Insertional effect following electrode implantation: an underreported but important phenomenon.

Deep brain stimulation has revolutionized the treatment of movement disorders and is gaining momentum in the treatment of several other neuropsychiatric disorders. In almost all applications of this therapy, the insertion of electrodes into the target has been shown to induce some degree of clinical improvement prior to stimulation onset. Disregarding this phenomenon, commonly referred to as 'insertional effect', can lead to biased results in clinical trials, as patients receiving sham stimulation may still experience some degree of symptom amelioration. Similar to the clinical scenario, an improvement in behavioural performance following electrode implantation has also been reported in preclinical models. From a neurohistopathologic perspective, the insertion of electrodes into the brain causes an initial trauma and inflammatory response, the activation of astrocytes, a focal release of gliotransmitters, the hyperexcitability of neurons in the vicinity of the implants, as well as neuroplastic and circuitry changes at a distance from the target. Taken together, it would appear that electrode insertion is not an inert process, but rather triggers a cascade of biological processes, and, as such, should be considered alongside the active delivery of stimulation as an active part of the deep brain stimulation therapy.

Predictors of Tumor Dynamics Over a 6-Week Course of Concurrent Chemoradiotherapy for Glioblastoma and the Effect on Survival.

PURPOSE: We present the final analyses of tumor dynamics and their prognostic significance during a 6-week course of concurrent chemoradiotherapy for glioblastoma in the Glioblastoma Longitudinal Imaging Observational study. METHODS AND MATERIALS: This is a prospective serial magnetic resonance imaging study in 129 patients with glioblastoma who had magnetic resonance imaging obtained at radiation therapy (RT) planning (F0), fraction 10 (F10), fraction 20 (F20), and 1-month post-RT. Tumor dynamics assessed included gross tumor volume relative to F0 (Vrel) and tumor migration distance (dmigration). Covariables evaluated included: corpus callosum involvement, extent of surgery, O6-methylguanine-DNA-methyltransferase methylation, and isocitrate dehydrogenase mutation status. RESULTS: The median Vrel were 0.85 (range, 0.25-2.29) at F10, 0.79 (range, 0.09-2.22) at F20, and 0.78 (range, 0.13-4.27) at 1 month after completion of RT. The median dmigration were 4.7 mm (range, 1.1-20.4 mm) at F10, 4.7 mm (range, 0.8-20.7 mm) at F20, and 6.1 mm (range, 0.0-45.5 mm) at 1 month after completion of RT. Compared with patients who had corpus callosum involvement (n = 26), those without corpus callosum involvement (n = 103) had significant Vrel reduction at F20 (P = .03) and smaller dmigration at F20 (P = .007). Compared with patients who had biopsy alone (n = 19) and subtotal resection (n = 71), those who had gross total resection (n = 38) had significant Vrel reduction at F10 (P = .001) and F20 (P = .001) and a smaller dmigration at F10 (P = .03) and F20 (P = .002). O6-Methylguanine-DNA-methyltransferase methylation and isocitrate dehydrogenase mutation status were not significantly associated with tumor dynamics. The median progression-free survival and overall survival (OS) were 8.5 months (95% CI, 6.9-9.9) and 20.4 months (95% CI, 17.6-25.2). In multivariable analyses, patients with Vrel ≥ 1.33 at F10 had worse OS (hazard ratio [HR], 4.6; 95% CI, 1.8-11.4; P = .001), and patients with dmigration ≥ 5 mm at 1-month post-RT had worse progression-free survival (HR, 1.76; 95% CI, 1.08-2.87) and OS (HR, 2.2; 95% CI, 1.2-4.0; P = .007). CONCLUSIONS: Corpus callosum involvement and extent of surgery are independent predictors of tumor dynamics during RT and can enable patient selection for adaptive RT strategies. Significant tumor enlargement at F10 and tumor migration 1-month post-RT were associated with poorer OS.

Adverse Effects of Deep Brain Stimulation for Treatment-Resistant Depression: A Scoping Review.

