Brain oscillations represent cyclical fluctuations in neural activity generated by large populations of neurons firing in synchrony. These oscillatory patterns are not merely epiphenomena but are central to a host of cognitive, sensory, and motor functions. Additionally, the brain’s responsiveness to external stimuli critically depends on these rapid rhythms governing neuronal excitability. Innovations that align brain stimulation to the ongoing oscillatory phase hold the promise of enhancing the efficacy and specificity of neuromodulation.

Historically, TMS—a noninvasive technique employing rapidly changing magnetic fields to induce electrical currents in the cortex—has been applied in a ballistic or temporally blind manner, without accounting for the brain’s intrinsic state at the moment of stimulation. However, mounting empirical evidence suggests that the brain’s instantaneous oscillatory phase profoundly influences how it reacts to TMS pulses. By timing stimulation to the phase of these oscillations, neuromodulation can be tuned to the brain’s moment-to-moment excitability window, leading to more robust and enduring neuroplastic effects.

The protocol places strong emphasis on the integration of EEG with TMS, known as EEG–TMS. EEG is used here not only as a passive recording tool but as a real-time monitoring and controlling system. This requires technical sophistication where EEG signals are reconstructed in source space via detailed anatomical models derived from MRI scans. Such source reconstruction enhances spatial accuracy, enabling researchers to identify and target specific cortical oscillations, which might otherwise be lost in the electrical noise and mixing inherent in scalp EEG signals.

The workflow involves several meticulously coordinated steps. It begins with obtaining high-resolution brain MRI images, which undergo segmentation to distinguish anatomical regions essential for building accurate forward and inverse models necessary for source localization. This step ensures that EEG signals can be precisely attributed to their cortical origins. Following anatomical modeling, baseline EEG recording without TMS validates the presence and characteristics of the target oscillation to ensure reliability and phase predictability.

Once the oscillatory feature of interest is reliably detected, the main experiment integrates real-time EEG analysis with the delivery of TMS pulses. A highly optimized computational pipeline calculates the phase of ongoing oscillations with millisecond accuracy and triggers TMS at predefined phases. This closed-loop system contrasts starkly with conventional open-loop TMS approaches, where timing is fixed or random relative to brain activity, thus lacking physiological relevance.

The advantage of this phase-locked stimulation is twofold. First, by synchronizing TMS with high-excitability oscillatory phases, the brain exhibits an increased sensitivity to induced electric fields, potentiating synaptic modifications. Second, by aligning with the natural rhythmicity of neural circuits, the induced plastic changes likely integrate more seamlessly with ongoing brain processes, potentially leading to longer-lasting therapeutic outcomes. Early data indicate that this approach may surpass traditional TMS in the induction of long-term potentiation or depression, mechanisms underlying learning and recovery.

This innovative methodology also opens the door to personalized brain stimulation therapies. Different individuals exhibit unique oscillatory profiles shaped by genetics, age, pathology, or cognitive state. Real-time EEG–TMS allows for adapting stimulation parameters to these individualized profiles, offering a tailored intervention that could improve treatment precision for neurological and psychiatric conditions such as depression, stroke, or epilepsy.

The implementation of this protocol necessitates moderate computational proficiency and standard neuroimaging and electrophysiological equipment. Neuroscientists work with TMS-compatible EEG systems capable of providing synchronized online data output, integrated with neuronavigation tools that guide coil positioning over targeted brain regions with anatomical precision. The entire procedure, including MRI acquisition, EEG baseline recording, and EEG–TMS sessions, spans approximately ten hours, reflecting its complexity but also its reproducibility given the right resources.

Importantly, this protocol represents an open framework adaptable to various oscillatory features, including frequency bands like alpha, beta, or gamma, and different cortical areas depending on desired functional outcomes. The flexibility also extends to clinical research, allowing the exploration of pathological oscillations in disease states and their modulation through phase-targeted stimulation.

The significance of this pioneering work transcends the technical. It showcases a paradigm shift from reactive to proactive neuromodulation strategies, where brain stimulation is no longer administered blindly but dynamically guided by the brain’s own activity patterns. Such precision neuroscience has profound implications for cognitive enhancement, neurorehabilitation, and the treatment of mental health disorders, promising interventions that are both scientifically grounded and clinically transformative.

Moreover, the real-time EEG–TMS approach exemplifies the merging of neurophysiology, neuroengineering, and computational neuroscience. It demonstrates how interdisciplinary collaboration can yield tools that harness the brain’s rhythmic nature, pushing the boundaries of what is possible in both basic research and translational applications.

The field of brain stimulation has evolved through the decades from rudimentary electrical currents to sophisticated magnetic coils. The integration of real-time brain state monitoring and stimulation triggers a new era, emphasizing not just where and how much stimulation is applied, but precisely when it is delivered within the brain’s temporal dynamics. This temporal specificity is arguably as crucial as spatial targeting in achieving desired neuromodulatory effects.

