The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has been linked to significant neurological complications, including neuroinflammation. This mini review explores the application of the radiopharmaceutical [18F]DPA-714 in neuroinflammation studies in post-SARS-CoV-2 patients using Positron Emission Tomography - Computed Tomography (PET-CT) imaging technology. [18F]DPA-714, a specific ligand for the translocator protein (TSPO), enables precise visualization and quantification of microglial activation, a key marker of neuroinflammation. Recent studies demonstrate that post-COVID-19 patients exhibit increased uptake of [18F]DPA-714 in various brain regions, correlating with persistent symptoms such as fatigue, cognitive dysfunction, and mood alterations. The application of [18F]DPA-714 in longitudinal studies can monitor the progression of neuroinflammation and evaluate the efficacy of therapeutic interventions, allowing personalized treatment adjustments. Additionally, exploring new TSPO ligands can complement data obtained with [18F]DPA-714, offering a more comprehensive view of neuroinflammatory processes. This article discusses the technical challenges in synthesizing and applying [18F]DPA-714, including the need for standardized imaging protocols and variability in binding due to genetic polymorphisms in TSPO. As a conclusion that [18F]DPA-714 is a valuable tool for research and treatment of neuroinflammation in post-SARS-CoV-2 patients, with significant implications for the development of personalized therapies and clinical monitoring.

This study investigated the long-term neuropsychiatric and neuropsychological impact of COVID-19 on children and their parents in households with COVID-19 exposure.

A prospective cohort study was conducted on 46 families attending the COVID-19 Follow-up Clinic at the Department for Women's and Children's Health, Padua (Italy) from December 2021 to November 2022. Self-perceived stress-related, emotional-behavioral, and post-traumatic stress (PTSD-related) symptoms were assessed in both children and parents. Children with underlying neuropsychiatric conditions were excluded from the study.

A total of 81 parents (median age = 38 years [IQR: 43-48], females = 44 [54.3%]), and 77 children (median age = 8 years [IQR: 5-11], females = 33 [42.9%]) participated in the study. Overall,125 (79%) and 33 (21%) participants were classified as COVID-19 cases and non-COVID-19 cases, respectively. The time interval between the COVID-19 family outbreak and the neuropsychiatric and psychological assessment was ≤4 months (median=3 months [IQR=0]) for 89 (56.3%) participants and >4 months for 69 (43.8%) (median=11.5 months [IQR=5-12]) participants. A total of 136 (86.1%) participants reported stress-related symptoms, with emotional stress being the most common. A positive correlation was observed between self-perceived stress-related symptoms in children and their parents within the same family (r=0.53, p=0.0005). Among children aged 6-18 years, 16 (37.2%) had clinical scores for internalizing symptoms at the Child Behavior Checklist (CBCL), while none children aged 1.5-5 years showed clinical score for internalizing symptoms. Similarly, total difficulty scores at the Strengths and Difficulties Questionnaire (SDQ 4-17) and assessment of PTSD-related symptoms through the Trauma Symptom Checklist for Young Children (TSCYC) questionnaire were within non-clinical cut-offs in 45 (84.9%) and 43 (75.4%) children aged 3-12 years, respectively. The Trauma Symptom Checklist for Children (TSCC) resulted in the non-clinical cut-off for 36 (92.3%) children aged 8-18 years. While a higher prevalence of self-perceived stress-related symptoms was found in COVID-19 cases compared to non-COVID-19 cases (p=.01), no differences were observed for emotional-behavioral and PTSD-related symptoms between the two groups.

This study documented the impact of the COVID-19 pandemic on Italian children and their family's stress levels. Further research is needed to confirm our findings and explore the long-term effects of the pandemic on families.

The long-term neurological effects of COVID-19, such as lack of concentration, loss of memory, and anxiety, present major concerns for COVID-19 Recovered Individuals (CRIs). Our study aims at understanding these long-term COVID-19 symptoms (LCS) and associated risk factors among the Indian cohort. In this two-part study, we analyze self-reported symptom information such as fatigue in different life spheres, symptoms experienced in past months, hospitalization status, and sex of Healthy Controls (HCs) and CRIs. In Study 1, we compare the symptoms of 62 CRIs (16 Females; 30.60   ±   10.34 years) with 36 hCs (11 Females; 27.53   ±   7.3 years). Chi-square analysis revealed that both the groups differ significantly from each other in terms of self-reported major symptoms experienced (MSEs) (p < 0.001) and major life spheres being affected by fatigue (MLSA) (p = 0.008). Further, in Study 2, we explore predictive models for these symptoms as reported by 57 of the CRIs (15 Females; 31.28   ±   10.50 years) using logistic regression and receiver operator characteristic (ROCs) information, with unrefreshing sleep, hospitalization status, and sex as the predictors for LCS. Statistical analysis reveals unrefreshing sleep as an important predictor of attention issues (odds ratio (OR) = 6.25, p = 0.003), anxiety issues (OR = 7.75, p = 0.018), and fatigue (OR = 5.83, p = 0.018) but was found non-significant for memory issues (OR = 1.86, p = 0.513) among CRIs. Hospitalization status and sex were not found to significantly affect these reported symptoms.

The aim of this study was to determine whether there is a relationship between the time since recovery from coronavirus disease 2019 (COVID-19) and alterations in executive functions. We also evaluate the emotional state of post-COVID-19 patients.

We assessed patients between 18 and 50 years old, who had a history of COVID-19 with mild, moderate, or severe illness. We used the Batería Neuropsicológica de Funciones Ejecutivas y Lóbulos Frontales-3 (BANFE-3), Mini-Mental State Examination (MMSE), and Mini-International Neuropsychiatric Interview (MINI), in addition to a semi-structured interview. Spearman's correlation coefficient was used, with a p value <0.05 indicating significance.

We evaluated 67 patients with a mean age of 34.6±9.6 years, most of whom had ≥13 years of schooling (n=55, 82.1%). Among them, 52 (77.6%) reported persistent symptoms after resolution of the condition, with fatigue being the most frequent (n=20, 29.9%). Most participants had an adequate score on the MMSE (n=60, 89.6%). However, 19 (28.4%) showed alterations in the BANFE-3 total score, with mental flexibility as the most affected function (n=25, 37.3%). In participants from the first COVID-19 wave, a negative correlation was observed between the standardized orbitofrontal area scores and the time since recovery from the infection (r=-0.841, p=0.016), suggesting a pattern of deterioration over time, mainly in stimulus inhibition (r=0.880, p=0.021). Regarding emotional state, 45 subjects (67.2%) exhibited emotional alterations, with anxiety symptoms being the most frequent (n=33, 49.3%). Furthermore, individuals with depressive symptoms (n=32, 47.8%) were more likely to experience executive function impairment after COVID-19 (ExpB 0.302, 95% CI 0.098-0.933, p=0.038).

COVID-19 could lead to alterations in executive functions, probably resulting from progressive damage to orbitofrontal area functions, mainly in stimulus inhibition. However, the generalizability of these findings is limited, highlighting the need for further research with robust methodology. Furthermore, depression appears to be an indicator of cognitive impairment in individuals recovering from COVID-19. Therefore, cognitive rehabilitation and psychological support are essential for patients affected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.

