Large Cohort Of Healthy Subjects Research Articles

Age-related differences in macromolecular resonances observed in ultra-short-TE STEAM MR spectra at 7T.

To understand how macromolecular content varies in the human brain with age in a large cohort of healthy subjects. In-vivo 1H-MR spectra were acquired using ultra-short TE STEAM at 7T in the posterior cingulate cortex. Macromolecular content was studied in 147 datasets from a cohort ranging in age from 19 to 89 y. Three fitting approaches were used to evaluate the macromolecular content: (1) a macromolecular resonances model developed for this study; (2) LCModel-simulated macromolecules; and (3) a combination of measured and LCModel-simulated macromolecules. The effect of age on the macromolecular content was investigated by considering age both as a continuous variable (i.e., linear regressions) and as a categorical variable (i.e., multiple comparisons among sub-groups obtained by stratifying data according to age by decade). While weak age-related effects were observed for macromolecular peaks at ˜0.9 (MM09), ˜1.2 (MM12), and ˜1.4 (MM14) ppm, moderate to strong effects were observed for peaks at ˜1.7 (MM17), and ˜2.0 (MM20) ppm. Significantly higher MM17 and MM20 content started from 30 to 40 y of age, while for MM09, MM12, and MM14, significantly higher content started from 60 to 70 y of age. Our findings provide insights into age-related differences in macromolecular contents and strengthen the necessity of using age-matched measured macromolecules during quantification.

Liver T1 and T2 mapping in a large cohort of healthy subjects: normal ranges and correlation with age and sex.

We established normal ranges for native T1 and T2 values in the human liver using a 1.5T whole-body imager (General Electric) and we evaluated their variation across hepatic segments and their association with age and sex. One-hundred healthy volunteers aged 20-70years (50% females) underwent MRI. Modified Look-Locker inversion recovery and multi-echo fast-spin-echo sequences were used to measure hepatic native global and segmental T1 and T2 values, respectively. T1 and T2 values exhibited good intra- and inter-observer reproducibility (coefficient of variation < 5%). T1 value over segment 4 was significantly lower than the T1 values over segments 2 and 3 (p < 0.0001). No significant regional T2 variability was detected. Segmental and global T1 values were not associated with age or sex. Global T2 values were independent from age but were significantly lower in males than in females. The lower and upper limits of normal for global T1 values were, respectively, 442ms and 705ms. The normal range for global T2 values was 35ms-54ms in males and 39ms-54ms in females. Liver T1 and T2 mapping is feasible and reproducible and the provided normal ranges may help to establish diagnosis and progression of various liver diseases.

Sex-specific reference values for total, central, and peripheral latency of motor evoked potentials from a large cohort.

Differentiating between physiologic and altered motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) is crucial in clinical practice. Some physical characteristics, such as height and age, introduce sources of variability unrelated to neural dysfunction. We provided new age- and height-adjusted normal values for cortical latency, central motor conduction time (CMCT), and peripheral motor conduction time (PMCT) from a large cohort of healthy subjects. Previously reported data from 587 participants were re-analyzed. Nervous system disorders were ruled out by clinical examination and magnetic resonance imaging. MEP latency was determined as stimulus-to-response latency through stimulation with a circular coil over the "hot spot" of the First Dorsal Interosseous and Tibialis Anterior muscles, during mild tonic contraction. CMCT was estimated as the difference between MEP cortical latency and PMCT by radicular magnetic stimulation. Additionally, right-to-left differences were calculated. For each parameter, multiple linear regression models of increasing complexity were fitted using height, age, and sex as regressors. Motor evoked potential cortical latency, PMCT, and CMCT were shown to be age- and height-dependent, although age had only a small effect on CMCT. Relying on Bayesian information criterion for model selection, MEP cortical latency and PMCT were explained best by linear models indicating a positive correlation with both height and age. Also, CMCT to lower limbs positively correlated with height and age. CMCT to upper limbs positively correlated to height, but slightly inversely correlated to age, as supported by non-parametric bootstrap analysis. Males had longer cortical latencies and CMCT to lower limbs, as well as longer PMCT and cortical latencies to upper limbs, even when accounting for differences in body height. Right-to-left-differences were independent of height, age, and sex. Based on the selected regression models, sex-specific reference values were obtained for all TMS-related latencies and inter-side differences, with adjustments for height and age, where warranted. A significant relationship was observed between height and age and all MEP latency values, in both upper and lower limbs. These set of reference values facilitate the evaluation of MEPs in clinical studies and research settings. Unlike previous reports, we also highlighted the contribution of sex.

