Persistence and emergence of new neuropsychological deficits following SARS-CoV-2 infection: A follow-up assessment of the Geneva COVID-COG cohort.

Background: Despite numerous observations of neuropsychological deficits immediately following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, little is known about what happens to these deficits over time and whether they are affected by changes in fatigue and any psychiatric symptoms. We aimed to assess the prevalence of neuropsychological deficits at 6-9 months and again at 12-15 months after coronavirus disease 2019 (COVID-19) and to explore whether it was associated with changes in fatigue and psychiatric symptoms. Methods: We administered a series of neuropsychological tests and psychiatric questionnaires to 95 patients (mean age = 57.12 years, standard deviation (SD) = 10.68; 35.79% women) 222 (time point 1 (T1)) and 441 (time point 2 (T2)) days on average after infection. Patients were categorised according to the severity of their respiratory COVID-19 symptoms in the acute phase: mild (no hospitalisation), moderate (conventional hospitalisation), and severe (hospitalisation in intensive care unit (ICU) plus mechanical ventilation). We ran Monte-Carlo simulation methods at each time point to generate a simulated population and then compared the cumulative percentages of cognitive disorders displayed by the three patient subgroups with the estimated normative data. We calculated generalised estimating equations for the whole sample to assess the longitudinal associations between cumulative neuropsychological deficits, fatigue, and psychiatric data (anxiety, depressive symptoms, posttraumatic stress disorder, and apathy). Results: Most participants (>50%) exhibited a decrease in their neuropsychological impairments, while approximately 25% showed an escalation in these cognitive deficits. At T2, patients in the mild subgroup remained free of accumulated neuropsychological impairments. Patients with moderate severity of symptoms displayed a decrease in the magnitude of cumulative deficits in perceptual and attentional functions, a persistence of executive, memory and logical reasoning deficits, and the emergence of language deficits. In patients with severe symptoms, perceptual deficits emerged and executive deficits increased, while attentional and memory deficits remained unchanged. Changes in executive functions were significantly associated with changes in depressive symptoms, but the generalised estimating equations failed to reveal any other significant effect. Conclusion: While most cumulative neuropsychological deficits observed at T1 persisted and even worsened over time in the subgroups of patients with moderate and severe symptoms, a significant proportion of patients, mainly in the mild subgroup, exhibited improved performances. However, we identified heterogeneous neuropsychological profiles both cross-sectionally and over time, suggesting that there may be distinct patient phenotypes. Predictors of these detrimental dynamics have yet to be identified.

Markers of limbic system damage following SARS-CoV-2 infection.

Alterations of the limbic system may be present in the chronic phase of SARS-CoV-2 infection. Our aim was to study the long-term impact of this disease on limbic system-related behaviour and its associated brain functional connectivity, according to the severity of respiratory symptoms in the acute phase. To this end, we investigated the multimodal emotion recognition abilities of 105 patients from the Geneva COVID-COG Cohort 223 days on average after SARS-CoV-2 infection (diagnosed between March 2020 and May 2021), dividing them into three groups (severe, moderate or mild) according to respiratory symptom severity in the acute phase. We used multiple regressions and partial least squares correlation analyses to investigate the relationships between emotion recognition, olfaction, cognition, neuropsychiatric symptoms and functional brain networks. Six to 9 months following SARS-CoV-2 infection, moderate patients exhibited poorer recognition abilities than mild patients for expressions of fear (P = 0.03 corrected), as did severe patients for disgust (P = 0.04 corrected) and irritation (P < 0.01 corrected). In the whole cohort, these performances were associated with decreased episodic memory and anosmia, but not with depressive symptoms, anxiety or post-traumatic stress disorder. Neuroimaging revealed a positive contribution of functional connectivity, notably between the cerebellum and the default mode, somatosensory motor and salience/ventral attention networks. These results highlight the long-term consequences of SARS-Cov-2 infection on the limbic system at both the behavioural and neuroimaging levels.

Cognitive Deficits in the Acute Phase of COVID-19: A Review and Meta-Analysis.

