George T. Mandybur

Stimulation of the Rat Subthalamic Nucleus is Neuroprotective Following Significant Nigral Dopamine Neuron Loss

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is efficacious in treating the motor symptoms of Parkinsons disease (PD). However, the impact of STN-DBS on the progression of PD is unknown. Previous preclinical studies have demonstrated that STN-DBS can attenuate the degeneration of a relatively intact nigrostriatal system from dopamine (DA)-depleting neurotoxins. The present study examined whether STN-DBS can provide neuroprotection in the face of prior significant nigral DA neuron loss similar to PD patients at the time of diagnosis. STN-DBS between 2 and 4 weeks after intrastriatal 6-hydroxydopamine (6-OHDA) provided significant sparing of DA neurons in the SN of rats. This effect was not due to inadvertent lesioning of the STN and was dependent upon proper electrode placement. Since STN-DBS appears to have significant neuroprotective properties, initiation of STN-DBS earlier in the course of PD may provide added neuroprotective benefits in addition to its ability to provide symptomatic relief.

Deep brain stimulation of the ventral intermediate nucleus of the thalamus in medically refractory orthostatic tremor: preliminary observations.

Orthostatic tremor (OT) is a disabling movement disorder associated with postural and gait impairment in the elderly. Medical therapy often yields insufficient benefit. We report the clinical and electrophysiological data on two patients with medication‐refractory OT treated with deep brain stimulation of the ventral intermediate thalamic nucleus (Vim DBS). Patient 1 underwent bilateral deep brain stimulation (DBS) and Patient 2 unilateral Vim DBS following 28 and 30 years of disease duration, respectively. Both patients showed increased latency to symptom onset after rising from a seated position, improved tolerance for prolonged standing, and slower crescendo of tremor severity when remaining upright. Postoperative evaluation demonstrated decreased amplitude of electromyographic activity with persistence of well‐defined oscillatory behavior showing strong coherence at 15 Hz between all muscles tested in the upper and lower limbs. Postural sway was unchanged. Clinical benefits have been sustained for over 18 months in Patient 1, and receded after 3 months in Patient 2. These findings support the consideration of bilateral Vim DBS implantation as a therapeutic option in patients with medically refractory OT. Further efficacy studies on chronic stimulation to disrupt the abnormal oscillatory activity in this disorder are warranted.

Language Representation in the Human Brain: Evidence from Cortical Mapping☆

The manner in which the human brain processes grammatical-syntactic and lexical-semantic functions has been extensively debated in neurolinguistics. The discreteness and selectivity of the representation of syntactic-morphological properties in the dominant frontal cortex and the representation of the lexical-semantics in the temporo-parietal cortex have been questioned. Three right-handed adult male neurosurgical patients undergoing left craniotomy for intractable seizures were evaluated using various grammatical and semantic tasks during cortical mapping. The sampling of language tasks consisted of trials with stimulation (experimental) and without stimulation (control) from sites in the dominant fronto-temporo-parietal cortex The sampling of language implicated a larger cortical area devoted to language (syntactic-morphological and lexical-semantic) tasks. Further, a large part of the fronto-parieto-temporal cortex was involved with syntactic-morphological functions. However, only the parieto-temporal sites were implicated with the ordering of lexicon in sentence construction. These observations suggest that the representation of language in the human brain may be columnar or multilayered.

Concept of arteriovenous malformation compartments and surgical management

Abstract Cerebral AVMs are known to be a source of intracranial hemorrhages and epileptic seizures. Their natural history indicates approximately 15% mortality and 35% morbidity over a 15-year period. This significant mortality and morbidity mandates a need for satisfactory treatment of this entity, ideally by elimination of AVMs. Microsurgical resection, endovascular embolization and radiosurgery (irradiation) are the three effective modes of treatment currently available. However, no objective criteria have been established for which mode(s) of treatment should be selected for individual patients with AVMs. Considering the complexity of AVMs and variable conditions of individual patients, neurosurgeons, intravascular interventionalists and radiosurgeons must make their own decisions on how to treat each patient based on their experience. In practice, treatment of small AVMs in non-functional areas is favored equally by each of these specialists, while they tend to avoid treatment of large AVMs, particularly those in functional areas of the brain. The authors report the surgical intervention of large AVMs, including those located in functional areas of the hemisphere by special techniques. One can demonstrate AVM compartments by using angiography and with the aid of color Doppler ultrasonography, each compartment can be outlined and dissected individually until all the compartments are isolated without causing any damage to the surrounding brain and the entireAVM is rendered shrunken and then removed. The concept of compartmental treatment of AVMs may be applied in the future to radiosurgery and intravascular embolization of large AVMs.