Left ventricular myocardial tissue characteristics and function among healthy subjects with varying atherosclerotic cardiovascular disease risk

Abstract The Atherosclerotic Cardiovascular Disease Risk (ASCVD) score by pooled cohort equation is a reliable predictor for future ASCVD events and is used to guide primary prevention in asymptomatic aging subjects. ASCVD risk is associated with burden of coronary artery disease as measured from computed tomography angiography. Purpose We aim to investigate the association between ASCVD risk and cardiac magnetic resonance (CMR) derived left ventricular (LV) myocardial tissue characteristics (T1 values) and LV systolic and diastolic ventricular function in a large cohort of healthy subjects. Methods We selected all healthy subjects who underwent CMR from the UK-Biobank cohort study. We collected patient characteristics, cardiovascular risk factors, blood pressure at CMR, medication use and cholesterol levels. We used AI-CMRQC, our quality-controlled tool for analysis of cardiovascular function metrics from CMR using artificial intelligence [1,2], to automatically extract septal T1 values from native T1 maps and LV ejection fraction (EF), peak ejection and early filling rates (PER, PEFR), peak systolic longitudinal strain and diastolic strain-rate, mitral valve annular plane systolic excursion and diastolic peak velocity from cine long and short axis acquisitions. Subjects were stratified for low (&amp;lt;7.5%), intermediate (7.5–21%) and high (&amp;gt;21%) ASCVD risk. One-way repeated measures ANOVA was used to examine the association between cardiovascular metrics and ASCVD risk groups. Results 12,493 healthy subjects were included (females n=6,000). Mean age was 62.7±7.5 years, 3.2% had diabetes, 12.5% received treatment for hypertension and 23% smoked. ASCVD risk score could be calculated in 9,487 subjects. Mean ASCVD risk was 12.7±9%. 38% of subjects had low, 43% intermediate and 19% high ASCVD risk. T1 values fell across the incremental ASCVD groups (low: 943±51 ms, intermediate: 921±47 ms, high: 918±50 ms, P&amp;lt;0.001). Indexed LV PEFR (low: 188±45 ml/ms·m2, intermediate: 170±48 ml/ms·m2, high: 147±45 ml/ms·m2, P&amp;lt;0.001), diastolic longitudinal strain rate (low: 1.25±0.36, intermediate: 1.20±0.37, high: 1.17±0.36, P&amp;lt;0.001) also fell consistently with incremental risk. A statistically significant, but clinically less relevant decrease was seen for LVEF (low: 59±6%, intermediate 58±6%, high: 57±6% p&amp;lt;0.001) and longitudinal systolic strain (low: 21±3.5%, intermediate: 21±3.4%, high: 21±3.5%). Conclusion Increasing ASCVD risk was associated with lower native T1 values and decreasing metrics of diastolic and systolic LV function. The fall in T1 might suggest fibrofatty replacement in the LV myocardium in patients with incremental ASCVD risk that could contribute to the observed deterioration of LV function. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NIHR MedTech cooperation awarded to Guy's and ST Thomas NHS Foundation Trust

A macroscopic link between interhemispheric tract myelination and cortico-cortical interactions during action reprogramming

Myelination has been increasingly implicated in the function and dysfunction of the adult human brain. Although it is known that axon myelination shapes axon physiology in animal models, it is unclear whether a similar principle applies in the living human brain, and at the level of whole axon bundles in white matter tracts. Here, we hypothesised that in humans, cortico-cortical interactions between two brain areas may be shaped by the amount of myelin in the white matter tract connecting them. As a test bed for this hypothesis, we use a well-defined interhemispheric premotor-to-motor circuit. We combined TMS-derived physiological measures of cortico-cortical interactions during action reprogramming with multimodal myelin markers (MT, R1, R2* and FA), in a large cohort of healthy subjects. We found that physiological metrics of premotor-to-motor interaction are broadly associated with multiple myelin markers, suggesting interindividual differences in tract myelination may play a role in motor network physiology. Moreover, we also demonstrate that myelination metrics link indirectly to action switching by influencing local primary motor cortex dynamics. These findings suggest that myelination levels in white matter tracts may influence millisecond-level cortico-cortical interactions during tasks. They also unveil a link between the physiology of the motor network and the myelination of tracts connecting its components, and provide a putative mechanism mediating the relationship between brain myelination and human behaviour.

