Cognitive Outcomes After Transcranial Magnetic Stimulation for the Treatment of Late-Life Depression: Résultats cognitifs après la stimulation magnétique transcrânienne pour le traitement de la dépression chez les personnes âgées
Open accessAbstract
Background: Late-life depression (LLD) is often accompanied by cognitive impairment, which may persist despite antidepressant treatment. Repetitive transcranial magnetic stimulation (rTMS) is an efficacious treatment for depression, with potential benefits on cognitive functioning. However, research on cognitive effects is inconclusive, relatively sparse in LLD, and predominantly focused on group-level cognitive changes. This study aimed to explore individual-level cognitive changes following rTMS treatment in patients with LLD. Method: Data were analyzed from 153 patients with LLD from the FOUR-D study (ClinicalTrials.gov identifier: NCT02998580) who received bilateral standard rTMS or theta burst stimulation (TBS) targeting the dorsolateral prefrontal cortex (DLPFC). Cognitive function was assessed pre- and post-treatment using measures of executive function, information processing speed, and learning and memory. Reliable change indices, adjusted for practice effects and test-retest reliability, were employed to evaluate individual-level cognitive changes. Chi-square tests examined if proportions of cognitive improvers differed from expected proportions. Results: Cognitive performance from baseline to end of treatment remained stable for most patients. Reliably improved performance was observed in 0.0% to 20.0% of participants across cognitive measures, while worsened performance was observed in 0.0% to 2.7%. A small but significant proportion (20.0%) of participants showed improvement in verbal learning. Conclusions: Bilateral standard rTMS or TBS of the DLPFC in LLD yielded no substantial cognitive enhancing effects, although a small proportion showed improved verbal learning after treatment. Importantly, both interventions were cognitively safe with relatively stable performance across time. Future research is needed to explore approaches to enhance the cognitive benefits of standard rTMS and TBS in patients with LLD.
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Written from the paper’s full text.
TL;DR
In 153 patients with late-life depression from the FOUR-D trial, bilateral standard rTMS or TBS to the DLPFC produced no substantial cognitive enhancement, and performance remained stable for most patients. A small but significant proportion (20.0%) showed reliable improvement in verbal learning, while reliable decline was rare (0.0%–2.7% across measures).
Key findings
- Most participants showed no reliable change: reliable improvement ranged from 0.0% (D-KEFS CWI Inhibition) to 20.0% (CVLT-II Total Trials 1–5), and reliable worsening ranged from 0.0% (D-KEFS CWI Inhibition) to 2.7% (D-KEFS CWI Color Naming). Overall, 25.5% (39/153) improved on at least one cognitive measure.
- Only verbal learning exceeded the expected 5% improvement rate: 30/150 participants (20.0%) reliably improved on CVLT-II Total Trials 1–5 (χ²(2) = 48.4, p < 0.001).
- Predictors of reliable CVLT-II Total Trials 1–5 improvement were lower baseline performance (p = 0.01, OR = 0.94, CI 0.90–0.98), higher premorbid IQ (p = 0.01, OR = 1.07, CI 1.02–1.13), and treatment response (p = 0.04, OR = 2.48, CI 1.05–6.00); MADRS change correlated weakly with RCI z-scores (ρ = −0.23, p = 0.005).
- No significant differences in reliable cognitive change were found across the three baseline cognitive subgroups after FDR correction, and treatment allocation (standard rTMS vs TBS) did not significantly predict improvement.
Methods
- Secondary analysis of 153 outpatients age 60 and older with major depressive disorder from the FOUR-D randomized non-inferiority trial (NCT02998580), comparing bilateral standard rTMS with bilateral TBS targeting the DLPFC over 20 sessions, with up to 10 additional sessions if remission was not achieved.
- Cognitive function was assessed pre- and post-treatment with the NIH Toolbox Flanker, D-KEFS Color-Word Interference, CVLT-II, MoCA, and TOPF; practice-adjusted reliable change indices (RCIPE) with a 90% confidence interval classified reliable improvement, no change, or decline.
- One-sample chi-square tests compared observed improvement proportions with the expected 5%; exploratory binary logistic regression with backward elimination examined predictors of reliable CVLT-II improvement; ANOVA and chi-square tests compared changes across three baseline cognitive subgroups (Cognitively Intact n = 84, Cognitively Diminished n = 25, Impaired Memory n = 39), with FDR correction.
Limitations
- Stated: there was no sham-TMS control group because the data came from a non-inferiority trial comparing two active rTMS types; RCIPE used published normative data from adults without clinical diagnoses, and for the CVLT-II only raw scores uncorrected for age were available, which may underestimate cognitive benefits in older depressed adults.
- Stated: participants who did not complete treatment or post-treatment cognitive assessment had lower baseline CVLT-II performance, limiting generalizability and potentially biasing findings; the sample was highly educated and predominantly white, limiting generalizability to other older adult populations.
- Evident from the text: cognitive assessments covered executive function, information processing speed, and learning/memory, with no longer-term follow-up beyond end of treatment reported; predictor and subgroup analyses were exploratory.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
13 of 42 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Theta burst stimulation is comparably effective to standard rTMS for depression.
