Grey-box modeling and hypothesis testing of functional near-infrared spectroscopy-based cerebrovascular reactivity to anodal high-definition tDCS in healthy humans.

Transcranial direct current stimulation (tDCS) has been shown to evoke hemodynamics response; however, the mechanisms have not been investigated systematically using systems biology approaches. Our study presents a grey-box linear model that was developed from a physiologically detailed multi-compartmental neurovascular unit model consisting of the vascular smooth muscle, perivascular space, synaptic space, and astrocyte glial cell. Then, model linearization was performed on the physiologically detailed nonlinear model to find appropriate complexity (Akaike information criterion) to fit functional near-infrared spectroscopy (fNIRS) based measure of blood volume changes, called cerebrovascular reactivity (CVR), to high-definition (HD) tDCS. The grey-box linear model was applied on the fNIRS-based CVR during the first 150 seconds of anodal HD-tDCS in eleven healthy humans. The grey-box linear models for each of the four nested pathways starting from tDCS scalp current density that perturbed synaptic potassium released from active neurons for Pathway 1, astrocytic transmembrane current for Pathway 2, perivascular potassium concentration for Pathway 3, and voltage-gated ion channel current on the smooth muscle cell for Pathway 4 were fitted to the total hemoglobin concentration (tHb) changes from optodes in the vicinity of 4x1 HD-tDCS electrodes as well as on the contralateral sensorimotor cortex. We found that the tDCS perturbation Pathway 3 presented the least mean square error (MSE, median <2.5%) and the lowest Akaike information criterion (AIC, median -1.726) from the individual grey-box linear model fitting at the targeted-region. Then, minimal realization transfer function with reduced-order approximations of the grey-box model pathways was fitted to the ensemble average tHb time series. Again, Pathway 3 with nine poles and two zeros (all free parameters), provided the best Goodness of Fit of 0.0078 for Chi-Square difference test of nested pathways. Therefore, our study provided a systems biology approach to investigate the initial transient hemodynamic response to tDCS based on fNIRS tHb data. Future studies need to investigate the steady-state responses, including steady-state oscillations found to be driven by calcium dynamics, where transcranial alternating current stimulation may provide frequency-dependent physiological entrainment for system identification. We postulate that such a mechanistic understanding from system identification of the hemodynamics response to transcranial electrical stimulation can facilitate adequate delivery of the current density to the neurovascular tissue under simultaneous portable imaging in various cerebrovascular diseases.

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.

Brain Damage and Patterns of Neurovascular Disorder after Ionizing Irradiation. Complications in Radiotherapy and Radiation Combined Injury.

Exposure to ionizing radiation, mechanical trauma, toxic chemicals or infections, or combinations thereof (i.e., combined injury) can induce organic injury to brain tissues, the structural disarrangement of interactive networks of neurovascular and glial cells, as well as on arrays of the paracrine and systemic destruction. This leads to subsequent decline in cognitive capacity and decompensation of mental health. There is an ongoing need for improvement in mitigating and treating radiation- or combined injury-induced brain injury. Cranial irradiation per se can cause a multifactorial encephalopathy that occurs in a radiation dose- and time-dependent manner due to differences in radiosensitivity among the various constituents of brain parenchyma and vasculature. Of particular concern are the radiosensitivity and inflammation susceptibility of: 1. the neurogenic and oligodendrogenic niches in the subependymal and hippocampal domains; and 2. the microvascular endothelium. Thus, cranial or total-body irradiation can cause a plethora of biochemical and cellular disorders in brain tissues, including: 1. decline in neurogenesis and oligodendrogenesis; 2. impairment of the blood-brain barrier; and 3. ablation of vascular capillary. These changes, along with cerebrovascular inflammation, underlie different stages of encephalopathy, from the early protracted stage to the late delayed stage. It is evident that ionizing radiation combined with other traumatic insults such as penetrating wound, burn, blast, systemic infection and chemotherapy, among others, can exacerbate the radiation sequelae (and vice versa) with increasing severity of neurogenic and microvascular patterns of radiation brain damage.

Computational feasibility of simulating changes in blood flow through whole-organ vascular networks from radiation injury.

