Correlation between Cranial Nerve Microstructural Characteristics and Vestibular Schwannoma Tumor Volume.

BACKGROUND AND PURPOSE: Vestibular schwannomas are common cerebellopontine angle tumors arising from the vestibulocochlear nerve and can result in cranial nerve dysfunction. Conventional MR imaging does not provide information that could correlate with cranial nerve compression symptoms of hearing loss or imbalance. We used multitensor tractography to evaluate the relationship between the WM microstructural properties of cranial nerves and tumor volume in a cohort of patients with vestibular schwannomas. MATERIALS AND METHODS: A retrospective study was performed in 258 patients with vestibular schwannomas treated at the Gamma Knife clinic at Toronto Western Hospital between 2014 and 2018. 3T MR images were analyzed in 160 surgically naïve patients with unilateral vestibular schwannomas. Multitensor tractography was used to extract DTI-derived metrics (fractional anisotropy and radial, axial, and mean diffusivities of the bilateral facial and vestibulocochlear nerves [cranial nerves VII/VIII]). ROIs were placed in the transition between cisternal and intracanalicular segments, and images were analyzed using the eXtended Streamline Tractography reconstruction method. Diffusion metrics were correlated with 3D tumor volume derived from the Gamma Knife clinic. RESULTS: DTI analyses revealed significantly higher fractional anisotropy values and a reduction in axial diffusivity, radial diffusivity, and mean diffusivity (all P < .001) within the affected cranial nerves VII and VIII compared with unaffected side. All specific diffusivities (axial, radial, and mean diffusivity) demonstrated an inverse correlation with tumor volume (axial, radial, and mean diffusivity, P < .01). CONCLUSIONS: Multitensor tractography allows the quantification of cranial nerve VII and VIII WM microstructural alterations in patients with vestibular schwannomas. Our findings support the hypothesis that tumor volume may cause microstructural alterations of the affected cranial nerves VII and VIII. This type of advanced imaging may represent a possible avenue to correlate diffusivities with cranial nerve function.

Lack of depotentiation at basal ganglia output neurons in PD patients with levodopa-induced dyskinesia.

Parkinson's disease (PD), characterized by the loss of dopaminergic nigrostriatal projections, is a debilitating neurodegenerative disease which produces bradykinesia, rigidity, tremor and postural instability. The dopamine precursor levodopa (L-Dopa) is the most effective treatment for the amelioration of PD signs and symptoms, but long-term administration can lead to disabling motor fluctuations and L-Dopa-induced dyskinesias. In animal models of PD, a form of plasticity called depotentiation, or the reversal of previous potentiation, is selectively lost after the development of dyskinetic movements following L-Dopa treatment. We investigated whether low frequency stimulation (LFS) in the globus pallidus internus (GPi) and substantia nigra pars reticulata (SNr) could induce depotentiation at synapses that had already undergone high frequency stimulation (HFS)-induced potentiation. To do so, we measured the field potentials (fEPs) evoked by stimulation from a nearby microelectrode in 28 patients undergoing implantation of deep brain stimulating (DBS) electrodes in the subthalamic nucleus (STN) or GPi. We found that GPi and SNr synapses in patients with less severe dyskinesia underwent greater depotentiation following LFS than in patients with more severe dyskinesia. This demonstration of impaired depotentiation in basal ganglia output nuclei in PD patients with dyskinesia is an important validation of animal models of levodopa-induced dyskinesia. The ability of a synapse to reverse previous potentiation may be crucial to the normal function of the BG, perhaps by preventing saturation of the storage capacity required in motor learning and optimal motor function. Loss of this ability at the output nuclei may underlie, or contribute to the cellular basis of dyskinetic movements.

Advances in the management of trigeminal neuralgia.

Trigeminal neuralgia (TN), one of the most intense forms of facial pain, has been the subject of great clinical interest. Significant advances have been made in its management, including surgical treatment and imaging of the trigeminal nerve and associated neurovascular compression. The different options for surgical treatment, recent advances in each as well as novel methods of imaging of the trigeminal nerve focusing on diffusion tensor imaging/tractography will be discussed.

Reduced paired pulse depression in the basal ganglia of dystonia patients.

