Pub Date : 2024-09-18DOI: 10.1101/2024.09.16.24313761
Katrina S Monroe, Dawn M Schiehser, Aaron W Parr, Alan N Simmons, Chelsea C Hays Weeks, Barbara A Bailey, Bahar Shahidi
Headache is the most common type of pain following mild traumatic brain injury. Roughly half of those with persistent post-traumatic headache (PPTH) also report neck pain which is associated with greater severity and functional impact of headache. This observational cohort study aimed to identify biological phenotypes to help inform mechanism-based approaches in the management of PPTH with and without concomitant neck pain. Thirty-three military Veterans (mean (SD) = 37±16 years, 29 males) with PPTH completed a clinical assessment, quantitative sensory testing, and magnetic resonance imaging of the brain and cervical spine. Multidimensional phenotyping was performed using a Random Forest analysis and Partitioning Around Medoids (PAM) clustering of input features from three biologic domains: 1) resting state functional connectivity (rsFC) of the periaqueductal gray (PAG), 2) quality and size of cervical muscles, and 3) mechanical pain sensitivity and central modulation of pain. Two subgroups were distinguished by biological features that included forehead pressure pain threshold and rsFC between the PAG and selected nodes within the default mode, salience, and sensorimotor networks. Compared to the High Pain Coping group, the Low Pain Coping group exhibited higher pain-related anxiety (p=0.009), higher pain catastrophizing (p=0.004), lower pain self-efficacy (p=0.010), and greater headache-related disability (p=0.012). Findings suggest that greater functional connectivity of pain modulation networks involving the PAG combined with impairments in craniofacial pain sensitivity, but not cervical muscle health, distinguish a clinically important subgroup of individuals with PPTH who are less able to cope with pain and more severely impacted by headache.
{"title":"Biological markers of brain network connectivity and pain sensitivity distinguish low coping from high coping Veterans with persistent post-traumatic headache","authors":"Katrina S Monroe, Dawn M Schiehser, Aaron W Parr, Alan N Simmons, Chelsea C Hays Weeks, Barbara A Bailey, Bahar Shahidi","doi":"10.1101/2024.09.16.24313761","DOIUrl":"https://doi.org/10.1101/2024.09.16.24313761","url":null,"abstract":"Headache is the most common type of pain following mild traumatic brain injury. Roughly half of those with persistent post-traumatic headache (PPTH) also report neck pain which is associated with greater severity and functional impact of headache. This observational cohort study aimed to identify biological phenotypes to help inform mechanism-based approaches in the management of PPTH with and without concomitant neck pain. Thirty-three military Veterans (mean (SD) = 37±16 years, 29 males) with PPTH completed a clinical assessment, quantitative sensory testing, and magnetic resonance imaging of the brain and cervical spine. Multidimensional phenotyping was performed using a Random Forest analysis and Partitioning Around Medoids (PAM) clustering of input features from three biologic domains: 1) resting state functional connectivity (rsFC) of the periaqueductal gray (PAG), 2) quality and size of cervical muscles, and 3) mechanical pain sensitivity and central modulation of pain. Two subgroups were distinguished by biological features that included forehead pressure pain threshold and rsFC between the PAG and selected nodes within the default mode, salience, and sensorimotor networks. Compared to the High Pain Coping group, the Low Pain Coping group exhibited higher pain-related anxiety (p=0.009), higher pain catastrophizing (p=0.004), lower pain self-efficacy (p=0.010), and greater headache-related disability (p=0.012). Findings suggest that greater functional connectivity of pain modulation networks involving the PAG combined with impairments in craniofacial pain sensitivity, but not cervical muscle health, distinguish a clinically important subgroup of individuals with PPTH who are less able to cope with pain and more severely impacted by headache.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1101/2024.09.16.24313764
Shihao Yang, Yaxi Luo, Meng Jiao, Neel Fotedar, Vikram R. Rao, Xinglong Ju, Shasha Wu, Xiaochen Xian, Hai Sun, Ioannis Karakis, Danilo Bernardo, Josh Laing, Patrick Kwan, Felix Rosenow, Feng Liu
Significance: Seizure semiology, the study of signs and clinical manifestations during seizure episodes, provides crucial information for inferring the location of epileptogenic zone (EZ). Given the descriptive nature of seizure semiology and recent advancements in large language models (LLMs), there is a potential to improve the localization accuracy of EZ by leveraging LLMs for interpreting the seizure semiology and mapping its descriptions to the corresponding EZs. This study introduces the Epilepsy Semiology Large Language Model, or EpiSemoLLM, the first fine-tuned LLM designed specifically for this purpose, built upon the Mistral-7B foundational model. Method: A total of 865 cases, each containing seizure semiology descriptions paired with validated EZs via intracranial EEG recording and postoperative surgery outcome, were collected from 189 publications. These collected data cohort of seizure semiology descriptions and EZs, as the high-quality domain specific data, is used to fine-tune the foundational LLM to improve its ability to predict the most likely EZs. To evaluate the performance of the fine-tuned EpiSemoLLM, 100 well-defined cases were tested by comparing the responses from EpiSemoLLM with those from a panel of 5 epileptologists. The responses were graded using the rectified reliability score (rRS) and regional accuracy rate (RAR). Additionally, the performance of EpiSemoLLM was compared with its foundational model, Mistral-7B, and various versions of ChatGPT, Llama as other representative LLMs. Result: In the comparison with a panel of epileptologists, EpiSemoLLM achieved the following score for regional accuracy rates (RAR) with zero-shot prompts: 60.71% for the frontal lobe, 83.33% for the temporal lobe, 63.16% for the occipital lobe, 45.83% for the parietal lobe, 33.33% for the insular cortex, and 28.57% for the cingulate cortex; and mean rectified reliability score (rRS) 0.291. In comparison, the epileptologists' averaged RAR scores were 64.83% for the frontal lobe, 52.22% for the temporal lobe, 60.00% for the occipital lobe, 42.50% for the parietal lobe, 46.00% for the insular cortex, and 8.57% for the cingulate cortex; and rectified reliability score (rRS) with mean of 0.148. Notably, the fine-tuned EpiSemoLLM outperformed its foundational LLM, Mistral-7B-instruct, and various versions of ChatGPT and Llama, particularly in localizing EZs in the insular and cingulate cortex. EpiSemoLLM offers valuable information for presurgical evaluations by identifying the most likely EZ location based on seizure semiology. Conclusion: EpiSemoLLM demonstrates comparable performance to epileptologists in inferring EZs from patients' seizure semiology, highlighting its value in epilepsy presurgical assessment. EpiSemoLLM outperformed epileptologists in interpreting seizure semiology with EZs originating from the temporal and parietal lobes, as well as the insular cortex. Conversely, epileptologists outperformed EpiSemoLLM regarding EZ locali
