Parkinson Disease: Eskandar EN

Gale JT, Amirnovin R, Williams ZM, Flaherty AW, Eskandar EN. · Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA. · Neurosci Biobehav Rev. · Pubmed #17466375 No free full text.

Abstract: Despite remarkable advances, the relationship between abnormal neuronal activity and the clinical manifestations of Parkinson disease (PD) remains unclear. Numerous hypotheses have emerged to explain the relationship between neuronal activity and symptoms such as tremor, rigidity and akinesia. Among these are the antagonist balance hypothesis wherein increased firing rates in the indirect pathway inhibits movement; the selectivity hypothesis wherein loss of neuronal selectivity leads to an inability to select or initiate movements; the firing pattern hypothesis wherein increased oscillation and synchronization contribute to tremor and disrupt information flow; and the learning hypothesis, wherein the basal ganglia are conceived as playing an important role in learning sensory-motor associations which is disrupted by the loss of dopamine. Deep brain stimulation (DBS) surgery provides a unique opportunity to assess these different ideas since neuronal activity can be directly recorded from PD patients. The emerging data suggest that the pathophysiologic changes include derangements in the overall firing rates, decreased neuronal selectivity, and increased neuronal oscillation and synchronization. Thus, elements of all hypotheses are present, emphasizing that the loss of dopamine results in a profound and multifaceted disruption of normal information flow through the basal ganglia that ultimately leads to the signs and symptoms of PD.

Eskandar EN, Cosgrove GR, Shinobu LA. · Massachusetts General Hospital, 15 Parkman St, ACC #331, Boston, MA 02114. · JAMA. · Pubmed #11754653 No free full text.

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Eskandar EN, Shinobu LA, Penney JB, Cosgrove GR, Counihan TJ. · Neurosurgery and Neurology Services, Movement Disorders Unit, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA. · J Neurosurg. · Pubmed #10701522 No free full text.

Abstract: OBJECT: Pallidotomy for the treatment of medically refractory Parkinson's disease (PD) has enjoyed renewed popularity. However, the optimal surgical technique, lesion location, and long-term effectiveness of pallidotomy remain subjects of debate. In this article the authors describe their surgical technique for performing pallidotomy without using microelectrode guidance, and the clinical and radiological results of this procedure. METHODS: Patients were evaluated preoperatively by using a battery of validated clinical rating scales and magnetic resonance (MR) imaging of the brain. Individuals with severe treatment-refractory idiopathic PD who were believed to be good candidates for surgery underwent computerized tomography scanning- and MR imaging-guided stereotactic pallidotomy. Intraoperative macrostimulation was used to optimize lesion placement and to avoid injury to nearby structures. Lesion location and size were calculated from MR imaging sequences of the brain obtained within the first 24 hours after surgery and again 3 months later. Clinical examinations were conducted at 1.5, 3, 6, 12, and 24 months after surgery. Seventy-five patients (mean age 61 years, range 38-79 years) underwent unilateral pallidotomy. Significant improvements were observed in the "off' period scores for the activities of daily living portion of the Unified Parkinson's Disease Rating Scale (UPDRS), the UPDRS motor scores, total "on" time, levodopa-induced dyskinesias, and contralateral tremor. These improvements were maintained 24 months postoperatively. The mean lesion volume measured on the immediate postoperative MR image was 73 +/- 5.4 mm3. Radiological analysis suggests that initial lesion volume does not predict outcome. The only permanent major complication was a single visual field defect. CONCLUSIONS: Pallidotomy performed without using microelectrode guidance is a safe and effective treatment for selected patients with medically refractory PD.

Amirnovin R, Williams ZM, Cosgrove GR, Eskandar EN. · Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Neurosurgery. · Pubmed #16543878 No free full text.

