Panic disorder (PD), which affects approximately 4% of the global population, is a major psychiatric condition characterized by recurrent panic attacks and marked behavioral changes [1]. Although its etiology remains incompletely understood, PD is believed to have a multifactorial origin, with early traumatic experiences in childhood potentially contributing to its development [2]. Although the etiopathological relationship between early trauma (ET) and PD is not yet fully clarified, previous studies have suggested that ET may trigger chronic stress responses that disrupt brain development during developmental periods and, consequently, increase vulnerability to PD in adulthood [3,4].

Although information on this etiopathological link remains limited, structural and functional neuroimaging studies have demonstrated that a history of ET can alter both brain structure and function, thereby heightening susceptibility to PD. Specifically, one functional neuroimaging study found that childhood trauma was associated with altered resting-state functional connectivity within the fear network model in patients with PD [5]. In addition, a structural neuroimaging study identified an association between ET and alterations in the fornix body among patients with PD [6]. Moreover, another study reported an interaction effect on cortical thickness in the insula and pars triangularis when considering the combined impact of PD diagnosis and ET exposure [7]. Given that both functional connectivity5 and white matter structures6 have been reported as neurobiological correlates of ET in PD, it remains unclear whether cortical gyrification reflects ET-related alterations in this disorder.

Cortical gyrification, quantified by the local gyrification index (LGI), reflects higher-order cortical folding and has been associated with other structural characteristics of the brain, including cortical thickness [8] and connectivity [9]. Alterations in cortical gyrification have been implicated in various anxiety disorders, such as PD [10] and generalized anxiety disorder [11]. Gyrification begins in the prenatal stage and continues to develop throughout early life. Gyri form as regions with greater neural connectivity move closer together, whereas sulci develop as regions with weaker connectivity diverge [9]. Earlier, gyrification patterns were thought to be largely established during early development; however, recent studies suggest that environmental factors during childhood and adolescence can meaningfully influence these patterns [9]. Accordingly, ET, as an environmental factor, may also affect gyrification. Because gyrification is considered a relatively stable neurodevelopmental marker, examining its interaction with ET exposure and PD diagnosis may provide valuable insights into neurodevelopmental vulnerabilities and inform early intervention approaches.

The effects of ET on cortical gyrification in adolescents have produced inconsistent results. For example, one study reported reduced gyrification in the lingual gyrus, insula, and pars opercularis among maltreated individuals [12], whereas another study found increased LGI in the superior parietal lobule (SPL) of the left hemisphere [13]. These discrepancies may stem from differences in the types of ET experienced by participants across studies, with the former involving more cases of physical abuse than the latter. Furthermore, comparisons between patients with PD and healthy controls (HCs) revealed significant gyrification differences, characterized by reductions in lateral cortical regions and increases in posteromedial areas [10]. Given the established evidence that ET can modify brain structure and enhance vulnerability to PD, it is plausible that ET induces gyrification changes that contribute to PD development.

The combined influence of childhood abuse and PD on cortical gyrification has not been extensively investigated. This study aims to enhance understanding of how ET contributes to the pathophysiology of PD through alterations in cortical gyrification. We hypothesize that individuals with a history of ET will display distinct gyrification patterns in PD compared with HCs. Furthermore, we hypothesize that gyrification in specific cortical regions will correlate with anxiety-related scale scores, thereby clarifying the interrelationship among ET, PD, and cortical gyrification.

To the best of our knowledge, this is the first study to investigate the interaction effects of PD diagnosis and ET exposure on cortical gyrification patterns. Specifically, our findings revealed a significant interaction between PD diagnosis and ET exposure in the SPL. Patients with PD who had experienced ET showed greater cortical gyrification in the SPL than those without ET exposure. In contrast, HCs without ET exposure exhibited higher SPL gyrification than ET-exposed HCs. Furthermore, our result implies that greater SPL gyrification might be associated with higher levels of anxiety symptom severity, including panic symptom severity and intolerance of uncertainty, across participants.

