The insula is a portion of the cerebral cortex folded deep within the lateral sulcus covered by the overlying opercula of the inferior frontal lobe and superior portion of the temporal lobe. The insula has been parsed into sub-regions based upon cytoarchitectonics and structural and functional connectivity with multiple lines of evidence supporting specific roles for each of these sub-regions in pain processing and interoception. In the past, causal interrogation of the insula was only possible in patients with surgically implanted electrodes. Here, we leverage the high spatial resolution combined with the deep penetration depth of low-intensity focused ultrasound (LIFU) to non-surgically modulate either the anterior insula (AI) or posterior insula (PI) in humans for effect on subjective pain ratings, electroencephalographic (EEG) contact head evoked potentials (CHEPs) and time-frequency power as well as autonomic measures including heart-rate variability (HRV) and electrodermal response (EDR). N = 23 healthy volunteers received brief noxious heat pain stimuli to the dorsum of their right hand during continuous heart-rate, EDR and EEG recording. LIFU was delivered to either the AI (anterior short gyrus), PI (posterior longus gyrus) or under an inert sham condition time-locked to the heat stimulus. Results demonstrate that single-element 500 kHz LIFU is capable of individually targeting specific gyri of the insula. LIFU to both AI and PI similarly reduced perceived pain ratings but had differential effects on EEG activity. LIFU to PI affected earlier EEG amplitudes around 300 milliseconds whereas LIFU to AI affected EEG amplitudes around 500 milliseconds. In addition, only LIFU to the AI affected HRV as indexed by an increase in standard deviation of N-N intervals (SDNN) and mean HRV low frequency power. There was no effect of LIFU to either AI or PI on EDR or blood pressure. Taken together, LIFU looks to be an effective method to individually target sub-regions of the insula in humans for site-specific effects on brain biomarkers of pain processing and autonomic reactivity that translates to reduced perceived pain to a transient heat stimulus. These data have implications for the treatment of chronic pain and several neuropsychological diseases like anxiety, depression and addiction that all demonstrate abnormal activity in the insula concomitant with dysregulated autonomic function.

Cortical ependymomas are currently not considered a subgroup of supratentorial ependymomas; however, there is a growing body of literature investigating the natural history of these lesions compared to supratentorial ependymomas. We performed a systematic literature review of cortical ependymomas with a focus on the natural history, clinical characteristics, and clinical outcomes of these lesions as compared to supratentorial ependymomas. Our search revealed 153 unique cases of cortical ependymomas. The mean age on presentation was 21.2 years. Males and females comprised 58.8% (90/153) and 41.2% (63/153) of cases, respectively. The most common presenting symptom was seizure activity occurring in 44.4% of the cohort (68/153). The recently recognized C11orf95-RELA fusion was identified in 13.7% of the cohort (21/153) and 95.5% of cases (21/22) reporting molecular characterization. World Health Organization grades 2 and 3 were reported in 52.3% (79/151) and 47.7% (72/151) of cases, respectively. The frontal lobe was involved in the majority of cases (54.9%, 84/153). Gross total resection was achieved in 80.4% of cases (123/153). Tumor recurrence was identified in 27.7% of cases (39/141). Mean clinical follow-up was 41.3 months. Mean overall survival of patients who expired was 27.4 months whereas mean progression-free survival was 15.0 months. Comparatively, cortical ependymomas with C11orf95- RELA fusions and supratentorial ependymomas with C11orf95 RELA fusions exhibited differing clinical outcomes. Further studies with larger sample sizes are necessary to investigate the significance of RELA fusions on survival in cortical ependymomas and to determine whether cortical ependymomas with C11orf95- RELA fusions should be classified as a distinct entity.

Introduction: Although several studies have investigated the efficacy and safety of transcranial magnetic stimulation (TMS) for pain relief in chronic orofacial pain disorders (COFP), significant variability in stimulation methodology and a lack of sham-controlled, double-blinded studies limit the conclusions which can be drawn from this literature. Objective To review the current literature on the use of TMS for COFP and propose an optimal, sham-controlled, double blinded randomized trial. Additionally, this study design is novel in its application of this treatment to a population of COFP patients whose pain can not be controlled pharmacologically during the vulnerable pre-surgical period. Proposed Methods: 34 COFP patients with poor pain control who are awaiting neurosurgical intervention will be randomized evenly into either the sham or true TMS condition and receive 5 consecutive days of treatment. Each stimulation session will be a train of 100 20-Hz pulses once per minute for 10 minutes focused on the contra-lateral M1 Hand area, a protocol and target which showed the most promise in prior studies. The sham condition will be achieved by using a sham-capable TMS coil and replicating the scalp sensation of stimulation using transcutaneous electrical nerve stimulation electrodes toggled on or off by a single unblinded study coordinator. The primary outcome measure will be change in reported pain on the Short Form McGill Pain Questionnaire (SFMPQ), completed by participants at several timepoints. Change in SFMPQ composite scores over time between groups may be analyzed with a repeated ANOVA among other exploratory analyses. Conclusion These proposed methods represent the most rigorous investigation of TMS for COFP-related pain that the authors are aware of. By combining the use of a sham condition, double-blinding, and the most promising stimulation protocol according to current literature, the results of this study would yield near-definitive evidence of TMS efficacy. Additionally, such a study could inform whether the adoption of TMS as a pre-surgical intervention might provide pain relief in this especially vulnerable setting.