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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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Aim/Introduction: The novel coronavirus disease (COVID-19) is caused by the respiratory infection of SARS-CoV-2 virus and is characterized by a multisystemic inflammation, presenting with a wide spectrum of symptoms. 18F-fluoro-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) is a promising imaging method in the evaluation of acute-phase and late changes in the central nervous system. Material(s) and Method(s): A single-centre, prospective clinical study (COMPOSIT study) was initiated where FDG-PET/CT was performed in adult COVID-19 patients during acute, infective state and 3 months later. Brain FDG-PET images were evaluated with a software utilizing a built-in, age-matched normal database and the degree of the differences (Z-scores) were investigated at the two imaging timepoints. Result(s): We present the data of 36 patients (14 women, 22 men), with a mean age of 52 years (42-75 years). In the acute, infective state, the majority of the patients presented with diffuse, significant cortical hypometabolism whereas at 3 months followup, the involved regions showed a marked and often complete metabolic normalization. The most common regions with residual hypometabolism at 3 monts were the medial prefrontal and medial temporal regions and the anterior cingulate. Also, these regions showed the proportionally lowest rates of normalization. Hypometabolism was the least frequent in the cerebellum at the acute, infective state and its FDG-uptake showed a nomalization in all but one case. Conclusion(s): Residual hypometabolism is common in the areas encompassing the orbitofrontal cortex and the limbic system while the cerebellar cortex was relatively spared. However, our study is limited by the corticosteroid-effect in the scans performed at the acute, infective state and furthermore, the fact that no metabolic data is available of the patients before SARS-CoV-2 infection.
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Aim/Introduction: The novel coronavirus disease (COVID-19) is caused by the respiratory infection of SARS-CoV-2 virus and is characterized by a multisystemic inflammation, presenting with a wide spectrum of symptoms. 18F-fluoro-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) is a promising imaging method in the evaluation of acute-phase and late changes in the central nervous system. Material(s) and Method(s): A single-centre, prospective clinical study (COMPOSIT study) was initiated where FDG-PET/CT was performed in adult COVID-19 patients during acute, infective state and 3 months later. Brain FDG-PET images were evaluated with a software utilizing a built-in, age-matched normal database and the degree of the differences (Z-scores) were investigated at the two imaging timepoints. Result(s): We present the data of 36 patients (14 women, 22 men), with a mean age of 52 years (42-75 years). In the acute, infective state, the majority of the patients presented with diffuse, significant cortical hypometabolism whereas at 3 months followup, the involved regions showed a marked and often complete metabolic normalization. The most common regions with residual hypometabolism at 3 monts were the medial prefrontal and medial temporal regions and the anterior cingulate. Also, these regions showed the proportionally lowest rates of normalization. Hypometabolism was the least frequent in the cerebellum at the acute, infective state and its FDG-uptake showed a nomalization in all but one case. Conclusion(s): Residual hypometabolism is common in the areas encompassing the orbitofrontal cortex and the limbic system while the cerebellar cortex was relatively spared. However, our study is limited by the corticosteroid-effect in the scans performed at the acute, infective state and furthermore, the fact that no metabolic data is available of the patients before SARS-CoV-2 infection.
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Background: Neurobiological measures may inform our understanding of individual differences in adolescents' general risk for and resilience to depressive symptoms, including during the COVID-19 pandemic. We tested a developmental model linking variation in amygdala-subgenual anterior cingulate cortex (sgACC) resting-state connectivity to perceived parenting experiences earlier in adolescence, to concurrent depressive symptoms before the pandemic, and to subsequent depressive symptoms during the pandemic. Methods: We used data from a longitudinal study that included three waves (N = 214 adolescents; ages 9-15 years at time 1 [T1], 11-17 years at T2, and 12-19 years during the pandemic at T3). We assessed positive parenting (warm and supportive) (T1), depressive symptoms (T1 to T3), and functional connectivity between the sgACC and basolateral (BLA) and centromedial amygdala (T1 and T2). We modeled associations among earlier positive parenting, amygdala-sgACC connectivity, and depressive symptoms before and during the pandemic. Results: Less positive parenting at T1 was associated prospectively with stronger BLA-sgACC connectivity at T2 (ß = -0.22) over and above the effect of BLA-sgACC connectivity at T1. Stronger BLA-sgACC connectivity, in turn, was associated with heightened depressive symptoms, both before the pandemic (r = 0.21) and during the pandemic (ß = 0.19; independent of the effect of pre-pandemic symptoms). Conclusions: Adolescents who experience less positive parenting may develop a pattern of BLA-sgACC connectivity that increases their risk for mental health problems. BLA-sgACC connectivity may be associated with depressive symptoms in general, including during periods of heightened risk for adolescents, such as the pandemic.
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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.
