Investigation of neurobiological responses to theta burst stimulation during recovery from mild traumatic brain injury (mTBI)

May combine two claims.

There are currently no treatments considered effective for acute or ongoing symptoms of mTBI.

“There are currently no treatments that are considered effective for acute (Gravel et al., 2013) or ongoing symptoms of mTBI (Prince & Bruhns, 2017).”

• cites Gravel et al., 2013 sourceSupported
• cites Prince & Bruhns, 2017 sourceDisputed

  The Prince and Bruhns citation is attached to ongoing symptoms, not acute symptoms. Section 7.2 acknowledges limited research on treatments for persistent post-concussive symptoms but reports adequate support for cognitive-behavioral therapy; Section 8 also describes growing support for intervention efficacy. That contradicts the categorical claim that no treatments are considered effective for ongoing symptoms. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

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

TEPs, particularly later TEPs, are influenced by somatosensory and auditory processing of the TMS pulse.

“While TEPs (particularly later TEPs) have been demonstrated to be influenced by somatosensory and auditory processing of the TMS pulse (Conde et al., 2019;Nikouline et al. 1999;Biabani et al. 2019;Biabani et al. 2021)”

• cites Conde et al., 2019 sourceSupported
• cites Nikouline et al. 1999 sourceNot checked — no full text of the source
• cites Biabani et al. 2019 sourceSupported

Classified as probably not a substantial claim.

Induction of long-lasting plasticity-related changes in cortical activity has promising application in neurological disorders.

“This has significant clinical and therapeutic implications, the induction of long lasting plasticity-related changes in cortical activity, yielding promising application in neurological disorders (Huerta & Volpe, 2009).”

• cites Huerta & Volpe, 2009 sourceSupported

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

Both rounds of component rejection following FastICA used a semiautomated artefact detection algorithm based on previous research and the TESA toolbox.

“Both rounds of component rejection following FastICA utilised a semiautomated artefact detection algorithm, based on previous research (Rogasch et al., 2014) and using TESA toolbox (Rogasch et al., 2017).”

• cites Rogasch et al., 2014 sourceNot checked — no full text of the source
• cites Rogasch et al., 2017 sourceSupported

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

Dysregulated connectivity is associated with higher self-reported symptoms and poorer cognitive performance, leading mTBI to be conceptualized as a disorder of brain connectivity and a disconnection syndrome.

“Associations have been reported between dysregulated connectivity, higher levels of self-reported symptoms and poorer cognitive performance, leading mTBI to be conceptualized as a “disorder of brain connectivity” (Hayes, Bigler, & Verfaellie, 2016) and a “disconnection syndrome” (Coyle, Ponsford, & Hoy, 2018).”

• cites Hayes, Bigler, & Verfaellie, 2016 sourceSupported
• cites Coyle, Ponsford, & Hoy, 2018 sourceNot checked — no full text of the source

May combine two claims.

EEG studies have demonstrated differences in ERP amplitude, increased alpha power, and poor fronto-parietal coherence during verbal and visuospatial working memory tasks in mTBI.

“Using EEG, differences in the amplitude of event-related potentials (ERPs) (Bernstein, 2002;Ozen, Itier, Preston, & Fernandes, 2013), increased alpha power (Arakaki et al., 2018) and poor coherence (the temporal dependence of neuronal activity across brain regions) between fronto-parietal regions during verbal and visuospatial working memory tasks has also been demonstrated in mTBI (Cudmore, 2000;”

• cites Bernstein, 2002 sourceNot checked — no full text of the source
• cites Ozen, Itier, Preston, & Fernandes, 2013 sourceNot checked — no full text of the source
• cites Arakaki et al., 2018 sourceSupported

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

iTBS is dose-dependent and repeated application may be of benefit.

“It has also been suggested that iTBS is dose-dependent and repeated application may be of benefit (Nettekoven et al., 2014).”

• cites Nettekoven et al., 2014 sourceSupported

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

In response to increased working memory load, mTBI participants show increased activation outside typical working memory circuitry, suggesting recruitment of additional resources as a possible compensatory response.

“In response to increased working memory load, mTBI participants have been shown to increase activation in areas outside typical working memory circuity, suggesting recruitment of additional resources as a possible compensatory response post-injury (Chen et al., 2012;Hillary, 2008).”