“Evidence indicates that TBS is comparably effective to standard rTMS for depression.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [9] Blumberger DM Mulsant BH Thorpe KE, et al. Effectiveness of standard sequential bilateral repetitive transcranial magnetic stimulation vs bilateral theta burst stimulation in older adults with depression: the FOUR-D randomized noninferiority clinical trial. JAMA Psychiatry. 2022; 79(11): 1065- 1073. 36129719 PMC9494264 source
- Premisecitation
Late-life depression is often accompanied by cognitive impairment, particularly in the domains of executive functioning, information processing speed, and learning and memory.
“Late-life depression (LLD) is often accompanied by cognitive impairment, particularly in the domains of executive functioning, information processing speed, and learning and memory.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [1] Koenig AM Bhalla RK Butters MA. Cognitive functioning and late-life depression. J Int Neuropsychol Soc. 2014; 20(5): 461- 467. 24685173 PMC4107679 source
The Introduction says cognitive impairment frequently accompanies late-life depression. The section “Cognitive Functioning in Late-Life Depression” lists episodic memory, processing speed, and executive functioning among deficits that often co-occur with it, but identifies only processing speed and executive functioning as particularly vulnerable; it does not give learning and memory the same emphasis. Page numbers are unavailable in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured
- Premisecitation
Cognitive impairments in late-life depression often persist even when depressive symptoms and severity improve.
“Importantly, cognitive impairments often persist even when there is improvement in depressive symptoms and severity.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [4] Bhalla RK Butters MA Mulsant BH, et al. Persistence of neuropsychologic deficits in the remitted state of late-life depression. Am J Geriatr Psychiatry. 2006; 14(5): 419- 427. 16670246 source
- cites [5] Bhalla RK Butters MA Becker JT, et al. Patterns of mild cognitive impairment after treatment of depression in the elderly. Am J Geriatr Psychiatry. 2009; 17(4): 308- 316. 19307859 PMC2782929 source
- Premisecitation
Both standard bilateral rTMS and bilateral TBS showed similar effectiveness in improving depressive symptoms.
“However, both treatments showed similar effectiveness in improving depressive symptoms, 9 which aligns with the lack of superior cognitive results from TBS in this study.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] Blumberger DM Mulsant BH Thorpe KE, et al. Effectiveness of standard sequential bilateral repetitive transcranial magnetic stimulation vs bilateral theta burst stimulation in older adults with depression: the FOUR-D randomized noninferiority clinical trial. JAMA Psychiatry. 2022; 79(11): 1065- 1073. 36129719 PMC9494264 source
- Findingown data
Reliable improvement in verbal learning was associated with a higher estimated premorbid IQ.
“which was associated with a higher estimated premorbid IQ and being a responder to rTMS treatment.”
Quote in the paperNot a substantial claim
- Findingown data
Treatment allocation (standard bilateral rTMS vs bilateral TBS) did not significantly predict improvements in verbal learning.
“Treatment allocation—whether participants received standard bilateral rTMS or bilateral TBS—did not significantly predict improvements in verbal learning.”
Quote in the paperSubstantial claim - Findingown data
There were no significant differences in demographic or clinical variables between participants lost to follow-up and those who underwent both assessments.
“There were no significant differences in demographic or clinical variables between participants lost to follow-up and those who underwent both assessments.”
Quote in the paperNot a substantial claim - Findingown data
There was a weak but significant correlation between the RCI z-scores of the CVLT-II Total Trials 1-5 and the MADRS change score (ρ = −0.23, p = 0.005).
“There was a weak but significant correlation between the RCI z-scores of the CVLT-II Total Trials 1–5 and the MADRS change score (ρ = −0.23, p = 0.005).”
Quote in the paperNot a substantial claim - Findingown data
No other variable, including treatment allocation (standard rTMS vs TBS), significantly predicted reliable improvement on the CVLT-II Total Trials 1-5.
“No other variable significantly predicted reliable improvement CVLT-II Total Trials 1–5, including treatment allocation (i.e., standard rTMS vs TBS).”
Quote in the paperNot a substantial claim - Findingown data
No evidence of significantly worsened performance on any cognitive measure was found.
“While our study observed no robust cognitive improvement after rTMS, we found no evidence of significantly worsened performance on any cognitive measure.”
Quote in the paperSubstantial claim - Findingown data
20.0% of participants showed reliable improvement in verbal learning on the CVLT-II Total Trials 1-5.
“A small but significant proportion (20.0%) of participants showed improvement in verbal learning.”
- Also stated in: § Practice-Adjusted Reliable Change Index · plain
“This was exceeded only by the percentage of participants who improved in verbal learning on the CVLT-II Total Trials 1–5, where 30 out of 150 participants (20.0%) had reliably improved performance.”
Quote in the paperSubstantial claim - Also stated in: § Practice-Adjusted Reliable Change Index · plain
- Findingown data
Across all measures, the percentage of participants who experienced a reliable cognitive decline ranged from 0% to 2.7%.
“Across all measures, the percentage of participants who experienced a reliable cognitive decline ranged from 0% to 2.7%”
Quote in the paperSubstantial claim - Findingown data
Cognitive performance from baseline to end of treatment remained stable (no reliable change) for most patients with late-life depression.
“Cognitive performance from baseline to end of treatment remained stable for most patients.”
