Nucleus basalis of Meynert neuronal activity in Parkinson’s disease

J Neurosurg 132:574–582, 2020

Neuronal loss within the cholinergic nucleus basalis of Meynert (nbM) correlates with cognitive decline in dementing disorders such as Alzheimer’s disease and Parkinson’s disease (PD). In nonhuman primates, the nbM firing pattern (5–40 Hz) has also been correlated with working memory and sustained attention. In this study, authors performed microelectrode recordings of the globus pallidus pars interna (GPi) and the nbM immediately prior to the implantation of bilateral deep brain stimulation (DBS) electrodes in PD patients to treat motor symptoms and cognitive impairment, respectively. Here, the authors evaluate the electrophysiological properties of the nbM in patients with PD.

METHODS Five patients (4 male, mean age 66 ± 4 years) with PD and mild cognitive impairment underwent bilateral GPi and nbM DBS lead implantation. Microelectrode recordings were performed through the GPi and nbM along a single trajectory. Firing rates and burst indices were characterized for each neuronal population with the patient at rest and performing a sustained-attention auditory oddball task. Action potential (AP) depolarization and repolarization widths were measured for each neuronal population at rest.

RESULTS In PD patients off medication, the authors identified neuronal discharge rates that were specific to each area populated by GPi cells (92.6 ± 46.1 Hz), border cells (34 ± 21 Hz), and nbM cells (13 ± 10 Hz). During the oddball task, firing rates of nbM cells decreased (2.9 ± 0.9 to 2.0 ± 1.1 Hz, p < 0.05). During baseline recordings, the burst index for nbM cells (1.7 ± 0.6) was significantly greater than those for GPi cells (1.2 ± 0.2, p < 0.05) and border cells (1.1 ± 0.1, p < 0.05). There was no significant difference in the nbM burst index during the oddball task relative to baseline (3.4 ± 1.7, p = 0.20). With the patient at rest, the width of the depolarization phase of APs did not differ among the GPi cells, border cells, and nbM cells (p = 0.60); however, during the repolarization phase, the nbM spikes were significantly longer than those for GPi high-frequency discharge cells (p < 0.05) but not the border cells (p = 0.20).

CONCLUSIONS Neurons along the trajectory through the GPi and nbM have distinct firing patterns. The profile of nbM activity is similar to that observed in nonhuman primates and is altered during a cognitive task associated with cholinergic activation. These findings will serve to identify these targets intraoperatively and form the basis for further research to characterize the role of the nbM in cognition.

Deep brain stimulation for dementias

Neurosurg Focus 45 (2):E8, 2018

The aim of this article is to review the authors’ and published experience with deep brain stimulation (DBS) therapy for the treatment of patients with Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD).

METHODS Two targets are current topics of investigation in the treatment of AD and PDD, the fornix and the nucleus basalis of Meynert. The authors reviewed the current published clinical experience with attention to patient selection, biological rationale of therapy, anatomical targeting, and clinical results and adverse events.

RESULTS A total of 7 clinical studies treating 57 AD patients and 7 PDD patients have been reported. Serious adverse events were reported in 6 (9%) patients; none resulted in death or disability. Most studies were case reports or Phase 1/2 investigations and were not designed to assess treatment efficacy. Isolated patient experiences demonstrating improved clinical response after DBS have been reported, but no significant or consistent cognitive benefits associated with DBS treatment could be identified across larger patient populations.

CONCLUSIONS PDD and AD are complex clinical entities, with investigation of DBS intervention still in an early phase. Recently published studies demonstrate acceptable surgical safety. For future studies to have adequate power to detect meaningful clinical changes, further refinement is needed in patient selection, metrics of clinical response, and optimal stimulation parameters.

Combined thalamic and subthalamic deep brain stimulation for tremor-dominant Parkinson’s disease

Acta Neurochir (2017) 159:265–269

Deep brain stimulation (DBS) in the thalamic ventral intermediate (Vim) or the subthalamic nucleus (STN) reportedly improves medication-refractory Parkinson’s disease (PD) tremor. However, little is known about the potential synergic effects of combined Vim and STN DBS.

We describe a 79-year-old man with medication-refractory tremor-dominant PD. Bilateral Vim DBS electrode implantation produced insufficient improvement. Therefore, the patient underwent additional unilateral left-sided STN DBS. Whereas Vim or STN stimulation alone led to partial improvement, persisting tremor resolution occurred after simultaneous stimulation.

The combination of both targets may have a synergic effect and is an alternative option in suitable cases.

