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Nucleus basalis of Meynert neuronal activity in Parkinson’s disease

Darrin J. Lee, Luka Milosevic, Robert Gramer, Sanskriti Sasikumar, Tameem M. Al-Ozzi, Philippe De Vloo, Robert F. Dallapiazza, Gavin J. B. Elias, Melanie Cohn, Suneil K. Kalia, William D. Hutchison, Alfonso Fasano, and Andres M. Lozano

OBJECTIVE

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.

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Deep brain stimulation for Parkinson’s disease: meta-analysis of results of randomized trials at varying lengths of follow-up

Alireza Mansouri, Shervin Taslimi, Jetan H. Badhiwala, Christopher D. Witiw, Farshad Nassiri, Vincent J. J. Odekerken, Rob M. A. De Bie, Suneil K. Kalia, Mojgan Hodaie, Renato P. Munhoz, Alfonso Fasano, and Andres M. Lozano

OBJECTIVE

Deep brain stimulation (DBS) is effective in the management of patients with advanced Parkinson’s disease (PD). While both the globus pallidus pars interna (GPi) and the subthalamic nucleus (STN) are accepted targets, their relative efficacy in randomized controlled trials (RCTs) has not been established beyond 12 months. The objective of this study was to conduct a meta-analysis of RCTs to compare outcomes among adults with PD undergoing DBS of GPi or STN at various time points, including 36 months of follow-up.

METHODS

The MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL databases were searched. Registries for clinical trials, selected conference proceedings, and the table of contents for selected journals were also searched. Screens were conducted independently and in duplicate. Among the 623 studies initially identified (615 through database search, 7 through manual review of bibliographies, and 1 through a repeat screen of literature prior to submission), 19 underwent full-text review; 13 of these were included in the quantitative meta-analysis. Data were extracted independently and in duplicate. The Cochrane Collaboration tool was used to assess the risk of bias. The GRADE evidence profile tool was used to assess the quality of the evidence. Motor scores, medication dosage reduction, activities of daily living, depression, dyskinesias, and adverse events were compared. The influence of disease duration (a priori) and the proportion of male patients within a study (post hoc) were explored as potential subgroups.

RESULTS

Thirteen studies (6 original cohorts) were identified. No difference in motor scores or activities of daily living was identified at 36 months. Medications were significantly reduced with STN stimulation (5 studies, weighted mean difference [WMD] −365.46, 95% CI −599.48 to −131.44, p = 0.002). Beck Depression Inventory scores were significantly better with GPi stimulation (3 studies; WMD 2.53, 95% CI 0.99–4.06 p = 0.001). The motor benefits of GPi and STN DBS for PD are similar.

CONCLUSIONS

The motor benefits achieved with GPi and STN DBS for PD are similar. DBS of STN allows for a greater reduction of medication, but not as significant an advantage as DBS of GPi with respect to mood. This difference is sustained at 36 months. Further long-term studies are necessary.

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Bilateral deep brain stimulation of the fornix for Alzheimer's disease: surgical safety in the ADvance trial

Francisco A. Ponce, Wael F. Asaad, Kelly D. Foote, William S. Anderson, G. Rees Cosgrove, Gordon H. Baltuch, Kara Beasley, Donald E. Reymers, Esther S. Oh, Steven D. Targum, Gwenn S. Smith, Constantine G. Lyketsos, and Andres M. Lozano

OBJECT

This report describes the stereotactic technique, hospitalization, and 90-day perioperative safety of bilateral deep brain stimulation (DBS) of the fornix in patients who underwent DBS for the treatment of mild, probable Alzheimer's disease (AD).

METHODS

The ADvance Trial is a multicenter, 12-month, double-blind, randomized, controlled feasibility study being conducted to evaluate the safety, efficacy, and tolerability of DBS of the fornix in patients with mild, probable AD. Intraoperative and perioperative data were collected prospectively. All patients underwent postoperative MRI. Stereotactic analyses were performed in a blinded fashion by a single surgeon. Adverse events (AEs) were reported to an independent clinical events committee and adjudicated to determine the relationship between the AE and the study procedure.

