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Cited by 14Transcranial Magnetic Stimulation StudiesTraumatic Brain Injury ResearchTraumatic Brain Injury and Neurovascular Disturbances

Theta burst stimulation to characterize changes in brain plasticity following mild traumatic brain injury: A proof-of-principle study

Open access
Tremblay, Sara, Vernet, Marine, Bashir, Shahid, Pascual-Leone, Alvaro, Théoret, Hugo·2015·Restorative Neurology and Neuroscience
DOI 10.3233/rnn-140459PMC PMC4850740
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Abstract

PURPOSE: Recent studies investigating the effects of mild traumatic brain injury (mTBI) suggest the presence of unbalanced excitatory and inhibitory mechanisms within primary motor cortex (M1). Whether these abnormalities are associated with impaired synaptic plasticity remains unknown. METHODS: The effects of continuous theta burst stimulation (cTBS) on transcranial magnetic stimulation-induced motor evoked potentials (MEPs) were assessed on average two weeks and six weeks following mTBI in five individuals. RESULTS: The procedure was well-tolerated by all participants. Continuous TBS failed to induce a significant reduction of MEP amplitudes two weeks after the injury, but response to cTBS normalized six weeks following injury, as a majority of patients became asymptomatic. CONCLUSIONS: These preliminary results suggest that cTBS can be used to assess M1 synaptic plasticity in subacute phase following mTBI and may provide insights into neurobiological substrates of symptoms and consequences of mTBI.

AI snapshot

Written from the paper’s full text.

TL;DR

In five individuals with mild traumatic brain injury (mTBI), continuous theta burst stimulation (cTBS) was feasible and well-tolerated, but it failed to suppress motor evoked potentials (MEPs) about two weeks post-injury and did suppress them about six weeks post-injury. These preliminary results suggest a short-lived alteration in primary motor cortex LTD-like synaptic plasticity after mTBI.

Key findings

  • cTBS was well-tolerated by all participants; the only side-effect associated with the procedure was mild neck pain for Case 2, though two patients reported mild discomfort during the procedure.
  • At session 1 (about two weeks post-mTBI; M = 14 ± 3 days), there was no significant reduction in MEP size compared with baseline at any time point.
  • At session 2 (about six weeks post-injury; sessions separated by 61 ± 19 days), significant MEP inhibition compared with baseline occurred at T0, T5, T20, T50, T60, T75, and T90; the session × time interaction was significant (F = 2.23, df = 10, p < 0.035).
  • Baseline MEP measures did not differ significantly between sessions (t(4) = −.07, p = .94).

Methods

  • Proof-of-principle case-series in five individuals with mTBI, assessed within two weeks post-injury and again approximately six weeks post-injury; all met American Academy of Neurology concussion criteria.
  • cTBS was applied over left primary motor cortex using 600 pulses (three pulses at 50 Hz, interstimulus interval 240 ms, triplet repetition rate about 4.17 Hz) at 80% of active motor threshold; MEPs were recorded from the right first dorsal interosseus muscle before and after cTBS at multiple time points.
  • Analysis used paired-sample t-tests and a within-subject repeated-measures MANOVA with session and 11 MEP time points as within-group factors; p < 0.05, no correction for multiple comparisons. One participant (Case 4) missed session 2, and missing data were replaced by the average data from the other four cases.

Limitations

  • Stated: the sample was very small and the study was exploratory, so no correction for multiple comparisons was applied; the authors state that larger prospective studies and comparison to normative values are needed.
  • Stated: one participant did not attend the second session, and missing data were replaced by the average of the other four cases.
  • Evident: the case-series design had no healthy control group and no blinding or randomization, limiting causal inference and generalizability.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3233/rnn-140459

Cites

47 of 47 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

4 of 28 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured

  • Findingown data

    The only side effect associated with the cTBS procedure was mild neck pain in one of five patients (Case 2).

    “Thus, the only side-effect associated with the procedure was a mild neck pain for Case 2.”
    • Also stated in: § Discussion · plain
      “The protocol was well-tolerated by all participants but induced a mild side-effect (neck pain) in one out of 5 patients.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The cTBS procedure was well-tolerated by all participants.

    “The procedure was well-tolerated by all participants.”
    • Also stated in: § Discussion · plain
      “The protocol was well-tolerated by all participants but induced a mild side-effect (neck pain) in one out of 5 patients.”
    Quote in the paperNot a substantial claim
  • Findingown data

    cTBS significantly inhibited MEPs compared to baseline at T0, T5, T20, T50, T60, T75 and T90 in session 2 (approximately six weeks post-mTBI).