This study explores the linkage between acute SARS-CoV-2 and car crashes across U.S. states, correlating with COVID-19 mitigation strategies, vaccination rates, and Long COVID prevalence. This investigation analyzed aggregate COVID-19 and car crash data spanning 2020-2023, with data collection occurring between March and May 2024. Analysis was done via a Poisson regression model, adjusted for population. Key variables included vaccination status, month-specific effects relating to initial pandemic shutdowns, and Long COVID rates. Results demonstrated a significant association between acute COVID-19 infections and an increase in car crashes, independent of Long COVID status to the tune of an OR of 1.25 [1.23-1.26]. This association was observed despite varying mitigation efforts and vaccination rates across states. The study found no protective effect of vaccination against car crashes, challenging prior assumptions about the benefits of vaccination. Notably, the risk associated with COVID-19 was found to be analogous to driving impairments seen with alcohol consumption at legal limits. Findings suggest significant implications for public health policies, especially in assessing the readiness of individuals recovering from COVID-19 to engage in high-risk activities such as pilots or nuclear plant employees. Further research is necessary to establish causation and explore the exact effects of COVID-19 within the CNS affecting cognition and behavior.

COVID-19 disease, caused by the SARS-CoV-2 virus, has significantly altered modern society and lifestyles. We investigated its impact on brain glucose metabolism by meta-analyzing existing studies that utilized 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans of the brain. We conducted a systematic search of MEDLINE and EMBASE databases from inception to August 2024 for English-language publications using the keywords "positron emission tomography", and "COVID-19". We included original research articles that reported changes in brain glucose metabolism following COVID-19 disease. ALE values from these studies were aggregated and tested against a null hypothesis that anticipated a random distribution of ALE values, which proved to be significantly higher than chance. We identified nine papers that met our inclusion criteria. Significant increases in brain glucose metabolism were noted in the left anterior cingulate gyrus, right thalamus, and brainstem. In children with COVID-19 disease, decreased glucose metabolism was observed in the right and left cerebellum, left amygdala/hippocampus, left anterior cingulate gyrus, and right amygdala. In adults with COVID-19 disease, decreased metabolism was seen in the right temporal lobe, brainstem (acute phase), left occipital lobe, left and right temporal lobe (chronic phase). In conclusion, COVID-19 disease impacts brain glucose metabolism, typically manifesting as areas of decreased metabolism in 18F-FDG PET scans, though increases are also observed. These changes in metabolism vary with the patient's age and the time elapsed between the diagnosis of COVID-19 disease and the PET scan.

This study aims to longitudinally investigate the associations between brain 18F-FDG-PET metabolism and neuropsychological assessment (NPA) in initially hospitalized patients with post-COVID-19 conditions (PCCs).

Patients with PCC and confirmed neurological impairment were prospectively included and underwent both brain 18F-FDG-PET and NPA at inclusion and one year later. Brain18F-FDG-PET metabolism was correlated with NPA tests. The identified hypometabolic clusters after quantitative voxel-by-voxel group analyses were correlated with the NPA results.

Twenty-three patients (51.0 ± 9.5 years; 9 women) were included. Brain 18F-FDG-PET metabolism was correlated with the results of the Hamilton Anxiety Rating Scale (HARS), episodic memory, executive function and autonomy tests (p-voxel < 0.005; p-cluster < 0.05 uncorrected). Two cerebellar hypometabolic clusters were found in patients with PCC at inclusion and one year later (n = 16, p-voxel < 0.005; p-cluster < 0.05 corrected). Cerebellar metabolism was associated with an abnormal HARS test at one year (p ≤ 0.04) but not at inclusion. At one year, no brain metabolic recovery and no significant improvement in NPA tests were observed.

Brain 18F-FDG-PET metabolism is associated with the results of neuropsychological tests in initially hospitalized patients with PCC, especially the metabolism of the cerebellum, which was found to be decreased in patients, and symptoms of anxiety experienced by patients. Similarly, brain 18F-FDG-PET hypometabolism and impairment in NPA tests did not significantly improve one year later.

Neurological symptoms often prominent in post-acute sequelae of COVID-19 (PASC) necessitate deeper understanding. Our objective was to investigate brain metabolism in PASC and examine correlations with neurological symptoms during both the acute and chronic stages.

Eighty-seven adults experiencing PASC with neurocognitive symptoms were recruited in the PERSICOR prospective study and examined using brain [ 18 F]FDG PET/CT. Comprehensive clinical variables including neurocognitive symptoms were evaluated. PET images were compared voxel-wise with SPM12 software ( P < 0.05, false discovery rate corrected) and volume-of-interest basis (BrainVisa software) with those of 55 healthy controls recruited before COVID-19 pandemic. We also investigated differences in brain metabolism according to the time interval after acute COVID-19. The correlation between brain metabolism and neurocognitive symptoms was assessed.

Frequently reported neurological symptoms included concentration difficulties (79%) and immediate/working memory impairments (66%). Significant hypometabolism was identified in regions previously identified in PASC: left fusiform gyrus (33% of patients), amygdala (23% on left, 28% on right), parahippocampal area (25% left, 24% right), and vermis (22%). The most substantial metabolism decreases were observed in the pons (5.5% decrease in the whole patient group vs controls) and right amygdala (-4.2%). Concentration and memory impairments correlated with decreased metabolism in prefrontal and mesial/inferior temporal areas, respectively ( P < 0.01 for both). A shorter interval between PET imaging and the acute phase of COVID-19 correlated with reduced glucose metabolism in the brainstem, thalamus, mesiotemporal lobe, frontobasal cortex, and olfactory bulb ( P < 10 -3 ).

This study underscores the links between neurological symptoms and cerebral hypometabolism in specific regions in PASC. These findings illuminate the complex neuropathophysiological mechanisms of PASC and pave the way for potential therapeutic interventions.

Most psychiatric disorders are heterogeneous and are attributed to the synergistic action of a multitude of factors. It is generally accepted that psychiatric disorders are the outcome of interactions between genetic predisposition and environmental perturbations, which involve psychosocial stress, or alterations in the physiological state of the organism. A number of hypotheses have been presented on such environmental influences that may include direct insults such as injury, malnutrition and hostile living conditions, or indirect sequelae following infection from viruses such as influenza, arboviruses, enteroviruses and several herpesviruses, or the differential expression of human endogenous retroviruses. It is known that the concept of viruses is far more extensive than their perception as mere agents of acute infections, or chronic debilitating diseases, such as AIDS or some forms of cancer. Notably, an apparent causal connection between viruses and the pathophysiology of diseases has been suggested; however, it remains unclear as to how to establish this causal connection. There are inherent difficulties in answering this question with certainty, which may be due to the multitude of genetic and environmental influences that can lead to psychopathology; the latent state of chronic infection exhibited by a number of neurotropic viruses; the late onset of psychiatric disorders with respect to the acute phase of viral infection at which detection tests would be successful; the complexity of the virome; and the existence of thousands of viral species. The present review aims to provide an outline of the conclusions that have thus far been reached regarding a possible association between viral infection and psychiatric disease, and the obstacles confronted during the quest for the truth behind the role of viruses.

