Soft X-ray induced radiation damage in thin freeze-dried brain samples studied by FTIR microscopy.

In order to push the spatial resolution limits to the nanoscale, synchrotron-based soft X-ray microscopy (XRM) experiments require higher radiation doses to be delivered to materials. Nevertheless, the associated radiation damage impacts on the integrity of delicate biological samples. Herein, the extent of soft X-ray radiation damage in popular thin freeze-dried brain tissue samples mounted onto Si3N4 membranes, as highlighted by Fourier transform infrared microscopy (FTIR), is reported. The freeze-dried tissue samples were found to be affected by general degradation of the vibrational architecture, though these effects were weaker than those observed in paraffin-embedded and hydrated systems reported in the literature. In addition, weak, reversible and specific features of the tissue-Si3N4 interaction could be identified for the first time upon routine soft X-ray exposures, further highlighting the complex interplay between the biological sample, its preparation protocol and X-ray probe.

Photobiomodulation improves the frontal cognitive function of older adults.

OBJECTIVES: The frontal lobe hypothesis of age-related cognitive decline suggests that the deterioration of the prefrontal cortical regions that occurs with aging leads to executive function deficits. Photobiomodulation (PBM) is a newly developed, noninvasive technique for enhancing brain function, which has shown promising effects on cognitive function in both animals and humans. This randomized, sham-controlled study sought to examine the effects of PBM on the frontal brain function of older adults. METHODS/DESIGNS: Thirty older adults without a neuropsychiatric history performed cognitive tests of frontal function (ie, the Eriksen flanker and category fluency tests) before and after a single 7.5-minute session of real or sham PBM. The PBM device consisted of three separate light-emitting diode cluster heads (633 and 870 nm), which were applied to both sides of the forehead and posterior midline, and delivered a total energy of 1349 J. RESULTS: Significant group (experimental, control) × time (pre-PBM, post-PBM) interactions were found for the flanker and category fluency test scores. Specifically, only the older adults who received real PBM exhibited significant improvements in their action selection, inhibition ability, and mental flexibility after vs before PBM. CONCLUSIONS: Our findings support that PBM may enhance the frontal brain functions of older adults in a safe and cost-effective manner.

A prospective study of cerebral, frontal lobe, and temporal lobe volumes and neuropsychological performance in children with primary brain tumors treated with cranial radiation.

BACKGROUND: Cranial radiation therapy (RT) is an important component in the treatment of pediatric brain tumors. However, it can result in long-term effects on the developing brain. This prospective study assessed the effects of cranial RT on cerebral, frontal lobe, and temporal lobe volumes and their correlation with higher cognitive functioning. METHODS: Ten pediatric patients with primary brain tumors treated with cranial RT and 14 age- and sex-matched healthy children serving as controls were evaluated. Quantitative magnetic resonance imaging and neuropsychological assessments (language, memory, auditory and visual processing, and vocabulary) were performed at the baseline and 6, 15, and 27 months after RT. The effects of age, the time since RT, and the cerebral RT dose on brain volumes and neuropsychological performance were analyzed with linear mixed effects model analyses. RESULTS: Cerebral volume increased significantly with age in both groups (P = .01); this increase in volume was more pronounced in younger children. Vocabulary performance was found to be significantly associated with a greater cerebral volume (P = .05) and a lower RT dose (P = .003). No relation was observed between the RT dose and the cerebral volume. There was no difference in the corresponding neuropsychological tests between the 2 groups. CONCLUSIONS: This prospective study found significant relations among the RT dose, cerebral volumes, and rate of vocabulary development among children receiving RT. The results of this study provide further support for clinical trials aimed at reducing cranial RT doses in the pediatric population. Cancer 2017;161-168. © 2016 American Cancer Society.

Radionecrosis of the frontal lobe as a consequence of malignant ethmoid tumor management: incidence, diagnosis, risk factors, prevention and management.

