Physical Activity Modulates Corticospinal Excitability of the Lower Limb in Young and Old Adults

Aging is associated with reduced neuromuscular function, which may be due in part to altered corticospinal excitability. Regular physical activity (PA) may ameliorate these age-related declines, but the influence of PA on corticospinal excitability is unknown. The purpose of this study was to determine the influence of age, sex, and PA on corticospinal excitability by comparing the stimulus-response curves of motor evoked potentials (MEP) in 28 young (22.4 ± 2.2 yr; 14 women and 14 men) and 50 old adults (70.2 ± 6.1 yr; 22 women and 28 men) who varied in activity levels. Transcranial magnetic stimulation was used to elicit MEPs in the active vastus lateralis muscle (10% maximal voluntary contraction) with 5% increments in stimulator intensity until the maximum MEP amplitude. Stimulus-response curves of MEP amplitudes were fit with a four-parameter sigmoidal curve and the maximal slope calculated (slopemax). Habitual PA was assessed with tri-axial accelerometry and participants categorized into either those meeting the recommended PA guidelines for optimal health benefits (\u3e10,000 steps/day, high-PA; n = 21) or those not meeting the guidelines (n = 41). The MEP amplitudes and slopemax were greater in the low-PA compared with the high-PA group (P \u3c 0.05). Neither age nor sex influenced the stimulus-response curve parameters (P \u3e 0.05), suggesting that habitual PA influenced the excitability of the corticospinal tract projecting to the lower limb similarly in both young and old adults. These findings provide evidence that achieving the recommended PA guidelines for optimal health may mediate its effects on the nervous system by decreasing corticospinal excitability

Physical Activity Modulates Corticospinal Excitability of the Lower Limb in Young and Old Adults

Aging is associated with reduced neuromuscular function, which may be due in part to altered corticospinal excitability. Regular physical activity (PA) may ameliorate these age-related declines, but the influence of PA on corticospinal excitability is unknown. The purpose of this study was to determine the influence of age, sex, and PA on corticospinal excitability by comparing the stimulus-response curves of motor evoked potentials (MEP) in 28 young (22.4 ± 2.2 yr; 14 women and 14 men) and 50 old adults (70.2 ± 6.1 yr; 22 women and 28 men) who varied in activity levels. Transcranial magnetic stimulation was used to elicit MEPs in the active vastus lateralis muscle (10% maximal voluntary contraction) with 5% increments in stimulator intensity until the maximum MEP amplitude. Stimulus-response curves of MEP amplitudes were fit with a four-parameter sigmoidal curve and the maximal slope calculated (slopemax). Habitual PA was assessed with tri-axial accelerometry and participants categorized into either those meeting the recommended PA guidelines for optimal health benefits (\u3e10,000 steps/day, high-PA; n = 21) or those not meeting the guidelines (n = 41). The MEP amplitudes and slopemax were greater in the low-PA compared with the high-PA group (P \u3c 0.05). Neither age nor sex influenced the stimulus-response curve parameters (P \u3e 0.05), suggesting that habitual PA influenced the excitability of the corticospinal tract projecting to the lower limb similarly in both young and old adults. These findings provide evidence that achieving the recommended PA guidelines for optimal health may mediate its effects on the nervous system by decreasing corticospinal excitability

Effects of Elevated H\u3csup\u3e+\u3c/sup\u3e And P\u3csub\u3ei\u3c/sub\u3e on The Contractile Mechanics of Skeletal Muscle Fibres From Young and Old Men: Implications for Muscle Fatigue in Humans

