A meta-analysis suggests that TMS targeting the hippocampal network selectively improves episodic memory
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eLife assessment
This meta-analysis provides a fundamental synthesis of evidence demonstrating that transcranial magnetic stimulation targeting the hippocampal-cortical network reliably enhances episodic memory performance across diverse study designs. The evidence is convincing, with rigorous methodology and consistent effects observed despite modest sample sizes and some heterogeneity in stimulation approaches. The work highlights the specificity of memory improvements to hippocampal-dependent memories and identifies key methodological factors-such as individualized targeting-that influence efficacy. Overall, this study offers a timely and integrative framework that will inform both basic memory research and the design of future clinical trials for cognitive enhancement.
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Abstract
Episodic memory is critically dependent on the hippocampal network and is frequently impaired in many clinical disorders. Recent findings highlight Hippocampal Indirectly Targeted Stimulation (HITS) as a promising, noninvasive transcranial magnetic stimulation (TMS) intervention to enhance episodic memory performance. Here, we report the first comprehensive meta-analysis of HITS effects on episodic memory, encompassing both healthy individuals and clinical populations. HITS robustly improved episodic memory, with effects selective for episodic memory versus other non-memory cognitive domains. Efficacy was significantly greater when memory performance was assessed using memory tasks sensitive to recollection, which is strongly linked to hippocampal network function, compared to recognition or other types of episodic memory tasks. Efficacy was also significantly greater when HITS was delivered before versus after the period of memory encoding. No serious adverse events were reported. These findings establish HITS as a safe and effective approach for episodic memory enhancement, with potential for clinical translation in memory disorders. Selectivity of effects for episodic memory generally and for recollection-format tests in particular indicates cognitive and mechanistic specificity, supporting the potential for targeted and selective neuromodulation of hippocampal networks and their associated functions.
Impact statement
Meta-analysis indicates that network-targeted noninvasive brain stimulation consistently enhances memory function supported by the hippocampal network, thus providing robust evidence that specific memory abilities rely on specific modifiable brain networks.
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eLife assessment
This meta-analysis provides a fundamental synthesis of evidence demonstrating that transcranial magnetic stimulation targeting the hippocampal-cortical network reliably enhances episodic memory performance across diverse study designs. The evidence is convincing, with rigorous methodology and consistent effects observed despite modest sample sizes and some heterogeneity in stimulation approaches. The work highlights the specificity of memory improvements to hippocampal-dependent memories and identifies key methodological factors-such as individualized targeting-that influence efficacy. Overall, this study offers a timely and integrative framework that will inform both basic memory research and the design of future clinical trials for cognitive enhancement.
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Reviewer #1 (Public review):
Summary:
Goicoechea et al. conducted a timely and thorough meta-analysis on the potential for indirect hippocampal targeted transcranial magnetic stimulation (TMS) to improve episodic memory. The authors included additional factors of interest in their meta-analysis, which can be used to inform the next generation of studies using this intervention. Their analysis revealed critical factors for consideration: TMS should be applied pre-encoding, individualized spatial targeting improves efficacy, and improvement of recollection was stronger than recognition.
Strengths:
As mentioned previously, the meta-analysis is timely and summarizes an emerging set of studies (over the past decade since Wang et al., Science 2014). Those outside of the field may not be aware of the robustness of improvements in episodic …
Reviewer #1 (Public review):
Summary:
Goicoechea et al. conducted a timely and thorough meta-analysis on the potential for indirect hippocampal targeted transcranial magnetic stimulation (TMS) to improve episodic memory. The authors included additional factors of interest in their meta-analysis, which can be used to inform the next generation of studies using this intervention. Their analysis revealed critical factors for consideration: TMS should be applied pre-encoding, individualized spatial targeting improves efficacy, and improvement of recollection was stronger than recognition.
