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Cerebrovascular variability interactions after acute ischemic stroke: insights from directionality analysis based on transfer entropy.
Dynamic cerebral autoregulation (CA) limits fluctuations of mean cerebral blood flow, approximated as mean cerebral blood velocity (MCBv) measured via transcranial Doppler ultrasound, in the presence of variations of mean arterial pressure (MAP). This mechanism is impaired after acute ischemic stroke (AIS). CA impairment is usually assessed by hypothesizing that MAP variations are completely responsible for MCBv changes, while disregarding the MCBv contributions to MAP variability. We exploited transfer entropy (TE) and conditional TE (CTE) to assess the strength of the directional interactions from MAP to MCBv and vice versa accounting for partial pressure of end-tidal carbon dioxide. Traditional markers were computed for comparison. We analyzed recordings from 34 control individuals (CTRL, age: 66 ± 7 yrs) and 48 AIS patients (age: 66 ± 13 yrs) acquired within 48 hours of stroke symptom onset. MCBv was recorded in both hemispheres including affected and unaffected hemispheres in AIS patients. AIS patients exhibited hypertension and hypocapnia. After AIS MCBv diminished, especially in the affected hemisphere. TE and CTE decreased along the pressure-to-flow pathway as well. Both directional markers tended to increase along the flow-to-pressure arm irrespective of the hemisphere. Traditional indexes could not detect any difference. Our analysis suggests that the CA impairment was characterized by an imbalance of information transfer within the MCBv-MAP closed loop with a reduced importance of the pressure-to-flow and increased relevance of the flow-to-pressure arm. The study stresses the relevance of assessing MCBv-MAP relationship in closed loop especially when variability of MAP and MCBv are considered.
Dynamics of Critical Closing Pressure Explain Cerebral Autoregulation Impairment in Acute Cerebrovascular Disease.
INTRODUCTION: Cerebral autoregulation (CA) is impaired in acute ischemic stroke (AIS) and is associated with worse patient outcomes, but the underlying physiological cause is unclear. This study tests whether depressed CA in AIS can be linked to the dynamic responses of critical closing pressure (CrCP) and resistance area product (RAP). METHODS: Continuous recordings of middle cerebral blood velocity (MCAv, transcranial Doppler), arterial blood pressure (BP), end-tidal CO2 and electrocardiography allowed dynamic analysis of the instantaneous MCAv-BP relationship to obtain estimates of CrCP and RAP. The dynamic response of CrCP and RAP to a sudden change in mean BP was obtained by transfer function analysis. Comparisons were made between younger controls (≤50 years), older controls (>50 years), and AIS patients. RESULTS: Data from 24 younger controls (36.4 ± 10.9 years, 9 male), 38 older controls (64.7 ± 8.2 years, 20 male), and 20 AIS patients (63.4 ± 13.8 years, 9 male) were included. Dynamic CA was impaired in AIS, with lower autoregulation index (affected hemisphere: 4.0 ± 2.3, unaffected: 4.5 ± 1.8) compared to younger (right: 5.8 ± 1.4, left: 5.8 ± 1.4) and older (right: 4.9 ± 1.6, left: 5.1 ± 1.5) controls. AIS patients also demonstrated an early (0-3 s) peak in CrCP dynamic response that was not influenced by age. CONCLUSION: These early transient differences in the CrCP dynamic response are a novel finding in stroke and occur too early to reflect underlying regulatory mechanisms. Instead, these may be caused by structural changes to cerebral vasculature.
Baseline serum ferritin predicts myocardial iron uptake following intravenous iron therapy - a hypothesis-generating study.
AIMS: Many patients with heart failure (HF) are iron-deficient. Intravenous (IV) iron therapy improves symptoms and reduces hospitalizations for HF. Several mechanisms have been proposed, including myocardial iron repletion. However, it is unknown if serum iron markers predict the extent of this repletion. To address this question, data from two clinical studies that evaluated changes in myocardial iron using cardiac magnetic resonance (CMR) were harnessed. METHODS AND RESULTS: The Myocardial-IRON trial measured change in myocardial iron, denoted by a decrease in CMR T1 and T2*, at 7 and 30 days after IV ferric carboxymaltose (FCM) in patients with iron deficiency (ID) and HF (n = 53). The STUDY trial measured myocardial and spleen iron at multiple timepoints after FCM in patients with ID without HF (n = 12). In this post-hoc analysis, we examined the association between baseline serum iron markers (transferrin saturation and ferritin) and change in myocardial iron in the weeks after FCM therapy. Changes in spleen iron were also examined, due its role as an intermediary in the redistribution of iron from iron-carbohydrate complexes such as FCM. In patients with or without HF, higher serum ferritin at baseline predicted lower rise in myocardial iron in the weeks after therapy with FCM. In contrast, higher serum ferritin at baseline predicted a greater rise in spleen iron. CONCLUSIONS: These data point towards the hypothesis that functional ID, which is characterized by elevated ferritin, could limit myocardial iron repletion after IV iron therapy, by favouring iron trapping in the spleen.
