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Background: Recent findings from the UK Biobank revealed that healthy adults who later became infected with SARS-CoV-2 had lower brain volumes in regions involved in risk-taking behavior and olfaction compared to individuals who did not become infected. We examined if similar pre-existing differences in brain regions correspond to SARS-CoV-2 infection among people with HIV (PWH) receiving suppressive ART. Method(s): Participants included adult Thai MSM enrolled in the acute HIV (AHI) cohort (RV254/SEARCH010) in Bangkok, Thailand. Participants underwent 3T MRI and clinical assessments (i.e., HIV disease metrics, cognitive testing, and self-reported mood and substance use). ART initiation occurred within 5 days of the MRI (median=same day). Regional brain volumes were summed across hemispheres and corrected for head size. Brain volumes and clinical indices were compared between participants with laboratory confirmed SARS-CoV-2 and those without a diagnosis of SARS-CoV-2 following ART initiation. Machine learning was utilized to identify variables at the time of enrollment into the cohort that predicted subsequent SARS-CoV-2 infection status. Result(s): 112 participants were included in the analysis. All study participants achieved viral suppression after ART and received SARS-CoV-2 vaccinations. Fifty-four participants became infected with SARS-CoV-2 during the observation period (median=79 weeks from ART initiation). Study participants who became infected with SARS-CoV-2 after ART had lower volumes at the time of enrollment in several subcortical brain regions with the most pronounced effect in the pallidum (p=.025). There were no associations between brain volumes and ratings of mood, demographics, or HIV disease indices. SARS-CoV-2 infection was two-fold higher among individuals who reported use of amyl nitrites (i.e., poppers) during chemsex. Machine learning with repeated cross validation revealed that lower orbital and medial frontal lobe, anterior cingulate, pallidum, vermis, and olfactory volumes, worse motor function, and higher education collectively predicted co-infection status (average AUC of 85%). Conclusion(s): Study findings point toward a risk phenotype for SARS-CoV-2 infection among PWH defined by pre-existing differences in brain volumes relevant to risk-taking behavior, emotion, and neuroHIV as well as behavioral factors such as inhalant use and lack of social distancing during chemsex. (Table Presented).
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Background: Post-acute sequelae of SARS-COV-2 infection (PASC) is associated with cognitive impairment (CI) with unclear pathogenesis though blood brain barrier (BBB) impairment and excitotoxic injury appear significant. Post-acute sequelae of SARS-COV-2 infection (PASC) is associated with cognitive impairment (CI) with unclear pathogenesis though blood brain barrier (BBB) impairment and excitotoxic injury appear significant. We hypothesized that PASC CI patients would have brain inflammation and BBB disruption using advanced MR imaging. Method(s): In this prospective longitudinal study, 14 patients with PASC CI (mild and non-hospitalised) were enrolled (mean age of 45;10 F and 4 M) and 10 sex and age matched healthy controls. 13 had a follow up MR at 9-12 months (mean 10 months). All participants underwent DCE perfusion (an index of BBB integrity with Ktrans as the measurement), Diffusion Tensor Imaging (DTI) and single voxel MR spectroscopy (MRS) of the frontal cortex/white matter and the brainstem in addition to brain anatomical MRI. Between group analyses were used to determine which MRI outcomes were significantly different from controls in patients with PASC CI. Result(s): The PASCI CI group showed significantly increased (ie BBB impairment) Ktrans, and increased region (Frontal white matter and Brain Stem)-specific areas in the brain (p=< 0.005), reduction in NAA (ie neuronal injury) and mild reduction of Glx (ie excitotoxicity) in the frontal white matter and brain stem (p=0.004), and reduction in white matter integrity (increased diffusivity -greater radial and mean diffusivity). Increased Ktrans was correlated with increased both radial and mean diffusivity (r=0.9) in all tested brain regions. Ktrans significantly improved in the follow up MR (p= 002596 Z=-2.794872) with no difference between subjects and controls indicating BBB normalisation (p= 0.442418, z= -0.144841). White matter integrity also improved especially in the fractional anisotropy values in the executive networks (p=< 0.00045). MRS showed significant improvement in the NAA in the frontal white matter but Glx remain high as compared to the controls (p=0.0006). Conclusion(s): PASC CI was characterised by reversible diffuse BBB impairment, neuronal/axonal and excitotoxic injury. BBB impairment was associated with white matter disruption. These are suggestive biomarkers for the presence, severity and prognosis of PASC CI. Such biomarkers could underpin appropriate trial design and timing of intervention.
