Neuroanatomical Correlates of Negative Symptoms in Schizophrenia

Kamalakannan, S. M. V.; Male, A. G.; Yilanli, M.; Lella, A.; Lee, J.; Quide, Y.; Green, M. J.; Cairns, M. J.; Carr, V. J.; Catts, S.; Henskens, F. A.; Jablensky, A.; Loughland, C.; Michie, P.; Mowry, B.; Pantelis, C.; Shall, U.; Scott, R. J.; Belger, A.; Bustillo, J.; Lim, K.; Ford, J. M.; Mathalon, D. H.; Preda, A.; Mueller, B.; Potkin, S. G.; Satterhwaite, T. D.; Gur, R. C.; Gur, R. E.; Banaj, N.; Vecchio, D.; Piras, F.; Ehrlich, S.; Bernardoni, F.; Borgwardt, S.; Cobia, D.; Alpert, K.; Wang, L.; Agartz, I.; Jonsson, E. G.; Kaiser, S.; Clotet, E. P.; Salvador, R.; Jaramillo, C. L.

doi:10.1101/2025.09.22.677864

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bioRxiv · 10.1101/2025.09.22.677864

Neuroanatomical Correlates of Negative Symptoms in Schizophrenia

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Abstract

BackgroundSchizophrenia is characterized by widespread structural brain abnormalities, but associations between structural abnormalities and negative symptom severity are not well understood. Negative symptoms have been conceptualized in a hierarchical structure of two second-order dimensions--motivation and pleasure (MAP) and expression (EXP)--and five first-order domains: anhedonia, avolition, and asociality (MAP), and blunted affect and alogia (EXP). A better understanding of the neural circuitry underlying negative symptom dimensions and domains is important given their reported association with poor functional outcome and lack of available treatments. Study DesignThe meta-analysis included 1,591 individuals with schizophrenia across 16 samples with structural imaging and Scale for Assessment of Negative Symptoms data. The study generated correlations of cortical thickness and subcortical volumes with the negative symptom dimensions and domains. Study resultsNegative symptoms showed mainly negative associations with cortical thickness and subcortical volumes. The effect sizes were small but there was a pattern of associations in predominantly frontal lobe cortical thickness and limbic subcortical volumes. The regional correlation patterns of cortical thickness and subcortical volumes with symptom domains support the conceptualized hierarchical structure of negative symptoms: correlations of MAP domains were stronger with the MAP than EXP dimension, and vice versa. Exploratory analyses with receptor densities further supported the hierarchy. ConclusionOur findings reveal small but consistent associations between negative symptom dimensions and predominantly prefrontal region cortical thickness, and limbic region volumes. These findings advance our understanding of the network of anatomical regions that may contribute to the severity of negative symptoms in schizophrenia.

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Kamalakannan, S. M. V., Male, A. G., Yilanli, M., Lella, A., Lee, J., Quide, Y., Green, M. J., Cairns, M. J., Carr, V. J., Catts, S., Henskens, F. A., Jablensky, A., Loughland, C., Michie, P., Mowry, B., Pantelis, C., Shall, U., Scott, R. J., Belger, A., Bustillo, J., Lim, K., Ford, J. M., Mathalon, D. H., Preda, A., Mueller, B., Potkin, S. G., Satterhwaite, T. D., Gur, R. C., Gur, R. E., Banaj, N., Vecchio, D., Piras, F., Ehrlich, S., Bernardoni, F., Borgwardt, S., Cobia, D., Alpert, K., Wang, L., Agartz, I., Jonsson, E. G., Kaiser, S., Clotet, E. P., Salvador, R., Jaramillo, C. L.. 2025-09-23. Neuroanatomical Correlates of Negative Symptoms in Schizophrenia. https://doi.org/10.1101/2025.09.22.677864

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