Association Between Brain Substructure Dose and Cognitive Outcomes in Children With Medulloblastoma Treated on SJMB03: A Step Toward Substructure-Informed Planning.

PURPOSE: To characterize the association between neurocognitive outcomes (memory and processing speed) and radiation (RT) dose to the hippocampus, corpus callosum (CC), and frontal white matter (WM) in children with medulloblastoma treated on a prospective study, SJMB03. PATIENTS AND METHODS: Patients age 3-21 years with medulloblastoma were treated at a single institution on a phase III study. The craniospinal RT dose was 23.4 Gy for average-risk patients and 36-39.6 Gy for high-risk patients. The boost dose was 55.8 Gy to the tumor bed. Patients underwent cognitive testing at baseline and once yearly for 5 years. Performance on tests of memory (associative memory and working memory) and processing speed (composite processing speed and perceptual speed) was analyzed. Mixed-effects models were used to estimate longitudinal trends in neurocognitive outcomes. Reliable change index and logistic regression were used to define clinically meaningful neurocognitive decline and identify variables associated with decline. RESULTS: One hundred and twenty-four patients were eligible for inclusion, with a median neurocognitive follow-up of 5 years. Mean right and left hippocampal doses were significantly associated with decline in associative memory in patients without posterior fossa syndrome (all P < .05). Mean CC and frontal WM doses were significantly associated with decline in both measures of processing speed (all P < .05). Median brain substructure dose-volume histograms were shifted to the right for patients with a decline in associative memory or processing speed. The odds of decline in associative memory and composite processing speed increased by 23%-26% and by 10%-15% for every 1-Gy increase in mean hippocampal dose and mean CC or frontal WM dose, respectively. CONCLUSION: Increasing RT dose to the CC or frontal WM and hippocampus is associated with worse performance on tests of processing speed and associative memory, respectively. Brain substructure-informed RT planning may mitigate neurocognitive impairment.

Night Photostimulation of Clearance of Beta-Amyloid from Mouse Brain: New Strategies in Preventing Alzheimer's Disease.

The deposition of amyloid-ß (Aß) in the brain is a risk factor for Alzheimer's disease (AD). Therefore, new strategies for the stimulation of Aß clearance from the brain can be useful in preventing AD. Transcranial photostimulation (PS) is considered a promising method for AD therapy. In our previous studies, we clearly demonstrated the PS-mediated stimulation of lymphatic clearing functions, including Aß removal from the brain. There is increasing evidence that sleep plays an important role in Aß clearance. Here, we tested our hypothesis that PS at night can stimulate Aß clearance from the brain more effectively than PS during the day. Our results on healthy mice show that Aß clearance from the brain occurs faster at night than during wakefulness. The PS course at night improves memory and reduces Aß accumulation in the brain of AD mice more effectively than the PS course during the day. Our results suggest that night PS is a more promising candidate as an effective method in preventing AD than daytime PS. These data are an important informative platform for the development of new noninvasive and nonpharmacological technologies for AD therapy as well as for preventing Aß accumulation in the brain of people with disorder of Aß metabolism, sleep deficit, elderly age, and jet lag.

Effects of Photobiomodulation on Changes in Cognitive Function and Regional Cerebral Blood Flow in Patients with Mild Cognitive Impairment: A Pilot Uncontrolled Trial.

BACKGROUND: Photobiomodulation (PBM) affects local blood flow regulation through nitric oxide generation, and various studies have reported on its effect on improving cognitive function in neurodegenerative diseases. However, the effect of PBM in the areas of the vertebral arteries (VA) and internal carotid arteries (ICA), which are the major blood-supplying arteries to the brain, has not been previously investigated. OBJECTIVE: We aimed to determine whether irradiating PBM in the areas of the VA and ICA, which are the major blood-supplying arteries to the brain, improved regional cerebral blood flow (rCBF) and cognitive function. METHODS: Fourteen patients with mild cognitive impairments were treated with PBM. Cognitive assessment and single-photon emission computed tomography were implemented at the baseline and at the end of PBM. RESULTS: Regarding rCBF, statistically significant trends were found in the medial prefrontal cortex, lateral prefrontal cortex, anterior cingulate cortex, and occipital lateral cortex. Based on the cognitive assessments, statistically significant trends were found in overall cognitive function, memory, and frontal/executive function. CONCLUSION: We confirmed the possibility that PBM treatment in the VA and ICA areas could positively affect cognitive function by increasing rCBF. A study with a larger sample size is needed to validate the potential of PBM.

