NEUR3101 Motor Control Lecture 21: Stroke and Rehabilitation PDF

NEUR3101 Motor control Lecture 21 Stroke and rehabilitation A/Prof Ingvars Birznieks  Learning Outcomes You should be able to: Describe the general consequences for movement control of upper motor neuron (UMN) syndromes Explain the common symptoms and t...

NEUR3101 Motor control Lecture 21 Stroke and rehabilitation A/Prof Ingvars Birznieks  Learning Outcomes You should be able to: Describe the general consequences for movement control of upper motor neuron (UMN) syndromes Explain the common symptoms and typical motor dysfunctions associated with stroke Identify recovery mechanisms after stroke Understand aims of rehabilitation programs In addition, this lecture will reinforce your understanding of the role of the descending tracts in the control of movement by appreciating the problems caused by the loss of input or nervous tissue damage. Consequences of diminished descending control of spinal motor neurons While input from the upper motor neurons essential for initiation of voluntary movements is excitatory, the majority of inputs controlling spinal reflexes are inhibitory supressing reflexes when they are not meaningful. The major inhibitory system originates from ventromedial bulbar reticular formation and runs via the dorsal reticulospinal tract. It is activated by the premotor cortex. If premotor cortex is damaged, the inhibition is removed. The excitatory counterpart is dorsal reticular formation which is not under direct cortical control and thus remains active after cortical damage. Thus the reduction in descending inhitory input to spinal interneurons result in exaggerated unrestricted flow of excitation reaching motor neurons. Also the intrinsic motoneuron excitability may increase to compensate for the reduction of functional activation of the spinal cord.  Signs and symptoms of UMN dysfunction … due to disinhibition of spinal reflexes hyperreflexia - exaggerated reflexes spasticity - muscular hypertonicity with increased tendon reflexes; unlike rigidity it is velocity dependant, i.e., the faster the muscle is stretched the greater resistance and more reflex activity; affects movement in one direction (usually antigravity muscles) https://youtu.be/gLZoYLxdXCQ (rigidity)* - an increased muscle tone leading to a resistance to passive movement throughout the range of motion in both directions. Residual muscle tone or tonus is partial contraction of the muscles during resting state. It is present in normal muscle. * NOTE: Rigidity is not a typical sign of UMN damage, rather it results from dysregulation of UMN function originating from the basal ganglia. clasp-knife phenomenon - a manifestation of corticospinal spasticity in which there is sudden release of the resistance to passive flexion/extension typically near the end of the range of joint movement https://youtu.be/re0WKy1zlY0 clonus – muscular spasm involving a series of brisk repeated rhythmic, monophasic (i.e., unidirectional) contractions and relaxations of a group of muscles https://youtu.be/UX75k8s5QUE myoclonus - very rapid, shock-like contraction(s) of a group of muscles, which are irregular in rhythm and amplitude  Signs and symptoms of UMN damage … due to disinhibition of spinal reflexes (continued) contracture - a permanent structural shortening of a muscle or joint usually in response to prolonged hypertonic spasticity producing deformity Babinski sign - reversal of cutaneous flexor reflex … due to lost voluntary control loss of dexterity slowness, and clumsiness Reversal of cutaneous flexor reflex Babinski sign The Babinski sign. Following the removal of descending corticospinal pathways, stroking the sole of the foot may cause an abnormal fanning of the toes and the extension of the big toe (positive Babinski sign). It is used as a diagnostic tool.  Reversal of cutaneous flexor reflex Babinski sign Infants will also show an extensor response. A baby's smaller toes will fan out and his big toe will dorsiflex slowly. This happens because the corticospinal pathways that run from the brain down the spinal cord are not fully myelinated at this age, so the reflex is not inhibited by the cerebral cortex. The extensor response disappears and gives way to the flexor response around 12 to 24 months of age. Signs of loss of UMN and LMN function Summary Lost input from the Lost input from the Upper motor neurons (UMN) Lower motor neurons (LMN) Spasticity and tone Increased, with ‘clasp knife’ quality Decreased Clonus Present Absent Fasciculations* Absent Present Absent, but disuse atrophy Muscle wasting eventually results Present Tendon reflexes Increased Decreased or absent Extensor plantar reflexes Flexor plantar reflexes Babinski sign (Positive) weak or not present Wider effects, but proximal muscles affected less. Weakness is more apparent in the upper limb extensors Specific muscle groups and lower limb flexors simply Distribution affected (e.g. in the distribution reflecting natural strength of of a spinal segment) muscles (note: UMN damage affects flexors and extensors equally). See doi:10.1136/practneurol-2016-001584 *Fasciculations are involuntary muscle twitches localised to small areas of a muscle.  