Cognitive Effects of Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease with GBA1 Pathogenic Variants.

Genetic subtyping of patients with Parkinson's disease (PD) may assist in predicting the cognitive and motor outcomes of subthalamic deep brain stimulation (STN-DBS). Practical questions were recently raised with the emergence of new data regarding suboptimal cognitive outcomes after STN-DBS in individuals with PD associated with pathogenic variants in glucocerebrosidase gene (GBA1-PD). However, a variety of gaps and controversies remain. (1) Does STN-DBS truly accelerate cognitive deterioration in GBA1-PD? If so, what is the clinical significance of this acceleration? (2) How should the overall risk-to-benefit ratio of STN-DBS in GBA1-PD be established? (3) If STN-DBS has a negative effect on cognition in GBA1-PD, how can this effect be minimized? (4) Should PD patients be genetically tested before STN-DBS? (5) How should GBA1-PD patients considering STN-DBS be counseled? We aim to summarize the currently available relevant data and detail the gaps and controversies that exist pertaining to these questions. In the absence of evidence-based data, all authors strongly agree that clinicians should not categorically deny DBS to PD patients based solely on genotype (GBA1 status). We suggest that PD patients considering DBS may be offered genetic testing for GBA1, where available and feasible, so the potential risks and benefits of STN-DBS can be properly weighed by both the patient and clinician. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Gut microbial metabolites in Parkinson's disease: Association with lifestyle, disease characteristics, and treatment status.

There is growing appreciation of the importance of the intestinal microbiota in Parkinson's disease (PD), and one potential mechanism by which the intestinal microbiota can communicate with the brain is via bacteria-derived metabolites. In this study, plasma levels of bacterial-derived metabolites including trimethylamine-N-oxide (TMAO), short chain fatty acids (SCFA), the branched chain fatty acid isovalerate, succinate, and lactate were evaluated in PD subjects (treatment naïve and treated) which were compared to (1) population controls, (2) spousal / household controls (similar lifestyle to PD subjects), and (3) subjects with multiple system atrophy (MSA). Analyses revealed an increase in the TMAO pathway in PD subjects which was independent of medication status, disease characteristics, and lifestyle. Lactic acid was decreased in treated PD subjects, succinic acid positively correlated with disease severity, and the ratio of pro-inflammatory TMAO to the putative anti-inflammatory metabolite butyric acid was significantly higher in PD subjects compared to controls indicating a pro-inflammatory shift in the metabolite profile in PD subjects. Finally, acetic and butyric acid were different between PD and MSA subjects indicating that metabolites may differentiate these synucleinopathies. In summary, (1) TMAO is elevated in PD subjects, a phenomenon independent of disease characteristics, treatment status, and lifestyle and (2) metabolites may differentiate PD and MSA subjects. Additional studies to understand the potential of TMAO and other bacterial metabolites to serve as a biomarker or therapeutic targets are warranted.

Increased Subthalamic Nucleus Deep Brain Stimulation Amplitude Impairs Inhibitory Control of Eye Movements in Parkinson's Disease.

BACKGROUND AND OBJECTIVES: Bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson's disease (PD) can have detrimental effects on eye movement inhibitory control. To investigate this detrimental effect of bilateral STN DBS, we examined the effects of manipulating STN DBS amplitude on inhibitory control during the antisaccade task. The prosaccade error rate during the antisaccade task, that is, directional errors, was indicative of impaired inhibitory control. We hypothesized that as stimulation amplitude increased, the prosaccade error rate would increase. MATERIALS AND METHODS: Ten participants with bilateral STN DBS completed the antisaccade task on six different stimulation amplitudes (including zero amplitude) after a 12-hour overnight withdrawal from antiparkinsonian medication. RESULTS: We found that the prosaccade error rate increased as stimulation amplitude increased (p < 0.01). Additionally, prosaccade error rate increased as the modeled volume of tissue activated (VTA) and STN overlap decreased, but this relationship depended on stimulation amplitude (p = 0.04). CONCLUSIONS: Our findings suggest that higher stimulation amplitude settings can be modulatory for inhibitory control. Some individual variability in the effect of stimulation amplitude can be explained by active contact location and VTA-STN overlap. Higher stimulation amplitudes are more deleterious if the active contacts fall outside of the STN resulting in a smaller VTA-STN overlap. This is clinically significant as it can inform clinical optimization of STN DBS parameters. Further studies are needed to determine stimulation amplitude effects on other aspects of cognition and whether inhibitory control deficits on the antisaccade task result in a meaningful impact on the quality of life.

