Neurorehabilitation after stroke using rTMS has been studied through several randomized controlled trials and meta-analyses for treatment of both acute and chronic motor and language deficits with positive results [13-18]. Surgical intervention for brain tumors, particularly when involving eloquent regions, carries a risk of neurologic complications with deficits involving motor and speech function. These deficits may be due to surgical damage to critical cortical and subcortical pathways, vascular injury, or disruption of critical network connections involved in complex neurologic functions. Evidence has supported the ability of rTMS to map eloquent regions involved in motor and speech function preoperatively to help guide intraoperative identification and thus preservation of these functional pathways . However, there is limited evidence for rTMS neurorehabilitation for motor and speech deficits acquired post-operatively in patients with brain tumors. Given the efficacy in stroke, investigations into the potential of targeted rTMS to improve post-operative outcomes in brain tumor patients has been pursued with promising results [26, 27]. We reviewed the current literature for data involving post-operative rTMS use for neurorehabilitation.
A review of the published literature through 2021 yielded five studies and a total number of 50 patients who received rTMS post-operatively (Table 1). Techniques varied with 4/5 studies using frameless stereotactic navigation for targeting. In addition, stimulation protocols varied, but mostly involved contralateral inhibitory stimulation of the primary motor cortex for motor rehabilitation. Most commonly, a frequency of 1-5 Hz and an intensity of 80-90% of motor threshold was utilized in conjunction with intense physical therapy and rehabilitation. Studies varied widely on the timeframe of initiating TMS post-operatively, but most studies prescribed a course of rTMS once daily for between 5 to 22 days. Heterogeneity exists regarding when to start treatment relative to surgery.
Importantly, post-operative rTMS was shown to be safe in the neuro-oncology population, as only five total patients experienced transient headache and no other adverse effects were noted, including wound issues. While the risk of seizures is the most severe known adverse effect of TMS, and although several cases have been reported to date, risk of seizure is believed to be less than 1% . Recent larger studies with glioma patients have demonstrated zero instances of seizure following rTMS post-operatively [23, 24]. TBS specifically has been associated with a lower estimated risk of 0.02% , and TBS protocols are therefore better suited to neurosurgical patients in general. The lack of seizures or any significant adverse effects after TMS use in brain tumor patients is further reassuring given that these patients are seen to be at higher risk for seizures. In one case report, one patient had known seizures related to her brain tumor and TMS did not induce any seizures while she was maintained on her anti-epileptic medication regimen . However, the overall risk must be evaluated on a case-by-case basis.
In terms of efficacy, rTMS in post-operative neuro-oncology patients did demonstrate benefits for both language and motor recovery. Overall data demonstrate a rate of 90% reported improvement of some motor or language function. These benefits were primarily shown when using a contralateral inhibitory TBS protocol for treatment of motor deficits, where rTMS was applied to the unaffected hemisphere. However, no comparative data exists in the neuro-oncology literature between iTBS or cTBS making it hard to draw conclusions on optimized treatment. One case report used ipsilateral stimulatory TBS for rehabilitation of expressive aphasia that did demonstrate global improvement but with diminishing recovery benefits after each rTMS session . These data are difficult to interpret, as deficit progression was concurrent with tumor progression within eloquent language regions. Nonetheless, these data are interesting as language function tends to be lateralized and contralateral inhibitory stimulation may not have the same benefits as with motor function. Further study into brain network guided rTMS may provide insight into the choice of using cTBS or iTBS in select cases. Specifically, given the complexity of language production, further research into ipsilateral excitatory stimulation versus network stimulation in patients with language dysfunction is warranted.
In the only published randomized controlled trial, contralateral TBS was used daily for 7 days post-operatively, but immediate changes in motor function were not statistically significant . However, after three months, statistically significant motor recovery was demonstrated as compared to sham controls. Although benefits were indeed seen immediately following TMS treatments, it appears these benefits may only become significant after several weeks or months. These data are difficult to interpret however given the natural potential for recovery following surgery in close proximity, but without disruption of eloquent regions.
Future Directions: Network Guided Approach for Individualized Targeting
Given the published support for the safety of rTMS-assisted neurorehabilitation following surgical management for brain tumors, future studies should be designed to better understand the potential efficacy of the treatment as well to better define treatment algorithms that optimize this efficacy. These studies are already ongoing in the stroke rehabilitation literature  and neuropsychiatric patients . From previous work, it is clear that the efficacy of rTMS treatment is highly related to the individual targets selected  as well as the precision in modulating those specific targets . Given that specific symptoms likely localize to specific underlying connections within brain networks, these concerns may be better addressed moving forward with improved consideration of patient-specific brain connectivity . Importantly, while patients may both present with the same post-operative functional deficits, they may require patient-specific targets to modulate specific networks  or even specific connectivity abnormalities . Furthermore, while many non-invasive stimulation protocols rely on standard craniometric measurements, millimeter differences over a patient’s scalp may selectively modulate completely different cortical subcortical connections that are unwarranted. However, an individualized neuroimaging-based approach which utilizes anatomically fine, parcel-guided rTMS to treat patient-specific connectivity abnormalities (Fig 2) provides one way to treat pathophysiologic signature profiles of patient-specific symptoms post-operatively more effectively [24, 36].
As the current published data regarding rTMS-assisted neurorehabilitation for brain tumor patients has been derived from case reports and limited series, interpretation of the potential efficacy of rTMS remains challenging. Additionally, natural post-operative neural reorganization processes with time may act as a confounding factor to these reports of motor and language recovery after TMS. As with stroke, which results in a fixed deficit, tumor progression may further compromise function and thus limit recovery efforts. While data from randomized controlled trials in stroke patients are otherwise promising, there is a need to address this factor in the post-operative neuro-oncologic population. This therefore calls for more randomized controlled trials in this population. Furthermore, the limited data led to challenges in quantifying the benefits of different parameters, though it does appear contralateral inhibitory TBS has been used successfully more frequently for motor deficit recovery. Future work should involve comparisons of different parameters and rTMS protocols to determine the most effective post-operative recovery modality.