{"title":"EpiSemoLLM: A Fine-tuned Large Language Model for Epileptogenic Zone Localization Based on Seizure Semiology with a Performance Comparable to Epileptologists","authors":"Shihao Yang, Yaxi Luo, Meng Jiao, Neel Fotedar, Vikram R. Rao, Xinglong Ju, Shasha Wu, Xiaochen Xian, Hai Sun, Ioannis Karakis, Danilo Bernardo, Josh Laing, Patrick Kwan, Felix Rosenow, Feng Liu","doi":"10.1101/2024.09.16.24313764","DOIUrl":"https://doi.org/10.1101/2024.09.16.24313764","url":null,"abstract":"Significance: Seizure semiology, the study of signs and clinical manifestations during seizure episodes, provides crucial information for inferring the location of epileptogenic zone (EZ). Given the descriptive nature of seizure semiology and recent advancements in large language models (LLMs), there is a potential to improve the localization accuracy of EZ by leveraging LLMs for interpreting the seizure semiology and mapping its descriptions to the corresponding EZs. This study introduces the Epilepsy Semiology Large Language Model, or EpiSemoLLM, the first fine-tuned LLM designed specifically for this purpose, built upon the Mistral-7B foundational model.\u0000Method: A total of 865 cases, each containing seizure semiology descriptions paired with validated EZs via intracranial EEG recording and postoperative surgery outcome, were collected from 189 publications. These collected data cohort of seizure semiology descriptions and EZs, as the high-quality domain specific data, is used to fine-tune the foundational LLM to improve its ability to predict the most likely EZs. To evaluate the performance of the fine-tuned EpiSemoLLM, 100 well-defined cases were tested by comparing the responses from EpiSemoLLM with those from a panel of 5 epileptologists. The responses were graded using the rectified reliability score (rRS) and regional accuracy rate (RAR). Additionally, the performance of EpiSemoLLM was compared with its foundational model, Mistral-7B, and various versions of ChatGPT, Llama as other representative LLMs.\u0000Result: In the comparison with a panel of epileptologists, EpiSemoLLM achieved the following score for regional accuracy rates (RAR) with zero-shot prompts: 60.71% for the frontal lobe, 83.33% for the temporal lobe, 63.16% for the occipital lobe, 45.83% for the parietal lobe, 33.33% for the insular cortex, and 28.57% for the cingulate cortex; and mean rectified reliability score (rRS) 0.291. In comparison, the epileptologists' averaged RAR scores were 64.83% for the frontal lobe, 52.22% for the temporal lobe, 60.00% for the occipital lobe, 42.50% for the parietal lobe, 46.00% for the insular cortex, and 8.57% for the cingulate cortex; and rectified reliability score (rRS) with mean of 0.148. Notably, the fine-tuned EpiSemoLLM outperformed its foundational LLM, Mistral-7B-instruct, and various versions of ChatGPT and Llama, particularly in localizing EZs in the insular and cingulate cortex. EpiSemoLLM offers valuable information for presurgical evaluations by identifying the most likely EZ location based on seizure semiology.\u0000Conclusion: EpiSemoLLM demonstrates comparable performance to epileptologists in inferring EZs from patients' seizure semiology, highlighting its value in epilepsy presurgical assessment. EpiSemoLLM outperformed epileptologists in interpreting seizure semiology with EZs originating from the temporal and parietal lobes, as well as the insular cortex. Conversely, epileptologists outperformed EpiSemoLLM regarding EZ locali","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1101/2024.09.16.24313705
idris demirsoy, Ali Ezzati, Bhargav Nallapu, Elham Ghanbare, Babak Khorsand
Background: Alzheimer's Disease (AD) has a lengthy asymptomatic preclinical phase during which individuals may show pathological signs like β-amyloid (Aβ) pathology and tau tangles without noticeable objective cognitive impairments. Subjective cognitive impairment reports may offer valuable and early insights into individuals' cognitive functioning and serve as indicators of early stages of cognitive decline. Objective: To investigate the associations of the item-level response to Cognitive Function Index (CFI) by participant and study partner with tau pathology and adjusted hippocampal volume (HVa). Method: Participants were 339 cognitively unimpaired, Aβ positive, individuals enrolled in the Anti-Amyloid Asymptomatic Alzheimer's (A4) Study who underwent tau-PET imaging. Participants and their study partners assessed subjective changes in cognition and function over the past year using the 15-item CFI questionnaire. For each CFI item, the relationship among tau, HVa, and CFI reports was investigated. Result: Participants were on average 72.38 (SD = 4.87) years old, 58.1% were female, and 23.6% were tau positive. Higher tauMTL was significantly associated with participant report of decline on three CFI items including depending on written notes, seeing a doctor for memory concern, and feeling lost while navigating. Higher tauMTL was associated with study partner report of decline on two different items: needing help from others to remember appointments/occasions and asking same questions. Additionally, HVa was linked to challenges with driving for participants and noticeable memory decline for study partners. Conclusion: We showed that early changes reported on specific items of the CFI are associated with higher tauMTL and lower HVa in Aβ+ participants. Different CFI items were associated with tau and hippocampal volume for participants and study partners, highlighting the importance of both perspective.
