Psychopharmacological assessment of antidepressant-like, anxiolytic, and sedative-hypnotic effects of tilia platyphyllos scop. Extract using experimental animal models

The prevalence of psychiatric disorders namely depression, anxiety, and sleep disturbances has been increased worldwide, particularly during the COVID-19 pandemic. In this regard, the interest of recent investigations is moved toward phytomedicines and bioactive substances derived from natural sources. Although Tilia platyphyllos Scop. contains high amounts of phenolic compounds such as quercetin, kaempferol, and catechin, there is no study on the possible effects of its extract on psychological disorders. The present study was carried out to determine the antidepressant-like, anxiolytic, and sedative-hypnotic effects of the hydroethanolic extract of T. platyphyllos leaves using forced swimming test (FST), tail suspension test (TST), elevated plus maze test (EPMT), pentobarbital-induced loss of righting reflex test and open field test (OFT). Following the ethanolic extraction of T. platyphyllos leaves, the extraction yield was 14% and the total phenolic and total flavonoid contents were found to be 135.23 +/- 0.14 mg gallic acid equivalent/g dry extract and 19.02 +/- 0.03 mg rutin equivalent/g dry extract, respectively. Both FTS and TST revealed a significant antidepressant-like activity for the tested extract at 400 mg/kg compared to the control group. In addition, the anxiolytic activity of the extract was proven through OFT and EPMT in the same dose. Finally, T. platyphyllos extract at 200 mg/kg and 400 mg/kg significantly increased the sleeping time when compared to the control group reflecting its potential hypnotic activity. Co-administration of T. platyphyllos extract at 400 mg/kg and flumazenil as the GABA-A receptor antagonist decreased the sleeping time but the observed effect was not statistically significant. Therefore, we cannot completely rule out the GABA-A receptor's involvement in the hypnotic activity of the extract. The biological results presented here led us to conclude that T. platyphyllos extract can be a prominent source of antidepressant, anxiolytic and hypnotic agents. Probably, the main phenolic compounds of T. platyphyllos such as quercetin, kaempferol, and catechin are involved in the observed effects. However, there is still a great need for additional investigations on the exact mechanisms.Copyright © 2022, Iranian Association of Pharmaceutical Scientists. All rights reserved.

The functional and structural changes in the hippocampus of COVID-19 patients.

Since the hippocampus is predominantly susceptible to injuries caused by COVID-19, there are increasing data indicating the likelihood of post-infection memory loss and quickening neurodegenerative disorders, such as Alzheimer's disease. This is due to the fact that the hippocampus has imperative functions in spatial and episodic memory as well as learning. COVID-19 activates microglia in the hippocampus and induces a CNS cytokine storm, leading to loss of hippocampal neurogenesis. The functional and structural changes in the hippocampus of COVID-19 patients can explain neuronal degeneration and reduced neurogenesis in the human hippocampus. This will open a window to explain memory and cognitive dysfunctions in "long COVID" through the resultant loss of hippocampal neurogenesis.

Diazepam and exercise training combination synergistically reduces lipopolysaccharide-induced anxiety-like behavior and oxidative stress in the prefrontal cortex of mice.

Anxiety-related disorders are among the most important risks for global health, especially in recent years due to the COVID-19 pandemic. Benzodiazepines like diazepam are generally used to treat anxiety disorders, but the overall outcome is not always satisfactory. This is why psychiatrists encourage patients with anxiety to change their lifestyle habits to decrease the risk of anxiety recurrence. However, the effect of diazepam and exercise in combination is unknown. This study aimed to investigate the effect of diazepam alone or in combination with swimming exercise on lipopolysaccharide (LPS)-induced anxiety-like behavior and oxidative stress in the hippocampus and prefrontal cortex of mice. Mice were exposed to diazepam and swimming exercise alone or in combination with each other and then received LPS. We assessed anxiety-like behavior using open field and light-dark box and measured oxidative markers including glutathione (GSH), malondialdehyde (MDA), and glutathione disulfide (GSSG) in the hippocampus and prefrontal cortex. The findings showed that LPS increased anxiety-related symptoms and oxidative stress by decreasing GSH and increasing MDA and GSSG levels in the prefrontal cortex but not in the hippocampus. Although diazepam alone did not reduce anxiety-like behavior and oxidative stress, it in combination with exercise significantly decreased anxiety-like behavior and oxidative stress in the prefrontal cortex of LPS-treated mice. This drug and exercise combination also displayed a more effective effect in comparison with exercise alone. Overall, this study suggests that diazepam in combination with swimming exercise has higher efficacy on anxiety-like behavior and oxidative stress than when they are used alone.

