There remains a high degree of scepticism about acupuncture since its theoretical basis has no clear reference in Western medical and scientific terms, making any associations between neurophysiology and specific acupuncture concepts difficult to determine. Using neuroimaging and engineering approaches to understand its physiological basis may engender greater acceptance of and improvement in the clinical application of acupuncture. Research into the efficacy of acupuncture has raised a number of difficult methodological issues, particularly in relation to the selection of appropriate controls. Separating specific effects from non-specific effects is complex because acupuncture is a physical, invasive, manual procedure involving time and ritual. Sham acupuncture results show only the difference between sham and real acupuncture not the real affect of acupuncture, and other controls may produce distinct subjective and objective effects. Point injection (the injection of a small amount of a substance at an acupoint), a recent innovation of traditional acupuncture, aims to enhance and prolong the stimulation effect in a standardised, reproducible manner. By providing precise, measurable acupoint stimulation applied incrementally in a specifically designed paradigm, an acupoint could act as its own control. This firstly requires injection to be validated against traditional needling. Aims 1. To develop an instrument for reproducible saline delivery at an acupoint. 2. To cross-validate saline acupoint injection (PI) with traditional needle acupuncture (TA). 3. To demonstrate central nervous system (CNS) effects of acupuncture both in health and chronic pain. Hypothesis The primary hypothesis is that stimulation of specific acupoints with linearly incremental saline injection produces differential effects within the CNS observable with functional magnetic resonance imaging (fMRI) allowing investigation of acupuncture in health and chronic pain. Novelty As neuroimaging has not yet clearly defined the brain structures that may be modulated by acupuncture, this project is exploratory in nature. It is expected that acupuncture effects can be robustly imaged with fMRI in healthy subjects and those suffering chronic pain. The demonstrated effects will result from the acupuncture process of progressive point stimulation by tissue distension rather than needle insertion or biological noise. It is proposed to examine the putative modulation of pain by acupuncture within the extensively mapped neuromatrix of cortical and subcortical regions, including the somatic, insula, and limbic cortices, and thalamus. Detailed information regarding differences in brain response between acupuncture in normal and diseased states will expand understanding of acupuncture as a clinical tool. The dilemma of sham stimulation or arbitrary controls will be addressed by confirming PI as a valid, reproducible stimulation method. Methods and Results A series of empirical experiments was designed and conducted to determine the effects of stimulation of different acupoints. 1. Chapters 1 and 3 outline the current understanding of acupuncture in the Western milieu and a review of the neuroimaging literature respectively. 2. In Chapter 2, the report of PI tested against TA in healthy volunteers to determine equivalence of physiological effect demonstrates no statistically significant differences between the methodologies. 3. Chapter 4 reports the design and validation of a task specific microprocessor controlled syringe driver. 4. Four differing acupoints were tested during an fMRI experiment described in Chapter 5; different activation areas were demonstrated across the acupoints providing early support for the hypothesis that different acupoints may have different effects. A subset of brain areas recognised within the pain neuromatrix was delineated, congruent spatially and directionally with those reported in pharmacological analgesia studies. 5. As outlined in Chapter 6, heart rate variability can be measured rapidly in a stressful environment to provide meaningful data on the response of the autonomic nervous system to acupuncture stimulation. 6. The hypothesis of different acupoints having different effects was tested in subjects suffering chronic pain by contrasting an accepted and a neutral acupoint, the results being reported in Chapter 7. Conclusion Despite a long history of clinical usage, appropriate scientific studies have not yet addressed the basic effectiveness and efficacy of acupuncture. This thesis presents a series of empirical studies designed to address a number of the questions arising in the literature and provides converging evidence of the manner in which different acupoints modulate the CNS, specifically within the pain neuromatrix.