{"title":"Association of Item-Level Responses to Cognitive Function Index with Tau Pathology and Hippocampal volume in The A4 Study","authors":"idris demirsoy, Ali Ezzati, Bhargav Nallapu, Elham Ghanbare, Babak Khorsand","doi":"10.1101/2024.09.16.24313705","DOIUrl":"https://doi.org/10.1101/2024.09.16.24313705","url":null,"abstract":"Background: Alzheimer's Disease (AD) has a lengthy asymptomatic preclinical phase during which individuals may show pathological signs like β-amyloid (Aβ) pathology and tau tangles without noticeable objective cognitive impairments. Subjective cognitive impairment reports may offer valuable and early insights into individuals' cognitive functioning and serve as indicators of early stages of cognitive decline.\u0000Objective: To investigate the associations of the item-level response to Cognitive Function Index (CFI) by participant and study partner with tau pathology and adjusted hippocampal volume (HVa).\u0000Method: Participants were 339 cognitively unimpaired, Aβ positive, individuals enrolled in the Anti-Amyloid Asymptomatic Alzheimer's (A4) Study who underwent tau-PET imaging. Participants and their study partners assessed subjective changes in cognition and function over the past year using the 15-item CFI questionnaire. For each CFI item, the relationship among tau, HVa, and CFI reports was investigated. Result: Participants were on average 72.38 (SD = 4.87) years old, 58.1% were female, and 23.6% were tau positive. Higher tauMTL was significantly associated with participant report of decline on three CFI items including depending on written notes, seeing a doctor for memory concern, and feeling lost while navigating. Higher tauMTL was associated with study partner report of decline on two different items: needing help from others to remember appointments/occasions and asking same questions. Additionally, HVa was linked to challenges with driving for participants and noticeable memory decline for study partners.\u0000Conclusion: We showed that early changes reported on specific items of the CFI are associated with higher tauMTL and lower HVa in Aβ+ participants. Different CFI items were associated with tau and hippocampal volume for participants and study partners, highlighting the importance of both perspective.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1101/2024.09.16.24313753
Sophie Sun, Victoria Madge, Jelena Djordjevic, Jean-François Gagnon, D. Louis Collins, Alain Dagher, Madeleine Sharp
The substantia nigra and locus coeruleus are among the first brain regions to degenerate in Parkinson's disease. This has important implications for early cognitive deficits as these nuclei are sources of ascending neuromodulators (i.e., dopamine and noradrenaline) that support various cognitive functions like learning, memory, and executive function. However, because most studies of the relationship between patterns of degeneration and cognition have either studied these neuromodulator systems in isolation or studied specific cognitive domains in isolation, it is unknown if degeneration in the substantia nigra and degeneration in the locus coeruleus independently and selectively contribute to different cognitive deficits in Parkinson's disease. To address this gap, we tested people with Parkinson's disease and older adults on tasks of positive reinforcement learning, attention/working memory, executive function, and memory to measure performance in domains of cognition specifically thought to be related to dopaminergic and noradrenergic function. Participants also underwent neuromelanin-sensitive magnetic resonance imaging which provides a measure of degeneration of dopamine neurons in the substantia nigra and of noradrenergic neurons in the locus coeruleus. Brain-behaviour relationships were evaluated by separate linear regressions predicting cognitive performance in each domain from substantia nigra and locus coeruleus neuromelanin signal intensities controlling for age, sex, and education. As expected, Parkinson's disease patients had significantly slower learning from positive feedback and lower performance on tests of attention/working memory, executive function, and memory than controls. Parkinson's patients also had lower neuromelanin signal intensity in the substantia nigra and locus coeruleus. Examining brain-behaviour relationships, we found that reduced neuromelanin signal in the substantia nigra in Parkinson's disease patients was independently associated with impaired positive reinforcement learning, controlling for changes in the locus coeruleus, but was not associated with other domains of cognition. In contrast, reduced neuromelanin signal in the locus coeruleus was independently associated with impairments in attention/working memory and executive function, controlling for changes in the substantia nigra, but not with reinforcement learning performance. These results show that substantia nigra degeneration and locus coeruleus degeneration independently and selectively contribute to cognitive deficits and therefore suggests that individual differences in the degree of neurodegeneration in these nuclei could explain the significant heterogeneity that exists in the cognitive and behavioural manifestations of Parkinson's disease. These findings also highlight the potential value of leveraging known brain-behaviour relationships to develop performance-based measures of cognition that reflect underlying patterns of neurodegeneration.
