Physiological Responses to Linear/Non-Linear Soccer Simulations.

Phys Responses JSCR

Our recent study investigated the Loughborough Intermittent Shuttle Test (LIST) (Nicholas et al., 2000) and it’s effects on neuromuscular fatigue when adjusted.

The problem with this ‘gold standard’ simulation is that, though it mimics the demands of a typical soccer game, it’s ecological validity was to be questioned.. how could it mimic the demands of a soccer game if the testing was completely linear (running in one straight direction)? Nonlinear running is frequently performed during soccer matches, with professional players completing 727 (+/-) 203 swerves and turns within a single match (Bloomfield et al., 2007). Such swerves require a great deal of rapid changes of direction and decelerations.

But to successfully complete these actions in soccer, repetitive demanding muscle contractions are necessary, particularly those of an eccentric nature and the cumulative effect of performing these type of contractions ultimately leads to fatigue, less efficient movement patterns (Small et al., 2009) and an increased risk of injury (Greig & Seigler, 2009). Research has also suggested that nonlinear running induces greater heart rate (HR), perceptual, and metabolic responses than straight-line (linear) running (Dellal et al., 2010), but this has also been questioned in recent studies, where they found similar drops in jump performance regardless of the type of running (Hader et al., 2016).

JSCR Infographic

Summary of study. Credit to Adam Johnson @PreventionPhys

The aim of our study was see if a modified version of the LIST could be incorporated mimic the demands of soccer while also achieving a similar amount of swerves and turns as reported in Bloomfield’s paper. The modified LIST allowed for the inclusion of 6 x 90degree and 1 x 180degree changes of direction (COD) per run. This meant that there was a total of 720-1008 COD’s within the whole protocol without altering total simulation time or activity time during the simulation.

COD

8 university football/rugby athletes too part measures including blood lactate, heart rate (maximum and average), jump height, peak landing and isometric force, and perceived fatigue were measured across the testing period. The running was monitored through Global Positioning System (GPS) trackers attached to each participant.

Results? 

Though participants found the modified LIST harder through perceived fatigue and heart rate measures, it portrayed no changes to jump height and isometric/landing forces. The modifed LIST did not change the total distance covered in the LIST but did change the amount of decelerations and the high speed running (HSR) distance. However,  greater HSR distances were directly related to reductions in isometric hamstring force.

What does this mean?

COD’s do seem to induce higher ratings of perceived fatigue but HSR distance plays a role in hamstring fatigue, indicating how important this GPS variable is for sport scientists and coaches alike when it comes to monitoring training load and managing fatigue. It also allows for changes to training (particularly related to small sided games or metabolic conditioning) by incorporating COD’s which could reduce HSR distance but still lead to higher or similar metabolic demands.

Limitations?

The modification to the LIST was based on multi-directional running at 1.5x the timing of the maximal effort run timing of each participant. The COD’s were positioned in a manner that did not alter total distance covered by the original LIST. However, such timings and COD positionings may have given participants enough time to run and change directions at a pace which did not require a great deal of side cutting mechanics but full body turns following lesser speeds of running.

The study would ideally have aimed to recruit a larger sample size of professional athletes to see if these results reflected the larger population of professional soccer players.

Full study available here: https://www.ncbi.nlm.nih.gov/pubmed/30138235

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An Introduction to Concussion within Combat Sports (Part 1)

All of these animals have shock absorbers built into their bodies. The woodpecker’s tongue extends through the back of the mouth out of the nostril, encircling the entire cranium. It is the anatomical equivalent of a safety belt for its brain. Human beings? Not a single piece of our anatomy protects us from those types of collisions. A human being will get concussed at sixty G’s. A common head-to-head contact on a football field? One hundred G’s.

From the film ‘Concussion’ in 2015 based on some real life events and people.

Now while the whole film, let alone the quote, may not be completely scientifically accurate (or even about concussions). It is a profound statement allowing us to recognize the amazing intricacy of design for each and every organism, yet how fragile and dependent we are upon these designs.

The brain sits in a pool of cerebrospinal fluid without any connection to the skull. As shown in the quick movie clip; the example of an apple in a slightly filled jar of water gives us a parable of how the brain moves with each impact to the skull (in this case, the jar). With each impact to the jar, it leads to the loss of integrity of the apple, eventually causing it to crack. In the case of the brain? It’s a lot more complex than that.. a neatly packed piece of jelly with specific functions, hitting onto the cranium and causing the jelly to be stretched and sheared at a microscopic level.

