B cell-targeting chimeric antigen receptor T cells as an emerging therapy in neuroimmunological diseases.

BACKGROUND: Neuroimmunology research and development has been marked by substantial advances, particularly in the treatment of neuroimmunological diseases, such as multiple sclerosis, myasthenia gravis, neuromyelitis optica spectrum disorders, and myelin oligodendrocyte glycoprotein antibody disease. With more than 20 drugs approved for multiple sclerosis alone, treatment has become more personalised. The approval of disease-modifying therapies, particularly those targeting B cells, has highlighted the role of immunotherapeutic interventions in the management of these diseases. Despite these successes, challenges remain, particularly for patients who do not respond to conventional therapies, underscoring the need for innovative approaches. RECENT DEVELOPMENTS: The approval of monoclonal antibodies, such as ocrelizumab and ofatumumab, which target CD20, and inebilizumab, which targets CD19, for the treatment of various neuroimmunological diseases reflects progress in the understanding and management of B-cell activity. However, the limitations of these therapies in halting disease progression or activity in patients with multiple sclerosis or neuromyelitis optica spectrum disorders have prompted the exploration of cell-based therapies, particularly chimeric antigen receptor (CAR) T cells. Initially successful in the treatment of B cell-derived malignancies, CAR T cells offer a novel therapeutic mechanism by directly targeting and eliminating B cells, potentially overcoming the shortcomings of antibody-mediated B cell depletion. WHERE NEXT?: The use of CAR T cells in autoimmune diseases and B cell-driven neuroimmunological diseases shows promise as a targeted and durable option. CAR T cells act autonomously, penetrating deep tissue and effectively depleting B cells, especially in the CNS. Although the therapeutic potential of CAR T cells is substantial, their application faces hurdles such as complex logistics and management of therapy-associated toxic effects. Ongoing and upcoming clinical trials will be crucial in determining the safety, efficacy, and applicability of CAR T cells. As research progresses, CAR T cell therapy has the potential to transform treatment for patients with neuroimmunological diseases. It could offer extended periods of remission and a new standard in the management of autoimmune and neuroimmunological disorders.

Treatment of concomitant myasthenia gravis and Lambert-Eaton myasthenic syndrome with autologous CD19-targeted CAR T cells.

Myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are autoimmune disorders affecting neuromuscular transmission. Their combined occurrence is rare, and treatment remains challenging. Two women diagnosed with concomitant MG/LEMS experienced severe, increasing disease activity despite multiple immunotherapies. Anti-CD19 chimeric antigen receptor (CAR) T cells have shown promise for treating autoimmune diseases. This report details the safe application of anti-CD19 CAR T cells for treating concomitant MG/LEMS. After CAR T cell therapy, both patients experienced rapid clinical recovery and regained full mobility. Deep B cell depletion and normalization of acetylcholine receptor and voltage-gated calcium channel N-type autoantibody levels paralleled major neurological responses. Within 2 months, both patients returned to everyday life, from wheelchair dependency to bicycling and mountain hiking, and remain stable at 6 and 4 months post-CAR T cell infusion, respectively. This report highlights the potential for anti-CD19 CAR T cells to achieve profound clinical effects in the treatment of neuroimmunological diseases.

Predictors for Adherence to Recommended Anticoagulation after Stroke Unit Discharge in Patients with Atrial Fibrillation.

