Neurophysiological Basis of Dyslexia and Neuroplasticity depended Rehabilitation: A comprehensive Overview.

                                                 

This article deals with  the current understanding about the Neurophysiological basis of developmental dyslexia and  Neuroplasticty depended rehabilitation of dyslexic children.Dyslexia or reading disability is characterized by  an individual experiencing  significant difficulty with speed and accuracy of word decoding, comprehension of text and spelling. Dyslexia being one of the most common developmental learning abnormality, its exact prevalence is not conclusively known. However epidemiological estimations varying greatly between 5 to 17% of the population ( Dyslexia International 2014). Developmental dyslexia can be classified as Phonological dyslexia which is characterized by difficulty in reading pseudo words ( New words that reader have never encountered) and surface dyslexia which is characterized by difficulty in reading exception words. These are words with inconsistent spelling eg-: hymn. Dyslexic children in the general schools have been poorly trained due to the inadequate knowledge of teachers and parents about the pathophysiology of dyslexia  and the means of rehabilitation to improve the quality of life and academic performance of dyslexic children.

 Neurobiology of reading 

. The ability to read letter strings require the translation of  visual codes (orthography) into pronunciations ( phonology) with meanings( semantics) emerging when the phonology  corresponds to a known word. FMRI studies have given a better understanding about the complex neurobiological mechanisms that govern the seemingly simple process of reading.These studies have demonstrated that reading activates a widely distributed neural circuits in occipito-temporal, posterior temporal,pre-central and inferior frontal gyri ( Turkeltaub P E & Eden GF 2002).  Reading engages bilaterally distributed set of brain regions. Anterior fusiform gyrus, middle temporal gyrus , angular gyrus and anterior left inferior frontal gyrus are sensitive to or engaged in semantic tasks ie. comprehending the meaning of words.Where as posterior left inferior frontal gyrus and bilateral supramarginal gyri  and angular gyrus are involved in processing the phonological tasks ( Cathy J Price & Andrea Mechelli 2005).

Brain Regions significant in Linguistic Function. 

Current research have demonstrated that acquisition of reading skills is reflected by progressively greater activation of left hemispheric occipital , frontal and temporal regions and less activation of right posterior hemispheric regions 
( Turkeltaub PE et all 2003). A neural network of reading can be strongly left lateralized by the age of 6 or 7 ( Galliard WD et all 2003).

 Pathophysiology of Dyslexia

Past 20 years of research in Neuropsychology  have consistently demonstrated that dyslexia is a deficit of language processing. Dyslexia involves deficit decoding of individual linguistic units called phonemes, which are the smallest detectable sounds in spoken words.Phonemes are the building blocks of linguistic system and is critical for developing spoken language. Phonological processing area of the brain , the superior temporal sulcus should break words into phonemic units before an individual can identify, understand, store or remember them ( Gregory Hickok 2009). In semantic dyslexia or acquired dyslexia which is not usually seen in children may have abnormal neuronal processing in the neuroantomical networks involved. It can also occur due to stroke and neurodegenerative conditions. Whereas speech requires blending the phonemes into complete words. children with difficulty in production of meaningful words may have abnormal neuronal activity or abnormal functional connectivity between the  brain regions involved in blending the phonemes.

Graphemes are the smallest unit in written language. It is a visual symbol of spoken phoneme.Studies have shown than individuals with dyslexia shows impaired phonological awareness and as a result can not adequately pair the visually processed graphemes with their associated phonemes( Paul L et all 2006). The process of associating a grapheme with its phoneme must occur fast enough to for reading fluency and the reader must also remember and retain the word read long enough to recall there meaning. Slow grapheme - phoneme processing appears to be the primary cause of dyslexic reading problem ( Erick R Crouch 2014)  

Pugh K R et all in 2000 reported that dyslexic readers who have difficulty in phonological assembly  have a disruption in the functional connection between angular gyrus and related occipital and temporal lobe sites. Their  findings also  supports the fact that neurobiological anomalies in developmental dyslexia are largely confined to phonological processing domain in the language dominant left hemisphere. FMRI studies shows dysfunction of the connection between cerebellum the agility brain and other cerebral language processing sites as possible etiology of dyslexia. Difference in cerebellar asymmetry  and gray matter volume are some of the consistent structural brain findings in dyslexic readers. It is assumed that impaired cerebro- cerebellar connectivity as the fundamental developmental abnormality leading to difference reading neuronal network ( Stoodly CJ & Stain JF 2013). More advancement functional analysis of brain may shed light into the exact mechanism that govern language functions and the exact neuropathology behind developmental and acquired dyslexia.

                           

FMRI Image 

Evidence for positive neuroplasticty in Developmental dyslexia.

Research in Neurophysiology using FMRI have demonstrated very strong evidence for positive neuroplasticity in children with developmental dyslexia. In a 2012 study published in proceedings of national academy of science by Jane.H & Steve G.Z et all. In their  research they studied the impact of classroom FM system use for 1 year on Neurophysiology and reading skills in dyslexic children. The researches found that FM system use reduced the variability of subcortical response to sound and this improvement was linked to concomitant increase in reading and phonological awareness. 

Ann M, Timothy AK & M A Just have published a novel longitudinal study in 2008 that provided strong evidence for Neuroplasticity in dyslexic children.Their research assessed the impact of intensive remedial instruction on cortical activation among children with dyslexia during semantic task. The cortical activation and improvement in semantic performance was assessed 3 times. Prior to remediation, 100 hours post remediation and 1 year post remediation in both dyslexic and Non-dyslexic children. The central finding was prior to intervention. the dyslexic had poor cortical activation in parital cortex bilaterally. Immediately after the instructions The semantic dyslexic children had signifcat improvement in cortical activation at left angular gyrus and left superior parital lobule. They also showed substantial gains in reading abilities.The activation in this regions continued to improve and finally resulted in normalization and significant improvement in semantic comprehension and reading. 

