Freezing of gait is a disabling symptom of Parkinson's disease that causes a paroxysmal inability to generate effective stepping. The underlying pathophysiology has recently migrated towards a ...dysfunctional supraspinal locomotor network, but the actual network derangements during ongoing gait freezing are unknown. We investigated the communication between the cortex and the subthalamic nucleus, two main nodes of the locomotor network, in seven freely-moving subjects with Parkinson's disease with a novel deep brain stimulation device, which allows on-demand recording of subthalamic neural activity from the chronically-implanted electrodes months after the surgical procedure. Multisite neurophysiological recordings during (effective) walking and ongoing gait freezing were combined with kinematic measurements and individual molecular brain imaging studies. Patients walked in a supervised environment closely resembling everyday life challenges. We found that during (effective) walking, the cortex and subthalamic nucleus were synchronized in a low frequency band (4-13 Hz). In contrast, gait freezing was characterized in every patient by low frequency cortical-subthalamic decoupling in the hemisphere with less striatal dopaminergic innervation. Of relevance, this decoupling was already evident at the transition from normal (effective) walking into gait freezing, was maintained during the freezing episode, and resolved with recovery of the effective walking pattern. This is the first evidence for a decoding of the networked processing of locomotion in Parkinson's disease and suggests that freezing of gait is a 'circuitopathy' related to a dysfunctional cortical-subcortical communication. A successful therapeutic approach for gait freezing in Parkinson's disease should aim at directly targeting derangements of neural network dynamics.
To investigate whether
(MP), a levodopa-containing leguminous plant growing in all tropical areas worldwide, may be used as alternative source of levodopa for indigent individuals with Parkinson ...disease (PD) who cannot afford long-term therapy with marketed levodopa preparations.
We investigated efficacy and safety of single-dose intake of MP powder from roasted seeds obtained without any pharmacologic processing. Eighteen patients with advanced PD received the following treatments, whose sequence was randomized: (1) dispersible levodopa at 3.5 mg/kg combined with the dopa-decarboxylase inhibitor benserazide (LD+DDCI; the reference treatment); (2) high-dose MP (MP-Hd; 17.5 mg/kg); (3) low-dose MP (MP-Ld; 12.5 mg/kg); (4) pharmaceutical preparation of LD without DDCI (LD-DDCI; 17.5 mg/kg); (5) MP plus benserazide (MP+DDCI; 3.5 mg/kg); (6) placebo. Efficacy outcomes were the change in motor response at 90 and 180 minutes and the duration of on state. Safety measures included any adverse event (AE), changes in blood pressure and heart rate, and the severity of dyskinesias.
When compared to LD+DDCI, MP-Ld showed similar motor response with fewer dyskinesias and AEs, while MP-Hd induced greater motor improvement at 90 and 180 minutes, longer ON duration, and fewer dyskinesias. MP-Hd induced less AEs than LD+DDCI and LD-DDCI. No differences in cardiovascular response were recorded.
Single-dose MP intake met all noninferiority efficacy and safety outcome measures in comparison to dispersible levodopa/benserazide. Clinical effects of high-dose MP were similar to levodopa alone at the same dose, with a more favorable tolerability profile.
NCT02680977.
Thalamic deep brain stimulation is a mainstay treatment for severe and drug-refractory essential tremor, but postoperative management may be complicated in some patients by a progressive cerebellar ...syndrome including gait ataxia, dysmetria, worsening of intention tremor and dysarthria. Typically, this syndrome manifests several months after an initially effective therapy and necessitates frequent adjustments in stimulation parameters. There is an ongoing debate as to whether progressive ataxia reflects a delayed therapeutic failure due to disease progression or an adverse effect related to repeated increases of stimulation intensity. In this study we used a multimodal approach comparing clinical stimulation responses, modelling of volume of tissue activated and metabolic brain maps in essential tremor patients with and without progressive ataxia to disentangle a disease-related from a stimulation-induced aetiology. Ten subjects with stable and effective bilateral thalamic stimulation were stratified according to the presence (five subjects) of severe chronic-progressive gait ataxia. We quantified stimulated brain areas and identified the stimulation-induced brain metabolic changes by multiple 18 F-fluorodeoxyglucose positron emission tomography performed with and without active neurostimulation. Three days after deactivating thalamic stimulation and following an initial rebound of symptom severity, gait ataxia had dramatically improved in all affected patients, while tremor had worsened to the presurgical severity, thus indicating a stimulation rather than disease-related phenomenon. Models of the volume of tissue activated revealed a more ventrocaudal stimulation in the (sub)thalamic area of patients with progressive gait ataxia. Metabolic maps of both patient groups differed by an increased glucose uptake in the cerebellar nodule of patients with gait ataxia. Our data suggest that chronic progressive gait ataxia in essential tremor is a reversible cerebellar syndrome caused by a maladaptive response to neurostimulation of the (sub)thalamic area. The metabolic signature of progressive gait ataxia is an activation of the cerebellar nodule, which may be caused by inadvertent current spread and antidromic stimulation of a cerebellar outflow pathway originating in the vermis. An anatomical candidate could be the ascending limb of the uncinate tract in the subthalamic area. Adjustments in programming and precise placement of the electrode may prevent this adverse effect and help fine-tuning deep brain stimulation to ameliorate tremor without negative cerebellar signs.
