Clinical and Experimental Pharmacology and Physiology (2015) 42, 394–405

doi: 10.1111/1440-1681.12363

SYMPOSIUM

Proceedings of the Australian Physiological Society Symposium

Using transcranial magnetic stimulation to quantify electrophysiological changes following concussive brain injury: A systematic review Brendan P Major, Mark A Rogers and Alan J Pearce School of Psychology, Deakin University, Melbourne, Victoria, Australia

SUMMARY Mild traumatic brain injury (mTBI) and sports concussion are a growing public health concern, with increasing demands for more rigorous methods to quantify changes in the brain post-injury. Electrophysiology, and in particular, transcranial magnetic stimulation (TMS), have been demonstrated to provide prognostic value in a range of neurological conditions; however, no review has quantified the efficacy of TMS in mTBI/concussion. In the present study, we present a systematic review and critical evaluation of the scientific literature from 1990 to 2014 that has used TMS to investigate corticomotor excitability responses at short-term (< 12 months), mediumterm (1–5 years), and long-term (> 5 years) post-mTBI/concussion. Thirteen studies met the selection criteria, with six studies presenting short-term changes, five studies presenting mediumterm changes, and two studies presenting long-term changes. Irrespective of time post-concussion, change in intracortical inhibition was the most reported observation. Other findings included increased stimulation threshold, and slowed neurological conduction time. Although currently limited, the data suggest that TMS has prognostic value in detecting neurophysiological changes post-mTBI/concussion. Key words: concussion, evoked potential, mild traumatic brain injury, systematic review, transcranial magnetic stimulation.

INTRODUCTION In the past decade, there has been a significant increase in public concern regarding concussions and mild traumatic brain injury (mTBI) sustained in contact sport. While TBI is a considerable global contributor to death and disability, particularly in children and young adults,1 mTBI is now being associated with long-term detrimental health consequences.2,3 Consequences of head impacts are usually observed through clinical signs of being dazed and/or confused, balance problems, transient amnesia, and

Correspondence: Dr Alan J Pearce, School of Psychology, Deakin University, 221 Burwood Highway, Burwood, Victoria 3125, Australia. Email: [email protected] Received 26 July 2014; revision 21 November 2014; accepted 23 November 2014.

sometimes loss in consciousness.4 However, there is a growing body of evidence to suggest that head impacts might, in some cases, result in continuing symptoms. For instance, it has been documented that in some cases a concussion might not resolve immediately, with symptoms remaining present in some cases for 7 years.5,6 In the long term, following a history of multiple sports concussions, an individual’s chances of ongoing health issues increase.7 Repetitive trauma could lead to distinct histopathological changes termed ‘chronic traumatic encephalopathy’.2,6,8,9 However, at present, chronic traumatic encephalopathy can only be diagnosed post-mortem.2 Animal models have provided evidence of changes underpinning concussion that include alterations in neurophysiology, biochemistry, and neurotransmitter activity.10,11 However, acute and long-term neurophysiological manifestations of repeated concussions are still relatively unknown.12 Current evidence in humans is limited to neurological reports, neurocognitive studies, and neuroimaging.13–16 Neurological investigations, particularly from boxing and American football, found self-reported neurological motor symptoms, including ataxia, spasticity, and Parkinsonism, stemming from repeated concussions.17 Cognitive impairments following multiple concussions include attention and/or memory.17 Despite these reported changes, the validity of testing methods has been questioned.18,19 Symptom observation involves subjective interpretation, and the results of neuropsychological studies have been disparate, reflecting the variability of the cohorts used, reliance on self-reporting, and the motivational status of the participant.20,21 As a result, there have been increasing calls for more rigorous methods to evaluate concussion.22 Advanced neuroimaging for concussion shows promise, but as it is outside the scope of this review, the reader is referred to a recent review by Dimou and Lagopoulos.12 Alternatively, electrophysiology techniques, which include electroencephalography and transcranial magnetic stimulation (TMS), have demonstrated prognostic value in neurology. Both electroencephalography and TMS are more economical to operate, and have the potential to provide real-time evaluation.23 Electroencephalography, however, has some limitations for application to the sporting club environment; for example, extensive pretesting preparation time and low signal-to-noise ratios limit the opportunity to test outside of the clinical laboratory.24 With less technical limitations, TMS has potential as an alternate prognostic technique to quantify neurophysiological changes fol-