Another promising study published in 2003 in the Proceedings of  National Academy of Science by Elise Temple et all demonstrated that behavioral interventions ameliorates dysfunctional neural mechanism in children with dyslexia. The researches did FMRI analysis pre and post intervention during phonological processing. The intervention consist of auditory processing and oral language training on 20 dyslexic children between  the age of 8 &12. The FMRI analysis showed increased cortical activation in multiple brain areas as compared to Post FMRI data in the study population. Increase in cortical activation were seen in  left temporo- parital cortex and left inferior frontal gyrus. The activation were observed to be closer to that of non-dyslexic children. Increased activity was observed in right hemisphere frontal and temporal regions and anterior cingulate gyrus. The researchers reported that children with dyslexia showed a correlation between the magnitude of increased activation in left temporo-parital cortex and improvement in oral language ability. 

List of  Non-invasive behavioral interventions and rehabilitation Methods.

• Wilson Reading 
• Spell Read Phonological Auditory Training ( P.A.T)
• Corrective reading 
• Failure free reading. 
• Focused auditory stimulation developed by Dr. Hodson
• Dore Program 
• Transcranial Magnetic Stimulation- This is the best method for inducing Neuroplasticity in children with dyslexia. All though it is noninvasive, presently it is not easily accessible. 

 The details of this methods will be discussed in the next article. I hope this article may provide the readers with a comprehensive overview about the neurophysiological basis of  linguistic abilities and Neurobiological basis of dyslexia .I also hope that this article provides good overview about the scientific evidence for intensive rehabilitation and behavioral intervention induced Neuroplasticity in Developmental dyslexia. 

Siby C Chacko MPE ( Exercise Physiology)          

References        

1)http://www.dyslexiainternational.org/Educational%20Authorities/About%20dyslexia%20ea.

2) Turkeltaub P E , Eden G F, Jhones K M, Zefero T A, Meta - Analaysis of the functional Neuroanatomy of single word reading : Method and Validation , Neuroimaging  16:765-780( 2002).

3) Cathy J Price, Andrea Mechelli , Reading and reading disturbance, Curr.Opinion in Neuro. 15:231-238 ( 2005).

4) Tukeltaub P E , Gareau L, Flowers D L, Zeffiro TA , Eden G F, Development of Neural Mechanism for reading. 6(7) 767-773 ( 2003).

5) Galliard WD, Balsamo LM, Ibrahim Z, Sacs BC, Xu B, FMRI identifies regional networks for reading in young children. Neurology 60: 94-100 ( 2003).

6) Gregory Hickok, The Functional Neuroanatomy of language. Phys. lif.rev.6(3)121-143 ( 2009).

7) http://reference.medscape.com/medline/abstract/16441886.

8)http://emedicine.medscape.com/article/1835801-overview#a0104.

9) Pugh K R, Menchel W E, Shaywitz BA, Fullbright R K, Constable RT, Skudlarski P , Marchione KE et all, The angular gyrus in developmental dyslexia: Task specific difference in functional connectivity with posterior cortex.Psycho.scie. 11(1) 51-6 ( 2000).

10) Stoodly C J , Stain JF, Cerebellar function in developmental dyslexia. Brain & lang. 12(2)267-76( 2013).

11) Jane H , Steven G Z & Nina Cruz. Assistive listening devices drive Neuroplasticity in children with dyslexia. Prs. Natl. acad. sci. USA109(41) 16731-16736( 2012).

12) Ann M, Timothy A k, M A Just. Modifying The brain activation of poor readers during sentence comprehension with extended remedial instruction. Nueropsycho. 46(10) 2580-2592 ( 2008).  

13) Elise Temple, Gayle K D, John D E G,  Neural deficit in children with dyslexia ameliorated by behavioral remediation: Evidence from FMRI . Proc. Natl. Acad. Sci. 100(5)_ 2860-65 ( 2003).

  

Exercise Prescription & Program designing for Geriatric Population: A Scientific Overview.

                      

This Article deals with the scientific aspects of exercise for Geriatric Population. In particular , this article attempts to provide a comprehensive overview of systematic Client Evaluation,   geriatric exercise program designing and prescription.   

Exercise is medicine. Ergo just as therapeutic drugs, exercise prescription and administration should be optimal. Inadequate and excessive exercise  may often yield either no results or hazardous outcomes. The volume , frequency and mode of exercise are so important when it comes geriatric exercise than any other population. As geriatric population often suffers from a cluster of aging related physiological changes,  physical changes and chronic ailments. However, research strongly supports the fact that, systematic exercise serves as a supportive and prophylactic therapy in preventing and improving the physio-psychological aspects of older adults suffering from ailments raging from cardio-pulmonary conditions , Metabolic and osteo-arthrological  conditions to even Cancer. 

However, There is a tendency among exercising older population and among personal Trainers to put the older client into some form of exercise without considering the frequency , volume and duration. In my own personal experience as an exercise specialist, I have come across with clients who have suffered from chronic and excessive exercise induced joint related problems in particular lumbago, knee pain, plantar fasciitis , shoulder and rotator cuff injuries etc. All though there have been a number of contributing factors to it, the most common causes are focusing just on one or two aspects of motor qualities , unscientific frequency , inadequate rest, poor exercise techniques, inadequate nutrition, poor pre-participation health screening and most of the time failure of the exercise practitioner to design and monitor a personalized training program based on the physical , physiological, psychological and medical aspects of the client. Discussing all these aspects in detail is beyond the scope of this article. However, in this article I would like to give an overview of systematic client evaluation and  general guidelines for geriatric exercise program designing & prescription. Based on current research and ACSM -AHA guidlines. 

Client Evaluation      

During client interview and Evaluation , the Exercise Practitioner (EP) should strive to obtain a detailed Social , Family, Occupational, dietary, previous exercise and Medical History. The EP should do a through physical and physiological evaluation. 