Deep brain stimulation (DBS) is an emerging therapy for treatment-resistant depression (TRD). Although adverse effects have been reported in early-phase and a few randomized clinical trials, little is known about its overall safety profile, which has been assumed to be similar to that of DBS for movement disorders. The objective of this study was to pool existing safety data on DBS for TRD. Following PRISMA guidelines, PubMed was searched for English articles describing adverse outcomes after DBS for TRD. Studies were included if they reported at least 5 patients with a minimal follow-up of 6 months. After abstract (n = 607) and full-article review (n = 127), 28 articles reporting on 353 patients met criteria for final inclusion. Follow-up of the studies retrieved ranged from 12 to 96 months. Hemorrhages occurred in 0.8% of patients and infections in 10.2%. The rate of completed suicide was 2.5%. Development or worsening of depressive symptoms, anxiety, and mania occurred in 18.4%, 9.1%, and 5.1%, respectively. There were some differences between targets, but between-study heterogeneity precluded statistical comparisons. In conclusion, DBS for TRD is associated with surgical and psychiatric adverse events. Hemorrhage and infection occur at rates within an accepted range for other DBS applications. The risk of suicide after DBS for TRD is 2.5% but may not represent a significant deviation from the natural history of TRD. Finally, risks of worsening depression, anxiety, and the incidence of mania should be acknowledged when considering DBS for TRD.

Dose-Escalated Radiation Therapy Is Associated With Improved Outcomes for High-Grade Meningioma.

PURPOSE: The optimal modern radiation therapy (RT) approach after surgery for atypical and malignant meningioma is unclear. We present results of dose escalation in a single-institution cohort spanning 2000 to 2021. METHODS AND MATERIALS: Consecutive patients with histopathologic grade 2 or 3 meningioma treated with RT were reviewed. A dose-escalation cohort (≥66 Gy equivalent dose in 2-Gy fractions using an α/ß = 10) was compared with a standard-dose cohort (<66 Gy). Outcomes were progression-free survival (PFS), cause-specific survival, overall survival (OS), local failure (LF), and radiation necrosis. RESULTS: One hundred eighteen patients (111 grade 2, 94.1%) were identified; 54 (45.8%) received dose escalation and 64 (54.2%) standard dose. Median follow-up was 45.4 months (IQR, 24.0-80.0 months) and median OS was 9.7 years (Q1: 4.6 years, Q3: not reached). All dose-escalated patients had residual disease versus 65.6% in the standard-dose cohort (P < .001). PFS at 3, 4, and 5 years in the dose-escalated versus standard-dose cohort was 78.9%, 72.2%, and 64.6% versus 57.2%, 49.1%, and 40.8%, respectively, (P = .030). On multivariable analysis, dose escalation (hazard ratio [HR], 0.544; P = .042) was associated with improved PFS, whereas ≥2 surgeries (HR, 1.989; P = .035) and older age (HR, 1.035; P < .001) were associated with worse PFS. The cumulative risk of LF was reduced with dose escalation (P = .016). Multivariable analysis confirmed that dose escalation was protective for LF (HR, 0.483; P = .019), whereas ≥2 surgeries before RT predicted for LF (HR, 2.145; P = .008). A trend was observed for improved cause-specific survival and OS in the dose-escalation cohort (P < .1). Seven patients (5.9%) developed symptomatic radiation necrosis with no significant difference between the 2 cohorts. CONCLUSIONS: Dose-escalated RT with ≥66 Gy for high-grade meningioma is associated with improved local control and PFS with an acceptable risk of radiation necrosis.

Seasonal pattern and depression outcomes from repetitive transcranial magnetic stimulation.

