Music and Metronomes Differentially Impact Motor Timing in People with and without Parkinson's Disease: Effects of Slow, Medium, and Fast Tempi on Entrainment and Synchronization Performances in Finger Tapping, Toe Tapping, and Stepping on the Spot Tasks

© 2019 Dawn Rose et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (https://creativecommons.org/licenses/by/4.0/).Introduction: Rhythmic Auditory Stimulation (RAS) has successfully helped regulate gait for people with Parkinson’s disease. However, the way in which different auditory cues and types of movements affect entrainment, synchronization and pacing stability has not been directly compared in different aged people with and without Parkinson's. Therefore, this study compared music and metronomes (cue types) in finger tapping, toe tapping and stepping on the spot tasks to explore the potential of RAS training for general use.Methods: Participants (aged 18-78 years) included people with Parkinson’s (n=30, Hoehn & Yahr Mean=1.78), Older (n=26), and Younger adult controls (n=36), as age may effect motor timing. Timed motor production was assessed using an extended synchronization-continuation task in cue type and movement conditions for slow, medium and fast tempi (81, 116 and 140 mean beats-per-minute respectively).Results: Analyses revealed main effects of cue and movement type but no between group interactions, suggesting no differences in motor timing between people with Parkinson's and controls. Music supported entrainment better than metronome in medium and fast tempi, and stepping on the spot enabled better entrainment and less asynchrony, as well as more stable pacing compared to tapping in medium and fast tempi. Age was not confirmed as a factor and no differences were observed in slow tempo.Conclusion: This is the first study to directly compare how different external auditory cues and movement types affect motor timing. The music and the stepping enabled participants to maintain entrainment once the external pacing cue ceased, suggesting endogenous mechanisms continued to regulate the movements. The superior performance of stepping on the spot suggests embodied entrainment can occur during continuous movement, and this may be related to emergent timing in tempi above 600 ms. These findings can be applied therapeutically to manage and improve adaptive behaviours for people with Parkinson’s.Peer reviewe

Bases expert statement on the use of music for movement among people with Parkinson's

First published in The Sport and Exercise Scientist, February 2020, Issue 63. Published by the British Association of Sport and Exercise Sciences – www.bases.org.uk.Music is an artistic auditory stimulus that unfolds over time. It can prime specific actions and prompt engagement in physical activity as well as heighten motivation during motor tasks (Karageorghis, 2020). Contrastingly, it can be used to downregulate arousal to facilitate the transition from an active to a sedentary state or to ameliorate anxiety. In therapeutic applications, musical features such as rhythm, melody and harmony have been shown to elicit psychological and physiological changes (Thaut & Hoemberg, 2014). Parkinson’s is a degenerative neurological condition in which the loss of dopamine neurons results in impaired initiation and control of movement, with common symptoms including tremor, postural instability and gait disturbance. There are also non-motor effects that include apathy, anxiety and depression. Medication does not alleviate all manifestations of the condition and there is presently no known cure (Obeso et al., 2017). It is notable that people with Parkinson’s are estimated to be 30% less active than agematched peers (Ramaswamy et al., 2018). Nonetheless, evidence is emerging that a range of exercise-based and social activities that involve musical engagement can serve to address the common symptoms and enhance quality of life (Thaut & Hoemberg, 2014). This statement brings together an international interdisciplinary team to outline what is known about music-related applications for people with Parkinson’s, and to provide recommendations for exercise and health practitioners.Peer reviewe

A general procedure to measure the pacing of body movements timed to music and metronome in younger and older adults

© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Finger-tapping tasks are classically used to investigate sensorimotor synchronization in relation to neutral auditory cues, such as metronomes. However, music is more commonly associated with an entrained bodily response, such as toe tapping, or dancing. Here we report an experimental procedure that was designed to bridge the gap between timing and intervention studies by directly comparing the effects of metronome and musical cue types on motor timing abilities across the three naturalistic voluntary actions of finger tapping, toe tapping, and stepping on the spot as a simplified case of whole body movement. Both pacing cues were presented at slow, medium, and fast tempi. The findings suggested that the task of stepping on the spot enabled better timing performances than tapping both in younger and older adults (75+). Timing performances followed an inverse U shape with best performances observed in the medium tempi that were set close to the spontaneous motor tempo in each movement type. Finally, music provided an entrainment effect in addition to pace setting that enabled better motor timing and greater stability than classically reported using a metronome. By applying time-stamp analyses to kinetic data, we demonstrate that tapping and stepping engage different timing modes. This work details the importance of translational research for a better understanding of motor timing. It offers a simple procedure that strengthens the validity of applying academic work and contributes in knowledge towards a wide range of therapeutic interventions.Peer reviewe

