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.

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.

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.

Transcranial infrared laser stimulation produces beneficial cognitive and emotional effects in humans.

This is the first controlled study demonstrating the beneficial effects of transcranial laser stimulation on cognitive and emotional functions in humans. Photobiomodulation with red to near-infrared light is a novel intervention shown to regulate neuronal function in cell cultures, animal models, and clinical conditions. Light that intersects with the absorption spectrum of cytochrome oxidase was applied to the forehead of healthy volunteers using the laser diode CG-5000, which maximizes tissue penetration and has been used in humans for other indications. We tested whether low-level laser stimulation produces beneficial effects on frontal cortex measures of attention, memory and mood. Reaction time in a sustained-attention psychomotor vigilance task (PVT) was significantly improved in the treated (n=20) vs. placebo control (n=20) groups, especially in high novelty-seeking subjects. Performance in a delayed match-to-sample (DMS) memory task showed also a significant improvement in treated vs. control groups as measured by memory retrieval latency and number of correct trials. The Positive and Negative Affect Schedule (PANAS-X), which tracks self-reported positive and negative affective (emotional) states over time, was administered immediately before treatment and 2 weeks after treatment. The PANAS showed that while participants generally reported more positive affective states than negative, overall affect improved significantly in the treated group due to more sustained positive emotional states as compared to the placebo control group. These data imply that transcranial laser stimulation could be used as a non-invasive and efficacious approach to increase brain functions such as those related to cognitive and emotional dimensions. Transcranial infrared laser stimulation has also been proven to be safe and successful at improving neurological outcome in humans in controlled clinical trials of stroke. This innovative approach could lead to the development of non-invasive, performance-enhancing interventions in healthy humans and in those in need of neuropsychological rehabilitation.

Differential expression of egr1 and activation of microglia following irradiation in the rat brain.

BACKGROUND: Little is known about the immediate effects of whole-brain gamma-irradiation. The authors hypothesize that Egr1 as an immediate early gene and microglia both participate in early reactions. MATERIAL AND METHODS: Both, expression of Egr1 and cellular distribution were studied in a temporal sequence in different brain regions of rats subjected to irradiation with 10 Gy. Brain tissue was examined using immunohistochemistry, real-time RT-PCR (reverse transcription-polymerase chain reaction), and Western blotting. RESULTS: Astroglia and oligodendroglia showed increased Egr1 immunoreactivity within the first hours following irradiation. This was accompanied by a strong peak in CD68 immunoreactivity histologically attributable to activated microglia. A high constitutive expression of Egr1 protein in the nuclei of activated neurons was reduced following irradiation and RT-PCR demonstrated significantly reduced levels of egr1-lv as a neuronal activity-related mRNA variant. CONCLUSION: The induction of Egr1 in glial cells, as well as the activation of microglia take place earlier than histological changes reported so far. The authors revealed a temporal sequence of reactions that point toward the initiation of an immediate inflammatory response including reduced neuronal activity.

Presynaptic alpha7 and non-alpha7 nicotinic acetylcholine receptors modulate [3H]d-aspartate release from rat frontal cortex in vitro.

The presynaptic nicotinic modulation of glutamatergic transmission in the CNS has been associated with activation of the alpha7 subtype of nicotinic acetylcholine receptor (nAChR) in sub-cortical regions, whereas in the frontal cortex, non-alpha7 nAChRs have been implicated. The aim of this investigation was to directly characterise nAChR-evoked release of excitatory amino acids from rat frontal cortex, by monitoring the release of [3H]D-aspartate from superfused synaptosomes or minces. Co-administration of a nAChR agonist with a depolarising stimulus enhanced [3H]D-aspartate release above the effect of depolarising agent alone. This enhancement was blocked by the nicotinic antagonist mecamylamine. Other experiments revealed that in the absence of a depolarising stimulus, the nAChR agonists nicotine, epibatidine and anatoxin-a could evoke the release of [3H]D-aspartate in a Ca2+- and concentration-dependant manner. Differential sensitivity to the alpha7- and beta2*-selective nAChR antagonists alpha-bungarotoxin (alpha-Bgt) and dihydro-beta-erythroidine (DHbetaE) implicated two nAChR subtypes (alpha7 and beta2*), and this was supported by using the subtype-selective agonists choline (10 mM; alpha7 selective, blocked by alpha-Bgt but not by DHbetaE) and 5-Iodo-A-85380 (10 nM; beta2*-selective, blocked by DHbetaE but not by alpha-Bgt). Immunocytochemistry showed that alpha-Bgt labelling was associated with structures immunopositive for vesicular glutamate transporters, in both frontal cortex sections and synaptosome preparations, supporting the presence of alpha7 nAChR on glutamatergic terminals in rat frontal cortex.

