Accurate classification of major brain cell types using in vivo imaging and neural network processing.

Comprehensive analysis of tissue cell type composition using microscopic techniques has primarily been confined to ex vivo approaches. Here, we introduce NuCLear (Nucleus-instructed tissue composition using deep learning), an approach combining in vivo two-photon imaging of histone 2B-eGFP-labeled cell nuclei with subsequent deep learning-based identification of cell types from structural features of the respective cell nuclei. Using NuCLear, we were able to classify almost all cells per imaging volume in the secondary motor cortex of the mouse brain (0.25 mm3 containing approximately 25,000 cells) and to identify their position in 3D space in a noninvasive manner using only a single label throughout multiple imaging sessions. Twelve weeks after baseline, cell numbers did not change yet astrocytic nuclei significantly decreased in size. NuCLear opens a window to study changes in relative density and location of different cell types in the brains of individual mice over extended time periods, enabling comprehensive studies of changes in cell type composition in physiological and pathophysiological conditions.

Brainstem Infarction in Immunodeficiency Identified as Adenosine Deaminase 2 Deficiency: Case Report.

PURPOSE: We present the case of a 24-year-old male with CNS granulomatosis due to an immunodeficiency syndrome which was identified as deficiency of adenosine deaminase 2 (DADA2) as a cause of brainstem infarction. METHODS: Case report and detailed description of the clinical course of diagnosis and treatment. CASE: The patient's medical history consisted of an unknown immunodeficiency syndrome. Based on former findings, common variable immunodeficiency (CVID) was diagnosed. The patient suffered from three consecutive brainstem strokes of unknown etiology within 3 years. An MRI scan detected gadolinium-enhancing, granulomatous-suspect lesions in the interpeduncular cistern, temporal lobe, and tegmentum. Laboratory analysis was compatible with CVID, with leukopenia and immunoglobulin deficiency. Because granulomatous CNS inflammation was suspected, the patient received methylprednisolone immunosuppressive therapy, which led to partially regressive MRI lesions. However, in contrast to imaging, the patient showed a progressive cerebellar syndrome, indicating plasma exchange therapy and immunoglobulin treatment, which led to rapid symptom amelioration. After a relapse and a further stroke, expanded analysis confirmed DADA2 (and not CVID) as the inflammatory cause for recurrent stroke. After starting the therapy with immunoglobulins and adalimumab, no further strokes occurred. CONCLUSION: We present the case of a young adult with diagnosis of DADA2 as a cause for recurrent strokes due to vasculitis. This stroke etiology is rare but should be considered as a cause of recurrent stroke of unknown origin in young patients to avoid a disabling disease course by disease-specific treatment options.

[Neurobiological and neurochemical mechanisms of placebo analgesia]. / Neurobiologische und neurochemische Mechanismen der Placeboanalgesie.

BACKGROUND: The efficacy of pain therapies can be substantially modulated by treatment expectations, which is reflected by the substantial placebo effects observed in pain (so called placebo analgesia). QUESTION: What is currently known about the neurobiological and neurochemical mechanisms underlying placebo analgesia? MATERIALS AND METHODS: A focused presentation of key publications in the field embedded in a structured overview of the mechanistic concepts and current theories according to recent evidence. RESULTS: Experimental studies with functional neuroimaging showed that the effect of placebo analgesia is reflected by changes in brain activity related to pain processing and cognitive control. The important neurotransmitters involved include opioids and dopamine. CONCLUSION: Placebo analgesia is associated with complex neurobiological and -physiological mechanisms. An advanced comprehension of these processes should be applied to optimize existing and future therapeutic approaches in pain therapy.

Media coverage of COVID-19 vaccination-associated cerebral venous sinus thrombosis was followed by a surge in emergency presentations due to headache - observations from a university hospital in Germany.