The present study aimed to identify the mechanisms responsible for the loss in muscle power and increased fatigability with ageing by integrating measures of whole‐muscle function with single fibre contractile mechanics. After adjusting for the 22% smaller muscle mass in old (73–89 years, n = 6) compared to young men (20–29 years, n = 6), isometric torque and power output of the knee extensors were, respectively, 38% and 53% lower with age. Fatigability was ∼2.7‐fold greater with age and strongly associated with reductions in the electrically‐evoked contractile properties. To test whether cross‐bridge mechanisms could explain age‐related decrements in knee extensor function, we exposed myofibres (n = 254) from the vastus lateralis to conditions mimicking quiescent muscle and fatiguing levels of acidosis (H+) (pH 6.2) and inorganic phosphate (Pi) (30 mm). The fatigue‐mimicking condition caused marked reductions in force, shortening velocity and power and inhibited the low‐ to high‐force state of the cross‐bridge cycle, confirming findings from non‐human studies that these ions act synergistically to impair cross‐bridge function. Other than severe age‐related atrophy of fast fibres (−55%), contractile function and the depressive effects of the fatigue‐mimicking condition did not differ in fibres from young and old men. The selective loss of fast myosin heavy chain II muscle was strongly associated with the age‐related decrease in isometric torque (r = 0.785) and power (r = 0.861). These data suggest that the age‐related loss in muscle strength and power are primarily determined by the atrophy of fast fibres, but the age‐related increased fatigability cannot be explained by an increased sensitivity of the cross‐bridge to H+ and Pi

A Role for Focal Adhesion Kinase in Vascular Smooth Muscle Cell Proliferation, Migration and Differentiation

Smooth muscle cells (SMC) are involved various vascular diseases, such as atherosclerosis, restenosis following balloon angioplasty and following venous bypass grafts. During the development of these vascular diseases and during normal vascular development, numerous changes occur within the vessel environment that enables SMC to phenotypically modulate between a contractile phenotype and a proliferative phenotype. The remodeling of the extracellular matrix, an increase in growth factors and contractile agonists have all been shown to initiate signaling pathways leading to an increase in SMC proliferation, migration, and differentiation. The tyrosine kinase, Focal Adhesion Kinase (FAK) plays a major role in the integration of the signals transmitted from these extracellular cues. The aim of this dissertation was to determine the SMC functions that are regulated by FAK. To address this goal, I evaluated two prominent signaling pathways; the Ras/Raf/Mek/Erk and Pi3-kinase/Rac/Pak/JNK cascades, both have been shown to be required for cell growth and motility in certain cell types. The data presented herein shows that FAK activity is required for PDGF-, AngII- and adhesion-mediated Rac1 activation. The p21-activated kinases (PAK) are downstream targets of various signaling cascades including PDGF-BB and integrins and are effectors for the GTPases Rac1 and Cdc42. Recently, it was shown that PAK activity is required for maximal activation of the canonical Ras/Raf/Mek/ERK MapKinase signaling cascade. Therefore, I aimed to determine the role of PAK within the ERK signaling cascade and found that adhesion-dependent activation of PAK may enhance growth factor-stimulated signaling and PAK may serve as a scaffold for the Raf/Mek/Erk signaling cascade in SMC. I also sought to determine if FAK activity plays a role SMC phenotypic modulation. I found that deletion of FAK or inactivation of FAK by FRNK (FAK related non-kinase) expression causes a significant increase SMC-specific gene expression. Additionally, the LIM protein, leupaxin, associates with FAK and can translocate from focal adhesions to the nucleus leading to increased SMC marker gene transcription. These data indicate that FAK may serve as a necessary regulator of SMC phenotypic modulation during vasculogensis, where FAK activation promotes a dedifferentiated proliferative phenotype and FAK inactivation induces a switch to a differentiated contractile phenotype

Age-related Deficits in Voluntary Activation: A Systematic Review and Meta-analysis

Whether there are age-related differences in neural drive during maximal effort contractions is not clear. This review determined the effect of age on voluntary activation during maximal voluntary isometric contractions. The literature was systematically reviewed for studies reporting voluntary activation quantified with the interpolated twitch technique (ITT) or central activation ratio (CAR) during isometric contractions in young (18–35 yr) and old adults (\u3e60 yr; mean, ≥65 yr). Of the 2697 articles identified, 54 were eligible for inclusion in the meta-analysis. Voluntary activation was assessed with electrical stimulation and transcranial magnetic stimulation on five different muscle groups. Random-effects meta-analysis revealed lower activation in old compared with young adults (d = −0.45; 95% confidence interval, −0.62 to −0.29; P \u3c 0.001), with moderate heterogeneity (52.4%). To uncover the sources of heterogeneity, subgroup analyses were conducted for muscle group, calculation method (ITT or CAR), and stimulation type (electrical stimulation or transcranial magnetic stimulation) and number (single, paired, or train stimulations). The age-related reduction in voluntary activation occurred for all muscle groups investigated except the ankle dorsiflexors. Both ITT and CAR demonstrated an age-related reduction in voluntary activation of the elbow flexors, knee extensors, and plantar flexors. ITT performed with paired and train stimulations showed lower activation for old than young adults, with no age difference for the single electrical stimulation. Together, the meta-analysis revealed that healthy older adults have a reduced capacity to activate some upper and lower limb muscles during maximal voluntary isometric contractions; however, the effect was modest and best assessed with at least paired stimulations to detect the difference