Antiepileptic activity of delta sleep-inducing peptide and its analogue in metaphit-provoked seizures in rats.

PROBLEM: Previous studies have shown that humoral, endogenous and somnogenic, delta sleep-inducing peptide (DSIP) has influence on insomnia, pain, adaptation to stress, epilepsy, etc. We investigated the potential of DSIP and its analogue DSIP-12 (a nonapeptide with alanine in position 2 of DSIP molecule substituted by beta-alanine) to antagonize metaphit (1-[1(3-isothiocyanatophenyl)-cyclohexyl]piperidine) induced generalized, reflex audiogenic seizures in adult male Wistar albino rats. METHODS: The rats divided in four groups received (i.p.): saline; metaphit; metaphit+DSIP; and metaphit+DSIP-12, respectively. Metaphit-treated animals displaying seizure in eight previous tests received DSIP or DSIP-12 and afterwards audiogenic stimuli were applied at hourly intervals for the next 30 h. The animals were exposed to sound stimulation 60 min after metaphit administration and further on at hourly intervals. Incidence and severity of seizures were behaviorally analyzed. Selected EEGs and power spectra were recorded and analyzed. RESULTS AND CONCLUSIONS: Metaphit led to hypersynchronous epileptiform activity (polyspikes and spike-wave complexes) and increased power spectra 0.5-30 h after the treatment. Severity of metaphit seizures increased with time to reach the peak 7-12 h after injection. DSIP and DSIP-12 significantly (*P<0.05 and **P<0.01) increased in delta and theta frequency bands and decreased the incidence, mean seizure grade and duration of metaphit convulsions. The results suggest that DSIP and DSIP-12 may be considered as potential antiepileptics in the animal model, DSIP-12 being more efficient than DSIP.

Distinct pattern of P3a event-related potential in borderline personality disorder.

P3a and P3b event-related brain potentials to auditory stimuli were recorded for 17 unmedicated patients with borderline personality disorder, 17 matched healthy controls and 100 healthy control participants spanning five decades. Using high-resolution fragmentary decomposition for single-trial event-related potential analysis, distinctive disturbances in P3a in borderline personality disorder patients were found: abnormally enhanced amplitude, failure to habituate and a loss of temporal locking with P3b. Normative age dependencies from 100 controls suggest that natural age-related decline in P3a amplitude is reduced in borderline personality disorder patients and is likely to indicate failure of frontal maturation. On the basis of the theories of Hughlings Jackson, this conceptualization of borderline personality disorder is consistent with an aetiological model of borderline personality disorder.

Voltammetric study of the control of striatal dopamine release by glutamate.

The central dopamine systems are involved in several aspects of normal brain function and are implicated in a number of human disorders. Hence, it is important to understand the mechanisms that control dopamine release in the brain. The striatum of the rat receives both dopaminergic and glutamatergic projections that synaptically target striatal neurons but not each other. Nevertheless, these afferents do form frequent appositional contacts, which has engendered interest in the question of whether they communicate with each other despite the absence of a direct synaptic connection. In this study, we used voltammetry in conjunction with carbon fiber microelectrodes in anesthetized rats to further examine the effect of the ionotropic glutamate antagonist, kynurenate, on extracellular dopamine levels in the striatum. Intrastriatal infusions of kynurenate decreased extracellular dopamine levels, suggesting that glutamate acts locally within the striatum via ionotropic receptors to regulate the basal extracellular dopamine concentration. Infusion of tetrodotoxin into the medial forebrain bundle or the striatum did not alter the voltammetric response to the intrastriatal kynurenate infusions, suggesting that glutamate receptors control a non-vesicular release process that contributes to the basal extracellular dopamine level. However, systemic administration of the dopamine uptake inhibitor, nomifensine (20 mg/kg i.p.), markedly decreased the amplitude of the response to kynurenate infusions, suggesting that the dopamine transporter mediates non-vesicular dopamine release. Collectively, these findings are consistent with the idea that endogenous glutamate acts locally within the striatum via ionotropic receptors to control a tonic, impulse-independent, transporter-mediated mode of dopamine release. Although numerous prior in vitro studies had suggested that such a process might exist, it has not previously been clearly demonstrated in an in vivo experiment.

