Identification of stress-induced epigenetic methylation onto dopamine D2 gene and neurological and behavioral consequences.

The D2 dopamine receptor (DRD2) gene has garnered substantial attention as one of the most extensively studied genes across various neuropsychiatric disorders. Since its initial association with severe alcoholism in 1990, particularly through the identification of the DRD2 Taq A1 allele, numerous international investigations have been conducted to elucidate its role in different conditions. As of February 22, 2024, there are 5485 articles focusing on the DRD2 gene listed in PUBMED. There have been 120 meta-analyses with mixed results. In our opinion, the primary cause of negative reports regarding the association of various DRD2 gene polymorphisms is the inadequate screening of controls, not adequately eliminating many hidden reward deficiency syndrome behaviors. Moreover, pleiotropic effects of DRD2 variants have been identified in neuropsychologic, neurophysiologic, stress response, social stress defeat, maternal deprivation, and gambling disorder, with epigenetic DNA methylation and histone post-translational negative methylation identified as discussed in this article. There are 70 articles listed in PUBMED for DNA methylation and 20 articles listed for histone methylation as of October 19, 2022. For this commentary, we did not denote DNA and/or histone methylation; instead, we provided a brief summary based on behavioral effects. Based on the fact that Blum and Noble characterized the DRD2 Taq A1 allele as a generalized reward gene and not necessarily specific alcoholism, it now behooves the field to find ways to either use effector moieties to edit the neuroepigenetic insults or possibly harness the idea of potentially removing negative mRNA-reduced expression by inducing "dopamine homeostasis."

Neurogenetics and Epigenetics of Loneliness.

Loneliness, an established risk factor for both, mental and physical morbidity, is a mounting public health concern. However, the neurobiological mechanisms underlying loneliness-related morbidity are not yet well defined. Here we examined the role of genes and associated DNA risk polymorphic variants that are implicated in loneliness via genetic and epigenetic mechanisms and may thus point to specific therapeutic targets. Searches were conducted on PubMed, Medline, and EMBASE databases using specific Medical Subject Headings terms such as loneliness and genes, neuro- and epigenetics, addiction, affective disorders, alcohol, anti-reward, anxiety, depression, dopamine, cancer, cardiovascular, cognitive, hypodopaminergia, medical, motivation, (neuro)psychopathology, social isolation, and reward deficiency. The narrative literature review yielded recursive collections of scientific and clinical evidence, which were subsequently condensed and summarized in the following key areas: (1) Genetic Antecedents: Exploration of multiple genes mediating reward, stress, immunity and other important vital functions; (2) Genes and Mental Health: Examination of genes linked to personality traits and mental illnesses providing insights into the intricate network of interaction converging on the experience of loneliness; (3) Epigenetic Effects: Inquiry into instances of loneliness and social isolation that are driven by epigenetic methylations associated with negative childhood experiences; and (4) Neural Correlates: Analysis of loneliness-related affective states and cognitions with a focus on hypodopaminergic reward deficiency arising in the context of early life stress, eg, maternal separation, underscoring the importance of parental support early in life. Identification of the individual contributions by various (epi)genetic factors presents opportunities for the creation of innovative preventive, diagnostic, and therapeutic approaches for individuals who cope with persistent feelings of loneliness. The clinical facets and therapeutic prospects associated with the current understanding of loneliness, are discussed emphasizing the relevance of genes and DNA risk polymorphic variants in the context of loneliness-related morbidity.

Personalized repetitive transcranial magnetic stimulation (prtms®) for post-traumatic stress disorder (ptsd) in military combat veterans.

