% of patients with nonspecific leg pain, 89.5% of patients with limb pain associated with root injury, and 73.9% of patients with nerve neuropathic pain. SCS was less effective for the control of allodynia or hyperpathia than for spontaneous pain associated with neuropathic pain syndromes. Third-party involvement did not influence outcome. There was a lesser incidence of surgical revisions when quadripolar leads were used than with monopolar electrodes. CONCLUSION: SCS is as effective for treating nonspecific limb pain as it is for treating neuropathic pain, including limb pain associated with root damage.

Does stimulation of the GPi control dyskinesia by activating inhibitory axons?

A 69-year-old woman with Parkinson's disease and levodopa-induced dyskinesias had a deep brain stimulation (DBS) electrode inserted into the right globus pallidus internus (GPi). During the operation, the GPi was mapped with dual microelectrode recordings. Stimulation through one microelectrode in GPi inhibited the firing of GPi neurons recorded with another microelectrode 600--1,000 microm distant. The inhibition could be obtained with pulse widths of 150 micros and intensities as low as 10 microA. Single stimuli inhibited GPi neurons for approximately 50 ms. Trains of 300 Hz stimuli inhibited GPi neuron firing almost completely. Postoperatively, stimulation through macroelectrode contacts located in the posterior ventral pallidum controlled the patient's dyskinesias. The effect could be obtained with pulse widths of 50 micros and frequencies as low as 70--80 Hz. We postulate stimulation of the ventral pallidum controls dyskinesias by activating large axons which inhibit GPi neurons.

History of lesioning for pain.

The history of open and subsequently stereotactic brain lesions for the relief of pain is traced. Important steps included recognition of the importance of the non-specific pain pathways and the differential effects of lesioning on nociceptive pain and on different elements of neuropathic pain. Although the advent of morphine infusion and deep brain stimulation has greatly eroded the number of destructive lesions made, new technical and conceptual advances must be carefully evaluated.

Microelectrode findings in the thalamus in chronic pain and other conditions.

Functional neurosurgery usually requires physiological corroboration of the target site, particularly by eliciting characteristic responses to stimulation, or else by microelectrode recording of single cell responses to appropriate stimuli. Understanding pain physiology with both strategies has proven elusive, particularly microelectrode recording in response to noxious or thermal stimuli. The limited experience with stimulation and recording in pain pathways of the brain will be reviewed as well as the apparently pathophysiological observations made in certain patients with neuropathic pain.

Microstimulation-induced inhibition of neuronal firing in human globus pallidus.

Neurosurgical treatment of Parkinson's disease (PD) frequently employs chronic high-frequency deep brain stimulation (DBS) within the internal segment of globus pallidus (GPi) and can very effectively reduce L-dopa-induced dyskinesias and bradykinesia, but the mechanisms are unknown. The present study examined the effects of microstimulation in GPi on the activity of neurons close to the stimulation site. Recordings were made from GPi using two fixed or independently controlled microelectrodes, with the electrode tips usually approximately 250 or >600 micrometer apart in PD patients undergoing stereotactic exploration to localize the optimal site for placement of a lesion or DBS electrode. The spontaneous activity of nearly all of the cells (22/23) recorded in GPi in three patients was inhibited by microstimulation at currents typically <10 microA (0.15-ms pulses at 5 Hz). The inhibition had a duration of 10-25 ms at threshold. These findings suggest that microstimulation within GPi preferentially excites the axon terminals of striatal and/or external pallidal neurons causing release of GABA and inhibition of GPi neurons.

Percutaeous radiofrequency facet rhizotomy--experience with 118 procdedures and reappraisal of its value.

