Decoding the clinical effects of low-grade glioma–induced cortical excitability

J Neurosurg 140:18–26, 2024

Patients with low-grade glioma (LGG) in eloquent regions often present with seizures, and findings on detailed neuropsychological testing are often abnormal. This study evaluated the association between cortical excitability, seizures, and cognitive function in patients with LGG.

METHODS LGG patients who underwent transcranial magnetic stimulation (TMS) from January 2021 to December 2022 were studied. Cortical excitability was measured using the resting motor thresholds (RMTs) of the upper and lower extremities. Early postoperative seizures served as the seizure endpoint. Neuropsychological assessment was completed prior to surgery contemporaneous with the TMS studies.

RESULTS A total of 31 patients were analyzed for seizure outcome. Median (interquartile range [IQR]) upper-extremity RMT was 39% (34%–46%) of maximum stimulator output, and the median (IQR) lower-extremity RMT was 69% (51%79%). Lower-extremity RMT was higher in patients with early postoperative seizures, especially in those with motor region tumors (p = 0.02); however, RMT was not associated with seizures at presentation or long-term seizure control. A total of 26 patients completed neuropsychological assessment. There were significant negative correlations between upper-extremity RMT and psychomotor processing speed (Wechsler Adult Intelligence Scale–Fourth Edition [WAIS-IV] Processing Speed Index r = −0.42, p = 0.031; WAIS-IV Coding r = −0.41, p = 0.036; WAIS-IV Symbol Search r = −0.39, p = 0.048), executive function (Trail Making Test Part B r = −0.41, p = 0.036), and hand dexterity (Grooved Pegboard Test r = −0.50, p = 0.047).

CONCLUSIONS RMT was positively correlated with early postoperative seizure risk and negatively correlated with psychomotor processing speed, executive function, and hand dexterity. These findings support the theory of local and regional resting oscillatory network dysfunction from a glioma-brain network.

Neurostimulation for treatment-resistant posttraumatic stress disorder

J Neurosurg 134:1715–1723, 2021

Posttraumatic stress disorder (PTSD) is a widespread and often devastating psychiatric condition. Core symptoms include intrusive and distressing thoughts, heightened reactivity, mood changes, cognitive impairments, and consequent avoidance of trauma-related stimuli. Symptoms of PTSD are often refractory to standard treatments, and neuromodulatory techniques have therefore drawn significant interest among the most treatment-resistant patients.

Transcranial magnetic stimulation has demonstrated minimal efficacy, and deep brain stimulation trials are currently ongoing.

PTSD is a disorder of neural circuitry; the current understanding includes involvement of the amygdala (basolateral and central nuclei), the prefrontal cortex (ventral medial and dorsolateral regions), and the hippocampus. Neuroimaging and optogenetic studies have improved the understanding of large-scale neural networks and the effects of microcircuitry manipulation, respectively.

This review discusses the current PTSD literature and ongoing neurostimulation trials, and it highlights the current understanding of neuronal circuit dysfunction in PTSD. The authors emphasize the anatomical correlations of PTSD’s hallmark symptoms, offer another potential deep brain stimulation target for PTSD, and note the need for continued research to identify useful biomarkers for the development of closed-loop therapies. Although there is hope that neuromodulation will become a viable treatment modality for PTSD, this concept remains theoretical, and further research should involve institutional review board–approved controlled prospective clinical studies.


Altered corticospinal microstructure and motor cortex excitability in gliomas

J Neurosurg 134:1368–1376, 2021

This prospective case-control study was conducted to examine whether spherical deconvolution (SD) can unveil microstructural abnormalities in the corticospinal tract (CST) caused by IDH-mutant gliomas. To determine the significance of abnormal microstructure, the authors investigated the correlation between diffusion parameters and neurophysiological data collected with navigated transcranial magnetic stimulation (nTMS).

METHODS Twenty participants (10 patients and 10 healthy controls) were recruited. Diffusion-weighted images were acquired on a 3-T MRI scanner using a cardiac-gated single-shot spin echo echo-planar imaging multiband sequence (TE 80 msec, TR 4000 msec) along 90 diffusion directions with a b-value of 2500 sec/mm2 (FOV 256 × 256 mm). Diffusion tensor imaging tractography and SD tractography were performed with deterministic tracking. The anterior portion of the ipsilateral superior peduncle and the precentral gyrus were used as regions of interest to delineate the CST. Diffusion indices were extracted and analyzed for significant differences between hemispheres in patients and between patient and control groups. A navigated brain stimulation system was used to deliver TMS pulses at hotspots at which motor evoked potentials (MEPs) for the abductor pollicis brevis, first digital interosseous, and abductor digiti minimi muscles are best elicited in patients and healthy controls. Functional measurements such as resting motor threshold (rMT), amplitude of MEPs, and latency of MEPs were noted. Significant differences between hemispheres in patients and between patients and controls were statistically analyzed. The Spearman rank correlation was used to investigate correlations between diffusion indices and functional measurements.