• cites Chen et al., 2012 sourceNot checked — no full text of the source
• cites Hillary, 2008 sourcePartly supported

  The ‘Current Findings in Clinical Imaging of WM’ section reports that PFC activation changes with working-memory load in people with mild TBI and discusses recruitment of PFC resources as a possible support mechanism (page unavailable). It does not establish that the additional activation is outside typical working-memory circuitry; it identifies PFC as the most consistent site of recruitment and notes that load-related PFC changes also occur in healthy adults. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

iTBS may have induced larger performance gains in lower capacity individuals, but this effect could have been averaged out by individuals with higher capacities and a greater number of epochs.

“iTBS may have induced larger performance gains in lower capacity individuals (Guse, Falkai, & Wobrock, 2010), however this effect could have been averaged out by individuals with higher capacities and a greater number of epochs.”

• cites Guse, Falkai, & Wobrock, 2010 sourceCould not verify

  The citation is attached to the suggestion that iTBS may produce larger gains in lower-capacity individuals, not to the citing authors’ subsequent explanation about averaging. The Discussion says studies were still underway to test theta-burst stimulation’s cognitive effects; the passages found on clinical status and baseline performance do not address whether iTBS benefits lower-capacity individuals more. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

May combine two claims.

Shearing forces during mTBI are thought to cause diffuse axonal injury, which results in dysregulated structural and functional connectivity.

“Because of the shearing forces during the mTBI injury, a complex spectrum of axonal abnormalities known as diffuse axonal injury (DAI) are thought to result in dysregulated structural and functional connectivity”

• cites Armstrong, Mierzwa, Marion, & Sullivan, 2016 sourceNot checked — no full text of the source
• cites Eierud et al., 2014 sourcePartly supported

  The Discussion reports white-matter abnormalities and altered fMRI activity after mTBI, and discusses imaging changes expected after TBI-induced axonal injury. It does not establish the claimed chain from shearing forces to diffuse axonal injury to dysregulated structural and functional connectivity; its discussion of the underlying mechanisms is cautious. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Medaglia, 2017 sourcePartly supported

  The TBI Epidemic and Basic Pathophysiology section says rotational forces can stretch and shear axons, causing focal and diffuse axonal damage. Nodes, Networks, and TBI links anatomical injury to changes in functional connectivity, and Scaling to Graph Theoretic Analyses reports functional connectivity disturbances. The paper presents these points for TBI generally; it does not explicitly establish the claimed sequence specifically for mild TBI or call the abnormalities diffuse axonal injury. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

Abnormal coherence and working memory impairments have been linked to diffuse axonal injury, highlighting a relationship between neurophysiology and cognition.

“Abnormal coherence (Sponheim et al., 2011) and working memory impairments (Chung et al., 2019) have been linked to DAI, highlighting the relationship between neurophysiology and cognition.”

• cites Sponheim et al., 2011Not matched

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

• cites Chung et al., 2019 sourcePartly supported

  The Discussion reports poorer working-memory performance alongside a microstructural measure associated with axon injury in patients with mild traumatic brain injury. It does not establish that these patients had diffuse axonal injury specifically. The separate abnormal-coherence claim is attributed to Sponheim et al., not to Chung et al. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

T-test designs were used because cluster-based permutation analyses implemented in Fieldtrip are not well suited to 2 x 2 designs.

“T-test designs were used as cluster based permutation analyses implemented in Fieldtrip (the analysis software most commonly used to examine TEPs) are not well suited to 2 x 2 designs (Oostenveld et al., 2011).”

• cites Oostenveld et al., 2011 sourcePartly supported

  Section 2.7.7 (page not available) describes FieldTrip’s statistical inference using parametric or nonparametric algorithms, and the Concluding Remarks identify its implementation of nonparametric permutation tests. Neither passage says those analyses are poorly suited to 2 × 2 designs or supports the claim that FieldTrip is the software most commonly used to examine TEPs. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

Preliminary evidence suggests that applying TBS to cognitively relevant areas such as the DLPFC modifies neurophysiology and can modulate cognitive performance.

“Furthermore, preliminary evidence suggests applying TBS to cognitively relevant areas, such as the dorsolateral prefrontal cortex (DLPFC) modifies neurophysiology and can modulate cognitive performance (Brunoni & Vanderhasselt, 2014).”