Individuals with major depressive disorder (MDD) may exhibit a seasonal pattern. The impact of a seasonal pattern in depressive symptoms on rTMS outcomes is unexplored. A retrospective analysis was performed on patients with MDD receiving open-label high frequency rTMS to the left dorsolateral prefrontal cortex. Having a seasonal pattern was defined as scoring ≥ 12 on the Personal Inventory for Depression and Seasonal Affective Disorder (PIDS). Primary outcomes included improvement in the Hamilton Depression Rating Scale (HAMD) and remission. Secondary analyses included the use of the self-rated Quick Inventory of Depressive Symptomatology (QIDS) to assess for changes in atypical neurovegetative symptoms. Multiple linear regression, multiple logistic regression, and linear mixed effects analyses were performed. 46 % (58/127) of the sample had a seasonal pattern. Seasonal pattern did not significantly influence improvement in HAMD (PIDS < 12, 7.8, SD 5.9; PIDS ≥ 12, 10.4, SD 4.9 or remission (PIDS < 12, 30 %; PIDS ≥ 12, 34 %). There were equivalent degrees of improvement in atypical neurovegetative symptoms over time as assessed using the QIDS. Depression with seasonal pattern was found to respond to rTMS treatment similarly to depression without seasonal pattern, suggesting that this may be a viable treatment for this group.

Relationship between apparent diffusion coefficient and survival as a function of distance from gross tumor volume on radiation planning MRI in newly diagnosed glioblastoma.

PURPOSE: To investigate the changes in apparent diffusion coefficient (ADC) within incrementally-increased margins beyond the gross tumor volume (GTV) on post-operative radiation planning MRI and their prognostic utility in glioblastoma. METHODS: Radiation planning MRIs of adult patients with newly diagnosed glioblastoma from 2017 to 2020 were assessed. The ADC values were normalized to contralateral normal white matter (nADC). Using 1 mm isotropic incremental margin increases from the GTV, the nADC values were calculated at each increment. Age, ECOG performance status, extent of resection and MGMT promoter methylation status were obtained from medical records. Using univariate and multivariable Cox regression analysis, association of nADC to progression-free and overall survival (PFS, OS) was assessed at each increment. RESULTS: Seventy consecutive patients with mean age of 53.6 ± 10.3 years, were evaluated. The MGMT promoter was methylated in 31 (44.3%), unmethylated in 36 (51.6%) and unknown in 3 (4.3%) patients. 11 (16%) underwent biopsy, 41 (44%) subtotal resection and 18 (26%) gross total resection. For each 1 mm increase in distance from GTV, the nADC decreased by 0.16% (p < 0.0001). At 1-5 mm increment, the nADC was associated with OS (p < 0.01). From 6 to 11 mm increment the nADC was associated with OS with the p-value gradually increasing from 0.018 to 0.046. nADC was not associated with PFS. CONCLUSION: The nADC values at 1-11 mm increments from the GTV margin were associated with OS. Future prospective multicenter studies are needed to validate the findings and to pave the way for the utilization of ADC for margin reduction in radiation planning.

What do we know about astrocytes and the antidepressant effects of DBS?

Treatment-resistant depression (TRD) is a debilitating condition that affects millions of individuals worldwide. Deep brain stimulation (DBS) has been widely used with excellent outcomes in neurological disorders such as Parkinson's disease, tremor, and dystonia. More recently, DBS has been proposed as an adjuvant therapy for TRD. To date, the antidepressant efficacy of DBS is still controversial, and its mechanisms of action remain poorly understood. Astrocytes are the most abundant cells in the nervous system. Once believed to be a "supporting" element for neuronal function, astrocytes are now recognized to play a major role in brain homeostasis, neuroinflammation and neuroplasticity. Because of its many roles in complex multi-factorial disorders, including TRD, understanding the effect of DBS on astrocytes is pivotal to improve our knowledge about the antidepressant effects of this therapy. In depression, the number of astrocytes and the expression of astrocytic markers are decreased. One of the potential consequences of this reduced astrocytic function is the development of aberrant glutamatergic neurotransmission, which has been documented in several models of depression-like behavior. Evidence from preclinical work suggests that DBS may directly influence astrocytic activity, modulating the release of gliotransmitters, reducing neuroinflammation, and altering structural tissue organization. Compelling evidence for an involvement of astrocytes in potential mechanisms of DBS derive from studies suggesting that pharmacological lesions or the inhibition of these cells abolishes the antidepressant-like effect of DBS. In this review, we summarize preclinical data suggesting that the modulation of astrocytes may be an important mechanism for the antidepressant-like effects of DBS.

