Effects of exercise on muscle activation and metabolism in multiple sclerosis

We investigated the role of metabolism in muscle fatigue during voluntary exercise in persons with mild multiple sclerosis (MS). Six MS and 8 healthy control subjects performed intermittent, progressive, isometric contractions of the ankle dorsiflexors, during which we measured maximum voluntary force (MVC), inorganic phosphate (Pi), phosphocreatine (PCr), and pH. During exercise. MVC fell sooner in MS, but by the end of exercise the relative decrease in MVC was similar in both groups. In contrast, at the end of exercise Pi/PCr increased to 1.86 ± 0.22 in controls but to only 0.66 ± 0.04 in MS (P < 0.01); likewise, pH was 6.75±0.04 in controls and unchanged (7.06 ± 0.04) in MS (P <0.01). The smaller metabolic change at the same relative exercise intensity suggests a failure of muscle activation that is present even in mild MS. Neurophsyiologic measures of activation indicated some central activation failure and no neuromuscular junction impairment in MS, and suggested that activation failure beyond the muscle membrane(excitation–contraction coupling) may be important in MS. We conclude that metabolic factors do not play a significant role in the development of muscle fatigue during voluntary exercise in mild MS. © 1994 John Wiley & Sons, Inc.     

Postexercise phosphocreatine resynthesis is slowed in multiple sclerosis

To determine whether skeletal muscle oxidative metabolism is impaired in multiple sclerosis (MS), ³¹ phosphorus magnetic resonance spectroscopy was used to measure the rate of intramuscular phosphocreatine (PCr) resynthesis following exercise in MS and controls. Thirteen MS patients underwent intermittent isometric tetanic contractions of the dorsiflexor muscles elicited by stimulation of the peroneal nerve. Eight healthy control subjects performed voluntary isometric exercise of the same muscles. During exercise, there were no differences between groups in the fall of either PCr or pH. However, the half-time (T-_1/2) of PCr recovery following exercise was significantly longer in MS (2.3 ± 0.3 min) compared to controls (1.2 ± 0.1 min, P < 0.02). These data provide evidence of slowed PCr resynthesis following exercise in MS, which indicates impaired oxidative capacity in the skeletal muscle of this group. This finding suggests that intramuscular changes consistent with deconditioning may be important in the altered muscle function of persons with MS. © 1994 John Wiley & Sons, Inc.     

磁共振质子波谱分析对多发性硬化的诊断价值

目的研究磁共振质子波谱分析(1HMRS)对多发性硬化(MS)的诊断价值。方法对29例MS患者(MS组)和26例正常志愿者(正常对照组)进行头颅MRI及1HMRS检查;计算其峰下面积,对脑部代谢产物氮-乙酰天门冬氨酸(NAA)、肌酸(Cr)、胆碱(Cho)的浓度进行定量,比较两组间NAA/Cr、Cho/Cr比值的差异。用扩展的功能障碍分级法(EDSS)对MS患者进行评分,分析MS组患者的NAA/Cr、Cho/Cr比值与EDSS评分之间的相关性。结果MS组的NAA/Cr、Cho/Cr比值分别为1.38±0.43、1.99±0.84,正常对照组为1.89±0.49、1.48±0.36。MS组的NAA/Cr比值显著低于正常对照组(P<0·05),Cho/Cr比值显著高于正常对照组(P<0·05)。MS组的NAA/Cr比值与EDSS评分之间呈负相关(r=-0.588,P<0·05),Cho/Cr比值与EDSS评分之间不相关(r=0·012,P>0·05)。结论MS患者的1HMRS检查有明显异常改变,NAA/Cr比值可反映MS患者临床神经功能障碍的程度。     

Altered task-induced cerebral blood flow and oxygen metabolism underlies motor impairment in multiple sclerosis