Emerging data suggest that post-traumatic stress disorder (PTSD) arises from disrupted brain default mode network (DMN) activity manifested by dysregulated encephalogram (EEG) alpha oscillations. Hence, we pursued the treatment of combat veterans with PTSD (n = 185) using an expanded form of repetitive transcranial magnetic stimulation (rTMS) termed personalized-rTMS (PrTMS). In this treatment methodology spectral EEG based guidance is used to iteratively optimize symptom resolution via (1) stimulation of multiple motor sensory and frontal cortical sites at reduced power, and (2) adjustments of cortical treatment loci and stimulus frequency during treatment progression based on a proprietary frequency algorithm (PeakLogic, Inc. San Diego) identifying stimulation frequency in the DMN elements of the alpha oscillatory band. Following 4 - 6 weeks of PrTMS® therapy in addition to routine PTSD therapy, veterans exhibited significant clinical improvement accompanied by increased cortical alpha center frequency and alpha oscillatory synchronization. Full resolution of PTSD symptoms was attained in over 50% of patients. These data support DMN involvement in PTSD pathophysiology and suggest a role in therapeutic outcomes. Prospective, sham controlled PrTMS® trials may be warranted to validate our clinical findings and to examine the contribution of DMN targeting for novel preventive, diagnostic, and therapeutic strategies tailored to the unique needs of individual patients with both combat and non-combat PTSD.

Preliminary Observations of Personalized Repetitive Magnetic Stimulation (PrTMS) Guided by EEG Spectra for Concussion.

There are no FDA-approved treatments for the chronic sequelae of concussion. Repetitive magnetic transcranial stimulation (rTMS) has been explored as a therapy but outcomes have been inconsistent. To address this we developed a personalized rTMS (PrTMS) protocol involving continual rTMS stimulus frequency adjustment and progressive activation of multiple cortical sites, guided by spectral electroencephalogram (EEG)-based analyses and psychological questionnaires. We acquired pilot clinical data for 185 symptomatic brain concussion patients who underwent the PrTMS protocol over an approximate 6 week period. The PrTMS protocol used a proprietary EEG spectral frequency algorithm to define an initial stimulation frequency based on an anteriorly graded projection of the measured occipital alpha center peak, which was then used to interpolate and adjust regional stimulation frequency according to weekly EEG spectral acquisitions. PrTMS improved concussion indices and normalized the cortical alpha band center frequency and peak EEG amplitude. This potentially reflected changed neurotransmitter, cognitive, and perceptual status. PrTMS may be a promising treatment choice for patients with persistent concussion symptoms. This clinical observational study was limited in that there was no control group and a number of variables were not recorded, such as time since injury and levels of depression. While the present observations are indeed preliminary and cursory, they may suggest further prospective research on PrTMS in concussion, and exploration of the spectral EEG as a concussion biomarker, with the ultimate goals of confirmation and determining optimal PrTMS treatment parameters.

Evidence for the DRD2 Gene as a Determinant of Reward Deficiency Syndrome (RDS).

Since 1990, published addiction psychiatry articles have exceeded 11,495. Several from Blum et al. showed the clinical relevance of the Genetic Addiction Risk Severity (GARS) test in identifying risk for reward deficiency behaviors in cohorts from polysubstance and pain clinics, post-surgical bariatrics, and DWI offenders facing prison time. Since Blum et al first published in JAMA (1990) concerning the association of the DRD2 gene polymorphism and severe alcoholism, confirmation has been mixed and controversial. More recently, however, a meta-analysis of 62 studies showed a significant association between DRD2 rs 1800497 and Alcohol Use Disorder (AUD). Other studies from Yale University showed that a haplotype block of the DRD2 gene A1 allele was associated with AUD and heroin dependence. GWAS studies of depression and suicide in 1.2 million veterans confirmed the first psychiatric candidate gene study finding from Blum et al. 1990; a significant association between the minor DRD2 allele, Taq A1 (rs 1800497 C>T) and severe alcoholism. Additionally, the DRD2 rs1800497 is associated with suicide behaviors robustly at P=1.77 × 10-7. Furthermore, DNA polymorphic alleles underlying SUD with multiple substances were mapped via chromatin refolding, revealed that the DRD2 gene and associated polymorphism(s) was the top gene signal (DRD2, P=7.9 × 10-12). Additionally, based on these investigations, we conclude that GWAS should end the controversy about the DRD2 gene being at least one determinant of Reward Deficiency Syndrome (RDS) first reported in the Royal Society of Medicine journaling 1996.