Malignant ethmoid tumors are treated by surgery followed by radiotherapy. This study aimed to evaluate the incidence, risk factors and outcome of radionecrosis of frontal lobe and determine preventive measures. Retrospective study of ethmoid malignancies treated from 2000 to 2011. All patients underwent surgery with/without anterior skull base resection using endoscopic or external approaches followed by irradiation (mean dose 64 Gy). Median follow-up was 50 months. Eight of 50 patients (16 %) presented with fronto-basal radionecrosis, connected to duraplasty, with a latent interval of 18.5 months. Although asymptomatic in six, radionecrosis triggered seizures and required surgery in two cases. Survival was not impacted. Risk factors included dyslipidemia, occurrence of epilepsy and dural resection. Radionecrosis may result from the combination of anterior skull base resection and radiotherapy for the treatment of ethmoid malignancies. Preventive measures rely on improving the duraplasty and optimization of the Gy-dose delivery.

Sex-specific radiation-induced microRNAome responses in the hippocampus, cerebellum and frontal cortex in a mouse model.

Ionizing radiation is an important treatment modality, but it is also a well-known genotoxic agent capable of damaging cells and tissues. Therefore radiation treatment can cause numerous side effects in exposed tissues and organs. Radiotherapy is a part of the front-line treatment regime for brain cancer patients, but can cause severe functional and morphological changes in exposed brain tissues. However, the mechanisms of radiation-induced effects in the brain are not well understood and are under-investigated. Recent data has implicated short RNAs, especially microRNAs, as important in radiation responses, yet nothing is known about radiation-induced changes in the brain microRNAome. We analyzed the effects of X-ray irradiation on microRNA expression in the hippocampus, frontal cortex, and cerebellum of male and female mice. Here, we report tissue-, time-, and sex-specific brain radiation responses, as well as show evidence of an interplay between microRNAs and their targets. Specifically, we show that changes in the expression of the miR-29 family may be linked, at least in part, to altered expression of de novo methyltransferase DNMT3a and changed global DNA methylation levels. Further, these sex-specific epigenetic changes may be correlated to the prevalence of radiation-induced cancers in males. We identified several microRNAs that can potentially serve as biomarkers of brain radiation exposure. In summary, our study may provide an important roadmap for further analysis of microRNA expression in different brain regions of male and female mice and for detailed dissection of radiation-induced brain responses.

Surgical treatment and radiation therapy of frontal lobe meningiomas in 7 dogs.

The cases of 7 adult dogs with generalized seizures managed by surgical excision and radiation therapy for frontal lobe meningiomas were reviewed. The neurological examination was unremarkable in 6 of the 7 dogs. Five dogs were operated on using a bilateral transfrontal sinus approach and 2 using a unilateral sinotemporal approach to the frontal lobe. One dog was euthanized 14 d after surgery; radiation therapy was initiated 3 wk after surgery in the remaining 6 dogs. Long-term follow-up consisted of neurological examination and magnetic resonance imaging (MRI) and/or computed tomography (CT) scan after radiation therapy. The mean survival time for dogs that had surgery and radiation therapy was 18 mo after surgery. Frontal lobe meningiomas have been associated with poor prognosis. However, the surgical approaches used in these cases, combined with radiation therapy, allow a survival rate for frontal lobe meningiomas similar to that for meningiomas located over the cerebral convexities.

Visuomotor Transformations Are Modulated by Focused Ultrasound over Frontal Eye Field.

Neuromodulation with focused ultrasound (FUS) is being widely explored as a non-invasive tool to stimulate focal brain regions because of its superior spatial resolution and coverage compared with other neuromodulation methods. The precise effects of FUS stimulation on specific regions of the brain are not yet fully understood. Here, we characterized the behavioral effects of FUS stimulation directly applied through a craniotomy over the macaque frontal eye field (FEF). In macaque monkeys making directed eye movements to perform visual search tasks with direct or arbitrary responses, focused ultrasound was applied through a craniotomy over the FEF. Saccade response times (RTs) and error rates were determined for trials without or with FUS stimulation with pulses at a peak negative pressure of either 250 or 425 kPa. Both RTs and error rates were affected by FUS. Responses toward a target located contralateral to the FUS stimulation were approximately 3 ms slower in the presence of FUS in both monkeys studied, while only one exhibited a slowing of responses for ipsilateral targets. Error rates were lower in one monkey in this study. In another search task requiring making eye movements toward a target (pro-saccades) or in the opposite direction (anti-saccades), the RT for pro-saccades increased in the presence of FUS stimulation. Our results indicate the effectiveness of FUS to modulate saccadic responses when stimulating FEF in awake, behaving non-human primates.