There remains a high degree of scepticism about acupuncture since its theoretical basis has no clear reference in Western medical and scientific terms, making any associations between neurophysiology and specific acupuncture concepts difficult to determine. Using neuroimaging and engineering approaches to understand its physiological basis may engender greater acceptance of and improvement in the clinical application of acupuncture. Research into the efficacy of acupuncture has raised a number of difficult methodological issues, particularly in relation to the selection of appropriate controls. Separating specific effects from non-specific effects is complex because acupuncture is a physical, invasive, manual procedure involving time and ritual. Sham acupuncture results show only the difference between sham and real acupuncture not the real affect of acupuncture, and other controls may produce distinct subjective and objective effects. Point injection (the injection of a small amount of a substance at an acupoint), a recent innovation of traditional acupuncture, aims to enhance and prolong the stimulation effect in a standardised, reproducible manner. By providing precise, measurable acupoint stimulation applied incrementally in a specifically designed paradigm, an acupoint could act as its own control. This firstly requires injection to be validated against traditional needling. Aims 1. To develop an instrument for reproducible saline delivery at an acupoint. 2. To cross-validate saline acupoint injection (PI) with traditional needle acupuncture (TA). 3. To demonstrate central nervous system (CNS) effects of acupuncture both in health and chronic pain. Hypothesis The primary hypothesis is that stimulation of specific acupoints with linearly incremental saline injection produces differential effects within the CNS observable with functional magnetic resonance imaging (fMRI) allowing investigation of acupuncture in health and chronic pain. Novelty As neuroimaging has not yet clearly defined the brain structures that may be modulated by acupuncture, this project is exploratory in nature. It is expected that acupuncture effects can be robustly imaged with fMRI in healthy subjects and those suffering chronic pain. The demonstrated effects will result from the acupuncture process of progressive point stimulation by tissue distension rather than needle insertion or biological noise. It is proposed to examine the putative modulation of pain by acupuncture within the extensively mapped neuromatrix of cortical and subcortical regions, including the somatic, insula, and limbic cortices, and thalamus. Detailed information regarding differences in brain response between acupuncture in normal and diseased states will expand understanding of acupuncture as a clinical tool. The dilemma of sham stimulation or arbitrary controls will be addressed by confirming PI as a valid, reproducible stimulation method. Methods and Results A series of empirical experiments was designed and conducted to determine the effects of stimulation of different acupoints. 1. Chapters 1 and 3 outline the current understanding of acupuncture in the Western milieu and a review of the neuroimaging literature respectively. 2. In Chapter 2, the report of PI tested against TA in healthy volunteers to determine equivalence of physiological effect demonstrates no statistically significant differences between the methodologies. 3. Chapter 4 reports the design and validation of a task specific microprocessor controlled syringe driver. 4. Four differing acupoints were tested during an fMRI experiment described in Chapter 5; different activation areas were demonstrated across the acupoints providing early support for the hypothesis that different acupoints may have different effects. A subset of brain areas recognised within the pain neuromatrix was delineated, congruent spatially and directionally with those reported in pharmacological analgesia studies. 5. As outlined in Chapter 6, heart rate variability can be measured rapidly in a stressful environment to provide meaningful data on the response of the autonomic nervous system to acupuncture stimulation. 6. The hypothesis of different acupoints having different effects was tested in subjects suffering chronic pain by contrasting an accepted and a neutral acupoint, the results being reported in Chapter 7. Conclusion Despite a long history of clinical usage, appropriate scientific studies have not yet addressed the basic effectiveness and efficacy of acupuncture. This thesis presents a series of empirical studies designed to address a number of the questions arising in the literature and provides converging evidence of the manner in which different acupoints modulate the CNS, specifically within the pain neuromatrix.