INTRODUCTION: Non-adherence to recommended secondary preventive anticoagulation in stroke patients with atrial fibrillation (AF) is a common phenomenon although the introduction of direct oral anticoagulants (DOACs) has simplified anticoagulation management for physicians as well as for patients. METHODS: We examined the adherence of secondary preventive anticoagulation in AF patients after re-integration in their social environment 6 to 12 weeks after stroke unit and rehabilitation clinic treatment and analyzed for predictors for adherence and non-adherence. We conducted a telephone survey in consecutive patients treated between January 2013 and December 2021 at our institutional stroke unit with an acute cerebrovascular ischemic event and we analyzed discharge letters of rehabilitation clinics of those patients not anticoagulated at follow-up. All patients had known or newly diagnosed AF and in all we had recommended secondary preventive anticoagulation. RESULTS: Follow-up information about anticoagulant intake could be obtained in 1348 of 1685 patients (80.0%) treated within the study period. Anticoagulation rate was 91.5% with 83.6% of patients receiving DOACs and 7.9% receiving vitamin K antagonists (VKAs). Adherence to recommended anticoagulation was associated with intake of the recommended anticoagulant already at discharge (adjusted OR, 18.357; CI, 9.637 to 34.969), recommendation of a specific DOAC and dose (in contrast to "DOAC" as drug category) (adjusted OR, 2.971; CI, 1.173 to 7.255), a lower modified Rankin Scale at discharge (per point; adjusted OR, 0.813; CI, 0.663 to 0.996), younger age (per year; adjusted odds ratio [OR], 0.951; confidence interval [CI], 0.926 to 0.976), and the absence of peripheral vascular disease (adjusted OR, 0.359; CI, 0.173 to 0.746). In patients already anticoagulated at discharge adherence was 98.5%, irrespective of a patient's age, functional deficit at discharge, and peripheral vascular disease. Avoidable obstacles for non-adherence in patients not on anticoagulants at stroke unit discharge were (1) non-implementation of recommended anticoagulation by rehabilitation physicians predominantly in patients with moderate-severe or severe stroke disability (2.1%), (2) delegation of anticoagulation start from rehabilitation physicians to general practitioners/resident radiologists (1.3%), and (3) rejection of recommended anticoagulation because of patients' severe stroke disability (0.5%). Non-avoidable obstacles were contraindications to anticoagulation (2.1%) and patients' refusal (0.7%). CONCLUSIONS: Commencing drug administration already during stroke unit hospitalization and providing an explanation for the selection of the recommended anticoagulant in discharge letters ensures high adherence at patients' re-integration in their social environment after acute stroke treatment. If drug administration cannot be commenced before discharge, education of rehabilitation physicians by stroke physicians and the involvement of stroke physicians into the post-stroke decision process might hinder avoidable obstacles.

Sensory nerve conduction studies in infants, children and teenagers - An update.

Objective: Nerve conduction studies (NCS) in children remain technically challenging and depend on the cooperation of the child. Motor NCS are not compromised by analgosedation but data for sensory NCS are lacking. Here, we ask whether sensory NCS is influenced by analgosedation. We also compare the present data with NCS studies from the 1990s regarding anthropometric acceleration of the contemporary paediatric population. Methods: Sensory NCS of the median nerve and sural nerve were performed in 182 healthy subjects aged 1 to 18 years during general anaesthesia and in 47 of them without analgosedation. Results: Sensory NCS was not influenced by midazolam or propofol. The sensory nerve action potential (SNAP) amplitude and the nerve conduction velocity (NCV) of the sural nerve as well as the SNAP of the median nerve show no significant age dependence in age range 1-18 years. The sensory NCV of the median nerve increased age-dependent. Conclusions: In clinical practice, analgosedation can be used for diagnostic NCS. Sensory NCS data show no relevant secular trend over the last 30 years. Differences due to technical inconsistency predominate. Significance: Analgosedation can improve diagnostic quality of sensory NCS in children. Additionally, we provide sensory NCS values from a large pediatric cohort.

Progesterone Receptor Membrane Component 1 (PGRMC1) Modulates Tumour Progression, the Immune Microenvironment and the Response to Therapy in Glioblastoma.

Progesterone Receptor Membrane Component 1 (PGRMC1) is a tumour-promoting factor in several types of cancer but its role in brain tumours is poorly characterized thus far. Our study aimed to determine the effect of PGRMC1 on glioblastoma (GBM) pathophysiology using two independent cohorts of IDH wild-type GBM patients and stable knockdown GBM models. We found that high levels of PGRMC1 significantly predicted poor overall survival in both cohorts of GBM patients. PGRMC1 promoted the proliferation, anchorage-independent growth, and invasion of GBM cells. We identified Integrin beta-1 (ITGB1) and TCF 1/7 as potential members of the PGRMC1 pathway in vitro. The levels of ITGB1 and PGRMC1 also correlated in neoplastic tissues from GBM patients. High expression of PGRMC1 rendered GBM cells less susceptible to the standard GBM chemotherapeutic agent temozolomide but more susceptible to the ferroptosis inducer erastin. Finally, PGRMC1 enhanced Interleukin-8 production in GBM cells and promoted the recruitment of neutrophils. The expression of PGRMC1 significantly correlated with the numbers of tumour-infiltrating neutrophils also in tissues from GBM patients. In conclusion, PGRMC1 enhances tumour-related inflammation and promotes the progression of GBM. However, PGRMC1 might be a promising target for novel therapeutic strategies using ferroptosis inducers in this type of cancer.