BACKGROUND: There have been many reports of percutaneous radiofrequency facet rhizotomy, perhaps better referred to as facet denervation, usually performed under general anaesthesia, with inconsistent success rates. OBJECTIVES: To report the authors' outcome data using both general and local anaesthesia and to reassess the value of this controversial procedure. METHODS: Our experience with 118 consecutive percutaneous radiofrequency facet rhizotomies performed on 90 patients in the Toronto Western Hospital was analyzed. Sixty percent of the procedures were performed under general anaesthesia, 40% under local anaesthesia. All patients had been temporarily virtually relieved of pain after local anaesthetic blockade of the subject facets by an independent radiologist. RESULTS: The patients were monitored from 1-33 (mean 5.6) months after surgery, with complete elimination or a greater than 50% subjective reduction of pain considered the criteria for success. For the first or only procedure this was 41% overall, 37% in cases done under local anaesthesia, 46% in cases done under general anaesthesia (difference not statistically significant p=0.52). There was no statistically significant difference in success rates for procedures performed in the cervical, thoracic or lumbosacral facets, with unilateral versus bilateral denervations, when two to three as compared with more than three facets were denervated, nor for operations done in patients who had had previous spinal surgery compared with those who had not. Results were not better regardless of whether hyperextension of the spine aggravated the patient's preoperative pain or not, and when the procedures were repeated in the same patient outcomes tended to be consistent, arguing against repetition of failed facet denervations. The morbidity was low, the chief problem being sensory loss and transient neuropathic pain in the distribution of cutaneous branches of posterior rami in the cervical and thoracic areas; mortality was zero. CONCLUSIONS: Percutaneous radiofrequency facet denervation is simple and safe, still worth considering in patients with disabling spinal pain that fails to respond to conservative treatment. The use of general anaesthesia shortens the operating time and the patient's discomfort without impairing success rate.

Human anterior cingulate cortex neurons modulated by attention-demanding tasks.

Recent imaging studies have implicated the anterior cingulate cortex (ACC) in various cognitive functions, including attention. However, until now, there was no evidence for changes in neuronal activity of individual ACC neurons during performance of tasks that require attention and effortful thought. We hypothesized these neurons must exist in the human ACC. In this study, we present electrophysiological data from microelectrode single neuron recordings in the human ACC of neuronal modulation during attention-demanding tasks in 19% of 36 neurons tested. These findings provide the first direct evidence of an influence of a cognitive state on the spontaneous neuronal activity of human ACC neurons.

Microelectrode-guided thalamotomy for Parkinson's disease.

OBJECTIVE: To describe the outcomes in our first 40 microelectrode-guided thalamotomies for parkinsonian tremor. METHODS: Twenty-four left-sided and 16 right-sided thalamotomies were performed between October 1984 and January 1996; the mean follow-up period was 35.8 months (range, 1-152 mo). The results were evaluated retrospectively and semiquantitatively by a disinterested observer (MNL) and correlated with the quality of the microelectrode recording and the number and size of radiofrequency lesions made. The first 20 and second 20 procedures were evaluated separately. RESULTS: At the last follow-up, the Unified Parkinson's Disease Rating Scale showed no or virtually no tremor in the upper limb in 75% of patients or in the lower limb in 73% of patients. No significant persistent complications were found. These results were achieved at the expense of having to repeat the procedure on 11 sides (in 5 because of technical problems and in 6 for no obvious reason). Total or nearly total abolition of tremor occurred after the first procedure in 40% of the first 20 operations and in 65% of the second 20. Eight of the first 20 procedures and 2 of the second 20 failed for technical reasons. Lesions were made larger in the second 20 procedures than in the first 20. With the use of an electrode with a 1.1 x 3-mm bare tip for 60 seconds, it seems that lesions had to be created at 60 degrees C or more to produce a successful result. CONCLUSION: Thalamotomy with microelectrode recording is an effective procedure with which to treat tremor in patients with Parkinson's disease and may involve fewer complications than conventional techniques. The procedure appears to involve a learning curve.

Activation of the anterior cingulate cortex by thalamic stimulation in patients with chronic pain: a positron emission tomography study.

OBJECT: Deep brain stimulation (DBS) of the sensory thalamus has been used to treat chronic, intractable pain. The goal of this study was to investigate the thalamocortical pathways activated during thalamic DBS. METHODS: The authors compared positron emission tomography (PET) images obtained before, during, and after DBS in five patients with chronic pain. Two of the five patients reported significant DBS-induced pain relief during PET scanning, and the remaining three patients did not report any analgesic effect of DBS during scanning. The most robust effect associated with DBS was activation of the anterior cingulate cortex (ACC). An anterior ACC activation was sustained throughout the 40 minutes of DBS, whereas a more posteriorly located ACC activation occurred at a delay after onset of DBS, although these activations were not dependent on the degree of pain relief reported during DBS. However, implications specific to the analgesic effect of DBS require further study of a larger, more homogeneous patient population. Additional effects of thalamic DBS were detected in motor-related regions (the globus pallidus, cortical area 4, and the cerebellum) and visual and association cortical areas. CONCLUSIONS: The authors demonstrate that the ACC is activated during thalamic DBS in patients with chronic pain.

Tremor arrest with thalamic microinjections of muscimol in patients with essential tremor.