{"title":"Selective effects of dopaminergic and noradrenergic degeneration on cognition in Parkinson's disease","authors":"Sophie Sun, Victoria Madge, Jelena Djordjevic, Jean-François Gagnon, D. Louis Collins, Alain Dagher, Madeleine Sharp","doi":"10.1101/2024.09.16.24313753","DOIUrl":"https://doi.org/10.1101/2024.09.16.24313753","url":null,"abstract":"The substantia nigra and locus coeruleus are among the first brain regions to degenerate in Parkinson's disease. This has important implications for early cognitive deficits as these nuclei are sources of ascending neuromodulators (i.e., dopamine and noradrenaline) that support various cognitive functions like learning, memory, and executive function. However, because most studies of the relationship between patterns of degeneration and cognition have either studied these neuromodulator systems in isolation or studied specific cognitive domains in isolation, it is unknown if degeneration in the substantia nigra and degeneration in the locus coeruleus independently and selectively contribute to different cognitive deficits in Parkinson's disease. To address this gap, we tested people with Parkinson's disease and older adults on tasks of positive reinforcement learning, attention/working memory, executive function, and memory to measure performance in domains of cognition specifically thought to be related to dopaminergic and noradrenergic function. Participants also underwent neuromelanin-sensitive magnetic resonance imaging which provides a measure of degeneration of dopamine neurons in the substantia nigra and of noradrenergic neurons in the locus coeruleus. Brain-behaviour relationships were evaluated by separate linear regressions predicting cognitive performance in each domain from substantia nigra and locus coeruleus neuromelanin signal intensities controlling for age, sex, and education.\u0000As expected, Parkinson's disease patients had significantly slower learning from positive feedback and lower performance on tests of attention/working memory, executive function, and memory than controls. Parkinson's patients also had lower neuromelanin signal intensity in the substantia nigra and locus coeruleus. Examining brain-behaviour relationships, we found that reduced neuromelanin signal in the substantia nigra in Parkinson's disease patients was independently associated with impaired positive reinforcement learning, controlling for changes in the locus coeruleus, but was not associated with other domains of cognition. In contrast, reduced neuromelanin signal in the locus coeruleus was independently associated with impairments in attention/working memory and executive function, controlling for changes in the substantia nigra, but not with reinforcement learning performance. These results show that substantia nigra degeneration and locus coeruleus degeneration independently and selectively contribute to cognitive deficits and therefore suggests that individual differences in the degree of neurodegeneration in these nuclei could explain the significant heterogeneity that exists in the cognitive and behavioural manifestations of Parkinson's disease. These findings also highlight the potential value of leveraging known brain-behaviour relationships to develop performance-based measures of cognition that reflect underlying patterns of neurodegeneration.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-15DOI: 10.1101/2024.09.14.24313588
Louis Beers, Jana Bouvain, Claus Reinsberger, Rasmus Jakobsmeyer, Rani Sarkis, Jong Woo Lee
Objective: To determine the relationship between electrodermal activity (EDA) and cardiac troponin in patients with paroxysmal sympathetic hyperactivity (PSH). Methods: This was a study with prospectively-identified patients and a retrospective analysis utilizing electrodermal data taken from the wrist-worn Empatica E4 device (Empatica Srl, Milan, Italy) and troponin values obtained from critically-ill patients with suspected PSH (N=10). The maximum EDA value and temporally-nearest cardiac troponin were correlated to test for significance using Pearson correlation coefficient. Results: A moderate correlation was found between EDA and troponin in 10 patients using the most temporally-proximal troponin to each patient's maximal EDA (r=0.634; p = 0.049). A subanalysis was performed excluding any patients whose available troponin data did not fall within seven days of their maximal EDA, which demonstrated a strong correlation (r=0.943; p = 0.005). No relationships between troponin and pulse, blood pressure, or temperature were found. Conclusions: This study establishes an association between wrist-worn EDA and a measure of possible myocardial injury in critically ill patients with PSH. Patients with elevated sympathetic activity may be at increased risk for concurrent cardiac injury or dysfunction, and thus EDA data from wrist-worn monitors may provide clinically significant data regarding sympathetic function.
