Exp Brain Res (2014) 232:1013–1023 DOI 10.1007/s00221-013-3812-x

RESEARCH ARTICLE

Neurophysiological assessment of fatigue in electrical injury patients Aidin Kashigar · Kaviraja Udupa · Joel Fish · Robert Chen 

Received: 31 July 2013 / Accepted: 15 December 2013 / Published online: 1 January 2014 © Springer-Verlag Berlin Heidelberg 2013

Abstract  To investigate for the presence of central and peripheral physiological fatigue in electrical injury (EI) patients with experiential fatigue. Eight EI patients and eight age-matched healthy volunteers were recruited. Motor evoked potentials (MEP) following transcranial magnetic stimulation (TMS) and M-waves from ulnar nerve stimulation at the wrist were measured from the right abductor digiti minimi. Fatigue was induced by 2 min of maximal voluntary contraction, and subjects were followed for 15 min of recovery. The experiment was performed twice for each subject. In one of the two sessions (randomly assigned), a blood pressure (BP) cuff was inflated during the first 75 s of recovery period to prolong muscle ischemia. Baseline measures showed no difference in central and peripheral conduction times. Cortical silent period was prolonged in patients compared to controls with no differences in abduction force. Decrement of MEP amplitude with consecutive TMS pulses was observed in the postrecovery period only with EI patients who had prolonged muscle ischemia induced by the BP cuff. The post-exercise M-wave area during contraction was significantly higher

A. Kashigar · K. Udupa · R. Chen  Toronto Western Research Institute, University Health Network, Toronto, ON, Canada A. Kashigar · K. Udupa · R. Chen  Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada J. Fish  Hospital for Sick Children, Toronto, ON, Canada R. Chen (*)  Toronto Western Hospital, 7MC‑411, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada e-mail: [email protected]

for patients. Prolonged cortical silent period in EI patients suggests that they had increased GABAB receptor-mediated cortical inhibition. The ischemia-induced decrement in consecutive MEP amplitudes post-exercise demonstrates greater physiological fatigue in EI patients after exercise. The greater increase in M-wave area of EI patients postexercise suggests larger decrease in conduction velocity of muscle action potentials with exercise. These findings provide preliminary physiological correlates for increased central and peripheral fatigue in EI patients with experiential fatigue. Keywords  Electrical injury · Fatigue · Transcranial magnetic stimulation · Central fatigue · Peripheral fatigue · Silent period

Introduction Electrical injury (EI) is the most common cause for workrelated burn injury (Mandelcorn et al. 2003). A review of 28 studies of the long-term sequelae of EI found fatigue to be the most common somatic complaint post-EI (Duff and McCaffrey 2001). Telephonic interviews of EI patients have shown fatigue as a common general symptom affecting 36 % of patients (Singerman et al. 2008). Fatigue can be broadly categorized into experiential fatigue and physiological fatigue. Experiential fatigue is defined as a subjective feeling of fatigue expressed by patients and measureable through a variety of fatigue questionnaires (Dittner et al. 2004). Physiological fatigue is defined as measurable fatigue and can be divided into central and peripheral fatigue. Central fatigue represents the failure of the nervous system to drive the muscle maximally as a result of exercise-induced reduction in neural drive or

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voluntary activation of the muscle. Peripheral fatigue is due to processes at or distal to the neuromuscular junction (Taylor et al. 2006). Transcranial magnetic stimulation (TMS) has been used to study cortical excitability during muscle fatigue (Brasil-Neto et al. 1993; Samii et al. 1996). Changes in M-waves produced by peripheral nerve stimulation can be used to measure peripheral fatigue (Wawrow et al. 2011). M-waves are affected by reductions in muscle ATPase activity during isometric contractions (Fowles et al. 2002). There is little prior research into the physiological causes of fatigue in EI. Peripheral neuropathy with lowvoltage injuries, including delayed peripheral neuropathies, has been reported (Dendooven et al. 1990; Grube et al. 1990; Parano et al. 1996; Suematsu et al. 1989). These findings suggest peripheral neuropathy as a potential source of fatigue in some patients. However, as fatigue may persist for many years after EI despite normal peripheral nerve function based on EMG and nerve conduction studies, it is important to look for other central and peripheral changes that might explain fatigue in this patient population (Haberal et al. 1996). The purpose of this study was to investigate whether physiological fatigue is present in EI patients with experiential fatigue. Furthermore, we aimed to categorize physiological fatigue into central and peripheral components. We hypothesized that experimental fatigue reported by EI patients is related to underlying physiological changes. We further hypothesized that the physiological changes include both central and peripheral fatigue.

