Chronic Disorders of Consciousness (DOC) are defined as disordered consciousness lasting longer than 28 days following severe brain injury, presenting a profound clinical and societal challenge. While advances in medical care have increased survival rates following severe brain injury, a significant number of patients fail to achieve meaningful recovery of consciousness. This persistent neurological impairment exerts profound multidimensional impacts, severely compromising patients’ quality of life and simultaneously imposing considerable socioeconomic burdens on caregivers and healthcare systems (1). The assessment of these patients predominantly relies on standardized behavioral scales, such as the Coma Recovery Scale-Revised (CRS-R). Conventional therapeutic strategies, including pharmacological and behavioral interventions, have demonstrated limited efficacy, particularly in the chronic stage of DOC. Therefore, the exploration of novel and effective therapeutic interventions is of paramount importance.

The neuropathophysiological underpinnings of DOC are increasingly understood as a dysfunction of large-scale brain networks, rather than isolated focal lesions. Critical among these is the disruption of the cortico-striatal-thalamic mesocircuit and the ascending reticular activating system, which are fundamental for arousal and awareness (2, 3). The thalamus, acting as a central hub for relaying sensory information and regulating cortical activity, is a lynchpin in the formation and maintenance of consciousness. Consequently, neuromodulation techniques aiming to restore consciousness often seek to upregulate excitatory thalamic output and re-establish network-level communication, promoting the recovery of behavioral responsiveness (4, 5). While interventions such as amantadine, transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) have shown some promise, particularly in sub-acute DOC patients (4, 6), their utility in chronic patients is less established. In addition, these modalities face inherent limitations: amantadine lacks target specificity due to its systemic effects, whereas tDCS and rTMS, although non-invasive, are largely confined to modulating superficial cortical regions, lacking the capability to directly and precisely engage deep subcortical structures such as the thalamus.

To overcome these limitations, transcranial focused ultrasound (tFUS) has emerged as a groundbreaking non-invasive neuromodulation modality. Its unique ability to deliver focused acoustic energy with high spatial precision (on the order of millimeters) to deep brain structures makes it an ideal candidate for targeting the thalamus in chronic DOC patients. Initial pioneering studies have demonstrated the feasibility, safety, and potential neuro-excitatory effects of tFUS. For instance, a landmark case report showed behavioral improvements following a single session of thalamic stimulation (7). Subsequent pilot studies and case series have corroborated these findings, reporting temporary gains in behavioral responsiveness in some acute and chronic DOC patients (8–10). However, the current body of evidence is predominantly based on single-session or short-term interventions. The cumulative therapeutic effects, long-term safety, and durability of repeated, multi-week tFUS administration remain largely unexplored. Furthermore, the precise network-level mechanisms by which thalamic tFUS promotes recovery—including alterations in functional connectivity and neurovascular coupling—are not yet fully elucidated.

Herein, we present the case of a patient with chronic DOC who underwent a 4-week therapeutic regimen of neuronavigation-guided tFUS targeting the central thalamus. The primary objective of this study was to investigate the cumulative behavioral effects and safety of this prolonged intervention. Furthermore, by employing a multimodal assessment strategy combining resting-state functional near-infrared (fNIRS) and electroencephalogram (EEG), we aimed to longitudinally track changes in cerebral hemodynamics and neural oscillations. Through this comprehensive approach, we sought to provide novel insights into the network-level mechanisms underlying tFUS-mediated recovery of consciousness.

This case explored the effectiveness and safety of 12 sessions of tFUS applied to the right central thalamus in an individual with chronic DOC under the guidance of neuronavigation. The transcranial focused ultrasound parameters in this study were well below the FDA recommendation of a maximum ISPPA of 190 W/cm² and a maximum ISPTA of 0.72 W/cm². Furthermore, the protocol adhered to the biophysical safety guidelines established in the recent ITRUSST consensus statement (12), maintaining a MI (0.74) significantly below the recommended threshold of 1.9 and ensuring a theoretical temperature rise of less than 2 °C.