Reduction of aggressive behaviour following hypothalamic deep brain stimulation: Involvement of 5-HT1A and testosterone.

BACKGROUND: Aggressive behaviour (AB) may occur in patients with different neuropsychiatric disorders. Although most patients respond to conventional treatments, a small percentage continue to experience AB despite optimized pharmacological management and are considered to be treatment-refractory. For these patients, hypothalamic deep brain stimulation (pHyp-DBS) has been investigated. The hypothalamus is a key structure in the neurocircuitry of AB. An imbalance between serotonin (5-HT) and steroid hormones seems to exacerbate AB. OBJECTIVES: To test whether pHyp-DBS reduces aggressive behaviour in mice through mechanisms involving testosterone and 5-HT. METHODS: Male mice were housed with females for two weeks. These resident animals become territorial and aggressive towards intruder mice placed in their cages. Residents had electrodes implanted in the pHyp. DBS was administered for 5 h/day for 8 consecutive encounters prior to the interaction with the intruder. After testing, blood and brains were recovered for measuring testosterone and 5-HT receptor density, respectively. In a second experiment, residents received WAY-100635 (5-HT1A antagonist) or saline injections prior to pHyp-DBS. After the first 4 encounters, the injection allocation was crossed, and animals received the alternative treatment during the next 4 encounters. RESULTS: DBS-treated mice showed reduced AB that was correlated with testosterone levels and an increase in 5-HT1A receptor density in the orbitofrontal cortex and amygdala. Pre-treatment with WAY-100635 blocked the anti-aggressive effect of pHyp-DBS. CONCLUSIONS: This study shows that pHyp-DBS reduces AB in mice via changes in testosterone and 5-HT1A mechanisms.

Re-irradiation for recurrent high-grade glioma: an analysis of prognostic factors for survival and predictors of radiation necrosis.

PURPOSE: Recurrent high-grade glioma (rHGG) is a heterogeneous population, and the ideal patient selection for re-irradiation (re-RT) has yet to be established. This study aims to identify prognostic factors for rHGG patients treated with re-RT. METHODS: We retrospectively reviewed consecutive adults with rHGG who underwent re-RT from 2009 to 2020 from our institutional database. The primary objective was overall survival (OS). Secondary endpoints included prognostic factors for early death (< 6 months after re-RT) and predictors of radiation necrosis (RN). RESULTS: For the 79 patients identified, the median OS after re-RT was 9.9 months (95% CI 8.3-11.6). On multivariate analyses, re-resection at progression (HR 0.56, p = 0.027), interval from primary treatment to first progression ≥ 16.3 months (HR 0.61, p = 0.034), interval from primary treatment to re-RT ≥ 23.9 months (HR 0.35, p < 0.001), and re-RT PTV volume < 112 cc (HR 0.27, p < 0.001) were prognostic for improved OS. Patients who had unmethylated-MGMT tumours (OR 12.4, p = 0.034), ≥ 3 prior systemic treatment lines (OR 29.1, p = 0.022), interval to re-RT < 23.9 months (OR 9.0, p = 0.039), and re-RT PTV volume ≥ 112 cc (OR 17.8, p = 0.003) were more likely to die within 6 months of re-RT. The cumulative incidence of RN was 11.4% (95% CI 4.3-18.5) at 12 months. Concurrent bevacizumab use (HR < 0.001, p < 0.001) and cumulative equivalent dose in 2 Gy fractions (EQD2, α/ß = 2) < 99 Gy2 (HR < 0.001, p < 0.001) were independent protective factors against RN. Re-RT allowed for less corticosteroid dependency. Sixty-six percent of failures after re-RT were in-field. CONCLUSION: We observe favorable OS rates following re-RT and identified prognostic factors, including methylation status, that can assist in patient selection and clinical trial design. Concurrent use of bevacizumab mitigated the risk of RN.

