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Using transcranial magnetic stimulation to quantify electrophysiological changes following concussive brain injury: A systematic review. Brendan P. Major, Mark A. Rogers, Alan J. Pearce. Cognitive Neuroscience Laboratory School of Psychology Deakin University Corresponding Author: Alan J Pearce PhD School of Psychology Deakin University 221 Burwood Highway Burwood, Victoria, 3125 AUSTRALIA Phone: +61 3 9251 7224 FAX: +61 3 9244 6858 Email: alan.pearce@deakin.edu.au

 

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Abstract

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),

has been demonstrated to provide prognostic value in a range of neurological conditions;

however, no review has quantified the efficacy of TMS in mTBI/concussion. We present a

systematic review and critical evaluation of the scientific literature from 1990-2014 that has

used TMS to investigate corticomotor excitability responses at short-term (<12 months),

medium-term (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 medium-term 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 suggests that TMS has prognostic value in detecting

neurophysiological changes post mTBI/concussion.

 

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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. Whilst TBI is

a considerable global contributor to death and disability, particularly in children and young

adults1, mTBI is now being associated with long-term detrimental health consequences2, 3.

Consequences of head impacts are usually observed through clinical signs of being dazed,

confused, balance problems, transient amnesia and sometimes loss in consciousness.4

However, there is a growing body of evidence to suggest that head impacts may, in some

cases, result in continuing symptoms. For instance it has been documented that in some cases

a concussion may 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 may 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 is still

relatively unknown12. Current evidence in humans is limited to neurological reports,

neurocognitive studies,13-15 and neuroimaging.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, 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,

 

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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 pre-

testing 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 following 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 (see

Figure 1).25, 27

There are a number of TMS-dependent measures that can be obtained to understand

corticospinal excitability and inhibition. These include (1) motor threshold (MT) defined as

the lowest stimulus intensity to lowest stimulus intensity to produce a detectable MEP;28, 29

(2) central motor conduction time (CMCT) being the latency period difference between

 

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stimulation of the motor cortex and stimulation of cervical nerves to onset of the MEP;29 (3)

the MEP waveform reflecting the excitability of motor cortex, corticospinal tract and motor

units in the target muscle26; and (4) cortical inhibition, quantified as absent 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 return of uninterrupted EMG activity,30 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 γ-aminobutyric acid type b receptor

(GABABR) activity.30, 31

<Figure 1 here>

Paired-pulse TMS protocols (see Figure 2 for examples) 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).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 ISIs between 1-5 ms, with a sub-threshold CS and a supra-

threshold TS, the test MEP is suppressed (compared to a single pulse MEP). Known as short-

interval intracortical inhibition (SICI), it is postulated that SICI is mediated by γ-aminobutyric

acid type A receptor (GABAAR) activity.32, 33 Conversely, ISIs of between 10-25 ms results in

the test MEP facilitated and is termed intracortical facilitiation34 possibly reflecting

glutamatergic N-methly-Daspartate (NMDAR) activity.35 When two suprathreshold stimuli

are presented at ISIs between 80-200 ms intervals, the TS is inhibited and termed long-

interval intracortical inhibition (LICI). Like cSP, LICI reflects GABABR actvity36 mediated

cortical inhibition, however it is thought that cSP and LICI derive from different neuronal

populations.37, 38

 

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<Figure 2 here>

With observations of motor abnormalities shortly after a concussion,39 as well being the

earliest clinical manifestation of repeated head injuries,17 it is reasonable to hypothesize that

the motor cortex can also be affected. 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

Figure 3 illustrates the flow of studies through the systematic review process returning an

initial yield of 668 citations. Of these, 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 TBI41). 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.

