Intractable Parkinson's Disease Research Articles

Pedunculopontine Nucleus Degeneration Contributes to Both Motor and Non-Motor Symptoms of Parkinson's Disease.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by hypokinetic motor features; however, patients also display non-motor symptoms like sleep disorders. The standard treatment for PD is dopamine replacement with L-DOPA; however, symptoms including gait deficits and sleep disorders are unresponsive to L-DOPA. Notably, these symptoms have been linked to aberrant activity in the pedunculopontine nucleus (PPN). Of late, clinical trials involving PPN deep brain stimulation (DBS) have been employed to alleviate gait deficits. Although preclinical evidence implicating PPN cholinergic neurons in gait dysfunction was initially promising, DBS trials fell short of expected outcomes. One reason for the failure of DBS may be that the PPN is a heterogenous nucleus that consists of GABAergic, cholinergic, and glutamatergic neurons that project to a diverse array of brain structures. Second, DBS trials may have been unsuccessful because PPN neurons are susceptible to mitochondrial dysfunction, Lewy body pathology, and degeneration in PD. Therefore, pharmaceutical or gene-therapy strategies targeting specific PPN neuronal populations or projections could better alleviate intractable PD symptoms. Unfortunately, how PPN neuronal populations and their respective projections influence PD motor and non-motor symptoms remains enigmatic. Herein, we discuss normal cellular and neuroanatomical features of the PPN, the differential susceptibility of PPN neurons to PD-related insults, and we give an overview of literature suggesting a role for PPN neurons in motor and sleep deficits in PD. Finally, we identify future approaches directed towards the PPN for the treatment of PD motor and sleep symptoms.

Effect of Subthalamic Nucleus Stimulation on Pedunculopontine Nucleus Neural Activity

Background: The pedunculopontine nucleus has recently been proposed as an alternative target for deep brain stimulation for the treatment of medically intractable Parkinson's disease. The suggested indication for pedunculopontine nucleus deep brain stimulation is severe and medically intractable axial symptoms such as gait and postural impairment. Objective: Our goal in this study was to describe the effects of subthalamic nucleus stimulation on pedunculopontine nucleus electrophysiological activity. Methods: Fourteen male Wistar rats were divided into a sham stimulation group and an experimental group. In both groups, electrodes were implanted bilaterally into the subthalamic nucleus and into the right pedunculopontine nucleus. Microelectrode recordings were carried out in both groups prior to and during subthalamic nucleus stimulation. Results: Subthalamic nucleus stimulation produced no clear inhibition of neuronal firing in the pedunculopontine nucleus. However, we found that stimulation of the subthalamic nucleus at 60 Hz produces some entrainment of pedunculopontine nucleus neuronal firing and a shift of subthalamic nucleus firing patterns to more tonic and random patterns. These results are consistent with the effects of deep brain stimulation on neuronal activity in the subthalamic nucleus and globus pallidus internus. Conclusion: The result of this study provides additional evidence to improve our understanding of the mechanism of subthalamic nucleus-deep brain stimulation, and its physiological consequences.

Exploring the effect of electrical muscle stimulation as a novel treatment of intractable tremor in Parkinson's disease

BackgroundAs the pathophysiology of tremor in Parkinson disease (PD) involves a complex interaction between central and peripheral mechanisms, we propose that modulation of peripheral reflex mechanism by electrical muscle stimulation (EMS) may improve tremor temporarily. ObjectivesTo determine the efficacy of EMS as a treatment for drug resistant tremor in PD patients. MethodsThis study was a single-blinded, quasi-experimental study involving 34 PD patients with classic resting tremor as confirmed by tremor analysis. The EMS was given at 50Hz over the abductor pollicis brevis and interrosseus muscles for 10s with identified tremor parameters before and during stimulation as primary outcomes. ResultsCompared to before stimulation, we observed a significant reduction in the root mean square (RMS) of the angular velocity (p<0.001) and peak magnitude (p<0.001) of resting tremor while tremor frequency (p=0.126) and dispersion (p=0.284) remained unchanged during stimulation. The UPDRS tremor score decreased from 10.59 (SD=1.74) before stimulation to 8.85 (SD=2.19) during stimulation (p<0.001). The average percentage of improvement of the peak magnitude and RMS angular velocity was 49.57% (SD=38.89) and 43.81% (SD=33.15) respectively. 70.6% and 61.8% of patients experienced at least 30% tremor attenuation as calculated from the peak magnitude and RMS angular velocity respectively. ConclusionsOur study demonstrated the efficacy of EMS in temporarily improving resting tremor in medically intractable PD patients. Although tremor severity decreased, they were not completely eliminated and continued with a similar frequency, thus demonstrating the role of peripheral reflex mechanism in the modulation of tremor, but not as a generator. EMS should be further explored as a possible therapeutic intervention for tremor in PD.

