A systematic review and meta-analysis proposed a neuropathway for schizophrenia that could potentially be used as a diagnostic tool for deficits in social cognition. These findings were published in Neuroscience and Biobehavioral Reviews.

Investigators from The Hong Kong Polytechnic University searched publication databases through January 2021 for studies of neuroimaging analyses among patients with schizophrenia and healthy controls. Differences in brain region activation while performing a Theory of Mind (ToM) task were synthesized using a seed-based d mapping approach to generate a potential neuropathway.

A total of 25 studies comprising 427 patients with schizophrenia and 405 healthy controls were reviewed. The patients and controls were aged mean 33.17 (SD, 8.21) and 32.01 (SD, 7.25) years, respectively.

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Among the schizophrenia cohort, patients had been diagnosed an average of 8.90 (SD, 8.31) years previously and most were taking antipsychotics.

The studies used functional magnetic resonance imaging or positron emission tomography scans to investigate neural activation during a total of 15 ToM tasks.

After correction, the schizophrenia cohort was found to have hypoactivation in the left superior frontal gyrus compared with controls (P <.005).

In general, during the ToM tasks, the schizophrenia cohort had 8 significant clusters compared with 8 differing clusters among the controls. During the affective processing of the ToM tasks, the schizophrenia cohort had 4 significant clusters compared with 6 among the controls. For the cognitive processing of the ToM tasks, the schizophrenia and control cohorts had 8 and 8 significant clusters, respectively.

On the basis of this pattern, the study authors proposed a neuropathway of ToM tasks in schizophrenia which starts at the left calcarine fissure. The signals are simultaneously transferred to the left and right inferior occipital gyrus and right and bilateral middle occipital gyrus.

Visual signals are then transferred through the dorsal stream to the bilateral middle temporal gyrus. Information is continuously processed from the middle temporal gyrus to the right parahippocampal gyrus and left and right inferior frontal gyrus. Information is exchanged between the right parahippocampal gyrus and bilateral superior frontal gyrus with the left middle frontal gyrus and right and left inferior frontal gyrus.

The study investigators also proposed a model for healthy control processing.

This study may have been limited by not evaluating data from patients on and off medication separately.

The study authors concluded, “Our hypothesized neuropathways during ToM tasks provide valuable initial evidence for a better understanding of social cognitive deficits in schizophrenia in a comprehensive and dynamic approach, and permit the exploration of diagnostic tools and cost-effective treatment. Electrophysiological techniques examining real-time neural activation during ToM tasks can be considered to test and verify our hypothesized neuropathways in patients with schizophrenia using neuroimaging techniques such as electroencephalography and functional near-infrared spectroscopy.”


Weng Y, Lin J, Ahorsu DK, Tsang HWH. Neuropathways of theory of mind in schizophrenia: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2022;104625. doi:10.1016/j.neubiorev.2022.104625