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Purpose: Radiation-induced cognitive decline is relatively common after treatment for primary and metastatic brain tumors; however, identifying dosimetric parameters that are predictive of radiation-induced cognitive decline is difficult due to the heterogeneity of patient characteristics. The memory function is especially susceptible to radiation effects after treatment. The objective of this study is to correlate volumetric radiation doses received by critical neuroanatomic structures to post–radiation therapy (RT) memory impairment. Methods and materials: Between 2008 and 2011, 53 patients with primary brain malignancies were treated with conventionally fractionated RT in prospectively accrued clinical trials performed at our institution. Dose-volume histogram analysis was performed for the hippocampus, parahippocampus, amygdala, and fusiform gyrus. Hopkins Verbal Learning Test-Revised scores were obtained at least 6 months after RT. Impairment was defined as an immediate recall score ≤15. For each anatomic region, serial regression was performed to correlate volume receiving a given dose (VD(Gy)) with memory impairment. Results: Hippocampal V53.4Gy to V60.9Gy significantly predicted post-RT memory impairment (P

Fractionated whole-brain irradiation (fWBI) is a mainstay of treatment for patients with intracranial neoplasia; however late-delayed radiation-induced normal tissue injury remains a major adverse consequence of treatment, with deleterious effects on quality of life for affected patients. We hypothesize that cerebrovascular injury and remodeling after fWBI results in ischemic injury to dependent white matter, which contributes to the observed cognitive dysfunction. To evaluate molecular effectors of radiation-induced brain injury (RIBI), real-time quantitative polymerase chain reaction (RT-qPCR) was performed on the dorsolateral prefrontal cortex (DLPFC, Brodmann area 46), hippocampus and temporal white matter of 4 male Rhesus macaques (age 6-11 years), which had received 40 Gray (Gy) fWBI (8 fractions of 5 Gy each, twice per week), and 3 control comparators. All fWBI animals developed neurologic impairment; humane euthanasia was elected at a median of 6 months. Radiation-induced brain injury was confirmed histopathologically in all animals, characterized by white matter degeneration and necrosis, and multifocal cerebrovascular injury consisting of perivascular edema, abnormal angiogenesis and perivascular extracellular matrix deposition. Herein we demonstrate that RIBI is associated with white matter-specific up-regulation of hypoxia-associated lactate dehydrogenase A (LDHA) and that increased gene expression of fibronectin 1 (FN1), SERPINE1 and matrix metalloprotease 2 (MMP2) may contribute to cerebrovascular remodeling in late-delayed RIBI. Additionally, vascular stability and maturation associated tumor necrosis super family member 15 (TNFSF15) and vascular endothelial growth factor beta (VEGFB) mRNAs were increased within temporal white matter. We also demonstrate that radiation-induced brain injury is associated with decreases in white matter-specific expression of neurotransmitter receptors SYP, GRIN2A and GRIA4. We additionally provide evidence that macrophage/microglial mediated neuroinflammation may contribute to RIBI through increased gene expression of the macrophage chemoattractant CCL2 and macrophage/microglia associated CD68. Global patterns in cerebral gene expression varied significantly between regions examined (P0.0001, Friedman's test), with effects most prominent within cerebral white matter.

INTRODUCTION: Radiation-induced cognitive decline (RICD) is a late effect of radiotherapy (RT) occurring in 30–50% of irradiated brain tumor survivors. In preclinical models, pioglitazone prevents RICD but there are little safety data on its use in non-diabetic patients. We conducted a dose-escalation trial to determine the safety of pioglitazone taken during and after brain irradiation. METHODS: We enrolled patients > 18 years old with primary or metastatic brain tumors slated to receive at least 10 treatments of RT (≤ 3 Gy per fraction). We evaluated the safety of pioglitazone at 22.5 mg and 45 mg with a dose-escalation phase and dose-expansion phase. Pioglitazone was taken daily during RT and for 6 months after. RESULTS: 18 patients with a mean age of 54 were enrolled between 2010 and 2014. 14 patients had metastatic brain tumors and were treated with whole brain RT. Four patients had primary brain tumors and received partial brain RT and concurrent chemotherapy. No DLTs were identified. In the dose-escalation phase, there were only three instances of grade ≥ 3 toxicity: one instance of neuropathy in a patient receiving 22.5 mg, one instance of fatigue in a patient receiving 22.5 mg and one instance of dizziness in a patient receiving 45 mg. The attribution in each of these cases was considered “possible.” In the dose-expansion phase, nine patients received 45 mg and there was only one grade 3 toxicity (fatigue) possibly attributable to pioglitazone. CONCLUSION: Pioglitazone was well tolerated by brain tumor patients undergoing RT. 45 mg is a safe dose to use in future efficacy trials.