Adipose tissue, systematic inflammation, and neurodegenerative diseases

Obesity is associated with several diseases, including mental health. Adipose tissue is distributed around the internal organs, acting in the regulation of metabolism by storing and releasing fatty acids and adipokine in the tissues. Excessive nutritional intake results in hypertrophy and proliferation of adipocytes, leading to local hypoxia in adipose tissue and changes in these adipokine releases. This leads to the recruitment of immune cells to adipose tissue and the release of pro-inflammatory cytokines. The presence of high levels of free fatty acids and inflammatory molecules interfere with intracellular insulin signaling, which can generate a neuroinflammatory process. In this review, we provide an up-to-date discussion of how excessive obesity can lead to possible cognitive dysfunction. We also address the idea that obesity-associated systemic inflammation leads to neuroinflammation in the brain, particularly the hypothalamus and hippocampus, and that this is partially responsible for these negative cognitive outcomes. In addition, we discuss some clinical models and animal studies for obesity and clarify the mechanism of action of anti-obesity drugs in the central nervous system.Copyright © 2023 Wolters Kluwer Medknow Publications. All rights reserved.

Sex differences in the neuroimmune modulation of learning and memory

The neuroimmune system is a specialized immune system in the brain crucial for both responding to illness and injury as well as regulating normal neural function and behavior. As such, it is perhaps not surprising that activation of the neuroimmune system results in significant impairments in synaptic plasticity and learning and memory mechanisms. In fact, neuroimmune dysregulation has been implicated in memory- and cognitive-related disorders including Alzheimer's disease, Post-Traumatic Stress disorder, and most recently long-COVID, a series of long-lasting cognitive impairments caused by the virus SARS-CoV-2. There are known sex differences in the neuroimmune response to various pathogens, and because the neuroimmune system is at the convergence of pathological and normal function, the immune cells and signaling mechanisms involved are well-poised to modulate memory processes differently in males and females which may contribute to sex differences in the prevalence or severity of memory-related disorders. Here, we aimed to investigate the interaction of neuroimmune and memory processes in both males and females using central administration of a viral mimic, polyinosinic:polycytidylic acid (poly I:C), in C57BL/6N mice. Poly I:C is synthetic, double-stranded RNA that stimulates several cell types involved in mounting an immune response in the brain including astrocytes, microglia, and neurons, making it an excellent tool for studying broad-based neuroinflammation. Poly I:C treatment induced significant inflammation in the hippocampus of both sexes. Males had a greater magnitude of response than females for cytokines IL-1alpha, IL-1beta, IL-6, IL-10, IFNalpha, TNFalpha, CCL2, and CXCL10. Additionally, while both males and females showed increased expression of the anti-viral Type I interferon beta, only males showed increased anti-viral Type I interferon alpha, highlighting a potentially important sex difference in the anti-viral response to poly I:C. We used a T-maze task and a contextual fear-based memory task to determine the effects of neuroinflammation on learning and memory mechanisms. Pre-training poly I:C did not impair learning in the T-maze task. In contrast, pre-training poly I:C disrupted learning of contextual fear conditioning in both males and females, and analysis of cFos levels revealed significant sex differences in hippocampal activation during context fear conditioning training with poly I:C on board. Together, these findings suggest that a similar behavioral deficit induced by poly I:C in males and females involve sex-specific molecular and signaling mechanisms of learning and memory. To further investigate this, we targeted Type I interferon signaling because of the sex difference in Type I interferon induction we found previously and the capacity for Type I interferons to modulate synaptic plasticity mechanisms. We found that inhibiting Type I interferon receptors prior to treatment with poly I:C attenuated the poly I:C-induced learning deficits in males, and we did not find the same effect in females. This suggests that Type I interferons play a more important role in modulating learning in males compared with females, and Type I interferon signaling is a potential target for understanding sex differences in biological mechanisms of memory impairment induced by neuroimmune activation. (PsycInfo Database Record (c) 2023 APA, all rights reserved)

