Abstract
Acerbo E, Jegou A, Lagarde S, Pizzo F, Makhalova J, Trébuchon A, Bénar C-G, Bartolomei F, Carron R. Epilepsia. 2025 Aug;66(8):2690-2702. doi: 10.1111/epi.18405. Epub 2025 Apr 19. Objective: Deep brain stimulation (DBS) is emerging as a promising therapy for patients with drug-resistant epilepsy, particularly those who are either unsuitable for or unresponsive to resective surgery. The potential benefit of DBS in these patients may stem from its ability to reduce excessive brain functional connectivity (FC). Given that patients undergoing presurgical evaluation in our institution are implanted with stereoelectroencephalographic (SEEG) electrodes in the thalamus, specifically in the pulvinar medialis (PuM), our aim was to investigate the impact of different stimulation frequencies on brain FC. We sought to determine whether specific frequencies were more effective in modulating FC. Methods: SEEG was used to investigate the effects of PuM stimulation across a broad frequency range (1-200 Hz) in a cohort of 14 patients with drug-resistant focal epilepsy. FC was assessed using the nonlinear correlation coefficient (h2) and node strength calculations. Results: Our findings revealed a reduction in FC at stimulation frequencies of 10 Hz and >90 Hz, contrasting with an increase in FC in the 20–80-Hz range. This modulation of FC extended beyond the epileptogenic zone, influencing all assessed brain lobes, with the parietal, insular, and subcortical regions particularly affected by high-frequency stimulation. Within the epileptogenic zone, however, the observed FC changes were notably more complex. Significance: These results underscore the potential of high-frequency stimulation to decrease interictal FC in epilepsy patients, although intermediate frequencies may exacerbate it and warrant caution. Crucially, this study highlights the effects of PuM stimulation on FC patterns, supporting the role of high-frequency thalamic stimulation as a promising DBS parameter for improving epilepsy management strategies.
Commentary
The pulvinar nucleus of the thalamus or “arm chair lined with numerous pillows” was named after its rounded shape in the back of the thalamus. Although commonly thought of as important for visual processing, this nucleus is in fact subdivided into 4 distinct territories with many broad-reaching cortical and subcortical connections each serving distinct visual and cognitive functions. One of these subnuclei, the pulvinar medialis (PuM) connects reciprocally with multimodal association cortex of the inferior parietal lobule, posterior temporal neocortex, frontopolar region, and many limbic structures especially the amygdala and cingulate gyrus. The PuM supports multisensory integration, salience-driven attention, and affective processing.1,2 Lesions of the PuM result in neglect syndromes, while preserved PuM connectivity has been associated with residual visual capacities or “blindsight” after primary visual cortex injury.3,4
Deep brain stimulation (DBS) is increasingly recognized as a promising therapeutic option for patients with drug-resistant epilepsy who are not candidates for resective surgery. While anterior and centromedian thalamic nuclei have been traditional DBS targets, 5 the pulvinar has recently gained attention for its widespread cortical projections and potential to modulate epileptic networks. In this study, 14 patients undergoing stereoelectroencephalography (SEEG) for presurgical evaluation of focal epilepsy included PuM implantation and stimulation across a wide frequency range (1-200 Hz) while quantifying changes in functional connectivity across all electrodes. The authors observed frequency-specific modulation of functional connectivity. It decreased at 10 Hz and >90 Hz (maximal at 130-150 Hz), and increased at 1 Hz and 20 to 80 Hz. These effects were most pronounced ipsilaterally, with greater modulation in parietal and subcortical regions, and displayed distinct patterns within and outside the epileptogenic zone.
Acerbo et al present compelling evidence that changes in stimulation parameters produce frequency-dependent and anatomically specific effects on large-scale cortical connectivity. What is the relationship between broad network-based FC measures and epilepsy? Evidence from studies using intracranial EEG support the concept that epileptogenic brain regions show abnormally elevated interregional functional connectivity.6,7 This is further supported by emerging evidence from other thalamic stimulation studies in epilepsy which show that high-frequency stimulation of the anterior nucleus of the thalamus reduces FC in cortical regions, and this reduction correlates with the degree of seizure reduction.8,9 Further evidence on the relationship between FC and epileptic potential comes from MR-based functional imaging which suggests a relationship between decreases in FC in the epileptogenic zone and seizures. 10
One word of caution. We presently know little with regards to the effects of PuM stimulation on cognition, especially long-term stimulation. Stimulation of the PuM could possibly exert complex and incompletely understood cognitive effects reflecting the nucleus's integrative role in attention, visual awareness, and affective processing, especially salience. Because the pulvinar participates in both excitatory and inhibitory thalamocortical loops, stimulation could enhance or disrupt these functions depending on frequency, laterality, and baseline network state. Consequently, the cognitive consequences of pulvinar stimulation remain uncertain and will require systematic behavioral and electrophysiologic investigation in both acute and chronic paradigms.