Episodic memory encoding and retrieval in face-name paired paradigm: An FNIRS study

Background: Episodic memory (EM) is particularly sensitive to pathological conditions and aging. In a neurocognitive context, the paired-associate learning (PAL) paradigm, which requires participants to learn and recall associations between stimuli, has been used to measure EM. The present study aimed to explore whether functional near-infrared spectroscopy (fNIRS) can be employed to determine cortical activity underlying encoding and retrieval. Moreover, we examined whether and how different aspects of task (i.e., novelty, difficulty) affects those cortical activities. Methods: Twenty-two male college students (age: M = 20.55, SD = 1.62) underwent a face-name PAL paradigm under 40-channel fNIRS covering fronto-parietal and middle occipital regions. Results: A decreased activity during encoding in a broad network encompassing the bilateral frontal cortex (Brodmann areas 9, 11, 45, and 46) was observed during the encoding, while an increased activity in the left orbitofrontal cortex (Brodmann area 11) was observed during the retrieval. Increased HbO concentration in the superior parietal cortices and decreased HbO concentration in the inferior parietal cortices were observed during encoding while dominant activation of left PFC was found during retrieval only. Higher task difficulty was associated with greater neural activity in the bilateral prefrontal cortex and higher task novelty was associated with greater activation in occipital regions. Conclusion: Combining the PAL paradigm with fNIRS provided the means to differentiate neural activity characterising encoding and retrieval. Therefore, the fNIRS may have the potential to complete EM assessments in clinical settings

Mahogunin Ring Finger 1 regulates pigmentation by controlling the pH of melanosomes in melanocytes and melanoma cells.

Mahogunin Ring Finger 1 (MGRN1) is an E3-ubiquitin ligase absent in dark-furred mahoganoid mice. We investigated the mechanisms of hyperpigmentation in Mgrn1-null melan-md1 melanocytes, Mgrn1-KO cells obtained by CRISPR-Cas9-mediated knockdown of Mgrn1 in melan-a6 melanocytes, and melan-a6 cells depleted of MGRN1 by siRNA treatment. Mgrn1-deficient melanocytes showed higher melanin content associated with increased melanosome abundance and higher fraction of melanosomes in highly melanized maturation stages III-IV. Expression, post-translational processing and enzymatic activity of the rate-limiting melanogenic enzyme tyrosinase measured in cell-free extracts were comparable in control and MGRN1-depleted cells. However, tyrosinase activity measured in situ in live cells and expression of genes associated with regulation of pH increased upon MGRN1 repression. Using pH-sensitive fluorescent probes, we found that downregulation of MGRN1 expression in melanocytes and melanoma cells increased the pH of acidic organelles, including melanosomes, strongly suggesting a previously unknown role of MGRN1 in the regulation of melanosomal pH. Among the pH regulatory genes upregulated by Mgrn1 knockdown, we identified those encoding several subunits of the vacuolar adenosine triphosphatase V-ATPase (mostly Atp6v0d2) and a calcium channel of the transient receptor potential channel family, Mucolipin 3 (Mcoln3). Manipulation of expression of the Mcoln3 gene showed that overexpression of Mcoln3 played a significant role in neutralization of the pH of acidic organelles and activation of tyrosinase in MGRN1-depleted cells. Therefore, lack of MGRN1 led to cell-autonomous stimulation of pigment production in melanocytes mostly by increasing tyrosinase specific activity through neutralization of the melanosomal pH in a MCOLN3-dependent manner

BLOC-2 targets recycling endosomal tubules to melanosomes for cargo delivery.