What is a stroke? Ischaemic Intracerebral Subarachnoid Hemorrhage Hemorrhage 80% 15% 5% Stroke, also known as cerebrovascular accident (CVA), is when impaired blood flow to the brain results in cell death. Stroke is characterised by acute onset and persistence of neurologic signs and symptoms beyond 24 hours. Ischaemic stroke often caused by thrombus is the most common type of stroke (accounts for about 80% of cases). A transient ischaemic attack (TIA) is caused by a temporary cut in blood supply to the brain, due to the partial blockage of an artery. While it is sometimes called a mini stroke, a TIA does not usually cause long-term brain damage. A TIA has identical symptoms to a stroke, but these last for less than 24 hours and are followed by a full recovery. A TIA is a powerful warning that an area of the brain is being deprived of blood and that a stroke may follow in the next few hours, days, weeks or months. Urgent medical attention is needed. ACE Check their FACE. Has their mouth drooped? RMS Can they lift both ARMS? PEECH Is their SPEECH slurred? Do they understand you? IME is critical. If you see any of these signs, call 000 now! Stroke incidence in Australia 60,000 new cases each year Death 475,000 25% survivors within a within a Disability month year 65% 20% 33% new stroke every 9 minutes National Stroke Foundation, 2017  Risk factors Diabetes Mellitus: 2 – 5 Excess alcohol consumption times greater risk Carotid atherosclerosis Age: >60 yrs risk of stroke doubles with every decade Hypercoagulable states Gender: male Some oral contraceptive pills Hypertension Atrial fibrillation Cigarette smoking Endocarditis Drug abuse, such as Obesity cocaine or amphetamine Hyperlipidemia Lack of exercise  Ischemic stroke http://www.uwmedicine.org/uwmed/Templates/content/uwmedicine  Mechanisms of Ischemic stroke Neuropathology Cerebral embolism Thrombus from elsewhere breaks off to lodge in brain blood vessels. Most often in the middle cerebral artery (MCA). Abrupt onset. Lysis of embolus may lodge fragments in distal branches and thus change symptoms. Possible secondary hemorrhage. Kandel, Principles of Neural Science  Mechanisms of Ischemic Neuropathology stroke Lacunar stroke Small (< 1.5cm) lesions caused by occlusions in deep branches of large vessels to subcortical structures (often in diabetes and hypertension). Often cause pure motor or pure sensory symptoms. Brainstem, internal capsule, basal ganglia, thalamus lesions are common, also multiple lesion sites are possible. More rapid and greater neurological recovery. http://www.uwmedicine.org/uwmed/Templates/content/uwmedicine  MechanismsHaemorrhagic of Neuropathology stroke Cerebral haemorrhage Common cause is rupture of aneurysm. Usually in deep branches of large vessels to subcortical structures (thalamus and putamen, 10% cerebellum). Neurological symptoms progress over time as haematoma and edema continues to increase. Very high mortality and severity of symptoms, but also more profound neurological recovery (as edema resolves and pressure is released). http://www.uwmedicine.org/uwmed/Templates/content/uwmedicine  MechanismsHaemorrhagic of Neuropathology stroke Subarachnoid haemorrhage (SAH) Common cause rupture of arterial aneurysm leading to bleeding into subarachnoid space. Aneurysmal SAH can cause cerebral vasospasm which appears several days after bleeding. This is because irritating blood byproducts cause the walls of an artery to contract. The cerebral vasospasm can produce ischemic neurological deficit identical to that produced by other causes of stroke. Up to 50% patients will re-bleed in 6 months. http://www.uwmedicine.org/uwmed/Templates/content/uwmedicine  Terminology Definitions Ataxia inability to coordinate muscle activity during voluntary actions – jerky movements. Often due to disorders of the cerebellum or the posterior spinal columns. May involve limbs, head, or trunk. Apraxia is characterized by loss of the ability to execute or carry out familiar movements, despite having the desire and physical ability. Aphasia impairment of language, affecting the production or comprehension of speech and the ability to read or write. Agnosia (a-gnosis, "non-knowledge", or loss of knowledge) is a loss of ability to recognize objects, persons, sounds, shapes or smells while the specific sense is not defective nor is there any significant memory loss.  Terminology Definitions Dyskinesia means "abnormal movement“; uncontrollable, often jerky movements that a person does not intend to make. Hemiparesis weakness on one side of the body. Person can still move the affected side of your body, but with reduced muscular strength. Dysphagia difficulty in swallowing due to problems in nerve or muscle control. Compromises nutrition and hydration and may lead to aspiration pneumonia & dehydration. Hemineglect or neglect syndrome inability of a person to process and perceive stimuli on one side of the body or environment, where that inability is not due to a lack of sensation. The effect of the location of lesion Cerebral vascular territories Anterior cerebral artery Middle cerebral artery Posterior cerebral artery The effect of the location of lesion Cerebral vascular territories MCA – Middle cerebral artery Kandel Schwartz & Jessel ACA – Anterior cerebral (2000).artery Principles of Neural PCA – Posterior cerebral Scienceartery 4/e McGraw-Hill.  Middle cerebral artery stroke Contralateral hemiparesis more pronounced in arm and face with leg less influenced. Gaze deviation away from the side of weakness towards the side of the cortical damage. Examples of symptoms which are hemisphere specific: Left (dominant) hemisphere aphasia (language disorders) some apraxias (including verbal) Right (non-dominant) hemisphere neglect syndrome Kandel Schwartz & Jessel (2000). Principles of Neural dressing apraxia Science 4/e McGraw-Hill.  