Abstract: OBJECTIVE: Subthalamic deep brain stimulation (DBS) has rapidly become the standard surgical therapy for medically refractory Parkinson disease. However, in spite of its wide acceptance, there is considerable variability in the technical approach. This study details our technique and experience in performing microelectrode recording (MER) guided subthalamic nucleus (STN) DBS in the treatment of Parkinson disease. METHODS: Forty patients underwent surgery for the implantation of 70 STN DBS electrodes. Stereotactic localization was performed using a combination of magnetic resonance and computed tomographic imaging. We used an array of three microelectrodes, separated by 2 mm, for physiological localization of the STN. The final location was selected based on MER and macrostimulation through the DBS electrode. RESULTS: The trajectory selected for the DBS electrode had an average pass through the STN of 5.6 +/- 0.4 mm on the left and 5.7 +/- 0.4 mm on the right. The predicted location was used in 42% of the cases but was modified by MER in the remaining 58%. Patients were typically discharged on the second postoperative day. Eighty-five percent of patients were sent home, 13% required short-term rehabilitation, and one patient required long-term nursing services. Seven complications occurred over 4 years. Four patients suffered small hemorrhages, one patient experienced a lead migration, one developed an infection of the pulse generator, and one patient suffered from a superficial cranial infection. CONCLUSION: Simultaneous bilateral MER-guided subthalamic DBS is a relatively safe and well-tolerated procedure. MER plays an important role in optimal localization of the DBS electrodes.

Gale JT, Shields DC, Jain FA, Amirnovin R, Eskandar EN. · Department of Neurosurgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, ACC-021, Boston, MA 02114, USA. · Brain Res. · Pubmed #19167367 No free full text.

Abstract: The pathophysiology of Parkinson disease (PD) is characterized by derangements in the discharge rates, bursting patterns, and oscillatory activity of basal ganglia (BG) neurons. In this study, subthalamic nucleus (STN) neuronal activity patterns in humans with PD were compared with that in the normal monkey during performance of similar volitional movements. Single-unit STN recordings were collected while PD patients and animals moved a joystick in the direction of targets presented on a monitor. When discharge rates in all PD human and normal monkey neurons were compared, no significant differences were observed. However, when neurons were classified by peri-movement response type (i.e., excited, inhibited, or unresponsive to movement) statistical differences were demonstrated - most significantly among PD excited neurons. Analysis of burst activity demonstrated inter- and intra-burst activities were greater in the PD human compared to the monkey irrespective of neuronal response type. Moreover, simultaneously recorded neurons in the human demonstrated consistent oscillatory synchronization at restricted frequency bands, whereas synchronized oscillatory neurons in the monkey were not restricted to distinct frequencies. During movement, discharge and burst rates were positively correlated, independent of subject or neuronal response type; however, rates and oscillatory activity were more strongly correlated in the PD human than the normal monkey. Interestingly, across all domains of analysis, STN neurons in PD demonstrated reduced response variability when compared to STN neurons in the normal monkey brain. Thus, the net effect of PD may be a reduction in the physiological degrees of freedom of BG neurons with diminished information carrying capacity.

Williams ZM, Neimat JS, Cosgrove GR, Eskandar EN. · Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, ACC-021, Boston, MA 02114, USA. · Exp Brain Res. · Pubmed #15635456 No free full text.

Abstract: Current models of basal ganglia function suggest that some manifestations of Parkinson disease (PD) arise from abnormal activity and decreased selectivity of neurons in the subthalamic nucleus (STN) and globus pallidus internus (Gpi). Our goal was to examine the timing and direction selectivity of neuronal activity relative to visually guided movements in the STN and Gpi of patients with PD. Recordings were made from 152 neurons in the STN and 33 neurons in the Gpi of awake subjects undergoing surgery for PD. Corresponding EMG data were obtained for half the cells. We employed a structured behavioral task in which the subjects used a joystick to guide a cursor to one of four targets displayed on a monitor. Each direction was tested over multiple trials. Movement-related modulation of STN activity began on average 264+/-10 ms before movement initiation and 92+/-13 ms before initial EMG activity, while modulation of Gpi activity began 204+/-21 ms before overt movement initiation. In the STN, 40% of cells demonstrated perimovement activity, and of these 64% were directionally selective. In Gpi, 45% of cells showed perimovement activity of which 80% were selective. In both nuclei, directionally selective cells had significantly lower baseline firing rates than nonselective cells (41+/-5 vs 59+/-4 spikes/s in STN, and 50+/-9 vs 74+/-15 spikes/s in Gpi). These results suggest that STN activity occurs earlier than previously reported, and that higher neuronal firing rates maybe associated with decreased direction selectivity in PD patients.

