Introduction: Peripheral nerve field stimulation (PNFS) for facial pain delivers subcutaneous electrical stimulation to reduce pain. Blood oxygenation level-dependent (BOLD) functional MRI (fMRI) can be used to characterize central effects of neuromodulation techniques such as deep brain stimulation and spinal cord stimulation (SCS). However, the safety and utility of MRI in patients with PNFS have not been established, limiting both clinical MRI use and the application of fMRI in this population. This study evaluated the MRI safety and feasibility of imaging an active SCS implant used for PNFS in patients with facial pain; and defined sequence parameters for concurrent BOLD fMRI acquisition. Methods: An anthropomorphic 3D-printed phantom filled with tissue-mimicking gel and fitted with an SCS implant replicating a patient with PNFS was used for in vitro safety testing. Two phantom experiments evaluated the relationship between (i) head-averaged specific absorption rate (SAR), (ii) time-averaged positive radiofrequency magnetic field component (B1rms+) and maximal temperature rises at critical locations (i.e., distal lead electrodes, cranial coiling, and implantable pulse generator) across clinical and research-based structural and fMRI sequences. For validation, a PNFS patient was scanned using localizer, T1-weighted magnetization-prepared rapid gradient echo, T2-weighted sampling perfection with application-optimized contrasts using different flip angle evolutions, and BOLD fMRI sequences informed by phantom experiments. Results: FMRI during active PNFS is safe under specific conditions, with temperature increases remaining below the 2°C threshold at all monitored locations. Heating had a stronger relationship with head SAR (higher adjusted coefficient of determination [R2] value) than B1rms+, particularly at distal lead electrodes. These in vitro findings informed selection of safe fMRI protocols for in vivo scanning. A patient (n = 1) underwent MRI with no device- or patient-related adverse events. Successful fMRI acquisition was achieved, demonstrating engagement of pain-related regions in the patient. Conclusion: Phantom testing confirmed the safety and feasibility of MRI with an active SCS device configured for facial PNFS. These findings, specific to the tested conditions, underscore the need for context-specific safety evaluations to enable safe MRI in such implantable medical devices.

The network changes elicited by deep brain stimulation (DBS) in Parkinson's disease (PD) remain incompletely understood. We used functional MRI (fMRI) during active stimulation of the subthalamic nucleus (STN) to identify brain networks associated with clinical improvement. Forty PD patients (61 y ±8, 40% female) underwent 3-Tesla fMRI during active stimulation. Stimulation-induced changes in brain activity were correlated with outcomes (tremor, rigidity, bradykinesia, and axial instability). Symptom-specific fMRI response maps revealed distributed networks associated with long-term motor improvement, but ROI-based models showed poor out-of-sample performance and limited spatial stability. In contrast, somatomotor network modulation demonstrated symptom-specific coupling preferentially in rigidity improvement (ΔR² = 0.24, pFDR = 0.01) and bradykinesia (ΔR² = 0.13, pFDR = 0.07). Normative connectivity explained variance less consistently. These findings support the use of patient-specific fMRI as a tool for studying the neural mechanisms of DBS and highlight the importance of distributed network engagement in mediating therapeutic benefit.

Transcranial ultrasound stimulation (TUS) is a promising noninvasive technique for modulating deep brain targets and circuits with high spatial precision. For its successful clinical translation, confirmation of target engagement, together with a deeper understanding of the effects of TUS, is essential. To advance these goals, we obtained direct measures of neural activity using electrodes implanted in the subthalamic nucleus (STN) in patients with Parkinson's disease (PD) during TUS of deep and superficial targets, guided by magnetic resonance imaging-based acoustic modeling and real-time neuronavigation. Seventeen patients were studied in the on-medication and off-deep brain stimulation states. Each patient received one active and one sham session in a randomized order, and 13 of 17 patients (76%) completed a third session, which was always active. Each active condition targeted a single site-either the primary motor cortex (M1), the globus pallidus internus (GPi), or the occipital cortex (control site)-with 10 patients per active target. TUS effects on the STN were found to be target specific. Stimulation of the M1 reduced STN beta oscillation activity compared with sham stimulation and was associated with improvements in motor signs. These effects were brain state specific, showing distinct modulation patterns at rest versus during movement. In contrast, TUS targeting the GPi increased beta activity relative to control conditions and did not improve motor signs. Our results provide mechanistic evidence that TUS can safely and selectively modulate pathological brain rhythms in the STN in PD, supporting its potential as a targeted, noninvasive therapeutic modality.

