TMS Bipolar Care: Advances in Neuromodulation Pathways

Transcranial magnetic stimulation (TMS) has emerged as a promising treatment for bipolar disorder, particularly for patients who struggle with medication side effects or inadequate response to conventional therapies. By using electromagnetic fields to modulate brain activity, TMS offers a non-invasive approach that targets neural circuits involved in mood regulation.

Recent advances have refined TMS protocols, enhancing its effectiveness and expanding its applications. Researchers are optimizing techniques such as coil positioning and neuroimaging-guided targeting to improve outcomes for both manic and depressive episodes.

Neuromodulation Pathways in Bipolar

Bipolar disorder is characterized by dysregulated neural circuits governing mood stability, with abnormalities in excitatory and inhibitory signaling contributing to both manic and depressive episodes. TMS primarily targets the prefrontal cortex and its connections to limbic structures, including the amygdala, hippocampus, and anterior cingulate cortex—key regions in emotional processing, reward sensitivity, and executive function. By modulating cortical excitability, TMS aims to restore functional balance in mood regulation.

TMS exerts its effects by altering synaptic plasticity through long-term potentiation (LTP) and long-term depression (LTD). High-frequency stimulation (above 5 Hz) enhances cortical excitability and is used to alleviate depressive symptoms by increasing activity in the left dorsolateral prefrontal cortex (DLPFC). Conversely, low-frequency stimulation (around 1 Hz) reduces excitability and is explored for mitigating manic symptoms by dampening hyperactivity in the right DLPFC. These frequency-dependent effects align with neurophysiological models suggesting mood episodes result from imbalances in prefrontal-limbic connectivity.

TMS also influences neurotransmitter systems implicated in bipolar disorder, including glutamate, gamma-aminobutyric acid (GABA), and dopamine. Magnetic resonance spectroscopy (MRS) studies show excitatory TMS protocols increase glutamatergic activity in the prefrontal cortex, contributing to antidepressant effects, while inhibitory TMS enhances GABAergic tone, potentially counteracting manic excitability. Additionally, TMS affects striatal dopamine release, which may help regulate reward processing abnormalities in bipolar disorder.

Types of TMS Approaches

TMS encompasses several techniques differing in stimulation patterns, depth of penetration, and therapeutic effects. These variations allow for tailored interventions based on symptom presentation in bipolar disorder. The primary approaches include repetitive TMS (rTMS), deep TMS (dTMS), and theta burst stimulation (TBS).

Repetitive TMS

Repetitive TMS (rTMS) delivers repeated magnetic pulses to a targeted brain region. The frequency of stimulation determines its effects on cortical excitability. High-frequency rTMS (10 Hz or higher) is commonly applied to the left DLPFC to enhance neural activity and alleviate depressive symptoms. Low-frequency rTMS (around 1 Hz) inhibits overactive regions, such as the right DLPFC, potentially benefiting manic episodes.

Clinical trials have demonstrated rTMS efficacy in bipolar depression. A 2020 meta-analysis in JAMA Psychiatry reported significant improvements in depressive symptoms compared to sham stimulation. However, its effectiveness in treating mania remains less established, with ongoing research exploring optimal parameters. The non-invasive nature of rTMS and its mild side effects—typically limited to scalp discomfort and transient headaches—make it a viable option for those who do not tolerate pharmacological treatments.

Deep TMS

Deep TMS (dTMS) uses specialized H-coils to penetrate deeper cortical and subcortical structures than conventional rTMS. This approach allows modulation of brain regions beyond the superficial prefrontal cortex, including the anterior cingulate cortex and insula, which are involved in mood regulation.

A 2021 randomized controlled trial in Brain Stimulation found that dTMS targeting the bilateral prefrontal cortex led to greater symptom reduction in bipolar depression compared to standard rTMS. The study also noted a lower risk of inducing manic episodes, a concern with high-frequency stimulation in bipolar patients. While dTMS requires specialized equipment and is less widely available, its ability to engage broader neural networks makes it a focus of ongoing research.

Theta Burst TMS

Theta burst stimulation (TBS) delivers bursts of stimulation that mimic endogenous theta rhythms associated with synaptic plasticity. TBS can be administered in two forms: intermittent TBS (iTBS), which enhances cortical excitability, and continuous TBS (cTBS), which suppresses neural activity.

A 2019 study in Biological Psychiatry found iTBS produced comparable antidepressant effects to conventional high-frequency rTMS while significantly reducing treatment duration. Since TBS protocols require only a few minutes per session, they offer a more time-efficient alternative to traditional TMS. However, research on cTBS for mania remains limited, with preliminary findings suggesting potential benefits in reducing hyperactivity and impulsivity. Further studies are needed to refine stimulation parameters and assess long-term efficacy.

Coil Positioning and Targeted Brain Regions

Optimizing coil placement in TMS for bipolar disorder is fundamental to achieving therapeutic effects, as different brain regions contribute uniquely to mood regulation. The dorsolateral prefrontal cortex (DLPFC) remains the most widely targeted area due to its role in executive function, emotional regulation, and connectivity with deeper limbic structures. Stimulation of the left DLPFC is associated with antidepressant effects, while modulation of the right DLPFC has been explored for managing manic symptoms. Precise coil positioning ensures accurate delivery of magnetic pulses, maximizing clinical efficacy while minimizing unintended effects.

The standard method for locating the DLPFC involves the “5 cm rule,” where the coil is positioned 5 cm anterior to the motor cortex hotspot. However, this lacks individualized precision and can lead to variability in treatment response. More advanced techniques, such as neuronavigation-assisted TMS, use structural MRI scans to guide coil placement based on each patient’s neuroanatomy. This enhances targeting accuracy by accounting for individual differences in cortical structure and functional connectivity. Functional MRI (fMRI) studies show that personalized DLPFC targeting, particularly regions with strong connectivity to the subgenual anterior cingulate cortex, correlates with greater symptom improvement.

Beyond the DLPFC, alternative targets have been investigated to refine TMS protocols for bipolar disorder. The ventromedial prefrontal cortex (vmPFC) and orbitofrontal cortex (OFC) are areas of interest due to their involvement in emotional processing and reward-related decision-making. Some research suggests stimulation of these regions may modulate affective dysregulation more directly than traditional DLPFC-targeted approaches. Additionally, deeper structures such as the anterior cingulate cortex (ACC) and insula, accessible via deep TMS, play a role in mood stabilization.

Protocol Adjustments for Mania and Depression

Tailoring TMS protocols for bipolar disorder requires adjustments to account for the distinct neurophysiological profiles of mania and depression. Frequency, intensity, and duration of stimulation influence cortical excitability, necessitating different approaches depending on a patient’s mood state. Selecting an appropriate protocol is essential to avoid exacerbating symptoms or triggering mood instability.

For bipolar depression, high-frequency stimulation (10 Hz or higher) targeting the left DLPFC has been the most studied approach. Randomized controlled trials demonstrate that increasing excitability in this region correlates with improved depressive symptoms, with response rates comparable to pharmacotherapy. Session parameters often involve daily treatments over four to six weeks, with stimulation intensities at 120% of the motor threshold to ensure adequate cortical engagement. However, concerns about treatment-emergent mania necessitate close monitoring, especially in individuals with a history of rapid cycling. Some clinicians mitigate this risk by starting with lower stimulation intensities or combining TMS with concurrent mood stabilizers.

Managing mania requires a different strategy, as excessive neural excitability underlies many of its symptoms. Low-frequency stimulation (around 1 Hz) applied to the right DLPFC has been explored to reduce hyperactivity and impulsivity. While research in this area is less extensive than for depression, preliminary findings suggest inhibitory TMS paradigms can help stabilize mood without inducing depressive symptoms. The challenge lies in determining optimal session durations and ensuring that treatment does not interfere with cognitive function.

Neuroimaging in TMS Treatment Planning

Advancements in neuroimaging have refined TMS precision for bipolar disorder by enabling individualized treatment planning. Traditional TMS protocols often rely on standardized anatomical landmarks, but variability in cortical structure and connectivity can lead to inconsistent outcomes. Integrating neuroimaging techniques such as functional MRI (fMRI) and diffusion tensor imaging (DTI) allows clinicians to tailor stimulation targets based on each patient’s neural architecture, improving symptom outcomes.

Functional MRI helps identify mood-regulating circuits, pinpointing regions of hypo- or hyperactivity associated with depressive and manic states. In bipolar depression, connectivity between the DLPFC and the subgenual anterior cingulate cortex (sgACC) is often disrupted, and targeting the most functionally connected portion of the DLPFC leads to stronger antidepressant effects. DTI further refines this approach by mapping white matter tracts linking the prefrontal cortex to limbic structures, optimizing network-wide modulation.

Beyond target selection, neuroimaging also plays a role in monitoring treatment response. Serial fMRI scans track changes in cortical activity over TMS sessions, providing objective markers of neural plasticity. Electroencephalography (EEG)-guided TMS is also emerging as a strategy to assess cortical excitability in real time. By combining these imaging modalities, researchers continue to refine neuromodulation strategies, expanding TMS’s therapeutic potential for bipolar disorder while minimizing variability in treatment outcomes.