Neglect (right hemisphere) The drawings on the right were made by patients with unilateral visual neglect following lesion of the right posterior parietal cortex. Kandel Principles of Neural Science 4/e  Anterior cerebral artery stroke Reduction of the function of the portions of the brain supplied by ACR: the medial aspects of the frontal and parietal lobes, basal ganglia, anterior fornix and anterior corpus callosum. Typical functional consequences: paralysis or weakness of the contralateral foot and leg, sensory loss in the contralateral foot and leg, gait apraxia, impairment of gait and stance, anosmia – problems with smell.  Posterior cerebral artery stroke Reduction of the function of the portions of the brain supplied by PCA: occipital lobe, a large portion of the thalamus, and the upper brainstem and midbrain. Mostly sensory dysfunction Symptoms related to visual system dysfunction and processing. Contralateral homonymous hemianopsia or hemianopia (loss of half of the visual field on the same side in both eyes). Kandel Schwartz & Jessel (2000). Principles of Neural Science 4/e McGraw-Hill.  Basilar artery stroke Patients with acute basilar artery occlusion have a mortality rate of greater than 85%. Sudden death/loss of consciousness. Proximal and mid portions of the basilar artery (pons) can result in patients being 'locked in' (patient is aware but cannot move or communicate verbally due to complete paralysis of nearly all voluntary muscles in the body, sometimes only eye movements are present). Somnolence, hallucinations and dreamlike behaviour. Coma, apnoea, cardiovascular instability. Kandel Schwartz & Jessel (2000). Principles of Neural Science 4/e McGraw-Hill.  Recovery after stroke Neurological deficits resulting from a stroke are often referred to as impairments. Functional deficits are often referred to as disabilities. Neurological recovery is defined as recovery of neurological impairments and is often the result of brain recovery/reorganization; it has been increasingly recognized as being influenced by rehabilitation.  Recovery after stroke Intrinsic neurological recovery and spontaneous reorganisation after stroke Peak spontaneous neurological recovery from stroke occurs within the first 1-3 months. This includes cortical reorganisation, cell function recovery but also adjusting the gain of spinal reflex loops to adapt to decreased descending input. At the spinal level the state of areflexia and muscle weakness that immediately follows a stroke is gradually replaced by the recovery of neuronal and network excitability, leading to improvements in residual motor function, but also increasing risk of developing spasticity. Spontaneous reorganisation after stroke may introduce maladaptive changes, especially if motor commands result in no movement and thus no proprioceptive feedback which would be able to uphold existing neural circuits and protect them from maladaptive plasticity.  Recovery after stroke Prominent recovery occurs during the first 3-6 months after the stroke and depends on rehabilitation procedures which promote brain plasticity and are required to establish new functional circuits replacing the damaged ones. A number of studies have shown that recovery may continue at a slower pace for at least 6 months. Some of the recovery is due to brain’s healing process, however, rehabilitation is crucial for promoting and shaping brain’s circuits during reorganisation period. This type of recovery and rehabilitation is critically time dependent! If rehabilitation is too late, there will be no effect as spontaneous healing/reorganisation processes will be finished and maladaptive changes may take place. In later stages the efficiency of rehabilitation relies on different plasticity mechanisms, which have no time limit.  Recovery after stroke Functional or adaptive recovery Functional recovery is defined as improvement in mobility and activities of daily living; it is significantly driven by rehabilitation. Function could be regained by learning compensatory movements. Functional recovery is influenced by neurological recovery but is not dependent on it. This recovery depends on the patient's motivation, ability to learn and family support as well as the quality and intensity of therapy.  Rehabilitation for stroke To relearn lost function damaged nervous system needs the same things that a normal nervous system needs to learn command signals, feedback about outcomes, intact brain regions to compare intended and actual movements. Many promising techniques that follow this principle proprioceptive stimulation of paretic or paralyzed limb, constraint induced therapy, augmented feedback systems, EMG assisted FES (functional electrical stimulation).  Rehabilitation for stroke Wii-hab  Muscle cramps Dr. Frederic von Wegner WARNING  This material has been reproduced and communicated to you by or on behalf of the University of New South Wales in accordance with section 113P of the Copyright Act 1968 (Act).  The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act.  