The colonic interleukin-19 aggravates the dextran sodium sulfate/stress-induced comorbidities due to colitis and anxiety.

Comorbidities due to inflammatory bowel disease (IBD) and anxiety are commonly acknowledged; however, their underlying basis is unclear. In the current study, we first conducted a clinical retrospective analysis to identify the enhancive incidence rate of IBD before or after the epidemic of Corona Virus Disease 2019 (COVID-19), with higher Generalized Anxiety Disorder-7 (GAD-7), as well as poorer Gastrointestinal Quality of Life Index (GIQLI). Then, the dextran sodium sulfate (DSS) and chronic unpredictable stress (CUS)-induced IBD and anxiety comorbid models were established with the correlational relations between symptoms of IBD and anxiety-related behaviors. We found dysfunctional up-regulation of a new inflammatory factor interleukin (IL)-19 in the colon of DSS/CUS treated mice. Overexpression of IL-19 in colon induced anxious phenotypes, and accelerated the anxious condition and symptoms of colitis in the DSS/CUS model by promoting the expression of inducible nitric oxide synthase (iNOS), IL-1ß, and IL-6 pro-inflammatory factors, and activating signal transducer and activator of transcription 3 (STAT3) signaling pathway in the colon. Furthermore, overexpression of IL-19 in the colon also reduced the expression levels of brain-derived neurotrophic factor (BDNF), extracellular signal-regulated kinase (ERK), and cAMP-response element binding protein (CREB) signaling pathways activity in the hippocampus. These results suggest that IL-19 was a pivotal player in DSS/CUS-induced comorbidities of colitis and anxiety with different signaling pathways for the colon and hippocampus, which provides a candidate gene to explore the pathophysiology of comorbidities due to colitis and anxiety.

Home alone: A population neuroscience investigation of brain morphology substrates.

As a social species, ready exchange with peers is a pivotal asset - our "social capital". Yet, single-person households have come to pervade metropolitan cities worldwide, with unknown consequences in the long run. Here, we systematically explore the morphological manifestations associated with singular living in ∼40,000 UK Biobank participants. The uncovered population-level signature spotlights the highly associative default mode network, in addition to findings such as in the amygdala central, cortical and corticoamygdaloid nuclei groups, as well as the hippocampal fimbria and dentate gyrus. Both positive effects, equating to greater gray matter volume associated with living alone, and negative effects, which can be interpreted as greater gray matter associations with not living alone, were found across the cortex and subcortical structures Sex-stratified analyses revealed male-specific neural substrates, including somatomotor, saliency and visual systems, while female-specific neural substrates centered on the dorsomedial prefrontal cortex. In line with our demographic profiling results, the discovered neural pattern of living alone is potentially linked to alcohol and tobacco consumption, anxiety, sleep quality as well as daily TV watching. The persistent trend for solitary living will require new answers from public-health decision makers. SIGNIFICANCE STATEMENT: Living alone has profound consequences for mental and physical health. Despite this, there has been a rapid increase in single-person households worldwide, with the long-term consequences yet unknown. In the largest study of its kind, we investigate how the objective lack of everyday social interaction, through living alone, manifests in the brain. Our population neuroscience approach uncovered a gray matter signature that converged on the 'default network', alongside targeted subcortical, sex and demographic profiling analyses. The human urge for social relationships is highlighted by the evolving COVID-19 pandemic. Better understanding of how social isolation relates to the brain will influence health and social policy decision-making of pandemic planning, as well as social interventions in light of global shifts in houseful structures.