Assessment of executive function in a rodent model of Type 1 diabetes.

This study examined the impact of Type 1 Diabetes Mellitus (T1DM) on executive function using a series of operant conditioning-based tasks in rats. Sprague Dawley rats were randomized to either non-diabetic (n = 12; 6 male) or diabetic (n = 14; 6 male) groups. Diabetes was induced using multiple low-dose streptozotocin injections. All diabetic rodents were insulin-treated using subcutaneous insulin pellet implants (9-15 mM). At week 14 of the study, rats were placed on a food restricted diet to induce 5-10 % weight loss. Rodents were familiarized and their set-shifting ability was tested on a series of tasks that required continuous adjustments to novel stimulus-reward paradigms in order to receive food rewards. Results showed no differences in the number of trials, nor number and type of errors made to successfully complete each task between groups. Therefore, we report no differences in executive function, or more specifically set-shifting abilities between non-diabetic and diabetic rodents that receive insulin.

Are We Getting High Cause the Thrill is Gone?

In the USA alone, opioid use disorder (OUD) affects approximately 27 million people. While the number of prescriptions may be declining due to increased CDC guidance and prescriber education, fatalities due to fentanyl-laced street heroin are still rising. Our laboratory has extended the overall concept of both substance and non-substance addictive behaviors, calling it "Reward Deficiency Syndrome (RDS)." Who are its victims, and how do we get this unwanted disorder? Is RDS caused by genes (Nature), environment (Neuro-epigenetics, Nurture), or both? Recent research identifies resting-state functional connectivity in the brain reward circuitry as a crucial factor. Analogously, it is of importance to acknowledge that the cumulative discharge of dopamine, governed by the nucleus accumbens (NAc) and modulated by an array of additional neurotransmitters, constitutes a cornerstone of an individual's overall well-being. Neuroimaging reveals that high-risk individuals exhibit a blunted response to stimuli, potentially due to DNA polymorphisms or epigenetic alterations. This discovery has given rise to the idea of a diminished 'thrill,' though we must consider whether this 'thrill' may have been absent from birth due to high-risk genetic predispositions for addiction. This article reviews this issue and suggests the general concept of the importance of "induction of dopamine homeostasis." We suggest coupling a validated genetic assessment (e.g., GARS) with pro-dopamine regulation (KB220) as one possible frontline modality in place of prescribing potent addictive opioids for OUD except for short time harm reduction. Could gene editing offer a 'cure' for this undesirable genetic modification at birth, influenced by the environment and carried over generations, leading to impaired dopamine and other neurotransmitter imbalances, as seen in RDS? Through dedicated global scientific exploration, we hope for a future where individuals are liberated from pain and disease, achieving an optimal state of well-being akin to the proverbial 'Garden of Eden'.

A Compact Battery-Powered rTMS Prototype.

This paper describes the design and testing of a compact, battery-powered repetitive Transcranial Magnetic Stimulation (rTMS) prototype. This device generates a 10 Hz magnetic pulse train with peak flux density of 100 mT at 2 cm distance. Circuit component design, including the inductor, switched LC resonator, and boost converter, are discussed in the context of weight and size reduction, and performance optimization. The experimental approach and rationale together with acquired results validating the rTMS prototype design are presented. To the best of our knowledge, this is the first comprehensive feasibility demonstration of an inexpensive, lightweight, and portable rTMS device able to generate therapeutic levels of current, pulse rise time, and number of pulses. The generated magnetic field was kept to 0.1 Tesla for safety and testing considerations, but nevertheless was very close to therapeutic intensity, with driving circuitry scalable to support much stronger fields.Clinical Relevance- This feasibility study of a compact, battery-powered rTMS prototype test platform aims to enable broader and more convenient rTMS treatment at home, in a small clinic, vessel, or field hospital, and potentially, on an ambulatory basis.

Equivalent Hypertrophy and Strength Gains in ß-Hydroxy-ß-Methylbutyrate- or Leucine-supplemented Men.