Phasic, Event-Related Transcutaneous Auricular Vagus Nerve Stimulation Modifies Behavioral, Pupillary, and Low-Frequency Oscillatory Power Responses.

Transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed to activate the locus ceruleus-noradrenaline (LC-NA) system. However, previous studies failed to find consistent modulatory effects of taVNS on LC-NA biomarkers. Previous studies suggest that phasic taVNS may be capable of modulating LC-NA biomarkers such as pupil dilation and alpha oscillations. However, it is unclear whether these effects extend beyond pure sensory vagal nerve responses. Critically, the potential of the pupillary light reflex as an additional taVNS biomarker has not been explored so far. Here, we applied phasic active and sham taVNS in 29 subjects (16 female, 13 male) while they performed an emotional Stroop task (EST) and a passive pupil light reflex task (PLRT). We recorded pupil size and brain activity dynamics using a combined Magnetoencephalography (MEG) and pupillometry design. Our results show that phasic taVNS significantly increased pupil dilation and performance during the EST. During the PLRT, active taVNS reduced and delayed pupil constriction. In the MEG, taVNS increased frontal-midline theta and alpha power during the EST, whereas occipital alpha power was reduced during both the EST and PLRT. Our findings provide evidence that phasic taVNS systematically modulates behavioral, pupillary, and electrophysiological parameters of LC-NA activity during cognitive processing. Moreover, we demonstrate for the first time that the pupillary light reflex can be used as a simple and effective proxy of taVNS efficacy. These findings have important implications for the development of noninvasive neuromodulation interventions for various cognitive and clinical applications.SIGNIFICANCE STATEMENT taVNS has gained increasing attention as a noninvasive neuromodulation technique and is widely used in clinical and nonclinical research. Nevertheless, the exact mechanism of action of taVNS is not yet fully understood. By assessing physiology and behavior in a response conflict task in healthy humans, we demonstrate the first successful application of a phasic, noninvasive vagus nerve stimulation to improve cognitive control and to systematically modulate pupillary and electrophysiological markers of the noradrenergic system. Understanding the mechanisms of action of taVNS could optimize future clinical applications and lead to better treatments for mental disorders associated with noradrenergic dysfunction. In addition, we present a new taVNS-sensitive pupillary measure representing an easy-to-use biomarker for future taVNS studies.

A Molecular Biomarker-Based Triage Approach for Targeted Treatment of Post-COVID-19 Syndrome Patients with Persistent Neurological or Neuropsychiatric Symptoms.

Approximately 30% of COVID-19 cases may experience chronic symptoms, known as post-COVID-19 syndrome (PCS). Common PCS symptoms can include fatigue, cognitive impairment, and persistent physical, neurological, and neuropsychiatric complaints. To improve healthcare and management of the current and future pandemics, we highlight the need for establishing interdisciplinary post-viral outpatient clinics comprised of specialists in fields such as psychiatry, psychotherapy, neurology, cardiology, pneumology, and immunology. In this way, PCS patients with a high health burden can receive modern diagnostics and targeted therapeutic recommendations. A key objective is to distinguish the "sick recovered" from the "healthy recovered." Our hypothesis is that there is a PCS subgroup with autoimmune-mediated systemic and brain-vascular dysregulation, which may lead to circulatory disorders, fatigue, cognitive impairment, depression, and anxiety. This can be clarified using a combination of specific antibody diagnostics and precise clinical, psychological, and apparative testing.

Comparative effectiveness of cladribine tablets versus fingolimod in the treatment of highly active multiple sclerosis: A real-world study.