Do not remove this notice Learning objectives - explain how scientifically based recommendations are derived (example: GRADE) - describe typical symptoms of exercise-associated muscle cramping (EAMC) - explain the hypotheses about EAMC pathophysiology - describe the rationale behind common treatment strategies - list some common treatment strategies and estimate their evidence level - describe idiopathic leg cramps - give examples for the connection of muscle cramps with serious disease Levels of evidence – how much do we know? - several systems exist, example: - GRADE: Grading of Recommendations, Assessment, Development and Evaluations - a transparent framework for developing and presenting summaries of evidence - a systematic approach for making clinical practice recommendations - a tool for grading the quality of evidence and making recommendations GRADE: certainty ratings Very low the true effect is probably markedly different from the estimated effect Low the true effect might be markedly different from the estimated effect Moderate the authors believe that the true effect is probably close to the estimated effect High the authors have a lot of confidence that the true effect is similar to the estimated effect GRADE DON’T DO treat treat - GRADE is subjective - evidence becomes less certain when: - there is a risk of bias - imprecision (does the clinical decision change when I move over the confidence interval?) - inconsistency (studies yield contradictory results) - indirectness: better!?? - publication bias (missing evidence?) treatment A treatment B x4 x2 placebo Placebo treatment A Placebo treatment B Young, BMJ Clin Evid, 2015 Muscle cramping – common symptoms - cramps = involuntary localised and painful muscle contractions - fasciculations are not cramps (few fascicles, not painful) - causality: unknown, different hypotheses (this lecture) fasciculations cramp needle EMG s - risk factors: - do not confound with causes - eliminating a risk factor is not automatically an efficient treatment => simplified and erroneous therapeutic implications Bischoff, EMG (Ge)  Muscle cramping: 4 forms 1. Benign forms a. Exercise associated muscle cramping (EAMC) b. Idiopathic leg cramps (benign nocturnal cramps) (c. Cramps associated with pregnancy) 2. Cramps and disease (neuromuscular, metabolic) Exercise-associated muscle cramping (EAMC) - cramps that occur during or immediately after exercise - pain/discomfort can have longer duration (>24 h) - prevalence up to 50%, e.g. marathon, triathlon - which muscles? multi-joint muscles (e.g. calf > foot > knee flexors) - considered benign, not a disease => unusually intense cramps may unmask other conditions Exercise-associated muscle cramping (EAMC) - cramps that occur during or immediately after exercise - pain/discomfort can have longer duration (>24 h) - prevalence up to 50%, e.g. marathon, triathlon - which muscles? multi-joint muscles (e.g. calf > foot > knee flexors) - considered benign, not a disease => unusually intense cramps may unmask other conditions - pathophysiological hypotheses: 1. neuromuscular control disorder 2. dehydration, electrolyte changes Pathophysiology – 2 hypotheses Hypothesis 1: neuromuscular control - the combination of several factors controlling muscle contraction leads to cramping - remember fatigue?...same factors! but unknown mechanisms lead to net overexcitability - factors: - myotatic reflex and Ia afferents (increased?) - GTO + Ib afferents (decreased?) => excitation of the α-motoneuron - data mostly from animal studies and electrical stimulation Katzberg, J Neurol, 2015 Pathophysiology – 2 hypotheses Hypothesis 2: dehydration / electrolytes - low evidence level - frequency seems to increase with ambient temperature and humidity - no controlled, standardized studies e.g. no fatigue measures - correlation dehydration – cramp risk has not been established - no significant differences in serum electrolyte concentrations between cramp / non-cramp subjects Katzberg, J Neurol, 2015  Pathophysiological concepts of EAMC Risk “Premature muscle factors fatigue” Nelson, Muscle & Nerve, 2016  Pathophysiological concepts of EAMC stretching? (controversy) COL5A1 CC ↓ (collagen type V) Nelson, Muscle & Nerve, 2016 Cramps: EMG correlates electrical stimulation after discharges Katzberg, J Neurol, 2015 Exercise-induced muscle cramping (EAMC) Acute interventions: - no high level (level I) evidence for any method - moderate evidence (level II-III): passive stretching - little evidence (level IV): pickle juice - no evidence: non-drug physical therapies, fluid substitution, many drugs problem: short duration of cramps, self-limiting before intervention is effective Prevention: low evidence for: - electrically induced cramps increases threshold (not practical) - quinine: no recommendation because of side-effects - TRP channel agonists - hyperventilation? Nelson, Muscle & Nerve, 2016 Idiopathic leg cramps Symptoms: - “benign nocturnal cramps” - spontaneously occurring, mostly at night, but also prolonged rest (sitting, lying) - which muscles: calf > others - more frequent with age Idiopathic leg cramps Symptoms: - “benign nocturnal cramps” - spontaneously occurring, mostly at night, but also prolonged rest (sitting, lying) - which muscles: calf > others - more frequent with age Treatment strategies: - acute: passive stretch of agonist or contract antagonist (low grade evidence) - prevention: - stretching: study protocol: 3 x 10 sec calf/hamstring stretch in the evening, 6 weeks) - quinine: level I evidence for efficacy (cramps less frequent, less intense), but: potentially serious side effects - Mg2+: probably not effective Muscle cramps: disease and medication side-effects - peripheral neuropathies: diabetes mellitus, alcohol - neuromuscular disease: amyotrophic lateral sclerosis (ALS) - metabolic disorders: thyroid, adrenal, liver, kidney disease - medication: - antidepressants (neuronal excitability?) - glucocorticoids (electrolytes? due to lower serum K+?) - diuretics (electrolytes?, renal loss of K+, Mg2+) - statins (direct effect on muscles?) Muscle cramps and disease Katzberg, J Neurol, 2015 Quinine: - natural substance, known for a long time (malaria, tonic water) - mechanism: reduces membrane excitability (neuromuscular junction, muscle fibre