Ingestion of proteins with high leucine content during resistance training (RT) can augment hypertrophy. Some data suggest that a leucine metabolite, ß-hydroxy, ß-methylbutyrate (HMB), is substantially more anabolically efficacious than leucine. PURPOSE: We aimed to test whether supplementation with HMB versus leucine, added to whey protein, would result in differential muscle hypertrophy and strength gains in young men performing RT. METHODS: Twenty-six resistance-trained men (23 ± 2 yr) performed 12 wk of RT with three phases. Phase 1: 8 wk of periodized RT (three training sessions per week). Phase 2: 2 wk overreaching period (five sessions per week). Phase 3: 2 wk taper (three sessions per week). Participants were randomly assigned to twice daily ingestion of: whey protein (25 g) plus HMB (1.5 g) (whey+HMB; n = 13) or whey protein (25 g) plus leucine (1.5 g) (whey+leu; n = 13). Skeletal muscle biopsies were performed before and after RT. Measures of fat- and bone-free mass, vastus lateralis (VL) muscle thickness and muscle cross-sectional area (CSA) (both by ultrasound), muscle fiber CSA, and 1-repetition maximum (1-RM) strength tests were determined. RESULTS: We observed increases in fat- and bone-free mass, VL muscle thickness, muscle CSA and fiber type CSA and 1-RM strength with no differences between groups at any phase. We observed no differences between groups or time-group interactions in hormone concentrations at any phase of the RT program. CONCLUSIONS: ß-Hydroxy-ß-methylbutyrate added to whey did not result in greater increases in any measure of muscle mass, strength, or hormonal concentration compared to leucine added to whey. Our results show that HMB is no more effective in stimulating RT-induced hypertrophy and strength gains than leucine.

A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults.

OBJECTIVE: We performed a systematic review, meta-analysis and meta-regression to determine if dietary protein supplementation augments resistance exercise training (RET)-induced gains in muscle mass and strength. DATA SOURCES: A systematic search of Medline, Embase, CINAHL and SportDiscus. ELIGIBILITY CRITERIA: Only randomised controlled trials with RET ≥6 weeks in duration and dietary protein supplementation. DESIGN: Random-effects meta-analyses and meta-regressions with four a priori determined covariates. Two-phase break point analysis was used to determine the relationship between total protein intake and changes in fat-free mass (FFM). RESULTS: Data from 49 studies with 1863 participants showed that dietary protein supplementation significantly (all p<0.05) increased changes (means (95% CI)) in: strength-one-repetition-maximum (2.49 kg (0.64, 4.33)), FFM (0.30 kg (0.09, 0.52)) and muscle size-muscle fibre cross-sectional area (CSA; 310 µm2 (51, 570)) and mid-femur CSA (7.2 mm2 (0.20, 14.30)) during periods of prolonged RET. The impact of protein supplementation on gains in FFM was reduced with increasing age (-0.01 kg (-0.02,-0.00), p=0.002) and was more effective in resistance-trained individuals (0.75 kg (0.09, 1.40), p=0.03). Protein supplementation beyond total protein intakes of 1.62 g/kg/day resulted in no further RET-induced gains in FFM. SUMMARY/CONCLUSION: Dietary protein supplementation significantly enhanced changes in muscle strength and size during prolonged RET in healthy adults. Increasing age reduces and training experience increases the efficacy of protein supplementation during RET. With protein supplementation, protein intakes at amounts greater than ~1.6 g/kg/day do not further contribute RET-induced gains in FFM.

Using landscape habitat associations to prioritize areas of conservation action for terrestrial birds.