<Figure 3 here>

 

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Study characteristics and TMS quality assessment

Table 1 shows characteristics for all studies. Sample sizes ranged from 1842, 43 to 60

participants.44 The mean number of concussions ranged from one to five, with an overall

mean of two. Mean age of participants tested ranged between 20.0 and 60.8 years of age, with

a predominance of males (381 males, 40 female). However, no gender differences were

reported in any studies that used mixed gender groups for both mTBI/sports concussion, and

healthy controls.42, 43, 45, 46

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,40, 43, 44, 47 motor control performance,44, 48 electrophysiology40, 49 and

neuroimaging.50

<Table 1 here>

Classification of brain injury

Classification and grading of mTBI was heterogeneous amongst the 13 studies. Six

studies40, 45-47, 49, 50 used the Glasgow coma scale (GCS). Of those six studies, four primarily

investigated sports concussion.40, 47, 49, 50 Consequently, they also used the American Academy

of Neurology (AAN) guidelines to grade concussion severity.51

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

comparison to a healthy control group. One study47 used the number of concussion injuries to

sub-categorize the investigated sample (multiple vs. single vs. control).

 

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Miller et al39 used the sideline concussion assessment tool, version 3 (SCAT 3) to grade

concussion severity. Two studies by De Beaumont et al 48 and Pearce et al 44 did not report

severity of injury. Pearce et al44 did however classify concussion according to Australian

Football League’s definition for concussion of having missed the following week’s game.52

Transcranial magnetic stimulation

All studies presented MT, with one study comparing inter-hemispheric MTs.45 Two studies

42, 43 presented both MEP latency and central motor conductive time, whilst one study

presented central motor conductive time only.45 All but one study measured MEP

amplitude.48 cSP was presented in all but three studies.42, 43, 46 Inter cortical facilitation were

presented in three studies,40, 47, 53 SICI in six studies,40, 44, 47, 49, 53, 54 and LICI in five studies.44,

48-50, 53

Short-term studies

Six studies investigated the acute changes in TMS measures post TBI/concussion (see

Table 2).39, 42, 43, 45, 53, 54 Chistyakov et al45 presented data two weeks post TBI, whilst

Livingston and colleagues42, 43 presented time-course data up to 10 days post-concussion in

athletes. Pearce et al,54 Power et al53 and Miller et al39 all investigated changes between 24

hours to 34 days post-injury.

The main findings were a decrease in MT post injury.42, 43, 45 Chistyakov et al.,45 Pearce et

al54 and Miller et al39 also reported an increase in cSP duration in mTBI individuals when

compared with controls and Chistyakov et al45 reported lengthened cSP in mild and moderate

head injuries.

<Table 2 here>

 

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Medium-term studies

Table 3 shows studies of people between 1-5 years post-concussion. Two studies compared

MT46, 47 whilst De Beaumont et al47 also measured MEP amplitude between two groups of

concussed participants (“single” and “multiple”) and compared to healthy controls with no

history of concussion. No differences were observed between any of the three groups for MT

and MEP amplitude. Conversely, Tallus et al46 found increased MT in those with mTBI

compared to non-injured controls.

Four studies measured cSP, with three reporting lengthened cSP duration in concussed

versus controls.47-49 De Beaumont et al47 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 may 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 non-concussed individuals.50

De Beaumont et al47 found no intracortical facilitation differences between single

concussion, multiple concussions and control groups. De Beaumont et al,47 and Tremblay et

al49 presented SICI data, with no differences between groups. Long intracortical inhibiton was

measured by Tremblay and colleagues,49, 50 and De Beaumont et al.48 Significant differences

in LICI were reported between concussed and control groups in two48, 49 of these three

studies.

<Table 3 here>

Long-term studies

 

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Table 4 presents the two studies reporting long-term neurophysiological changes after a

history of concussions.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 al44 found a shortening in

cSP duration and associated increases in SICI and LICI in older retired Australian football

players an average 22 years after last concussion.

<Table 4 here>

DISCUSSION

Whilst extensively used to quantify changes in neurological conditions26, 55 there has been

no review that has evaluated the efficiency of TMS in mTBI/concussion. 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, collectively these studies

have shown potential in 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,39, 42, 43, 45, 54 two of two in the ‘long-term’ (>5 years).40, 44 In the ‘medium-term’ (1-5

years), four studies out of 5 reported a difference.46-49 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

 

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seen in MEP amplitude, SICI or intracortical facilitation. Other reported findings, but 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,56

evidence suggests that cSP is generated predominately via activation of cortical inhibitory

neurons in the motor cortex30, 57-59 and mediated by γ-Aminobutyric acid (GABAB) receptor

activity.59 Evidence for this has been demonstrated in pharmacological studies demonstrating