RESULTS

Between June 6, 2012, and April 28, 2014, a total of 42 patients with mild, probable AD were treated with bilateral fornix DBS (mean age 68.2 ± 7.8 years; range 48.0–79.7 years; 23 men and 19 women). The mean planned target coordinates were x = 5.2 ± 1.0 mm (range 3.0–7.9 mm), y = 9.6 ± 0.9 mm (range 8.0–11.6 mm), z = −7.5 ± 1.2 mm (range −5.4 to −10.0 mm), and the mean postoperative stereotactic radial error on MRI was 1.5 ± 1.0 mm (range 0.2–4.0 mm). The mean length of hospitalization was 1.4 ± 0.8 days. Twenty-six (61.9%) patients experienced 64 AEs related to the study procedure, of which 7 were serious AEs experienced by 5 patients (11.9%). Four (9.5%) patients required return to surgery: 2 patients for explantation due to infection, 1 patient for lead repositioning, and 1 patient for chronic subdural hematoma. No patients experienced neurological deficits as a result of the study, and no deaths were reported.

CONCLUSIONS

Accurate targeting of DBS to the fornix without direct injury to it is feasible across surgeons and treatment centers. At 90 days after surgery, bilateral fornix DBS was well tolerated by patients with mild, probable AD.

Clinical trial registration no.: NCT01608061 (clinicaltrials.gov)

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Clinical outcomes and complications of peripheral nerve field stimulation in the management of refractory trigeminal pain: a systematic review and meta-analysis

Can Sarica, Christian Iorio-Morin, David H. Aguirre-Padilla, Michelle Paff, Samuelle-Arianne Villeneuve, Artur Vetkas, Kazuaki Yamamoto, Nardin Samuel, Vanessa Milano, Aaron Loh, Brendan Santyr, Ajmal Zemmar, Andres M. Lozano, and Mojgan Hodaie

OBJECTIVE

Peripheral nerve field stimulation (PNFS) is a tool in the armamentarium of treatment options for trigeminal pain. The efficacy of this modality in mitigating trigeminal pain remains unclear. The aim of this study was to examine the existing literature on PNFS and elucidate pain score outcomes associated with its use in patients with trigeminal pain.

METHODS

A systematic review and meta-analysis was performed in accordance with the PRISMA framework. The PubMed, Web of Science, and Scopus databases were queried on June 10, 2020. Studies reporting pain outcomes in more than 5 adult patients treated with PNFS for facial pain were included. The primary outcome of the study was the mean difference in the visual analog scale (VAS) score from the last follow-up to baseline, and it was analyzed by an inverse-variance, random-effect model. The risk of bias was assessed using the Newcastle-Ottawa Scale and a funnel plot.

RESULTS

Of the 4597 studies screened for inclusion, 46 relevant full-text articles were assessed for eligibility. Eleven observational cohort studies from the 46 articles were found to be eligible, and reported on a total of 109 patients. In 86% (94/109) of cases, trial stimulation was successful and followed by a permanent system implantation. VAS scores improved by 75% (mean difference 6.32/10 points, 95% CI 5.38–7.27 points) compared to baseline. Seventy-six percent (42/55) of patients became medication free or required lower doses of medications. The complication rate necessitating surgical revision was estimated at 32% per procedure.

CONCLUSIONS

These findings support the belief that PNFS provides effective, long-term pain control for trigeminal pain. Statistical heterogeneity was considerable across all studies. Future work should be aimed at conducting double-blind randomized controlled trials to determine the utility of PNFS for treating various forms of trigeminal pain for which limited therapeutic options exist.