Predicting species distributions has long been a valuable tool to plan and focus efforts for biodiversity conservation, particularly because such an approach allows researchers and managers to evaluate species distribution changes in response to various threats. Utilizing data from a long-term monitoring program and land cover data sets, we modeled the probability of occupancy and colonization for 38 bird Species of Greatest Conservation Need (SGCN) in the robust design occupancy modeling framework, and used results from the best models to predict occupancy and colonization on the Iowa landscape. Bird surveys were conducted at 292 properties from April to October, 2006-2014. We calculated landscape habitat characteristics at multiple spatial scales surrounding each of our surveyed properties to be used in our models and then used kriging in ArcGIS to create predictive maps of species distributions. We validated models with data from 2013 using the area under the receiver operating characteristic curve (AUC). Probability of occupancy ranged from 0.001 (SE < 0.001) to 0.995 (SE = 0.004) for all species and probability of colonization ranged from 0.001 (SE < 0.001) to 0.999 (SE < 0.001) for all species. AUC values for predictive models ranged from 0.525-0.924 for all species, with 17 species having predictive models considered useful (AUC > 0.70). The most important predictor for occupancy of grassland birds was percentage of the landscape in grassland habitat, and the most important predictor for woodland birds was percentage of the landscape in woodland habitat. This emphasizes the need for managers to restore specific habitats on the landscape. In an era during which funding continues to decrease for conservation agencies, our approach aids in determining where to focus limited resources to best conserve bird species of conservation concern.

Clinical efficacy and safety of surface imaging guided radiosurgery (SIG-RS) in the treatment of benign skull base tumors.

Frameless, surface imaging guided radiosurgery (SIG-RS) is a novel platform for stereotactic radiosurgery (SRS) wherein patient positioning is monitored in real-time through infra-red camera tracking of facial topography. Here we describe our initial clinical experience with SIG-RS for the treatment of benign neoplasms of the skull base. We identified 48 patients with benign skull base tumors consecutively treated with SIG-RS at a single institution between 2009 and 2011. Patients were diagnosed with meningioma (n = 22), vestibular schwannoma (n = 20), or nonfunctional pituitary adenoma (n = 6). Local control and treatment-related toxicity were retrospectively assessed. Median follow-up was 65 months (range 61-72 months). Prescription doses were 12-13 Gy in a single fraction (n = 18), 8 Gy × 3 fractions (n = 6), and 5 Gy × 5 fractions (n = 24). Actuarial tumor control rate at 5 years was 98%. No grade ≥3 treatment-related toxicity was observed. Grade ≤2 toxicity was associated with symptomatic lesions (p = 0.049) and single fraction treatment (p = 0.005). SIG-RS for benign skull base tumors produces clinical outcomes comparable to conventional frame-based SRS techniques while enhancing patient comfort.

Single-Isocenter Frameless Volumetric Modulated Arc Radiosurgery for Multiple Intracranial Metastases.

BACKGROUND: Stereotactic radiosurgery (SRS) is a well-accepted treatment for patients with intracranial metastases, but outcomes with volumetric modulated arc radiosurgery (VMAR) are poorly described. OBJECTIVE: To report our initial clinical experience applying a novel single-isocenter technique to frameless VMAR for simultaneous treatment of multiple intracranial metastases. METHODS: We performed a retrospective analysis of 15 patients undergoing frameless VMAR for multiple intracranial metastases using a single, centrally located isocenter in the period 2009 and 2011. Of these, 3 patients were treated for progressive or recurrent intracranial disease. A total of 62 metastases (median, 3 per patient; range, 2-13) were treated to a median dose of 20 Gy (range, 15-30 Gy). Three patients were treated with fractionated SRS. Follow-up including clinical examination and magnetic resonance imaging (MRI) occurred every 3 months. RESULTS: The median follow-up for all patients was 7.1 months (range, 1.1-24.3), with 11 patients (73.3%) followed until death. For the remaining 4 patients alive at the time of analysis, the median follow-up was 19.6 months (range, 9.2-24.3). Local control at 6 and 12 months was 91.7% (95% confidence interval [CI], 84.6%-100.0%) and 81.5% (95% CI, 67.9%-100.0%), respectively. Regional failure was observed in 9 patients (60.0%), and 7 patients (46.7%) received salvage therapy. Overall survival at 6 months was 60.0% (95% CI, 40.3%-88.2%). Grade 3 or higher treatment-related toxicity was not observed. The median total treatment time was 7.2 minutes (range, 2.8-13.2 minutes). CONCLUSION: Single-isocenter, frameless VMAR for multiple intracranial metastases is a promising technique that may provide similar clinical outcomes compared with conventional radiosurgery.