Assessment of the Effects of Unilateral Electrode Dysfunction in Patients With Parkinson Disease Undergoing Bilateral Subthalamic Nucleus Deep Brain Stimulation

Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) is the gold standard surgical treatment for medically intractable Parkinson disease, and unilateral electrodes are reported to have beneficial effects. However, assessment of patients after electrode failure needs to be established. To assess the effects of the remaining unilateral electrode in Parkinson disease after bilateral STN-DBS. Between May 2000 and March 2009, 8 patients had unilateral STN-DBS after bilateral STN-DBS. We assessed clinical outcome by comparing the Unified Parkinson Disease Rating Scale (UPDRS) motor score, activities of daily living, levodopa-equivalent daily dosages, and quality of life according to the Short-Form 36 Health Survey between patients with unilateral and bilateral electrodes. Although ipsilateral and axial UPDRS motor scores were compromised, UPDRS motor scores contralateral to the side of the implant remained unaltered after removal of 1 electrode. Although physical aspects of quality of life declined significantly with a unilateral electrode, pain and social functioning were not significantly affected. No significant changes in activities of daily living, Hoehn and Yahr stage, or levodopa-equivalent daily dosage were observed after removal of 1 electrode. The UPDRS motor score with unilateral STN-DBS was compromised relative to bilateral STN-DBS for ipsilateral motor and axial symptoms. When 1 electrode is compromised, revision of that electrode will eventually be required, but not immediately in all patients. If a patient tolerates loss of 1 electrode according to motor score while maintaining activities of daily living and quality of life, it is possible to wait and observe the situation instead of immediately revising the electrode.

A cost analysis of intraoperative microelectrode recording during subthalamic stimulation for Parkinson's disease

Deep brain stimulation of the subthalamic nucleus is the standard of care for treating medically intractable Parkinson's disease. Although the adjunct of microelectrode recording improves the targeting accuracy of subthalamic nucleus deep brain stimulation in comparison with image guidance alone, there has been no investigation of the financial cost of intraoperative microelectrode recording. This study was performed to address this issue. A comprehensive literature search of large subthalamic nucleus deep brain stimulation series (minimum, 75 patients) was performed, revealing a mean operating room time of 223.83 minutes for unilateral and 279.79 minutes for simultaneous bilateral implantation. The baseline operating room time was derived from the published operating room time for subthalamic nucleus deep brain stimulation without microelectrode recording. The total cost (operating room, anesthesia, neurosurgery) was then calculated based on hospitals geographically representative of the entire United States. The average cost for subthalamic nucleus deep brain stimulation implantation with microelectrode recording per patient is $26,764.79 for unilateral, $33,481.43 for simultaneous bilateral, and $53,529.58 for staged bilateral. For unilateral implantation, the cost of microelectrode recording is $19,461.75, increasing the total cost by 267%. For simultaneous bilateral implantation, microelectrode recording costs $20,535.98, increasing the total cost by 159%. For staged bilateral implantation, microelectrode recording costs $38,923.49, increasing the total cost by 267%. Microelectrode recording more than doubles the cost of subthalamic nucleus deep brain stimulation for Parkinson's disease and more than triples the cost for unilateral and staged bilateral procedures. The cost burden of microelectrode recording to subthalamic nucleus deep brain stimulation requires the clinical efficacy of microelectrode recording to be proven in a prospective evidence-based manner in order to curtail the potential for excessive financial burden to the health care system.