Hermansky-Pudlak syndrome (HPS) is a group of disorders characterized by the malformation of lysosome-related organelles, such as pigment cell melanosomes. Three of nine characterized HPS subtypes result from mutations in subunits of BLOC-2, a protein complex with no known molecular function. In this paper, we exploit melanocytes from mouse HPS models to place BLOC-2 within a cargo transport pathway from recycling endosomal domains to maturing melanosomes. In BLOC-2-deficient melanocytes, the melanosomal protein TYRP1 was largely depleted from pigment granules and underwent accelerated recycling from endosomes to the plasma membrane and to the Golgi. By live-cell imaging, recycling endosomal tubules of wild-type melanocytes made frequent and prolonged contacts with maturing melanosomes; in contrast, tubules from BLOC-2-deficient cells were shorter in length and made fewer, more transient contacts with melanosomes. These results support a model in which BLOC-2 functions to direct recycling endosomal tubular transport intermediates to maturing melanosomes and thereby promote cargo delivery and optimal pigmentation

Functional Interaction between Type III-Secreted Protein IncA of Chlamydophila psittaci and Human G3BP1

Chlamydophila (Cp.) psittaci, the causative agent of psittacosis in birds and humans, is the most important zoonotic pathogen of the family Chlamydiaceae. These obligate intracellular bacteria are distinguished by a unique biphasic developmental cycle, which includes proliferation in a membrane-bound compartment termed inclusion. All Chlamydiaceae spp. possess a coding capacity for core components of a Type III secretion apparatus, which mediates specific delivery of anti-host effector proteins either into the chlamydial inclusion membrane or into the cytoplasm of target eukaryotic cells. Here we describe the interaction between Type III-secreted protein IncA of Cp. psittaci and host protein G3BP1 in a yeast two-hybrid system. In GST-pull down and co-immunoprecipitation experiments both in vitro and in vivo interaction between full-length IncA and G3BP1 were shown. Using fluorescence microscopy, the localization of G3BP1 near the inclusion membrane of Cp. psittaci-infected Hep-2 cells was demonstrated. Notably, infection of Hep-2 cells with Cp. psittaci and overexpression of IncA in HEK293 cells led to a decrease in c-Myc protein concentration. This effect could be ascribed to the interaction between IncA and G3BP1 since overexpression of an IncA mutant construct disabled to interact with G3BP1 failed to reduce c-Myc concentration. We hypothesize that lowering the host cell c-Myc protein concentration may be part of a strategy employed by Cp. psittaci to avoid apoptosis and scale down host cell proliferation

Intracellular Bacteria Encode Inhibitory SNARE-Like Proteins

Pathogens use diverse molecular machines to penetrate host cells and manipulate intracellular vesicular trafficking. Viruses employ glycoproteins, functionally and structurally similar to the SNARE proteins, to induce eukaryotic membrane fusion. Intracellular pathogens, on the other hand, need to block fusion of their infectious phagosomes with various endocytic compartments to escape from the degradative pathway. The molecular details concerning the mechanisms underlying this process are lacking. Using both an in vitro liposome fusion assay and a cellular assay, we showed that SNARE-like bacterial proteins block membrane fusion in eukaryotic cells by directly inhibiting SNARE-mediated membrane fusion. More specifically, we showed that IncA and IcmG/DotF, two SNARE-like proteins respectively expressed by Chlamydia and Legionella, inhibit the endocytic SNARE machinery. Furthermore, we identified that the SNARE-like motif present in these bacterial proteins encodes the inhibitory function. This finding suggests that SNARE-like motifs are capable of specifically manipulating membrane fusion in a wide variety of biological environments. Ultimately, this motif may have been selected during evolution because it is an efficient structural motif for modifying eukaryotic membrane fusion and thus contribute to pathogen survival

Rab4A organizes endosomal domains for sorting cargo to lysosome-related organelles

Sorting endosomes (SEs) are the regulatory hubs for sorting cargo to multiple organelles, including lysosome-related organelles such as melanosomes in melanocytes. In parallel, melanosome biogenesis is initiated from SEs with the processing and sequential transport of melanocyte-specific proteins toward maturing melanosomes. However, the mechanism of cargo segregation on SEs is largely unknown. RNAi screening in melanocytes revealed that knockdown of Rab4A results in defective melanosome maturation. Rab4A-depletion increases vacuolar endosomes and disturbs the cargo sorting, which in turn lead to the mislocalization of melanosomal proteins to lysosomes, cell surface and exosomes. Rab4A localizes to the SEs and forms endosomal complex with AP-3 adaptor, Rabenosyn-5 effector and KIF3 motor, which possibly coordinates cargo segregation on SEs. Consistently, inactivation of Rabenosyn-5 or KIF3A/B phenocopied the defects observed in Rab4A-knockdown melanocytes. Further, Rabenosyn-5 associates with Rabaptin-5 or Rabip4/4' and differentially regulate cargo sorting from SEs. Thus, Rab4A acts a key regulator of cargo segregation on SEs