Open access

Magnetic resonance imaging–guided focused ultrasound thalamotomy for essential tremor: 5-year follow-up results

G. Rees Cosgrove, Nir Lipsman, Andres M. Lozano, Jin Woo Chang, Casey Halpern, Pejman Ghanouni, Howard Eisenberg, Paul Fishman, Takaomi Taira, Michael L. Schwartz, Nathan McDannold, Michael Hayes, Susie Ro, Binit Shah, Ryder Gwinn, Veronica E. Santini, Kullervo Hynynen, and W. Jeff Elias

OBJECTIVE

The objective of this study was to evaluate, at 4 and 5 years posttreatment, the long-term safety and efficacy of unilateral MRI-guided focused ultrasound (MRgFUS) thalamotomy for medication-refractory essential tremor in a cohort of patients from a prospective, controlled, multicenter clinical trial.

METHODS

Outcomes per the Clinical Rating Scale for Tremor (CRST), including postural tremor scores (CRST Part A), combined hand tremor/motor scores (CRST Parts A and B), and functional disability scores (CRST Part C), were measured by a qualified neurologist. The Quality of Life in Essential Tremor Questionnaire (QUEST) was used to assess quality of life. CRST and QUEST scores at 48 and 60 months post-MRgFUS were compared to those at baseline to assess treatment efficacy and durability. All adverse events (AEs) were reported.

RESULTS

Forty-five and 40 patients completed the 4- and 5-year follow-ups, respectively. CRST scores for postural tremor (Part A) for the treated hand remained significantly improved by 73.3% and 73.1% from baseline at both 48 and 60 months posttreatment, respectively (both p < 0.0001). Combined hand tremor/motor scores (Parts A and B) also improved by 49.5% and 40.4% (p < 0.0001) at each respective time point. Functional disability scores (Part C) increased slightly over time but remained significantly improved through the 5 years (p < 0.0001). Similarly, QUEST scores remained significantly improved from baseline at year 4 (p < 0.0001) and year 5 (p < 0.0003). All previously reported AEs remained mild or moderate, and no new AEs were reported.

CONCLUSIONS

Unilateral MRgFUS thalamotomy demonstrates sustained and significant tremor improvement at 5 years with an overall improvement in quality-of-life measures and without any progressive or delayed complications.

Clinical trial registration no.: NCT01827904 (ClinicalTrials.gov)

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A literature review of magnetic resonance imaging sequence advancements in visualizing functional neurosurgery targets

Alexandre Boutet, Aaron Loh, Clement T. Chow, Alaa Taha, Gavin J. B. Elias, Clemens Neudorfer, Jurgen Germann, Michelle Paff, Ludvic Zrinzo, Alfonso Fasano, Suneil K. Kalia, Christopher J. Steele, David Mikulis, Walter Kucharczyk, and Andres M. Lozano

OBJECTIVE

Historically, preoperative planning for functional neurosurgery has depended on the indirect localization of target brain structures using visible anatomical landmarks. However, recent technological advances in neuroimaging have permitted marked improvements in MRI-based direct target visualization, allowing for refinement of “first-pass” targeting. The authors reviewed studies relating to direct MRI visualization of the most common functional neurosurgery targets (subthalamic nucleus, globus pallidus, and thalamus) and summarize sequence specifications for the various approaches described in this literature.

METHODS

The peer-reviewed literature on MRI visualization of the subthalamic nucleus, globus pallidus, and thalamus was obtained by searching MEDLINE. Publications examining direct MRI visualization of these deep brain stimulation targets were included for review.

RESULTS

A variety of specialized sequences and postprocessing methods for enhanced MRI visualization are in current use. These include susceptibility-based techniques such as quantitative susceptibility mapping, which exploit the amount of tissue iron in target structures, and white matter attenuated inversion recovery, which suppresses the signal from white matter to improve the distinction between gray matter nuclei. However, evidence confirming the superiority of these sequences over indirect targeting with respect to clinical outcome is sparse. Future targeting may utilize information about functional and structural networks, necessitating the use of resting-state functional MRI and diffusion-weighted imaging.

CONCLUSIONS

Specialized MRI sequences have enabled considerable improvement in the visualization of common deep brain stimulation targets. With further validation of their ability to improve clinical outcomes and advances in imaging techniques, direct visualization of targets may play an increasingly important role in preoperative planning.