TMS to measure concussive brain injury lowing acute concussion injuries and long-term manifestations of multiple concussions.18 Transcranial magnetic stimulation TMS is a well-established, validated technique to quantify excitation and inhibition of the primary motor cortex, the spinal nerve roots, and the peripheral motor pathway (corticospinal).25,26 TMS employs time-varying magnetic fields that induce electrical currents in conductive neural tissue. When applied over the motor cortex, the response is recorded and measured as a motor-evoked potential (MEP) in the electromyogram of the target muscle (Fig. 1).25,27 There are a number of TMS-dependent measures that can be obtained to understand corticospinal excitability and inhibition. These include: (i) motor threshold (MT), defined as the lowest stimulus intensity to lowest stimulus intensity to produce a detectable MEP;28,29 (ii) central motor conduction time, being the latency period difference between stimulation of the motor cortex and stimulation of cervical nerves to the onset of the MEP;29 (iii) the MEP waveform, reflecting the excitability of the motor cortex, corticospinal tract, and motor units in the target muscle26; and (iv) cortical inhibition, quantified as absent electromyography (EMG) from 50 to 300 ms following the MEP, and known as the cortical silent period (cSP). Measured from the onset of the MEP to the return of uninterrupted EMG activity, the initial 50 ms of the cSP is thought to reflect spinal inhibitory mechanisms, and the remaining duration (> 50 ms) due to intracortical inhibitory mechanisms mediated by GABA type b receptor (GABABR) activity.30,31 Paired-pulse TMS protocols deliver two pulses through the same coil, a conditioning stimulus (CS) with an intensity either above or below MT followed by a secondary test stimulus (TS) (Fig. 2).23 The timing of these pulses, known as the interstimulus interval (ISI), and the stimulation intensities of each pulse, dictate the result of the test stimulus. For example, at short ISI between 1 and 5 ms, with a subthreshold CS and a supra-threshold TS, the test MEP is suppressed (compared to a single-pulse MEP). Known as shortinterval intracortical inhibition (SICI), it is postulated that SICI is mediated GABA type A receptor activity.32,33 Conversely, ISI of between 10 and 25 ms result in the test MEP facilitated and is termed ‘intracortical facilitation’, possibly reflecting glutamatergic N-methyl-D-aspartate activity.34,35 When two supra-threshold

Fig. 1 Example of a motor-evoked potential (MEP). Illustration shows an overlay of 10 MEP sweeps, with the dark MEP line illustrating mean MEP amplitude. (a) Latency duration is measured from stimulus artifact to MEP onset. (b) Peak-to-peak MEP amplitude. (c) Silent period duration is measured from onset of MEP to the return of EMG. (d) Return of EMG activity.

395

stimuli are presented at ISI between 80- and 200-ms intervals, the TS is inhibited and termed ‘long-interval intracortical inhibition’ (LICI). Like cSP, LICI reflects GABABR activity-mediated cortical inhibition; however, it is thought that cSP and LICI derive from different neuronal populations.36–38 With observations of motor abnormalities shortly after a concussion, as well being the earliest clinical manifestation of repeated head injuries, it is reasonable to hypothesize that the motor cortex can also be affected.17,39 TMS, therefore, is a particularly suitable technique to quantify central excitatory and inhibitory changes following a concussion, as well as neuroplastic changes following multiple concussions injuries.40 With TMS being increasingly utilized in concussion research, we present a systematic review and critical evaluation of the literature on the prognostic value of TMS across short-, medium-, and long-term changes in motor cortex with regards to concussion injuries.

