Glioblastoma remodelling of human neural circuits decreases survival.

Gliomas synaptically integrate into neural circuits1,2. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth1-4 and gliomas increasing neuronal excitability2,5-8. Here we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumour tissue biopsies and cell biology experiments, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain. Site-directed biopsies from regions within the tumour that exhibit high functional connectivity between the tumour and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumour cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumour regions compared with tumour regions with less functional connectivity. Pharmacological inhibition of thrombospondin-1 using the FDA-approved drug gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumour progression and impairs cognition.

Altered excitatory and inhibitory neuronal subpopulation parameters are distinctly associated with tau and amyloid in Alzheimer's disease.

Background: Neuronal- and circuit-level abnormalities of excitation and inhibition are shown to be associated with tau and amyloid-beta (Aß) in preclinical models of Alzheimer's disease (AD). These relationships remain poorly understood in patients with AD. Methods: Using empirical spectra from magnetoencephalography and computational modeling (neural mass model), we examined excitatory and inhibitory parameters of neuronal subpopulations and investigated their specific associations to regional tau and Aß, measured by positron emission tomography, in patients with AD. Results: Patients with AD showed abnormal excitatory and inhibitory time-constants and neural gains compared to age-matched controls. Increased excitatory time-constants distinctly correlated with higher tau depositions while increased inhibitory time-constants distinctly correlated with higher Aß depositions. Conclusions: Our results provide critical insights about potential mechanistic links between abnormal neural oscillations and cellular correlates of impaired excitatory and inhibitory synaptic functions associated with tau and Aß in patients with AD. Funding: This study was supported by the National Institutes of Health grants: K08AG058749 (KGR), F32AG050434-01A1 (KGR), K23 AG038357 (KAV), P50 AG023501, P01 AG19724 (BLM), P50-AG023501 (BLM and GDR), R01 AG045611 (GDR); AG034570, AG062542 (WJ); NS100440 (SSN), DC176960 (SSN), DC017091 (SSN), AG062196 (SSN); a grant from John Douglas French Alzheimer's Foundation (KAV); grants from Larry L. Hillblom Foundation: 2015-A-034-FEL (KGR), 2019-A-013-SUP (KGR); grants from the Alzheimer's Association: AARG-21-849773 (KGR); PCTRB-13-288476 (KAV), and made possible by Part the CloudTM (ETAC-09-133596); a grant from Tau Consortium (GDR and WJJ), and a gift from the S. D. Bechtel Jr. Foundation.

Clinical Validation of the Champagne Algorithm for Evoked Response Source Localization in Magnetoencephalography.

Magnetoencephalography (MEG) is a robust method for non-invasive functional brain mapping of sensory cortices due to its exceptional spatial and temporal resolution. The clinical standard for MEG source localization of functional landmarks from sensory evoked responses is the equivalent current dipole (ECD) localization algorithm, known to be sensitive to initialization, noise, and manual choice of the number of dipoles. Recently many automated and robust algorithms have been developed, including the Champagne algorithm, an empirical Bayesian algorithm, with powerful abilities for MEG source reconstruction and time course estimation (Wipf et al. 2010; Owen et al. 2012). Here, we evaluate automated Champagne performance in a clinical population of tumor patients where there was minimal failure in localizing sensory evoked responses using the clinical standard, ECD localization algorithm. MEG data of auditory evoked potentials and somatosensory evoked potentials from 21 brain tumor patients were analyzed using Champagne, and these results were compared with equivalent current dipole (ECD) fit. Across both somatosensory and auditory evoked field localization, we found there was a strong agreement between Champagne and ECD localizations in all cases. Given resolution of 8mm voxel size, peak source localizations from Champagne were below 10mm of ECD peak source localization. The Champagne algorithm provides a robust and automated alternative to manual ECD fits for clinical localization of sensory evoked potentials and can contribute to improved clinical MEG data processing workflows.

Optimizing Magnetoencephalographic Imaging Estimation of Language Lateralization for Simpler Language Tasks.

