Perigenual anterior cingulate cortex and its structural covariance as predictors for future body fat gain in young adults.

OBJECTIVE: This study aimed to examine whether baseline gray matter (GM) volume and structural covariance patterns could predict body fat gain over 1 to 2 years in a relatively large sample. METHODS: Voxel-based morphometry (VBM) analysis was applied to examine the association between baseline GM volume and body fat gain in 502 participants over 1 to 2 years. Furthermore, this study tested whether the structural covariances between the regions identified as seeds from VBM analysis and the rest of the brain were associated with future body fat gain. RESULTS: A significant positive association was observed between baseline GM volume in the perigenual anterior cingulate cortex (pgACC) and body fat gain over 1 to 2 years. Furthermore, relative to those with lower future body fat gain, pgACC covaried more extensively with the middle frontal gyrus, middle temporal gyrus, inferior temporal gyrus, and cerebellum in participants with higher future body fat gain. CONCLUSIONS: Using VBM and structural covariance network analysis, the current study revealed that higher GM volume of pgACC and its increased structural covariances with specific brain regions were associated with future weight gain, which may guide the development of more effective prevention and treatment interventions for obesity.

Tropism of SARS-CoV-2 for human cortical astrocytes.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly severe impact on respiratory function. Neurological symptoms, which range in severity, accompany as many as one-third of COVID-19 cases, indicating a potential vulnerability of neural cell types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized stem-cell-derived cortical organoids as well as primary human cortical tissue, both from developmental and adult stages. We find significant and predominant infection in cortical astrocytes in both primary tissue and organoid cultures, with minimal infection of other cortical populations. Infected and bystander astrocytes have a corresponding increase in inflammatory gene expression, reactivity characteristics, increased cytokine and growth factor signaling, and cellular stress. Although human cortical cells, particularly astrocytes, have no observable ACE2 expression, we find high levels of coronavirus coreceptors in infected astrocytes, including CD147 and DPP4. Decreasing coreceptor abundance and activity reduces overall infection rate, and increasing expression is sufficient to promote infection. Thus, we find tropism of SARS-CoV-2 for human astrocytes resulting in inflammatory gliosis-type injury that is dependent on coronavirus coreceptors.

Epileptic seizures in the emergency room: clinical and electroencephalographic findings associated with brain perfusion patterns on computed tomography.

BACKGROUND: Diagnosis of epileptic seizures, particularly regarding status epilepticus (SE), may be challenging in an emergency room setting. The aim of the study was to study the diagnostic yield of perfusion computed tomography (pCT) in patients with single epileptic seizures and SE. METHODS: We retrospectively reviewed the records of patients who followed an acute ischemic stroke pathway during a 9-month period and who were finally diagnosed with a single epileptic seizure or SE. Perfusion maps were visually analyzed for the presence of hyperperfusion and hypoperfusion. Clinical data, EEG patterns, and neuroimaging findings were compared. RESULTS: We included 47 patients: 20 (42.5%) with SE and 27 (57.5%) with single epileptic seizure. Of 18 patients who showed hyperperfusion on pCT, 12 were ultimately diagnosed with SE and eight had EEG findings compatible with an SE pattern. Focal hyperperfusion on pCT had a sensitivity of 60% (95% CI 36.4-80.2) and a specificity of 77.8% (95% CI 57.2-90.6) for predicting a final diagnosis of SE. The presence of cerebral cortical and thalamic hyperperfusion had a high specificity for predicting SE presence. Of note, 96% of patients without hyperperfusion on pCT did not show an SE pattern on early EEG. CONCLUSIONS: In acute settings, detection by visual analysis of focal cerebral cortical hyperperfusion on pCT in patients with epileptic seizures, especially if accompanied by the highly specific feature of thalamic hyperperfusion, is suggestive of a diagnosis of SE and requires clinical and EEG confirmation. The absence of focal hyperperfusion makes a diagnosis of SE unlikely.

