Phiroz E. Tarapore

Language mapping with navigated repetitive TMS: proof of technique and validation.

OBJECTIVE Lesion-based mapping of speech pathways has been possible only during invasive neurosurgical procedures using direct cortical stimulation (DCS). However, navigated transcranial magnetic stimulation (nTMS) may allow for lesion-based interrogation of language pathways noninvasively. Although not lesion-based, magnetoencephalographic imaging (MEGI) is another noninvasive modality for language mapping. In this study, we compare the accuracy of nTMS and MEGI with DCS. METHODS Subjects with lesions around cortical language areas underwent preoperative nTMS and MEGI for language mapping. nTMS maps were generated using a repetitive TMS protocol to deliver trains of stimulations during a picture naming task. MEGI activation maps were derived from adaptive spatial filtering of beta-band power decreases prior to overt speech during picture naming and verb generation tasks. The subjects subsequently underwent awake language mapping via intraoperative DCS. The language maps obtained from each of the 3 modalities were recorded and compared. RESULTS nTMS and MEGI were performed on 12 subjects. nTMS yielded 21 positive language disruption sites (11 speech arrest, 5 anomia, and 5 other) while DCS yielded 10 positive sites (2 speech arrest, 5 anomia, and 3 other). MEGI isolated 32 sites of peak activation with language tasks. Positive language sites were most commonly found in the pars opercularis for all three modalities. In 9 instances the positive DCS site corresponded to a positive nTMS site, while in 1 instance it did not. In 4 instances, a positive nTMS site corresponded to a negative DCS site, while 169 instances of negative nTMS and DCS were recorded. The sensitivity of nTMS was therefore 90%, specificity was 98%, the positive predictive value was 69% and the negative predictive value was 99% as compared with intraoperative DCS. MEGI language sites for verb generation and object naming correlated with nTMS sites in 5 subjects, and with DCS sites in 2 subjects. CONCLUSION Maps of language function generated with nTMS correlate well with those generated by DCS. Negative nTMS mapping also correlates with negative DCS mapping. In our study, MEGI lacks the same level of correlation with intraoperative mapping; nevertheless it provides useful adjunct information in some cases. nTMS may offer a lesion-based method for noninvasively interrogating language pathways and be valuable in managing patients with peri-eloquent lesions.

Preoperative multimodal motor mapping: a comparison of magnetoencephalography imaging, navigated transcranial magnetic stimulation, and direct cortical stimulation.

OBJECT Direct cortical stimulation (DCS) is the gold-standard technique for motor mapping during craniotomy. However, preoperative noninvasive motor mapping is becoming increasingly accurate. Two such noninvasive modalities are navigated transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG) imaging. While MEG imaging has already been extensively validated as an accurate modality of noninvasive motor mapping, TMS is less well studied. In this study, the authors compared the accuracy of TMS to both DCS and MEG imaging. METHODS Patients with tumors in proximity to primary motor cortex underwent preoperative TMS and MEG imaging for motor mapping. The patients subsequently underwent motor mapping via intraoperative DCS. The loci of maximal response were recorded from each modality and compared. Motor strength was assessed at 3 months postoperatively. RESULTS Transcranial magnetic stimulation and MEG imaging were performed on 24 patients. Intraoperative DCS yielded 8 positive motor sites in 5 patients. The median distance ± SEM between TMS and DCS motor sites was 2.13 ± 0.29 mm, and between TMS and MEG imaging motor sites was 4.71 ± 1.08 mm. In no patients did DCS motor mapping reveal a motor site that was unrecognized by TMS. Three of 24 patients developed new, early neurological deficit in the form of upper-extremity paresis. At the 3-month follow-up evaluation, 2 of these patients were significantly improved, experiencing difficulty only with fine motor tasks; the remaining patient had improvement to 4/5 strength. There were no deaths over the course of the study. CONCLUSIONS Maps of the motor system generated with TMS correlate well with those generated by both MEG imaging and DCS. Negative TMS mapping also correlates with negative DCS mapping. Navigated TMS is an accurate modality for noninvasively generating preoperative motor maps.

