Altered Theory of Mind in Parkinson's Disease and Impact on Caregivers: A Pilot Study.

Mild cognitive impairment (MCI) in Parkinson's disease (PD) includes deficits in theory of mind (ToM). However, associations between ToM and caregiver burden and distress are still unclear. The objective of this pilot study was to preliminarily explore the relation between ToM and caregiver burden and distress in a sample of PD-MCI patients. Twelve PD-MCI patients were evaluated on a ToM task (Faux Pas), whereas their caregivers were assessed on caregiver burden (Zarit Burden Interview-12 items) and distress (Neuropsychiatric Inventory-Distress). Cognitive ToM was significantly associated with caregiver distress, but caregiver burden was associated with the severity of patient psychiatric symptoms.

Improvement in Quality of Life with OnabotulinumtoxinA for Cervical Dystonia: POSTURe.

INTRODUCTION: Symptoms of cervical dystonia (CD) can vary in severity and cause significant pain. OnabotulinumtoxinA is an approved treatment for CD. This study assessed health-related quality of life (HRQoL) in patients with CD who received multiple onabotulinumtoxinA treatments. METHODS: This prospective, observational standard-of-care study was conducted at multiple neurology centers in Québec, Canada. Patients reported the health impact of CD using the Cervical Dystonia Impact Profile (CDIP)-58, before and after up to eight onabotulinumtoxinA treatments. Other measures included the Cervical Dystonia Severity Rating Scale by physician, employment status using the Work Productivity Questionnaire and pain using the Pain Numeric Rating Scale (PNRS). Adverse events (AEs) were recorded. RESULTS: Sixty-two patients were enrolled (safety population, n = 61; modified efficacy population, n = 58). Participants were mostly females who were employed; most (79.3%) had torticollis. In all, 21/62 patients (33.9%) discontinued the study. At the final visit, there was a statistically significant (p < 0.001) improvement in all eight CDIP-58 subscales, particularly head and neck symptoms (-31.0) and psychosocial functioning (-28.2). Employment increased from baseline (55%) to the end of the study (64%), and there was improvement in work productivity. There was a significant (p < 0.0001) reduction in pain measured by the PNRS, from -0.5 post-treatment 1 to -2.4 at end of study. AEs (neck pain, muscular weakness, dysphagia, nausea) were consistent with onabotulinumtoxinA use. CONCLUSION: These real-world data indicate that after repeated, long-term use, onabotulinumtoxinA continues to be a safe and effective treatment for CD, improving HRQoL and work productivity.

[Geriatric pathways and organisation in response to the needs of EDS]. / Organisation et filières gériatriques en réponse aux besoins des SAU.

The emergency department remains the main method of admission for older people to hospital. The management of old elderly in these departments is a complex subject. It's particularities and the specificities of the evaluation of their health contribute to the difficulties of the care teams. For the elderly, a visit to the emergency room is a significant medical event in the care process that can have repercussions on their functional decline. The promotion of a geriatric culture in emergency departments is essential and can be done in different ways, but collaboration between emergency physicians and geriatricians remains essential for successful care adapted to the specific characteristics of elderly patients.

Portrait of blood-derived extracellular vesicles in patients with Parkinson's disease.

The production of extracellular vesicles (EV) is a ubiquitous feature of eukaryotic cells but pathological events can affect their formation and constituents. We sought to characterize the nature, profile and protein signature of EV in the plasma of Parkinson's disease (PD) patients and how they correlate to clinical measures of the disease. EV were initially collected from cohorts of PD (n = 60; Controls, n = 37) and Huntington's disease (HD) patients (Pre-manifest, n = 11; manifest, n = 52; Controls, n = 55) - for comparative purposes in individuals with another chronic neurodegenerative condition - and exhaustively analyzed using flow cytometry, electron microscopy and proteomics. We then collected 42 samples from an additional independent cohort of PD patients to confirm our initial results. Through a series of iterative steps, we optimized an approach for defining the EV signature in PD. We found that the number of EV derived specifically from erythrocytes segregated with UPDRS scores corresponding to different disease stages. Proteomic analysis further revealed that there is a specific signature of proteins that could reliably differentiate control subjects from mild and moderate PD patients. Taken together, we have developed/identified an EV blood-based assay that has the potential to be used as a biomarker for PD.

SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease.

BACKGROUND: SMPD1 (acid-sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD. METHODS: SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid-sphingomyelinase activity was measured by a mass spectrometry-based assay in the New York cohort. α-Synuclein levels were measured in vitro following CRISPR/Cas9-mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)-M17 cells. Lysosomal localization of acid-sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid-sphingomyelinase structure was performed. RESULTS: SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6-8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid-sphingomyelinase activity was associated with a 3.5- to 5.8-year earlier onset of PD in the lowest quartile versus the highest quartile of acid-sphingomyelinase activity (P = 0.01-0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α-synuclein levels in HeLa and BE(2)-M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid-sphingomyelinase to the lysosome. CONCLUSIONS: Our results support an association between SMPD1 variants, acid-sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid-sphingomyelinase activity may lead to α-synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society.

Goal management training ® home-based approach for mild cognitive impairment in Parkinson's disease: a multiple baseline case report.

Approximately 30% of patients with Parkinson's disease experience mild cognitive impairment (PD-MCI), often affecting executive functions. Our objective was to assess tolerability, safety and preliminarily efficacy of Goal Management Training® (GMT) for PD-MCI. GMT was administered at home, for five weeks. Dysexecutive Questionnaire (DEX), Parkinson Disease Questionnaire (PDQ-39), Zoo Map Test and Dementia Rating Scale-II were administered before, one and four weeks after Adapted-GMT. Reliable Change Index (RCI) was calculated. One participant completed GMT with caregiver. Executive complaints decreased (DEX RCIs between -2.10 and -1.68), PDQ-39 was maintained (RCI = -0.18). Adapted-GMT seems safe for PD-MCI, but efficacy remains doubtful.

The influence of vascular risk factors on cognitive function in early Parkinson's disease.

OBJECTIVES: Hypertension, dyslipidemia, diabetes, and obesity are well-established risk factors for cognitive impairment and dementia in older adults. In contrast, previous studies that have assessed the impact of vascular risk factors (VRFs) on cognition in Parkinson's disease (PD) have had methodological limitations and reported conflicting findings. We address this question in a large well-characterized cohort of de novo PD patients. METHODS: A total of 367 untreated and non-demented patients aged 50 years and older with early PD (H&Y = 1.0-2.0) underwent a comprehensive clinical and neuropsychological assessment at baseline and 24 months later. A series of linear mixed models were used to determine the effects of VRFs on cognition while controlling for patient and disease characteristics. The outcomes included norm-referenced Z-scores of global cognition, visuospatial skills, verbal episodic memory, semantic verbal fluency, attention, and working memory tests. RESULTS: A longer history of hypertension and a higher pulse pressure were significant predictors of lower Z-scores on immediate and delayed free recall, recognition, and verbal fluency tests. On average, every 10 mmHg increase in pulse pressure was associated with a 0.08 reduction on the cognitive Z-scores. The effects were independent of age, education, disease duration, motor impairment, medication, and depressive symptoms. Other VRFs were not associated with cognitive outcomes. CONCLUSIONS: Our results are consistent with previous studies suggesting that hypertension exerts a detrimental effect on memory and verbal fluency in early PD. Management of blood pressure and cardiovascular health may be important to reduce risk of cognitive decline in PD. Copyright © 2017 John Wiley & Sons, Ltd.

Smoking history is associated to cognitive impairment in Parkinson's disease.