One lingering effect of the COVID-19 pandemic created by SARS-CoV-2 is the emergence of Long COVID (LC), characterized by enduring neurological sequelae affecting a significant portion of survivors. This review provides a thorough analysis of these neurological disruptions with respect to cognitive dysfunction, which broadly manifest as chronic insomnia, fatigue, mood dysregulation, and cognitive impairments with respect to cognitive dysfunction. Furthermore, we characterize how diagnostic tools such as PET, MRI, EEG, and ultrasonography provide critical insight into subtle neurological anomalies that may mechanistically explain the Long COVID disease phenotype. In this review, we explore the mechanistic hypotheses of these neurological changes, which describe CNS invasion, neuroinflammation, blood-brain barrier disruption, and gut-brain axis dysregulation, along with the novel vascular disruption hypothesis that highlights endothelial dysfunction and hypoperfusion as a core underlying mechanism. We lastly evaluate the clinical treatment landscape, scrutinizing the efficacy of various therapeutic strategies ranging from antivirals to anti-inflammatory agents in mitigating the multifaceted symptoms of LC.

Fatigue has been characterized as a post COVID-19 condition known to persist months after SARS-CoV-2 infection. COVID-19 has been reported to be associated with impaired cognitive function, including disorders in attention, memory, information processing, and executive functions. The objective of this study was to determine if post-COVID fatigue, manifested as tiredness while performing low-intensity physical activity, has a detrimental effect on neuropsychological performance, to achieve this, we randomly selected 20 participants with post-COVID fatigue and 20 SARS-CoV-2 negative age-matched controls from a database of 360 residents of Tijuana, Baja California in a cross-sectional study design. All 40 participants responded to a health survey, along with a neuropsychological assessment test via telephone call. Statistical analysis was performed using a multiple linear regression model including the following independent variables: study condition (post-COVID fatigue or negative control), sex, age, years of education, hypertension, asthma, administration of supplemental oxygen during COVID-19 recovery, and the hour at which the evaluation started. Significant regression analysis was obtained for all global parameters of the assessment, including BANFE-2 score (p = 0.021, R2 Adj. = 0.263), NEUROPSI score (p = 0.008, R2 Adj. = 0.319), and total errors (p = 0.021, R2 Adj. = 0.263), with significant regression coefficients for study condition on two global parameters, BANFE-2 score (p = 0.028, β = - 0.371) and NEUROPSI score (p = 0.010, β = -0.428). These findings suggest that the presence of post-COVID fatigue is a factor associated with a decrease in neuropsychological performance.

Post-COVID syndrome manifests with numerous neurological and cognitive symptoms, the precise origins of which are still not fully understood. As females and older adults are more susceptible to developing this condition, our study aimed to investigate how post-COVID syndrome alters intrinsic brain dynamics in older adults and whether biological sex and cognitive training might modulate these effects, with a specific focus on older females. The participants, aged between 60 and 75 years, were divided into three experimental groups: healthy old female, post-COVID old female and post-COVID old male. They underwent an adaptive task-switching training protocol. We analysed multiscale entropy and spectral power density of resting-state EEG data collected before and after the training to assess neural signal complexity and oscillatory power, respectively. We found no difference between post-COVID females and males before training, indicating that post-COVID similarly affected both sexes. However, cognitive training was effective only in post-COVID females and not in males, by modulating local neural processing capacity. This improvement was further evidenced by comparing healthy and post-COVID females, wherein the latter group showed increased finer timescale entropy (1-30 ms) and higher frequency band power (11-40 Hz) before training, but these differences disappeared following cognitive training. Our results suggest that in older adults with post-COVID syndrome, there is a pronounced shift from more global to local neural processing, potentially contributing to accelerated neural aging in this condition. However, cognitive training seems to offer a promising intervention method for modulating these changes in brain dynamics, especially among females.

The COVID-19 pandemic has taught myriad lessons and left several questions we are yet to comprehend. Initially, the scientific community was concerned with the management of acute disease and immunization. Once the peak of the pandemic receded, it became clear that a proportion of patients were far from fully recovered. Researchers started to recognize those persisting symptoms as a new entity termed 'Long COVID,' where neurological symptoms are evident and have a major impact on quality of life.

The main purpose of this narrative review is to analyze and synthesize the current literature regarding Long COVID, its relation to the nervous system, and to explore the evidence on treatments for persistent neurological symptoms. The most common reported and observed neurologic manifestations include fatigue, cognitive impairment, pain, polyneuropathy, and neuropsychiatric disorders. A variety of pharmacologic and non-pharmacologic therapies have been evaluated and yielded mixed results. Many of them focused on immunomodulation and none currently have U.S. FDA approval.

Challenges remain in terms of clinical characterization and prognosis of Long COVID, besides understanding its pathophysiology. Standardization of biomarkers and diagnostic criteria will allow the use of common nomenclature and data elements in the design of future clinical studies.

Autonomic dysfunction is a well-recognized complication associated with post-COVID-19 syndrome (PCS). ANS maladaptation could underlie a potential pathogenetic mechanism of PCS, contributing to PCS symptoms. However, there remains an ongoing debate regarding whether autonomic and neuropathic symptoms observed in PCS patients are indicative of central or peripheral ANS pathology. The purpose of this study is to investigate both the central and peripheral nervous systems of ANS in patients with PCS.

We evaluated the integrity of the peripheral ANS using sympathetic skin response (SSR) and examined the central ANS using functional near-infrared spectroscopy (fNIRS) covering the fronto-parietal cortex in PCS patients (n = 7) and matched healthy controls (n = 7). Functional connectivity, topological parameters of fNIRS brain network were analyzed. To compare the SSR and fNIRS parameters between patients and age-matched healthy controls, Mann-Whitney U tests were performed for each parameter separately. The AUC of each topological metric of fNIRS network was utilized as a statistical scalar for comparison. To characterize the correlation between SSR and significantly different topological metrics of fNIRS network, Spearman correlation analysis was performed.

The latencies of palmar SSR were significantly prolonged in the patients with PCS than the controls (p < 0.05). 34 functional connections showed a significant increase (p < 0.05, uncorrected). Regional nodal properties revealed that the fronto-parietal networks of PCS patients had a higher degree in primary somatosensory cortex (S1) (p < 0.001, corrected) and motor cortex, a lower node efficiency in dorsolateral prefrontal cortex (DLPFC), and a higher efficiency in S1 (p < 0.05, uncorrected). Latencies of palmar SSR were significantly positively correlated with zFC within sensorimotor cortex, and node efficiency/degree of S1 (p < 0.01). Amplitudes of palmar and plantar SSR were significantly positively correlated with node efficiency of DLPFC (p < 0.05).

Our findings suggest that there were alternations in both central and peripheral parts of ANS in PCS patients. These preliminary results indicate that PCS may lead to changes in both the peripheral and central aspects of ANS, which would help to extend the understanding of the role of the ANS in PCS, offering new perspectives on evaluation and treatment.

This study has been registered with the Chinese Clinical Trial Registration Center (registration number: ChiCTR2200064342; registration date:2022/10/3).

Disturbed sleep is prevalent after corona virus disease (COVID-19). However, little is known of post infectious prevalence, course, predictors and treatment of chronic insomnia.