THE CURRENT ROLE OF MICROSURGERY FOR POSTERIOR CIRCULATION ANEURYSMS : A SELECTIVE APPROACH IN THE ENDOVASCULAR ERA. Commentary

OBJECTIVEDuring the past decade, management of posterior circulation aneurysms has shifted away from microsurgery. Currently, microsurgical clipping is considered a primary, competitive alternative to endovascular coiling, or more commonly, a secondary alternative when endovascular therapy is unfavorable. We present a large, multidisciplinary team experience with posterior circulation aneurysms in an institution that continues to use microsurgery as a primary treatment modality for selected aneurysms. METHODSDuring a 9-year period, 217 patients with 228 posterior circulation aneurysms were treated microsurgically; they included 106 basilar bifurcation, 27 posterior cerebral artery, 23 superior cerebellar artery, eight anteroinferior cerebellar artery, five basilar trunk, 47 posteroinferior cerebellar artery, and 12 vertebral artery aneurysms. Overall, 81% of patients presented with hemorrhage, and 33% of the aneurysms were large or giant in size. RESULTSDirect clipping was performed in 75% of cases, and the overall rate of angiographic aneurysm obliteration was 98.1%. Sixteen patients (7.4%) died after surgery, 25 patients (11.5%) experienced transient neurological deterioration, and 17 patients (7.8%) experienced permanent neurological deterioration. At late follow-up (mean duration, 13.6 mo), 144 patients had good outcomes (Glasgow Outcome Scale scores of 5 or 4, 66%), and 184 patients (85%) either improved or were unchanged relative to their preoperative baseline. Overall, mean Glasgow Outcome Scale scores improved from 3.60 to 3.97. CONCLUSIONDespite increasing reliance on endovascular therapy with posterior circulation aneurysms, there is a role for microsurgical therapy. Microsurgery remains a competitive, primary therapy for superior cerebellar artery, P1 posterior cerebral artery, distal anteroinferior cerebellar artery, and posteroinferior cerebellar artery aneurysms. Microsurgery has become a secondary therapy for P2 posterior cerebral artery, basilar trunk, proximal anteroinferior cerebellar artery, vertebrobasilar junction, and vertebral artery aneurysms when endovascular therapy is unfavorable. The preferred therapy for basilar bifurcation aneurysms remains unclear. Collaborative, multidisciplinary teams are strengthened and results are improved by offering competitive treatment alternatives for patients to consider and select. Rather than abandoning the posterior circulation prematurely, aneurysm surgeons should maintain technical proficiency with these lesions.

Global and regional functional connectivity maps of neural oscillations in focal epilepsy

Intractable focal epilepsy is a devastating disorder with profound effects on cognition and quality of life. Epilepsy surgery can lead to seizure freedom in patients with focal epilepsy; however, sometimes it fails due to an incomplete delineation of the epileptogenic zone. Brain networks in epilepsy can be studied with resting-state functional connectivity analysis, yet previous investigations using functional magnetic resonance imaging or electrocorticography have produced inconsistent results. Magnetoencephalography allows non-invasive whole-brain recordings, and can be used to study both long-range network disturbances in focal epilepsy and regional connectivity at the epileptogenic zone. In magnetoencephalography recordings from presurgical epilepsy patients, we examined: (i) global functional connectivity maps in patients versus controls; and (ii) regional functional connectivity maps at the region of resection, compared to the homotopic non-epileptogenic region in the contralateral hemisphere. Sixty-one patients were studied, including 30 with mesial temporal lobe epilepsy and 31 with focal neocortical epilepsy. Compared with a group of 31 controls, patients with epilepsy had decreased resting-state functional connectivity in widespread regions, including perisylvian, posterior temporo-parietal, and orbitofrontal cortices (P < 0.01, t-test). Decreased mean global connectivity was related to longer duration of epilepsy and higher frequency of consciousness-impairing seizures (P < 0.01, linear regression). Furthermore, patients with increased regional connectivity within the resection site (n = 24) were more likely to achieve seizure postoperative seizure freedom (87.5% with Engel I outcome) than those with neutral (n = 15, 64.3% seizure free) or decreased (n = 23, 47.8% seizure free) regional connectivity (P < 0.02, chi-square). Widespread global decreases in functional connectivity are observed in patients with focal epilepsy, and may reflect deleterious long-term effects of recurrent seizures. Furthermore, enhanced regional functional connectivity at the area of resection may help predict seizure outcome and aid surgical planning.

Optimal timing of pulse onset for language mapping with navigated repetitive transcranial magnetic stimulation