Technical considerations for noncoplanar proton-beam therapy of patients with tumors proximal to the optic nerve.

PURPOSE: To investigate technical feasibilities of noncoplanar proton-beam therapy (PBT) on dose reduction to critical organs. MATERIAL AND METHODS: The degree of mechanical precision, rotational limitations of the gantry and the treatment couch were evaluated, and dose-volume histograms were compared for noncoplanar and coplanar PBT. Following these studies, three patients with tumors proximal to the optic nerve underwent noncoplanar PBT. RESULTS: Noncoplanar PBT offered advantage in dose reduction to the optic nerve when compared to coplanar therapy. This advantage was more significant if the tumor reduced in size during treatment. None experienced radiation injury to the optic nerve during a short follow-up time of 7-12 months. CONCLUSION: Noncoplanar PBT appears to reduce doses to organs at risk.

Cerebral microbleeds in adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiation.

Cranial radiation therapy is associated with white matter-specific brain injury, cortical volume loss, mineralization, microangiopathy and neurocognitive impairment in survivors of childhood acute lymphoblastic leukemia. In this retrospective cross-sectional analysis, neurocognitive testing and 3 T brain MRI's were obtained in 101 survivors treated with cranial radiation. Small focal intracerebral hemorrhages only visible on exquisitely sensitive MRI sequences were identified and localized using susceptibility weighted imaging. Modified Poisson regression was used to assess the effect of cranial radiation on cumulative number and location of microbleeds in each brain region, and multiple linear regression was used to evaluate microbleeds on neurocognitive outcomes, adjusting for age at diagnosis and sex. At least one microbleed was present in 85% of survivors, occurring more frequently in frontal lobes. Radiation dose of 24 Gy conveyed a 5-fold greater risk (95% CI 2.57-10.32) of having multiple microbleeds compared to a dose of 18 Gy. No significant difference was found in neurocognitive scores with either the absence or presence of microbleeds or their location. Greater prevalence of microbleeds in our study compared to prior reports is likely related to longer time since treatment, better sensitivity of SWI for detection of microbleeds and the use of a 3 T MRI platform.

Radio-induced low-grade glioma: report of two cases and review of the literature.

With the increasing number of cancer survivors, we can observe a population that will present a higher risk of developing secondary long-term toxicities related to adjuvant chemo and radiotherapy regimens. Among these, children surviving from acute lymphoblastic leukemia (ALL) that were treated with prophylactic cranial irradiation represent a group of patients at a high risk of developing secondary brain tumors. Radiation-induced intracranial tumors have been documented since 1950, and today, more than one-hundred cases have been described. We report our experience with two young patients who were hospitalized for low grade gliomas and had a positive anamnesis for ALL and consequent radiotherapy.

Reductions in neural activity underlie behavioral components of repetition priming.

Repetition priming is a nonconscious form of memory that is accompanied by reductions in neural activity when an experience is repeated. To date, however, there is no direct evidence that these neural reductions underlie the behavioral advantage afforded to repeated material. Here we demonstrate a causal linkage between neural and behavioral priming in humans. fMRI (functional magnetic resonance imaging) was used in combination with transcranial magnetic stimulation (TMS) to target and disrupt activity in the left frontal cortex during repeated classification of objects. Left-frontal TMS disrupted both the neural and behavioral markers of priming. Neural priming in early sensory regions was unaffected by left-frontal TMS--a finding that provides evidence for separable conceptual and perceptual components of priming.

Corticostriatal stimulation compensates for medial frontal inactivation during interval timing.