Vasculature is necessary to the healthy function of most tissues. In radiation therapy, injury of the vasculature can have both beneficial and detrimental effects, such as tumor starvation, cardiac fibrosis, and white-matter necrosis. These effects are caused by changes in blood flow due to the vascular injury. Previously, research has focused on simulating the radiation injury of vasculature in small volumes of tissue, ignoring the systemic effects of local damage on blood flow. Little is known about the computational feasibility of simulating the radiation injury to whole-organ vascular networks. The goal of this study was to test the computational feasibility of simulating the dose deposition to a whole-organ vascular network and the resulting change in blood flow. To do this, we developed an amorphous track-structure model to transport radiation and combined this with existing methods to model the vasculature and blood flow rates. We assessed the algorithm's computational scalability, execution time, and memory usage. The data demonstrated it is computationally feasible to calculate the radiation dose and resulting changes in blood flow from 2 million protons to a network comprising 8.5 billion blood vessels (approximately the number in the human brain) in 87 hours using a 128-node cluster. Furthermore, the algorithm demonstrated both strong and weak scalability, meaning that additional computational resources can reduce the execution time further. These results demonstrate, for the first time, that it is computationally feasible to calculate radiation dose deposition in whole-organ vascular networks. These findings provide key insights into the computational aspects of modeling whole-organ radiation damage. Modeling the effects radiation has on vasculature could prove useful in the study of radiation effects on tissues, organs, and organisms.

Non-invasive treatment with near-infrared light: A novel mechanisms-based strategy that evokes sustained reduction in brain injury after stroke.

Ischemic stroke is a debilitating disease that causes significant brain injury. While restoration of blood flow is critical to salvage the ischemic brain, reperfusion can exacerbate damage by inducing generation of reactive oxygen species (ROS). Recent studies by our group found that non-invasive mitochondrial modulation with near-infrared (NIR) light limits ROS generation following global brain ischemia. NIR interacts with cytochrome c oxidase (COX) to transiently reduce COX activity, attenuate mitochondrial membrane potential hyperpolarization, and thus reduce ROS production. We evaluated a specific combination of COX-inhibitory NIR (750 nm and 950 nm) in a rat stroke model with longitudinal analysis of brain injury using magnetic resonance imaging. Treatment with NIR for 2 h resulted in a 21% reduction in brain injury at 24 h of reperfusion measured by diffusion-weighted imaging (DWI) and a 25% reduction in infarct volume measured by T2-weighted imaging (T2WI) at 7 and 14 days of reperfusion, respectively. Additionally, extended treatment reduced brain injury in the acute phase of brain injury, and 7 and 14 days of reperfusion, demonstrating a >50% reduction in infarction. Our data suggest that mitochondrial modulation with NIR attenuates ischemia-reperfusion injury and evokes a sustained reduction in infarct volume following ischemic stroke.

Learning Hemodynamic Effect of Transcranial Infrared Laser Stimulation Using Longitudinal Data Analysis.

Transcranial infrared laser stimulation (TILS) is a promising noninvasive intervention for neurological diseases. Though some experimental work has been done to understand the mechanism of TILS, the reported statistical analysis of data is quite simple and could not provide a comprehensive picture on the effect of TILS. This study learns the effect of TILS on hemodynamics of the human brain from experimental data using longitudinal data analysis methods. Specifically, repeated measures analysis of variance (ANOVA) is first applied to confirm the significance of the TILS effect and its characteristics. Based on that, two parametric mixed-effect models and non-parametric functional mixed-effect model are proposed to model the population-level performance and individual variation of this effect. Interpretations on the fitted models are provided, and comparison of the three proposed models in terms of fitting and prediction performance is made to select the best model. According to the selected model, TILS increases the concentration of oxygenated hemoglobin in the brain and this effect sustains even after the treatment stops. Also, there is considerable variation among individual responses to TILS.

Transcranial Photobiomodulation Therapy in the Cognitive Rehabilitation of Patients with Cranioencephalic Trauma.