BACKGROUND: Cladribine tablets and fingolimod have similar marketing authorisations in Europe for the treatment of patients with highly active relapsing multiple sclerosis (HA-RMS). In the absence of direct head-to-head studies, real-world data are important to assess the comparative effectiveness of these oral disease-modifying therapies (DMTs). The primary objective of the present study was to compare relapse rates between patients who received either cladribine tablets or fingolimod. METHODS: This multicentre retrospective study conducted in the United Kingdom and Germany assessed non-inferiority in relapse rates of cladribine tablets versus fingolimod in HA-RMS patients over a 12-month period. Eligible patients who initiated treatment with cladribine tablets or fingolimod at least 12 months prior to the screening date were sampled consecutively until the target sample size was reached. Patients were censored at discontinuation of study treatment, commencement of another DMT, death, loss to follow-up, or at 12 months post-baseline, whichever happened earliest. The primary analytic timeframe for physician-confirmed relapse outcomes was the study effectiveness period (nine months of follow-up after an initial 12 weeks of treatment). Propensity score analysis was applied based on the inverse probability of treatment weighting approach. RESULTS: The primary analytic cohort consisted of 1,095 HA-RMS patients: 610 (55.7%) receiving cladribine tablets and 485 (44.3%) receiving fingolimod. Fewer patients discontinued cladribine tablets and/or switched to another DMT compared with fingolimod (0.2% versus 3.5%, respectively). The primary endpoint, adjusted annualised relapse rate (ARR), was 0.10 (95% confidence interval [CI]: 0.07-0.14) for cladribine tablets and 0.14 (95% CI: 0.10-0.20) for fingolimod. The adjusted ARR ratio of cladribine tablets versus fingolimod was 0.68 (95% CI: 0.42-1.11). Given the entire 95% CI was less than the non-inferiority margin of 1.2, cladribine tablets was non-inferior to fingolimod. CONCLUSIONS: In this real-world retrospective cohort study, cladribine tablets demonstrated comparable effectiveness to fingolimod at one year following treatment initiation. The full treatment dosage of cladribine tablets is completed over two years and so these results may be conservative.

Effects of transcutaneous auricular vagus nerve stimulation paired with tones on electrophysiological markers of auditory perception.

BACKGROUND: Transcutaneous auricular vagus nerve stimulation (taVNS) has been introduced as a non-invasive alternative to invasive vagus nerve stimulation (iVNS). While iVNS paired with tones has been highlighted as a potential effective therapy for the treatment of auditory disorders such as tinnitus, there is still scarce data available confirming the efficacy of non-invasive taVNS. Here, we assessed the effect of taVNS paired with acoustic stimuli on sensory-related electrophysiological responses. METHODS: A total of 22 healthy participants were investigated with a taVNS tone-pairing paradigm using a within-subjects design. In a single session pure tones paired with either active taVNS or sham taVNS were repeatedly presented. Novel tones without electrical stimulation served as control condition. Auditory event related potentials and auditory cortex oscillations were compared before and after the tone pairing procedure between stimulation conditions. RESULTS: From pre to post pairing, we observed a decrease in the N1 amplitude and in theta power to tones paired with sham taVNS while these electrophysiological measures remained stable for tones paired with active taVNS a pattern mirroring auditory sensory processing of novel, unpaired control tones. CONCLUSION: Our results demonstrate the efficacy of a short-term application of non-invasive taVNS to modulate auditory processing in healthy individuals and, thereby, have potential implications for interventions in auditory processing deficits.

Functional and structural readouts for early detection of retinal involvement in multiple sclerosis.

Introduction: The retina, a window into the brain, allows for the investigation of many disease-associated inflammatory and neurodegenerative changes affecting the central nervous system (CNS). Multiple sclerosis (MS), an autoimmune disease targeting the CNS, typically impacts on the visual system including the retina. Hence, we aimed to establish innovative functional retinal measures of MS-related damage, e.g., spatially resolved non-invasive retinal electrophysiology, backed by established morphological retinal imaging markers, i.e., optical coherence tomography (OCT). Methods: 20 healthy controls (HC) and 37 people with MS [17 without history of optic neuritis (NON) and 20 with (HON) history of optic neuritis] were included. In this work, we differentially assessed photoreceptor/bipolar cells (distal retina) and retinal ganglion cell (RGC, proximal retina) function besides structural assessment (OCT). We compared two multifocal electroretinography-based approaches, i.e., the multifocal pattern electroretinogram (mfPERG) and the multifocal electroretinogram to record photopic negative response (mfERG PhNR ). Structural assessment utilized peripapillary retinal nerve fiber layer thickness (pRNFL) and macular scans to calculate outer nuclear thickness (ONL) and macular ganglion cell inner plexiform layer thickness (GCIPL). One eye was randomly selected per subject. Results: In NON, photoreceptor/bipolar cell layer had dysfunctional responses evidenced by reduced mfERG PhNR -N1 peak time of the summed response, but preserved structural integrity. Further, both NON and HON demonstrated abnormal RGC responses as evidenced by the photopic negative response of mfERG PhNR (mfPhNR) and mfPERG indices (P < 0.05). Structurally, only HON had thinned retina at the level of RGCs in the macula (GCIPL, P < 0.01) and the peripapillary area (pRNFL, P < 0.01). All three modalities showed good performance to differentiate MS-related damage from HC, 71-81% area under curve. Conclusion: In conclusion, while structural damage was evident mainly for HON, functional measures were the only retinal read-outs of MS-related retinal damage that were independent of optic neuritis, observed for NON. These results indicate retinal MS-related inflammatory processes in the retina prior to optic neuritis. They highlight the importance of retinal electrophysiology in MS diagnostics and its potential as a sensitive biomarker for follow-up in innovative interventions.