Mechanisms of action underlying the effect of repetitive transcranial magnetic stimulation on mood: behavioral and brain imaging studies.

In a set of experiments, we applied 10-Hz repetitive transcranial magnetic stimulation (rTMS) over the left mid-dorsolateral frontal cortex (MDLFC) to investigate rTMS-induced changes in affective state and neural activity in healthy volunteers. In Experiment 1, we combined 10-Hz rTMS with a speech task to examine rTMS-induced changes in paralinguistic aspects of speech production, an affect-relevant behavior strongly linked to the ACC. In Experiment 2, we combined 10-Hz rTMS with positron emission tomography (PET) and used partial least squares (PLS) to identify a pattern of brain regions whose connectivity with the site of stimulation varied as a function of rTMS. The results of Experiment 1 revealed that following stimulation of the left MDLFC, subjects reported having less positive affect and vitality and displayed more monotonous speech. In Experiment 2, results revealed that 10-Hz rTMS influenced the covariation between blood flow at the site of stimulation (ie the left MDLFC) and blood flow in a number of affect-relevant brain regions including the perigenual anterior cingulate gyrus, insula, thalamus, parahippocampal gyrus, and caudate nucleus. Taken together, our results suggest that changes in affect and affect-relevant behaviour following 10-Hz rTMS applied over the left MDLFC may be related to changes in neural activity in brain regions widely implicated in affective states, including a frontocingulate circuit.

Effects of external qi-therapy on emotions, electroencephalograms, and plasma cortisol.

The authors investigated the effect of external Qi-therapy (EQT) on changes in encephalograms (EEGs) and circulating cortisol concentrations. Ten college students participated in crossover sessions, receiving EQT or placebo treatment with their eyes open. Subjects reported improved emotions of satisfaction, relaxation, and calmness during EQT as compared to levels reported during placebo treatments. There were significant differences in the proportions of alpha and beta EEG waves between the two sessions, and the relative strengths of alpha waves were higher during EQT than during control sessions (p < .05). Plasma cortisol concentrations during EQT were significantly lower than during control sessions p < .05). Thus, Qi-therapy was more effective in inducing relaxation than placebo treatment.

Preclinical evaluation of a novel device for delivering brachytherapy to the margins of resected brain tumor cavities.

OBJECT: The objectives of this study were to evaluate the safety and performance of a new brachytherapy applicator in the treatment of resected brain tumors in a canine model. METHODS: The brachytherapy applicator is an inflatable balloon catheter that is implanted in the resection cavity remaining after a brain tumor has been debulked. After implantation the balloon is inflated with Iotrex, a sterile solution containing organically bound iodine-125. The low-energy photons emitted by the iodine-125 deposit a therapeutic radiation dose across short distances from the surface of the balloon. After delivery of a prescribed radiation dose to the targeted volume, the radioactive fluid is retrieved and the catheter removed. Small resections of the right frontal lobe were performed in large dogs. Magnetic resonance (MR) images were obtained and used to assess tissue response and to measure the conformance between the resection cavity wall and the balloon surface. In four animals a dose ranging from 36 to 59 Gy was delivered. Neurological status and histological characteristics of the brain were assessed in all dogs. Implantation and explantation as well as inflation and deflation of the device were easily accomplished and well tolerated. The device was easily visualized on MR images, which demonstrated the expected postsurgical changes. The resection cavity and the balloon were highly conformal (range 93-100%). Histological changes to the cavity margin were consistent with those associated with surgical trauma. Additionally, radiation-related changes were observed at the margins of the resection cavity in dogs in which the brain was irradiated. CONCLUSIONS: This balloon catheter and 125I radiotherapy solution system can safely and reliably deliver radiation to the margins of brain cavities created by tumor resection. Results of this study showed that intracranial pressure changes due to balloon inflation and deflation were unremarkable and characteristic of the imaging properties and radiation safety profile of the device prior to its clinical evaluation. Clinically relevant brachytherapy (adequate target volume and total dose) was accomplished in all four animals subjected to treatment.

