Non-suicidal self-injury (NSSI) involves deliberate, self-inflicted harm to one’s body without the intent of suicide. It is classified as NSSI disorder, positioned under the “Conditions for Further Study” in both the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and its 2022 revision, the DSM-5, Text Revision (DSM-5-TR). In the DSM- 5-TR, NSSI is defined as engaging in self-injurious behavior intentionally causing bleeding, wounding, or pain to one’s body surface for five or more days over the past year [1].

Recent meta-analyses reveal a lifetime prevalence of NSSI at 22.1% among children and adolescents, with the highest rates observed in adolescents aged 10-17 years (17.2%). This prevalence gradually decreases with age to 13.4% in young adults and 5.5% in older adults [2-4]. Longitudinal studies focusing on youth NSSI indicate a prevalence peak between 15 and 17 years, followed by a decline in young adulthood [5]. Females consistently exhibit higher prevalence rates than males, consistent with findings from a study on Korean adolescents [6,7]. Owing to its adverse effects on family and interpersonal relationships, and its association with an elevated risk of future suicidal behavior, NSSI among adolescents necessitates urgent attention and intervention [8-10].

NSSI often coexists with various mental health conditions, including borderline personality disorder, mood disorders, anxiety disorders, substance use disorders, and post-traumatic stress disorder—or, it may manifest independently [11]. Adolescents engaging in NSSI commonly employ self-injury to momentarily alleviate intense negative emotions or as a form of self-punishment [12,13]. Compared to counterparts without NSSI, these adolescents exhibit more severe psychiatric symptoms, greater functional impairment, and increased difficulties in emotion regulation [14,15]. Influences from peers engaged in NSSI and social media are also significant factors [16]. Despite various proposed treatment approaches, there remains a lack of well-defined, effective interventions specifically tailored for adolescents with NSSI, highlighting the need for a deeper understanding [17,18].

Beyond these clinical and psychosocial correlates, recent neuroimaging reviews have begun to uncover the neurobiological underpinnings of NSSI and related self-harm in youth. These studies suggest changes in fronto-limbic circuits, including the amygdala, insula, and anterior cingulate cortex, as well as large-scale networks implicated in emotion regulation, salience processing, and self-referential thinking [19]. Within this broader context, structural brain magnetic resonance imaging (MRI) provides a neurobiological approach to investigate NSSI mechanisms. Previous studies comparing female adolescents meeting NSSI diagnostic criteria with healthy controls (HCs) identified smaller volumes in the insula and anterior cingulate cortex in the NSSI group [20]. Another study reported decreased gray matter volume in specific brain regions in adolescents with a history of NSSI [21]. Our previous research on subcortical volumes in female adolescents with NSSI revealed differences in the volumes of the left amygdala and thalamus compared to controls [22]. However, research into structural brain changes in individuals meeting NSSI diagnostic criteria, particularly adolescents, remains limited.

Although a few studies have examined adolescent NSSI, they have primarily focused on comparing specific brain volumes with those of HC groups. Gray-matter volume is jointly determined by cortical surface area and cortical thickness, which represent at least partly distinct and highly heritable phenotypes; accordingly, volumetric measures may obscure alterations that are specific to cortical thickness [23]. Considering that changes in cortical thickness during adolescence are associated with brain development and maturation, analyzing cortical thickness in adolescent NSSI patients is believed to offer valuable insights into the development of specific cortical regions [24]. In this context, our study expands the conventional focus on brain volume by comparing cortical thickness between female adolescents and young adults with NSSI and HCs and exploring its association with related factors.