COVID-19 vaccination may enhance hippocampal neurogenesis in adults.

Emerging evidence suggests a detrimental impact of COVID-19 illness on the continued hippocampal neurogenesis in adults. In contrast, the existing literature supports an enhancing effect of COVID-19 vaccination on adult hippocampal neurogenesis. Vaccines against respiratory infections, including influenza, have been shown to enhance hippocampal neurogenesis in adult-age animals. We propose that a similar benefit may happen in COVID-19 vaccinated adults. The vaccine-induced enhancement of the hippocampal neurogenesis in adults thus may protect against age-related cognitive decline and mental disorders. It alsohints at an added mental health benefit of the COVID-19 vaccination programs in adults.

GALR2 and Y1R agonists intranasal infusion enhanced adult ventral hippocampal neurogenesis and antidepressant-like effects involving BDNF actions.

Dysregulation of adult hippocampal neurogenesis is linked to major depressive disorder (MDD), with more than 300 million people diagnosed and worsened by the COVID-19 pandemic. Accumulating evidence for neuropeptide Y (NPY) and galanin (GAL) interaction was shown in various limbic system regions at molecular-, cellular-, and behavioral-specific levels. The purpose of the current work was to evaluate the proliferating role of GAL2 receptor (GALR2) and Y1R agonists interaction upon intranasal infusion in the ventral hippocampus. We studied their hippocampal proliferating actions using the proliferating cell nuclear antigen (PCNA) on neuroblasts or stem cells and the expression of the brain-derived neurothrophic factor (BDNF). Moreover, we studied the formation of Y1R-GALR2 heteroreceptor complexes and analyzed morphological changes in hippocampal neuronal cells. Finally, the functional outcome of the NPY and GAL interaction on the ventral hippocampus was evaluated in the forced swimming test. We demonstrated that the intranasal infusion of GALR2 and the Y1R agonists promotes neuroblasts proliferation in the dentate gyrus of the ventral hippocampus and the induction of the neurotrophic factor BDNF. These effects were mediated by the increased formation of Y1R-GALR2 heteroreceptor complexes, which may mediate the neurites outgrowth observed on neuronal hippocampal cells. Importantly, BDNF action was found necessary for the antidepressant-like effects after GALR2 and the Y1R agonists intranasal administration. Our data may suggest the translational development of new heterobivalent agonist pharmacophores acting on Y1R-GALR2 heterocomplexes in the ventral hippocampus for the novel therapy of MDD or depressive-affecting diseases.

Predicting gene regulatory networks from multi-omics to link genetic risk variants and neuroimmunology to Alzheimer's disease phenotypes