Nocebo effects describe all negative outcomes for well-being brought about by negative health-related expectations. Media coverage of drug side effects can fuel nocebo effects and lead to increased symptom reports. This retrospective observational analysis of emergency reports at the neurological emergency room at University Hospital Essen, Germany, examines whether media communication about a cumulation of very rare cases of cerebral venous sinus thrombosis (CVST) after COVID-19 vaccination with the AstraZeneca compound (ChAdOx-1 nCoV-19) was followed by an increase in weekly presentation rates of patients with the main complaint of headache, a symptom commonly occurring as a vaccination reaction but also communicated as a warning symptom for CVST. The rate of headache presentations increased by 171.7% during the five weeks after the first announcement of CVSTs in Germany on 11 March 2021, compared to the five weeks immediately prior. Furthermore, more young women sought consultation for headache, reflecting the communicated at-risk profile for CVST. The increased rate of headache presenters contributed to a 32.1% rise in total neurological emergency cases, causing an increased strain on the emergency facility after the side effect risk was publicized. We discuss a causal role of negative side effect expectations after vaccination with AstraZeneca as a driver for this increase. While transparent communication about benefits and potential side effects is crucial for vaccination acceptance, increased vigilance toward nocebo effects in health-related media communication is needed due to its potential harm to the individual and society, especially when emergency medical resources are stretched thin.

Cytokines (IL1ß, IL6, TNFα) and serum cortisol levels may not constitute reliable biomarkers to identify individuals with post-acute sequelae of COVID-19.

Background: Post-acute sequelae of COVID-19 (PASC) comprise a broad spectrum of symptoms such as fatigue, general weakness, compromised attention and sleep or anxiety disorders. PASC represents a medical and socio-economic challenge. Objectives: Our study evaluated cytokines (IL-1ß, IL-6 and TNFα) and cortisol levels in a cohort of typical patients with PASC, suffering concentration problems, fatigue and difficulties finding words. Design: This was a prospective cohort study. Four groups were analysed and compared: those who had never contracted SARS-CoV-2 (n = 13), infected but had no PASC (n = 34), infected with former PASC that resolved (n = 40) and patients with ongoing PASC after infection (n = 91). Methods: Cytokine and cortisol serum levels were determined in patients' blood samples. Results: Cytokine levels of IL-1ß, IL-6, TNFα and cortisol levels did not differ between groups analysed. Conclusion: This may indicate a non-organic/psychosomatic genesis of PASC; further studies are needed to elucidate the underlying causes of PACS, and non-organic causes should not be overlooked.

Without clear biological markers for people who will continue to present with post-acute sequelae of COVID-19 (PASC) should we now focus on psychological factors? Many people across the globe are still suffering from post-acute sequelae of COVID-19 (PASC), commonly called post-COVID. Typical symptoms of PASC include severe tiredness (fatigue), concentration deficits (brain fog) or difficulty finding words. We need a better understanding of how these symptoms arise to find ways to help patients. Our team of researchers set out to explore this. We posed the question: could measurements of immune system activity provide an identifier for people who are susceptible to post-COVID? The participants in our study were divided into four groups: 1. A group of 13 people who had never contracted SARS-CoV-2. 2. A group of 34 people who had been infected with SARS-CoV-2 but had no PASC. 3. A group of 40 people who had been infected with SARS-CoV-2 and had already suffered from PASC that had now resolved. 4. A group of 91 people who were no longer sick with COVID-19 but were still suffering from PASC. Serum samples from all participants were taken to measure cytokine and cortisol levels. People with PASC could not be identified by testing their blood samples for cytokines (IL-1ß, IL-6, TNFα) or cortisol. No difference between the four groups was found on any marker. Measuring these cytokines or cortisol is, therefore, unlikely to be useful in predicting which patients will suffer from PASC. Continuation of symptoms long after COVID-19 has passed is distressing for many people worldwide. Psychological factors may play a role and need to be studied further in order to help this patient population.

Brain morphology predicts individual sensitivity to pain: a multicenter machine learning approach.