Vocal tract resonances in singing: variation with laryngeal mechanism for male operatic singers in chest and falsetto registers

International audienceSeven male operatic singers sang the same notes and vowels in their chest and their falsetto registers, covering the overlap frequency range where two main laryngeal mechanisms can be identified by means of electroglottography: M1 in chest register and M2 in falsetto register. Glottal contact quotients determined using electroglottography were typically lower by 0.27 in M2 than in M1. Vocal tract resonance frequencies were measured by using broadband excitation at the lips and found to be typically lower in M2 than in M1 sung at the same pitch and vowel; R1 typically by 65 Hz and R2 by 90 Hz. These shifts in tract resonances were only weakly correlated with the changes in the contact quotient or laryngeal height that were measured simultaneously. There was considerable variability in the resonance tuning strategies used by the singers, and no evidence of a uniform systematic tuning strategy used by all singers. A simple model estimates that the shifts in resonance frequencies are consistent with the effective glottal area in falsetto register (M2) being 60%-70% of its value in chest register (M1)

Differential Effects of Aging and Physical Activity on Corticospinal Excitability of Upper and Lower Limb Muscles

Corticospinal tract excitability can be altered by age, physical activity (PA), and possibly sex, but whether these effects differ between upper and lower limb muscles is unknown. We determined the influence of age, PA, and sex on corticospinal excitability of an upper limb and a lower limb muscle during submaximal contractions by comparing stimulus-response curves of motor evoked potentials (MEPs). Transcranial magnetic stimulation (TMS) was used to evoke stimulus-response curves in active muscles by incrementally increasing the stimulator intensity from below the active motor threshold (AMT) until a plateau in MEP amplitudes was achieved. Stimulus-response curves were analyzed from the first dorsal interosseous (FDI) of 30 young (23.9 ± 3.8 yr) and 33 older (72.6 ± 5.6 yr) men and women and the vastus lateralis (VL) of 13 young (23.2 ± 2.2 yr) and 25 older (72.7 ± 5.5 yr) men and women. Corticospinal excitability was determined by fitting the curves with a four-parameter sigmoidal curve and calculating the maximal slope (slopemax). PA was assessed with triaxial accelerometry, and participants were dichotomized into high-PA (\u3e10,000 steps/day, n = 15) or low-PA (n = 43) groups. Young adults had larger FDI MEP amplitudes (% maximum amplitude of compound muscle action potential) at higher TMS intensities (120–150% AMT) and greater slopemax than older adults (P \u3c 0.05), with no differences between high- and low-PA groups (P \u3e 0.05). VL MEP amplitudes and slopemax, however, were lower in the high-PA than low-PA participants, with no age or sex differences. These data suggest that aging and PA, but not sex, differentially influence the excitability of the corticospinal tracts projecting to muscles of the upper compared with the lower limb

The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients

The genetic background for interindividual variability of the polymorphic CYP2D6 enzyme activity remains incompletely understood and the role of NFIB genetic polymorphism for this variability was evaluated in this translational study. We investigated the effect of NFIB expression in vitro using 3D liver spheroids, Huh7 cells, and the influence of the NFIB polymorphism on metabolism of risperidone in patients in vivo. We found that NFIB regulates several important pharmacogenes, including CYP2D6. NFIB inhibited CYP2D6 gene expression in Huh7 cells and NFIB expression in livers was predominantly nuclear and reduced at the mRNA and protein level in carriers of the NFIB rs28379954 T>C allele. Based on 604 risperidone treated patients genotyped for CYP2D6 and NFIB, we found that the rate of risperidone hydroxylation was elevated in NFIB rs28379954 T>C carriers among CYP2D6 normal metabolizers, resulting in a similar rate of drug metabolism to what is observed in CYP2D6 ultrarapid metabolizers, with no such effect observed in CYP2D6 poor metabolizers lacking functional enzyme. The results indicate that NFIB constitutes a novel nuclear factor in the regulation of cytochrome P450 genes, and that its polymorphism is a predictor for the rate of CYP2D6 dependent drug metabolism in vivo