Magnetoencephalographic imaging (MEGI) offers a non-invasive alternative for defining preoperative language lateralization in neurosurgery patients. MEGI indeed can be used for accurate estimation of language lateralization with a complex language task - auditory verb generation. However, since language function may vary considerably in patients with focal lesions, it is important to optimize MEGI for estimation of language function with other simpler language tasks. The goal of this study was to optimize MEGI laterality analyses for two such simpler language tasks that can have compliance from those with impaired language function: a non-word repetition (NWR) task and a picture naming (PN) task. Language lateralization results for these two tasks were compared to the verb-generation (VG) task. MEGI reconstruction parameters (regions and time windows) for NWR and PN were first defined in a presurgical training cohort by benchmarking these against laterality indices for VG. Optimized time windows and regions of interest (ROIs) for NWR and PN were determined by examining oscillations in the beta band (12-30 Hz) a marker of neural activity known to be concordant with the VG laterality index (LI). For NWR, additional ROIs include areas MTG/ITG and for both NWR and PN, the postcentral gyrus was included in analyses. Optimal time windows for NWR were defined as 650-850 ms (stimulus-locked) and -350 to -150 ms (response-locked) and for PN -450 to -250 ms (response-locked). To verify the optimal parameters defined in our training cohort for NWR and PN, we examined an independent validation cohort (n = 30 for NWR, n = 28 for PN) and found high concordance between VG laterality and PN laterality (82%) and between VG laterality and NWR laterality (87%). Finally, in a test cohort (n = 8) that underwent both the intracarotid amobarbital procedure (IAP) test and MEG for VG, NWR, and PN, we identified excellent concordance (100%) with IAP for VG + NWR + PN composite LI, high concordance for PN alone (87.5%), and moderate concordance for NWR alone (66.7%). These findings provide task options for non-invasive language mapping with MEGI that can be calibrated for language abilities of individual patients. Results also demonstrate that more accurate estimates can be obtained by combining laterality estimates obtained from multiple tasks. MEGI.

The impact of high functional connectivity network hub resection on language task performance in adult low- and high-grade glioma.

OBJECTIVE: Gliomas are intrinsic brain tumors with the hallmark of diffuse white matter infiltration, resulting in short- and long-range network dysfunction. Preoperative magnetoencephalography (MEG) can assist in maximizing the extent of resection while minimizing morbidity. While MEG has been validated in motor mapping, its role in speech mapping remains less well studied. The authors assessed how the resection of intraoperative electrical stimulation (IES)-negative, high functional connectivity (HFC) network sites, as identified by MEG, impacts language performance. METHODS: Resting-state, whole-brain MEG recordings were obtained from 26 patients who underwent perioperative language evaluation and glioma resection that was guided by awake language and IES mapping. The functional connectivity of an individual voxel was determined by the imaginary coherence between the index voxel and the rest of the brain, referenced to its contralesional pair. The percentage of resected HFC voxels was correlated with postoperative language outcomes in tasks of increasing complexity: text reading, 4-syllable repetition, picture naming, syntax (SYN), and auditory stimulus naming (AN). RESULTS: Overall, 70% of patients (14/20) in whom any HFC tissue was resected developed an early postoperative language deficit (mean 2.3 days, range 1-8 days), compared to 33% of patients (2/6) in whom no HFC tissue was resected (p = 0.16). When bifurcated by the amount of HFC tissue that was resected, 100% of patients (3/3) with an HFC resection > 25% displayed deficits in AN, compared to 30% of patients (6/20) with an HFC resection < 25% (p = 0.04). Furthermore, there was a linear correlation between the severity of AN and SYN decline with percentage of HFC sites resected (p = 0.02 and p = 0.04, respectively). By 2.2 months postoperatively (range 1-6 months), the correlation between HFC resection and both AN and SYN decline had resolved (p = 0.94 and p = 1.00, respectively) in all patients (9/9) except two who experienced early postoperative tumor progression or stroke involving inferior frontooccipital fasciculus. CONCLUSIONS: Imaginary coherence measures of functional connectivity using MEG are able to identify HFC network sites within and around low- and high-grade gliomas. Removal of IES-negative HFC sites results in early transient postoperative decline in AN and SYN, which resolved by 3 months in all patients without stroke or early tumor progression. Measures of functional connectivity may therefore be a useful means of counseling patients about postoperative risk and assist with preoperative surgical planning.