INTRODUCTION: Patients with Parkinson's disease (PD) are more likely to suffer from cognitive impairment and dementia than healthy older adults. The aim of this study was to investigate smoking history as a risk factor for cognitive decline in PD. METHOD: One hundred thirty-nine PD patients aged 50 years and older (Hoehn and Yahr = 1-3) were recruited from a clinical database. Global cognitive function was assessed with the Mini-Mental State Examination (MMSE) and smoking history was investigated as part of a standard clinical interview. A multiple linear regression analysis was used to develop a model for predicting participants' MMSE scores from age, education, Hoehn and Yahr stage, disease duration, the number of vascular risk factors and the number of smoking pack-years. RESULTS: The regression model significantly accounted for 22.9% of the variance in MMSE scores. Significant predictors were education (ß = .312, p < .001), age (ß = -.215, p = .013) and total smoking pack-years (ß = -.180, p = .029). In former smokers, the number of years since quitting had no effect on global cognition and there were no significant difference between patients who had quit smoking more than 10 years ago and those who had quit less than 10 years ago, F(1, 63) = 1.72, p = .195. CONCLUSION: Smoking history was associated to global cognitive impairment in PD even in patients who had quit smoking. These results are in line with findings in healthy older adults that have linked smoking to cognitive impairment, global brain atrophy and functional changes. Future studies should consider a broader assessment of cognitive functions.

Intermittent Theta-Burst Stimulation of the Right Dorsolateral Prefrontal Cortex to Promote Metaphor Comprehension in Parkinson Disease: A Case Study.

This single-case research-designed study explored whether intermittent theta-burst stimulation (iTBS) of the right dorsolateral prefrontal cortex (DLPFC) could improve metaphor comprehension in people with Parkinson disease (PD) and language impairments. A right-handed participant with PD diagnosed 9 years ago, receiving long-term treatment with levodopa, and with metaphor comprehension impairment was recruited to undergo 10 sessions of sham stimulation (in 2wk), a washout period (6wk), and then 10 sessions of iTBS (in 2wk). Clinical scores of metaphor comprehension and motor evaluation (Unified Parkinson Disease Rating Scale part III) and transcranial magnetic stimulation to test the excitability of the primary motor cortex (M1) were used at baseline, postsham, post-iTBS, and at 3 follow-ups (8, 14, and 20wk post-iTBS). Metaphor comprehension was improved after iTBS, and the highest scores were obtained 8 weeks later (P=.01). This improvement was correlated with the increase of the right M1 excitability (r=-.86, P=.03) and with the decrease of transcallosal inhibition latency from the left to the right hemisphere (r=-.88, P=.02). Sham yielded no effect (P>.05). Administration of iTBS over the right DLPFC improved metaphor comprehension likely by a long-term influence on brain synaptic plasticity, including improvement of interhemispheric dialogue. More studies are warranted to confirm these findings in larger samples of participants with PD.

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish.

Treatment-resistant seizures affect about a third of patients suffering from epilepsy. To fulfill the need for new medications targeting treatment-resistant seizures, a number of rodent models offer the opportunity to assess a variety of potential treatment approaches. The use of such models, however, has proven to be time-consuming and labor-intensive. In this study, we performed pharmacological characterization of the allylglycine (AG) seizure model, a simple in vivo model for which we demonstrated a high level of treatment resistance. (d,l)-Allylglycine inhibits glutamic acid decarboxylase (GAD) - the key enzyme in γ-aminobutyric acid (GABA) biosynthesis - leading to GABA depletion, seizures, and neuronal damage. We performed a side-by-side comparison of mouse and zebrafish acute AG treatments including biochemical, electrographic, and behavioral assessments. Interestingly, seizure progression rate and GABA depletion kinetics were comparable in both species. Five mechanistically diverse antiepileptic drugs (AEDs) were used. Three out of the five AEDs (levetiracetam, phenytoin, and topiramate) showed only a limited protective effect (mainly mortality delay) at doses close to the TD50 (dose inducing motor impairment in 50% of animals) in mice. The two remaining AEDs (diazepam and sodium valproate) displayed protective activity against AG-induced seizures. Experiments performed in zebrafish larvae revealed behavioral AED activity profiles highly analogous to those obtained in mice. Having demonstrated cross-species similarities and limited efficacy of tested AEDs, we propose the use of AG in zebrafish as a convenient and high-throughput model of treatment-resistant seizures.

Impact of the LSVT on vowel articulation and coarticulation in Parkinson's disease.