RESULTS The flow of studies through the systematic review process, returning an initial yield of 668 citations, is illustrated in Fig. 3. Of these citations, 252 were removed due to duplication. After screening the title and abstract of the remaining 406 studies, 369 were removed, as they failed to meet the inclusion criteria (e.g. used repetitive TMS or were severe TBI).41 Of the 37 full-text articles that were examined, 10 met the inclusion criteria and were retained for review; the reference list of these papers was examined, and 17 further articles were retrieved based on title and abstract. Following full-text examination, three were retained, making a total of 13 studies. Study characteristics and TMS quality assessment The characteristics for all studies are shown in Table 1. Sample sizes ranged from 18 to 60 participants.42–44 The mean number of concussions ranged from one to five, with an overall mean of two. The mean age of participants tested ranged between 20 and 60.8 years of age, with a predominance of males (381 males, 40 female). However, no sex differences were reported in any studies that used mixed-gender groups for both mTBI/sports concussion and healthy controls.42,43,45,46

396

BP Major et al.

(a)

(b)

Fig. 2 Example of paired pulse transcranial magnetic stimulation (TMS) measures. (a) Short intracortical inhibition (SICI) waveform (right) next to a singlepulse motor-evoked potential (MEP) (left); and (b) long intracortical inhibition waveform. (a) Following a double pulse (in this illustration with an interval of 3 ms, right) the inhibited smaller SICI waveform (on right) is calculated to a single-pulse MEP taken separately (left, as indicated by broken double line) and expressed as a ratio. (b) Long intracortical inhibition (LICI) occurs after a double TMS pulse with an interval of 100 ms, with the second inhibited waveform on right, calculated as a ratio of the first waveform on left.

Studies included in this review were between-groups quasi-experimental designs. TMS methodological quality scores were moderate to high, with a median interquartile range of 21 (4.5). Ten of the 13 studies also presented complementary assessments. These included neurocognitive measures, motor control performance, electrophysiology, and neuroimaging.18,40,43,44,47–49

Miller et al.39 used the side-line concussion assessment tool, version 3 (SCAT 3) to grade concussion severity. Two studies by Pearce et al. and De Beaumont et al. did not report the severity of injury.44,47 However, Pearce et al.51 did classify concussion according to the Australian Football League’s definition for concussion of having missed the following week’s game.

Classification of brain injury

Transcranial magnetic stimulation

The classification and grading of mTBI was heterogeneous amongst the 13 studies. Six studies used the Glasgow Coma Scale (GCS). Of those six studies, four primarily investigated sports concussion.18,40,45,46,48,49 Consequently, they also used the American Academy of Neurology guidelines to grade concussion severity.50 Chistyakov et al.45 used the GCS to grade the severity of mTBI in each individual, and then, based on the results, separated the sample into four experimental groups (minor, moderate, and two mild–moderate groups); between group comparisons were, run as well as a comparison to a healthy control group. One study used the number of concussion injuries to subcategorize the investigated sample (multiple vs single vs control).18

All studies presented MT, with one study comparing inter-hemispheric MT.45 Two studies presented both MEP latency and central motor conductive time, while one study presented central motor conductive time only.42,43,45 All but one study measured MEP amplitude.47 cSP was presented in all but three studies.42,43,46 Inter-cortical facilitation was presented in three studies, SICI in six studies, and LICI in five studies.18,40,44,47–49,52,53 Short-term studies Six studies investigated the acute changes in TMS measures postTBI/concussion (Table 2).39,42,43,45,52,53 Chistyakov et al. presented data 2 weeks’ post-TBI, whereas Livingston et al. presented

TMS to measure concussive brain injury

397

Records idenƟfied through database searching (n = 668)

Records aŌer duplicates removed (n = 406)

Records screened for Ɵtle and abstract (n = 406)

Records excluded (n = 369)

Full-text arƟcles assessed for eligibility (n = 37)

Full-text arƟcles excluded (n = 27) •

Used a RepeƟƟve TMS protocol Used TMS as a treatment Severity of concussion too severe TMS not assessing changes in the motor