{"title":"The Relationship Between Electrodermal Activity and Cardiac Troponin in Patients with Paroxysmal Sympathetic Hyperactivity","authors":"Louis Beers, Jana Bouvain, Claus Reinsberger, Rasmus Jakobsmeyer, Rani Sarkis, Jong Woo Lee","doi":"10.1101/2024.09.14.24313588","DOIUrl":"https://doi.org/10.1101/2024.09.14.24313588","url":null,"abstract":"Objective:\u0000To determine the relationship between electrodermal activity (EDA) and cardiac troponin in patients with paroxysmal sympathetic hyperactivity (PSH). Methods:\u0000This was a study with prospectively-identified patients and a retrospective analysis utilizing electrodermal data taken from the wrist-worn Empatica E4 device (Empatica Srl, Milan, Italy) and troponin values obtained from critically-ill patients with suspected PSH (N=10). The maximum EDA value and temporally-nearest cardiac troponin were correlated to test for significance using Pearson correlation coefficient. Results:\u0000A moderate correlation was found between EDA and troponin in 10 patients using the most temporally-proximal troponin to each patient's maximal EDA (r=0.634; p = 0.049). A subanalysis was performed excluding any patients whose available troponin data did not fall within seven days of their maximal EDA, which demonstrated a strong correlation (r=0.943; p = 0.005). No relationships between troponin and pulse, blood pressure, or temperature were found. Conclusions:\u0000This study establishes an association between wrist-worn EDA and a measure of possible myocardial injury in critically ill patients with PSH. Patients with elevated sympathetic activity may be at increased risk for concurrent cardiac injury or dysfunction, and thus EDA data from wrist-worn monitors may provide clinically significant data regarding sympathetic function.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-14DOI: 10.1101/2024.09.13.24313431
Bhooma Rajagopalan Aravamuthan, Emma Lott, Esra Pehlivan, Keerthana Chintalapati, Deborah Grenard, Desiree Roge, Rose Gelineau-Morel, Dante Kyle, Christie Becu, Michael C Kruer, Linn Katus, Paul Gross, Amy F. Bailes, Cerebral Palsy Research Network
Background and Objectives: Dystonia is a common, debilitating, and often treatment refractory motor symptom of cerebral palsy (CP), affecting 70-80% of this population based on research assessments. However, routine clinical evaluation for dystonia in CP has failed to match these expected numbers. Addressing this diagnostic gap is a medical imperative because the presence of dystonia rules in or out certain treatments for motor symptoms in CP. Therefore, our objective was to optimize rates of clinical dystonia screening to improve rates of clinical dystonia diagnosis. Methods: Using the quality improvement (QI) infrastructure of the Cerebral Palsy Research Network (CPRN), we developed and implemented interventions to increase the documentation percentage of five features of dystonia in young people with CP, aged 3-21 years old. This QI initiative was implemented by seven physiatry and pediatric movement disorders physicians at four tertiary-care pediatric hospitals between 10/10/21 and 7/1/23. We collected visit data cross-sectionally across all participating sites every 2 weeks and tracked our progress using control charts. Results: We assessed 847 unique visits, mostly for established patients (719/847, 85%) who were 9.2 years old on average (95% CI 8.8-9.5). By 4/10/22, the mean percentage of dystonia screening elements documented across all sites rose from 39% to 90% and the mean percentage of visits explicitly documenting the presence or absence of dystonia rose from 65% to 94%. By 10/23/22, the percentage of visits diagnosing dystonia rose from 57% to 74%. These increases were all sustained through the end of the study period in 7/1/23. Discussion: Using a rigorous QI-driven process across four member sites of a North American learning health network (CPRN), we demonstrated that we could increase screening for dystonia and that this was associated with increased clinical dystonia diagnosis, matching expected research-based rates. We propose that similar screening should take place across all sites caring for people with CP.
{"title":"Multi-center improvement in screening for dystonia in young people with cerebral palsy","authors":"Bhooma Rajagopalan Aravamuthan, Emma Lott, Esra Pehlivan, Keerthana Chintalapati, Deborah Grenard, Desiree Roge, Rose Gelineau-Morel, Dante Kyle, Christie Becu, Michael C Kruer, Linn Katus, Paul Gross, Amy F. Bailes, Cerebral Palsy Research Network","doi":"10.1101/2024.09.13.24313431","DOIUrl":"https://doi.org/10.1101/2024.09.13.24313431","url":null,"abstract":"Background and Objectives: Dystonia is a common, debilitating, and often treatment refractory motor symptom of cerebral palsy (CP), affecting 70-80% of this population based on research assessments. However, routine clinical evaluation for dystonia in CP has failed to match these expected numbers. Addressing this diagnostic gap is a medical imperative because the presence of dystonia rules in or out certain treatments for motor symptoms in CP. Therefore, our objective was to optimize rates of clinical dystonia screening to improve rates of clinical dystonia diagnosis. Methods: Using the quality improvement (QI) infrastructure of the Cerebral Palsy Research Network (CPRN), we developed and implemented interventions to increase the documentation percentage of five features of dystonia in young people with CP, aged 3-21 years old. This QI initiative was implemented by seven physiatry and pediatric movement disorders physicians at four tertiary-care pediatric hospitals between 10/10/21 and 7/1/23. We collected visit data cross-sectionally across all participating sites every 2 weeks and tracked our progress using control charts. Results: We assessed 847 unique visits, mostly for established patients (719/847, 85%) who were 9.2 years old on average (95% CI 8.8-9.5). By 4/10/22, the mean percentage of dystonia screening elements documented across all sites rose from 39% to 90% and the mean percentage of visits explicitly documenting the presence or absence of dystonia rose from 65% to 94%. By 10/23/22, the percentage of visits diagnosing dystonia rose from 57% to 74%. These increases were all sustained through the end of the study period in 7/1/23. Discussion: Using a rigorous QI-driven process across four member sites of a North American learning health network (CPRN), we demonstrated that we could increase screening for dystonia and that this was associated with increased clinical dystonia diagnosis, matching expected research-based rates. We propose that similar screening should take place across all sites caring for people with CP.