Evidence from epidemiological studies in Northern Hemisphere countries has consistently suggested that a relationship exists between birth seasons and the risk of mental disorders (1), with the risk of developing schizophrenia (Sz) and related disorders being approximately 5-10% higher for winter/spring births (2, 3). Vitamin D deficiency or gestational exposure to infection and the associated inflammatory response during winter may increase susceptibility to Sz by affecting prenatal neurodevelopment, such as synapse formation and interneuron migration (4–6). However, previous magnetic resonance imaging (MRI) studies failed to detect a significant effect of birth seasons on ventricular (3) or hippocampal (7) volumes or various neurodevelopmental markers (e.g., gross gyral patterns in the orbitofrontal and insular regions) (8) that are characteristic of Sz. Nevertheless, a more comprehensive brain assessment, particularly of brain characteristics closely reflecting early neurodevelopment, such as whole-brain cortical gyrification patterns (9, 10), may provide more detailed insights into the effects of birth seasons on the brain morphology of patients with the Sz spectrum.

MRI studies on Sz and schizotypal (SzTypal) disorder, often described as a milder form within the Sz spectrum (11, 12), revealed shared brain characteristics, such as increased gyrification in the fronto- parietal regions (13) and a reduction in cortical thickness in the medial temporal and frontal regions (14), potentially reflecting a common vulnerability to psychopathology. While the cortical volume or thickness may be significantly affected by various factors after birth (e.g., antipsychotic medication and an active brain pathology during the early stages of Sz) (15), the cortical gyrification pattern is considered to mainly be formed during gestation and remains stable after birth (16, 17). Therefore, changes in cortical gyrification commonly observed in the Sz spectrum may more closely reflect an early neurodevelopmental pathology (including the disruption of neural development associated with seasonality) (10). While human cortical folding is likely to be more genetically mediated compared to other surface characteristics (e.g., curvature, cortical thickness or volume, and surface area), higher order sulci formed during late embryonic period are reported to be less heritable and more influenced by environmental factors than ontologically older sulci (18). However, to the best of our knowledge, the potential effects of birth seasons on the comprehensive surface morphology in patients with the Sz spectrum have not yet been examined using MRI.

Therefore, the present MRI study aimed to expand our preliminary negative study of selected brain regions (8) by using whole-brain cortical surface morphometrics, particularly the local gyrification index (LGI). We predicted that increased brain gyrification in the Sz spectrum (13) would be more pronounced in winter-born patients than in summer-born patients due to potential adverse effects associated with a winter birth on neurodevelopment in utero (4, 6). We also examined cortical thickness, a representative parameter of focal gray matter changes among the parameters in the surface-based approach (e.g., volume, area) (14, 19), but predicted a weaker relationship with respect to birth seasons due to various potential confounding factors during the course of illness.

To the best of our knowledge, this is the first MRI study using whole-brain surface-based morphometry that revealed significant relationships between brain morphological changes and birth seasons in patients with Sz and SzTypal disorder. Winter-born patients with Sz, particularly those in the first-episode subgroup, were characterized by a higher LGI in diverse cortical regions than that in summer-born patients with Sz. This effect of birth seasons on gyrification remained significant when patient groups (Sz and SzTypal) were categorized together as a whole Sz spectrum group. We found no significant effect of birth seasons on cortical thickness in the Sz or SzTypal group; however, the right superior frontal region was thinner in winter-born patients than in summer-born patients in the whole Sz spectrum group. Therefore, the present results suggest that the brain morphological characteristics of the Sz spectrum, particularly the widespread hyper-gyrification pattern, are more evident in winter-born than in summer-born patients, which supports the role of the disruption of neural development associated with birth seasons on the pathophysiology of the Sz spectrum.

The present whole-brain cortical surface analysis supports our previous hypothesis that winter-born patients with Sz spectrum disorders show greater brain changes, particularly increased brain gyrification, than summer-born patients. The present structural MRI study cannot address the mechanisms underlying the relationship between winter-born and brain hyper-gyrification in our sample; nevertheless, evidence from immunological (36, 37) and animal (38) studies have suggested that prenatal environmental factors associated with winter, such as maternal vitamin D deficiency (5) or infection (e.g., influenza, toxoplasmosis, and meningococcal disease) (3), may disrupt synapse formation and interneuron migration during prenatal neurodevelopment due to inflammatory and immune reactions (4, 6, 39). Neuroimaging evidence has also supported the relationship between brain dysconnectivity and hyper-gyrification in Sz, which may underlie various clinical symptoms and cognitive performance of the patients (10).

In the present study, the effects of seasonality on brain gyrification were more pronounced in Sz than in SzTypal disorder, a milder form within the Sz spectrum (12), supporting greater and/or more prolonged neurodevelopmental deviations potentially leading to the overt and sustained psychosis observed in full-blown Sz (40). We have previously reported in the current sample (13) that both Sz and SzTypal patients exhibited a significantly higher LGI in diverse cortical regions, particularly in the frontal and temporo-limbic regions as well as parietal cortex, as compared with controls, but its extent was broader in Sz especially for the right prefrontal and left occipital regions. The brain regions with hyper-gyrification in winter-born patients( Figures 1 , 2 ) were largely overlapping with those brain regions. However, the lack of a significant effect of birth seasonality on prefrontal gyrification, which was previously shown to be markedly increased in Sz spectrum patients (13) and related to executive dysfunction in first-episode Sz (41), may reflect regional specificity in the trajectories of gyral formation; cortical folding predominantly occurs during gestation (17), whereas brain surface morphology may be partly affected by a late brain maturation process during adolescence particularly in the frontal region (42), which is considered to be changed in Sz (43–45) but may be largely unaffected by the birth season.