• • AddiƟonal records idenƟfied through reference lists (n = 17)

Studies included in iniƟal quanƟtaƟve synthesis (n = 10)

•

Studies included in final quanƟtaƟve synthesis (n = 13)

Fig. 3 Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart of search method.36

time-course data up to 10 days’ post-concussion in athletes.42,43,45 Miller et al., Pearce et al., and Power et al. and all investigated changes between 24 h and 34 days’ post-injury.39,52,53 The main findings were a decrease in MT post-injury.42,43,45 Miller et al., Chistyakov et al., and Pearce et al. also reported an increase in cSP duration in mTBI individuals when compared with controls, and Chistyakov et al. reported lengthened cSP in mild and moderate head injuries.39,45,53 Medium-term studies Studies of people between 1 and 5 years’ post-concussion are shown in Table 3. Two studies compared MT, while De Beaumont et al. also measured MEP amplitude between two groups of concussed participants (‘single’ and ‘multiple’) and compared to healthy controls with no history of concussion.18,46 No differences were observed between any of the three groups for MT and MEP amplitude. Conversely, Tallus et al.46 found increased MT in those with mTBI compared to non-injured controls. Four studies measured cSP, with three reporting lengthened cSP duration in concussed patients versus controls.18,47,48 De Beaumont et al.18 only reported a lengthening of cSP in a sub group of individuals who received another concussion after they had initially been tested. Time since concussion and number of concussions might have played a role in this group reaching statistical significance when the single concussion group did not.

One study showed no difference between concussed and nonconcussed individuals.49 De Beaumont et al.18 found no intracortical facilitation differences between single concussion, multiple concussions, and control groups. In their studies, De Beaumont et al. and Tremblay et al. presented SICI data, with no differences between groups.18,48 Long intracortical inhibition was measured by De Beaumont et al. and Tremblay et al.47–49 Significant differences in LICI were reported between concussed and control groups in two of these three studies.47,48 Long-term studies The two studies reporting long-term neurophysiological changes after a history of concussions are presented in Table 4.40,44 De Beaumont et al.40 found a significant lengthening of cSP in older, retired athletes, an average of 34 years after their last concussion, compared to age-related controls with no concussion history. Conversely, Pearce et al.44 found a shortening in cSP duration and associated increases in SICI and LICI in older, retired Australian football players, an average 22 years after their last concussion.

DISCUSSION While extensively used to quantify changes in neurological conditions, there has been no review that has evaluated the efficiency of

TMS Score

23

21

14

17

17

20

22

24

28

22

Reference

Chistyakov et al.,45

De Beaumont et al.,18

De Beaumont et al.,47

De Beaumont et al.,40

Livingston et al.,42

Livingston et al.,43

Miller et al.,39

Pearce et al.,44

Pearce et al.,53

Power et al.,52 TBI Control

TBI Control TBI – professional TBI – amateur Controls TBI Control

6

Control

X < 24 h X 6–34 days X

47.6  6.8 25.1  4.5 20.2  1.2 20.3  1.5

8 8

7 7

20 8 15

8 8 20 20+ years

X

X < 24 h X < 24 h

48.8  6.9

9.1 1.3 .9 1.3

20

   

72 h X 20+ years

58.9 20.4 20 20.4

20.8  1.2 21.1  1.3 49.7  5.7

3

3 3 3

21 6 6 6

X 30 + years

Control TBI Control TBI

60.8  5.2

2.6 2.8 2.5 3.4

15 19

   

Control TBI

23.4 22.9 22.5 22.3

X 31.0  22.1 months 59.1  69.5 months X 19  13.7 months

2 weeks 2 weeks

15 15 15 15 21

33.2  13.2

Age

2 weeks 2 weeks 5

F

Time since last concussion

11 9

9 7

M

Population

Concussion Diffuse brain injury Focal lesion Combined lesion Control Multiple Single Control TBI