- Also stated in: § Practice-Adjusted Reliable Change Index · plain
“Most participants showed no reliable change in performance on cognitive measures (Table 2).”
Quote in the paperSubstantial claim - Also stated in: § Practice-Adjusted Reliable Change Index · plain
- Findingown data
Participants who did not complete treatment or undergo post-treatment cognitive assessment showed significantly worse baseline performance on the CVLT-II Total Trials 1-5, Short-Delay Free Recall, and Long-Delay Free Recall.
“However, participants who did not complete treatment or undergo post-treatment cognitive assessment showed significantly worse performance at baseline on the CVLT-II Total Trials 1–5 (t(19.81) = 3.68, p = 0.001), the CVLT-II Short-Delay Free Recall (t(19.05) = 2.73, p = 0.013), and the CVLT-II Long-Delay Free Recall (t(18.44) = 3.12, p = 0.006).”
Quote in the paperNot a substantial claim - Findingown data
25.5% (39/153) of participants showed a reliable improvement in at least one cognitive measure.
“Overall, 25.5% (39/153) of participants showed a reliable improvement in at least one cognitive measure.”
Quote in the paperNot a substantial claim - Findingown data
A higher premorbid IQ was associated with higher odds of showing a reliable improvement on the CVLT-II Total Trials 1-5 (p = 0.01, OR = 1.07, CI 1.02-1.13).
“A lower baseline performance on this measure (p = 0.01, OR = 0.94, CI 0.90–0.98), a higher premorbid IQ (p = 0.01, OR = 1.07, CI 1.02–1.13), and being a responder to rTMS/TBS treatment (p = 0.04, OR = 2.48, CI 1.05–6.00) were associated with higher odds of showing a reliable improvement on the CVLT-II Total Trials 1–5.”
Quote in the paperNot a substantial claim - Findingown data
The percentage of reliable cognitive decline (0-2.7%) is below the 5% expected to be due solely to measurement error.
“which is below the 5% expected to be due solely to measurement error.”
Quote in the paperSubstantial claim - Findingown data
Being a responder to rTMS/TBS treatment was associated with higher odds of showing a reliable improvement on the CVLT-II Total Trials 1-5 (p = 0.04, OR = 2.48, CI 1.05-6.00).
“A lower baseline performance on this measure (p = 0.01, OR = 0.94, CI 0.90–0.98), a higher premorbid IQ (p = 0.01, OR = 1.07, CI 1.02–1.13), and being a responder to rTMS/TBS treatment (p = 0.04, OR = 2.48, CI 1.05–6.00) were associated with higher odds of showing a reliable improvement on the CVLT-II Total Trials 1–5.”
Quote in the paperNot a substantial claim - Findingown data
A small but statistically significant proportion of participants (20%) experienced reliable improvements in verbal learning.
“A small but statistically significant proportion of participants (i.e., 20%) experienced reliable improvements in verbal learning”
- Also stated in: § Discussion · plain
“with only a small proportion of participants showing reliable improvement in verbal learning.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Reliable improvement in verbal learning was associated with being a responder to rTMS treatment (≥50% reduction in MADRS score).
“which was associated with a higher estimated premorbid IQ and being a responder to rTMS treatment.”
- Also stated in: § Discussion · hedged
“A reliable improvement in verbal learning was more likely in patients who responded to treatment (i.e., showed a reduction ≥ 50% from baseline in MADRS score).”
Quote in the paperSubstantial claim - Also stated in: § Discussion · hedged
- Findingown data
Reliably worsened cognitive performance was observed in 0.0% to 2.7% of participants across cognitive measures.
“Reliably improved performance was observed in 0.0% to 20.0% of participants across cognitive measures, while worsened performance was observed in 0.0% to 2.7%.”
- Also stated in: § Practice-Adjusted Reliable Change Index · plain
“Conversely, the percentage of participants showing a reliable worsened performance ranged from 0.0% (on the DKEFS-CWI Inhibition Task) to 2.7% (on the DKEFS-CWI Color Task) (Table 2).”
Quote in the paperSubstantial claim - Also stated in: § Practice-Adjusted Reliable Change Index · plain
- Findingown data
After FDR correction, no significant differences in RCI z-scores were found across the three baseline cognitive subgroups in any cognitive measure.
“After FDR-correction, no significant differences in RCI z-scores were found across the three baseline cognitive subgroups in any cognitive measure, nor in percentages of participants showing reliable improvement, no change, or worsened performance (Table 3).”
Quote in the paperSubstantial claim - Findingown data
For most cognitive measures, the percentage of participants exhibiting a reliable increase or decrease in performance fell within the expected 5% range based on the distribution of RCIs.
“Notably, for most cognitive measures, the percentage of participants exhibiting a reliable increase or decrease in performance fell within the expected 5% range based on the distribution of RCIs.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: RCI z-scores are normally distributed, so that 5% of participants are expected to show decline, 90% no change, and 5% improvement.
- Findingown data
A lower baseline performance on the CVLT-II Total Trials 1-5 was associated with higher odds of showing a reliable improvement on that measure (p = 0.01, OR = 0.94, CI 0.90-0.98).
