Background
Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by progressive cognitive decline and memory impairment with an insidious and irreversible pathological process. As the global population ages, AD imposes a heavy burden on families and society: one new case is diagnosed every 3 seconds worldwide. Advanced-stage patients lose full self-care ability, and the associated medical and nursing costs account for over 1.3% of the global GDP.
Current clinical treatments mainly focus on symptomatic relief: cholinesterase inhibitors and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine only alleviate symptoms but cannot halt pathological progression. Recently approved anti-β-amyloid (Aβ) monoclonal antibodies (e.g., lecanemab, donanemab) target the underlying pathological mechanisms but suffer from high costs, limited applicability, and potential long-term side effects. The core bottlenecks in AD diagnosis and treatment lie in "difficulty in early diagnosis" and "high invasiveness of targeted interventions." Developing precise, minimally invasive technologies that integrate the entire process of "diagnosis-treatment-monitoring" has become crucial to overcoming the predicament in this field.
Core Content
I. Technical Foundation: EBCI as a Minimally Invasive and Precise Platform for AD Diagnosis and Treatment
As an innovative subtype of invasive brain-computer interfaces (BCIs), the Endovascular Brain-Computer Interface (EBCI) enables electrode delivery to target brain regions via endovascular intervention without craniotomy, combining high signal acquisition precision with minimally invasive safety.
1. Core Technical Advantages
·Anatomical Advantage: Leveraging the natural pathways of cerebral blood vessels, EBCI can reach key deep brain regions involved in AD, such as the fornix and basal nuclei of Meynert: core nodes of memory circuits that are inaccessible to traditional non-invasive BCIs and require craniotomy for traditional invasive BCIs. Clinical anatomical studies confirm that intracerebral veins with diameters of 0.4-1.4 mm in AD patients directly connect the thalamic fornix and anterior nucleus, providing a natural implantation pathway for EBCI.
·Minimally Invasive Advantage: Via femoral artery or internal jugular vein intervention, the surgical trauma is significantly lower than that of traditional invasive BCIs (e.g., subdural electrode arrays). Human clinical trial data show that patients can ambulate 24 hours after EBCI implantation, with a postoperative infection rate of <1%.
·Signal Acquisition Advantage: The collected Local Field Potential (LFP) signals are comparable in quality to those from subdural electrode arrays, with signal intensity 2-5 times higher than that of scalp Electroencephalography (EEG), while avoiding inflammatory reactions caused by blood-brain barrier disruption. In sheep models, EBCI can stably record neural signals for up to 190 days, and signal stability has been maintained for over 12 months without significant attenuation in human clinical studies.
2. Hardware Evolution History
EBCI hardware has undergone five generations of technological innovation, gradually achieving the goals of "miniaturization, stabilization, and long-term usability":
·First-generation Guidewire Electrodes (1973): 100-300 μm in diameter, made of stainless steel or nitinol, enabling the first intravascular recording of brain electrical signals, but with a signal duration of only a few hours.
·Microwire/Nanowire Electrodes (1998-2005): Reduced to 20-50 μm (microwires) or nanoscale (nanowires), using materials such as platinum-iridium alloy and carbon nanotubes, improving signal acquisition precision but prone to displacement after implantation.
·Catheter-based Electrodes (2010 onwards): 200-500 μm in outer diameter, with gold/platinum electrodes embedded in polyurethane/silicone catheters, enhancing biocompatibility but susceptible to blood flow interference during long-term implantation.
·Stent Electrodes (2015 onwards): 2-4 mm in outer diameter, featuring a nitinol or cobalt-chromium alloy framework with platinum/gold electrodes on the surface. The self-expanding design allows fixation to the vascular wall, preventing displacement. Preoperative cleaning of the electrode surface via cyclic voltammetry reduces impedance from 6.26±6.7 kΩ to 2.21±1.2 kΩ, significantly improving signal stability.
·Latest Progress: The Stentrode developed by Synchron in collaboration with NVIDIA integrates AI, achieving a 3-fold increase in neural signal decoding speed through the Holoscan platform and linkage with Apple Vision Pro. It can interpret users' cognitive intentions via the self-supervised learning model "Chiral™," laying the foundation for complex interactions in AD patients.