Automated non-invasive pressure-volume loop analysis of cardiac aging in a large cohort of healthy community dwellers

Abstract Background/Introduction Pressure-volume loops (PVloops) provide a wealth of information on cardiac function that is not readily available from cardiac imaging alone. Methods To estimate left ventricular (LV) PVloops non-invasively have been available, but have so far not been used to interrogate ventricular function in large patient cohorts, due to the complexity of estimating PVloops. A new method was recently validated that construct PVloops non-invasively from cine cardiac magnetic resonance (CMR), based on the time-varying elastance model [1]. At the same time, we have validated a framework for automated, quality controlled analysis of cine CMR in large cohorts of patients/subjects [2]. Combining these two methods could automated PVloop estimation, enabling analysis of ventricular pressure-volume relationships in large study populations. Purpose Evaluate if CMR-based non-invasive PVloops can be used to interrogate the impact of cardiac ageing on LV function occurring in a large population of healthy community dwellers. Methods Non-invasive PVloops were calculated from a full cardiac cycle LV volume curve and brachial blood pressure data using a recently validated method based on the time-varying elastance model [1], in 7,650 healthy community dwellers from the UKBiobank population study. The LV volume curve was automatically obtained using our state-of-the-art, quality controlled deep learning (DL) based cine CMR analysis framework [2]. External Work, pressure-volume-area (PVA), end-systolic pressure (Pes), ventricular elastance (Ees, an estimate of contractility) and arterial elastance (Ea) and energy per ejected volume (EEV: PVA/ stroke volume) were calculated from the PVloops. We performed univariate regression between PVloop parameters and age. We also calculated the additional impact of cardiovascular risk-factors in a multivariate analysis. Results See results in table 1. With age, LV volumes fall (p&amp;lt;0.001) in healthy subjects, while systolic blood pressure and Pes increases (both p&amp;lt;0.001). As a result of the higher afterload, PVA (p=0.894) and EW (p=0.499) do not significantly change with age despite a lower SV. Arterial elastance (Ea) increased, and so did contractility, as measured by Ees (p&amp;lt;0.001). Due to all these changes, EEV increased with age (p&amp;lt;0.001). In multivariate analysis, cardiovascular risk factors hypercholesterolemia and hypertension negatively impacted Pes, PVA, Ees and EEV. Diabetes and smoking habits did not. Conclusion Non-invasive CMR-based PVloop analyses capture the impact of known changes occurring during cardiac ageing on cardiac work, contractility and energetic expenditure. Obtaining PVloops automatically using our AI analysis system in this large cohort of healthy subjects allows to formulate reference for assessment of cardiac disease. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The authors acknowledge financial support (support) the National Institute for Health Research (NIHR) Cardiovascular MedTech Co-operative (previously existing as the Cardiovascular Healthcare Technology Co-operative 2012 - 2017) award to the Guy's and St Thomas' NHS Foundation Trust, in partnership with King's College London and the NIHR comprehensive Biomedical Research Centre of the Guy's &amp; St Thomas' NHS Foundation Trust. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health Univariate regression analysisExample of estimated PV loop