Implementing Acute Stroke Services in Sub-Saharan Africa: Steps, Progress, and Perspectives from the Tanzania Stroke Project.
INTRODUCTION: Stroke is a leading cause of morbidity and mortality globally, with Africa bearing a disproportionately high burden of poor outcomes. In sub-Saharan Africa, acute stroke care remains inconsistent, with organized stroke units being either absent or rarely available, contributing to the high stroke mortality rates in the region. To address this issue, the Tanzania Stroke Project (TSP) was launched, aimed at establishing acute stroke services at two of the largest tertiary care centers in collaboration with the Tanzanian Ministry of Health, the World Stroke Organization, and Hospital Directorates. METHODS: TSP utilized a three-tier implementation approach to establish a more organized stroke care system in two large academic hospitals. Here, we detail the process of this initiative, which took place between August 2023 and August 2024. The three-tier approach included (1) the establishment of stroke registries; (2) the training of healthcare workers (HCWs); and (3) the development of acute stroke protocols and establishment of stroke units at Muhimbili National Hospital-Mloganzila and Bugando Medical Center in Tanzania. RESULTS: In tier one (stroke registry), two comprehensive stroke registries were established, including 460 adults (mean age 60 ± 15 years). Hemorrhagic stroke was the most common subtype, accounting for 59% of cases (n = 269). Premorbid hypertension was the most prevalent risk factor, affecting 81% (n = 373) of the patients. More than half of patients (58%, n = 171) arrived at the hospital after 24 h from stroke symptoms. Only 11% (n = 50/452) had documented swallowing screenings, and among patients with intracerebral hemorrhage, 11% (n = 28/251) achieved the target for blood pressure control, while 47% (n = 99/213) met blood glucose control targets. The in-hospital mortality rate was 27% (n = 93/340). In tier two (training of HCWs), extensive evidence-based mentorship training was provided with higher participation rates among HCWs at Bugando Medical Center compared to Muhimbili National Hospital-Mloganzila (57% [29/51] vs. 23% [7/31], p = 0.002). In tier three (stroke unit protocols), stroke protocols were developed based on the training and current evidence, leading to the establishment of dedicated stroke units at each facility, with a minimum of 8 beds per unit. The full impact of these implementations has yet to be fully assessed. CONCLUSION: This was the first initiative to implement stroke services at two large tertiary healthcare centers in Tanzania. Our findings highlight the importance of multilevel stakeholder engagement through a 3-tier approach in countries starting to establish stroke services and the need for ongoing quality-of-care monitoring and continuous efforts to sensitize both HCWs and the broader community.
The spatiotemporal distribution of human pathogens in ancient Eurasia
Abstract Infectious diseases have had devastating effects on human populations throughout history, but important questions about their origins and past dynamics remain1. To create an archaeogenetic-based spatiotemporal map of human pathogens, we screened shotgun-sequencing data from 1,313 ancient humans covering 37,000 years of Eurasian history. We demonstrate the widespread presence of ancient bacterial, viral and parasite DNA, identifying 5,486 individual hits against 492 species from 136 genera. Among those hits, 3,384 involve known human pathogens2, many of which had not previously been identified in ancient human remains. Grouping the ancient microbial species according to their likely reservoir and type of transmission, we find that most groups are identified throughout the entire sampling period. Zoonotic pathogens are only detected from around 6,500 years ago, peaking roughly 5,000 years ago, coinciding with the widespread domestication of livestock3. Our findings provide direct evidence that this lifestyle change resulted in an increased infectious disease burden. They also indicate that the spread of these pathogens increased substantially during subsequent millennia, coinciding with the pastoralist migrations from the Eurasian Steppe4,5.