SO what is a ‘Concussion’?

Concussion, also known as Mild Traumatic Brain Injury (mTBI), is an injury through impact to the head (brain) which causes temporary losses in brain function.

It has been previously described as “a complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces” (Quality Standards Subcomittee, 1997)

It makes up 80-90% of TBI cases but is notably distinguishable from other forms of TBI because, there are no gross pathologies such as a hemorrhage or identifiable damage of the neural structure through conventional neuroimaging techniques such as MRI (Noble & Hesdorffer, 2013). This means it is quite difficult to diagnose and has many generic symptoms which can easily make it a condition which is misdiagnosed or more importantly, ignored or unnoticed.

How does it happen/What causes it?

giphy

Concussion is caused by acceleration, deceleration and rotational forces applied directly or indirectly to the head, leading to the damage of brain tissue. These forces can occur from direct or indirect impacts, hence concussions are not only the result of impact to the head, but from impact to the body resulting in head movement (e.g. car accidents involving a whiplash {coup-contrecoup})

(Note: The amount of movement in the picture above is not an accurate representation of brain movement within the cranium, but gives us an idea of the acceleration/deceleration forces on the brain during impact that leads to stretching of brain tissue)

Image result for concussion

The principal causes of head trauma in combat sports include straight impact blows to the face (e.g. jabs and front kicks) leading to linear acceleration of the head or impact from an angle (e.g. roundhouse kicks, hooks and uppercuts) leading to rotational acceleration (Unterharn-scheidt, 1995). High incidences are also seen within sports such as American Football, Hockey, Rugby, Football (soccer) and Basketball (Harmon et al., 2013). These are the results of head on head collisions and collisions with the ball or ground.

 

Image result for concussion sports

The movement of the brain within the skull can lead to shearing of cells along with stretching and disruptions at the structure of the neurons within the brain. It is said that a 15% stretch of the neuron length will result in biochemical changes (such as membrane depolarization and deregulated release of neurotransmitters) resulting in an acute failure of neurons leading to a concussion (Gaetz, 2004).

Through studies observing biomechanical forces to the brain, severity of impact to the brain has been observed to increase with weight class. In addition, it has been reported that the punch of a professional boxer may generate forces on impact that are equivalent to a 6kg bowling ball rolling at 20mph (Athaet et al., 1985)

Some studies have suggested changes in neural function even after standard header practices within soccer, which may suggest that with each exposure to head impact, there is an increased risk of concussion.

How prevalent is it?

The Centre for Disease Control and Prevention (CDC) reports an estimate of 135,000 patients per year to arrive at emergency departments with concussions from sports or recreational activity (Laker, 2011).

Within combat sports, particularly boxing and kickboxing, concussions account for approximately a third (33%) of injuries experienced by fighters . Similarly, 28.3% of fight stoppages within MMA have been reported due to head trauma with a rate of 15-16 concussions per 100 bouts (Curran-Sills & Abedin, 2018; Hutchison et al., 2014; Buse, 2006). It is most frequently observed in American football, especially linemen and linebackers, who are reported to be exposed to more than 1000 impacts per season (Crisco et al., 2010).

Even the sport of soccer/football has been observed to have significant rates of concussion with reports of 1/5th of injuries within high school games to be due to concussion (Kerr et al., 2018)

What are the symptoms?

Typically, clinical symptoms straight after a concussion include:

  • Headaches
  • Nausea
  • Loss of consciousness,
  • Blurriness
  • Fatigue
  • Loss of motor control (balance/coordination)
  • Loss of memory, concentration and attention
  • Change in mood states

(McCrory et al., 2012; Ropper & Gorson, 2007; Hall et al., 2005).

Most recover within days to weeks. However, 10-15% may experience persistent issues even after a year (Hall et al., 2005; Sterr et al., 2006).

Though loss of consciousness (e.g. Knockouts) is generally attributed to concussion, it is important to note that this is only known to occur in 10-20% of cases (Giza & Hovda, 2001), indicating it still may occur 80-90% of the time, regardless of an obvious sign.

However, even if these symptoms are eventually not apparent..

with newer electrophysiological techniques, researchers now question that though many of these symptoms may eventually go away, has the brain actually recovered?