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Background Management of patients with multiple sclerosis (MS) and evidence of disease activity during treatment with cladribine tablets represents a challenging point. Objectives To report a patient with highly active multiple sclerosis (HAMS) who has been early switched from cladribine to alemtuzumab owing to tumultuous clinical and radiological activity Methods A single retrospective case report. Results. Treatment with alemtuzumab has led to a complete suppression of disease activity without any evidence of infections or acquired autoimmune diseases. Conclusion Our report suggests that an early switch from cladribine to alemtuzumab, may be safe and efficacious in selected HAMS cases.Copyright © 2022 The Authors
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Introduction: (IFITM3) is an innate immune protein that has been identified as a novel gamma-secretase (gammas) modulator. FYN is a kinase that stabilizes IFITM3 on the membrane, primes APP for amyloidogenic gammas processing and mediates tau oligomerization. The purpose of this study is to explore the role of FYN and IFITM3 in AD and COVID-19, expanding on previous research from our group. Method(s): A 520 gene signature containing FYN and IFITM3 (termed Ia) was extracted from a previously published meta-analysis of Alzheimer's disease (AD) bulk- and single nuclei sequencing data. Exploratory analyses involved meta-analysis of bulk and single cell RNA data for IFITM3 and FYN differential expression per CNS site and cellular type. Confirmatory analyses, gene set enrichment analysis (GSEA) on Ia was performed to detect overlapping enriched biological networks between COVID-19 with AD. Result(s): Bulk RNA data analysis revealed that IFITM3 and FYN were overexpressed in two CNS regions in AD vs. Controls: the temporal cortex Wilcoxon p-value=1.3e-6) and the parahippocampal cortex Wilcoxon p-value=0.012). Correspondingly, single cell RNA analysis of IFITM3 and FYN revealed that it was differentially expressed in neurons, glial and endothelial cells donated b AD patients, when compared to controls. Discussion(s): IFITM3 and FYN were found as interactors within biological networks overlapping between AD and SARS-CoV-2 infection. Within the context of SARS-CoV-2 induced tau aggregation and interactions between tau and Ab1-42, the FYN - IFITM3 regulome may outline an important innate immunity element responsive to viral infection and IFN-I signaling in both AD and COVID-19.Copyright © 2021 The Authors
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Aim/Introduction: Neurological sequelae of Covid-19 have been widely documented by anatomic and functional methods [1,2]. Brain metabolism studies using 18F-FDG PET/CT during the subacute phase of the disease have also been published [1]. On the other hand, there is a lack of information about the influence of SARS-Cov2 infection on brain metabolism during the acute phase of the disease. The aim of this study was to identify and quantify changes in brain metabolism during the acute onset of Covid-19. Material(s) and Method(s): We studied 23 patients (13 women, median age 55.5[33-78] years) hospitalized with positive nasopharyngeal swab test (RT-PCR) for Covid-19 and requiring supplemental oxygen. Dedicated PET/CT images of the brain were acquired for 10 minutes, 1h after injection of 4.4 MBq/kg of 18F-FDG. Visual analysis was performed by two nuclear medicine specialists and one radiologist. Quantitative analysis was performed using dedicated software. 18F-FDG uptake in multiple brain regions was evaluated and the standard deviation (SD) of brain uptake in each region was automatically calculated in comparison with a group of normal subjects. More than 2 SD above or below the control group was considered significant in each area. Result(s): Serum C-reactive protein at admission ranged from 6.43 to 189.0 mg/L (mean 97.0 +/- 55.5 mg/L). The mean supplemental oxygen demand was 2.8 +/- 1.5 L/min. PET/CT images were acquired between 4 and 20 days of symptoms (mean 12.9 +/- 3.8 days). The images showed increased glycolytic metabolism in basal ganglia and relatively reduced brain metabolism in cortical regions. Basal ganglia metabolism was bilaterally increased in 18/23 (78.3%) and normal in 5 (21.7%) patients. Lenticular nucleus presented increased metabolism in 21/23 (91.3%) and was normal in 2 (8.7%) patients. Frontal and parietal lobes metabolism was respectively reduced in 9/24 (37.6%) and 8/23 (34.8%) patients. The whole brain metabolism was normal in 20/23 (86.9%) patients. Olfactory cortex metabolism was normal in 18/23 (78.3%) patients. Conclusion(s): Brain metabolism is clearly affected during the acute phase of SARS-Cov2 infection. The most frequent finding was increased basal ganglia metabolism, with most patients presenting marked lenticular nucleus hypermetabolism. Frontal and parietal lobes presented reduced metabolism in some patients. Interestingly, olfactory cortex is not affected in most patients, suggesting that anosmia, reported by some patients, is not related to the direct involvement of the brain by the disease.