Motor Cortical Network Plasticity in Patients With Recurrent Brain Tumors.

Objective: The adult brain's potential for plastic reorganization is an important mechanism for the preservation and restoration of function in patients with primary glial neoplasm. Patients with recurrent brain tumors requiring multiple interventions over time present an opportunity to examine brain reorganization. Magnetoencephalography (MEG) is a noninvasive imaging modality that can be used for motor cortical network mapping which, when performed at regular intervals, offers insight into this process of reorganization. Utilizing MEG-based motor mapping, we sought to characterize the reorganization of motor cortical networks over time in a cohort of 78 patients with recurrent glioma. Methods: MEG-based motor cortical maps were obtained by measuring event-related desynchronization (ERD) in ß-band frequency during unilateral index finger flexion. Each patient presented at our Department at least on two occasions for tumor resection due to tumor recurrence, and MEG-based motor mapping was performed as part of preoperative assessment before each surgical resection. Whole-brain activation patterns from first to second MEG scan (obtained before first and second surgery) were compared. Additionally, we calculated distances of activation peaks, which represent the location of the primary motor cortex (MC), to determine the magnitude of movement in motor eloquent areas between the first and second MEG scan. We also explored which demographic, anatomic, and pathological factors influence these shifts. Results: The whole-brain activation motor maps showed a subtle movement of the primary MC from first to second timepoint, as was confirmed by the determination of motor activation peaks. The shift of ipsilesional MC was directly correlated with a frontal-parietal tumor location (p < 0.001), presence of motor deficits (p = 0.021), and with a longer period between MEG scans (p = 0.048). Also, a disengagement of wide areas in the contralesional (ipsilateral to finger movement) hemisphere at the second time point was observed. Conclusions: MEG imaging is a sensitive method for depicting the plasticity of the motor cortical network. Although the location of the primary MC undergoes only subtle changes, appreciable shifts can occur in the setting of a stronger and longer impairment of the tumor on the MC. The ipsilateral hemisphere may serve as a reservoir for functional recovery.

Language Neuroplasticity in Brain Tumor Patients Revealed by Magnetoencephalography.

Little is known about language impairment in brain tumor patients, especially in the presurgical phase. Impairment in this population may be missed because standardized tests fail to capture mild deficits. Additionally, neuroplasticity may also contribute to minimizing language impairments. We examined 14 presurgical patients with brain tumors in the language-dominant hemisphere using magnetoencephalography (MEG) while they performed a demanding picture-word interference task, that is, participants name pictures while ignoring distractor words. Brain tumor patients had behavioral picture-naming effects typically observed in healthy controls. The MEG responses also showed the expected pattern in its timing and amplitude modulation typical of controls, but with an altered spatial distribution of right hemisphere sources, in contrast to the classic left hemisphere source found in healthy individuals. This finding supports tumor-induced neural reorganization of language before surgery. Crucially, the use of electrophysiology allowed us to show the "same" neuronal response in terms of its timing and amplitude modulation in the right hemisphere, supporting the hypothesis that the processes performed by the right hemisphere following reorganization are similar in nature to those (previously) performed by the left hemisphere. We also identified one participant with a fast-growing tumor affecting large parts of critical language areas and underlying ventral and dorsal white matter tracts who showed a deviant pattern in behavior and in the MEG event-related responses. In conclusion, our results attest to the validity of using a demanding picture-naming task in presurgical patients and provide evidence for neuroplasticity, with the right hemisphere performing similar computations as the left hemisphere typically performs.

Magnetoencephalography imaging of high frequency oscillations strengthens presurgical localization and outcome prediction.