Background: Genome-wide association studies have found many genetic risk variants associated with Alzheimer's disease (AD). However, how these risk variants affect deeper phenotypes such as disease progression and immune response remains elusive. Also, our understanding of cellular and molecular mechanisms from disease SNPs to various phenotypes is still limited. To address these problems, we performed an integrative multi-omics analysis of genotype, transcriptomics, and epigenomics for revealing gene regulatory mechanisms from disease variants to AD phenotypes. Method(s): First, given population gene expression data of a cohort, we construct and cluster its gene co-expression network to identify modules for various AD phenotypes. Next, we predict transcription factors (TFs) regulating co-expressed genes and SNPs interrupting TF binding sites on regulatory elements. Finally, we construct a gene regulatory network (GRN) linking SNPs, interrupted TFs, and regulatory elements to target genes and modules for AD phenotypes. This network provides systematic insights into gene regulatory mechanisms from SNPs to phenotypes. We looked at our GRNs relating to genes from shared AD-Covid pathways (e.g. NFKB Pathway) and used machine learning to prioritize those genes for predicting Covid-19 severity. Result(s): Our analysis predicted cross-region-conserved and region-specific GRNs in 3 regions Hippocampus, Dorsolateral Prefrontal Cortex (DLPFC), Lateral Temporal Lobe (LTL). For instance, SNPs rs13404184 and rs61068452 disrupt SPI1 binding and regulation of INPP5D in Hippocampus and LTL. While rs4802200 disrupts E2F7 regulation of KCNN4 (belongs to AD LTL module), rs117863556 interrupts REST regulation of GAB2 in DLPFC. Further, we used Covid-19 as a proxy for immune dysregulation to identify possible regulatory mechanisms for AD neuroimmunology. Decision Curve Analysis suggest our AD-Covid genes along with linked SNPs (that outperform known genes) can be potential novel biomarkers for neuroimmunology. Finally, our results are open-source available as a comprehensive AD functional genomic map, providing deeper mechanistic understanding of the interplay among multi-omics, regions, gene functions, phenotypes. Conclusion(s): Our pipeline predicts how non-coding risk SNPs may be associated with changes in regulation and subsequent expression of genes associated with different phenotypes and pathways in AD. Moreover, we flagged 51 potential AD-neuroinflammatory risk genes, which may be early biomarkers as neuroinflammation may begin decades before clinical onset. Copyright © 2022 the Alzheimer's Association.

Randomized Controlled Trial of Social Ballroom Dancing and Treadmill Walking: Preliminary Findings on Executive Function and Neuroplasticity From Dementia-at-Risk Older Adults.

This randomized controlled trial (NCT03475316) examined the relative efficacy of 6 months of social ballroom dancing and treadmill walking on a composite executive function score, generated from digit symbol substitution test, flanker interference, and walking while talking tasks. Brain activation during functional magnetic resonance imaging (fMRI) versions of these executive function tasks were secondary outcomes. Twenty-five dementia-at-risk older adults (memory impairment screen score of ≥3 to ≤6 and/or an Alzheimer's disease-8 Dementia Screening Interview of ≥1) were randomized in June 2019 to March 2020-16 completed the intervention before study termination due to the COVID-19 (eight in each group). Composite executive function scores improved post-intervention in both groups, but there was no evidence for between-group differences. Social dancing, however, generated greater improvements on digit symbol substitution test than treadmill walking. No intervention-related differences were observed in brain activation-although less hippocampal atrophy (tertiary) was observed following social dancing than treadmill walking. These preliminary findings are promising but need to be confirmed in future large-scale and sufficiently powered randomized controlled trials.

Cortical and subcortical grey matter volume alterations in neuropsychiatric long-COVID syndrome episode

Introduction Neuropsychiatric symptoms are among the most common sequelae of long-COVID-19 and highly diminish the patient's quality of life. As accumulating evidence suggests an impact of survived SARS-CoV-2-infection on brain physiology, it appears necessary to further investigate brain structural changes in relation to clinical long-COVID symptoms. Understanding the pathogenic processes in neuropsychiatric long-COVID will be vital to identify targeted therapy and to ease the months long-lasting symptoms. Methods The present cross-sectional study investigated 3T-MRI scans from long-COVID patients (n=30) with neuropsychiatric symptoms, and healthy controls matched for age and gender (n=20). Whole-brain comparison of grey matter volume (GMV) was conducted by voxel-based morphometry using the CAT12 software package. To determine whether changes in GMV are predicted by neuropsychiatric symptom burden and / or initial severity of symptoms of COVID19 and time since onset of COVID-19, we performed multiple linear regression analysis. Results Enlarged GMV in long-COVID patients was present in several clusters (p<0.05, FWE- corr-ected) spanning frontotemporal areas, insula, hippocampus, amygdala, basal ganglia, and thalamus in both hemispheres when compared to controls. Time since onset of COVID-19 was a significant regressor in three of these clusters (anatomically located in right inferior frontal gyrus, lateral and posterior orbital gyrus, anterior parts of the insula, left superior, middle and inferior temporal gyrus and left postcentral and precentral gyrus). Conclusion Grey matter alterations in limbic and secondary olfactory areas are present in neuropsychiatric long-COVID patients. Some GMV alterations were inversely associated with time elapsed since acute COVID-19, suggesting higher GMV with shorter time since onset of COVID-19. Detection of associations between GMV and clinical symptoms might be difficult, because of heterogenous clinical presentation. Larger samples and longitudinal data in neuropsychiatric long-COVID patients are required to further clarify the mediating mechanisms between COVID-19 and GMV.