As this protocol is adopted and refined, it will be critical to explore its effects across different populations and disorders. Questions about optimal oscillatory targets, stimulation intensities, and long-term outcomes remain open, offering fertile ground for future investigations. Additionally, ethical considerations about manipulating brain states in real-time will require careful handling as the technology moves closer to clinical and possibly consumer applications.

In conclusion, the protocol detailed by Zrenner and colleagues offers a robust, technically sophisticated avenue to harness the brain’s oscillatory landscape for precisely timed, personalized, and potentially more effective neurostimulation. This milestone advances the frontier of neurotechnology by transforming brain stimulation from a static intervention into a dynamic, brain-state-responsive process, with profound implications for neuroscience research and clinical practice.

Subject of Research:
Oscillatory brain state-dependent stimulation using combined electroencephalography and transcranial magnetic stimulation.

Article Title:
Oscillatory brain state-dependent stimulation with transcranial magnetic stimulation combined with electroencephalography.

Article References:
Zrenner, C., Belardinelli, P. & Ziemann, U. Oscillatory brain state-dependent stimulation with transcranial magnetic stimulation combined with electroencephalography. Nat Protoc (2026). https://doi.org/10.1038/s41596-025-01309-7

Image Credits:
AI Generated

DOI:
https://doi.org/10.1038/s41596-025-01309-7

In the traditional clinical practice of TMS, clinicians have largely relied on historical reports linking lesion locations to behavioral or emotional symptoms, alongside neuroimaging studies highlighting dysfunction in frontal brain regions. This approach, while successful in many cases, necessarily narrows the scope of potential targets to a limited region of the brain—primarily the dorsolateral prefrontal cortex and adjacent prefrontal neuronal networks. These sites have been repeatedly validated as effective loci to alleviate symptoms in treatment-resistant depression and related illnesses. Yet, this focus raises the question: are there modifiable, posterior brain hubs implicated in psychiatric symptoms that remain unexplored by neuromodulation?

Emerging research suggests that the brain is a deeply interconnected organ, with psychiatric disorders reflecting dysfunction not only in frontal executive circuits but also in posterior regions such as the occipital cortex, precuneus, inferior parietal lobules, and cerebellum. These areas, traditionally associated with perceptual processes, self-referential thought, spatial cognition, and motor control, have gained recognition for their involvement in mood regulation, attention, and cognitive integration. Despite this, they have been conspicuously understudied as possible TMS targets in clinical trials, leaving a gap in both our understanding of neuropsychiatric circuitry and the full therapeutic potential of TMS.

In a timely and insightful Perspective article, McCalley and colleagues illuminate the landscape of posterior brain targets in neuropsychiatric disorders and propose an expansion of TMS paradigms. They argue that broadening target selection to incorporate these posterior regions could unlock novel therapeutic avenues that engage distinct neural networks, potentially offering relief for patients who are resistant to conventional prefrontal stimulation. This shift necessitates both a careful examination of the functional neuroanatomy involved and rigorous testing of safety and efficacy in future clinical settings.

The occipital cortex, long associated primarily with visual processing, has recently been implicated in affective disorders due to its connectivity with limbic and frontal brain regions. Neuroimaging studies have demonstrated altered activity patterns in the occipital lobe in individuals with depression and anxiety, revealing hyperconnectivity or hypoconnectivity that correlates with symptom severity. Targeting the occipital cortex with TMS could modulate early sensory processing, which in turn might influence higher-order cognitive and emotional circuits. Such an approach challenges the traditional focus on “executive” regions and underscores the role of sensory information processing in mood regulation.

Equally compelling is the precuneus, a central node in the default mode network (DMN), known for its role in self-referential thinking, episodic memory retrieval, and conscious awareness. Aberrant DMN activity has been robustly linked to depressive rumination and other maladaptive cognitive patterns seen in psychiatric illnesses. The precuneus’s accessibility to magnetic stimulation offers a tantalizing target to reshape network dynamics associated with negative self-focus, potentially alleviating persistent depressive symptoms or anxiety disorders. Early pilot studies hint at the feasibility of modulating this region noninvasively, though comprehensive clinical trials are warranted.

The inferior parietal lobules represent another posterior cortical area that holds therapeutic promise. These brain regions integrate multisensory information and contribute to attentional control and sensorimotor integration. Dysfunctions here have been observed in schizophrenia and mood disorders, where patients manifest aberrant perception, attentional bias, or impaired reality monitoring. By leveraging TMS to recalibrate activity in the inferior parietal lobules, clinicians may restore balance within distributed cortical networks, improving both cognitive and affective symptoms. However, the intricacy of this region’s functions requires precise targeting and modulation protocols to avoid undesired side effects.