RESULTS The hindrance modulated orientational anisotropy (HMOA), measured with SD tractography, is lower in the hemisphere ipsilateral to glioma (p = 0.028). The rMT in the hemisphere ipsilateral to a glioma is significantly greater than that in the contralateral hemisphere (p = 0.038). All measurements contralateral to the glioma, except for the mean amplitude of MEPs (p = 0.001), are similar to those of healthy controls. Mean diffusivity and axial diffusivity from SD tractography are positively correlated with rMT in the hemisphere ipsilateral to glioma (p = 0.02 and 0.006, respectively). The interhemispheric difference in HMOA and rMT is correlated in glioma patients (p = 0.007).

CONCLUSIONS SD tractography can demonstrate microstructural abnormality within the CST of patients with IDH1- mutant gliomas that correlates to the functional abnormality measured with nTMS.

Neurophysiological examination combined with functional intraoperative navigation using TMS in patients with brain tumor near the central region

Acta Neurochirurgica (2019) 161:1853–1864

Feasibility and value of non-invasive transcranial magnetic brain stimulation (TMS MAGVENTURE® MagPro R30 Denmark) for preoperative diagnosis and surgical planning of brain tumor operations in everyday clinical practice.

Methods A prospective monocentric study was conducted, which included preoperative neurological and electrophysiological examination, TMS, and display of functional data in the navigation system (LOCALITE® TMS Navigator Germany). During surgery, the TMS data were correlated with the intraoperative monitoring (IOM). Twenty-four hours to 96 h and after at least 3 months, follow-ups with neurological, electrophysiological examinations and TMS stimulation were performed.

Results Twenty-five patients with tumors in or near by the primary motor cortex region were included in the study. Twenty-one patients completed preoperative and first postoperative TMS and the neurological examination. Eight of 21 patients showed slight worsening of primary motor cortex function, 8 patients had an unchanged state, and 4 patients showed an improvement early after surgery. The changes of the electrophysiological examination like significant delay of the latency and/or reduced amplitudes matched well with the postoperative neurological outcome: if patients showed a worsening of the SEP’s and MEP’s, the postoperative results revealed deterioration.

Conclusion A preoperatively performed TMS using the MAGVENTURE® MagPro R30 and the LOCALITE® TMS Navigator could be established in our clinical daily practice and allowed a safe and reliable mapping of the primary motor cortex in order to minimize the risk of postoperative neurological deficits and improve the neurological outcome of the patients.

Navigated transcranial magnetic stimulation for glioma removal- prognostic value in motor function recovery from postsurgical neurological deficits

J Neurosurg 127:877–891, 2017

The aim of the present study was to evaluate the usefulness of navigated transcranial magnetic stimulation (nTMS) as a prognostic predictor for upper-extremity motor functional recovery from postsurgical neurological deficits.

METHODS Preoperative and postoperative nTMS studies were prospectively applied in 14 patients (mean age 39 ± 12 years) who had intraparenchymal brain neoplasms located within or adjacent to the motor eloquent area in the cerebral hemisphere. Mapping by nTMS was done 3 times, i.e., before surgery, and 1 week and 3 weeks after surgery. To assess the response induced by nTMS, motor evoked potential (nTMS-MEP) was recorded using a surface electromyography electrode attached to the abductor pollicis brevis (APB). The cortical locations that elicited the largest electromyography response by nTMS were defined as hotspots. Hotspots for APB were confirmed as positive responsive sites by direct electrical stimulation (DES) during awake craniotomy. The distances between hotspots and lesions (DHS-L) were measured. Postoperative neurological deficits were assessed by manual muscle test and dynamometer. To validate the prognostic value of nTMS in recovery from upper-extremity paresis, the following were investigated: 1) the correlation between DHS-L and the serial grip strength change, and 2) the correlation between positive nTMS-MEP at 1 week after surgery and the serial grip strength change.