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background and Objectives Autoimmune-associated epilepsy (AAE), a condition which responds favorably to immune therapies but not traditional anti-seizure interventions, is emerging as a significant contributor to cases of drug-resistant epilepsy. Current standards for the diagnosis of AAE rely on screening for known neuronal autoantibodies in patient serum or cerebrospinal fluid. However, this diagnostic method fails to capture a subset of drug-resistant epilepsy patients with suspected AAE who respond to immunotherapy yet remain seronegative (snAAE) for known autoantibodies. Methods To identify potential biomarkers for snAAE, we evaluated the most comprehensive panel of assayed cytokines and autoantibodies to date, comparing patients with snAAE, anti-seizure medication (ASM) responsive epilepsy, and patients with other neuroinflammatory diseases. Results We found a unique signature of 14 cytokines significantly elevated in snAAE patients including: GM-CSF, MCP-2/CCL8, MIP-1a/CCL3, IL-1RA, IL-6, IL-8, IL-9, IL-10, IL-15, IL-20, VEGF-A, TNF-b, LIF, and TSLP. Based on prior literature, we highlight IL-6, IL-8, IL-10, IL-13, VEGF-A, and TNF-b as potentially actionable cytokine biomarkers for snAAE, which could be of diagnostic utility in clinical evaluations of snAAE patients. Autoantibody-ome screening failed to identify autoantibodies targeting neuronal channel proteins in snAAE patients. Interestingly, ASM-responsive epilepsy patients displayed elevations in the proportion of autoantibodies targeting brain plasma membrane proteins, possibly pointing to the presence of immune hyperactivity/dysfunction despite well-controlled seizure activity and suggesting ASM-responsive patients may experience disease progression independent of seizure activity (PISA). Discussion Overall, our findings suggest that simply expanding existing autoantibody screens may not sufficiently enhance diagnostic power for snAAE. Instead, we propose that cytokine analysis may serve as a promising diagnostic avenue for identifying immune dysregulation in AAE patients and enabling opportunities for trials of immunotherapies.
{"title":"Altered Cytokine Profile in Clinically Suspected Seronegative Autoimmune Associated Epilepsy","authors":"Katherine Motovilov, Cole Maguire, Deborah Briggs, Esther Melamed","doi":"10.1101/2024.09.13.24310337","DOIUrl":"https://doi.org/10.1101/2024.09.13.24310337","url":null,"abstract":"Background and Objectives\u0000Autoimmune-associated epilepsy (AAE), a condition which responds favorably to immune therapies but not traditional anti-seizure interventions, is emerging as a significant contributor to cases of drug-resistant epilepsy. Current standards for the diagnosis of AAE rely on screening for known neuronal autoantibodies in patient serum or cerebrospinal fluid. However, this diagnostic method fails to capture a subset of drug-resistant epilepsy patients with suspected AAE who respond to immunotherapy yet remain seronegative (snAAE) for known autoantibodies. Methods\u0000To identify potential biomarkers for snAAE, we evaluated the most comprehensive panel of assayed cytokines and autoantibodies to date, comparing patients with snAAE, anti-seizure medication (ASM) responsive epilepsy, and patients with other neuroinflammatory diseases. Results\u0000We found a unique signature of 14 cytokines significantly elevated in snAAE patients including: GM-CSF, MCP-2/CCL8, MIP-1a/CCL3, IL-1RA, IL-6, IL-8, IL-9, IL-10, IL-15, IL-20, VEGF-A, TNF-b, LIF, and TSLP. Based on prior literature, we highlight IL-6, IL-8, IL-10, IL-13, VEGF-A, and TNF-b as potentially actionable cytokine biomarkers for snAAE, which could be of diagnostic utility in clinical evaluations of snAAE patients. Autoantibody-ome screening failed to identify autoantibodies targeting neuronal channel proteins in snAAE patients. Interestingly, ASM-responsive epilepsy patients displayed elevations in the proportion of autoantibodies targeting brain plasma membrane proteins, possibly pointing to the presence of immune hyperactivity/dysfunction despite well-controlled seizure activity and suggesting ASM-responsive patients may experience disease progression independent of seizure activity (PISA). Discussion\u0000Overall, our findings suggest that simply expanding existing autoantibody screens may not sufficiently enhance diagnostic power for snAAE. Instead, we propose that cytokine analysis may serve as a promising diagnostic avenue for identifying immune dysregulation in AAE patients and enabling opportunities for trials of immunotherapies.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.12.24313557
Daria Pressler, Sarah Dugan, Amu De Silva, Michael A Riley, Sarah M Schwab-Farrell
People with stroke (PwS) often exhibit altered postural control, and concomitant stroke-related communication disorders (e.g., aphasia, dysarthria) may be an underrecognized risk factor for post-stroke falls. This heightened fall risk may be related to alterations in postural control that emerge during different speaking and listening conditions. This study evaluated how variations in the relative articulatory demands during speech production-termed "oral-motor complexity"-affect postural center of pressure (COP) patterns among PwS, both with communication disorders (PwS-CDis) and without (PwS). Three groups of adults (PwS, PwS-CDis, and a nondisabled Control group) stood on a force platform while completing four 30-second quiet stance trials, followed by twelve 30-second trials randomized across three experimental conditions of varying oral-motor complexities ("ba", "puh tuh kuh", "rah shah lah nah"). COP variability (SD) was significantly higher during experimental conditions compared to quiet stance, regardless of group and movement plane. Differences in nonlinear time-dependent metrics were found across oral-motor task conditions, particularly among PwS-CDis, suggesting oral-motor complexity may influence underlying postural-motor organization. Distinct temporal-dynamical patterns observed in PwS-CDis indicate a possible link between pathology, postural control, and speech motor tasks, which is relevant when evaluating postural control in individuals with stroke-related communication disorders.