Strengths:
As mentioned previously, the meta-analysis is timely and summarizes an emerging set of studies (over the past decade since Wang et al., Science 2014). Those outside of the field may not be aware of the robustness of improvements in episodic memory from hippocampal targeted TMS. The authors were quite thorough in including additional factors that are important for the interpretation of these findings. These factors also address the differences in approach across studies. The evidence that individualized spatial targeting improves TMS efficacy is consistent with recent advances in TMS for major depressive disorder. The specificity of the cognitive improvements to recollection of episodic memory and not for other cognitive domains is consistent with hippocampal targeting. The authors also plan to post the complete dataset on an open-source repository, which enables additional analysis by other researchers.
Weaknesses:
The write-up is succinct and emphasizes the scientific decisions that underlie key differences in the various experimental designs. While the manuscript is written for a scientific audience, the authors are likely aware that findings like this will be of broad appeal to the field of neurology, where treatments for memory loss are desperately needed. For this reason, the authors could consider including a statement regarding an interpretation of this meta-analysis from a clinical standpoint. Statements such as 'safe and effective' imply a clinical indication, and yet the manuscript does not engage with clinical trials terminology such as blinding, parallel arm versus crossover design, and trial phase. While the authors might prefer not to engage with this terminology, it can be confusing when studies delivering intervention-like five days of consecutive TMS (e.g., Wang et al., 2014) are clustered with studies that delivered online rhythmic TMS, which tests target engagement (e.g., Hermiller et al., 2020). While the 'sessions' variable somewhat addresses the basic-science versus intervention-like approach, adding an explicit statement regarding this in the discussion might help the reader navigate the broad scope of approaches that are utilized in the meta-analysis.
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Reviewer #2 (Public review):
Summary:
In 2014, Wang et al. showed that noninvasive stimulation of a parietal site, connected functionally to the hippocampus, increased resting state connectivity throughout a canonical network associated with episodic memory. It also produced a memory boost, which correlated with the connectivity increase across subjects. Their discovery that an imaging biomarker could be used to target a network (rather than a single cortical site) in individual subjects and provide a scaling measure of target modulation should have revolutionized the noninvasive neuromodulation field. This meta-analysis by members of the same group covers memory effects from noninvasive stimulation of various nodes of the "hippocampal" network.
Strengths:
This is a very timely summary and meta-analysis of this very promising …
Reviewer #2 (Public review):
Summary:
In 2014, Wang et al. showed that noninvasive stimulation of a parietal site, connected functionally to the hippocampus, increased resting state connectivity throughout a canonical network associated with episodic memory. It also produced a memory boost, which correlated with the connectivity increase across subjects. Their discovery that an imaging biomarker could be used to target a network (rather than a single cortical site) in individual subjects and provide a scaling measure of target modulation should have revolutionized the noninvasive neuromodulation field. This meta-analysis by members of the same group covers memory effects from noninvasive stimulation of various nodes of the "hippocampal" network.
Strengths:
This is a very timely summary and meta-analysis of this very promising application of TMS. To the limited extent of my expertise in meta-analysis, the methodology seems rigorous, and the central finding, that high-frequency stimulation of nodes in the hippocampal network reproducibly improves event recall, is amply supported. This should provide impetus for larger clinical trials and further quantification of the optimal dose, duration of effect, etc.
Weaknesses:
My critical comments are mainly on the framing and argument:
(1) While the introduction centers on the role of the hippocampus in episodic memory and posits hippocampal neuromodulation by TMS as causative, the true mechanism may be more complex. Clean hippocampal lesions in primates cause focal loss of spatial and place memory, and I am aware of no specific evidence that the hippocampus does more than this in humans. Moreover, there is evidence that lateral parietal TMS also reaches neighboring temporal lobe regions, which contribute to episodic memory. The hippocampus may, therefore, be a reliable deep seed for connectivity-based targeting of the episodic memory network, but might not be the true or only functional target.
(2) The meta-analysis combines studies with confirmation of targeting and target-network engagement from fMRI and studies without independent evidence of having stimulated the putative target (e.g., Koch et al). That seems like a more important methodological distinction than merely the use of any individual targeting method. In my experience, atlas-based estimates are at least as accurate as eyeballing cortical areas in individuals. Hence, entering individual functional targeting as a factor might reveal an effect on efficacy.