membrane + action potential) - level I evidence exists for efficacy against cramping (Cochrane Review) - but possibly fatal (!) side effects: - cardiac arrhythmia - thrombocytopenia (low platelets) - teratogenic (developmental malformations) => no clear recommendation https://en.wikipedia.org/wiki/Quinine Magnesium salts - theory: - Mg2+ ions are “antagonists” of Ca2+ ions - “stabilization” of the membrane potential - inhibition of intracellular Ca2+ release via RyR receptors - Garrison et al., Cochrane Review 2012: Magnesium for skeletal muscle cramps - Conclusions: - EAMC: no randomized controlled trials (RCT) - Mg2+ is unlikely to provide clinically meaningful cramp prophylaxis to older adults experiencing skeletal muscle cramps - pregnancy related rest cramps: literature not conclusive - disease related cramps: no RCTs for e.g. amyotrophic lateral sclerosis - but: big $$$ market TRP / TRPV channel agonists - TRP = transient receptor potential channel (A-ankyrin, V-vanilloid) activators: chili, wasabi etc. - Craighead et al., Muscle & Nerve, 2017: - TRP agonists may reduce EAMC by increasing cramp threshold - cramp duration not altered, less subjective cramp soreness - no adverse effects on performance - Behringer et al., Eur J Appl Physiol, 2018: - TRPA1, TRPV1 randomized, double-blind, placebo controlled study - possible short-term effect on cramp threshold, no clear overall effect => no conclusive evidence, strong effect unlikely Pickle juice - anecdotal evidence: US football match with high ambient temperature: several players stopped with severe cramps => those that drank pickle juice improved, hypothesis: high Na+ content - Miller et al. Reflex inhibition of electrically induced muscle cramps in hypohydrated humans. Med Sci Sports Exerc 2010; 42: 953 – 961 experimental muscle cramps (3% weight loss by sweating) => treatment pickle juice vs. salt-free water => cramp duration almost -50% with pickle juice Mechanism? NaCl seems obvious… but: effect after 85 sec (pickle juice in stomach...) => reflex hypothesis (tongue, oral cavity receptors) => spinal cord => motor neuron excitability ↓ Diverse drug therapies Katzberg, J Neurol, 2015 Non-drug therapies - kinesio taping, compression garments - massage therapy - corrective exercise - stretching - hyperventilation => small samples, laboratory-based studies => lack of RCTs => low evidence Thank you!  Sarcopenia and Muscular dystrophies Dr. Frederic von Wegner WARNING  This material has been reproduced and communicated to you by or on behalf of the University of New South Wales in accordance with section 113P of the Copyright Act 1968 (Act).  The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act.  Do not remove this notice Learning objectives - give a definition of sarcopenia - discuss the relationship between risk factors and pathomechanisms in sarcopenia - name some laboratory and clinical findings in sarcopenia - which treatment strategies for sarcopenia exist - describe the clinical course of Duchenne muscular dystrophy (DMD) - what is the cause, what are the pathomechanisms of DMD? - explain the relationship between cell mechanics and excitability in DMD - discuss the relationship between physical exercise and DMD Sarcopenia - sarx (gr.) = flesh, sarco- = muscle (endoplasmic ret. => sarcoplasmic ret., plasmalemma => sarcolemma,...) - penia = lack of (leukopenia, …) - concept over time: low muscle mass → low muscle strength → earlier diagnosis, better predictor of adverse outcome - sarcopenia is a muscle disease (muscle failure), not normal ageing - not only muscle quantity, also muscle quality - a progressive disease Cruz-Jentoft 2019 Grip strength and age colours: birth cohorts percentiles: 10, 25, 50, 75, 90 statistical cut-off threshold for force loss screening Cruz-Jentoft 2019 Sarcopenia Public health relevance: - prevalence: depends on method: (1-30% community, >10% in acute hospital care and long-term care) - increased risk of falls and fractures - limits daily living activities => loss of independece, quality of life ↓ - mobility disorders - associations / correlations with: cardiac + respiratory problems, cognitive deficits - health costs ↑ (hospitalisation) - when hospitalized, sarcopenia patients generate more costs (x 2), old+young! Woo 2017 Cruz-Jentoft 2019 Sarcopenia: SARC-F screening tool - evaluated in 3 large populations - sensitivity: low to moderate - specificity: very high => severe cases reliably detected mild cases can escape Woo 2017 Sarcopenia – objective criteria - muscle strength: grip strength, handheld dynamometer, chair stand test - muscle quantity: magnetic resonance imaging, computer tomography - X-ray absorptiometry (DXA) - bioelectric impedance analysis (BIA), portable - physical performance: gait speed, + balance test, +chair stand test, 400 m walk rd test - lumbar 3 vertebra imaging (CT) – correlates with whole-body muscle - mid-thigh muscle measurement (MRI, CT) - muscle quality measurement (high-sensitivity MRI for example) measures e.g. fat infiltration - muscle ultrasound imaging - serum biomarkers (under evaluation): inflammation, metabolism,... Cruz-Jentoft 2019 Sarcopenia – subtypes - forms: primary (age-related) and secondary (inflammatory, cancer, inactivity, nutrition) - time course: acute ( type I/II ratio increases with age => loosely packed fibres in aged subj. (connective tissue) Lexell, 1988 Ageing atrophy: some correlations decreasing muscle area 60% type I: 40% type I: decreasing muscle fibre N Lexell, 1988 Sarcopenia - management - non-pharmacologic: - resistance and strength training both effective in prevention