Jonathan O. Dostrovsky

Neuropathic pain: redefinition and a grading system for clinical and research purposes.

Pain usually results from activation of nociceptive afferents by actually or potentially tissue-damaging stimuli. Pain may also arise by activity generated within the nervous system without adequate stimulation of its peripheral sensory endings. For this type of pain, the International Association for the Study of Pain introduced the term neuropathic pain, defined as “pain initiated or caused by a primary lesion or dysfunction in the nervous system.” While this definition has been useful in distinguishing some characteristics of neuropathic and nociceptive types of pain, it lacks defined boundaries. Since the sensitivity of the nociceptive system is modulated by its adequate activation (e.g., by central sensitization), it has been difficult to distinguish neuropathic dysfunction from physiologic neuroplasticity. We present a more precise definition developed by a group of experts from the neurologic and pain community: pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. This revised definition fits into the nosology of neurologic disorders. The reference to the somatosensory system was derived from a wide range of neuropathic pain conditions ranging from painful neuropathy to central poststroke pain. Because of the lack of a specific diagnostic tool for neuropathic pain, a grading system of definite, probable, and possible neuropathic pain is proposed. The grade possible can only be regarded as a working hypothesis, which does not exclude but does not diagnose neuropathic pain. The grades probable and definite require confirmatory evidence from a neurologic examination. This grading system is proposed for clinical and research purposes. GLOSSARY: IASP = International Association for the Study of Pain; MS = multiple sclerosis; NeuPSIG = IASP Special Interest Group on Neuropathic Pain.

Chronic anterior thalamus stimulation for intractable epilepsy.

Summary:  Purpose: A significant number of patients with epilepsy remain poorly controlled despite antiepileptic medication (AED) treatment and are not eligible for resective surgery. Novel therapeutic methods are required to decrease seizure burden in this population. Several observations have indicated that the anterior thalamic region plays an important role in the maintenance and propagation of seizures. We investigated neuromodulation of the anterior thalamus by using deep‐brain stimulation (DBS) in patients with intractable seizures.

Mechanisms of deep brain stimulation

High frequency electrical stimulation by means of electrodes implanted into the brain (deep brain stimulation; DBS) recently has become an accepted technique for the treatment of several movement disorders and in particular for Parkinsons disease. Because the effects produced by DBS are similar to those produced by making a lesion in the same region, it has been proposed that the overall effect of DBS is to inhibit the neural activity in the region stimulated. However, whether this is actually the case is presently not known, but various mechanisms have been proposed in an attempt to explain how DBS could mimic the effects of a lesion. We describe the various mechanisms that have been proposed to account for the inhibition or disruption of the pathologic outflow by high‐frequency DBS, ranging from depolarisation block to stimulation‐evoked release of γ‐aminobutyric acid and describes preliminary findings that show that stimulation within these structures can result in inhibition.

Unilateral pedunculopontine stimulation improves falls in Parkinson's disease

Postural instability and falls are a major source of disability in patients with advanced Parkinsons disease. These problems are currently not well addressed by either pharmacotherapy nor by subthalamic nucleus deep-brain stimulation surgery. The neuroanatomical substrates of posture and gait are poorly understood but a number of important observations suggest a major role for the pedunculopontine nucleus and adjacent areas in the brainstem. We conducted a double-blinded evaluation of unilateral pedunculopontine nucleus deep-brain stimulation in a pilot study in six advanced Parkinsons disease patients with significant gait and postural abnormalities. There was no significant difference in the double-blinded on versus off stimulation Unified Parkinsons Disease Rating Scale motor scores after 3 or 12 months of continuous stimulation and no improvements in the Unified Parkinsons Disease Rating Scale part III scores compared to baseline. In contrast, patients reported a significant reduction in falls in the on and off medication states both at 3 and 12 months after pedunculopontine nucleus deep-brain stimulation as captured in the Unified Parkinsons Disease Rating Scale part II scores. Our results suggest that pedunculopontine nucleus deep-brain stimulation may be effective in preventing falls in patients with advanced Parkinsons disease but that further evaluation of this procedure is required.

Deep brain stimulation for Parkinson's disease: disrupting the disruption

Many people are disabled by Parkinsons disease (PD) despite the drug treatments that are currently available. For these patients, neurosurgery has the potential to help restore their function. The most effective neurosurgical procedures to date use electrical stimulation--deep brain stimulation (DBS)--of small targets in the brain by use of a pacemaker-like device to deliver constant stimulation. Although these operations can produce striking results, the mechanism by which delivery of electrical stimulation to targets deep in the brain can restore function in the motor system is not clear. This type of surgery probably works by interfering with and shutting down abnormal brain activity in areas where the current is delivered, such as the thalamus, globus pallidus, or the subthalamic nucleus. With this abnormal neuronal activity neutralised, motor areas of the brain can resume their function and normal movements are reinstated. Current research is aimed at elucidating how DBS works and using this information to develop better treatments for patients with PD and other neurological disorders.

