Flipping the classroom in neurological bedside teaching: a prospective controlled study.

BACKGROUND: Bedside teaching is essential to foster core clinical competences in medical education, especially in Neurology. However, bedside skills are declining and new concepts to enhance the effectiveness of bedside teaching are needed, also in view of limited in-person teaching possibilities in the ongoing pandemic situation. If theoretical knowledge is taught prior to in-person sessions this might allow to better focus on practical application aspects during bedside teaching. We thus aimed to answer the question to what extent such an approach can enhance the effectiveness of neurological bedside teaching. METHODS: In this prospective controlled study, neurological bedside courses following a traditional and a flipped classroom (FC) approach were compared with regards to their effects on theoretical knowledge and practical skills of medical students. Evaluations were obtained from 161 students and their lecturers participating in a neurological bedside teaching course at a German university hospital between October 2020 and July 2021. Students were randomly assigned to course dates. However, the 74 students assigned to course dates from May to July 2021 completed a mandatory online preparation course prior to the bedside teaching. These students served as the interventional group (IG) and the remaining 87 students formed the control group (CG). Ratings of knowledge and skills provided by the students and their lecturers on numerical rating scales served as primary outcome measures. Moreover, the time needed to recapitulate theoretical contents during the in-person teaching session was assessed as a secondary outcome measure. Group comparisons were performed using t-statistics. RESULTS: Theoretical knowledge upon entering the course was rated significantly higher in the IG by the students (p < 0.001) and lecturers (p = 0.003). Lecturers also rated the practical skills of students in the IG significantly higher (p < 0.001). Furthermore, significantly less time was needed to recapitulate theoretical contents during the in-person session in the IG (p = 0.03). CONCLUSIONS: Using a FC approach enhances the effectiveness of in-person neurological bedside teaching. Thus, these concepts are particularly valuable in the ongoing pandemic situation. Moreover, they might allow to reuse e-learning contents developed during the pandemic and to develop future bedside teaching concepts.

Fatigue, depression, and pain in multiple sclerosis: How neuroinflammation translates into dysfunctional reward processing and anhedonic symptoms.

Fatigue, depression, and pain affect the majority of multiple sclerosis (MS) patients, which causes a substantial burden to patients and society. The pathophysiology of these symptoms is not entirely clear, and current treatments are only partially effective. Clinically, these symptoms share signs of anhedonia, such as reduced motivation and a lack of positive affect. In the brain, they are associated with overlapping structural and functional alterations in areas involved in reward processing. Moreover, neuroinflammation has been shown to directly impede monoaminergic neurotransmission that plays a key role in reward processing. Here, we review recent neuroimaging and neuroimmunological findings, which indicate that dysfunctional reward processing might represent a shared functional mechanism fostering the symptom cluster of fatigue, depression, and pain in MS. We propose a framework that integrates these findings with a focus on monoaminergic neurotransmission and discuss its therapeutic implications, limitations, and perspectives.

Effectiveness of non-bedside teaching during the COVID-19 pandemic: a quasi-experimental study.

BACKGROUND: The COVID-19 pandemic poses a huge challenge for clinical teaching due to contact restrictions and social distancing. Medical teachers have to balance potential risks and benefits of bedside teaching, especially in course formats intended to foster practical clinical skills. In this context, we aimed to address the question, whether presence-based teaching formats without patient involvement are suitable to teach practical skills. METHODS: In this quasi-experimental study, presence-based teaching formats with and without patient contact were retrospectively compared regarding their effects on medical students' theoretical knowledge and practical skills, i.e. the performance and clinical interpretation of the neurological exam. To this end, evaluations from 102 students and their lecturers participating in a neurological bedside teaching course at a German university hospital between October 2020 and April 2021 were obtained. Students were initially randomly assigned to course dates. However, 53 students assigned to courses in November and December 2020, were not able to go bedside due to contact restrictions. These students formed the interventional group and the remaining 49 students the control group. The primary outcome measures were students' overall grading of the course (school grades, 1-6) as well as ratings of knowledge and skills provided by the students themselves and their lecturers on a numerical rating scale (0-10). Comparison between groups was performed using frequentist and Bayesian t-statistics. RESULTS: The teaching format without patient contact received a significantly poorer overall grade by the students (p = 0.018). However, improvements in the students' self-ratings of knowledge and skills did not differ between the two formats (all p > 0.05, BF10max = 0.42). Moreover, especially practical skills were even rated significantly better in the group without patient contact by the lecturers (p < 0.001). CONCLUSIONS: Teaching formats without patient contact are less well-received by the students. However, they are able to teach practical skills regarding the performance and clinical interpretation of examination techniques. Still, the evaluations obtained might not adequately capture the importance of bedside teaching in preparing future physicians for their practice. Perspectively, hybrid teaching approaches including flipped-classroom concepts hold considerable potential to enhance effectiveness of bedside teaching in the present pandemic situation and in the future.