Extravascular optical coherence tomography of cerebral vessel walls in vivo.

PURPOSE: Evaluation of extravascular, microscope integrated OCT (iOCT) as an in vivo imaging modality of cerebral blood vessels and as an intraoperative imaging method. METHODS: Microscope integrated optical coherence tomography of major cerebral arteries (n = 13) and superficial sylvian veins (n = 5) and one incidental cerebral vasospasm (n = 1) in (n = 10) patients. Post procedural analysis of OCT volume scans, microscopic images and videos during the time of scan as well as measurements of the diameter of vessel walls and its layers with an accuracy of 7.5 µm. RESULTS: iOCT was feasible during vascular microsurgical procedures. In all scanned arteries a clear delineation of the physiological three layered vessel wall composition could be achieved. Pathological arteriosclerotic alterations of cerebral artery walls could precisely be demonstrated. Major superficial cortical veins conversely presented a mono layered composition. First in vivo measurements of vascular mean diameters were possible. Cerebral artery walls showed a diameter of 296 µm, tunica externa 78 µm, media 134 µm and interna 84 µm. CONCLUSION: For the first time the microstructural composition of cerebral blood vessels could be illustrated in vivo. Due to an outstanding spatial resolution a clear definition of physiological and pathological characteristics was possible. Therefore, microscope integrated optical coherence tomography holds promise for basic research in the field of cerebrovascular arteriosclerotic diseases and for intraoperative guidance during microvascular surgery.

Effects of repetitive twice-weekly transcranial direct current stimulations on fatigue and fatigability in people with multiple sclerosis.

Fatigue is associated with a dramatically decreased quality of life in people with multiple sclerosis (pwMS). It refers to a constant subjective feeling of exhaustion and performance decline, known as fatigability. However, inconsistency and heterogeneity in defining and assessing fatigue have led to limited advances in understanding and treating MS-associated fatigue. Transcranial direct current stimulation (tDCS) has emerged as a promising, non-pharmaceutical treatment strategy for subjective fatigue. However, whether repetitive tDCS also have long-term effects on time-on-task performance has not yet been investigated. This pseudorandomized, single-blinded, and sham-controlled study investigated tDCS effects on behavioral and electrophysiological parameters. 18 pwMS received eight twice-weekly 30 min stimulations over the left dorsolateral prefrontal cortex. Fatigability was operationalized as time-on-task-related changes in reaction time variability and P300 amplitude. Additionally, subjective trait and state fatigue ratings were assessed. The results revealed an overall decrease in subjective trait fatigue ratings that lasted at least four weeks after the stimulations. However, the ratings declined after both anodal and sham tDCS. No effects were found on subjective state fatigue and objective fatigability parameters. Linear Mixed Models and Bayesian Regression models likewise favored the absence of a tDCS effect on fatigability parameters. The results confirm the complex relationship between MS-associated fatigue and fatigability. Reliable and clinically relevant parameters need to be established to extend the potential of tDCS for treating fatigability. Furthermore, our results indicate that consecutive stimulations rather than twice-weekly stimulations should be the preferred stimulation scheme in future studies.

Vessel distance mapping: A novel methodology for assessing vascular-induced cognitive resilience.

