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Hiroki Toda, Clement Hamani and Andres Lozano

Deep brain stimulation (DBS) has become a mainstay of treatment for patients with movement disorders. This modality is directed at modulating pathological activity within basal ganglia output structures by stimulating some of their nuclei, such as the subthalamic nucleus (STN) and the globus pallidus internus (GPi), without making permanent lesions. With the accumulation of experience, indications for the use of DBS have become clearer and the effectiveness and limitations of this form of therapy in different clinical conditions have been better appreciated. In this review the authors discuss the efficacy of DBS in the treatment of dystonia and levodopa-induced dyskinesias. The use of DBS of the STN and GPi is very effective for the treatment of movement disorders induced by levodopa. The relative benefits of using the GPi as opposed to the STN as a target are still being investigated. Bilateral GPi stimulation is gaining importance in the therapeutic armamentarium for the treatment of dystonia. The DYT1 forms of generalized dystonia and cervical dystonias respond to DBS better than secondary dystonia does. Discrimination between the diverse forms of dystonia and a better understanding of the pathophysiological features of this condition will serve as a platform for improved outcomes.

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Jason A. Brodkey, Ronald R. Tasker, Clement Hamani, Mary Pat McAndrews, Jonathan O. Dostrovsky and Andres M. Lozano

Object. Thalamic neurons firing at frequencies synchronous with tremor are thought to play a critical role in the generation and maintenance of tremor. The authors studied the incidence and locations of neurons with tremor-related activity (TRA) in the thalamus of patients with varied pathological conditions—including Parkinson disease (PD), essential tremor (ET), multiple sclerosis (MS), and cerebellar disorders—to determine whether known differences in the effectiveness of thalamic stereotactic procedures for these tremors could be correlated to differences in the incidence or locations of TRA cells.

Methods. Seventy-five operations were performed in 61 patients during which 686 TRA cells were recorded from 440 microelectrode trajectories in the thalamus. The locations of the TRA cells in relation to electrophysiologically defined thalamic nuclei and the commissural coordinates were compared among patient groups.

The authors found that TRA cells are present in patients with each of these disorders and that these cells populate several nuclei in the ventral lateral tier of the thalamus. There were no large differences in the locations of TRA cells among the different diagnostic classes, although there was a difference in the incidence of TRA cells in patients with PD, who had greater than 3.8 times more cells per thalamic trajectory than patients with ET and approximately five times more cells than patients with MS or cerebellar disorders.

Conclusions. There was an increased incidence of TRA in the thalamus of patients with PD. The location of thalamic TRA cells in patients with basal ganglia and other tremor disorders was similar.

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Hiroki Toda, Clement Hamani, Adrian P. Fawcett, William D. Hutchison and Andres M. Lozano

Object

To examine the influence of deep brain stimulation on hippocampal neurogenesis in an adult rodent model.

Methods

Rats were anesthetized and treated for 1 hour with electrical stimulation of the anterior nucleus of the thalamus (AN) or sham surgery. The animals were injected with 5′-bromo-2′-deoxyuridine (BrdU) 1–7 days after surgery and killed 24 hours or 28 days later. The authors counted the BrdU-positive cells in the dentate gyrus (DG) of the hippocampus. To investigate the fate of these cells, they also stained sections for doublecortin, NeuN, and GFAP and analyzed the results with confocal microscopy. In a second set of experiments they assessed the number of DG BrdU-positive cells in animals treated with corticosterone (a known suppressor of hippocampal neurogenesis) and sham surgery, corticosterone and AN stimulation, or vehicle and sham surgery.

Results

Animals receiving AN high-frequency stimulation (2.5 V, 90 μsec, 130 Hz) had a 2- to 3-fold increase in the number of DG BrdU-positive cells compared with nonstimulated controls. This increase was not seen with stimulation at 10 Hz. Most BrdU-positive cells assumed a neuronal cell fate. As expected, treatment with corticosterone significantly reduced the number of DG BrdU-positive cells. This steroid-induced reduction of neurogenesis was reversed by AN stimulation.

Conclusions

High-frequency stimulation of the AN increases the hippocampal neurogenesis and restores experimentally suppressed neurogenesis. Interventions that increase hippocampal neurogenesis have been associated with enhanced behavioral performance. In this context, it may be possible to use electrical stimulation to treat conditions associated with impairment of hippocampal function.

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Denys Fontaine, Clement Hamani and Andres Lozano

Object

The authors systematically reviewed the published literature to evaluate the efficacy of and adverse effects after motor cortex stimulation (MCS) for chronic neuropathic pain.

Methods

A search of the PubMed database (1991–2006) using the key words “motor cortex,” “stimulation,” and “pain” yielded 244 articles. Only original nonduplicated articles were selected for further analysis; 14 studies were identified for critical review. All were series of cases and none was controlled. The outcomes in 210 patients were assessed and expressed as the percentage of patients that improved with the procedure.

Results

A good response to MCS (pain relief ≥ 40–50%) was observed in ~ 55% of patients who underwent surgery and in 45% of the 152 patients with a postoperative follow-up ≥ 1 year. Visual analog scale scores were provided in 76 patients, revealing an average 57% improvement in the 41 responders. A good response was achieved in 54% of the 117 patients with central pain and 68% of the 44 patients with trigeminal neuropathic pain. Adverse effects were reported in 10 studies, including 157 patients. Infections (5.7%) and hardware-related problems (5.1%) were relatively common complications. Seizures occurred in 19 patients (12%) in the early postoperative period, but no chronic epilepsy was reported.