Ⅱ. Core Mechanisms: Three Pathways Regulating Memory and Cognitive Function in AD
Through the bidirectional functions of signal acquisition and neural modulation, EBCI intervenes in the AD process from diagnosis to treatment through multiple dimensions. Its core mechanisms are validated by both clinical studies and animal experiments, forming a "diagnosis-stimulation-feedback" trinity treatment framework:
1. Early Diagnosis: Capturing Electrophysiological Biomarkers in the Preclinical Stage of AD
Early cognitive symptoms of AD are subtle, and traditional imaging (e.g., structural MRI) and cerebrospinal fluid (CSF) testing have limitations: in a cohort of pathologically confirmed early-onset AD, 37.5% of patients present with non-memory-related symptoms (most commonly behavioral and executive function deficits), and 53% of atypical patients are misdiagnosed initially. EBCI enables long-term dynamic monitoring of brain electrical signals to capture AD-specific electrophysiological features, achieving "diagnosis before symptom onset":
·Abnormal Frequency Rhythms: In the preclinical stage of AD, θ-wave (4-8 Hz) power increases, while α-wave (8-15 Hz) and β-wave (16-31 Hz) power decrease. An elevated θ/α ratio is a core indicator predicting the conversion from Mild Cognitive Impairment (MCI) to AD, with an accuracy of 78%-85%.
·Changes in Event-Related Potentials: Studies confirm that the P300 latency is significantly prolonged in MCI or AD patients compared to healthy controls, and pro-cognitive drug treatment can modulate P300 parameters. The amplitude of Steady-State Visual Evoked Potentials (SSVEP) decreases, and these indicators are significantly correlated with cognitive scale scores.
·Weakened Brain Network Functional Connectivity: The cross-regional connectivity strength of the default mode network and hippocampal-fornix circuit in AD patients is 30%-40% lower than that in healthy individuals, particularly in the θ and α frequency bands.
The combined SSVEP-P300 dual-stimulation paradigm further improves diagnostic efficacy: Kasawala et al. developed an LED stimulation system that evokes SSVEP via 7-10 Hz flash and P300 via target events, achieving an AD classification accuracy of 86.25%, significantly higher than the 70% threshold of traditional EEG. Additionally, EBCI can dynamically monitor electrophysiological changes within 1-3 months, effectively distinguishing AD-related MCI from non-AD-related MCI and addressing the diagnostic challenge for patients intolerant to CSF testing.
2. Deep Brain Stimulation (DBS): Targeted Regulation of Memory Circuits
The pathological core of AD lies in the dysfunction of memory-related neural circuits: Aβ deposition and excessive tau phosphorylation lead to decreased synaptic plasticity and neurotransmitter imbalance in key nodes such as the fornix and basal nuclei of Meynert. EBCI achieves precise stimulation via the vascular pathway, with mechanisms including:
·Core Target Regulation:
oFornix: As a key connection pathway between the hippocampus and limbic system, EBCI stimulation increases glucose metabolism in the temporal and parietal lobes (opposing the progression of AD) and promotes the release of neurotrophic factors. Both Phase I (n=6) and Phase II (n=42) trials confirm that 12 months of continuous stimulation slows cognitive decline in mild AD patients.
oBasal Nuclei of Meynert: The cholinergic neural center: stimulation enhances cortical cholinergic transmission and improves synaptic plasticity, with significant improvements in attention and executive function scores in 6 patients in Phase I trials.
·Pathological Mechanism Intervention: γ-frequency (40 Hz) stimulation activates microglia, promoting Aβ clearance, while enhancing synaptic protein expression and neurogenesis. Continuous stimulation for 4 weeks in sheep models reduces Aβ deposition by over 35%.
·Technical Advantages: The high conductivity of blood vessels reduces EBCI stimulation voltage by 30%-40% compared to traditional DBS, minimizing damage to surrounding brain tissue. The multi-contact ring electrode design allows software-adjustable electric field distribution to compensate for stimulation deviations caused by electrode displacement. EBCI's unique anatomical advantage enables stimulation of deep brain regions with less trauma, avoiding craniotomy-related damage while maintaining DBS efficacy. By decoding signals from target brain regions, EBCI enables closed-loop regulation, which is more personalized, rational, and flexible than single-frequency open-loop stimulation, resulting in better therapeutic outcomes.
3. Neurofeedback Training: Reshaping Cognitive Regulation Capabilities
Cognitive decline in AD patients hinders traditional BCI training, but EBCI overcomes this limitation through simplified paradigms and precise feedback, forming multiple core training models:
·θ/α Ratio Regulation Paradigm: Targeting the overactivation of θ-waves and weakening of α-waves in AD patients, visual/auditory feedback guides patients to autonomously regulate brain activity. Surmeli et al. conducted 30 training sessions (twice weekly) in 10 AD patients, resulting in an average 2% increase in the total Cambridge Cognitive Examination (CAMCOG) score and a 4%-6% improvement in memory and learning subdomain scores, with no further cognitive decline observed 6 months postoperatively.
·Personalized Targeted Training: Quantitative analysis of patients' EEG patterns is performed by comparing with healthy population databases to identify abnormal frequency bands and brain regions (e.g., weakened prefrontal α-waves, enhanced temporal θ-waves), and targeted training programs are designed. This model is effective for both AD and vascular dementia, with a 2-3 point improvement in the Mini-Mental State Examination (MMSE) score compared to baseline.