“A lower baseline performance on this measure (p = 0.01, OR = 0.94, CI 0.90–0.98), a higher premorbid IQ (p = 0.01, OR = 1.07, CI 1.02–1.13), and being a responder to rTMS/TBS treatment (p = 0.04, OR = 2.48, CI 1.05–6.00) were associated with higher odds of showing a reliable improvement on the CVLT-II Total Trials 1–5.”
Quote in the paperNot a substantial claim - Findingown data
Reliably improved cognitive performance was observed in 0.0% to 20.0% of participants across cognitive measures.
“Reliably improved performance was observed in 0.0% to 20.0% of participants across cognitive measures, while worsened performance was observed in 0.0% to 2.7%.”
Quote in the paperSubstantial claim - Findingown data
Bilateral standard rTMS or TBS to the DLPFC had limited effects on cognition across the domains of executive function and information processing speed in patients with late-life depression.
“Overall, our findings indicated that bilateral standard rTMS or TBS to the DLPFC had limited effects on cognition across the domains of executive function and information processing speed.”
- Also stated in: § Discussion · boosted
“our study demonstrated limited cognitive benefits after bilateral standard rTMS or bilateral TBS for the treatment of LLD”
Quote in the paperSubstantial claim - Also stated in: § Discussion · boosted
- Findingown data
After FDR correction, no significant differences were found across the three baseline cognitive subgroups in the percentages of participants showing reliable improvement, no change, or worsened performance.
“After FDR-correction, no significant differences in RCI z-scores were found across the three baseline cognitive subgroups in any cognitive measure, nor in percentages of participants showing reliable improvement, no change, or worsened performance (Table 3).”
Quote in the paperNot a substantial claim - Findingown data
The difference between the observed percentage of reliable improvement on the CVLT-II Total Trials 1-5 (20.0%) and the expected percentage was significant (χ2(2) = 48.4, p < 0.001).
“This difference between the observed percentage with the expected percentage was significant (χ2(2) = 48.4, p < 0.001).”
Quote in the paperNot a substantial claim- The authors state this as an assumption: RCI z-scores are normally distributed, so that 5% of participants are expected to show decline, 90% no change, and 5% improvement.
- Findingown data
No significant improvements in executive function were observed among patients with late-life depression.
“Contrary to our hypothesis, we observed no significant improvements in executive function among patients with LLD.”
Quote in the paperSubstantial claim - Study design and conductcitation
RCIPE was used in this study because of its demonstrated usefulness in assessing cognitive change in older adults compared to alternative change score methods.
“To account for measurement error and practice effects inherent in repeated neuropsychological assessments, we used RCIPE 37 because of its demonstrated usefulness in assessing cognitive change in older adults compared to alternative change score methods.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [37] Chelune GJ Naugle RI Lüders H, et al. Individual change after epilepsy surgery: practice effects and base-rate information. Neuropsychology. 1993; 7(1): 41- 52.
Not checked in the free run.
- cites [47] Frerichs RJ Tuokko HA. A comparison of methods for measuring cognitive change in older adults. Arch Clin Neuropsychol. 2005; 20(3): 321- 333. 15797168 source
- Premisecitation
Antidepressant medications tend to be only partially beneficial for many patients with late-life depression, who still have significant depressive symptoms.
“Antidepressant medications are widely used in treating LLD, yet tend to be only partially beneficial for many patients who still have significant depressive symptoms.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Kok RM Reynolds CFIII. Management of depression in older adults: a review. JAMA. 2017; 317(20): 2114- 2122. 28535241 source
- Premisecitation
Other rTMS studies in late-life depression found no significant changes in cognitive function after treatment.
“However, other studies found no significant changes in cognitive function after treatment.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [34] Cristancho P Arora J Nishino T, et al. A pilot randomized sham controlled trial of bilateral iTBS for depression and executive function in older adults. Int J Geriatr Psychiatry. 2023; 38(1): e5851. 36494919 source
- cites [35] Ilieva IP Alexopoulos GS Dubin MJ, et al. Age-Related repetitive transcranial magnetic stimulation effects on executive function in depression: a systematic review. Am J Geriatr Psychiatry. 2018; 26(3): 334- 346. 29111132 source
- cites [36] Mosimann UP Schmitt W Greenberg BD, et al. Repetitive transcranial magnetic stimulation: a putative add-on treatment for major depression in elderly patients. Psychiatry Res. 2004; 126(2): 123- 133. 15123391 source
- Interpretationcitation
The cognitive benefits of rTMS treatment may be underestimated in older adults with depression because practice effects may be different compared to the normative sample.
“the cognitive benefits of rTMS treatment may be underestimated in older adults with depression because the practice effects may be different compared to the normative sample.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [70] Calamia M Markon K Tranel D. Scoring higher the second time around: meta-analyses of practice effects in neuropsychological assessment. Clin Neuropsychol. 2012; 26(4): 543- 570. 22540222 source
- Premisecitation
Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex is a well-established treatment for patients with treatment-resistant depression.
“Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) is a well-established treatment for patients with treatment-resistant depression (TRD).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Fitzgerald PB. An update on the clinical use of repetitive transcranial magnetic stimulation in the treatment of depression. J Affect Disord. 2020; 9: 90- 103. 32697721 source
- Interpretationown data
Bilateral standard rTMS or TBS of the dorsolateral prefrontal cortex in late-life depression yielded no substantial cognitive enhancing effects.