Differences in cortical gyrification patterns observed in neuropsychiatric disorders may reflect dysregulated or immature cortical organization and connectivity [30]. Although earlier research regarded gyrification primarily as a reflection of early developmental and genetic influences [31], more recent evidence suggests that gyrification can continue to change throughout adolescence and adulthood [32]. Among various developmental influences, ET has been particularly associated with alterations in cortical gyrification. For instance, one study demonstrated hypogyrification in the lingual gyrus and insula of children who had experienced maltreatment [12].

In patients with PD, previous studies have reported hypogyrification in the lateral brain regions extending from the frontoparietal to temporal areas and hypergyrification in the posteromedial cortical regions compared with HC [10]. The observed hypergyrification in posteromedial regions has been interpreted as a compensatory mechanism for managing panic symptoms in PD [10]. Moreover, another study found that individuals in the early stages of schizophrenia, mood disorders, and autism spectrum disorder exhibited increased LGI, which later declined by mid-adulthood. This pattern suggests that hypergyrification may represent a transient, stage-dependent alteration occurring during the early phase of illness [30]. Therefore, given the established association between gyrification and cortical connectivity [33], our finding of altered SPL gyrification may indicate abnormalities in connectivity between the SPL and related neural networks.

Previous research on adults with a history of childhood trauma but without neuropsychiatric disorders has reported a negative association between childhood abuse history and both gray matter volume and cortical surface area in the SPL [34]. This study on ET in HCs supports our present findings, as ET-exposed HCs exhibited hypogyrification in the SPL compared with unexposed HCs. Our results revealed distinct SPL gyrification patterns between patients with PD and HCs. In conjunction with a previous study demonstrating an interaction between PD diagnosis and ET exposure on cortical thickness [7], our findings support the notion that ET may exert unique neurodevelopmental effects on individuals with a pre-existing vulnerability to PD.

The SPL, located within the parietal cortex, is involved in visuospatial integration, attentional shifting, and interoceptive processing [35,36]. Individuals exposed to ET consistently exhibited heightened vigilance toward bodily and environmental cues [35,36], which may increase demands on neural systems responsible for integrating visuospatial signals with spatial attention. In this context, the SPL may represent a critical neural substrate underlying the PD diagnosis-by-ET interactions. Furthermore, interoceptive processing appears to be a key mechanism linking SPL function to PD vulnerability. Previous neuroimaging studies have demonstrated that patients with PD show increased SPL activation in response to interoceptive stimuli than HCs, reflecting heightened attentional engagement with and monitoring of internal bodily signals. This altered interoceptive-attentional state may contribute to exaggerated threat interpretations of ambiguous bodily sensations, a core feature of PD. Collectively, given its integrative role across visuospatial processing, attentional shifting, and interoception, the SPL may exhibit compensatory hypergyrification in individuals vulnerable to PD following ET exposure.

Previous studies have demonstrated associations between structural alterations in the superior parietal region and anxiety disorders [11,37,38]. Specifically, patients with generalized anxiety disorder exhibited hypergyrification in the superior parietal region compared with HCs [11]. In patients with PD, altered activation of the bilateral SPL during both interoceptive and exteroceptive perception has also been reported compared with HCs [38].

ET can exert lasting adverse effects on psychological and behavioral functioning, potentially leading to various anxiety disorders [39,40]. Evidence suggests that ET may influence brain structure in patients with PD by increasing resting-state functional connectivity between the insula and thalamus and the parietal and temporal lobes [5]. Prior research has consistently shown that PD is strongly associated with a history of ET [41]. Considering the evidence that ET can alter brain structure in PD [5], it is plausible that ET specifically affects brain morphology in the SPL, thereby heightening vulnerability to PD.