Prefrontal dysfunction is a common feature of brain diseases such as schizophrenia and contributes to deficits in executive functions, including working memory, attention, flexibility, inhibitory control, and timing of behaviors. Currently, few interventions improve prefrontal function. Here, we tested whether stimulating the axons of prefrontal neurons in the striatum could compensate for deficits in temporal processing related to prefrontal dysfunction. We used an interval-timing task that requires working memory for temporal rules and attention to the passage of time. Our previous work showed that inactivation of the medial frontal cortex (MFC) impairs interval timing and attenuates ramping activity, a key form of temporal processing in the dorsomedial striatum (DMS). We found that 20-Hz optogenetic stimulation of MFC axon terminals increased curvature of time-response histograms and improved interval-timing behavior. Furthermore, optogenetic stimulation of terminals modulated time-related ramping of medium spiny neurons in the striatum. These data suggest that corticostriatal stimulation can compensate for deficits caused by MFC inactivation and they imply that frontostriatal projections are sufficient for controlling responses in time.

Time course of blood oxygenation level-dependent signal response after theta burst transcranial magnetic stimulation of the frontal eye field.

The aim of the current study was to examine the effect of theta burst repetitive transcranial magnetic stimulation (rTMS) on the blood oxygenation level-dependent (BOLD) activation during repeated functional magnetic resonance imaging (fMRI) measurements. Theta burst rTMS was applied over the right frontal eye field in seven healthy subjects. Subsequently, repeated fMRI measurements were performed during a saccade-fixation task (block design) 5, 20, 35, and 60 min after stimulation. We found that theta burst rTMS induced a strong and long-lasting decrease of the BOLD signal response of the stimulated frontal eye field at 20 and 35 min. Furthermore, less pronounced alterations of the BOLD signal response with different dynamics were found for remote oculomotor areas such as the left frontal eye field, the pre-supplementary eye field, the supplementary eye field, and both parietal eye fields. Recovery of the BOLD signal changes in the anterior remote areas started earlier than in the posterior remote areas. These results show that a) the major inhibitory impact of theta burst rTMS occurs directly in the stimulated area itself, and that b) a lower effect on remote, oculomotor areas can be induced.

Neuro-inflammatory response in rats chronically exposed to (137)Cesium.

After the Chernobyl nuclear accident, behavioural disorders and central nervous system diseases were frequently observed in populations living in the areas contaminated by (137)Cs. Until now, these neurological disturbances were not elucidated, but the presence of a neuro-inflammatory response could be one explanation. Rats were exposed for 3 months to drinking water contaminated with (137)Cs at a dose of 400Bqkg(-1), which is similar to that ingested by the population living in contaminated areas in the former USSR countries. Pro-inflammatory and anti-inflammatory cytokine genes were assessed by real-time PCR in the frontal cortex and the hippocampus. At this level of exposure, gene expression of TNF-alpha and IL-6 increased in the hippocampus and gene expression of IL-10 increased in the frontal cortex. Concentration of TNF-alpha, measured by ELISA assays, was also increased in the hippocampus. The central NO-ergic pathway was also studied: iNOS gene expression and cNOS activity were significantly increased in the hippocampus. In conclusion, this study showed for the first time that sub-chronic exposure with post-accidental doses of (137)Cs leads to molecular modifications of pro- and anti-inflammatory cytokines and NO-ergic pathway in the brain. This neuro-inflammatory response could contribute to the electrophysiological and biochemical alterations observed after chronic exposure to (137)Cs.

Atypical teratoid/rhabdoid tumour: 7-year event-free survival with gross total resection and radiotherapy in a 7-year-old boy.

CASE STUDY: We report the case of a 7-year-old boy who presented in 1998 a tumour of the left frontal lobe. Initially diagnosed as anaplastic ependymoma, the boy was treated by gross total resection followed by radiotherapy at the operated site. In July 2005, an orbital tumour was discovered and resected. The tumour was composed of sheets of rhabdoid cells which diffusely expressed vimentin and focally epithelial membrane antigen (EMA) and alpha-smooth actin by immunohistochemistry. The first tumour was re-examined. Small foci of rhabdoid cells were found. Immunohistochemistry anti-INI1 performed on both tumours was negative. Molecular techniques performed on frozen specimen of the orbital tumour confirmed the diagnosis of atypical teratoid/rhabdoid tumour (ATRT). DISCUSSION: We discuss the pathological criteria for diagnosis of ATRT and the usefulness of early radiotherapy in the light of the recent literature.