In Physical evaluation -Special emphasis should be placed postural analysis. If you identify any postural abnormalities do not jump into correcting it, until and unless you understand the pathology behind it. For instance , if you come across with a case of kypho-scoliosis in a 70 year old woman and if you try to touch that before understanding the pathology of vertebral joints and bones, it may end -up so badly. In such situation advice the client to consult her GP and obtain a clinical clearance. As in this case if it is due to chronic fusion of spinal joints and if there is formation of osteophytes, a corrective exercise may harm.However, if you develop a clinical understanding of the condition, you may in fact be able to tailor a clinically sound exercise regimen  that can improve her quality of life and may help to prevent the condition from worsening. It should always be remembered that , all though exercise is medicine, it is not always so. Hence, it is vital to know the do's and do not's. 

In physiological evaluation- It is always important to do a through evaluation of cardio-pulmonary system which should include BP , PFT, ECG. Any abnormality should be ruled out with the help of a Medical practitioner, exercise physiologist or a clinical exercise physiologist. 

  

In Neurological and musculoskeletal evaluation - Strength, flexibility and balance and co-ordination using standard Manuel Tests. 

In Metabolic profile Evaluation -  Blood routine, Blood glucose level and lipid profile should be obtained. 

In Nutritional evaluation- You should obtain a detailed summery of the type of food , amount of food and frequency + timing. This will be an important thing in determining between calorie in put vs out put. Well it may also connote clues that have clinical significance. 

Social, Family and occupational evaluation- This will help the EP to develop an understanding about the psycho-behavioral aspects of the client and motivation behind exercise. Perhaps the occupational Hx alone will help the EP to make out the etiology of some of the musculoskeletal  conditions that troubles the client. So that the EP can modify the exercise patterns,anticipate the prognosis with exercise, develop effective motivational strategies to support the client. Moreover it will help to develop a confident relationship between the client and practitioner. 

In fact a systematic Evaluation of the client is the most important and most underestimated aspect of  Exercise testing and prescription. It is important for all categories of clients. 

Guidelines for Geriatric Exercise Program Designing.    

Again , these are only guidelines and not protocols. Hence it should be used based on the on the basis of Client Evaluation and scientific judgement of the Exercise Practitioner. These guidelines are based on American College of Sports Medicine  ( ACSM) and American Heart Association (AHA) Recommendations and based on current research. 

Cardiovascular Training 

       

Strength Training    

Flexibility Training 

Balance and Co-ordination Training

I hope My colleagues and other Fitness and exercise science  professional will find this article informative. 

Siby C Chacko MPE ( Exercise Physiology ) 

References:

1) http://www.todaysgeriatricmedicine.com/news/ex_092210_03.shtml

2) Kashinath Padhiary , The art of history taking 2nd edition (2009)

3) Kay.A .Van Norman , Exercise and wellness for Older Adults:2nd Edition ( 1995)

4) Wojtek Chodzko _Zajko PhD ACSM's Exercise for Older Adults ( 2013) 

Obesity, type II Diabetes Mellitus and Physical Exercise: A scientific Overview.

This article address the relationship between Obesity and T2DM as well as the prophylactic and therapeutic effect of systematic physical exercise in managing T2DM. The distinguishing feature of T2DM is insulin resistance and higher than average levels of circulating Insulin.According to WHO ,T2DM comprises 90% of people with diabetes around the world and is largely the result of excess body weight and inactivity( 2013).Obesity is considered as one of the primary causes of T2DM in people who are genetically predisposed to it.  Many studies have identified systematic exercise as a prophylactic and therapeutic means for treating T2DM.
                               

Treatment Triad 

Relationship between Obesity and Insulin Resistance. 

According to WHO "a BMI ( Body Mass Index) greater than or equal to 30 in  a person is deemed as obesity. Obesity is a silent epidemic that has deleterious impact on hormonal and bio-energetic storage and metabolism in human body.All though many aspects of  mechanism is yet to know ,Obesity is regraded as both co-morbid condition and one of the precipitating factors of Insulin resistance in patients with T2DM. Besides T2DM obesity has been implicated as a risk factor for Coronary artery diseases , hypertension and certain forms of Cancer.

 In physiological  terms Obesity is characterized by increased adipose tissue mass.Insulin is a critical regulator of virtually all aspects of adipocyte physiology. Under normal physiological circumstances, Insulin promotes adipocytes triglyceride storage by stimulating glucose transport , lipogenesis  and by inhibiting lipolysis. Insulin  also increases the adipocyte uptake of fatty acids derived from circulating lipoproteins  by a cellular cascade mediated by enzyme lipoprotein lipase. Insulin's metabolic effect on adipose tissue are mediated by a broad array of tissue-specific actions , which involve rapid phosphorylation and changes in specific gene expression( BarbaraB.K and J.F .Miller2000). 

A number of mechanisms of insulin resistance have been identified so far in obese patients , in particular obese patients with T2DM. The chief manifestation of insulin resistance in both population are decreased insulin stimulated glucose transport and metabolism in adipocytes and skeletal muscle along with impaired suppression of hepatic glucose output. The major functional  defect that leads to insulin resistance in adipose tissue is the down-regulation   of   insulin responsive glucose transporter GLUT4. In vitro analysis of adipocytes and myocytes of obese T2DM patients have also demonstrated reduction in insulin binding to its receptors , reduced insulin receptor phosphorylation & tyrosine kinase activity as well as reduction in phosphorylation of Insulin receptor substrates (IRSs). A study conducted by Rondinone et all demonstrated that reduced IRS-1 expression results in decreased IRS-1 mediated PI3K activity and IRS-2 becomes the primary docking protein for PI3K. In addition to glucose metabolism PI3K signaling pathway is an important mediator of cell growth proliferation and survival signals. In contrast to Rondinone's findings Goldstin et all demonstrated that in the myocytes of obese T2DM patients IRS-1 and IRS-2 levels are normal but PI3K activity associated with both IRSs are impaired by the catalytic action of an enzyme  called PTP-1B ( 2000). central obesity have been implicated as a chief concern for precipitating Insulin resistance more than peripheral obesity. A study conducted by  CL McTernnan et all  showed an 418%  increase in resistin mRNA expression in  the subcutaneous abdominal and Omental fat. Increased levels of adipocytes derived cytokine Resistin in abdominal fat could lead to increased insulin resistance and increased glucose intolerance (2002). 