In total, 110 inpatients with NSSI and 34 potential HCs were initially screened. In the NSSI group, 25 patients were excluded because of structural brain abnormalities or MRI artifacts, leaving 85 eligible patients. In the HC group, one individual was excluded owing to a self-reported history of self-injurious behavior, leaving 33 eligible HCs. From the 85 eligible NSSI patients, 33 were selected so that their age distribution would closely match that of the 33 HCs, resulting in a total of 66 participants (33 in each group) who entered the cortical thickness analysis. Owing to errors during the FreeSurfer process, one participant was excluded from the analysis in each group. Consequently, 32 participants from each group (NSSI group: mean age 15.47±3.20 years; HC group: mean age 15.56±4.83 years) were included in the final analysis, resulting in a total of 64 participants. The sociodemographic and clinical characteristics of both groups are outlined in Table 1. No statistically significant difference was observed in average age between the groups (p>0.05), and both groups exclusively comprised females, right-handed participants of Asian ethnicity. The IQ was significantly higher in the HC group compared to the NSSI group (p<0.05). However, as the IQ scores of both groups fell within the normal range and there was a possibility that the NSSI group’s scores may have been influenced by psychiatric symptoms at the time of testing, IQ was not considered a relevant variable in this study.

Clinical information related to the NSSI group revealed the following: the mean age of onset for self-injurious behavior was 14.25±3.26 years, and the average duration of illness at the time of assessment was 16.55±15.30 months. The mean score on CRS NSSI was 2.56±0.66, with most patients categorized in Stages 2 (n=14) and 3 (n=15). Out of the 32 NSSI patients, 10 had a history of previous suicide attempts. The most prevalent DSM-5 diagnosis in the NSSI group was depressive disorders (n=23), followed by adjustment disorders (n=4); bipolar and related disorders (n=2); disruptive, impulse-control, and conduct disorders (n=2); and anorexia nervosa (n=1).

A statistically significant intergroup difference in average cortical thickness was observed in both hemispheres, with p-values of 0.001 for the left as well as right hemisphere (Table 2). In cortical thickness analyses performed after controlling for age as a covariate, the NSSI group exhibited significantly thinner cortical thickness in the right cingulate cortex compared to the HC group (corrected p-values <0.05) (Table 3, Figures 1 and 2). No significant intergroup difference in cortical thickness was observed in the left hemisphere.

Additionally, correlations between cortical thickness in the right cingulate cortex and clinical variables were investigated. A total of 13 patients in the NSSI group underwent SAIC, TAIC, and CDI assessments. Pearson correlation analyses were performed to examine the correlations between the right cingulate cortex thickness and related variables. A weak negative correlation was observed between the thickness of the right cingulate cortex and the SAIC scores (r=-0.547, p=0.053), albeit without reaching statistical significance. No statistically significant correlation was identified between the thickness of the right cingulate cortex and the TAIC scores (r=-0.257, p=0.396) or CDI scores (r=-0.231, p=0.447) (Table 4 and Figure 3). Additionally, the age-controlled partial correlation analyses did not reveal any statistically significant correlations between the right cingulate cortex thickness and the SAIC (r=-0.550, p=0.064), TAIC (r=-0.258, p=0.419), or CDI (r=-0.190, p=0.555) scores.

This study was conducted to investigate the structural differences in the cortical thickness of the brain between female youth diagnosed with NSSI as per DSM-5 and a HC group, and to determine the association between these structural differences and the clinical characteristics of the NSSI group. The analysis revealed thinner right cingulate cortex areas in the NSSI group compared to the HCs. To the best of our knowledge, this study has the largest sample size among structural brain imaging studies examining groups meeting the DSM-5 criteria for NSSI and therefore may provide important information on the neurobiological characteristics of youth with NSSI, although these alterations may also relate to broader vulnerability to psychopathology.

Both the NSSI and HC groups comprised female righthanded participants with no significant difference in average age. While the HC group exhibited higher overall IQ scores, this difference was not considered a confounding variable because of the potential impact of the NSSI group’s psychiatric symptoms on their test performance. The mean age of selfharm onset for the NSSI group (14.25±3.26 years) aligned with previous research findings [3]. Additionally, 31.25% of the NSSI group reported a history of suicide attempts, consistent with the 14%-70% lifetime prevalence observed in adolescent NSSI patients [11]. The majority of DSM-5 diagnoses in the NSSI group were mood-related, indicating a homogenous profile among the female youth participants.