Materials and methods Subjects We studied 8 electrical injury patients and 8 healthy volunteers (all men, patients aged 46.0 ± 7.8 years, volunteers 45.4 ± 7.5 years). Electrical injury patients were recruited from St. John’s Rehabilitation Hospital in Toronto. Patients were selected based on the past complaint of fatigue after electrical injury. Age- and sex-matched volunteers without prior electrical injury were recruited for the control group. There were two left-handed subjects, one in each group. Exclusion criteria included history of stroke, seizures, cardiovascular, neuromuscular or psychiatric disorders, uncontrolled hypertension above 160/100 mmHg, and presence of non-removable metallic objects in head and neck area. Subjects with history of diabetes mellitus, renal failure, and alcohol abuse were excluded since these diseases are predisposing causes for neuropathy (Haberal et al. 1996).

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Standard protocol approvals, registrations, and patient consents The study was approved by the University Health Network and St. John’s Rehabilitation Hospital Research ethics boards. Written informed consent was obtained from all participants. Study design The subjects were studied in two sessions. In the first session, the subjects underwent neurological examination by a neurologist and completed a fatigue severity scale questionnaire (Krupp et al. 1989). In addition, the EI patients completed the Burn-Specific Health Scale-Brief questionnaire consisting of 40 Likert scale questions (Kildal et al. 2001). Each session was divided into three parts: baseline measurements, induction of fatigue period, and recovery period (Fig. 1). Subjects came for two separate sessions (with and without the blood pressure cuff assigned randomly) separated at least by one week. Subjects were provided with practice sessions before data collection, and rest periods were provided between the practice and recording periods. The following parameters were recorded during the resting period and while performing maximal voluntary contraction (MVC). A train of 5 TMS were delivered at rest, while single-pulse TMS was delivered during MVC with recording of the cortical silent period and MEP amplitudes. EMG recordings Subjects were seated in a comfortable chair, and surface electromyograms (EMG) were recorded from the right abductor digiti minimi (ADM) with 9-mm-diameter Ag– AgCl electrodes with the active electrode placed over the muscle belly and the reference electrode over the right fifth metacarpophalangeal joint. EMG was monitored on a computer screen and with a loudspeaker. The signal was amplified and band-pass filtered (2 Hz–2.5 kHz, Intronix Technologies Corporation model 2024F, Bolton, Ontario, Canada), digitized at 10 kHz by an analog-to-digital interface (Micro 1401, Cambridge Electronics Design, Cambridge, UK), and stored in a computer for off-line analysis. Force transducer recordings Abduction force of the ADM muscle was measured using a custom-designed apparatus. The subject’s right hand was secured using hook-and-loop fasteners. The fifth digit was inserted securely into a moveable block connected to a tension/compression S beam (LCCA-25, Omega Engineering, Stamford, Connecticut, USA), which was used to measure abduction force of the ADM muscle.

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Voluntary force

A

cathode placed distally. To calculate the nerve conduction velocity, the ulnar nerve was also stimulated with the electrode at the elbow.