Adipocytes also act as an endocrine organ by secreting numerous peptide hormones and cytokines. Through such secreted products adipocytes influence its on biology in autocrine fashion . It has paracrine effect on brain , vasculature, pancreatic beta cells that produce insulin, gonads.  Of these secretory products , one that is chiefly implicated in T2DM and insulin resistance is a cytokine called Tumor Necrosis Factor- alpha ( TNF-Alpha). In addition to Inflammatory cytokine TNF -Alpha,elevated levels of  CRP , Resistin and Leptin  are also noticed in T2DM obese patients as opposed to T2DM non obese patients( D Hansen2010). 

Mechanism of Insulin Resistance in Skeletal Muscle.

In the postprandial state , skeletal muscle is the predominate site of insulin mediated glucose uptake. Skeletal muscle insulin resistance is considered to be the primary defect that manifest decades before the manifestation of overt hyperglycemia result from pancreatic beta cell failure. Gulli et all demonstrated that in patients with T2DM  impaired muscle glycogen synthesis secondary to reduced Glycogen synthase activity is the earliest detectable defect ( 1992). Increased circulating levels of free fatty acids particularly saturated fatty acids affects intracellular signaling pathways in skeletal muscles. Elevated serum saturated fatty acids inhibits insulin mediated intracellular downstream signalling by activating enzyme kinases such as PKCs , IKK beta, JNK and p38 MAP Kinase. They catalyze the phosphorylation of serine residues in IRS-1 inhibiting its activity and directing it for degradation by the proteasome. Such effects culminate with a reduction in the phosphorylation of tyrosin residues of IRS-1 and thus inhibits insulin mediated downwstream signal transduction. This ultimately results in insulin resistance and reduced glucose uptake by the myocytes ( A R Martins et all 2012).                        

     

Physical Activity Improves Insulin Sensitivity.

A large number of studies have corroborated the fact that systematic physical activity reduces insulin resistance and improves insulin sensitivity . American Diabetic Association and ACSM  have recommended systematic exercise as a first line choice for the prevention and treatment of insulin resistance.Systematic exercise is an integral part of any good treatment plan for the management of T2DM along with pharmaco-nutritional interventions. Systematic exercise has an array of benefits in both T2DM patients just as it has in healthy population. In T2DM patients exercise act not only as a catalyst of insulin sensitivity but as a prophylaxis for cardio-vascular complications. The role of exercise in improving insulin sensitivity in skeletal muscle was first reported by Richter et all in 1982 in a study they published in Journal on clinical investigation . The study was conducted on rats in Neil Ruderman's Laboratory. There study showed an increase in insulin sensitivity and glucose uptake lasted for 4 hours post exercise.In 1983 John Ivy et all expanded richter's finding by using  hind limb perfusion to show post exercise glucose uptake lasted for 2 days.  

A very vivid picture of exercise induced glucose uptake by skeletal muscles are yet to unleash. different type of exercise such as aerobic or resistance exercise mediate these process by influencing different cellular signaling pathways of glucose metabolism and uptake in skeletal muscles. 

Aerobic Exercise and Insulin Sensitivity.

Transcapillary  transport of insulin is one of the important determinants of insulin sensitivity. skeletal muscle capilary density is lower in older adults with impaired glucose tolerance.  A study published by S J prior et all in 2014 have demonstrated that 6 months of aerobic training with an emphasis on weight loss and improving insulin sensitivity in older adults with impaired glucose tolerance have demonstrated that increased capillary density caused by exercise induced angeogenesis increases  Insulin sensitivity and glucose tolerance. evidence also suggest that acute aerobic exercise stimulates glucose transport in skeletal muscle by translocating GLUT4 transporters to the cell surface.In skeletal muscles GLUT4 is distributed in two intracellular populations an endosomal pool that remains unaltered in post exercise and a storage population that is markedly GLUT4 depleted in response to both aerobic exercise and insulin treatment. It is this storage compartment that trigger GLUT4 translocation to the cell surface in response to exercise and insulin treatment( Eva T et all 2001).  A meta analysis of RCT's published in Journal Metabolism in 2014 also suggests that systematic aerobic training is therapeutic for patients with T2DM .It helps to significantly reduce systemic inflammatory responses by reducing inflammatory cytokines CRP and IL-6 ( Hayashino.Y et all 2014). exercise professionals and clinicians when recommending aerobic activities for patients , it is salient to follow the guidelines of ACSM and ADA for aerobic exercise prescription for T2DM and Metabolic disorders.However , each client is unique and guidelines should be followed intelligently.

Resistance Training  and Insulin Sensitivity.

Research have only recently been started focusing on the Therapeutic benefits of resistance training for a number of Chronic diseases including T2DM and Obesity. In fact it has been demonstrated to be safe and effective for elderly and obese patients than that of aerobic exercise. Many studies have corroborated the notion that resistance training is just as effective as aerobic training to improve skeletal muscle insulin sensitivity. A study conducted in 1998 by Errickson J et all have concluded that resistance training increases insulin sensitivity primarily by increase in non-oxidative glucose metabolism. Many studies also concluded that resistance training can enhance muscle strength, increase lean muscle mass . In addition to brain , skeletal muscle being the largest site for glucose disposal increased lean muscle mass may significantly improve insulin sensitivity. A different study conducted by Erickson et all to identify the effect of resistance training on T2DM have also concluded that a 2/week progressive resistance training for 3 months results in a significant improvement in HbA1c levels. there subjects pre Intervention levels of HbA1c were 8.8%  and was reduced post exercise to 8.2%. A novel RCT published by Mads.K.Holten et all in journal Diabetes(2004) have concluded that resistance training increases protein content of GLUT4 , Insulin receptor , protein kinase B-a/beta, glycogen synthase and glycogen synthase activity, which are indicators of increased insulin activity in skeleton muscles.In this study they followed a resistance training program that consist of strength training for 30min./3times /week for 6 weeks.A 2007 study has reported that whole body insulin resistance as estimated by the Homeostasis Model Assessment(HOMA-IR) has been shown to improve by 25% after 16 weeks of whole body strength training 3 times per week in older Hispainc adults with T2DM ( N.Brooks et all 2007).