• cites Brunoni & Vanderhasselt, 2014 sourcePartly supported

  The Introduction describes how non-invasive stimulation can alter cortical activity, and the meta-analysis reports improved working-memory performance after rTMS over the DLPFC. However, the paper evaluates rTMS and tDCS, not theta-burst stimulation (TBS), so it does not establish the claim specifically for TBS. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

The potential of non-invasive brain stimulation for diagnostic and therapeutic purposes in mTBI has been proposed but not yet comprehensively explored.

“The potential of non-invasive brain stimulation (NIBS) for diagnostic and therapeutic purposes in mTBI has been proposed, but not yet comprehensively explored (Demirtas-Tatlidede, Vahabzadeh-Hagh, Bernabeu, Tormos, & Pascual-Leone, 2012).”

• cites Demirtas-Tatlidede, Vahabzadeh-Hagh, Bernabeu, Tormos, & Pascual-Leone, 2012 sourcePartly supported

  The Conclusion (section 7; page unavailable) says noninvasive brain stimulation has potential diagnostic and therapeutic utility in TBI, while evidence remains sparse. The paper discusses diagnostic TMS studies involving mild TBI (section 4.3), but frames its therapeutic proposals around TBI generally rather than specifically mTBI (section 5). The mTBI-specific therapeutic part of the claim is therefore not established by this copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Frontally, N45 amplitude decreased (became more negative) in controls following iTBS, whilst N45 amplitude increased (became more negative) in mTBI participants following iTBS.

“Inspection of graphs suggested frontally N45 amplitude decreased (became more negative) in controls, whilst N45 amplitude increased (became more negative) in mTBI participants following iTBS.”

May combine two claims.

iTBS did not induce changes in digit span accuracy, neural response strength, or the topographical distribution of neural activity in either control or mTBI participants at any time point.

“we found that iTBS did not induce changes in digit span accuracy, neural response strength or the topographical distribution of neural activity in either control or mTBI participants at any time point.”

May combine two claims.

There was no effect of iTBS on neural response strength (GFP), topography (TANOVA), or working memory performance (digit span accuracy) at any time point for either mTBI or controls.

“There was no effect of iTBS on neural response strength (GFP), topography (TANOVA) or working memory performance (digit span accuracy) at any time point for either mTBI or controls (p > 0.05).”

• Also stated in: § 4. Discussion · plain

  “Secondly, iTBS did not significantly modulate neurophysiology during a working memory task nor behavioral working performance at any time point.”

May combine two claims.

At 6-month follow up, iTBS induced an increase in amplitude of the P200 TEP component in mTBI participants, with differences greatest in the left frontal region.

“At 6-month follow up, iTBS induced an increase in amplitude of the P200 TEP component in mTBI participants (N = 13, p = 0.016).Differences were greatest in the left frontal region (see Figure 3B).”

May combine two claims.

In the posterior region, N45 amplitude increased (became more negative) in controls, whilst N45 amplitude decreased (became less negative) in mTBI participants following iTBS.

“In the posterior region, results were in the opposite direction, N45 amplitude increased (became more negative) in controls, whilst N45 amplitude decreased (became less negative) in mTBI participants.”

May combine two claims.

In the mTBI group at the sub-acute timepoint, iTBS induced a reduction of the N45 TEP component amplitude (became less negative), with differences greatest in the fronto-central region.

“In the mTBI group, at the sub-acute timepoint, we found that iTBS induced a reduction of the N45 TEP component amplitude (the amplitude became less negative) (N = 29, p = 0.022).Differences were greatest in the fronto-central region (see Figure 3A).”

May combine two claims.

No clear relationship between iTBS-modulated TEP components and recovery was demonstrated in mTBI, and poor consistency across time points in the control group limited interpretation of findings in mTBI.

“No clear relationship between iTBS modulated TEP components and recovery was demonstrated in mTBI and poor consistency across time points in the control group limited interpretation of findings in mTBI.”

May combine two claims.

The findings did not replicate previous iTBS-induced working memory improvements in controls, and there was no evidence to suggest iTBS modulated digit span accuracy in the mTBI sample.

“Regarding cognitive performance, our findings did not replicate previous iTBS induced working memory improvements in controls, and there was no evidence to suggest iTBS modulated digit span accuracy in our mTBI sample.”

