Hopf-GAE

Physics-Informed Graph Neural Network for Normative Brain Dynamics

Anomaly Detection in Major Depressive Disorder via Stuart-Landau–Grounded Denoising Graph Autoencoder with Coupled Edge-Node Reconstruction

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Overview

This repository contains the Hopf-GAE, a physics-informed deep learning architecture that detects depression-related dynamical abnormalities without ever training on depressed brains. Rather than framing MDD detection as binary classification (which fails at $n = 19$), the model learns a normative manifold of healthy brain dynamics and scores MDD subjects by how far they deviate from it.

The key innovations:

1. Biophysically grounded node features — every node carries the per-region bifurcation parameter $a_j$, natural frequency $\omega_j$, and goodness-of-fit $\chi^2_j$ estimated by the Stuart-Landau / Hopf bifurcation framework via the SL-UKF_Neural_Criticality_MDD & · SL-UKF_Neural_Criticality_MDDvsHC pipeline, plus Yeo 7-network one-hot encodings (11 features per ROI). To our knowledge, the first use of biophysically estimated dynamical parameters as node features in any GNN for fMRI.

2. Multi-relational graph attention — three edge types (PLV phase synchrony, MVAR Granger causality, SC structural connectivity) with learned per-relation attention weights and edge-attribute-aware attention.

3. Coupled edge-node bottleneck — edge decoders operate on the trainable latent $𝐳$ via concatenation $[𝐳_i | 𝐳_j]$, creating a gradient path from the edge loss through the shared bottleneck into the node reconstruction pathway. When decoupled (edge decoders on frozen $𝐡$), the connectivity branch has identically zero effect on the anomaly score.

4. Physics-only scoring — anomaly scores use reconstruction error on $(a_j, \omega_j, \chi^2_j)$ exclusively. Four additional connectivity-derived features shape $𝐳$ during training but are excluded from the score, preventing connectivity-derived features from diluting the dynamical anomaly signal.

5. Denoising graph autoencoder — Gaussian noise injection ($\sigma = 0.1$) on encoder input and dropout ($p = 0.3$) on the latent code replace the variational bottleneck, which collapsed in all tested configurations due to low within-HC variance of bifurcation parameters.

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The $n = 19$ Problem

Classification (insufficient data) Binary classification: active NF vs. sham Trained on 18 subjects per fold Memorized subject identity → Cohen's $d$ of $-6$ to $-11$ Implausibly large vs. UKF reference $d = -0.835$ Verdict: classification fails at this sample size

Normative anomaly detection (this work) Train exclusively on healthy controls ($n = 295$ sessions) MDD subjects are test-only — never seen during training Overfitting eliminated by construction HC vs MDD: $d = +3.02$, $p = 7.3 \times 10^{-10}$ All 4 intervention scales survive FDR correction HC holdout false positive rate: 0/36 (0.0%) Seed robustness: CV = 3.9% across 10 initializations Verdict: "how far from healthy?" not "which group?"

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Architecture

Node Features (11-dimensional per ROI)

Feature	Dim	Source	Meaning
$a_j$	1	SL-UKF_Neural_Criticality_MDD	Bifurcation parameter — distance from critical point
$\omega_j$	1	Hilbert phase	Natural oscillation frequency (Hz)
$\chi^2_j$	1	UKF fit	Goodness-of-fit (model–data agreement)
Network one-hot	8	Yeo 7 + Subcortical	Functional network membership

Reconstruction Targets (7-dimensional per ROI)

Feature	Weight	Source	Enters Score?
$a_j$	2.0	UKF	Yes
$\omega_j$	1.0	Hilbert	Yes
$\chi^2_j$	1.0	UKF fit	Yes
PLV node strength	0.5	Edge aggregation	No — shapes $𝐳$ only
MVAR in-strength	0.5	Edge aggregation	No — shapes $𝐳$ only
MVAR out-strength	0.5	Edge aggregation	No — shapes $𝐳$ only
Within-network PLV	0.5	Edge aggregation	No — shapes $𝐳$ only

Edge Types (3 relations)

Relation	Type	Source	Encoder Weight (Conv₁)
PLV	Undirected	Phase Locking Value	0.76
SC	Undirected	$\exp(-d/40\text{mm})$	0.19
MVAR	Directed	Lasso-MVAR	0.05

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Model Components

Multi-Relational Graph Attention Convolution

Each GAT layer maintains separate learnable projections $W_r$ and attention vectors $𝐚_r$ for each edge relation $r \in {\text{PLV}, \text{MVAR}, \text{SC}}$, with edge attributes incorporated into the attention computation:

$$h_j^{(l+1)} = \text{ELU}!\left( \sum_{r \in R} \alpha_r \sum_{i \in \mathcal{N}_r(j)} \alpha_{ij}^{(r)} , w_{ij}^{(r)} , W_r , h_i^{(l)} \right)$$

where $\alpha_r$ are learned relation-importance weights (softmax-normalized).