{"title":"Oral-motor complexity influences center of pressure patterns in adults with stroke-related communication disorders","authors":"Daria Pressler, Sarah Dugan, Amu De Silva, Michael A Riley, Sarah M Schwab-Farrell","doi":"10.1101/2024.09.12.24313557","DOIUrl":"https://doi.org/10.1101/2024.09.12.24313557","url":null,"abstract":"People with stroke (PwS) often exhibit altered postural control, and concomitant stroke-related communication disorders (e.g., aphasia, dysarthria) may be an underrecognized risk factor for post-stroke falls. This heightened fall risk may be related to alterations in postural control that emerge during different speaking and listening conditions. This study evaluated how variations in the relative articulatory demands during speech production-termed \"oral-motor complexity\"-affect postural center of pressure (COP) patterns among PwS, both with communication disorders (PwS-CDis) and without (PwS). Three groups of adults (PwS, PwS-CDis, and a nondisabled Control group) stood on a force platform while completing four 30-second quiet stance trials, followed by twelve 30-second trials randomized across three experimental conditions of varying oral-motor complexities (\"ba\", \"puh tuh kuh\", \"rah shah lah nah\"). COP variability (SD) was significantly higher during experimental conditions compared to quiet stance, regardless of group and movement plane. Differences in nonlinear time-dependent metrics were found across oral-motor task conditions, particularly among PwS-CDis, suggesting oral-motor complexity may influence underlying postural-motor organization. Distinct temporal-dynamical patterns observed in PwS-CDis indicate a possible link between pathology, postural control, and speech motor tasks, which is relevant when evaluating postural control in individuals with stroke-related communication disorders.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.11.24313483
Bryan T Klassen, Matthew R Baker, Michael A Jensen, Gabriela Ojeda Valencia, Kai Joshua Miller
The motor thalamus plays a crucial role in the integration and modulation of sensorimotor information and projects to the primary motor cortex. While voltage power spectral changes in the motor cortex with movement have been well-characterized, the corresponding activity in the motor thalamus, particularly broadband (sometimes referred to as high gamma) power, remains unclear. The present study aims to characterize spectral changes in the motor thalamus during hand movements of 15 subjects undergoing awake deep brain stimulation surgery targeting the ventral intermediate (VIM) nucleus of the thalamus for disabling tremor. We analyzed power changes in subject-specific low frequency oscillations (<30 Hz) and broadband power (captured in 65-115 Hz band) of serial field potential recordings. Consistent with previous studies, we found widespread decreases in low-frequency oscillations with movement. Importantly, in most subjects we also observed a significant increase in broadband power, primarily in the inferior recording sites corresponding with estimated VIM region. One subject also performed an imagined movement task during which low frequency oscillatory power was suppressed. These electrophysiologic changes may be leveraged as biomarkers for thalamic functional mapping, DBS targeting, and closed loop applications.
