Evidence for Altered Basal Ganglia-Brainstem Connections in Cervical Dystonia

Background: There has been increasing interest in the interaction of the basal ganglia with the cerebellum and the brainstem in motor control and movement disorders. In addition, it has been suggested that these subcortical connections with the basal ganglia may help to coordinate a network of regions involved in mediating posture and stabilization. While studies in animal models support a role for this circuitry in the pathophysiology of the movement disorder dystonia, thus far, there is only indirect evidence for this in humans with dystonia. Methodology/Principal Findings: In the current study we investigated probabilistic diffusion tractography in DYT1-negative patients with cervical dystonia and matched healthy control subjects, with the goal of showing that patients exhibit altered microstructure in the connectivity between the pallidum and brainstem. The brainstem regions investigated included nuclei that are known to exhibit strong connections with the cerebellum. We observed large clusters of tractography differences in patients relative to healthy controls, between the pallidum and the brainstem. Tractography was decreased in the left hemisphere and increased in the right hemisphere in patients, suggesting a potential basis for the left/right white matter asymmetry we previously observed in focal dystonia patients. Conclusions/Significance: These findings support the hypothesis that connections between the basal ganglia and brainstem play a role in the pathophysiology of dystonia

Associations between depressive symptoms and disease progression in older patients with chronic kidney disease: results of the EQUAL study

Background Depressive symptoms are associated with adverse clinical outcomes in patients with end-stage kidney disease; however, few small studies have examined this association in patients with earlier phases of chronic kidney disease (CKD). We studied associations between baseline depressive symptoms and clinical outcomes in older patients with advanced CKD and examined whether these associations differed depending on sex. Methods CKD patients (>= 65 years; estimated glomerular filtration rate <= 20 mL/min/1.73 m(2)) were included from a European multicentre prospective cohort between 2012 and 2019. Depressive symptoms were measured by the five-item Mental Health Inventory (cut-off <= 70; 0-100 scale). Cox proportional hazard analysis was used to study associations between depressive symptoms and time to dialysis initiation, all-cause mortality and these outcomes combined. A joint model was used to study the association between depressive symptoms and kidney function over time. Analyses were adjusted for potential baseline confounders. Results Overall kidney function decline in 1326 patients was -0.12 mL/min/1.73 m(2)/month. A total of 515 patients showed depressive symptoms. No significant association was found between depressive symptoms and kidney function over time (P = 0.08). Unlike women, men with depressive symptoms had an increased mortality rate compared with those without symptoms [adjusted hazard ratio 1.41 (95% confidence interval 1.03-1.93)]. Depressive symptoms were not significantly associated with a higher hazard of dialysis initiation, or with the combined outcome (i.e. dialysis initiation and all-cause mortality). Conclusions There was no significant association between depressive symptoms at baseline and decline in kidney function over time in older patients with advanced CKD. Depressive symptoms at baseline were associated with a higher mortality rate in men

Brain simulation as a cloud service: The Virtual Brain on EBRAINS

The Virtual Brain (TVB) is now available as open-source services on the cloud research platform EBRAINS (ebrains.eu). It offers software for constructing, simulating and analysing brain network models including the TVB simulator; magnetic resonance imaging (MRI) processing pipelines to extract structural and functional brain networks; combined simulation of large-scale brain networks with small-scale spiking networks; automatic conversion of user-specified model equations into fast simulation code; simulation-ready brain models of patients and healthy volunteers; Bayesian parameter optimization in epilepsy patient models; data and software for mouse brain simulation; and extensive educational material. TVB cloud services facilitate reproducible online collaboration and discovery of data assets, models, and software embedded in scalable and secure workflows, a precondition for research on large cohort data sets, better generalizability, and clinical translation

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Group differences for voxel-wise probabilistic diffusion tractography contrast (12 cervical dystonia patients versus 12 matched controls).

*<p>Met significance criteria (p<0.00011 [p<0.05 corrected, or t = 4.70] for t values, and 291 voxels for cluster threshold).</p><p>Negative t values indicate that tractography measures were reduced in cervical dystonia patients relative to control subjects. Positive t values indicate that tractography measures were elevated in cervical dystonia patients relative to control subjects. Note that all regions included in the cluster are reported; however, only one peak within the cluster was required to reach statistical significance (t>4.12). t values are reported for all regions exhibiting peaks of 3.5 or greater. L = left hemisphere; R = right hemisphere; wm = white matter.</p

Clinical characteristics of cervical dystonia patients.

*<p>subjects included in 2006 study using different analyses.</p><p>BFM: Burke Fahn Marsden dystonia rating scale.</p><p>Tsui: Tsui rating scale for cervical dystonia.</p><p>TW: Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) for cervical dyston.</p

Regions of probabilistic diffusion tractography that were significantly different between cervical dystonia patients and controls.

<p>(A) shows reduced tractography from the left AL seed region, and (B) shows elevated tractography from the right pallidal seed region. Arrows point to the region through which we drew ROIs in our previous DTI study, which includes AL fibers. <i>A priori</i> segmented regions are shown as reference points: Pink = red nucleus; White = substantia nigra; Blue = pedunculopontine nucleus. MNI talairach coordinates are indicated for each two dimensional image. Lower images in each panel show three dimensional rendering of clusters; the image for the left AL includes the AL seed region in green, and the patient/control difference is shown in blue. t maps and three dimensional clusters are superimposed on the average FA map for all 24 subjects in the study for anatomical reference, and are thresholded at t = +/−2.07 (the threshold used to identify difference clusters, p<0.05, uncorrected, for df = 22). The color bars indicate the range of t values in each panel, from +/−2.07 to the peak t value for each contrast. Warm tones (red, orange, yellow) indicate regions in which cervical dystonia patients exhibited elevated tractography relative to control subjects. Cool tones (blues) indicate regions in which cervical dystonia patients exhibited reduced tractography relative to control subjects. Three dimensional images are shown in mono-color rather than graded/multi-color to illustrate location rather than significance. LH: left hemisphere; RH: right hemisphere.</p

Probabilistic diffusion tractography and overlap with <i>a priori</i> areas of evaluation (AOEs) used for the FA and MD contrasts.

<p>(A) Examples of tractography from the left ansa lenticularis (AL) seed region, averaged across control subjects (before contrasts were conducted), thresholded at 500 (samples). Note that tractography bifurcated at the level of the substantia nigra (see axial image). (B) Examples of tractography from the left pallidal seed region, averaged across control subjects (before contrasts were conducted), thresholded at 500. Like AL tractography, pallidal tractography bifurcated at the level of the substantia nigra (see axial image). There were also two projections to the thalamus, one superior and one more ventral (see sagittal image). (C) Intersection of tractography with segmentations of our <i>a priori</i> AOEs, including (in descending order) the ansa lenticularis (green), the substantia nigra (white), the red nucleus (pink), the pedunculopontine nucleus (blue), and the superior cerebellar peduncle (peach). Tractography maps are superimposed on the average FA map for all 24 subjects in the study. (D) Example of type Ib GPi neuron from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031654#pone.0031654-Parent1" target="_blank">[21]</a>, showing extensive arborization, including to the RN and PPN (reprinted with permission from The Journal of Comparative Neurology). MNI talairach coordinates are indicated for all images. LH: left hemisphere; RH: right hemisphere.</p