Frozen Encoder (5,485 parameters)

Two multi-relational GAT layers ($11 \to 32 \to 32$) with a masked residual connection produce per-ROI embeddings $𝐡_j \in ℝ^{32}$. The masked residual projects the input through input_proj ($11 \to 32$) but zeros the physics features $(a_j, \omega_j, \chi^2_j)$ — forcing the encoder to reconstruct dynamics through graph message passing rather than shortcutting via identity. A physics head ($32 \to 16 \to 1$) validates the encoder during pre-training ($R^2_{\text{graph}} = 0.964$, $R^2_{\text{roi}} = 0.616$). The encoder is frozen after pre-training.

Trainable Denoising GAE (586 parameters)

Denoising: During training, Gaussian noise ($\sigma = 0.1$) is injected on the encoder input $𝐱$, preventing the bottleneck from learning identity-like mappings.

Node path: Deterministic projection $𝐡_j \to z_j \in ℝ^6$ → dropout ($p = 0.3$) → linear decoder ($6 \to 7$) → reconstructed $(a, \omega, \chi^2, s_\text{PLV}, s_\text{MVAR-in}, s_\text{MVAR-out}, \text{PLV}_\text{within})$.

Edge path (coupled): Three MLP edge decoders predict edge existence from $[𝐳_i | 𝐳_j]$ for PLV, SC, and MVAR independently. Each MLP is $12 \to 8 \to 1$ with ELU activation. Concatenation (not absolute difference) is used because directed edges (MVAR) require asymmetric input.

Graph-level loss: Per-graph mean and standard deviation of the bifurcation parameter $a$ are reconstructed, ensuring the decoder preserves population-level distributional properties.

Component	Shape	Parameters	Status
$f_z$ (bottleneck)	$32 \to 6$	198	Trainable
Linear decoder	$6 \to 7$	49	Trainable
Edge decoders (PLV, SC, MVAR)	$12 \to 8 \to 1$ each	339	Trainable
Total trainable		586

Physics-Only Anomaly Scoring

$$S = \frac{1}{N} \sum_{j=1}^{N} \left[ 2(a_j - \hat{a}_j)^2 + (\omega_j - \hat{\omega}_j)^2 + (\chi^2_j - \hat{\chi}^2_j)^2 \right]$$

z-scored against HC norms: $S_z = (S - \mu_\text{HC}) / \sigma_\text{HC}$. No component of the scoring function is derived from or optimized against clinical group membership.

Loss function (GAE training):

$$\mathcal{L} = \underbrace{\sum_{f} w_f (x_f - \hat{x}_f)^2}_{\text{feature-weighted node recon}} + ; \lambda_g \cdot \underbrace{(\text{MSE}(\mu_a, \hat{\mu}_a) + \text{MSE}(\sigma_a, \hat{\sigma}_a))}_{\text{graph-level } a \text{ statistics}} + ; \lambda_e \cdot \underbrace{\sum_{r} \text{BCE}(\hat{A}_r, A_r)}_{\text{3-relation edge recon}}$$

with $\lambda_g = 0.1$, $\lambda_e = 0.5$.

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Parameter Budget

Total parameters:                            6,071
├── Frozen encoder:                          5,485  (90%)
│   ├── conv1 (3-relation GAT, 11→32):       1,286
│   ├── conv2 (3-relation GAT, 32→32):       3,302
│   ├── input_proj (masked residual, 11→32):   352
│   └── physics_head (32→16→1):                545
└── Trainable GAE:                             586  (10%)
    ├── fc_z (32→6):                           198
    ├── linear_decoder (6→7):                   49
    └── edge_decoders (3 × MLP 12→8→1):        339

Coupled architecture: 3.2× fewer trainable params than decoupled (586 vs 1,882)

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Data Isolation

┌────────────┬─────────────────┬──────────────┬──────────────┬──────────────┬──────────────┐
│  Synthetic │    HC train     │  HC holdout  │   HC test    │  MDD rest1   │  MDD rest2   │
│  n = 200   │ 24 subj (199s)  │ ~5 subj (36s)│ 6 subj (60s) │   19 subj    │   18 subj    │
│  Stage 1   │    Stage 2      │  Test only   │  Test only   │  Test only   │  Test only   │
└────────────┴─────────────────┴──────────────┴──────────────┴──────────────┴──────────────┘
 Synthetic + HC train = train  |  HC holdout + HC test + MDD = never trained on

The HC train/test split is by subject (not session) to prevent leakage. HC holdout subjects (~15%) provide an unbiased false positive rate estimate (0/36 = 0.0%). MDD subjects are never seen during any training stage. HC train vs. test overfitting check: $p = 0.875$.