RESULTS From the presurgical nTMS study, MEPs from targeted muscles were identified in 13 cases from affected hemispheres. In one case, MEP was not evoked due to a huge tumor. Among 9 cases from which intraoperative DES mapping for hand motor area was available, hotspots for APB identified by nTMS were concordant with DES-positive sites. Compared with the adjacent group (DHS-L < 10 mm, n = 6), the nonadjacent group (DHS-L ≥ 10 mm, n = 7) showed significantly better recovery of grip strength at 3 months after surgery (p < 0.01). There were correlations between DHS-L and recovery of grip strength at 1 week, 3 weeks, and 3 months after surgery (r = 0.74, 0.68, and 0.65, respectively). Postsurgical nTMS was accomplished in 13 patients. In 9 of 13 cases, nTMS-MEP from APB muscle was positive at 1 week after surgery. Excluding the case in which nTMS-MEP was negative from the presurgical nTMS study, recoveries in grip strength were compared between 2 groups, in which nTMS-MEP at 1 week after surgery was positive (n = 9) or negative (n = 3). Significant differences were observed between the 2 groups at 1 week, 3 weeks, and 3 months after surgery (p < 0.01). Positive nTMS-MEP at 1 week after surgery correlated well with the motor recovery at 1 week, 3 weeks, and 3 months after surgery (r = 0.87, 0.88, and 0.77, respectively).

CONCLUSIONS Navigated TMS is a useful tool for identifying motor eloquent areas. The results of the present study have demonstrated the predictive value of nTMS in upper-extremity motor function recovery from postsurgical neurological deficits. The longer DHS-L and positive nTMS-MEP at 1 week after surgery have prognostic values of better recovery from postsurgical neurological deficits.


Protocol for motor and language mapping by navigated TMS in patients and healthy volunteers

Acta Neurochir (2017) 159:1187–1195

Navigated transcranial magnetic stimulation (nTMS) is increasingly used for preoperative mapping of motor function, and clinical evidence for its benefit for brain tumor patients is accumulating. In respect to language mapping with repetitive nTMS, literature reports have yielded variable results, and it is currently not routinely performed for presurgical language localization. The aim of this project is to define a common protocol for nTMS motor and language mapping to standardize its neurosurgical application and increase its clinical value.

Methods: The nTMS workshop group, consisting of highly experienced nTMS users with experience of more than 1500 preoperative nTMS examinations, met in Helsinki in January 2016 for thorough discussions of current evidence and personal experiences with the goal to recommend a standardized protocol for neurosurgical applications.

Results: nTMS motor mapping is a reliable and clinically validated tool to identify functional areas belonging to both normal and lesioned primary motor cortex. In contrast, this is less clear for language-eloquent cortical areas identified by nTMS. The user group agreed on a core protocol, which enables comparison of results between centers and has an excellent safety profile. Recommendations for nTMS motor and language mapping protocols and their optimal clinical integration are presented here.

Conclusion: At present, the expert panel recommends nTMS motor mapping in routine neurosurgical practice, as it has a sufficient level of evidence supporting its reliability. The panel recommends that nTMS language mapping be used in the framework of clinical studies to continue refinement of its protocol and increase reliability.

Mapping of cortical language function by functional magnetic resonance imaging and repetitive navigated transcranialmagnetic stimulation in 40 healthy subjects

Mapping of cortical language function by functional magnetic resonance imaging and repetitive navigated transcranial magnetic stimulation in 40 healthy subjects

Acta Neurochir (2016) 158:1303–1316

Functional magnetic resonance imaging (fMRI) is considered to be the standard method regarding noninvasive language mapping. However, repetitive navigated transcranial magnetic stimulation (rTMS) gains increasing importance with respect to that purpose. However, comparisons between both methods are sparse.

Methods We performed fMRI and rTMS language mapping of the left hemisphere in 40 healthy, right-handed subjects in combination with the tasks that are most commonly used in the neurosurgical context (fMRI: word-generation=WGEN task; rTMS: object-naming=ON task). Different rTMS error rate thresholds (ERTs) were calculated, and Cohen’s kappa coefficient and the cortical parcellation system (CPS) were used for systematic comparison of the two techniques.

Results Overall, mean kappa coefficients were low, revealing no distinct agreement. We found the highest agreement for both techniques when using the 2-out-of-3 rule (CPS region defined as language positive in terms of rTMS if at least 2 out of 3 stimulations led to a naming error). However, kappa for this threshold was only 0.24 (kappa of <0, 0.01–0.20, 0.21– 0.40, 0.41–0.60, 0.61–0.80 and 0.81–0.99 indicate less than chance, slight, fair, moderate, substantial and almost perfect agreement, respectively).

Conclusions Because of the inherent differences in the underlying physiology of fMRI and rTMS, the different tasks used and the impossibility of verifying the results via direct cortical stimulation (DCS) in the population of healthy volunteers, one must exercise caution in drawing conclusions about the relative usefulness of each technique for language mapping. Nevertheless, this study yields valuable insights into these two mapping techniques for the most common language tasks currently used in neurosurgical practice.