Improved understanding of target-specific changes in brain activity during deep-brain stimulation (DBS) for Parkinson's disease (PD) may refine target selection. Here, we study the network effects of active DBS using functional magnetic resonance imaging (fMRI) during stimulation of the subthalamic nucleus (STN) and globus pallidus internus (GPi). About 36 PD patients (62.5 ± 8.1 years, 18 GPi-DBS, 39% female) underwent prospective fMRI during active DBS. DBS produced distributed cortical modulation associated with clinical improvement at the group level. Network modeling revealed symptom-specific coupling, with somatomotor network modulation significantly associated with gait improvement (ΔR² = 0.40, pFDR = 0.03) and showing a weaker association with bradykinesia improvement (ΔR² = 0.32, pFDR = 0.06). Unexpectedly, somatomotor network modulation showed a nominal association with variability in verbal fluency outcomes (ΔR² = 0.28, pFDR = 0.08), whereas language and cognitive networks demonstrated minimal explanatory value. A comparable relationship between network modulation and verbal fluency was not observed in STN-DBS. These findings demonstrate that DBS therapeutic effects are best understood as modulation of distributed functional networks rather than focal regions, with target-dependent network coupling potentially underlying differential cognitive outcomes.

Effects of deep brain stimulation (DBS) depend on millimetric accuracy and are commonly studied across populations by registering patient scans to a stereotactic space. Multiple factors contribute to estimates of electrode position, but the millimetric contributions of these factors remain poorly quantified. We previously validated 32 anatomical fiducials (AFIDs) to measure AFID registration error (AFRE), which can capture focal misregistration not observed using volume-based methods. To this end, we used the AFIDs framework to examine the effects of misregistration on electrode position in stereotactic space, leveraging a retrospective series of patients who underwent subthalamic nucleus (STN) DBS. Raters independently localized DBS electrodes and AFIDs on patient scans, which were non-linearly registered to a common stereotactic (MNI) space. AFIDs provided intuitive measures of registration accuracy, with AFREs ranging from 1.49 mm to 6.85 mm across brain regions. Subcortical AFIDs in proximity to the DBS target (STN) had AFREs that spatially covaried, suggesting consistent spatial patterns of misregistration to stereotactic space. These identified spatial patterns account for 28% of the variance in electrode position along the axis of maximum variance, corresponding to a median of 0.64 mm (range of 0.05 to 2.05 mm). The AFIDs framework provides millimetric estimates of registration accuracy in DBS, while allowing the uncoupling of registration-related factors from other sources of variance in electrode position. Furthermore, they can be employed for estimating registration-related variance in population studies, for quality control, and to provide a basis for comparison as well as optimization of registration parameters and software.

The success of deep brain stimulation (DBS) relies on applying carefully titrated therapeutic stimulation at specific targets. Once implanted, the electrical stimulation parameters at each electrode contact can be modified. Iteratively adjusting the stimulation parameters enables testing for the optimal stimulation settings. Due to the large parameter space, the currently employed empirical testing of individual parameters based on acute clinical response is not sustainable. Within the constraints of short clinical visits, optimization is particularly challenging when clinical features lack immediate feedback, as seen in DBS for dystonia and depression and with the cognitive and axial side effects of DBS for Parkinson's disease. A personalized approach to stimulation parameter selection is desirable as the increasing complexity of modern DBS devices also expands the number of available parameters. This review describes three emerging imaging and electrophysiological methods of personalizing DBS programming. Normative connectome-base stimulation utilizes large datasets of normal or disease-matched connectivity imaging. The stimulation location for an individual patient can then be varied to engage regions associated with optimal connectivity. Electrophysiology-guided open- and closed-loop stimulation capitalizes on the electrophysiological recording capabilities of modern implanted devices to individualize stimulation parameters based on biomarkers of success or symptom onset. Finally, individual functional MRI (fMRI)-based approaches use fMRI during active stimulation to identify parameters resulting in characteristic patterns of functional engagement associated with long-term treatment response. Each method provides different but complementary information, and maximizing treatment efficacy likely requires a combined approach.