Groups

X

X X X

Miss a game

Mild X Miss a game

X

X Grades 1–3

X

X Grades 2– 3

X Grades 1–3 Grades 1–3 X X

Mild–moderate Mild–moderate

Minor Moderate

Severity of concussion

SCAT 2

X

AFL

SCAT

Head Injury Scale

Head Injury Scale

GCS & AAN

X

GCS

GCS

Severity scale used

Table 1 Overview of all studies. Sample population, severity, and time since concussion, as well as complementary assessments

1 X

X 1 X

Average 3.1

1 X Average 3.1

X

X 1

X

X 1–5

X 2+ 1 X 1–5

1 1

1 1

No. concussions

University

Australian football

Former recreational & professional football

General

University

University

Former University

University

University

Hospital

Recruitment population

(continued)

Spatial working memory Fine motor dexterity, reaction time, implicit learning, attention Voluntary muscle activation and sensation of force

Fine dexterity & associated learning Visuomotor reaction time

Internet-based neurocognitive Concussion resolution index None

Centre of pressure oscillation Centre of pressure displacement RAM Mini-mental score RAM Flanker task None

NFL neuropsychological testing

None

Additional assessment(s)

398 BP Major et al.

AAN& GCS

X Grades 1–2 X Grades 1–3 X X 3.1 years X 23.2 months X 3 6 16 14 12 14

1.7

13.2 1.1 1.1

33.6  22  22  X 22.4 

4 4

24

23

Tremblay et al.,49

Tremblay et al.,48

AAN, American Academy of Neurology; AFL, Australian Football League; GCS, Glasgow Coma Scale; NFL, National Football League; RAM, rapid alternating movement task; SCAT, sports concussion assessment tool; TBI, traumatic brain injury; X, not stated or unknown.

University

Proton magnetic resonance spectroscopy Somatosensory-evoked potential University

X 1.88 X 3.25 X AAN & GCS

1 3.8 years 35.9  15.9

14.1  0.8

6.1 years 43.7  11.6 7 4 21 Tallus et al.,46

TBI – symptomatic TBI – asymptomatic Controls TBI Control TBI Control

Age F

TMS Score Reference

Table 1. (continued)

Groups

M

Population

Time since last concussion

14.8  0.4

Severity of concussion

GCS

Severity scale used

1

No. concussions

Hospital

Recruitment population

Magnetic resonance imaging

Additional assessment(s)

TMS to measure concussive brain injury

399

TMS in mTBI/concussion.26,54 This systematic review has presented TMS studies that measured corticomotor activity following a concussion or as a consequence of multiple concussions. Despite the limited number of published studies, research designs, and population cohorts tested, these studies collectively have shown potential in the prognostic value of TMS for mTBI/concussion research when used in the correct setting. Of the 13 studies reviewed, 11 reported statistical significance in one or more measures. Five of six studies in the short-term (< 12 months) group reported significant changes, and two of two in the long-term (> 5 years) group.39,40,42–45,53 In the medium-term (1–5 years) group, four out of five studies reported a difference.18,46–48 In a subgroup reported in Table 3, De Beaumont et al.18 reported a difference in cSP for athletes who had suffered multiple concussions compared to the control group. The most consistently observed finding was a change in intracortical inhibition via alterations in cSP. Eight studies reported changes in cSP when compared with no changes seen in MEP amplitude, SICI, or intracortical facilitation. Other reported findings, although not consistent across studies, were increased MT slowing in central motor conduction time and changes in intracortical facilitation and LICI. Despite the majority of studies presenting MEP amplitude, no significant differences were found between concussed and non-concussed controls on that measure. Although mechanisms contributing to the generation of the cSP remain complex, evidence suggests that cSP is generated predominately via the activation of cortical inhibitory neurons in the motor cortex, and mediated by GABABR activity.30,55–58 Evidence for this has been demonstrated in pharmacological studies demonstrating that GABABR agonists and GABA reuptake inhibitors can lengthen the cSP duration.31,58 Despite the complexity underlying the mechanisms contributing to cortical inhibition, the cSP is a reliable measure, allowing for assessment of cortical inhibition in health and disease.26,30 For example, in healthy populations, aging is associated with a longer cSP.59 However, abnormally short or long cSP has been observed in a number of clinical conditions. Movement disorders, such as Parkinson’s disease, have shown a significant reduction in cSP associated with decreased facilitation of interneurons in the basal ganglia-thalamocortical circuits.60 Similarly, in amyotrophic lateral sclerosis, the cSP has been shown to be significantly reduced or abolished, particularly in those early in the disease progression that have been associated with dysfunction of GABAB-mediated receptor inhibition.61 Conversely, in Huntington’s disease, the cSP is abnormally prolonged due to increased excitation of inhibitory interneurons resulting from degeneration of the striatum, and correlates with the severity of chorea.62 Limited literature on psychiatric conditions, such as major unipolar depression and schizophrenia, has also reported abnormally-altered cSP.63,64 In this review, cSP was lengthened in all but three studies that presented cSP data for short-, medium-, and long-term concussed athletes. Powers et al.52 presented no differences in cSP between groups measuring acute-phase concussions in college athletes between 1 and 4 weeks’ post-concussion. Similarly, in mediumterm studies, Tremblay et al.49 found no difference in cSP duration. However, in long-term studies, Pearce et al.44 found, in a cohort of Australian football players, a reduction in cSP compared to healthy controls. Evidence of intracortical dysfunction in previously-concussed athletes presents immediately and is