Acute, Low-Dose Neutron Exposures Adversely Impact Central Nervous System Function.

A recognized risk of long-duration space travel arises from the elevated exposure astronauts face from galactic cosmic radiation (GCR), which is composed of a diverse array of energetic particles. There is now abundant evidence that exposures to many different charged particle GCR components within acute time frames are sufficient to induce central nervous system deficits that span from the molecular to the whole animal behavioral scale. Enhanced spacecraft shielding can lessen exposures to charged particle GCR components, but may conversely elevate neutron radiation levels. We previously observed that space-relevant neutron radiation doses, chronically delivered at dose-rates expected during planned human exploratory missions, can disrupt hippocampal neuronal excitability, perturb network long-term potentiation and negatively impact cognitive behavior. We have now determined that acute exposures to similar low doses (18 cGy) of neutron radiation can also lead to suppressed hippocampal synaptic signaling, as well as decreased learning and memory performance in male mice. Our results demonstrate that similar nervous system hazards arise from neutron irradiation regardless of the exposure time course. While not always in an identical manner, neutron irradiation disrupts many of the same central nervous system elements as acute charged particle GCR exposures. The risks arising from neutron irradiation are therefore important to consider when determining the overall hazards astronauts will face from the space radiation environment.

Effects of 1.5 and 4.3 GHz microwave radiation on cognitive function and hippocampal tissue structure in Wistar rats.

Previous studies have shown that single-frequency microwave radiation can lead to cognitive decline in rats. However, few studies have focused on the combined effects of irradiation with different frequencies of microwaves. Our research aimed to investigate the effects of 1.5 GHz and 4.3 GHz microwave radiation, singly and in combination, on cognitive function and hippocampal tissue structure in rats. A total of 140 male Wistar rats were randomly divided into 4 groups: the S group (sham radiation group), L10 group (10 mW/cm2 1.5 GHz group), C10 group (10 mW/cm2 4.3 GHz band group) and LC10 group (10 mW/cm2 1.5 and 4.3 GHz multi-frequency radiation group). For 1-28 days after microwave radiation, we analyzed the average escape latency for the Morris water maze task, electroencephalograms, change in hippocampal tissue structure and ultrastructure, content of the Nissl body in the hippocampus, and activities of lactate dehydrogenase and succinate dehydrogenase. Compared to the S group, all exposure groups showed varying degrees of learning and memory decline and hippocampal structural damage. The results showed that 1.5 GHz and 4.3 GHz microwave radiation was able to induce cognitive impairment and hippocampal tissue damage in rats and combined radiation with both frequencies caused more serious injuries, but none of these damaging effects varied with microwave frequency.

Systemic HDAC3 inhibition ameliorates impairments in synaptic plasticity caused by simulated galactic cosmic radiation exposure in male mice.

Deep space travel presents a number of measurable risks including exposure to a spectrum of radiations of varying qualities, termed galactic cosmic radiation (GCR) that are capable of penetrating the spacecraft, traversing through the body and impacting brain function. Using rodents, studies have reported that exposure to simulated GCR leads to cognitive impairments associated with changes in hippocampus function that can persist as long as one-year post exposure with no sign of recovery. Whether memory can be updated to incorporate new information in mice exposed to GCR is unknown. Further, mechanisms underlying long lasting impairments in cognitive function as a result of GCR exposure have yet to be defined. Here, we examined whether whole body exposure to simulated GCR using 6 ions and doses of 5 or 30 cGy interfered with the ability to update an existing memory or impact hippocampal synaptic plasticity, a cellular mechanism believed to underlie memory processes, by examining long term potentiation (LTP) in acute hippocampal slices from middle aged male mice 3.5-5 months after radiation exposure. Using a modified version of the hippocampus-dependent object location memory task developed by our lab termed "Objects in Updated Locations" (OUL) task we find that GCR exposure impaired hippocampus-dependent memory updating and hippocampal LTP 3.5-5 months after exposure. Further, we find that impairments in LTP are reversed through one-time systemic subcutaneous injection of the histone deacetylase 3 inhibitor RGFP 966 (10 mg/kg), suggesting that long lasting impairments in cognitive function may be mediated at least in part, through epigenetic mechanisms.