运动丘脑在整合和调制感觉运动信息方面起着至关重要的作用，并投射到初级运动皮层。虽然运动皮层的电压功率频谱变化已被充分描述，但运动丘脑的相应活动，尤其是宽带（有时称为高伽马）功率，仍不清楚。本研究旨在描述 15 名接受以丘脑腹侧中间核（VIM）为靶点的清醒深部脑刺激手术治疗失能性震颤的受试者手部运动时运动丘脑的频谱变化。我们分析了序列场电位记录中特定受试者低频振荡（30 Hz）和宽带功率（65-115 Hz 频段捕获）的功率变化。与之前的研究一致，我们发现低频振荡随运动而普遍下降。重要的是，在大多数受试者中，我们还观察到宽带功率显著增加，主要是在与估计的 VIM 区域相对应的下部记录点。一名受试者还完成了一项想象运动任务，其间低频振荡功率受到抑制。这些电生理变化可作为丘脑功能绘图、DBS 定位和闭环应用的生物标记。
{"title":"Spectral Changes in Motor Thalamus Field Potentials during Movement","authors":"Bryan T Klassen, Matthew R Baker, Michael A Jensen, Gabriela Ojeda Valencia, Kai Joshua Miller","doi":"10.1101/2024.09.11.24313483","DOIUrl":"https://doi.org/10.1101/2024.09.11.24313483","url":null,"abstract":"The motor thalamus plays a crucial role in the integration and modulation of sensorimotor information and projects to the primary motor cortex. While voltage power spectral changes in the motor cortex with movement have been well-characterized, the corresponding activity in the motor thalamus, particularly broadband (sometimes referred to as high gamma) power, remains unclear. The present study aims to characterize spectral changes in the motor thalamus during hand movements of 15 subjects undergoing awake deep brain stimulation surgery targeting the ventral intermediate (VIM) nucleus of the thalamus for disabling tremor. We analyzed power changes in subject-specific low frequency oscillations (<30 Hz) and broadband power (captured in 65-115 Hz band) of serial field potential recordings. Consistent with previous studies, we found widespread decreases in low-frequency oscillations with movement. Importantly, in most subjects we also observed a significant increase in broadband power, primarily in the inferior recording sites corresponding with estimated VIM region. One subject also performed an imagined movement task during which low frequency oscillatory power was suppressed. These electrophysiologic changes may be leveraged as biomarkers for thalamic functional mapping, DBS targeting, and closed loop applications.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"65 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.12.24313567
Abhimanyu Mahajan, Kevin R Duque, Alok Kumar Dwivedi, Jesus Abanto, Luca Marsili, Emily J Hill, Ameya Saraf, Kelsey J McDonald, Adebukunola Arowosegbe, Heba A Deraz, Aaron Bloemer, Alberto J Espay
Introduction Daytime sleepiness, reported in about 50% of patients with Parkinson disease (PD), is associated with high morbidity, poor quality of life and increased risk for accidents. While an association between dysautonomia and daytime sleepiness in early, de-novo PD has been reported, our understanding of the role of medications, cognitive status and disease duration on this relationship is inadequate. Methods Data were analyzed from the prospective Cincinnati Cohort Biomarkers Program. The primary outcome of interest was daytime sleepiness, as measured by the Epworth Sleepiness Scale (ESS). The primary exposure variable was orthostatic hypotension (OH) with a sub-analysis for the neurogenic OH (nOH) subtype. Regression analyses were carried out adjusting for the following covariates: age, sex, disease duration, education, comorbidities, anti-cholinergic burden, levodopa equivalent dose (LEDD), motor subscore of the Movement disorder society-unified Parkinson disease rating scale, Hoehn and Yahr stage (H&Y), Beck Depression Inventory, and Beck Anxiety Inventory. Results Data on 456 subjects with PD were analyzed. OH was strongly associated with ESS scores, particularly in those with anticholinergic medication use after adjusting for all covariates (RC, 4.30; p<0.001). This adjusted association was more pronounced in men with early disease duration, early H&Y stage, no cognitive decline, and LEDD≤750 mg. Similar results were noted with nOH. Conclusions OH is associated with daytime sleepiness to a greater extent in male patients with early disease and magnified by such prescribing practices as anticholinergic medication use and dopaminergic dosage in early PD. This relationship is independent of cognitive decline.
{"title":"Exploring the intersection between orthostatic hypotension and daytime sleepiness in Parkinson disease","authors":"Abhimanyu Mahajan, Kevin R Duque, Alok Kumar Dwivedi, Jesus Abanto, Luca Marsili, Emily J Hill, Ameya Saraf, Kelsey J McDonald, Adebukunola Arowosegbe, Heba A Deraz, Aaron Bloemer, Alberto J Espay","doi":"10.1101/2024.09.12.24313567","DOIUrl":"https://doi.org/10.1101/2024.09.12.24313567","url":null,"abstract":"Introduction\u0000Daytime sleepiness, reported in about 50% of patients with Parkinson disease (PD), is associated with high morbidity, poor quality of life and increased risk for accidents. While an association between dysautonomia and daytime sleepiness in early, de-novo PD has been reported, our understanding of the role of medications, cognitive status and disease duration on this relationship is inadequate. Methods\u0000Data were analyzed from the prospective Cincinnati Cohort Biomarkers Program. The primary outcome of interest was daytime sleepiness, as measured by the Epworth Sleepiness Scale (ESS). The primary exposure variable was orthostatic hypotension (OH) with a sub-analysis for the neurogenic OH (nOH) subtype. Regression analyses were carried out adjusting for the following covariates: age, sex, disease duration, education, comorbidities, anti-cholinergic burden, levodopa equivalent dose (LEDD), motor subscore of the Movement disorder society-unified Parkinson disease rating scale, Hoehn and Yahr stage (H&Y), Beck Depression Inventory, and Beck Anxiety Inventory. Results\u0000Data on 456 subjects with PD were analyzed. OH was strongly associated with ESS scores, particularly in those with anticholinergic medication use after adjusting for all covariates (RC, 4.30; p<0.001). This adjusted association was more pronounced in men with early disease duration, early H&Y stage, no cognitive decline, and LEDD≤750 mg. Similar results were noted with nOH. Conclusions\u0000OH is associated with daytime sleepiness to a greater extent in male patients with early disease and magnified by such prescribing practices as anticholinergic medication use and dopaminergic dosage in early PD. This relationship is independent of cognitive decline.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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