Prefrontal gamma oscillations reflect ongoing pain intensity in chronic back pain patients.

Chronic pain is a major health care issue characterized by ongoing pain and a variety of sensory, cognitive, and affective abnormalities. The neural basis of chronic pain is still not completely understood. Previous work has implicated prefrontal brain areas in chronic pain. Furthermore, prefrontal neuronal oscillations at gamma frequencies (60-90 Hz) have been shown to reflect the perceived intensity of longer lasting experimental pain in healthy human participants. In contrast, noxious stimulus intensity has been related to alpha (8-13 Hz) and beta (14-29 Hz) oscillations in sensorimotor areas. However, it is not fully understood how the intensity of ongoing pain as the key symptom of chronic pain is represented in the human brain. Here, we asked 31 chronic back pain patients to continuously rate their ongoing pain while simultaneously recording electroencephalography (EEG). Time-frequency analyses revealed a positive association between ongoing pain intensity and prefrontal beta and gamma oscillations. No association was found between pain and alpha or beta oscillations in sensorimotor areas. These findings indicate that ongoing pain as the key symptom of chronic pain is reflected by neuronal oscillations implicated in the subjective perception of longer lasting pain rather than by neuronal oscillations related to the processing of objective nociceptive input. The findings, thus, support a dissociation of pain intensity from nociceptive processing in chronic back pain patients. Furthermore, although possible confounds by muscle activity have to be taken into account, they might be useful for defining a neurophysiological marker of ongoing pain in the human brain.

Prevalence of neuropathic pain in early multiple sclerosis.

BACKGROUND: Pain is considered a frequent symptom in multiple sclerosis. Neuropathic pain is the type of pain most closely related to the pathology of multiple sclerosis and its prevalence estimates vary largely. OBJECTIVE: We prospectively assessed the prevalence of neuropathic pain in patients with early multiple sclerosis and investigated the association of neuropathic pain with other clinical parameters. METHODS: A total of 377 outpatients with multiple sclerosis at an early disease stage were included in this prospective study. Mean disease duration was 4.2 years, mean Expanded Disability Status Scale (EDSS) score was 1.6, 96.8% of patients were classified as having relapsing-remitting multiple sclerosis. Neuropathic pain was assessed using the PainDETECT questionnaire (PDQ). Depression, fatigue and cognition were assessed using the Beck Depression Inventory (BDI), the Fatigue Scale for Motor and Cognitive Functions (FSMC) and the Paced Auditory Serial Addition Test. RESULTS: PDQ scores indicative of neuropathic pain were found in 4.2% of patients. Regression analysis revealed EDSS, BDI and FMSC scores as strongest predictors of PDQ scores. CONCLUSIONS: Neuropathic pain appears to be less frequent in early multiple sclerosis than expected and is significantly associated with disability, depression and fatigue. The assessment and therapy of pain in multiple sclerosis should thus take into account neuropsychiatric symptoms already at early disease stages.

Resting-state EEG and MEG biomarkers of pathological fatigue - A transdiagnostic systematic review.