Late-delayed radiation-induced brain injury (RIBI) is a major adverse effect of fractionated whole-brain irradiation (fWBI). Characterized by progressive cognitive dysfunction, and associated cerebrovascular and white matter injury, RIBI deleteriously affects quality of life for cancer patients. Despite extensive morphological characterization of the injury, the pathogenesis is unclear, thus limiting the development of effective therapeutics. We previously reported that RIBI is associated with increased gene expression of the extracellular matrix (ECM) protein fibronectin (FN1). We hypothesized that fibronectin contributes to perivascular ECM, which may impair diffusion to the dependent parenchyma, thus contributing to the observed cognitive decline. The goal of this study was to determine the localization of fibronectin in RIBI and further characterize the composition of perivascular ECM, as well as identify the cell of origin for FN1 by in situ hybridization. Briefly, fibronectin localized to the vascular basement membrane of morphologically normal blood vessels from control comparators and animals receiving fWBI, and to the perivascular space of edematous and fibrotic vascular phenotypes of animals receiving fWBI. Additional mild diffuse parenchymal staining in areas of vascular injury suggested blood-brain-barrier disruption and plasma fibronectin extravasation. Perivascular ECM lacked amyloid and contained lesser amounts of collagens I and IV, which localized to the basement membrane. These changes occurred in the absence of alterations in microvascular area fraction or microvessel density. Fibronectin transcripts were rarely expressed in control comparators, and were most strongly induced within cerebrovascular endothelial and vascular smooth muscle cells after fWBI. Our results demonstrate that fibronectin is produced by cerebrovascular endothelial and smooth muscle cells in late-delayed RIBI and contributes to perivascular ECM, which we postulate may contribute to diffusion barrier formation. We propose that pathways that antagonize fibronectin deposition and matrix assembly or enhance degradation may serve as potential therapeutic targets in RIBI.

Purpose Neurotoxic effects of brain irradiation include cognitive impairment in 50% to 90% of patients. Prior studies have suggested that donepezil, a neurotransmitter modulator, may improve cognitive function. Patients and Methods A total of 198 adult brain tumor survivors ≥ 6 months after partial- or whole-brain irradiation were randomly assigned to receive a single daily dose (5 mg for 6 weeks, 10 mg for 18 weeks) of donepezil or placebo. A cognitive test battery assessing memory, attention, language, visuomotor, verbal fluency, and executive functions was administered before random assignment and at 12 and 24 weeks. A cognitive composite score (primary outcome) and individual cognitive domains were evaluated. Results Of this mostly middle-age, married, non-Hispanic white sample, 66% had primary brain tumors, 27% had brain metastases, and 8% underwent prophylactic cranial irradiation. After 24 weeks of treatment, the composite scores did not differ significantly between groups (P = .48); however, significant differences favoring donepezil were observed for memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016). Significant interactions between pretreatment cognitive function and treatment were found for cognitive composite (P = .01), immediate recall (P = .05), delayed recall (P = .004), attention (P = .01), visuomotor skills (P = .02), and motor speed and dexterity (P < .001), with the benefits of donepezil greater for those who were more cognitively impaired before study treatment. Conclusion Treatment with donepezil did not significantly improve the overall composite score, but it did result in modest improvements in several cognitive functions, especially among patients with greater pretreatment impairments.

Fractionated whole-brain irradiation (fWBI), used to treat brain metastases, often leads to neurologic injury and cognitive impairment. The cognitive effects of irradiation in nonhuman primates (NHP) have been previously published; this report focuses on corresponding neuropathologic changes that could have served as the basis for those effects in the same study. Four rhesus monkeys were exposed to 40 Gy of fWBI [5 Gy × 8 fraction (fx), 2 fx/week for four weeks] and received anatomical MRI prior to, and 14 months after fWBI. Neurologic and histologic sequelae were studied posthumously. Three of the NHPs underwent cognitive assessments, and each exhibited radiation-induced impairment associated with various degrees of vascular and inflammatory neuropathology. Two NHPs had severe multifocal necrosis of the forebrain, midbrain and brainstem. Histologic and MRI findings were in agreement, and the severity of cognitive decrement previously reported corresponded to the degree of observed pathology in two of the animals. In response to fWBI, the NHPs showed pathology similar to humans exposed to radiation and show comparable cognitive decline. These results provide a basis for implementing NHPs to examine and treat adverse cognitive and neurophysiologic sequelae of radiation exposure in humans.

Stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) for brain metastases can avoid WBRT toxicities, but with risk of subsequent distant brain failure (DBF). Sole use of number of metastases to triage patients may be an unrefined method. Data on 1354 patients treated with SRS monotherapy from 2000 to 2013 for new brain metastases was collected across eight academic centers. The cohort was divided into training and validation datasets and a prognostic model was developed for time to DBF. We then evaluated the discrimination and calibration of the model within the validation dataset, and confirmed its performance with an independent contemporary cohort. Number of metastases (≥8, HR 3.53 p = 0.0001), minimum margin dose (HR 1.07 p = 0.0033), and melanoma histology (HR 1.45, p = 0.0187) were associated with DBF. A prognostic index derived from the training dataset exhibited ability to discriminate patients' DBF risk within the validation dataset (c-index = 0.631) and Heller's explained relative risk (HERR) = 0.173 (SE = 0.048). Absolute number of metastases was evaluated for its ability to predict DBF in the derivation and validation datasets, and was inferior to the nomogram. A nomogram high-risk threshold yielding a 2.1-fold increased need for early WBRT was identified. Nomogram values also correlated to number of brain metastases at time of failure (r = 0.38, p

To assess the long-term effects of fractionated whole brain irradiation (fWBI) using diffusion tensor imaging (DTI) and behavior in a pediatric rodent model for the clinical presentation of adult pediatric cancer survivors.Five-week-old, male F344xBN rats were randomized to receive 0, 5, or 6.5 Gy fractions biweekly for 3 weeks, resulting in Sham, Irradiated-30 (IR-30) and IR-39 Gy total dose groups. Magnetic Resonance Imaging occurred at 1, 3, 6 and 9 months with behavioral assessment at 10-11 months post-fWBI.Irradiation reduced brain size (p0.001) and body weight (p0.001) proportionate to dose. At 1 month post-fWBI and throughout follow-up, diffusion was reduced in IR-30 and IR-39 relative to shams (p0.001). IR-30 but not IR-39 rats were impaired relative to Shams on the reversal trial of the Morris Water Maze (p0.05), and IR-30 rats preferred a striatum- mediated strategy (p0.06).Hippocampal performance was impaired in IR-30 but not IR-39 animals. While gross size differences exist, white matter integrity is preserved in rats after fWBI at 5 weeks. This significant departure from childhood cancer survivors and single fraction rodent studies where white matter degradation is a prominent feature are discussed.