Autism genes converge on asynchronous development of shared neuron classes.

Genetic risk for autism spectrum disorder (ASD) is associated with hundreds of genes spanning a wide range of biological functions1-6. The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals7,8. Here we used organoid models of the human cerebral cortex to identify cell-type-specific developmental abnormalities that result from haploinsufficiency in three ASD risk genes-SUV420H1 (also known as KMT5B), ARID1B and CHD8-in multiple cell lines from different donors, using single-cell RNA-sequencing (scRNA-seq) analysis of more than 745,000 cells and proteomic analysis of individual organoids, to identify phenotypic convergence. Each of the three mutations confers asynchronous development of two main cortical neuronal lineages-γ-aminobutyric-acid-releasing (GABAergic) neurons and deep-layer excitatory projection neurons-but acts through largely distinct molecular pathways. Although these phenotypes are consistent across cell lines, their expressivity is influenced by the individual genomic context, in a manner that is dependent on both the risk gene and the developmental defect. Calcium imaging in intact organoids shows that these early-stage developmental changes are followed by abnormal circuit activity. This research uncovers cell-type-specific neurodevelopmental abnormalities that are shared across ASD risk genes and are finely modulated by human genomic context, finding convergence in the neurobiological basis of how different risk genes contribute to ASD pathology.

Structural brain correlates of burnout severity in medical professionals: A voxel-based morphometric study.

Occupational burnout has become a pervasive problem, especially among medical professionals who are highly vulnerable to burnout. Since the beginning of the COVID-19 pandemic, medical professionals have faced greater levels of stress. It is critical to increase our understanding of the neurobiological mechanisms of burnout among medical professionals for the benefit of healthcare systems. Therefore, in this study, we investigated structural brain correlates of burnout severity in medical professionals using a voxel-based morphometric technique. Nurses in active service underwent structural magnetic resonance imaging. Two core dimensions of burnout, namely, emotional exhaustion and depersonalization, were assessed using self-reported psychological questionnaires. Levels of emotional exhaustion were found to be negatively correlated with gray matter (GM) volumes in the bilateral ventromedial prefrontal cortex (vmPFC) and left insula. Moreover, levels of depersonalization were negatively correlated with GM volumes in the left vmPFC and left thalamus. Altogether, these findings contribute to a better understanding of the neural mechanisms of burnout and may provide helpful insights for developing effective interventions for medical professionals.

Fatal case of simply influenza A (H3N2)-associated encephalitis in immunocompetent patient.

Influenza virus-associated encephalopathy/encephalitis is a rare entity in adults that can lead to severe neurological sequelae and even death. The clinical presentation can be quite diverse. This absence of a typical presentation along with the difficulty detecting the virus in the cerebrospinal fluid represents a diagnostic challenge. We present the case of a 79-year-old male with sudden onset of decreased consciousness and signs of right hemisphere damage. The presence of influenza A (H3N2) virus in respiratory sample along with compatible findings in cranial magnetic resonance led to the diagnosis. The patient died without responding to treatment with antivirals and immunomodulators and the anatomopathological study did not detect infectious agent. Early diagnostic suspicion is essential to establish adequate treatment and improve the prognosis.

Neuropathology and Inflammatory Cell Characterization in 10 Autoptic COVID-19 Brains.

COVID-19 presents with a wide range of clinical neurological manifestations. It has been recognized that SARS-CoV-2 infection affects both the central and peripheral nervous system, leading to smell and taste disturbances; acute ischemic and hemorrhagic cerebrovascular disease; encephalopathies and seizures; and causes most surviving patients to have long lasting neurological symptoms. Despite this, typical neuropathological features associated with the infection have still not been identified. Studies of post-mortem examinations of the cerebral cortex are obtained with difficulty due to laboratory safety concerns. In addition, they represent cases with different neurological symptoms, age or comorbidities, thus a larger number of brain autoptic data from multiple institutions would be crucial. Histopathological findings described here are aimed to increase the current knowledge on neuropathology of COVID-19 patients. We report post-mortem neuropathological findings of ten COVID-19 patients. A wide range of neuropathological lesions were seen. The cerebral cortex of all patients showed vascular changes, hyperemia of the meninges and perivascular inflammation in the cerebral parenchyma with hypoxic neuronal injury. Perivascular lymphocytic inflammation of predominantly CD8-positive T cells mixed with CD68-positive macrophages, targeting the disrupted vascular wall in the cerebral cortex, cerebellum and pons were seen. Our findings support recent reports highlighting a role of microvascular injury in COVID-19 neurological manifestations.

