Fronto-parietal and fronto-temporal EEG coherence as predictive neuromarkers of transcutaneous auricular vagus nerve stimulation response in treatment-resistant schizophrenia: A machine learning study
Authors: Yapeng Cui, Ruoxi Yun, Shumin Zhang, Yi Gong, Zhiqin Li, Ying Chen, Mingbing Su, Dongniya Wu, +11 more
Organizations: Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xian, 710126, China. · Wearable BCI and Intelligent Rehabilitation Innovation Lab, Guangzhou Institute of Technology, Xidian University, Guangzhou, 510530, China. · School of Second Clinical Medicine/The Second Affiliated Hospital, Yunnan University of Chinese Medicine, Kunming, 650500, China. · Kunming Mental Hospital, Kunming, 650000, China.
Response variability limits the clinical utility of transcutaneous auricular vagus nerve stimulation (taVNS) for negative symptoms in treatment-resistant schizophrenia (TRS). This study aimed to develop an electroencephalography (EEG)-based machine learning (ML) model to predict individual response and explore associated neurophysiological mechanisms. We used ML to develop and validate predictive models based on pre-treatment EEG data features (power, coherence, and dynamic functional connectivity) from 50 TRS patients enrolled in the taVNS trial, within a nested cross-validation framework. Participants received 20 sessions of active or sham taVNS (n = 25 each) over two weeks, followed by a two-week follow-up. The prediction target was the percentage change in the positive and negative syndrome scale-factor score for negative symptoms (PANSS-FSNS) from baseline to post-treatment, with further evaluation of model specificity and neurophysiological relevance.The optimal model accurately predicted taVNS response in the active group, with predicted PANSS-FSNS changes strongly correlated with observed changes (r = 0.87, p < .001); permutation testing confirmed performance above chance (p < .001). Nine consistently retained features were identified, predominantly fronto-parietal and fronto-temporal coherence features. Negligible predictive performance in the sham group and failure to predict positive symptom change support the predictive specificity of this oscillatory signature for taVNS-related negative symptom improvement. Two coherence features within fronto-parietal-temporal networks showed post-taVNS changes significantly associated with symptom improvement, suggesting dual roles as predictors and potential therapeutic targets. EEG oscillatory neuromarkers enable accurate prediction of individual taVNS response in TRS, supporting mechanism-informed precision neuromodulation strategies.
Depression is a mental condition that can lead to suicide and self-harm. Predicting the outcome of depression treatment is one of the most difficult tasks for clinicians. Among various treatment options, repetitive Transcranial Magnetic Stimulation (rTMS) is a widely used non-invasive method. Predicting rTMS response using Electroencephalogram (EEG) data is difficult because of high inter-subject variability and limited features from single-domain analysis. We introduce two fusion techniques, montage and blending, to overcome these limitations and extract richer features from EEG-derived Time-Frequency (TF) images. We then propose a lightweight custom Convolutional Neural Network (CNN) trained on fused TF representations. \textcolor{black}{We use a primary dataset of 15 patients and a secondary dataset of 46 patients. We run two sets of experiments. The first set uses segment-level 10-fold cross-validation. In this setup segments from the same patient can appear in both training and testing. The Montage CWT_ST fusion reaches 99.90% accuracy on the primary dataset and 91.90% on the secondary dataset. The second set uses strict subject-disjoint cross-validation. All segments of a patient stay in one fold and no patient appears in both training and testing. Performance collapses. We test four time-frequency methods, six fusion mechanisms, and fourteen model architectures. With one exception, every configuration on both cohorts falls between AUC 0.31 and 0.54 and every 95% confidence interval contains 0.5. A patient-level permutation test on the best standalone method returns p=0.703. The best subject-level result is Montage CWT_ST on the primary cohort, which reaches AUC 0.874±0.183 and 82.7% accuracy.
Wael Korani, Md Fahimul Kabir Chowdhury, Mohammed Aledhari +2
Schizophrenia is a debilitating neuropsychiatric disorder characterized by profound cortical network dysregulation, for which objective, clinically translatable EEG based biomarkers remain underdeveloped. Existing automated classification pipelines rely predominantly on static power spectral density features inherently blind to amplitude modulation dynamics and cross-frequency coupling, phenomena central to schizophrenia pathophysiology, while adopting epoch level cross validation strategies that introduce temporal data leakage, artificially inflate reported performance. This study introduces a mathematically principled diagnostic framework integrating the multi-order Wavelet Scattering Transform(WST), strict Leave One Subject Out (LOSO) cross-validation, and SHAP explainability for simultaneous EEG classification and biomarker discovery. Hierarchical WST coefficients capturing multi-scale amplitude modulation structure were extracted from resting state multichannel EEG. Subject-level ANOVA with Benjamini Hochberg false discovery rate correction identified significant biomarkers, with Random Forest and SVM classifiers evaluated under strict LOSO cross validation and subject-level majority voting. Second-order scattering coefficients encoding cross frequency coupling dominated the discriminative biomarker set, with gamma-band features most prevalent, demonstrating that temporal amplitude modulation constitutes the primary electrophysiological signature of schizophrenia. Electrode P3 was identified as the single most discriminative site. Under rigorous subject independent evaluation, the Random Forest achieved 90.48% accuracy (AUC = 0.9339; sensitivity = 95.56%). The proposed WST framework establishes a rigorous, interpretable standard for EEG-driven psychiatric biomarker discovery that can also be applicable in the detection of schizophrenia subtypes in the future.
Repetitive transcranial magnetic stimulation (rTMS) is a non invasive therapy for Major Depressive Disorder (MDD). In this study, we generate images using two time frequency methods to represent EEG signals: Fourier-Bessel Series Expansion with Euclidean Distance (FBSE-ED) and Discrete Wavelet Transform (DWT). We propose an efficient deep learning classifier to predict the outcome of rTMS depression therapy. In this study, we use a private rTMS databases to train a lightweight custom Convolutional Neural Network (CNN) using 10-fold cross validation strategy in order to avoid any bias in our results. The results show that the FBSE-ED representation achieves the highest classification accuracy of 93.60%, outperforming traditional time-frequency technique (DWT). In addition, the proposed architecture with FBSE-ED image representation technique outperforms more complex EEG-Specific deep learning models (EEGNet, DeepConvNet, SleepEEGNet) by 3.62-10.72% and pretrained models (Xception, DenseNet201, and MobileNetV2) by 23.03-27.35%. For more experiments, we utilize another private rTMS database as test database to show the robustness of the proposed model. Our results suggest that integrating advanced signal decomposition with deep learning can facilitate early prediction of rTMS treatment response and support more targeted clinical decision-making. The proposed framework is interpretable, computationally efficient, and well-suited for deployment in real-world local psychiatric clinics.
Wael Korani, Md Fahimul Kabir Chowdhury, Sadam AlQadi +3
Department of Data science, University of North Texas, Texas, USA · Department of Computer Science, University of North Texas, Texas, USA · Department of Information science, University of North Texas, Texas, USA +1