scholarly journals Intranasal Allopregnanolone Confers Rapid Seizure Protection: Evidence for Direct Nose-to-Brain Delivery

2021 ◽  
Author(s):  
Dorota Zolkowska ◽  
Chun-Yi Wu ◽  
Michael A. Rogawski
Keyword(s):  
Adverse Effects ◽  
Screen Test ◽  
Brain Regions ◽  
Seizure Threshold ◽  
Brain Delivery ◽  
Intranasal Delivery ◽  
Behavioral Impairment ◽  
Loss Of Righting Reflex ◽  
Ptz Test ◽  
Central Nervous System Activity

AbstractAllopregnanolone, a positive modulator of GABAA receptors with antiseizure activity, has potential in the treatment of seizure emergencies. Instillation of allopregnanolone in 40% sulfobutylether-β-cyclodextrin into the nose in mice rapidly elevated the seizure threshold in the timed intravenous pentylenetetrazol (ED50, 5.6 mg/kg), picrotoxin (ED50, 5.9 mg/kg), and bicuculline seizure tests. The effect peaked at 15 min, decayed over 1 h, and was still evident in some experiments at 6 h. Intranasal allopregnanolone also delayed the onset of seizures in the maximal PTZ test. At an allopregnanolone dose (16 mg/kg) that conferred comparable effects on seizure threshold as the benzodiazepines midazolam and diazepam (both at doses of 1 mg/kg), allopregnanolone caused minimal sedation or motor toxicity in the horizontal screen test whereas both benzodiazepines produced marked behavioral impairment. In addition, intranasal allopregnanolone failed to cause loss-of-righting reflex in most animals, but when the same dose was administered intramuscularly, all animals became impaired. Intranasal allopregnanolone (10 mg/kg) caused a rapid increase in brain allopregnanolone with a Tmax of ~5 min after initiation of the intranasal delivery. High levels of allopregnanolone were recovered in the olfactory bulb (Cmax, 16,000 ng/mg) whereas much lower levels (Cmax, 670 ng/mg) were present in the remainder of the brain. We conclude that the unique ability of intranasal allopregnanolone to protect against seizures without inducing behavioral adverse effects is due in part to direct nose-to-brain delivery, with preferential transport to brain regions relevant to seizures. Benzodiazepines are commonly administered intranasally for acute seizure therapy, including for the treatment of acute repetitive seizures, but are not transported from nose-to-brain. Intranasal allopregnanolone acts with greater speed, has less propensity for adverse effects, and has the ability to overcome benzodiazepine refractoriness. This is the first study demonstrating rapid functional central nervous system activity of a nose-to-brain-delivered steroid. Intranasal delivery circumvents the poor oral bioavailability of allopregnanolone providing a route of administration permitting its evaluation as a treatment for diverse neuropsychiatric indications.

scholarly journals Mechanisms Underlying the Cognitive and Behavioural Effects of Maternal Obesity

Nutrients ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 240
Author(s):  
Kyoko Hasebe ◽  
Michael D. Kendig ◽  
Margaret J. Morris
Keyword(s):  
Animal Models ◽  
Adverse Effects ◽  
Gut Microbiome ◽  
Maternal Obesity ◽  
Maternal Diet ◽  
Affective State ◽  
Brain Regions ◽  
Brain Network ◽  
Physical And Mental Health ◽  
Obesogenic Diet

The widespread consumption of ‘western’-style diets along with sedentary lifestyles has led to a global epidemic of obesity. Epidemiological, clinical and preclinical evidence suggests that maternal obesity, overnutrition and unhealthy dietary patterns programs have lasting adverse effects on the physical and mental health of offspring. We review currently available preclinical and clinical evidence and summarise possible underlying neurobiological mechanisms by which maternal overnutrition may perturb offspring cognitive function, affective state and psychosocial behaviour, with a focus on (1) neuroinflammation; (2) disrupted neuronal circuities and connectivity; and (3) dysregulated brain hormones. We briefly summarise research implicating the gut microbiota in maternal obesity-induced changes to offspring behaviour. In animal models, maternal obesogenic diet consumption disrupts CNS homeostasis in offspring, which is critical for healthy neurodevelopment, by altering hypothalamic and hippocampal development and recruitment of glial cells, which subsequently dysregulates dopaminergic and serotonergic systems. The adverse effects of maternal obesogenic diets are also conferred through changes to hormones including leptin, insulin and oxytocin which interact with these brain regions and neuronal circuits. Furthermore, accumulating evidence suggests that the gut microbiome may directly and indirectly contribute to these maternal diet effects in both human and animal studies. As the specific pathways shaping abnormal behaviour in offspring in the context of maternal obesogenic diet exposure remain unknown, further investigations are needed to address this knowledge gap. Use of animal models permits investigation of changes in neuroinflammation, neurotransmitter activity and hormones across global brain network and sex differences, which could be directly and indirectly modulated by the gut microbiome.