Patient-specific models of deep brain stimulation: Influence of field model complexity on neural activation predictions

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become the surgical therapy of choice for medically intractable Parkinson's disease. However, quantitative understanding of the interaction between the electric field generated by DBS and the underlying neural tissue is limited. Recently, computational models of varying levels of complexity have been used to study the neural response to DBS. The goal of this study was to evaluate the quantitative impact of incrementally incorporating increasing levels of complexity into computer models of STN DBS. Our analysis focused on the direct activation of experimentally measureable fiber pathways within the internal capsule (IC). Our model system was customized to an STN DBS patient and stimulation thresholds for activation of IC axons were calculated with electric field models that ranged from an electrostatic, homogenous, isotropic model to one that explicitly incorporated the voltage-drop and capacitance of the electrode-electrolyte interface, tissue encapsulation of the electrode, and diffusion-tensor based 3D tissue anisotropy and inhomogeneity. The model predictions were compared to experimental IC activation defined from electromyographic (EMG) recordings from eight different muscle groups in the contralateral arm and leg of the STN DBS patient. Coupled evaluation of the model and experimental data showed that the most realistic predictions of axonal thresholds were achieved with the most detailed model. Furthermore, the more simplistic neurostimulation models substantially overestimated the spatial extent of neural activation.

Staged bilateral deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease

Several investigators have described the efficacy and safety of unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) for the treatment of Parkinson's disease (PD). Some patients who underwent unilateral STN DBS required additional surgery on the contralateral side because the unilateral treatment was insufficient. The goal of this study was to assess the efficacy and safety of staged bilateral STN DBS compared to the simultaneous bilateral procedure. Ten patients with medically intractable PD underwent staged bilateral STN DBS, and 12 patients underwent a simultaneous bilateral procedure. Clinical assessments were performed preoperatively and 6 months after the last surgery using the Unified Parkinson's Disease Rating Scale (UPDRS), motor and activity of daily living (ADL) subscores, and Hoehn and Yahr stages. Both the staged and simultaneous groups experienced significant improvement in the UPDRS motor and ADL scores, and the Hoehn and Yahr stages. There were no statistical differences between the two groups in the percent improvement in UPDRS scores. The rate of adverse events in the staged group (20%) was less than that of the simultaneous group (42%), although the difference was not statistically significant. Both the staged bilateral STN DBS and the simultaneous bilateral procedure are effective and safe treatment options, but the staged bilateral procedure may be regarded as the preferred choice for the treatment of some patients.

Deep Brain Stimulation of the Globus Pallidus Internus in the Parkinsonian Primate: Local Entrainment and Suppression of Low-Frequency Oscillations

Competing theories seek to account for the therapeutic effects of high-frequency deep brain stimulation (DBS) of the internal globus pallidus (GPi) for medically intractable Parkinson's disease. To investigate this question, we studied the spontaneous activity of 102 pallidal neurons during GPiDBS in two macaques rendered parkinsonian by administration of MPTP. Stimulation through macroelectrodes in the GPi (> or =200 microA at 150 Hz for 30 s) reduced rigidity in one animal and increased spontaneous movement in both. Novel artifact subtraction methods allowed uninterrupted single-unit recording during stimulation. GPiDBS induced phasic (78% of cells) or sustained (22%) peristimulus changes in firing in both pallidal segments. A subset of cells responded at short latency (<2 ms) in a manner consistent with antidromic driving. Later phasic increases clustered at 3- to 5-ms latency. Stimulation-induced decreases were either phasic, clustered at 1-3 ms, or sustained, showing no peristimulus modulation. Response latency and magnitude often evolved over 30 s of stimulation, but responses were relatively stable by the end of that time. GPiDBS reduced mean firing rates modestly and only in GPi (-6.9 spikes/s). Surprisingly, GPiDBS had no net effect on the prevalence or structure of burst firing. GPiDBS did reduce the prevalence of synchronized low-frequency oscillations. Some cell pairs became synchronized instead at the frequency of stimulation. Suppression of low-frequency oscillations did not require high-frequency synchronization, however, or even the presence of a significant peristimulus response. In summary, the therapeutic effects of GPiDBS may be mediated by an abolition of low-frequency synchronized oscillations as a result of phasic driving.