SARS-CoV-2 Infected Pediatric Cerebral Cortical Neurons: Transcriptomic Analysis and Potential Role of Toll-like Receptors in Pathogenesis.

Different mechanisms were proposed as responsible for COVID-19 neurological symptoms but a clear one has not been established yet. In this work we aimed to study SARS-CoV-2 capacity to infect pediatric human cortical neuronal HCN-2 cells, studying the changes in the transcriptomic profile by next generation sequencing. SARS-CoV-2 was able to replicate in HCN-2 cells, that did not express ACE2, confirmed also with Western blot, and TMPRSS2. Looking for pattern recognition receptor expression, we found the deregulation of scavenger receptors, such as SR-B1, and the downregulation of genes encoding for Nod-like receptors. On the other hand, TLR1, TLR4 and TLR6 encoding for Toll-like receptors (TLRs) were upregulated. We also found the upregulation of genes encoding for ERK, JNK, NF-κB and Caspase 8 in our transcriptomic analysis. Regarding the expression of known receptors for viral RNA, only RIG-1 showed an increased expression; downstream RIG-1, the genes encoding for TRAF3, IKKε and IRF3 were downregulated. We also found the upregulation of genes encoding for chemokines and accordingly we found an increase in cytokine/chemokine levels in the medium. According to our results, it is possible to speculate that additionally to ACE2 and TMPRSS2, also other receptors may interact with SARS-CoV-2 proteins and mediate its entry or pathogenesis in pediatric cortical neurons infected with SARS-CoV-2. In particular, TLRs signaling could be crucial for the neurological involvement related to SARS-CoV-2 infection.

Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19.

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, neurological symptoms increasingly moved into the focus of interest. In this prospective cohort study, we assessed neurological and cognitive symptoms in hospitalized coronavirus disease-19 (COVID-19) patients and aimed to determine their neuronal correlates. Patients with reverse transcription-PCR-confirmed COVID-19 infection who required inpatient treatment primarily because of non-neurological complications were screened between 20 April 2020 and 12 May 2020. Patients (age > 18 years) were included in our cohort when presenting with at least one new neurological symptom (defined as impaired gustation and/or olfaction, performance < 26 points on a Montreal Cognitive Assessment and/or pathological findings on clinical neurological examination). Patients with ≥2 new symptoms were eligible for further diagnostics using comprehensive neuropsychological tests, cerebral MRI and 18fluorodeoxyglucose (FDG) PET as soon as infectivity was no longer present. Exclusion criteria were: premorbid diagnosis of cognitive impairment, neurodegenerative diseases or intensive care unit treatment. Of 41 COVID-19 inpatients screened, 29 patients (65.2 ± 14.4 years; 38% female) in the subacute stage of disease were included in the register. Most frequently, gustation and olfaction were disturbed in 29/29 and 25/29 patients, respectively. Montreal Cognitive Assessment performance was impaired in 18/26 patients (mean score 21.8/30) with emphasis on frontoparietal cognitive functions. This was confirmed by detailed neuropsychological testing in 15 patients. 18FDG PET revealed pathological results in 10/15 patients with predominant frontoparietal hypometabolism. This pattern was confirmed by comparison with a control sample using voxel-wise principal components analysis, which showed a high correlation (R2 = 0.62) with the Montreal Cognitive Assessment performance. Post-mortem examination of one patient revealed white matter microglia activation but no signs of neuroinflammation. Neocortical dysfunction accompanied by cognitive decline was detected in a relevant fraction of patients with subacute COVID-19 initially requiring inpatient treatment. This is of major rehabilitative and socioeconomic relevance.