Fatigue is a highly prevalent and disabling symptom of many disorders and syndromes, resulting from different pathomechanisms. However, whether and how different mechanisms converge and result in similar symptomatology is only partially understood, and transdiagnostic biomarkers that could further the diagnosis and treatment of fatigue are lacking. We, therefore, performed a transdiagnostic systematic review (PROSPERO: CRD42022330113) of quantitative resting-state electroencephalography (EEG) and magnetoencephalography (MEG) studies in adult patients suffering from pathological fatigue in different disorders. Studies investigating fatigue in healthy participants were excluded. The risk of bias was assessed using a modified Newcastle-Ottawa Scale. Semi-quantitative data synthesis was conducted using modified albatross plots. After searching MEDLINE, Web of Science Core Collection, and EMBASE, 26 studies were included. Cross-sectional studies revealed increased brain activity at theta frequencies and decreased activity at alpha frequencies as potential diagnostic biomarkers. However, the risk of bias was high in many studies and domains. Together, this transdiagnostic systematic review synthesizes evidence on how resting-state M/EEG might serve as a diagnostic biomarker of pathological fatigue. Beyond, this review might help to guide future M/EEG studies on the development of fatigue biomarkers.

New concepts in neurology education: successful implementation of flipped classroom lectures.

In order to inspire and attract young people to Neurology, we must offer high-quality and attractive teaching! To improve neurological education at our Medical School (Technical University of Munich), we converted the main lecture into an e-learning concept using a flipped classroom model. Students had to prepare with a video and a text as well as answering multiple choice questions before each lecture. As a further incentive, students with ≥ 80% right answers in multiple choice questions received a bonus for the final exam. During the lectures, predominantely patient cases were discussed to apply, improve and enhance the previously acquired knowledge. The realignment of the main lecture in Neurology into a flipped classroom model was very successful and was further optimized in the following semesters based on the evaluations obtained for the new concept. Moreover, this enabled us to quickly switch to remote teaching during the COVID-19 pandemic, while still offering lectures of high quality. In addition, this new teaching concept attracts students for Neurology. Furthermore, the exemplary conversion of the Neurology main lecture to a flipped classroom concept also serves as best practice and motivation to adapt other courses in our faculty and far beyond.

Longitudinal resting-state electroencephalography in patients with chronic pain undergoing interdisciplinary multimodal pain therapy.

ABSTRACT: Chronic pain is a major healthcare issue posing a large burden on individuals and society. Converging lines of evidence indicate that chronic pain is associated with substantial changes of brain structure and function. However, it remains unclear which neuronal measures relate to changes of clinical parameters over time and could thus monitor chronic pain and treatment responses. We therefore performed a longitudinal study in which we assessed clinical characteristics and resting-state electroencephalography data of 41 patients with chronic pain before and 6 months after interdisciplinary multimodal pain therapy. We specifically assessed electroencephalography measures that have previously been shown to differ between patients with chronic pain and healthy people. These included the dominant peak frequency; the amplitudes of neuronal oscillations at theta, alpha, beta, and gamma frequencies; as well as graph theory-based measures of brain network organization. The results show that pain intensity, pain-related disability, and depression were significantly improved after interdisciplinary multimodal pain therapy. Bayesian hypothesis testing indicated that these clinical changes were not related to changes of the dominant peak frequency or amplitudes of oscillations at any frequency band. Clinical changes were, however, associated with an increase in global network efficiency at theta frequencies. Thus, changes in chronic pain might be reflected by global network changes in the theta band. These longitudinal insights further the understanding of the brain mechanisms of chronic pain. Beyond, they might help to identify biomarkers for the monitoring of chronic pain.

Modulating Brain Rhythms of Pain Using Transcranial Alternating Current Stimulation (tACS) - A Sham-Controlled Study in Healthy Human Participants.

Chronic pain is a major health care problem. A better mechanistic understanding and new treatment approaches are urgently needed. In the brain, pain has been associated with neural oscillations at alpha and gamma frequencies, which can be targeted using transcranial alternating current stimulation (tACS). Thus, we investigated the potential of tACS to modulate pain and pain-related autonomic activity in an experimental model of chronic pain in 29 healthy participants. In 6 recording sessions, participants completed a tonic heat pain paradigm and simultaneously received tACS over prefrontal or somatosensory cortices at alpha or gamma frequencies or sham tACS. Concurrently, pain ratings and autonomic responses were collected. Using the present setup, tACS did not modulate pain or autonomic responses. Bayesian statistics confirmed a lack of tACS effects in most conditions. The only exception was alpha tACS over somatosensory cortex where evidence was inconclusive. Taken together, we did not find significant tACS effects on tonic experimental pain in healthy humans. Based on our present and previous findings, further studies might apply refined stimulation protocols targeting somatosensory alpha oscillations. TRIAL REGISTRATION: The study protocol was pre-registered at ClinicalTrials.gov (NCT03805854). PERSPECTIVE: Modulating brain oscillations is a promising approach for the treatment of pain. We therefore applied transcranial alternating current stimulation (tACS) to modulate experimental pain in healthy participants. However, tACS did not modulate pain, autonomic responses, or EEG oscillations. These findings help to shape future tACS studies for the treatment of pain.