Orientadora: Mary Marcondes / Banca: Márcia Dalastra Laurenti / Banca: Raimundo Souza Lopes / Banca: Silvia Regina Ricci / Banca: Márcia Rita Fernandes Machado / Resumo: A leishmaniose visceral é uma antropozoonose, que vem aumentando no Brasil em número de casos e já sendo endêmica em vários estados. Os cães, considerados o principal reservatório doméstico, são de grande importância na manutenção do ciclo epidemiológico da leishmania visceral, já que a mesma é mais prevalente na população canina que na humana, e também podem servir como modelo experimental da doença. Partindo-se da hipótese de que a leishmaniose visceral causa uma neuropatia periférica em cães, o presente ensaio teve como objetivos analisar as alterações eletroneurográficas e histopatológicas dos nervos radial, ulnar, tibial e peroneal de cães naturalmente acometidos pela doença. Assim, 33 cães naturalmente acometidos por leishmaniose visceral, e quatro cães sem a doença foram submetidos a exames eletroneurográficos e retirada de fragmentos dos nervos para análise histopatológica. Os resultados obtidos neste trabalho permitiram concluir que cães com leishmaniose visceral podem apresentar velocidade de condução nervosa motora diminuída, caracterizando um quadro de neuropatia periférica; apresentar alterações histopatológicas indicativas de uma neuropatia periférica; e que as principais alterações histopatológicas nos nervos radial, ulnar, tibial e peroneal de cães com leishmaniose visceral foram aumento de tecido conjuntivo no endoneuro, variação no diâmetro de fibras nervosas, degeneração axonal, infiltrado inflamatório no perineuro e no tecido adiposo, desmielinização e aumento de tecido conjuntivo no perineuro. / Abstract: Visceral leishmaniasis is an antropozoonosis, that is increasing in Brazil in number of cases and already being endemic in several states. The dogs, considered the main domestic reservoir, are of great importance in the maintenance of the epidemic cycle of the visceral leishmania, since the same is more prevalent in the canine population than in the human, and they can also serve as experimental model of the disease. Breaking of the hypothesis that the leishmaniasis visceral cause an outlying neuropathy in dogs, the present study aimed to analyze the alterations electroneurographics and histopathologics of the radial, ulnar, tibial and peroneal nerves of dogs attacked by the disease. Like this, 33 dogs naturally attacked by visceral leishmaniasis, and four dogs without the disease were submitted to eletroneurography and retreat of fragments of the nerves for analysis. The results obtained in this work allowed to end that dogs with visceral leishmaniasis can present reduced motor nerve conduction velocity, characterizing a neuropathy; to present histopathologics alterations indicative of an outlying neuropathy; and that the main alterations in the radial, ulnar, tibial and peroneal nerves of dogs with visceral leishmaniasis were increase of conjunctive tissue in the endoneurium, variation in the diameter of nervous fibers, degeneration axonal, infiltrated inflammatory in the perineurium and in the adipous tissue, desmielinization and increase of conjunctive tissue in the perineurium. / Doutor

A hanseníase é doença crônica causada pelo Mycobaterium leprae e possui como característica a alteração de sensibilidade cutânea, causando deformidades de mãos e pés. O tratamento compreende o uso de medicamentos (PQT) e o Ministério da Saúde (MS) preconiza o uso de palmilhas tipo Plataforma para Tarso (PT) como tratamento complementar. Há na literatura muitos artigos sobre o uso de palmilhas para melhora do equilíbrio e redistribuição da pressão plantar em pacientes neuropáticos, mas não foram encontrados estudos que incluíssem as palmilhas PT. Neste estudo comparou-se o equilíbrio do paciente hanseniano com valores de normalidade pré-definidos e também comparou-se prospectivamente a influência da palmilha PT no paciente com hanseníase, por meio de testes de equilíbrio estático e dinâmico realizados com o aparelho Balance Master (NeuroCom Int. Inc.) antes e após 3 meses de uso. Foram selecionados 40 pacientes em tratamento no HCFMRP, dos quais 19 mantiveram o seguimento à pesquisa (68,4% do sexo masculino, com média etária de 51,95), e todos com mesma classificação operacional Multibacilar. Os testes delinearam o comportamento destes pacientes com relação aos controles involuntário de equilíbrio (sistemas sensoriais-teste modifCTSIB) e voluntário de excursão do Centro de Gravidade Corporal (COG; teste LOS), bem como a estabilidade da marcha (teste WA). Os resultados obtidos com o modifCTSIB mostraram que os pacientes com hanseníase, para o controle do equilíbrio (de acordo com a relação entre testes com olhos abertos e fechados, e para superfície estável e instável; valor p<0,01 para todas as correlações aplicadas), são mais dependentes do sistema visual que do somatossensorial, em relação à normalidade. As palmilhas PT não influenciaram na modulação dos sistemas sensoriais (p>0,05). No entanto o uso das palmilhas