OBJECTIVE:: We investigate the patterns of failure in the treatment of glioblastoma (GBM) based on clinical target volume (CTV) margin size, dose delivered to the site of initial failure, and the use of temozolomide and intensity-modulated radiotherapy (IMRT). METHODS:: Between August 2000 and May 2010, 161 patients with GBM were treated with radiotherapy with or without concurrent temozolomide. Patients were treated with CTV expansions that ranged from 5 to 20 mm using a shrinking field technique. Patterns of failure and time to progression and overall survival were compared based on CTV margin, use of temozolomide, and use of IMRT. Kaplan Meier analysis was used to estimate survival times, and χ test was used for comparison of cohorts. RESULTS:: For patients treated with 5-, 10-, and 15- to 20-mm CTV, 79%, 77%, and 86% experienced failures in the 60 Gy volume, respectively. Forty-eight percent, 55%, and 66% of patients with 5-, 10-, and 15- to 20-mm CTV experienced failures in the 46 Gy volume, respectively. There was no statistical difference between patients treated with 5-, 10-, 15- to 20-mm margins with regard to 60 Gy failure (P=0.76), 46 Gy failure (P=0.51), or marginal failure (P=0.73). Eighty percent of patients receiving temozolomide experienced failures in the 60 Gy volume. There was no increased likelihood of marginal failures in patients receiving IMRT (P=0.97). CONCLUSIONS:: Modern treatment techniques including use of concurrent temozolmide, limited CTV margin size, and IMRT have not greatly changed the patterns of failure of GBM.

Radiation-induced taste and smell disturbances are prevalent in patients receiving brain radiation therapy, although the mechanisms underlying these toxicities are poorly understood. We report the results of a single institution prospective clinical trial aimed at correlating self-reported taste and smell disturbances with radiation dose delivered to defined areas within the brain and nasopharynx.Twenty-two patients with gliomas were enrolled on a prospective observational trial in which patients underwent a validated questionnaire assessing taste and smell disturbances at baseline and at 3 and 6 weeks after commencement of brain radiation therapy. Fourteen patients with glioblastoma, 3 patients with grade 3 gliomas, and 5 patients with low grade gliomas participated. Median dose to tumor volume was 60 Gy (range, 45-60 Gy). Dose-volume histogram (DVH) analysis was performed for specific regions of interest that were considered potential targets of radiation damage, including the thalamus, temporal lobes, nasopharynx, olfactory groove, frontal pole, and periventricular stem cell niche. The %v10 (percent of region of interest receiving 10 Gy), %v40, and %v60 were calculated for each structure. Data from questionnaires and DVH were analyzed using stepwise regression.Twenty of 22 patients submitted evaluable questionnaires that encompassed at least the entire radiation therapy course. Ten of 20 patients reported experiencing some degree of smell disturbance during radiation therapy, and 14 of 20 patients experienced taste disturbances. Patients reporting more severe taste toxicity also reported more severe toxicities with sense of smell (r(2) = 0.60, P.006). Tumor location in the temporal lobe predicted for increased severity of taste toxicity (F3, 16 = 1.44, P.06). The nasopharynx was the only structure in which the DVH data predicted the presence of radiation-induced taste changes (r(2) = 0.28, P.02).Radiation-induced taste toxicity appears to be more common in temporal lobe tumors, and may be related to the dose received by the nasopharynx.

Fractionated whole-brain irradiation for the treatment of intracranial neoplasia causes progressive neurodegeneration and neuroinflammation. The long-term consequences of single-fraction high-dose irradiation to the brain are unknown. To assess the late effects of brain irradiation we compared transcriptomic gene expression profiles from non-human primates (NHP; rhesus macaques Macaca mulatta) receiving single-fraction total-body irradiation (TBI; n = 5, 6.75–8.05 Gy, 6–9 years prior to necropsy) to those receiving fractionated whole-brain irradiation (fWBI; n = 5, 40 Gy, 8 × 5 Gy fractions; 12 months prior to necropsy) and control comparators (n = 5). Gene expression profiles from the dorsolateral prefrontal cortex (DLPFC), hippocampus (HC) and deep white matter (WM; centrum semiovale) were compared. Stratified analyses by treatment and region revealed that radiation-induced transcriptomic alterations were most prominent in animals receiving fWBI, and primarily affected white matter in both TBI and fWBI groups. Unsupervised canonical and ontologic analysis revealed that TBI or fWBI animals demonstrated shared patterns of injury, including white matter neuroinflammation, increased expression of complement factors and T-cell activation. Both irradiated groups also showed evidence of impaired glutamatergic neurotransmission and signal transduction within white matter, but not within the dorsolateral prefrontal cortex or hippocampus. Signaling pathways and structural elements involved in extracellular matrix (ECM) deposition and remodeling were noted within the white matter of animals receiving fWBI, but not of those receiving TBI. These findings indicate that those animals receiving TBI are susceptible to neurological injury similar to that observed after fWBI, and these changes persist for years postirradiation. Transcriptomic profiling reaffirmed that macrophage/microglial-mediated neuroinflammation is present in radiation-induced brain injury (RIBI), and our data provide novel evidence that the complement system may contribute to the pathogenesis of RIBI. Finally, these data challenge the assumption that the hippocampus is the predilection site of injury in RIBI, and indicate that impaired glutamatergic neurotransmission may occur in white matter injury.