SURGERY FOR MOVEMENT DISORDERS

Movement disorders, such as Parkinson's disease, tremor, and dystonia, are among the most common neurological conditions and affect millions of patients. Although medications are the mainstay of therapy for movement disorders, neurosurgery has played an important role in their management for the past 50 years. Surgery is now a viable and safe option for patients with medically intractable Parkinson's disease, essential tremor, and dystonia. In this article, we provide a review of the history, neurocircuitry, indication, technical aspects, outcomes, complications, and emerging neurosurgical approaches for the treatment of movement disorders.

Unilateral deep brain stimulation of the subthalamic nucleus for Parkinson disease

The object of this study was to assess the results of unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) for management of advanced Parkinson disease (PD). A clinical series of 24 patients (mean age 71 years, range 56-80 years) with medically intractable PD, who were undergoing unilateral magnetic resonance imaging-targeted, electrophysiologically guided STN DBS, completed a battery of qualitative and quantitative outcome measures preoperatively (baseline) and postoperatively, using a modified Core Assessment Program for Intracerebral Transplantations protocol. The mean follow-up period was 9 months. Statistically significant improvement was observed in the Unified Parkinson's Disease Rating Scale (UPDRS) Part II score (18%), the total UPDRS PART III score (31%), the contralateral UPDRS Part III score (63%), and scores for axial motor features (19%), contralateral tremor (88%), rigidity (60%), bradykinesia (54%), and dyskinesia (69%), as well as the Parkinson's Disease Quality of Life questionnaire score (15%) in the on-stimulation state compared with baseline. Ipsilateral symptoms improved by approximately 15% or less. Performance on the Purdue pegboard test improved in the contralateral hand in the on-stimulation state compared with the off-stimulation state (38%, p < 0.05). The daily levodopa-equivalent dose was reduced by 21% (p = 0.018). Neuropsychological tests revealed an improvement in mental flexibility and a trend toward reduced letter fluency. There were no permanent surgical complications. Of the 16 participants with symmetrical disease, five required implantation of the DBS unit on the second side. Unilateral STN DBS is an effective and safe treatment for selected patients with advanced PD. Unilateral STN DBS provides improvement of contralateral motor symptoms of PD as well as quality of life, reduces requirements for medication, and possibly enhances mental flexibility. This method of surgical treatment may be associated with a reduced risk and may provide an alternative to bilateral STN DBS for PD, especially in older patients or patients with asymmetry of parkinsonism.

Restricted ablative lesions in motor portions of GPi in primates produce extensive loss of motor-related neurons and degeneration of the lenticular fasciculus

Deep brain stimulation (DBS) of the internal pallidum (GPi) and the subthalamic nucleus and to a lesser extent, ablative lesioning, are broadly utilized to treat patients with medically intractable Parkinson's disease and other movement disorders. Beneficial outcomes however are not uniform and adverse cognitive and behavioral are significant risks. Surgical outcomes of GPi surgeries might be improved by approaches that better account for the course of motor and non-motor pallidothalamic projections. Although several studies, including our own tracer investigations, suggest that motor projections from GPi principally form the lenticular fasciculus and non-motor projections primarily contribute to the ansa lenticularis, other schemes have perpetuated. Presently, to corroborate the course of pallidothalamic projections and to assess the feasibility of selectively targeting the motor circuit of GPi, radiofrequency lesions were placed in the motor portion of GPi in monkeys. Degenerating pallidothalamic fibers were visualized with amino cupric staining techniques and regional cell counts in GPi were compared with control hemispheres. Lesions restricted to posterior motor portions of GPi produced selective degeneration of LF and only damaged AL if the lesions extended more anteriorly. Marked secondary neuronal loss occurred well beyond the principal lesions but was mainly confined to the posterolateral motor region of GPi. These findings corroborate the original pallidothalamic outflow scheme proposed by Ranson and Ranson. Conceivably, a restrictive lesion or a DBS probe could be placed in the centroposterior portion of GPi to selectively target both local motor-related neurons and traversing pallidothalamic fibers originating from more posterior and lateral motor regions.