“Bilateral standard rTMS or TBS of the DLPFC in LLD yielded no substantial cognitive enhancing effects, although a small proportion showed improved verbal learning after treatment.”
Quote in the paperSubstantial claim - Premisecitation
Practice-adjusted reliable change indices can be used to detect improved or worsened cognitive performance in individuals beyond measurement error and practice effects.
“Practice-adjusted reliable change indices (RCIPE) can be used to detect improved or worsened cognitive performance in individuals beyond measurement error and practice effects, 37 which can address this limitation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [37] Chelune GJ Naugle RI Lüders H, et al. Individual change after epilepsy surgery: practice effects and base-rate information. Neuropsychology. 1993; 7(1): 41- 52.
Not checked in the free run.
- Premisenone given
Studies investigating cognitive changes following rTMS have primarily relied on group-level analyses, which may mask changes at the individual (patient) level.
“Studies investigating cognitive changes following rTMS have primarily relied on group-level analyses, which may mask changes at the individual (i.e., patient) level.”
Quote in the paperSubstantial claim - Study design and conductnone given
Randomized participants who did not complete treatment or follow-up cognitive assessments had lower baseline cognitive performance.
“randomized participants who did not complete treatment or follow-up cognitive assessments had lower baseline cognitive performance.”
Quote in the paperSubstantial claim - Interpretationown data
The high education level and predominantly white demographic of the participants may limit the generalizability of the findings to other older adult populations.
“Moreover, the high education level and predominantly white demographic of our participants may limit the generalizability of our findings to other older adult populations.”
Quote in the paperNot a substantial claim - Interpretationcitation
Improvements in verbal learning may be secondary to improvement in mood.
“This association has also been observed in prior rTMS studies,17,36 suggesting that improvements in verbal learning may be secondary to improvement in mood.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [17] Gregory EC Torres IJ Blumberger DM, et al. Repetitive transcranial magnetic stimulation shows longitudinal improvements in memory in patients with treatment-resistant depression. Neuromodul: Technol Neural Interface. 2022; 25(4): 596- 605. 35088728 source
- cites [36] Mosimann UP Schmitt W Greenberg BD, et al. Repetitive transcranial magnetic stimulation: a putative add-on treatment for major depression in elderly patients. Psychiatry Res. 2004; 126(2): 123- 133. 15123391 source
- Interpretationown data
DLPFC-rTMS may have no or weak beneficial impacts on executive function.
“Taken together, these findings suggest that DLPFC-rTMS may have no or weak beneficial impacts on executive function.”
Quote in the paperSubstantial claim
- May combine two claims. 15
- Classified as probably not a substantial claim. 6
- The quote only partly states this claim. 1
May combine two claims.
PremisecitationSome rTMS studies in late-life depression have reported improvements in attention and immediate memory, executive function, verbal fluency and visuospatial abilities, and global cognitive function.
“Some rTMS studies in LLD have reported improvements in attention and immediate memory, 29 executive function,30,31 verbal fluency and visuospatial abilities, 32 and global cognitive function.”
Quote in the paperNot a substantial claim1 of 4 sources checked- cites [29] Pan W Hu X Zhu D, et al. The cognitive effects of adjunctive repetitive transcranial magnetic stimulation for late-onset depression: a randomized controlled trial with 4 week follow-up. Front Psychiatry. 2023; 14: 1240261. 37614650 PMC10442575 source
- cites [30] Cristancho P Kamel L Araque M, et al. iTBS to relieve depression and executive dysfunction in older adults: an open label study. Am J Geriatr Psychiatry. 2020; 28(11): 1195- 1199. 32268978 source
- cites [31] Jorge RE Moser DJ Acion L, et al. Treatment of vascular depression using repetitive transcranial magnetic stimulation. Arch Gen Psychiatry. 2008; 65(3): 268- 276. 18316673 source
- cites [32] Fabre I Galinowski A Oppenheim C, et al. Antidepressant efficacy and cognitive effects of repetitive transcranial magnetic stimulation in vascular depression: an open trial. Int J Geriatr Psychiatry. 2004; 19(9): 833- 842. 15352140 source
May combine two claims.
PremisecitationCognitive impairments in late-life depression significantly reduce quality of life and increase the risk of neurodegenerative disorders such as Alzheimer's disease and related dementias.
“These impairments significantly reduce quality of life and increase the risk of neurodegenerative disorders such as Alzheimer's disease and related dementias.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [2] Livingston G Huntley J Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the lancet commission. Lancet. 2020; 396(10248): 413- 446. 32738937 PMC7392084 source
The section on Depression reports that late-life depressive symptoms are associated with increased dementia risk, while noting that depression can also be an early sign of dementia. It does not establish that cognitive impairments in late-life depression themselves increase that risk or significantly reduce quality of life. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
PremisecitationThe dorsolateral prefrontal cortex is a key node within the cognitive control network, which is thought to subserve executive functions such as response inhibition, set-shifting, and planning.