A Validated Model to Predict Severe Weight Loss in Amyotrophic Lateral Sclerosis
ABSTRACTSevere weight loss in amyotrophic lateral sclerosis (ALS) is common, multifactorial, and associated with shortened survival. Using longitudinal weight data from over 6000 patients with ALS across three cohorts, we built an accelerated failure time model to predict the risk of future severe (≥ 10%) weight loss using five single‐timepoint clinical predictors: symptom duration, revised ALS Functional Rating Scale, site of onset, forced vital capacity, and age. Model performance and generalisability were evaluated using internal–external cross‐validation and random‐effects meta‐analysis. The overall concordance statistic was 0.71 (95% CI 0.63–0.79), and the calibration slope and intercept were 0.91 (0.69–1.13) and 0.05 (−0.11–0.21). This study highlights clinical factors most associated with severe weight loss in ALS and provides the basis for a stratification tool.
Visualizing PIEZO1 localization and activity in hiPSC-derived single cells and organoids with HaloTag technology.
PIEZO1 is critical to numerous physiological processes, transducing diverse mechanical stimuli into electrical and chemical signals. Recent studies underscore the importance of visualizing endogenous PIEZO1 activity and localization to understand its functional roles. To enable physiologically and clinically relevant studies on human PIEZO1, we genetically engineered human induced pluripotent stem cells (hiPSCs) to express a HaloTag fused to endogenous PIEZO1. Combined with advanced imaging, our chemogenetic platform allows precise visualization of PIEZO1 localization dynamics in various cell types. Furthermore, the PIEZO1-HaloTag hiPSC technology facilitates the non-invasive monitoring of channel activity across diverse cell types using Ca2+-sensitive HaloTag ligands, achieving temporal resolution approaching that of patch clamp electrophysiology. Finally, we use lightsheet microscopy on hiPSC-derived neural organoids to achieve molecular scale imaging of PIEZO1 in three-dimensional tissue. Our advances establish a platform for studying PIEZO1 mechanotransduction in human systems, with potential for elucidating disease mechanisms and targeted drug screening.
Optimal markers of treatment response to vasodilatory drugs in small vessel disease: An OxHARP Trial analysis.
BACKGROUND AND AIMS: Vasodilating drugs targeting the endothelium could reduce long-term harms due to cerebral small vessel disease (cSVD) but there are no commonly-accepted methods to measure short-term disease activity or drug response. In the OxHARP clinical trial, we determined the most sensitive physiological markers of treatment response to sildenafil versus placebo on either transcranial ultrasound (TCD) and MRI, and their validity compared to disease severity and other measures of other physiological mechanisms. METHODS: In the OxHARP double-blind, randomised, placebo-controlled crossover trial we measured aortic blood pressure, mean flow velocity (MFV), cerebral pulsatility, cerebrovascular conductance index (CVCi=MFV/aortic mean BP), cerebral perfusion (pcASL-MRI) and cerebrovascular reactivity to inhaled CO2 on transcranial ultrasound (CVR-TCD) and MRI in white (CVR-WM), grey (CVR-GM) and white matter hyperintensities (CVR-WMH). Effects of 3 weeks of sildenafil were compared to placebo. Validity of markers were determined by between-visit repeatability (ICC); associations with CVR-TCD, CVR-WMH and CVR-GM; associations with other markers; the magnitude of response, and sensitivity, to sildenafil. RESULTS: In 69 participants, repeatability was greatest for MFV, pulsatilty, CVCi and CVR-WMH (ICC>0.8), very good for CVR-TCD and GM-perfusion (ICC>0.7), and good for CVR-GM (ICC<0.6). CVR-TCD was associated with CVR on MRI (CVR-WMH: r2=0.12, p=0.02; CVR-GM: r2=0.22, p=0.001), whilst blood flow measures on TCD (MFV, CVCi) were associated with CVR-TCD and perfusion-MRI (all p<0.05). All markers were associated with WMH volume and improved by sildenafil, but CVCi was most sensitive, requiring only 20 patients for a crossover trial at 80% power, compared to 26 for GM-perfusion or 84 for CVR-GM. CONCLUSIONS: Multiple markers were associated with cSVD, but no single marker reflected all physiological drug effects. CVCi and grey matter perfusion on MRI were the most sensitive markers of disease activity and drug response, although CVR indices may be more specific for endothelial dysfunction.
Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus.