(3) The funnel plot and Egger's regression for episodic memory outcomes suggested possible bias, and the average sample size of 23 is small, contributing to the likelihood of false positive results. It would be informative, therefore, to know how many or which studies had formal power estimates and what the predicted effect sizes were.
(4) In the Discussion, the authors might provide a comparison between the effect size for memory improvement found here with those reported for other brain-targeted interventions and behavioral strategies. It may also be worthwhile pointing out that HITS/memory is one of the very few, or perhaps the only, neuromodulatory effects on cognition that has been extensively reproduced and survived rigorous meta-analysis.
(5) The section of the Discussion on specificity compares HITS to transcranial electrical stimulation without specifying an anatomical target or intended outcome. A better contrast might be the enormous variety of cognitive and emotional effects claimed for TMS of the dorsolateral prefrontal cortex.
(6) With reference to why other nodes in the episodic memory network have not been tested, current flow modeling shows TMS of the medial prefrontal cortex is unlikely to be achievable without stronger stimulation of the convexity under the coil, in addition to being uncomfortable. The lateral temporal lobe has been stimulated without undue discomfort.
(7) Finally, a critical question hanging over the clinical applicability of HITS and other neuromodulation techniques is how well they will work on a damaged substrate. Functional and/or anatomical imaging might answer this question and help screen for likely responders. The authors' opinion on this would be informative.
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Reviewer #3 (Public review):
Summary:
The manuscript by Goicoechea et al. assesses the influence of hippocampal-network targeted TMS to parietal cortex on episodic memory using a meta-analytic approach. This is an important contribution to the literature, as the number of studies using this approach to modulate memory/hippocampal function has clearly increased since the initial publication by Wang et al. 2014. This manuscript makes an important contribution to the literature. In general, the analysis is straightforward and the conclusions are well-supported by the results; I have mostly minor comments/concerns.
Strengths:
(1) A meta-analysis across published work is used to evaluate the influence of hippocampal-network-targeted TMS in parietal cortex on episodic memory. By pooling results across studies, the meta-analytic effects …
Reviewer #3 (Public review):
Summary:
The manuscript by Goicoechea et al. assesses the influence of hippocampal-network targeted TMS to parietal cortex on episodic memory using a meta-analytic approach. This is an important contribution to the literature, as the number of studies using this approach to modulate memory/hippocampal function has clearly increased since the initial publication by Wang et al. 2014. This manuscript makes an important contribution to the literature. In general, the analysis is straightforward and the conclusions are well-supported by the results; I have mostly minor comments/concerns.
Strengths:
(1) A meta-analysis across published work is used to evaluate the influence of hippocampal-network-targeted TMS in parietal cortex on episodic memory. By pooling results across studies, the meta-analytic effects demonstrate an influence of TMS on memory across the diversity of many details in study design (specific tasks, stimuli, TMS protocols, study populations).
(2) Selectivity with regard to episodic memory vs. non-episodic memory tasks is evaluated directly in the meta-analysis.
(3) The investigation into supplemental factors as predictors of TMS's influence on memory was tested. This is helpful given the diversity of study designs in the literature. This analysis helps to shed light on which study designs, e.g., TMS protocols, etc., are most effective in memory modulation.
Weaknesses:
(1) My only significant concern is how studies are categorized in the 'Timing' factor (when stimulation is applied). Currently, protocols in which TMS is administered across days are categorized as 'pre-encoding' in the Timing factor. This has the potential to be misleading and may lead to inaccurate conclusions. When TMS is administered across multiple days, followed by memory encoding and retrieval (often on a subsequent day), it is not possible to attribute the influence of TMS to a specific memory phase (i.e., encoding or retrieval) per se. Thus, labeling multi-day TMS studies as 'pre-encoding' may be misleading to readers, as it may imply that the influence of TMS is due to modulation of encoding mechanisms per se, which cannot be concluded. For example, multi-day TMS protocols could be labeled as 'pre-retrieval' and be similarly accurate. This approach also pools results from TMS protocols with temporal specificity (i.e., those applied immediately during encoding and not on board during memory testing) and without temporal specificity (i.e., the case of multi-day TMS) regarding TMS timing. Given the variety of paradigms employed in the literature, and to maximize the utility/accuracy of this analysis, one suggestion is to modify the categories within the Timing factor, e.g., using labels like 'Temporally-Specific' and 'Temporally Non-specific'. The 'Temporally-Specific' category could be subdivided based on the specific memory process affected: 'encoding', 'retrieval', or 'consolidation' (if possible). I think this would improve the accuracy of the approach and help to reach more meaningful conclusions, given the variety of protocols employed in the literature.