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Background: Most neuropsychiatric disorders are moderately heritable but characterized by many genetic risk variants with weak effects. As such, it is difficult to point to direct causes or elucidate mechanisms of action. Despite the ease in gathering genetic data from humans, genetic data does not easily explain mechanistic effects. Gene expression on the other hand, which can more easily explain mechanistic effects, is harder to gather, especially in brain regions that are critical to the understanding of neuropsychiatric disease. To address this, we developed methods to impute genetically regulated gene expression (GReX) from genotypes and imputed GReX in over 440,000 European individuals in the Million Veteran Program (MVP) for a wide variety of tissues and cell types. Method(s): We use EpiXcan (based on PrediXcan) to develop machine learning models from training genotype, expression, and epigenetic data. We use custom scripts to impute individual GReX and perform a variety of downstream association analyses, including GReX Phenome Wide Association Studies (PheWAS) and Transcriptome Wide Association Studies (TWAS). Result(s): Results show an overlap in Schizophrenia genes identified by individual level TWAS and those identified by summary level TWAS informed by GWAS. TWASs for neuropsychiatric phenotypes identify genes established in the literature, but also novel targets. Inverse-variance meta-analyzed single gene imputation efforts across ancestries confirm clinical results obtained from COVID-19 positive individuals in both IL10RB and IFNAR2. GReX PheWAS for these particular genes using a novel negative binomial distribution for phecodes confirm COVID-19 related phenotypes. Finally, we describe various enriched pathways found in a COVID-19 TWAS, including immunological pathways. Discussion(s): GReX presents a unique solution to integrate effects across the genome and increase sample size in gene expression analyses. We are pursuing the creation of additional EpiXcan models, improved statistical methods for downstream association analyses, and replication efforts across biobanks. We plan to perform these analyses in all ancestries, available EpiXcan and PrediXcan models, and phenotypes. Disclosure: Nothing to disclose. Copyright © 2022
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Background: The addictive use of digital games is a rising phenomenon, especially in adolescents and under the COVID-19 pandemic (Paschke et al., 2021). A better understanding of the new International Classification of Diseases, 11th Revision (ICD-11) diagnosis gaming disorder (GD) is urgently needed. Imaging studies report alterations in cognitive control, affective and motor regions in affected adolescents (Schettler et al., 2022). At the same time, they show deficits in self-rated emotion regulation. Objectives: The study aimed to investigate the neural correlates of emotional dysregulation in adolescents with GD and neural alterations under therapy at the very first time. Methods: In a functional magnetic resonance imaging study, 20 inpatients and outpatients with GD and 20 healthy peers were examined (aged 12-18 years) at two measurement points with a 12-week interval. Within the interval, patients received therapy as described by Wendt et al. (2021). The cognitive-reappraisal paradigm of Ochsner et al. (2004) was applied to measure emotion regulation abilities. Findings: First interim analyses revealed a positive linear relationship between the severity of initial addiction symptoms and activity changes within the dorsolateral prefrontal cortex - a brain region related to top-down emotion regulation. This relationship decreased over the 12 weeks but only in the patients group. Conclusion: Adolescents with GD seem to show higher cognitive-control effort when dealing with negative emotions which could be addressed by therapy. Data collection will be completed in December 2021. Therefore, results of high novelty and clinical relevance will be presented to the scientific community for the very first time.