Oxyhemoglobin produces necrosis, not apoptosis, in astrocytes.

OBJECTIVE Subarachnoid blood, resulting from traumatic brain injury or subarachnoid hemorrhage, has been linked with cell injury and stress gene induction. We investigated whether oxyhemoglobin (OxyHb), a major component in blood clots, exerts a cytotoxic effect on cultured astrocyte cells, and the pattern of cell death. METHODS A murine astrocyte cell line was used (passages 28-35). Cell growth studies were performed 24, 48, and 72 h after exposure to OxyHb (1, 10, and 30 microM). Western blot analysis of poly adenosine diphosphate [ADP]-ribose polymerase (PARP) cleavage and TUNEL stain analysis were performed to determine the presence of apoptosis. Cells treated with OxyHb were also evaluated with transmission electron microscopy to determine changes that may have occurred at the ultra-structural level. RESULTS OxyHb (10-30 microM), after 72-h incubation, inhibited cell growth. Western blot analysis of PARP and TUNEL staining for the presence of apoptosis were essentially negative in all groups. Ultrastructural analysis revealed an abundance of necrosis and random occurrences of apoptosis in a few cells. CONCLUSION Cultured astrocytes exposed to OxyHb causing cell growth inhibition could possibly be a result of cellular cytotoxicity and necrosis.

Endoscopic procedures for resection of arteriovenous malformations

BACKGROUND Resection of arteriovenous malformations (AVMs), particularly those located in functional areas, requires precision. To enhance that precision, endoscope-assisted microsurgery has been employed at Loma Linda University. METHODS Twenty-five consecutive cases of AVM were treated microsurgically with endoscopic assistance. Patients were divided into two groups: (1) those having AVMs in functional areas, and (2) those whose AVMs extended into the ventricle, either in the trigonal area or the capsulocaudatothalamic area. The endoscope was inserted into the subarachnoid space to interrupt communicating venules around the major draining vein and into the cleavage developed between the AVM venous loops and surrounding brain tissue as shunting arterioles and communicating venules were interrupted. For surgery of intraventricular AVMs, the curved endoscope was inserted into the ventricle, providing visualization of the AVM core, which was dissected from the ventricular side. RESULTS AVMs were totally resected in all cases except for two patients with capsulocaudatothalamic AVMs, which were decreased in size sufficiently to receive radiosurgery. CONCLUSION Endoscope-assisted microsurgery enhances magnification, illumination, and technical precision while the surgeon is dissecting the AVM core vessels and while operating on AVMs extending into the ventricle.

Electrophysiologic Monitoring for Placement of Laminectomy Leads for Spinal Cord Stimulation Under General Anesthesia

Objectives:  Spinal cord stimulation (SCS) is a valid option for intractable neuropathic pain syndromes, yet some patients cannot undergo the standard awake procedure. Our retrospective study chronicles laminectomy‐electrode placement for SCS under general anesthesia and use of compound muscle action potentials (CMAPs) to guide placement in the absence of patient verbal feedback.

Cytotoxicity of ventricular cerebrospinal fluid from Parkinson patients: Correlation with clinical profiles and neurochemistry

Abstract Other investigators have reported that the cerebrospinal fluid (CSF) from patients with Parkinsons disease (PD) might contain endogenous dystrophic factors. Using CSF samples drawn from individual PD patients during surgery, we investigated the toxic effect of ventricular CSF (vCSF) on the growth of PC12 cells and the correlation between the clinical profiles of the patients and CSF neurochemistry. Ventricular CSF samples from 28 patients with PD or essential tremor (ET) were collected during ventriculography for stereotactic pallidotomy or thalamotomy. PC12 cells were incubated with 20% vCSF from both clinical groups for up to 72 h. Microdialysis was used to analyze four neurochemical parameters (glucose, lactate, pyruvate, and glutamate) in each vCSF sample. We observed that vCSF drawn from PD patients exerted nonspecific growth inhibition on PC12 cells in a time-dependent manner. The growth inhibitory action of PD–vCSF decreased significantly after heat treatment. Microdialysis demonstrated no statistical differences between PD and ET samples among the four parameters studied. In addition, PC12 cell survival after 72 h incubation with PD-vCSF correlated with no neurochemical parameter or individual clinical profile (age, onset age, duration of disease, Hoehn & Yahr stage, disease progression rate), except for a slight correlation between vCSF and disease progression rate in heat treated samples from female patients. One or more endogenous cytotoxic factors in PD-vCSF inhibit PC12 cell growth. This factor or factors are partially sensitive to heat which suggests proteins or peptides as possible agents. The cytotoxic effect of PD-vCSF did not directly correlate with any clinical profiles studied or energy metabolism of PD brain.