Decreased inhibition and aberrant plasticity are key features in the pathophysiology of dystonia. Impaired short interval cortical inhibition and resultant increased excitability have been described for various forms of dystonia using paired pulse methods with transcranial magnetic stimulation of motor cortex. It is hypothesized that, in addition to cortical abnormalities, impairments in basal ganglia function may lead to dystonia but a deficit of inhibition within the basal ganglia has not been demonstrated to date. To examine the possibility that impaired inhibition and synaptic plasticity within the basal ganglia play a role in dystonia, the present study used a pair of microelectrodes to test paired pulse inhibition in the globus pallidus interna (GPi) and substantia nigra pars reticulata (SNr) of dystonia and PD patients undergoing implantation of deep brain stimulating (DBS) electrodes. We found that there was less paired pulse depression of local field evoked potentials in the basal ganglia output nuclei of dystonia patients compared with Parkinson's disease patients on dopaminergic medication. Paired pulse depression could be restored following focal high frequency stimulation (HFS). These findings suggest that abnormalities exist in synaptic function of striatopallidal and/or striatonigral terminals in dystonia patients and that these abnormalities may contribute to the pathophysiology of dystonia, either independent of, or in addition to the increased excitability and plasticity observed in cortical areas in dystonia patients. These findings also suggest that HFS is capable of enhancing striatopallidal and striatonigral GABA release in basal ganglia output nuclei, indicating a possible mechanism for the therapeutic benefits of DBS in the GPi of dystonia patients.

Subthalamic deep brain stimulation at individualized frequencies for Parkinson disease.

OBJECTIVES: The oscillation model of Parkinson disease (PD) states that, in the subthalamic nucleus (STN), increased θ (4-10 Hz) and ß (11-30 Hz) frequencies were associated with worsening whereas γ frequencies (31-100 Hz) were associated with improvement of motor symptoms. However, the peak STN frequency in each band varied widely from subject to subject. We hypothesized that STN deep brain stimulation (DBS) at individualized γ frequencies would improve whereas θ or ß frequencies would worsen PD motor signs. METHODS: We prospectively studied 13 patients with PD. STN local field potential (LFP) was recorded after electrode implantations, in the OFF and then in ON dopaminergic medication states while patients performed wrist movements. Six individual peak frequencies of the STN LFP power spectra were obtained: the greatest decrease in θ and ß and greatest increase in γ frequencies in the ON state (MED) and during movements (MOVE). Eight DBS frequencies were applied including 6 MED and MOVE frequencies, high frequency (HF) used for chronic stimulation, and no stimulation. The patients were assessed using the motor Unified Parkinson's Disease Rating Scale (mUPDRS). RESULTS: STN DBS at γ frequencies (MED and MOVE) and HF significantly improved mUPDRS scores compared to no stimulation and both γ frequencies were not different from HF. DBS at θ and ß frequencies did not worsen mUPDRS scores compared to no stimulation. CONCLUSION: Short-term administration of STN DBS at peak dopamine-dependent or movement-related γ frequencies were as effective as HF for reducing parkinsonian motor signs but DBS at θ and ß frequencies did not worsen PD motor signs. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that STN DBS at patient-specific γ frequencies and at usual high frequencies both improved mUPDRS scores compared to no stimulation and did not differ in effect.

Levodopa enhances synaptic plasticity in the substantia nigra pars reticulata of Parkinson's disease patients.

Parkinson's disease, caused by the loss of dopaminergic nigrostriatal projections, is a debilitating neurodegenerative disease characterized by bradykinesia, rigidity, tremor and postural instability. The dopamine precursor levodopa (L-dopa) is the most effective treatment for the amelioration of Parkinson's disease signs and symptoms, but long-term administration can lead to disabling motor fluctuations and L-dopa -induced dyskinesias (LIDs). Studies in rat striatal slices have shown dopamine to be an essential component of activity-dependent synaptic plasticity at the input to the basal ganglia, but dopamine is also released from ventrally projecting dendrites of the substantia nigra pars compacta (SNc) on the substantia nigra pars reticulata (SNr), a major output structure of the basal ganglia. We characterized synaptic plasticity in the SNr using field potentials evoked with a nearby microelectrode (fEPs), in 18 Parkinson's disease patients undergoing implantation of deep brain stimulating (DBS) electrodes in the subthalamic nucleus (STN). High frequency stimulation (HFS--four trains of 2 s at 100 Hz) in the SNr failed to induce a lasting change in test fEPs (1 Hz) amplitudes in patients OFF medication (decayed to baseline by 160 s). Following oral L-dopa administration, HFS induced a potentiation of the fEP amplitudes (+29.3% of baseline at 160 s following a plateau). Our findings suggest that extrastriatal dopamine modulates activity-dependent synaptic plasticity at basal ganglia output neurons. Dopamine medication state clearly impacts fEP amplitude, and the lasting nature of the increase is reminiscent of LTP-like changes, indicating that aberrant synaptic plasticity may play a role in the pathophysiology of Parkinson's disease.