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Aims: Activation of microglial cells represents the most common neu-ropathological change in fatal cases of COVID-19 with particular prominence in the brainstem. However, detailed assessments are lacking. Here, we assessed reactive microglia in COVID-19 tissue and tested for disease-specific activation patterns. Methods: We used an early-(Iba1) and a late-stage (CD68) immuno-histochemistry marker for microglial activation in human post-mortem brainstem and frontal lobe tissues in eight fatal COVID-19 cases, seven septic controls and six non-septic controls. We quantified the level of microglial activation employing a Qu-Path-based automated approach. Using a mixed three-way ANOVA, we tested for effects and interactions of brain region, microglial marker and group. Results: Reactive microglia were detected in all cases across brain regions and antibodies. However, COVID-19 brains exhibited significantly higher levels of microglial activation than septic and control brains, especially of late-stage microglia (CD68+). Irrespective of disease, microglia activation was significantly more pronounced and further progressed (CD68+) in brainstem tissues, particularly the medulla, than in the frontal lobe. Whilst survival time from admission marginally significantly correlated with the level of reactive microglia in COVID-19, no associations were found between neuroinflammation and either gender or age at death. Conclusions: Whilst the brainstem demonstrates a disease-independent high susceptibility to inflammation, microglial activation in COVID-19 (COVID-19 microglia encephalopathy) is specific and of importance for understanding the involvement of the CNS in this disease.
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SARS-CoV-2, the causative agent of COVID-19, typically manifests as a respiratory illness although extrapulmonary involvement, such as in the gastrointestinal tract and nervous system, are increasingly recognised. Through immunohistochemistry against the SARS-CoV-2 nucleocapsid protein (NP), we aimed to characterise the multisystem viral tropism of SARS-CoV-2. FFPE tissue was obtained from 16 PCR-confirmed post-mortem COVID cases. Of these cases, 10 were full-body, 5 were brain only and 1 was a brain biopsy. Brain regions studied included frontal cortex, medulla, cerebellum, pons and olfactory bulb. Neurological symptoms featured in the cohort included brainstem encephalitis, acute disseminated encephalomyelitis (ADEM) and brain infarction. Immunohistochemistry of digestive system tissues revealed presence of SARS-CoV-2 NP in neurons of the myenteric plexus, a site of high ACE-2 expression, the entry receptor for SARS-CoV-2 and one of the earliest affected cells in Parkinson's disease (PD). Within the brain, staining was widespread in all sampled regions but limited to endothelial cells only (including in the olfactory bulb). Furthermore, in the full-body post-mortem cases, positivity in brain endothelia was restricted to cases exhibiting multiorgan tissue positivity (3/9 cases). The average time from symptom onset to time of death was shorter in positively versus negatively stained postmortem cases (mean = 10.3 days vs mean = 20.3 days, p = 0.0416) suggesting NP detection was confined to the infectious period. Together, our findings provide evidence for enteric nervous system but not brain neuroinvasion of SARS-CoV-2 as well as potential insights into long-term complications of COVID-19 and PD pathogenesis.
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Internet gaming addiction (IGA) is a growing concern among adolescents, exacerbated by recent COVID-19 restrictions. The World Health Organization has recently included IGA in the 11th International Classification of Diseases. However, the validity and reliability of the proposed criteria are subjected to controversy 1. Despite growing neurobiological evidence in IGA, most systematic reviews have focused on adults or mixed adult/adolescent populations. Therefore, this systematic review explored the neuroimaging literature in adolescents with IGA. Altogether, 2263 primary studies were identified from PubMed, CINAHL Plus, PsycINFO, and Web of Science. After applying inclusion and exclusion criteria (appropriate title, , comparison group used within study, English-language, neuroimaging, and mean age under 18), 25 articles were included in this review. Functional and structural brain alterations in IGA were noted across several imaging modalities, including electroencephalogram (EEG), functional magnetic resonance imaging (fMRI), and structural magnetic resonance imaging (MRI). Compared with healthy controls, adolescents with IGA demonstrated functional impairment in emotional regulation, reward-seeking, inattention and, inhibition control circuits, leading to increased risky decision making. Structural changes in gray and white matter were noted due to repetitive brain stimulation associated with visual, auditory, and spatial working memory. With regards to brain region processing self-concept, adolescents utilize the medial prefrontal region while having game character thoughts, compared to adults who utilize the left angular gyrus 2. In conclusion, adolescents with IGA showed common neurological findings consistent with other behavioral addictions and psychiatric disorders. Future studies are needed for potential neuroimaging markers that apply to diagnosis and informing treatment.