To estimate the prevalence of chronic insomnia three and twelve months after hospitalisation for COVID-19, to identify predictors of chronic insomnia, and to evaluate the feasibility of a nurse-administered digital cognitive behavioural therapy for insomnia (dCBTi) protocol.

Patients hospitalised at Akershus University Hospital (Norway) for COVID-19 between February-June 2020 were eligible. The 94 patients that consented to participate were contacted by phone and interviewed with a modified DUKE structured interview three- and twelve months after discharge. Participants with chronic insomnia after twelve months were offered a nurse-administered dCBTi treatment protocol. Outcome measurements were sleep efficiency (SE) calculated by standard formulas (0-100 %) and the Bergen Insomnia Scale (BIS) (0-42).

At three-month follow-up, 22 persons (23 %) fulfilled the diagnostic criteria for chronic insomnia. At twelve-month follow-up, 23 fulfilled the diagnostic criteria. The odds ratios for chronic insomnia after twelve months were 0.857 (0.742-0.989) for body mass index (BMI), and 0.239 (0.069-0.821) for male sex. Ten participated in the dCBTi feasibility study. Five completed the treatment protocol. SE improved, but not significantly. The BIS score improved significantly from 24 to 12 (p-value = 0.036).

Chronic insomnia remained stable three- and twelve months post COVID-19 hospitalisation. Female sex and low BMI were independent predictors of chronic insomnia twelve months post infection, but only 50 % of participants completed the protocol. Completers significantly reduced insomnia symptoms.

The coronavirus disease 2019 (COVID-19) pandemic has led to a variety of health challenges, with "long COVID" emerging as a widespread and debilitating post-acute syndrome among a considerable number of infected patients. This PET review synthesizes current evidence of the neurologic and psychiatric sequelae of COVID. This review also explores the pathophysiological mechanisms of these results, including astrocyte dysfunction and glutamate dysregulation, as well as the multimodal comparison to MR imaging findings. The findings underscore the potential for long-term brain injury. Additionally, the authors discuss the role of advanced imaging multimodal techniques in diagnosing, monitoring, and guiding treatment strategies for long COVID.

COVID infection has been associated with long term sequalae (Long COVID) which include neurological and behavioral effects in thousands of patients, but the etiology and scope of symptoms is not well understood. This paper reviews long term sequelae of COVID on brain and mental health in patients with the Long COVID syndrome.

This was a literature review which queried databases for Pubmed, Psychinfo, and Medline for the following topics for January 1, 2020-July 15, 2023: Long COVID, PASC, brain, brain imaging, neurological, neurobiology, mental health, anxiety, depression.

Tens of thousands of patients have developed Long COVID, with the most common neurobehavioral symptoms anosmia (loss of smell) and fatigue. Anxiety and mood disorders are elevated and seen in about 25% of Long COVID patients. Neuropsychological testing studies show a correlation between symptom severity and cognitive dysfunction, while brain imaging studies show global decreases in gray matter and alterations in olfactory and other brain areas.

Studies to date show an increase in neurobehavioral disturbances in patients with Long COVID. Future research is needed to determine mechanisms.

Post-intensive care syndrome (PICS) encompasses persistent physical, psychological, and cognitive impairments. The coronavirus disease of 2019 (COVID-19) pandemic highlighted parallels between PICS and "long COVID". There is an overlap between the 2 in risk factors, symptoms, and pathophysiology. Physical impairments in both include weakness and fatigue. Cognitive impairments include executive dysfunction in PICS and "brain fog" in long COVID. Mental health issues consist of depression, anxiety, and posttraumatic stress disorder in both disease states. Long COVID and PICS impact families, with multifaceted effects on physical health, mental well-being, and socioeconomic stability. Understanding these syndromes is crucial for comprehensive patient care and family support.

Although the impact of post-acute COVID-19 syndrome (PACS) on patients and public health is undeniably significant, its etiology remains largely unclear. Much research has been conducted on the pathophysiology, shedding light on various aspects; however, due to the multitude of symptoms and clinical conditions that directly or indirectly define PACS, it is challenging to establish definitive causations. In this exploration, through systematically reviewing the latest pathophysiological findings related to the neurological symptoms of the syndrome, we aim to examine how psychosocial and neuropsychological symptoms may overlap with neurological ones, and how they may not only serve as risk factors but also contribute to the persistence of some primary symptoms of the disorder. Findings from our synthesis suggest that psychological and psychosocial factors, such as anxiety, depression, and loneliness, may interact with neurological symptoms in a self-reinforcing feedback loop. This cycle seems to be affecting both physical and psychological distress, potentially increasing the persistence and severity of PACS symptoms. By pointing out this interaction, in this review study, we attempt to offer a new perspective on the interconnected nature of psychological, psychosocial, and neurological factors, emphasizing the importance of integrated treatment approaches to disrupt this cycle and improve outcomes when possible.

This review investigates the therapeutic potential of vagal nerve stimulation (VNS) in managing long COVID, a condition marked by persistent symptoms following acute SARS-CoV-2 infection. Long COVID manifests as ongoing fatigue, cognitive impairment, and autonomic dysfunction, hypothesized to arise from sustained inflammatory and neurological dysregulation. The vagus nerve, central to modulating systemic inflammation and autonomic homeostasis, represents a promising therapeutic target for symptom alleviation through VNS. A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science to identify studies evaluating VNS in the context of long COVID. Preliminary evidence from small-scale pilot studies suggests VNS may attenuate systemic inflammation through activation of the cholinergic anti-inflammatory pathway (CAP), thus restoring autonomic balance and ameliorating symptoms such as fatigue, cognitive dysfunction, and anxiety. In targeting the inflammatory cascade that underlies both acute COVID-19 pathophysiology and its prolonged sequelae, VNS holds potential as an innovative intervention for persistent post-viral symptoms. While these initial findings indicate promise, current data remain limited in scope and robustness, underscoring the need for larger, controlled trials to validate the efficacy and mechanisms of VNS in long COVID management. Establishing a clearer understanding of VNS's impact on inflammation and autonomic regulation in this context is crucial to inform clinical guidelines and therapeutic strategies for long COVID, potentially offering a targeted approach for mitigating this disabling condition.

Post-acute sequelae of COVID-19 can present as multi-organ pathology, with neuropsychiatric symptoms being the most common symptom complex, characterizing long COVID as a syndrome with a significant disease burden for affected individuals. Several typical symptoms of long COVID, such as fatigue, depressive symptoms and cognitive impairment, are also key features of other psychiatric disorders such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and major depressive disorder (MDD). However, clinically successful treatment strategies are still lacking and are often inspired by treatment options for diseases with similar clinical presentations, such as ME/CFS. Acetylcarnitine, the shortest metabolite of a class of fatty acid metabolites called acylcarnitines and one of the most abundant blood metabolites in humans can be used as a dietary/nutritional supplement with proven clinical efficacy in the treatment of MDD, ME/CFS and other neuropsychiatric disorders. Basic research in recent decades has established acylcarnitines in general, and acetylcarnitine in particular, as important regulators and indicators of mitochondrial function and other physiological processes such as neuroinflammation and energy production pathways. In this review, we will compare the clinical basis of neuropsychiatric long COVID with other fatigue-associated diseases. We will also review common molecular disease mechanisms associated with altered acetylcarnitine metabolism and the potential of acetylcarnitine to interfere with these as a therapeutic agent. Finally, we will review the current evidence for acetylcarnitine as a supplement in the treatment of fatigue-associated diseases and propose future research strategies to investigate the potential of acetylcarnitine as a treatment option for long COVID.

