Treatment of Refractory Bipolar Depression With Stereotactic Radiosurgery Targeting the Subgenual Cingulate Cortex.

Background The subgenual cingulate cortex (SGC) has been identified as a key structure within multiple neural circuits whose dysfunction is implicated in the neurobiology of depression. Deep brain stimulation in the SGC is thought to reduce and normalize local metabolism, causing normalization of circuit behavior and an improvement in depressive symptoms. We hypothesized that nonablative stereotactic radiosurgery (SRS) to the SGC would reduce local metabolism and reduce the severity of depression in patients with treatment-resistant bipolar depression. Methods Under the FDA's Humanitarian Device Exemption program, patients were screened for inclusion and exclusion criteria. Three volunteers meeting the criteria provided informed consent. Bilateral SGC targets were irradiated to a maximum dose of 75 Gy in one fraction. Subjects were followed for one year following the procedure with mood assessments (Hamilton Depression Rating Scale (HDRS), Clinical Global Impression-Improvement, Clinical Global Impression-Severity, and Young Mania Rating Scale), neurocognitive testing (Delis-Kaplan Executive Function System, Wechsler Adult Intelligence Scale III digit span, and California Verbal Learning Test II), and imaging. Further imaging was completed approximately two years after the procedure. Clinical improvement was defined as a ≥50% reduction in HDRS. Results Two of the three subjects showed clinical improvement in depressive symptoms during the follow-up period, while one subject showed no change in symptom severity. One of three subjects was hospitalized for the emergence of an episode of psychotic mania after discontinuing antipsychotic medications against medical advice but promptly recovered with the reinstitution of an antipsychotic. Sequential assessments did not reveal impairment in any cognitive domain assessed. For one of the three subjects, MRI imaging showed evidence of edema at 12 months post-SRS, which resolved at 22 months post-procedure. In a second of three patients, there was evidence of local edema at the target site at long-term follow-up. All imaging changes were asymptomatic. Conclusion Radiosurgical targeting of the SGC may be a noninvasive strategy for the reduction of severe depression in treatment-resistant bipolar disorder. Two out of three patients showed clinical improvement. While these results are promising, further study, including improvements in target selection and dosing considerations, is needed.

Dosimetric Comparison of Dedicated Radiosurgery Platforms for the Treatment of Essential Tremor: Technical Report.

Essential tremor (ET) is one of the most common adult movement disorders. As the worldwide population ages, the incidence and prevalence of ET is increasing. Although most cases can be managed conservatively, there is a subset of ET that is refractory to medical management. By virtue of being "reversible", deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) of the thalamus is one commonly accepted intervention. As an alternative to invasive and expensive DBS, there has been a renaissance in treating ET with lesion-based approaches, spearheaded most recently by high-intensity focused ultrasound (HIFU), the hallmark of which is that it is non-invasive. Meanwhile, stereotactic radiosurgical (SRS) lesioning of VIM represents another time-honored lesion-based non-invasive treatment of ET, which is especially well suited for those patients that cannot tolerate open neurosurgery and is now also getting a "second look". While multiple SRS platforms have been and continue to be used to treat ET, there is little in the way of dosimetric comparison between different technologies. In this brief technical report we compare the dosimetric profiles of three major radiosurgical platforms (Gamma Knife, CyberKnife Robotic Radiosurgery, and Zap-X Gyroscopic Radiosurgery (GRS)) for the treatment of ET. In general, the GRS and Gamma Knife were shown to have the best theoretical dosimetric profiles for VIM lesioning. Nevertheless the relevance of such superiority to clinical outcomes requires future patient studies.

Socio-economic disparities influence likelihood of post-operative radiation to resection cavities of metastatic brain tumors.