Clinical outcomes of palliative radiation therapy for children.

PURPOSE: In contrast to studies of adults, there are limited published data regarding palliative radiation therapy (RT) for children, and further study is greatly needed. METHODS AND MATERIALS: We performed a retrospective review of all pediatric patients referred to our radiation oncology department over a 5-year span from January 1, 2007, to December 31, 2011. RESULTS: Of 244 total pediatric patients referred, a subset of 45 (18.4%) were treated specifically with palliative intent for a total of 83 courses of RT. Follow-up data until study closure or death were available for 98% of patients. The median survival after initiation of palliative RT was 6.5 months. Overall, 23% of the children were alive at last follow-up visit, and 77% were deceased. The prescribed RT was completed in 93% of courses; 7% of courses were discontinued because of clinical deterioration due to systemic disease progression. The overall symptom response rate (partial or complete) was 72%. Overall response rate by symptom was 80% for bone pain, 55% for dyspnea or chest pain, 58% for neurologic symptoms, 50% for bleeding, and 100% for liver pain or ascites. Response rates by histology were 100% for leukemias, 91% for neuroblastoma, 76% for Ewing sarcoma, 64% for rhabdomyosarcoma, 54% for osteosarcoma, and 50% for primary central nervous system neoplasms. For responders, the median time from RT initiation to response was 1 week. For 7% of patients, a repeat course of RT for the same site and symptom was performed. No patients experienced RTOG (Radiation Therapy Oncology Group) grade 3 or greater acute or late toxicities. CONCLUSIONS: RT is a useful palliative tool for pediatric patients that merits continued use and further study.

Magnetic Resonance Therapy Improves Clinical Phenotype and EEG Alpha Power in Posttraumatic Stress Disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a disabling and prevalent psychiatric disorder with limited effective treatment options. In addition to the clinical features of the disease, pathologic changes in the electroencephalogram (EEG), including decreased alpha power, have been reported. OBJECTIVES: To determine if magnetic brain stimulation can induce normalization of EEG abnormalities and improve clinical symptoms in PTSD in a preliminary, open-label evaluation. MATERIALS AND METHODS: We reviewed prospectively-collected data on 21 veterans that were consecutively-treated for PTSD. Magnetic resonance therapy (MRT) was administered for two weeks at treatment frequencies based on frequency-domain analysis of each patient's dominant alpha-band EEG frequencies and resting heart rate. Patients were evaluated on the PTSD checklist (PCL-M) and pre- and post-treatment EEGs before and after MRT. RESULTS: Of the 21 patients who initiated therapy, 16 completed treatment. Clinical improvements on the PCL-M were seen in these 16 patients, with an average pre-treatment score of 54.9 and post-treatment score of 31.8 (P < 0.001). In addition, relative global EEG alpha-band (8 - 13 Hz) power increased from 32.0 to 38.5 percent (P = 0.013), and EEG delta-band (1 - 4 Hz) power decreased from 32.3 percent to 26.8 percent (P = 0.028). CONCLUSIONS: These open-label data show trends toward normalization of EEG and concomitant clinical improvement using magnetic stimulation for PTSD.

Bevacizumab: radiation combination produces restricted diffusion on brain MRI.