Increased gamma oscillatory activity in the subthalamic nucleus during tremor in Parkinson's disease patients.

Rest tremor is one of the main symptoms in Parkinson's disease (PD), although in contrast to rigidity and akinesia, the severity of the tremor does not correlate well with the degree of dopamine deficiency or the progression of the disease. Studies suggest that akinesia in PD patients is related to abnormal increased beta (15-30 Hz) and decreased gamma (35-80 Hz) synchronous oscillatory activity in the basal ganglia. Here we investigated the dynamics of oscillatory activity in the subthalamic nucleus (STN) during tremor. We used two adjacent microelectrodes to simultaneously record neuronal firing and local field potential (LFP) activity in nine PD patients who exhibited resting tremor during functional neurosurgery. We found that neurons exhibiting oscillatory activity at tremor frequency are located in the dorsal region of STN, where neurons with beta oscillatory activity are observed, and that their activity is coherent with LFP oscillations in the beta frequency range. Interestingly, in 85% of the 58 sites examined, the LFP exhibited increased oscillatory activity in the low gamma frequency range (35-55 Hz) during periods with stronger tremor. Furthermore, in 17 of 26 cases where two LFPs were recorded simultaneously, their coherence in the gamma range increased with increased tremor. When averaged across subjects, the ratio of the beta to gamma coherence was significantly lower in periods with stronger tremor compared with periods of no or weak tremor. These results suggest that resting tremor in PD is associated with an altered balance between beta and gamma oscillations in the motor circuits of STN.

Long-term follow-up of patients with thalamic deep brain stimulation for epilepsy.

The authors describe long-term follow-up (mean, 5 years) in patients with anterior (AN) (n = 6) or centromedian (n = 2) thalamic deep brain stimulation (DBS) for epilepsy. Five patients (all AN) had > or = 50% seizure reduction, although benefit was delayed in two until years 5 to 6, after changes in antiepileptic drugs. DBS electrode implantation in AN patients was followed by seizure reduction 1 to 3 months before active stimulation, raising the possibility of a beneficial microthalamotomy effect.

Deep brain stimulator electrodes used for lesioning: proof of principle.

OBJECTIVE: Patients with chronically implanted deep brain stimulator (DBS) electrodes can encounter complications requiring hardware removal. We assessed the safety and efficacy of using implanted DBS electrodes to create a therapeutic lesion before their removal. METHODS: Revision or removal of the DBS electrodes was required in two patients who had previously undergone DBS implantation. We conducted a series of in vitro experiments to confirm that the DBS electrodes could be used to generate radiofrequency lesions and to assess the relationship between radiofrequency parameters and lesion size. With this information, and with the approval of the hospital ethical review board, implanted electrodes were used to create incremental radiofrequency lesions in the thalamus in one patient and in the subthalamic nucleus in another. The procedures were performed under local anesthesia with contiguous contacts of the DBS lead connected to the active and reference sites of the RF generator to create a bipolar lesion. RESULTS: A 51-year-old man with essential tremor and a thalamic DBS required repeated battery changes secondary to tolerance and high voltage demands. Rather than replacing the battery, a radiofrequency thalamotomy was performed by using the existing left DBS electrode. At the 6-month follow-up examination, successful lesioning provided near complete tremor control. A second patient, a 50-year-old man with Parkinson's disease who had undergone bilateral subthalamic deep brain stimulation, developed skin erosion over the DBS hardware. A subthalamic nucleus lesion was made through the right DBS electrode. Lesion position and size were confirmed with magnetic resonance imaging. CONCLUSION: Lesions can be made through chronically implanted DBS electrodes in a safe, graded fashion and can produce therapeutic benefit.