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Objective: This study investigates the chronic effects of COVID-19 on brain microstructure. Background: Microstructural differences have previously been detected in comparisons of COVID-19 patients with controls, particularly in the insula, cuneus, inferior temporal and anterior cingulate regions. Design/Methods: Here we report diffusion magnetic resonance imaging (3 T Siemens MRI) findings from 20 participants (mean age: 45.3, 55% female), both immediately after recovery and at a 3-month follow-up. Fractional anisotropy (FA), mean diffusivity (MD), mode of diffusivity (MO), free water fraction (F), tissue-specific FA (FAt) and tissue-specific MD (MDt) were obtained using DTI data with b=700 and 1400 (DIPY free-water model). Regions of interest in the grey matter and white matter were delineated using FreeSurfer. To assess differences between baseline and follow-up, a paired t-test, the Wilcoxon Test and Friedman Test were performed, corrected for false-discovery rate of 0.05. Effect size (Cohen's d) was also computed (d>0.45 deemed large effect). Results: All three tests revealed decreased F in the hippocampus and decreased MD in the parahippocampal region of the WM at follow-up. In the GM, F was increased in the medial orbitofrontal region. In the WM, MD was increased in the paracentral region and MDt was increased in the parahippocampal and lateral orbitofrontal regions. Conclusions: These results suggest that microstructural abnormalities persist following recovery. Increased extracellular fluid (i.e. F and MD) in the frontal lobe suggest spreading of COVID-19 impact, while decreased F and MD in the hippocampal region suggest debris accumulation as part of the inflammatory process. None of the regions affected in sub-acute COVID-19 appear to fully recover within three months.
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Background-Aim: A potential link has been investigated between hyposmia after COVID-19 and an increased risk to develop neurological long-term sequelae also in patients who experienced mild or moderate disease. Hyposmia is a common feature PD and parkinsonism has been reported after COVID-19 suggesting a potential link between SARS-CoV2 infection and PD. [18F]FDG PET may represent a suitable tool to capture potential common metabolic signature of hyposmia after COVID-19 and in PD patients. We aimed to evaluate brain metabolic correlates of isolated persistent hyposmia after mild-to-moderate COVID-19 and to compare them with metabolic signature of hyposmia in drug-naive PD patients. Methods: Forty-four patients who experienced hyposmia after SARSCOV2 infection underwent brain [18F]FDG-PET in the first 6 months after recovery. Olfaction was assessed by means of the 16-item ''Sniffin-Sticks'' test and patients were classified as with or without persistent hyposmia (COVID-hyposmia and COVID-no-hyposmia respectively). Brain [18F]FDG-PET of post-COVID subgroups were compared in SPM12. COVID-hyposmia patients were also compared with eighty-two drug-naïve PD patients with hyposmia. Multiple-regression- analysis was used to identify correlations between olfactory test-scores and brain metabolism in patients' subgroups. Results: COVID-hyposmia patients (n = 21) exhibited significant hypometabolism in bilateral gyrus rectus and orbitofrontal cortex with respect to COVID-non-hyposmia (n = 23) (p<0.002) and in middle and superior temporal gyri, medial/middle frontal gyri and right insula with respect to PD-hyposmia (p<0.012). With respect to COVIDhyposmia, PD-hyposmia patients showed hypometabolism in inferior/ middle occipital gyri and cuneus bilaterally. Olfactory test-scores were directly correlated with metabolism in bilateral rectus and medial frontal gyri and in right middle temporal and anterior-cingulate gyri in COVID-hyposmia patients (p<0.006) and with bilateral cuneus/precuneus and left lateral occipital-cortex in PD-hyposmia patients (p<0.004). Conclusions: Metabolic signature of persistent hyposmia after COVID-19 encompasses cortical regions involved in olfactory perception and does not overlap metabolic correlates of hyposmia in PD. An impairment in olfactory judgement seem to underlie hyposmia in PD patients while a more restricted perception deficit seems to explain hyposmia in COVID-19. The potential long term neurological sequelae of COVID-19 are of interest from the clinical and economical point of view. Studies targeting symptoms common to COVID-19 and chronic neurological diseases and aiming to explore potential common pathways are of interest also to avoid unjustified claims about a future high incidence of neurodegenerative diseases secondary to the SARS-CoV-2 pandemic.
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Drug addiction is on the rise during these COVID-19 times that intensify the factors contributing to relapse and overdose across drugs of abuse and continents. Using a multimodal approach (neuropsychology, fMRI, ERP), human neuroimaging studies in my lab have elucidated core mechanisms underlying drug addiction, with a focus on the role of the dopaminergic mesocorticolimbic circuit, especially the prefrontal cortex, in higher-order cognitive and emotional dysfunction in this population. Our theoretical model is called iRISA (Impaired Response Inhibition and Salience Attribution), postulating that abnormalities in the orbitofrontal cortex and anterior cingulate cortex (and other cortical regions underlying higher order executive function), contribute to the core clinical symptoms in addiction. Specifically, our program of research is guided by the working hypothesis that drug addicted individuals disproportionately attribute salience and value to their drug of choice at the expense of other reinforcing stimuli, with a concomitant decrease in the ability to inhibit maladaptive drug use. Our complex and multifaceted dataset has allowed us to study the impact of abstinence on recovery in these brain-behavior compromises in treatment-seeking addicted individuals, where non-linear relationships exemplify incubation of craving while other trajectories of change, including in white matter tracks and for small subcortical regions (such as the habenula), are also explored. Novel paradigm shifts in the lab include the use of naturalistic and dynamic stimuli for enhanced generalizability and validity, in addition to development of effective neurorehabilitation strategies (including cognitive reappraisal, mindfulness, and transcranial direct current stimulation) in drug addiction. Keywords: Neuroimaging, drug addiction
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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