The mammalian suprachiasmatic nucleus (SCN), situated in the ventral hypothalamus, directs daily cellular and physiological rhythms across the body. The SCN clockwork is a self-sustaining transcriptional-translational feedback loop (TTFL) that in turn coordinates the expression of clock-controlled genes (CCGs) directing circadian programmes of SCN cellular activity. In the mouse, the transcription factor, ZFHX3 (zinc finger homeobox-3), is necessary for the development of the SCN and influences circadian behaviour in the adult. The molecular mechanisms by which ZFHX3 affects the SCN at transcriptomic and genomic levels are, however, poorly defined. Here, we used chromatin immunoprecipitation sequencing to map the genomic localization of ZFHX3-binding sites in SCN chromatin. To test for function, we then conducted comprehensive RNA sequencing at six distinct times-of-day to compare the SCN transcriptional profiles of control and ZFHX3-conditional null mutants. We show that the genome-wide occupancy of ZFHX3 occurs predominantly around gene transcription start sites, co-localizing with known histone modifications, and preferentially partnering with clock transcription factors (CLOCK, BMAL1) to regulate clock gene(s) transcription. Correspondingly, we show that the conditional loss of ZFHX3 in the adult has a dramatic effect on the SCN transcriptome, including changes in the levels of transcripts encoding elements of numerous neuropeptide neurotransmitter systems while attenuating the daily oscillation of the clock TF Bmal1. Furthermore, various TTFL genes and CCGs exhibited altered circadian expression profiles, consistent with an advanced in daily behavioural rhythms under 12 h light-12 h dark conditions. Together, these findings reveal the extensive genome-wide regulation mediated by ZFHX3 in the central clock that orchestrates daily timekeeping in mammals.
Quantification of Optical Coherence Tomography Features in >3500 Patients with Inherited Retinal Disease Reveals Novel Genotype-Phenotype Associations.
PURPOSE: To quantify spectral-domain optical coherence tomography (SD-OCT) images cross-sectionally and longitudinally in a large cohort of molecularly characterized patients with inherited retinal disease (IRDs) from the UK. DESIGN: Retrospective study of imaging data. PARTICIPANTS: Patients with a clinical and molecularly confirmed diagnosis of IRD who have undergone macular SD-OCT imaging at Moorfields Eye Hospital (MEH) between 2011 and 2019. We retrospectively identified 4,240 IRD patients from the MEH database (198 distinct IRD genes), including 69,664 SD-OCT macular volumes. METHODS: Eight features of interest were defined: retina, fovea, intraretinal cystic spaces (ICS), subretinal fluid (SRF), subretinal hyper-reflective material (SHRM), pigment epithelium detachment (PED), ellipsoid zone loss (EZ-loss) and retinal pigment epithelium loss (RPE-loss). Manual annotations of five b-scans per SD-OCT volume was performed for the retinal features by four graders based on a defined grading protocol. A total of 1,749 b-scans from 360 SD-OCT volumes across 275 patients were annotated for the eight retinal features for training and testing of a neural-network-based segmentation model, AIRDetect-OCT, which was then applied to the entire imaging dataset. MAIN OUTCOME MEASURES: Performance of AIRDetect-OCT, comparing to inter-grader agreement was evaluated using Dice score on a held-out dataset. Feature prevalence, volume and area were analysed cross-sectionally and longitudinally. RESULTS: The inter-grader Dice score for manual segmentation was ≥90% for retina, ICS, SRF, SHRM and PED, >77% for both EZ-loss and RPE-loss. Model-grader agreement was >80% for segmentation of retina, ICS, SRF, SHRM, and PED, and >68% for both EZ-loss and RPE-loss. Automatic segmentation was applied to 272,168 b-scans across 7,405 SD-OCT volumes from 3,534 patients encompassing 176 unique genes. Accounting for age, male patients exhibited significantly more EZ-loss (19.6mm 2 vs 17.9mm 2 , p<2.8×10 -4 ) and RPE-loss (7.79mm 2 vs 6.15mm 2 , p<3.2×10 -6 ) than females. RPE-loss was significantly higher in Asian patients than other ethnicities (9.37mm 2 vs 7.29mm 2 , p<0.03). ICS average total volume was largest in RS1 (0.47mm 3 ) and NR2E3 (0.25mm 3 ), SRF in BEST1 (0.21mm 3 ) and PED in EFEMP1 (0.34mm 3 ). BEST1 and PROM1 showed significantly different patterns of EZ-loss (p<10 -4 ) and RPE-loss (p<0.02) comparing the dominant to the recessive forms. Sectoral analysis revealed significantly increased EZ-loss in the inferior quadrant compared to superior quadrant for RHO (Δ=-0.414 mm 2 , p=0.036) and EYS (Δ=-0.908 mm 2 , p=1.5×10 -4 ). In ABCA4 retinopathy, more severe genotypes (group A) were associated with faster progression of EZ-loss (2.80±0.62 mm 2 /yr), whilst the p.(Gly1961Glu) variant (group D) was associated with slower progression (0.56 ±0.18 mm 2 /yr). There were also sex differences within groups with males in group A experiencing significantly faster rates of progression of RPE-loss (2.48 ±1.40 mm 2 /yr vs 0.87 ±0.62 mm 2 /yr, p=0.047), but lower rates in groups B, C, and D. CONCLUSIONS: AIRDetect-OCT, a novel deep learning algorithm, enables large-scale OCT feature quantification in IRD patients uncovering cross-sectional and longitudinal phenotype correlations with demographic and genotypic parameters.
