Many neurological and psychiatric disorders involve dysregulation of subcortical structures. Transcranial temporal interference stimulation (tTIS) is a novel, non-invasive method developed to selectively modulate deep brain regions and associated neural circuits. A systematic review was conducted to evaluate human applications of tTIS (PROSPERO ID: CRD42024559678). MEDLINE, Embase, APA PsycINFO, CENTRAL, ClinicalTrials.gov, and WHO ICTRP were searched up to December 12, 2024. Studies involving human applications of tTIS were eligible. Methodological quality was appraised using the NIH and modified Oxford Centre for Evidence-Based Medicine tools. Forty-eight records were reviewed (20 published studies, 28 ongoing trials). Of published studies, 16 single-session and 4 multi-session studies assessed safety, mechanistic outcomes, or therapeutic effects of tTIS in 820 participants. Stimulation was most commonly delivered at beta (20 Hz) or gamma (30-130 Hz) envelope frequencies. Neuroimaging studies support target engagement of the motor cortex, basal ganglia, and hippocampus in humans, particularly when stimulation is paired with behavioural tasks. Preliminary clinical findings in small samples demonstrated acute symptom improvements in bradykinesia and tremor within 60 minutes following a single tTIS session in Parkinson's disease and essential tremor. Reported adverse events across studies were mild (e.g., tingling, itching). Emerging trials increasingly utilize multi-session protocols (2-40 sessions) and are extending tTIS to patients with neurological and psychiatric disorders, particularly epilepsy and depression. Phase 1 studies demonstrate that tTIS is safe, well-tolerated, and capable of engaging deep brain targets in humans. Well-controlled Phase 2 trials are needed to assess its therapeutic potential in patient populations.

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.

Nigrosome-1, a substructure in the dorsolateral substantia nigra, is characterized by the “swallow tail sign” (STS)—a dorsolateral nigral hyperintensity (DNH)—on susceptibility-weighted MRI in healthy individuals. Loss of the STS reflects degeneration of nigrosome-1 and serves as a recognized diagnostic marker for Parkinson’s disease (PD). However, its value in predicting disease severity and deep brain stimulation (DBS) outcomes remains unclear. We retrospectively analyzed 27 PD patients who underwent 3 T susceptibility map-weighted imaging (SMWI) derived from quantitative susceptibility mapping (QSM) prior to DBS. Nigrosome integrity was graded on a four-point scale, and patients were grouped as fully abnormal (Grade 4) or non-fully abnormal (Grades 1–3). No significant group differences were found in baseline motor severity or postoperative improvement, although the non-fully abnormal group showed lower absolute postoperative UPDRS III scores. Nigrosome grading showed no consistent association with symptom lateralization, including contralateral tremor severity or DBS responsiveness. These findings suggest that nigrosome integrity assessed by SMWI MRI—while a validated diagnostic biomarker for PD—showed no moderate-to-large effects with either disease severity or DBS outcomes. Although small effects cannot be excluded, their clinical relevance would be uncertain. Nigral imaging should be interpreted within a broader multimodal framework including clinical, imaging, and biochemical data.

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, p_FDR = 0.01) and bradykinesia (ΔR² = 0.13, p_FDR = 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.