Collaboration is the foundation for innovative discoveries, as individuals with different backgrounds come together and combine their unique expertise. In the current article, an educational researcher and two neuroscientists relate their experiences in establishing a successful collaborative effort. The marriage of neuroscientific findings with educational research has begun to further advance educational approaches. Initial functional magnetic resonance imaging (fMRI) findings indicate that direct interplay between educational interventions and brain-based measures of sensory, motor, and cognitive processes provides an important link among cognitive processing and psychometric measures. If neuroimaging results support existing theoretical constructs of brain organization, then testable hypotheses may be designed to determine which educational interventions will be effective. The neuropsychological approach may provide school psychologists and teachers with an extensive array of fMRI-based, developmentally appropriate instructional strategies for enhancing the functional organization of the developing brain of children. Promising suggestions and strategies for educational researchers, school psychologists, and neuroscientists are included.

In this study, the effects of a potentially lethal radiation exposure on the brain for long-term cognitive sequelae were investigated using Rhesus macaques ( Macaca mulatta ) adopted from other facilities after analysis of acute radiation response via the Centers for Medical Countermeasures against Radiation (CMCR) network. Fifty-nine animals were given the opportunity to participate in cognitive cage-side testing. The animals that received single-dose gamma irradiation were significantly less likely to engage in cognitive testing than the controls, suggesting that irradiated animals may have differences in cognitive ability. Five irradiated (6.75-8.05 Gy) and three naïve control animals self-selected, were extensively trained and administered a simple visual discrimination with reversal (SVD+R) task 2-3 times per week for 11-18 months. Each session consisted of 30 trials in which the animals were required to choose the correct visual stimulus for a food reward. After the initial presentation, the stimulus that signaled the presence of food was twice reversed once the animal reached criterion (90% accuracy across four consecutive sessions). While the limited sample size precluded definitive statistical analysis, irradiated animals took longer to reach the criterion subsequent to reversal than did control animals, suggesting a relative deficiency in cognitive flexibility. These results provide preliminary data supporting the potential use of a nonhuman primate model to study radiation-induced, late-delayed cognitive deficits.

Introduction The goal of this study was to determine if clinically relevant endpoints were changed by improved MRI resolution during radiosurgical treatment planning. Methods and Materials Between 2003 and 2008, 200 consecutive patients with brain metastases treated with Gamma Knife radiosurgery (GKRS) using either 1.5 T or 3.0 T MRI for radiosurgical treatment planning were retrospectively analysed. The number of previously undetected metastases at time of radiosurgery, distant brain failures, time delay to whole brain radiotherapy (WBRT), overall survival and likelihood of neurological death were determined. Results Additional metastases were detected in 31.3% and 24.5% of patients at time of radiosurgery with 3.0 T and 1.5 T MRI, respectively (P = 0.27). Patients with multiple metastases at diagnostic scan were more likely to have additional metastases detected by 3.0 T MRI (P

The demand for science trainees to have appropriate responsible conduct of research instruction continues to increase the attention shown by federal agencies and graduate school programs to the development of effective ethics curriculums. However, it is important to consider that the main learning environment for science graduate students and post-doctoral research fellows is within a laboratory setting. Here we discuss an internal laboratory program of weekly 15-minute ethics discussions implemented and used over the last 3 years in addition to the graduate school’s program of scientific integrity training. During this time, the environment and culture within our laboratory has changed to place greater emphasis on the ethical implications of our own research and the research we evaluate. We still struggle with how to accurately assess this behavioral change; although, we present preliminary survey results on the evaluation and impact of this style of curriculum for ethics instruction in our laboratory.

Caffeine is a commonly used neurostimulant that also produces cerebral vasoconstriction by antagonizing adenosine receptors. Chronic caffeine use results in an adaptation of the vascular adenosine receptor system presumably to compensate for the vasoconstrictive effects of caffeine. We investigated the effects of caffeine on cerebral blood flow (CBF) in increasing levels of chronic caffeine use. Low (mean = 45 mg/day), moderate (mean = 405 mg/day), and high (mean = 950 mg/day) caffeine users underwent quantitative perfusion magnetic resonance imaging on four separate occasions: twice in a caffeine abstinent state (abstained state) and twice in a caffeinated state following their normal caffeine use (native state). In each state, there were two drug conditions: participants received either caffeine (250 mg) or placebo. Gray matter CBF was tested with repeated-measures analysis of variance using caffeine use as a between-subjects factor, and correlational analyses were conducted between CBF and caffeine use. Caffeine reduced CBF by an average of 27% across both caffeine states. In the abstained placebo condition, moderate and high users had similarly greater CBF than low users; but in the native placebo condition, the high users had a trend towards less CBF than the low and moderate users. Our results suggest a limited ability of the cerebrovascular adenosine system to compensate for high amounts of daily caffeine use.