STN DBS for Parkinson’s disease: results from a series of ten consecutive patients implanted under general anaesthesia with intraoperative use of 3D fluoroscopy to control lead placement

Artis Zeego

Acta Neurochir (2016) 158:1783–1788

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a recognised treatment for advanced Parkinson’s disease (PD). We present our results of 10 consecutive patients implanted under general anaesthesia (GA) using intraoperative robotic three-dimensional (3D) fluoroscopy (Artis Zeego; Siemens, Erlangen, Germany).

Method Ten patients (nine men, one woman) with a mean age of 57.6 (range, 41–67) years underwent surgery between October 2013 and January 2015. The mean duration of PD was 9.2 [1–10] year. The procedure was performed under GA: placement of the stereotactic frame, implantation of the electrodes (Lead 3389; Medtronic, Minnesota,MN, USA) and 3D intraoperative fluoroscopic control (Artis Zeego) with image fusion with the preoperative MRI scans. All patients were evaluated preoperatively and 6 months postoperatively.

Results The mean operative time was 240.1 (185–325) min. Themean Unified Parkinson’s Disease Rating Scale (UPDRS) II OFF medication decreased from 23.9 preoperatively to 15.7 postoperatively. The mean OFF medication UPDRS III decreased from 41 to 11.6 and the UPDRS IV decreased from 10.6 to 7. The mean preoperative and postoperative L-Dopa doses were 1,178.5 and 696.5 mg, respectively. Two complications were recorded: one episode of transient confusion (24 h) and one internal pulse generator (IPG) infection.

Conclusions With improvement in preoperative magnetic resonance imaging (MRI) and the ability to control the position of the leads intraoperatively using Artis Zeego, we now perform this procedure under GA. Our results are comparable to others reported. The significant decrease in the duration of surgery could be associated with a reduced rate of complications (infection, loss of patient collaboration). However, this observation needs to be confirmed.

Interventional magnetic resonance imaging‑guided subthalamic nucleus deep brain stimulation for Parkinson’s disease: Patient selection


Surg Neurol Int 02-Aug-2016;7:

Interventional magnetic resonance imaging (iMRI) guided deep brain stimulation (DBS) for Parkinson’s disease (PD) has been shown to be effective. The costs of a dedicated intraoperative MRI may be prohibitive. The procedure can also be performed in a diagnostic scanner, however this presents challenges for utilization of time when the scanner is used both as a diagnostic and an interventional unit. This report outlines our novel methodology for patient selection for implantation in a diagnostic MR scanner, as an attempt to streamline the use of resources. A retrospective review of our outcomes is also presented.

Methods: DBS candidacy evaluation included a PD questionnaire‑39. Anxiety, age, difficulties in communication and body habitus were factors that were assessed in selecting patients for this technique. Eleven patients underwent iMRI‑guided DBS implantation in the subthalamic nucleus. All patients were implanted bilaterally. Unified PD rating scale (UPDRS) part III and L‑dopa dose were compared pre‑ and post‑stimulation. A cohort of 11 DBS patients not selected for iMRI‑guided DBS were also reported for comparison.

Results: For the iMRI‑guided patients, mean “Off” UPDRS III score was 47.6 (standard deviation [SD] 8.26). Postoperative “On” medication, “On” stimulation UPDRS III was 13.6 (SD 5.23). Mean preoperative L‑dopa dose was 1060 mg (SD 474.3) and mean postoperative L‑dopa dose was 320 (SD 298.3).

Conclusion: iMRI‑guided DBS is a newly emerging technique for surgical treatment of patients with PD. We present a novel scoring system for patient selection assessing anxiety, age, ability to communicate, and body habitus to identify patients who will be benefited most from this technique.

Parkinson’s disease outcomes after intraoperative CT-guided “asleep” deep brain stimulation in the globus pallidus internus

Parkinson’s disease outcomes after intraoperative CT-guided “asleep” deep brain stimulation in the globus pallidus internus

J Neurosurg 124:902–907, 2016

Recent studies show that deep brain stimulation can be performed safely and accurately without microelectrode recording or test stimulation but with the patient under general anesthesia. The procedure couples techniques for direct anatomical targeting on MRI with intraoperative imaging to verify stereotactic accuracy. However, few authors have examined the clinical outcomes of Parkinson’s disease (PD) patients after this procedure. The purpose of this study was to evaluate PD outcomes following “asleep” deep brain stimulation in the globus pallidus internus (GPi).

Methods The authors prospectively examined all consecutive patients with advanced PD who underwent bilateral GPi electrode placement while under general anesthesia. Intraoperative CT was used to assess lead placement accuracy. The primary outcome measure was the change in the off-medication Unified Parkinson’s Disease Rating Scale motor score 6 months after surgery. Secondary outcomes included effects on the 39-Item Parkinson’s Disease Questionnaire (PDQ-39) scores, on-medication motor scores, and levodopa equivalent daily dose. Lead locations, active contact sites, stimulation parameters, and adverse events were documented.