The clinically meaningful behavioral recovery observed in this patient provides preliminary evidence supporting the therapeutic potential of multi-session thalamic tFUS in chronic DOC. This outcome aligns with and extends the pioneering work initiated by Monti and subsequently advanced by Cain and colleagues (7–10), who first established thalamic neuromodulation as a viable strategy. Our patient’s emergence from a minimally conscious state, marked by a substantial increase in the CRS-R score from 11 to 20 and the consistent ability to follow commands and use objects, suggests a potential treatment effect. A noteworthy observation from our longitudinal intervention is the apparent cumulative nature of this benefit. While Monti’s seminal 2016 case described immediate behavioral gains, subsequent investigations by the same group involving repeated stimulation sessions have also suggested a potential cumulative effect (8–10). Our study aligns with and extends this emerging evidence, demonstrating that in the chronic setting, progress materialized gradually over the course of twelve treatment sessions, whereas no significant behavioral changes were observed within the first hour following any individual sonication session. Notably, neurophysiological improvements (fNIRS/EEG) emerged after just two weeks (six sessions), preceding the substantial behavioral recovery observed in the final two weeks. This temporal dissociation suggests that neural changes may need to accumulate to a critical threshold before manifesting as overt clinical improvements. This observation suggests a potential action in the chronic setting. While tFUS may facilitate immediate network re-engagement in the post-acute brain, we hypothesize that its therapeutic impact in chronic states might rely on cumulative neurophysiological changes. This hypothesis is consistent with preclinical evidence showing that repeated ultrasound stimulation can upregulate brain-derived neurotrophic factor (BDNF) and modulate synaptic strength (13, 14). Besides, we must critically evaluate the potential contribution of concomitant treatments, specifically the ongoing administration of amantadine and multisensory stimulation. While these interventions were maintained at stable dosages and frequencies prior to and during the study, preventing them from explaining the sudden inflection in recovery, their potential synergistic interaction with tFUS remains an important consideration. Moreover, a six-month video follow-up confirmed sustained clinical gains, with the patient remaining conscious and responsive to commands, suggesting that the observed changes may represent a lasting shift rather than transient modulation.

The fNIRS data provide a potential neurobiological correlate for the observed clinical improvement of the patient, indicating that thalamic tFUS was associated with enhanced cortical functional connectivity. Our observation that connectivity enhancement was most pronounced in the prefrontal cortex aligns with the established understanding of DOC as a disconnection syndrome, where frontal network integrity is critically impaired (15, 16). This finding contributes to a growing body of evidence suggesting that diverse neuromodulatory techniques (11, 17, 18), including vagus nerve stimulation and deep brain stimulation, converge on a common mechanistic pathway: the reactivation of coherent brain-wide communication. While these studies collectively validate the principle of enhancing connectivity for DOC treatment, our results offer a more granular insight that distinguishes the action of tFUS. The distinct spatiotemporal evolution of network recovery, beginning in the hemisphere ipsilateral to the thalamic stimulation and subsequently expanding to achieve bilateral integration, provides a fascinating window into the neuromodulatory cascade. This suggests that tFUS does not merely induce a diffuse, global increase in brain activity. Instead, it appears to initiate a targeted, propagating wave of neuroplasticity. This finding underscores the unique capacity of focused ultrasound to selectively engage a critical subcortical node and trigger a structured, downstream reorganization of the cortical functional architecture, a mechanism that may be fundamental to its therapeutic effect in chronic brain injury.

The longitudinal EEG analysis offers electrophysiological insights for the recovery of the patient, showing a targeted reduction of the aberrant slow-wave activity that is a well-established hallmark of severe brain injury. Our primary finding that clinical improvement is associated with the normalization of prefrontal Delta and Theta power positions thalamic tFUS alongside other effective neuromodulatory interventions, such as intermittent theta burst stimulation, that have been linked to suppression of pathological oscillations (16). Although excessive slow-wave activity is consistently reported in DOC (19–22), our data document its progressive reduction in association with targeted subcortical stimulation. Intriguingly, the therapeutic effect was characterized by a distinct reciprocal pattern: a suppression of pathological slow-wave bands accompanied by a concurrent and mild re-emergence of Alpha and Beta frequencies. This spectral shift is a critical finding. It suggests that thalamic tFUS acts primarily by disrupting the dominant, low-frequency network dynamics that inhibit cortical function. By effectively quieting this pervasive slow-wave “noise,” the intervention appears to create a permissive electrophysiological environment that facilitates the renormalization of physiological high-frequency rhythms, which are essential for global cortical arousal and information processing.