Physiologically patterned weak magnetic fields applied over left frontal lobe increase acceptance of false statements as true.

Fifty men and women were exposed to only one of four experimentally generated magnetic fields over the left prefrontal region (above the eyebrow) or to a sham field immediately after the words "true" or "false" were presented following statements of definitions of words for a "foreign language". Three of the patterns (25 Hz, 50 Hz, or burst-firing) with intensities between 1 and 10 microT were presented for 1 s during the refutation process (immediately after the offset of "true" or "false") for specific statements from a total of 28 statements. The fourth pattern was a variable approximately 7-10 Hz (10 nT) field generated from the circuitry that was present continuously during the entire experiment. When the statements were presented again, the groups who had received the burst-firing ("limbic") or 25 Hz pulsed magnetic fields during the refutation process accepted about twice the number of false statements as true compared to those exposed to the 50 Hz field or sham-field conditions. The treatments did not significantly affect the numbers of true statements accepted as false. These results suggest that the appropriately pulsed magnetic field during the refutation process of what one has been told or has heard can increase the probability a person will accept a false statement as true.

Bright light exposure before bedtime impairs response inhibition the following morning: a non-randomized crossover study.

INTRODUCTION: Bright light exposure in the late evening can affect cognitive function the following morning either by changing the biological clock and/or disturbing sleep, but the evidence for this effect is scarce, and the underlying mechanism remains unknown. In this study, we first aimed to evaluate the effect of bright light exposure before bedtime on frontal lobe activity the following morning using near-infrared spectroscopy (NIRS) during a Go/NoGo task. Second, we aimed to evaluate the effects of bright light exposure before bedtime on polysomnographic measures and on a frontal lobe function test the following morning. METHODS: Twenty healthy, young males (mean age, 25.5 years) were recruited between September 2013 and August 2014. They were first exposed to control light (150 lux) before bedtime (from 20:00 h to 24:00 h) for 2 days and then to bright light (1,000 lux) before bedtime for an additional 5 days. We performed polysomnography (PSG) on the final night of each light exposure period (on nights 2 and night 7) and performed NIRS, which measures the concentrations of oxygenated and deoxygenated hemoglobin (OxyHb and DeoxyHb, respectively), coupled with a Go/NoGo task the following morning (between 09:30 h and 11:30 h). The participants also completed frontal lobe function tests the following morning. RESULTS: NIRS showed decreased hemodynamic activity (lower OxyHb and a tendency toward higher DeoxyHb concentration) in the right frontal lobe during the NoGo block after 1000-lux light exposure compared with that during the NoGo block after 150-lux light exposure. The commission error rate (ER) during the Go/NoGo task was higher after 1000-lux light exposure than that during the Go/NoGo task after 150-lux light exposure (1.24 ± 1.09 vs. 0.6 ± 0.69, P = 0.002), suggesting a reduced inhibitory response. CONCLUSION: This study shows that exposure to bright light before bedtime for 5 days impairs right frontal lobe activation and response inhibition the following morning.

Diffusion tensor magnetic resonance imaging finding of discrepant fractional anisotropy between the frontal and parietal lobes after whole-brain irradiation in childhood medulloblastoma survivors: reflection of regional white matter radiosensitivity?

PURPOSE: To test the hypothesis that fractional anisotropy (FA) is more severely reduced in white matter of the frontal lobe compared with the parietal lobe after receiving the same whole-brain irradiation dose in a cohort of childhood medulloblastoma survivors. METHODS AND MATERIALS: Twenty-two medulloblastoma survivors (15 male, mean [+/- SD] age = 12.1 +/- 4.6 years) and the same number of control subjects (15 male, aged 12.0 +/- 4.2 years) were recruited for diffusion tensor magnetic resonance imaging scans. Using an automated tissue classification method and the Talairach Daemon atlas, FA values of frontal and parietal lobes receiving the same radiation dose, and the ratio between them were quantified and denoted as FFA, PFA, and FA(f/p), respectively. The Mann-Whitney U test was used to test for significant differences of FFA, PFA, and FA(f/p) between medulloblastoma survivors and control subjects. RESULTS: Frontal lobe and parietal lobe white matter FA were found to be significantly less in medulloblastoma survivors compared with control subjects (frontal p = 0.001, parietal p = 0.026). Moreover, these differences were found to be discrepant, with the frontal lobe having a significantly larger difference in FA compared with the parietal lobe. The FA(f/p) of control and medulloblastoma survivors was 1.110 and 1.082, respectively (p = 0.029). CONCLUSION: Discrepant FA changes after the same irradiation dose suggest radiosensitivity of the frontal lobe white matter compared with the parietal lobe. Special efforts to address the potentially vulnerable frontal lobe after treatment with whole-brain radiation may be needed so as to balance disease control and treatment-related morbidity.