Stimuli occurring in multiple sensory modalities that are temporally synchronous or spatially coincident can be integrated together to enhance perception. Additionally, the semantic content or meaning of a stimulus can influence cross-modal interactions, improving task performance when these stimuli convey semantically congruent or matching information, but impairing performance when they contain non-matching or distracting information. Attention is one mechanism that is known to alter processing of sensory stimuli by enhancing perception of task-relevant information and suppressing perception of task-irrelevant stimuli. It is not known, however, to what extent attention to a single sensory modality can minimize the impact of stimuli in the unattended sensory modality and reduce the integration of stimuli across multiple sensory modalities. Our hypothesis was that modality-specific selective attention would limit processing of stimuli in the unattended sensory modality, resulting in a reduction of performance enhancements produced by semantically matching multisensory stimuli, and a reduction in performance decrements produced by semantically non-matching multisensory stimuli. The results from two experiments utilizing a cued discrimination task demonstrate that selective attention to a single sensory modality prevents the integration of matching multisensory stimuli that is normally observed when attention is divided between sensory modalities. Attention did not reliably alter the amount of distraction caused by non-matching multisensory stimuli on this task; however, these findings highlight a critical role for modality-specific selective attention in modulating multisensory integration.

Introduction In this study, we assessed clinical outcomes of patients with brain metastases from a gastrointestinal (GI) primary cancer and patterns of failure after stereotactic radiosurgery including failure within the radiosurgical volume, distant failure and leptomeningeal failure (LMF). We also assessed other factors associated with the patients’ neurologic and extraneuraxial disease that may affect clinical outcomes. Methods We reviewed our institutional series of 62 consecutive patients with brain metastases treated with stereotactic radiosurgery, which included 17 patients with oesophageal, 44 patients with colorectal and one patient with anal canal primary. The median marginal dose to the radiosurgery volume was 17 Gy (range 10–24 Gy). Thirteen patients were treated with whole-brain radiotherapy (WBRT) prior to GKS. Results The median dose delivered to the margin of the tumour was 17 Gy (range: 10–24 Gy). The median largest tumour diameter was 2.7 cm (range: 0.60–6.1 cm). The median overall survival (OS) was 7.1 months with a median follow-up of 6.1 months and a range of 0–31.7 months. Freedom from local failure was 86.5% and 62.2% at 6 and 12 months respectively. Freedom from distant failure was 73.2% and 42.2% at 6 and 12 months, respectively, and 40% of patients died of neurologic death. LMF occurred in seven patients, all of whom had colorectal primaries. Multivariate analysis revealed that craniotomy for resection of brain metastasis (HR = 2.63, P

The ability to accurately process brief, successive acoustic signals rapidly presented to the central nervous system is believed to underlie successful language development. The limits of temporal resolution of the auditory system, often assessed using gap detection tasks, has been widely studied in relation to developing and decoding speech. In the present study, a reflex modification paradigm was used to investigate potential shifts in gap detection thresholds in rats across development, with test sessions beginning on postnatal day (P) 15, P35 and P64. We found that thresholds decreased over the course of development. These thresholds were determined to lie between 10 and 20 ms for the P15 and P35 groups, and between 5 and 10 ms for the P64 group. Moreover, we observed improvements in gap detection thresholds in all age groups over 5 days of testing, including the youngest age group (P15). These later results suggest that experience-dependent plasticity mechanisms at the level of sensory processing are operational and observable both very early in development, and also in adult animals. The present findings also demonstrate maturational improvements in silent gap detection using a pre-pulse inhibition paradigm.

Adult male rats with induced microgyric lesions exhibit significant deficits in rapid auditory processing, as well as morphological alterations in the medial geniculate nucleus (MGN) of the thalamus. These findings are considered striking in light of similar anatomical and auditory processing anomalies in language disabled humans. Given evidence from clinical and animal studies that acoustic experience may alter sensory processing at behavioral and neurophysiological levels, the current study examined effects of developmental exposure to auditory stimulation on behavioral and anatomical indices in microgyric and sham rats. Stimulation (E7-P 70) included: (1). chronic white noise (80 dB) with standard housing; (2). 3 h/day of 78 dB filtered light classical music with social housing; or (3). standard acoustic environment (control) with standard housing. Microgyric effects on auditory processing and thalamic morphology were evident regardless of environmental condition. In sum, the effects of microgyria on brain and behavior appear to be robust, and largely orthogonal to any main effect of acoustic stimulation on auditory processing. These findings suggest that a more active form of acoustic stimulation (e.g., training) may be required to ameliorate the deleterious behavioral and anatomical consequences of focal microgyric lesions.

We investigate the differences in molecular signature and clinical outcomes between multiple lesion glioblastoma (GBM) and single focus GBM in the modern treatment era. Between August 2000 and May 2010, 161 patients with GBM were treated with modern radiotherapy techniques. Of this group, 33 were considered to have multiple lesion GBM (25 multifocal and 8 multicentric). Patterns of failure, time to progression and overall survival were compared based on whether the tumor was considered a single focus or multiple lesion GBM. Genomic groupings and methylation status were also investigated as a possible predictor of multifocality in a cohort of 41 patients with available tissue for analysis. There was no statistically significant difference in overall survival (p < 0.3) between the multiple lesion tumors (8.2 months) and single focus GBM (11 months). Progression free survival was superior in the single focus tumors (7.1 months) as compared to multi-focal (5.6 months, p = 0.02). For patients with single focus, multifocal and multicentric GBM, 81, 76 and 88 % of treatment failures occurred in the 60 Gy volume (p < 0.5), while 54, 72, and 38 % of treatment failures occurred in the 46 Gy volume (p < 0.4). Out of field failures were rare in both single focus and multiple foci GBM (7 vs 3 %). Genomic groupings and methylation status were not found to predict for multifocality. Patterns of failure, survival and genomic signatures for multiple lesion GBM do not appreciably differ when compared to single focus tumors.