A Novel DBS Paradigm for Axial Features in Parkinson's Disease: A Randomized Crossover Study.

BACKGROUND: High-frequency (130-185 Hz) deep brain stimulation (DBS) of the subthalamic nucleus is more effective for appendicular than axial symptoms in Parkinson's disease (PD). Low-frequency (60-80 Hz) stimulation (LFS) may reduce gait/balance impairment but typically results in worsening appendicular symptoms. We created a "dual-frequency" programming paradigm (interleave-interlink, IL-IL) to address both axial and appendicular symptoms. In IL-IL, 2 overlapping LFS programs are applied to the DBS lead, with the overlapping area focused on the optimal cathode. The nonoverlapping area (LFS) is thought to reduce gait/balance impairment, whereas the overlapping area (high-frequency stimulation, HFS) aims to control appendicular symptoms. METHODS: We performed a randomized, double-blind crossover trial comparing patients' previously optimized IL-IL and conventional HFS paradigms. Each arm was 2 weeks in duration. The primary outcome measure was the patient/caregiver Modified Clinical Global Impression Severity (CGI-S). Secondary outcome measures included blinded motor evaluations, timed tests, patient/caregiver questionnaires, and Personal KinetiGraphs (PKG). RESULTS: Twenty-five patients were enrolled, and 20 completed. The patient/caregiver CGI-S for gait/balance (P = 0.01) and appendicular symptom control (P = 0.001), and the blinded rater MDS-UPDRS-III (-5.22, P = 0.02), CGI-S gait/balance (P = 0.01), and CGI-S speech (P = 0.02) were better while on IL-IL. Scores on Parkinson's Disease Quality of Life (P = 0.002) and Freezing-of-Gait Questionnaires (P = 0.04) were better on IL-IL. The Timed-Up-and-Go was 9.8% faster (P = 0.01), with 11.8% reduction in steps (P = 0.001) on IL-IL. There was no difference in PKG bradykinesia (P = 0.18) or tremor (P = 0.23) between paradigms. CONCLUSIONS: Our results prompt consideration of this novel programming paradigm (IL-IL) for PD patients with axial symptom impairment as a new treatment option for both axial and appendicular symptoms. © 2020 International Parkinson and Movement Disorder Society.

Operative Technique and Workflow of Deep Brain Stimulation Surgery With Pre-existing Cochlear Implants.

BACKGROUND: Deep brain stimulation (DBS) surgery in patients with pre-existing cochlear implants (CIs) poses various challenges. We previously reported successful magnetic resonance imaging (MRI)-based, microelectrode recording (MER)-guided subthalamic DBS surgery in a patient with a pre-existing CI. Other case reports have described various DBS procedures in patients with pre-existing CIs using different techniques, leading to varying issues to address. A standardized operative technique and workflow for DBS surgery in the setting of pre-existing CIs is much needed. OBJECTIVE: To provide a standardized operative technique and workflow for DBS lead placement in the setting of pre-existing CIs. METHODS: Our operative technique is MRI-based and MER-guided, following a workflow involving coordination with a neurotology team to remove and re-implant the internal magnets of the CIs in order to safely perform DBS lead placement, altogether within a 24-h time frame. Intraoperative nonverbal communication with the patient is easily possible using a computer monitor. RESULTS: A 65-yr old woman with a 10-yr history of craniocervical dystonia and pre-existing bilateral CIs underwent successful bilateral pallidal DBS surgery at our institution. No merging errors or difficulties in targeting globus pallidus internus were experienced. Also, inactivated CIs do not interfere with MER nor with stimulation, and intraoperative communication with the patient using a computer monitor proved feasible and satisfactory. CONCLUSION: DBS procedures are safe and feasible in patients with pre-existing CIs if precautions are taken following our workflow.