The purpose of this study was to investigate the impact of the Lee Silverman Voice Treatment (LSVT®) on vowel articulation and consonant-vowel (C-V) coarticulation in dysarthric speakers with Parkinson's disease (PD). Nine Quebec French speakers diagnosed with idiopathic PD underwent the LSVT®. Speech characteristics were compared before and after treatment. Vowel articulation was measured using acoustic vowel space and calculated with the first (F1) and second formant (F2) of the vowels /i/, /u/ and /a/. C-V coarticulation was measured using locus equations, an acoustic metric based on the F2 transitions within vowels in relation to the preceding consonant. The relationship between these variables, speech loudness and vowel duration was also analysed. Results showed that vowel contrast increased in F1/F2 acoustic space after administration of the LSVT®. This improvement was associated with the gain in speech loudness and longer vowel duration. C-V coarticulation patterns between consonant contexts showed greater distinctiveness after the treatment. This improvement was associated with the gain in speech loudness only. These results support the conclusions of previous studies investigating the relationship between the LSVT®, speech loudness and articulation in PD. These results expand clinical understanding of the treatment and indicate that loud speech changes C-V coarticulation patterns. Clinical applications and theoretical considerations are discussed.

Effect of Hepatic Impairment on the Pharmacokinetics of Fenfluramine and Norfenfluramine.

Fenfluramine (Fintepla®) is approved for the treatment of seizures associated with the rare epileptic encephalopathies Dravet syndrome and Lennox-Gastaut syndrome. Fenfluramine is extensively metabolized; thus, patients with hepatic impairment (HI) might experience changes in exposure to fenfluramine or its metabolites. In this phase 1 study, we investigated the pharmacokinetics (PK) and safety of a single oral dose of 0.35 mg/kg fenfluramine in subjects with mild (n = 8), moderate (n = 8), or severe (n = 7) HI (Child-Pugh A/B/C, respectively) and healthy control subjects (n = 22) matched for sex, age, and BMI. All subjects underwent serial sampling to determine total plasma concentrations of fenfluramine and its active metabolite, norfenfluramine. Hepatic impairment was associated with increases in fenfluramine exposures, mainly area-under-the-curve (AUC). Geometric least squares mean ratios (90% confidence intervals) for fenfluramine AUC0-∞ in mild, moderate, and severe HI versus healthy controls were 1.98 (1.36-2.90), 2.13 (1.43-3.17), and 2.77 (1.82-4.24), respectively. Changes in exposure to norfenfluramine in mild, moderate, and severe HI were minimal compared with normal hepatic function. Exposures to fenfluramine and norfenfluramine in all HI groups were within the ranges that have been characterized in the overall development program, including ranges examined in exposure-response relationships for efficacy and safety in patients, and determined to have an acceptable safety profile. Mild and moderate HI had a modest effect on fenfluramine exposure that was not clinically meaningful, whereas the higher fenfluramine exposure in severe HI may require dose reduction based on general caution in this population. The modest decrease in norfenfluramine exposure is not considered clinically relevant.

Infection of the Ex Vivo Tonsil Model by HTLV-1 Envelope-Pseudotyped Viruses.

Human T-cell leukemia virus type 1 (HTLV-1) is the causal agent of adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis. Its tropism is known to be broad in cultured cell lines, while in vivo data support a more selective transmission toward CD4+ T cells and the limited targeting of other hematopoietic cell types. An essential condition for HTLV-1 infection is cell-to-cell contact, to which both virological synapse and viral biofilm have been suggested to strongly contribute. As cell lines and animal models each present their own limitations in studying HTLV-1 replication, we have explored the use of an ex vivo model based on the secondary lymphoid tonsillar tissue. HIV-1 luciferase-expressing pseudotyped viruses bearing the HTLV-1 envelope protein at their surface were first shown to recapitulate the wide spectrum of infectivity of HTLV-1 toward various cell lines. Tonsil fragments were next exposed to pseudotyped viruses and shown to be reproducibly infected. Infection by HTLV-1 Env-pseudotyped viruses was blocked by different anti-gp46 antibodies, unlike infection by HIV-1 virions. The dose-dependent infection revealed a gradual increase in luciferase activity, which was again sensitive to anti-gp46 antibodies. Overall, these results suggest that the ex vivo tonsil model represents a reliable alternative for studying HTLV-1 replication and potentially viral latency, as well as early clonal formation.