The neural mechanisms underlying motor impairment in multiple sclerosis (MS) remain unknown. Motor cortex dysfunction is implicated in blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies, but the role of neural–vascular coupling underlying BOLD changes remains unknown. We sought to independently measure the physiologic factors (i.e., cerebral blood flow (ΔCBF), cerebral metabolic rate of oxygen (ΔCMRO₂), and flow–metabolism coupling (ΔCBF/ΔCMRO₂), utilizing dual-echo calibrated fMRI (cfMRI) during a bilateral finger-tapping task. We utilized cfMRI to measure physiologic responses in 17 healthy volunteers and 32 MS patients (MSP) with and without motor impairment during a thumb-button-press task in thumb-related (task-central) and surrounding primary motor cortex (task-surround) regions of interest (ROIs). We observed significant ΔCBF and ΔCMRO₂ increases in all MSP compared to healthy volunteers in the task-central ROI and increased flow–metabolism coupling (ΔCBF/ΔCMRO₂) in the MSP without motor impairment. In the task-surround ROI, we observed decreases in ΔCBF and ΔCMRO₂ in MSP with motor impairment. Additionally, ΔCBF and ΔCMRO₂ responses in the task-surround ROI were associated with motor function and white matter damage in MSP. These results suggest an important role for task-surround recruitment in the primary motor cortex to maintain motor dexterity and its dependence on intact white matter microstructure and neural–vascular coupling.     

Magnetization transfer can predict clinical evolution in patients with multiple sclerosis

The clinical course of multiple sclerosis (MS) is highly variable ranging from benign to aggressive, and is difficult to predict. Since magnetization transfer (MT) imaging can detect focal abnormalities in normal-appearing white matter (NAWM) before the appearance of lesions on conventional MRI, we hypothesized that changes in MT might be able to predict the clinical evolution of MS. We assessed MR data from MS patients who were subsequently followed clinically for 5 years. We computed the mean MT ratio (MTr) in gray matter, in lesions identified on T2-weighted MRI, and in NAWM, as well as in a thick central brain slice for each patient. Patients were divided into stable and worsening groups according to their change in Expanded Disability Status Scale (EDSS) scores over 5 years. We calculated the sensitivity, specificity, predictive value, and odds ratio of the baseline MTr measures in order to assess their prognostic utility. We found significant differences in baseline MTr values in NAWM (p = 0.005) and brain slice (p = 0.03) between clinically stable and worsening MS patients. When these MTr values were compared with changes in EDSS over 5 years, a strong correlation was found between the EDSS changes and MTr values in both NAWM (SRCC = −0.76, p < 0.001) and in the brain slice (SRCC = 0.59, p = 0.01). Baseline NAWM MTr correctly predicted clinical evolution in 15/18 patients (1 false positive and 2 false negatives), yielding a positive predictive value of 77.78 %, a negative predictive value of 88.89 %, and an odds ratio of 28. The relationship between 5-year changes in EDSS and MTr values in T2 weighted MRI lesions was weaker (SRCC = −0.43, p = 0.07). Our data support the notion that the quantification of MTr in the NAWM can predict the clinical evolution of MS. Lower MTr values predict poorer long-term clinical outcome. Abnormalities of MTr values in the NAWM are more relevant to the development of future patient disability than those in the T2-weighted MRI lesions. Received: 3 May 2001, Received in revised form: 11 October 2001, Accepted: 22 October 2001     

Linking structural, metabolic and functional changes in multiple sclerosis

In patients with multiple sclerosis (MS), conventional magnetic resonance imaging (MRI) has markedly improved our ability to detect the macroscopic abnormalities of the brain and spinal cord. New quantitative magnetic resonance (MR) approaches with increased sensitivity to subtle normal-appearing white matter (NAWM) and grey matter changes and increased specificity to the heterogeneous pathological substrates of MS may give information complementary to conventional MRI. Magnetization transfer imaging (MTI) and diffusion-weighted imaging (DWI) have the potential to provide important information on the structural changes occurring within and outside T2-visible lesions. Magnetic resonance spectroscopy (MRS) adds information on the biochemical nature of such changes. Functional MRI might quantify the efficiency of brain plasticity in response to MS injury and improve our understanding of the link between structural damage and clinical manifestations. The present review summarizes how the application of these MR techniques to the study of MS is dramatically changing our understanding of how MS causes irreversible neurological deficits.     

Quadriceps low‐frequency fatigue and muscle pain are contraction‐type‐dependent

Eccentric contractions are thought to induce greater low‐frequency fatigue (LFF) and delayed‐onset muscle soreness (DOMS) than concentric contractions. In this study we induced a similar amount of eccentric quadriceps muscle fatigue during either a concentric or eccentric fatigue task to compare LFF and DOMS. Subjects (n = 22) performed concentric or eccentric fatigue tasks using 75% of the pre‐fatigue maximal voluntary contraction (MVC) torque, and both tasks ended when the MVC eccentric torque decreased by 25% pre‐fatigue. When subjects reached the failure criterion during the eccentric and concentric tasks, the concentric MVC was 78 ± 9.8% and 64 ± 8.4% of initial, respectively. LFF was greater after the concentric than the eccentric protocols (22 ± 12.4% and 15 ± 7.6% increase, respectively; P < 0.01). DOMS was over 100% greater for the eccentric protocol. These results indicate that DOMS is not dependent on the events that contribute to LFF. Muscle Nerve, 2010     