The Impact of Microelectrode Recording on Lead Location in Deep Brain Stimulation for the Treatment of Movement Disorders.

OBJECTIVE: During deep brain stimulation (DBS) surgery, microelectrode recording (MER) leads to target refinement from the initial plan in 30% to 47% of hemispheres; however, it is unclear whether the DBS lead ultimately resides within the MER-optimized target in relation to initial radiographic target coordinates in these hemispheres. This study aimed to determine the frequency of discordance between radiographic and neurophysiologic nucleus and whether target optimization with MER leads to a significant change in DBS lead location away from initial target. METHODS: Consecutive cases of DBS surgery with MER using intraoperative computed tomography were included. Coordinates of initial anatomic target (AT), MER-optimized target (MER-O) and DBS lead were obtained. Hemispheres were categorized as "discordant" (D) if there was a suboptimal neurophysiologic signal despite accurate targeting of AT. Hemispheres where the first MER pass was satisfactory were deemed "concordant" (C). Coordinates and radial distances between 1) AT/MER-O; 2) MER-O/DBS; and 3) AT/DBS were calculated and compared. RESULTS: Of the 273 hemispheres analyzed, 143 (52%) were D, and 130 (48%) were C. In C hemispheres, DBS lead placement error (mean ± standard error of the mean) was 0.88 ± 0.07 mm. In D hemispheres, MER resulted in significant migration of DBS lead (mean AT-DBS error 2.11 ± 0.07 mm), and this distance was significantly greater than the distance between MER-O and DBS (2.11 vs. 1.09 mm, P < 0.05). Directional assessment revealed that the DBS lead migrated in the intended direction as determined by MER-O in D hemispheres, except when the intended direction was anterolateral. CONCLUSIONS: Discordance between radiographic and neurophysiologic target was seen in 52% of hemispheres, and MER resulted in appropriate deviation of the DBS lead toward the appropriate target. The actual value of the deviation, when compared with DBS lead placement error in C hemispheres, was, on average, small.

Optimization of Microelectrode Recording in Deep Brain Stimulation Surgery Using Intraoperative Computed Tomography.

BACKGROUND: Microelectrode recording (MER) is used to confirm targeting accuracy during deep brain stimulation (DBS) surgery. We describe a technique using intraoperative computed tomography (CT) extrapolation (iCTE) to predetermine and adjust the trajectory of the guide tube to improve microelectrode targeting accuracy. We hypothesized that this technique would decrease the number of MER tracks and operative time, while increasing the recorded length of the subthalamic nucleus (STN). METHODS: Thirty-nine patients with Parkinson's disease who underwent STN DBS before the iCTE method were compared with 33 patients undergoing STN DBS using iCTE. Before dural opening, a guide tube was inserted and rested on dura. Intraoperative computed tomography (iCT) was performed, and a trajectory was created along the guide tube and extrapolated to the target using targeting software. If necessary, headstage adjustments were made to correct for error. The guide tube was inserted, and MER was performed. iCT was performed with the microelectrode tip at the target. Coordinates were compared with planned/adjusted track coordinates. Radial error between the MER track and the planned/adjusted track was calculated. Cases before and after implementation of iCTE were compared to determine the impact of iCTE on operative time, number of MER tracks and recorded STN length. RESULTS: The use of iCTE reduced the average radial MER track error from 1.90 ± 0.12 mm (n = 54) to 0.84 ± 0.09 mm (n = 49) (P < 0.001) while reducing the operative time for bilateral lead placement from 272 ± 9 minutes (n = 30) to 233 ± 10 minutes (n = 24) (P < 0.001). The average MER tracks per hemisphere was reduced from 2.24 ± 0.13 mm (n = 66) to 1.75 ± 0.09 mm (n = 63) (P < 0.001), whereas the percentage of hemispheres requiring a single MER track for localization increased from 29% (n = 66) to 43% (n = 63). The average length of recorded STN increased from 4.01 ± 0.3 mm (n = 64) to 4.75 ± 0.28 mm (n = 56) (P < 0.05). CONCLUSION: iCTE improves microelectrode accuracy and increases the first-pass recorded length of STN, while reducing operative time. Further studies are needed to determine whether this technique leads to less morbidity and improved clinical outcomes.