Loss of heterozygosity analysis in an anaplastic oligodendroglioma arising after radiation therapy.

OBJECTIVE AND IMPORTANCE: Oligodendroglial tumors rarely occur after radiation therapy. Here, we report a rare case of anaplastic oligodendroglioma arising after radiation therapy, in which genetic analysis was performed. CLINICAL PRESENTATION AND INTERVENTION: A 41-year-old man who had received radiation therapy for a tumor of the suprasellar and pineal regions 31 years previously, presented with headache and progressive right hemiparesis. Magnetic resonance (MR) images revealed a ring-enhanced mass lesion in the left frontal lobe. Total removal of the tumor was performed through left frontoparietal craniotomy, and the histologic diagnosis was anaplastic oligodendroglioma. Using 23 microsatellite markers, the allelic status of chromosomes 1p, 10, 17p and 19q was evaluated by a PCR-based loss of heterozygosity (LOH) assay. Markers on chromosomes 1p, 17p and 19q revealed LOH, but none of the markers on chromosome 10 showed LOH. Based on the genetic analysis, this tumor was considered to be sensitive to chemotherapy. Two courses of chemotherapy, with procarbazine, ACNU and vincristine, were performed. However, tumor recurrence was detected only 3 months after the surgery. Despite additional radiochemotherapy, the tumor aggressively increased in size and the patient died with multiple recurrent tumors 1 year after surgery. CONCLUSION: The anaplastic oligodendroglioma presented in this report showed a more aggressive clinical course than was expected from the genetic analysis. The significance of 1p and 19q LOH in radiation-induced oligodendroglial tumors might differ from that in spontaneous counterparts.

Neurochemical differences in learning and memory paradigms among rats supplemented with anthocyanin-rich blueberry diets and exposed to acute doses of 56Fe particles.

The protective effects of anthocyanin-rich blueberries (BB) on brain health are well documented and are particularly important under conditions of high oxidative stress, which can lead to "accelerated aging." One such scenario is exposure to space radiation, consisting of high-energy and -charge particles (HZE), which are known to cause cognitive dysfunction and deleterious neurochemical alterations. We recently tested the behavioral and neurochemical effects of acute exposure to HZE particles such as 56Fe, within 24-48h after exposure, and found that radiation primarily affects memory and not learning. Importantly, we observed that specific brain regions failed to upregulate antioxidant and anti-inflammatory mechanisms in response to this insult. To further examine these endogenous response mechanisms, we have supplemented young rats with diets rich in BB, which are known to contain high amounts of antioxidant-phytochemicals, prior to irradiation. Exposure to 56Fe caused significant neurochemical changes in hippocampus and frontal cortex, the two critical regions of the brain involved in cognitive function. BB supplementation significantly attenuated protein carbonylation, which was significantly increased by exposure to 56Fe in the hippocampus and frontal cortex. Moreover, BB supplementation significantly reduced radiation-induced elevations in NADPH-oxidoreductase-2 (NOX2) and cyclooxygenase-2 (COX-2), and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) in the hippocampus and frontal cortex. Overall results indicate that 56Fe particles may induce their toxic effects on hippocampus and frontal cortex by reactive oxygen species (ROS) overload, which can cause alterations in the neuronal environment, eventually leading to hippocampal neuronal death and subsequent impairment of cognitive function. Blueberry supplementation provides an effective preventative measure to reduce the ROS load on the CNS in an event of acute HZE exposure.