Ciclesonide activates glucocorticoid signaling in neonatal rat lung but does not trigger adverse effects in the cortex and cerebellum.

Synthetic glucocorticoids (sGCs) such as dexamethasone (DEX), while used to mitigate inflammation and disease progression in premature infants with severe bronchopulmonary dysplasia (BPD), are also associated with significant adverse neurologic effects such as reductions in myelination and abnormalities in neuroanatomical development. Ciclesonide (CIC) is a sGC prodrug approved for asthma treatment that exhibits limited systemic side effects. Carboxylesterases enriched in the lower airways convert CIC to the glucocorticoid receptor (GR) agonist des-CIC. We therefore examined whether CIC would likewise activate GR in neonatal lung but have limited adverse extra-pulmonary effects, particularly in the developing brain. Neonatal rats were administered subcutaneous injections of CIC, DEX or vehicle from postnatal days 1-5 (PND1-PND5). Systemic effects linked to DEX exposure, including reduced body and brain weight, were not observed in CIC treated neonates. Furthermore, CIC did not trigger the long-lasting reduction in myelin basic protein expression in the cerebral cortex nor cerebellar size caused by neonatal DEX exposure. Conversely, DEX and CIC were both effective at inducing the expression of select GR target genes in neonatal lung, including those implicated in lung-protective and anti-inflammatory effects. Thus, CIC is a promising, novel candidate drug to treat or prevent BPD in neonates given its activation of GR in neonatal lung and limited adverse neurodevelopmental effects. Furthermore, since sGCs such as DEX administered to pregnant women in pre-term labor can adversely affect fetal brain development, the neurological-sparing properties of CIC, make it an attractive alternative for DEX to treat pregnant women severely ill with respiratory illness, such as with asthma exacerbations or COVID-19 infections.

Inflammatory Response Leads to Neuronal Death in Human Post-Mortem Cerebral Cortex in Patients with COVID-19.

The recent coronavirus disease of 2019 (COVID-19) pandemic has adversely affected people worldwide. A growing body of literature suggests the neurological complications and manifestations in response to COVID-19 infection. Herein, we explored the inflammatory and immune responses in the post-mortem cerebral cortex of patients with severe COVID-19. The participants comprised three patients diagnosed with severe COVID-19 from March 26, 2020, to April 17, 2020, and three control patients. Our findings demonstrated a surge in the number of reactive astrocytes and activated microglia, as well as low levels of glutathione along with the upregulation of inflammation- and immune-related genes IL1B, IL6, IFITM, MX1, and OAS2 in the COVID-19 group. Overall, the data imply that oxidative stress may invoke a glial-mediated neuroinflammation, which ultimately leads to neuronal cell death in the cerebral cortex of COVID-19 patients.

Psychological status after insulo-opercular resection in patients with epilepsy: Depression, anxiety, and quality of life.