The risk of further concussions and musculoskeletal injuries have been reported to increase in athletes with previous concussions (Guskiewicz et al., 2003; Herman et al., 2016; Nordstrom et al., 2014), which suggests that some of these concussion-related changes to the brain have not yet truly healed. Some research also suggests that in some cases, the brain to muscle pathway still portray signs of disrupted neural pathways even after 9 months post concussion (Lewine et al., 2007; Huang et al., 2009; Lewis et al., 2017).

STAY TUNED FOR:

  • Part 2: Concussion diagnosis tools and management

An Introduction to Acute Fatigue within Sport

Definition

Muscle fatigue most often occurs during strenuous dynamic physical activity (James, Scheurmann & Smith, 2010) and within sport, can be explained as a reduction of maximal force or power that is associated with sustained exercise, or the inability to produce or maintain a required force or power output (Celine et al., 2011).


Causes/Classifications

Neuromuscular fatigue is a vast topic of research and though many of the causes are still obscure, it is agreed to be the result of a combination of central and peripheral factors (Allen, Lamb, & Westerblad, 2008; Enoka & Duchateau, 2008; Fitts, 1994; Waldron & Highton, 2014).

Vaguely put, central fatigue is related to the brain and central nervous system while peripheral fatigue is to do with the muscles themselves and the substances related to contracting them.

In a few more words, central fatigue is related to reduced central motor drive of the central nervous system (CNS) due to changes in the synaptic concentration of neurotransmitters and therefore its ability to recruit available motor units (Davis and Bailey, 1997).

Peripheral fatigue on the other hand, relates to limitations of muscle capacity through biochemical changes (Waldron & Highton, 2014), such as an increase in blood lactate concentration and hydrogen ion accumulation (Mohr, Krustup & Bangsbo, 2003). It occurs at, or distal to, the neuromuscular junction and is thought to be linked to several mechanisms such as failure of excitation-contraction coupling, a disruption in neuromuscular transmission and the inhibition of muscle contraction through either the build-up or depletion of metabolites (Kent-Braun, 1999).

neuromuscular-junction-12-638

Lactate and hydrogen ions (H+) production is the result of glucose breakdown. If a sufficient amount of oxygen is not available to the working muscles then hydrogen ion concentrations begin to rise and the muscles, including blood flow to the muscles, become acidic. This acidic environment blocks neuromuscular transmission (signal to and from the brain and muscle), slowing down the individual in order to allow more oxygen to get to the working muscles.

Decreased work rate within sports has been affiliated with reduction in muscle glycogen content (Saltin, 1991) while other factors such as physiological changes within the muscle cell, dehydration and a reduction of recruitable muscle fibres for force production have also been suggested (Saltin, 1973; Jacobs et al., 1982; Bangsbo, 1994). Sjersted and Sjoogard (2000) hypothesized that the sarcolemma was one of the sites of fatigue due to its inability of maintaining sodium and potassium concentrations during repeated stimulation. As a result of inefficiency of the sodium/potassium pump, potassium concentrations increase outside the membrane, in turn decreasing the amount within the membrane. This leads to depolarization of the cell, thus reducing action potential amplitude.

Recovery from peripheral fatigue where it relates to metabolic factors and impairments in neuromuscular transmission is known as high frequency fatigue and has been shown to occur within shorts periods of time following exhaustive exercise (Bruton, Lannergren, & Westerblad, 1998; Saltin, Radegran, Koskolou, & Roach, 1998). Low frequency fatigue on the other hand, is related to peripheral fatigue due to impairments within the excitation-contraction coupling process, and occurs as a result of repeated short intervals of repeated muscle stimulation. This type of fatigue is more prominent following eccentric exercise and is likely the cause of a longer lasting neuromuscular fatigue (Keeton & Binder-Macleod, 2006).


Effects/Presentation/Monitoring

Fatigue within sports is primarily identified through a decline in performance (Reilly, 1994). A fatigue effect has been reported to be noticeable in soccer, particularly within the second half due to an observation of decreased work rate (Reilly and Thomas, 1976). Bangsbo et al (1991) reported a 5% greater distance covered within the first half by professional soccer players,

Fatigue been shown to impair sprinting mechanics and joint stability. Such a combination of factors is likely to predispose players to injury during tasks that have high mechanical demands. (Greig, 2009). Fatigue leads to altered movement patterns of athletes into more stressful positions (Borotikar et al., 2008), and has been reported to be a direct contributor towards injuries such anterior cruciate ligament (ACL) injury via promotion of high risk biomechanics (McLean & Samorezov, 2009)