(2) As the scope of the meta-analysis is limited to TMS applied to parietal or superior occipital cortex, it is important to highlight this in the Introduction/Abstract. The 'HITS' terminology suggests a general approach that would not necessarily be restricted to parietal/nearby cortical sites.
Minor:
(1) To reduce the number of study factors tested, data reduction was performed via Lasso regression to remove factors that were not unique predictors of the influence of TMS on memory. This approach is reasonable; however, one limitation is that factors strongly correlated with others (and predict less unique variance) will be dropped. This may result in a misrepresentation, i.e., if readers interpret factors left out of this analysis as not being strongly related to the influence of TMS on memory. I do see and appreciate the paragraph in the Discussion which appropriately addresses this issue. However, it may be worth also considering an alternative analysis approach, if the authors have not already done so, which explicitly captures the correlation structure in the data (i.e., shown in Figure S2) using a tool like PCA or an appropriate factor analysis. Then, this shared covariance amongst factors can be tested as predictors of the influence of TMS - e.g., by testing whether component scores for dominant PCs are indeed predictive of the influence of TMS. This complementary approach would capture rather than obfuscate the extent to which different factors are correlated and assess their joint (rather than independent) influence on memory, potentially resulting in more descriptive conclusions. For example, TMS intensity and protocol may jointly influence memory.
(2) Given the specific focus on TMS applied to parietal cortex to modulate hippocampal and related network function, it would be fruitful if the authors could consider adding discussion/speculation regarding whether this approach may be effectively broadened using other stimulation methods (e.g., tACS, tDCS), how it may compare to other non-invasive brain stimulation methods with depth penetration to target hippocampal function directly (transcranial temporal interference, or transcranial focused ultrasound), and/or how or whether other stimulation sites may or may not be effective.
(3) Studies were only included in the meta-analysis if they contained objective episodic memory tests. How were studies handled that included both objective and subjective memory, or other non-episodic memory measures? For example, Yazar et al. 2014 showed no influence of TMS on objective recall, but an impairment in subjective confidence. I assume confidence was not included in the meta-analysis. Similarly, Webler et al. 2024 report results from both the mnemonic similarity task (presumably included) and a fear conditioning paradigm (presumably excluded). Please clarify in the methods how these distinctions were handled.
(4) The analysis comparing memory to non-memory measures is important, showing the specificity of stimulation. Did the authors consider further categorizing the non-memory tasks into distinct domains (i.e., language, working memory, etc.)? If possible, this could provide a finer detail regarding the selectivity of influences on memory vs. other aspects of cognition. It is likely that other aspects of cognition dependent on hippocampal function may be modulated as well, i.e., tasks with high relational/associative processing demands.
(5) In the analysis of the Intensity factor, how were studies using Active (rather than resting) MT categorized? Only resting MT is mentioned in Table S1. This is important as the original theta-burst TMS protocol from Huang et al. 2005 determines intensity based on Active Motor Threshold.
(6) Is there a reason why the study by Koen et al. 2018 (Cognitive Neuroscience) was not included? TMS was performed during encoding to the left AG, and objective memory was assessed, so it would seemingly meet the inclusion criterion.
(7) It would be helpful to briefly differentiate the current meta-analysis from that performed by Yeh & Rose (How can transcranial magnetic stimulation be used to modulate episodic memory?: A systematic review and meta-analysis, 2019, Frontiers in Psychology) (other than being more current).
(8) For transparency and to facilitate further understanding of the literature and potential data re-use, it would be great if the authors consider sharing a supplementary table or file that describes how individual studies/memory measures were categorized under the factors listed in Table S1.
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