Hippocampal and amygdalar increased BDNF expression in the extinction of opioid-induced place preference.

The opioid crisis was exacerbated during the COVID-19 pandemic in the United States with alarming statistics about overdose-related deaths. Current treatment options, such as medication assisted treatments, have been unable to prevent relapse in many patients, whereas cue-based exposure therapy have had mixed results in human trials. To improve patient outcomes, it is imperative to develop animal models of addiction to understand molecular mechanisms and identify potential therapeutic targets. We previously found increased brain derived neurotrophic factor (bdnf) transcript in the ventral striatum/nucleus accumbens (VS/NAc) of rats that extinguished morphine-induced place preference. Here, we expand our study to determine whether BDNF protein expression was modulated in mesolimbic brain regions of the reward system in animals exposed to extinction training. Drug conditioning and extinction sessions were followed by Western blots for BDNF in the hippocampus (HPC), amygdala (AMY) and VS/NAc. Rears, as a measure of withdrawal-induced anxiety were also measured to determine their impact on extinction. Results showed that animals who received extinction training and successfully extinguished morphine CPP significantly increased BDNF in the HPC when compared to animals deprived of extinction training (sham-extinction). This increase was not significant in animals who failed to extinguish (extinction-resistant). In AMY, all extinction-trained animals showed increased BDNF, regardless of behavior phenotype. No BDNF modulation was observed in the VS/NAc. Finally, extinction-trained animals showed no difference in rears regardless of extinction outcome, suggesting that anxiety elicited by drug withdrawal did not significantly impact extinction of morphine CPP. Our results suggest that BDNF expression in brain regions of the mesolimbic reward system could play a key role in extinction of opioid-induced maladaptive behaviors and represents a potential therapeutic target for future combined pharmacological and extinction-based therapies.

Effects of Two Distinct Psychoactive Microbes, Lacticaseibacillus rhamnosus JB-1 and Limosilactobacillus reuteri 6475, on Circulating and Hippocampal mRNA in Male Mice.

Discovery of the microbiota-gut-brain axis has led to proposed microbe-based therapeutic strategies in mental health, including the use of mood-altering bacterial species, termed psychobiotics. However, we still have limited understanding of the key signaling pathways engaged by specific organisms in modulating brain function, and evidence suggests that bacteria with broadly similar neuroactive and immunomodulatory actions can drive different behavioral outcomes. We sought to identify pathways distinguishing two psychoactive bacterial strains that seemingly engage similar gut-brain signaling pathways but have distinct effects on behaviour. We used RNAseq to identify mRNAs differentially expressed in the blood and hippocampus of mice following Lacticaseibacillus rhamnosus JB-1, and Limosilactobacillus reuteri 6475 treatment and performed Gene Set Enrichment Analysis (GSEA) to identify enrichment in pathway activity. L. rhamnosus, but not L. reuteri treatment altered several pathways in the blood and hippocampus, and the rhamnosus could be clearly distinguished based on mRNA profile. In particular, L. rhamnosus treatment modulated the activity of interferon signaling, JAK/STAT, and TNF-alpha via NF-KB pathways. Our results highlight that psychobiotics can induce complex changes in host gene expression, andin understanding these changes, we may help fine-tune selection of psychobiotics for treating mood disorders.