I hope this brief scientific overview of the molecular mechanism of insulin resistance , the link between Obesity and T2DM as well as the therapeutic and prophylactic benefits of systematic exercise will enable practitioners in the area of exercise physiology , clinical exercise physiology and fitness science to develop a better and scientific understanding on the topic. It may also help you to develop more scientific and pragmatic exercise interventions.Once again this article is intended to promote scientific and evidence based practice of exercise science among all the exercise science professionals as well as to enrich my grip on the topic ultimately. I hope this article will be efficacious and informative to all.  

Siby C Chacko BPE,MPE( Exercise Physiology)                                            

References

1) http://www.who.int/mediacentre/factsheets/fs312/en/      

2) Barbara BK and JF Miller , Cellular mechanisms of insulin       resistance. J.Clin.Inves. 

    106(4) 471-481( 2000).

3) Rondinone CM, Wang LM, Lonnroth .P, IRS-1 reduced and        IRS-2 is the main docking site for PI3K 

     in adipocytes of subjects with NIDDM. 

    94(8) 4971-4975    (1997).

4) Goldstein BJ, Bitnner KA , White MF , Harbeck M , Tyrosin       dephosphorylation and deactivation of  IRS-1 by PTB-1B. 

     Possible facilitation by the fromation of ternary 

    complex with the Grb adaptor protein. 

     J.of Bio.chem. 275(6) 4283-4289 ( 2000).

5) Mc Ternnan CL, Mc Ternnan PG, Harte AL and 

    Levick PL et all. resistin , Central Obesity and T2DM

    The lancet 359(9300) 46-7.

6) D Hansenn, P Dendale , LJC Van Loon ,

    Plasma adipokine and inflammatory marker concentrations 

    are altered as opposed to non-obese T2DM patients. 

     Eur. J.App.Physio 109(3) 397-404 (2010).

7) Gulli G, ferrannin M , stern M , Haffiner S , Defronzo RA

     The metabolic profile of NIDDM is fully 

     established in glucose -tolerant offsprings of 2 mexican

      NIIDM parents,iab. 41(12) 1575-1586.

8) A R Martins, Renato TN, Renata G , M A Vinolo, 

    William TF et all mechanism underlying

    skeletal muscle   insulin resistance induced by fatty acids 

     :Importance of the mitochondrial function.

     L.H&D .Vol .11 ( 2012).  

9) Charles M.Tipton, History of Exercise Physiology, 

     Human kinetics.

10) http://care.diabetesjournals.org/content/early/2014/02/27/dc13-2358.full.pdf+html

11) Eva T, Lidia S, Manuel P, Antonio Z ,

      The insulin sensitive GLUT4 storage compartment is a

     postendocytic and heterogeneous population Recruited

      by acute exercise.

     Biochem, Biophy res.comu. 284(2) 490-495 (2001).

12) Erickkson J , tuominnen J, Valle T, Sundberg S et all.

       Aerobic endurance exercise or circuit type

       resistance training for individuals with impaired glucose    tolerance. Horm. metab.res. 30(1) 37-41(1998).

13)  Erikson J, Timela S, Errickosn K, Parvieaeinen S ,    Peltonen J  and Kujala U Resistance training in the treatment of NIDDM. Int. J. Spot.Med.18(4) 242-246( 1997).

14) MK Holten, Morten Z, M Gaster, C Jauel, Jorgan FPW and F Dela. Strength training increases

      Insulin mediated glucose uptake, GLUT4 content and Insulin signaling in skeletal muscles in patients 

      with T2DM , Diabets 53(2) 294-305(2004).

15) N.Brooks , Jennifer EL, PL Gordon, Ronenn R, ME Nelson and CC Scepa, Strength training improves

       muscle quality and insulin sensitivity in Hispanic older adults with T2DM.

       Inta.J.med.Sci 4(1) 19-27( 2007) 

Anti-ageing and Therapeutic Effect of Exercise on Brain: A Neurophysiological Perspective.

                                

In this article I discuss about the effect of exercise on brain health. A huge number of research have studied the effect of exercise on cardio-vascular system,endocrine system and musculoskeletal system.Many studies have provided evidence for the positive and prophylactic effect of exercise on these systems in disease and health.However as of 2014 number of research have explored the effect of exercise on brain health. In this article I wish to provide a research based overview of neurophysiological effect and therapeutic effect of exercise on CNS health, Neurodegenerative diseases and aging.

A number of studies have observed beneficial neurophysiologial effect of acute and chronic exercise in Human and animals.A study published in 2005 in Journal of Neurobiology of Ageing by psychiatrist Ronald Stanton Duman PhD states that exercise and enriched environment increases neurotrophic support in human brain by increasing cerebral blood Flow (CBF),the expression of Neurotropic Factors like BDNF, IGF-1, VEGF , NT-3,FGF-2 , GDNF , EGF and NGF as well as the induction of pro-inflammatory process by exercise promote neurogenesis, angeogenesis and synaptogenesis. 