The association between cerebral blood supply and cognition has been widely discussed in the recent literature. One focus of this discussion has been the anatomical variability of the circle of Willis, with morphological differences being present in more than half of the general population. While previous studies have attempted to classify these differences and explore their contribution to hippocampal blood supply and cognition, results have been controversial. To disentangle these previously inconsistent findings, we introduce Vessel Distance Mapping (VDM) as a novel methodology for evaluating blood supply, which allows for obtaining vessel pattern metrics with respect to the surrounding structures, extending the previously established binary classification into a continuous spectrum. To accomplish this, we manually segmented hippocampal vessels obtained from high-resolution 7T time-of-flight MR angiographic imaging in older adults with and without cerebral small vessel disease, generating vessel distance maps by computing the distances of each voxel to its nearest vessel. Greater values of VDM-metrics, which reflected higher vessel distances, were associated with poorer cognitive outcomes in subjects affected by vascular pathology, while this relation was not observed in healthy controls. Therefore, a mixed contribution of vessel pattern and vessel density is proposed to confer cognitive resilience, consistent with previous research findings. In conclusion, VDM provides a novel platform, based on a statistically robust and quantitative method of vascular mapping, for addressing a variety of clinical research questions.

Cytokine alterations in CSF and serum samples of patients with a first episode of schizophrenia: results and methodological considerations.

We determined cytokine levels in paired serum/CSF samples from first-episode schizophrenia (FES) participants (n = 20) and controls (n = 21) using a 13-plex immunoassay. Applying strictly-determined detection limits, 12 cytokines were found in serum and two in CSF. Higher serum MCP-1 levels (p = 0.007) were present in FES versus controls, which correlated with serum IgG (R = - 0.750; p = 0.013). Finally, IL-18 levels correlated with body weight in FES (R = 0.691; p = 0.041). This study demonstrates potential limitations in the sensitivity of multiplex cytokine assays for CSF studies in mental disorders and suggests that some published studies in this area should be re-evaluated.

Propionate exerts neuroprotective and neuroregenerative effects in the peripheral nervous system.

In inflammatory neuropathies, oxidative stress results in neuronal and Schwann cell (SC) death promoting early neurodegeneration and clinical disability. Treatment with the short-chain fatty acid propionate showed a significant immunoregulatory and neuroprotective effect in multiple sclerosis patients. Similar effects have been described for patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Therefore, Schwann cell's survival and dorsal root ganglia (DRG) outgrowth were evaluated in vitro after propionate treatment and application of H2O2 or S-nitroso-N-acetyl-D-L-penicillamine (SNAP) to evaluate neuroprotection. In addition, DRG resistance was evaluated by the application of oxidative stress by SNAP ex vivo after in vivo propionate treatment. Propionate treatment secondary to SNAP application on DRG served as a neuroregeneration model. Histone acetylation as well as expression of the free fatty acid receptor (FFAR) 2 and 3, histone deacetylases, neuroregeneration markers, and antioxidative mediators were investigated. ß-hydroxybutyrate was used as a second FFAR3 ligand, and pertussis toxin was used as an FFAR3 antagonist. FFAR3, but not FFAR2, expression was evident on SC and DRG. Propionate-mediated activation of FFAR3 and histone 3 hyperacetylation resulted in increased catalase expression and increased resistance to oxidative stress. In addition, propionate treatment resulted in enhanced neuroregeneration with concomitant growth-associated protein 43 expression. We were able to demonstrate an antioxidative and neuroregenerative effect of propionate on SC and DRG mediated by FFAR3-induced histone acetylases expression. Our results describe a pathway to achieve neuroprotection/neuroregeneration relevant for patients with immune-mediated neuropathies.

Long-term opioid therapy and mental health comorbidity in patients with chronic pain.