Objective: This research evaluated the hemodynamic conditions before and after the transcranial photobiomodulation therapy (PBMT) and investigated neurocognitive changes before and after treatment. Background: Traumatic brain injury (TBI) is the major cause of morbidity and mortality among individuals 21-60 years old and causes ∼500,000 people to be hospitalized in Brazil annually. Some survivors develop an irreversible decrease in neurological function, and the mortality rate is as high as 70% in severe cases. PBMT is an alternative to treat secondary injuries due to TBI. Methods: This multidisciplinary clinical study was carried out on 10 chronic adult patients with severe TBI, who were treated with PBMT with an optical device containing 13 sets of 4 light emitting diodes, and underwent hemodynamic transcranial Doppler and neuropsychological evaluation at three different times: pre-PBMT, post-PBMT (after a week), and late-PBMT, which occurred 3 months after the last session. The patients received PBMTs three times a week, for 6 weeks. PBMTs were performed for 18 sessions for 6 weeks and 30 min per session. Results: The results found an alteration in the cerebral blood flow (CBF) as well as a consequent increase of the cerebral oxygenation that helped to improve the cerebral function. Conclusions: The PBMT contributed to increased CBF, evidenced mainly by the increased left peak systolic velocity, which consequently increased the hemodynamic response after the PBMT and impacts on the peripheral cerebral perfusion contributing to improved cerebral function.

Photobiomodulation Mitigates Cerebrovascular Leakage Induced by the Parkinsonian Neurotoxin MPTP.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson's disease (PD) as it specifically damages the nigrostriatal dopaminergic pathway. Recent studies in mice have, however, provided evidence that MPTP also compromises the integrity of the brain's vasculature. Photobiomodulation (PBM), the irradiation of tissue with low-intensity red light, mitigates MPTP-induced loss of dopaminergic neurons in the midbrain, but whether PBM also mitigates MPTP-induced damage to the cerebrovasculature has not been investigated. This study aimed to characterize the time course of cerebrovascular disruption following MPTP exposure and to determine whether PBM can mitigate this disruption. Young adult male C57BL/6 mice were injected with 80 mg/kg MPTP or isotonic saline and perfused with fluorescein isothiocyanate FITC-labelled albumin at various time points post-injection. By 7 days post-injection, there was substantial and significant leakage of FITC-labelled albumin into both the substantia nigra pars compacta (SNc; p < 0.0001) and the caudate-putamen complex (CPu; p ≤ 0.0003); this leakage partly subsided by 14 days post-injection. Mice that were injected with MPTP and treated with daily transcranial PBM (670 nm, 50 mW/cm2, 3 min/day), commencing 24 hours after MPTP injection, showed significantly less leakage of FITC-labelled albumin in both the SNc (p < 0.0001) and CPu (p = 0.0003) than sham-treated MPTP mice, with levels of leakage that were not significantly different from saline-injected controls. In summary, this study confirms that MPTP damages the brain's vasculature, delineates the time course of leakage induced by MPTP out to 14 days post-injection, and provides the first direct evidence that PBM can mitigate this leakage. These findings provide new understanding of the use of the MPTP mouse model as an experimental tool and highlight the potential of PBM as a therapeutic tool for reducing vascular dysfunction in neurological conditions.

The neurovascular response is attenuated by focused ultrasound-mediated disruption of the blood-brain barrier.

Focused ultrasound (FUS)-induced disruption of the blood-brain barrier (BBB) is a non-invasive method to target drug delivery to specific brain areas that is now entering into the clinic. Recent studies have shown that the method has several secondary effects on local physiology and brain function beyond making the vasculature permeable to normally non-BBB penetrant molecules. This study uses functional MRI methods to investigate how FUS BBB opening alters the neurovascular response in the rat brain. Nine rats underwent actual and sham FUS induced BBB opening targeted to the right somatosensory cortex (SI) followed by four runs of bilateral electrical hind paw stimulus-evoked fMRI. The neurovascular response was quantified using measurements of the blood oxygen level dependent (BOLD) signal and cerebral blood flow (CBF). An additional three rats underwent the same FUS-BBB opening followed by stimulus-evoked fMRI with high resolution BOLD imaging and BOLD imaging of a carbogen-breathing gas challenge. BOLD and CBF measurements at two different stimulus durations demonstrate that the neurovascular response to the stimulus is attenuated in both amplitude and duration in the region targeted for FUS-BBB opening. The carbogen results show that the attenuation in response amplitude, but not duration, is still present when the signaling mechanism originates from changes in blood oxygenation instead of stimulus-induced neuronal activity. There is some evidence of non-local effects, including a possible global decrease in baseline CBF. All effects are resolved by 24 h after FUS-BBB opening. Taken together, these results suggest that FUS-BBB opening alters that state of local brain neurovascular physiology in such a way that hinders its ability to respond to demands for increased blood flow to the region. The mechanisms for this effect need to be elucidated.