Results Thirty-five patients (24 males, 11 females) had a mean age of 61 years at lead implantation. The mean radial error off plan was 0.8 mm. Mean coordinates for the active contact were 21.4 mm lateral, 4.7 mm anterior, and 0.4 mm superior to the midcommissural point. The mean off-medication motor score improved from 48.4 at baseline to 28.9 (40.3% improvement) at 6 months (p < 0.001). The PDQ-39 scores improved (50.3 vs 42.0; p = 0.03), and the levodopa equivalent daily dose was reduced (1207 vs 1035 mg; p = 0.004). There were no significant adverse events.

Conclusions Globus pallidus internus leads placed with the patient under general anesthesia by using direct anatomical targeting resulted in significantly improved outcomes as measured by the improvement in the off-medication motor score at 6 months after surgery.

Intraoperative MRI and DBS for Parkinson disease


J Neurosurg 124:62–69, 2016

The degree of clinical improvement achieved by deep brain stimulation (DBS) is largely dependent on the accuracy of lead placement. This study reports on the evaluation of intraoperative MRI (iMRI) for adjusting deviated electrodes to the accurate anatomical position during DBS surgery and acute intracranial changes.

MethodsTwo hundred and six DBS electrodes were implanted in the subthalamic nucleus (STN) in 110 patients with Parkinson disease. All patients underwent iMRI after implantation to define the accuracy of lead placement. Fifty-six DBS electrode positions in 35 patients deviated from the center of the STN, according to the result of the initial postplacement iMRI scans. Thus, we adjusted the electrode positions for placement in the center of the STN and verified this by means of second or third iMRI scans. Recording was performed in adjusted parameters in the x-, y-, and z-axes.

ResultsFifty-six (27%) of 206 DBS electrodes were adjusted as guided by iMRI. Electrode position was adjusted on the basis of iMRI 62 times. The sum of target coordinate adjustment was -0.5 mm in the x-axis, -4 mm in the y-axis, and 15.5 mm in the z-axis; the total of distance adjustment was 74.5 mm in the x-axis, 88 mm in the y-axis, and 42.5 mm in the z-axis. After adjustment with the help of iMRI, all electrodes were located in the center of the STN. Intraoperative MRI revealed 2 intraparenchymal hemorrhages in 2 patients, brain shift in all patients, and leads penetrating the lateral ventricle in 3 patients.

ConclusionsThe iMRI technique can guide surgeons as they adjust deviated electrodes to improve the accuracy of implanting the electrodes into the correct anatomical position. The iMRI technique can also immediately demonstrate acute changes such as hemorrhage and brain shift during DBS surgery.

Electrophysiological validation of STN-SNr boundary depicted by susceptibility-weighted MRI

Electrophysiological validation of STN-SNr boundary depicted by susceptibility-weighted MRI

Acta Neurochir (2015) 157:2129–2134

Direct targeting of subthalamic nucleus (STN) without secondary electrophysiological verification during deep brain stimulation (DBS) is replacing atlas-based indirect targeting techniques. Recent groups have reported increased contrast and better delineation of STN and substantia nigra (SNr) in susceptibility-weighted imaging protocols (SWI). We aim to validate the STN-SNr boundary seen in MRISWI by correlating with intraoperative microelectrode recordings (MER) as a part of developing a multi-contrast DBSMRI planning protocol.

Methods Prospective service evaluation involving electrophysiological verification by correlation of MER trajectory and STN-SNr boundary seen in SWI in seven consecutive patients undergoing DBS surgery were analyzed. The angle of inclination of the STN-SNr boundary and DBS trajectory in the coronal plane were calculated. Considering 4-mm dispersion of a coronal 3 MER array, we predicted, measured, and correlated the depths at which each electrode engaged the boundary.

Results All central microelectrodes identified the STN-SNr boundary within 1 mm of the predicted depth with 100 % accuracy. Ninety percent of the lateral MER identified the STN-SNr boundary as predicted from SWI and angle of the encounter of the MER front.

Conclusions The study demonstrates that STN morphology can be depicted using SWI MRI and coincides reliably with the electrophysiological MER boundary. Thus, this imaging modality can be used to refine STN direct targeting protocols in DBS surgery for PD.