OBJECTIVES: Evidence suggests that patients with chronic pain and mental illness are more likely to receive long-term opioid therapy (LTOT) and at higher doses but are also at increased risk of experiencing opioid-related harm. This study investigates LTOT and its relationship to mental illness in the setting of a university-based outpatient pain clinic with liaison psychiatric care. METHODS: Retrospective analysis of patients with chronic pain admitted between 2011 and 2015. After a 1-year treatment period, patients with non-opioid treatment, guideline-recommended LTOT, and high-dose LTOT were compared, and multiple regression analysis was performed to identify predictors of higher opioid dosage. RESULTS: Of 769 patients, 46% received LTOT (opioids for >90 consecutive days), 13% at high dosage (>120 oral morphine milligram equivalents [MME] / day). Two thirds of all patients had mental illness. The prevalence of psychiatric diagnoses and prescription rate of psychotropic medication did not significantly differ between groups. Pain chronicity stages, use of antidepressants, and sex significantly predicted MME/day but explained only a minor part of the variance. The association with antidepressants can be attributed to the prescription of antidepressants for analgesic purposes rather than for treating depression. No association with any other type of psychiatric disorders was observed. CONCLUSION: This study shows that mental health comorbidity is highly prevalent but that the prescribed opioid dosage is independent of it in the clinical setting of this study. The concept of liaison psychiatric care might have essentially contributed to the "detachment" of opioid prescription and psychiatric conditions but cannot be isolated from other potentially contributing factors within this single-center observational study.

Fatigability-related oscillatory brain activity changes in people with MS.

BACKGROUND: Fatigue, a multidimensional and challenging symptom associated with various underlying conditions, can manifest as a subjective feeling and a performance fatigability. The latter is often defined as an objectively measurable performance decline with time on task. Both syndromes are highly prevalent in people with multiple sclerosis (pwMS) and are often resistant to medical therapy. In the absence of valid and reliable objective parameters, the current cognitive fatigue diagnosis remains purely subjective. Assessing brain wave activity changes has repeatedly been a viable strategy for monitoring cognitive fatigue in healthy subjects. In this study, we aimed to investigate oscillatory brain activity changes and their associations with subjective fatigue in pwMS. METHODS: We enrolled 21 pwMS and 21 healthy controls (HC) in this study. Subjects performed a sustained attention task divided into six blocks over the course of 30 minutes, and underwent resting state EEGs before and after the task. During the task, subjects were repeatedly asked to rate their subjective levels of mental fitness, mental exhaustion, and mind wandering. Using Linear Mixed Models, we explored fatigability-related changes by focusing on the time course of changes in reaction time variability, subjective ratings of fatigability, as well as frontomedial theta, and occipital alpha power. We further investigated initial and fatigability-induced differences between pwMS and HC at rest. Finally, Pearson correlations were used to examine the relationship between subjective fatigue and objective fatigability parameters. RESULTS: Our results revealed a systematically stronger fatigability development in pwMS that was objectively measurable. PwMS reported lower mental fitness levels and demonstrated greater variability in reaction times with time on task. Occipital alpha power significantly increased during the task. Especially for upper alpha power, this increase was significantly more prominent in pwMS compared to HC. However, the time-on-task-induced changes in our study were not associated with the subjective fatigue ratings. CONCLUSIONS: The results of this study expand the understanding of the neural mechanisms underlining cognitive fatigability and may complement the fatigue diagnosis and therapy monitoring with quantitative objective methods.

I spy with my little eye: The detection of changes in emotional faces and the influence of facial feedback in Parkinson disease.

BACKGROUND AND PURPOSE: Parkinson disease (PD) is a progressive neurodegenerative disorder that affects the motor system but also involves deficits in emotional processing such as facial emotion recognition. In healthy participants, it has been shown that facial mimicry, the automatic imitation of perceived facial expressions, facilitates the interpretation of the emotional states of our counterpart. In PD patients, recent studies revealed reduced facial mimicry and consequently reduced facial feedback, suggesting that this reduction might contribute to the prominent emotion recognition deficits found in PD. METHODS: We investigated the influence of facial mimicry on facial emotion recognition. Twenty PD patients and 20 healthy controls (HCs) underwent a classical facial mimicry manipulation (holding a pen with the lips, teeth, or nondominant hand) while performing an emotional change detection task with faces. RESULTS: As expected, emotion recognition was significantly influenced by facial mimicry manipulation in HCs, further supporting the hypothesis of facial feedback and the related theory of embodied simulation. Importantly, patients with PD, generally and independent from the facial mimicry manipulation, were impaired in their ability to detected emotion changes. Our data further show that PD patients' facial emotional recognition abilities are completely unaffected by mimicry manipulation, suggesting that PD patients cannot profit from an artificial modulation of the already impaired facial feedback. CONCLUSIONS: These findings suggest that it is not the hypomimia and the absence of facial feedback per se, but a disruption of the facial feedback loop, that leads to the prominent emotion recognition deficit in PD patients.