Amirnovin R, Williams ZM, Cosgrove GR, Eskandar EN. · Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114-3117, USA. · J Neurosci. · Pubmed #15601936 links to  free full text

Abstract: There is considerable evidence that abnormal oscillatory activity in the basal ganglia contributes to the pathogenesis of Parkinson's disease. However, little is known regarding the relationship of oscillations to volitional movements. Our goal was to evaluate the dynamics of oscillatory activity at rest and during movement. We performed microelectrode recordings from the subthalamic nucleus (STN) of patients undergoing deep brain stimulation surgery. During recordings, the patients used a joystick to guide a cursor to one of four targets on a monitor. We recorded 184 cells and 47 pairs of cells in 11 patients. At rest, 26 cells (14%) demonstrated significant oscillatory activity, with a mean frequency of 18 Hz. During movement, this oscillatory activity was either reduced or completely abolished in all of the cells. At rest, 18 pairs (38%) of cells in five patients exhibited synchronized oscillatory activity, with a mean frequency of 15 Hz. In 17 of the 18 pairs, both of the cells exhibited oscillations, and, in one pair, only one of the cells was oscillatory. These synchronized oscillations were also significantly decreased with movement. There was a strong inverse correlation between firing rates and oscillatory activity. As the firing rates increased with movement, there was a decrease in oscillatory activity. These findings suggest that visually guided movements are associated with a dampening and desynchronization of oscillatory activity in STN neurons. One possible explanation for these observations is that the increased cortical drive associated with movement preparation and execution leads to a transient dampening of STN oscillations, hence facilitating movement.

Williams ZM, Neimat J, Cosgrove GR, Eskandar EN. · Department of Neurosurgery, Massachusetts General Hospital, Boston 02114, USA. · Clin Neurosurg. · Pubmed #15571159 No free full text.

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Eskandar EN, Flaherty A, Cosgrove GR, Shinobu LA, Barker FG. · Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. · J Neurosurg. · Pubmed #14609166 No free full text.

Abstract: OBJECT: The surgical treatment of Parkinson disease (PD) has undergone a dramatic shift, from stereotactic ablative procedures toward deep brain stimulaion (DBS). The authors studied this process by investigating practice patterns, mortality and morbidity rates, and hospital charges as reflected in the records of a representative sample of US hospitals between 1996 and 2000. METHODS: The authors conducted a retrospective cohort study by using the Nationwide Inpatient Sample database; 1761 operations at 71 hospitals were studied. Projected to the US population, there were 1650 inpatient procedures performed for PD per year (pallidotomies, thalamotomies, and DBS), with no significant change in the annual number of procedures during the study period. The in-hospital mortality rate was 0.2%, discharge other than to home was 8.1%, and the rate of neurological complications was 1.8%, with no significant differences between procedures. In multivariate analyses, hospitals with larger annual caseloads had lower mortality rates (p = 0.002) and better outcomes at hospital discharge (p = 0.007). Placement of deep brain stimulators comprised 0% of operations in 1996 and 88% in 2000. Factors predicting placement of these devices in analyses adjusted for year of surgery included younger age, Caucasian race, private insurance, residence in higher-income areas, hospital teaching status, and smaller annual hospital caseload. In multivariate analysis, total hospital charges were 2.2 times higher for DBS (median dollar 36,000 compared with dollar 12,000, p < 0.001), whereas charges were lower at higher-volume hospitals (p < 0.001). CONCLUSIONS: Surgical treatment of PD in the US changed significantly between 1996 and 2000. Larger-volume hospitals had superior short-term outcomes and lower charges. Future studies should address long-term functional end points, cost/benefit comparisons, and inequities in access to care.

Counihan TJ, Shinobu LA, Eskandar EN, Cosgrove GR, Penney JB. · Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, USA. · Neurology. · Pubmed #11274323 No free full text.

Abstract: The authors assessed clinical outcome for up to one year after staged bilateral pallidotomy in 14 patients with advanced PD. One year after surgery, dyskinesias were virtually abolished and there were significant reductions in "off" time (67%) and activities of daily living "off" scores (24%), as well as nonsignificant reduction in "off" motor score (39%); "on" scores were unchanged. One patient developed a visual field deficit; two had transient confusion. Staged bilateral pallidotomy improves motor function in selected patients with advanced PD.