Improving the accuracy of microelectrode recording in deep brain stimulation surgery with intraoperative CT.

Microelectrode recording (MER) is used to confirm electrophysiological signals within intended anatomic targets during deep brain stimulation (DBS) surgery. We describe a novel technique called intraoperative CT-guided extrapolation (iCTE) to predict the intended microelectrode trajectory and, if necessary, make corrections in real-time before dural opening. Prior to dural opening, a guide tube was inserted through the headstage and rested on dura. Intraoperative CT (iCT) was obtained, and a trajectory was extrapolated along the path of the guide tube to target depth using targeting software. The coordinates were recorded and compared to initial plan coordinates. If needed, adjustments were made using the headstage to correct for error. The guide tube was then inserted and MER ensued. At target, iCT was performed and microelectrode tip coordinates were compared with planned/adjusted track coordinates. Radial error between MER track and planned/adjusted track was calculated. For comparison, MER track error prior to the iCTE technique was assessed retrospectively in patients who underwent MER using iCT, whereby iCT was performed following completion of the first MER track. Forty-seven MER tracks were analyzed prior to iCTE (pre-iCTE), and 90 tracks were performed using the iCTE technique. There was no difference between radial error of pre-iCTE MER track and planned trajectory (2.1±0.12mm) compared to iCTE predicted trajectory and planned trajectory (1.76±0.13mm, p>0.05). iCTE was used to make trajectory adjustments which reduced radial error between the newly corrected and final microelectrode tip coordinates to 0.84±0.08mm (p<0.001). Inter-rater reliability was also tested using a second blinded measurement reviewer which showed no difference between predicted and planned MER track error (p=0.53). iCTE can predict and reduce trajectory error for microelectrode placement compared with the traditional use of iCT post MER.

Comparison of neuropathology in Parkinson's disease subjects with and without deep brain stimulation.

BACKGROUND: The aim of this postmortem study was to compare, in Parkinson's disease subjects with and without bilateral subthalamic nucleus deep brain stimulation (STN-DBS), the loss of pigmented neurons within the substantia nigra and pathological alpha-synuclein density within the SN and other brain regions. METHODS: PD subjects were identified from the Arizona Study of Aging and Neurodegenerative Disorders database (STN-DBS = 11, non-DBS = 156). Pigmented neuron loss scores within the substantia nigra as well as alpha-synuclein density scores within the substantia nigra and 9 other brain regions were compared, the latter individually and in summary as the Lewy body brain load score. RESULTS: DBS subjects had higher alpha-synuclein density scores within the substantia nigra, olfactory bulb, and locus ceruleus, as well as higher total Lewy body brain load scores when compared with non-DBS subjects. No differences in substantia nigra pigmented neuron loss scores were found. CONCLUSIONS: STN-DBS subjects tend to have higher alpha-synuclein density scores, but do not have a differential loss of substantia nigra pigmented neurons. © 2016 International Parkinson and Movement Disorder Society.

Use of intraoperative CT to predict the accuracy of microelectrode recording during deep brain stimulation surgery. A proof of concept study.