Pulsed Transcranial Red/Near-Infrared Light Therapy Using Light-Emitting Diodes Improves Cerebral Blood Flow and Cognitive Function in Veterans with Chronic Traumatic Brain Injury: A Case Series.

Objective: This study explored the outcome of applying red/near-infrared light therapy using light-emitting diodes (LEDs) pulsed with three different frequencies transcranially to treat traumatic brain injury (TBI) in Veterans. Background: Photobiomodulation therapy (PBMT) using LEDs has been shown to have positive effects on TBI in humans and animal models. Materials and methods: Twelve symptomatic military Veterans diagnosed with chronic TBI >18 months post-trauma received pulsed transcranial PBMT (tPBMT) using two neoprene therapy pads containing 220 infrared and 180 red LEDs, generating a power output of 3.3 W and an average power density of 6.4 mW/cm2 for 20 min, thrice per week over 6 weeks. Outcome measures included standardized neuropsychological test scores and qualitative and quantitative single photon emission computed tomography (SPECT) measures of regional cerebral blood flow (rCBF). Results: Pulsed tPBMT significantly improved neuropsychological scores in 6 of 15 subscales (40.0%; p < 0.05; two tailed). SPECT analysis showed increase in rCBF in 8 of 12 (66.7%) study participants. Quantitative SPECT analysis revealed a significant increase in rCBF in this subgroup of study participants and a significant difference between pre-treatment and post-treatment gamma ray counts per cubic centimeter [t = 3.77, df = 7, p = 0.007, 95% confidence interval (95,543.21-21,931.82)]. This is the first study to report quantitative SPECT analysis of rCBF in regions of interest following pulsed tPBMT with LEDs in TBI. Conclusions: Pulsed tPBMT using LEDs shows promise in improving cognitive function and rCBF several years after TBI. Larger, controlled studies are indicated.

Effects of Home Photobiomodulation Treatments on Cognitive and Behavioral Function, Cerebral Perfusion, and Resting-State Functional Connectivity in Patients with Dementia: A Pilot Trial.

Objective: To examine the effects of transcranial and intranasal photobiomodulation (PBM) therapy, administered at home, in patients with dementia. Background: This study sought to replicate and build upon a previously published case series report describing improved cognitive function in five patients with mild-to-moderate dementia after 12 weeks of transcranial and intranasal near-infrared (NIR) PBM therapy. Materials and methods: Eight participants (mean age: 79.8 ± 5.8 years old) diagnosed with dementia by their physicians were randomized to 12 weeks of usual care (UC, n = 4) or home PBM treatments (n = 4). The NIR PBM treatments were administered by a study partner at home three times per week with the Vielight Neuro Gamma device. The participants were assessed with the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) subscale and the Neuropsychiatric Inventory (NPI) at baseline and 6 and 12 weeks, and with arterial spin-labeled perfusion magnetic resonance imaging (MRI) and resting-state functional MRI at baseline and 12 weeks. Results: At baseline, the UC and PBM groups did not differ demographically or clinically. However, after 12 weeks, there were improvements in ADAS-cog (group × time interaction: F1,6 = 16.35, p = 0.007) and NPI (group × time interaction: F1,6 = 7.52, p = 0.03), increased cerebral perfusion (group × time interaction: F1,6 = 8.46, p < 0.03), and increased connectivity between the posterior cingulate cortex and lateral parietal nodes within the default-mode network in the PBM group. Conclusions: Because PBM was well tolerated and associated with no adverse side effects, these results support the potential of PBM therapy as a viable home treatment for individuals with dementia.

Effect of radiochemotherapy on the cognitive function and diffusion tensor and perfusion weighted imaging for high-grade gliomas: A prospective study.