Whole brain proton irradiation in adult Sprague Dawley rats produces dose dependent and non-dependent cognitive, behavioral, and dopaminergic effects.

Proton radiotherapy causes less off-target effects than X-rays but is not without effect. To reduce adverse effects of proton radiotherapy, a model of cognitive deficits from conventional proton exposure is needed. We developed a model emphasizing multiple cognitive outcomes. Adult male rats (10/group) received a single dose of 0, 11, 14, 17, or 20 Gy irradiation (the 20 Gy group was not used because 50% died). Rats were tested once/week for 5 weeks post-irradiation for activity, coordination, and startle. Cognitive assessment began 6-weeks post-irradiation with novel object recognition (NOR), egocentric learning, allocentric learning, reference memory, and proximal cue learning. Proton exposure had the largest effect on activity and prepulse inhibition of startle 1-week post-irradiation that dissipated each week. 6-weeks post-irradiation, there were no effects on NOR, however proton exposure impaired egocentric (Cincinnati water maze) and allocentric learning and caused reference memory deficits (Morris water maze), but did not affect proximal cue learning or swimming performance. Proton groups also had reduced striatal levels of the dopamine transporter, tyrosine hydroxylase, and the dopamine receptor D1, effects consistent with egocentric learning deficits. This new model will facilitate investigations of different proton dose rates and drugs to ameliorate the cognitive sequelae of proton radiotherapy.

Prenatal and early postnatal exposure to radiofrequency waves (900 MHz) adversely affects passive avoidance learning and memory.

Prenatal and early postnatal are the most sensitive and high-risk periods to expose to electromagnetic fields (EMFs). This study aimed to investigate the effect of prenatal and early postnatal exposure to 900 MHz radiofrequency waves (RFWs) emitted from a base transceiver station antenna on passive avoidance learning and memory (PALM) and hippocampus histomorphology. Female Sprague Dawley rats (190-230 g) were paired with males. The mated rats, confirmed by observing a vaginal plug, were divided into two groups; control and exposed. The control group (n = 7) was not exposed to RFW. The exposed group was divided into three subgroups (n = 8); exposed Ⅰ, exposed during the gestational period (fetal life), and exposed Ⅱ and Ⅲ (postnatal exposure), exposed to RFW during the first 21 days of life, for 2 h/d and 4 h/d, respectively. PALM was evaluated by a shuttle box in 45-day-old pups. Learning and memory of animals were demonstrated as the duration of remaining within the light area, which is called the lighting time. Histological sections were prepared from brain tissues and stained with hematoxylin and eosin. An impairment in the PALM performance was noticed in all exposed subgroups (Ⅰ, Ⅱ, and Ⅲ) (p < 0.05). Learning (short-term memory) and retention (long-term memory) behaviors were more affected in exposed subgroup Ⅰ (prenatal exposed) compared to other postnatal exposed subgroups (Ⅱ and Ⅲ). Also, a mild decrease in the density of pyramidal cells was observed in the hippocampus of exposed subgroups (Ⅰ and Ⅲ). Prenatal and early postnatal exposure to 900 MHz RFW adversely affected PALM performance and hippocampus tissue in rat pups with more impact for prenatal period exposure.

Cranial irradiation impairs juvenile social memory and modulates hippocampal physiology.