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A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression

Clinical article

Andres M. Lozano, Peter Giacobbe, Clement Hamani, Sakina J. Rizvi, Sidney H. Kennedy, Theodore T. Kolivakis, Guy Debonnel, Abbas F. Sadikot, Raymond W. Lam, Andrew K. Howard, Magda Ilcewicz-Klimek, Christopher R. Honey, and Helen S. Mayberg

Object

Deep brain stimulation (DBS) has been recently investigated as a treatment for major depression. One of the proposed targets for this application is the subcallosal cingulate gyrus (SCG). To date, promising results after SCG DBS have been reported by a single center. In the present study the authors investigated whether these findings may be replicated at different institutions. They conducted a 3-center prospective open-label trial of SCG DBS for 12 months in patients with treatment-resistant depression.

Methods

Twenty-one patients underwent implantation of bilateral SCG electrodes. The authors examined the reduction in Hamilton Rating Scale for Depression (HRSD-17) score from baseline (RESP50).

Results

Patients treated with SCG DBS had an RESP50 of 57% at 1 month, 48% at 6 months, and 29% at 12 months. The response rate after 12 months of DBS, however, increased to 62% when defined as a reduction in the baseline HRSD-17 of 40% or more. Reductions in depressive symptomatology were associated with amelioration in disease severity in patients who responded to surgery.

Conclusions

Overall, findings from this study corroborate the results of previous reports showing that outcome of SCG DBS may be replicated across centers.

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Deep brain stimulation for extreme behaviors associated with autism spectrum disorder converges on a common pathway: a systematic review and connectomic analysis

Han Yan, Lior M. Elkaim, Flavia Venetucci Gouveia, Joelene F. Huber, Jurgen Germann, Aaron Loh, Juan Carlos Benedetti-Isaac, Paresh K. Doshi, Cristina V. Torres, David J. Segar, Gavin J. B. Elias, Alexandre Boutet, G. Rees Cosgrove, Alfonso Fasano, Andres M. Lozano, Abhaya V. Kulkarni, and George M. Ibrahim

OBJECTIVE

Individuals with autism spectrum disorder (ASD) may display extreme behaviors such as self-injury or aggression that often become refractory to psychopharmacology or behavioral intervention. Deep brain stimulation (DBS) is a surgical alternative that modulates brain circuits that have yet to be clearly elucidated. In the current study the authors performed a connectomic analysis to identify brain circuitry engaged by DBS for extreme behaviors associated with ASD.

METHODS

A systematic review was performed to identify prior reports of DBS as a treatment for extreme behaviors in patients with ASD. Individual patients’ perioperative imaging was collected from corresponding authors. DBS electrode localization and volume of tissue activated modeling were performed. Volumes of tissue activated were used as seed points in high-resolution normative functional and structural imaging templates. The resulting individual functional and structural connectivity maps were pooled to identify networks and pathways that are commonly engaged by all targets.

RESULTS

Nine patients with ASD who were receiving DBS for symptoms of aggression or self-injurious behavior were identified. All patients had some clinical improvement with DBS. Connectomic analysis of 8 patients (from the systematic review and unpublished clinical data) demonstrated a common anatomical area of shared circuitry within the anterior limb of the internal capsule. Functional analysis of 4 patients identified a common network of distant brain areas including the amygdala, insula, and anterior cingulate engaged by DBS.

CONCLUSIONS

This study presents a comprehensive synopsis of the evidence for DBS in the treatment of extreme behaviors associated with ASD. Using network mapping, the authors identified key circuitry common to DBS targets.