Myocardial T2 values by a segmental approach with healthy ageing and gender

Abstract Funding Acknowledgements Type of funding sources: None. Introduction. No data are available in literature about normal ranges for T2 in human myocardium using GE scanners. Aims. Our aims were to obtain myocardial regional and global T2 values as a reference for normality for the first time using a GE scanner and to assess their association with physiological variables. Methods. A stratified approach was adopted for healthy volunteers recruitment, ensuring the presence of 10 participants for both genders in each age decile: 20–30, 30–40, 40-50, 50-60, 60-70 years. Basal, medium, and apical short-axis slices of the left ventricle were acquired by a multi-echo fast-spin-echo (MEFSE) sequence. Image analysis was performed with a commercially available software package. T2 value was assessed in all 16 myocardial segments and global value was the mean. Results. The global T2 value averaged across all subjects was 52.2 ± 2.5 ms (range: 47.0-59.9 ms). Inter-study, intra-observer, and inter-observer reproducibility was good (coefficient of variation &amp;lt; 5%). The 3.6% of segments was excluded because of artifacts and/or partial-volume effects. Segmental T2 values differed significantly (P &amp;lt; 0.0001), with the lowest value in the basal anterolateral segment (50.0 ± 3.5 ms) and the highest in the apical lateral segment (54.9 ± 5.1 ms). Mean T2 was significantly lower in the basal slice compared to both medium (51.0 ± 2.4 vs 51.8 ± 2.6 ms; P &amp;lt; 0.0001) and apical slices (51.0 ± 2.4 vs 54.2 ± 3.7 ms; P &amp;lt; 0.0001), and in the medium slice than in the apical slice (51.8 ± 2.6 vs 54.2 ± 3.7 ms; P &amp;lt; 0.0001). Aging was associated with increased segmental and global T2 values. Females showed higher T2 values than males. T2 values were not correlated to heart rate. Mean T2 values, standard deviation, and lower and upper limits of normal for all 16 myocardial segments are shown in Figure 1 for males and in Figure 2 for females, considering separately each age group. Conclusion. The optimized MEFSE sequence allows for robust, reliable, and reproducible quantification of segmental T2 values. T2 values differ among myocardial slices and are influenced by age and gender, making mandatory to define gender- and age-specific segmental reference values for distinguishing between healthy and diseased myocardium. The normal ranges defined in this study on a large cohort of healthy subjects could be used as reference by other sites using the same sequence, allowing them to recruit a smaller population and accelerating the spread of myocardial T2 mapping in the clinical arena.

Propionate Fermentative Genes of the Gut Microbiome Decrease in Inflammatory Bowel Disease.

Changes in the gut microbiome have been associated with inflammatory bowel disease. A protective role of short chain fatty acids produced by the gut microbiota has been suggested as a causal mechanism. Nevertheless, multi-omic analyses have failed to identify a clear link between changes in specific taxa and disease states. Recently, metagenomic analyses unveiled that gut bacterial species have a previously unappreciated genomic diversity, implying that a geno-centric approach may be better suited to identifying the mechanisms involved. Here, we quantify the abundance of terminal genes in propionate-producing fermentative pathways in the microbiome of a large cohort of healthy subjects and patients with inflammatory bowel disease. The results show that propionate kinases responsible for propionate production in the gut are depleted in patients with Crohn’s disease. Our results also indicate that changes in overall species abundances do not necessarily correlate with changes in the abundances of metabolic genes, suggesting that these genes are not part of the core genome. This, in turn, suggests that changes in strain composition may be as important as changes in species abundance in alterations of the gut microbiome associated with pathological conditions.

Prevalence and distribution of cartilage and bone damage at metacarpal head in healthy subjects.

To determine the prevalence and distribution of the ultrasound (US) findings indicating cartilage and bone damage at the metacarpal head (MH) in a group of healthy subjects (HS), and their association with the clinical and US data. We also aimed to provide standard reference values of cartilage thickness. US scans of the dorsal aspect of the metacarpophalangeal joints (MCPj) from 2nd to 5th finger of both hands were performed in 179 HS. The presence of cartilage damage, osteophytes and bone erosions was recorded. Cartilage damage, osteophytes and bone erosions were found in at least one MCPj in 30 (16.8%), 17 (9.5%) and 4 (2.2%) out of 179 HS, respectively. Signs of cartilage damage were found in 91 out of 1432 MHs (6.4%). Blurring of the chondrosynovial margin, minimal and severe thinning were detected in 73.7%, 26.3% and 0% of the 91 MHs, respectively. Osteophytes and bone erosions were found in 31 (2.2%) and in 4 (0.3%) MCPjs. The thickness of the MH cartilage ranged between 0.41 and 1.10 mm in males and between 0.36 and 1.03 mm in females. A significant association was found between cartilage thickness and age (r=-0.33, p<0.001), sex (rpb=0.42, p<0.001), height (r=0.39, p<0.001) and osteophytes in the same joint (v=-0.54, p<0.001) and between working condition and osteophytes (v=0.31, p=0.021). This cross-sectional study reports the prevalence of US findings of joint damage in a large cohort of HS. Moreover, standard reference values of the MH cartilage thickness in HS are provided.