Non-mental health inpatient and emergency care hospital costs associated with four mental disorders in Europe: a modelling study.
BackgroundThe prevalence of physical health conditions is higher among people with mental disorders than the general population, and these conditions have subsequent excess costs. Estimating the magnitude of these excess costs would support better integrated mental and physical health care. The aim of this study was to estimate the excess annual hospital costs of non-mental health related inpatient and emergency care utilisation for four mental disorders in 32 European countries.MethodsIn this modelling study, we obtained data on the working-age population (aged 20-64 years) of 32 European countries from the European Statistical Agency, the 2019 Global Burden of Disease, Injuries, and Risk Factors Study, epidemiological and cost evidence syntheses, and listed country-specific estimates. We estimated the non-mental health inpatient costs and emergency care hospital costs associated with the excess physical health burden of alcohol use disorders, bipolar disorder, depressive disorders, and schizophrenia in purchasing power standard Euros (PPS€) for 2019. Total physical comorbidity hospital costs were calculated by summing attributable non-mental health inpatient and emergency hospital costs across all physical health diagnoses by ICD-10 category for each mental disorder in all countries. Excess costs represent the proportion of total costs that were attributable to the excess physical health burden. People with lived experiences informed the original project plans.FindingsIn 2019, there were 312·5 million people of working age across 32 European countries. Total annual non-mental health inpatient and emergency care hospital costs were PPS€20·3 billion for alcohol use disorders, PPS€6·7 billion for bipolar disorder, PPS€26·5 billion for depressive disorders, and PPS€1·8 billion for schizophrenia, with considerable variation observed among countries. The proportion of excess costs were 59·4% (PPS€12·1 billion) for alcohol use disorder, 56·7% (PPS€3·8 billion) for bipolar disorder, 52·7% (PPS€14·0 billion) for depressive disorders, and 35·6% (PPS€0·7 billion) for schizophrenia.InterpretationThese first comprehensive European estimates indicate that non-mental health inpatient and emergency care hospital costs contributed substantially to the total costs associated with four mental disorders. The excess costs equated to 1·8% of the included countries' overall health-care expenditure and 0·16% of their gross domestic products. Estimates are conservative because they are limited to diagnosed mental disorders prevalent among working-age adults. A 1·0% reduction in the excess physical health burden of these mental disorders could lead to annual savings of more than PPS€190 million in non-mental health hospital costs in Europe.FundingEuropean College of Neuropsychopharmacology.
A single dose of lamotrigine induces a positive memory bias in healthy volunteers.
BACKGROUND: Lamotrigine has been shown to be effective in the long-term treatment and relapse prevention of depression in bipolar disorder. However, the neuropsychological mechanisms underlying these effects are unclear. We investigated the effects of lamotrigine on a battery of emotional processing tasks in healthy volunteers, previously shown to be sensitive to antidepressant drug action in similar experimental designs. METHODS: Healthy volunteers (n = 36) were randomized in a double-blind design to receive a single dose of placebo or 300 mg lamotrigine. Mood and subjective effects were monitored throughout the study period, and emotional processing was assessed using the Oxford Emotional Test Battery (ETB) 3 hours post-administration. RESULTS: Participants receiving lamotrigine showed increased accurate recall of positive versus negative self-descriptors, compared to those in the placebo group. There were no other significant effects on emotional processing in the ETB, and lamotrigine did not affect ratings of mood or subjective experience. CONCLUSIONS: Lamotrigine did not induce widespread changes in emotional processing. However, there was increased positive bias in emotional memory, similar to the effects of antidepressants reported in previous studies. Further work is needed to assess whether similar effects are seen in the clinical treatment of patients with bipolar disorder and the extent to which this is associated with its clinical action in relapse prevention.