This study aimed to explore the effects of radiochemotherapy on the neurocognitive function of patients with high-grade gliomas (HGG). The mini-mental state examination (MMSE), Montreal Cognitive Assessment (MoCA), event-related potential P300 (ERP-P300), and specific MRI parameters were compared, and the associations between specific MRI parameters and different doses of radiation were determined for before and up to 12 months after radiotherapy. There were no significant differences in MMSE, MoCA, or ERP-P300 before and after radiotherapy. Compared with pre-radiochemotherapy, fractional anisotropy (FA) in the contralateral hippocampus decreased at 6 and 9 months after radiotherapy. FA in the ipsilateral hippocampus before radiochemotherapy decreased compared with 6 months after radiotherapy. Compared to the end of radiotherapy, as well as 3- and 6-months post-radiotherapy, the regional cerebral blood volume (rCBV) in the genu of the corpus was significantly lower at 12 months post-radiotherapy. Some MRI parameters in different regions of the brain were negatively correlated with the mean and maximum dose. There was no significant effect of radiochemotherapy on the neurocognitive functioning of patients with HGGs found before radiochemotherapy until 12 months after radiotherapy. The radiation-induced FA decrease in the bilateral hippocampus preceded cognitive dysfunction, and DTI of the hippocampus may provide a useful biomarker for predicting radiation-induced neurocognitive impairment in patients with HGGs.

Radiation-induced vascular changes in the intracranial irradiation field in medulloblastoma survivors: An MRI study.

BACKGROUND AND PURPOSE: While survival times after treatment of medulloblastoma are increasing, little is known about radiochemotherapy (RCT)-induced cerebrovascular changes. High resolution vessel wall imaging (VWI) sequences are an emerging tool for the evaluation of cerebrovascular diseases. We performed VWI in medulloblastoma long-term survivors to screen for late sequelae of RCT. MATERIAL AND METHODS: Twenty-two pediatric medulloblastoma survivors (mean age 25.8 years (10-53 years); 16.3 years (mean) post primary RCT (range 1-45 years)) underwent 2D VWI-MRI. Vessel wall thickening, contrast enhancement and luminal narrowing were analyzed. The findings were correlated with the patients' radiation protocols. RESULTS: Vessel wall changes were observed the intracranial internal carotid artery (ICA) and the vertebrobasilar circulation (VBC) in 14 of 22 patients (63.6%). In multivariate analysis, time after RCT (OR = 1.38, p < 0.05) was strongest independent predictor for development of vessel wall alterations. The dose of radiation was not a relevant predictor. CONCLUSIONS: With longer follow-up time intracranial vessel wall changes are observed more frequently in medulloblastoma survivors. Thus VWI is a useful tool to monitor vessel wall alterations of cranially irradiated patients, creating the prerequisite for further treatment of late sequelae.

Utility of Magnetic Resonance Perfusion Imaging in Quantifying Active Tumor Fraction and Radiation Necrosis in Recurrent Intracranial Tumors.

BACKGROUND: Ancillary criteria to identify tumor recurrence such as the McDonald criteria or Response Assessment in Neuro-Oncology criteria can provide false diagnoses. Magnetic resonance perfusion (MRP) imaging has been proposed to differentiate post-treatment changes from recurrence. We investigated the utility of MRP to quantify the histological fraction of active tumor (AT), treatment-related changes, and radiation necrosis in recurrent post-treatment intracranial tumors. METHODS: We conducted an exploratory single-blind study of patients with intracranial glioblastoma or metastases with previous radiation therapy and MRP before surgery. Biopsy specimens (n = 19) were analyzed for the percentage of AT, radiation necrosis, and treatment effect. Nonparametric Spearman's rho analysis and multivariable analysis of covariance were performed to assess the correlation between quantitative MRP and AT histological fraction. RESULTS: The mean patient age was 58 ± 11.5 years. The mean relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) were 1.33 ± 0.71 and 1.34 ± 0.73, respectively. On analysis of covariance, significant associations were identified between increased rCBF (P = 0.0004) and increased rCBV (P = 0.007) and percentage of AT. A significant interaction was identified between rCBF and rCBV and tumor histological features (glioblastoma vs. metastases; P = 0.003 and P = 0.03, respectively). An rCBF >1 predicted a mean AT fraction of ≥53% for all intracranial tumors and 74% for glioblastoma. CONCLUSION: MRP can help quantitatively predict tumor recurrence and/or progression for glioblastomas. The AT histological fraction correlated with quantitative radiologic measurements, including rCBV and rCBF. For metastases, MRP might not be as useful in predicting the AT fraction. Clinicians must be judicious with their use of MRP in predicting tumor recurrence and radiation necrosis.