Neurodegenerative diseases (NDs) result from the transformation and accumulation of misfolded proteins within the nervous system. Several mathematical models have been proposed to investigate the ...biological processes underlying NDs, focusing on the kinetics of polymerization and fragmentation at the microscale and on the spread of neural damage at a macroscopic level. The aim of this work is to bridge the gap between microscopic and macroscopic approaches proposing a toy partial differential model able to take into account both the short-time dynamics of the misfolded proteins aggregating in plaques and the long-term evolution of tissue damage. Using mixtures theory, we consider the brain as a biphasic material made of misfolded protein aggregates and of healthy tissue. The resulting Cahn–Hilliard type equation for the misfolded proteins contains a growth term depending on the local availability of precursor proteins, that follow a reaction–diffusion equation. The misfolded proteins also possess a chemotactic mass flux driven by gradients of neural damage, that is caused by local accumulation of misfolded protein and that evolves slowly according to an Allen-Cahn equation. The diffuse interface approach is new for NDs and allows both to consider five different time-scales, from phase separation to neural damage propagation, and to reduce the computational costs compared to existing multi-scale models, allowing a time-step adaptivity. We present here numerical simulations in a simple two-dimensional domain, considering both isotropic and anisotropic mobility coefficients of the misfolded protein and the diffusion of the neural damage, finding that the spreading front of the neural damage follows the direction of the largest eigenvalue of the mobility tensor. In both cases, we computed two biomarkers for quantifying the aggregation in plaques and the evolution of neural damage, that are in qualitative agreement with the characteristic Jack curves for many NDs.
•We bridge the gap between phenomena at different spatial and time scales.•5 timescales describe the plaques aggregation and the evolution of tissue damage.•We quantify plaques aggregation and neural damage evolution with biomarkers.•Misfolded proteins possess a chemotactic flux driven by gradients of neural damage.•Simulations may help identify undiscovered spreading pathways of the neural damage.
Deep brain stimulation (DBS) of the subthalamic nucleus or the globus pallidus is an established treatment for Parkinson's disease (PD) that yields a marked and lasting improvement of motor symptoms. ...Yet, DBS benefit on gait disturbances in PD is still debated and can be a source of dissatisfaction and poor quality of life. Gait disturbances in PD encompass a variety of clinical manifestations and rely on different pathophysiological bases. While gait disturbances arising years after DBS surgery can be related to disease progression, early impairment of gait may be secondary to treatable causes and benefits from DBS reprogramming. In this review, we tackle the issue of gait disturbances in PD patients with DBS by discussing their neurophysiological basis, providing a detailed clinical characterization, and proposing a pragmatic programming approach to support their management.
•T cell therapy can be an effective immunotherapeutic strategy for treating cancer.•Combining T cell therapy and vessel activation promotes T cells delivery in the tumor.•The tumor evolution is ...studied with a theoretical and numerical model.•The tumor-T cells interaction is modeled by a Michaelis Menten law.•The model has a threshold behavior for the number of T-cells in the target organ.
T cell therapy has become a new therapeutic opportunity against solid cancers. Predicting T cell behaviour and efficacy would help therapy optimization and clinical implementation. In this work, we model responsiveness of mouse prostate adenocarcinoma to T cell-based therapies. The mathematical model is based on a Cahn-Hilliard diffuse interface description of the tumour, coupled with Keller-Segel type equations describing immune components dynamics. The model is fed by pre-clinical magnetic resonance imaging data describing anatomical features of prostate adenocarcinoma developed in the context of the Transgenic Adenocarcinoma of the Mouse Prostate model. We perform computational simulations based on the finite element method to describe tumor growth dynamics in relation to local T cells concentrations. We report that when we include in the model the possibility to activate tumor-associated vessels and by that increase the number of T cells within the tumor mass, the model predicts higher therapeutic effects (tumor regression) shortly after therapy administration. The simulated results are found in agreement with reported experimental data. Thus, this diffuse-interface mathematical model well predicts T cell behavior in vivo and represents a proof-of-concept for the role such predictive strategies may play in optimization of immunotherapy against cancer.