In patients with medically refractory epilepsy, resective surgery is the mainstay of therapy to achieve seizure freedom. However, ∼20-50% of cases have intractable seizures post-surgery due to the imprecise determination of epileptogenic zone. Recent intracranial studies suggest that high frequency oscillations between 80 and 200 Hz could serve as one of the consistent epileptogenicity biomarkers for localization of the epileptogenic zone. However, these high frequency oscillations are not adopted in the clinical setting because of difficult non-invasive detection. Here, we investigated non-invasive detection and localization of high frequency oscillations and its clinical utility in accurate pre-surgical assessment and post-surgical outcome prediction. We prospectively recruited 52 patients with medically refractory epilepsy who underwent standard pre-surgical workup including magnetoencephalography (MEG) followed by resective surgery after determination of the epileptogenic zone. The post-surgical outcome was assessed after 22.14 ± 10.05 months. Interictal epileptic spikes were expertly identified, and interictal epileptic oscillations across the neural activity frequency spectrum from 8 to 200 Hz were localized using adaptive spatial filtering methods. Localization results were compared with epileptogenic zone and resected cortex for congruence assessment and validated against the clinical outcome. The concordance rate of high frequency oscillations sources (80-200 Hz) with the presumed epileptogenic zone and the resected cortex were 75.0% and 78.8%, respectively, which is superior to that of other frequency bands and standard dipole fitting methods. High frequency oscillation sources corresponding with the resected cortex, had the best sensitivity of 78.0%, positive predictive value of 100% and an accuracy of 78.84% to predict the patient's surgical outcome, among all other frequency bands. If high frequency oscillation sources were spatially congruent with resected cortex, patients had an odds ratio of 5.67 and 82.4% probability of achieving a favourable surgical outcome. If high frequency oscillations sources were discordant with the epileptogenic zone or resection area, patient has an odds ratio of 0.18 and only 14.3% probability of achieving good outcome, and mostly tended to have an unfavourable outcome (χ2 = 5.22; P = 0.02; φ = -0.317). In receiver operating characteristic curve analyses, only sources of high-frequency oscillations demonstrated the best sensitivity and specificity profile in determining the patient's surgical outcome with area under the curve of 0.76, whereas other frequency bands indicate a poor predictive performance. Our study is the first non-invasive study to detect high frequency oscillations, address the efficacy of high frequency oscillations over the different neural oscillatory frequencies, localize them and clinically validate them with the post-surgical outcome in patients with medically refractory epilepsy. The evidence presented in the current study supports the fact that HFOs might significantly improve the presurgical assessment, and post-surgical outcome prediction, where it could widely be used in a clinical setting as a non-invasive biomarker.

Phase I trial of caudate deep brain stimulation for treatment-resistant tinnitus.

OBJECTIVE: The objective of this open-label, nonrandomized trial was to evaluate the efficacy and safety of bilateral caudate nucleus deep brain stimulation (DBS) for treatment-resistant tinnitus. METHODS: Six participants underwent DBS electrode implantation. One participant was removed from the study for suicidality unrelated to brain stimulation. Participants underwent a stimulation optimization period that ranged from 5 to 13 months, during which the most promising stimulation parameters for tinnitus reduction for each individual were determined. These individual optimal stimulation parameters were then used during 24 weeks of continuous caudate stimulation to reach the endpoint. The primary outcome for efficacy was the Tinnitus Functional Index (TFI), and executive function (EF) safety was a composite z-score from multiple neuropsychological tests (EF score). The secondary outcome for efficacy was the Tinnitus Handicap Inventory (THI); for neuropsychiatric safety it was the Frontal Systems Behavior Scale (FrSBe), and for hearing safety it was pure tone audiometry at 0.5, 1, 2, 3, 4, and 6 kHz and word recognition score (WRS). Other monitored outcomes included surgery- and device-related adverse events (AEs). Five participants provided full analyzable data sets. Primary and secondary outcomes were based on differences in measurements between baseline and endpoint. RESULTS: The treatment effect size of caudate DBS for tinnitus was assessed by TFI [mean (SE), 23.3 (12.4)] and THI [30.8 (10.4)] scores, both of which were statistically significant (Wilcoxon signed-rank test, 1-tailed; alpha = 0.05). Based on clinically significant treatment response categorical analysis, there were 3 responders determined by TFI (≥ 13-point decrease) and 4 by THI (≥ 20-point decrease) scores. Safety outcomes according to EF score, FrSBe, audiometric thresholds, and WRS showed no significant change with continuous caudate stimulation. Surgery-related and device-related AEs were expected, transient, and reversible. There was only one serious AE, a suicide attempt unrelated to caudate neuromodulation in a participant in whom stimulation was in the off mode for 2 months prior to the event. CONCLUSIONS: Bilateral caudate nucleus neuromodulation by DBS for severe, refractory tinnitus in this phase I trial showed very encouraging results. Primary and secondary outcomes revealed a highly variable treatment effect size and 60%-80% treatment response rate for clinically significant benefit, and no safety concerns. The design of a phase II trial may benefit from targeting refinement for final DBS lead placement to decrease the duration of the stimulation optimization period and to increase treatment effect size uniformity.Clinical trial registration no.: NCT01988688 (clinicaltrials.gov).

