Temporal interference stimulation: A new paradigm for non-invasive deep brain stimulation-mechanistic insights, clinical advances, and future directions.

Deep-brain Neuromodulation in Parkinson's Disease: Convergent Mechanisms and Translational Stratification of Deep Brain Stimulation and Low-intensity Focused Ultrasound.

Parkinson's disease (PD) involves not only dopaminergic degeneration but also pathological changes in cortico-basal ganglia-thalamocortical circuits and broader disease-relevant biological processes. Deep-brain neuromodulation has emerged as an important therapeutic strategy for motor dysfunction. Among the available approaches, deep brain stimulation (DBS) is the most established modality, whereas low-intensity focused ultrasound (LIFUS), a form of transcranial ultrasound stimulation, represents a promising but earlier-stage, non-invasive platform. This review discusses DBS and LIFUS from a shared mechanistic and translational perspective. Current evidence suggests that the two modalities may engage partially overlapping mechanistic domains associated with motor deficit improvement, including modulation of abnormal network activity, promotion of synaptic and axonal remodeling, attenuation of neuroinflammation and cellular stress, and possible interaction with α-synuclein-related pathology. At the same time, they differ substantially in evidentiary depth, clinical maturity and translational readiness. DBS remains the clinical benchmark, with durable motor benefits and an expanding mechanistic framework that now extends beyond circuit correction to neurotrophic, proteinopathic, neuroimmune and adaptive biomarker-guided mechanisms. By contrast, LIFUS offers non-invasive access to deep brain targets and shows encouraging pre-clinical effects on inflammation, apoptosis, synaptic integrity and neurovascular function, but its clinical evidence remains limited. Overall, deep-brain neuromodulation in PD should be viewed as a multi-dimensional therapeutic framework rather than a group of isolated technologies. Future progress will depend on tighter integration of circuit physiology, pathology-relevant biomarkers, model selection and standardized translational endpoints.

Neuromodulation in Alzheimer's disease: a review with illustrative pilot data using focused ultrasound.

Alzheimer's disease (AD) is increasingly characterized as a disorder of large-scale brain networks driven by synaptic dysfunction, excitation-inhibition imbalance, and progressive breakdown of hippocampal-cortical communication. While recently developed disease-modifying therapies target molecular pathology, their clinical benefits remain modest, underscoring the need for interventions that target dysfunctional circuits. Neuromodulatory techniques such as transcranial magnetic stimulation, transcranial electrical stimulation, and deep brain stimulation demonstrate safety and act at network/system levels to engage target sites yet are limited by their ability to modulate deep anatomic structures and/or their invasiveness. Focused ultrasound (FUS) offers the distinct capability of modulating cortical and deep subcortical networks noninvasively and with anatomic precision. Preclinical studies demonstrate that FUS neuromodulation can influence mechanosensitive ion channels, synaptic plasticity, neurotrophic signaling, and oscillatory dynamics, with downstream effects on distributed memory networks. Early human investigations similarly suggest FUS neuromodulation can alter functional connectivity within default mode, frontoparietal, and limbic networks. Together, these findings support a framework in which FUS may help reshape pathological network states that emerge prior to irreversible neurodegeneration. Here, we present a narrative review of evidence across neuromodulation approaches to define principles of circuit engagement in AD and discuss a network-based rationale for ultrasound interventions. As an illustration of this framework, we also report preliminary findings from a Phase I pilot study of FUS neuromodulation in amyloid-positive mild cognitive impairment demonstrating safety, tolerability, and measurable modulation of hippocampal connectivity. We conclude mechanistic biomarkers of network response may accelerate translational development and guide future controlled trials.

Central medial thalamic nucleus–targeted temporal interference stimulation promotes arousal: translational evidence from optimized preclinical models to patients with disorders of consciousness

Patients with disorders of consciousness (DoC) lack effective non-invasive neuromodulation therapies capable of targeting deep-brain arousal circuits. Temporal interference stimulation (TIS) offers potential for non-invasive deep brain targeting. However, its efficacy, optimal stimulation parameters, and underlying neural mechanisms remain to be systematically investigated. We constructed a rodent TIS electrode configuration with cathode affixed to the masseter muscle to achieve free-moving stimulation in mice, and optimized stimulation parameters in isoflurane-anesthetized C57 mice, validated using righting reflex assays. Target specificity was confirmed by comparing Central Medial Thalamic Nucleus (CM) stimulation with that of the caudate putamen. Neuronal activation was assessed via calcium imaging, c-Fos staining, and electrocorticography. Biosafety was evaluated through acute and 7-day repeated histopathological analyses and open-field testing. Preliminary feasibility was assessed in two patients with chronic DoC using Coma Recovery Scale–Revised and functional near-infrared spectroscopy. Optimal TIS parameters (60 s, 0.8 mA, 10 Hz) significantly promoted arousal, accelerated righting reflex recovery, and increased respiratory rate. CM-targeted TIS preferentially activated CM neurons, enhanced cortical beta/gamma oscillations, and suppressed delta activity. No tissue damage, neuronal loss, microglial activation, or motor deficits were observed under acute or repeated stimulation. In two patients, 10 Hz TIS transiently improved consciousness ratings and enhanced functional connectivity and right Broca’s area activation. CM-targeted TIS is a promising non-invasive deep neuromodulation strategy, supported by a translational evidence chain from preclinical optimization, mechanistic validation, and biosafety assessment to preliminary clinical feasibility. Chinese Clinical Trial Registry, ChiCTR2500114570. Registered 15 December 2025.

NeuroImage: Clinical

Effects of 40 Hz Brain Stimulation Across Modalities: A Comparative Narrative Review

This narrative review synthesizes preclinical and early-phase clinical evidence for 40 Hz non-invasive brain stimulation across five delivery modalities and concludes that multisensory combined stimulation currently represents the approach with the most promising early translational signal.

Functional ultrasound imaging in preclinical brain stimulation: from multimodal readouts to closed-loop neuromodulation

Understanding how brain stimulation engages neural circuits requires readouts that combine rapid monitoring, access to deep structures, and high spatiotemporal resolution. Few existing modalities can provide this combination. This minireview summarizes recent advances in the application of functional ultrasound (fUS) imaging to preclinical brain stimulation, with an emphasis on its value as an advanced functional imaging modality across different stimulation paradigms. Building on ultrafast ultrasound, fUS captures cerebral hemodynamic changes associated with neural activity, enabling near-real-time hemodynamic monitoring with high spatiotemporal resolution. We survey the applications of fUS across optogenetic stimulation, deep brain stimulation (DBS), and focused ultrasound (FUS) stimulation, covering its role in mapping stimulation-evoked network responses and characterizing parameter-dependent neuromodulation effects. We further argue that the unique compatibility between fUS as a readout and FUS as an effector points toward a fully integrated read–write closed-loop neuromodulation framework, in which fUS continuously monitors brain hemodynamic states and feeds these signals back into an adaptive controller to deliver FUS. Together, these directions position fUS as an effective and promising tool for examining the mechanisms of brain function and its responses to stimuli and for developing precise, adaptive neuromodulation strategies.