Results From a Long-Term Observational Follow-Up Study of a Single Dose of Psilocybin for a Treatment-Resistant Episode of Major Depressive Disorder.
Background: The largest randomized study of psilocybin to date demonstrated the efficacy of COMP360 25 mg (Compass Pathways' investigational proprietary pharmaceutical-grade synthesized psilocybin formulation) in participants with treatment-resistant depression (COMP 001), compared with 10 mg and 1 mg doses. Here, we report findings from COMP 004, a 52-week observational follow-up of patients from COMP 001 and COMP 003, a small open-label study of the coadministration of 25 mg COMP360 with continuing antidepressant treatment. Methods: Adverse events (AEs) were collected over the full 52-week period. The primary efficacy endpoint was time to a prespecified depressive event over the 52 weeks following COMP360 administration in COMP 001 participants, presented as Kaplan-Meier estimates. A post hoc analysis included only participants that entered COMP 004. Data were collected from July 2020 to July 2022. Results: Sixty-six participants entered COMP 004 (COMP 001, n = 58 [25 mg group n = 22, 10 mg group n = 19, 1 mg group n = 17]; COMP 003, n = 8). Few AEs were reported post-entry into COMP 004, with 1 AE of mild suicidal ideation in the 1 mg group deemed possibly related to study drug. For all COMP 001 patients (n = 233), median time to depressive event was greater for the 25 mg group (92 days) compared to the 10 mg (83 days) and 1 mg (62 days) groups, with the majority of participants having had a depressive event by Week 12 (25 mg n = 37/75, 10 mg n = 38/79, 1 mg n = 44/75). The post hoc supplementary analysis of those who enrolled in COMP 004 from COMP 001 exhibited the difference between groups more strikingly (25 mg, 189 days; 10 mg, 43 days; 1 mg, 21 days); however, only 10 participants experienced a depressive event post-COMP 004 enrollment (25 mg n = 6, 10 mg n = 3, 1 mg n = 1) from COMP 001 and none from COMP 003. At COMP 004 entry, the 1 mg group had the highest number of participants on antidepressant medication (n = 10; 10 mg, n = 9; 25 mg, n = 6) and generally initiated treatment earlier. Conclusion: Over 52 weeks, a single administration of 25 mg psilocybin suggested longer maintenance of antidepressant effect than both 1 mg and 10 mg. Larger long-term studies are required to confirm these findings and provide clarity on the longer-term effects of psilocybin. Trial Registration: ClinicalTrials.gov identifier: NCT04519957.
Serum Neurofilament Light Chain and Structural and Functional Nerve Fiber Loss in Painful and Painless Diabetic Polyneuropathy.
AIMS: To explore associations between the axonal protein neurofilament light chain (NfL) and severity of diabetic polyneuropathy (DPN) and pain. METHODS: We performed cross-sectional analysis of a subset of the PiNS/DOLORisk cohort of people with DPN with and without neuropathic pain. Biobank samples were analyzed for serum NfL (s-NfL) using single molecule array. DPN was defined by Toronto criteria for probable or confirmed DPN. Painful DPN (PDPN) was evaluated according to IASP criteria. Measures of DPN severity included clinical DPN scales, quantitative sensory testing (QST) and intraepidermal nerve fiber density (IENFD). RESULTS: Participants with confirmed (N = 172) or probable DPN (N = 29) were included. There was no s-NfL difference between participants with DPN (N = 79, 22.8 ng/L [IQR 17.4; 31.3]) and PDPN (N = 122, 22.2 ng/L [16.0; 34.4]). S-NfL was not associated with pain severity or DPN severity evaluated by clinical DPN scales. Higher s-NfL was associated with lower IENFD (13.6 % [95 % CI 3.1; 22.9], unit = 1 fiber/mm, N = 24) and more pronounced loss of nerve fiber function measured by QST (p-trend = 0.02). CONCLUSIONS: Higher s-NfL was associated with nerve fiber dysfunction and loss quantified by QST and IENFD, but not with pain or clinical DPN scales. S-NfL may reflect the severity of nerve fiber damage underlying DPN.
