Reduced Heterogeneity of Neuromodulation Outcomes With MRI-Guided Versus Scalp-Based Targeting for Auditory Verbal Hallucinations: A Meta-Analysis
DOI: Pending DOI
Synopsis
Auditory verbal hallucinations (AVH) often persist despite available treatments, and clinical outcomes of neuromodulation vary substantially across studies. We conducted a meta-analysis of sham-controlled neuromodulation trials for AVH, comparing TPJ-centered MRI/MNI-guided targeting, surface-based targeting, and alternative brain-based approaches. MRI/MNI-guided targeting produced the largest treatment effects and showed no detectable between-study heterogeneity, whereas surface-based targeting remained effective but yielded highly variable outcomes. Exploratory E-field modeling indicated that MRI-guided targeting engaged more posterior temporoparietal and language-related regions. These findings raise the possibility that differences in cortical target engagement may contribute to the greater consistency observed with MRI-guided targeting.
Background
Auditory verbal hallucinations (AVH) remain among the most disabling symptoms of schizophrenia and often persist despite optimized pharmacological treatment. Neuromodulation approaches, particularly repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), have therefore emerged as promising adjunctive interventions. Converging neuroimaging evidence implicates distributed frontotemporal language and auditory networks in AVH pathophysiology, providing a rationale for targeted neuromodulation. However, treatment outcomes remain highly variable across studies despite generally favorable effects of TPJ-targeted stimulation. One potential source of this variability is target localization strategy. Whereas most studies rely on scalp-based approaches based on external cranial landmarks, MRI-guided targeting incorporates subject-specific neuroanatomical information and may allow more precise and consistent localization of stimulation targets, potentially improving engagement of symptom-relevant cortical regions and networks. The extent to which targeting strategy contributes to variability in AVH treatment outcomes remains unclear.
Methods
A systematic review identified 43 sham-controlled randomized trials of rTMS and tDCS for auditory verbal hallucinations (AVH) published between 1999 and July 2025. Effect sizes (Hedges' g) were pooled using random-effects meta-analysis. To evaluate the influence of target localization strategy, studies were categorized according to target localization strategy: (1) TPJ-centered MRI/MNI-guided targeting, defined as MRI-navigated stimulation of the left TPJ using predefined MNI coordinates transformed into individual anatomical space; (2) surface-based targeting, including conventional scalp-localization approaches such as the Hoffman procedure and EEG 10-20 positioning methods1 ; and (3) alternative brain-based targeting, including individualized fMRI-guided targets, anatomical landmark-based approaches, and MRI/MNI-guided targets outside the TPJ. Subgroup analyses compared pooled efficacy and between-study heterogeneity across targeting strategies. To explore whether TPJ-centered MRI/MNI-guided and surface-based targeting approaches engage different cortical regions, exploratory E-field modeling was performed using the TPJ targets employed in the MRI/MNI-guided studies and a conventional Hoffman-based TPJ target. Spatial distributions of the modeled electric fields were compared to assess differences in cortical engagement between targeting approaches
Results
A significant subgroup effect was observed (Qm(2)=11.80, p=.003; Figure 1). TPJ-centered MRI/MNI-guided targeting demonstrated the largest treatment effect (g=-0.94, 95% CI=-1.31 to -0.56, p<.001) and no detectable between-study heterogeneity (τ²=0.00). In contrast, surface-based targeting remained effective (g=-0.39, 95% CI=-0.62 to -0.16, p<.001) but exhibited substantial heterogeneity (τ²=0.30; PI=-1.49 to 0.71), indicating highly variable outcomes across studies. Non-TPJ/alternative brain-based targeting was not associated with significant clinical benefit (g=-0.07, 95% CI=-0.40 to 0.26, p=.680).
Comparative E-field modeling demonstrated distinct field distributions between the TPJ-centered MNI target used in Chen et al. (2019) and Hua et al. (2024) (MNI: −51, −31, 23) 2-3 and a scalp-based Hoffman target (−65, −44, 37) derived from five participants in our prior pilot TMS study. Relative to the Hoffman target, the MNI-guided target produced a broader and more posterior field distribution, with greater engagement of temporoparietal and posterior language regions. Difference mapping further demonstrated that the largest field increases associated with the MNI target were concentrated within posterior temporoparietal cortex.
Discussion
TPJ-centered MRI/MNI-guided targeting was associated with both larger treatment effects and substantially lower between-study heterogeneity than surface-based targeting approaches. Although surface-based targeting remained effective overall, treatment effects varied considerably across studies, suggesting that variability in cortical target engagement may contribute to the inconsistent outcomes reported in the AVH neuromodulation literature.
Preliminary E-field modeling demonstrated that MRI-guided targeting produced a broader and more posterior field distribution, with greater engagement of temporoparietal and posterior language regions relative to a scalp-based target. These findings raise the possibility that more consistent engagement of AVH-relevant cortical networks may contribute to the reduced heterogeneity observed across MRI-guided studies, although this hypothesis remains to be tested directly.
Several limitations should be considered. The MRI/MNI-guided subgroup included only a small number of studies, reflecting the limited adoption of TPJ-centered MRI-guided targeting within the AVH literature to date and restricting the precision of heterogeneity estimates. In addition, the E-field analyses were exploratory and cannot establish a causal relationship between field distribution and clinical response. Future studies integrating individualized targeting, E-field modeling, and clinical response measures will be needed to determine whether consistent engagement of posterior temporoparietal regions contributes to improved treatment reliability in AVH.
Disclosures
Nothing to disclose by any authors.
References
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2. Chen, X., Ji, G. J., Zhu, C., Bai, X., Wang, L., He, K., ... & Wang, K. (2019). Neural correlates of auditory verbal hallucinations in schizophrenia and the therapeutic response to theta-burst transcranial magnetic stimulation. Schizophrenia bulletin, 45(2), 474-483.
3. Hua, Q., Wang, L., He, K., Sun, J., Xu, W., Zhang, L., ... & Ji, G. J. (2024). Repetitive transcranial magnetic stimulation for auditory verbal hallucinations in schizophrenia: A randomized clinical trial. JAMA network Open, 7(11), e2444215-e2444215.