With advancements in team sports performance analysis such as player tracking technology, fatigue is a popular topic of interest and has usually been associated with variables such as running performance, distance covered from baseline, along with reported changes in neuromuscular force or sprinting ability (Rampinini et al., 2011). Basic physiological measures such as heart rate and blood lactate provide a useful index of overall physiological strain and anaerobic energy yield in response to high intensity situations respectively (Reilly & Thomas, 1997; Reilly, 1997). Thus, combining these variables with a measurement in decrease of muscular force overtime within match play may help indicate acute neuromuscular fatigue.

sbw_gpsport

Other ways include monitoring training load through session RPE’s (rate of perceived exertion) or/and RSI (Reactive strength index). These are easily obtained through a set of numbers based on session time and perceived exertion or using a jump mat and monitoring jump performance which is custom for most professional athletes particularly within team sports. An example and some uses for these two methods are summarised in the below picture.

RSI RPE

Sport scientists and S&C coaches may prefer to use other methods of further analysis through a combination of the above mentioned factors or equations such as the Fatigue Index equation (Fitzsimons, Dawson, Ward & Wilkinson, 1993) based on peak running speed/peak force produced and sum of general running speeds or general force produced, depending on the athlete being monitored.

Charcot-Marie-Tooth Disease (CMT): Brief Etiology, Clinical Presentation and Rehabilitative considerations.

CMT is a genetically heterogenous disorder which effects the motor and sensory peripheral nerves and may also be known clinically as Hereditary Motor and Sensory Neuropathy (HMSN); in the rare occasion where it only effects motor nerves, it is recognised as Distal Hereditary Motor Neuro(no)pathy (dHMN) (Pareyson & Marchesi, 2009). It is one of the most common hereditary neuromuscular disorders with an occurrence of 40 incidences in every 100,000 individuals (Martyn & Hughes, 1997). CMT is caused by mutation of genes responsible for encoding various proteins such as compact/non-compact myelin, Schwann cells and axons which are involved in everyday functions of the body such as mitochondrial metabolism, axonal transport and maintenance of myelin (Barisic et al., 2008; Szigeti & Lupski, 2009; Hoogendijk et al., 1994). Regardless of the defects that primarily effect the myelin or axon, the common end pathway seen of CMT is degenerative process at the axon involving the largest and longest fibres (Pareyson, Scaori & Laura, 2006; Schrerer & Wrabetz, 2009; Krajewski et al., 2000).

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Figure 1. Visual representation of the location of the axon and myelin (nawrot.psych.ndsu.nodak.edu)

Unlike early onset foot conditions such as Congenital Talipes Equinovarus (Clubfoot) which is treated within the first years of birth (Dobbs & Gurnett, 2009), CMT usually occurs over the first 2 decades of life and then progresses relatively thereafter over decades, and neither is it restricted to the feet as it may progress from the feet to the entire lower limb region and even the upper limbs in some subtypes of the condition (Pareyson & Marchesi, 2009).

Though the diagnostic process may be complicated, there are at least 25 specific genes that have been identified to be associated with CMT and 70% of patients are now able to receive a precise molecular genetic diagnosis. The process generally includes identification and definition of the clinical phenotype, identification of the inheritance pattern, electrophysiological examination and a molecular analysis (Pareyson & Marchesi, 2009). The molecular diagnosis can be significantly aided by clinical information/findings of the patients including the age of CMT onset, severity of the disease and presence of uncommon features which still may be associated with CMT such as optic atrophy, vocal cord palsy and glaucoma (Shy et al, 2005; Pareyson, Scaori & Laura, 2006; Barisic et al., 2008; Reilly, 2007; Szigeti & Lupski, 2009).