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Safety assessment of spine MRI in deep brain stimulation patients

Alexandre Boutet, Gavin J. B. Elias, Robert Gramer, Clemens Neudorfer, Jürgen Germann, Asma Naheed, Nicole Bennett, Bryan Li, Dave Gwun, Clement T. Chow, Ricardo Maciel, Alejandro Valencia, Alfonso Fasano, Renato P. Munhoz, Warren Foltz, David Mikulis, Ileana Hancu, Suneil K. Kalia, Mojgan Hodaie, Walter Kucharczyk, and Andres M. Lozano

OBJECTIVE

Many centers are hesitant to perform clinically indicated MRI in patients who have undergone deep brain stimulation (DBS). Highly restrictive guidelines prohibit the use of most routine clinical MRI protocols in these patients. The authors’ goals were to assess the safety of spine MRI in patients with implanted DBS devices, first through phantom model testing and subsequently through validation in a DBS patient cohort.

METHODS

A phantom was used to assess DBS device heating during 1.5-T spine MRI. To establish a safe spine protocol, routinely used clinical sequences deemed unsafe (a rise in temperature > 2°C) were modified to decrease the rise in temperature. This safe phantom-based protocol was then used to prospectively run 67 spine MRI sequences in 9 DBS participants requiring clinical imaging. The primary outcome was acute adverse effects; secondary outcomes included long-term adverse clinical effects, acute findings on brain MRI, and device impedance stability.

RESULTS

The increases in temperature were highest when scanning the cervical spine and lowest when scanning the lumbar spine. A temperature rise < 2°C was achieved when 3D sequences were modified to 2D and when the number of slices was decreased by the minimum amount compared to routine spine MRI protocols (but there were still more slices than allowed by vendor guidelines). Following spine MRI, no acute or long-term adverse effects or acute findings on brain MR images were detected. Device impedances remained stable.

CONCLUSIONS

Patients with DBS devices may safely undergo spine MRI with a fewer number of slices compared to those used in routine clinical protocols. Safety data acquisition may allow protocols outside vendor guidelines with a maximized number of slices, reducing the need for radiologist supervision.

Clinical trial registration no.: NCT03753945 (ClinicalTrials.gov).

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Successful magnetic resonance–guided focused ultrasound treatment of tremor in patients with a skull density ratio of 0.4 or less

Artur Vetkas, Alexandre Boutet, Can Sarica, Jurgen Germann, Dave Gwun, Kazuaki Yamamoto, Hyun Ho Jung, Afnan Alkhotani, Nardin Samuel, Stefan Lang, Christopher R. Conner, Gavin J. B. Elias, Cletus Cheyuo, Clement Chow, Brendan Santyr, Christian Iorio-Morin, Andrew Z. Yang, Carolina Candeias da Silva, Alfonso Fasano, Suneil K. Kalia, and Andres M. Lozano

OBJECTIVE

The use of magnetic resonance–guided focused ultrasound (MRgFUS) for the treatment of tremor-related disorders and other novel indications has been limited by guidelines advocating treatment of patients with a skull density ratio (SDR) above 0.45 ± 0.05 despite reports of successful outcomes in patients with a low SDR (LSDR). The authors’ goal was to retrospectively analyze the sonication strategies, adverse effects, and clinical and imaging outcomes in patients with SDR ≤ 0.4 treated for tremor using MRgFUS.

METHODS

Clinical outcomes and adverse effects were assessed at 3 and 12 months after MRgFUS. Outcomes and lesion location, volume, and shape characteristics (elongation and eccentricity) were compared between the SDR groups.

RESULTS

A total of 102 consecutive patients were included in the analysis, of whom 39 had SDRs ≤ 0.4. No patient was excluded from treatment because of an LSDR, with the lowest being 0.22. Lesioning temperatures (> 52°C) and therapeutic ablations were achieved in all patients. There were no significant differences in clinical outcome, adverse effects, lesion location, and volume between the high SDR group and the LSDR group. SDR was significantly associated with total energy (rho = −0.459, p < 0.001), heating efficiency (rho = 0.605, p < 0.001), and peak temperature (rho = 0.222, p = 0.025).

CONCLUSIONS

The authors’ results show that treatment of tremor in patients with an LSDR using MRgFUS is technically possible, leading to a safe and lasting therapeutic effect. Limiting the number of sonications and adjusting the energy and duration to achieve the required temperature early during the treatment are suitable strategies in LSDR patients.