Whenever a person first comes in for TMS as treatment for Depression, our psychiatrist explains that we are stimulating the Dorsal-lateral Prefrontal Cortex–the part of your brain in charge of working memory, planning, cognitive control, decision-making, and complex problem-solving. While this is accurate, the mechanism that TMS uses to create an experience of minimal depression is more complex, and there are many explanations around exactly what is going on. In this post, I will review the prominent understanding of the brain structures that TMS effects to hopefully enlighten the skeptic within us all.
Understanding the Basics: How TMS Works
Before diving into the specific brain regions and mechanisms, it’s important to understand how TMS actually works. When we deliver a TMS pulse, we’re creating a brief but powerful magnetic field that passes through the skull and induces electrical currents in the brain tissue beneath. These induced currents can activate neurons, but not in the way many people might imagine.
Rather than directly stimulating the cell bodies (somas) of neurons, TMS primarily activates the axons – the long projections that neurons use to send signals to other cells. More specifically, TMS tends to activate myelinated axons, which are wrapped in an insulating material that makes them more responsive to electrical stimulation. This preferential activation of myelinated axons occurs because they have a much shorter response time (around 150-300 microseconds) compared to cell bodies, which require relatively longer stimulation to activate.
The Surface Matters: Why Location Is Critical
One of the most important things to understand about TMS is that its effects are strongest near the surface of the brain and decrease rapidly with depth. When we target the left DLPFC, we’re most strongly stimulating the crown (top) and lip regions of the gyri (the ridges of the brain’s folded surface). The electromagnetic field generated by TMS decays quickly as it penetrates deeper into the brain tissue.
This means that when we say we’re stimulating the DLPFC, we’re primarily activating the most superficial layers of the cortex in the targeted gyrus. The axons that run parallel to the brain’s surface in these areas are particularly susceptible to stimulation, especially at points where they bend or branch in the crown and lip regions of the gyrus. This spatial relationship between the TMS-induced field and neural tissue is crucial for understanding both the possibilities and limitations of TMS treatment.
Complex Networks: Beyond Direct Stimulation
While TMS directly activates neurons in the superficial layers of the targeted area, its effects ripple through neural networks in fascinating ways. When we stimulate the DLPFC, we’re actually influencing an intricate web of interconnected brain regions through multiple mechanisms. The initial activation is just the beginning of a complex cascade of neural events.
The direct effects of TMS begin with the activation of both excitatory (glutamatergic) and inhibitory (GABAergic) neurons in the superficial cortical layers. This dual activation is crucial because it means TMS doesn’t simply excite the brain – it modulates the delicate balance between excitation and inhibition. The stimulation of axon terminals and branches in the crown and lip regions of the gyrus leads to the activation of local microcircuits within the targeted area, creating a complex pattern of neural activity.
The effects of TMS propagate through the brain’s networks in multiple directions. Signals travel forward (orthodromic) along activated axons to connected brain regions, while simultaneously traveling backward (antidromic) along these same pathways. This bidirectional propagation activates trans-synaptic connections to other brain areas, leading to changes in the functional connectivity between different brain networks. Recent research has shown that these network-level effects may be just as important as the local effects in determining the therapeutic outcomes of TMS treatment.
State-Dependent Effects: The Brain’s Dynamic Response
One of the most fascinating aspects of TMS is its state-dependency – the fact that its effects can vary dramatically depending on the brain’s current state of activity. Think of it like trying to have a conversation – the success of the interaction depends heavily on the current state of the participants. While this is a simplification, it helps us understand why the brain’s response to TMS isn’t always the same.
When we deliver a TMS pulse, research has shown that the response depends on several critical factors. The current activity level of the targeted brain region and its intrinsic excitability fundamentally shape how it will respond to stimulation. The overall brain state matters tremendously too–studies have demonstrated that the same TMS protocol can have notably different effects depending on whether someone is resting or actively engaged in a task.
This state dependency isn’t just about whether someone is resting or active; it reflects the complex interactions between ongoing neural activity and the stimulation we’re delivering. The source of these state-dependent effects lies in how TMS interacts with both local neural circuits in the stimulated area and broader brain networks. These interactions can lead to different outcomes even when using identical stimulation parameters.