and treatment, affect protein synthesis/degradation balance Sarcopenia - management - non-pharmacologic: - resistance and strength training both effective in prevention and treatment, affect protein synthesis/degradation balance - pharmacological: - not approved: DHEA (Androsterone-like > metabolism), GH (growth hormone) increases muscle mass, but not strength/function IGF (insuline-like growth factor) testosterone: increases muscle mass and strength, but: risk↑ for: prostate cancer, virilization, cardiovasc. events - under investigation: vitamin D, myostatin,... Sarcopenia - management - non-pharmacologic: - resistance and strength training both effective in prevention and treatment, affect protein synthesis/degradation balance - pharmacological: - not approved: DHEA (Androsterone-like > metabolism), GH (growth hormone) increases muscle mass, but not strength/function IGF (insuline-like growth factor) testosterone: increases muscle mass and strength, but: risk↑ for: prostate cancer, virilization, cardiovasc. events - under investigation: vitamin D, myostatin,... - nutrition: - curcuma, ginger, grape seed (and more) ? - malnutrition in elderly Sarcopenia: physical activity works - ‘common sense’ recommendation seems to work: physical activity prevents sarcopenia - different types of PA similar effects Steffl, 2017 Sarcopenia Cruz-Jentoft 2019  Muscular dystrophies Hereditary and progressive diseases that lead to: - muscle necrosis (cell death) - and replacement of muscle by connective and fat tissue Muscular dystrophies Example dystrophies associated with sarcolemmal proteins and enzymes e.g.: LGMD: limb girdle muscular dystrophy → proximal muscles shoulder, hip DMD: Duchenne BMD: Becker Amato, Neuromuscular Disorders Muscular dystrophies Examples of dystrophies associated with sarcomeric and nuclear proteins LGMD – limb girdle muscular dystrophy → proximal muscles shoulder, hip MEB: muscle, eye, brain OPMD: oculo-pharyngeal (...) Amato, Neuromuscular Disorders Muscular dystrophies… too many ??? Amato, Neuromuscular Disorders Duchenne muscular dystrophy  X-chromosomal recessive disease  1/3 of cases spontaneous mutations  incidence: 1/3500 (male births) = ↑  initially normal development  2-6 yrs: ‘waddling’ gait, Gower’s sign https://en.wikipedia.org/wiki/X-linked_recessive_inheritance Duchenne muscular dystrophy  X-chromosomal recessive disease  1/3 of cases spontaneous mutations  incidence: 1/3500 (male births) = ↑  initially normal development  2-6 yrs: ‘waddling’ gait, Gower’s sign https://en.wikipedia.org/wiki/X-linked_recessive_inheritance Duchenne muscular dystrophy (DMD)  X-chromosomal recessive disease  1/3 of cases spontaneous mutations  incidence: 1/3500 (male births) = ↑  initially normal development  2-6 yrs: ‘waddling’ gait, Gower’s sign  problems with running  calf pseudohypertrophy  = fatty degeneration  generalization over years,  cardiac muscle affected  early death from respiratory  complications (< 30 y) https://en.wikipedia.org/wiki/X-linked_recessive_inheritance DMD pathology: dystrophin - giant 427 kDa protein - actinin/spectrin family - structural protein, N-terminus binds actin - binds many other structural proteins, e.g.: - dystroglycan - syntrophin - mutations → short, unstable and dysfunctional variants Muntoni, Lancet Neurol, 2003 DMD pathology: dystrophin healthy - giant 427 kDa protein - actinin/spectrin family - structural protein, N-terminus binds actin - binds many other structural proteins, e.g.: - dystroglycan - syntrophin - mutations → short, unstable and dysfunctional variants DMD dystrophin antibody staining Muntoni, Lancet Neurol, 2003 Amato, Neuromuscular Disorders Muntoni, Lancet Neurol, 2003 DMD cellular changes Amato, Neuromuscular Disorders Becker muscular dystrophy - ‘short dystrophin’ atrophy fat intrusion Amato, Neuromuscular Disorders DMD and excitability changes: Ca2+ currents mdx mouse model Friedrich, PLoS One, 2008 DMD and excitability changes: Ca2+ currents model of dystrophin-DHPR interaction (mouse) gene therapy Friedrich, PLoS One, 2008 Structural defects and cell mechanics - advanced structural microscopy shows: - disruptions of myofibrils - split fibres (progressive) - what does that mean for contractions? - what does that mean for physical therapy and exercise recommendations in DMD? Friedrich, Biophys J, 2010 Pathological cell mechanics 20 µm cell instability → damage → pathological shear forces → damage - cell damage: → uncontrolled Ca2+ influx → apoptosis (programmed cell death) Friedrich, Biophys J, 2010 DMD and exercise Kostek, Exerc Sports Sci Rev, 2017 DMD and exercise - in animals: - voluntary wheel running: positive effects on force, fatigue resistance in mdx limb muscles, controversial results in diaphragm, cardiac: all effects (↑↓) found (negative: dilation, wall thinning, ejection fraction ↓) - swimming: beneficial for most limb muscles, more strength, shorter relaxation time (= improved Ca2+ handling), less fatigue cardiac and respiratory muscles: more fibrosis, more inflammation - forced running: increased muscle damage, impaired function, plasma-CK ↑ progressive loss of force, extremely bad: downhill running (eccentric contr.) Spaulding, Med Sci Sports Exerc, 2018 DMD and exercise - in animals: - voluntary wheel running: positive effects on force, fatigue resistance in mdx limb muscles, controversial results in diaphragm, cardiac: all effects (↑↓) found (negative: dilation, wall thinning, ejection fraction ↓) - swimming: beneficial for most limb muscles, more strength, shorter relaxation time (= improved Ca2+ handling), less fatigue cardiac and