A CLASSIC CASE OF CREUTZFELDT-JAKOB DISEASE (CJD)

CASE: A 64-year-old woman was brought in by husband for inability to care for patient. Previously active, she developed gait instability, slurred speech, and memory lapse to the point of selective mutism and being bed-bound within three months. Her medical history was notable for hypertension and Covid four months prior. She had had mild upper respiratory symptoms and recovered in ten days. Examination revealed general encephalopathy, dysarthria, limited ability to follow commands. She had decreased strength but increased tone and rigidity in all extremities. She had rhythmic jaw movement and bradykinesia with scatter myoclonic movements. Cerebellar exam was notable for ataxia, but she had normal cranial nerve and sensory exams and normal reflexes. MRI of the brain revealed restricted diffusion and T2/Flair signal abnormality involving bilateral basal ganglia, ventral medial thalami, hippocampi, and cerebral cortices. Toxic metabolic workup was unrevealing. CSF was positive for 14-3-3 protein and elevated total tau protein, confirming Creutzfeldt-Jakob disease. IMPACT/DISCUSSION: Creutzfeldt-Jakob Disease (CJD) is a prion disease with one in a million prevalence. Patients present with rapidly progressing dementia, myoclonus, and signs of cerebellar, corticospinal and extrapyramidal involvement including nystagmus, ataxia, hyperreflexia, spasticity, hypokinesia, bradykinesia, dystonia, and rigidity. CJD is fatal within months to two years. Patients with end stage disease may have akinetic mutism. Magnetic resonance imaging (MRI), electroencephalogram (EEG), and cerebrospinal fluid (CSF) analysis are important for evaluation of CJD. Most sensitive in early stages, MRI Brain commonly shows hyperintense signal involving the cerebral cortex, corpus striatum, caudate, and putamen. EEG may capture pattern of periodic bi-or triphasic period sharp wave complexes. CSF might detect 14-3-3 protein with elevation of tau protein but real-time quaking-induced conversion (RT-QuIC) has the highest specificity for diagnosis for CJD. Though brain biopsy is the sole method of definitive diagnosis, results of MRI, EEG, and CSF analysis along with presenting signs and symptoms are sufficient for clinical diagnosis of CJD. Our patient's dementia, myoclonus, ataxia, hypokinesia, bradykinesia, dystonia, and rigidity all progressing to akinetic mutism within three months are classic presentation of CJD. EEG was normal, but MRI with hyperintensity of basal ganglia and cerebral cortices and CSF analysis with positive 14-3-3 and elevated tau proteins are all lead to diagnosis of CJD. CONCLUSION: This case illustrates a classic case of a Creutzfeldt-Jakob Disease, a rare prion disease marked by rapidly progressive dementia with neuropsychiatric features.

COVID-19 causes neuronal degeneration and reduces neurogenesis in human hippocampus.

Recent investigations of COVID-19 have largely focused on the effects of this novel virus on the vital organs in order to efficiently assist individuals who have recovered from the disease. In the present study we used hippocampal tissue samples extracted from people who died after COVID-19. Utilizing histological techniques to analyze glial and neuronal cells we illuminated a massive degeneration of neuronal cells and changes in glial cells morphology in hippocampal samples. The results showed that in hippocampus of the studied brains there were morphological changes in pyramidal cells, an increase in apoptosis, a drop in neurogenesis, and change in spatial distribution of neurons in the pyramidal and granular layer. It was also demonstrated that COVID-19 alter the morphological characteristics and distribution of astrocyte and microglia cells. While the exact mechanism(s) by which the virus causes neuronal loss and morphology in the central nervous system (CNS) remains to be determined, it is necessary to monitor the effect of SARS-CoV-2 infection on CNS compartments like the hippocampus in future investigations. As a result of what happened in the hippocampus secondary to COVID-19, memory impairment may be a long-term neurological complication which can be a predisposing factor for neurodegenerative disorders through neuroinflammation and oxidative stress mechanisms.

