Massive disasters could lead to substantial rises in mental health problems, both in the immediate aftermath and persisting over extended durations (1, 2). COVID-19, as a natural disaster, often causes widespread mental health issues (3). It represents a novel form of traumatic event with profound mental health repercussions, including the development of post-traumatic stress disorder (PTSD) and general psychological distress (e.g., depression, anxiety, and stress) (4). Specifically, one month after the COVID-19 outbreak, the prevalence of acute PTSD symptoms among the Chinese public was 4.6% (5). After one year of the COVID-19 pandemic, the prevalence of PTSD symptoms among Chinese residents rose to 9.28% (6). In critically ill survivors, this figure is even higher (7). PTSD resulting from COVID-19 is often accompanied by generalized anxiety, depression (8), increased stigma (9), and a host of negative social issues (10). Compared to PTSD, which is characterized by psychotic features, general distress, as a more prevalent psychological health issue, has a higher detection rate during COVID-19. More than one-third of adults in the general population experience psychological distress related to COVID-19 (11, 12), and it might remain stable (13, 14). Meanwhile, a significant body of behavioral research has illustrated a reciprocal relationship between PTSD and psychological distress (15, 16). Considering the common comorbidity between post-traumatic stress and general distress, investigating their underlying neurobehavioral mechanisms could lay the groundwork for intervention strategies.

As such a behavioral influential factor for PTSD and general distress, fear is a biologically basic emotion, typically conceptualized as an adaptive yet transient state triggered by encountering a threatening stimulus (17), for example, in the face of any catastrophic, deadly pandemic (18). Particularly during the initial peak of community outbreaks of COVID-19, individuals grappled with uncertainties about their future and potential threats to their lives, making fear a prominent emotion (19, 20). In March 2020, Ahorsu et al. developed a scale for measuring fear of COVID-19 (21), catalyzing subsequent research on fear (22). It is noteworthy that individual differences in the fear of COVID-19 may exist. These variances could be associated with factors such as sex, age, level of education, understanding of COVID-19, perceptions of government pandemic response (23),individuals emotional regulation strategies (24), tolerance of uncertainty (25), cultural background (26), and others. Previous study has shown that the highest levels of fear of COVID-19 were observed in the Asian region (26). The intensity and manifestations of COVID-19 fear demonstrate significant variation across cultural contexts. A comparative study examining psychological responses to the pandemic among university students in Poland and Japan revealed that Japanese participants exhibited markedly higher levels of COVID-19 fear than their Polish counterparts. This disparity potentially stems from Japan’s geographical proximity to the pandemic’s origin and its collectivist culture’s emphasis on group harmony (27). Additional research indicates that during the Omicron variant of the COVID-19 pandemic, Chinese individuals demonstrated greater emphasis on individual absolute responsibility towards the collective and avoided becoming “troublemakers” compared to Koreans. They exhibited more protective behaviors to alleviate psychological distress such as anxiety through their inner sense of shame and fear of stigma (28).

Fear of COVID-19 has been associated with various negative psychological health issues in the general population, such as stress, anxiety, depression, sleep problems, suicidal ideation (29, 30). A meta-analysis revealed a strong positive correlation between fear of COVID-19 and post-traumatic stress (r = 0.54, n = 8,752), as well as distress symptoms (r = 0.53, n = 11,785) (31). Additionally, a longitudinal study conducted across multiple countries found that fear of COVID-19 significantly predicts the development of PTSD (32, 33). And patients diagnosed with PTSD exhibit compromised fear inhibition (34). Previous studies have shown the significant role of fear conditioning in posttraumatic stress disorder (PTSD) (35), where inadequate fear memory extinction may contribute to the onset of PTSD (36). The impact of fear on PTSD may involve neural mechanisms in brain regions such as the prefrontal cortex, hippocampus, and amygdala (37). Moreover, extensive previous studies indicated a positive correlation between fear of COVID-19 and individual distress (38–41). The fear of COVID-19 might exert its impact on distress through external factors, such as disruptions in lifestyle and leisure restrictions (42), and through psychological characteristics such as expressive suppression, cognitive reappraisal, and intolerance of uncertainty (43). A cross-global study (including Asian countries) demonstrates cultural differences in the relationship between emotion regulation strategies and mental health indicators during the COVID-19 epidemic. In individualistic cultures, individuals tend to employ strategies that maintain their authentic emotional experiences and inner states, such as cognitive reappraisal, which modifies emotional impact by altering event perception and correlates with fewer psychological issues. In collectivist cultures (Asian countries), individuals more frequently utilize expressive inhibition to maintain social harmony and group interests by concealing their emotions, particularly negative ones, which strongly correlates with anxiety and depression symptoms (44). Research indicates that prolonged suppression and concealment of these emotions may result in emotional disorders and mental health problems. A study of undergraduate nursing students in China revealed that poor emotional regulation during COVID-19 (such as using expressive suppression strategies) significantly increases psychological distress symptoms, including depression, anxiety, and PTSD -like symptoms (45). This suggests that within a collectivist cultural context, the specific emotion regulation strategies adopted by individuals significantly influence the psychological distress arising from their perception of COVID-19 risks.