Validity of the 30‐item geriatric depression scale in patients with Parkinson's disease

Depression in Parkinson's disease (dPD) is difficult to diagnose because depressive symptoms can overlap with symptoms of Parkinson's disease (PD). Subject-rated scales such as the 30-item Geriatric Depression Scale (GDS) may be useful in screening for dPD. There were 57 patients (33 men, 24 women; mean age, 58.6 years [SD +/- 8.4]) enrolled in a study of pallidotomy for intractable PD who were evaluated for depression before and after surgery. Subjects were evaluated using the 17-item Hamilton Depression Rating Scale (HDRS), Structured Clinical Interview for Diagnostic and Statistical Manual-III (SCID), and the GDS. SCID was used to diagnose major depression with confirmation by an expert geropsychiatrist. Receiver-operating curves (ROC) were used to identify cutoff points with maximal discriminant validity for diagnosing dPD. A total of 213 evaluation time points were included for the 52 patients with time points that included a valid SCID diagnosis, GDS, and HDRS. A ROC established points of maximum specificity/sensitivity for the GDS at a cutoff of 9/10 (sensitivity = 0.809, specificity = 0.837, positive predictive value [PPV] = 0.584, negative predictive value [NPV] = 0.939) and for the HDRS at a cutoff of 12/13 (sensitivity = 0.810, specificity = 0.821, PPV = 0.580, NPV = 0.934). The GDS was moderately correlated with the HDRS (Pearson's r = 0.54; P < 0.001). The GDS is useful in screening for dPD. A cutoff score of 9/10 has acceptable discriminant validity for dPD, and the GDS has a moderate correlation with the HDRS in PD patients.

L'éthique au secours de la psychochirurgie ?

Recent successes of deep brain stimulation in intractable Parkinson's disease are reviving interest in a neurosurgical approach for the treatment of severe mental disorders. In April 2002, the French National Committee on Medical Ethics (NCME) gave very positive encouragement to such an approach, by arguing in favour of the progress of the techniques that have been developed, their efficacy and general safety. Is this judgement scientifically justified? Scrutinizing the argumentation exposed by the NCME reveals a quite different situation : the efficacy of “functional” neurosurgery of mental illnesses has yet to be proven ; the undesirable side-effects remain as frequent as disabling ; there has been no real major conceptual change. Psychosurgical reductionism remains attractive. Psychiatrists should worry that a national agency for medical ethics could settle such a difficult question as psychosurgery without acknowledging their experience in the matter nor showing the most elementary impartiality this requires. A question with quite serious consequences, as the history of their specialty unfortunately demonstrates.

Hypersexuality After Right Pallidotomy for Parkinson’s Disease

The authors describe hypersexuality following atypical right pallidotomy for intractable Parkinson's Disease (PD). This patient and literature review suggest important roles for the pallidum in sexual behavior and dopamine in sexual arousal.

Motor and Cognitive Sequelae of Unilateral Pallidotomy in Intractable Parkinson's Disease: Electronic Measurement of Motor Steadiness is a Useful Outcome Measure

This study examined the short-term motor and cognitive sequelae of unilateral posterolateral pallidotomy for patients with intractable Parkinson's Disease (PD). Unique to this study was the inclusion of electronic motor steadiness instrumentation among pre- and postsurgical assessment procedures. Fifteen PD patients underwent right-sided surgery and 10 underwent left-sided surgery; patients were evaluated 1 month presurgery and approximately 3 months postsurgery. Motorically, there were no significant changes in grooved pegboard or maze-drawing performances, but patients evidenced significantly improved steadiness, particularly in the hand contralateral to the side of surgery. Cognitively, there were no significant decrements on postsurgery composite variables comprised of well-known tests of attention, executive functioning, delayed memory or recognition memory; these findings were similar for patients with either left- or right-sided surgery. There was, however, a significant change in language abilities among a subset of patients. This change was evident in the decline in verbal fluency in PD patients who underwent left-sided pallidotomy, a finding that has consistently emerged in pallidotomy outcome studies. This decline is discussed in terms of evidence that suggests that the basal ganglia consist of several separate, but parallel circuits, some of which are important for cognition.

