Alon Y. Mogilner

Central motor loop oscillations in parkinsonian resting tremor revealed magnetoencephalography

A variety of clinical and experimental findings suggest that parkinsonian resting tremor results from the involuntary activation of a central mechanism normally used for the production of rapid voluntary alternating movements. However, such central motor loop oscillations have never been directly demonstrated in parkinsonian patients. Using magnetoencephalography, we recorded synchronized and tremor-related neuromagnetic activity over wide areas of the frontal and parietal cortex. The spatial and temporal organization of this activity was studied in seven patients suffering from early-stage idiopathic Parkinsons disease (PD). Single equivalent current dipole (ECD) analysis and fully three-dimensional distributed source solutions (magnetic field tomography, MFT) were used in this analysis. ECD and MFT solutions were superimposed on high-resolution MRI. The findings indicate that 3 to 6 Hz tremor in PD is accompanied by rhythmic subsequent electrical activation at the diencephalic level and in lateral premotor, somatomotor, and somatosensory cortex. Tremor-evoked magnetic activity can be attributed to source generators that were previously described for voluntary movements. The interference of such slow central motor loop oscillations with voluntary motor activity may therefore constitute a pathophysiologic link between tremor and bradykinesia in PD. NEUROLOGY 1996;46:1359-1370

Complications of deep brain stimulation surgery

Although technological advances have reduced device-related complications, DBS surgery still carries a significant risk of transient and permanent complications. We report our experience in 86 patients and 149 DBS implants. Patients with Parkinson’s disease, essential tremor and dystonia were treated. There were 8 perioperative, 8 postoperative, 9 hardware-related complications and 4 stimulation-induced side effects. Only 5 patients (6%) sustained some persistent neurological sequelae, however, 26 of the 86 patients undergoing 149 DBS implants in this series experienced some untoward event with the procedure. Although there were no fatalities or permanent severe disabilities encountered, it is important to extend the informed consent to include all potential complications.

Comparison of anatomic and neurophysiological methods for subthalamic nucleus targeting.

OBJECTIVE The subthalamic nucleus (STN) has recently become the surgical target of choice for the treatment of medically refractory idiopathic Parkinsons disease. A number of anatomic and physiological targeting methods have been used to localize the STN. We retrospectively reviewed the various anatomic targeting methods and compared them with the final physiological target in 15 patients who underwent simultaneous bilateral STN implantation of deep brain stimulators. METHODS The x, y, and z coordinates of our localizing techniques were analyzed for 30 STN targets. Our final targets, as determined by single-cell microelectrode recording, were compared with the following: 1) targets selected on coronal magnetic resonance inversion recovery and T2-weighted imaging sequences, 2) the center of the STN on a digitized scaled Schaltenbrand-Wahren stereotactic atlas, 3) targeting based on a point 13 mm lateral, 4 mm posterior, and 5 mm inferior to the midcommissural point, and 4) a composite target based on the above methods. RESULTS All anatomic methods yielded targets that were statistically significantly different (P < 0.001) from the final physiological targets. The average distance error between the final physiological targets and the magnetic resonance imaging-derived targets was 2.6 +/- 1.3 mm (mean +/- standard deviation), 1.7 +/- 1.1 mm for the atlas-based method, 1.5 +/- 0.8 mm for the indirect midcommissural method, and 1.3 +/- 1.1 mm for the composite method. Once the final microelectrode-refined target was determined on the first side, the final target for the contralateral side was 1.3 +/- 1.2 mm away from its mirror image. CONCLUSION Although all anatomic targeting methods provide accurate STN localization, a combination of the three methods offers the best correlation with the final physiological target. In our experience, direct magnetic resonance targeting was the least accurate method.

Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: long-term results from a randomized, multicenter, double-blinded, controlled study.