interferiu negativamente no teste LOS, para as variáveis distância final percorrida e máxima excursão do COG somente no ponto para frente e para esquerda (p<0,01), e favoreceu o controle direcional do COG no mesmo ponto (p=0,02). Na análise dos prontuários foram identificados déficits sensitivos com maior frequência nos antepés esquerdos. O teste WA revelou que os pacientes apresentaram a marcha mais lenta em relação ao padrão de normalidade, e aumentaram a velocidade de marcha (p=0,04) e o comprimento do passo (p=0,04) após o uso das palmilhas. Concluiu-se que as palmilhas tipo PT favoreceram a estabilidade para a marcha e para o controle voluntário do equilíbrio. E ainda foi observado que os pacientes tornaram-se dependentes das palmilhas, fator importante a ser considerado pelo serviço de Saúde após a alta medicamentosa / Leprosy is a chronic disease caused by the Mycobacterium leprae with sensitivity impairment as a characteristic that could lead to deformities of hands and feet. The Ministry of Health of Brazil (MS) recommends the use of platform for Tarsus (PT) insoles as a complementary treatment to the Multi-drug Therapy (MDT). Many articles in literature discussed the use of insoles for improving balance and redistribution of plantar pressure in neuropathic patients, but there are no studies that included PT insoles. This study compared the balance control values for the leprosy patient with normal standards and also prospectively compared the influence of PT insole in patients with leprosy, by means of static and dynamic tests performed with the Balance Master (NeuroCom Int. Inc.) device, before and after 3 months. 40 patients following treatment in HCFMRP were selected, of which 19 completed the follow-up to the survey (68.4% male, mean age 51.95), all classified operationally as Multibacillary. The tests outlined the behavior of these patients with regard to involuntary balance control (modifCTSIB sensory test) and voluntary excursion of the Body Center of Gravity (COG; LOS test) as well as the gait stability (WA test). The results obtained with the modifCTSIB showed that patients with leprosy are more dependent on the visual system than the somatosensation for balance controlwhen compared to normal values (according to the relationship between tests with open and closed eyes, and stable and unstable surface; p <0.01 for all applied correlations). The insoles PT did not influence the modulation of the sensory systems (p> 0.05). However the use of insoles interfered negatively in the LOS test for the variables end point and maximum excursion of the COG only on the forward to left position (p <0.01), and favored the directional control of COG at the same position (p= 0.02). The analysis of the patients file revealed that sensitivity deficits were identified more frequently in the left forefeet, which might explain the observed differences for the excursion of the COG only in this region. The WA test showed that patients have slower walking patters compared to normal values but had their walking speed (p = 0.04) and the length of their step increased (p = 0.04) after the use of the insoles. It was concluded that the PT insoles favored gait stability and voluntary control of body balance. It was also observed that patients become dependent on the insoles, an important factor to be considered by the Health service after the PQT discharge

Chemotherapy Induced Peripheral Neuropathy (CIPN) is a common problem among cancer patients who receive a wide range of chemotherapy. This problem causes a decline in quality of life and increased disabilities. CIPN assessment instruments are either subjective, objective, or a combination of both. So far, there is no agreement on the best way for assessment. The goal of this study was to explore the relationships among subjective and objective CIPN assessment instruments. Specifically, this study aimed to 1) evaluate the relationship between the Total Neuropathy Score-reduced (mainly objective) and patients’ function, as measured by the interference scale of the Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (subjective); and 2) evaluate the relationship between the Total Neuropathy Score-reduced and neuropathy symptom experience, as measured by the symptom experience scale of the Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (Subjective). To achieve those aims, a secondary data analysis for 56 participants who participated in a study entitled: Group Acupuncture for Treatment of Neuropathy from Chemotherapy was done. After Pearson correlations were calculated, the study found that there is a positive, weak relationship between the TNSr and the symptom experience scale of the CIPNAT(r=0.34). A positive, week relationship was found between the TNSr and the interference with activity scale of the CIPNAT(r=0.28). These results suggest that objective and subjective assessment are not highly correlated, and likely measure different aspects of CIPN. A comprehensive assessment approach is needed for decision making in the clinical oncology setting.