    “A significant inhibition of the MEPs compared to baseline at T0, T5, T20, T50, T60, T75 and T90 was observed for session 2 (Table 2).”
    • Also stated in: § Discussion · hedged
      “Significant cTBS-related suppression of MEPs was observed 6 weeks post-mTBI suggesting a resolution of plasticity abnormalities beyond the acute phase.”
    Quote in the paperSubstantial claim
  • Findingown data

    A majority of patients became asymptomatic by six weeks post-injury.

    “as a majority of patients became asymptomatic.”
    Quote in the paperNot a substantial claim
  • Findingown data

    There was no significant difference between baseline MEP measures from session 1 and session 2 (t(4) = -.07, p = .94).

    “A paired-sample t-test revealed no significant difference between baseline MEP measures from both session (t(4) = -.07, p = .94).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 15
  • May combine two claims. 10
  • The quote only partly states this claim. 2

  • Classified as probably not a substantial claim.

    Premisecitation

    Animal studies have shown that bursts of 3-5 pulses at 50-100 Hz (theta rhythm) induce LTP/LTD when applied to the motor cortex or hippocampus.

    “Animal studies have shown that bursts of 3-5 pulses at 50-100 Hz (theta rhythm) induce LTP/LTD when applied to the motor cortex or hippocampus (Hess & Donoghue, 1996; Larson, et al., 1986).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Hess & Donoghue, 1996 source

      The Long-Term Potentiation section reports theta-burst-induced LTP in adult rat motor-cortex slices, but only with transient disinhibition or simultaneous stimulation of horizontal and vertical pathways; theta bursts alone failed. The Long-Term Depression section instead reports LTD after 2 Hz stimulation for 10 minutes. Our copy does not specify bursts of 3–5 pulses at 50–100 Hz or present hippocampal results for that protocol. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Larson, et al., 1986 source

  • May combine two claims.

    Premisecitation

    M1 alterations in glutamate and abnormal interactions between M1 GABA and glutamate have been shown in the acute and chronic phases of TBI and sport-related mTBI using magnetic resonance spectroscopy.

    “M1 alterations in glutamate (Babikian et al., 2006; Henry et al, 2010; Shutter et al., 2004) and abnormal interactions between M1 GABA and glutamate (Tremblay et al., 2014) have been shown in the acute and chronic phases of TBI and sport-related mTBI using magnetic resonance spectroscopy.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Babikian et al., 2006 source

      The Abstract and Discussion (pages unspecified in our copy) describe MRS measurements of glutamate/glutamine (Glx) after pediatric TBI, with scans acquired about 6 days after injury. The measured regions were occipital gray matter and parieto-occipital white matter, not M1; this paper does not establish chronic-phase or sport-related mTBI findings. The GABA interaction is attributed to a different citation in the sentence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Henry et al, 2010 source
    • cites Shutter et al., 2004 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Continuous TBS has many advantages over other techniques, including short application time, low intensity of stimulation, and reasonable intra-subject reproducibility over two separate sessions.

    “This method has many advantages over other techniques such as its short application time (Huang et al., 2005), low intensity of stimulation (Huang et al., 2005) and reasonable intra-subject reproducibility over two seperate sessions (Vernet et al., 2014).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Huang et al., 2005 source
    • cites Vernet et al., 2014 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The cTBS paradigm used in this study was recently shown to induce significant suppression of MEPs in healthy controls.

    “This paradigm was recently shown to induce significant suppression of MEPs in healthy controls (see Vernet et al., 2014).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Vernet et al., 2014 source

      The Results (section 3; page unavailable) say that cTBS suppressed MEPs on average in healthy participants, although some showed the opposite response. The copy does not report that suppression itself was statistically significant; the significance tests in section 3.1 compare visits, not post-cTBS MEPs with baseline. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Two patients reported mild discomfort during the procedure.

    “Two patients reported the presence of mild discomfort during the procedure.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    MEP suppression following cTBS could be related to LTD-like processes mediated by NMDA receptors, as NMDA-r antagonist memantine was shown to block the after effects of cTBS.

    “it has been suggested that MEP suppression following stimulation could be related to long-term depression (LTD)-like processes mediated by N-methyl-D-aspartate receptors (NMDA-r), as NMDA-r antogatonist memantine was shown to block the after effects of cTBS (Huang et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Huang et al., 2007 source

  • May combine two claims.

