BrainPrompt+: Multi-Level Brain Prompt Learning for Knowledge-Guided Neurological Disorder Identification

Accurate identification of neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and Autism Spectrum Disorder (ASD) is challenging due to subtle early-stage symptoms and heterogeneous brain dynamics. Resting-state functional MRI (rs-fMRI) enables the construction of functional brain networks, where Graph Neural Networks (GNNs) have shown promise for disease classification. However, existing GNN-based methods face three key limitations: correlation-based graph construction introduces noise and negative edges; domain knowledge about brain regions is ignored; and demographic or clinical metadata are fused through simplistic encodings. To overcome these limitations, we propose BrainPrompt+, a knowledge-guided framework that integrates Large Language Models (LLMs) with multi-level natural language prompts. Five types of prompts are introduced: spectral (frequency-domain BOLD features), spatial (inter-ROI connectivity), ROI (anatomical and functional knowledge), disease (progression stages), and subject (demographic context). These prompts are encoded by a frozen LLM and incorporated into a GNN pipeline, unifying imaging, clinical, and external knowledge in a semantically enriched and interpretable manner. Experiments on three rs-fMRI datasets show that BrainPrompt+ consistently outperforms state-of-the-art baselines, achieving accuracy gains of up to 8.93%. Biomarker analysis further demonstrates that the highlighted ROIs align with established neuroscience findings, confirming the interpretability of the model. BrainPrompt+ thus establishes a flexible and generalizable paradigm for knowledge-guided brain network analysis. The source code is available at https://github.com/AngusMonroe/BrainPromptPlus.