Abstract Neurological features are common in mitochondrial diseases because tissues depending upon oxidative phosphorylation bear the brunt of the pathogenesis. The 3243A>G mutation in the MTTL1 gene in mitochondrial DNA is regarded as the most frequent mitchondrial point mutation and classically presents with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Myopathy and peripheral neuropathy have been documented in patients with mitochondrial diseases, but not properly characterised in patients with the 3243A>G mutation. We have previously determined the prevalence of patients with this mutation in a defined population in northern Finland. The clinical spectrum and molecular aspects of myopathy and peripheral neuropathy are analysed here in a population-based cohort of patients with 3243A>G. Fifty patients were examined neurologically in order to define the frequency of myopathy and its histological, ultrastructural and clinical features. The frequency and phenotypic variability of peripheral neuropathy were determined in 32 patients and muscle computed tomography findings recorded in 24 patients. Finally, variations in mutation heteroplasmy were analysed in 10 patients using single muscle fibre PCR analysis. The frequency of peripheral neuropathy was 22% (95% confidence interval (CI), 9–40%) and that of clinical myopathy 50% (95% CI, 36–64%). Moderate limb weakness was the most common myopathic feature, but mild weakness and external ophthalmoplegia were also present. CT scans revealed myopathic changes in 54% of the patients (95% CI, 33–76%), most frequently in the pelvic muscles. The incidence of myopathy was highest in the fifth decade of life, and higher age and male gender increased the risk of neuropathy. Muscle histology was abnormal in 72% of the cases examined (95% CI, 55–86%). The presence of intramitochondrial crystals and COX-negative fibres and variations in the size and shape of mitochondria were more common in the muscle of myopathic patients. Single muscle fibre analysis pointed to a correlation between the mutation load in ragged red fibres and in adjacent histologically normal fibres, and the proportion of 3243A>G in histologically normal muscle fibres showed a pattern compatible with random genetic drift. The results indicate that myopathy and peripheral neuropathy are common in patients with the 3243A>G and that myopathy is highly variable in presentation. Segregation of 3243A>G in individual muscle fibres showed a complex process with random and non-random elements.

Human histidyl-tRNA synthetase (HARS) is an aminoacyl-tRNA synthetase (AARS) that catalyzes the attachment of the amino acid histidine to histidyl-tRNA (tRNAHis) in a two-step reaction that is essential for protein translation. Currently, two human diseases, Usher Syndrome IIIB (USH3B) and an inherited peripheral neuropathy, Charcot Marie Tooth Syndrome (CMT), have been linked genetically to single point mutations in the HARS gene. The recessive HARS USH3B mutation encodes an Y454S substitution localized at the interface between the anticodon-binding domain and the catalytic domain of the opposing subunit. Patients with Usher Syndrome IIIB lose their sight and hearing during their second decade of life, and clinicians have observed that the onset of deafness and blindness may be episodic and correlate with febrile illness. Furthermore, some young USH3B patients present with a fatal form of acute respiratory distress. In addition to the single HARS mutation linked to Usher Syndrome, eight other mutations in the HARS gene are associated with CMT, an inherited peripheral neuropathy. Peripheral neuropathies are associated with progressive and length-dependent damage of the motor and sensory neurons that transmit information to the spinal cord. The age of onset and phenotypic severity of CMT linked to HARS is highly variable. When expressed in a yeast model system, the HARS variants are dominantly lethal, and confer defects in axonal guidance and locomotor deficiencies when expressed in C.elegans. Here, the biochemical characterization of the HARS USH3B and three peripheral neuropathy variants are described. The approaches included enzyme kinetic analysis with purified HARS enzymes to monitor catalytic deficiencies, differential scanning fluorimetry (DSF) to evaluate structural instability, and cellular models to detect physiological effects of axonal outgrowth by CMT variants. The results suggest that Usher Syndrome IIIB is unlikely to be a consequence of a simple loss of aminoacylation function, while HARS-linked peripheral neuropathy variants all share common catalytic defects in aminoacylation. The HARS system represents a notable example in which two different complex human diseases arise from distinct mutations in the same parent gene. By understanding the biochemical basis of these inherited mutations and their link to Usher Syndrome and CMT, it may be possible to develop mechanism-based therapies to improve the quality of life of patients afflicted with them.

Lower motor neuron diseases and peripheral neuropathies are two groups of diseases that include multiple rare disorders where many causes are unknown and definitive treatments are unavailable. Understanding the molecular etiology of these genetic diseases provides an opportunity for rapid diagnosis, preconception genetic counseling and, in a subset, direction for the development of future treatment options. The recent introduction of whole exome sequencing (WES) marks a new era in Mendelian genetic disease research as the majority of the coding region of the genome can be sequenced in a timely and cost-effective manner. In this study, WES was used to investigate the molecular etiology of a cohort of 37 patients presenting with lower motor neuron disease or peripheral neuropathy. A molecular diagnosis was determined for seven patients informing the diagnostic utility of WES. Novel phenotypes were found for three genes originally associated with a different disorder. Finally, the foundation has been laid, through the use of functional studies and large scale data-sharing, to identify novel disease-causing genes for lower motor neuron disease and peripheral neuropathy.