Six patients undergoing stereotactic procedures for essential tremor received microinjections of muscimol (a gamma-aminobutyric acid-A [GABA(A)] agonist) into the ventralis intermedius thalamus in areas where tremor-synchronous cells were identified electrophysiologically with microelectrode recordings and where tremor reduction occurred with electrical microstimulation. Injections of muscimol but not saline consistently reduced tremor in each patient. The effect had a mean latency of 7 minutes and lasted an average of 9 minutes. We propose that GABA-mediated thalamic neuronal inhibition may represent a mechanism underlying the effectiveness of surgery for tremor and that GABA analogues could potentially be used therapeutically.

A comparison of the burst activity of lateral thalamic neurons in chronic pain and non-pain patients.

Thalamic neurons are known to switch their firing from a tonic pattern during wakefulness to a bursting pattern during sleep. Several studies have described the existence of bursting activity in awake chronic pain patients and have suggested that this activity is abnormal and may be related to their pain. However, we have frequently observed bursting activity in awake non-pain patients suggesting that there may not be a causal relationship between thalamic bursting activity and chronic pain. To examine this issue more rigorously we compared the incidence and pattern of bursting activity of lateral thalamic neurons of both pain and non-pain patients in a state of wakefulness. Recordings were obtained from lateral thalamic areas of different groups of patients (n = 91) suffering from pain disorders (e.g. anaesthesia dolorosa, phantom limb pain, trigeminal neuralgia, post-stroke pain) and motor disorders (e.g. Parkinson's disease, essential tremor) during stereotactic surgical procedures for the treatment of pain and movement disorders. Burst indices (the number of bursting cells per electrode track) were computed for all the explorations in the two groups. The burst indices in the pain and non-pain groups (1.73 +/- 0.28 and 1.14 +/- 0.16, respectively) were not significantly different from each other. The bursts were analyzed to see if they fulfilled the criteria of low-threshold calcium spike (LTS)-evoked bursts characterized by (i) a shortening of the first interspike interval with an increase in the number of interspike intervals in the burst and also (ii) a progressive prolongation of successive interspike intervals. LTS-evoked bursts were identified in 27/47 (57%) bursting cells in pain patients and 15/32 (47%) cells in non-pain patients. These data demonstrate that the occurrence of bursting activity and of LTS-evoked bursts in the human thalamus is prevalent in both pain and non-pain patients. This suggests that the bursting activity of thalamic neurons in pain patients is not necessarily related to the occurrence of their pain.

Thalamic relay site for cold perception in humans.

The neural pathways subserving the sensation of temperature are virtually unknown. However, recent findings in the monkey suggest that the sensation of cold may be mediated by an ascending pathway relaying in the posterior part of the thalamic ventromedial nucleus (VMpo). To test this hypothesis we examined the responses of neurons to thermal stimulation of the skin and determined the perceptual effects of microstimulation in the VMpo region in awake patients undergoing functional stereotactic surgery. In 16 patients, microstimulation in the VMpo region evoked cold sensations in a circumscribed body part. Furthermore, at some of these sites thalamic neurons were found that responded to innocuous cooling of the skin area corresponding to the stimulation-evoked cold sensations. These data provide the first direct demonstration of a pathway mediating cold sensation and its location in the human thalamus.

Relationship of lesion location to clinical outcome following microelectrode-guided pallidotomy for Parkinson's disease.

The purpose of this study was to examine the relationship between lesion location and clinical outcome following globus pallidus internus (GPi) pallidotomy for advanced Parkinson's disease. Thirty-three patients were prospectively studied with extensive neurological examinations before and at 6 and 12 months following microelectrode-guided pallidotomy. Lesion location was characterized using volumetric MRI. The position of lesions within the posteroventral region of the GPi was measured, from anteromedial to posterolateral along an axis parallel to the internal capsule. To relate lesion position to clinical outcome, hierarchical multiple regression analysis was used. The variance in outcome measures that was related to preoperative scores and lesion volume was first calculated, and then the remaining variance attributable to lesion location was determined. Lesion location along the anteromedial-to-posterolateral axis within the GPi influenced the variance in total score on the Unified Parkinson's Disease Rating Scale in the postoperative 'off' period, and in 'on' period dyskinesia scores. Within the posteroventral GPi, anteromedial lesions were associated with greater improvement in 'off' period contralateral rigidity and 'on' period dyskinesia, whereas more centrally located lesions correlated with better postoperative scores of contralateral akinesia and postural instability/gait disturbance. Improvement in contralateral tremor was weakly related to lesion location, being greater with posterolateral lesions. We conclude that improvement in specific motor signs in Parkinson's disease following pallidotomy is related to lesion position within the posteroventral GPi. These findings are consistent with the known segregated but parallel organization of specific motor circuits in the basal ganglia, and may explain the variability in clinical outcome after pallidotomy and therefore have important therapeutic implications.

