Evaluating a Speech-Specific and a Computerized Step-Training-Specific Rhythmic Intervention in Parkinson's Disease: A Cross-Over, Multi-Arms Parallel Study

Background:Recent studies suggest movements of speech and gait in patients with Parkinson's Disease (PD) are impaired by a common underlying rhythmic dysfunction. If this being the case, motor deficits in speech and gait should equally benefit from rhythmic interventions regardless of whether it is a speech-specific or step-training-specific approach.Objective:In this intervention trial, we studied the effects of two rhythmic interventions on speech and gait. These rhythmic intervention programs are similar in terms of intensity and frequency (i.e., 3x per week, 45 min-long sessions for 4 weeks in total), but differ regarding therapeutic approach (rhythmic speech vs. rhythmic balance-mobility training).Methods:This study is a cross-over, parallel multi-arms, single blind intervention trial, in which PD patients treated with rhythmic speech-language therapy (rSLT; N = 16), rhythmic balance-mobility training (rBMT; N = 10), or no therapy (NT; N = 18) were compared to healthy controls (HC; N = 17; matched by age, sex, and education: p > 0.82). Velocity and cadence in speech and gait were evaluated at baseline (BL), 4 weeks (4W-T1), and 6 months (6M-T2) and correlated.Results:Parameters in speech and gait (i.e., speaking and walking velocity, as well as speech rhythm with gait cadence) were positively correlated across groups (p < 0.01). Statistical analyses involved repeated measures ANOVA across groups and time, as well as independent and one-samples t-tests for within groups analyses. Statistical analyses were amplified using Reliable Change (RC) and Reliable Change Indexes (RCI) to calculate true clinically significant changes due to the treatment on a patient individual level. Rhythmic intervention groups improved across variables and time (total Mean Difference: 3.07 [SD 1.8]; 95% CI 0.2–11.36]) compared to the NT group, whose performance declined significantly at 6 months (p < 0.01). HC outperformed rBMT and NT groups across variables and time (p < 0.001); the rSLT performed similarly to HC at 4 weeks and 6 months in speech rhythm and respiration.Conclusions:Speech and gait deficits in PD may share a common mechanism in the underlying cortical circuits. Further, rSLT was more beneficial to dysrhythmic PD patients than rBMT, likely because of the nature of the rhythmic cue.

Mutational screening of the TPO and DUOX2 genes in Argentinian children with congenital hypothyroidism due to thyroid dyshormonogenesis.

Purpose Primary congenital hypothyroidism (CH) is the most common endocrine disease in children and one of the preventable causes of both cognitive and motor deficits. We present a genetic and bioinformatics investigation of rational clinical design in 16 Argentine patients suspected of CH due to thyroid dyshormonogenesis (TDH). Methods Next-Generation Sequencing approach was used to identify variants in Thyroid Peroxidase (TPO) and Dual Oxidase 2 (DUOX2) genes. A custom panel targeting 7 genes associated with TDH [(TPO, Iodothyrosine Deiodinase I (IYD), Solute Carrier Family 26 Member 4 (SLC26A4), Thyroglobulin (TG), (DUOX2), Dual Oxidase Maturation Factor 2 (DUOXA2), Solute Carrier Family 5 Member 5 (SLC5A5)] and 4 associated with thyroid dysembryogenesis [PAX8, FOXE1, NKX2-1, Thyroid Stimulating Hormone Receptor (TSHR)] has been designed. Additionally, bioinformatic analysis and structural modeling were carried out to predict the disease-causing potential variants. Results Five novel variants have been identified, two in TPO: c.2749-2A>C and c.2752_2753delAG, [p.Ser918Cysfs*62] and three variants in DUOX2 gene: c.425C>G [p.Pro142Arg]; c.790delC [p.Leu264Cysfs*57] and c.2695delC [p.Gln899Serfs*21]. Seventeen identified TPO, DUOX2 and IYD variants were previously described. We identified potentially pahogenic bi-allelic variants in TPO and DUOX2 in 8 and 2 patients, respectively. We also detected a potentially pathogenic mono-allelic variant in TPO and DUOX2 in 4 and 1 patients respectively. Only two patients were heterozygous for digenic variants in TPO/IYD and in TPO/DUOX2 genes. Conclusions 22 variants have been identified associated with TDH. All described novel mutations occur in domains important for protein structure and function, predicting the TDH phenotype.