Science

2019 ◽  
pp. 257-269
Author(s):  
Candy Gunther Brown
Keyword(s):  
Adverse Effects ◽  
Scientific Evidence ◽  
Health Benefits ◽  
Brain Regions ◽  
History Of ◽  
Behavioral Therapies ◽  
Small Sample Sizes ◽  
Citation Bias ◽  
Anxiety Depression ◽  
Meditative Practices

Chapter 12 contextualizes scientific claims about health benefits and considers evidence of adverse effects. The chapter argues that scientific support for school-based yoga, mindfulness, and meditation is weaker than often claimed and falls short of demonstrating that programs are secular, safe, or superior to alternatives. Low-quality studies report health benefits, using uncontrolled, pre-post designs, or nonactive controls, with small sample sizes, and high risk of bias, including expectation bias, researcher allegiance, publication bias, and citation bias; higher quality studies show less efficacy. Scientific evidence is not equivalent to evidence of secularity; research studies report that meditation in religious contexts, as well as prayer and Bible reading, can benefit health and activate specific brain regions. Some participants report challenging experiences with meditative practices, including anxiety, depression, physical pain, reexperiencing of traumatic memories, anger, and suicidality. Meditative practices may be contraindicated for participants with a history of trauma, PTSD, addiction, psychosis, anxiety, depression, or suicidality. Research shows that alternatives, such as aerobic exercise, math, music, nutritious food, or different behavioral therapies, can produce comparable benefits, including training the brain through neuroplasticity. Yet marketers rarely disclose risks of adverse effects, screen for contraindications, or provide information about alternatives.

scholarly journals Inactivation of Prefrontal Cortex Delays Emergence From Sevoflurane Anesthesia

2021 ◽  
Vol 15 ◽  
Author(s):  
Emma R. Huels ◽  
Trent Groenhout ◽  
Christopher W. Fields ◽  
Tiecheng Liu ◽  
George A. Mashour ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Brain Regions ◽  
Association Cortex ◽  
Sprague Dawley ◽  
Subcortical Structures ◽  
Behavioral Arousal ◽  
Barrel Field ◽  
Loss Of Righting Reflex ◽  
Parietal Association Cortex ◽  
Righting Reflex

Studies aimed at investigating brain regions involved in arousal state control have been traditionally limited to subcortical structures. In the current study, we tested the hypothesis that inactivation of prefrontal cortex, but not two subregions within parietal cortex—somatosensory barrel field and medial/lateral parietal association cortex—would suppress arousal, as measured by an increase in anesthetic sensitivity. Male and female Sprague Dawley rats were surgically prepared for recording electroencephalogram and bilateral infusion into prefrontal cortex (N = 13), somatosensory barrel field (N = 10), or medial/lateral parietal association cortex (N = 9). After at least 10 days of post-surgical recovery, 156 μM tetrodotoxin or saline was microinjected into one of the cortical sites. Ninety minutes after injection, rats were anesthetized with 2.5% sevoflurane and the time to loss of righting reflex, a surrogate for loss of consciousness, was measured. Sevoflurane was stopped after 45 min and the time to return of righting reflex, a surrogate for return of consciousness, was measured. Tetrodotoxin-mediated inactivation of all three cortical sites decreased (p < 0.05) the time to loss of righting reflex. By contrast, only inactivation of prefrontal cortex, but not somatosensory barrel field or medial/lateral parietal association cortex, increased (p < 0.001) the time to return of righting reflex. Burst suppression ratio was not altered following inactivation of any of the cortical sites, suggesting that there was no global effect due to pharmacologic lesion. These findings demonstrate that prefrontal cortex plays a causal role in emergence from anesthesia and behavioral arousal.

scholarly journals Sensitization to Chronic Stress-Induced Depression and Anxiety Modulated by Gut-Brain-Axis Immunity