Variability in lesion location after microelectrode-guided pallidotomy for Parkinson's disease: anatomical, physiological, and technical factors that determine lesion distribution.

OBJECT: To understand the factors that determine the distribution of lesions after microelectrode-guided pallidotomy for Parkinson's disease, the authors quantitatively characterized lesion location in a cohort of patients who were prospectively followed to determine the effects of pallidotomy on clinical outcome. METHODS: Thirty-three patients underwent volumetric magnetic resonance (MR) imaging after surgery to allow quantitative lesion localization in relation to conventional intraventricular landmarks and, alternatively, more anatomically relevant landmarks. The validity of the method was verified in a cohort of postpallidotomy patients who underwent concurrent volumetric and stereotactic MR imaging in an external head frame. Lesions were distributed over a considerable distance in the anteroposterior (8.8 mm) and mediolateral (8.7 mm) dimensions in relation to the anterior commissure and wall of the third ventricle, respectively. Less variation was seen in lesion location in the dorsoventral dimension (4.8 mm) in relation to the intercommissural plane. CONCLUSIONS: Lesion distribution was not random: lesion locations in the anteroposterior and mediolateral dimensions were highly correlated, such that lesions were distributed from anteromedial to posterolateral, parallel to the border of the globus pallidus internus with the obliquely oriented internal capsule. The factors that led to variability in lesion location were variation in third ventricle width and the oblique anteromedial-to-posterolateral course of the internal capsule. This demonstration of variability of lesion location in a cohort of patients who experienced excellent clinical benefits and minimal postoperative complications emphasizes the importance of anatomical variations in determining lesion position and the need for physiological corroboration for correct lesion placement.

Thalamic stimulation and functional magnetic resonance imaging: localization of cortical and subcortical activation with implanted electrodes. Technical note.

The utility of functional magnetic resonance (fMR) imaging in patients with implanted thalamic electrodes has not yet been determined. The aim of this study was to establish the safety of performing fMR imaging in patients with thalamic deep brain stimulators and to determine the value of fMR imaging in detecting cortical and subcortical activity during stimulation. Functional MR imaging was performed in three patients suffering from chronic pain and two patients with essential tremor. Two of the three patients with pain had undergone electrode implantation in the thalamic sensory ventralis caudalis (Vc) nucleus and the other had undergone electrode implantation in both the Vc and the periventricular gray (PVG) matter. Patients with tremor underwent electrode implantation in the ventralis intermedius (Vim) nucleus. Functional MR imaging was performed during stimulation by using a pulse generator connected to a transcutaneous extension lead. Clinically, Vc stimulation evoked paresthesias in the contralateral body, PVG stimulation evoked a sensation of diffuse internal body warmth, and Vim stimulation caused tremor arrest. Functional images were acquired using a 1.5-tesla MR imaging system. The Vc stimulation at intensities provoking paresthesias resulted in activation of the primary somatosensory cortex (SI). Stimulation at subthreshold intensities failed to activate the SI. Additional stimulation-coupled activation was observed in the thalamus, the secondary somatosensory cortex (SII), and the insula. In contrast, stimulation of the PVG electrode did not evoke paresthesias or activate the SI, but resulted in medial thalamic and cingulate cortex activation. Stimulation in the Vim resulted in thalamic, basal ganglia, and SI activation. An evaluation of the safety of the procedure indicated that significant current could be induced within the electrode if a faulty connecting cable (defective insulation) came in contact with the patient. Simple precautions, such as inspection of wires for fraying and prevention of their contact with the patient, enabled the procedure to be conducted safely. Clinical safety was further corroborated by performing 86 MR studies in patients in whom electrodes had been implanted with no adverse clinical effects. This is the first report of the use of fMR imaging during stimulation with implanted thalamic electrodes. The authors' findings demonstrate that fMR imaging can safely detect the activation of cortical and subcortical neuronal pathways during stimulation and that stimulation does not interfere with imaging. This approach offers great potential for understanding the mechanisms of action of deep brain stimulation and those underlying pain and tremor generation.