Based on nerve conduction studies and nerve pathology, CMT can be classified into two types: Demyelinating CMT which is characterised by slow nerve conduction velocities (<35 m/s in the upper limb motor nerves) and is further split into CMT-1 or CMT-4. This split is based on inheritance identification, with CMT-1 presenting itself as autosomal dominant (defect in a dominant non sex specific chromosome) and CMT-4 as autosomal recessive (defect in a recessive non sex specific chromosome). The second type of CMT is axonal and these are characterised by relatively faster nerve conduction velocities (>35 m/s) and pathological evidence of chronic axonal degeneration. Autosomal dominant forms such as CMT-1, CMT-2, dHMN are the most common expressions of CMT in cases while autosomal recessive forms are slightly more rare and severe with an early onset and can be either demyelinating or axonal such as CMT-4, AR-CMT-2 and AR-dHMN. (Ouvrier, Geevasingha, & Ryan, 2007; Vallat, Tazir, Magdelaine, & Sturtz, 2005). However, with the knowledge of CMT being consistently further enhanced, research has begun to find many subtypes in between some of the above mentioned, most importantly CMT-X or x linked CMT (CMT-X1), which is a form of the disease carried by the parent in the x-chromosome (responsible for determining the child’s sex) and is then passed down. This type of CMT cannot be transferred from male to male (therefore a son cannot inherit this from his father) but it is still found to be more common in men (Pareyson, Scaori & Laura, 2006; Barisic et al., 2008).

CMT4

Figure 2. Some of the most common symptoms of CMT

Due to most forms of CMT being an autosomal disorder, it is not specific to gender and effects both men and women equally (Dyck, Chance, Lebo & Carney, 1993). All muscles and muscle fiber types are effected with the distal muscles being effected the most severely (Tsairis, 1974; Borg & Ericson-Gripenstedt, 2002; Erikson, Ansved & Borg, 1998). Symptoms include muscle wastage, muscle weakness, atrophy in the lower limb muscles (particularly the calves), reduced (or absent) deep tendon reflexes, change in gait with difficulty in walking/running, arched feet with development of ‘hammer toes’ and muscle cramps. In some cases, the hands are also affected, along with the fore arms, leading to hand tremors and a clawed hand posture. Sensory loss generally follows a similar pathway (from lower to upper limb) causing loss of sensation within the feet and hands in terms of pain, vibration and touch (Shy et al, 2005; Pareyson, Scaori & Laura, 2006; Barisic et al., 2008; Jani-Acsadi, Krajewski, & Shy, 2008; Reilly, 2007; Szigeti & Lupski, 2009). Onset has been recorded in some cases at such early age that it has caused hypotonia (‘floppy baby syndrome’) and delayed motor development, whilst in other cases, CMT has not fully expressed itself until much later on in life (Pareyson & Marchesi, 2009).

Rehabilitative Considerations

Unfortunately, there is currently still no effective or known drug therapy for CMT, leaving treatment limited to rehabilitation therapy or surgical procedures in the case of skeletal deformities or soft tissue abnormalities, while clinical and animal trials are still currently in the works (Young, De Jonghe, Stögbauer, & Butterfass‐Bahloul, 2008; Sackley et al, 2009). This means the management of CMT in patients requires an interdisciplinary approach with the collaboration of a neurologist, physiotherapist/qualified strength coach and other professionals (Erikson, Ansved & Borg, 1998).

The biggest implication of training patients with a neuromuscular disease such as CMT is the ‘overwork hypothesis’ within which research has pointed towards weakness being further induced from resistance training or general overload (Vinci et al., 2003; van Pomeren et al., 2009). This originated from the study of Kilmer et al., (1994) who observed an increase in injury after a high intensity home based resistance training programme, and concluded that increases in training frequency, volume and particularly intensity is a major risk for patients suffering a neuromuscular disease. Lindeman et al., (1995) found improvements in strength and functional ability after a moderate -high intensity training programme in CMT patients, suggesting that high intensity training is possibly a grey area for training prescription.

Chetlin et al., (2004) observed a twelve week home based resistance training programme focused on improving strength, body composition and activities of daily living, and found that activities of daily living and strength were significantly improved from baseline in both men and women. The programme used in the experimental design placed emphasis on the knee and elbow extensors and flexors, with resistance exercises such as tricep extensions, bicep curls, leg extensions and leg curls. This suggests that moderate exercises can be safe and effective for CMT patients to improve strength and performance in day to day activities.

Though it is yet to be a proven method of rehabilitative therapy for CMT patients, it has been theorised that passive stretching of the ankle flexors and extensors could be prescribed within programming to help counteract tendon retractions and improve it’s reflex ability (Refshauge et al., 2006). Matjacić and Zupan, (2006) also observed the effects of passive stretching along with exercises aimed at general muscle strengthening and balance either guided by a physical therapist or by the set balance apparatus, over a twelve-session intervention and concluded postural and dynamic balance training to be a useful training modality to improve balance and mobility. They suggested this may be due to an improvement in utilisation of compensatory balance and movement strategies of the proximal muscle groups as the distal lower limbs wiuld have been significantly weakened due to CMT.