Tremor Asymmetry and the Development of Bilateral Phase-Specific Deep Brain Stimulation for Postural Tremor.
BACKGROUND: Tremor phase-locked deep brain stimulation (DBS) has been shown to modulate symptom severity in postural tremor, including essential and dystonic tremor, with less energy than existing systems. Previous studies focused on unilateral stimulation; it remains unknown how tremor asymmetry interacts with stimulation in the context of bilateral phase-locked DBS. METHODS: Archival limb acceleration from nine essential tremor patients was analyzed for asymmetries in tremor amplitude, frequency, and instability, and their relationship with continuous high-frequency DBS (cDBS). Bilateral phase-locked DBS was tested in one essential tremor and one dystonic tremor patient. RESULTS: Postural tremor is asymmetric, with larger tremor power linked to smaller amplitude and frequency stability in one hand. These asymmetries were significantly reduced during cDBS, with greater effects on larger amplitude tremors. Bilateral phasic DBS effects were also asymmetric. CONCLUSIONS: This study enhances understanding of tremor asymmetry and its relationship with DBS, offering insights for patient-specific tremor treatments. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Target selection signals causally influence human perceptual decision making.
The ability to form decisions is a foundational cognitive function which is impaired across many psychiatric and neurological conditions. Understanding the neural processes underpinning clinical deficits may provide insights into the fundamental mechanisms of decision making. The N2c has been identified as an EEG signal indexing the efficiency of early target selection, which subsequently influences the timing of perceptual reports through modulating neural evidence accumulation rates. Evidence for the contribution of the N2c to human decision making however has thus far come from correlational research in neurologically healthy individuals. Here, we capitalised on the superior temporal resolution of EEG to show that unilateral brain lesions in male and female humans were associated with specific deficits in both the timing and strength of the N2c in the damaged hemisphere, with corresponding deficits in the timing of perceptual reports contralaterally. The extent to which the N2c influenced clinical deficits in perceptual reporting speed depended on neural rates of evidence accumulation. This work provides causal evidence that the N2c indexes an early, hemisphere-specific process supporting human decision making. This non-invasive EEG marker could be used to monitor novel approaches for remediating clinical deficits in perceptual decision making across a range of brain disorders.Significance Statement Understanding how particular brain processes contribute to decision-making is crucial for our treatment of psychiatric and neurological disorders. This study provides causal evidence linking deficits in speed of visual processing to specific well-delineated EEG signals representing early target selection and evidence accumulation, in individuals with brain lesions. By showing how these lesions disrupt perceptual decisions, this work identifies a potential biomarker for decision-making deficits. This EEG measure offers a promising, non-invasive tool to track and refine treatments aimed at restoring decision-making abilities in affected patients.
Stimulation of the human ventral tegmental area increases strategic betting.
Learning is a fundamental aspect of human behaviour and is essential for adapting to new environments and situations. The ventral tegmental area is a critical brain area containing neurons that release dopamine to signal reward, drive learning, and bias decision-making. Human data on ventral tegmental area's effects on cognition are scarce, and no studies have causally manipulated the human ventral tegmental area. Here we studied a unique group of patients who had deep brain stimulation surgery in the ventral tegmental area, to improve pain due to trigeminal autonomic cephalalgias refractory to medical therapy. In this study, we asked how deep brain stimulation, which aimed to inhibit the ventral tegmental area, affected reward-related learning and decision-making. Patients performed a reversal learning task while their deep brain stimulation was switched on vs. off, in a powerful within-subject design. In the task, patients learned to choose between two options to win money, based on previous outcomes, but also made post-decision bets based on whether they thought they were likely to win. This allowed us to also investigate the effect of electrical stimulation within the ventral tegmental area on betting behaviour. We found that stimulation did not affect learning in this group of patients but led to a more strategic betting behaviour. First, stimulation reduced the bias where healthy people tend to bet similarly to the previous trial. Second, when on stimulation, bets were more strongly linked to the actual value of the choice. The data indicate that disrupting ventral tegmental area signals by electrical stimulation reduces the perseverative betting bias, permitting more strategic decision-making. We interpret this to mean that mesolimbic dopaminergic signals in humans may be important in producing persistence of reward-driven behaviours over time.