Image-guided, frameless stereotactic sectioning of the corpus callosum in children with intractable epilepsy.

Corpus callosotomy is an effective neurosurgical procedure for children with intractable atonic or drop attack seizures. While this procedure has not changed significantly over the past three decades, some technical issues remain to be resolved. These include the intraoperative determination of the extent of the callosotomy, the need to stage the procedure, as well as side of approach of craniotomy. We report our 8-year experience with corpus callosotomy using a frameless stereotactic image-guided system (ISG Viewing Wand). Seventeen children with atonic seizures underwent sectioning of the corpus callosum. The mean patient age was 10.5 years. Six children underwent complete callosotomy while 11 underwent resection of the anterior two-thirds. MRI 3D reconstruction of the sagittal sinus and draining cerebral veins was undertaken in all cases. The side of the craniotomy was determined on the basis of favorability of the draining veins with respect to the extent of the callosotomy. The extent of the callosotomy was determined by intraoperative feedback using the ISG Viewing Wand((R)). Nine of 11 patients in the partial callosotomy group and 4 of 6 patients in the complete callosotomy group showed significant improvement in atonic seizures. We conclude that the use of frameless stereotaxy can function as an important adjunct in the planning and conduction of successful sectioning of the corpus callosum in children with intractable seizures.

Total resection of an intracerebral hemangioendothelioma in an infant. Case report and review of the literature.

Hemangioendotheliomas (HEs) are vasoformative tumors rarely seen in the CNS. Histopathological features determining aggressive phenotypes have not been well defined. Potential cytogenetic alterations in these tumors have not been previously reported. We present a 4-month-old male infant with a temporal lobe HE. Fluorescence in situ hybridization and spectral karyotype analysis revealed translocation of chromosome 11q23. This case constitutes the first report of a gross total resection of an intracerebral HE in the pediatric age group, and of potential cytogenetic alterations involved in its pathogenesis. Based on our report and review of the literature, we note a discrepancy between histopathological criteria of aggressive tumor biology and clinical behavior. Further study of chromosomal abnormalities may be helpful in defining factors associated with a higher risk of malignant behavior. We conclude that gross total resection is currently the best available treatment option for these tumors, regardless of histology.

Regulation of intracellular calcium and preprotachykinin neurotransmitter precursor gene expression by patterned electrical stimulation in rat sympathetic neurons.

Experiments were performed to test several predictions of the hypothesis that activity pattern-dependent changes in intracellular free calcium concentration ([Ca2+]i) might play a role in the translation of altered patterns of neuronal activity into changes in neurotransmitter gene expression. It was shown that (1) the Ca2+ channel blocker cadmium prevented depolarization-induced preprotachykinin-I (PPT-I) gene repression in rat sympathetic neurons; (2) the magnitudes of transient rises in [Ca2+]i were dependent upon the pattern in which a fixed number of depolarizing stimuli were delivered; and (3) stimulation at 10 Hz for 24 h did not repress PPT-I mRNA, while the same number of pulses delivered in 0.2 s bursts of 50 Hz caused a highly significant reduction to 30 +/- 2.5% of control levels.

Deletions in herpes simplex virus glycoprotein D define nonessential and essential domains.

Herpes simplex virus glycoprotein D (gD) is a major component of the virion envelope and infected cell membranes and is essential for virus entry into cells. We have recently shown that gD interacts with a limited number of cell surface receptors which are required for virus penetration into cells. To define domains of gD which are required for aspects of virus replication including receptor binding, deletion mutations of 5 to 14 amino acids were constructed by using oligonucleotide-directed mutagenesis. Plasmids containing mutant genes for gD were assayed for the ability to rescue a recombinant virus, F-gD beta, in which beta-galactosidase sequences replace gD-coding sequences. Effects on global folding and posttranslational processing of the molecules were assessed by using a panel of monoclonal antibodies which recognize both continuous and discontinuous epitopes. A region near the amino terminus (residues 7 to 21) of gD which is recognized by monoclonal antibodies able to neutralize herpes simplex virus in the absence of complement was not essential for function. In addition, virtually all of the cytoplasmic domain of gD and an extracellular domain close to the membrane were dispensable. In contrast, deletion mutations in the central region of the molecule, save for one exception, led to alterations in global folding of the molecule and maturation of the protein was inhibited.