This perspective paper explores the untapped potential of artificial intelligence (AI), particularly machine learning-based dimension reduction techniques in multimodal neuroimaging analysis of Long COVID fatigue. The complexity and high dimensionality of neuroimaging data from modalities such as positron emission tomography (PET) and magnetic resonance imaging (MRI) pose significant analytical challenges. Deep neural networks and other machine learning approaches offer powerful tools for managing this complexity and extracting meaningful patterns. The paper discusses current challenges in neuroimaging data analysis, reviews state-of-the-art AI approaches for dimension reduction and multimodal integration, and examines their potential applications in Long COVID research. Key areas of focus include the development of AI-based biomarkers, AI-informed treatment strategies, and personalized medicine approaches. The authors argue that AI-driven multimodal neuroimaging analysis represents a paradigm shift in studying complex brain disorders like Long COVID. While acknowledging technical and ethical challenges, the paper emphasizes the potential of these advanced techniques to uncover new insights into the condition, which might lead to improved diagnostic and therapeutic strategies for those affected by Long COVID fatigue. The broader implications for understanding and treating other complex neurological and psychiatric conditions are also discussed.

COVID-19, caused by SARS-CoV-2, presents diverse symptoms, including neurological manifestations. This study investigated COVID-19's neurological sequelae, focusing on the central nervous system's involvement through cerebral glycolytic metabolism assessed via PET/CT. Twenty-two patients with mild long COVID cognitive symptoms and 20 healthy volunteers without cognitive, psychiatric, or neurological impairments and no history of COVID-19 infection underwent cerebral PET/CT scans using [18F]FDG to assess cerebral metabolism. The study meticulously evaluated the uptake of [18F]FDG in various brain regions, employing the CortexID Suite software for quantitative analysis. The analysis focused on identifying areas of hypometabolism and hypermetabolism, indicative of altered glucose metabolism possibly related to COVID-19's neurological impact. No statistically significant differences were found between the mild COVID and healthy groups. Although our sample was too small to generate a statistical difference between groups, future studies should explore some findings, such as hypometabolism in 15 regions and hypermetabolism in 11 regions in the mild COVID group. These changes, especially in areas linked to executive functions, sensory perception, and emotional regulation, suggest nuanced alterations in brain function. Our study did not find significant glycolytic metabolic changes in patients with mild long COVID. However, areas of glycolytic hypometabolism and hypermetabolism found in some patients showed biological plausibility with the cognitive and affective symptoms they presented. Future investigations with a larger sample size should be correlated with neuropsychological and neuropsychiatric examinations to confirm this relationship.

Long COVID is a condition characterised by persistent symptoms after a SARS-CoV-2 infection, with neurological manifestations being particularly frequent. Existing research suggests that long COVID patients not only report cognitive symptoms but also exhibit measurable cognitive impairment. Neuroimaging studies have identified structural alterations in brain regions linked to cognitive functions. However, most of these studies have focused on patients within months of their initial infection. This study aims to explore the longer-term cognitive effects and brain structural changes in long COVID patients, approximately two years post-infection, in a cohort from San Martín, Buenos Aires, Argentina.

We conducted a cross-sectional study involving 137 participants: 109 with long COVID symptoms and 28 healthy controls. The participants underwent an initial clinical assessment, completed a structured questionnaire and standardised scales, underwent a cognitive assessment, and had a brain MRI scan. Structural MRI images were processed via FreeSurfer and FSL to obtain volumetric measures for subcortical and cortical regions, along with regional cortical thickness. Differences between groups for these variables were analysed using ANCOVA, with permutation tests applied to correct for multiple comparisons.

Long COVID patients reported persistent cognitive symptoms such as memory problems and brain fog, with higher levels of fatigue and reduced quality of life compared to controls. Despite subjective cognitive complaints, cognitive tests did not reveal significant differences between groups, except for the TMT-A (p = 0.05). MRI analysis revealed decreased volume in the cerebellum (p = 0.03), lingual gyrus (p = 0.04), and inferior parietal regions (p = 0.03), and reduced cortical thickness in several areas, including the left and right postcentral gyri (p = 0.02, p = 0.03) and precuneus (p = 0.01, p = 0.02).

This study highlights the enduring impact of long COVID on quality of life and physical activity, with specific brain structural changes identified two years post-infection. Although cognitive tests did not show clear impairment, the observed brain atrophy and significant reduction in quality of life emphasize the need for comprehensive interventions and further longitudinal studies to understand the long-term effects of long COVID on cognition and brain health.

Following the Omicron wave in early 2022, an estimated 60-70% of the French population was infected with the SARS-CoV-2 virus. One out of ten infected subjects could have persistent symptoms three months after infection, representing a public health challenge.

The persistent symptoms may be secondary to diverse entities with distinct mechanisms. While organic infection sequelae occur mainly after severe COVID-19, some symptoms appear to be essentially psychological in origin; in addition, many subjects present stereotyped symptoms of fluctuating intensity with no identified anatomical or psychic substratum, often in the aftermath of a benign infection. The most frequent complaints are fatigue, pain, dyspnea and difficulty concentrating.

The hypotheses explored to explain these symptoms include: persistent immune dysfunction, inducted autoimmunity, and microbiome disturbances. Persistent viral antigens may lie at the crossroads of these mechanisms. To date, these different etiological avenues have yet to lead to the development of diagnostic tests or specific therapeutic strategies.

Prolonged symptoms after COVID-19 correspond to heterogeneous nosological entities with poorly understood mechanisms.

Neurologic complications of long COVID-19 syndrome are one of the leading causes of global disability. In particular, post-COVID-19 cognitive dysfunction and dysautonomia in the form of postural orthostatic tachycardia syndrome (POTS) markedly affect patient quality of life and ability to return to work. The underlying pathophysiology of post-COVID-19 neurologic complications is unknown but is likely multifactorial with immune dysregulation and microvascular dysfunction playing central roles. Specific pathogenic factors with supportive evidence to date include cytokine-mediated inflammation, autoantibodies, immune exhaustion, disruption of the renin-angiotensin system, reduced serotonin levels, and microglial activation. The prevalence of post-COVID-19 cognitive dysfunction ranges from 10% to 88% and is affected by viral variant and hospitalization status among other factors, whereas that of long COVID-19 POTS is unknown due to referral bias and varying definitions. Treatment is largely supportive and often incorporates combined modalities. Marginal benefits with cognitive behavioral therapy, hyperbaric oxygen therapy, and supplements have been found for post-COVID-19 brain fog, whereas established POTS therapies aimed at improving venous return and reducing heart rate may reduce symptoms of long COVID-19 POTS. Although significant recovery has been noted for many cases of post-COVID-19 brain fog and POTS, prospective studies have revealed evidence of persistent symptoms and neurologic deficits a year after infection in some patients. Further studies that provide insight into the underlying pathophysiology of long COVID-19 are needed for development of target directed therapy.