May combine two claims.

In the current study, iTBS did not reliably modulate neurophysiology or cognitive performance in mTBI participants or controls.

“In the current study, iTBS did not reliably modulate neurophysiology or cognitive performance in mTBI participants or controls.”

May combine two claims.

Cluster-based analyses demonstrated that iTBS did not reliably modulate neurophysiological activity, and no differences were found in cognitive performance in either mTBI or control group participants across any assessment time point.

“Cluster-based analyses demonstrated iTBS did not reliably modulate neurophysiological activity, and no differences were found in cognitive performance in either mTBI or control group participants across any of the assessment time points.”

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

Prior to statistical analysis, automatic outlier detection using multidimensional scaling in RAGU was used to detect and exclude extreme values.

“Prior to statistical analysis, automatic outlier detection using multidimensional scaling in RAGU was used to detect and exclude extreme values.”

May combine two claims.

The consistency of iTBS-induced changes in neurophysiology across time points was poor, limiting interpretation of observed changes at specific time points.

“Firstly, the consistency of iTBS induced changes in neurophysiology (as measured by TEP's and revealed by comparisons across the time points) was poor, limiting our interpretation of observed changes at specific time points.”

May combine two claims.

iTBS can be applied to investigate post-injury plasticity and cognitive performance, providing information on how brain changes may affect cognition following mTBI.

“In summary, iTBS can be applied to investigate post injury plasticity and cognitive performance, providing information on how brain changes may affect cognition following mTBI.”

• AssumptionRests on an assumption: iTBS commonly induces a long-term potentiation (LTP)-like excitatory plastic effect and cTBS induces a long-term depression (LTD)-like inhibitory effect.

May combine two claims.

Control participants had a greater number of total available epochs than mTBI participants at all time points, because mTBI participants had lower digit span accuracy scores, resulting in fewer available epochs.

“However, control participants had a greater number of total available epochs than mTBI participants at all time points (p < 0.05).This was because mTBI participants had lower digit span accuracy scores, which resulted in fewer available epochs.”

Classified as probably not a substantial claim.

A 2 x 2 repeated measures ANCOVA for cognitive performance included estimated pre-morbid IQ (WTAR) as a covariate to control for its potential influence.

“To investigate group differences and iTBS-induced changes in cognitive performance (as measured by digit span accuracy), a 2 x 2 repeated measures ANCOVA was performed with CONDITION (Pre_iTBS vs Post_iTBS) as a within subject factor, GROUP (control vs mTBI) as a between subject factor and estimated pre-morbid IQ (WTAR) as a co-variate (to control for the potential influence of pre-morbid IQ).”

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

Attrition resulted in different samples at each time point.

“Attrition resulted in different samples at each time point and demographic and clinical characteristics are reported in Table 1.”

Classified as probably not a substantial claim.

Following pre-processing, participants were included only if they had provided at least 15 artefact-free correct epochs for both Pre_iTBS and Post_iTBS time points.

“Following pre-processing participants were included only if they had provided =>15 artefact free correct epochs for both Pre_iTBS and Post_iTBS time points.”

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

During TMS-EEG, participants listened to white noise through intra-auricular earphones to reduce the influence of auditory processing of the TMS click.

“During TMS-EEG, participants listened to white noise through intra-auricular earphones (Etymotic Research, ER3-14A, USA) to reduce the influence of auditory processing of the TMS click (Rogasch et al., 2014).”

• cites Rogasch et al., 2014 sourceNot checked — no full text of the source

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

White matter integrity within a stimulated network influences the behavioral response to stimulation.

“a recent paper that combined NIBS with neuroimaging demonstrated white matter integrity within a stimulated network influences the behavioral response to stimulation (Li et al., 2019).”

• cites Li et al., 2019Not matched

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

May combine two claims.

No participants had a history of seizures, psychiatric or neurological illnesses, unstable medical conditions, were pregnant, or were taking prescribed medication known to directly or significantly influence EEG findings.

“No participants had a history of seizures, psychiatric or neurological illnesses, unstable medical conditions, were pregnant or taking prescribed medication known to directly or significantly influence EEG findings.”

Classified as probably not a substantial claim.

Repetitive TMS has been shown to modify neuronal activity locally and distally.