OBJECTIVES: Intraoperative computed tomography (iCT) is currently used to confirm the target location of the microelectrode (ME) during microelectrode recording (MER) and ultimate location of deep brain stimulation (DBS) leads at our institution. We evaluated whether iCT can be used to predict the trajectory and accuracy of the ME track. PATIENTS AND METHODS: Intraoperative imaging profiles of ten consecutive patients who had undergone DBS surgery were retrospectively reviewed. We found that cranial iCT, in addition to visualizing the target, also visualizes the extra-cranial segment of the guide tube (ECGT) used to insert the ME. We propose a hypothetical technique that extrapolates the trajectory of only the ECGT down to target depth using planning software. In order to provide a proof of concept analysis of this hypothetical technique, we retrospectively assessed post MER placement iCT studies and used planning software to visualize only the ECGT. An extrapolated vector was drawn along the long axis of the ECGT down to the same depth (z) as the ME. The obtained x and y coordinates were subsequently recorded and compared to the x and y coordinates of the ME tip to validate this technique. RESULTS: The average radial error between ECGT trajectory coordinates and final ME tip coordinates was 0.93±0.1mm (mean±SEM). CONCLUSION: The use of iCT to predict accuracy of microelectrode location is feasible. In the future, performing iCT before guide tube penetration of dura can allow for trajectory prediction and if needed, correction of the ME, thereby potentially improving accuracy and reducing the number of MER tracks.

Severe, Symptomatic, Self-limited Unilateral DBS Lead Edema Following Bilateral Subthalamic Nucleus Implantation: Case Report and Review of the Literature.

INTRODUCTION: Symptomatic edema around a deep-brain stimulation (DBS) lead is a rare complication of DBS surgery. Although this phenomenon is not fully understood, clinical presentation of DBS lead edema can be severe enough to prompt treatment. There is a paucity of literature on the clinical course and treatment of DBS lead edema. CASE REPORT: We present a 65-year-old man with Parkinson disease who developed unilateral DBS lead edema after bilateral subthalamic nucleus lead placement. Infectious, inflammatory, and ischemic causes were thoroughly investigated and ruled out. Clinical symptoms and radiographic changes all returned to normal with supportive care alone. CONCLUSIONS: Lead edema is a rare complication after DBS surgery. It is important to recognize the benign clinical course of DBS lead edema to counsel patients and avoid unnecessary treatment such as hardware removal.

Advances in functional neurosurgery for Parkinson's disease.

Functional neurosurgery for Parkinson's disease has become a mainstream concept with DBS as the prime modality. This article reviews the latest and, in the eyes of the authors, the most important developments in DBS, lesioning and gene therapy. In DBS, emerging advances have focused on the timing of surgery relative to disease duration and severity, and new targets, technologies, and equipment. For lesions, new ultrasound techniques are emerging based on successes in other movement disorders. Gene and cellular therapies, including stem cells, remain only in the research realm.

Pathological tremor prediction using surface electromyogram and acceleration: potential use in 'ON-OFF' demand driven deep brain stimulator design.

OBJECTIVE: We present a proof of concept for a novel method of predicting the onset of pathological tremor using non-invasively measured surface electromyogram (sEMG) and acceleration from tremor-affected extremities of patients with Parkinson's disease (PD) and essential tremor (ET). APPROACH: The tremor prediction algorithm uses a set of spectral (Fourier and wavelet) and nonlinear time series (entropy and recurrence rate) parameters extracted from the non-invasively recorded sEMG and acceleration signals. MAIN RESULTS: The resulting algorithm is shown to successfully predict tremor onset for all 91 trials recorded in 4 PD patients and for all 91 trials recorded in 4 ET patients. The predictor achieves a 100% sensitivity for all trials considered, along with an overall accuracy of 85.7% for all ET trials and 80.2% for all PD trials. By using a Pearson's chi-square test, the prediction results are shown to significantly differ from a random prediction outcome. SIGNIFICANCE: The tremor prediction algorithm can be potentially used for designing the next generation of non-invasive closed-loop predictive ON-OFF controllers for deep brain stimulation (DBS), used for suppressing pathological tremor in such patients. Such a system is based on alternating ON and OFF DBS periods, an incoming tremor being predicted during the time intervals when DBS is OFF, so as to turn DBS back ON. The prediction should be a few seconds before tremor re-appears so that the patient is tremor-free for the entire DBS ON-OFF cycle and the tremor-free DBS OFF interval should be maximized in order to minimize the current injected in the brain and battery usage.