Effects of transcranial LED therapy on the cognitive rehabilitation for diffuse axonal injury due to severe acute traumatic brain injury: study protocol for a randomized controlled trial.

BACKGROUND: Photobiomodulation describes the use of red or near-infrared light to stimulate or regenerate tissue. It was discovered that near-infrared wavelengths (800-900 nm) and red (600 nm) light-emitting diodes (LED) are able to penetrate through the scalp and skull and have the potential to improve the subnormal cellular activity of compromised brain tissue. Different experimental and clinical studies were performed to test LED therapy for traumatic brain injury (TBI) with promising results. One of the proposals of this present study is to develop different approaches to maximize the positive effects of this therapy and improve the quality of life of TBI patients. METHODS/DESIGN: This is a double-blinded, randomized, controlled trial of patients with diffuse axonal injury (DAI) due to a severe TBI in an acute stage (less than 8 h). Thirty two patients will be randomized to active coil helmet and inactive coil (sham) groups in a 1:1 ratio. The protocol includes 18 sessions of transcranial LED stimulation (627 nm, 70 mW/cm2, 10 J/cm2) at four points of the frontal and parietal regions for 30 s each, totaling 120 s, three times per week for 6 weeks, lasting 30 min. Patients will be evaluated with the Glasgow Outcome Scale Extended (GOSE) before stimulation and 1, 3, and 6 months after the first stimulation. The study hypotheses are as follows: (1) transcranial LED therapy (TCLT) will improve the cognitive function of DAI patients and (2) TCLT will promote beneficial hemodynamic changes in cerebral circulation. DISCUSSION: This study evaluates early and delayed effects of TCLT on the cognitive rehabilitation for DAI following severe acute TBI. There is a paucity of studies regarding the use of this therapy for cognitive improvement in TBI. There are some experimental studies and case series presenting interesting results for TBI cognitive improvement but no clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03281759 . Registered on 13 September 2017.

Susceptibility-weighted magnetic resonance imaging of cerebrovascular sequelae after radiotherapy for pediatric brain tumors.

BACKGROUND AND PURPOSE: Due to sensitive neuroimaging techniques, cerebrovascular complications such as cerebral microbleeds (CMB) and cerebral cavernous malformations (CCM) are increasingly recognized as considerable late effects after treatment for pediatric brain tumor. The aim of this study was to analyze CMB in a cohort of patients after cranial irradiation therapy for medulloblastoma or other pediatric brain tumors using susceptibility-weighted magnetic resonance imaging (SWI). MATERIALS AND METHODS: Forty former pediatric brain tumor patients were enrolled in this prospective cross-sectional study and examined by cranial MRI including SWI sequences. Cerebral microbleeds, clinical symptoms and disability were evaluated. RESULTS: Thirty-six (90%) of the examined individuals (mean follow-up age 22.2 y; mean follow-up time 13.5 y) were affected by CMB. Longer follow-up time and higher craniospinal irradiation doses correlated with higher total lesion count (p < 0.01). Thirteen patients (32.5%) presented with clinical symptoms. Individuals with CMB were more severely disabled than patients without CMB (p < 0.05). CONCLUSIONS: Cerebrovascular sequelae occur frequently after treatment for pediatric brain tumor. In this study, a remarkable part of pediatric brain tumor patients presents with CMB. As a sign of vascular damage, they can cause clinical symptoms and may correspond to neurocognitive decline. Further studies are needed to standardize MRI protocols and to improve quality of long-term follow-up.

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.

Photon vs. proton radiochemotherapy: Effects on brain tissue volume and perfusion.