BackgroundDeep brain stimulation targeting the subcallosal cingulate (SCC-DBS) is a promising therapy for treatment-resistant depression. However, the lack of a consistent, rapid behavioural response to SCC-DBS complicates the selection of optimal stimulation settings following implantation, requiring a prolonged and burdensome trial-and-error process. Immediate biomarkers of effective stimulation could overcome this problem.MethodsIn this proof-of-concept study, three patients with SCC-DBS implants were scanned at 3 T using a block-design paradigm in which stimulation alternated between "ON" and "OFF" states in 30-s cycles during a single 6.5-min acquisition. Scans were performed using participants' clinically optimized parameters. Blood-oxygen-level-dependent (BOLD) response maps were generated by contrasting DBS-ON and DBS-OFF conditions, and exploratory correlations with clinical outcome-indexed by percentage reduction in Hamilton Depression Rating Scale scores at 12 months-were also assessed.ResultsContrasting stimulation settings enabled the identification of regional BOLD signal changes associated with DBS, revealing consistent hemodynamic changes in several brain regions during active stimulation. Specifically, the precuneus, posterior cingulate cortex, middle frontal gyrus, and frontal pole exhibited decreased BOLD responses during active DBS, while the occipital cortex, middle temporal gyrus, inferior parietal lobule, and superior frontal gyrus showed increased BOLD responses. Exploratory analysis further suggested a potential correlation between precuneus BOLD signal change and clinical improvement (R = -0.98, ppermute = 0.09).ConclusionThese findings speak to the utility of block-design fMRI with cycling DBS stimulation as a tool to identify objective, brain-based biomarkers of effective SCC-DBS, potentially expediting stimulation parameter selection and therapeutic optimization.

BACKGROUND:Deep brain stimulation (DBS) is an established treatment for movement disorders such as Parkinson's disease (PD) and essential tremor (ET). However, the decision between unilateral, staged bilateral, or simultaneous bilateral DBS remains controversial, influenced by clinical presentation, patient preferences, and economic factors. OBJECTIVE:The aim was to compare motor score improvements, adverse events (AE), incremental benefits, and progression with unilateral to bilateral procedures and the rationale for second-side surgery. METHODS:This systematic review examined studies on patients treated with unilateral or bilateral (simultaneous or staged) DBS from 1999 to 2025, focusing on outcomes, safety, and efficacy. RESULTS:In PD, unilateral DBS targeting the subthalamic nucleus (STN) or globus pallidus internus (GPi) improves motor scores by up to 37%, whereas bilateral DBS yields improvements of up to 66%. Unilateral DBS provides up to 75% improvement in contralateral symptoms but only up to 28% in ipsilateral symptoms. More than half of PD patients eventually opt for second-side surgery due to worsening symptoms. In ET, unilateral ventral intermediate nucleus (VIM) DBS improves hand tremor by up to 89%, with staged bilateral procedures offering an additional 77% to 89% improvement contralaterally. Axial tremor improves by up to 60% with unilateral VIM DBS and a further 60% after bilateral surgery. Bilateral VIM DBS is linked to more AEs, such as gait disorders and dysarthria, whereas STN and GPi DBS have comparable risks. Staged surgeries are associated with longer surgical times and increased revisions and programming. CONCLUSIONS:Individualized treatment decisions are essential, with bilateral DBS providing superior long-term outcomes for both PD and ET.

INTRODUCTION:In Parkinson's disease (PD) patients, modulation of the fibre tracts of the cortico-basal ganglia-thalamo-cortical loop is the presumed mechanism of action of deep brain stimulation (DBS) of the subthalamic nucleus (STN). Therefore, we explored patient-individual cortical structural connectivity of the volume of tissue activated (VTA), as well as DBS-induced modulation of fibre tracts connecting the STN with cortical and subcortical nodes, and their correlation with therapeutic effects. METHODS:A retrospective cohort of n = 69 PD patients treated with bilateral DBS of the STN was analysed. Clinical response was assessed from the DBS-induced change in the UPDRS-III motor scores (total and symptom-specific sub-scores) under regular medication after a median follow-up of 9.0 (range 2.6-20.2) months. Tractography based on patient-individual diffusion-weighted MRI was employed in two ways. Whole-brain tractography was used to identify the cortical connections of fibres passing the VTAs, and reconstruction of specific white matter pathways of the motor loop connecting the STN with the basal ganglia and cortex was used to identify the proportion of fibres within these pathways which was modulated by STN-DBS. This proportion of pathway modulation was used in a correlative analysis with clinical outcomes. RESULTS:Fibres traversing the VTAs were primarily connected to the supplementary motor area (SMA) and to a lesser degree to the premotor cortex. Within the pathways connecting the STN with the cortical and subcortical nodes, on average 30-40% (range 10-80%) of the fibres were modulated by STN-DBS. This proportion correlated significantly with the percentage change in UPDRS motor score for fibres connecting the STN with the SMA (ρ = 0.28), pre-SMA (ρ = 0.26), ventral and dorsal premotor cortices (ρ = 0.26 and ρ = 0.29, respectively), and the globus pallidus externus (ρ = 0.26) and internus (ρ = 0.29). Also, good clinical responses for both tremor and rigidity were associated with a significantly (p < 0.05) higher proportion of modulated fibres for the same cortico- and sub-cortico-STN connections. CONCLUSION:Patient-individual tractography reveals that, in PD, most of the cortical fibres traversing the VTA are connected to the SMA. In addition, clinical efficacy is related to the proportion of DBS-affected fibres connecting the STN with nodes of both the hyperdirect (cortex-STN) and the indirect pathways (STN-basal ganglia). As such, patient-specific tractography, in particular in the basal ganglia, could be used in a clinical context as a tool to guide therapy.