The median survival for patients with brain metastases has improved significantly over time due to earlier detection,1 better brain-directed2 and systemic therapies.3 With the advent of improved salvage therapies for intracranial metastases including radiosurgery and stereotactic radiotherapy, many patients with intracranial metastases will ultimately die from their systemic disease burden. As patients live longer, there has been an incentive to delay or avoid the neurocognitive toxicities associated with whole brain radiotherapy, as these toxicities continue to worsen with longer survival time.4 With increased use of stereotactic radiosurgery (SRS) in the management of brain metastases, the ability to determine the optimal patient population for this technique has become paramount. Identifying suitable patients for upfront SRS versus whole brain radiotherapy (WBRT) will not only contribute to the quality of life of the patient, but also help ease the societal tensions in determining meaningful use of expensive medical resources. There are certainly populations that may benefit from upfront whole brain radiotherapy for their brain metastases. These populations likely include patients with numerous lesions [Yamamoto et al], those with rapid intracranial progression after initial SRS, and those with poor overall prognosis. Elucidation of those patient and disease characteristics that can predict for the latter two factors will become vital in the triage of patients to the proper treatment modality. While several publications have described factors that predict for survival of patients with brain metastases,5,6 relatively little evidence exists to describe factors that predict for early distant brain failure (DBF) after Gamma Knife radiosurgery. A single series published out of the University of Alabama Birmingham identified factors such as

Utilizing rodent models, prior research has demonstrated a significant association between focal neocortical malformations (i.e. induced microgyria, molecular layer ectopias), which are histologically similar to those observed in human dyslexic brains, and rate-specific auditory processing deficits as seen in language impaired populations. In the current study, we found that ectopic NZB/BINJ mice exhibit significant impairments in detecting a variable duration 5.6 kHz tone embedded in a 10.5 kHz continuous background, using both acoustic reflex modification and auditory event-related potentials (AERP). The current results add further support to the association between focal cortical malformations and impaired auditory processing, and the notion that these auditory effects may occur regardless of the cortical location of the anomaly.

In a retrospective review to assess neuroanatomical targets of radiation-induced cognitive decline, dose volume histogram (DVH) analyses of specific brain regions of interest (ROI) are correlated to neurocognitive performance in 57 primary brain tumor survivors.Neurocognitive assessment at baseline included Trail Making Tests A/B, a modified Rey-Osterreith Complex Figure, California or Hopkins Verbal Learning Test, Digit Span, and Controlled Oral Word Association. DVH analysis was performed for multiple neuroanatomical targets considered to be involved in cognition. The %v10 (percent of ROI receiving 10 Gy), %v40, and %v60 were calculated for each ROI. Factor analysis was used to estimate global cognition based on a summary of performance on individual cognitive tests. Stepwise regression was used to determine which dose volume predicted performance on global factors and individual neurocognitive tests for each ROI.Regions that predicted global cognitive outcomes at doses60 Gy included the corpus callosum, left frontal white matter, right temporal lobe, bilateral hippocampi, subventricular zone, and cerebellum. Regions of adult neurogenesis primarily predicted cognition at %v40 except for the right hippocampus which predicted at %v10. Regions that did not predict global cognitive outcomes at any dose include total brain volume, frontal pole, anterior cingulate, right frontal white matter, and the right precentral gyrus.Modeling of radiation-induced cognitive decline using neuroanatomical target theory appears to be feasible. A prospective trial is necessary to validate these data.

Background: Caffeine is a known vasoconstrictor that reduces resting cerebral blood flow (CBF) throughout the brain. This effect may be problematic in functional magnetic resonance imaging (fMRI) research, as the blood oxygen level-dependent (BOLD) signal is a complex interaction of CBF and other factors that are dependent on changes in neural activity. It is unknown whether changes in the BOLD signal during an fMRI experiment could be affected by subjects' recent use or abstinence from dietary caffeine. Methods: Here, we report two similar studies (n=45 and 17) that measure the effects of caffeine on BOLD activation, BOLD time course parameters, and CBF. Using a factorial design, low, moderate, and high caffeine consumers received either caffeine (250 mg) or placebo during normal caffeine use (satiated state) or after 30 hours of abstention (abstinent state). The fMRI of a reaction time task and resting-state CBF were collected. Results: In general, acute caffeine administration reduced the time to peak ...

Technological developments in radiation therapy and other cancer therapies have led to a progressive increase in five-year survival rates over the last few decades. Although acute effects have been largely minimized by both technical advances and medical interventions, late effects remain a concern. Indeed, the need to identify those individuals who will develop radiation-induced late effects, and to develop interventions to prevent or ameliorate these late effects is a critical area of radiobiology research. In the last two decades, preclinical studies have clearly established that late radiation injury can be prevented/ameliorated by pharmacological therapies aimed at modulating the cascade of events leading to the clinical expression of radiation-induced late effects. These insights have been accompanied by significant technological advances in imaging that are moving radiation oncology and normal tissue radiobiology from disciplines driven by anatomy and macrostructure to ones in which important quantitative functional, microstructural, and metabolic data can be noninvasively and serially determined. In the current article, we review use of positron emission tomography (PET), single photon emission tomography (SPECT), magnetic resonance (MR) imaging and MR spectroscopy to generate pathophysiological and functional data in the central nervous system, lung, and heart that offer the promise of, (1) identifying individuals who are at risk of developing radiation-induced late effects, and (2) monitoring the efficacy of interventions to prevent/ameliorate them.

Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive long enough (>6 months) to experience radiation-induced brain injury. Prior to 1970, the human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after single doses >30 Gy; white matter necrosis occurs at fractionated doses >60 Gy. Although white matter necrosis is uncommon with modern techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become important, because they have profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. Given its central role in memory and neurogenesis, the majority of these studies have focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis. These data have been interpreted to suggest that shielding the hippocampus will prevent clinical radiation-induced cognitive impairment. However, this interpretation may be overly simplistic. Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of demyelination and/or white matter necrosis similar to what is observed clinically, suggesting that more subtle molecular, cellular and/or microanatomic modifications are involved in this radiation-induced brain injury. Given that radiation-induced cognitive impairment likely reflects damage to both hippocampal- and non-hippocampal-dependent domains, there is a critical need to investigate the microanatomic and functional effects of radiation in various brain regions as well as their integration at clinically relevant doses and schedules. Recently developed techniques in neuroscience and neuroimaging provide not only an opportunity to accomplish this, but they also offer the opportunity to identify new biomarkers and new targets for interventions to prevent or ameliorate these late effects.

The goal of this study was to determine if clinically relevant endpoints were changed by improved MRI resolution during radiosurgical treatment planning.Between 2003 and 2008, 200 consecutive patients with brain metastases treated with Gamma Knife radiosurgery (GKRS) using either 1.5 T or 3.0 T MRI for radiosurgical treatment planning were retrospectively analysed. The number of previously undetected metastases at time of radiosurgery, distant brain failures, time delay to whole brain radiotherapy (WBRT), overall survival and likelihood of neurological death were determined.Additional metastases were detected in 31.3% and 24.5% of patients at time of radiosurgery with 3.0 T and 1.5 T MRI, respectively (P = 0.27). Patients with multiple metastases at diagnostic scan were more likely to have additional metastases detected by 3.0 T MRI (P 0.1). Median time to distant brain failure was 4.87 months and 5.43 months for the 3.0 T and 1.5 T cohorts, respectively (P = 0.44). Median time to WBRT was 5.8 months and 5.3 months for the 3.0 T and 1.5 T cohorts, respectively (P = 0.87). Median survival was 6.4 months for the 3.0 T cohort, and 6.1 months for the 1.5 T cohort (P = 0.71). Likelihood of neurological death was 25.3% and 16.7% for the 3.0 and 1.5 T populations, respectively (P = 0.26).The 3.0 T MRI-based treatment planning for GKRS did not appear to affect the likelihood of distant brain failure, the need for WBRT or the likelihood of neurological death in this series.

Objective We conducted a process evaluation to (a) assess the effectiveness of a new problem-based learning curriculum designed to teach professionalism and scientific integrity to biomedical graduate students and (b) modify the course to enhance its relevance and effectiveness. The content presented realistic cases and issues in the practice of science, to promote skill development and to acculturate students to professional norms of science. Method We used 5-step Likert-scaled questions, open-ended questions, and interviews of students and facilitators to assess curricular effectiveness. Results Both facilitators and students perceived course objectives were achieved. For example, respondents preferred active learning over lectures; both faculty and students perceived that the curriculum increased their understanding of norms, role obligations and responsibilities of professional scientists. They also reported an increased ability to identify ethical situations and felt that they had developed skills in moral reasoning and effective group work. Conclusions These data helped to improve course implementation and instructional material. For example, to correct a negative perception that this was an ‘ethics’ course, we redesigned case debriefing activities to reinforce learning objectives and important skills. We refined cases to be more engaging and relevant for students, and gave facilitators more specific training and resources for each case. The problem-based learning small group strategy can stimulate an environment whereby participants are more aware of ethical implications of science, and increase their socialisation and open communication about professional behaviour.

Greater than 50% of adults and ~ 100% of children who survive > 6 months after fractionated partial or whole-brain radiotherapy develop cognitive impairments. Noninvasive methods are needed for detecting and tracking the radiation-induced brain injury associated with these impairments. Using magnetic resonance imaging, we sought to detect structural changes associated with brain injury in our rodent model of fractionated whole-brain irradiation (fWBI) induced cognitive impairment and to compare those changes with alterations that occur during the aging process. Middle aged rats were given a clinically relevant dose of fWBI (40 Gy: two 5 Gy fractions/week for 4 weeks) and scanned approximately 1 year post-irradiation to obtain whole-brain T2 and diffusion tensor images (DTI); control groups of sham-irradiated age-matched and young rats were also scanned. No gross structural changes were evident in the T2 structural images, and no detectable fWBI-induced DTI changes in fractional anisotropy (FA) were found in heavily myelinated white matter (corpus callosum, cingulum, and deep cortical white matter). However, significant fWBI-induced variability in FA distribution was present in the superficial parietal cortex due to an fWBI-induced decline in FA in the more anterior slices through parietal cortex. Young rats had significantly lower FA values relative to both groups of older rats, but only within the corpus callosum. These findings suggest that targets of the fWBI-induced change in this model may be the less myelinated or unmyelinated axons, extracellular matrix, or synaptic fields rather than heavily myelinated tracts.

Determining when, if, and how information from separate sensory channels has been combined is a fundamental goal of research on multisensory processing in the brain. This can be a particular challenge in psychophysical data, as there is no direct recording of neural output. The most common way to characterize multisensory interactions in behavioral data is to compare responses to multisensory stimulation with the race model, a model of parallel, independent processing constructed from the probability of responses to the two unisensory stimuli which make up the multisensory stimulus. If observed multisensory reaction times are faster than those predicted by the model, it is inferred that information from the two channels is being combined rather than processed independently. Recently, behavioral research has been published employing capacity analyses where comparisons between two conditions are carried out at the level of the integrated hazard function. Capacity analyses seem to be particularly appealing technique for evaluating multisensory functioning, as they describe relationships between conditions across the entire distribution curve, are relatively easy and intuitive to interpret. The current paper presents capacity analysis of a behavioral data set previously analyzed using the race model. While applications of capacity analyses are still somewhat limited due to their novelty, it is hoped that this exploration of capacity and race model analyses will encourage the use of this promising new technique both in multisensory research and other applicable fields.