Insular epilepsy is increasingly recognized in epilepsy surgery centers. Recent studies suggest that resection of an epileptogenic zone that involves the insula as a treatment for drug-resistant seizures is associated with good outcomes in terms of seizure control. However, despite the existing evidence of a role of the insula in emotions and affective information processing, the long-term psychological outcome of patients undergoing these surgeries remain poorly documented. A group of 27 adults (18 women) who underwent an insulo-opercular resection (in combination with a part of the temporal lobe in 10, and of the frontal lobe in 5) as part of epilepsy surgery at our center between 2004 and 2019 completed psychometric questionnaires to assess depression (Beck Depression Inventory - 2nd edition; BDI-II), anxiety (State-Trait Anxiety Inventory, Trait Version; STAI-T), and quality of life (Patient Weighted Quality of Life In Epilepsy; QOLIE-10-P). Scores were compared to those of patients who had standard temporal lobe epilepsy (TLE) surgery with similar socio-demographic and disease characteristics. Seizure control after insular epilepsy surgery was comparable to that observed after TLE surgery, with a majority of patients reporting being seizure free (insular: 63.0%; temporal: 63.2%) or having rare disabling seizures (insular: 7.4%; temporal: 18.4%) at the time of questionnaire completion. Statistical comparisons revealed no significant group difference on scores of depression, anxiety, or quality of life. Hemisphere or extent of insular resection had no significant effect on the studied variables. In the total sample, employment status and seizure control, but not location of surgery, significantly predicted quality of life. Self-reported long-term psychological status after insulo-opercular resection as part of epilepsy surgery thus appears to be similar to that observed after TLE surgery, which is commonly performed in epilepsy surgery centers.

Modelling the Anatomic Distribution of Neurologic Events in Patients with COVID-19: A Systematic Review of MRI Findings.

BACKGROUND: Neurologic events have been reported in patients with coronavirus disease 2019 (COVID-19). However, a model-based evaluation of the spatial distribution of these events is lacking. PURPOSE: Our aim was to quantitatively evaluate whether a network diffusion model can explain the spread of small neurologic events. DATA SOURCES: The MEDLINE, EMBASE, Scopus, and LitCovid data bases were searched from January 1, 2020, to July 19, 2020. STUDY SELECTION: Thirty-five case series and case studies reported 317 small neurologic events in 123 unique patients with COVID-19. DATA ANALYSIS: Neurologic events were localized to gray or white matter regions of the Illinois Institute of Technology (gray-matter and white matter) Human Brain Atlas using radiologic images and descriptions. The total proportion of events was calculated for each region. A network diffusion model was implemented, and any brain regions showing a significant association (P < .05, family-wise error-corrected) between predicted and measured events were considered epicenters. DATA SYNTHESIS: Within gray matter, neurologic events were widely distributed, with the largest number of events (∼10%) observed in the bilateral superior temporal, precentral, and lateral occipital cortices, respectively. Network diffusion modeling showed a significant association between predicted and measured gray matter events when the spread of pathology was seeded from the bilateral cerebellum (r = 0.51, P < .001, corrected) and putamen (r = 0.4, P = .02, corrected). In white matter, most events (∼26%) were observed within the bilateral corticospinal tracts. LIMITATIONS: The risk of bias was not considered because all studies were either case series or case studies. CONCLUSIONS: Transconnectome diffusion of pathology via the structural network of the brain may contribute to the spread of neurologic events in patients with COVID-19.

Neuroinvasion of SARS-CoV-2 in human and mouse brain.

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

Infection of Brain Organoids and 2D Cortical Neurons with SARS-CoV-2 Pseudovirus.

Since the global outbreak of SARS-CoV-2 (COVID-19), infections of diverse human organs along with multiple symptoms continue to be reported. However, the susceptibility of the brain to SARS-CoV-2, and the mechanisms underlying neurological infection are still elusive. Here, we utilized human embryonic stem cell-derived brain organoids and monolayer cortical neurons to investigate infection of brain with pseudotyped SARS-CoV-2 viral particles. Spike-containing SARS-CoV-2 pseudovirus infected neural layers within brain organoids. The expression of ACE2, a host cell receptor for SARS-CoV-2, was sustained during the development of brain organoids, especially in the somas of mature neurons, while remaining rare in neural stem cells. However, pseudotyped SARS-CoV-2 was observed in the axon of neurons, which lack ACE2. Neural infectivity of SARS-CoV-2 pseudovirus did not increase in proportion to viral load, but only 10% of neurons were infected. Our findings demonstrate that brain organoids provide a useful model for investigating SARS-CoV-2 entry into the human brain and elucidating the susceptibility of the brain to SARS-CoV-2.