# RACF: A Multimodal Deep Learning Framework for Parkinson's Disease Diagnosis Using SNP and MRI Data
## 4 Discussion
### Biological Validation from Genetic and Imaging Perspectives
#### 4.2.2 Imaging Analysis  
The imaging explainability analysis in this study, conducted using the Grad-CAM technique, revealed key brain regions that the model focuses on in sMRI images (Figure 5). The results show that the regions most significantly activated by the model are concentrated in the basal ganglia (particularly the caudate nucleus and globus pallidus) and the substantia nigra pars compacta. These regions exhibit pathological changes that are highly consistent with the core pathological mechanisms of PD, further validating the biological plausibility of the RACF model's localized predictions. A deeper analysis of the brain regions identified by the model is presented below, considering typical pathological features and imaging findings in PD.  
The basal ganglia are a central component of the cortical-basal ganglia-thalamic circuit, and their dysfunction directly leads to PD motor symptoms, such as bradykinesia and tremor [36]. In this study, the model's strong focus on the caudate nucleus and globus pallidus (Figure 5) is closely associated with the significant reduction of dopaminergic input to the basal ganglia in PD patients. The caudate nucleus, as part of the striatum, receives dopaminergic projections from the substantia nigra pars compacta, and its volume reduction and decreased metabolism have been confirmed as early markers of PD in multiple imaging studies [37]. For example, studies using Diffusion Tensor Imaging (DTI) have shown that PD patients exhibit a significant decline in white matter integrity in the caudate nucleus, which correlates negatively with UPDRS motor scores [38]. The globus pallidus, as an output nucleus of the basal ganglia, may become over-activated and exacerbate motor dysfunction by inhibiting the thalamocortical pathway. This phenomenon is reflected in resting-state functional MRI (fMRI) studies, where increased functional connectivity between the globus pallidus and motor cortex has been observed in PD patients [39]. The findings of the model align with these previous observations, suggesting that RACF is capable of capturing the critical contributions of structural and functional abnormalities in the basal ganglia to PD diagnosis.  
The progressive loss of dopaminergic neurons in the substantia nigra pars compacta is the most prominent pathological feature of PD [4]. The activation observed in the substantia nigra by the model (Figure 5) is directly associated with increased iron deposition and volume shrinkage in this region in PD patients. Quantitative Susceptibility Mapping (QSM) analysis has shown that the magnetic susceptibility values in the substantia nigra of PD patients are approximately 30% higher than in healthy controls, and this increase is significantly correlated with disease severity [40]. Furthermore, ultrastructural changes in the substantia nigra, such as the reduction of neuromelanin, can be detected by neuromelanin-sensitive MRI (NM-MRI), with signal intensity reductions corresponding to the early pathological stages in the Braak staging system [41]. The model's focus on the substantia nigra may reflect its sensitivity to neurodegenerative changes, which aligns with post-mortem studies showing that dopaminergic neuron loss in the substantia nigra can reach 45% in PD patients [42].  
The results from the imaging analysis in this study have significant clinical translational potential. First, the model's specific focus on the basal ganglia and substantia nigra could provide imaging targets for the early diagnosis of PD. For example, combining measurements of substantia nigra volume (using tools such as FreeSurfer) with functional connectivity analysis of the caudate nucleus could lead to the development of more sensitive PD diagnostic models [43]. Second, dynamic changes in these regions could serve as biomarkers for disease progression. Longitudinal studies have shown that the degree of atrophy in the caudate nucleus of PD patients is significantly higher than that of healthy controls [44].