Estimating brain age from structural MRI and MEG data: Insights from dimensionality reduction techniques

Brain age prediction studies aim at reliably estimating the difference between the chronological age of an individual and their predicted age based on neuroimaging data, which has been proposed as an informative measure of disease and cognitive decline. As most previous studies relied exclusively on magnetic resonance imaging (MRI) data, we hereby investigate whether combining structural MRI with functional magnetoencephalography (MEG) information improves age prediction using a large cohort of healthy subjects (N = 613, age 18–88 years) from the Cam-CAN repository. To this end, we examined the performance of dimensionality reduction and multivariate associative techniques, namely Principal Component Analysis (PCA) and Canonical Correlation Analysis (CCA), to tackle the high dimensionality of neuroimaging data. Using MEG features (mean absolute error (MAE) of 9.60 years) yielded worse performance when compared to using MRI features (MAE of 5.33 years), but a stacking model combining both feature sets improved age prediction performance (MAE of 4.88 years). Furthermore, we found that PCA resulted in inferior performance, whereas CCA in conjunction with Gaussian process regression models yielded the best prediction performance. Notably, CCA allowed us to visualize the features that significantly contributed to brain age prediction. We found that MRI features from subcortical structures were more reliable age predictors than cortical features, and that spectral MEG measures were more reliable than connectivity metrics. Our results provide an insight into the underlying processes that are reflective of brain aging, yielding promise for the identification of reliable biomarkers of neurodegenerative diseases that emerge later during the lifespan.

Long-Term Neuroanatomical Consequences of Childhood Maltreatment: Reduced Amygdala Inhibition by Medial Prefrontal Cortex.

Similar to patients with Major depressive disorder (MDD), healthy subjects at risk for depression show hyperactivation of the amygdala as a response to negative emotional expressions. The medial prefrontal cortex is responsible for amygdala control. Analyzing a large cohort of healthy subjects, we aimed to delineate malfunction in amygdala regulation by the medial prefrontal cortex in subjects at increased risk for depression, i.e., with a family history of affective disorders or a personal history of childhood maltreatment. We included a total of 342 healthy subjects from the FOR2107 cohort (www.for2107.de). An emotional face-matching task was used to identify the medial prefrontal cortex and right amygdala. Dynamic Causal Modeling (DCM) was conducted and neural coupling parameters were obtained for healthy controls with and without particular risk factors for depression. We assigned a genetic risk if subjects had a first-degree relative with an affective disorder and an environmental risk if subjects experienced childhood maltreatment. We then compared amygdala inhibition during emotion processing between groups. Amygdala inhibition by the medial prefrontal cortex was present in subjects without those two risk factors, as indicated by negative model parameter estimates. Having a genetic risk (i.e., a family history) did not result in changes in amygdala inhibition compared to no risk subjects. In contrast, childhood maltreatment as environmental risk has led to a significant reduction of amygdala inhibition by the medial prefrontal cortex. We propose a mechanistic explanation for the amygdala hyperactivity in subjects with particular risk for depression, in particular childhood maltreatment, caused by a malfunctioned amygdala downregulation via the medial prefrontal cortex. As childhood maltreatment is a major environmental risk factor for depression, we emphasize the importance of this potential early biomarker.

Intersubject Variability and Normalization Strategies for Spinal Cord Total Cross-Sectional and Gray Matter Areas.