TBI Control

TBI Control

TBI Control TBI Control

TBI Control

Control Minor Mild Moderate

40.2 42.3 55.9* 60.7* 72 h 49.13  1.7 45.07  1.7 Pre 44.1  5.0 41.3  8.2 56  6.4 59.5  9.6 Day 1 52.4  8.8* 55.7  6 Day 1 52.4  8.8* 55.7  6

MEP threshold stimulation (%)

Day 54.5  55.3  Day 54.5  55.3 

10 7.0* 5.7 10 7.0* 5.7

2 months 46  3.24 44.75  1.88 10 days 44.4  5.1 41.8  7.9

TBI Control

TBI Control

TBI Control TBI Control

TBI Control

Control Minor Mild Moderate

29.9  32.1  12.1  15.3  72 h 0.53  0.99  Pre 0.38  0.32  0.92  0.83  Day 0.38  0.40  Day 0.38  0.40  0.14 0.14 0.2 0.16 1 0.16 0.17 1 0.16 0.17

0.08 0.19

9.9% 13.5% 9.3% 12.7%

MEP amplitude

Day 10 0.37  0.21 0.32  0.23 Day 10 0.37  0.21 0.32  0.23

2 months 0.95  0.07 0.63  0.15 10 days 0.34  0.16 0.31  0.15

X

TBI Control X

X

X

X

1.1  0.14 1.9  0.31

ICF changes

X

TBI Control TBI Control X

X

X

10 days 0.28  0.12 0.27  0.12 0.41  0.13 0.47  0.14

SICI changes

X

TBI Control X

X

X

X

0.63  0.27 0.57  0.26

LICI changes

X

TBI Control TBI Control X

TBI Control

Control Minor Mild Moderate 72 h 111.5  9.4* 85.7  6.5 48 h 135.4  26.8* 117.7  20.0 158  25 ms 173  41 ms

cSP changes at 130%

150.8 ms 151.9 ms 196.1 ms* 194.7 ms* 2 months 112.01  6.06* 95.69  7.26 96 h 137.1  26.8* 114.3  16.1

Data from studies investigating neurophysiological changes immediately to 1 year following mTBI. Resting and active measures were taken (MEP and cSP), as well as paired-pulse measure intra cortical facilitation (ICF), short latency intracortical inhibition (SICI), and long latency intracortical inhibition (LICI). *Significant difference between groups (P < 0.05). cSP, cortical silent period; MEP, motor-evoked potential stimulus; mTBI, mild traumatic brain injury; TBI, traumatic brain injury; X, not stated or unknown.

