William D. Hutchison

Pain-related neurons in the human cingulate cortex.

Although it is widely accepted that the cortex participates in pain perception, there is no direct evidence for the existence of cortical neurons that respond to noxious or painful stimuli in humans. Anatomical and neurophysiological studies in animals as well as brain imaging and evoked potential studies in humans suggest that the anterior cingulate cortex (ACC) is an important area for processing sensory information related to pain. We have now identified single neurons in ACC that respond selectively to painful thermal and mechanical stimuli, supporting a role for the ACC in pain perception.

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.

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

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

Bilateral globus pallidus stimulation for Huntington's disease

Bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) was performed in a patient with Huntingtons disease (HD) with severe chorea. Stimulation at 40 and 130Hz improved chorea. Stimulation at 130Hz slightly worsened bradykinesia overall, whereas 40Hz had little effect. A [15O] H2O positron emission tomography showed increased regional cerebral blood flow in motor decision making and execution areas more evident at 40Hz. Adjustment of stimulation parameters in GPi DBS may have the potential to optimize the motor response in HD, improving chorea without aggravating bradykinesia. Ann Neurol 2004

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.

Altered pain and temperature perception following cingulotomy and capsulotomy in a patient with schizoaffective disorder.

&NA; Recent studies have renewed interest in the role of limbic structures, such as the cingulate cortex, in nociception. To investigate the involvement of the limbic system in pain and temperature perception further, we have quantified ratings of innocuous and noxious thermal stimuli in a patient with schizoaffective disorder before and after 2 surgical procedures. Psychophysical tests were conducted at a control session prior to surgery. Postoperative test sessions were conducted up to 10 weeks after bilateral cingulotomy and for 3 months after a subsequent bilateral anterior internal capsulotomy. A contact thermal stimulator delivered ascending (39–50°C) and descending (22‐2°C) series of stimuli to the patients volar forearm. The patient was trained to rate the innocuous warmth and cold and the pain associated with each stimulus. A cold pressor test was used to obtain a measure of cold pain tolerance. Compared to pre‐operative levels, cingulotomy/capsulotomy resulted in moderately diminished warmth perception and an elevated heat pain threshold and increased ratings to suprathreshold noxious heat stimuli (hyperpathia). Prior to surgery, the patient perceived all cold stimuli as cold but not painful. However, after cingulotomy and capsulotomy, cold stimuli were rated significantly colder and stimuli less than or equal to 12°C evoked pain. Compared to normal control subjects, the patients ratings of innocuous and noxious cold stimuli were reduced pre‐operatively but elevated postoperatively and cold pain tolerance was elevated pre‐operatively but reduced postoperatively. These altered ratings of noxious heat and cold stimuli were reflected on both a pain intensity and pain affect (unpleasantness) scale. In summary, these data suggest that cingulotomy and capsulotomy disinhibited the patients noxious heat and cold appreciation. These findings provide support for a role of the cingulate cortex and frontal cortical regions in the perception of innocuous and noxious thermal stimuli and suggest that under normal conditions, these areas may act to suppress the subjective intensity of noxious heat and cold.

Levodopa response in long-term bilateral subthalamic stimulation for Parkinson's disease

Subthalamic nucleus deep brain stimulation (STN‐DBS) is effective in advanced Parkinsons disease (PD), but its effects on the levodopa response are unclear. We studied the levodopa response after long‐term STN‐DBS, STN‐DBS efficacy and predictive value of preoperative levodopa response to long‐term DBS benefit in 33 PD patients with bilateral STN‐DBS. Patients were assessed using the Unified Parkinsons Disease Rating Scale preoperatively (with and without medications) and postoperatively (without medications or stimulation, with only medications or stimulation, and with both medications and stimulation). Levodopa response significantly decreased postoperatively by 31.1% at 3 years and 32.3% at 5 years, possibly related to the reduction in medication requirement, direct STN stimulation effect or PD progression. STN‐DBS alone significantly improved motor scores (37.2% at 3 years and 35.1% at 5 years) and activities of daily living scores (27.1% at 3 years and 19.2% at 5 years). Anti‐PD drugs were significantly reduced by 47.9% at 3 years and 39.8% at 5 years. However, the magnitude of the preoperative response to levodopa did not predict DBS benefit at 3 and 5 years.

New developments in understanding the etiology of Parkinson's disease and in its treatment

Important recent advances have been made in understanding the etiology and pathogenesis of Parkinsons disease, as well as in developing novel treatments. Two newly identified genes, alpha-synuclein and parkin, have been linked to parkinsonism. In addition, disturbances to the normal basal ganglia circuits in Parkinsons patients are being described at both anatomical and physiological levels. These developments provide a strong scientific basis for novel medical and surgical strategies to treat the profound motor disturbances in patients with Parkinsons disease.

Selective enhancement of rapid eye movement sleep by deep brain stimulation of the human pons.

Animal studies suggest that rapid eye movement (REM) sleep is governed by the interaction of REM‐promoting and REM‐inhibiting nuclei in the pontomesencephalic tegmentum. The pedunculopontine nucleus is proposed to be REM promoting. Using polysomnography, we studied sleep in five parkinsonian patients undergoing unilateral pedunculopontine nucleus deep brain stimulation (DBS). We demonstrated a near doubling of nocturnal REM sleep between the DBS “off” and DBS “on” states, without significant changes in other sleep states. This represents the first demonstration that DBS can selectively modulate human sleep, and it supports an important role for the pedunculopontine nucleus region in modulating human REM sleep. Ann Neurol 2009;66:110–114