There is much debate and research devoted to determining the best practice for teaching responsible conduct of research (RCR) to trainees as federally required (1, 2). The majority of institutional programs require trainees (i.e., graduate students and postdoctoral fellows) to attend instruction isolated from the laboratory. However, laboratory behavior is our field's “hidden curriculum,” and the principal investigator and senior laboratory staff represent the professional role models that trainees see on a daily basis, whether good or bad (3). At Wake Forest, over the past 3 years, we have implemented a program of 15-minute discussions that takes place after our weekly journal club. This amounts to about 11 to 12 hours of training per year. Each laboratory member takes a turn selecting a topic, many of which are also being discussed among scientists, policy-makers, and taxpayers. All laboratory personnel attend, and discussions include a variety of viewpoints as well as discourse on the policies for best practices within the laboratory. We believe that by moving the ethical discussion into the laboratory environment and empowering individual scientists at all seniority levels to actively participate in expanding their own awareness of RCR issues facing research and science policy, we can change the culture of the laboratory itself for the better.

The goal of the present study was to determine if older adults benefited from attention to a specific sensory modality in a voluntary attention task and evidenced changes in voluntary or involuntary attention when compared to younger adults. Suppressing and enhancing effects of voluntary attention were assessed using two cued forced-choice tasks, one that asked participants to localize and one that asked them to categorize visual and auditory targets. Involuntary attention was assessed using the same tasks, but with no attentional cues. The effects of attention were evaluated using traditional comparisons of means and Cox proportional hazards models. All analyses showed that older adults benefited behaviorally from selective attention in both visual and auditory conditions, including robust suppressive effects of attention. Of note, the performance of the older adults was commensurate with that of younger adults in almost all analyses, suggesting that older adults can successfully engage crossmodal attention processes. Thus, age-related increases in distractibility across sensory modalities are likely due to mechanisms other than deficits in attentional processing.

The field of research regarding the effects of habitual caffeine use is immense and frequently utilizes self-report measures of caffeine use. However, various self-report measures have different methodologies, and the accuracy of these different methods has not been compared.Self-reported caffeine use was estimated from two methods (a retrospective interview of weekly caffeine use and a 7-day prospective diary; n = 79). These estimates were then tested against salivary caffeine concentrations in a subset of participants (n = 55).The estimates of caffeine use (mg/day) from the interview- and diary-based methods correlated with one another (r = 0.77) and with salivary caffeine concentrations (r = 0.61 and 0.68, respectively). However, almost half of the subjects who reported more than 600 mg/day in the interview reported significantly less caffeine use in the diary.Self-report measures of caffeine use are a valid method of predicting actual caffeine levels. Estimates of high caffeine use levels may need to be corroborated by more than one method.

Even the healthiest older adults experience changes in cognitive and sensory function. Studies show that older adults have reduced neural responses to sensory information. However, it is well known that sensory systems do not act in isolation but function cooperatively to either enhance or suppress neural responses to individual environmental stimuli. Very little research has been dedicated to understanding how aging affects the interactions between sensory systems, especially cross-modal deactivations or the ability of one sensory system (e.g., audition) to suppress the neural responses in another sensory system cortex (e.g., vision). Such cross-modal interactions have been implicated in attentional shifts between sensory modalities and could account for increased distractibility in older adults. To assess age-related changes in cross-modal deactivations, functional MRI studies were performed in 61 adults between 18 and 80 years old during simple auditory and visual discrimination tasks. Results within visual cortex confirmed previous findings of decreased responses to visual stimuli for older adults. Age-related changes in the visual cortical response to auditory stimuli were, however, much more complex and suggested an alteration with age in the functional interactions between the senses. Ventral visual cortical regions exhibited cross-modal deactivations in younger but not older adults, whereas more dorsal aspects of visual cortex were suppressed in older but not younger adults. These differences in deactivation also remained after adjusting for age-related reductions in brain volume of sensory cortex. Thus, functional differences in cortical activity between older and younger adults cannot solely be accounted for by differences in gray matter volume.

Age-related alterations in white matter have the potential to profoundly affect cognitive functioning. In fact, magnetic resonance imaging (MRI) studies using fractional anisotropy (FA) to measure white matter integrity reveal a positive correlation between FA and behavioral performance in older adults. Confounding these results are imaging studies demonstrating age-related white matter atrophy in some areas displaying altered FA, suggesting changes in diffusion may be simply an epiphenomenon of tissue loss. In the current study, structural MRI techniques were used to identify the relationship between white matter integrity and decreased volume in healthy aging adults. The data demonstrated that white matter atrophy did in fact account for differences in some areas, but significant FA decreases remained across much of the white matter after adjusting for atrophy. Results suggest a complex relationship between changes in white matter integrity and volume. FA appears to be more sensitive than volume loss to changes in normal appearing tissue, and these FA changes may actually precede white matter atrophy in some brain areas. As such, the ability to detect early white matter alterations may facilitate development of targeted treatments that prevent or slow age-related white matter degradation and associated cognitive sequelae.