A novel and accurate full-length HTT mouse model for Huntington’s disease

Here, we report the generation and characterization of a novel Huntington’s disease (HD) mouse model BAC226Q by using a bacterial artificial chromosome (BAC) system, expressing full-length human HTT with ~226 CAG-CAA repeats and containing endogenous human HTT promoter and regulatory elements. BAC226Q recapitulated a full-spectrum of age-dependent and progressive HD-like phenotypes without unwanted and erroneous phenotypes. BAC226Q mice developed normally, and gradually exhibited HD-like psychiatric and cognitive phenotypes at 2 months. From 3 to 4 months, BAC226Q mice showed robust progressive motor deficits. At 11 months, BAC226Q mice showed significant reduced life span, gradual weight loss and exhibited neuropathology including significant brain atrophy specific to striatum and cortex, striatal neuronal death, widespread huntingtin inclusions, and reactive pathology. Therefore, the novel BAC226Q mouse accurately recapitulating robust, age-dependent, progressive HD-like phenotypes will be a valuable tool for studying disease mechanisms, identifying biomarkers, and testing gene-targeting therapeutic approaches for HD.

Up-And-Down γ-Synuclein Transcription in Dopamine Neurons Translates Into Changes in Dopamine Neurotransmission and Behavioral Performance in Mice

The synuclein family consists of α-, β-, and γ-Synuclein (α-Syn, β-Syn, and γ-Syn), expressed in the neurons and concentrated in synaptic terminals. While α-Syn is at the center of interest due to its implication in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, limited information exists on the other members. The current study aimed at investigating the biological role of γ-Syn controlling the midbrain dopamine (DA) function. We generated two different mouse models with i) γ-Syn overexpression induced by an adeno-associated viral vector and ii) γ-Syn knockdown induced by a ligand-conjugated antisense oligonucleotide, to modify the endogenous γ-Syn transcription levels in midbrain DA neurons. The progressive overexpression of γ-Syn decreased DA neurotransmission in the nigrostriatal and mesocortical pathways. In parallel, mice evoked motor deficits in the rotarod and impaired cognitive performance as assessed by novel object recognition, passive avoidance, and Morris water maze tests. Conversely, acute γ-Syn knockdown selectively in DA neurons facilitated forebrain DA neurotransmission. Importantly, modifications in γ-Syn expression did not induce the loss of DA neurons or changes in α-Syn expression. Collectively, our data strongly suggest that DA re-lease/re-uptake processes in the nigrostriatal and mesocortical pathways are partially dependent on SNc/VTA γ-Syn transcription levels, and are linked to modulation of DA transporter function, similar to α-Syn.

A striatal plasticity that supports the long-term preservation of motor function in Parkinsonian mice.

Motor deficits of Parkinsons disease (PD) such as rigidity, bradykinesia and akinesia result from a progressive loss of nigrostriatal dopamine neurons. No therapies exist that slow their degeneration and the most effective treatments for the motor symptoms: L-dopa -the precursor to dopamine, and deep brain stimulation can produce dyskinesias and are highly invasive, respectively. Hence, alternative strategies targeted to slow the progression or delay the onset of motor symptoms are still highly sought. Here we report the identification of a long-term striatal plasticity mechanism that delays for several months, the onset of motor deficits in a mouse PD model. Specifically, we show that a one-week transient daily elevation of midbrain dopamine neuron activity during depletion preserves the connectivity of direct but not indirect pathway projection neurons. The findings are consistent with the balance theory of striatal output pathways and suggest a novel approach for treating the motor symptoms of PD.

Sleep and circadian rhythms in Parkinson’s disease and preclinical models

The use of animals as models of human physiology is, and has been for many years, an indispensable tool for understanding the mechanisms of human disease. In Parkinson’s disease, various mouse models form the cornerstone of these investigations. Early models were developed to reflect the traditional histological features and motor symptoms of Parkinson’s disease. However, it is important that models accurately encompass important facets of the disease to allow for comprehensive mechanistic understanding and translational significance. Circadian rhythm and sleep issues are tightly correlated to Parkinson’s disease, and often arise prior to the presentation of typical motor deficits. It is essential that models used to understand Parkinson’s disease reflect these dysfunctions in circadian rhythms and sleep, both to facilitate investigations into mechanistic interplay between sleep and disease, and to assist in the development of circadian rhythm-facing therapeutic treatments. This review describes the extent to which various genetically- and neurotoxically-induced murine models of Parkinson’s reflect the sleep and circadian abnormalities of Parkinson’s disease observed in the clinic.