The effects of lithium on muscle contractile function in humans

A side effect of lithium (Li⁺) treatment is fatigue. Li⁺ decreases inositol triphosphate (IP₃) accumulation and IP₃ may play a role in excitation-contraction (E-C) coupling in skeletal muscle. Li⁺ carbonate (600 mg b.i.d. × 6 days) was administered in a randomized, double-blind fashion to 12 males to measure the effect upon muscle contractile function: peak twitch torque (PTT), time to PTT, half-relaxation time, maximal voluntary contraction strength (MVC), percent motor unit activation, M-wave characteristics, and tetanic torque (3 min at 15 and 50 Hz). Li⁺ resulted in a significant decrease in 15- and 50-Hz tetanic torque (P < 0.001), MVC, and resting PTT (P < 0.05). There were no effects of Li⁺ upon any of the other measured variables. Li⁺ had a negative effect upon E-C coupling and did not affect central motor unit recruitment. Elucidation of the role of IP₃ in E-C coupling may help to understand fatigue in some neuromuscular disorders. © 1996 John Wiley & Sons, Inc.     

MR correlates of cerebral atrophy in patients with multiple sclerosis

Objective To investigate the in-vivo correlates of brain atrophy in patients with multiple sclerosis (MS) by assessing the relationship between normalized measures of brain volume (NBV) and other magnetic resonance (MR) measures of tissue damage. Background Brain atrophy diffusely occurs and progressively increases in patients with MS. Nevertheless, the mechanisms leading to brain atrophy in this disease are not fully understood. Methods MR examinations were performed in 20 patients with relapsing-remitting MS. Conventional MRI was used to assess NBV and total brain T2-hyperintense and T1-hypointense lesion volumes. Proton MR spectroscopic imaging and diffusion tensor MR imaging were also performed for large portions of brain containing mainly normal-appearing tissue to provide indices of tissue damage, including N-acetylaspartate to creatine ratio (NAA/Cr) and mean diffusivity (). Results Values of NBV correlated significantly with those of average brain (r = -0.58, p = 0.007) and NAA/Cr (r = 0.67, p < 0.001). The relationship of these markers of tissue damage to NBV was also found when NAA/Cr and were computed together in a composite MR score (r = 0.70, p < 0.001). In contrast, NBV values did not correlate with measurements of average lesion , T₂ and T₁ weighted total brain MRI lesion volumes. Conclusions This study suggests that brain atrophy in MS is not simply due to axonal loss, but rather reflects a more generalized process that involves various brain tissue components. Damage to the normal-appearing tissue rather than the extent and intrinsic pathology of macroscopic lesions seems to be important in the destructive process leading to MS-related irreversible cerebral atrophy. Received: 13 September 2001 Received in revised form: 18 January 2002 Accepted: 4 March 2002     

Malignant hyperthermia: Effects of sarcoplasmic reticulum Ca2+ pump inhibition

In porcine malignant hyperthermia-susceptible (MHS) skeletal muscles, calcium release is abnormal and resting calcium may be elevated. Thus MHS muscles may have prolonged twitch relaxation and lower fusion frequencies, which would be augmented by inhibition of sarcoplasmic reticulum (SR) Ca²⁺ adenosine triphosphatase (ATPase) activity; bundles of intact muscle cells from MHS and normal pigs were used to investigate this possibility. Cooling and low-frequency stimulation, in combination, enhanced twitch fusion and prolonged twitch relaxation significantly more in MHS than in normal muscles (e.g., 34 ± 4% versus 16 ± 4% fusion, and 82.4 ± 9.4 ms versus 43.2 ± 7.8 ms half-relaxation time, for MHS and normal muscles, respectively). Similarly, inhibition of the SR Ca²⁺ ATPase by cyclopiazonic acid resulted in significantly greater twitch fusion in MHS muscles. These results were consistent with predicted effects of enhanced SR Ca²⁺ release and/or elevated resting calcium in MHS muscles and indicate that cooling during a malignant hyperthermia crisis could actually increase the force of muscle contractures. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:361–366, 1998.     