OBJECT Within the primary motor cortex, navigated transcranial magnetic stimulation (nTMS) has been shown to yield maps strongly correlated with those generated by direct cortical stimulation (DCS). However, the stimulation parameters for repetitive nTMS (rTMS)-based language mapping are still being refined. For this purpose, the present study compares two rTMS protocols, which differ in the timing of pulse train onset relative to picture presentation onset during object naming. Results were the correlated with DCS language mapping during awake surgery. METHODS Thirty-two patients with left-sided perisylvian tumors were examined by rTMS prior to awake surgery. Twenty patients underwent rTMS pulse trains starting at 300 ms after picture presentation onset (delayed TMS), whereas another 12 patients received rTMS pulse trains starting at the picture presentation onset (ONSET TMS). These rTMS results were then evaluated for correlation with intraoperative DCS results as gold standard in terms of differential consistencies in receiver operating characteristics (ROC) statistics. Logistic regression analysis by protocols and brain regions were conducted. RESULTS Within and around Brocas area, there was no difference in sensitivity (onset TMS: 100%, delayed TMS: 100%), negative predictive value (NPV) (onset TMS: 100%, delayed TMS: 100%), and positive predictive value (PPV) (onset TMS: 55%, delayed TMS: 54%) between the two protocols compared to DCS. However, specificity differed significantly (onset TMS: 67%, delayed TMS: 28%). In contrast, for posterior language regions, such as supramarginal gyrus, angular gyrus, and posterior superior temporal gyrus, early pulse train onset stimulation showed greater specificity (onset TMS: 92%, delayed TMS: 20%), NPV (onset TMS: 92%, delayed TMS: 57%) and PPV (onset TMS: 75%, delayed TMS: 30%) with comparable sensitivity (onset TMS: 75%, delayed TMS: 70%). Logistic regression analysis also confirmed the greater fit of the predictions by rTMS that had the pulse train onset coincident with the picture presentation onset when compared to the delayed stimulation. Analyses of differential disruption patterns of mapped cortical regions were further able to distinguish clusters of cortical regions standardly associated with semantic and pre-vocalization phonological networks proposed in various models of word production. Repetitive nTMS predictions by both protocols correlate well with DCS outcomes especially in Brocas region, particularly with regard to TMS negative predictions. CONCLUSIONS With this study, we have demonstrated that rTMS stimulation onset coincident with picture presentation onset improves the accuracy of preoperative language maps, particularly within posterior language areas. Moreover, immediate and delayed pulse train onsets may have complementary disruption patterns that could differentially capture cortical regions causally necessary for semantic and pre-vocalization phonological networks.

Potassium channel gene therapy can prevent neuron death resulting from necrotic and apoptotic insults

Necrotic insults such as seizure are excitotoxic. Logically, membrane hyperpolarization by increasing outwardly conducting potassium channel currents should attenuate hyperexcitation and enhance neuron survival. Therefore, we overexpressed a small‐conductance calcium‐activated (SK2) or voltage‐gated (Kv1.1) channel via viral vectors in cultured hippocampal neurons. We found that SK2 or Kv1.1 protected not only against kainate or glutamate excitotoxicity but also increased survival after sodium cyanide or staurosporine. In vivo overexpression of either channel in dentate gyrus reduced kainate‐induced CA3 lesions. In hippocampal slices, the kainate‐induced increase in granule cell excitability was reduced by overexpression of either channel, suggesting that these channels exert their protective effects during hyperexcitation. It is also important to understand any functional disturbances created by transgene overexpression alone. In the absence of insult, overexpression of Kv1.1, but not SK2, reduced baseline excitability in dentate gyrus granule cells. Furthermore, while no behavioral disturbances during spatial acquisition in the Morris water maze were observed with overexpression of either channel, animals overexpressing SK2, but not Kv1.1, exhibited a memory deficit post‐training. This difference raises the possibility that the means by which these channel subtypes protect may differ. With further development, potassium channel vectors may be an effective pre‐emptive strategy against necrotic insults.

Magnetoencephalographic imaging of resting-state functional connectivity predicts postsurgical neurological outcome in brain gliomas.

BACKGROUND The removal of brain tumors in perieloquent or eloquent cortex risks causing new neurological deficits in patients. The assessment of the functionality of perilesional tissue is essential to avoid postoperative neurological morbidity. OBJECTIVE To evaluate preoperative magnetoencephalography-based functional connectivity as a predictor of short- and medium-term neurological outcome after removal of gliomas in perieloquent and eloquent areas. METHODS Resting-state whole-brain magnetoencephalography recordings were obtained from 79 consecutive subjects with focal brain gliomas near or within motor, sensory, or language areas. Neural activity was estimated using adaptive spatial filtering. The mean imaginary coherence between voxels in and around brain tumors was compared with contralesional voxels and used as an index of their functional connectivity with the rest of the brain. The connectivity values of the tissue resected during surgery were correlated with the early (1 week postoperatively) and medium-term (6 months postoperatively) neurological morbidity. RESULTS Patients undergoing resection of tumors with decreased functional connectivity had a 29% rate of a new neurological deficit 1 week after surgery and a 0% rate at 6-month follow-up. Patients undergoing resection of tumors with increased functional connectivity had a 60% rate of a new deficit at 1 week and a 25% rate at 6 months. CONCLUSION Magnetoencephalography connectivity analysis gives a valuable preoperative evaluation of the functionality of the tissue surrounding tumors in perieloquent and eloquent areas. These data may be used to optimize preoperative patient counseling and surgical strategy.