The brain structures of the fear circuitry often exhibit potential overlap with other common mood disorders, such as anxiety (46). Although the pivotal role of the amygdala in fear is widely acknowledged, it does not necessarily mean that the experience of fear originates solely from this brain region. The subjective experience of fear might rely more on brain areas responsible for cognitive processes, such as the lateral and medial prefrontal cortex, parietal neocortex, and insula (47). Additionally, these brain regions may overlap with those implicated in PTSD and distress. Structural and functional MRI studies in individuals with PTSD and distress have revealed changes in brain regions, including the hippocampus, amygdala, inferior parietal lobule, and insula (48–50), suggesting a potential shared neural architecture underlying fear. Notably, ample evidence suggests the involvement of distinct brain regions and neural circuits in specific object-related fears (51). For instance, compared to snake phobia, dental phobia shows an increase in volume of the right subgenual anterior cingulate cortex, left insula, left orbitofrontal cortex, and left prefrontal cortex (52). And the brain regions involved in fear of pain include the anterior cingulate cortex, the anterior part of the posterior cingulate cortex, and the dorsomedial prefrontal cortex (53). It is worth noting that synaptic plasticity within the fear circuitry (54) underscores the necessity of investigating neural mechanisms behind specific fears. We haven’t found literature specifically addressing pre-pandemic brain structure predicting fear related to COVID-19. However, one study identified pre-pandemic neural connectivity patterns predicting heightened fear symptoms during the COVID-19 peak, with key predictors including connections such as those between the right dorsal anterior cingulate cortex and the left insula, and between the left ventromedial prefrontal cortex and the right dorsolateral prefrontal cortex, among others (55). Therefore, we have grounds to speculate that certain brain structures may predict fear of COVID-19 during the peak of community outbreaks. Furthermore, considering the predictive capacity of COVID-19 fear for PTSD and general distress in behavioral studies, along with their shared neural architecture in specific brain regions, we anticipate that these brain areas may indirectly impact long-term PTSD symptoms and general distress through the fear of COVID-19 during community outbreak peaks.

In summary, this study aims to construct a longitudinal mediation model through three follow-up measurements to investigate the effects of Pre-Pandemic Brain Structure on Posttraumatic Stress and General Distress in the third measurement (T3), as well as the mediating role of COVID-19 fear in the second measurement (T2). Assuming the model is shown in Figure 1.

This prospective longitudinal study aimed to explore the neural structural basis of individual differences in fear of COVID-19 during the peak of the COVID-19 outbreak in Chinese communities, as well as the neurobehavioral mechanisms by which this fear increased individual PTSD symptoms and general distress one year later. Data were obtained through structural brain imaging before the COVID-19 outbreak, behavioral assessments during the peak of the COVID-19 community outbreak, and one year later. Whole-brain multiple regression analysis and mediation analysis revealed that increased GMV in the bilateral insular cortex in baseline was associated with heightened fear of COVID-19 during the peak of the outbreak. Additionally, this fear mediated the impact of bilateral insular GMV on PTSD symptoms and general distress one year later. Our findings provided new evidence for the structural neural basis of fear of COVID-19 and offer novel neurobehavioral pathways for mitigating the long-term psychological effects of COVID-19 on mental health issues (PTSD symptoms and general distress).