Cranial and craniospinal irradiation are the oldest central nervous system prophylaxis treatments considered for pediatric patients with acute lymphoblastic leukemia (ALL). However, survivors of childhood ALL that received cranial radiotherapy are at increased risk for deficits in neurocognitive skills. The continuous and dynamic response of normal tissue after irradiation has been identified as one of the causative factors for cognitive changes after cranial radiation therapy. The aim of our study was to investigate the radiation effects on social behavior and neuronal morphology in the hippocampus of adult mice. Twenty-oneday-old male C57BL/6 mice were irradiated with the small-animal radiation research platform (SARRP). Animals were given a single 10-Gy dose of radiation of X-ray cranial radiation. One month following irradiation, animals underwent behavioral testing in the Three-Chamber Sociability paradigm. Radiation affected social discrimination during the third stage eliciting an inability to discriminate between the familiar and stranger mouse, while sham successfully spent more time exploring the novel stranger. Proteomic analysis revealed dysregulation of metabolic and signaling pathways associated with neurocognitive dysfunction such as mitochondrial dysfunction, Rac 1 signaling, and synaptogenesis signaling. We observed significant decreases in mushroom spine density in the Cornu Ammonis 2 of the hippocampus, which is associated with sociability processing.

Jet Lag Recovery and Memory Functions Are Correlated with Direct Light Effects on Locomotion.

Jet lag is a circadian disruption that affects millions of people, resulting, among other things, in extreme sleepiness and memory loss. The hazardous implications of such effects are evident in situations in which focus and attention are required. Remarkably, there is a limited understanding of how jet lag recovery and associated memory loss vary year round under different photoperiods. Here we show, using different cycles representing winter, summer, and equinox in male mice, that jet lag recovery and memory vary significantly with photoperiod changes. We uncover a positive correlation of acute light effects on circadian-driven locomotion (known as negative masking) with photoentrainment speed and memory enhancement during jet lag. Specifically, we show that enhancing or reducing negative masking is correlated with better or worse memory performance, respectively. This study indicates that in addition to timed-light exposure for phase shifting, the negative masking response could also be biologically relevant when designing effective treatments of jet lag.

Short and long-term evaluation of the impact of proton minibeam radiation therapy on motor, emotional and cognitive functions.

Radiotherapy (RT) is one of the most frequently used methods for cancer treatment. Despite remarkable advancements in RT techniquesthe treatment of radioresistant tumours (i.e. high-grade gliomas) is not yet satisfactory. Finding novel approaches less damaging for normal tissues is of utmost importance. This would make it possible to increase the dose applied to tumours, resulting in an improvement in the cure rate. Along this line, proton minibeam radiation therapy (pMBRT) is a novel strategy that allows the spatial modulation of the dose, leading to minimal damage to brain structures compared to a high dose (25 Gy in one fraction) of standard proton therapy (PT). The aim of the present study was to evaluate whether pMBRT also preserves important cerebral functions. Comprehensive longitudinal behavioural studies were performed in irradiated (peak dose of 57 Gy in one fraction) and control rats to evaluate the impact of pMBRT on motor function (motor coordination, muscular tonus, and locomotor activity), emotional function (anxiety, fear, motivation, and impulsivity), and cognitive function (learning, memory, temporal processing, and decision making). The evaluations, which were conducted over a period of 10 months, showed no significant motor or emotional dysfunction in pMBRT-irradiated rats compared with control animals. Concerning cognitive functions, similar performance was observed between the groups, although some slight learning delays might be present in some of the tests in the long term after irradiation. This study shows the minimal impact of pMBRT on the normal brain at the functional level.

CORM-3 Regulates Microglia Activity, Prevents Neuronal Injury, and Improves Memory Function During Radiation-induced Brain Injury.

OBJECTIVE: This study aims to explore in detail, the mechanism of the carbon monoxide releasing molecule-3 (CORM-3) in regulating the activity of microglia (MG) in the treatment of radiation brain injury (RBI). METHODS: The brain injury models of BV2 cells and Balb/C mice were established and randomly divided into three groups: the normal control group (CON), the single radiation group (RAD), and the radiation plus CORM-3 intervention group (RAD+CORM). Immunofluorescence was used to observe the effects on activation of the MG. The expressions of inflammatory factors, such as intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS), were detected by Western blot. Neuron apoptosis and regeneration in the radiation brain injury (RBI) model were detected by neuronal nuclear antigen (NeuN)+TUNEL and NeuN+BrdU double staining. A Morris water maze was used to assess the spatial learning and memory of the mice. RESULTS: Within 48 h after radiation, CORM-3 inhibited activation of the MG, blocked the phosphorylation of P38, and increased the expression of ICAM-1 and iNOS. Therefore, CORM-3 might alleviate MG-mediated neuronal apoptosis and promote neural regeneration in the subgranular zone (SGZ) of the dentate gyrus of the hippocampus. CORM-3 could increase the swimming distance and platform-stay time of the mice in the target platform quadrant after radiation. CONCLUSION: CORM-3 could effectively improve the inflammatory response induced by activation of the MG, reduce neuronal apoptosis, promote neural regeneration, and improve the learning and memory performance of mice after radiation.