Dynamics of brain function in patients with chronic pain assessed by microstate analysis of resting-state electroencephalography.

ABSTRACT: Chronic pain is a highly prevalent and severely disabling disease that is associated with substantial changes of brain function. Such changes have mostly been observed when analyzing static measures of resting-state brain activity. However, brain activity varies over time, and it is increasingly recognized that the temporal dynamics of brain activity provide behaviorally relevant information in different neuropsychiatric disorders. Here, we therefore investigated whether the temporal dynamics of brain function are altered in chronic pain. To this end, we applied microstate analysis to eyes-open and eyes-closed resting-state electroencephalography data of 101 patients suffering from chronic pain and 88 age- and sex-matched healthy controls. Microstate analysis describes electroencephalography activity as a sequence of a limited number of topographies termed microstates that remain stable for tens of milliseconds. Our results revealed that sequences of 5 microstates, labelled with the letters A to E, consistently described resting-state brain activity in both groups in the eyes-closed condition. Bayesian analysis of the temporal characteristics of microstates revealed that microstate D has a less predominant role in patients than in controls. As microstate D has previously been related to attentional networks and functions, these abnormalities might relate to dysfunctional attentional processes in chronic pain. Subgroup analyses replicated microstate D changes in patients with chronic back pain, while patients with chronic widespread pain did not show microstates alterations. Together, these findings add to the understanding of the pathophysiology of chronic pain and point to changes of brain dynamics specific to certain types of chronic pain.

Longitudinal prevalence and determinants of pain in multiple sclerosis: results from the German National Multiple Sclerosis Cohort study.

Pain is frequent in multiple sclerosis (MS) and includes different types, with neuropathic pain (NP) being most closely related to MS pathology. However, prevalence estimates vary largely, and causal relationships between pain and biopsychosocial factors in MS are largely unknown. Longitudinal studies might help to clarify the prevalence and determinants of pain in MS. To this end, we analyzed data from 410 patients with newly diagnosed clinically isolated syndrome or relapsing-remitting MS participating in the prospective multicenter German National MS Cohort Study (NationMS) at baseline and after 4 years. Pain was assessed by self-report using the PainDETECT Questionnaire. Neuropsychiatric assessment included tests for fatigue, depression, and cognition. In addition, sociodemographic and clinical data were obtained. Prevalence of pain of any type was 40% and 36% at baseline and after 4 years, respectively, whereas prevalence of NP was 2% and 5%. Pain of any type and NP were both strongly linked to fatigue, depression, and disability. This link was even stronger after 4 years than at baseline. Moreover, changes in pain, depression, and fatigue were highly correlated without any of these symptoms preceding the others. Taken together, pain of any type seems to be much more frequent than NP in early nonprogressive MS. Moreover, the close relationship between pain, fatigue, and depression in MS should be considered for treatment decisions and future research on a possible common pathophysiology.

Perceptual and motor responses directly and indirectly mediate the effects of noxious stimuli on autonomic responses.

Autonomic responses are an essential component of pain. They serve its adaptive function by regulating homeostasis and providing resources for protective and recuperative responses to noxious stimuli. To be adaptive and flexible, autonomic responses are not only determined by noxious stimulus characteristics, but likely also shaped by perceptual and motor responses to noxious stimuli. However, it is not fully known how noxious stimulus characteristics, perceptual responses, and motor responses interact in shaping autonomic responses. To address this question, we collected perceptual, motor, and autonomic responses to brief noxious laser stimuli of different intensities in 47 healthy human participants. Multilevel 2-path mediation analyses revealed that perceptual, but not motor responses mediated the translation of noxious stimuli into autonomic responses. Multilevel 3-path mediation analyses further specified that motor responses indirectly related to autonomic responses through their close association with perceptual responses. These findings confirm that autonomic responses are not only a reflexive reaction to noxious stimuli, but directly and indirectly shaped by perceptual and motor responses, respectively. These effects of motor and perceptual processes on autonomic responses likely allow for the integration of contextual processes into protective and regulatory autonomic responses, aiding adaptive and flexible coping with threat.