    Interpretationreasoning

    The hypoexcitatory or hyperinhibitory state of M1 intracortical networks could prevent the injured brain from responding adequately to cTBS and therefore be an accurate marker of early abnormal plasticity.

    “In the present study, the hypoexcitatory or hyperinhibitory state of M1 intracortical networks could prevent the injured brain from responding adequately to the effects of cTBS and therefore be an accurate marker of early abnormal plasticity.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Continuous TBS is thought to involve several neural mechanisms including long-term depression (LTD), and inhibitory mechanisms modulated by GABAergic transmission.

    “Continuous TBS is thought to involve several neural mechanisms including long-term depression (LTD), and inhibitory mechanisms modulated by GABAergic transmission (Cárdenas-Morales et al., 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cárdenas-Morales et al., 2010 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Modulation of GABA receptors and glutamate receptors has been proposed as a possible mechanism explaining excitability changes following TBS.

    “Modulation of GABA receptors (Thickbroom, 2007) and glutamate receptors (Glu-r) (Huang et al., 2007) has also been proposed as a possible mechanism explaining excitability changes following TBS.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Thickbroom, 2007 source
    • cites Huang et al., 2007 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Relaxation of the measured muscle was controlled by continuous visual EMG monitoring.

    “Relaxation of the measured muscle was controlled by continuous visual EMG monitoring.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    All participants met the concussion criteria of the American Academy of Neurology.

    “All participants were first seen by a neurologist and had to meet the concussion criteria of the American Academy of Neurology (Neurology, 1997).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Neurology, 1997 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Motor threshold was determined according to the recommendations of the International Federation for Clinical Neurophysiology.

    “Motor threshold (MT) was determined according to the recommendations of the International Federation for Clinical Neurophysiology (Rossini et al., 1994).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rossini et al., 1994 source

  • May combine two claims.

    Premisecitation

    Increased intracortical inhibition and decreased intracortical facilitation have been reported in the acute and sub-acute phases of mTBI.

    “More specifically, increased intracortical inhibition (Chistyakov et al., 2001; Pearce et al., 2014b; Miller et al., 2014) and decreased intracortical facilitation (Powers et al., 2014) have been reported in the acute and sub-acute phases of mTBI.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Chistyakov et al., 2001

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Pearce et al., 2014b

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Miller et al., 2014

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    No correction for multiple comparisons was applied because of the very small sample and exploratory purpose.

    “Because of the very small sample and the exploratory purpose of the present case report, no correction for multiple comparisons was applied.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Missing data for one participant (case 4) who did not attend session 2 were replaced by the average data from the other 4 cases.

    “One participant (case 4) did not come to the second session. For statistical analyses, the missing data were replaced by the average data from the 4 other cases.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Interpretationcitation

    The present data are in line with the hypothesis that TBS targets both excitatory and inhibitory networks within the human motor cortex.

    “The present data are in line with this hypothesis since M1 alterations in glutamate (Babikian et al., 2006; Henry et al, 2010; Shutter et al., 2004) and abnormal interactions between M1 GABA and glutamate (Tremblay et al., 2014) have been shown in the acute and chronic phases of TBI and sport-related mTBI using magnetic resonance spectroscopy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Taken together, these studies suggest the presence of impaired balance between primary motor cortex excitatory and inhibitory mechanisms following mTBI both in the acute and chronic phases, which may be related to abnormal M1 plasticity.

    “Taken together, these studies suggest the presence of impaired balance between primary motor cortex excitatory and inhibitory mechanisms following mTBI both in the acute and chronic phases, which may be related to abnormal M1 plasticity.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Interpretationown data

    cTBS can be safely applied in the acute phase of mTBI.

    “The protocol was well-tolerated by all participants but induced a mild side-effect (neck pain) in one out of 5 patients.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    Neuronavigation was used to ensure stable coil positioning and target the same cortical location within each session.

    “In order to ensure stable coil positioning over the stimulation site during the experimentation and to ensure that the exact same cortical location was targeted within each study session as defined by each individual's brain MRI, a Nexstim eXimia Neuronavigation system was used.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    De Beaumont et al. (2012) reported that increased silent period durations in concussed athletes, presumably reflecting faulty GABAB transmission, were negatively correlated with the level of synaptic plasticity induced with paired associative stimulation.

    “De Beaumont et al. (2012) reported that increased silent period durations in concussed athletes, presumably reflecting faulty GABAB transmission, were negatively correlated with the level of synaptic plasticity induced with paired associative stimulation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites De Beaumont et al., 2012 source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Chronic alterations in synaptic plasticity, possibly reflecting faulty LTP- and LTD-like mechanisms, were found after multiple concussions and were associated with intracortical inhibition abnormalities.