Long-COVID is a multisystem disease characterized by a varied presentation of symptoms. According to most recent research, the most common symptom of long-COVID is fatigue, which up to this date lacks a universally accepted definition. This study aimed to investigate neurocognitive and physical manifestations of neurological long-COVID, particularly fatigue and its relation with autonomic disfunction, cognitive impairment (known as, brain fog), and depressive symptoms. Furthermore, the study provided insights into predictors of fatigue in long-COVID.

The included patients (n=141) were referred to the neuro-long-COVID ambulatory service of Trieste from 30 September 2021-02 March 2022. Patients were given self-reporting questionnaires to screen for fatigue, autonomic dysfunction, cognitive impairment and depressive symptoms. The questionnaires adopted for these conditions to be assessed were Fatigue Severity Scale (FSS), COMPASS-31, Prospective-Retrospective Memory Questionnaire (PRMQ), and Beck Depression Inventory (BDI). Participants were divided into two groups, fatigued and non-fatigued patients, based on FSS scoring (scores > 4.67 indicate fatigued patients). The questionnaire scores of the two groups were then compared.

Fatigued patients had significantly higher scores in COMPASS (p<0.001, Cohen's d=1.077), BDI (p<0.001, Cohen's d=0.862), and PRMQ ( p<0.001, Cohen's d=1.159). Furthermore, the multivariate regression analysis showed that predictors of fatigue in long-COVID were symptomatological burden in acute infection (OR=1.38, 95 % CI 1.020-1.887, p=0.037) and in long-COVID (OR=1.78, 95 % CI 1.133-2.2824, p=0.013), COMPASS-31>16 (OR=3.44, 95 % CI 1240-9.560, p=0.018) and BDI>15 (OR=5.1, 95 % CI 1.715-15.164, p=0.003).

This study showed associations between fatigue, dysautonomia and depression, as well as with symptom burden in acute and long-COVID.

PREAMBLEThe Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote the science, technology, and practical application of nuclear medicine. The European Association of Nuclear Medicine (EANM) is a professional nonprofit medical association that facilitates communication worldwide between individuals pursuing clinical and research excellence in nuclear medicine. The EANM was founded in 1985. The EANM was founded in 1985. SNMMI and EANM members are physicians, technologists, and scientists specializing in the research and practice of nuclear medicine.The SNMMI and EANM will periodically define new guidelines for nuclear medicine practice to help advance the science of nuclear medicine and to improve the quality of service to patients throughout the world. Existing practice guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated.Each practice guideline, representing a policy statement by the SNMMI/EANM, has undergone a thorough consensus process in which it has been subjected to extensive review. The SNMMI and EANM recognize that the safe and effective use of diagnostic nuclear medicine imaging requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guideline by those entities not providing these services is not authorized.These guidelines are an educational tool designed to assist practitioners in providing appropriate care for patients. They are not inflexible rules or requirements of practice and are not intended, nor should they be used, to establish a legal standard of care. For these reasons and those set forth below, both the SNMMI and the EANM caution against the use of these guidelines in litigation in which the clinical decisions of a practitioner are called into question.The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by the physician or medical physicist in light of all the circumstances presented. Thus, there is no implication that an approach differing from the guidelines, standing alone, is below the standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology subsequent to publication of the guidelines.The practice of medicine includes both the art and the science of the prevention, diagnosis, alleviation, and treatment of disease. The variety and complexity of human conditions make it impossible to always reach the most appropriate diagnosis or to predict with certainty a particular response to treatment.Therefore, it should be recognized that adherence to these guidelines will not ensure an accurate diagnosis or a successful outcome. All that should be expected is that the practitioner will follow a reasonable course of action based on current knowledge, available resources, and the needs of the patient to deliver effective and safe medical care. The sole purpose of these guidelines is to assist practitioners in achieving this objective.

Many COVID-19 survivors still experience long-term effects of an acute infection, most often characterised by neurological, cognitive and psychiatric sequelae. The treatment of this condition is challenging, and many hypotheses have been proposed. Non-invasive vagus nerve stimulation using slow-paced breathing (SPB) could stimulate both central nervous system areas and parasympathetic autonomic pathways, leading to neuromodulation and a reduction in inflammation. The aim of the present study was to evaluate physical, cognitive, emotional symptoms, executive functions and autonomic cardiac modulation after one month of at-home slow breathing intervention.

6655 healthcare workers (HCWs) were contacted via a company email in November 2022, of which N = 58 HCWs were enrolled as long COVID (cases) and N = 53 HCWs as controls. A baseline comparison of the two groups was performed. Subsequently each case was instructed on how to perform a resonant SPB using visual heart rate variability (HRV) biofeedback. They were then given a mobile video tutorial breathing protocol and asked to perform it three times a day (morning, early afternoon and before sleep). N = 33 cases completed the FU. At T0 and T1, each subject underwent COVID-related, psychosomatic and dysfunctional breathing questionnaires coupled with heart rate variability and manual dexterity assessments.

After one month of home intervention, an overall improvement in long-COVID symptoms was observed: confusion/cognitive impairment, chest pain, asthenia, headache and dizziness decreased significantly, while only a small increase in manual dexterity was found, and no relevant changes in cardiac parasympathetic modulation were observed.

Coronavirus disease 2019 (COVID-19) has been associated with brain functional, structural, and cognitive changes that persist months after infection. Most studies of the neurologic outcomes related to COVID-19 focus on severe infection and aging populations. Here, we investigated the neural activities underlying COVID-19 related outcomes in a case-control study of mildly infected youth enrolled in a longitudinal study in Lombardy, Italy, a global hotspot of COVID-19. All participants (13 cases, 27 controls, mean age 24 years) completed resting-state functional (fMRI), structural MRI, cognitive assessments (CANTAB spatial working memory) at baseline (pre-COVID) and follow-up (post-COVID). Using graph theory eigenvector centrality (EC) and data-driven statistical methods, we examined differences in ECdelta (i.e., the difference in EC values pre- and post-COVID-19) and Volumetricdelta (i.e., the difference in cortical volume of cortical and subcortical areas pre- and post-COVID) between COVID-19 cases and controls. We found that ECdelta significantly between COVID-19 and healthy participants in five brain regions; right intracalcarine cortex, right lingual gyrus, left hippocampus, left amygdala, left frontal orbital cortex. The left hippocampus showed a significant decrease in Volumetricdelta between groups (p = 0.041). The reduced ECdelta in the left amygdala associated with COVID-19 status mediated the association between COVID-19 and disrupted spatial working memory. Our results show persistent structural, functional and cognitive brain changes in key brain areas associated with olfaction and cognition. These results may guide treatment efforts to assess the longevity, reversibility and impact of the observed brain and cognitive changes following COVID-19.