Infectious disease pandemics could cause significant trauma, potentially resulting in PTSD and enduring psychological distress. Moreover, PTSD and psychological distress may co-occur and share similar risk factors such as the degree of trauma exposure, isolation and quarantine, social inequalities, and job responsibilities (75). Our findings corroborated that fear of COVID-19 during the peak of community outbreaks could predict PTSD symptoms and general distress one year later. Additionally, this association remained unaffected by sex, age, total GMV, subjective socioeconomic status and life events. This aligns with previous literature emphasizing the predictive role of fear in PTSD and general distress (32, 33). As is well known, cultural background factors play an important role in shaping emotional responses and risk perception. Research indicates that countries with collectivist cultures, particularly China, emphasize individual emotional restraint and strengthen avoidance strategies (such as the culture of tolerance) to maintain social harmony and group interests (44). This approach may deplete cognitive resources and diminish individuals’ ability to utilize cognitive reappraisal and other strategies, resulting in emotional regulation difficulties and ultimately perpetuating fear as PTSD symptoms or general psychological distress. Difficulty in emotion regulation likely represents the key psychological mechanism connecting COVID-19 fear and long-term symptoms in this study.

PTSD could be considered a condition characterized by dysregulation of fear processes. The effectiveness of exposure-based therapy and cognitive processing therapy in treating PTSD by reducing fear through “extinction” learning based on Pavlovian conditioning reaffirms the relationship between fear and PTSD (76). Norrholm et al.’s study found that high fear levels could predict PTSD symptoms, suggesting that measuring fear load may aid in comparing specific fears and their impact on psychological issues (77). The pathways through which fear impacts PTSD might be associated with fear conditioning dysfunction, failure of trauma-related fear memory extinction, and fear reconsolidation (35). For more common general distress, which includes stress, anxiety, and depression, it significantly impacts the psychological well-being of both current and future populations (78). The fear of COVID-19 has consistently shown incremental validity in explaining significant indicators of psychological distress (79). Previous study has shown that in populations experiencing broad distress, there might be dysregulation in fear circuits, but the causal relationship remains unclear (80). Our study revealed that fear of COVID-19 at the peak of the outbreak could positively predict individuals’ general distress one year later. These findings reveal that interventions targeting fear during the peak of major infectious disease outbreaks may effectively reduce the development of long-term psychiatric disorders and common psychological issues in the population. They provide valuable insights for the timing of psychological interventions at different stages of the human response to high-threat lethal infectious diseases.

Our study findings indicated that individuals with larger insular GMV experienced greater fear of COVID-19 during peak outbreaks in COVID-19 communities. This is consistent with previous findings from functional magnetic resonance imaging studies, which showed heightened insular responses associated with higher levels of fear (81). The insula played a pivotal role in contributing to the processing of cognitive, emotional, and primal responses to fear stimuli (82). Different neuronal populations within the insula might encode various processes of conditioned fear (83). The insular cortex was considered responsible for integrating consciousness (including cognition, emotion, and bodily states), and had also been suggested to facilitate higher-level appraisal and anticipatory processes relevant to the conscious perception of fear (84). The insula was involved in individuals’ responses to unpredictable threats (85). Previous study indicated that the insula exhibited sensitivity to significant environmental stimuli and suggested that an enlargement in its GMV could potentially bolster an individual’s capacity to recognize fear even at low levels of awareness (86). This ability might be linked to its role in directing attention towards significant stimuli in the environment, and increased insula GMV was associated with prioritized allocation of attentional resources to threatening stimuli (87). Another investigation into GMV among university students revealed a positive correlation between insula volume and emotional monitoring abilities (88), which might also contribute to heightened fear. Furthermore, the positive correlation observed between insula grey matter volume and individual social network metrics might serve as a contributing factor (89). Amid the COVID-19 pandemic, individuals might face increased risk of COVID-19 exposure due to complex social networks, thus indirectly heightening fear of COVID-19.