·Affective BCI Expansion: For severe AD patients, emotional cues such as "laughter-crying" replace active learning, and blood oxygen level-dependent (BOLD) signals are used to identify "yes/no" cognitive states, providing a basic communication channel for patients with severe cognitive impairment.
4. The ultimodal Integration: Improving Diagnostic and Therapeutic Precision
The combined application of EBCI and functional Near-Infrared Spectroscopy (fNIRS) simultaneously collects electrophysiological signals and cerebral hemodynamic information, addressing the limitations of single-modal approaches. fNIRS monitors changes in hippocampal blood oxygen levels in AD patients, complementing LFP signals recorded by EBCI to enhance the reliability of neurofeedback training. Additionally, this combination avoids magnetic field interference and noise issues associated with fMRI, improving comfort during long-term monitoring, particularly for elderly AD patients.
Ⅲ. Pathological and Clinical Correlation: Stratified Application Across Different AD Stages
EBCI's minimally invasive and targeted advantages make it suitable for clinical needs across different AD stages, with unique benefits in elderly patients:
1. Mild AD/MCI Stage: Early Warning and Intervention
At this stage, patients' cognitive function has not yet significantly declined, but traditional DBS carries excessive surgical risks (intracranial hemorrhage rate of 3%-5%), and non-invasive technologies lack sufficient targeting. EBCI plays a role in the following ways:
·Diagnosis: Dynamic monitoring of indicators such as the θ/α ratio and P300 latency, with a diagnostic accuracy exceeding 86%.
·Treatment: Low-intensity stimulation of the fornix and basal nuclei of Meynert combined with neurofeedback training slows cognitive decline: clinical studies show that the magnitude of MMSE score reduction in the intervention group is significantly smaller than that in the control group after 12 months.
·Target Population: Particularly suitable for elderly patients with comorbid hypertension or diabetes, for whom the risk of craniotomy complications is increased by 2-3 times. EBCI has a vascular injury rate of <3% and a thrombosis rate of 0%-2%, significantly lower than traditional invasive technologies.
2. Moderate AD Stage: Synergistic Effect of Combined Therapy
Pathological damage is already evident in moderate AD patients, and single-drug therapy has limited efficacy. EBCI can be used in combination with anti-Aβ antibodies:
·Monitoring: EBCI collects electrophysiological signals around the fornix monthly to real-time evaluate treatment efficacy: traditional PET-Aβ only reflects pathological clearance, while EBCI captures the recovery of neural circuit function (e.g., enhanced θ-γ coupling), avoiding ineffective treatment where "pathology improves but cognition does not benefit" (occurring in over 30% of AD patients).
·Treatment: DBS stimulation enhances the protective effect of antibodies on neural circuits and promotes cognitive-related brain functions such as synaptic protein expression and neurogenesis.
3. Severe AD Stage: Functional Preservation and Nursing Support
Severe AD patients experience severe cognitive decline, with core needs of preserving residual cognition and basic communication abilities:
·Neurofeedback training focuses on attention and emotional regulation, maintaining patients' arousal levels through simplified audio feedback to preserve residual cognition as much as possible.
·Affective BCI enables basic "yes/no" communication, helping patients express needs (e.g., hunger, pain), reducing nursing difficulty, and improving quality of life.
Ⅳ. Future Prospects
By deeply integrating "technology-mechanism-application," EBCI provides a new paradigm for the minimally invasive diagnosis and treatment of AD. However, it currently faces limitations such as limited clinical evidence (lack of multi-center, large-sample long-term follow-up data), the need for further electrode miniaturization, and high costs. Future research will focus on three aspects:
1. Technological Optimization:
Promote electrode miniaturization (target diameter <1 mm) and navigation precision. Combine magnetic control catheters with intravascular Optical Coherence Tomography (OCT) real-time imaging to control electrode implantation error within 0.5 mm.
2. Mechanism Deepening:
Clarify the regulatory effect of EBCI on adult hippocampal neurogenesis, and explore the dose-effect relationship between "stimulation frequency-synaptic plasticity-cognitive improvement" to provide a basis for formulating personalized stimulation parameters.
3. Clinical Translation:
Conduct multi-center, large-sample clinical trials to verify the efficacy of EBCI in different AD subtypes (e.g., Aβ-type, tau-type), develop simplified devices suitable for primary medical settings, and reduce technical costs.
4. Ethical and Regulatory Considerations:
Further explore issues such as biocompatibility of long-term implantation, safety of electrode extraction, and protection of neural signal privacy.
With the development of AI integration (e.g., real-time signal decoding, adaptive adjustment of stimulation parameters) and multimodal combination technologies, EBCI is expected to become a core tool for the precise diagnosis and treatment of AD, providing a new path for overcoming this major neurodegenerative disease.
Sources: https://spj.science.org/doi/10.34133/research.1049
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