Livingston et al.,43

Power et al.,52 Livingston et al.,42

Pearce et al.,53

Miller et al.,39

Chistyakov et al.,45

Reference

Table 2 Studies investigating short-term responses (5 years) following the participants’ last concussion/mTBI

SICI changes

    

0.11 0.18 14.0 19.0 17.0

LICI changes

cSP changes at 120%

402

reported to be stable and long lasting.44,53 This could indicate a shift of excitability more towards inhibition following mTBI. It must be noted that in acute studies, Chistyakov et al. only reported change in cSP duration in mild-to-moderate head injuries, and in medium-term studies, De Beaumont et al.18,45 found that changes were only seen in the group that had repeated concussion, and not in a single concussion group. This evidence could suggest that changes in cSP duration could be dependent on several factors, such as time since injury, injury severity, and overall number of injuries sustained. Until further research on measuring intracortical inhibition with concussion is conducted, we can only speculate on the reasons for these differing results. These include the characteristics of the cohorts measured (age, type of head injury, and sport played), and the number of concussions sustained. For example, Powers et al.52 utilized an ‘active’ control of eight participants who had not sustained a concussion in the previous 12 months, but did self-report a history of previous concussions. Trembley et al. suggested that the difference in findings between their own and previous studies could lie in the lower number of concussions sustained in their cohort, while the participants in Pearce et al.’s study were on average 10–12 years younger and played a different sport to those studied by De Beaumont et al.18,44,46,47,49 With TMS relatively underutilized in mTBI/concussion research, the present review is currently limited in terms of the total number of papers presented and the number of laboratory groups publishing in this field. Therefore, caution is required when considering these findings until more investigations are completed, providing an opportunity to undertake a meta-analysis. A further factor to be mindful of with TMS is that abnormalities uncovered by this technique are not condition specific, and the results must be interpreted in the context of other clinical and functional data.26 The majority of studies in the present review presented complementary measures, allowing for interpretation. For example, De Beaumont et al., Livingston et al., and Pearce et al. included neurocognitive testing; De Beaumont et al., Pearce et al., and Power et al. completed motor task testing; electroencephalography- and somatosensory-evoked potentials and neuroimaging data were also presented in the studies by De Beaumont et al. and Trembley et al., respectively.18,40,43,44,47–49,52 In conclusion, despite limited studies, TMS is useful to quantify corticomotor changes following concussion. This reliable and noninvasive technique is relatively inexpensive, potentially portable, and shows excellent promise in the field of concussion assessment. Further studies should incorporate co-registration of TMS with advanced neuroimaging, as well as incorporating biomarker measures that can further validate the intracortical inhibition measures currently being observed in TMS concussion research.

METHODS Search strategy The following electronic databases were searched between January and April 2014: MedlinePlus, PsychINFO, Sports Discus, Cinahl Complete, Web of Science, and Scopus. Databases were searched using combination and/or variations of the following terms: ‘transcranial magnetic stimulation’, ‘silent period’, ‘single pulse’, ‘paired pulse’, ‘motor evoked potential’, ‘Motor