BACKGROUND:The magnitude and factors associated with levodopa equivalent daily dose (LEDD) reduction in deep brain stimulation (DBS) of the globus pallidus interna (GPi) for Parkinson's Disease (PD) remain unclear. OBJECTIVE:To investigate LEDD reduction in GPi DBS and its correlation with anatomical/clinical characteristics. METHODS:A consecutive cohort of 74 patients who had undergone GPi DBS was analyzed. Regression and probabilistic efficacy mapping were performed to evaluate factors predicting LEDD reduction. RESULTS:32.4% of GPi individuals experienced significant LEDD reduction (>30%). Anteromedial GPi stimulation was associated with higher LEDD reduction. CONCLUSION:Anteromedial stimulation of the GPi appears to be associated with medication reduction, challenging the idea that GPi DBS is ineffective at reducing LEDD. Further prospective study will be needed to validate these findings.

Optimizing the resection volume to maximize clinical benefits and minimize postoperative deficits is crucial to neurosurgeons and their patients. While conventional magnetic resonance imaging (MRI) provides surgical planning guidance by visualizing the relationship between the pathology and nearby structures, it does not show brain function. Functional MRI (fMRI) can supplement invasive tests to determine hemispheric dominance and localize eloquent brain functions and serves as a useful adjunct in surgical planning. To provide an accurate answer to the clinical query, expertise is required to define the most appropriate task and image post-processing decisions. Evidence-based guidelines for these aspects are required to enable the implementation of fMRI as a routine clinical test beyond specialized centers. Recently, fMRI has been shown to provide localizing information for more complex cognitive operations in neurosurgical settings, helping to minimize disruption of whole brain networks following neurosurgery. Furthermore, fMRI has been utilized in other branches of neurosurgery, paving the way for personalized stereotactic functional neurosurgeries for movement and psychiatric disorders.

Unilateral versus bilateral implantation is a critical surgical consideration for deep brain stimulation in Parkinson's disease; however, the differing therapeutic effects remain incompletely understood. Using functional magnetic resonance imaging during active stimulation, we show that bilateral stimulation reinforces the recruitment of key motor hubs while reducing non-motor responses seen with unilateral stimulation and correlates with improved outcomes. This suggests a potential mechanistic basis for better motor function following bilateral stimulation.

Background: Deep brain stimulation (DBS) in Parkinson’s disease (PD) requires extensive trial-and-error programming, often taking over a year to optimize. An objective, rapid biomarker of stimulation success is needed. Our team developed a functional magnetic resonance imaging (fMRI)-based algorithm to identify optimal DBS settings. This study prospectively compared fMRI-guided programming with standard-of-care (SoC) clinical programming in a double-blind, crossover, non-inferiority trial. Methods: Twenty-two PD-DBS patients were prospectively enrolled for fMRI using a 30-sec DBS-ON/OFF cycling paradigm. Optimal settings were identified using our published classification algorithm. Subjects then underwent >1 year of SoC programming. Clinical improvement was assessed under SoC and fMRI-determined stimulation conditions. Results: fMRI optimization significantly reduced the time required to determine optimal settings (1.6 vs. 5.6 months, p<0.001). Unified Parkinson’s Disease Rating Scale (UPDRSIII) improved comparably with both approaches (23.8 vs. 23.6, p=0.9). Non-inferiority was demonstrated within a predefined margin of 5 points ( p =0.0018). SoC led to greater tremor improvement (p=0.019), while fMRI showed greater bradykinesia improvement (p=0.040). Conclusions: This is the first prospective evaluation of an algorithm able to suggest stimulation parameters solely from the fMRI response to stimulation. It suggests that fMRI-based programming may achieve equivalent outcomes in less time than SoC, reducing patient burden while potentially enhancing bradykinesia response.