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Key Design Decisions

Coupled edge decoders on $𝐳$ (not $𝐡$) — Edge decoders receive the trainable latent $𝐳$ via concatenation $[𝐳_i | 𝐳_j]$, creating a gradient path: $∇ℒ_{edge} → MLP_r → [𝐳_i, 𝐳_j] → W_z$. Three independent observations confirm functional coupling: (1) 10% improvement in HC–MDD separation ($d = 2.75 \to 3.02$) with 3.2× fewer trainable parameters; (2) inverted-U dose-response curve for $\lambda_\text{edge}$ peaking at 0.50; (3) optimal $d_z$ shifts from 4 (decoupled) to 6 (coupled). ROI ranking correlation between coupled and decoupled: $\rho = 0.952$.

Physics-only scoring (not Fisher LDA) — An earlier design used Fisher LDA to weight anomaly score components, but this introduced circularity: scoring weights were informed by the labels being tested, inflating effect sizes by ~2.8×. The physics-only score is strictly label-free.

Denoising autoencoder (not variational) — The variational bottleneck ($\mu, \log\sigma^2$, reparameterization, KL divergence) was tested across multiple architectural configurations. KL collapsed to negligible values in all cases because within-HC variance of $(a, \omega, \chi^2)$ is too low for variational regularization.

Linear decoder (49 parameters) — An MLP decoder can learn a mean-output shortcut: memorize the HC population mean and output it regardless of $z$, achieving low reconstruction loss without $z$ carrying per-ROI information. A linear layer cannot learn this shortcut — it must use $z$ to reconstruct per-ROI variation.

Expanded reconstruction targets (7 features) — Reconstructing only $(a, \omega, \chi^2)$ allows the bottleneck to ignore connectivity structure. Adding PLV/MVAR-derived features forces $z$ to encode both dynamical and connectivity information per ROI. Only the physics features enter the anomaly score.

Node-level (not graph-level) bottleneck — Graph-level pooling into a single $z$ vector could be bypassed by the frozen encoder embeddings. Node-level bottleneck gives each ROI its own $z_j$, forcing per-ROI dynamical information through the bottleneck.

Concatenation $[𝐳_i | 𝐳_j]$ (not absolute difference) — Directed edges (MVAR) require asymmetric input: $[𝐳_i | 𝐳_j] \neq [𝐳_j | 𝐳_i]$. Absolute difference would destroy directionality information.

Feature-weighted reconstruction — Weights $[2, 1, 1, 0.5, 0.5, 0.5, 0.5]$ on the 7 reconstruction targets emphasize the physics features while still requiring accurate connectivity reconstruction.

Outlier threshold: HC mean $+ 6 \times$ SD — Sweeping from 3× to 10× revealed that aggressive thresholds exclude the majority of MDD subjects, while lenient thresholds exclude none. 6× SD removes only genuinely extreme values (1 subject: SA_E4051) while preserving maximum sample size.

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Key Results

Metric	Value	95% CI	UKF Reference
HC vs MDD separation	$d = +3.02$, $p = 7.3 \times 10^{-10}$	—	—
Permutation null (10,000)	$p < 0.0001$	—	—
HC holdout FP rate	0/36 (0.0%)	—	—
HC holdout vs MDD	$d = +2.28$	—	—
Overfitting check	$p = 0.875$	—	—
Seed robustness (10 runs)	$d = 2.91 \pm 0.12$ (CV 3.9%)	—	—
Whole-brain intervention	$d = +1.31$, FDR $p = 0.043^*$	$[0.38, 2.89]$	$d = -0.84$, $p = 0.080$
Circuit intervention	$d = +1.19$, FDR $p = 0.050^*$	$[0.33, 2.58]$	$d = -1.09$, $p = 0.027$
Limbic intervention	$d = +1.32$, FDR $p = 0.043^*$	$[0.55, 2.43]$	—
Subcortical intervention	$d = +1.61$, FDR $p = 0.042^*$	$[0.57, 3.98]$	—
Circuit enrichment (top-10)	2.19× (7/10), hypergeom $p = 0.013$	—	—
Circuit enrichment (top-15)	2.30× (11/15), hypergeom $p = 0.0008$	—	—
Circuit vs non-circuit	$d = +0.37$, $p = 0.023$	—	—
Heterogeneity (raw $a$, whole-brain)	$d = +1.33$, $p = 0.017$	—	$d = +1.01$, $p = 0.042$
Heterogeneity (raw $a$, circuit)	$d = +1.44$, $p = 0.008$	—	$d = +1.01$, $p = 0.042$
#1 anomalous ROI	RH Default PFCdPFCm	—	Converges with Ch. 5 cluster
#1 anomalous network	Limbic	—	—