Long-term UVA exposure to the eye compromises memory and learning ability in mice via corticotropin-releasing hormone type 2 receptor.

Long-term eye exposure to ultraviolet (UV)A can effect memory and learning ability. However, the underlying mechanism behind these effects remain unknown. In this study, we used HR-1 mice to study effects of long-term UVA eye irradiation. The eyes or dorsal skin of the mice were exposed to UVA at the dose of 110kj/m2 using an FL20SBLB-A lamp three times a week over 12 months. We measured the levels of reactive oxygen species, corticotropin-releasing hormone (CRH), urocortin 2, and CRH type 2 receptor (CRHR-2) in the brain of treated and control animals. Their memory and learning ability following exposure to UVA was analyzed by the standard water maze test. Our results showed that the levels of reactive oxygen species, CRH, urocortin 2, and CRHR-2 increased significantly following long-term UVA irradiation, and the effects were more pronounced in animals subjected to eye irradiation than those subjected to dorsal skin irradiation. Furthermore, the UVA exposure led to an increase in the levels of ß-amyloid and microglia in the brain. These results indicated that UVA eye irradiation potentially mediated a decline in memory and learning ability via enhancing levels of urocortin 2, microglia, and ß-amyloid in the brain.

Predictions of cognitive detriments from galactic cosmic ray exposures to astronauts on exploration missions.

For the first-time we report on predictions on cognitive detriments from galactic cosmic ray (GCR) exposures on long-duration space missions outside the protection of the Earth's magnetosphere and solid body shielding. Estimates are based on a relative risk (RR) model of the fluence response for proton and heavy ion in rodent studies using the widely used novel object recognition (NOR) test, which estimates detriments in recognition or object memory. Our recent meta-analysis showed that linear and linear-quadratic dose response models were not accurate, while exponential increasing fluence response models based on particle track structure provided good descriptions of rodent data for doses up to 1 Gy. Using detailed models of the GCR environment and particle transport in shielding and tissue, we predict the excess relative risk (ERR) for NOR detriments for several long-term space mission scenarios. Predictions suggest ERR < 0.15 for most space mission scenarios with ERR<0.1 for 1-year lunar surface missions, and about ERR~0.1 for a 1000 day Mars mission for average solar cycle conditions. We discuss possible implications of these ERR levels of cognitive performance detriments relative to other neurological challenges such as rodent models of Alzheimer's disease (AD), Parkinson's disease (PD) and traumatic brain injury (TBI). Comparisons suggest a small but potentially clinically significant risk for possible space mission scenarios.

Effects of transcranial photobiomodulation and methylene blue on biochemical and behavioral profiles in mice stress model.

The effectiveness of transcranial photobiomodulation (tPBM) and methylene Blue (MB) in treating learning and memory impairments is previously reported. In this study, we investigated the effect of tPBM and MB in combination or alone on unpredictable chronic mild stress (UCMS)-induced learning and memory impairments in mice. Fifty-five male BALB/c mice were randomly allocated to five groups: control, laser sham + normal saline (NS), tPBM + NS, laser sham + MB, and tPBM + MB. All groups except the control underwent UCMS and were treated simultaneously for 4 weeks. Elevated plus maze (EPM) was used to evaluate anxiety-like behaviors. Novel object recognition (NOR) test and Barnes maze tests were used to evaluate learning and memory function. The serum cortisol and brain nitric oxide (NO), reactive oxygen species (ROS), total antioxidant capacity (TAC), glutathione peroxidase (GPx), and superoxide dismutase (SOD) levels were measured by spectrophotometric methods. Behavioral tests revealed that UCMS impaired learning and memory, and treatment with PBM, MB, and their combination reversed these impairments. Levels of NO, ROS, SOD activity in brain, and serum cortisol levels significantly increased while brain GPx activity and total antioxidant capacity significantly decreased in the sham + NS animals when compared with the controls. A significant improvement was observed in treatment groups due to reversion of the aforementioned molecular analysis caused by UCMS when it was compared with control levels. Both tPBM and MB in combination or alone have significant therapeutic effects on learning and memory impairments in UCMS-received animals.