Stimulation sites in the subthalamic nucleus projected onto a mean 3-D atlas of the thalamus and basal ganglia


Acta Neurochir (2013) 155:1655–1660

In patients with severe forms of Parkinson’s disease (PD), deep brain stimulation (DBS) commonly targets the subthalamic nucleus (STN). Recently, the mean 3-D Morel-Atlas of the basal ganglia and the thalamus was introduced. It combines information contained in histological data from ten post-mortem brains. We were interested whether the Morel-Atlas is applicable for the visualization of stimulation sites.
In a consecutive PD patient series, we documented preoperative MRI planning, intraoperative target adjustment based on electrophysiological and neurological testing, and perioperative CT target reconstruction. The localization of the DBS electrodes and the optimal stimulation sites were projected onto the Morel-Atlas.
We included 20 patients (median age 62 years). The active contact had mean coordinates Xlat = ±12.1 mm, Yap = −1.8 mm, Zvert = −3.2 mm. There was a significant difference between the initially planned site and the coordinates of the postoperative active contact site (median 2.2 mm). The stimulation site was, on average, more anterior and more dorsal. The electrode contact used for optimal stimulation was found within the STN of the atlas in 38/40 (95 %) of implantations.
The cluster of stimulation sites in individual patients—as deduced from preoperative MR, intraoperative electrophysiology and neurological testing—showed a high degree of congruence with the atlas. The mean 3D Morel Atlas is thus a useful tool for postoperative target visualization. This represents the first clinical evaluation of the recently created atlas.

Long-term Recordings of Local Field Potentials From Implanted Deep Brain Stimulation Electrodes

Neurosurgery 71:804–814, 2012 

Deep brain stimulation (DBS) of the subthalamic nucleus is an effective treatment for Parkinson disease. However, DBS is not responsive to an individual’s disease state, and programming parameters, once established, do not change to reflect disease state. Local field potentials (LFPs) recorded from DBS electrodes are being investigated as potential biomarkers for the Parkinson disease state. However, no patient data exist about what happens to LFPs over the lifetime of the implant.

OBJECTIVE: We investigated whether LFP amplitude and response to limb movement differed between patients implanted acutely with subthalamic nucleus DBS electrodes and patients implanted 2 to 7 years previously.

METHODS: We recorded LFPs at DBS surgery time (9 subjects), 3 weeks after initial placement (9 subjects), and 2 to 7 years (median: 3.5) later during implanted programmable generator replacement (11 sides). LFP power-frequency spectra for each of 3 bipolar electrode derivations of adjacent contacts were calculated over 5-minute resting and 30-second movement epochs. Monopolar impedance data were used to evaluate trends over time.

RESULTS: There was no significant difference in b-band LFP amplitude between initial electrode implantation (OR) and 3-week post-OR times (P = .94). However, b-band amplitude was lower at implanted programmable generator replacement times than in OR (P = .008) and post-OR recordings (P = .039). Impedance measurements declined over time (P < .001).

CONCLUSION: Postoperative LFP activity can be recorded years after DBS implantation and demonstrates a similar profile in response to movement as during acute recordings, although amplitude may decrease. These results support the feasibility of constructing a closed-loop, patient-responsive DBS device based on LFP activity.

Is MRI a reliable tool to locate the electrode after deep brain stimulation surgery? Comparison study of CT and MRI for the localization of electrodes after DBS

Acta Neurochir (2010) 152:2029–2036. DOI 10.1007/s00701-010-0779-2

MRI has been utilized to localize the electrode after deep brain stimulation, but its accuracy has been questioned due to image distortion. Under the hypothesis that MRI is not adequate for evaluation of electrode position after deep brain stimulation, this study is aimed at validating the accuracy of MRI in electrode localization in comparison with CT scan. Methods Sixty one patients who had undergone STN DBS were enrolled for the analysis. Using mutual information technique, CT and MRI taken at 6 months after the operation were fused. The x and y coordinates of the centers of electrodes shown of CT and MRI were compared in the fused images to calculate average difference at five different levels. The difference of the tips of the electrodes, designated as the z coordinate, was also calculated. Results The average of the distance between the centers of the electrodes in the five levels estimated in the fused image of brain CT and MRI taken at least 6 months after STN DBS was 1.33 mm (0.1–5.8 mm). The average discrepancy of x coordinates for all five levels between MRI and CT was 0.56±0.54 mm (0–5.7 mm), the discrepancy of y coordinates was 1.06±0.59 mm (0–3.5 mm), and for the z coordinate, it was 0.98±0.52 mm (0–3.1 mm) (all p values <0.001). Notably, the average discrepancy of x coordinates at 3.5 mm below AC–PC level, i.e., at the STN level between MRI and CT, was 0.59±0.42 mm (0–2.4 mm); the discrepancy of y coordinates was 0.81±0.47 mm (0–2.9 mm) (p values<0.001). Conclusions The results suggest that there was significant discrepancy between the centers of electrodes estimated by CT and MRI after STN DBS surgery.