Using Beatboxing for Creative Rehabilitation After Laryngectomy:Experiences From a Public Engagement Project

Laryngectomy is the surgical removal of the larynx (voice box), usually performed in patients with advanced stages of throat cancer. The psychosocial impact of losing the voice is significant, affecting a person’s professional and social life in a devastating way, and a proportion of this patient group subsequently must overcome depression (22–30%) and social isolation (40%). The profound changes to anatomical structures involved in voicing and articulation, as a result of surgery, radiotherapy or chemotherapy (separately or in combination with one another), introduce challenges faced in speech rehabilitation and voice production that complicate social reintegration and quality of life. After laryngectomy, breathing, voicing, articulation and tongue movement are major components in restoring communication. Regular exercise of the chest, neck and oropharyngeal muscles, in particular, is important in controlling these components and keeping the involved structures supple. It is, however, a difficult task for a speech therapist to keep the patient engaged and motivated to practice these exercises. We have adopted a multidisciplinary approach to explore the use of basic beatboxing techniques to create a wide variety of exercises that are seen as fun and interactive and that maximize the use of the structures important in alaryngeal phonation. We herein report on our empirical work in developing patients’ skills, particularly relating to voiced and unvoiced consonants to improve intelligibility. In collaboration with a professional beatboxing performer, we produced instructional online video materials to support patients working on their own and/or with support from speech therapists. Although the present paper is focused predominantly on introducing the structure of the conducted workshops, the rationale for their design and the final public engagement performance, we also include feedback from participants to commence the critical discourse about whether this type of activity could lead to systematic underlying research and robustly assessed interventions in the future. Based on this exploratory work, we conclude that the innovative approach that we employed was found to be engaging, useful, informative and motivating. We conclude by offering our views regarding the limitations of our work and the implications for future empirical research

Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits

Clinical response of clozapine is closely associated with serum concentration. Although tobacco smoking is the key environmental factor underlying interindividual variability in clozapine metabolism, recent genome-wide studies suggest that CYP1A and NFIB genetic variants may also be of significant importance, but their quantitative impact is unclear. We investigated the effects of the rs2472297 C>T (CYP1A) and rs28379954 T>C (NFIB) polymorphisms on serum concentrations in smokers and nonsmokers. The study retrospectively included 526 patients with known smoking habits (63.7% smokers) from a therapeutic drug monitoring service in Norway. Clozapine dose-adjusted concentrations (C/D) and patient proportions with subtherapeutic levels (<1070 nmol/L) were compared between CYP1A/NFIB variant allele carriers and homozygous wild-type carriers (noncarriers), in both smokers and nonsmokers. Clozapine C/D was reduced in patients carrying CYP1A-T and NFIB-C variants versus noncarriers, both among smokers (−48%; p < 0.0001) and nonsmokers (−35%; p = 0.028). Patients who smoke carrying CYP1A-T and NFIB-C variants had a 66% reduction in clozapine C/D versus nonsmoking noncarriers (p < 0.0001). The patient proportion with subtherapeutic levels was 2.9-fold higher in patients who smoke carrying NFIB-C and CYP1A-T variants versus nonsmoking noncarriers (p < 0.0001). In conclusion, CYP1A and NFIB variants have significant and additive impact on clozapine dose requirements for reaching target serum concentrations. Patients who smoke carrying the studied CYP1A and NFIB variants, comprising 2.5% of the study population, may need threefold higher doses to prevent risk of clozapine undertreatment. The results suggest that pre-emptive genotyping of NFIB and CYP1A may be utilized to guide clozapine dosing and improve clinical outcomes in patients with treatment-resistant schizophrenia. © 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics