Why do opposite left and right prefrontal stimulation protocols for depression produce similar clinical results?

Why can stimulating opposite sides produce similar symptom relief?

The leading explanation is that depression involves large-scale brain networks rather than a single over- or under-active spot on one side. The dorsolateral prefrontal cortex (DLPFC) is a key node in networks that help regulate emotion, and it connects to limbic regions involved in mood. Stimulating either the left or right DLPFC may therefore push the same distributed network toward a more regulated state, even though the coil is placed on opposite sides. In a study of 44 patients aged 50–79 with chronic major depression, accelerated intermittent theta burst stimulation (aiTBS) delivered to either the left or right DLPFC produced no statistically significant difference in the magnitude of improvement in depression, anxiety, or anhedonia symptoms [2]. That equivalence is consistent with the idea that the therapeutic target is a network, not a hemisphere.

A separate sequential bilateral protocol combined high-frequency stimulation to the left DLPFC with excitatory intermittent theta burst stimulation to the right DLPFC and reported a 66% response rate and 24% remission rate in 38 patients with treatment-resistant depression [1]. The authors noted that this result was higher than the roughly 29% response rate reported in a meta-analysis of standard high-frequency left unilateral stimulation, and they suggested that adding excitatory right-sided stimulation may have therapeutic benefits by altering connectivity among the default mode, salience, and central executive networks [1]. That is a proposed mechanism, not a proven cause, but it fits the broader picture that mood improvement can arise from shifting network dynamics rather than from correcting a one-sided deficit.

If the outcomes are similar, why do the brain connectivity changes differ?

Similar symptom relief does not mean the brain is changing in the same way. In the direct left-versus-right comparison, patients receiving right DLPFC aiTBS showed significant decreases in functional connectivity between the default mode network and limbic networks from baseline to end of treatment, whereas patients receiving left DLPFC aiTBS showed limited connectivity changes [2]. The authors concluded that connectivity changes associated with treatment were asymmetric and may reflect hemispheric lateralization of functional network responses to iTBS [2]. In plain terms, the two sides may reach a comparable clinical destination through different routes.

This matters for how we interpret “equivalent efficacy.” The equivalence in that study was measured by symptom scales—depression, anxiety, and anhedonia—in a late-life population, not by identical brain changes [2]. The same clinical score improvement can therefore sit on top of different network rearrangements. The finding also comes from an open-label study without a sham control, so the comparison is between two active protocols rather than against placebo. The scope is older adults with chronic depression, and the authors called for further work to confirm comparative efficacy and network dynamics [2].

What does this mean for choosing or combining left and right stimulation?

The practical implication is that the side of stimulation may be less important than engaging the right network with an adequate dose and targeting approach. The sequential bilateral study used connectivity-guided reasoning to argue that excitatory right-sided stimulation may add benefit beyond the traditional “left-excitatory/right-inhibitory” strategy, and its authors explicitly called for expanding treatment approaches beyond that lateralization assumption [1]. That is a rationale for testing new protocols, not proof that right-sided excitation is superior; the study was retrospective, naturalistic, had no sham control, and did not directly compare its protocol against unilateral or other bilateral protocols [1].

Other work in older adults points in a similar direction: a prolonged intermittent theta burst protocol to the left DLPFC produced a 43.5% response rate and 34.8% remission rate in 23 older adults with treatment-resistant depression, and the authors described the reduction as comparable to standard sequential bilateral rTMS/iTBS in the FOUR-D trial [3]. That comparison is across studies rather than a head-to-head randomized trial, so it supports the general observation that different left-sided and bilateral approaches can land in a similar clinical range. A 2025 sequential bilateral study targeting the right orbitofrontal cortex and left DLPFC also reported treatment effects in depression, but it did not directly compare opposite-side protocols [5]. Taken together, the evidence is consistent with the idea that multiple stimulation geometries can produce meaningful antidepressant effects, while the underlying network changes and the best protocol for a given patient remain open questions.

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