Our study also found that larger insular GMV at T1 were associated with more PTSD symptoms and general distress one year later. In structural and functional MRI studies related to the pathophysiology of PTSD, the insula has been demonstrated to exhibit high reproducibility (49). A meta-analysis of voxel-based morphometry studies found a positive correlation between grey matter in the left insula and PTSD symptoms (90). Increased activation of the insular cortex may heighten individuals’ responsiveness to emotional processing (91), exacerbating psychological distress such as stress, discomfort, and avoidance induced by uncertainty (92). And the link between the insular cortex and psychological distress might involve dysregulation of corticotropin-releasing factor (CRF), CRF receptor 1, and cannabinoid receptor 1 (93). Therapeutic interventions targeting the insular cortex, such as transcranial magnetic stimulation (94), selective serotonin reuptake inhibitors, and cognitive-behavioral therapy (95), have demonstrated effectiveness in reducing stress, anxiety, and negative emotions, thus underscoring the pivotal role of the insular cortex in the onset or progression of PTSD symptoms and general distress disorders. Furthermore, our study findings also revealed that larger gray matter volumes in the insula at T1 could indirectly influence higher levels of post-traumatic stress disorder (PTSD) symptoms and general distress one year later through higher levels of fear of COVID-19 at T2. The insular cortex might contribute to the development of long-term psychological disorders through fear generalization (96). Studies suggested its involvement in modulating the frequency of intrusive memories through fear acquisition and extinction (97), as well as facilitating the progression of long-term PTSD symptoms and general distress through mechanisms such as re-experiencing (98) and the associated memory extinction deficits (99). Our findings suggest that intervening on fear during peak COVID-19 outbreaks could reduce long-term PTSD symptoms and psychological distress, providing insights into identifying target areas for mental health interventions at different stages of future outbreaks.

This study has several limitations that warrant attention. Firstly, there was an undeniable presence of social desirability bias in self-reported questionnaire surveys. Future research should incorporate clinical interview style assessments or objective physiological indicators as supplements to enhance data robustness and reduce such biases. Secondly, our results detected changes in insular GMV, with no positive results for other brain regions such as the hippocampus and amygdala, which have been reported to be linked with fear-related processing (100). This might be attributed to the fact that the samples came from various sources, and only GMV was measured, neglecting other brain structures such as topology and white matter. It is suggested that future research can integrate multimodal neuroimaging data, such as resting state functional connectivity, task state fMRI, and cortical thickness analysis, particularly examining fear-related neural networks including the amygdala insula prefrontal cortex, in order to more deeply reveal the neurodynamic mechanisms of fear processing and subsequent development of psychiatric symptoms. Thirdly, our sample is only composed of Chinese university students, which has an advantage in sample homogeneity but limits the generalizability of the research results to other age groups, cultural backgrounds, or broader community populations. Additionally, we do not explore the potential influence of gender or cultural factors on COVID-19 fear and psychological distress. Future research should aim to conduct in a sample with greater demographic diversity, including groups of different ages, genders, occupations, and cultural backgrounds, and engage in multi center collaboration to validate the generalizability of the findings of this study. Finally, although MRI data collection was conducted before the outbreak of COVID-19, it was impossible to check whether individuals were infected with COVID-19 before the outbreak. Although the possibility of infection is very low, the fact remains that COVID-19 may affect the brain (101). Furthermore, subsequent studies should consider the possibility of asymptomatic infections or other unmeasured neurological confounding factors.

In conclusion, our study provides novel evidence of the structural neural influences on fear during the peak of the COVID-19 community outbreak, revealing the potential critical role of bilateral insular GMV in driving fear levels related to COVID-19. Moreover, we found that COVID-19 fear might serve as a significant mediating factor influencing the relationship between the insular cortex and the development of future PTSD symptoms and general distress. These findings could aid in identifying vulnerable populations susceptible to fear during infectious disease (like COVID-19) outbreaks and guide targeted interventions. Furthermore, they inform the selection of brain regions for interventions [e.g., repetitive transcranial magnetic stimulation (102) targeting long-term mental and psychological issues associated with COVID-19, thereby assisting in mitigating the prevalence of long-term psychological issues stemming from COVID-19.