Effect of neutron-gamma radiation on dopamine and serotonin metabolism in the rat brain: a regional analysis.

The concentrations of dopamine (DA) and its metabolites and the levels of 5-hydroxyindoleacetic acid (5-HIAA), the metabolite of serotonin, were determined in discrete cerebral areas of rats 3 hr after (neutron-gamma) irradiation at 4 and 7 Gy. After the 7 Gy irradiation, no significant effect was observed. After the 4 Gy exposure, the most marked difference between irradiated and control rats was in the levels of DA and its metabolites in the striatum. We observed a decrease of DA, HVA, and DOPAC levels in the striatum and an opposite pattern in the substantia nigra. Whatever the brain area observed, an increase of 5-HIAA levels was noted.

Corticotropin-releasing factor antagonist blocks microwave-induced decreases in high-affinity choline uptake in the rat brain.

Acute (45-min) irradiation with pulsed low-level microwaves (2450-MHz, 2 microseconds pulses at 500 pps, average power density of 1 mW/cm2, whole-body average specific absorption rate of 0.6 W/kg) decreased sodium-dependent high-affinity choline uptake (HACU) activity in the frontal cortex and hippocampus of the rat. These effects were blocked by pretreating the animals before exposure with intracerebroventricular injection of the specific corticotropin-releasing factor (CRF) receptor antagonist, alpha-helical-CRF9-41 (25 micrograms). Similar injection of the antagonist had no significant effect on HACU in the brain of the sham-exposed rats. These data suggest that low-level microwave irradiation activates CRF in the brain, which in turn causes the changes in central HACU.

Acute low-level microwave exposure and central cholinergic activity: studies on irradiation parameters.

Sodium-dependent high-affinity choline uptake was measured in the striatum, frontal cortex, hippocampus, and hypothalamus of rats after acute exposure (45 min) to pulsed (2 microseconds, 500 pps) or continuous-wave 2,450-MHz microwaves in cylindrical waveguides (Guy et al.: Radio Science 14:63-74, 1979) or miniature anechoic chambers (Guy: Journal of Microwave Power 14:327-338, 1979). In all exposure conditions, the average whole-body specific absorption rate was at 0.6 W/kg. Decrease in choline uptake was observed in the frontal cortex after microwave exposure in all of the above irradiation conditions. Regardless of the exposure system used, hippocampal choline uptake was decreased after exposure to pulsed but not continuous-wave microwaves. Striatal choline uptake was decreased after exposure to either pulsed or continuous-wave microwaves in the miniature anechoic chamber. No significant change in hypothalamic choline uptake was observed under any of the exposure conditions studied. We conclude that depending on the parameters of the radiation, microwaves can elicit specific and generalized biological effects.

Low-level microwave irradiations affect central cholinergic activity in the rat.

Sodium-dependent high-affinity choline uptake was measured in various regions of the brains of rats irradiated for 45 min with either pulsed or continuous-wave low-level microwaves (2,450 MHz; power density, 1 mW/cm2; average whole-body specific absorption rate, 0.6 W/kg). Pulsed microwave irradiation (2-microseconds pulses, 500 pulses/s) decreased choline uptake in the hippocampus and frontal cortex but had no significant effect on the hypothalamus, striatum, and inferior colliculus. Pretreatment with a narcotic antagonist (naloxone or naltrexone; 1 mg/kg i.p.) blocked the effect of pulsed microwaves on hippocampal choline uptake but did not significantly alter the effect on the frontal cortex. Irradiation with continuous-wave microwaves did not significantly affect choline uptake in the hippocampus, striatum, and hypothalamus but decreased the uptake in the frontal cortex. The effect on the frontal cortex was not altered by pretreatment with narcotic antagonist. These data suggest that exposure to low-level pulsed or continuous-wave microwaves leads to changes in cholinergic functions in the brain.