PURPOSE: Irradiating the surgical bed of resected brain metastases improves local and distant disease control. Over time, stereotactic radiosurgery (SRS) has replaced whole brain radiotherapy (WBRT) as the treatment standard of care because it minimizes long-term damage to neuro-cognition. Despite this data and growing adoption, socio-economic disparities in clinical access can result in sub-standard care for some patient populations. We aimed to analyze the clinical and socio-economic characteristics of patients who did not receive radiation after surgical resection of brain metastasis. METHODS: Our sample was obtained from Clinformatics® Data Mart Database and included all patients from 2004 to 2021 who did or did not receive radiation treatment within sixty days after resection of tumors metastatic to the brain. Regression analysis was done to identify factors responsible for loss to adjuvant radiation treatment. RESULTS: Of 8362 patients identified who had undergone craniotomy for resection of metastatic brain tumors, 3430 (41%) patients did not receive any radiation treatment. Compared to patients who did receive some form of radiation treatment (SRS or WBRT), patients who did not get any form of radiation were more likely to be older (p = 0.0189) and non-white (p = 0.008). Patients with Elixhauser Comorbidity Index ≥3 were less likely to receive radiation treatment (p < 0.01). Fewer patients with household income ≥ $75,000 did not receive radiation treatment (p < 0.01). CONCLUSION: Age, race, household income, and comorbidity status were associated with differential likelihood to receive post-operative radiation treatment.

Patterns of Progression in Patients With Newly Diagnosed Glioblastoma Treated With 5-mm Margins in a Phase 1/2 Trial of 5-Fraction Stereotactic Radiosurgery With Concurrent and Adjuvant Temozolomide.

PURPOSE: In patients with newly diagnosed glioblastoma (GBM), tumor margins of at least 20 mm are the standard of care. We sought to determine the pattern of tumor progression in patients treated with 5-fraction stereotactic radiosurgery with 5-mm margins. METHODS AND MATERIALS: Thirty adult patients with newly diagnosed GBM were treated with 5-fraction stereotactic radiosurgery in escalated doses from 25 to 40 Gy with a 5-mm total treatment margin. Progression was scored as "in-field" if the recurrent tumor was within or contiguous with the 5-mm margin, "marginal" if between 5 and 20 mm, and "distant" if entirely occurring greater than 20 mm. As geometric patterns of progression do not reflect the biologic dose received, we calculated the minimum equi-effective dose in 2 Gy (EQD2) per day at the site of tumor recurrence. Progression was "dosimetrically in-field" if covered by a minimum EQD2 per day of 48 Gy10. RESULTS: From 2010 to 2016, 27 patients had progressed. Progression was in-field in 17 (63%), marginal in 3 (11%), and distant in 7 (26%) patients. In the 3 patients with marginal progression, the minimum EQD2 to recurrent tumor were 48 Gy10, 56 Gy10 (both considered dosimetrically in-field), and 7 Gy10 (ie, dosimetrically out-of-field). Median overall survival was 12.1 months for in-field (95% confidence interval [CI], 8.9-17.6), 15.1 months (95% CI, 10.1 to not achieved) for marginal, and 21.4 months (95% CI, 11.2-33.5) for distant progression. Patients with radiation necrosis were less likely to have in-field progression (1 of 7; 14%) compared with those without radiation necrosis (16 of 20; 80%; P = .003); those with necrosis had a median overall survival of 27.2 months (95% CI, 11.2-48.3) compared with 11.7 months (95% CI, 8.9-17.6) for patients with no necrosis (P = .077). CONCLUSIONS: In patients with newly diagnosed GBM treated with a 5-mm clinical target volume margin, 3 patients (11%) had marginal progression within 5 to 20 mm; only 1 patient (4%) may have dosimetrically benefitted from conventional 20-mm margins. Radiation necrosis was associated with in-field tumor control.

Impact of socio-economic factors on radiation treatment after resection of metastatic brain tumors: trends from a private insurance database.

BACKGROUND: Stereotactic radiosurgery (SRS) to the surgical bed of resected brain metastases is now considered the standard of care due to its advantages over whole brain radiation therapy (WBRT). Despite the upward trend in SRS adoption since the 2000s, disparities have been reported suggesting that socio-economic factors can influence SRS utilization. OBJECTIVE: To analyze recent trends in SRS use and identify factors that influence treatment. METHODS: We conducted a retrospective cohort study with the Optum Commercial Claims and Encounters Database and included all patients from 2004 to 2021 who received SRS or WBRT within 60 days after resection of tumors metastatic to the brain. RESULTS: A total of 3495 patients met the inclusion and exclusion criteria. There were 1998 patients in the SRS group and 1497 patients in the WBRT group. SRS use now supersedes WBRT by a wide margin. Lung, breast and colon were the most common sites of primary tumor. Although we found no significant differences based on race among the treatment groups, patients with annual household income greater than $75,000 and those with some college or higher education are significantly more likely to receive SRS (OR 1.44 and 1.30; 95% CI 1.18-1.76 and 1.08-1.56; P = 0.001 and 0.005, respective). Patients with Elixhauser Comorbidity Index of three or more were significantly more likely to receive SRS treatment. CONCLUSION: The use of post-surgical SRS for brain metastasis has increased significantly over time, however education and income were associated with differential SRS utilization.