This meta-analysis was conducted to quantify the risk of patients exhibiting cognitive deficits in the acute phase of COVID-19 at the time of the first variants (i.e., before the vaccine) and quantify the potential vulnerability of older patients and those who experienced more severe respiratory symptoms. To this end, we searched the LitCovid and EMBASE platforms for articles, including preprints, and included all studies (n = 48) that featured a measurement of cognition, which encompassed 2233 cases of COVID-19. Of these, 28 studies reported scores on global cognitive efficiency scales administered in the acute phase of COVID-19 (up to 3 months after infection). We were able to perform a meta-analysis of proportions on 24 articles (Npatients = 943), and a logistic regression on 18 articles (Npatients = 518). The meta-analysis for proportion indicated that 52.31% of patients with COVID-19 exhibited cognitive deficits in the acute phase. This high percentage, however, has to be interpreted taking in consideration the fact that the majority of patients were hospitalized, and some presented neurological complications, such as encephalopathy. A bootstrap procedure with random resampling revealed that an age of 59 was the threshold at which one would be more prone to present cognitive deficits. However, the severity of respiratory symptoms did not influence the scores on a global cognitive efficiency scale. Overall, our results indicated that neuropsychological deficits were a major consequence of the acute phase of the first forms of COVID-19.

Motor Symptom Asymmetry Predicts Cognitive and Neuropsychiatric Profile Following Deep Brain Stimulation of the Subthalamic Nucleus in Parkinson's Disease: a 5-Year Longitudinal Study.

INTRODUCTION: Risk factors (e.g., motor symptom asymmetry) for short- and long-term cognitive and neuropsychiatric symptoms following deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson's disease have yet to be fully identified. The objectives of the present study were to determine whether motor symptom asymmetry in Parkinson's disease is one such risk factor and to identify predictors of subnormal cognitive decline. METHODS: A total of 26 patients receiving STN-DBS (13 with left-sided motor symptoms and 13 with right-sided ones) underwent follow-up neuropsychological, depression and apathy assessments over a 5-year period. Nonparametric intergroup comparisons were performed on raw scores, as well as Cox regression analyses on standardized Mattis Dementia Rating Scale scores. RESULTS: Compared with patients who had predominantly left-sided symptoms, right-sided patients scored higher on both apathy (at 3 months and 36 months) and depressive symptoms (at 6 months and 12 months) and scored lower on global cognitive efficiency (at 36 months and 60 months). Survival analyses revealed that only right-sided patients had subnormal standardized dementia scores, which were negatively associated with the number of perseverations in the Wisconsin Card Scoring Test. CONCLUSION: Right-sided motor symptoms are a risk factor for more severe short- and long-term cognitive and neuropsychiatric symptoms following STN-DBS, confirming literature findings on left hemispheric vulnerability.

Brain functional connectivity alterations associated with neuropsychological performance 6-9 months following SARS-CoV-2 infection.

Neuropsychological deficits and brain damage following SARS-CoV-2 infection are not well understood. Then, 116 patients, with either severe, moderate, or mild disease in the acute phase underwent neuropsychological and olfactory tests, as well as completed psychiatric and respiratory questionnaires at 223 ± 42 days postinfection. Additionally, a subgroup of 50 patients underwent functional magnetic resonance imaging. Patients in the severe group displayed poorer verbal episodic memory performances, and moderate patients had reduced mental flexibility. Neuroimaging revealed patterns of hypofunctional and hyperfunctional connectivities in severe patients, while only hyperconnectivity patterns were observed for moderate. The default mode, somatosensory, dorsal attention, subcortical, and cerebellar networks were implicated. Partial least squares correlations analysis confirmed specific association between memory, executive functions performances and brain functional connectivity. The severity of the infection in the acute phase is a predictor of neuropsychological performance 6-9 months following SARS-CoV-2 infection. SARS-CoV-2 infection causes long-term memory and executive dysfunctions, related to large-scale functional brain connectivity alterations.

Reward-Based Learning and Emotional Habit Formation in the Cerebellum.