respiratory muscles: more fibrosis, more inflammation - forced running: increased muscle damage, impaired function, plasma-CK ↑ progressive loss of force, extremely bad: downhill running (eccentric contr.) - in humans: - mostly respiratory muscle training => increased resp. endurance, pressure, vital capacity - limb muscles: unknown risk, ethical problem, few studies, muscle probably able to adapt to training, but unknown effects on cardiac + respiratory function Spaulding, Med Sci Sports Exerc, 2018  DMD summary 1. DMD is a lethal, frequent hereditary disease of skeletal and cardiac muscle affecting children and young adult men 2. the cause is a lack of the giant structural protein dystrophin 3. dystrophin links many proteins providing membrane and cellular stability 4. dystrophin pathology is associated with changes in excitability 5. pathological cell mechanics can accelerate cell damage and cell death 6. the optimum amount and type of exercise is still unknown Thank you!  Plasticity and adaptation to training and disuse Dr. Frederic von Wegner WARNING  This material has been reproduced and communicated to you by or on behalf of the University of New South Wales in accordance with section 113P of the Copyright Act 1968 (Act).  The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act.  Do not remove this notice Learning objectives - what is skeletal muscle fibre plasticity? - name intracellular signaling pathways involved in plasticity and how they are linked - name experimental procedures to induce fibre plasticity - describe adaptation mechanisms to different types of exercise - describe changes in the nervous system contributing to training effects Skeletal muscle fibre plasticity cellular mechanisms  External & internal factors: hypertrophy vs. atrophy behaviour: elimination of microgravity, - training vs. disuse synergists hindlimb suspension experimental: - overload, electrical stimulation vs. unloading, denervation internal/hormonal: - androgens (testosterone) beta-agonists (adrenaline) IGF-1 vs. myostatin, glucocorticoids external (drugs): - beta-agonists, androgens growth hormones vs. glucocorticoids Blaauw, 2013  External & internal factors: hypertrophy vs. atrophy behaviour: elimination of microgravity, - training vs. disuse synergists hindlimb suspension experimental: - overload, electrical stimulation vs. unloading, denervation internal/hormonal: - androgens (testosterone) beta-agonists (adrenaline) IGF-1 vs. myostatin, glucocorticoids external (drugs): - beta-agonists, androgens growth hormones vs. remember glucocorticoids doping? Blaauw, 2013  External & internal factors: fast vs. slow fibre types CLFS: chronic low-frequency electrical stimulation Blaauw, 2013  Experimental fibre type transition slow fast - electrical stim. of rat fast fibre - time-to-peak (TTP) ~ fibre type (Prac 5!) - only low-frequency stim. achieves fast (low TTP) to slow (high TTP) transition Blaauw, 2013  Experimental fibre type transition slow slow fast fast - electrical stim. of rat fast fibre - same number of pulses/day - time-to-peak (TTP) ~ fibre type (Prac 5!) => only low freq. stim (10 Hz) achieves - only low-frequency stim. achieves fast-to-slow transition fast (low TTP) to slow (high TTP) transition Blaauw, 2013  Experimental fibre type transition tetanus - force-frequency curve (Prac-5!) - fast-like behaviour: - higher fusion freq. slow - lower twitch-tetanus ratio => only low freq. stim ( the fast fibre (FDL) will turn into a slow fibre phenotype - also, the intracellular biochemistry, e.g. Ca2+ buffers, adapt to the slow type Buller, 1960  Observed fibre type transitions masticatory - myosin heavy chain transitions observed in experiments - gene transcription and protein translation seems to be constrained (not any transition is possible) extraocular - the combination of factors can increase the range of plasticity, e.g. hyperthyroidism and mech. unloading: 1 → 2B Schiaffino, 2011 Plasticity and training Adaptation to exercise Sensing ‘muscle stress’: - 4 stressors: mechanical load, neuronal activation, hormonal adjustment metabolic disturbance (Hoppeler, 2016) - a) resistance/strength training => mechanical stress dominates - b) endurance training => metabolic changes more pronounced - both: the associated nerve impulses and Ca2+ transients start molecular events that lead to future adaption to new exposures to the same kind of ‘stress’ Adaptation to exercise Sensing ‘muscle stress’: - 4 stressors: mechanical load, neuronal activation, hormonal adjustment metabolic disturbance (Hoppeler, 2016) - a) resistance/strength training => mechanical stress dominates - b) endurance training => metabolic changes more pronounced - both: the associated nerve impulses and Ca2+ transients start molecular events that lead to future adaption to new exposures to the same kind of ‘stress’ - Questions: - how can ‘running around’ lead to the formation of new mitochondria? - how can a few dozen contractions of our arm muscles (+weight) make that muscle grow!? Fibre type adaptation in athletes - % ST: proportion of slow-twitch fibres - muscles adapt their fibre type composition to specific requirements elite power lifter elite marathon 85% type II 90% type I mATPase (4,2), Whyte, The Physiol. of Traning Tesch, 1985 Endurance vs. resistance exercise Endurance Exercise: - repeated low-intensity contractions - low force, low fatigue, aerobic system - cycling, swimming,... - typical transitions: type IIX → IIA - fast IIX fibres → slower (more economical) II A fibres slow I fibres → faster type I fibres - myosin light chain changes type II: fast MLC → slow MLC type I: slow MLC → fast MLC - mitochondrial biogenesis: PGC-1α (increase in size, then number) => ‘aerobic fitness’ Qaisar, 2016 Endurance vs. resistance exercise Endurance Exercise: Resistance Exercise: - repeated low-intensity contractions - low-frequency, high-intensity contract. - low force, low fatigue, aerobic system (e.g. 80% MVC) - cycling, swimming,... - type II hypertrophy: - typical transitions: type IIX → IIA actin-myosin synthesis, more myofibrils - fast IIX fibres → slower (more in parallel (cross-sect. area ↑) economical) II A fibres - protein synthesis and degradation slow I fibres → faster type I fibres increase → hypertrophy delayed - myosin light chain changes re-structuring of the muscle type II: fast MLC → slow MLC - mechanical forces activate focal type I: slow MLC → fast MLC adhesion kinase (FAK) → activation - mitochondrial biogenesis: PGC-1α of the mTOR pathway (increase in size, then number) => ‘aerobic fitness’ Qaisar, 2016 resistance: endurance: protein gene translation expression Qaisar, 2016 Simplified model: endurance vs. strength - ‘endurance’ pathway: 1. low frequency stimulation and sustained contractions 2a. Ca2+ / calmodulin / CaM-Kinase 2b. AMPK ‘master switch’ (AMP/ATP ↑) 3. mitochondrial proliferation ↑ 4. slow fiber programs - resistance (‘strength’) pathway: 1. high-frequency stimulation 2. AMPK ‘master switch’ (AMP/ATP ↓) 2. mTOR Hoppeler, 2011 Changes due to inactivity - muscle biopsy after 37 days of bed rest - myosin ATPase staining (A) - B-D: mRNA autoradiography B: MHC-β (slow) transcript C: MHC-2A transcript D: MHC-2X transcript 11: MHC-1 protein, but MHC-2X mRNA 12: + MHC-2X, + MHC-2A mRNA 13: MHC-2X and MHC-β (slow) mRNA => transitional fibres after rest 1 → 2X Andersen, 1999 Fibre type changes due to inactivity slow fibres ↓ fast fibres (2X) ↑ Andersen, 1999 Neural plasticity and exercise Neural drive and neural enhancement - what happens during early training? - muscle fibre protein synthesis increases after the first training session but: hypertrophy needs weeks to occur - however, training increases max. strength within a few days (knee extensors, wrist flexors, elbow extensors…, Gabriel 2006) - strength after rest periods: after 35 contractions in 1 day, strength increases were present after 2 weeks rest comparison with biochemical data: metabolic changes unlikely => altered neural drive (increasing sEMG amplitudes without hypertrophy) => peripheral / central? => nervous system ‘learned’ maximal activation Gabriel 2006 Neural plasticity and training - motor unit firing rate - strength training => increases in MVC motor unit firing rate ipsi- and contralateral to training side - probably important in early adaptation (e.g. first week) after that: motor program optimization with variable changes in firing rate - firing patterns: doublets often occur at contraction onset, at high contraction speeds => rapid rise in Ca2+ possibly optimized during early training (hypothesis) - Motor Unit synchronisation? Hypothesis unproven due to methodological limitations (e.g. sEMG) Gabriel 2006 Neural plasticity and training - spinal changes - increased motor neuron excitability due to (voluntary) suppression of descending inhibition - measured as increased H-reflex (V-reflex during contraction) - learning experiments (operant conditioning): stretch reflex changes with verbal command given (Carp, 1995) Gabriel 2006 Neural plasticity and training - spinal changes - increased motor neuron excitability due to (voluntary) suppression of descending inhibition - measured as increased H-reflex (V-reflex during contraction) - learning experiments (operant conditioning): stretch reflex changes with verbal command given (Carp, 1995) - motor cortex output - motor imagery experiments (mental practice, no movement) - motor cortex activation can be measured (fMRI, TMS) - imagined max. efforts increase real MVC force (Bowers 1966) - depends on the target muscle, role: rehabilitation > sports Gabriel 2006 Neural plasticity and training - cross transfer - motor neuron facilitation by activation of the contralateral heteronymous muscle (Schantz 1989) example: (short) contraction left knee flexor => right knee ext. + contraction left knee ext. => right knee ext. - - more effective with contralateral eccentric contraction - neural effect likely, no changes in biochemical properties of ipsilat. muscle (spinal, cortical?) Baehr, Top. diagnosis in Neurology Neural plasticity and training - agonist-antagonist-interaction - simplified model: training reduces antagonist co-activation antagonist just counteracts agonist’s action - one convincing study using knee ext. strength training showed MVC force reduction in antagonist => optimizes force production - other target: joint stability / mechanical stress for joint stabilization, antagonist co-activation may be optimal e.g. increased M. triceps brachii strength and co-activation in elbow-flexor training => task-dependence, no definitive conclusions yet Baehr, Top. diagnosis in Neurology Summary 1. Adaptation to training happens across all levels: brain, spinal cord, muscle 2. muscle fiber plasticity is regulated by mechanical forces (neuro-)electrical input hormones 3. the current model for cellular pathways for endurance and resistance training: resistance: mTOR – translation / protein synth. / hypertrophy – fast fibre programs endurance: Ca2+, ATP (AMPK) – gene expression – slow fibre programs 4. neural adaptation faster than fibre re-programming motor unit: excitability changes and firing rate adaptation brain: motor program learning / training Thank you!