Safety and tolerability of navigated TMS for preoperative mapping in neurosurgical patients

OBJECTIVE Navigated transcranial magnetic stimulation (nTMS) is a non-invasive technique for pre-surgical motor and language mapping in patients with brain lesions. This study examines the safety and tolerability of nTMS in a large, multi-center cohort of neurosurgical patients. METHODS Functional mapping with monopulse and repetitive nTMS was performed in 733 patients. In this cohort, 57% of patients had left-sided tumors, 50% had frontal tumors, and 50% had seizures secondary to the lesion. Side effects and pain intensity related to the procedure were documented. RESULTS Patients undergoing monopulse stimulation underwent an average of 490 pulses while those undergoing repetitive stimulation received an average of 2268 pulses. During monopulse stimulation, 5.1% reported discomfort (VAS 1-3), and 0.4% reported pain (VAS>3). During repetitive stimulation, 23.4% reported discomfort and 69.5% reported pain. No seizures or other adverse events were observed. CONCLUSIONS nTMS is safe and well-tolerated in neurosurgical patients. Clinicians should consider expanding nTMS to patients with frequent seizures, but more evaluation is necessary to evaluate this risk fully. SIGNIFICANCE nTMS is safe and well-tolerated, even in neurosurgical patients with persistent occasional seizure secondary to a lesion. It should be considered in any patient with a lesion in a presumed peri-eloquent or eloquent brain region.

Wet heat exposure: a potentially reversible cause of low semen quality in infertile men

OBJECTIVE To evaluate the recovery of semen quality in a cohort of infertile men after known hyperthermic exposure to hot tubs, hot baths or whirlpool baths. MATERIALS AND METHODS A consecutive cohort of infertile men had a history remarkable for wet heat exposure in the forms of hot tubs, Jacuzzi or hot baths. Clinical characteristics and exposure parameters were assessed before exposure was discontinued, and semen parameters analyzed before and after discontinuation of hyperthermic exposure. A significant seminal response to withdrawal of hyperthermia was defined as >or= 200% increase in the total motile sperm count (TMC = volume x concentration x motile fraction) during follow-up after cessation of wet heat exposure. RESULTS Eleven infertile men (mean age 36.5 years, range 31-44) exposed to hyperthermia were evaluated pre and post-exposure. Five patients (45%) responded favorably to cessation of heat exposure and had a mean increase in total motile sperm counts of 491%. This increase was largely the result of a statistically significant increase in sperm motility from a mean of 12% at baseline to 34% post-intervention (p = 0.02). Among non-responders, a smoking history revealed a mean of 5.6 pack-years, compared to 0.11 pack-years among responders. The prevalence of varicoceles was similar in both cohorts. CONCLUSIONS The toxic effect of hyperthermia on semen quality may be reversible in some infertile men. We observed that the seminal response to exposure elimination varies biologically among individuals and can be profound in magnitude. Among non-responders, other risk factors that could explain a lack of response to elimination of hyperthermia should be considered.

Rathke cleft cysts in pediatric patients: presentation, surgical management, and postoperative outcomes

OBJECT Rathke cleft cysts (RCC) are benign sellar lesions most often found in adults, and more infrequently in children. They are generally asymptomatic but sometimes require surgical treatment through a transsphenoidal corridor. The purpose of this study was to compare adult versus pediatric cases of RCC. METHODS The authors retrospectively reviewed presenting symptoms, MR imaging findings, laboratory study results, and pathological findings in 147 adult and 14 pediatric patients who underwent surgery for treatment of RCCs at the University of Californial at San Francisco between 1996 and 2008. RESULTS In both the adult and pediatric groups, most patients were female (78% of adults, 79% of pediatric patients, p = 0.9). Headache was the most common symptom in both groups (reported by 50% of pediatric patients and 33% of adults, p = 0.2). Preoperative hypopituitarism occurred in 41% of adults and 45% of pediatric patients (p = 0.8). Growth delay, a uniquely pediatric finding, was a presenting sign in 29% of pediatric patients. Visual complaints were a presenting symptom in 16% of adult and 7% of pediatric patients (p = 0.4). There was no difference between median cyst size in adults versus pediatric patients (1.2 cm in both, p = 0.7). Temporary or permanent postoperative diabetes insipidus occurred in 12% of adults and 21% of pediatric patients (p = 0.4). Kaplan-Meier analysis revealed an 8% RCC recurrence rate at 2 years for each group (p = 0.5). CONCLUSIONS The incidence of RCCs is much lower in the pediatric population; however, symptoms, imaging findings, and outcomes are similar, suggesting that pediatric RCCs arise from growth of remnants of the embryonic Rathke pouch earlier in life than adult RCCs but do not differ in any other way. It is important to consider RCCs in the differential diagnosis when pediatric patients present with visual impairment, unexplained headache, or hypopituitarism including growth delay. Although the average RCC size was similar in our pediatric and adult patient groups, the smaller size of the pituitary gland in pediatric patients suggests an increased relative RCC size.