“The repetitive application of TMS (rTMS), has been shown to modify neuronal activity locally and distally (Wassermann & Lisanby, 2001).”

• cites Wassermann & Lisanby, 2001 sourceNot checked — no full text of the source

May combine two claims.

Structural connectivity may mediate response to stimulation, and an individualized approach to NIBS parameters may be necessary in mTBI.

“This suggests structural connectivity may mediate response to stimulation and an individualized approach to NIBS parameters may be necessary in mTBI.”

• cites Li et al., 2019Not matched

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

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

mTBI was classified as an initial GCS score of 13-15, loss of consciousness less than 30 minutes, and post-traumatic amnesia less than 24 hours.

“mTBI was classified as exhibiting an initial Glasgow Coma Scale (GCS) score of 13-15, loss of consciousness < 30 minutes and post-traumatic amnesia (PTA) < 24 hours (Carroll et al., 2004).”

• cites Carroll et al., 2004 sourceNot checked — no full text of the source

May combine two claims.

The temporal window post iTBS, single dose, and choice of stimulation intensity may have mediated the findings.

“As such, the temporal window post iTBS, single dose, and choice of stimulation intensity may have mediated our findings.”

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

Participant attrition prevented the inclusion of time point as an additional within-subject factor, so analyses were conducted separately for each time point.

“Participant attrition prevented the inclusion of time point as an additional within subject factor for the repeated measures analyses (see Table 1 for sample sizes for each group and time point). Instead analyses were conducted separately for each time point (BL, 3-month and 6-month follow up).”

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

The epoched data from Pre_iTBS and Post_iTBS time points were concatenated and analysed concurrently to avoid bias in component rejection.

“The epoched data from two time points (Pre_iTBS and Post_iTBS) were concatenated and analysed concurrently to avoid bias in component rejection.”

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

Electrode impedances were kept below 5 kΩ throughout the recording.

“Electrode impedances were kept below 5 kΩ throughout the recording.”

May combine two claims.

The authors have previously reported an increased N100 amplitude in mTBI participants compared to controls, a TEP associated with inhibitory processes.

“we have previously reported an increased N100 amplitude in mTBI participants compared to controls, a TEP that has also been associated with inhibitory processes (Coyle et al, 2022a,b).”

• cites Coyle et al, 2022a,bNot matched

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

May combine two claims.

Different sample sizes at each time point prevented repeated measures analyses, which increased multiple comparisons, reducing power and possibly introducing additional variability.

“Different sample sizes at each time point prevented us from completing repeated measures analyses, which increased the multiple comparisons in our study, reducing power and possibly introducing additional variability into our data set.”

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

iTBS at 75% of RMT results in maximal neurophysiologic change.

“Recent research suggesting iTBS at 75% of RMT results in maximal neurophysiologic change (Chung et al., 2018).”

• cites Chung et al., 2018Not matched

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

May combine two claims.

The mTBI and control groups did not differ significantly on sex, age, or pre-morbid intelligence, but controls had a higher level of education.

“The groups did not differ significantly on measures of sex, age and pre-morbid intelligence (all p > .05),however controls had a higher level of education (p = .035)(Table 1).”

May combine two claims.

Improvements in working memory, increased synchronisation of task-related theta, and current density changes in resting alpha activity have been reported following iTBS in healthy controls.

“Improvements in working memory and increased synchronisation of task-related theta (Hoy et al., 2015) and current density changes in resting alpha activity (Grossheinrich et al., 2009) have been reported following iTBS in healthy controls.”

• cites Hoy et al., 2015Not matched

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

• cites Grossheinrich et al., 2009 sourceNot checked — no full text of the source

May combine two claims.

The study had a relatively small sample with attrition over time.

“Our study had a relatively small sample with attrition over time.”

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

One of the key challenges in mTBI diagnosis and prognosis is heterogeneity, and the diffuse and dynamic nature of mTBI may make each injury potentially unique.

“One of the key challenges in mTBI diagnosis and prognosis is heterogeneity, and it has been proposed that the diffuse and dynamic nature of mTBI may make each injury potentially unique (Bigler & Maxwell, 2012;Coyle et al., 2018).”

• cites Bigler & Maxwell, 2012 sourceNot checked — no full text of the source
• cites Coyle et al., 2018 sourceNot checked — no full text of the source