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Introduction: Post traumatic stress disorder (PTSD) is due to exposure to extreme lifetime traumatic events and there seems to be no cure. In COVID-19 era PTSD is very common among people due to permanent disability and death of near and dear ones. These people suffer daily from the recurring thoughts of reliving the trauma again. I chose this topic because I came across so many people with post COVID-19 stress and depression. Aims: To determine alternative ways to treat PTSD rather than the use of traditional therapies. Materials and methods: Yoga is a whole body and mind practice that in stills peace and empowerment. A total of 30 minutes yoga daily is beneficial at the cellular and even genetic level to enhance the immune system and reduce stress. Balancing the stress-response system: shift from sympathetic (energy burning) to parasympathetic (energy recharging) helps in dealing with post COVID-19 stress and depression. Results: Previous studies have shown effect of yoga on hippocampus which is thought to be responsible for intrusive memories and flashbacks that occur in people with this PTSD. Yoga helps in learning to tolerate feelings and sensations by increasing the capacity for introspection, moderate arousal and learning that after confrontation with physical helplessness it is essential to engage in taking effective action. Sensory input can automatically stimulate hormonal secretions and activation of brain regions involved in attention and memory. Conclusion: People doing yoga showed significant decrease in frequency of intrusions and severity of hyperarousal symptoms. These people reported a sense of awareness that they had not experienced before and learned to sense and focus on their bodies after the yoga sessions.
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Background: Depression and anxiety impact recovery and quality of life in 1 in 3 stroke survivors. Caregivers also experience burnout. Creative art-based therapy boosts feelings of accomplishment, self-esteem, and neuroplasticity by stimulating diverse brain regions. Few outpatient art therapy programs exist for stroke survivors and caregivers, limited further during the COVID-19 pandemic. We aim to implement an outpatient, student-run virtual art therapy curriculum using a patient-carer team approach to foster a supportive peer community, reduce depressive symptoms in survivors, and increase relief for caregivers. Methods: A multidisciplinary team of stroke physician, nurse, occupational therapist, clinic managers, and undergraduate student volunteers created an evidenced-based art therapy curriculum feasible for stroke survivors. An art educator trained volunteers in empathetic communication, teaching techniques, and patient privacy. Participants pre-registered for weekly 1 hour classes held via video conference and received art materials by mail. We administered surveys at initial registration and quarterly. An institutional grant provided funding. Results: From September 2020 - July 2021, Healing Strokes hosted 30 classes using the curriculum (Table 1) for 71 survivors and caregivers from 9 states at a 1:5 volunteer-to-participant ratio. 20 participants (14 survivors, 6 caregivers) self-reported benefits of peer support, creative inspiration, increased sense of accomplishment, and improvement in speech and fine motor skills. Conclusion: Implementation of a virtual outpatient art-based therapy program for stroke survivors and caregivers is feasible with participants self-reporting benefits in functional recovery and mood. Post-stroke supportive care programs can expand to include art therapy during a pandemic. Future studies can validate the impact on peer support, function, and post-stroke depression and anxiety. (Figure Presented).
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Introduction: Burnout has become a major concern in health care systems and has also been a critical issue during the COVID-19 pandemic. As many as 76% of medical professionals report burnout symptoms that may lead to medical errors, substance abuse, and even suicide [1,2]. Meanwhile, previous studies report on the importance of peoples’ sense of coherence (SOC) or control over work for dealing with burnout experience which implicates a stress-coping capacity involving comprehensibility, manageability, and meaningfulness. However, little is known on how SOC cognitively modulates burnout experiences, as neural substrates for SOC and burnout are insufficiently explored [2,3]. Aim: We aimed to investigate neurocognitive mechanisms of SOC and burnout in medical professionals. Methods: We recruited early-career registered nurses and forty-one were enrolled in this study. This study was approved by the institutional review board of Kyoto University and was conducted in accordance with the Code of Ethics of the World Medical Association. Participants were recruited by advertisements in the hospitals. Participants’ SOC and burnout levels were investigated using the sense of coherence scale and Maslach Burnout Inventory (MBI) [3]. Higher scores of SOC and MBI represented a greater sense of coherence and more burnout experience, respectively. We used functional magnetic resonance imaging