Combined noninvasive language mapping by navigated transcranial magnetic stimulation and functional MRI and its comparison with direct cortical stimulation

Combined noninvasive language mapping by navigated transcranial magnetic stimulation and functional MRI and its comparison with direct cortical stimulation


J Neurosurg 123:212–225, 2015

Repetitive navigated transcranial magnetic stimulation (rTMS) is now increasingly used for preoperative language mapping in patients with lesions in language-related areas of the brain. Yet its correlation with intraoperative direct cortical stimulation (DCS) has to be improved. To increase rTMS’s specificity and positive predictive value, the authors aim to provide thresholds for rTMS’s positive language areas. Moreover, they propose a protocol for combining rTMS with functional MRI (fMRI) to combine the strength of both methods.

Methods The authors performed multimodal language mapping in 35 patients with left-sided perisylvian lesions by using rTMS, fMRI, and DCS. The rTMS mappings were conducted with a picture-to-trigger interval (PTI, time between stimulus presentation and stimulation onset) of either 0 or 300 msec. The error rates (ERs; that is, the number of errors per number of stimulations) were calculated for each region of the cortical parcellation system (CPS). Subsequently, the rTMS mappings were analyzed through different error rate thresholds (ERT; that is, the ER at which a CPS region was defined as language positive in terms of rTMS), and the 2-out-of-3 rule (a stimulation site was defined as language positive in terms of rTMS if at least 2 out of 3 stimulations caused an error). As a second step, the authors combined the results of fMRI and rTMS in a predefined protocol of combined noninvasive mapping. To validate this noninvasive protocol, they correlated its results to DCS during awake surgery.

Results The analysis by different rTMS ERTs obtained the highest correlation regarding sensitivity and a low rate of false positives for the ERTs of 15%, 20%, 25%, and the 2-out-of-3 rule. However, when comparing the combined fMRI and rTMS results with DCS, the authors observed an overall specificity of 83%, a positive predictive value of 51%, a sensitivity of 98%, and a negative predictive value of 95%.

Conclusions In comparison with fMRI, rTMS is a more sensitive but less specific tool for preoperative language mapping than DCS. Moreover, rTMS is most reliable when using ERTs of 15%, 20%, 25%, or the 2-out-of-3 rule and a PTI of 0 msec. Furthermore, the combination of fMRI and rTMS leads to a higher correlation to DCS than both techniques alone, and the presented protocols for combined noninvasive language mapping might play a supportive role in the language-mapping assessment prior to the gold-standard intraoperative DCS.

Brain surface reformatted imaging (BSRI) for intraoperative neuronavigation in brain tumor surgery

Brain surface reformatted imaging (BSRI) for intraoperative neuronavigation in brain tumor surgery

Acta Neurochir (2015) 157:265–274

For safe resection of lesions situated in or near eloquent brain regions, determination of their spatial and functional relationship is crucial. Since functional magnetic resonance imaging and intraoperative neurophysiological mapping are not available in all neurosurgical departments, we aimed to evaluate brain surface reformatted imaging (BSRI) as an additional display mode for neuronavigation.

Methods Eight patients suffering from perirolandic tumors were preoperatively studied withMRI and navigated transcranial magnetic stimulation (nTMS). Afterwards, the MRI was automatically transformed into BSR images in neuronavigation software (Brainlab, Brainlab AG, Feldkirchen, Germany). One experienced neuroradiologist, one experienced neurosurgeon, and two residents determined hand representation areas ipsilateral to each tumor on two-dimensional (2D) MR images and on BSR images. All results were compared to results from intraoperative direct cortical mapping of the hand motor cortex and to preoperative nTMS results.

Results Findings from nTMS and intraoperative direct cortical mapping of the hand motor cortex were congruent in all cases. Hand representation areas were correctly determined on BSR images in 81.3%and on 2D-MR images in 93.75%(p= 0.26). In a subgroup analysis, experienced observers showed more familiarity with BSRI than residents (96.9 vs. 84.4 % correct results, p=0.19), with an equal error rate for 2D-MRI. The time required to define hand representation areas was significantly shorter using BSRI than using standard MRI (mean 27.4 vs. 40.4 s, p=0.04).

Conclusions With BSRI, a new method for neuronavigation is now available, allowing fast and easy intraoperative localization of distinct brain regions.

A Comparison of Language Mapping by Preoperative Navigated Transcranial Magnetic Stimulation and Direct Cortical Stimulation During Awake Surgery


Neurosurgery 72:808–819, 2013

Navigated transcranial magnetic stimulation (nTMS) is increasingly used in presurgical brain mapping. Preoperative nTMS results correlate well with direct cortical stimulation (DCS) data in the identification of the primary motor cortex. Repetitive nTMS can also be used for mapping of speech-sensitive cortical areas.