The quantification of spinal cord (SC) atrophy by MRI has assumed an important role in assessment of neuroinflammatory/neurodegenerative diseases and traumatic SC injury. Recent technical advances make possible the quantification of gray matter (GM) and white matter tissues in clinical settings. However, the goal of a reliable diagnostic, prognostic or predictive marker is still elusive, in part due to large intersubject variability of SC areas. Here, we investigated the sources of this variability and explored effective strategies to reduce it. One hundred twenty-nine healthy subjects (mean age: 41.0 ± 15.9) underwent MRI on a Siemens 3T Skyra scanner. Two-dimensional PSIR at the C2-C3 vertebral level and a sagittal 1 mm3 3D T1-weighted brain acquisition extended to the upper cervical cord were acquired. Total cross-sectional area and GM area were measured at C2-C3, as well as measures of the vertebra, spinal canal and the skull. Correlations between the different metrics were explored using Pearson product-moment coefficients. The most promising metrics were used to normalize cord areas using multiple regression analyses. The most effective normalization metrics were the V-scale (from SienaX) and the product of the C2-C3 spinal canal diameters. Normalization methods based on these metrics reduced the intersubject variability of cord areas of up to 17.74%. The measured cord areas had a statistically significant sex difference, while the effect of age was moderate. The present work explored in a large cohort of healthy subjects the source of intersubject variability of SC areas and proposes effective normalization methods for its reduction.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio among Patients with Vestibular Neuritis

Objective: To compare the level of the inflammatory markers (IM) neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) among healthy subjects and those presenting with vestibular neuritis (VN). Methods: A cross-sectional retrospective study was conducted in a tertiary hospital setting. The medical records of patients (20–60 years old) who were hospitalized between the years 2005 and 2014 with the diagnosis of VN were retrieved. Inclusion criteria were: (1) acute vertigo lasting for at least 24 h, (2) absence of auditory complaints, (3) presence of horizontal unidirectional nystagmus during physical examination, (4) absence of neurological symptoms or signs. The levels of the IM were compared with levels reported among two large cohorts of healthy subjects, within the same age range. Results: A statistically significant difference was found between the levels of NLR in VN subjects compared with controls, with higher levels of NLR in VN subjects (p < 0.001), while no significant difference was found between both groups concerning the levels of PLR. Conclusion: Higher levels of IM were found among VN patients, with significantly higher levels of NLR, but not PLR. This may suggest a possible inflammatory etiology of VN.

Cut off value in each gender and decade of 10-s grip and release and 10-s step test: A comparative study between 454 patients with cervical spondylotic myelopathy and 818 healthy subjects

ObjectivesThe purpose of this study was to establish the clinical cut-off values of the 10-s grip and release (G&R) and 10-s step quantitative tests for the diagnosis of cervical spondylotic myelopathy (CSM) and to elucidate the aging variation and gender difference of those values in a large cohort of healthy subjects. Patients and methodsPatients with CSM (n = 454) and asymptomatic subjects (n = 818) were included. Subjects were aged 40–70 years; according to their age, they were categorized by decades. The 10-s G&R and 10-s step tests were used to quantitatively assess performance. The receiver operating characteristic (ROC) curves were plotted to evaluate the cut-off value of the 10-s G&R and 10-s step tests for determining the presence or absence of CSM in each gender and decade. ResultsThe cut-off values in the G&R test were 20 in 40 s, 19 in 50 s, 17 in 60 s, and 16 in 70 s groups respectively. The cut-off values in the 10-s step test were 19 in 40 s, 18 in 50 s, 16 in 60 s, and 15 in 70 s groups respectively. The cut-off value of the G&R test in females was lower than that in the males. The cut-off value of 10-s step test was lower in the females than in the males in 40 s and 50 s groups. ConclusionsThe cut-off values in the 10-s G&R test and 10-s step decreased with age. When these quantifiable tests are used as screening tests of CSM, age and gender difference should be considered.

Network localization of cervical dystonia based on causal brain lesions.