Patients with CMT have also been reported to present reduced peak oxygen consumption (Vo2 Max) values and a generally decreased aerobic capacity and it has been suggested moderate aerobic exercise may improve functional ability and aerobic capacity but this is yet to be further studied and proven (El Mhandi et al., 2007).

In summary, though it may be difficult for a strength coach, physiotherapist or patient to conclude much on exercise prescriptions and recommendations from this brief overview on the current literature in the field of CMT, it is however safe to conclude:

  • Resistance exercise can be beneficial if the patients level of weakness is not severe, and if the rate of progression of the disease is relatively slow.
  • High-intensity resistance exercises/programmes have no advantage over moderate intensity training programmes (Kilmer, 2002).

 

References:

Barisic, N., Claeys, K. G., Sirotković‐Skerlev, M., Löfgren, A., Nelis, E., De Jonghe, P., & Timmerman, V. (2008). Charcot‐Marie‐Tooth Disease: A Clinico‐genetic Confrontation. Annals of human genetics72(3), 416-441.

Borg, K., & Ericson-Gripenstedt, U. (2002). Muscle biopsy abnormalities differ between Charcot-Marie-Tooth type 1 and 2: reflect different pathophysiology?. Exercise and sport sciences reviews30(1), 4-7.

Chetlin, R. D., Gutmann, L., Tarnopolsky, M. A., Ullrich, I. H., & Yeater, R. A. (2004). Resistance training exercise and creatine in patients with Charcot–Marie–Tooth disease. Muscle & nerve30(1), 69-76.

Dyck, P., Chance, P., Lebo, R., Carney, J. (1993). Hereditary motor and sensory neuropathies. In: Dyck P, Thomas P, editors. Peripheral neuropathy, 3rd ed. Philadelphia: WB Saunders; p 1094- 136.

Dyck, P. J., Karnes, J. L., & Lambert, E. H. (1989). Longitudinal study of neuropathic deficits and nerve conduction abnormalities in hereditary motor and sensory neuropathy type 1. Neurology39(10), 1302-1302.

El Mhandi, L., Calmels, P., Camdessanché, J. P., Gautheron, V., & Féasson, L. (2007). Muscle strength recovery in treated Guillain-Barré syndrome: a prospective study for the first 18 months after onset. American Journal of Physical Medicine & Rehabilitation86(9), 716-724.

Ericson, U., Ansved, T., & Borg, K. (1998). Charcot‐Marie‐Tooth disease type 1 and 2‐an immunohistochemical study of muscle fibre cytoskeletal proteins and a maker for muscle fibre cytoskeletal proteins and a marker for muscle fibre regeneration. European journal of neurology5(6), 545-551.

Herrmann, D. N. (2008). Experimental therapeutics in hereditary neuropathies: the past, the present, and the future. Neurotherapeutics5(4), 507-515.

Hoogendijk, J. E., de Visser, M., Bolhuis, P. A., Hart, A. A., & de Visser, B. W. O. (1994). Hereditary motor and sensory neuropathy type I: clinical and neurographical features of the 17p duplication subtype. Muscle & nerve17(1), 85-90.

Houlden, H., Laura, M., Wavrant–De Vrièze, F., Blake, J., Wood, N., & Reilly, M. M. (2008). Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporadic distal HMN/CMT type 2. Neurology71(21), 1660-1668.

Jani-Acsadi, A., Krajewski, K., & Shy, M. E. (2008, April). Charcot-Marie-Tooth neuropathies: diagnosis and management. In Seminars in neurology (Vol. 28, No. 02, pp. 185-194). © Thieme Medical Publishers.

Kilmer, D. D. (2002). Response to resistive strengthening exercise training in humans with neuromuscular disease. American journal of physical medicine & rehabilitation81(11), S121-S126.

Kilmer, D. D., Wright, N. C., & Aitkens, S. (2005). Impact of a home-based activity and dietary intervention in people with slowly progressive neuromuscular diseases. Archives of physical medicine and rehabilitation86(11), 2150-2156.

Kilmer, D. D., McCrory, M. A., Wright, N. C., Aitkens, S. G., & Bernauer, E. M. (1994). The effect of a high resistance exercise program in slowly progressive neuromuscular disease. Archives of physical medicine and rehabilitation75(5), 560-563.