MEG imaging of recurrent gliomas reveals functional plasticity of hemispheric language specialization.

In patients with gliomas, changes in hemispheric specialization for language determined by magnetoencephalography (MEG) were analyzed to elucidate the impact of treatment and tumor recurrence on language networks. Demonstration of reorganization of language networks in these patients has significant implications on the prevention of postoperative functional loss and recovery. Whole-brain activity during an auditory verb generation task was estimated from MEG recordings in a group of 73 patients with recurrent gliomas. Hemisphere of language dominance was estimated using the language laterality index (LI), a measure derived from the task. The initial scan was performed prior to resection; patients subsequently underwent surgery and adjuvant treatment. A second scan was performed upon recurrence prior to repeat resection. The relationship between the shift in LI between scans and demographics, anatomic location, pathology, and adjuvant treatment was analyzed. Laterality shifts were observed between scans; the median percent change was 29.1% across all patients. Laterality shift magnitude and relative direction were associated with the initial position of language dominance; patients with increased lateralization experienced greater shifts than those presenting more bilateral representation. A change in LI from left or right to bilateral (or vice versa) occurred in 23.3% of patients; complete switch occurred in 5.5% of patients. Patients with tumors within the language-dominant hemisphere experienced significantly greater shifts than those with contralateral tumors. The majority of patients with glioma experience shifts in language network organization over time which correlate with the relative position of language lateralization and tumor location.

White matter microstructure predicts cognitive training-induced improvements in attention and executive functioning in schizophrenia.

We examined the relationship between white matter microstructure in schizophrenia using diffusion tensor imaging (DTI) and cognitive improvements induced by 70h (~16weeks) of cognitive training. We measured anatomical connectivity in 48 patients with schizophrenia (SZ) and 28 healthy control participants (HC) at baseline, and then examined the relationship between anatomical connectivity at baseline and training-induced cognitive gains in 30 SZ who performed diffusion imaging after completing 70h of training. Compared with healthy control participants, individuals with schizophrenia showed reduced white matter integrity at baseline, as indexed by fractional anisotropy metrics, in bilateral posterior corona radiata, bilateral retrolenticular internal capsules, bilateral posterior thalamic radiation, left anterior corona radiata, left superior longitudinal fasciculus, left sagittal stratum, right cerebral peduncle and the genu and splenium of the corpus callosum. After training, schizophrenia participants showed significant gains in attention/vigilance, speed of processing, verbal learning, visual learning and executive functioning. White matter integrity within the right fronto-occipital fasciculus predicted training-induced improvements in attention/vigilance, while white matter integrity within the right corticospinal tract and bilateral medial lemnisci predicted cognitive training-induced improvements in executive functioning, areas that did not show white matter tract deficits at baseline. These findings suggest that preserved white matter integrity connecting long-range prefrontal-thalamic-sensorimotor areas may be an important determinant for training-induced neurocognitive plasticity.

Magnetoencephalographic imaging of ictal high-frequency oscillations (80-200 Hz) in pharmacologically resistant focal epilepsy.