Studies have also shown that physical exercise modulates the major CNS neurotransmitters that are associated with ones state of alertness( Norepinephrine),pleasure and reward system(Dopamine) and the level of anxiety( serotonin).Besides that changes in the level of these neurotransmitters may have different consequences depending on the type of receptors and cortical areas that are activated (Sarbadhikari SN & Saha AK 2006). A study published in BJSM in 2004 by Dietrich, titled 'Endocannabenoids and exercise' says that regular physical exercise can cause a sense of well being and euphoria,anxiolytic effects,sedation and decreased sensitivity to pain in humans by promoting release of opioids and endocannabenoids. Systematic exercise and proper diet that is rich in anti-oxidants have very positive impact in brain health. Adhering to diet that is rich in anti-oxidants and anti-inflammatory components in combination with physical exercise participation would have significantly better results.Moreover,elevated Vascular Endothelial Growth Factor(VEGF) levels,accelerated metabolism might contribute to enhanced angeogenesis( Periera AC et all 2007).  

In the last decade a number of studies have come up with promising evidence for considering exercise as a supportive prophylactic and  therapeutic means in the treatment plans of Neuropsychatric diseases such as Major Depressive Disorder(MDD), Dementia and Parkinsons disease. Smaller hippocampal volume, which may be due to fewer Granule Neurons(GN) in the Dentate Gyrus(DG) is identified in patients suffering from MDD ( Boldrin M et all 2013). Exercise increases beta endorphin levels which might play a significant role in  enhancing the birth of new neurons in the Dentate Gyrus. exercise also increases levels of VEGF and BDNF that may play a critical role in promoting the survival of new neurons in the Denate Gyrus which is indicated to undergo pathologic changes in MDD (B.R.Christie2006). Rethorst et all reviewed  75 RCTs comparing exercise versus no treatment or wait list control. 58 of the 75 studies were included in a Meta-Analysis which showed a clinically significant effect of exercise on MDD.( ES:0.80,95%CI-0.90 to 0.67). 

  Clinical Studies in human demonstrate that various modalities and systematic exercise can improve cognitive capacity in patients with PD.Cognitive dysfunction in Parkinsons Disease(PD) is associated with impaired executive function( Higginson CI et all 2003). In 2013 Fisher et all published an RCT in Neuroreport. Which analysed whether Treadmill exercise promotes Striatal D2 binding potential in patients with early parkinsons disease. 4 patients with early PD where randomized to receive intensive exercise( treadmil training sessions/3/week for 8 weeks) or no exercise. 2 healthy age- matched individuals participated in treadmill training. Alterations in the DA-D2R binding potential as a marker for receptor expression were determined using PET imaging with (18F) Fallypride. Turning perfromance of the patients with PD as a measure for postural control  and UPDR scale scores pre-exercise and post exercise were determined. The results showed an exercise -induced inrease in 18F binding potential as well as improved postural control in patients with early PD who exercised. The researches concluded that exercise leads to positive  Neuroplasticty in dopamenergic signaling and contributes to improved postural control in early stage PD. 

A number of studies have also showed that Progressive Resistance Exercise also helps to enhance functionality and quality of life of patients with PD. Patients with mild to moderate PD can obtain increase in performance or strength similar to that of normal adults in the same age in a resistance training program. Resistance training can produce functional improvements in gait and may therefore be useful as part of a physical rehabilitation and/ or health maintenance program for patients with PD( Scabdalis et all 2001).

Caerphilly Cohort study, A study that monitored the health habits of 2235 men over a period of 35 years have confirmed exercise significantly reduces the risk of Dementia along with other 4 healthy behaviors low body weight, No-smoking, low alcohol , healthy diet.People who consistently followed 4 or 5 of these behaviors experienced a 60% decline in dementia and cognitive decline with exercise being the strongest mitigating factor( Peter Elwood et all 2013). A study  conducted by Yerokhvin et all in 2012  analysed whether strengthening exercise programs help to improve verbal memory in patients with early dementia.This study evaluated the effect of a 10 weeks strengthening exercise intervention on cognitive function and EEG in a sample of 13 older adults with early Dementia and 9 normative controls. Results revealed beneficial effect of strengthening exercise on verbal memory coupled with frontal beta and delta power asymmetries and N200 amplitude asymmetry. Results of the study showed that strength training programs helps to enhance cognitive efficiency in people with early stage dementia.Physical exercise improves the efficiency of the capillary system and and increases the O2 supply to the brain.Thus enhancing metabolic activity and oxygen uptake in neurons and increases neurotropin levels and resistance to stress. Regular exercise and active lifestyle during adulthood have been associated with reduced risk and protective effects for mild cognitive impairment and Alzheimer's disease( Perla Kaliman 2011). Apolipoprotein (APOE) is a gene that produces an important protein called Apoplipoprotein E which is essential for packing cholesterol and other fats and carrying them through the circulation. Carriers of an allelic variant of APOE gene called APOE epsilon4 are at increased risk of Alzheminer's Disease(AD).APOE e4 causes increased deposit of amyloid beta peptides and amyloid plaques in the brain tissue of carriers of this variant. Amyloid beta peptides and amyloid plaques causes progressive death of neurons in the brain and triggers signs of AD.In APOEe4 carriers compared to non-carriers greater level of physical activity may be more effective in reducing amyloid burden and are associated with greater activation of Semantic memory related neural circuits( J C Smith et all 2013).    

These research finding conclude that systematic exercise and healthy diet and way of living    is a prophylactic and supportive therapeutic means in promoting brain health, preventing or preventing the progress of Neuropsychatric and Neurodegenerative conditions and a supportive therapy for array of Neuropsychatric conditions. Systematic exercise and lifestyle is also a potent mediator of anti-ageing effect in ageing brain. I hope this article will provide a scientific understanding of the neurophysiological effect of exercise and a research based understanding of the prophylactic and therapeutic effect of exercise on brain health. The main purpose of this article is like my every other articles to promote evidence based practice of exercise science among Exercise Physiologists , Clinical Exercise Specialists, Health and Fitness Specialists and other Exercise Professionals. I hope everyone will find this article informative as well.        