“The DLPFC is a key node within the cognitive control network, 13 which is thought to subserve executive functions, such as response inhibition, set-shifting, and planning.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [13] Niendam TA Laird AR Ray KL, et al. Meta-analytic evidence for a superordinate cognitive control network subserving diverse executive functions. Cogn Affect Behav Neurosci. 2012; 12(2): 241- 268. 22282036 PMC3660731 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCognitive improvements following rTMS have been observed in younger adults with depression across various domains including learning and memory, attention, executive function, and psychomotor processing speed.
“Cognitive improvements following rTMS have been observed in younger adults with depression across various domains including learning and memory,16–18 attention, 19 executive function19–24 and psychomotor processing speed.”
Quote in the paperNot a substantial claim2 of 9 sources checked- cites [16] Fitzgerald PB Hoy K Daskalakis ZJ, et al. A randomized trial of the anti-depressant effects of low- and high-frequency transcranial magnetic stimulation in treatment-resistant depression. Depress Anxiety. 2009; 26(3): 229- 234. 19105212 source
- cites [17] Gregory EC Torres IJ Blumberger DM, et al. Repetitive transcranial magnetic stimulation shows longitudinal improvements in memory in patients with treatment-resistant depression. Neuromodul: Technol Neural Interface. 2022; 25(4): 596- 605. 35088728 source
- cites [18] Kavanaugh BC Aaronson ST Clarke GN, et al. Neurocognitive effects of repetitive transcranial magnetic stimulation with a 2-coil device in treatment-resistant Major depressive disorder. J ECT. 2018; 34(4): 258- 265. 29613944 source
- cites [19] Hopman HJ Choy HY Ho WS, et al. The effects of repetitive transcranial magnetic stimulation antidepressant response on cold cognition: a single-arm prospective longitudinal study. Neuropsychiatr Dis Treat. 2021; 17: 1647- 1658. 34079262 PMC8165208 source
The Results (OTS; page unavailable) report faster performance on an executive-function task, supporting the executive-function portion for which this citation appears in the citing sentence. The study did not establish that the improvement was specific to younger adults: participants were 18–57 years old, and the Discussion (Executive Function; page unavailable) says practice effects could also explain the change. Its Results found no improvement on the learning and memory tests, while the Discussion (Sustained Attention; page unavailable) says processing speed did not improve. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [20] Asgharian Asl F Vaghef L. The effectiveness of high-frequency left DLPFC-rTMS on depression, response inhibition, and cognitive flexibility in female subjects with major depressive disorder. J Psychiatr Res. 2022; 149: 287- 292. 35313201 source
- cites [21] Chen Y Li X Wang L, et al. Effects of repetitive transcranial magnetic stimulation on cognitive function in patients with stress-related depression: A randomized double-blind fMRI and 1H-MRS study. Front Neurol.. 2022; 13: 844606. 35493813 PMC9051398 source
- cites [22] Corlier J Burnette E Wilson AC, et al. Effect of repetitive transcranial magnetic stimulation (rTMS) treatment of major depressive disorder (MDD) on cognitive control. J Affect Disord. 2020; 265: 272- 277. 32090751 source
- cites [23] Moser DJ Jorge RE Manes F, et al. Improved executive functioning following repetitive transcranial magnetic stimulation. Neurology. 2002; 58(8): 1288- 1290. 11971103 source
- cites [24] Schaffer DR Okhravi HR Neumann SA. Low-Frequency transcranial magnetic stimulation (LF-TMS) in treating depression in patients with impaired cognitive functioning. Arch Clin Neuropsychol. 2021; 36(5): 801- 814. 33140093 source
May combine two claims.
PremisecitationrTMS uses focused magnetic field pulses to modify neural activity at the stimulation site and can induce structural and functional connectivity changes in distributed brain networks, including the cognitive control network.
“rTMS uses focused magnetic field pulses to modify neural activity at the stimulation site and can induce structural and functional connectivity changes in distributed brain networks, 14 including the cognitive control network.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [14] To WT De Ridder D Hart Jr. J, et al. Changing brain networks through non-invasive neuromodulation. Front Hum Neurosci. 2018; 12: 128. 29706876 PMC5908883 source
The Introduction describes rTMS magnetic pulses and their effects on cortical excitability. The MACRO-Level section reports changes in functional connectivity beyond the stimulation site, including after stimulation of cognitive-control regions. The passages support functional network changes, but not the claimed structural connectivity changes; no page numbers are provided in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [15] Schiena G Franco G Boscutti A, et al. Connectivity changes in major depressive disorder after rTMS: a review of functional and structural connectivity data. Epidemiol Psychiatr Sci. 2021; 30: e59.
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductcitationA 90% confidence interval for reliable change was employed to identify significant cognitive change beyond measurement error and practice effects, consistent with prevailing RCI literature.
“To identify if a patient's cognitive score has significantly changed beyond measurement error and practice effects, a 90% confidence interval for reliable change was employed, consistent with prevailing RCI literature.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [51] Duff K. Evidence-Based indicators of neuropsychological change in the individual patient: relevant concepts and methods. Arch Clin Neuropsychol. 2012; 27(3): 248- 261. 22382384 PMC3499091 source
- cites [52] Stein J Luppa M Brähler E, et al. The assessment of changes in cognitive functioning: reliable change indices for neuropsychological instruments in the elderly - a systematic review. Dement Geriatr Cogn Disord. 2010; 29(3): 275- 286. 20375509 source
May combine two claims.