Natural product-derived therapies for treating drug-resistant epilepsies: From ethnopharmacology to evidence-based medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Epilepsy is one of the most prevalent neurological human diseases, affecting 1% of the population in all age groups. Despite the availability of over 25 anti-seizure medications (ASMs), which are approved in most industrialized countries, approximately 30% of epilepsy patients still experience seizures that are resistant to these drugs. Since ASMs target only limited number of neurochemical mechanisms, drug-resistant epilepsy (DRE) is not only an unmet medical need, but also a formidable challenge in drug discovery. AIM: In this review, we examine recently approved epilepsy drugs based on natural product (NP) such as cannabidiol (CBD) and rapamycin, as well as NP-based epilepsy drug candidates still in clinical development, such as huperzine A. We also critically evaluate the therapeutic potential of botanical drugs as polytherapy or adjunct therapy specifically for DRE. METHODS: Articles related to ethnopharmacological anti-epileptic medicines and NPs in treating all forms of epilepsy were collected from PubMed and Scopus using keywords related to epilepsy, DRE, herbal medicines, and NPs. The database clinicaltrials.gov was used to find ongoing, terminated and planned clinical trials using herbal medicines or NPs in epilepsy treatment. RESULTS: A comprehensive review on anti-epileptic herbal drugs and natural products from the ethnomedical literature is provided. We discuss the ethnomedical context of recently approved drugs and drug candidates derived from NPs, including CBD, rapamycin, and huperzine A. Recently published studies on natural products with preclinical efficacy in animal models of DRE are summarized. Moreover, we highlight that natural products capable of pharmacologically activating the vagus nerve (VN), such as CBD, may be therapeutically useful to treat DRE. CONCLUSIONS: The review highlights that herbal drugs utilized in traditional medicine offer a valuable source of potential anti-epileptic drug candidates with novel mechanisms of action, and with clinical promise for the treatment of drug-resistant epilepsy (DRE). Moreover, recently developed NP-based anti-seizure medications (ASMs) indicate the translational potential of metabolites of plant, microbial, fungal and animal origin.

Clinical validity of the Mattis Dementia Rating Scale-2 in Parkinson disease with MCI and dementia.

The utility of the Mattis Dementia Rating Scale 2 (MDRS-2) in screening for dementia in Parkinson disease (PD) is well documented. However, little is known about its sensitivity to mild cognitive impairment in PD (PD-MCI). This study sought to document the validity of the MDRS-2 for diagnoses of PD-MCI and dementia in PD (PDD). Twenty-two healthy controls (HCs), 22 PD-MCI, and 16 PDD were compared on each MDRS-2 subscales and MDRS-2 total standard scores. Patients with PDD performed significantly worse than the other groups (all Ps < .05) on the MDRS-2 total and on all subscales, except attention. PD-MCI had significant lower scores than HCs on the MDRS-2 total and on initiation/perseveration and memory subscales. The optimal cutoff score for PD-MCI diagnosis was ≤ 140/144 and ≤ 132/144 for PDD. These findings suggest that MDRS-2 is a useful tool to identify dementia but that there might be a ceiling effect in the MDRS-2 cutoff score to diagnose MCI in PD.

Goal management training and psychoeducation / mindfulness for treatment of executive dysfunction in Parkinson's disease: A feasibility pilot trial.