SUMMARY
Serpentinites are polymineralic rocks distributed almost ubiquitously across the globe in active tectonic regions. Magnetite-rich serpentinites are found in the low-strain domains of ...serpentinite shear zones, which act as potential sites of nucleation of unstable slip. To assess the potential of earthquake nucleation in these materials, we investigate the link between mechanical properties and fabric of these rocks through a suite of laboratory shear experiments. Our experiments were done at room temperature and cover a range of normal stress and slip velocity from 25 to 100 MPa and 0.3 to 300 µm s−1, respectively. We show that magnetite-rich serpentinites are ideal materials since they display strong sensitivity to the loading rate and are susceptible to nucleation of unstable slip, especially at low forcing slip velocities. We also aim at the integration of mechanical and microstructural results to describe the underlying mechanisms that produce the macroscopic behaviour. We show that mineralogical composition and mineral structure dictates the coexistence of two deformation mechanisms leading to stable and unstable slip. The weakness of phyllosilicates allows for creep during the interseismic phase of the laboratory seismic cycle while favouring the restoration of a load-bearing granular framework, responsible of the nucleation of unstable events. During dynamic slip, fault zone shear fabric determines the mode of slip, producing either asymmetric or Gaussian slip time functions for either fast or slow events. We report rate/state friction parameters and integrate our mechanical data with microstructural observations to shed light on the mechanisms dictating the complexity of laboratory earthquakes. We show that mineralogical and fabric heterogeneities control fault slip behaviour.
Individual receptor neurons in the peripheral olfactory organ extend long axons into the olfactory bulb forming synapses with projection neurons in spherical neuropil regions, called glomeruli. ...Generally, odor map formation and odor processing in all vertebrates is based on the assumption that receptor neuron axons exclusively connect to a single glomerulus without any axonal branching. We comparatively tested this hypothesis in multiple fish and amphibian species (both sexes) by applying sparse cell electroporation to trace single olfactory receptor neuron axons. Sea lamprey (jawless fish) and zebrafish (bony fish) support the unbranched axon concept, with 94% of axons terminating in single glomeruli. Contrastingly, axonal projections of the axolotl (salamander) branch extensively before entering up to six distinct glomeruli. Receptor neuron axons labeled in frog species (Pipidae, Bufonidae, Hylidae, and Dendrobatidae) predominantly bifurcate before entering a glomerulus and 59 and 50% connect to multiple glomeruli in larval and postmetamorphotic animals, respectively. Independent of developmental stage, lifestyle, and adaptations to specific habitats, it seems to be a common feature of amphibian olfactory receptor neuron axons to frequently bifurcate and connect to multiple glomeruli. Our study challenges the unbranched axon concept as a universal vertebrate feature and it is conceivable that also later diverging vertebrates deviate from it. We propose that this unusual wiring logic evolved around the divergence of the terrestrial tetrapod lineage from its aquatic ancestors and could be the basis of an alternative way of odor processing.
The formation of an odor map in the olfactory bulb of vertebrates is based on the general assumption that axons of individual olfactory receptor neurons do not branch and connect to single glomeruli. Here, we show that this general principle does not apply to the olfactory system of amphibians, which exhibits a multi‐glomerular wiring scheme and a putatively different odor coding strategy. Our data underline the need to acknowledge biological diversity to fully understand odor coding in vertebrates.
Unfavourable working conditions are associated with poor mental health and many studies show that teachers are at risk of this.
To investigate if and to what extent specific dimensions of working ...conditions are associated with symptoms of depression and anxiety in teachers in state schools in Italy.
A cross-sectional questionnaire survey of Italian state schoolteachers using the Karasek Job Content Questionnaire, the Self-Rating Anxiety Scale (SAS) and the Center for Epidemiologic Studies Depression Scale (CES-D). We tested the hypotheses that high job demand, low decision latitude and low support are associated with anxiety and depression in teachers using a correlation matrix and hierarchical multiple regression models.
113/180 (63%) of schoolteachers invited to participate completed the survey. 49% scored above the cut-off on CES-D and 11% on SAS. CES-D was positively correlated with job demand (r = 0.517, P < 0.01) and negatively with social support (r = -0.226, P < 0.05). SAS was positively correlated with job demand (r = 0.408, P < 0.01). Hierarchical multiple regression analysis showed that job demand was significantly associated with CES-D and SAS scores, explaining 28 and 25% of variance respectively.
About half of the teachers in this study scored above the threshold for depression and ~1 in 10 for anxiety on self-rating questionnaires. Poor mental health in teachers is significantly associated with high job demand and low social support. These results should be confirmed in larger, more representative samples.
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