There is growing evidence of the cerebellum's contribution to emotion processing from neuroimaging studies of healthy function and clinical studies of cerebellar patients. As demonstrated initially in the motor domain, one of the cerebellum's functions is to construct internal models of an individual's state and make predictions about how future behaviors will impact that state. By utilizing widespread connections with neocortex and subcortical regions such as the basal ganglia, the cerebellum can monitor and modulate precisely timed patterns of events using prediction and reward-based error feedback in a diverse range of tasks including auditory emotion prosody recognition. In coordination with a broader affective network, the cerebellum helps to select and refine emotional responses that are the most rewarded in a particular context, strengthening neural activity in relevant regions to form a representational chunk. This chunked set of affective stimuli, cognitive evaluations, and physiological responses subsequently can be enacted as a unitary response (i.e., an emotional habit) more quickly and with less attentional control than for a novel stimulus or goal-oriented action. Such emotional habits can allow for efficient, automatic, stimulus-triggered responses while maintaining the flexibility to adapt output when prediction errors signal a renewed need for cerebellar modification of cortical activity, or, conversely, may lead to behavioral or mood disorders when habitual responses persist despite negative consequences.

Functional connectivity underlying cognitive and psychiatric symptoms in post-COVID-19 syndrome: is anosognosia a key determinant?

Lack of awareness of cognitive impairment (i.e. anosognosia) could be a key factor for distinguishing between neuropsychological post-COVID-19 condition phenotypes. In this context, the 2-fold aim of the present study was to (i) establish the prevalence of anosognosia for memory impairment, according to the severity of the infection in the acute phase and (ii) determine whether anosognosic patients with post-COVID syndrome have a different cognitive and psychiatric profile from nosognosic patients, with associated differences in brain functional connectivity. A battery of neuropsychological, psychiatric, olfactory, dyspnoea, fatigue and quality-of-life tests was administered 227.07 ± 42.69 days post-SARS-CoV-2 infection to 102 patients (mean age: 56.35 years, 65 men, no history of neurological, psychiatric, neuro-oncological or neurodevelopmental disorder prior to infection) who had experienced either a mild (not hospitalized; n = 45), moderate (conventional hospitalization; n = 34) or severe (hospitalization with intensive care unit stay and mechanical ventilation; n = 23) presentation in the acute phase. Patients were first divided into two groups according to the presence or absence of anosognosia for memory deficits (26 anosognosic patients and 76 nosognosic patients). Of these, 49 patients underwent an MRI. Structural images were visually analysed, and statistical intergroup analyses were then performed on behavioural and functional connectivity measures. Only 15.6% of patients who presented mild disease displayed anosognosia for memory dysfunction, compared with 32.4% of patients with moderate presentation and 34.8% of patients with severe disease. Compared with nosognosic patients, those with anosognosia for memory dysfunction performed significantly more poorly on objective cognitive and olfactory measures. By contrast, they gave significantly more positive subjective assessments of their quality of life, psychiatric status and fatigue. Interestingly, the proportion of patients exhibiting a lack of consciousness of olfactory deficits was significantly higher in the anosognosic group. Functional connectivity analyses revealed a significant decrease in connectivity, in the anosognosic group as compared with the nosognosic group, within and between the following networks: the left default mode, the bilateral somatosensory motor, the right executive control, the right salient ventral attention and the bilateral dorsal attention networks, as well as the right Lobules IV and V of the cerebellum. Lack of awareness of cognitive disorders and, to a broader extent, impairment of the self-monitoring brain system, may be a key factor for distinguishing between the clinical phenotypes of post-COVID syndrome with neuropsychological deficits.

Preservation of Person-Specific Semantic Knowledge in Semantic Dementia: Does Direct Personal Experience Have a Specific Role?

Semantic dementia patients seem to have better knowledge of information linked to the self. More specifically, despite having severe semantic impairment, these patients show that they have more general information about the people they know personally by direct experience than they do about other individuals they know indirectly. However, the role of direct personal experience remains debated because of confounding factors such as frequency, recency of exposure, and affective relevance. We performed an exploratory study comparing the performance of five semantic dementia patients with that of 10 matched healthy controls on the recognition (familiarity judgment) and identification (biographic information recall) of personally familiar names vs. famous names. As expected, intergroup comparisons indicated a semantic breakdown in semantic dementia patients as compared with healthy controls. Moreover, unlike healthy controls, the semantic dementia patients recognized and identified personally familiar names better than they did famous names. This pattern of results suggests that direct personal experience indeed plays a specific role in the relative preservation of person-specific semantic meaning in semantic dementia. We discuss the role of direct personal experience on the preservation of semantic knowledge and the potential neurophysiological mechanisms underlying these processes.