ABSTRACT: Sensitivity to pain shows a remarkable interindividual variance that has been reported to both forecast and accompany various clinical pain conditions. Although pain thresholds have been reported to be associated to brain morphology, it is still unclear how well these findings replicate in independent data and whether they are powerful enough to provide reliable pain sensitivity predictions on the individual level. In this study, we constructed a predictive model of pain sensitivity (as measured with pain thresholds) using structural magnetic resonance imaging-based cortical thickness data from a multicentre data set (3 centres and 131 healthy participants). Cross-validated estimates revealed a statistically significant and clinically relevant predictive performance (Pearson r = 0.36, P < 0.0002, R2 = 0.13). The predictions were found to be specific to physical pain thresholds and not biased towards potential confounding effects (eg, anxiety, stress, depression, centre effects, and pain self-evaluation). Analysis of model coefficients suggests that the most robust cortical thickness predictors of pain sensitivity are the right rostral anterior cingulate gyrus, left parahippocampal gyrus, and left temporal pole. Cortical thickness in these regions was negatively correlated to pain sensitivity. Our results can be considered as a proof-of-concept for the capacity of brain morphology to predict pain sensitivity, paving the way towards future multimodal brain-based biomarkers of pain.

Oropharyngeal swab for SARS-CoV-2 test causing atypical internal carotid artery dissection and stroke in a patient after mild COVID-19.

We report a patient who had recovered from pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presenting with acute cerebral ischemia due to atypical dissection of the left internal carotid artery immediately after an oropharyngeal swab (OPS) for SARS-CoV-2 RT-PCR testing. The symptoms consisting of right-side hemiparesis and aphasia improved after systemic thrombolysis and the patient recovered completely in the further course. We demonstrate findings from imaging (computed tomography, magnetic resonance imaging, neurovascular ultrasound) among other investigations and discuss coronavirus disease 2019 (COVID-19)-related vessel wall vulnerability as well as tissue injury posed by the swab procedure as underlying causes of the dissection. Individuals performing OPSs during the corona pandemic should be aware of this so far undescribed complication.

Anti-GFAP-antibody positive postinfectious acute cerebellar ataxia and myoclonus after COVID-19: a case report.

We present a case of acute cerebellar ataxia and myoclonus with detected anti-GFAP-antibodies in a patient recently recovered from COVID-19. Main symptoms consisted of acute gait and limb ataxia and myoclonus. The patient improved considerably upon treatment with high-dose intravenous (IV) steroids. While cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) findings were unremarkable, anti-GFAP-antibodies were detected in the patient's serum and disappeared upon clinical remission at a 3-month follow-up. This case suggests that anti-GFAP-antibodies might be associated with some of the increasingly observed cases of postinfectious acute cerebellar ataxias in COVID-19 patients and aid in the diagnosis of this autoimmune complication. We recommend searching for these antibodies in serum and CSF in suspected cases. Early steroid treatment may prove beneficial for these patients.

Cellular correlates of gray matter volume changes in magnetic resonance morphometry identified by two-photon microscopy.

Magnetic resonance imaging (MRI) of the brain combined with voxel-based morphometry (VBM) revealed changes in gray matter volume (GMV) in various disorders. However, the cellular basis of GMV changes has remained largely unclear. We correlated changes in GMV with cellular metrics by imaging mice with MRI and two-photon in vivo microscopy at three time points within 12 weeks, taking advantage of age-dependent changes in brain structure. Imaging fluorescent cell nuclei allowed inferences on (i) physical tissue volume as determined from reference spaces outlined by nuclei, (ii) cell density, (iii) the extent of cell clustering, and (iv) the volume of cell nuclei. Our data indicate that physical tissue volume alterations only account for 13.0% of the variance in GMV change. However, when including comprehensive measurements of nucleus volume and cell density, 35.6% of the GMV variance could be explained, highlighting the influence of distinct cellular mechanisms on VBM results.