Baseline measurements

Transcranial magnetic stimulation (TMS) Repeated 3 times

Time UNS at rest TMS train

TMS with MVC

Induction of fatigue measurements BP cuff inflated

Voluntary force

B

UNS with MVC

10sec

Time UNS

TMS

TMS

UNS

TMS

TMS

UNS

UNS

TMS

Baseline measurements

UNS

TMS

Recovery measurements

Voluntary force

C

UNS

BP cuff maintained inflated

Repeated 8 times (2min intervals)

Time TMS train

UNS at rest

TMS with MVC

Four Magstim 2002 stimulators (Magstim, Whitland, Dyfed, UK) were connected to a custom-made “4 into 1 combining module,” which connects the outputs of four magnetic stimulators to a 7-cm figure-of-eight stimulating coil. Using this setup, we can generate up to 4 magnetic pulses with 4 different stimulus intensities at short intervals delivered through the same coil. The coil was placed over the left motor cortex (M1) at the optimal position for eliciting motor evoked potential (MEP) from the ADM muscle. The coil was held with the handle at about 45 degrees to the mid-sagittal line, approximately perpendicular to the central sulcus, inducing a posterior-to-anterior current in the brain using monophasic TMS. The direction of induced current in the brain was from posterior to anterior and was optimal to activate the corticospinal neurons trans-synaptically (Kaneko et al. 1996; Werhahn et al. 1994).

UNS with MVC

Fig. 1  Overview of the study protocol. a Overview of baseline measurements performed. b Overview of the measurements performed during the 2 min of induction of fatigue protocol. Blood pressure cuff was inflated for last two measurements (1 TMS and 1 UNS measurements) during the ischemia sessions. c Overview of the measurements performed during the 15-min recovery period. Blood pressure cuff remained inflated during the first set of post-exercise measurements in the ischemia sessions

The resting motor threshold (RMT) was defined as the minimum stimulator output that induced MEPs of greater than 50 μV in at least 5 out of 10 consecutive trials (Chen et al. 2008). MEP recruitment curve was measured with subject at rest using 10 MEPs at 100, 120, 140, and 160 % of RMT with the different intensities applied at random order. The maximum M-wave threshold was defined as the minimum stimulation current needed to stimulate ulnar nerve to induce the maximal peak-to-peak M-wave in the ADM muscle. M-wave and F-wave latencies were also measured. Subjects were provided with visual feedback of the abduction force produced, and the MVC was recorded. TMS was applied at 140 % RMT, and UNS was given at 150 % of maximal M-wave threshold. UNS and TMS measurements were also obtained during MVC (Fig. 1a). The subjects maximally abducted their fifth digit for three seconds with stimulation given after two seconds. TMS was performed in trains of 5 pulses at 0.3-Hz frequency to assess for influence of consecutive stimuli. Train of TMS pulses were given only during resting state (baseline and recovery period measures). All four measurements (UNS and TMS at rest, UNS and TMS with MVC) were repeated four times.

Ulnar nerve stimulation (UNS)

Induction of fatigue measurements

UNS was applied at the right wrist with a standard bar electrode using a constant current stimulator (DS7A, Digitimer, Welwyn Garden City, UK, pulse width 0.2 ms) with the

Subjects were instructed to maximally contract their ADM muscle for 2 min. TMS and UNS were administered alternately every 10 s (Fig. 1b). In one of the two sessions

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Table 1  Clinical features of patients studied Patient

Age

Time since injury (years)

Voltage (V)

1

55

2.8

347

2 3 4 5 6 7

41 50 39 36 42 50

4.1 1.2 1.3 1.1 2.0 1

7,200 109 600 13,800 16,000 600

8

56

6.8

480

Entry

Exit

Medications

Right hand

Left hand

Right arm Right forearm Left hand Right forearm Right hand Right hand

Right foot N/A Right hand Left hand Right foot Right hand

Quetiapine, Methylphenidate, Escitalopram, Clonazepam Simvastatin, Tamsulosin Lisinopril None Hydrochlorothiazide Sulindac Bupropion Rosuvastatin, Nifedipine None None Morphine Celecoxib, Duloxetine

Left and right hand

Right foot

None

(randomly assigned), a blood pressure (BP) cuff was inflated around the right arm to 150 mmHg at 15 s before the end of the 2-min MVC and maintained inflated for the first 75 s of the recovery period. This was performed to investigate for the effect of prolonged muscle ischemia (Pitcher and Miles 1997).

EI patients, and healthy volunteers) and session (withinsubject factor, ischemia vs. no ischemia) on the parameters measured. If ANOVA showed significant main effects, post hoc Fisher’s protected least significance difference tests were used for further analysis. Significance was defined as p