and measured resting-state brain activity. We identified brain regions associated with SOC and burnout levels by correlating these trait scores to the regional fractional amplitude of low frequency fluctuations (fALFF). Subsequently, we investigated whether participants’ levels of SOC impacted their fALFF-burnout association by mediation analysis. Results: SOC and the depersonalization dimension of burnout were negatively correlated. The fALFF in the mid dorsolateral prefrontal cortex (DLPFC) correlated positively with SOC scores, and negatively with the depersonalization dimension of burnout. Based on the above correlations, we conducted a mediation analysis and observed that SOC mediates the negative relationship between DLPFC activity and burnout severity (p < 0.05). That is, the participants’ depersonalization level was better explained by their SOC level, together with their resting-state brain activity (fALFF of the DLPFC), rather than the brain activity level alone. Conclusions: The results suggest that our participants’ burnout severity associates with decreased SOC and prefrontal activity those of which may support cognitive control. It is possible that they may facilitate flexible shifting of perspective and optimistic reappraisal of work-stress. In effect, workplace stressors may be acknowledged as being more meaningful than distressing. Meanwhile, without sufficient SOC, frequent exposures to stressors can lead to maladaptive coping to exhibit emotional numbing or depersonalization. The results also suggest that the sense of coherence/control and burnout effect can be generalized and carried over into no-task, spontaneous brain activity to a certain extent. The further approach in this line may pave the ways to illuminate which intervention and training effectively impact the subjective experience of burnout in medical education. No conflict of interest
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Background: A high prevalence of depression, anxiety, insomnia and PTSD has been reported in COVID-19 survivors [1]. This is similar to what previously observed in other Coronavirus-related diseases such as SARS and MERS [2]. The pathophysiology of post-infection neuropsychiatric symptoms is likely to be multifactorial, with a role played by inflammatory and immunological factors [3], but it is still largely unknown;we thus investigated COVID-19 survivors via 3T MRI imaging to identify neural underpinnings of post-infection neuropsychiatric symptoms in order to further elucidate their complex pathophysiology. Methods: Covid-19 survivors were recruited during an ongoing prospective cohort study at IRCCS San Raffaele Hospital in Milan;psychopathology was initially measured via several self-report questionnaires (Impact of Events Scale-Revised (IES-R), Zung Self-Rating Depression Scale (ZSDS), 13-item Beck's Depression Inventory (BDI));subsequently patients (n=28) underwent 3T MRI scanning (Philips 3T Ingenia CX scanner with 32-channel sensitivity encoding SENSE head coil). T1 weighted images were processed using Computational Anatomy Toolbox (CAT12) for Statistical Parametric Mapping 12 (SPM12) in Matlab R2016b;segmentation into Gray Matter, White Matter and cerebrospinal fluid, bias regularization, non-linear modulation and normalization to MNI space were performed;measures of Total Intracranial Volume (TIV) were obtained and images were smoothed with an 8-mm full width at half maximum Gaussian filter. Multiple regressions were performed using SPM12 software package: with no a priori regions of interest selected, whole-brain gray matter volumes were used as dependent variables, psychometric scales scores as independent variables, and age, sex and TIV as nuisance covariates. Results: After VBM regression analysis covarying for age, sex and TIV, ZSDS Index scores were inversely correlated with gray matter volume in the Bilateral Anterior Cingulate Cortex (MNI 2, 24, 28, cluster level pFWE = 0.045, k=767);furthermore 3 cluster were identified comprising again the anterior cingulate cortex and the insular cortex bilaterally in which IES-R scores were inversely correlated with gray matter volumes (Cluster 1: MNI -30, 9, 3, cluster level pFWE = 0.005, k=1284;Cluster 2: MNI 36, -3, -3, cluster level pFWE = 0.037, k=773;Cluster 3: MNI 9, 30, 28, cluster level pFWE = 0.038, k=766). No other statistical significant result was found. Conclusions: Our study identified an inverse correlation between anterior cingulate cortex volumes and depressive symptomatology, measured via ZSDS, and between bilateral insulae and anterior cingulate cortex volumes and the degree of distress in response to the traumatic event, measured via the IES-R. Analogous findings have already been reported in patients with Major depression [4] and PTSD [5], and our study confirms the role of volumetric reductions of these brain regions in depressive and post-traumatic symptomatology. Given the nature of our study it is not possible to infer whether the reduction of gray matter volume is a consequence of the Covid-19 infection itself or, as it appears more likely, precede the infection acting as predisposing factor for the subsequent development of depressive and post-traumatic symptomatology. No conflict of interest