OBJECTIVE: The current cohort study compares the safety and effectiveness of preoperative nTMS with DCS mapping during awake surgery for the identification of language areas in patients with left-sided cerebral lesions.

METHODS: Twenty patients with tumors in or close to left-sided language eloquent regions were examined by repetitive nTMS before surgery. During awake surgery, language-eloquent cortex was identified by DCS. nTMS results were compared for accuracy and reliability with regard to DCS by projecting both results into the cortical parcellation system.

RESULTS: Presurgical nTMS maps showed an overall sensitivity of 90.2%, specificity of 23.8%, positive predictive value of 35.6%, and negative predictive value of 83.9% compared with DCS. For the anatomic Broca’s area, the corresponding values were a sensitivity of 100%, specificity of 13.0%, positive predictive value of 56.5%, and negative predictive value of 100%, respectively.

CONCLUSION: Good overall correlation between repetitive nTMS and DCS was observed, particularly with regard to negatively mapped regions. Noninvasive inhibition mapping with nTMS is evolving as a valuable tool for preoperative mapping of language areas. Yet its low specificity in posterior language areas in the current study necessitates further research to refine the methodology.

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

J Neurosurg 117:354–362, 2012

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.


Influence of Navigated Transcranial Magnetic Stimulation on Surgical Planning for Tumors in or Near the Motor Cortex

Neurosurgery 70:1248–1257, 2012 DOI: 10.1227/NEU.0b013e318243881e 

Brain tumor surgery near the motor cortex requires careful planning to achieve the optimal balance between completeness of tumor resection and preservation of motor function. Navigated transcranial magnetic stimulation (nTMS) can be used to map functionally essential motor areas preoperatively.

OBJECTIVE: To evaluate how much influence, benefit, and impact nTMS has on the surgical planning for tumors near the motor cortex.

METHODS: This study reviewed the records of 73 patients with brain tumors in or near the motor cortex, mapped preoperatively with nTMS. The surgical team prospectively classified how much influence the nTMS results had on the surgical planning. Stepwise regression analysis was used to explore which factors predict the amount of influence, benefit, and impact nTMS has on the surgical planning.

RESULTS: The influence of nTMS on the surgical planning was as follows: it confirmed the expected anatomy in 22% of patients, added knowledge that was not used in 23%, added awareness of high-risk areas in 27%, modified the approach in 16%, changed the planned extent of resection in 8%, and changed the surgical indication in 3%.

CONCLUSION: nTMS had an objective benefit on the surgical planning in one fourth of the patients and a subjective benefit in an additional half of the patients. It had an impact on the surgery itself in just more than half of the patients. By mapping the spatial relationship between the tumor and functional motor cortex, nTMS improves surgical planning for tumors in or near the motor cortex.

Preoperative Functional Mapping for Rolandic Brain Tumor Surgery: Comparison of Navigated Transcranial Magnetic Stimulation to Direct Cortical Stimulation

Neurosurgery 69:581–589, 2011 DOI: 10.1227/NEU.0b013e3182181b89

Transcranial magnetic stimulation (TMS) is the only noninvasive method for presurgical stimulation mapping of cortical function. Recent technical advancements have significantly increased the focality and usability of the method.

OBJECTIVE: To compare the accuracy of a 3-dimensional magnetic resonance imaging– navigated TMS system (nTMS) with the gold standard of direct cortical stimulation (DCS).

METHODS: The primary motor areas of 20 patients with rolandic tumors were mapped preoperatively with nTMS at 110% of the individual resting motor threshold. Intraoperative DCS was available from 17 patients. The stimulus locations eliciting the largest electromyographic response in the target muscles (‘‘hotspots’’) were determined for both methods.

RESULTS: The nTMS and DCS hotspots were located on the same gyrus in all cases. The mean 6 SEM distance between the nTMS and DCS hotspots was 7.83 6 1.18 mm for the abductor pollicis brevis (APB) muscle (n = 15) and 7.07 6 0.88 mm for the tibialis anterior muscle (n = 8). When a low number of DCS stimulations was performed, the distance between the nTMS and DCS hotspots increased substantially (r = 20.86 for APB). After the exclusion of the cases with , 15 DCS APB responses, the mean 6 SEM distance between the hotspots was only 4.70 6 1.09 mm for APB (n = 8).

CONCLUSION: Peritumoral mapping of the motor cortex by nTMS agreed well with the gold standard of DCS. Thus, nTMS is a reliable tool for preoperative mapping of motor function.