AIMS: The purpose of this paper is to investigate the effect of bevacizumab (BEV) on the diffusion properties of irradiated brain gliomas. MATERIALS & METHODS: Neuroimaging studies and medical records of 44 patients undergoing treatment for cerebral gliomas were reviewed. MRIs were analyzed for presence of restricted diffusion, time to onset, pattern/location, duration of restriction, and persistence of restriction post-treatment with BEV. RESULTS: Patchy confluent areas of diffusion restriction on MRI were found in 12 patients. All 12 patients received radiation therapy followed by BEV therapy. Diffusion restriction appeared 3 to 21 months after onset of radiation and 1 to 6 months after starting BEV therapy, increased in size over time, and persisted up to 23 months while on BEV. Restricted diffusion was observed in areas that received 60 Gy or more of radiation. Areas of restricted diffusion showed low T1 and increased T2 signal intensity, minimal or no contrast enhancement, and low cerebral blood volume. A thin perimeter of susceptibility outlined the restricted areas on susceptibility-weighted images in nine patients (75%). Small focal areas of tumor recurrence within larger regions of restricted diffusion were evident in only four patients (33%). In seven patients (58%) the area of restricted diffusion showed necrosis or radiation change on histology or no metabolic activity on MR spectroscopy or PET. CONCLUSION: Restricted diffusion associated with BEV-treated cerebral gliomas occurs in regions of high-dose radiation and does not indicate high-cellularity of tumor recurrence.

Frameless single-isocenter intensity modulated stereotactic radiosurgery for simultaneous treatment of multiple intracranial metastases.

PURPOSE: Stereotactic radiosurgery (SRS) is well accepted treatment for patients with intracranial metastases, but the role of frameless radiosurgery is not well defined. Here, we describe our clinical experience applying a novel single-isocenter technique to frameless intensity modulated stereotactic radiosurgery (IMRS) for simultaneous treatment of multiple intracranial metastases. METHODS AND MATERIALS: Between 2006 and 2012, 100 consecutive patients received frameless IMRS for multiple intracranial metastases using a single, centrally-located isocenter. Among these, 29 patients were treated for progressive or recurrent intracranial disease. A total of 465 metastases (median, 4 per patient, range, 2-18) were treated to a median dose of 20 Gy (range, 15-50 Gy). Follow-up including clinical examination and magnetic resonance imaging (MRI) occurred every 3 months. RESULTS: Median follow-up for all patients was 4.3 months (range, 0.2-58.3 months), with 83 patients (83.0%) followed until their death. For the remaining 17 patients alive at the time of analysis, median follow-up was 9.2 months (range, 2.2-58.3 months). Overall survival at 6 months was 49.5% [95% confidence interval (CI), 35.3-63.6%]. Local control at 6 and 12 months was 88.9% (95% CI, 79.1-98.6%) and 81.5% (95% CI, 65.2-97.7%), respectively. Regional failure was observed in 39 patients (39%), and 25 patients (25%) received salvage therapy. Grade 3 or greater treatment-related toxicity was observed in 4 patients (4%) and included intracranial hemorrhage, seizure, and radionecrosis. Median total treatment time was 17.2 minutes (range, 2.8-55.3 minutes). CONCLUSIONS: Single-isocenter IMRS for multiple intracranial metastases can produce clinical outcomes comparable to those of conventional radiosurgery techniques.

Neurocognitive assessment following whole brain radiation therapy and radiosurgery for patients with cerebral metastases.

The treatment of metastatic brain lesions remains a central challenge in oncology. Because most chemotherapeutic agents do not effectively cross the blood-brain barrier, it is widely accepted that radiation remains the primary modality of treatment. The mode by which radiation should be delivered has, however, become a source of intense controversy in recent years. The controversy involves whether patients with a limited number of brain metastases should undergo whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) delivered only to the radiographically visible tumours. Survival is comparable for patients treated with either modality. Instead, the controversy involves the neurocognitive function (NCF) of radiating cerebrum that appeared radiographically normal relative to effects of the growth from micro-metastatic foci. A fundamental question in this debate involves quantifying the effect of WBRT in patients with cerebral metastasis. To disentangle the effects of WBRT on neurocognition from the effects inherent to the underlying disease, we analysed the results from randomised controlled studies of prophylactic cranial irradiation in oncology patients as well as studies where patients with limited cerebral metastasis were randomised to SRS versus SRS+WBRT. In aggregate, these results suggest deleterious effects of WBRT in select neurocognitive domains. However, there are insufficient data to resolve the controversy of upfront WBRT versus SRS in the management of patients with limited cerebral metastases.