This study examined the association between neuropathy limitations and depression in chemotherapy patients currently on treatment with a taxane-based, platinum-based or plant alkaloid chemotherapy drug. The Overall Neuropathy Limitations Scale (ONLS) and the Beck Depression Inventory-Short Form (BDI-SF) were used to assess neuropathy limitations and depression in 24 chemotherapy patients with reported symptoms of peripheral neuropathy. Average age of patients was 65 years, 66.6% were female, and average number of chemotherapy cycles completed was 5.6. Of the 24 patients, 37.5% of patients were on a single agent taxane-based drug, 37.5% of patients were on a taxane-based drug with a platinum based drug, 16.6% of patients were on a plant alkaloid, and 8.3% were on a combination of a taxane-based and another non-neurotoxic chemotherapy drug. The scores on both the BDI-SF and ONLS were very low. The mean score on the BDI-SF was 4.1 with a standard deviation of 2.7. The mean score on the ONLS was 2.2 with a standard deviation of 1.5. The study showed a non-significant relationship between neuropathy limitations and depression in chemotherapy patients. These findings show no association between neuropathy limitations and depression. Although all of these patients had symptoms of peripheral neuropathy, they were not severe enough to interfere with daily activities. The lack of relationship was not unexpected given the low scores on both the BDI-SF and ONLS. Future research should re-evaluate this relationship with a larger, more diverse sample.

>Magister Scientiae - MSc / Background: Patients who suffer from diabetic peripheral neuropathy in the leg experience a greater risk of developing gait deviations due to a decrease in strength of the lower extremities, especially the tibialis anterior and triceps surea muscle groups. Aim: The aim of the study was to determine the effect of an exercise training programme on blood pressure, fasting blood glucose, muscle strength, range of motion, balance and gait pattern deviations in patients with diabetic neuropathies. Methods: A total of fourteen participants, who had been diagnosed with diabetic peripheral neuropathy or nocturnal allodynia in either one or both extremities, were asked to participate in this study. Participants were purposively selected from two private Podiatry practices based on their signs and symptoms of diabetic neuropathy, age, gender and doctor’s clearance to participate in any form of physical activity. Dependent variables included isometric strength of the muscles surrounding the hip, knee and ankle, the range of motion of the ankle in plantarflexion and dorsiflexion using goniometry, an assessment of balance using the stork stand test, and a gait pattern analysis, using the modified Tinetti Gait pattern Assessment Scale. Study design: The study was a single-blinded, pre-test and post-test experimental study design using a quantitative approach. Intervention: The researcher (a registered biokineticist) developed a scientifically-based exercise intervention programme to specifically target the entire kinetic chain, and to reduce fall risks, improve quality of life and to assist in developing a standard protocol for patients with DPN. The intervention programme consisted of a combination of ankle, hip and knee rehabilitation, including gait pattern specific rehabilitation. The intervention took place 2-3 times a week for 45 minutes per session and was divided in four categories: Range of motion exercises, strengthening exercises, balance and proprioception and gait pattern training exercises. Results: The Mann-Whitney and Wilcoxon Sign Rank Tests were used to evaluate the differences in dependent variables from pre- to post-intervention. The level of significance was set at p<0.05. An increase in range of motion only in the left ankle dorsiflexion were observed and an increase in balance time for the left leg were observed in the intervention group after a 10-week follow up assessment. Clinical significance was observed in the intervention group, post-intervention, with a decrease in systolic (-9.09%) and diastolic blood pressure (-13.89%) and a decrease in blood glucose levels (-17.89%), however, an increase in these variables was observed in the control group post-intervention. An increase in plantarflexion, 8% (left) and 8% (right) and dorsiflexion 5.26% (left) and an 11.11% (right) increase in range of motion for both left and right ankles, and balance time for both legs, 200% (left) and 159% (right) was observed in the intervention group post-intervention. Although the muscular strength variables showed a mix of an increase and decrease in strength post-intervention in the intervention group, however a clinically significant decreased amount was observed in the control group post-intervention for the majority of muscular strength variables. Conclusions: Although not many findings of this study are statistically significant, clinical significance were observed with most of the variables of this study. The findings of this study can assist future researchers in the development of exercise interventions for patients who suffers from DPN.