INTRODUCTION: As there is currently no pharmacological treatment for Parkinson's Disease Mild Cognitive Impairment (PD-MCI) with executive dysfunctions, specific cognitive interventions must be investigated. Most previous studies have tested bottom-up cognitive training programs but have not shown very good results. OBJECTIVES: The aim of this study was to test ease of implementation, differential safety and preliminary efficacy of two top-down (strategy-learning) home-based, individualized, cognitive interventions: Goal Management Training (GMT), adapted for PD-MCI (Adapted-GMT), and a psychoeducation program combined with mindfulness exercises (PSYCH-Mind). METHODS: This was a single-blind block-randomized between-group comparative study. Twelve PD-MCI with mild executive dysfunctions were divided in four blocks and randomly assigned to any of the two interventions. The participants were included if they had PD-MCI diagnosis (no dementia), with stabilized medication. Both groups (Adapted-GMT and PSYCH-mind) received five intervention sessions each lasting 60-90 minutes for five weeks. Measures were collected at baseline, mid-point, one-week, four-week and 12-week follow-ups. Executive functions were assessed with the Dysexecutive questionnaire (DEX) and the Zoo Map Test (ZMT). Quality of life (QoL) and psychiatric symptoms were also evaluated. Repeated measures ANCOVAs (mixed linear analysis) were applied to all outcomes. RESULTS: There was one drop out, and both interventions were feasible and acceptable. Despite the small sample size limiting statistical power, patients of both groups significantly improved executive functions per the DEX-patient (Time: F(4,36) = 2.96, p = 0.033, CI95%: 10.75-15.23) and DEX-caregiver scores (Time: F(4,36) = 6.02, p = 0.017, CI95%: 9.63-17.23). Both groups significantly made fewer errors between measurement times on the ZMT (Time: F(3,36) = 16.66, p = 0.001, CI95%: 1.07-2.93). However, QoL significantly increased only in PSYCH-Mind patients at four-week follow-up (interaction Time*Group: F(4,36) = 5.31, p = 0.002, CI95%: 15.33-25.61). CONCLUSION: Both interventions were easily implemented and proved to be safe. Because both interventions are arguably cost-effective, these pilot findings, although promising, need to be replicated in large samples. CLINICALTRIALS.GOV IDENTIFIER: NCT04636541.

Widespread alterations in microRNA biogenesis in human Huntington's disease putamen.

Altered microRNA (miRNA) expression is a common feature of Huntington's disease (HD) and could participate in disease onset and progression. However, little is known about the underlying causes of miRNA disruption in HD. We and others have previously shown that mutant Huntingtin binds to Ago2, a central component of miRNA biogenesis, and disrupts mature miRNA levels. In this study, we sought to determine if miRNA maturation per se was compromised in HD. Towards this end, we characterized major miRNA biogenesis pathway components and miRNA maturation products (pri-miRNA, pre-miRNA, and mature) in human HD (N = 41, Vonsattel grades HD2-4) and healthy control (N = 25) subjects. Notably, the striatum (putamen) and cortex (BA39) from the same individuals were analyzed in parallel. We show that Ago2, Drosha, and Dicer were strongly downregulated in human HD at the early stages of the disease. Using a panel of HD-related miRNAs (miR-10b, miR-196b, miR-132, miR-212, miR-127, miR-128), we uncovered various types of maturation defects in the HD brain, the most prominent occurring at the pre-miRNA to mature miRNA maturation step. Consistent with earlier findings, we provide evidence that alterations in autophagy could participate in miRNA maturation defects. Notably, most changes occurred in the striatum, which is more prone to HTT aggregation and neurodegeneration. Likewise, we observed no significant alterations in miRNA biogenesis in human HD cortex and blood, strengthening tissue-specific effects. Overall, these data provide important clues into the underlying mechanisms behind miRNA alterations in HD-susceptible tissues. Further investigations are now required to understand the biological, diagnostic, and therapeutic implications of miRNA/RNAi biogenesis defects in HD and related neurodegenerative disorders.