In vivo 31P NMR spectroscopy shows an increase in glycerophosphorylcholine concentration without alterations in mitochondrial function in the prefrontal cortex of medicated schizophrenic patients at rest

The (31)P NMR localised method was used to study the metabolism of phospholipid and high energy phosphate in the prefrontal cortex. The spectra were taken from patients with schizophrenia (11 males) receiving neuroleptic medication, and were compared to normal controls (15 males). Their spectral intensities were analysed using a non-linear least-squares method with a prior knowledge of the fixed chemical shifts and linewidths, leading to further resolution into resonances of glycerophosphorylethanolamine (GPE), glycerophosphorylcholine (GPC), phosphorylethanolamine (PE) and phosphorylcholine (PC). The metabolite concentrations were calculated referring to the spectral intensities of phosphate phantoms with known concentrations. T1 values of phantom and cerebrum were estimated from a series of localised inversion recovery spectra to correct for the signal saturation effects. The schizophrenic patients showed an increased concentration of GPC but not GPE, PE or PC. Furthermore, no difference was observed regarding the concentration of high-energy phosphates such as phosphocreatine, inorganic phosphate and ATP. The patients did not show any differences in mitochondrial function such as phosphorylation potential and the ratio of the rate of ATP synthesis. Thus, an increase in GPC concentration in the prefrontal cortex could be characteristic of the pathophysiology of schizophrenia with mild negative symptoms.     

Serum carnitine and disabling fatigue in multiple sclerosis

Abstract The serum concentrations of total, free and acylcarnitine were compared in 25 patients with multiple sclerosis (MS) and among age- and sex-matched normal controls by the new enzymatic cycling method in order to clarify whether the fatigue in MS might be due to possible carnitine-related fatty acid metabolic abnormalities in the mitochondria of skeletal muscles. Patients with MS were divided into those with and those without excessive fatigue. Levels of total and free carnitine were not significantly different between MS patients and normal controls. Levels of acylcarnitine, whose decrease in chronic fatigue syndrome has been reported, were also similar between MS patients and normal controls. There was no difference in these carnitine levels between MS patients with and without excessive fatigue. We argue that acylcarnitine deficiency and fatty acid metabolic dysfunction in mitochondria are not relevant to the excessive fatigue in patients with MS, and further explanatory investigations are to be sought.     

Beta-Interferon treatment does not always slow the progression of axonal injury in multiple sclerosis

Progression of disability in multiple sclerosis (MS) appears related to axonal damage, which is at least in part associated with white matter lesions. Beta-interferon (BIFN) substantially reduces new inflammatory activity in MS and a recent report suggested that it may reverse a component of axonal injury. To test the generalisability of this conclusion, particularly in a population with relatively active disease, we used magnetic resonance spectroscopy measures to test whether BIFN can reverse or arrest progression of axonal injury in patients with MS. Eleven patients with a history of active (median, 1.5 relapses/year) relapsing-remitting MS were treated with BIFN and responses to treatment were monitored with serial MRI and single voxel magnetic resonance spectroscopic measurements of relative concentrations of brain N-acetylaspartate (NAA), a measure of axonal integrity from a central, predominantly white matter brain region. BIFN treatment was associated with a significant reduction in relapse rate (p = 0.007) and white matter water T2 relaxation time (p = 0.047) over 12 months. Also consistent with a treatment effect, white matter T2-hyperintense lesion loads did not increase. However, the central white matter NAA/creatine ratio (NAA/Cr, which was reduced over 16 % in patients relative to healthy controls at the start of treatment), continued to decrease in the patients over the period of observation (mean 6.2 % decrease, p = 0.02). For individual patients the magnitude of the NAA/Cr decrease was correlated with the frequency of relapses over the two years prior to treatment (r = −0.76, p = 0.006). These data suggest that reduction of new inflammatory activity with BIFN does not invariably halt progression of axonal injury. Nonetheless, there appears to be a relationship between the rate of progression of axonal injury and relapse rate over the previous two years. The consequences of reduced inflammation on pathological progression relevant to disability therefore may be present, but substantially delayed. Alternatively, distinct mechanisms may contribute to the two processes. Received: 12 April 2002, Received in revised form: 12 August 2002, Accepted: 3 September 2002 Correspondence to P. M. Matthews     

Combined electromyography-31P-magnetic resonance spectroscopy study of human muscle fatigue during static contraction