There are many exciting questions still to be explored about state dependency in TMS. For instance, researchers might investigate how factors like time of day, sleep patterns, or recent physical activity could influence TMS responsiveness. We might also examine how various medications interact with TMS effects, and whether certain brain states could be intentionally induced to optimize treatment outcomes. Understanding these potential influences could help develop more personalized and effective TMS protocols.
This state dependency helps explain several important clinical observations: why TMS treatments might work better for some people than others, and why the timing of TMS pulses relative to brain activity can be crucial for therapeutic effects. As our understanding of these state-dependent effects grows, we’re moving toward more sophisticated approaches to TMS therapy that take into account the brain’s dynamic nature.
Future research into state dependency might investigate whether targeted cognitive or emotional exercises during TMS could enhance its therapeutic effects, or whether certain physiological states might make the brain more receptive to treatment. These kinds of investigations could lead to more refined and effective treatment protocols.
Beyond the Target: The Whole-Brain Response
When we deliver TMS, we’re initiating a complex cascade of events that extends far beyond our intended target. Every TMS pulse creates a multisensory experience that engages multiple brain systems simultaneously. The loud clicking sound from the coil activates the auditory system, while the mechanical stimulation activates scalp nerves and muscles. There’s also potential stimulation of cranial nerves, and the mechanical vibration can activate various skin receptors.
These “co-stimulation” effects aren’t just side effects to be ignored – they’re an integral part of how TMS influences brain function. The brain’s response to TMS is always a combination of direct neural stimulation and these peripheral effects. This complexity needs to be considered when interpreting TMS effects and designing treatment protocols.
Understanding TMS in Depression Treatment
When we use TMS to treat depression by targeting the left DLPFC, we’re engaging multiple systems that work together to influence mood and behavior. The local effects begin with direct activation of neurons in superficial layers of the DLPFC, leading to modulation of local circuits involved in emotional regulation and cognitive control. This initial activation creates changes in the balance of excitatory and inhibitory activity, which can help normalize disrupted patterns of neural activity often seen in depression.
But the effects don’t stop there. TMS induces network-level changes, modulating connections between the DLPFC and deeper structures like the anterior cingulate cortex. These changes in functional connectivity extend to other regions involved in mood regulation, and there’s evidence that TMS can influence dopamine release in connected subcortical structures. Over time, repeated TMS sessions can lead to adaptive changes, including long-term changes in synaptic strength (plasticity), normalized patterns of brain activity, and restored network dynamics.
Looking Forward: Optimizing Treatment Through Understanding
Understanding the complex mechanisms of TMS has important implications for how we can optimize treatment. Coil positioning, for instance, isn’t just about finding the right spot – it’s about understanding how the induced current will flow through the unique anatomy of each person’s brain. The exact placement and orientation of the coil can significantly influence which neural elements are activated and how the effects propagate through neural networks.
Stimulation parameters should be carefully considered as research develops. The intensity should account for the depth of the target, and pulse timing can be optimized based on brain state. Different protocols might be needed for different subregions, and individual differences in anatomy and network connectivity can influence treatment outcomes.
This understanding points toward a more personalized approach to TMS treatment. The brain state during treatment may affect outcomes, and combination with other interventions might enhance effects. As our understanding of these mechanisms continues to grow, we’re better equipped to refine and improve TMS protocols for better therapeutic outcomes.
Conclusion
While we often speak of “stimulating the DLPFC,” the reality is far more complex and, in my opinion, interesting. TMS creates a cascade of effects that begin with activation of superficial axons and spread through connected networks. Understanding these mechanisms helps us appreciate the possibilities of TMS as a therapeutic tool, while pointing the way toward more personalized and effective treatments.
This complexity also reminds us why thorough assessment and careful monitoring during treatment are essential. While we may not be able to precisely control all the effects of TMS, understanding what we’re actually stimulating helps us use this powerful tool more effectively to help those struggling with depression and other conditions that respond to TMS treatment.
I would like to acknowledge Siebner and colleagues for their thorough contribution to the field of TMS through their journal publication “Transcranial magnetic stimulation of the brain: What is stimulated? – A consensus and critical position paper”.
Works Cited
Hartwig R. Siebner, et al., Transcranial magnetic stimulation of the brain: What is stimulated? – A consensus and critical position paper, Clinical Neurophysiology, Volume 140, 2022, Pages 59-97, ISSN 1388-2457, https://doi.org/10.1016/j.clinph.2022.04.022.
