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.

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.

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.

Effects of pulsed electromagnetic fields on learning and memory abilities of STZ-induced dementia rats.

INTRODUCTION: Recent studies have shown that pulsed electromagnetic field (EMF) has therapeutic potential for dementia, but the associated neurobiological effects are unclear. This study aimed to determine the effects of pulsed EMF on Streptozotocin (STZ)-induced dementia rats. METHODS: Forty Sprague-Dawley rats were randomly allocated to one of the four groups: (i) control, (ii) normal saline injection (sham group), (iii) STZ injection (STZ group) and (iv) STZ injection with pulsed EMF exposure (PEMF, 10 mT at 20 Hz) (STZ + MF group). Morris water maze was used to assess the learning and memory abilities. Insulin growth factors 1 and 2 (IGF-1 and IGF-2) gene expression were determined by quantitative PCR. RESULTS: The results showed that the mean escape latency in STZ-induced dementia rats was reduced by 66% under the exposure of pulsed EMF. Compared with the STZ group, the swimming distance and the time for first crossing the platform decreased by 55 and 41.6% in STZ + MF group, respectively. Furthermore, the IGF-2 gene expression significantly increased compared to that of the STZ group. CONCLUSIONS: Our findings indicate that the pulsed EMF exposure can improve the ability of learning and memory in STZ-induced dementia rats and this effect may be related to the process of IGF signal transduction, suggesting a potential role for the pulsed EMF for the amelioration of cognition impairment.

Illumination with 630 nm Red Light Reduces Oxidative Stress and Restores Memory by Photo-Activating Catalase and Formaldehyde Dehydrogenase in SAMP8 Mice.

AIMS: Pharmacological treatments for Alzheimer's disease (AD) have not resulted in desirable clinical efficacy over 100 years. Hydrogen peroxide (H2O2), a reactive and the most stable compound of reactive oxygen species, contributes to oxidative stress in AD patients. In this study, we designed a medical device to emit red light at 630 ± 15 nm from a light-emitting diode (LED-RL) and investigated whether the LED-RL reduces brain H2O2 levels and improves memory in senescence-accelerated prone 8 mouse (SAMP8) model of age-related dementia. RESULTS: We found that age-associated H2O2 directly inhibited formaldehyde dehydrogenase (FDH). FDH inactivity and semicarbazide-sensitive amine oxidase (SSAO) disorder resulted in endogenous formaldehyde (FA) accumulation. Unexpectedly, excess FA, in turn, caused acetylcholine (Ach) deficiency by inhibiting choline acetyltransferase (ChAT) activity in vitro and in vivo. Interestingly, the 630 nm red light can penetrate the skull and the abdomen with light penetration rates of ∼49% and ∼43%, respectively. Illumination with LED-RL markedly activated both catalase and FDH in the brains, cultured cells, and purified protein solutions, all reduced brain H2O2 and FA levels and restored brain Ach contents. Consequently, LED-RL not only prevented early-stage memory decline but also rescued late-stage memory deficits in SAMP8 mice. INNOVATION: We developed a phototherapeutic device with 630 nm red light, and this LED-RL reduced brain H2O2 levels and reversed age-related memory disorders. CONCLUSIONS: The phototherapy of LED-RL has low photo toxicity and high rate of tissue penetration and noninvasively reverses aging-associated cognitive decline. This finding opens a promising opportunity to translate LED-RL into clinical treatment for patients with dementia. Antioxid. Redox Signal. 00, 000-000.

In vivo and in vitro neuroprotective effects of Panax ginseng glycoproteins.

The root of Panax ginseng C. A. Mey (Araliaceae) has medicinal value in complex system of Traditional Chinese medicines for its use in improving cognitive function. A glycoproteins named PGL-1 was extracted from ginseng which subjected to through a macroporous resin, hollow-fiber ultrafiltration and dialyzed. The glycoproteins has a molecular weight in the range from 0.4 to 4.4kDa, with an average molecular mass of 1.6kDa. HPLC analysis revealed that the compositions of glycoproteins included fucose, mannose, rhamnose, glucose, galacturonic acid, N-acetylglucosamine and N-acetylgalactosamine. Glycan of PGL-1 has a backbone of →4)-Rha-(1→, →4)-Fuc -(1→, →6)-Gal-(1→, →4)-GalA-(1→, →4)-GlcNAc-(1→ and →4)-GalNAc-(1→,and (→3,6)-Man-(1→) was distributed in branches. The (1→)-Fuc, (1→)-Glc and (1→)-GlcNAc or (1→)-GalNAc were regarded as a terminal residue. The Morris water maze test revealed that the PGL-1 can effectively alleviate the memory impairment symptoms of rats induced by Aß25-35. All dose groups showed significant activity of protective effect on apoptosis SH-SY5Y induced by Aß25-35, and obviously inhibited the S phase arrest. Compared with Aß25-35 treatment alone, a significant reduction in NO concentration and NOS activity was detected in cells co-administered with glycoproteins. Thus, glycoproteins derived from ginseng might be a promising anti-AD reagent.