Multi-centre analysis of networks and genes modulated by hypothalamic stimulation in patients with aggressive behaviours.

Deep brain stimulation targeting the posterior hypothalamus (pHyp-DBS) is being investigated as a treatment for refractory aggressive behavior, but its mechanisms of action remain elusive. We conducted an integrated imaging analysis of a large multi-centre dataset, incorporating volume of activated tissue modeling, probabilistic mapping, normative connectomics, and atlas-derived transcriptomics. Ninety-one percent of the patients responded positively to treatment, with a more striking improvement recorded in the pediatric population. Probabilistic mapping revealed an optimized surgical target within the posterior-inferior-lateral region of the posterior hypothalamic area. Normative connectomic analyses identified fiber tracts and functionally connected with brain areas associated with sensorimotor function, emotional regulation, and monoamine production. Functional connectivity between the target, periaqueductal gray and key limbic areas - together with patient age - were highly predictive of treatment outcome. Transcriptomic analysis showed that genes involved in mechanisms of aggressive behavior, neuronal communication, plasticity and neuroinflammation might underlie this functional network.

The return of the lesion for localization and therapy.

Historically, pathological brain lesions provided the foundation for localization of symptoms and therapeutic lesions were used as a treatment for brain diseases. New medications, functional neuroimaging and deep brain stimulation have led to a decline in lesions in the past few decades. However, recent advances have improved our ability to localize lesion-induced symptoms, including localization to brain circuits rather than individual brain regions. Improved localization can lead to more precise treatment targets, which may mitigate traditional advantages of deep brain stimulation over lesions such as reversibility and tunability. New tools for creating therapeutic brain lesions such as high intensity focused ultrasound allow for lesions to be placed without a skin incision and are already in clinical use for tremor. Although there are limitations, and caution is warranted, improvements in lesion-based localization are refining our therapeutic targets and improved technology is providing new ways to create therapeutic lesions, which together may facilitate the return of the lesion.

Hypofractionated stereotactic radiosurgery (HSRS) as a salvage treatment for brain metastases failing prior stereotactic radiosurgery (SRS).

INTRODUCTION: Various treatment options exist to salvage stereotactic radiosurgery (SRS) failures for brain metastases, including repeat SRS and hypofractionated SRS (HSRS). Our objective was to report outcomes specific to salvage HSRS for brain metastases that failed prior HSRS/SRS. METHODS: Patients treated with HSRS to salvage local failures (LF) following initial HSRS/SRS, between July 2010 and April 2020, were retrospectively reviewed. The primary outcomes were the rates of LF, radiation necrosis (RN), and symptomatic radiation necrosis (SRN). Univariable (UVA) and multivariable (MVA) analyses using competing risk regression were performed to identify predictive factors for each endpoint. RESULTS: 120 Metastases in 91 patients were identified. The median clinical follow up was 13.4 months (range 1.1-111.1), and the median interval between SRS courses was 13.1 months (range 3.0-56.5). 115 metastases were salvaged with 20-35 Gy in 5 fractions and the remaining five with a total dose ranging from 20 to 24 Gy in 3-fractions. 67 targets (56%) were postoperative cavities. The median re-treatment target volume and biological effective dose (BED10) was 9.5 cc and 37.5 Gy, respectively. The 6- and 12- month LF rates were 18.9% and 27.7%, for RN 13% and 15.6%, and for SRN were 6.1% and 7.0%, respectively. MVA identified larger re-irradiation volume (hazard ratio [HR] 1.02, p = 0.04) and shorter interval between radiosurgery courses (HR 0.93, p < 0.001) as predictors of LF. Treatment of an intact target was associated with a higher risk of RN (HR 2.29, p = 0.04). CONCLUSION: Salvage HSRS results in high local control rates and toxicity rates that compare favorably to those single fraction SRS re-irradiation experiences reported in the literature.