OBJECTIVE: Specificity of ictal high-frequency oscillations (HFOs) in identifying epileptogenic abnormality is significant, compared to the spikes and interictal HFOs. The objectives of the study were to detect and to localize ictal HFOs by magnetoencephalography (MEG) for identifying the seizure onset zone (SOZ), evaluate the cortical excitability from preictal to ictal transition, and establish HFO concordance rates with other modalities and postsurgical resection. METHODS: Sixty-seven patients with drug-resistant epilepsy had at least 1 spontaneous seizure each during MEG acquisition, and analysis was carried out on 20 seizures from 20 patients. Ictal MEG data were bandpass filtered (80-200 Hz) to visualize, review, and analyze the HFOs co-occurring with ictal spikes. Source montages were generated on both hemispheres, mean fast Fourier transform was computed on virtual time series for determining the preictal to ictal spectral power transition, and source reconstruction was performed with sLORETA and beamformers. The concordance rates of ictal MEG HFOs (SOZ) was estimated with 4 reference epileptogenic regions. RESULTS: In each subject, transient bursts of high-frequency oscillatory cycles, distinct from the background activity, were observed in the periictal continuum. Time-frequency analysis showed significant spectral power surge (85-160 Hz) during ictal state (P < .05) compared to preictal state, but there was no variation in the peak HFO frequencies (P > .05) for each subgroup and at each source montage. HFO source localization was consistent between algorithms (k = 0.857 ± 0.138), with presumed epileptogenic zone (EZ) comparable to other modalities. In patients who underwent surgery (n = 6), MEG HFO SOZ was concordant with the presumed EZ and the surgical resection site (100%), and all were seizure-free during follow-up. SIGNIFICANCE: HFOs could be detected in the MEG periictal state, and its sources were accurately localized. During preictal to ictal transition, HFOs exhibited dynamic augmentation in intrinsic epileptogenicity. Spatial overlap of ictal HFO sources was consistent with EZ determinants and the surgical resection area.

The sensitivity and significance of lateralized interictal slow activity on magnetoencephalography in focal epilepsy.

OBJECTIVE: Asymmetric large-amplitude slow activity is sometimes observed on interictal electroencephalography (EEG) in epilepsy. However, few studies have examined slowing during magnetoencephalography (MEG) recordings, which are performed primarily to localize interictal spikes. Also, no prior investigations have compared the sensitivity of MEG to scalp EEG in detecting slow rhythms. METHODS: We performed a retrospective cohort study of focal epilepsy patients who received MEG followed by surgical resection at our institution. We examined MEG, simultaneous EEG, and long-term EEG recordings for prominent asymmetric slow activity (delta-range, 1-4 Hz), and evaluated post-operative seizure outcomes. RESULTS: We studied 132 patients with ≥ 1 year post-operative follow-up (mean, 3.6 years). Mean age was 27 (range, 3-68) years, and 55% of patients were male. Asymmetric large-amplitude slow wave activity was observed on interictal MEG in 21 of 132 (16%) patients. Interictal slowing lateralized to the hemisphere of resection in all but one (95%) patient. Among the 21 patients with interictal MEG slowing, 11 (52%) individuals had similarly lateralized EEG slowing, 7 patients had no EEG slowing, and 3 had bilateral symmetric EEG slowing. Meanwhile, none of the 111 patients without lateralized MEG slowing had asymmetric EEG slowing, suggesting significantly higher sensitivity of MEG versus EEG in detecting asymmetric slowing (χ(2)=63.4, p<0.001). MEG slowing was associated with shorter epilepsy duration with an odds ratio of 5.4 (1.7-17.0, 95% confidence interval). At last follow-up, 92 (70%) patients were seizure free (Engel I outcome), with no difference in seizure freedom rates between patients with (71%) or without (69%) asymmetric MEG slowing (χ(2)=0.4, p=0.99). SIGNIFICANCE: MEG has higher sensitivity than scalp EEG in detecting asymmetric slow activity in focal epilepsy, which reliably lateralizes to the epileptogenic hemisphere. Other uses of MEG beyond spike localization may further improve presurgical evaluations in epilepsy.