Neuroinflammation and Behavioral Deficit in Rotenone-Induced Neurotoxicity in Rats and the Possible Effects of Butanolic Extract of Centaurea Africana

Background: Many studies have used rotenone (ROT) to create an experimental animal model of Parkinson's disease (PD) because of its ability to induce similar behavioral and motor deficits. PD is the most common age-related motoric neurodegenerative disorder. Neuroinflammation and apoptosis play an important role in the pathogenesis of this disease. Objective: This study investigated the effect of butanolic (n-BuOH) extract of Centaurea africana (200 mg/kg, 16 days) on a ROT-induced neurotoxicity model in male Wistar albino rats. Methods: Estimation of Tumor Necrosis Factor (TNF-α) and Nitric Oxide (NO) levels along with the myeloperoxidase (MPO) activity in brains was carried out in order to evaluate neuro-inflammation. Oxidative stress, Caspase 3 activity (apoptosis), and behavioral alterations were also evaluated. Results: In behavior assessment, using Ludolph Movement Analysis Scale, all ROT treated animals showed a decreased locomotor activity. The mitochondrial dysfunction induced by ROT was expressed by a decreased activity of complex I of the mitochondrial respiratory chain and increased lipid peroxidation and caspase 3. Co-treatment with the n-BuOH extract significantly restored the activity of complex I (65.41%) compared to treatment with ROT alone. The n-BuOH extract also reduced the neuroinflammation in rat brains by reducing MPO activity (75.12%), NO levels (77.43%), and TNF-α (71.48%) compared to the group treated with ROT. Conclusion: The obtained results indicated that C. africana n-BuOH extract exhibited a protective effect in rats.

Disconnections in Personal Neglect

Personal neglect is a disorder in the perception and representation of the body that causes the patients to behave as if the contralesional side of their body does not exist. This clinical condition has not been adequately investigated in the past as it has been considered a symptom of unilateral spatial neglect, which has mainly been studied with reference to extrapersonal space. Only a few studies with small samples have investigated the neuroanatomical correlates of personal neglect, and these have mainly focused on discrete cortical lesions and modular accounts, as well as being based on the hypothesis that this disorder is associated with somatosensory and spatial deficits. In the present study, we tested the novel hypothesis that personal neglect may be associated not only with discrete cortical and subcortical lesions, but also with disconnections of white matter tracts. We performed an advanced lesion analyses in a large sample of 104 right hemisphere damaged patients, 68 of whom were suffering from personal neglect. Results from the analyses of the grey and white matter were controlled for co-occurrent clinical variables such as extrapersonal neglect, anosognosia for hemiplegia and motor deficits, along with other lesion-related variables such as lesion size, the interval from the lesion onset to neuroimaging recordings. Our results reveal that personal neglect is associated with lesions in a medial network which involves the temporal cortex (Heschl’s gyrus), the ventro-lateral nuclei of the thalamus, and the fornix. This suggests that personal neglect involves a convergence between sensorimotor processes, spatial representation and the processing of self-referred information (episodic memory).

Combined transcranial Direct Current Stimulation and robot-assisted arm training in patients with stroke: a systematic review

Background: Upper limb motor deficits in patients with severe stroke often remain unresolved over time. Combining transcranial Direct Current Stimulation with robotic therapy is an innovative neurorehabilitation approach that holds promise to improve upper limb impairment after stroke. Objective: To investigate the effects of robotic training in combination with transcranial Direct Current Stimulation for treating poststroke upper limb impairment. Methods: PubMed, MEDLINE, Cochrane Library, and EMBASE electronic databases were searched using keywords, MeSH terms, and strings: “Stroke”[MeSH] AND (“Upper Extremity”[MeSH] OR “upper limb”) AND (“Transcranial Direct Current Stimulation” [MeSH] OR “tDCS”) AND (“robotics” OR “robotic therapy”). Full-text articles published in English up to October 2020 were included. Each was rated for quality according to the Physiotherapy Database (PEDro) score: eight out of eleven scored more than 8 points; their results were considered reliable for this review. Results: Of the total of 171 publications retrieved, 11 met the inclusion criteria. The results of studies that examined the same outcome measures were pooled to draw conclusions on the effectiveness of transcranial Direct Current Stimulation and robot-assisted training in corticomotor excitability, upper limb kinematics, muscle strength and tone, function, disability, and quality of life after stroke. Conclusions: To date, there is insufficient evidence to support the hypothesis that transcranial Direct Current Stimulation enhances the effects of robot-assisted arm training in poststroke patients. Further studies with more accurate, comparable and standardized methodology are needed in order to better define the effects of robotic training in combination with transcranial Direct Current Stimulation on poststroke upper limb impairment. Therefore, given the scarce resources available to rehabilitation researches, other, more promising approaches should be given attention.