Siby C Chacko BPE,MPE( Exercise Physiology)              

REFERENCES

1) Duman RS, Neurotropic factors and regulation of mood: Role of exercise science and metabolism.

    Neuro bio.ag. 1:88-93(2005).

2) Sarbadhikari SN & Saha AK,Moderate exercise and chronic exercise produces counteractive 

    effect on different areas of brain by acting through various neurotransmitter receptor sub-types: 

    A hypothesis. theor.bio&med model 3:33(2006).

3) Dietrich A, Mcdaniel WF, Endocannabenoids and exercise, BJSM , 38:536-541(2004).

4) Periera AC, Huddleston DE, Brickman AM, Sousunov AA,Hen R,McKhann GM, Sloan R,

    Gag FH, Brown TR, Small SA. An in vivo corelate of exercise induced neurogensis in adult 

     dentate gyrus. proc.natl.acad.sci USA 104:5638-5643(2007).

5) Boldrin M , Santiago AN, Hen R, Dwork AJ, Rosoklija GB, Tamir.H, Arango V and Johnmann J

    Hippocampal granule neurons number and dentate gyrus volume in anti-depressant treated and 

    Untreated Major Depression.38(6) 1068-1077 (2013).

6) B R Christie. Anti-Depressive effect of exercise evidence for an adult

     Neurogenesis hypothesis?.J.Pscyc.Neuroscience 31(2) 84-92 (2006).

7) Rethorst CD, Wipfli BM, Landers DM, The anti- depressive effect of exercise a meta-analysis of 

    randomized controlled Trials. Spot.MEd. 39: 491-511(2009).

8) Higginson CI , King DS, Levine D, Wheellock VL, Khamphay NO and Sigvardit KA.

    The relationship between verbal memory and Parkinson disease.Brain cogn 52(3) 343-352(2003).

9) FisherBE, Li Q, Nacca A, Saleem GJ, Song J, Yip J,Hui JS ,Jackowec MW and Petzinger GM.

     Treadmill exercise promotes Striatal D2 binding potential in patients with early parkinsons disease.

      Neuroreprt 24(10) 509-514 (2013).

10) Scandalis , Thomas A DO, Bosak, Andrew BA, Berliner,Jefrry C BS, Helman,Laura L BS, 

       Wells, Micheal R.Resistance training and Gait Function in patients with parkinosn's disease.

        AJPMR 80(1): 38-43( 2001).

11) Peter Elwood. Julieta Galanti, Janet Pickering, Stephen Phalmer, Antony Bayer, Yoav Ben Sholmo,

      Marcus Longly and John Gallacher. Healthy lifestyle reduces the incidence of chronic diseases and 

      dementia:Evidence from the Caerphilly Cohort study. DOI: 10.1371/journal pone.0081877( 2013).

12) Yerkhin V, anderson HC, Hogan MJ, Dunnam M, Huber D, Osborne S, Shulan M.

       Neuropsychological and Neurophysiological effect of strengthening exercise for early Dementia: 

       A pilot study. Ag. Neuropsycho&cog.J of normo& dysfunctional dev. VOl.19(3)380-401(20120.

13) P kaliman, Marcelina P , JF Lalanza, Antoni C, Rosa ME, Merce P. Neurophysiological and epigenetic 

       effect of Physical Exercise on the aging process.Ageing R Rev. 10(4) 475-486 (20110.

14) J C Smith,Kristy AN, John LW, M Seidenberg, SM rao.Physical activity and Brain function in older 

      adults at increased risk for Alzhemier's disease.Brain. sci.3:54-83(2013).

   

     

      

     

Molecular Cascades of Resistance Training induced Skeletal Muscle Hypertrophy: A Molecular Physiological perspective.

In this article I discuss of a relatively new topic,The Cellular and Molecular Cascades of Skeletal Muscle Hypertrophy. It is perhaps a hot area for research in Molecular Exercise Physiology and Exercise genetics in vogue. Exercise Physiologist and Exercise practitioners may be very familiar with the Physiological Mechanism of Skeletal muscle hypertrophy.Muscle hypertrophy can be considered distinct and separate from muscle hyperplasia. During hypertrophy contractile elements enlarge and the extracellular matrix expands to support growth (Vierck J et all 2000). However muscle volumaization depends on both hypertrophy and hyperplasia. This article will provide a research based understanding of biomolecular cross talks and cascades that regulate resistance training induced muscle growth.This article's prime focus is on IGF-1(Insulin Like Growth Factor-1) mediated skeletal muscle hypertrophy through the activation of sarcoplasmic (cellular) signaling pathway PI3k/Akt/mTOR ( Mammalian Target of Rapamycin).
 A profound understanding of molecular and genetic factors that mediate skeletal muscle hypertrophy and the impact of mechanical loading on such molecular processes will enable Nutritionists,exercise physiologists & practitioners to develop new and more effective supplements and training protocols for athletes to prevent Over Training Syndrome and recover from OTS. It will also be helpful for rehabilitation specialists,clinical exercise physiologist & HFS's to develop systematic therapeutic resistance training programs for the management and prevention of  Cancer Cachexia , HIV induced Cachexia , other diseases and againg induced muscle wasting.         

For a conceptual understanding of the topic, I will briefly discuss What IGF-1 is ? and What PI3k/Akt/mTOR pathway is ? accompanied by brief reviews of current research on the role of mechanical loading of skeletal muscle on the IGF-1 mediated PI3k/Akt/mTOR pathway activation & skeletal muscle Hypertrophy.