Non-ablative doses of focal ionizing radiation alters function of central neural circuits.

BACKGROUND: Modulation of pathological neural circuit activity in the brain with a minimum of complications is an area of intense interest. OBJECTIVE: The goal of the study was to alter neurons' physiological states without apparent damage of cellular integrity using stereotactic radiosurgery (SRS). METHODS: We treated a 7.5 mm-diameter target on the visual cortex of Göttingen minipigs with doses of 40, 60, 80, and 100 Gy. Six months post-irradiation, the pigs were implanted with a 9 mm-wide, eight-shank multi-electrode probe, which spanned the radiation focus as well as the low-exposure neighboring areas. RESULTS: Doses of 40 Gy led to an increase of spontaneous firing rate, six months post-irradiation, while doses of 60 Gy and greater were associated with a decrease. Subjecting the animals to visual stimuli resulted in typical visual evoked potentials (VEP). At 40 Gy, a significant reduction of the P1 peak time, indicative of higher network excitability was observed. At 80 Gy, P1 peak time was not affected, while a minor reduction at 60 Gy was seen. No distance-dependent effects on spontaneous firing rate, or on VEP were observed. Post-mortem histology revealed no evidence of necrosis at doses below 60 Gy. In an in vitro assay comprising of iPS-derived human neuron-astrocyte co-cultures, we found a higher vulnerability of inhibitory neurons than excitatory neurons with respect to radiation, which might provide the cellular mechanism of the disinhibitory effect observed in vivo. CONCLUSION: We provide initial evidence for a rather circuit-wide, long-lasting disinhibitory effect of low sub-ablative doses of SRS.

Phase I/II Dose-Escalation Trial of 3-Fraction Stereotactic Radiosurgery for Resection Cavities From Large Brain Metastases: Health-related Quality of Life Outcomes.

OBJECTIVES: We investigated differences in quality of life (QoL) in patients enrolled on a phase I/II dose-escalation study of 3-fraction resection cavity stereotactic radiosurgery (SRS) for large brain metastases. METHODS: Eligible patients had 1 to 4 brain metastases, one of which was a resection cavity 4.2 to 33.5 cm3. European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaires core-30 (QLQ-30) and brain cancer specific module (QLQ-BN20) were obtained before SRS and at each follow-up. Nine scales were analyzed (global health status; physical, social, and emotional functioning; motor dysfunction, communication deficit, fatigue, insomnia, and future uncertainty). QoL was assessed with mixed effects models. Differences ≥10 points with q-value (adjusted P-value to account for multiplicity of testing) <0.10 were considered significant. RESULTS: Between 2009 and 2014, 50 enrolled patients completed 277 QoL questionnaires. Median questionnaire follow-up was 11.8 months. After SRS, insomnia demonstrated significant improvement (q=0.032, -17.7 points at 15 mo post-SRS), and future uncertainty demonstrated significant worsening (q=0.018, +9.9 points at 15 mo post-SRS). Following intracranial progression and salvage SRS, there were no significant QoL changes. The impact of salvage whole brain radiotherapy could not be assessed because of limited data (n=4 patients). In the 28% of patients that had adverse radiation effect, QoL had significant worsening in 3 metrics (physical functioning, q=0.024, emotional functioning q=0.001, and future uncertainty, q=0.004). CONCLUSIONS: For patients treated with 3-fraction SRS for large brain metastasis cavities, 8 of 9 QoL metrics were unchanged or improved after initial SRS. Intracranial tumor progression and salvage SRS did not impact QoL. Adverse radiation effect may be associated with at least short-term QoL impairments, but requires further investigation.

Neuromodulation via Focal Radiation: Radiomodulation Update.