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 1174-1174
Author(s):  
Giulio Pasinetti
Keyword(s):  
Chronic Stress ◽  
Brain Regions ◽  
Multivariate Adaptive Regression Splines ◽  
Depression And Anxiety ◽  
Behavioral Impairment ◽  
Funding Sources ◽  
Adaptive Immune Cells ◽  
Promising Therapeutic Target ◽  
Adaptive Regression ◽  
Neuro Inflammation

Abstract Objectives Chronic stress manifests as depressive- and anxiety-like impairments while recurrent stress elicits disproportionate psychiatric responses linked to stress-induced immunological priming. The microbiota-gut-brain-axis is a promising therapeutic target for stress-induced behavioral impairment as it simultaneous alters the immunological landscape of the periphery and brain by modulating innate and adaptive immune cells’ activity at barrier sites. Methods Immunophenotyping of the ileum, spleen and PBMCs verified that the synbiotic's impact on ileal barrier immunity, and not inflammatory or microglial activation in limbic brain regions, best associated to stress- and synbiotic-induced behavioral responses via the microbiota-ILC3-Treg axis. A multivariate adaptive regression splines (MARS) analysis predicted that immune responses in the brain and periphery create a cross-tissue biological signature of stress-induced behavior. Ileal and splenic IL-1 and IL-6 release and the ileal Treg/Th17 cell ratio associated to limbic chemotactic chemokine and prefrontal cortex IL-1 release, which associated to behavioral deficits. Results In this study, a combination of probiotics and prebiotics (i.e., synbiotic) promoted behavioral resilience to chronic and recurrent stress by promoting regulatory T cell (Treg) activation and reducing the T helper (Th)17 to Treg ratio by modulating ileal innate lymphoid cell (ILC)3 activity. Synbiotics also normalized gut microbiome diversity and composition in response to stress while interactions of the genera Lactobacillus with Faecalibaculum, Blautia or Bifidobacterium spp. best associated to depressive-like behavior during the stress protocol. Conclusions This analysis shows how resilience to stress-induced behavioral impairment depends on the gut-brain-axis and that synbiotics indiscriminately attenuate peripheral- and neuro-inflammation associated with chronic and recurrent stress-induced depression and anxiety. Funding Sources Grant AT008661 from the NIH's ODS and the NCCIH.

scholarly journals Monitoring Autonomic and Central Nervous System Activity by Permutation Entropy during Short Sojourn in Antarctica

Entropy ◽  
2019 ◽  
Vol 21 (9) ◽  
pp. 893 ◽  
Author(s):  
H. Birol Çotuk ◽  
Adil Deniz Duru ◽  
Şamil Aktaş
Keyword(s):  
Power Analysis ◽  
Spectral Band ◽  
Brain Regions ◽  
Permutation Entropy ◽  
Testing Conditions ◽  
Band Power ◽  
Nervous System Activity ◽  
Central Nervous System Activity ◽  
The Brain ◽  
Ordinal Pattern

The aim of this study was to monitor acute response patterns of autonomic and central nervous system activity during an encounter with Antarctica by synchronously recording heart rate variability (HRV) and electroencephalography (EEG). On three different time-points during the two-week sea journey, the EEG and HRV were recorded from nine male scientists who participated in “The First Turkish Antarctic Research Expedition”. The recordings were performed in a relaxed state with the eyes open, eyes closed, and during a space quantity perception test. For the EEG recordings, the wireless 14 channel EPOC-Emotiv device was used, and for the HRV recordings, a Polar heart rate monitor S810i was used. The HRV data were analyzed by time/frequency domain parameters and ordinal pattern statistics. For the EEG data, spectral band power in the conventional frequency bands, as well as permutation entropy values were calculated. Regarding HRV, neither conventional nor permutation entropy calculations produced significant differences for the different journey time-points, but only permutation entropy was able to differentiate between the testing conditions. During the cognitive test, permutation entropy values increased significantly, whereas the conventional HRV parameters did not show any significant differences. In the EEG analysis, the ordinal pattern statistics revealed significant transitions in the course of the sea voyage as permutation entropy values decreased, whereas spectral band power analysis could not detect any significant difference. Permutation entropy analysis was further able to differentiate between the three testing conditions as well between the brain regions. In the conventional spectral band power analysis, alpha band power could separate the three testing conditions and brain regions, and beta band power could only do so for the brain regions. This superiority of permutation entropy in discerning subtle differences in the autonomic and central nervous system’s responses to an overwhelming subjective experience renders it suitable as an analysis tool for biomonitoring in extreme environments.

