Neurophysiological mechanisms of spinal cord stimulation: From the perspective of disorder of consciousness

To the Editor: Spinal cord stimulation (SCS) is a neuromodulation method originally used to treat neuropathic pain, poststroke hemiplegia, and spinal cord injury. Recently, it has demonstrated unique value in various conditions [Supplementary Figure 1, https://links.lww.com/CM9/C889], including disorder of consciousness (DOC). Multiple studies confirm that SCS can significantly improve consciousness in patients with DOC [Supplementary Table 1, https://links.lww.com/CM9/C889].[1] However, due to limited understanding of the neural mechanisms and anatomical basis of the conduction pathways, its clinical application remains challenging. This study explores the neurophysiological basis of SCS’s arousal effect from three aspects: (1) neural conduction pathways, (2) key regulatory mechanisms of the nuclei, and (3) optimization of clinical applications. SCS stimulates the spinal nerves with pulsed currents, resulting in nerve impulses transmitted to the cerebral cortex through three pathways: (1) the dorsal column–medial lemniscus pathway, (2) the spinothalamic tract (STT), and (3) the trigeminal nerve pathway [Figure 1].Figure 1: The upward conduction pathways of SCS. AI: Anterior insula; ARAS: Ascending reticular activating system; CL: Central lateral nucleus; dACC: Dorsal anterior cingulate cortex; GPi: Globus pallidus internus; M1: Primary motor cortex; MDvc: Ventral caudal part of the medial dorsal nucleus; mPFC: Medial prefrontal cortex; PPN: Pedunculopontine nucleus; S1: Primary somatosensory cortex; S2: Secondary somatosensory cortex; SCS: Spinal cord stimulation; STT: Spinothalamic tract; VMpo: Posterior portion of the ventral medial nucleus; VPI: Ventral posterior inferior nucleus; VPL: Ventral posterolateral thalamic nucleus.Dorsal column–medial lemniscus pathway: Depolarization of neurons is induced by stimulating large-diameter proprioceptive afferents (primarily Aα and Aβ fibers)in the dorsal column beneath the electrode, generating both ascending and retrograde action potentials.[2] These ascending signals travel through the gracile and cuneate fasciculi, cross the midline at the medulla oblongata, and continue up the medial thalamic tract to the ventral posterolateral (VPL) nucleus of the thalamus. Studies have shown that SCS has an inhibitory effect on somatosensory-evoked potentials in a dose-dependent manner, indicating that SCS on the same nerve fibers generated action potentials in the opposite direction and caused them to collide.[3] Notably, this pathway can activate the pedunculopontine nucleus (PPN), a key brainstem nucleus, during conduction, providing direct evidence for the regulation of the arousal system by SCS. Spinothalamic tract: Spinal cord stimulation can activate both lateral and anterior STT.[2] The lateral STT projects to the anterior insula and dorsal anterior cingulate cortex, whereas the anterior STT projects to the somatosensory cortex and central lateral nucleus (CL). Through a series of studies, De Ridder and Vanneste[4] have established that different modes of SCS can selectively regulate these two pathways. Both tonic and burst SCS inhibit the anterior STT, whereas burst SCS has been shown to be more effective in regulating the lateral STT. This functional differentiation suggests that symptom-targeted treatment in patients with DOC may be achievable by adjusting the stimulation parameters.[4,5] Trigeminal nerve pathway: The therapeutic effects of high-level cervical SCS are hypothesized to be attributed to the trigeminal nerve conduction system. Anatomical studies have demonstrated that the stimulation current can act directly on the trigeminocervical complex (TCC),[6] which includes the mesencephalic nucleus, principal trigeminal nucleus (PN), spinal trigeminal nucleus (SN), and C1–C2 dorsal horn neurons in the spinal cord.[7] The caudal portion of the SN is located at the C2–C4 level of the cervical spinal cord, and its nerve fibers converge with the STT and ascend to the thalamus. Furthermore, there is a considerable amount of collateral connectivity between the trigeminal thalamic tract, originating from the PN and SN, and the brainstem reticular formation.[8] This provides a novel perspective for understanding the arousal effect of high cervical SCS. The following section introduces the key nuclei regulating SCS ascending conduction pathways. Pedunculopontine nucleus: As a core component of the ascending reticular activation system (ARAS), it plays a key role in regulating consciousness.[9,10] In patients with Parkinson’s disease with freezing of gait, SCS can activate somatosensory input to the PPN and reduce striatal inhibition, restoring motor control.[11] The mesocircuit model of DOC, the striatum, and the PPN are crucial nodes in the loop. The loss of striatal inhibition of the pallidum results in increased inhibition of the PPN, leading to DOC.[12] The PPN contains cholinergic, glutamatergic, and gamma-aminobutyric acid (GABA) neurons, and their neural projections to the thalamus are important for maintaining wakefulness.[13] Animal experiments have shown that the selective activation of glutamatergic neurons can induce wakefulness in anesthetized animals.[14] This provides direct evidence of the wake-promoting mechanism of the SCS. Central lateral nucleus: The intralaminar and midline nuclei, which include the CL nucleus, are recognized as nonspecific arousal systems that provide the necessary arousal in cortical and subcortical areas to support information-processing associated with consciousness.[15] The CL nucleus and adjacent regions have reciprocal monosynaptic connections with medial frontal regions involved in arousal modulation, receive dense innervation from brainstem arousal system, and project diffusely to the striatum.[16] A 50 Hz stimulus applied to the CL nucleus awakened the macaques from a stable anesthetized state, and enhanced coherence between the thalamus and frontoparietal cortex was observed.[17] In patients with DOC, the degree of damage to the CL nucleus has been significantly correlated with their level of consciousness. The evidence indicates that SCS may activate the CL nucleus through the anterior STT, thereby regulating prefrontal cortex excitability. Functional magnetic resonance imaging (fMRI) studies have demonstrated that SCS treatment can significantly enhance functional connectivity in the default mode network of patients with DOC, and this effect may be closely related to the regulation of the CL nucleus.[18] Trigeminocervical complex: The therapeutic effect of high cervical SCS may be partially achieved by regulating the TCC. However, the components of the TCC have not been clearly defined. It is responsible for receiving pain signals from the head and face and transmitting them to the thalamus, while also forming functional connections with the ARAS through the trigeminal thalamic tract.[7] Electrical stimulation of the trigeminal nerve, an established treatment for trigeminal neuralgia, is believed to regulate the function. Trigeminal nerve electrical stimulation has the potential to treat DOC,[19] whereas high cervical SCS can treat trigeminal neuralgia—suggesting shared therapeutic effects.[20] These clinical observations further support the previously described anatomical and functional mechanisms. Currently, SCS therapy for DOC primarily uses two frequencies: 5 and 70 Hz.[1] In contrast, the mainstream stimulation frequency for pain therapy ranges from 30 to 100 Hz.[21] The mechanism behind neuropathic pain therapy is to replace pathological pain with tolerable abnormal sensations, whereas arousal therapy aims to replace missing ascending activation signals with rhythmic electrical stimulation. These frequency differences suggest that they activate different neuronal categories within the same conduction pathway, thereby producing multiple therapeutic effects. The mechanism of SCS treatment for DOC is still in the exploratory stage, and the current frequency selection is based more on clinical experience rather than mechanistic research. Therefore, future research should focus on the specific effects of different frequencies on consciousness-related circuits and provide supporting evidence at the molecular and cellular levels. Funding This work was supported by grants from the National Natural Science Foundation of China (No. 81771128), National Key Research and Development Program (No. 2023YFB4706100), and Beijing Natural Science Foundation (No. 23G10455). Conflicts of interest None.