When radiation is focally delivered to brain tissue at sub-ablative doses, neural activity may be altered. When done at a specific brain circuit node or connection, this is referred to as "radiomodulation." Radiation-induced effects on brain tissue, basic science, and clinical research that supports the radiomodulation hypothesis are reviewed in this article. We review progress in defining the necessary parameters in terms of dose, volumes, and anatomical location. It may be possible to deliver therapeutic neuromodulation that is non-invasive, non-destructive, and durable.

Self-Shielding for the ZAP-X®: Revised Characterization and Evaluation.

The ZAP-X® is a newly designed, self-contained, and first-of-its-kind self-shielded therapeutic radiation therapy device dedicated to brain and head and neck stereotactic radiosurgery (SRS). By using an S-band linear accelerator (linac) and employing integrated minimal but sufficient shielding, the ZAP-X does not typically require a radiation bunker. At the same time, the self-shielded features of the ZAP-X are designed for more consistency of radiation protection, reducing the risk to radiation workers and others potentially exposed from a poorly designed or constructed radiotherapy vault. This study postulates that a radiosurgical system can be self-shielded, such that it produces radiation exposure levels deemed safe to the public while operating under a full clinical workload. The goal of self-shielding is achieved under all but the most exceptional clinical conditions. This work is intended to serve as guidance for the radiation safety evaluations of future ZAP-X treatment operations, following local or regional applicable regulatory requirements, and utilizing the unique provision of all or most of the required shielding material as an integral part of the device.

The Stanford stereotactic radiosurgery experience on 7000 patients over 2 decades (1999-2018): looking far beyond the scalpel.

OBJECTIVE: The CyberKnife (CK) has emerged as an effective frameless and noninvasive method for treating a myriad of neurosurgical conditions. Here, the authors conducted an extensive retrospective analysis and review of the literature to elucidate the trend for CK use in the management paradigm for common neurosurgical diseases at their institution. METHODS: A literature review (January 1990-June 2019) and clinical review (January 1999-December 2018) were performed using, respectively, online research databases and the Stanford Research Repository of patients with intracranial and spinal lesions treated with CK at Stanford. For each disease considered, the coefficient of determination (r2) was estimated as a measure of CK utilization over time. A change in treatment modality was assessed using a t-test, with statistical significance assessed at the 0.05 alpha level. RESULTS: In over 7000 patients treated with CK for various brain and spinal lesions over the past 20 years, a positive linear trend (r2 = 0.80) in the system's use was observed. CK gained prominence in the management of intracranial and spinal arteriovenous malformations (AVMs; r2 = 0.89 and 0.95, respectively); brain and spine metastases (r2 = 0.97 and 0.79, respectively); benign tumors such as meningioma (r2 = 0.85), vestibular schwannoma (r2 = 0.76), and glomus jugulare tumor (r2 = 0.89); glioblastoma (r2 = 0.54); and trigeminal neuralgia (r2 = 0.81). A statistically significant difference in the change in treatment modality to CK was observed in the management of intracranial and spinal AVMs (p < 0.05), and while the treatment of brain and spine metastases, meningioma, and glioblastoma trended toward the use of CK, the change in treatment modality for these lesions was not statistically significant. CONCLUSIONS: Evidence suggests the robust use of CK for treating a wide range of neurological conditions.

Effects of Focal Ionizing Radiation of the Squid Stellate Ganglion on Synaptic and Axonal Transmission in the Giant-Fiber Pathway.

Ionizing radiation is clinically used to treat neurological problems and reduce pathological levels of neural activity in the brain, but its cellular-level mechanisms are not well understood. Although spontaneous and stimulated synaptic activity has been produced in rodents by clinically and environmentally relevant doses of radiation, the effects on basic excitability properties of neurons have seldom been reported. This study examined the effects of focused ionizing radiation on synaptic transmission and action potential generation in the squid giant-fiber system, which includes the giant synapse between a secondary interneuron and the tertiary giant motor axons. Radiation of 140-300 Gy was delivered to a stellate ganglion of a living squid over several minutes, with the contralateral stellate ganglion serving as an internal control. No qualitative changes in the efficacy of synaptic transmission were noted in conjunction with stimulation of the input to the giant synapse, although in one irradiated ganglion, the refractory period increased from about 5 ms to more than 45 seconds. Small but significant changes in the action potential recorded from the giant motor axon in response to electrical stimulation were associated with an increased maximum rate of fall and a shortened action potential duration. Other action-potential parameters, including resting potential, overshoot, the maximum rate of the rise, and the refractory period were not significantly changed. Attempts to account for the observed changes in the action potential were carried through a Hodgkin-Huxley model of the action potential. This approach suggests that an increase in the maximum voltage-gated potassium conductance of about 50% mimics the action potential shortening and increased rate of fall that was experimentally observed. We propose that such an effect could result from phosphorylation of squid potassium channels.