scholarly journals Electroencephalography in Assessment of Autism Spectrum Disorders: A Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Maja Milovanovic ◽  
Roberto Grujicic
Keyword(s):  
Pyramidal Cells ◽  
Quantitative Eeg ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Gabaergic Interneuron ◽  
Behavioral Impairment ◽  
Epileptiform Discharges ◽  
Co Morbidity ◽  
Spectrum Disorders ◽  
Neurochemical Changes

Electroencephalography (EEG) can further out our understanding of autistic spectrum disorders (ASD) neurophysiology. Epilepsy and ASD comorbidity range between 5 and 46%, but its temporal relationship, causal mechanisms and interplay with intellectual disability are still unknown. Epileptiform discharges with or without seizures go as high as 60%, and associate with epileptic encephalopathies, conceptual term suggesting that epileptic activity can lead to cognitive and behavioral impairment beyond the underlying pathology. Seizures and ASD may be the result of similar mechanisms, such as abnormalities in GABAergic fibers or GABA receptor function. Epilepsy and ASD are caused by a number of genetic disorders and variations that induce such dysregulation. Similarly, initial epilepsy may influence synaptic plasticity and cortical connection, predisposing a growing brain to cognitive delays and behavioral abnormalities. The quantitative EEG techniques could be a useful tool in detecting and possibly measuring dysfunctions in specific brain regions and neuronal regulation in ASD. Power spectra analysis reveals a U-shaped pattern of power abnormalities, with excess power in the low and high frequency bands. These might be the consequence of a complicated network of neurochemical changes affecting the inhibitory GABAergic interneurons and their regulation of excitatory activity in pyramidal cells. EEG coherence studies of functional connectivity found general local over-connectivity and long-range under-connectivity between different brain areas. GABAergic interneuron growth and connections are presumably impaired in the prefrontal and temporal cortices in ASD, which is important for excitatory/inhibitory balance. Recent advances in quantitative EEG data analysis and well-known epilepsy ASD co-morbidity consistently indicate a role of aberrant GABAergic transmission that has consequences on neuronal organization and connectivity especially in the frontal cortex.

scholarly journals Transient Distraction and Attentional Control during a Sustained Selective Attention Task

2016 ◽  
Vol 28 (7) ◽  
pp. 935-947 ◽  
Author(s):  
Elise Demeter ◽  
Marty G. Woldorff
Keyword(s):  
Steady State ◽  
Frontal Cortex ◽  
Visual Presentation ◽  
Brain Regions ◽  
Behavioral Impairment ◽  
Attention Task ◽  
Detection Rates ◽  
Frontal Negativity ◽  
Continuous Arterial Spin Labeling ◽  
Visual Evoked

Distracting stimuli in the environment can pull our attention away from our goal-directed tasks. fMRI studies have implicated regions in right frontal cortex as being particularly important for processing distractors [e.g., de Fockert, J. W., & Theeuwes, J. Role of frontal cortex in attentional capture by singleton distractors. Brain and Cognition, 80, 367–373, 2012; Demeter, E., Hernandez-Garcia, L., Sarter, M., & Lustig, C. Challenges to attention: A continuous arterial spin labeling (ASL) study of the effects of distraction on sustained attention. Neuroimage, 54, 1518–1529, 2011]. Less is known, however, about the timing and sequence of how right frontal or other brain regions respond selectively to distractors and how distractors impinge upon the cascade of processes related to detecting and processing behaviorally relevant target stimuli. Here we used EEG and ERPs to investigate the neural consequences of a perceptually salient but task-irrelevant distractor on the detection of rare target stimuli embedded in a rapid, serial visual presentation (RSVP) stream. We found that distractors that occur during the presentation of a target interfere behaviorally with detection of those targets, reflected by reduced detection rates, and that these missed targets show a reduced amplitude of the long-latency, detection-related P3 component. We also found that distractors elicited a right-lateralized frontal negativity beginning at 100 msec, whose amplitude negatively correlated across participants with their distraction-related behavioral impairment. Finally, we also quantified the instantaneous amplitude of the steady-state visual evoked potentials elicited by the RSVP stream and found that the occurrence of a distractor resulted in a transient amplitude decrement of the steady-state visual evoked potential, presumably reflecting the pull of attention away from the RSVP stream when distracting stimuli occur in the environment.