GABAB receptor agonists and GABA reuptake inhibitors can lengthen the cSP duration.31, 59

Despite the complexity underlying the mechanisms contributing to cortical inhibition, the cSP

is a reliable measure,30 allowing for assessment of cortical inhibition in health and disease.26

For example, in healthy populations, aging is associated with a longer cSP.60 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 (see review by Wolters et al61). 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.62 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.63 Limited literature on psychiatric conditions, such

as major unipolar depression and schizophrenia, has also reported abnormally altered cSP.64,

65

 

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In this review, across short-, medium-, and long-term concussed athletes, cSP was

lengthened in all but three studies that presented cSP data. Measuring acute phase

concussions in college athletes between one and four weeks post-concussion, Powers et al53

presented no differences in cSP between groups. Similarly, in medium-term studies,

Tremblay et al50 found no difference in cSP duration. However, in long-term studies, Pearce

et al44 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 reported to be stable and long lasting.44, 54 This may indicate a shift of

excitability more towards inhibition following mTBI. It must be noted that in acute studies

Chistyakov et al45 only reported change in cSP duration in “mild to moderate” head injuries

and in medium term studies De Beaumont et al47 changes were only seen in the group that had

repeated concussion and not in single concussion group. This evidence may suggest that

changes in cSP duration maybe 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 al53 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 al50 suggested the difference in findings

between their own and previous studies may lie in the lower number of concussions sustained

in their cohort46-48 whilst the participants in Pearce et al44 were on-average 10-12 years

younger, and played a different sport to those studied by De Beaumont et al.47

With TMS relatively underutilized in mTBI/concussion research, this review is currently

limited in terms of the total number of papers presented, and the number of laboratory groups

 

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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 this review presented complimentary measures

allowing for interpretation. For example, De Beaumont et al,40, 47, 48 Livingston et al43 and

Pearce et al 44 included neurocognitive testing; De Beaumont and colleagues,40, 48 Pearce et

al,44 and Power et al53 completed motor task testing; electroencephalography and

somatosensory evoked potentials, and neuroimaging data were also presented in the studies

by De Beaumont et al,40 and Trembley and colleagues49, 50 respectively.

In conclusion, despite limited studies, TMS is useful to quantify corticomotor changes

following concussion. This reliable and non-invasive 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, SportsDiscus, 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 Evoked Potential, gamma-aminobutyric acid, GABA, motor cortex,

excitation, inhibition, motor threshold, facilitate, neurophysiology, intracortic*, concussion*,

 

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mild traumatic brain injury, trauma and head injury. Two authors (BM & AP) then

independently screened the titles and abstract 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. Full

text PDFs of articles were obtained and exported with their citations into Endnote (X7,

Thompson Reuters), with no further modification of references. Figure 3 outlines studies

removed following application of criteria according to Preferred Reporting Items for

Systematic Reviews and Meta-Analyses (PRISMA) guidelines.66 The PRISMA guidelines are

used by the Cochrane Collaboration to help authors improve the reporting of systematic

reviews and meta-analyses. PRISMA is generally focused to report on randomized trials.

However, PRISMA can also be used as a basis for reporting systematic reviews of quasi-

experimental research. Although no meta-analyses was completed in this study, it was

important to outline the steps completed in this systematic review to determine studies for

presentation in this review.

Criteria for Inclusion

Each database search was limited to peer reviewed, full text publications printed in English

between years 1990–2014. Exclusion criteria were applied to each search (1) Non-peer or

limited review conference proceedings, (2) Conference abstracts, (3) Books, and (4) Theses

(PhD, Masters, Honours). Only studies conducted on humans aged over 18 years were

included. One study67 was excluded because relevant TMS results were previously reported.46

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,26

rather than as a prognostic method to assess corticomotor excitability which was the aim of

this review. Because of the difficulty delineating between sports concussion and mTBI in the

 

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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 months54, or conversely decades later.40, 44 The average time, as opposed to

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 and colleagues47, 48 set 9 months and 10 months for their inclusion criteria.