Thalamic Deep Brain Stimulation for Orthostatic Tremor: A Multicenter International Registry

We report the accumulated experience with ventral intermediate nucleus deep brain stimulation for medically refractory orthostatic tremor.

Thalamic deep brain stimulation and gait in orthostatic tremor: Vim-DBS AND GAIT IN ORTHOSTATIC TREMOR

Orthostatic tremor (OT) is a rare hyperkinetic disorder of weight-bearing limbs, characterized by postural unsteadiness when standing and a high-frequency tremor of 13-18 Hz. Neuroimaging studies in OT have demonstrated a role of the cerebellothalamocortical network. The role of thalamic connections, implicated in the response to ventral intermediate nucleus deep brain stimulation (Vim-DBS) in OT patients, remains unclear. Eight years ago, we reported a 74-year-old woman after undergoing bilateral Vim-DBS for medication-resistant OT. She had failed clonazepam (10 mg/day), valproate (500 mg/ day), and primidone (225 mg/day). Before surgery her upright stationary posture was <30 seconds, and she required assistance for standing and walking. After Vim-DBS, the latency between rising and symptom onset increased from 30 seconds to 5 minutes, but moderate gait and postural disability persisted, gradually worsening over years despite numerous attempts to optimize DBS settings. She reported imbalance and a tendency to fall backward. The neurological examination revealed wide-based gait, but nerve conduction studies did not show signs of peripheral neuropathy. To examine the long-term efficacy of Vim-DBS in OT and study the heretofore-unexamined Vim-DBS efficacy on gait, we performed a gait analysis-assisted assessment of DBS settings (Supplementary Material). Spatiotemporal gait parameters, dynamic stability index, and coefficient of variation of step length and swing phase were analyzed in 3 different conditions: (1) DBS-OFF; (2) DBS-ON at baseline (left: contact 2-/case1, 3.9 V, 90 microseconds, 185 Hz; right: contact 9-/case1, 3.9 V, 90 microseconds, 185 Hz); and (3) optimized DBS-ON. The active contacts were confirmed (14.2 mm [left] and 12.0 mm [right] lateral to mid-commissural point; 7.2 mm [left] and 4.9 mm [right] anterior to posterior commissure, and 2.3 mm [left] and 0.3 mm [right] superior to anteriorposterior commissural plane), whereas a reduction of stimulation intensity (decreasing voltage by 0.3 V and pulse width by 30 microseconds bilaterally) was found to be associated with objective and subjective gait improvements. Both optimized and baseline DBS-ON conditions improved gait velocity and step length, reducing the spatial and temporal variability of gait when compared with DBSOFF (Fig. 1). However, the baseline DBS-ON condition, which resulted in being supratherapeutic, was associated with worsening of dynamic balance in the mediolateral and anteroposterior axes, as measured by step width and dynamic stability index. These data suggest that Vim-DBS may exert complex and multifaceted modulation of gait in OT, with 2 main stimulationdependent outcomes: (1) improvement of OT symptoms, which may result in increased gait velocity and step length; and (2) potential induction of gait ataxia, which may result in increased stride width and time spent on double support. The complexity of these Vim-DBS-mediated outcomes has been described in essential tremor, in which the suppression of tremor usually correlates with improvement in ataxic gait, whereas supratherapeutic stimulation may result in reemergence of ataxia. Although these single-case observations need to be confirmed in larger studies, we suggest that the OT impairs gait in part by the persistence of high-frequency tremor on weight-bearing limbs during the single-support phase of walking (Fig. 1). An integrated clinical/gait analysis approach may be necessary to assist the optimal programming of Vim-DBS stimulation parameters to effectively modulate the severity of OT symptoms.