Hippocampus-first and memory-first: data-driven multiscale progression subtypes across the mental health spectrum

<p>Background: Mental disorders involve interacting disturbances across biological, psychological, and social scales. Our group previously proposed a multiscale model of psychosis in which hippocampal-cortical dysconnectivity contributes to episodic memory deficits, negative symptoms, and poorer functioning, with machine-learning work identifying hippocampus-first and memory-first progression subtypes. Here, we tested whether analogous subtypes involving hippocampal-cortical connectivity, verbal memory, anhedonia, and social functioning emerge transdiagnostically across the mental health spectrum. Methods: We applied Subtype and Stage Inference (SuStaIn), combining clustering and disease progression modeling, to a UK Biobank subsample (N=3785), including adults with lifetime ICD-10 psychiatric diagnoses (n = 1859) and matched controls (n = 1926). Markers included bilateral resting-state functional hippocampal-cortical connectivity, verbal memory, anhedonia, and social visits, a structural index of social connection. Model fit was evaluated using 3-fold cross-validation across 1- to 4- subtype solutions. Results: Cross-validation showed the largest fit improvement from one to two disease subtypes, which were retained as the primary solution. Stage-0 individuals formed a normative group (Subtype 0; n = 2500). Subtype 1 (n=607) followed a hippocampus-first pattern, progressing from hippocampal-cortical dysconnectivity to reduced social functioning, verbal memory impairment, and anhedonia. Subtype 2 (n=678) followed a memory-first pattern, beginning with verbal memory deficits, followed by anhedonia, reduced social functioning, hippocampal-cortical dysconnectivity, and more severe memory impairment. Subtype 2 showed higher diagnostic prevalence, comorbidity, and socioeconomic deprivation. Conclusions: These findings suggest hippocampus-first and memory-first multiscale progression patterns extend beyond psychosis across diagnosed and non-diagnosed individuals, supporting a dimensional and transdiagnostic account of multiscale psychiatric vulnerability.</p>