However the average times frame for each mTBI group was 19.0 months for De Baumont et

al 48, 59.1 and 31.0 months for time post single and multiple concussions respectively, again

for De Beaumont and colleagues47, and 23.2 and 36.1 months for Tremblay et al.49, 50

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.68 A TMS

checklist was used to assess the methodological quality of studies.69 This checklist aimed to

indicate if the TMS methodological quality of a study could be a possible source of study

bias.70 The checklist (supplementary material appendix A) covers participant characteristics,

methodology and results analysis.69 Single pulse TMS protocols were evaluated on a 27-item

 

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checklist. A single score for each item on the checklist was given if it was reported in the

study.

 

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                        Figure 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. Latency duration is measured from stimulus artifact to MEP onset and is shown at (a), peak to peak MEP amplitude is shown at (b). Silent Period duration is measured from onset of MEP to return of EMG at (c). Return of EMG activity is shown at (d). Figure from the authors’ personal collection.  

a

b

c d

1  mV  

100  ms  

 

 

                        Figure 2. Example of paired pulse TMS measures. (a) Short intracortical inhibition (SICI) waveform (right) next to a single pulse MEP (left); and (b) long intracortical inhibition waveform. (a) Following a double pulse (in this illustration with an interval of 3 ms, on right) the inhibited smaller SICI waveform (on right) is calculated to a single pulse MEP taken separately (on 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 wavefom on left. Figure from the authors’ personal collection.  

100  ms    

1  mV  

Records  identified  through  database  searching  (n  =  668)  

Additional  records  identified  through  reference  lists  

(n  =  17)  

Records  after  duplicates  removed  (n  =  406)  

Records  screened  for  title  and  abstract  (n  =  406)  

Records  excluded  (n  =369)  

Full-­‐text  articles  assessed  for  eligibility  (n  =  37)  

Full-­‐text  articles  excluded  (n  =  27)  

 • Used  a  Repetitive  

TMS  protocol  • Used  TMS  as  a  

treatment  • Severity  of  

concussion  too  severe  

• TMS  not  assessing  changes  in  the  motor  cortex  

Studies  included  in  initial  quantitative  synthesis  

(n  =  10)  

Studies  included  in  final  quantitative  synthesis  

(n  =  13)  

Figure 3. PRISMA flowchart of search method.36

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

 

Reference TMS Score Groups

Population Time since last concussion

Severity of concussion

Severity scale used

No. of concussions

Recruitment population Additional assessment(s)

M F Age

Chistyakov et al.,45 23

Concussion 9

33.2 ± 13.2

2 weeks Minor

GCS

1

Hospital None Diffuse brain injury 7 2 weeks Moderate 1

Focal lesion 11 2 weeks Mild - mod 1 Combined lesion 9 2 weeks Mild - mod 1

Control 15 5 X X X

De Beaumont et al., 47 21 Multiple 15 23.4 ± 2.6 31 ± 22.1 months Grade 1 - 3

GCS 2+

University NFL neuropsychological testing Single 15 22.9 ± 2.8 59.1 ± 69.5 months Grade 1 - 3 1

Control 15 22.5 ± 2.5 X X X

De Beaumont et al., 48 14 TBI 21 22.3 ± 3.4

19 ± 13.7 months X X

1 - 5 University

Centre of pressure oscillation Centre of pressure

displacement

Control 15 X X X Rapid Alternating Movement (RAM) Task

De Beaumont et al., 40 17 TBI 19 60.8 ± 5.2 30+ Years Grade 2 - 3 GCS & AAN

1 - 5 Former University

Mini-mental score RAM Task

Control 21 58.9 ± 9.1 X X X Flanker Task

Livingston et al., 42 17 TBI 6 3 20.4 ± 1.3 < 24 Hours Head injury scale University None

Control 6 3 20 ± .9 X X X

Livingston et al., 43 20 TBI 6 3 20.4 ± 1.3 < 24 Hours Grade 1 - 3 Head injury scale

1 University Internet based neurocognitive

Control 6 3 X X X Concussion resolution index

Miller et al., 39 22 TBI 8 7 20.8 ± 1.2 72 Hours Mild SCAT 1 General None Control 8 7 21.1 ± 1.3 X X x

Pearce et al., 44 24 TBI - Professional 20 49.7 ± 5.7 20 + years miss a game

AFL Average 3.1 Former

recreational & professional

football

Fine Dexterity & associated learning

TBI - amateur 20 48.8 ± 6.9 20 + years miss a game Average 3.1 Visuomotor reaction time Controls 20 47.6 ± 6.8 X X X Spatial working memory

Pearce et al., 54 28 TBI 8 25.1± 4.5 < 24 Hours X X 1 Australian football

Fine motor dexterity, reaction time, implicit learning,

attention Control 15 X X X

Power et al., 53 22 TBI 8 20.2 ± 1.2 6 - 34 Days X SCAT 2 1 University Voluntary muscle activation and sensation of force Control 8 20.3 ± 1.5 X X

Tallus et al., 46 21 TBI - Symptomatic 4 7 43.7 ± 11.6 6.1 years 14.8 ± .4

GCS 1

Hospital Magnetic resonance imaging TBI - Asymptomatic 4 4 35.9 ± 15.9 3.8 years 14.1 ± .8 1 Controls 6 3 33.6 ± 13.2 X X X

Tremblay et al., 50 24 TBI 16 22 ± 1.1 3.1 years Grade 1 - 2 AAN & GCS

1.88 University Proton magnetic resonance spectroscopy

Control 14 22 ± 1.1 X X X

Tremblay et al., 49 23 TBI 12 ? 23.2 months Grade 1 - 3 AAN& GCS

3.25 University Somatosensory evoked potential

Control 14 22.4 ± 1.7 X X X

GCS: Glasgow coma scale; AAN: American Academy of Neurology; SCAT/SCAT2: Sports concussion assessment tool: ‘X’ refers to not stated or unknown

 

 

Table  2.  Studies investigating short-term responses (<12 months) following a concussion/mTBI    

Reference MEP Threshold % Stim MEP Amplitude ICF Changes SICI changes LICI Changes cSP Changes @ 130%

Chistyakov et al., 45

Control 40.2 Control 29.9 ± 9.9 %

X X X

Control 150.8 ms

Minor 42.3 Minor 32.1 ± 13.5 % Minor 151.9 ms

Mild 55.9 * Mild 12.1 ± 9.3 % Mild 196.1 ms*

Moderate 60.7 * Moderate 15.3 ± 12.7 % Moderate 194.7 ms*

Miller et al., 39 72 Hrs 2 Months 72 Hrs 2 Months

x x x 72 Hrs 2 Months

TBI 49.13 ± 1.7 46 ± 3.24 TBI .53 ± .08 .95 ± .07 TBI 111.5 ± 9.4* 112.01 ± 6.06*

Control 45.07 ± 1.7 44.75 ± 1.88 Control .99 ±.19 .63 ± .15 Control 85.7 ± 6.5 95.69 ± 7.26

Pearce et al., 54 Pre 10 days Pre 10 days

X 10 days

X 48 Hrs 96 Hrs

TBI 44.1 ± 5 44.4 ± 5.1 TBI .38 ± .14 .34 ± .16 TBI .28 ± .12 TBI 135.4 ± 26.8* 137.1 ± 26.8*

Control 41.3 ± 8.2 41.8 ± 7.9 Control .32 ± .14 .31 ± .15 Control .27 ± .12 Control 117.7 ± 20 114.3 ± 16.1

Power et al., 53 TBI 56 ± 6.4 TBI .92 ± .2 TBI 1.1 ±

.14 TBI .41 ± .13 TBI .63 ± .27 TBI 158 ± 25 ms

Control 59.5 ± 9.6 Control .83 ± .16 Control 1.9 ± .31 Control .47 ± .14 Control .57 ±