Lichenoid Keratosis Skin Biopsy: A Case Report of Malignant Hospital Charges.

Skin cancers are the most common malignancy and are especially common among light-skinned individuals in sun-exposed areas. While in many cases, a characteristic or classic appearance of the lesion is sufficient to make a definitive diagnosis, shave biopsy remains an important procedure when diagnosing many such raised lesions. Over the span of two months, a 66-year-old Caucasian male noted the appearance of a small, raised pruritic scaly lesion over his right upper chest. The differential diagnosis included both cancerous and benign lesions. During a 15-minute clinic visit, a simple shave biopsy was performed, and additionally, 10 small actinic keratoses on the patient's arms, legs, and back were treated with cryotherapy using liquid nitrogen. Later, a histologic examination of the biopsied lesion revealed a benign lichenoid keratosis. The patient was billed $10,187 for this outpatient experience.

An Intracortical Implantable Brain-Computer Interface for Telemetric Real-Time Recording and Manipulation of Neuronal Circuits for Closed-Loop Intervention.

Recording and manipulating neuronal ensemble activity is a key requirement in advanced neuromodulatory and behavior studies. Devices capable of both recording and manipulating neuronal activity brain-computer interfaces (BCIs) should ideally operate un-tethered and allow chronic longitudinal manipulations in the freely moving animal. In this study, we designed a new intracortical BCI feasible of telemetric recording and stimulating local gray and white matter of visual neural circuit after irradiation exposure. To increase the translational reliance, we put forward a Göttingen minipig model. The animal was stereotactically irradiated at the level of the visual cortex upon defining the target by a fused cerebral MRI and CT scan. A fully implantable neural telemetry system consisting of a 64 channel intracortical multielectrode array, a telemetry capsule, and an inductive rechargeable battery was then implanted into the visual cortex to record and manipulate local field potentials, and multi-unit activity. We achieved a 3-month stability of the functionality of the un-tethered BCI in terms of telemetric radio-communication, inductive battery charging, and device biocompatibility for 3 months. Finally, we could reliably record the local signature of sub- and suprathreshold neuronal activity in the visual cortex with high bandwidth without complications. The ability to wireless induction charging combined with the entirely implantable design, the rather high recording bandwidth, and the ability to record and stimulate simultaneously put forward a wireless BCI capable of long-term un-tethered real-time communication for causal preclinical circuit-based closed-loop interventions.

The Zap-X Radiosurgical System in the Treatment of Intracranial Tumors: A Technical Case Report.

BACKGROUND AND IMPORTANCE: The Zap-X system (Zap Surgical Systems Inc, San Carlos, California) is a radically new surgical robot designed for brain and head and neck radiosurgery. It represents the first new dedicated brain stereotactic radiosurgery platform in almost half a century optimizing the goals of safety, speed, and accuracy. The Zap-X system was used in a required Chinese National Medical Products Administration clinical study. In early January 2020, 2 patients were treated with the Zap-X robot prior to a national COVID-19 lockdown. Both were closely followed via clinical exam and magnetic resonance imaging (MRI) imaging. Prospectively collected data were used to generate this report. CLINICAL PRESENTATION: Two female patients, each harboring either a trigeminal schwannoma or petroclival meningioma, were treated with the Zap-X robot. Respective tumor volumes were 2.60 and 4.02 cm3. A radiation dose of 13 Gy was prescribed to the 50% isodose line. At 8 mo of follow-up, preoperative symptoms were either resolved or stable and MRI imaging demonstrated a 31% and 56% reduction in lesion volume, respectively. In both patients, symptoms improved, and tumor volumes decreased, whereas no major complication was observed. CONCLUSION: Given only 2 patients and short-term follow-up, any conclusions about the safety and efficacy of the Zap-X radiosurgery robot are preliminary. However, in the absence of any other published outcomes to date, this small case series may be of interest to many radiosurgical specialists.