Brain dysfunction in chronic pain patients assessed by resting-state electroencephalography.

Chronic pain is a common and severely disabling disease whose treatment is often unsatisfactory. Insights into the brain mechanisms of chronic pain promise to advance the understanding of the underlying pathophysiology and might help to develop disease markers and novel treatments. Here, we systematically exploited the potential of electroencephalography to determine abnormalities of brain function during the resting state in chronic pain. To this end, we performed state-of-the-art analyses of oscillatory brain activity, brain connectivity, and brain networks in 101 patients of either sex suffering from chronic pain. The results show that global and local measures of brain activity did not differ between chronic pain patients and a healthy control group. However, we observed significantly increased connectivity at theta (4-8 Hz) and gamma (>60 Hz) frequencies in frontal brain areas as well as global network reorganization at gamma frequencies in chronic pain patients. Furthermore, a machine learning algorithm could differentiate between patients and healthy controls with an above-chance accuracy of 57%, mostly based on frontal connectivity. These results suggest that increased theta and gamma synchrony in frontal brain areas are involved in the pathophysiology of chronic pain. Although substantial challenges concerning the reproducibility of the findings and the accuracy, specificity, and validity of potential electroencephalography-based disease markers remain to be overcome, our study indicates that abnormal frontal synchrony at theta and gamma frequencies might be promising targets for noninvasive brain stimulation and/or neurofeedback approaches.

Motor Responses to Noxious Stimuli Shape Pain Perception in Chronic Pain Patients.

Pain serves vital protective functions, which crucially depend on appropriate motor responses to noxious stimuli. Such responses not only depend on but can themselves shape the perception of pain. In chronic pain, perception is often decoupled from noxious stimuli and motor responses are no longer protective, which suggests that the relationships between noxious stimuli, pain perception, and behavior might be changed. We here performed a simple experiment to quantitatively assess the relationships between noxious stimuli, perception and behavior in 22 chronic pain patients and 22 age-matched healthy human participants. Brief noxious and tactile stimuli were applied to the participants' hands and participants performed speeded motor responses and provided perceptual ratings of the stimuli. Multi-level moderated mediation analyses assessed the relationships between stimulus intensity, perceptual ratings and reaction times for both stimulus types. The results revealed a significantly stronger involvement of motor responses in the translation of noxious stimuli into perception than in the translation of tactile stimuli into perception. This significant influence of motor responses on pain perception was found for both chronic pain patients and healthy participants. Thus, stimulus-perception-behavior relationships appear to be at least partially preserved in chronic pain patients and motor-related as well as behavioral interventions might harness these functional relationships to modulate pain perception.

Dopamine precursor depletion influences pain affect rather than pain sensation.

Pain is a multidimensional experience, which includes sensory, cognitive, and affective aspects. Converging lines of evidence indicate that dopaminergic neurotransmission plays an important role in human pain perception. However, the precise effects of dopamine on different aspects of pain perception remain to be elucidated. To address this question, we experimentally decreased dopaminergic neurotransmission in 22 healthy human subjects using Acute Phenylalanine and Tyrosine Depletion (APTD). During APTD and a control condition we applied brief painful laser stimuli to the hand, assessed different aspects of pain perception, and recorded electroencephalographic responses. APTD-induced decreases of cerebral dopaminergic activity did not influence sensory aspects of pain perception. In contrast, APTD yielded increases of pain unpleasantness. The increases of unpleasantness ratings positively correlated with effectiveness of APTD. Our finding of an influence of dopaminergic neurotransmission on affective but not sensory aspects of phasic pain suggests that analgesic effects of dopamine might be mediated by indirect effects on pain affect rather than by direct effects on ascending nociceptive signals. These findings contribute to our understanding of the complex relationship between dopamine and pain perception, which may play a role in various clinical pain states.