All four intervention scales survive Benjamini-Hochberg FDR correction. Active group shows approximately stable anomaly (AWAY from HC), sham moves toward HC (decreased anomaly). Post-exclusion analysis: $n = 18$ MDD subjects (11 active, 7 sham).

Per-Feature Decomposition

Feature	Cohen's $d$	Direction
$\chi^2$ (model fit)	+6.07	MDD worse reconstructed
$a$ (bifurcation)	+5.91	MDD worse reconstructed
MVAR in-strength	+5.17	MDD worse reconstructed
MVAR out-strength	+4.93	MDD worse reconstructed
$\omega$ (frequency)	−1.76	MDD better reconstructed
PLV within-network	+1.43	MDD worse reconstructed
PLV node strength	+1.29	MDD worse reconstructed

The reversed sign on $\omega$ is theoretically predicted: MDD alters distance from the bifurcation point without necessarily shifting intrinsic oscillation frequency.

Top 10 Anomalous ROIs

Rank	ROI	Network	Circuit?
1	RH Default PFCdPFCm	Default Mode	✓
2	LH Limbic TempPole₁	Limbic	✓
3	LH Limbic TempPole₂	Limbic	✓
4	LH Default Temp₅	Default Mode	✓
5	LH Cont Cing₂	Frontoparietal
6	LH Default Par₁	Default Mode
7	RH SalVentAttn FrOperIns₁	Salience/VentAttn
8	NAcc-rh	Subcortical	✓
9	LH Default Temp₃	Default Mode	✓
10	RH Default PFCdPFCm₃	Default Mode	✓

Coupled vs Decoupled Ablation

Architecture	Trainable Params	HC–MDD $d$	Edge decoder input
Coupled (edge on $𝐳$)	586	+3.02	$[𝐳_i | 𝐳_j]$, dim 12
Decoupled (edge on $𝐡$)	1,882	+2.75	$|𝐡_i - 𝐡_j|$, dim 32

Coupled architecture achieves higher separation with 3.2× fewer trainable parameters.

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Upstream Dependencies

The Hopf-GAE consumes outputs from the R biophysical pipeline (SL-UKF_Neural_Criticality_MDD & · SL-UKF_Neural_Criticality_MDDvsHC):

Input	File	Format
Bifurcation parameters	results/v3/sl_stage1_results_216roi.csv	CSV (one row per ROI per subject per session)
PLV matrices	results/v3/plv/plv_all_216roi.rds	R list, keyed "subject_id|session"
MVAR matrices	results/v3/s2_mvar_all_216roi.rds	R list, keyed "subject_id|session"
HC comparison data	results/ch5_v4def/ch5_v4def_results.rds	R list

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Requirements

Python packages torch, torch_geometric, numpy, pandas, scipy, statsmodels, pyreadr, scikit-learn, matplotlib

Upstream (R pipeline) pracma, MASS, Matrix, dplyr, tidyr, ggplot2, scales, glmnet, igraph, parallel, zoo

System: Python ≥ 3.9 · PyTorch ≥ 2.0 · PyTorch Geometric ≥ 2.4 · R ≥ 4.2 (for upstream pipeline only)

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Quick Start

# 1. Ensure upstream pipeline has been run
# (github.com/skaraoglu/UKF-MDD)

# 2. Install Python dependencies
pip install torch torch_geometric pyreadr scikit-learn statsmodels

# 3. Run the full pipeline
jupyter execute main_analysis.ipynb

# Pipeline stages:
#   S1–S6:   Data loading, graph construction, quality control
#   S7–S10:  Synthetic pre-training (encoder, 100 epochs)
#   S11–S12: HC data loading + augmentation, GAE training (200 epochs)
#   S13:     Anomaly scoring (physics-only, z-scored against HC norms)
#   S14:     Statistical analysis (FDR, permutation tests, enrichment)

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Citation

If you use this architecture or build on this work, please cite:

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Built with PyTorch Geometric · Node dynamics from SL-UKF_Neural_Criticality_MDD · SL-UKF_Neural_Criticality_MDDvsHC· Parcellation: Schaefer 2018 + Melbourne Subcortex