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.

1950 MHz radiofrequency electromagnetic fields do not aggravate memory deficits in 5xFAD mice.

The increased use of mobile phones has generated public concern about the impact of radiofrequency electromagnetic fields (RF-EMF) on health. In the present study, we investigated whether RF-EMFs induce molecular changes in amyloid precursor protein (APP) processing and amyloid beta (Aß)-related memory impairment in the 5xFAD mouse, which is a widely used amyloid animal model. The 5xFAD mice at the age of 1.5 months were assigned to two groups (RF-EMF- and sham-exposed groups, eight mice per group). The RF-EMF group was placed in a reverberation chamber and exposed to 1950 MHz electromagnetic fields for 3 months (SAR 5 W/kg, 2 h/day, 5 days/week). The Y-maze, Morris water maze, and novel object recognition memory test were used to evaluate spatial and non-spatial memory following 3-month RF-EMF exposure. Furthermore, Aß deposition and APP and carboxyl-terminal fragment ß (CTFß) levels were evaluated in the hippocampus and cortex of 5xFAD mice, and plasma levels of Aß peptides were also investigated. In behavioral tests, mice that were exposed to RF-EMF for 3 months did not exhibit differences in spatial and non-spatial memory compared to the sham-exposed group, and no apparent change was evident in locomotor activity. Consistent with behavioral data, RF-EMF did not alter APP and CTFß levels or Aß deposition in the brains of the 5xFAD mice. These findings indicate that 3-month RF-EMF exposure did not affect Aß-related memory impairment or Aß accumulation in the 5xFAD Alzheimer's disease model. Bioelectromagnetics. 37:391-399, 2016. © 2016 The Authors Bioelectromagnetics published by Wiley Periodicals, Inc. on behalf of Bioelectromagnetics Society.

Transcranial low-level laser therapy enhances learning, memory, and neuroprogenitor cells after traumatic brain injury in mice.

The use of transcranial low-level laser (light) therapy (tLLLT) to treat stroke and traumatic brain injury (TBI) is attracting increasing attention. We previously showed that LLLT using an 810-nm laser 4 h after controlled cortical impact (CCI)-TBI in mice could significantly improve the neurological severity score, decrease lesion volume, and reduce Fluoro-Jade staining for degenerating neurons. We obtained some evidence for neurogenesis in the region of the lesion. We now tested the hypothesis that tLLLT can improve performance on the Morris water maze (MWM, learning, and memory) and increase neurogenesis in the hippocampus and subventricular zone (SVZ) after CCI-TBI in mice. One and (to a greater extent) three daily laser treatments commencing 4-h post-TBI improved neurological performance as measured by wire grip and motion test especially at 3 and 4 weeks post-TBI. Improvements in visible and hidden platform latency and probe tests in MWM were seen at 4 weeks. Caspase-3 expression was lower in the lesion region at 4 days post-TBI. Double-stained BrdU-NeuN (neuroprogenitor cells) was increased in the dentate gyrus and SVZ. Increases in double-cortin (DCX) and TUJ-1 were also seen. Our study results suggest that tLLLT may improve TBI both by reducing cell death in the lesion and by stimulating neurogenesis.

Laser acupuncture improves memory impairment in an animal model of Alzheimer's disease.

The burden of Alzheimer's disease is continually rising globally, especially in the Asia-Pacific region. Unfortunately, the efficacy of the therapeutic strategy is still very limited. Because the effect of acupuncture at HT7 can improve learning and memory, the beneficial effect of laser acupuncture, a noninvasive form of acupuncture, at HT7 on memory improvement in patients with Alzheimer's disease has been a focus of research. To elucidate this issue, we used AF64A, a cholinotoxin, to induce memory impairment in male Wistar rats, which weighed 180-220 g. Then, the animals were treated with laser acupuncture either at HT7 or at a sham acupoint once daily for 10 minutes for a period of 14 days. Spatial memory assessments were performed at 1, 7, and 14 days after AF64A administration and at the end of the experiment, and the changes in the malondialdehyde (MDA) level and in the superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and acetylcholinesterase (AChE) activities in the hippocampus were recorded. The results showed that laser acupuncture significantly suppressed AChE activity in the hippocampus. Although laser acupuncture enhanced SOD and CAT activities, no reduction in MDA level in this area was observed. Therefore, laser acupuncture at HT7 is a potential strategy to attenuate memory impairment in patients with Alzheimer's disease. However, further research, especially on the toxicity of laser acupuncture following repetitive exposure, is essential.

Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation.

BACKGROUND AND PURPOSE: Whole-brain irradiation (WBI) therapy produces learning and memory deficits in patients with brain tumours. Although the pathological cascade of cognitive deficits remains unknown, it may involve reduced neurogenesis within the hippocampus. Baicalein is a flavonoid derived from the roots of Huangqin, Scutellaria baicalensis Georgi, and has been shown to have antioxidant effects. Here, we have investigated the protective effects of baicalein on irradiation-induced impairments in hippocampal neurogenesis and cognitive function. EXPERIMENTAL APPROACH: Radioprotective effects of baicalein were evaluated in C17.2 neural progenitor cells and 6-week-old male C57BL/6 mice during hippocampal neurogenesis. Mice were given a single dose of 5 Gy WBI. Changes in hippocampal neurogenesis, oxidative stress and BDNF-pCREB signalling were evaluated. Morris water maze and passive avoidance test were used to assess learning and memory. KEY RESULTS: Baicalein protected neural progenitor cells against irradiation-induced necrotic cell death. Pretreatment with baicalein attenuated the irradiation-induced impairment of hippocampal neurogenesis by modulating oxidative stress and elevating BDNF-pCREB signalling. Furthermore, baicalein prevented the spatial learning and memory retention deficits follwing WBI. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that baicalein can be viewed as a potential therapeutic agent that protects against the impaired neurogenesis induced by WBI, and its neurocognitive consequences.

Electromagnetic treatment to old Alzheimer's mice reverses ß-amyloid deposition, modifies cerebral blood flow, and provides selected cognitive benefit.

Few studies have investigated physiologic and cognitive effects of "long-term" electromagnetic field (EMF) exposure in humans or animals. Our recent studies have provided initial insight into the long-term impact of adulthood EMF exposure (GSM, pulsed/modulated, 918 MHz, 0.25-1.05 W/kg) by showing 6+ months of daily EMF treatment protects against or reverses cognitive impairment in Alzheimer's transgenic (Tg) mice, while even having cognitive benefit to normal mice. Mechanistically, EMF-induced cognitive benefits involve suppression of brain ß-amyloid (Aß) aggregation/deposition in Tg mice and brain mitochondrial enhancement in both Tg and normal mice. The present study extends this work by showing that daily EMF treatment given to very old (21-27 month) Tg mice over a 2-month period reverses their very advanced brain Aß aggregation/deposition. These very old Tg mice and their normal littermates together showed an increase in general memory function in the Y-maze task, although not in more complex tasks. Measurement of both body and brain temperature at intervals during the 2-month EMF treatment, as well as in a separate group of Tg mice during a 12-day treatment period, revealed no appreciable increases in brain temperature (and no/slight increases in body temperature) during EMF "ON" periods. Thus, the neuropathologic/cognitive benefits of EMF treatment occur without brain hyperthermia. Finally, regional cerebral blood flow in cerebral cortex was determined to be reduced in both Tg and normal mice after 2 months of EMF treatment, most probably through cerebrovascular constriction induced by freed/disaggregated Aß (Tg mice) and slight body hyperthermia during "ON" periods. These results demonstrate that long-term EMF treatment can provide general cognitive benefit to very old Alzheimer's Tg mice and normal mice, as well as reversal of advanced Aß neuropathology in Tg mice without brain heating. Results further underscore the potential for EMF treatment against AD.

No effects of mobile phone use on cortical auditory change-detection in children: an ERP study.

We investigated the effect of mobile phone use on the auditory sensory memory in children. Auditory event-related potentials (ERPs), P1, N2, mismatch negativity (MMN), and P3a, were recorded from 17 children, aged 11-12 years, in the recently developed multi-feature paradigm. This paradigm allows one to determine the neural change-detection profile consisting of several different types of acoustic changes. During the recording, an ordinary GSM (Global System for Mobile Communications) mobile phone emitting 902 MHz (pulsed at 217 Hz) electromagnetic field (EMF) was placed on the ear, over the left or right temporal area (SAR(1g) = 1.14 W/kg, SAR(10g) = 0.82 W/kg, peak value = 1.21 W/kg). The EMF was either on or off in a single-blind manner. We found that a short exposure (two 6 min blocks for each side) to mobile phone EMF has no statistically significant effects on the neural change-detection profile measured with the MMN. Furthermore, the multi-feature paradigm was shown to be well suited for studies of perception accuracy and sensory memory in children. However, it should be noted that the present study only had sufficient statistical power to detect a large effect size.