BACKGROUND:The efficacy and adverse events (AEs) of bilateral magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomies for essential tremor (ET) have not been compared to those of deep brain stimulation (DBS). Furthermore, it is uncertain whether second-side thalamotomies can be positioned differently from the first without compromising effectiveness. OBJECTIVE:We aimed to indirectly compare bilateral MRgFUS and DBS, while identifying optimal lesion/stimulation locations. METHODS:We retrospectively examined 41 ET patients who received either bilateral thalamic DBS (n = 22) or MRgFUS (n = 19) surgery. The primary outcome was the comparison of modalities for change in Clinical Rating Scale for Tremor (CRST) from baseline to post second surgery. We characterized AEs, generated probabilistic maps, and tracked streamlines intersecting lesions. First-side lesions were always intentionally placed ventrally (z = 0/+2 mm above the intercommissural plane [ICP]), and second-side lesions were placed dorsally (z = +3 mm above ICP). RESULTS:Tremor scores improved significantly after second surgeries (MRgFUS: 56.3 ± 7.1 to 24.2 ± 10.4, P < 0.001; DBS: 58.8 ± 11.6 to 25.0 ± 13, P < 0.05, mean follow-up: 23/26 months), with no differences between modalities. Following first surgeries, scores were MRgFUS: 37.9 ± 7.9 and DBS: 35.2 ± 13.6, with significant improvement from baseline (P < 0.001, mean follow-up: 40/73 months). All AEs were grade 1-2, with AE-free rates of 41% for DBS and 32% for MRgFUS. First-side lesions exhibited maximal efficacy in the ventral Vim, extending to posterior subthalamic area (PSA), whereas second-side lesions demonstrated maximal efficacy in the dorsomedial Vim-Vop border. DBS maps corroborated this finding and confined to Vim-Vop border. Lesions intersecting with networks interconnected with the supplementary motor area, in addition to M1, were associated with improved outcomes. CONCLUSIONS:The efficacies of bilateral MRgFUS and DBS appear comparable. MRgFUS probabilistic maps vary with different targeting methods, revealing two distinct sweet spots: dorsal Vim-Vop border and ventral Vim/PSA. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Transcranial ultrasound stimulation (TUS) offers precise, non-invasive neuromodulation, though its impact on human deep brain structures remains underexplored. Here we examined TUS-induced changes in the basal ganglia of 10 individuals with movement disorders (Parkinson’s disease and dystonia) and 15 healthy participants. Local field potentials were recorded using deep brain stimulation (DBS) leads in the globus pallidus internus (GPi). Compared to sham, theta burst TUS (tbTUS) increased theta power during stimulation, while 10 Hz TUS enhanced beta power, with effects lasting up to 40 min. In healthy participants, a stop-signal task assessed tbTUS effects on the GPi, with pulvinar stimulation serving as an active sham. GPi TUS prolonged stop-signal reaction times, indicating impaired response inhibition, whereas pulvinar TUS had no effect. These findings provide direct electrophysiological evidence of TUS target engagement and specificity in deep brain structures, suggesting its potential as a noninvasive DBS strategy for neurological and psychiatric disorders. Transcranial ultrasound stimulation (TUS) is a non-invasive method to modulate deep brain activity. Using direct recordings from implanted electrodes, we showed that TUS engages the human globus pallidus internus, with effects on neural oscillations and behavior.

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BACKGROUND:Stimulation-induced dyskinesia (SID) is a poorly studied and usually transient manifestation of subthalamic deep brain stimulation (STN DBS) for Parkinson's disease (PD), which can be troubling for patients. OBJECTIVES:The aim of our study was to describe the features and management of SID in PD patients undergoing STN DBS. METHODS:We conducted a retrospective study among 86 STN DBS patients. Clinical features and volume of tissue activated (VTA) were correlated to SID occurrence. RESULTS:SID was identified in 28 (32.6%) patients and persisted for 6 months in six patients (7.0%). VTA overlap with the right motor STN was associated (P < 0.02) with SID. Weaning dopaminergic drugs and reducing the DBS amplitude were the most used strategies to control SID. CONCLUSIONS:SID is a relatively common complication of STN DBS and can be persistent. It often requires specific postoperative management strategies.