PremisecitationIn contrast to electroconvulsive therapy, rTMS is recognized for its cognitive safety and potential to improve certain cognitive functions in treatment-resistant depression.
“In contrast to electroconvulsive therapy (ECT), rTMS is recognized for its cognitive safety 11 and potential to improve certain cognitive functions in TRD.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [11] Schulze-Rauschenbach SC Harms U Schlaepfer TE, et al. Distinctive neurocognitive effects of repetitive transcranial magnetic stimulation and electroconvulsive therapy in major depression. Br J Psychiatry. 2005; 186: 410- 416. 15863746 source
- cites [12] Serafini G Pompili M Murri MB, et al. The effects of repetitive transcranial magnetic stimulation on cognitive performance in treatment-resistant depression. A systematic review. NPS. 2015; 71(3): 125- 139. 25925699 source
May combine two claims.
PremisecitationFindings on cognitive effects of rTMS have been inconsistent, and large meta-analyses have not demonstrated robust cognitive effects, with only modest effects observed in specific cognitive tasks.
“However, findings have been inconsistent and large meta-analyses have not demonstrated robust cognitive effects, 27 with only modest effects observed in specific cognitive tasks.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [27] Martin DM McClintock SM Forster J, et al. Does therapeutic repetitive transcranial magnetic stimulation cause cognitive enhancing effects in patients with neuropsychiatric conditions? A systematic review and meta-analysis of randomised controlled trials. Neuropsychol Rev. 2016; 26(3): 295- 309. 27632386 PMC5949868 source
- cites [28] Martin DM McClintock SM Forster JJ, et al. Cognitive enhancing effects of rTMS administered to the prefrontal cortex in patients with depression: a systematic review and meta-analysis of individual task effects. Depress Anxiety. 2017; 34(11): 1029- 1039. 28543994 source
May combine two claims.
Findingown data153 participants were included in this analysis, assessed at both time points on at least one cognitive measure.
“resulting in the inclusion of 153 participants in this analysis who were assessed at both time points on at least one cognitive measure (mean [SD] age, 66.7 [6.0] years; 56% female, Table 1).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataBoth bilateral standard rTMS and TBS were cognitively safe, with relatively stable cognitive performance across time in patients with late-life depression.
“Importantly, both interventions were cognitively safe with relatively stable performance across time.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHigh-frequency rTMS and intermittent TBS are thought to exert excitatory effects on neuronal activity, while low-frequency rTMS and continuous TBS are believed to be inhibitory, although these effects show substantial inter-individual variability.
“While high-frequency rTMS and iTBS are thought to exert excitatory effects on neuronal activity, low-frequency rTMS and cTBS are believed to be inhibitory, although these effects show substantial inter-individual variability.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Ziemann U Siebner HR. Inter-subject and inter-session variability of plasticity induction by non-invasive brain stimulation: boon or bane? Brain Stimul. 2015; 8(3): 662- 663. 25704341 source
Classified as probably not a substantial claim.
Study design and conductown dataA false discovery rate correction was applied to account for multiple tests across cognitive measures.
“A false discovery rate (FDR) correction was applied to account for multiple tests across cognitive measures and p-values < 0.05 were considered statistically significant.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductreasoningThere was no sham-TMS control group because the data came from a non-inferiority trial comparing two types of rTMS.
“since the current data was drawn from a non-inferiority trial that compared two types of rTMS, there was no sham-TMS control group.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductcitationRCIPE were calculated using published normative data derived from adults without clinical diagnoses, and for the CVLT-II only raw scores uncorrected for age were available.
“we calculated RCIPE using published normative data, which was derived from adults without clinical diagnoses, and for the CVLT-II, only raw scores uncorrected for age were available.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50] Woods SP Delis DC Scott JC, et al. The California verbal learning test–second edition: test-retest reliability, practice effects, and reliable change indices for the standard and alternate forms. Arch Clin Neuropsychol. 2006; 21(5): 413- 420. 16843636 source
Probably not a substantial claim: may not pass S4 (based).
Study design and conductnone givenRCIPE were used to effectively control for measurement error and practice effects of repeated neuropsychological testing.
“RCIPE were used to effectively control for measurement error and practice effects of repeated neuropsychological testing.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThese findings reinforce the literature demonstrating the cognitive safety of rTMS, supporting its use in treating late-life depression without the risk of cognitive decline.
“These findings reinforce the extensive literature demonstrating the cognitive safety of rTMS, 55 supporting its use in treating LLD without the risk of cognitive decline.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [55] Iimori T Nakajima S Miyazaki T, et al. Effectiveness of the prefrontal repetitive transcranial magnetic stimulation on cognitive profiles in depression, schizophrenia, and Alzheimer’s disease: a systematic review. Prog Neuro-Psychopharmacol Biol Psychiatry. 2019; 88: 31- 40. 29953934 source
May combine two claims.
Interpretationown dataImprovement in verbal learning was predicted by a higher premorbid IQ, which is indicative of greater cognitive reserve and may facilitate cognitive recovery or improvement after rTMS.
“Notably, improvement in verbal learning was predicted by a higher premorbid IQ which is indicative of greater cognitive reserve and may facilitate cognitive recovery or improvement after rTMS.”