Short days increase hypothalamic-pituitary-adrenal axis responsiveness.

Individuals dramatically alter physiology and behavior to adapt to seasonal changes in their environment. To cope with winter stressors such as reduced food availability and low temperatures, central stress responses are presumably modulated at the level of the hypothalamic-pituitary-adrenal (HPA) axis, but the details remain unspecified. We examined the effects of long or short photoperiods (day lengths) on corticosterone responses to restraint, HPA negative feedback sensitivity, glucocorticoid receptor gene expression in the hippocampus, the role of corticosterone in spatial learning, and corticosterone responses to stressors associated with the spatial water maze task in adult male white-footed mice (Peromyscus leucopus). Short days increased corticosterone responses to restraint, increased hippocampal glucocorticoid receptor expression, enhanced corticosterone negative feedback on the HPA axis, and increased sensitivity to dexamethasone suppression of corticosterone. Although spatial learning and memory performance (via water maze) of all mice was impaired after pharmacological corticosterone inhibition, both water maze exposure and treatment injections alone were sufficient to increase short-day, but not long-day, corticosterone concentrations. Thus, the effects of corticosterone on spatial learning in these mice may be complicated by photoperiodic differences in stressor response to the learning task itself. Overall, these results suggest that photoperiod-evoked modification of the HPA axis and its potential behavioral consequences may be adaptive for winter survival.

Effects of long-term continuous exposure to light on memory and anxiety in mice.

The studies on the relationship between the light/dark cycle and memory function mostly used protocols of acute disruption of the circadian rhythm. The aim of the present study is to verify the effects of long-term continuous exposure to light on memory, anxiety and motor parameters of mice tested in the plus-maze discriminative avoidance task. Mice were conditioned to choose between the two enclosed arms (one aversive and one non-aversive) while avoiding the open arms of a modified elevated plus-maze apparatus. Memory was evaluated by the time spent in the aversive enclosed arm, anxiety was evaluated by the time spent in the open arms and locomotor behavior was evaluated by number of entries in the arms of the maze. The results showed that long-term (35-42 days) continuous light exposure did not modify memory or anxiety parameters but increased locomotor activity. While the increase in locomotor behavior is in line with previous studies, the unexpected absence of alterations in memory and anxiety (reported to be influenced by the circadian rhythm) is discussed.

[The effect of antioxidants on functional brain disorders caused by low-intensity ionizing radiation]. / Issledovanie vliianiia antioksidantov na narusheniia funktsional'noi aktivnosti mozga, vyzvannye ioniziruiushchim izlucheniem maloi moshchnosti.

The effects of daily intraperitoneal injections of alpha-tocopherol (30 mg/kg per day) and synthetic antioxidant IHFAN-30 (30 mg/day) in rats were compared during low-level ionizing radiation (10 days, dose rate 5 mGy/h, total dose 1.2 Gy). There were analysed: (1) amplitude of population spike of hippocampal slices; (2) endogenous phosphorylation in vitro of hippocampal synaptic proteins in the presence of cAMP; (3) formation, manifestation and reduction of food-procuring reflex. The findings showed that antioxidants made some correction of the functional state of hippocampal slices and cAMP-dependent phosphorylation system activity in brain cells from irradiated animals. No influence on training and memory functions was detected.

[The characteristics of perceptive learning and memory in psychopathological states]. / Osobennosti pertseptivnogo obucheniia i pamiati pri psikhopatologicheskikh sostoianiiakh.

Dynamics is studied of visual images recognition in patients with schizophrenia under the influence of small doses of ionizing radiation used with therapeutic purpose. Functional state of the brain is evaluated by amplitude-temporal parameters of visual and auditory EPs. After conducted therapy no changes in responses to light flashes are found, and in auditory EPs in a part (the first group) of patients there is an increase of the component N1 amplitude in the frontal area. The same group is characterized by lower parameters of visual images recognition. Conclusion is made about the presence of non-specific changes of visual gnosis in patients with schizophrenia and about involvement of the associative frontal structures in pathologic process. Possible mechanisms of disturbance of the perceptive learning and memory processes in schizophrenia are discussed.