Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample (n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes (‘biotypes’) defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82–93%) sensitivity and specificity for depression subtypes in multisite validation (n = 711) and out-of-sample replication (n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy (n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.

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Sensory stimuli undergoing sudden changes draw attention and preferentially enter our awareness. We used event-related functional magnetic-resonance imaging (fMRI) to identify brain regions responsive to changes in visual, auditory and tactile stimuli. Unimodally responsive areas included visual, auditory and somatosensory association cortex. Multimodally responsive areas comprised a right-lateralized network including the temporoparietal junction, inferior frontal gyrus, insula and left cingulate and supplementary motor areas. These results reveal a distributed, multimodal network for involuntary attention to events in the sensory environment. This network contains areas thought to underlie the P300 event-related potential and closely corresponds to the set of cortical regions damaged in patients with hemineglect syndromes.

Stimulus salience depends both on behavioral context and on other factors such as novelty and frequency of occurrence. The temporo-parietal junction (TPJ) responds preferentially to behaviorally relevant stimuli and is thought to play a general role in detecting salient stimuli. If so, it should respond preferentially to novel or infrequent events, even in a neutral behavioral context. To test this hypothesis, we used event-related functional magnetic resonance imaging (fMRI) to identify brain regions sensitive to the novelty of visual, auditory, and tactile stimuli during passive observation. Cortical regions with a greater response to novel than familiar stimuli across all modalities were identified at two sites in the TPJ region: the supramarginal gyrus (SMG) and superior temporal gyrus. The right inferior frontal gyrus (IFG), right anterior insula, left anterior cingulate cortex (ACC), and left inferior temporal gyrus also showed sensitivity to novelty. The novelty-sensitive TPJ activation in SMG overlaps a region previously identified as sensitive behavioral context. This region may play a general role in identifying salient stimuli, whether the salience is due to the current behavioral context or not. The IFG activation overlaps regions previously identified as responsive to nonnovel sensory events regardless of behavioral context. The IFG may therefore play a general role in stimulus evaluation rather than a specific role in identifying novel stimuli. The ACC activation lies in a region active during complex response-selection tasks, suggesting a general role in detecting and/or planning responses to salient events. A frontal-parietal-cingulate network may serve to identify and evaluate salient sensory stimuli in general.