Glycogen Synthase Kinase 3ß in the Ventral Hippocampus is Important for Cocaine Reward and Object Location Memory.

The ventral hippocampus is a component of the neural circuitry involved with context-associated memory for reward and generation of appropriate behavioral responses to context. Glycogen synthase kinase 3 beta (GSK3ß) has been linked to the maintenance of synaptic plasticity, contextual memory retrieval, and is involved in the reconsolidation of cocaine-associated contextual memory. In this study, the effects of targeted downregulation of GSK3ß in the ventral hippocampus were examined on a series of behavioral tests for assessing drug reward-context association and non-reward related memory. The Cre/loxP site-specific recombination system was used to knockdown GSK3ß through bilateral stereotaxic delivery of an adeno-associated virus expressing Cre-recombinase (AAV-Cre) into the ventral hippocampus of adult mice homozygous for a floxed GSK3ß allele. GSK3ß floxed mice injected with AAV-Cre had a loss of 56-75% of GSK3ß in the ventral hippocampus and displayed diminished development of cocaine conditioned place preference, but not morphine place preference as compared with wild-type mice injected with AAV-Cre or GSK3ß floxed mice injected with a control virus, AAV-GFP. Impaired object location memory was observed in mice with GSK3ß downregulation in the ventral hippocampus, but novel object recognition remained intact. These results indicate that GSK3ß signaling in the ventral hippocampus is differentially involved in the formation of place-drug reward association dependent upon drug class. Additionally, ventral hippocampal GSK3ß signaling is important in detection of discrete spatial cues, but not recognition memory for objects.

Cranial irradiation in juvenile mice leads to early and sustained defects in the stem and progenitor cell pools and late cognitive impairments.

Cranial irradiation is used in combination with other therapies as a treatment for brain tumours and is thought to contribute to long-term cognitive deficits. Several rodent models have demonstrated that these cognitive deficits may be correlated with damage to neural progenitor cells in the subventricular zone (SVZ) and dentate gyrus (DG), the two neurogenic niches of the brain. Studies in rodent models typically assess the proliferating progenitor population, but rarely investigate the effect of cranial irradiation on the neural stem cell pool. Further, few studies evaluate the effects in juveniles, an age when children typically receive this treatment. Herein, we examine the cellular and behavioural effects of juvenile cranial irradiation on stem and progenitor populations in the two neurogenic regions of the brain and assess cognitive outcomes. We found regionally distinct effects of cranial irradiation in the juvenile brain. In the SVZ, we observed a defect in the stem cell pool and a concomitant decrease in proliferating cells that were maintained for at least one week. In the DG, a similar defect in the stem cell pool and proliferating cells was observed and persisted in the stem cell population. Finally, we demonstrated that cranial irradiation resulted in late cognitive deficits. This study demonstrates that juvenile cranial irradiation leads to regionally distinct defects in the stem and progenitor populations, and late cognitive deficits, which may be important factors in determining therapeutic targets and timing of interventions following cranial irradiation.

Radiofrequency electromagnetic radiation-induced behavioral changes and their possible basis.