TMS to measure concussive brain injury Evoked Potential’, ‘gamma-amino butyric acid’, ‘GABA’, ‘motor cortex’, ‘excitation’, ‘inhibition’, ‘motor threshold’, ‘facilitate’, ‘neurophysiology’, ‘intracortic*’, ‘concussion*’, ‘mild traumatic brain injury’, ‘trauma’, and ‘head injury’. Two authors (BM & AP) then independently screened the titles and abstracts of search results, excluding duplicate articles or articles that did not meet the selection criteria. Any disagreements were resolved through discussion with the third author (MR). All references of included articles were screened. The full-text PDF of articles were obtained and exported with their citations into Endnote (X7; Thompson Reuters, Toronto, Ontario, Canada), with no further modifications of references. The studies that were removed following the application of criteria according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines are outlined in Fig. 3.65 The PRISMA guidelines are used by the Cochrane Collaboration to help authors improve the reporting of systematic reviews and meta-analyses. PRISMA generally focuses on reporting on randomized trials. However, PRISMA can also be used as a basis for reporting systematic reviews of quasi-experimental research. Although no meta-analyses were completed in the present study, it was important to outline the steps completed here to determine the studies for presentation in the present review. Criteria for inclusion Each database search was limited to peer-reviewed, full-text publications printed in English between 1990 and 2014. Exclusion criteria were applied to each search: (i) non-peer or limited review conference proceedings; (ii) conference abstracts; (iii) books; and (iv) theses (PhD, masters, honours). Only studies conducted on humans aged over 18 years were included. One study was excluded because relevant TMS results were previously reported.46,66 Studies investigating both mTBI and sports concussions were included for review. Repetitive TMS differs in that it is used as a neuromodulation technique for therapeutic interventions, rather than as a prognostic method to assess corticomotor excitability, which was the aim of the present review.26 Because of the difficulty delineating between sports concussion and mTBI in the published literature, articles pertaining to mTBI injuries and sports concussions, quantified by TMS, were included. Allocation of studies To investigate whether neurophysiological changes post-injury were time dependent, studies were separated into three groups based on time from last injury. These were short term (< 12 months), medium term (1–5 years), and long term (> 5 years). Categories were created in an effort to illustrate changes post-mTBI/concussion, as revealed by TMS, from several weeks to months, or conversely, decades later.40,44,53 The average time, as opposed to the minimum time from concussion to investigation, was used for group classification, as several studies set minimum timeframes between injury and investigation. For example, De Beaumont et al. set 9 and 10 months for their inclusion criteria.18,47 However the average timeframe for each mTBI group was 19 months for De Beaumont et al.; 59.1 and 31 months for time post-single and multiple concussions,

403

respectively, again for De Beaumont and colleagues; and 23.2 and 36.1 months for Tremblay et al.49 Data extraction and quality assessment Two authors performed data extraction and quality assessment (BM & AP). Disagreement was reconciled by mutual agreement by all authors. A meta-analysis was not feasible due to the heterogeneity of dependent variables between studies. Results were therefore qualitatively synthesized and descriptively summarized using previously-published methods.67 A TMS checklist was used to assess the methodological quality of studies.68 This checklist aimed to indicate if the TMS methodological quality of a study could be a possible source of study bias.69 The checklist covers participant characteristics, methodology, and result analysis (Appendix 1).68 Single-pulse TMS protocols were evaluated on a 27-item checklist. A single score for each item on the checklist was given if it was reported in the study.

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APPENDIX 1 Final checklist Were the following participant factors

Reported?

Controlled?

Age of subjects Gender of subjects Handedness of subjects Subjects prescribed medication Use of CNS active drugs (e.g. anti-consultants) Presences of neurological/psychiatric disorders when studying healthy subjects Any medical conditions History of specific repetitive motor activity Were the following methodological factors Position and contact of EMG electrodes Amount of relaxation/contraction of target muscles Prior motor activity of the muscle to be tested Level of relaxation of muscles other than those being tested Coil type (size and geometry) Coil orientation Direction of induced current in the brain Coil location and stability (with or without a neuro-navigation system) Type of stimulator used (e.g. brand) Stimulation intensity Pulse shape (monophasic or biphasic) Determination of optimal hotspot The time between days of testing Subject attention (level of arousal) during testing Method for determining threshold (active/resting) Number of MEP measures made Paired pulse only: Intensity of test pulse Paired pulse only: Intensity of conditioning pulse Paired pulse only: Inter-stimulus interval Were the following analytical factors Method for determining MEP size during analysis Size of unconditional MEP

□ □ □ □ □ □

□ N/A □ □ □ □

□ □

□ □

□ □ □ N/A □ □ □ □

□ □ □ □ □ □ □ □

□ □ □ □ □ □ □ □ □ □ □

□ □ □ □ □ □ □ □ □ □ □

□ □

□ □

CNS, central nervous system; EMG, electromyography; MEP, motor-evoked potential; N/A, not applicable.

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