Vocal responses to perturbations in voice auditory feedback in individuals with Parkinson's disease.

BACKGROUND: One of the most common symptoms of speech deficits in individuals with Parkinson's disease (PD) is significantly reduced vocal loudness and pitch range. The present study investigated whether abnormal vocalizations in individuals with PD are related to sensory processing of voice auditory feedback. Perturbations in loudness or pitch of voice auditory feedback are known to elicit short latency, compensatory responses in voice amplitude or fundamental frequency. METHODOLOGY/PRINCIPAL FINDINGS: Twelve individuals with Parkinson's disease and 13 age- and sex-matched healthy control subjects sustained a vowel sound (/α/) and received unexpected, brief (200 ms) perturbations in voice loudness (±3 or 6 dB) or pitch (±100 cents) auditory feedback. Results showed that, while all subjects produced compensatory responses in their voice amplitude or fundamental frequency, individuals with PD exhibited larger response magnitudes than the control subjects. Furthermore, for loudness-shifted feedback, upward stimuli resulted in shorter response latencies than downward stimuli in the control subjects but not in individuals with PD. CONCLUSIONS/SIGNIFICANCE: The larger response magnitudes in individuals with PD compared with the control subjects suggest that processing of voice auditory feedback is abnormal in PD. Although the precise mechanisms of the voice feedback processing are unknown, results of this study suggest that abnormal voice control in individuals with PD may be related to dysfunctional mechanisms of error detection or correction in sensory feedback processing.

Effect of intraoperative subthalamic nucleus DBS on human single-unit activity in the ipsilateral and contralateral subthalamic nucleus.

OBJECT: Insight may be gained into the physiological mechanisms of deep brain stimulation (DBS) by analyzing local and contralateral subthalamic nucleus (STN) single-unit activity during activation of previously placed DBS electrodes. Special techniques are required to perform such analysis due to the presence of a large stimulus artifact. The purpose of this study was to determine the effects of DBS stimulation on single unit activity acquired from patients undergoing new or revised DBS placements. METHODS: Subthalamic nucleus single unit activity was acquired from awake patients during activation of a previously implanted STN DBS electrode. Stimulation was contralateral to the recording site in 4 cases and ipsilateral in 3. Data were acquired at stimulation frequencies of 30, 60, and 130 Hz and with other stimulation parameters at clinically effective settings. Cells were included if they showed kinesthetic activity before and after the stimulation paradigm and if their action potential morphology was maintained throughout the experiment. Analysis of single-unit activity acquired before, during, and after stimulation was performed employing a time-domain algorithm to overcome the stimulus artifact. RESULTS: Both ipsilateral and contralateral acute stimulation resulted in reversible STN firing rate suppression. The degree of suppression became greater as stimulus frequency increased and was significant at 60 Hz (t-test, p < 0.05) and 130 Hz (p < 0.01). Suppression with ipsilateral 130-Hz stimulation ranged between 52.8% and 99.8%, whereas with similar contralateral STN stimulation, the range was lower (1.9%-50.3%). Return to baseline activity levels typically occurred within seconds after stimulation ended. CONCLUSIONS: Stimulation of the STN at clinically effective frequencies has an acute suppressive rather than an excitatory effect on STN single-unit activity. The effect is bilateral, even though the degree of suppression is greater on the ipsilateral than the contralateral STN. The authors' algorithm helps reveal this effect in human patients.

Selective left, right and bilateral stimulation of subthalamic nuclei in Parkinson's disease: differential effects on motor, speech and language function.