Metabolic changes measured by ³¹P-magnetic resonance spectroscopy and surface electromyograms were simultaneously recorded during isometric contraction of forearm flexor muscles sustained at 60% of maximal force until exhaustion. Throughout the fatigue trial, energy in the low-frequency (L) band continuously increased whereas energy in the high-frequency (H) band first increased and then fell only prior to exhaustion. PCr content decreased linearly. Intracellular pH (pHi) transiently increased during the first 22 s of trial. The triggering of acidosis was associated with critical PCr values (35–70% of initial content) and decreased electromyogram (EMG) energy in the H band. Linear relationships were only found between energy in the L band, pHi, and PCr content. The interindividual variability of metabolic and EMG changes was high despite standardized conditions of contraction. Maximal PCr consumption was correlated with the maximal pHi decrease measured at the end of the trial. Overall, there was no correlation between H/L EMG ratio and changes in muscle metabolism. © 1996 John Wiley & Sons, Inc.     

fMRI changes in relapsing-remitting multiple sclerosis patients complaining of fatigue after IFNbeta-1a injection

If fatigue in multiple sclerosis (MS) is related to an abnormal activation of the sensorimotor brain network, the activity of such a network should vary with varying fatigue. We studied 22 patients treated with interferon beta 1a (IFNbeta-1a; Avonex, Biogen, Cambridge, MA) with no fatigue (10) and with reversible fatigue (12). fMRI examinations were performed: 1) the same day of IFNbeta-1a injection (no fatigue; entry), 2) the day after IFNbeta-1a injection (fatigue; time 1), and 3) 4 days after IFNbeta-1a injection (no fatigue; time 2). Patients performed a simple motor task with the right, clinically unaffected hand. At time 1, compared with entry and time 2, MS patients with reversible fatigue showed an increased activation of the thalamus bilaterally. In MS patients without fatigue thalamus was more activated at entry than at time 1. In both groups at entry the primary SMC and the SMA were more activated than at times 1 and 2. At entry and time 1, when compared to patients with reversible fatigue, those without showed increased activations of the SII. Conversely, patients with reversible fatigue had increased activations of the thalamus and of several regions of the frontal lobes. An abnormal recruitment of the fronto-thalamic circuitry is associated with IFNbeta-1a-induced fatigue in MS patients.     

Blepharoclonus in multiple sclerosis

OBJECTIVE: Keane described 2 patients with gaze-evoked blepharoclonus (BLC), a form of reflex BLC, and multiple sclerosis (MS). A search for common areas of demyelination and focal axonal atrophy (T1 black holes) of the central nervous system (CNS) in 11 patients with MS exhibiting eyelid closure BLC was conducted employing magnetic resonance imaging (MRI). Finding lesions in common CNS locations on these patients can help to elucidate the pathogenesis of this restricted movement disorder. MATERIALS AND METHODS: Eleven adult patients with relapsing-remitting, primary or secondary progressive MS were studied. MRI views were completed employing a 1.5-tesla scanner. Contrast Axial T1 imaging was obtained in 9 patients. RESULTS: TL blackholes were not identified. Ten patients had multiple, scattered periventricular (PV) areas of demyelination. Four patients exhibited brainstem lesions of diverse but inconsistent locations including midbrain, cerebellar peduncle, pons and medulla. In 2 of the patients the brainstem lesions were transient but BLC persisted after the lesions regressed. CONCLUSION: No common areas of CNS demyelination or focal axonal atrophy were identified on these patients with MS and BLC. The pathogenesis and clinical significance of BLC in MS remains to be elucidated.     

Evidence for abnormal tau phosphorylation in early aggressive multiple sclerosis

Although progression in multiple sclerosis is pathologically dominated by neurodegeneration, the underlying mechanism is unknown. Abnormal hyperphosphorylation of tau is implicated in the aetiopathogenesis of some common neurodegenerative disorders. We recently demonstrated the association of insoluble tau with established secondary progressive MS, raising the hypothesis that its accumulation is relevant to disease progression. In order to begin to determine the temporal emergence of abnormal tau with disease progression in MS, we examined tau phosphorylation in cerebral tissue from a rare case of early aggressive MS. We report tau hyperphosphorylation occurring in multiple cell types, with biochemical analysis confirming restriction to the soluble fraction. The absence of sarcosyl-insoluble tau fraction in early disease and its presence in secondary progression raises the possibility that insoluble tau accumulates with disease progression. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. J. M. Anderson and R. Patani are co-first authors.