Conclusions

The results of the authors' review of the literature suggest that MCS is safe and effective in the treatment of chronic neuropathic pain. Results must be considered with caution, however, as none of the trials were blinded or controlled. Studies with a better design are mandatory to confirm the efficacy of MCS for chronic neuropathic pain.

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Nasir Raza Awan, Andres Lozano and Clement Hamani

Deep brain stimulation (DBS) has been used to treat various neurological and psychiatric disorders. Over the years, the most suitable surgical candidates and targets for some of these conditions have been characterized and the benefits of DBS well demonstrated in double-blinded randomized trials. This review will discuss some of the areas of current investigation and potential new applications of DBS.

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Clement Hamani, Helen Mayberg, Brian Snyder, Peter Giacobbe, Sidney Kennedy and Andres M. Lozano

Object

Deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG), including Brodmann area 25, is currently being investigated for the treatment of major depressive disorder (MDD). As a potential emerging therapy, optimal target selection within the SCG has still to be determined. The authors compared the location of the electrode contacts in responders and nonresponders to DBS of the SCG and correlated the results with clinical outcome to help in identifying the optimal target within the region. Based on the location of the active contacts used for long-term stimulation in responders, the authors suggest a standardized method of targeting the SCG in patients with MDD.

Methods

Postoperative MR imaging studies of 20 patients with MDD treated with DBS of the SCG were analyzed. The authors assessed the location of the active contacts relative to the midcommissural point and in relation to anatomical landmarks within the medial aspect of the frontal lobe. For this, a grid with 2 main lines was designed, with 1 line in the anterior-posterior and 1 line in the dorsal-ventral axis. Each of these lines was divided into 100 units, and data were converted into percentages. The anterior-posterior line extended from the anterior commissure (AC) to the projection of the anterior aspect of the corpus callosum (CCa). The dorsal-ventral line extended from the inferior portion of the CC (CCi) to the most ventral aspect of the frontal lobe (abbreviated “Fr” for the formula).

Results

Because the surgical technique did not vary across patients, differences in stereotactic coordinates between responders and nonresponders did not exceed 1.5 mm in any axis (x, y, or z). In patients who responded to the procedure, contacts used for long-term stimulation were in close approximation within the SCG. In the anterior-posterior line, these contacts were located within a 73.2 ± 7.7 percentile distance from the AC (with the AC center being 0% and the line crossing the CCa being 100%). In the dorsal-ventral line, active contacts in responders were located within a 26.2 ± 13.8 percentile distance from the CCi (with the CCi edge being 0% and the Fr inferior limit being 100%). In the medial-lateral plane, most electrode tips were in the transition between the gray and white matter of SCG.

Conclusions

Active contacts in patients who responded to DBS were relatively clustered within the SCG. Because of the anatomical variability in the size and shape of the SCG, the authors developed a method to standardize the targeting of this region.

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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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Sérgio A. F. Dantas, Eduardo J. L. Alho, Juliano J. da Silva, Nilson N. Mendes Neto, Erich Talamoni Fonoff and Clement Hamani

Hypothalamic deep brain stimulation (DBS) has been used for more than a decade to treat cluster headache (CH) but its mechanisms remain poorly understood. The authors have successfully treated a patient with CH using hypothalamic DBS and found that the contact used for chronic stimulation was located in a white matter region posterior to the mammillary bodies. Fiber tracts crossing that region were the medial forebrain bundle and those interconnecting the hypothalamus and brainstem, including the dorsal longitudinal fasciculus. Because the stimulation of axons is an important mechanism of DBS, some of its clinical effects in CH may be related to the stimulation of fibers interconnecting the hypothalamus and brainstem.

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Manish Ranjan, Gavin J. B. Elias, Alexandre Boutet, Jidan Zhong, Powell Chu, Jurgen Germann, Gabriel A. Devenyi, M. Mallar Chakravarty, Alfonso Fasano, Kullervo Hynynen, Nir Lipsman, Clement Hamani, Walter Kucharczyk, Michael L. Schwartz, Andres M. Lozano and Mojgan Hodaie

OBJECTIVE

Tractography-based targeting of the thalamic ventral intermediate nucleus (T-VIM) is a novel method conferring patient-specific selection of VIM coordinates for tremor surgery; however, its accuracy and clinical utility in magnetic resonance imaging–guided focused ultrasound (MRgFUS) thalamotomy compared to conventional indirect targeting has not been specifically addressed. This retrospective study sought to compare the treatment locations and potential adverse effect profiles of T-VIM with indirect targeting in a large cohort of MRgFUS thalamotomy patients.

METHODS

T-VIM was performed using diffusion tractography outlining the pyramidal and medial lemniscus tracts in 43 MRgFUS thalamotomy patients. T-VIM coordinates were compared with the indirect treatment coordinates used in the procedure. Thalamotomy lesions were delineated on postoperative T1-weighted images and displaced (“translated”) by the anteroposterior and mediolateral difference between T-VIM and treatment coordinates. Both translated and actual lesions were normalized to standard space and subsequently overlaid with areas previously reported to be associated with an increased risk of motor and sensory adverse effects when lesioned during MRgFUS thalamotomy.

RESULTS

T-VIM coordinates were 2.18 mm anterior and 1.82 mm medial to the “final” indirect treatment coordinates. Translated lesions lay more squarely within the boundaries of the VIM compared to nontranslated lesions and showed significantly less overlap with areas associated with sensory adverse effects. Translated lesions overlapped less with areas associated with motor adverse effects; however, this difference was not significant.

CONCLUSIONS

T-VIM leads to the selection of more anterior and medial coordinates than the conventional indirect methods. Lesions moved toward these anteromedial coordinates avoid areas associated with an increased risk of motor and sensory adverse effects, suggesting that T-VIM may improve clinical outcomes.