Deep brain stimulation (DBS) of the subthalamic nucleus improves the motor symptoms of Parkinson's disease, but may produce a worsening of speech and language performance at rates and amplitudes typically selected in clinical practice. The possibility that these dissociated effects might be modulated by selective stimulation of left and right STN has never been systematically investigated. To address this issue, we analyzed motor, speech and language functions of 12 patients implanted with bilateral stimulators configured for optimal motor responses. Behavioral responses were quantified under four stimulator conditions: bilateral DBS, right-only DBS, left-only DBS and no DBS. Under bilateral and left-only DBS conditions, our results exhibited a significant improvement in motor symptoms but worsening of speech and language. These findings contribute to the growing body of literature demonstrating that bilateral STN DBS compromises speech and language function and suggests that these negative effects may be principally due to left-sided stimulation. These findings may have practical clinical consequences, suggesting that clinicians might optimize motor, speech and language functions by carefully adjusting left- and right-sided stimulation parameters.

Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson's disease.

The objective of the study was to compare the pharmacokinetics, motor effects, and safety of IPX066, a novel extended-release formulation of carbidopa-levodopa, with an immediate-release carbidopa-levodopa formulation in advanced Parkinson's disease. We performed an open-label crossover study in 27 subjects with advanced Parkinson's disease experiencing motor fluctuations on levodopa therapy. Subjects were randomized 1:1 to 8 days' treatment with either immediate-release carbidopa-levodopa followed by IPX066 or IPX066 followed by immediate-release carbidopa-levodopa. Pharmacokinetic and motor assessments were undertaken on day 1 for 8 hours (following a single dose) and on day 8 for 12 hours (during multiple-dose administration). Following a single dose of IPX066 or immediate-release carbidopa-levodopa, plasma levodopa concentrations increased at a similarly rapid rate and were sustained above 50% of peak concentration for 4 hours with IPX066 versus 1.4 hours with immediate-release carbidopa-levodopa (P < .0001). Multiple-dose data showed IPX066 substantially reduced variability in plasma levodopa concentrations despite a lower dosing frequency (mean, 3.5 vs 5.4 administrations per day). In addition, total levodopa exposure during IPX066 treatment was approximately 87% higher, whereas the increase in levodopa C(max) was approximately 30% compared with immediate-release carbidopa-levodopa. Both products were well tolerated. IPX066 provided more sustained plasma levodopa concentrations than immediate-release carbidopa-levodopa. Larger, longer-term, well-controlled studies should be conducted to provide rigorous assessment of the clinical effects of IPX066.

Stereotactic techniques and perioperative management of DBS in dystonia.

This article reviews the available literature related to the surgical technique for implantation of deep brain stimulation (DBS) hardware for the treatment of dystonia. Topics covered include stereotactic targeting, selection of specific hardware components, site of placement of the cable connectors and pulse generators, and postoperative documentation of electrode location. Techniques in stereotactic neurosurgery are rapidly evolving, and there is no Class I evidence to unequivocally validate any specific technique described. Nevertheless, the guidelines provided may assist surgical teams in tailoring a rational approach to DBS implantation in dystonia.

Intraoperative neurophysiology in DBS for dystonia.

Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) has been demonstrated to be an effective therapy for the treatment of primary dystonia as well as tardive dystonia. Results for other forms of secondary dystonia have been less consistent. Although a number of target sites have been explored for the treatment of dystonia, most notably the motor thalamus, the target of choice remains the sensorimotor portion of the GPi. Although the optimal site within the GPi has not been determined, most centers agree that the optimal site involves the posteroventral lateral "sensorimotor" portion of the GPi. Microelectrode recording (MER) can be used to identify boundaries of the GPi and nearby white matter tracts, including the corticospinal tract and optic tract, and the sensorimotor GPi. However, whether or not the use of MER leads to improved outcomes compared with procedures performed without MER has not been determined. Currently, there is no evidence to support or refute the hypothesis that mapping structures with MER provides better short- or long-term outcomes. Centers using MER do not report a preference of one system over another, but there have not been any studies to compare the relative benefits or risks of using more than 1 electrode simultaneously. Comparison studies of different target structures and targeting techniques in dystonia have not been performed. Additional research, which includes comparative studies, is needed to advance our understanding and optimization of DBS targets, techniques, and approaches along with their relative benefits and risks in dystonia.