This case study provides a multi-modal description of recovery, where the convergence of behavioral, hemodynamic, and electrophysiological data offers a mechanistic window into how targeted thalamic neuromodulation can reverse pathological signatures of chronic brain injury. The central thalamus, as a critical hub within the ascending reticular activating system, plays an indispensable role in maintaining cortical arousal by coordinating activity across large-scale brain networks (23). Our findings suggest that tFUS effectively leveraged this strategic position. The primary proposed mechanism involves mechanical effects, whereby low-intensity acoustic pressure waves may act upon mechanosensitive ion channels within the neuronal membrane, directly altering ionic flux and, consequently, neuronal excitability and synaptic transmission (24, 25). This direct, non-thermal modulation of thalamic neuronal firing provides a plausible biophysical trigger for the observed downstream cascade. Specifically, by altering the firing patterns within the thalamus, tFUS appears to have rebalanced pathological thalamocortical dynamics, leading to the profound suppression of aberrant frontal Delta and Theta slow-wave activity observed in our EEG data. By lifting this inhibitory brake, tFUS created a permissive neurophysiological environment for the re-emergence of coherent high-frequency rhythms and metabolically demanding network activity, as evidenced by the robust enhancement of functional connectivity in our fNIRS results (26). Moreover, the restorative process is likely multifactorial, as preclinical studies have suggested that tFUS can also confer neuroprotective benefits by enhancing cerebral blood flow, promoting the clearance of metabolic waste via the glymphatic system, and reducing neuroinflammation (27, 28). Therefore, the integrated findings paint a cohesive picture: precise tFUS of the thalamus initiates a therapeutic cascade via direct mechanotransduction, which in turn normalizes cortical rhythms, allows dormant large-scale networks to resume communication through a combination of neuroplastic and physiological enhancements, and ultimately enables the return of observable, conscious behavior. These observations, while limited to a single case, provide preliminary evidence warranting further controlled investigation.

The inferential power of this study is inherently constrained by its single-case design. While the multi-modal evidence presented is persuasive and internally consistent, the remarkable recovery observed in this individual cannot be generalized to the heterogeneous population of patients with chronic DOC. Regarding the natural history of the disease, we acknowledge that while late recovery is possible, epidemiological data indicate that meaningful functional improvement is significantly less frequent in chronic hemorrhagic etiologies compared to traumatic cases (29). Specifically, longitudinal studies have reported that only a small minority of patients with chronic anoxic brain injury recover consciousness after three months, with probabilities estimated to be as low as < 17% in similar chronic timeframes (30). The patient had exhibited a stable clinical plateau with no signs of awakening for 4 months prior to enrollment, yet suggested a clear trajectory of improvement that was temporally time-locked to the four-week tFUS intervention window. The temporal coincidence with the intervention makes spontaneous recovery less probable given the prior prolonged stability. To rigorously establish this relationship and control for potential placebo effects, a randomized, double-blind, sham-controlled clinical trial is imperative. We acknowledge this necessity, and such a trial is presently being undertaken by our group to systematically validate these promising findings. A further methodological limitation relates to the assumptions regarding transcranial acoustic propagation and the absence of patient-specific acoustic simulations. In this study, targeting relied on neuronavigation assuming homogeneous skull acoustic properties and ideal wave propagation, without individual correction for skull-induced phase aberrations and attenuation. As demonstrated by Cain et al., such aberrations can distort or displace the ultrasound focus toward adjacent structures (e.g., globus pallidus), potentially affecting target engagement and dosimetry accuracy despite precise anatomical navigation (31). Future multi-patient trials must incorporate numerical acoustic modeling (e.g., k-Wave based on individual CT data) to rigorously correct for these skull effects, ensuring precise targeting accuracy and dosimetry. An additional limitation concerns the interpretation of the EEG findings. The analysis focused primarily on prefrontal electrodes, as global topography revealed the most pronounced and consistent longitudinal reductions in slow-wave power in prefrontal regions, whereas posterior parietal regions showed no distinct temporal changes in this patient. This regional prioritization was chosen to highlight the most robust physiological signals linked to clinical recovery in this single-case report. Nevertheless, a comprehensive understanding of tFUS effects on consciousness-related circuits requires simultaneous assessment of both prefrontal and posterior parietal networks in our ongoing randomized controlled trial.

In conclusion, this case report provides preliminary multi-modal evidence suggesting that multi-session, low-intensity tFUS targeting the central thalamus may facilitate the recovery of consciousness in a patient with a chronic DOC. We observed a tight coupling between the clinical emergence, a progressive reintegration of large-scale cortical networks measured by fNIRS, and a concurrent normalization of pathological slow-wave oscillations captured by EEG. These convergent findings suggest a plausible therapeutic cascade wherein targeted, non-invasive neuromodulation of a critical subcortical hub may help modulate core pathophysiological features of the chronically injured brain. While acknowledging the clear limitations inherent to a single-case study, this work provides a strong mechanistic rationale for the continued, rigorous investigation of tFUS through larger, sham-controlled clinical trials to definitively establish its role as a novel intervention for restoring consciousness.