Effects of Focal Radiation on [18 F]-Fluoro-D-Glucose Positron Emission Tomography in the Brains of Miniature Pigs: Preliminary Findings on Local Metabolism.

OBJECTIVES: It would be a medically important advance if durable and focal neuromodulation of the brain could be delivered noninvasively and without ablation. This ongoing study seeks to elucidate the effects of precisely delivered ionizing radiation upon focal brain metabolism and the corresponding cellular integrity at that target. We hypothesize that focally delivered ionizing radiation to the brain can yield focal metabolic changes without lesioning the brain in the process. MATERIALS AND METHODS: We used stereotactic radiosurgery to deliver doses from 10 Gy to 120 Gy to the left primary motor cortex (M1) of Lee Sung miniature pigs (n = 8). One additional animal served as a nonirradiated control. We used positron emission tomography-computed tomography (PET-CT) to quantify radiation dose-dependent effects by calculating the ratio of standard uptake values (SUV) of 2-deoxy-2-[18 F]-fluoro-D-glucose (18 F-FDG) between the radiated (left) and irradiated (right) hemispheres across nine months. RESULTS: We found that the FDG-PET SUV ratio at the targeted M1 was significantly lowered from the pre-radiation baseline measurements for animals receiving 60 Gy or higher, with the effect persisting at nine months after radiosurgery. Only at 120 Gy was a lesion suggesting ablation visible at the M1 target. Animals treated at 60-100 Gy showed a reduced signal in the absence of an identifiable lesion, a result consistent with the occurrence of neuromodulation. CONCLUSION: Focal, noninvasive, and durable changes in brain activity can be induced without a magnetic resonance imaging (MRI)-visible lesion, a result that may be consistent with the occurrence of neuromodulation. This approach may provide new venues for the investigation of neuromodulatory treatments for disorders involving dysfunctional brain circuits. Postmortem pathological analysis is needed to elucidate whether there have been morphological changes not detected by MRI.

A Perspective of International Collaboration Through Web-Based Telecommunication-Inspired by COVID-19 Crisis.

The tsunami effect of the COVID-19 pandemic is affecting many aspects of scientific activities. Multidisciplinary experimental studies with international collaborators are hindered by the closing of the national borders, logistic issues due to lockdown, quarantine restrictions, and social distancing requirements. The full impact of this crisis on science is not clear yet, but the above-mentioned issues have most certainly restrained academic research activities. Sharing innovative solutions between researchers is in high demand in this situation. The aim of this paper is to share our successful practice of using web-based communication and remote control software for real-time long-distance control of brain stimulation. This solution may guide and encourage researchers to cope with restrictions and has the potential to help expanding international collaborations by lowering travel time and costs.

Radionecrosis and cellular changes in small volume stereotactic brain radiosurgery in a porcine model.

Stereotactic radiosurgery (SRS) has proven an effective tool for the treatment of brain tumors, arteriovenous malformation, and functional conditions. However, radiation-induced therapeutic effect in viable cells in functional SRS is also suggested. Evaluation of the proposed modulatory effect of irradiation on neuronal activity without causing cellular death requires the knowledge of radiation dose tolerance at very small tissue volume. Therefore, we aimed to establish a porcine model to study the effects of ultra-high radiosurgical doses in small volumes of the brain. Five minipigs received focal stereotactic radiosurgery with single large doses of 40-100 Gy to 5-7.5 mm fields in the left primary motor cortex and the right subcortical white matter, and one animal remained as unirradiated control. The animals were followed-up with serial MRI, PET scans, and histology 6 months post-radiation. We observed a dose-dependent relation of the histological and MRI changes at 6 months post-radiation. The necrotic lesions were seen in the grey matter at 100 Gy and in white matter at 60 Gy. Furthermore, small volume radiosurgery at different dose levels induced vascular, as well as neuronal cell changes and glial cell remodeling.