    “Moreover, chronic alterations in synaptic plasticity, possibly reflecting faulty long term potentiation (LTP) – and long term depression (LTD) - like mechanisms were found after multiple concussions, and were associated with intracortical inhibition abnormalities (De Beaumont et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites De Beaumont et al., 2012 source

  • May combine two claims.

    Premisecitation

    Continuous TBS is a repeated TMS protocol that induces long lasting reduction of corticospinal excitability and allows non-invasive and rapid assessment of motor cortex plasticity.

    “Continuous theta-burst stimulation (cTBS) is a repeated TMS protocol that induces long lasting reduction of corticospinal excitability and allows non-invasive and rapid assessment of motor cortex plasticity (Huang et al., 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Huang et al., 2005 source
22 of 22

  • The authors state this as an assumption.

    The integrity of synaptic plasticity mechanisms following human mTBI in the acute phase has not been investigated.

    “To our knowledge, the integrity of synaptic plasticity mechanisms following human mTBI in the acute phase has yet to be investigated.”

  • The authors state this as an assumption.

    Whether the abnormalities in M1 excitatory/inhibitory mechanisms are associated with impaired synaptic plasticity remains unknown.

    “Whether these abnormalities are associated with impaired synaptic plasticity remains unknown.”

  • The paper relies on this without support.

    Impairments in M1 plasticity could prevent adaptive plastic changes following injury and may themselves be the cause of pathological processes and functional disability.

    “This is of major importance since impairments in M1 plasticity could prevent adaptive plastic changes to occur following injury and may themselves be the cause of pathological processes and functional disability.”

  • The paper relies on this without support.

    Altered metabolite interactions and plasticity mechanisms within M1 could be a key feature of mTBI pathophysiology.

    “As recent studies have suggested that altered metabolite interactions and plasticity mechanisms within M1 could be a key feature of mTBI pathophysiology, the goal of the present proof-of-principle study was to determine whether cTBS could be used to assess the integrity of plasticity mechanisms in the acute and sub-acute phases of mTBI.”
4 of 4

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Consistentt(4) = -0.07reported p = .94 · recomputed p = .948

    “t(4) = -.07, p = .94”

1 of 1

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Second visit timing conflicts with the reported six-week follow-up

    Major

    The first visit averaged 14 days after injury, and the visits were separated by an average of 61 days. That places the second visit at about 75 days, or nearly 11 weeks after injury, rather than six weeks; the paper's conclusion about recovery by six weeks depends on this timing.

1 of 1

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Related

Authors
Tremblay, S., Vernet, M., Bashir, S., Pascual-Leone, A., & Théoret, H.
Affiliations
  • Centre Hospitalier Universitaire Sainte-Justine (CA)
  • Beth Israel Deaconess Medical Center (US)
  • Berenson-Allen Center for Non-Invasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, USA, 02215
Corresponding author
Théoret, Hugo
ORCID
Venue
Restorative Neurology and Neuroscience
Publisher
SAGE Publications
Published
2015-10-05
Volume
33
Issue
5
Pages
611-620
ISSN
  • 0922-6028 (ISSN-L)
  • 1878-3627
DOI
10.3233/rnn-140459
PMC
PMC4850740
OpenAlex
W164909400
Semantic Scholar
c1dab56db257abb66879fcef8bf5bcc41027181f
Cited by
14
References
47
Citations by year
2026: 1 · 2022: 3 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 1
FWCI
1.07
Type
journal article
Language
en
Open access
Locations
  • Restorative Neurology and Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
Funders
  • National Institutes of Health (UL1TR000170)
  • Canadian Institutes of Health Research
  • National Institute of Mental Health (R21 MH099196)
  • National Institute of Neurological Disorders and Stroke (R01NS073601, R21NS082870, R21NS085491)
  • National Center for Research Resources (UL1RR025758)
  • National Center for Advancing Translational Sciences
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD069776)
Topics
  • Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
mild traumatic brain injury, continuous theta burst stimulation, synaptic plasticity, primary motor cortex, motor evoked potentials, excitation-inhibition balance, subacute phase, transcranial magnetic stimulation
MeSH terms
Adult, Brain Injuries, Electromyography, Feasibility Studies, Female, Humans, Male, Motor Cortex, Neuronal Plasticity, Evoked Potentials, Motor, Transcranial Magnetic Stimulation, Young Adult

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