Neuropsychological and Quality of Life Changes Following Unilateral Thalamic Deep Brain Stimulation in Parkinson's Disease: A One-Year Follow-up

The long-term neuropsychological and quality of life (QOL) outcomes of unilateral thalamic deep brain stimulation (DBS) in patients with intractable Parkinson's disease (PD) have not heretofore been described. Six patients diagnosed with PD underwent unilateral DBS implantation into a verified thalamic VIM nucleus target. Participants completed presurgical neuropsychological evaluation and follow-up assessment at approximately one year postsurgery. Compared to their presurgical scores, PD patients exhibited significant improvement on measures of conceptualization, verbal memory, emotional adjustment, and QOL at one-year follow-up. A few nominal declines were observed across the battery of tests. These data provide preliminary support for the long-term neurocognitive safety and QOL improvements following thalamic stimulation in patients with PD.

Surgical Treatment of Mental Illness: Impact of Imaging

Surgical Treatment of Mental Illness: Impact of Imaging

Deep Brain Stimulation for Advanced Parkinson's Disease

Deep brain stimulation (DBS) is a new and promising technique for the treatment of movement disorders. Medically intractable Parkinson's disease (PD) is one of the most common indications for DBS. There are three possible subcortical targets for PD, depending on the symptomatology (i.e., the motor subdivision of the thalamus, the globus pallidus internus, the subthalamic nucleus [STN]). Thalamic stimulation has been well established as a safe and effective treatment for essential tremor and the tremor associated with PD. Globus pallidus internus and STN DBS are being investigated for the treatment of all the cardinal signs of PD. This article describes the pathophysiology of PD, the surgical treatment history of PD, surgical techniques used for DBS implants, and the role the perioperative nurse has in the care of the patients undergoing these procedures.

Neuropsychological Outcome Following Unilateral Stereotactic Pallidotomy in Intractable Parkinson's Disease

Neuropsychological functioning was examined at baseline and 2- to 3-month follow-up in 40 subjects with advanced Parkinson's disease (PD) who underwent unilateral posteroventral pallidotomy. Most subjects demonstrated improved verbal learning, visual memory, confrontation naming, and figural fluency at follow-up. Right pallidotomy was associated with decreased cognitive flexibility and increased verbal fluency, whereas Left pallidotomy uniquely resulted in a decline in verbal fluency. Significant motor improvement was demonstrated in both groups. Pallidotomy appears to be an effective treatment for advanced PD, providing a significant improvement in motor functioning, while resulting in few deleterious neurocognitive changes in most cases.

Clinical outcome of unilateral stereotactic pallidotomy without microelectrode recording for intractable Parkinson's disease

To study the effects of unilateral stereotactic pallidotomy performed without microelectrode recording for advanced Parkinson's disease. Stereotactic coordinates were calculated by comparing preoperative inversion recovery MRI sequences with intraoperative CT scans. Conventional stereotactic stimulation techniques were employed to confirm correct probe placement. Patients were assessed using a modified CAPIT protocol with the off-state UPDRS motor score as the primary efficacy measure. A statistically significant decline in off-state UPDRS motor scores occurred at 2months (21% improvement in 32 patients) and also at 1year postoperatively (30% improvement in 12 patients). Levodopa-induced dyskinesias on the side contralateral to surgery were reduced 97% in the cohort with 1year of follow-up. No deleterious effects of surgery on global neuropsychological functioning were seen. A major surgical complication (mild but persistent hemiparesis) occurred in one patient. We believe that stereotactic pallidotomy can be performed safely and effectively without microelectrode recording when coordinates are calculated using CT with comparison to preoperative MRI sequences.