Cervical dystonia is a neurological disorder characterized by sustained, involuntary movements of the head and neck. Most cases of cervical dystonia are idiopathic, with no obvious cause, yet some cases are acquired, secondary to focal brain lesions. These latter cases are valuable as they establish a causal link between neuroanatomy and resultant symptoms, lending insight into the brain regions causing cervical dystonia and possible treatment targets. However, lesions causing cervical dystonia can occur in multiple different brain locations, leaving localization unclear. Here, we use a technique termed 'lesion network mapping', which uses connectome data from a large cohort of healthy subjects (resting state functional MRI, n = 1000) to test whether lesion locations causing cervical dystonia map to a common brain network. We then test whether this network, derived from brain lesions, is abnormal in patients with idiopathic cervical dystonia (n = 39) versus matched controls (n = 37). A systematic literature search identified 25 cases of lesion-induced cervical dystonia. Lesion locations were heterogeneous, with lesions scattered throughout the cerebellum, brainstem, and basal ganglia. However, these heterogeneous lesion locations were all part of a single functionally connected brain network. Positive connectivity to the cerebellum and negative connectivity to the somatosensory cortex were specific markers for cervical dystonia compared to lesions causing other neurological symptoms. Connectivity with these two regions defined a single brain network that encompassed the heterogeneous lesion locations causing cervical dystonia. These cerebellar and somatosensory regions also showed abnormal connectivity in patients with idiopathic cervical dystonia. Finally, the most effective deep brain stimulation sites for treating dystonia were connected to these same cerebellar and somatosensory regions identified using lesion network mapping. These results lend insight into the causal neuroanatomical substrate of cervical dystonia, demonstrate convergence across idiopathic and acquired dystonia, and identify a network target for dystonia treatment.

An easily applicable method to analyse the ankle-foot power absorption and production during walking

BackgroundPower and work at the ankle joint during gait are usually computed considering the foot as a rigid body [1–6] (Ankle Joint method, AJ). The foot is instead a deformable structure and can absorb and produce work by pronation/supination, foot arch deformation and other intrinsic movements. A different approach, named “the Distal Shank method (DS)” [7–12] considers all these aspects without increasing the complexity of the protocol, and thus it seems promising for clinical applications [12].Research questions: a) To characterize the differences in power and work computed using the two mentioned methods for a relatively large number of subjects walking at different velocities, barefoot and with different shoes; b) To assess the practical feasibility of the DS method for clinical applications. Materials and methodsEighteen healthy subjects were evaluated while walking barefoot at slow, natural and fast velocity. Shod walking was analysed at natural velocity. Four subjects were also analysed while walking in high-heel shoes. The power at the ankle joint was computed with both the AJ and the DS methods. We then compared the obtained results. ResultsThe DS method showed a consistent negative peak of power absorption during the load acceptance phase, barely visible with the AJ method. The maximum power production calculated with the DS method was significantly lower. The work at the end of the stride cycle was lower with the DS method, and in most conditions even negative, thus indicating higher energy dissipation. SignificanceWe confirmed on a large cohort of healthy subjects and in different walking conditions that neglecting foot deformations during gait leads to underestimate power absorption and overestimate power production. The DS method does not require a complex gait analysis protocol, nor additional time for the analysis, and can provide information of clinical interest, related to foot mechanical alterations.

Phrenic Nerve Conduction in Healthy Subjects.

Assessment of diaphragm compound muscle action potential by noninvasive phrenic nerve stimulation at the neck is well described. However, normal values in a large cohort of healthy subjects are lacking. Our objective was to determine reference values of phrenic nerve conduction in healthy subjects. We recruited 155 healthy subjects (25-79 years old) and measured mean amplitude (PhrenAmp) and latency (PhrenLat) of motor responses according to Bolton's method. The lower limit for PhrenAmp was 0.28 and 0.25 mV and the upper limit for PhrenLat was 8.41 and 8.56 ms for right and left side, respectively. PhrenLat was correlated with age. PhrenAmp, PhrenLat and area were significantly higher in men. Tolerance to phrenic nerve stimulation was excellent. Our study provides normative values of phrenic nerve motor responses in a large cohort of healthy subjects and identifies age and sex as factors of variation. Muscle Nerve 59:451-456, 2019.

Normative data for the segmental acquisition of contact heat evoked potentials in cervical dermatomes.