BACKGROUND AND PURPOSE: To compare the structural and hemodynamic changes of healthy brain tissue in the cerebral hemisphere contralateral to the tumor following photon and proton radiochemotherapy. MATERIALS AND METHODS: Sixty-seven patients (54.9 ±14.0 years) diagnosed with glioblastoma undergoing adjuvant photon (n = 47) or proton (n = 19) radiochemotherapy with temozolomide after tumor resection underwent T1-weighted and arterial spin labeling MRI. Changes in volume and perfusion before and 3 to 6 months after were compared between therapies. RESULTS: A decrease in gray matter (GM) (-2.2%, P<0.001) and white matter (WM) (-1.2%, P<0.001) volume was observed in photon-therapy patients compared to the pre-radiotherapy baseline. In contrast, for the proton-therapy group, no significant differences in GM (0.3%, P = 0.64) or WM (-0.4%, P = 0.58) volume were observed. GM volume decreased with 0.9% per 10 Gy dose increase (P<0.001) and differed between the radiation modalities (P<0.001). Perfusion decreased in photon-therapy patients (-10.1%, P = 0.002), whereas the decrease in proton-therapy patients, while comparable in magnitude, did not reach statistical significance (-9.1%, P = 0.12). There was no correlation between perfusion decrease and either dose (P = 0.64) or radiation modality (P = 0.94). CONCLUSIONS: Our results show that the tissue volume decrease depends on radiation dose delivered to the healthy hemisphere and differs between treatment modalities. In contrast, the decrease in perfusion was comparable for both irradiation modalities. We conclude that proton therapy may reduce brain-volume loss when compared to photon therapy.

Physiological Effects of Continuous Colored Light Exposure on Mayer Wave Activity in Cerebral Hemodynamics: A Functional Near-Infrared Spectroscopy (fNIRS) Study.

We are increasingly exposed to colored light, but its impact on human physiology is not yet extensively investigated. In the present study we aimed to determine the effects of colored light on human cerebral Mayer wave activity (MWA). We measured oxy- ([O2Hb]), deoxy- ([HHb]), total hemoglobin ([tHb]) concentrations and tissue oxygen saturation (StO2) by functional near-infrared spectroscopy (fNIRS) in the left and right pre-frontal cortex (L-PFC, R-PFC) of 17 subjects (median age: 29 years, 6 women). In a randomized crossover design subjects were exposed to blue, red, green, and yellow LED light for 10 min. Pre-light (8 min, baseline) and post-light (15 min, recovery) conditions were darkness. MWA was calculated from band-pass filtered fNIRS signals (~0.08-0.12 Hz). The medians from the last 3 min of each period (baseline, light exposure, recovery) were statistically analyzed. MWA was increased during red and green light vs. baseline and after blue light exposure in recovery in the L-PFC. MWA differed depending on the chosen frequency range, filter design, and type of signals to analyze (raw intensity, hemoglobin signal from multi-distance method or modified Beer-Lambert law, or within hemoglobin signals).

Radiation induces progenitor cell death, microglia activation, and blood-brain barrier damage in the juvenile rat cerebellum.

Posterior fossa tumors are the most common childhood intracranial tumors, and radiotherapy is one of the most effective treatments. However, irradiation induces long-term adverse effects that can have significant negative impacts on the patient's quality of life. The purpose of this study was to characterize irradiation-induced cellular and molecular changes in the cerebellum. We found that irradiation-induced cell death occurred mainly in the external germinal layer (EGL) of the juvenile rat cerebellum. The number of proliferating cells in the EGL decreased, and 82.9% of them died within 24 h after irradiation. Furthermore, irradiation induced oxidative stress, microglia accumulation, and inflammation in the cerebellum. Interestingly, blood-brain barrier damage and blood flow reduction was considerably more pronounced in the cerebellum compared to other brain regions. The cerebellar volume decreased by 39% and the migration of proliferating cells to the internal granule layer decreased by 87.5% at 16 weeks after irradiation. In the light of recent studies demonstrating that the cerebellum is important not only for motor functions, but also for cognition, and since treatment of posterior fossa tumors in children typically results in debilitating cognitive deficits, this differential susceptibility of the cerebellum to irradiation should be taken into consideration for future protective strategies.