scholarly journals Antioxidant Effects ofSatureja hortensisL. Attenuate the Anxiogenic Effect of Cisplatin in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Igor Kumburovic ◽  
Dragica Selakovic ◽  
Tatjana Juric ◽  
Nemanja Jovicic ◽  
Vladimir Mihailovic ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Adverse Effects ◽  
Anxiolytic Effect ◽  
Optimal Dose ◽  
Brain Regions ◽  
Male Rats ◽  
High Dose ◽  
Tissue Samples ◽  
Anxiogenic Effect ◽  
Antioxidant Effects

Numerous adverse effects of cisplatin-based therapy are usually accompanied by enhanced oxidative damage and cell apoptosis in various tissues. Even neurotoxic manifestations of cisplatin administration, such as the anxiogenic effect, appear along with the increased oxidative stress and apoptotic indicators in certain brain regions. Thirty-five Wistar albino male rats were divided into seven groups: control, cisplatin (received a single dose of cisplatin: 7.5 mg/kg), three groups with oral administration ofSatureja hortensisL. methanolic extract (SH) (low: 50 mg/kg, middle: 100 mg/kg, and high dose: 200 mg/kg) along with cisplatin application, a group with the extract in high dose alone, and a silymarin group (cisplatin and silymarin: 100 mg/kg), in order to evaluate the antioxidant effects of SH on cisplatin-induced increase in the anxiety level. After completing 10-day pretreatments, behavioral testing was performed in the open field and the elevated plus maze, followed by an investigation of oxidative stress and apoptosis parameters in hippocampal tissue samples. Cisplatin administration resulted in anxiogenic-like behavior, increased lipid peroxidation, and proapoptotic markers accompanied by the decline in antioxidant and antiapoptotic defense. The administration of extract alone did not significantly alter any of the estimated parameters. When applied along with cisplatin, SH in a dose of 100 mg/kg induced the significant anxiolytic effect with concomitant recovery of antioxidant and antiapoptotic activity indicators, while both lower and higher doses of the extract failed to improve the adverse effects of cisplatin administration. The beneficial effects of the middle dose of SH were equivalent to the same dose of silymarin, as a “golden standard.” Our results indicate that the antioxidant supplementation with SH in an optimal dose significantly improved the oxidative status and it had antiapoptotic effect in the rat hippocampus disturbed by cisplatin administration, which was accompanied with attenuation of cisplatin-induced anxiogenic effect.

scholarly journals Optimal flickering light stimulation for entraining gamma waves in the human brain

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kanghee Lee ◽  
Yeseung Park ◽  
Seung Wan Suh ◽  
Sang-Su Kim ◽  
Do-Won Kim ◽  
...  
Keyword(s):  
Visual Cortex ◽  
Adverse Effects ◽  
White Light ◽  
Light Stimulus ◽  
Red Light ◽  
Brain Regions ◽  
Amyloid Burden ◽  
Color Intensity ◽  
Light Stimulation ◽  
Flickering Light

AbstractAlthough light flickering at 40 Hz reduced Alzheimer’s disease (AD) pathologies in mice by entraining gamma waves, it failed to reduce cerebral amyloid burden in a study on six patients with AD or mild cognitive impairment. We investigated the optimal color, intensity, and frequency of the flickering light stimulus for entraining gamma waves in young adults. We compared the event-related synchronization (ERS) values of entrained gamma waves between four different light colors (white, red, green, and blue) in the first experiment and four different luminance intensities in the second experiment. In both experiments, we compared the ERS values of entrained gamma waves between 10 different flickering frequencies from 32 to 50 Hz. We also examined the severity of six adverse effects in both experiments. We compared the propagation of gamma waves in the visual cortex to other brain regions between different luminance intensities and flickering frequencies. We found that red light entrained gamma waves most effectively, followed by white light. Lights of higher luminance intensities (700 and 400 cd/m2) entrained stronger gamma waves than those of lower luminance intensities (100 and 10 cd/m2). Lights flickering at 34–38 Hz entrained stronger and more widely spread beyond the visual cortex than those flickering at 40–50 Hz. Light of 700 cd/m2 resulted in more moderate-to-severe adverse effects than those of other luminance intensities. In humans, 400 cd/m2 white light flickering at 34–38 Hz was most optimal for gamma entrainment.

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