Contact heat evoked potentials (CHEPs) represent a neurophysiological approach to assess conduction in the spinothalamic tract. The aim of this study was to establish normative values of CHEPs acquired from cervical dermatomes (C4, C6, C8) and examine the potential confounds of age, sex, and height. 101 (49 male) healthy subjects of three different age groups (18–40, 41–60, and 61–80 years) were recruited. Normal (NB, 35–52 °C) followed by increased (IB, 42–52 °C) baseline stimulation protocols were employed to record CHEPs. Multi-variate linear models were used to investigate the effect of age, sex, and height on the CHEPs parameters (i.e., N2 latency, N2P2 amplitude, rating of perceived intensity). Compared to NB, IB stimulation reduced latency jitter within subjects, yielding larger N2P2 amplitudes, and decreased inter-subject N2 latency variability. Age was associated with reduced N2P2 amplitude and prolonged N2 latency. After controlling for height, male subjects had significantly longer N2 latencies than females during IB stimulation. The study provides normative CHEPs data in a large cohort of healthy subjects from segmentally examined cervical dermatomes. Age and sex were identified as important factors contributing to N2 latency and N2P2 amplitude. The normative data will improve the diagnosis of spinal cord pathologies.

The Voxel-Wise Functional Connectome Can Be Efficiently Derived from Co-activations in a Sparse Spatio-Temporal Point-Process

Large efforts are currently under way to systematically map functional connectivity between all pairs of millimeter-scale brain regions based on large neuroimaging databases. The exploratory unraveling of this “functional connectome” based on functional Magnetic Resonance Imaging (fMRI) can benefit from a better understanding of the contributors to resting state functional connectivity. In this work, we introduce a sparse representation of fMRI data in the form of a discrete point-process encoding high-amplitude events in the blood oxygenation level-dependent (BOLD) signal and we show it contains sufficient information for the estimation of functional connectivity between all pairs of voxels. We validate this method by replicating results obtained with standard whole-brain voxel-wise linear correlation matrices in two datasets. In the first one (n = 71), we study the changes in node strength (a measure of network centrality) during deep sleep. The second is a large database (n = 1147) of subjects in which we look at the age-related reorganization of the voxel-wise network of functional connections. In both cases it is shown that the proposed method compares well with standard techniques, despite requiring only data on the order of 1% of the original BOLD signal time series. Furthermore, we establish that the point-process approach does not reduce (and in one case increases) classification accuracy compared to standard linear correlations. Our results show how large fMRI datasets can be drastically simplified to include only the timings of large-amplitude events, while still allowing the recovery of all pair-wise interactions between voxels. The practical importance of this dimensionality reduction is manifest in the increasing number of collaborative efforts aiming to study large cohorts of healthy subjects as well as patients suffering from brain disease. Our method also suggests that the electrophysiological signals underlying the dynamics of fMRI time series consist of all-or-none temporally localized events, analogous to the avalanches of neural activity observed in recordings of local field potentials (LFP), an observation of potentially high neurobiological relevance.

Physiologic correlates of tricuspid annular plane systolic excursion in 1168 healthy subjects

BackgroundTAPSE provides a simple, reproducible estimate of the longitudinal function of the right ventricle (RV). However, the normal limits and physiologic correlates of tricuspid annular plane systolic excursion (TAPSE) are not exactly known. The aim of this study was to explore the full spectrum of TAPSE values and determine the physiologic correlates of TAPSE. Methods and resultsFrom June 2007 to December 2013, 1168 healthy subjects [mean age 45.1±16years, range 16 to 92; 555 (47.5%) men] underwent comprehensive transthoracic echocardiography (TTE) as recommended by current guidelines. TAPSE values were higher in men than women (24.0±3.5 vs 23.2±3.0mm, p value<0.0001) but did not vary according to age. On multivariable linear regression analysis, cardiac output, RV basal and longitudinal dimensions were the only variables independently associated with TAPSE (β coefficient=0.161, 0.116 and 0.115 respectively). On the other hand echocardiographically-derived systolic pulmonary artery pressure (SPAP), pulmonary vascular resistance and mitral E/e′ ratio were significantly higher in older subjects. Therefore a significant decrease of TAPSE/SPAP was detected in >60years old cohort (p=0.0001). ConclusionsOur large cohort of healthy subjects provides sex and age-based TAPSE and TAPSE/SPAP normal cut-offs. TAPSE was found to be higher in men but not influenced by age. It was mainly correlated with echo-Doppler indices reflecting pre-load as opposed to afterload. On the other hand a significant decrease of TAPSE/SPAP with older age was registered as a direct consequence of increased SPAP with aging.