The Coronavirus disease 2019 (COVID-19), an illness caused by a SARS-CoV-2 viral infection, has been associated with neurological and neuropsychiatric disorders, revealing its impact beyond the respiratory system. Most related research involved individuals with post-acute or persistent symptoms of COVID-19, also referred to as long COVID or Post-Acute Sequelae of COVID-19 (PASC). In this longitudinal unique report, we aimed to describe the acute supraspinal and corticospinal changes and functional alterations induced by a COVID-19 infection using neuroimaging, neurophysiological and clinical assessment of a participant during acute infection, as compared to three other visits where the participant had no COVID-19. The results favor a multisystem impairment, impacting cortical activity, functional connectivity, and corticospinal excitability, as well as motor and cardiovascular function. The report suggests pathophysiological alteration and impairment already present at the acute stage, that if resolved tend to lead to a full clinical recovery. Such results could be also insightful into PASC symptomatology.

Severe acute respiratory syndrome coronavirus 2 infection often involves the nervous system, leading to cognitive dysfunctions, fatigue and many other neurological signs that are becoming increasingly recognized. Despite mild forms of the disease accounting for most cases worldwide, research on the pathophysiology driving mild coronavirus disease 2019 (COVID-19) has received little attention. In this respect, recent evidence has pointed out that around 30-40% of non-critical, mild-to-moderate severity COVID-19 survivors may display cognitive disturbances several months post-illness. Hence, the impact of COVID-19 on the brain structure and function, through potential neuropathological mechanisms underpinning cognitive alterations in post-mild COVID-19 infections, remains largely unexplored. This retrospective multicentre observational cohort study, entirely based on a healthcare worker sample (n = 65; 55% females, aged 21-61), investigated the cognitive status and the structural and functional brain integrity among non-hospitalized individuals who developed mild COVID-19 symptoms during the occurrence of severe acute respiratory syndrome coronavirus 2 variants Alpha to Delta, compared with healthy controls tested before the pandemic onset. All evaluations were performed at an average of 9-month follow-up post-infection period. Participants completed a comprehensive neuropsychological assessment and structural and functional MRI exams. Radiological inspection sought to detect the presence of white matter hyperintensities on axial fluid-attenuated inversion recovery images. Global and regional grey matter integrity assessment, analysing changes in grey matter volumes and cortical thinning, and functional connectivity alterations of resting-state brain networks were also conducted. Regression analyses tested the relationships between the presence of specific cognitive impairments and potential structural and functional brain findings. Our results revealed that clinical, cognitive screening and neuropsychological examinations were average between both groups, except for specific impairments related to executive functions in the mild COVID-19. Compared to healthy controls, mild COVID-19 subjects exhibited increased juxtacortical white matter hyperintensities, thalamic and occipital volume loss and diminished resting-state functional connectivity involving the left precuneus and cuneus in default-mode network and affecting the right angular gyrus and left precuneus in the dorsal attentional network. Reduced thalamic volume was the only variable selected in the final model explaining the observed executive function impairment in mild COVID-19. The presence of cognitive, structural and functional brain abnormalities over time suggests that the action of widespread neurovascular and inflammatory phenomena on the nervous system might also occur in mild forms following COVID-19 infection rather than permanent brain damage linked to the direct or indirect action of the virus. Our findings emphasize the need to pay attention to the long-term brain-related consequences of mild COVID-19 infections during the original stream.

The COVID-19 pandemic has led to millions of confirmed cases worldwide, resulting in numerous deaths and hospitalizations. Long-term symptoms after infection or vaccination, known as Post-acute COVID-19 Syndrome (PACS) or Post-acute COVID-19 Vaccination Syndrome (PACVS), present a challenge for the healthcare system. Among the various neurological symptoms, cognitive impairments are frequently observed in PACS/PACVS patients. This study aimed to understand cognitive deficits in PACS/PACVS patients and evaluated potential treatment options, including phosphatidylcholine and computer-assisted cognitive training (CCT).

The Neuro-COVID Outpatient Clinic at Evangelic Hospital Vienna evaluated n = 29 PACS/PACVS patients from May 2023 to October 2023. Enrolled patients were divided into three therapy schemes: Group A received phosphatidylcholine, B received phosphatidylcholine plus access to a computer-assisted cognitive training program, and C (divided into two subgroups) served as a control group. Cognitive impairments were evaluated in multiple assessments (initial and during therapy) using the COGBAT test. Simultaneously, an assessment of the quality of life was conducted using the WHOQOL-BREF.

Primary cognitive impairments, especially attentional deficits were notably evident compared to the general population. While all treatment groups showed cognitive improvement (significant or with a positive trend, but without reaching the level of statistical significance) after therapy, no significant interaction was found between assessment time points and treatment schemes for overall cognitive performance, attention, memory, and executive functions, suggesting consistency across the groups. The WHOQOL-BREF primarily demonstrated deficits in the domains of physical health and psychological well-being.

This study examined the impact of PACS/PACVS on cognitive performance and evaluated phosphatidylcholine and CCT as potential treatment options. Patients with PACS/PACVS showed notable cognitive deficits, especially in the domain attention. While the effectiveness of phosphatidylcholine and CCT in treating cognitive deficits was inconclusive, the study indicated the possibility of spontaneous remission of cognitive deficits in PACS/PACVS.

The actual role of coronavirus disease 2019 (COVID-19) in brain damage has been increasingly reported, necessitating a meta-analysis to collate and summarize the inconsistent findings from functional imaging and voxel-based morphometry (VBM) studies. A comprehensive voxel-wise meta-analysis of the whole brain was conducted to identify alterations in functional activity and gray matter volume (GMV) between COVID-19 patients and healthy controls (HCs) by using Seed-based d Mapping software. We included 15 functional imaging studies (484 patients with COVID-19, 534 HCs) and 9 VBM studies (449 patients with COVID-19, 388 HCs) in the analysis. Overall, patients with COVID-19 exhibited decreased functional activity in the right superior temporal gyrus (STG) (extending to the right middle and inferior temporal gyrus, insula, and temporal pole [TP]), left insula, right orbitofrontal cortex (OFC) (extending to the right olfactory cortex), and left cerebellum compared to HCs. For VBM, patients with COVID-19, relative to HCs, showed decreased GMV in the bilateral anterior cingulate cortex/medial prefrontal cortex (extending to the bilateral OFC), and left cerebellum, and increased GMV in the bilateral amygdala (extending to the bilateral hippocampus, STG, TP, MTG, and right striatum). Moreover, overlapping analysis revealed that patients with COVID-19 exhibited both decreased functional activity and increased GMV in the right TP (extending to the right STG). The multimodal meta-analysis suggests that brain changes of function and structure in the temporal lobe, OFC and cerebellum, and functional or structural alterations in the insula and the limbic system in COVID-19. These findings contribute to a better understanding of the pathophysiology of brain alterations in COVID-19. SIGNIFICANCE STATEMENT: This first large-scale multimodal meta-analysis collates existing neuroimaging studies and provides voxel-wise functional and structural whole-brain abnormalities in COVID-19. Findings of this meta-analysis provide valuable insights into the dynamic brain changes (from infection to recovery) and offer further explanations for the pathophysiological basis of brain alterations in COVID-19.

Dysfunction of cerebral microcirculation due to SARS-CoV-2 infection has been postulated to be a plausible mechanism for the neurological symptoms of post-COVID-19 conditions (neuro-PCC), affecting oxygen homeostasis in the brain. In this study, we aimed to investigate the balance between cerebral oxygen delivery and consumption, measured by oxygen extraction fraction (OEF), in patients with neuro-PCC.