Gender Differences in Hippocampal/Parahippocampal Functional Connectivity Network in Patients Diagnosed with Chronic Insomnia Disorder.

Background: Gender differences in hippocampal and parahippocampal gyrus (HIP/PHG) volumes have been reported in sleep disorders. Therefore, this study investigated the moderating effect of gender on the relationship between chronic insomnia disorder (CID) and the HIP/PHG functional connectivity (FC) network. Methods: For this study, 110 patients diagnosed with CID (43 men and 67 women) and 60 matched good sleep control (GSC) (22 men and 38 women) were recruited. These participants underwent resting-state functional magnetic resonance imaging scans, after which a 2 × 2 (diagnosis × gender) analysis of variance was used to detect the main and interactive effect of insomnia and gender on their HIP/PHG FC networks. Results: Although the main effect of insomnia on the HIP FC network was observed in the bilateral cerebellar tonsil, superior frontal gyrus, and the medial orbitofrontal cortex, effects on the PHG FC network were observed in the bilateral HIP and amygdala. In contrast, the main effect of gender on the HIP FC network was observed in the right cerebellum posterior lobe, the dorsolateral prefrontal cortex (DLPFC), and the supplemental motor area. Of note, the interactive effect of both insomnia and gender was observed in FCs between the right HIP and the dorsal anterior cingulate cortex, and then between the right PHG and DLPFC. Moreover, the FC between the right PHG and left DLPFC was positively associated with anxiety scores in the female patients with CID. Conclusion: Our study identified that gender differences in brain connectivity existed between the HIP/PHG and executive control network in patients diagnosed with CID, these results will eventually extend our understanding of the important role that gender plays in the pathophysiology of CID.

Post-acute sequelae of SARS-CoV-2 infection (PASC): peripheral, autonomic, and central nervoussystem featuresin a child

Objective: To describe treatment with intravenous immune globulin (IVIG) of severe central, peripheral and autonomic (CNS, PNS, ANS) post-acute sequelae of SARS-CoV-2 infection (PASC) in a child. Background: PASC is defined as failure to recover from acute COVID-19 in those persistently symptomatic for>30 days from onset of infection with any pattern of tissue injury that remains evolving including the nervous system. Design/Methods: A child underwent extensive evaluation of the CNS, PNS and ANS according to the authors protocol for COVID-19 neurologic illness. Results: A 12-year-old girl was initially well until March 2020 until exposure to other family members testing positive for COVID-19 infection she contracted an upper respiratory infection illness with loss of taste, and excessive fatigue followed in July 2020 by burning, weakness, slurred speech and impaired cognition leading to a bedbound state and a concern she was suffering from conversion disorder. Examination in September 2020 showed mild delirium, tetraparesis, stocking sensory loss and areflexia. Electrodiagnosis showed mixed chronic distal demyelinating and axonal changes. Epidermal nerve fiber studies showed reduced calf and thigh densities. Autonomic studies showed symptomatic hypotension with tilting and reflex tachycardia. Brain FDG PET/MRI showed hypometabolism of bilateral anterior and mesial temporal, superior parietal, and lateral occipital lobes, anterior cingulate cortices, and the cerebellar hemispheres with hippocampus volumes <5% of age-matched controls. Lumbar puncture showed a total protein of 136 mg/dL. EEG and Mayo Clinic ENS2 panel did not show evidence of autoimmune encephalitis. From October 2020 to February 2021, she received monthly 2 g/kg/month of intravenous immune globulin (IVIg) with overall clinical improvement. Conclusions: The underlying basis of PASC, especially in the CNS, has not yet been fully appreciated awaiting controlled clinical and autopsy studies. IVIg is effective initial therapy of PASC to modulate neurologic post-infectious immunity. COVID Long Hauler and Long COVID are inappropriate terms for PASC.