Generative Embedding for Model-Based Classification of fMRI Data

Decoding models, such as those underlying multivariate classification algorithms, have been increasingly used to infer cognitive or clinical brain states from measures of brain activity obtained by functional magnetic resonance imaging (fMRI). The practicality of current classifiers, however, is restricted by two major challenges. First, due to the high data dimensionality and low sample size, algorithms struggle to separate informative from uninformative features, resulting in poor generalization performance. Second, popular discriminative methods such as support vector machines (SVMs) rarely afford mechanistic interpretability. In this paper, we address these issues by proposing a novel generative-embedding approach that incorporates neurobiologically interpretable generative models into discriminative classifiers. Our approach extends previous work on trial-by-trial classification for electrophysiological recordings to subject-by-subject classification for fMRI and offers two key advantages over conventional methods: it may provide more accurate predictions by exploiting discriminative information encoded in ‘hidden’ physiological quantities such as synaptic connection strengths; and it affords mechanistic interpretability of clinical classifications. Here, we introduce generative embedding for fMRI using a combination of dynamic causal models (DCMs) and SVMs. We propose a general procedure of DCM-based generative embedding for subject-wise classification, provide a concrete implementation, and suggest good-practice guidelines for unbiased application of generative embedding in the context of fMRI. We illustrate the utility of our approach by a clinical example in which we classify moderately aphasic patients and healthy controls using a DCM of thalamo-temporal regions during speech processing. Generative embedding achieves a near-perfect balanced classification accuracy of 98% and significantly outperforms conventional activation-based and correlation-based methods. This example demonstrates how disease states can be detected with very high accuracy and, at the same time, be interpreted mechanistically in terms of abnormalities in connectivity. We envisage that future applications of generative embedding may provide crucial advances in dissecting spectrum disorders into physiologically more well-defined subgroups. Author Summary: Neurological and psychiatric spectrum disorders are typically defined in terms of particular symptom sets, despite increasing evidence that the same symptom may be caused by very different pathologies. Pathophysiological classification and effective treatment of such disorders will increasingly require a mechanistic understanding of inter-individual differences and clinical tools for making accurate diagnostic inference in individual patients. Previous classification studies have shown that functional magnetic resonance imaging (fMRI) can be used to differentiate between healthy controls and neurological or psychiatric patients. However, these studies are typically based on descriptive patterns and indirect measures of neural activity, and they rarely afford mechanistic insights into the underlying condition. In this paper, we address this challenge by proposing a classification approach that rests on a model of brain function and exploits the rich discriminative information encoded in directed interregional connection strengths. Based on an fMRI dataset acquired from moderately aphasic patients and healthy controls, we illustrate that our approach enables more accurate classification and deeper mechanistic insights about disease processes than conventional classification methods.