Recovering from depression with repetitive transcranial magnetic stimulation (rTMS): a systematic review and meta-analysis of preclinical studies

Abstract

Repetitive transcranial magnetic stimulation (rTMS) has gained growing interest for the treatment of major depression (MDD) and treatment-resistant depression (TRD). Most knowledge on rTMS comes from human studies as preclinical application has been problematic. However, recent optimization of rTMS in animal models has laid the foundations for improved translational studies. Preclinical studies have the potential to help identify optimal stimulation protocols and shed light on new neurobiological-based rationales for rTMS use. To assess existing evidence regarding rTMS effects on depressive-like symptoms in rodent models, we conducted a comprehensive literature search in accordance with PRISMA guidelines (PROSPERO registration number: CRD42019157549). In addition, we conducted a meta-analysis to determine rTMS efficacy, performing subgroup analyses to examine the impact of different experimental models and neuromodulation parameters. Assessment of the depressive-like phenotype was quite homogeneous whilst rTMS parameters among the 23 included studies varied considerably. Most studies used a stress-induced model. Overall, results show a largely beneficial effect of active rTMS compared to sham stimulation, as reflected in the statistically significant recovery of both helplessness (SDM 1.34 [1.02;1.66]) and anhedonic (SDM 1.87 [1.02;2.72]) profiles. Improvement of the depressive-like phenotype was obtained in all included models and independently of rTMS frequency. Nonetheless, these results have limited predictive value for TRD patients as only antidepressant-sensitive models were used. Extending rTMS studies to other MDD models, corresponding to distinct endophenotypes, and to TRD models is therefore crucial to test rTMS efficacy and to develop cost-effective protocols, with the potential of yielding faster clinical responses in MDD and TRD.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1. PRISMA flow diagram for preclinical studies.

Diagram of the literature search (identification) and selection process (screening, eligibility, inclusion).

Fig. 2. Forest plot (effect size and 95% CI) of individual comparisons of animals receiving active vs. sham rTMS intervention on the helplessness profile for subgroup analyses based on animal models.

a chronic unpredictable stress model; b other models; c healthy model. Notes. Horizontal lines represent 95% CIs. The area of each square is proportional to the study weight in the analysis. The diamond represents pooled estimates from random-effects meta-analysis. Red line represents the overall effect. Studies with multiple experimental groups (i.e., exposed to rTMS intervention with a different number of pulses per intervention or a different intensity) are split in multiple lines (indicated by a, b, c, d); these were considered as independent comparisons in the meta-analysis after correcting the total number of control animals by dividing the number of animals in the control group by the number of intervention groups served. A: active rTMS intervention; S: sham rTMS intervention; SDM: standardized mean difference; SE: standard error; CI: confidence interval.

Fig. 3. Forest plot (effect size and 95% CI) of individual comparisons of animals receiving active vs. sham rTMS intervention on the helplessness profile for subgroup analyses based on rTMS frequency.

a high: >5 Hz; b low: <5 Hz (excluding = 5 Hz, i.e., Xue et al. 2019b, Sachdev et al. 2002b). Notes. Horizontal lines represent 95% CIs. The area of each square is proportional to the study weight in the analysis. The diamond represents pooled estimates from random-effects meta-analysis. Red line represents the overall effect. Studies with multiple experimental groups (i.e., exposed to rTMS intervention with a different number of pulses per intervention or a different intensity) are split in multiple lines (indicated by a, b, c, d); these were considered as independent comparisons in the meta-analysis after correcting the total number of control animals by dividing the number of animals in the control group by the number of intervention groups served. A: active rTMS intervention; S: sham rTMS intervention; SDM: standardized mean difference; SE: standard error; CI: confidence interval.

Fig. 4. Forest plot (effect size and 95% CI) of individual comparisons of animals receiving active (n = 86 animals) vs. sham (n = 74 animals) rTMS intervention on the anhedonic profile (overall effect).

Notes. Horizontal lines represent 95% CIs. The area of each square is proportional to the study weight in the analysis. The diamond represents pooled estimates from random-effects meta-analysis. Red line represents the overall effect. Studies with multiple experimental groups (i.e., exposed to rTMS intervention with a different number of pulses per intervention or a different intensity) are split in multiple lines (indicated by a, b, c, etc.); these were considered as independent comparisons in the meta-analysis after correcting the total number of control animals by dividing the number of animals in the control group by the number of intervention groups served. A: active rTMS intervention; S: sham rTMS intervention; SDM: standardized mean difference; SE: standard error; CI: confidence interval.

Fig. 5. Risk of bias assessment, score (%) per risk of bias item.

The RoB tool for animal studies contains 10 entries related to selection bias, performance bias, detection bias, attrition bias, reporting bias and other biases. For each entry, signaling questions were formulated to facilitate judgment: “yes” indicates low risk of bias, “no” indicates high risk of bias, and “unclear” indicates an unclear risk of bias. If one of the relevant signaling questions is answered with “no,” this indicates high risk of bias for that specific entry. Assessing reporting bias was judge as “not applicable” for 2 items. In this respect it should be noted that the “Reporting bias” item was prospectively included in the SYRCLE’s tool (in agreement with the Cochrane’s tool) although at present difficult to assess, as protocols for animal studies are not yet mandatorily registered in central, publicly accessible databases,.