Background Recent studies evaluated short-term efficacy and safety of peripheral nerve stimulation (PNS) of the occipital nerves for managing chronic migraine. We present 52-week safety and efficacy results from an open-label extension of a randomized, sham-controlled trial. Methods In this institutional review board-approved, randomized, multicenter, double-blinded study, patients were implanted with a neurostimulation system, randomized to an active or control group for 12 weeks, and received open-label treatment for an additional 40 weeks. Outcomes collected included number of headache days, pain intensity, migraine disability assessment (MIDAS), Zung Pain and Distress (PAD), direct patient reports of headache pain relief, quality of life, satisfaction and adverse events. Statistical tests assessed change from baseline to 52 weeks using paired t-tests. Intent-to-treat (ITT) analyses of all patients (N = 157) and analyses of only patients who met criteria for intractable chronic migraine (ICM; N = 125) were performed. Results Headache days were significantly reduced by 6.7 (±8.4) days in the ITT population (p < 0.001) and by 7.7 (±8.7) days in the ICM population (p < 0.001). The percentages of patients who achieved a 30% and 50% reduction in headache days and/or pain intensity were 59.5% and 47.8%, respectively. MIDAS and Zung PAD scores were significantly reduced for both populations. Excellent or good headache relief was reported by 65.4% of the ITT population and 67.9% of the ICM population. More than half the patients in both cohorts were satisfied with the headache relief provided by the device. A total of 183 device/procedure-related adverse events occurred during the study, of which 18 (8.6%) required hospitalization and 85 (40.7%) required surgical intervention; 70% of patients experienced an adverse event. Conclusion Our results support the 12-month efficacy of PNS of the occipital nerves for headache pain and disability associated with chronic migraine. More emphasis on adverse event mitigation is needed in future research. Trial registration: Clinical trials.gov (NCT00615342).

Neurophysiological refinement of subthalamic nucleus targeting.

OBJECTIVEAdvances in image-guided stereotactic surgery, microelectrode recording techniques, and stimulation technology have been the driving forces behind a resurgence in the use of functional neurosurgery for the treatment of movement disorders. Despite the dramatic effects of deep brain stimulation (DBS) techniques in ameliorating the symptoms of Parkinson’s disease, many critical questions related to the targeting, effects, and mechanisms of action of DBS remain unanswered. In this report, we describe the methods used to localize the subthalamic nucleus (STN) and we present the characteristics of encountered cells. METHODS Twenty-six patients with idiopathic Parkinson’s disease underwent simultaneous, bilateral, microelectrode-refined, DBS electrode implantation into the STN. Direct and indirect magnetic resonance imaging-based anatomic targeting was used. Cellular activity was analyzed for various neurophysiological parameters, including firing rates and interspike intervals. Physiological targeting confirmation was obtained by performing macrostimulation through the final DBS electrode. RESULTS The average microelectrode recording time for each trajectory was 20 minutes, with a mean of 5.2 trajectories/patient. Typical trajectories passed through the anterior thalamus, zona incerta/fields of Forel, STN, and substantia nigra-pars reticulata. Each structure exhibited a characteristic firing pattern. In particular, recordings from the STN exhibited an increase in background activity and an irregular firing pattern, with a mean rate of 47 Hz. The mean cell density was 5.6 cells/mm, with an average maximal trajectory length of 5.3 mm. Macrostimulation via the DBS electrode yielded mean sensory and motor thresholds of 4.2 and 5.7 V, respectively. CONCLUSION The principal objectives of microelectrode recording refinement of anatomic targeting are precise identification of the borders of the STN and thus determination of its maximal length. Microelectrode recording also allows identification of the longest and most lateral segment of the STN, which is our preferred target for STN DBS electrode implantation. Macrostimulation via the final DBS electrode is then used primarily to establish the side effect profile for postoperative stimulation. Microelectrode recording is a helpful targeting adjunct that will continue to facilitate our understanding of basal ganglion physiological features.

Tourette syndrome deep brain stimulation: A review and updated recommendations

Deep brain stimulation (DBS) may improve disabling tics in severely affected medication and behaviorally resistant Tourette syndrome (TS). Here we review all reported cases of TS DBS and provide updated recommendations for selection, assessment, and management of potential TS DBS cases based on the literature and implantation experience. Candidates should have a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V) diagnosis of TS with severe motor and vocal tics, which despite exhaustive medical and behavioral treatment trials result in significant impairment. Deep brain stimulation should be offered to patients only by experienced DBS centers after evaluation by a multidisciplinary team. Rigorous preoperative and postoperative outcome measures of tics and associated comorbidities should be used. Tics and comorbid neuropsychiatric conditions should be optimally treated per current expert standards, and tics should be the major cause of disability. Psychogenic tics, embellishment, and malingering should be recognized and addressed. We have removed the previously suggested 25‐year‐old age limit, with the specification that a multidisciplinary team approach for screening is employed. A local ethics committee or institutional review board should be consulted for consideration of cases involving persons younger than 18 years of age, as well as in cases with urgent indications. Tourette syndrome patients represent a unique and complex population, and studies reveal a higher risk for post‐DBS complications. Successes and failures have been reported for multiple brain targets; however, the optimal surgical approach remains unknown. Tourette syndrome DBS, though still evolving, is a promising approach for a subset of medication refractory and severely affected patients.

Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial

BACKGROUND Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted. METHODS Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4-6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162. FINDINGS Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery. INTERPRETATION This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy. FUNDING Abbott (previously St Jude Medical).

Integration of functional brain mapping in image-guided neurosurgery.

Magnetoencephalographic (MEG) brain mapping was performed in 90 patients with lesions associated with eloquent sensorimotor cortex. The MEG-derived sensorimotor mapping information was utilised for risk analysis and planning. Subsequently, these patients underwent either stereotactic volumetric resection, stereotactic biopsy or non-surgical management of their lesions. In seventeen patients, the MEG sensorimotor localization was integrated into an operative stereotactic database (consisting of CT, MRI and digital angiography) to be used in an interactive fashion during computer-assisted stereotactic volumetric resection procedures. The spatial relationship between the MEG derived functional anatomy, the structural/radiological anatomy and the pathology could then be viewed simultaneously, thereby affording a safer trajectory and approach. In addition, the real-time availability of functional mapping information in an interactive fashion helped reduce surgical risk and minimise functional morbidity. All of these patients had resection of their lesions with no change in their neurological status. In conclusion, MEG is a non-invasive, accurate, and reproducible method for pre-operative assessment of patients with lesions associated with eloquent sensory and motor cortex. The interactive use of MEG functional mapping in the operating room can allow for a safer approach and resection of these eloquent cortex lesions.

Nocardia abscess of the choroid plexus: Clinical and pathological case report

OBJECTIVE Cerebral Nocardia abscesses are rare, accounting for approximately 1 to 2% of all cerebral abscesses. Prompt aggressive surgical treatment involving craniotomy and excision of these lesions has been advocated by many authors, because these lesions have significantly higher morbidity and mortality rates than do most other cerebral abscesses. We report an atypical presentation of cerebral nocardiosis localized to the choroid plexus of the lateral ventricle. CLINICAL PRESENTATION A 56-year-old man presented with a 3-week history of fever, cough, and progressive headache and an ensuing 3-day history of progressive lethargy, confusion, and gait ataxia. Radiographic studies demonstrated a loculated contrast-enhancing left lateral ventricular lesion with significant perilesional parenchymal edema that was thought preoperatively to be a neoplasm. INTERVENTION The patient underwent a craniotomy for resection of the lesion. Intraoperatively, a reddish gray lesion with purulent exudate was encountered within the left lateral ventricle intimately adherent to the choroid plexus as well as to the ependyma and subependymal veins. A frozen section demonstrated an organizing abscess wall. The lesion was resected in its entirety, and multiple cultures were sent for analysis. CONCLUSION Microbiology cultures grew Nocardia asteroides. A course of intravenous antibiotics was started, which included trimethoprim-sulfamethoxazole, amikacin, and ceftriaxone. Two weeks after surgery, at the time of discharge, the patients neurological status had improved considerably. Although Nocardia abscesses have been documented to occur throughout the central nervous system, the presentation of a lesion confined to the choroid plexus of the lateral ventricle with significant parenchymal edema is unusual and demonstrates that Nocardia abscesses must be considered in the differential diagnosis of a contrast-enhancing intraventricular mass lesion involving the choroid plexus.

Neurostimulation and functional brain imaging

Abstract Recent advancements in functional neuroimaging have furthered our understanding of the normal and pathological brain. These non-invasive imaging modalities have allowed us to study the human brain in vivo. Concurrently, the revival of neurostimulation in the treatment of pain, movement disorders, and epilepsy has allowed the synergistic combination of these two technologies. Several studies focusing on the use of functional imaging in patients with implanted neurostimulation devices are reviewed. The anticipated roles of these two disciplines are discussed. [Neurol Res 2000; 22: 318–325]