Perhaps most intriguingly, the cerebellum—a structure historically relegated to motor coordination—has surfaced as a critical player in the regulation of emotion and cognition. The cerebellum is richly interconnected with the prefrontal cortex, limbic system, and associative sensory areas, and its involvement in psychiatric disorders such as depression, bipolar disorder, and autism spectrum conditions is increasingly recognized. Preliminary TMS studies have begun to explore cerebellar stimulation, noting possible benefits in mood stabilization and cognitive enhancement. This new frontier of neuromodulation could redefine therapeutic boundaries and challenge preconceived notions of localized brain function.

While posterior TMS targets offer exciting prospects, several technical and safety considerations must be addressed in their clinical implementation. The unique neuroanatomy and deeper cortical positioning of some posterior regions necessitate refined coil designs and stimulation parameters to achieve effective yet safe neuromodulation. In addition, the functional heterogeneity within posterior regions requires careful mapping to avoid off-target effects that could exacerbate symptoms or trigger unintended cognitive disruptions. Long-term studies will be critical to establish optimal dosing, session frequency, and durability of therapeutic gains.

Another challenge lies in integrating multi-modal imaging techniques, such as functional MRI, diffusion tensor imaging, and magnetoencephalography, to accurately identify suitable posterior targets based on individual neurocircuitry profiles. Personalized medicine approaches, combining advanced neuroimaging with computational modeling of electromagnetic field distribution, could tailor TMS protocols to each patient’s unique brain architecture. This precision medicine paradigm promises to maximize efficacy while minimizing adverse effects, heralding a new age in psychiatric treatment.

The few existing clinical trials investigating posterior TMS targets have yielded encouraging but preliminary results. Some studies targeting the occipital cortex have shown improvements in visual processing and mood symptoms, while cerebellar stimulation has demonstrated potential in enhancing executive function and reducing anxiety. These nascent data suggest that posterior TMS might complement or, in some cases, surpass traditional prefrontal approaches, especially for patients with resistant or atypical presentations. Nonetheless, replication in larger, randomized controlled studies remains an essential next step.

Combining posterior TMS targets with established prefrontal stimulation protocols could provide synergistic effects by engaging both sensory and executive neural networks. Multi-site stimulation paradigms might modulate dysfunctional connectivity more holistically than unilateral targeting, offering a richer therapeutic landscape. However, this complexity mandates careful clinical design to avoid overstimulation or desynchronization of critical neural circuits.

Ethically, expanding TMS beyond the frontal cortex compels the psychiatric community to balance innovation with caution. Given the emerging nature of posterior target research, informed consent processes must transparently communicate the experimental status of these interventions and potential unknown risks. Enhanced monitoring for adverse events and cognitive side effects will be necessary, alongside long-term follow-up to ascertain sustained benefits or late-emerging complications.

The consideration of posterior brain regions for neuromodulation reflects a broader paradigm shift in psychiatry—one that embraces the brain’s intrinsic network architecture rather than isolated loci. Modern psychiatric disorders are increasingly conceptualized as circuitopathies, involving complex interplay across distributed brain regions. TMS targeting posterior cortical and cerebellar nodes exemplifies this network-based approach, leveraging evolving neurobiological insights to refine therapeutic strategies.

In conclusion, the expansion of TMS applications to include posterior brain targets heralds a promising avenue for addressing unmet clinical needs in psychiatric treatment. While frontal lobe stimulation has established a robust therapeutic foundation, integrating occipital, parietal, precuneal, and cerebellar targets may enrich outcomes and offer new hope for patients with refractory conditions. Continued interdisciplinary collaboration among neuroscientists, clinicians, and engineers will be crucial to fully realize this potential and translate neuroanatomical discoveries into impactful, patient-centered therapies.

The contributions of McCalley et al. firmly anchor this emerging discussion in a rigorous scientific framework, emphasizing the importance of careful, methodical exploration of posterior neural hubs. Their Perspective calls on the psychiatric and neuromodulation communities to venture beyond conventional boundaries in pursuit of more comprehensive, network-oriented treatments. As research accelerates in this domain, TMS may well transform from a predominantly frontal cortex tool into an exquisite, multi-target instrument capable of reshaping the future of mental health care.

Subject of Research:
Transcranial magnetic stimulation targeting posterior brain regions for psychiatric disorder treatment.

Article Title:
Illuminating posterior targets for transcranial magnetic stimulation beyond the prefrontal cortex.

Article References:

McCalley, D.M., Sanderson, L.L., Dowdle, L.T. et al. Illuminating posterior targets for transcranial magnetic stimulation beyond the prefrontal cortex.
Nat. Mental Health (2025). https://doi.org/10.1038/s44220-025-00433-3

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