Krajewski, K. M., Lewis, R. A., Fuerst, D. R., Turansky, C., Hinderer, S. R., Garbern, J., & Shy, M. E. (2000). Neurological dysfunction and axonal degeneration in Charcot–Marie–Tooth disease type 1A. Brain123(7), 1516-1527.

Lindeman, E., Leffers, P., Spaans, F., Drukker, J., Reulen, J., Kerckhoffs, M., & Köke, A. (1995). Strength training in patients with myotonic dystrophy and hereditary motor and sensory neuropathy: a randomized clinical trial. Archives of physical medicine and rehabilitation76(7), 612-620.

Martyn, C.N., Hughes, R.A.C. (1997). Epidemiology of peripheral neuropathy. Journal of Neurology, Neurosurgery and Psychiatry. 62: 310–318.

Matjacić, Z., & Zupan, A. (2006). Effects of dynamic balance training during standing and stepping in patients with hereditary sensory motor neuropathy. Disability and rehabilitation28(23), 1455-1459.

Ouvrier, R., Geevasingha, N., & Ryan, M. M. (2007). Autosomal‐recessive and X‐linked forms of hereditary motor and sensory neuropathy in childhood. Muscle & nerve36(2), 131-143.

Pareyson, D., Scaioli, V., & Laurà, M. (2006). Clinical and Electrophysiological Aspects of Charcot-Marie-Tooth Disease. NeuroMolecular Medicine,8(1-2), 3-22.

Raeymaekers, P., Timmerman, V., Nelis, E., De Jonghe, P., Hoogenduk, J. E., Baas, F., & Van Broeckhoven, C. (1991). Duplication in chromosome 17p11. 2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). Neuromuscular Disorders1(2), 93-97.

Refshauge, K. M., Raymond, J., Nicholson, G., & van den Dolder, P. A. (2006). Night splinting does not increase ankle range of motion in people with Charcot-Marie-Tooth disease: a randomised, cross-over trial. Australian Journal of Physiotherapy52(3), 193-199.

Reilly, M. M. (2007). Sorting out the inherited neuropathies. Practical neurology7(2), 93-105.

Sackley, C., Disler, P. B., Turner‐Stokes, L., Wade, D. T., Brittle, N., & Hoppitt, T. (2009). Rehabilitation interventions for foot drop in neuromuscular disease. The Cochrane Library.

Scherer, S. S., & Wrabetz, L. (2008). Molecular mechanisms of inherited demyelinating neuropathies. Glia56(14), 1578-1589.

Shy, M. E. (2006). Therapeutic strategies for the inherited neuropathies. Neuromolecular medicine8(1-2), 255-278.

Shy, M., Lupski, J.R., Chance, P.F., Klein, C.J., Dyck, P.J. (2005). Hereditary motor and sensory neuropathies: an overview of clinical, genetic, electrophysiologic and pathologic features. In: Dyck PJ, Thomas PK, eds. Peripheral neuropathy 4th edn. Philadelphia: Elsevier Saunders. 1623–58.

Szigeti, K., & Lupski, J. R. (2009). Charcot–Marie–Tooth disease. European Journal of Human Genetics17(6), 703-710.

Szigeti, K., Garcia, C. A., & Lupski, J. R. (2006). Charcot-Marie-Tooth disease and related hereditary polyneuropathies: molecular diagnostics determine aspects of medical management. Genetics in Medicine8(2), 86-92.

Tsairis, P. (1974). Muscle Biopsy: A Modern Approach. Archives of Neurology31(2), 143-143.

Vallat, J. M., Tazir, M., Magdelaine, C., & Sturtz, F. (2005). Autosomal-recessive Charcot-Marie-Tooth diseases. Journal of Neuropathology & Experimental Neurology64(5), 363-370.

van Pomeren, M., Selles, R. W., van Ginneken, B. T., Schreuders, T. A., Janssen, W. G., & Stam, H. J. (2009). The hypothesis of overwork weakness in Charcot-Marie-Tooth: a critical evaluation. Journal of rehabilitation medicine41(1), 32-34.

Vinci, P., Esposito, C., Perelli, S. L., Antenor, J. A. V., & Thomas, F. P. (2003). Overwork weakness in Charcot-Marie-Tooth disease. Archives of physical medicine and rehabilitation84(6), 825-827.

Young, P., De Jonghe, P., Stögbauer, F., & Butterfass‐Bahloul, T. (2008). Treatment for Charcot‐Marie‐Tooth disease. The Cochrane Library.