25 participants with neuro-PCC (8 previously hospitalized and 17 not hospitalized) and 59 age-matched healthy controls were studied. Global OEF was quantified using TRUST MRI and compared across the three groups. Associations between OEF and neurobehavioral measures were also evaluated in participants with neuro-PCC.

OEF was significantly different (one-way ANCOVA-p=0.046) among the three groups, after accounting for age and sex. On post-hoc analyses, previously hospitalized neuro-PCC participants had significantly higher OEF (42.40 ± 5.40 %) than both uninfected controls (37.70 ± 5.09 %, p=0.032) and neuro-PCC participants without hospitalization (37.02 ± 5.05 %, p=0.015). Within the participants with neuro-PCC, OEF was significantly associated with locomotor function assessed with the 4-m walk gait speed score (β=-0.03, r=0.34, p=0.003).

Participants with neuro-PCC had altered cerebral OEF, which is also associated with slower locomotion. OEF is a promising marker for studying neuro-PCC.

This study compared brain glucose metabolism using FDG-PET in the caudate nucleus, putamen, globus pallidus, thalamus, and dorsolateral prefrontal cortex (DLPFC) among patients with Long COVID, patients with fatigue, people with multiple sclerosis (PwMS) patients with fatigue, and COVID recovered controls. PwMS exhibited greater hypometabolism compared to long COVID patients with fatigue and the COVID recovered control group in all studied brain areas except the globus pallidus (effect size range 0.7-1.5). The results showed no significant differences in glucose metabolism between patients with Long COVID and the COVID recovered control group in these regions. These findings suggest that long COVID fatigue may involve non-CNS systems, neurotransmitter imbalances, or psychological factors not captured by FDG-PET, while MS-related fatigue is associated with more severe frontal-striatal circuit dysfunction due to demyelination and neurodegeneration. Symmetrical standardized uptake values (SUVs) between hemispheres in all groups imply that fatigue in these conditions may be related to global or network-level alterations rather than hemisphere-specific changes. Future studies should employ fine-grained analysis methods, explore other brain regions, and control for confounding factors to better understand the pathophysiology of fatigue in MS and long COVID. Longitudinal studies tracking brain glucose metabolism in patients with Long COVID could provide insights into the evolution of metabolic patterns as the condition progresses.

Observational studies have suggested that SARS-CoV-2 infection increases the risk of neurological diseases, but it remains unclear whether the association is causal. The present study aims to evaluate the causal relationships between SARS-CoV-2 infections and neurological diseases and analyzes the potential routes of SARS-CoV-2 entry at the cellular level. We performed Mendelian randomization (MR) analysis with CAUSE method to investigate causal relationship of SARS-CoV-2 infections with neurological diseases. Then, we conducted single-cell RNA sequencing (scRNA-seq) analysis to obtain evidence of potential neuroinvasion routes by measuring SARS-CoV-2 receptor expression in specific cell subtypes. Fast gene set enrichment analysis (fGSEA) was further performed to assess the pathogenesis of related diseases. The results showed that the COVID-19 is causally associated with manic (delta_elpd, - 0.1300, Z-score: - 2.4; P = 0.0082) and epilepsy (delta_elpd: - 2.20, Z-score: - 1.80; P = 0.038). However, no significant effects were observed for COVID-19 on other traits. Moreover, there are 23 cell subtypes identified through the scRNA-seq transcriptomics data of epilepsy, and SARS-CoV-2 receptor TTYH2 was found to be specifically expressed in oligodendrocyte and astrocyte cell subtypes. Furthermore, fGSEA analysis showed that the cell subtypes with receptor-specific expression was related to methylation of lysine 27 on histone H3 (H3K27ME3), neuronal system, aging brain, neurogenesis, and neuron projection. In summary, this study shows causal links between SARS-CoV-2 infections and neurological disorders such as epilepsy and manic, supported by MR and scRNA-seq analysis. These results should be considered in further studies and public health measures on COVID-19 and neurological diseases.

Persistent fatigue is a major symptom of the so-called 'long-COVID syndrome', but the pathophysiological processes that cause it remain unclear. We hypothesized that fatigue after COVID-19 would be associated with altered cortical activity in premotor and motor regions.

We used transcranial magnetic stimulation combined with EEG (TMS-EEG) to explore the neural oscillatory activity of the left primary motor area (l-M1) and supplementary motor area (SMA) in a group of sixteen post-COVID patients complaining of lingering fatigue as compared to a sample of age-matched healthy controls. Perceived fatigue was assessed with the Fatigue Severity Scale (FSS) and Fatigue Rating Scale (FRS).

Post-COVID patients showed a remarkable reduction of beta frequency in both areas. Correlation analysis exploring linear relation between neurophysiological and clinical measures revealed a significant inverse correlation between the individual level of beta oscillations evoked by TMS of SMA with the individual scores in the FRS (r(15) = -0.596; p = 0.012).

Post-COVID fatigue is associated with a reduction of TMS-evoked beta oscillatory activity in SMA.

TMS-EEG could be used to identify early alterations of cortical oscillatory activity that could be related to the COVID impact in central fatigue.

A hypometabolic profile involving the limbic areas, brainstem and cerebellum has been identified in long COVID patients using [18F]fluorodeoxyglucose (FDG)-PET. This study was conducted to evaluate possible recovery of brain metabolism during the follow-up of patients with prolonged symptoms.

Fifty-six adults with long COVID who underwent two brain [18F]FDG-PET scans in our department between May 2020 and October 2022 were retrospectively analysed, and compared to 51 healthy subjects. On average, PET1 was performed 7 months (range 3-17) after acute COVID-19 infection, and PET2 was performed 16 months (range 8-32) after acute infection, because of persistent severe or disabling symptoms, without significant clinical recovery. Whole-brain voxel-based analysis compared PET1 and PET2 from long COVID patients to scans from healthy subjects (p-voxel < 0.001 uncorrected, p-cluster < 0.05 FWE-corrected) and PET1 to PET2 (with the same threshold, and secondarily with a less constrained threshold of p-voxel < 0.005 uncorrected, p-cluster < 0.05 uncorrected). Additionally, a region-of-interest (ROI) semiquantitative anatomical approach was performed for the same comparisons (p < 0.05, corrected).

PET1 and PET2 revealed voxel-based hypometabolisms consistent with the previously reported profile in the literature. This between-group analysis comparing PET1 and PET2 showed minor improvements in the pons and cerebellum (8.4 and 5.2%, respectively, only significant under the less constrained uncorrected p-threshold); for the pons, this improvement was correlated with the PET1-PET2 interval (r = 0.21, p < 0.05). Of the 14,068 hypometabolic voxels identified on PET1, 6,503 were also hypometabolic on PET2 (46%). Of the 7,732 hypometabolic voxels identified on PET2, 6,094 were also hypometabolic on PET1 (78%). The anatomical ROI analysis confirmed the brain hypometabolism involving limbic region, the pons and cerebellum at PET1 and PET2, without significant changes between PET1 and PET2.

Subjects with persistent symptoms of long COVID exhibit durable deficits in brain metabolism, without progressive worsening.