The primary objective of mobile phone technology is to achieve communication with any person at any place and time. In the modern era, it is impossible to ignore the usefulness of mobile phone technology in cases of emergency as many lives have been saved. However, the biological effects they may have on humans and other animals have been largely ignored and not been evaluated comprehensively. One of the reasons for this is the speedy uncontrollable growth of this technology which has surpassed our researching ability. Initiated with the first generation, the mobile telephony currently reaches to its fifth generation without being screened extensively for any biological effects that they may have on humans or on other animals. Mounting evidences suggest possible non-thermal biological effects of radiofrequency electromagnetic radiation (RF-EMR) on brain and behavior. Behavioral studies have particularly concentrated on the effects of RF-EMR on learning, memory, anxiety, and locomotion. The literature analysis on behavioral effects of RF-EMR demonstrates complex picture with conflicting observations. Nonetheless, numerous reports suggest a possible behavioral effect of RF-EMR. The scientific findings about this issue are presented in the current review. The possible neural and molecular mechanisms for the behavioral effects have been proposed in the light of available evidences from the literature.

Quantitative Imaging Biomarkers of Damage to Critical Memory Regions Are Associated With Post-Radiation Therapy Memory Performance in Brain Tumor Patients.

PURPOSE: We used quantitative magnetic resonance imaging to prospectively analyze the association between microstructural damage to memory-associated structures within the medial temporal lobe and longitudinal memory performance after brain radiation therapy (RT). METHODS AND MATERIALS: Patients with a primary brain tumor receiving fractionated brain RT were enrolled on a prospective trial (n = 27). Patients underwent high-resolution volumetric brain magnetic resonance imaging, diffusion-weighted imaging, and neurocognitive testing before and 3, 6, and 12 months post-RT. Medial temporal lobe regions (hippocampus; entorhinal, parahippocampal, and temporal pole white matter [WM]) were autosegmented, quantifying volume and diffusion biomarkers of WM integrity (mean diffusivity [MD]; fractional anisotropy [FA]). Reliable change indices measured changes in verbal (Hopkins Verbal Learning Test-Revised) and visuospatial (Brief Visuospatial Memory Test-Revised [BVMT-R]) memory. Linear mixed-effects models assessed longitudinal associations between imaging parameters and memory. RESULTS: Visuospatial memory significantly declined at 6 months post-RT (mean reliable change indices, -1.3; P = .012). Concurrent chemotherapy and seizures trended toward a significant association with greater decline in visuospatial memory (P = .053 and P = .054, respectively). Higher mean dose to the left temporal pole WM was significantly associated with decreased FA (r = -0.667; P = .002). Over all time points, smaller right hippocampal volume (P = .021), lower right entorhinal FA (P = .023), greater right entorhinal MD (P = .047), and greater temporal pole MD (BVMT-R total recall, P = .003; BVMT-R delayed recall, P = .042) were associated with worse visuospatial memory. The interaction between right entorhinal MD (BVMT-R total recall, P = .021; BVMT-R delayed recall, P = .004) and temporal pole FA (BVMT-R delayed recall, P = .024) significantly predicted visuospatial memory performance. CONCLUSIONS: Brain tumor patients exhibited visuospatial memory decline post-RT. Microstructural damage to critical memory regions, including the hippocampus and medial temporal lobe WM, were associated with post-RT memory decline. The integrity of medial temporal lobe structures is critical to memory performance post-RT, representing possible avoidance targets for memory preservation.

New Concerns for Neurocognitive Function during Deep Space Exposures to Chronic, Low Dose-Rate, Neutron Radiation.

As NASA prepares for a mission to Mars, concerns regarding the health risks associated with deep space radiation exposure have emerged. Until now, the impacts of such exposures have only been studied in animals after acute exposures, using dose rates ∼1.5×105 higher than those actually encountered in space. Using a new, low dose-rate neutron irradiation facility, we have uncovered that realistic, low dose-rate exposures produce serious neurocognitive complications associated with impaired neurotransmission. Chronic (6 month) low-dose (18 cGy) and dose rate (1 mGy/d) exposures of mice to a mixed field of neutrons and photons result in diminished hippocampal neuronal excitability and disrupted hippocampal and cortical long-term potentiation. Furthermore, mice displayed severe impairments in learning and memory, and the emergence of distress behaviors. Behavioral analyses showed an alarming increase in risk associated with these realistic simulations, revealing for the first time, some unexpected potential problems associated with deep space travel on all levels of neurological function.