.26 Control 173 ± 41 ms

Livingston et al., 42

Day 1 Day 10 Day 1 Day 10

X X X X TBI 52.4 ± 8.8* 54.5 ± 7.0* TBI 0.38 ± .16 0.37 ± .21

Control 55.7 ± 6 55.3 ± 5.7 Control .40 ± .17 0.32 ± .23

Livingston et al.,43

Day 1 Day 10 Day 1 Day 10

X X X X TBI 52.4 ± 8.8* 54.5 ± 7.0* TBI 0.38 ± .16 0.37 ± .21

Control 55.7 ± 6 55.3 ± 5.7 Control 0.40 ± .17 0.32 ± .23

Data from studies investigating neurophysiological changes immediately to 1 year following mTBI. Motor evoked potential stimulus and amplitude response (MEP). Resting and active measures were taken (MEP and cSP) as well as paired pulse measure Intra cortical facilitation (ICF), Short latency intracortical inhibition (SICI), Long Latency intracortical inhibition (LICI). * Represents a significant difference between groups (P<.05)

 

 

Table 3. Studies investigating medium-term responses (1-5 years) following a concussion/mTBI

 Reference MEP Threshold % Stim MEP Amplitude ICF Changes SICI changes LICI Changes cSP Changes @ 120%

De Beaumont et al., 47

Control 53 ± 9.53 Control 1.6 ± .16 % Control 1.88 ± .35 Control 0.66

X

Control: 101.4 ± 7.12

Single 56 ± 18.27 Single 0.77 ± .2 % Single 2.16 ± .41 Single 0.84 Single 124 ± 5.9

Multiple 53 ± 7.19 Multiple 1.6 ± .36 % Multiply 1.49 ± .26 Multiple 0.8 Multiple 129.8 ± 5.42*

De Beaumont et al., 48 X Not reported X X

Control .52 ± .034 Control 142.8 ± 4.05

TBI .27 ± .051* TBI 165.76 ± 5.01*

Tallus et al., 46

Control 43 ± .08

Not reported X X X X Recovered 54.6 ± 3.4 *

Symptomatic 52.5 ± 3.1 *

Tremblay et al., 50 X Not reported X X

Control: 76.14 ± 18.39 Control: 141 ± 10.38

TBI 61.25 ± 20.16 TBI 137.92 ± 13.45

Tremblay et al., 49 X Not reported X

Ratio Ratio Msec

Control .40 ± .17 Control .42 ± .23 Control 137.38 ± 27.95

TBI .31 ± .17 TBI .23 ± .21* TBI 166.78 ± 31.08*

Data from studies investigating neurophysiological changes 1 year following mTBI up to 5 years post injury. Motor evoked potential stimulus and amplitude response (MEP). Resting and active measures were taken (MEP and cSP) as well as paired pulse measure Intra cortical factilitation (ICF), Short latency intracortical inhibition (SICI), Long Latency intracortical inhibition (LICI).

* Represents a significant difference between groups (P<.05)

   

 

 

Table 4. Studies investigating the long-term responses (>5 years) following the participant’s last concussion/mTBI

   

Reference MEP Threshold % Stim MEP Amplitude ICF Changes SICI changes LICI Changes cSP Changes @ 120%

De Beaumont et al., 40

Control 41.06 ± 2.16 Control 1.73 ± .42 % Control 1.22 ± 1.2 Control .92 ± .11

X

Control 126.9 ± 5.12

TBI 40.76 ± 1.26 TBI 2.49 ± .3 % TBI 2.02 ± .36 TBI .92 ± .18 TBI 156.89 ± 5.97*

Pearce et al., 44 Not reported

Control 23.9 ± 11.71 %

X

Control 25 ± 14 Control 38 ±17 Control 135.12 ± 17.70

Professional 19.7 ± 8.25 % Professional 38 ± 19 Professional 49 ± 19 Professional 95.0 ± 29.03*

Ameteur 22.2 ± 10.01 % Ameteur 35 ± 17 Ameteur 52 ± 17 Ameteur 101.21 ± 22.64*

Data from studies investigating neurophysiological changes more than 5 years following mTBI. Motor evoked potential stimulus and amplitude response (MEP). Resting and active measures were taken (MEP and cSP) as well as paired pulse measure Intra cortical factilitation (ICF), Short latency intracortical inhibition (SICI), Long Latency intracortical inhibition (LICI). * Represents a significant difference between groups

 

Supplementary 1. TMS methods checklist.44