Characteristics of the bursting pattern of action potentials that occurs in the thalamus of patients with central pain

Neurons in the somatosensory thalamus of patients with central pain following spinal cord injury fire in bursts of action potentials more frequently than do similar neurons in patients without pain. Furthermore, the characteristic firing pattern within these bursts is similar to that which is shown to be associated with the occurrence of calcium spikes in intracellular studies of thalamic nuclei. This finding may have significant implications for the etiology and treatment of central pain states.

Neuronal oscillations in the basal ganglia and movement disorders: evidence from whole animal and human recordings.

Neuronal oscillations underlie a number of physiological processes, such as respiration, diurnal rhythms of the sleep-wake cycle, and gait. Oscillatory activity can be observed in many different brain regions and can be synchronized across these different regions or nuclei. Oscillatory activity has

Phantom sensations generated by thalamic microstimulation

Many amputees have a sense of their missing ‘phantom’ limb. Amputation can alter the representation of the bodys surface in the cerebral cortex and thalamus,, but it is unclear how these changes relate to such phantom sensations. One possibility is that, in amputees who experience phantom sensations, the region of the thalamus that originally represented the missing limb remains functional and can give rise to phantom sensations even when some thalamic ‘limb’ neurons begin to respond to stimulation of other body regions. Here we use microelectrode recording and microstimulation during functional stereotactic mapping of the ventrocaudal thalamus in amputees to determine both the responses of the neurons to stimulation of the skin and the perceptual effects of electrical activation of these neurons. Thalamic mapping revealed an unusually large thalamic stump representation, consistent with the findings from animal experiments. We also found that thalamic stimulation in amputees with a phantom limb could evoke phantom sensations, including pain, even in regions containing neurons responsive to tactile stimulation of the stump. These findings support the hypothesis that the thalamic representation of the amputated limb remains functional in amputees with phantoms.

Pallidal neuronal activity: Implications for models of dystonia

Dystonia is a neurological syndrome involving sustained contractions of opposing muscles leading to abnormal movements and postures. Recent studies report abnormally low pallidal neuronal activity in patients with generalized dystonia, suggesting hyperkinetic disorders result from underactive basal ganglia output. We examined this hypothesis in 11 patients with segmental and generalized dystonia undergoing microelectrode exploration of the internal globus pallidus (GPi) before pallidotomy or deep brain stimulation (DBS) implantation. The mean firing rates and firing patterns were compared with those in six patients with Parkinsons disease (PD). In seven patients who underwent surgery under local anesthesia, the mean GPi firing rate was 77Hz, similar to the 74Hz observed in the PD patients. However, in three dystonic patients under propofol anesthesia, GPi mean firing rate was much reduced (31Hz), and the firing pattern was distinguished by long pauses in activity, as reported by others. Low‐dose propofol in one other dystonia patient also seemed to suppress GPi firing. These results indicate that an abnormally low basal ganglia output is not the sine qua non of dystonia. The widely accepted pathophysiological models of dystonia that propose global decreases in basal ganglia output need to be viewed with caution in light of these findings. Ann Neurol 2003

Human anterior cingulate cortex neurons encode cognitive and emotional demands.

The cortical mechanisms and substrates of cognitive and emotional demands are poorly understood. Lesion studies and functional imaging implicate the anterior cingulate cortex (ACC). The caudal ACC (cACC) has been implicated in cognitive processes such as attention, salience, interference, and response competition, mostly on the basis of neuroimaging results. To test the hypothesis that individual cACC neurons subserve these functions, we monitored neuronal activity from single cells in the cACC while subjects were engaged in a mental arithmetic task, the cognitively demanding counting Stroop task, and/or the emotional Stroop interference task. We now report the first direct measures of single neurons in humans identifying a population of cACC neurons that respond differentially or in a graded manner to cognitively demanding high- and low-conflict Stroop tasks, including those with emotional valence. These data indicate that cACC neurons may be acting as salience detectors when faced with conflict and difficult or emotional stimuli, consistent with neuroimaging results of cACC responses to abrupt sensory, novel, task-relevant, or painful stimuli.