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.

Resection of Motor Eloquent Metastases Aided by Preoperative nTMS-Based Motor Maps-Comparison of Two Observational Cohorts.

INTRODUCTION: Preoperative mapping of motor areas with navigated transcranial magnetic stimulation (nTMS) has been shown to improve surgical outcomes for peri-Rolandic lesions and, in particular, for gliomas. However, the impact of this technique on surgical outcomes for peri-Rolandic metastatic lesions is yet unknown. OBJECTIVE: To investigate the impact of nTMS on surgical outcomes for peri-Rolandic metastatic lesions, various clinical parameters were analyzed in our international study group. METHODS: Two prospectively enrolled cohorts were compared by investigating patients receiving preoperative nTMS (2010-2015; 120 patients) and patients who did not receive preoperative nTMS (2006-2015; 130 patients). Tumor location, pathology, size, and preoperative deficits were comparable. RESULTS: The nTMS group showed a lower rate of residual tumor on postoperative magnetic resonance imaging (odds ratio 0.3025; 95% confidence interval 0.1356-0.6749). On long-term follow-up, surgery-related paresis was decreased in the nTMS group (nTMS vs. non-nTMS; improved: 30.8 vs. 13.1%, unchanged: 65.8 vs. 73.8%, worse: 3.4 vs. 13.1% of patients; p = 0.0002). Moreover, the nTMS group received smaller craniotomies (nTMS: 16.7 ± 8.6 cm2 vs. non-nTMS: 25.0 ± 17.1 cm2; p < 0.0001). Surgical time differed significantly between the two groups (nTMS: 128.8 ± 49.4 min vs. non-nTMS: 158.0 ± 65.8 min; p = 0.0002). CONCLUSION: This non-randomized study suggests that preoperative motor mapping by nTMS may improve the treatment of patients undergoing surgical resection of metastases in peri-Rolandic regions. These findings suggest that further evaluation with a prospective, randomized trial may be warranted.

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.

Epileptogenic zone localization using magnetoencephalography predicts seizure freedom in epilepsy surgery.

OBJECTIVE: The efficacy of epilepsy surgery depends critically upon successful localization of the epileptogenic zone. Magnetoencephalography (MEG) enables noninvasive detection of interictal spike activity in epilepsy, which can then be localized in three dimensions using magnetic source imaging (MSI) techniques. However, the clinical value of MEG in the presurgical epilepsy evaluation is not fully understood, as studies to date are limited by either a lack of long-term seizure outcomes or small sample size. METHODS: We performed a retrospective cohort study of patients with focal epilepsy who received MEG for interictal spike mapping followed by surgical resection at our institution. RESULTS: We studied 132 surgical patients, with mean postoperative follow-up of 3.6 years (minimum 1 year). Dipole source modeling was successful in 103 patients (78%), whereas no interictal spikes were seen in others. Among patients with successful dipole modeling, MEG findings were concordant with and specific to the following: (1) the region of resection in 66% of patients, (2) invasive electrocorticography (ECoG) findings in 67% of individuals, and (3) the magnetic resonance imaging (MRI) abnormality in 74% of cases. MEG showed discordant lateralization in ~5% of cases. After surgery, 70% of all patients achieved seizure freedom (Engel class I outcome). Whereas 85% of patients with concordant and specific MEG findings became seizure-free, this outcome was achieved by only 37% of individuals with MEG findings that were nonspecific to or discordant with the region of resection (χ(2) = 26.4, p < 0.001). MEG reliability was comparable in patients with or without localized scalp electroencephalography (EEG), and overall, localizing MEG findings predicted seizure freedom with an odds ratio of 5.11 (95% confidence interval [CI] 2.23-11.8). SIGNIFICANCE: MEG is a valuable tool for noninvasive interictal spike mapping in epilepsy surgery, including patients with nonlocalized findings receiving long-term EEG monitoring, and localization of the epileptogenic zone using MEG is associated with improved seizure outcomes.

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 Broca's 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 Broca's 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.

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.

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.