IGF-1

Insulin Like Growth Factor-1 or Somatomedian C is a protein that in human is encoded by IGF-1 gene.( Jansen.M et All 1983). It is a cellular signaling molecule which  has a molecular structure similar to that of insulin. In human it is chiefly secreted by liver and skeletal muscle tissue. It acts like growth hormone in both autocrine and paracrine manner on skeletal muscle tissue by binding to IGF-1r. It plays an important  anabolic role in adult skeletal muscle  growth. IGF-1 isforms  have  significant role in cellular processes of many tissue types. IGF-1r's are mainly expressed in satellite cell population. Satellite cells are the mononuclear progenitor cells of skeletal muscles.For several years research have focused on IGF-1 mediated skeleltal muscle growth in response to resistance exercise.Many studies have found exercise induces IGF-secretion.IGF-1 isoforms binds to specific receptors in muscles cell surface and activates growth stimulating pathway( PI3k/Akt/mTOR Path way).To date several isoforms of IGF-1 have been found in human and other animals. 
Of which IGF-1c isoform has been observed to be increasingly expressed at the onset of satellite cell proliferation in response to muscle cell damage induced by muscle lengthening contractions in human(McKay BR et all 2008).
IGF1/PI3k/Akt/mTORcomplex is a potent stimulator of sarcoplasmic growth.IGF1/PI3k/Akt/mTOR complex stimulates skeletal muscle hypertrophy by inhibiting the effect of a protein called Myostatin ( a member of TGF-beta family). Deletion or inhibition of Myostatin causes an increase in skeletal muscle size because myostatin acts both to inhibit the myoblast differentiation and to block the Akt pathway( David J Glass 2011). 

PI3k/Akt/mTOR pathway

It is an intracellular signaling pathway contributes to  Muscle Hypertrophy. It is activated by IGF-1 and has a number of downstream effects which either promote protein synthesis( proteogenesis) or prevent protein breakdown ( proteolysis). The IGF-1 mediated downstream signaling cascades of PI3k/Akt/mTOR pathway is complex and will be difficult for those with little back-ground in molecular physiology to understand. Therefore, I will try to present in a simple and comprehensible manner for Exercise Physiologist and exercise professionals in general. IGF-1 acts in a hormone like manner by binding to IGF-1r in skeletal muscle tissue, especially in satellite cells. Ligand binded IGF-1r activates intracellular signaling transducer enzyme PI3k ( phospho ionosetide 3 kinase) this in turn lead to the activation of Akt or PKB( Protein Kinase B).It is an enzyme that  plays key role in glucose metabolism, cell proliferation, transcription and cell migration. IGF-1/PI3k/Akt complex binds to mTOR or Mammalian Target of Rapamycin. Specifically to mTOR isoform Mammalian Target Of Rapamycin Complex-1. It is a protein that in human is encoded by MTOR gene.It act as a catalyst of Cell growth, proliferation, Cell motility , cell survival, protein synthesis and transcription.
 IGF-1's pro-hypertrophy activity comes predominantly through its ability to activate PI3k/Akt signaling pathway ( Glass DJ 2010). The IGF1/PI3k/Akt/mTOR pathway, which has been shown to induce, hypertrophy, prevent induction of requisite atrophy mediators namely the Muscle Specific Ubiquitin Ligases (MAFBx) and Muscle RING-finger protein1( MuRF1)(Trevor.M.Stitt et All 2004). Akt phosphoryates and inactivates Tuberosclerosis Complex 2 ( TSC2) resulting in the activation of mTOR. mTOR phosphorylates 70KDa ribosomal S6 protein kinase (p70S6K1) resulting in an increase in muscle protein synthesis( Peter Tiidus, A Russel Tupling,Michael Houston 2012). The Mammalian Target of Rapamycin complex 1(mTORC1) pathway is the primary regulator of skeletal muscle growth. Bodine et all in 2001 reported that the over expression of Akt in mice resulted in an astonishing amount of skeletal muscle hypertrophy mediated by the activation of mTORC1 signaling pathway.2011 Miyazaki et all demonstrated IGF-1/PI3k/Akt non-depended activation of mTORC1 and skeletal muscle hypertrophy in C57BL/6J mice.However so far no studies in human have reported supportive evidence for IGF-1/PI3k/Akt non- depended activation of mTORC1 pathway( mTOR).  
       

IGF-1/PI3k/Akt/mTOR Pathway 

     

                             

  

     Siby C Chacko BPE,MPE ( Exercise Physiology)

References

1) Vierck J, O'Reilly,B.Hossner,K.Antonio,J.Byrne,K.Bucci.L and Dodson, Satellite cell regulation
    Following miotruma caused by resistance exercise. Cell.Bio.Int. 24: 263-272 (2000)

2) Jansen.M, Van Schaic FM,Ricker AT,Bulock.B, Woods.DE, Gabby K H and Nussbum AL , Sequence of cDNA Human Insulin Like Growth factor - 1 precursor.Nature: 306(5943) 609-11.(1983).

3) David J Glass , PI3 kinase regulation of skeletal muscle hypertrophy and atrophy. curr.top.in.micro bio
   and immuno Vol. 346 pp 267-278(2010)

4) Mc Kay BR,O'Reilly,Philips SM, Tarnopolsky MA and Parise.G, Co- expression of IGF
    Family members with Myogenic regulatory factors with folowing acute damaging muscle  
    lengthening contractions in Human. J.Physio.586: 5549-5560 (2008).

5)  David J Glass , PI3 kinase regulation of skeletal muscle hypertrophy and atrophy. curr.top.in.micro bio
   and immuno Vol. 346 pp 267-278(2010). 

6) Trevor.N.Stitt, Doreen Drujan, Brian A Clark, Frank Panaro,David J Glass et all.
     The IGF-1?PI3k/Akt pathway Prevents expression of Muscle Atrophy induced Ubiquitin Ligases
      by inhibiting FOXO Transcription factors. Mollecular Cell Vol.14(3)pp-395-403 (2004).

7) Peter Tiidus, A Russel Tupling,Michael , Houston , Biochemistry Primer for exercise Science 4th edition
     chap-3 pp:39-70 (2012).

8) Bodine SC , Stitt.T.N, Gonzalez.M,Kline W.O,Glass DJ et all . Akt/mTOR pathway is a crucial 
    regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat.cell.bio 3(11)1014-1019(2001).