Quote in the paperSubstantial claimMay combine two claims. The quote only partly states this claim.
Interpretationown dataThe lower baseline cognitive performance of non-completers limits generalizability of the results and could have biased the findings.
“This limits generalizability of our results and could have biased our findings.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe lack of a substantial effect on executive function may be due to the focus on treating depression rather than executive dysfunction, as well as the relatively short treatment duration and assessment periods used in these studies.
“This lack of a substantial effect may be due to the focus on treating depression rather than executive dysfunction, as well as the relatively short treatment duration and assessment periods used in these studies.”
Quote in the paperSubstantial claim
The authors state this as an assumption.
RCI z-scores are normally distributed, so that 5% of participants are expected to show decline, 90% no change, and 5% improvement.
“Assuming that RCI z-scores are normally distributed, then it is expected that 5% of participants show “decline” (i.e., smaller than expected improvement), 90% would show “no change” (i.e., expected levels of improvement), and 5% would show “improvement” (i.e., larger than expected improvement).”
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(19.81) = 3.68reported p = .001 · recomputed p = .001
“t(19.81) = 3.68, p = .001”
- Consistentt(19.05) = 2.73reported p = .013 · recomputed p = .013
“t(19.05) = 2.73, p = .013”
- Consistentt(18.44) = 3.12reported p = .006 · recomputed p = .006
“t(18.44) = 3.12, p = .006”
- Consistentχ²(2) = 48.4reported p < .001 · recomputed p < .001
“χ2(2) = 48.4, p < .001”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Self-check results appear here once an independent check has confirmed them.
Cited works that were retracted
Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.
Cites a retracted work: 10.1016/s0140-6736(20)30367-6
MajorThe cited work was retracted on 2023-05-01 (notice 10.1016/s2468-2667(23)00083-x), before this paper was published (2025-01-29). Its authors could have known.
Cited work 10.1016/s0140-6736(20)30367-6 · retracted 2023-05-01 · notice 10.1016/s2468-2667(23)00083-x · this paper published 2025-01-29
“10.1016/S0140-6736(20)30367-6”
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Göke, K., McClintock, S. M., Mah, L., Rajji, T., Lee, H. H., Nestor, S., Downar, J., Noda, Y., Daskalakis, Z., Mulsant, B., et al. (2024) · Biological Psychiatry: Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2024.07.009 · Cited by 12 · see citing works
Self-citationWang, X., Fan, X., Zhang, L., Liu, X., & Ji, Z. (2023) · Medicine · doi:10.1097/md.0000000000034841 · Cited by 11 · see citing works
Gregory, E. C., Torres, I. J., Blumberger, D. M., Downar, J., Daskalakis, Z. J., & Vila-Rodriguez, F. (2022) · Neuromodulation: Technology at the Neural Interface · doi:10.1016/j.neurom.2021.10.001 · Cited by 10 · see citing works
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Hopman, H. J., Choy, H. Y., Ho, W. S., Lu, H., Wong, W. H. O., & Chan, S. M. S. (2021) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s307119 · Cited by 5 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Delis DC, Kramer JH, Kaplan E, et al. California Verbal Learning Test – Second Edition Manual. London: Pearson; 2000.
- Wechsler D. Test of premorbid functioning. San Antonio, TX: The Psychological Corporation.
Cited by
Still being checked.
- Authors
- Göke, K., McClintock, S. M., Mah, L., Rajji, T. K., Lee, H. H., Nestor, S. M., Downar, J., Noda, Y., Daskalakis, Z. J., Mulsant, B. H., & Blumberger, D. M.
- Affiliations
- Centre for Addiction and Mental Health (CA)
- The University of Texas Southwestern Medical Center (US)
- University of Toronto (CA)
- Sunnybrook Health Science Centre (CA)
- Keio University (JP)
- UC San Diego Health System (US)
- Corresponding author
- Blumberger, Daniel M.
- ORCID
- Venue
- The Canadian Journal of Psychiatry
- Publisher
- SAGE Publications
- Published
- 2025-01-29
- Volume
- 71
- Issue
- 7
- Pages
- 498-508
- ISSN
- 0706-7437 (ISSN-L)
- 1497-0015
- PMC
- PMC11783421
- OpenAlex
- W4407001138
- Semantic Scholar
- fc2d3fca080879551bffabe8d72adea2e98070dd
- Cited by
- 4
- References
- 68
- Citations by year
- 2026: 3 · 2025: 1
- FWCI
- 1.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Canadian Journal of Psychiatry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Funders
- Canadian Institutes of Health Research (PJT-148840)
- Topics
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- geriatric depression, repetitive transcranial magnetic stimulation, theta burst stimulation, dorsolateral prefrontal cortex, cognitive outcomes, executive function, processing speed, learning and memory, verbal learning, cognitive safety, older adults
- MeSH terms
- Dorsolateral Prefrontal Cortex, Cognitive Enhancement, Aged, Aged, 80 and over, Depressive Disorder, Female, Humans, Male, Middle Aged, Randomized Controlled Trials as Topic, Outcome Assessment, Health Care, Transcranial Magnetic Stimulation, Executive Function, Cognitive Dysfunction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-28.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-28.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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