Involvement of the thalamic parafascicular nucleus in mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE) is characterized by focal seizures, associated with hippocampal sclerosis, and often resistance to antiepileptic drugs. The parafascicular nucleus (PF) of the thalamus is involved in the generation of physiological oscillatory rhythms. It receives excitatory inputs from the cortex and inhibitory inputs from the basal ganglia, a system implicated in the control of epileptic seizures. The aim of this study was to examine the involvement of the PF in the occurrence of hippocampal paroxysmal discharges (HPDs) in a chronic animal model of MTLE in male mice. We recorded the local field potential (LFP) and the extracellular and intracellular activity of hippocampal and PF neurons during spontaneous HPDs in vivo. The end of the HPDs was concomitant with a slow repolarization in hippocampal neurons leading to an electrical silence. In contrast, it was associated in the PF with a transient increase in the power of the 10-20 Hz band in LFPs and a depolarization of PF neurons resulting in a sustained firing. We tested the role of the PF in the control of HPDs by single 130 Hz electrical stimulation of this nucleus and bilateral intra-PF injection of NMDA and GABA(A) antagonist and agonist. High-frequency PF stimulation interrupted ongoing HPDs at an intensity devoid of behavioral effects. NMDA antagonist and GABA(A) agonist suppressed hippocampal discharges in a dose-dependent way, whereas NMDA agonist and GABA(A) antagonist increased HPDs. Altogether, these data suggest that the PF nucleus plays a role in the modulation of MTLE seizures.

Dentate gyrus and hilus transection blocks seizure propagation and granule cell dispersion in a mouse model for mesial temporal lobe epilepsy.

Epilepsy-associated changes of the anatomical organization of the dentate gyrus and hilus may play a critical role in the initiation and propagation of seizures in mesial temporal lobe epilepsy (MTLE). This study evaluated the role of longitudinal projections in the propagation of hippocampal paroxysmal discharges (HPD) in dorsal hippocampus by performing a selective transection in a mouse model for MTLE obtained by a single unilateral intrahippocampal injection of kainic acid (KA). Full transections of the dentate gyrus and hilus were performed in the transverse axis at 22 days after KA injection when spontaneous HPD were fully developed. They: (i) significantly reduced the occurrence of HPD; (ii) increased their duration at the KA injection site; (iii) abolished their spread along the longitudinal axis of the hippocampal formation and; (iv) limited granule cell dispersion (GCD) of the dentate gyrus posterior to the transection. These data suggest that: (i) longitudinal projections through the dentate gyrus and hilus are involved in HPD spread; (ii) distant hippocampal circuits participate in the generation and cessation of HPD and; (iii) GCD requires continuous HPD to develop, even when seizures are established. Our data reveal a critical role for longitudinal projections in the generation and spread of hippocampal seizures.

The Impact of Clear Speech on the Perceptual and Acoustic Properties of Fricative-Vowel Sequences in Speakers With Dysarthria.

Purpose Studies have reported that clear speech has the potential to influence suprasegmental and segmental aspects of speech, in both healthy and dysarthric speakers. While the impact of clear speech has been studied on the articulation of individual segments, few studies have investigated its effects on coarticulation with multisegment sequences such as fricative-vowel. Objectives The goals of this study are to investigate, in healthy and dysarthric speech, the impact of clear speech on (a) the perception of anticipatory vowel coarticulation in fricatives and (b) the acoustic characteristics of this effect. Method Ten speakers with dysarthria secondary to idiopathic Parkinson's disease were recruited as well as 10 age- and sex-matched healthy speakers. A sentence reading task was performed in natural and clear speaking conditions. The sentences contained words with the initial fricatives /s/ and /ʃ/ preceded by /ə/ and followed by the vowels /i/, /y/, /u/, or /a/. For the perceptual measurements, five listeners were recruited and were asked to predict the upcoming word by listening only to the isolated fricative. Acoustic analyses consisted of spectral moment analysis (M1-M4) on averaged time series. Results Perceptual findings report that identification rates were improved with clear speech for the speakers with dysarthria, but only for the fricative-/i/ sequences. Error pattern analysis indicates that this improvement is associated with an increase in the roundness parameter (lip spreading) identification. Acoustic results are unclear for M1 and M3 but suggest that M2 and M4 differentiation between the rounded versus unrounded vowel contexts is increased with clear speech for the speakers with dysarthria. Discussion Taken together, these findings suggest that clear speech may improve lip coordination in dysarthric speakers with Parkinson's disease. However, the impact of clear speech on the acoustic measures of fricative spectral moments is somewhat limited. This suggests that these metrics, when taken individually, do not capture the entire complexity of fricative-vowel coarticulation.