Our study demonstrated that the interaction between PD diagnosis and ET exposure influenced cortical gyrification in the gyrus portion of the SPL and revealed significant correlations between SPL gyrification and both PDSS and IUS scores. Whereas previous literature has reported correlations between LGI values in the posterior cingulate cortex and precuneus and panic symptom severity [10], our findings suggest the possibility of the association of the hypergyrification of the SPL is associated with both panic symptom severity and intolerance of uncertainty.

We propose a neurodevelopmental model of vulnerability to PD, building upon previous studies showing that individuals with high intolerance of uncertainty tend to interpret ambiguous interoceptive signals as threatening [42], and that such ambiguous interoceptive stimuli are particularly likely to be perceived as anxiety-related in patients with PD [43]. The observed crossover interaction suggests that ET may lead to divergent neurodevelopmental outcomes depending on an individual’s underlying vulnerability to PD.

One plausible interpretation of the observed hypogyrification in ET-exposed HCs is that it reflects an adaptive neurodevelopmental process, such as experience-dependent synaptic pruning or accelerated cortical maturation. Previous studies have reported that early adversity may be associated with region-specific reductions in cortical complexity, potentially reflecting neural adaptation rather than pathological disruption of development [12]. In HCs, ET may promote more efficient pruning of neural circuits involved in visuospatial integration and attentional allocation within the SPL, thereby reducing cortical folding and potentially increasing neural efficiency. This adaptive pruning process may confer resilience against maladaptive hypervigilance and excessive interoceptive monitoring [35].

In contrast, while ET may be associated with hypogyrification in HCs, it may exert different neurodevelopmental effects on individuals predisposed to PD, as reflected by the observed hypergyrification of the SPL. We hypothesize that hypergyrification of the SPL may represent a neural substrate underlying dysregulated interoceptive awareness in individuals susceptible to PD, a notion supported by previous findings of increased activation in superior parietal regions during interoceptive perception in patients with PD [40]. This altered interoceptive state, when combined with heightened intolerance of uncertainty, may precipitate the development of PD. Our findings suggest that ET may result in distinct patterns of brain structural alterations in individuals vulnerable to PD compared with those without such susceptibility.

These findings carry several clinical implications. First, ETrelated alterations in SPL gyrification may serve as a potential neuroimaging biomarker for identifying individuals at heightened risk of developing PD following early adversity. Second, although SSRI medication dosages did not differ significantly between groups, and sensitivity analysis excluding participants with high benzodiazepine and SSRI medication doses was conducted, the use of other psychotropic medications may have differed in treatment duration, dosage, or medication history, thereby potentially influencing brain structure. Third, differences in ET subtypes across studies may contribute to inconsistencies in the brain regions associated with ET or PD compared with previous studies [10,12]. However, our results underscore the importance of ET-informed approaches in the assessment and treatment of PD, as the neurobiological impact of ET appears to differ fundamentally between individuals who develop PD and those who do not. Fourth, ET exposure was assessed using the self-report-based ETISR-SF and operationally defined using a binary classification of the presence or absence of ET. Retrospective self-reported measures may be subject to recall bias and may not fully capture the complexity or accuracy of past traumatic experiences. Additionally, defining ET exposure based on endorsement of a single item represents a relatively inclusive threshold and does not account for differences in trauma type or severity. These methodological factors may have influenced the classification of ET exposure and the interpretation of the findings. Future studies with larger samples and prospective designs are needed to examine trauma type- specific and severity-dependent effects to improve the robustness and interpretability of results. Fifth, because SPL hypergyrification may reflect dysregulated interoceptive processing driven by intolerance of uncertainty, patients with PD who have a history of ET may particularly benefit from therapeutic interventions targeting intolerance of uncertainty and interoceptive dysregulation, such as cognitive-behavioral therapy or interoceptive exposure.

In conclusion, our findings indicate that ET exerts distinct effects on brain structure in patients with PD compared with HCs, particularly in the gyrus portion of the SPL. These results suggest that ET may influence neurodevelopmental processes by altering the gyrification pattern of the SPL, thereby increasing vulnerability to PD.