In contrast to the present results supporting epidemiological findings that link winter-born and the risk of Sz, the majority of MRI studies failed to detect a significant effect of winter-born on brain changes characteristic to Sz. As reviewed by Torrey et al. (3), earlier results of the relationship between birth seasons and ventricular sizes in Sz have been decidedly contradictory. In contrast to the findings of animal studies showing that pre- and perinatal inflammation induced changes in the histology of the hippocampus (46) or the maldevelopment of white matter (47), human MRI studies revealed the contribution of ‘summer’ births to a smaller hippocampal volume in a combined sample of Sz, depression, and HC subjects (7) or to the widespread disruption of the integrity of white matter in Sz (20). Further, our previous study using a partially overlapping Sz spectrum sample (8) identified insular hypergyria, which is a common brain characteristic of the Sz spectrum (23), in summer-born subjects irrespective of their diagnosis (i.e., Sz, SzTypal, and HC). Although these MRI findings appear to reflect environmental risk factors associated with winter in the early gestation stages in summer-born subjects, this hypothesis does not explain the established epidemiological findings of the increased risk of Sz in winter-born subjects. On the other hand, maternal infection during the second trimester, but not the first or third trimester, was also shown to increase the risk of Sz (48). Therefore, the actual timing of seasonal factors on brain development associated with the risk of Sz remains unclear (3) and warrants further study in a more integrated manner.

As predicted, birth seasons did not significantly affect cortical thickness in the Sz or SzTypal group; we only found a small cluster in the right superior frontal region where winter-born patients had thinner gray matter than summer-born patients when both patient groups were combined. Based on cortical thinning in diverse fronto-temporal regions in our Sz and SzTypal patients relative to HC subjects (14), the present results indicate that cortical thickness is not a useful measure for assessing the potential role of early environmental factors associated with birth seasonality in the pathophysiology of the Sz spectrum. This may be due to various factors that affect gray matter volume/thickness after birth, such as active reductions in gray matter around the onset of psychosis in Sz (15).

There are potential confounding factors that need to be considered. While brain gyrification is considered to better reflect early neurodevelopment than cortical thickness/volume as a stable biomarker of psychosis (44, 45), it is not entirely unaffected by disease chronicity or antipsychotic medication (49). Since the present patient groups had received antipsychotic medication for substantial periods ( Table 1 ), even the first-episode Sz subgroup [mean dose = 10.3 ± 8.8 mg/day (haloperidol equivalent), duration = 7.7 ± 12.2 months], further studies on patients with antipsychotic-naïve and/or in earlier illness stages (e.g., clinical high risk for psychosis) are required to reduce these confounding factors (50, 51). Furthermore, although the present study screened for severe obstetric complications (e.g., fetal distress), more detailed clinical information (e.g., birth weeks, birth weight, pre-/perinatal infections, prenatal smoking exposure, and maternal vitamin D deficiency) on participants will be required to provide more detailed insights into the mechanisms responsible for the established epidemiological finding of birth seasonality in the Sz spectrum. Information on smoking habits of the study participants, which could also affect brain morphology (52), was also unavailable. It should be also noted that the HC group was not balanced for the season of birth as compared with patient groups (i.e., trend towards higher winter-born rate). This did not affect our main finding that birth seasons had a significant effect on brain morphology in the Sz spectrum, but their general role in normal brain development should be further tested in a larger and well-balanced healthy cohort. Moreover, we divided participants into the summer- and winter-born groups, as described in previous studies (7, 8, 20); however, several epidemiological studies examined the relationship between birth seasons and the risk of Sz using a more detailed classification based on the four seasons or birth months (2). However, the present study was considered underpowered to examine brain changes using such a detailed classification due to the small number of participants and the comprehensive nature of the brain assessment. In addition, birth season-by-diagnosis interaction on brain morphology was detected only at a relatively liberal threshold of uncorrected p < 0.01, which may be also due to the small sample size. Finally, because the relationship between birth seasonality and the risk of illness has also been reported in other neuropsychiatric disorders (e.g., bipolar disorder) (1, 53), the disease specificity of the present results needs to be tested in future.

In conclusion, the present MRI study expanded our previous findings on the Sz spectrum in demonstrating that seasonal birth significantly contributed to brain morphological changes in the patient group, particularly increased gyrification in diverse cortical regions (13). The present results appear to provide support for the relationship between winter-born and the increased risk of the Sz spectrum (2, 3), where the disruption of neural development may occur due to environmental factors associated with seasonality in utero. Further studies on a larger transdiagnostic sample in combination with more detailed clinical data (e.g., obstetric complications and maternal viral infection) and immune biomarkers are needed to clarify the relationship between pre-/perinatal environmental factors and the risk of neuropsychiatric disorders.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Committee of Medical Ethics of the University of Toyama. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin.

MT: Formal Analysis, Investigation, Methodology, Resources, Writing – original draft, Writing – review & editing. TT: Conceptualization, Funding acquisition, Investigation, Methodology, Resources, Supervision, Writing – review & editing. YT: Formal Analysis, Investigation, Methodology, Resources, Supervision, Validation, Writing – review & editing. DS: Formal Analysis, Funding acquisition, Methodology, Resources, Supervision, Validation, Writing – review & editing. HK: Resources, Writing – review & editing. KS: Resources, Writing – review & editing. YY: Resources, Writing – review & editing. NT: Funding acquisition, Writing – review & editing. KN: Methodology, Supervision, Writing – review & editing. MS: Conceptualization, Funding acquisition, Supervision, Writing – review & editing.