This study compared cortical thickness differences between the NSSI and HC groups. Previous studies on patients with various psychiatric disorders, such as depression, schizophrenia, and bipolar disorder, have reported abnormalities in cortical thickness [37-39]. While the brain cortical structure is typically quantified by surface area, cortical thickness, and gray-matter volume, previous studies on NSSI patients predominantly focused on gray-matter volume [19]. However, despite high heritability in cortical thickness and surface area, there is no known correlation between these two measures, suggesting that cortical volume measurements might be influenced by unrelated genetic factors [23]. Hence, this study specifically compared the cortical thickness in NSSI patients—a novel approach in this research area. Our findings align with those of previous brain imaging studies in NSSI patients, which have shown involvement of specific brain areas. Structural brain imaging studies of NSSI adolescents have revealed reduced volumes of the insula and anterior cingulate cortex compared to HCs [20]. Functional MRI studies have shown increased neural activation in the amygdala, hippocampus, and anterior cingulate cortex in NSSI adolescents compared to HCs, indicating heightened activity in these regions [40,41]. Additionally, increased neural activity, specifically in the cingulate cortex, has been observed in NSSI patients. Our study builds upon these findings by employing a novel approach to analyze cortical thickness, providing further neurobiological evidence that cingulate cortex alterations may be involved in NSSI. The cingulate cortex, situated within the brain’s limbic lobe, encompasses various regions, including the anterior, retro-splenial, mid, and posterior cingulate cortex [42]. Of these, the anterior cingulate cortex plays a central role in emotional and behavioral regulation, serving a crucial function in conflict resolution and contributing to the processing and response to emotional stimuli as part of the salience network with the insula [43-47]. The observed reduced thickness in the cingulate cortex of NSSI patients thus suggests a potential link to difficulties in regulating negative emotions and impulsivity, and may be one neural correlate of the pathophysiological processes associated with NSSI [48].

Additional correlation analyses between SAIC, TAIC, and CDI scores and the cortical thickness of the right cingulate cortex in the NSSI group did not yield statistically significant results. However, it is well-documented that adolescents with NSSI experience greater anxiety and depression compared to their non-NSSI counterparts [49]. Additionally, they use self-injury as a tool to cope with these negative emotions [11]. Given the cingulate cortex’s involvement in processing conflict situations and emotional regulation, investigating its correlation with depression and anxiety in adolescents with NSSI is considered significant. Future studies with larger sample sizes may provide more substantial findings [43,45,46].

This study has a few limitations. First, the majority of the participants were diagnosed with mood disorders, particularly depression (22 out of 32, 68.8%). While the study population was relatively homogenous, it is noteworthy that previous research has shown that adults with depression exhibit reduced cingulate cortex thickness compared to HCs. This raises the possibility that the observed thinning of the right cingulate cortex may be influenced by the high prevalence of depressive disorders in our sample, rather than being specific to NSSI [37]. Future research should aim to recruit a more diverse sample encompassing a broader range of conditions. Additionally, it should compare NSSI patients with non-NSSI patients in addition to HCs to better isolate the specific neuroanatomical characteristics associated with NSSI. Second, although this study had a larger sample size compared to previous NSSI research, it focused exclusively on female youth, who represent the group with the highest prevalence of NSSI. This narrow focus limits the generalizability of our findings to male and adult NSSI patients. This will have to be addressed in future research by expanding the study population to include both sexes and various age groups. Third, a few of the clinical variables, namely SAIC, TAIC, and CDI, were only assessed for a subset of the NSSI group. Although partial correlation analysis was performed in this study, adjusted for age, which is known to correlate with cortical thickness, the partial administration of these tests raises concerns about potential bias and confounding factors. Given that the correlation between SAIC and target cortex thickness was statistically significant (p=0.053) despite a small sample size, further studies with larger sample sizes and comprehensive clinical assessments could provide more significant results. Finally, while participants were recruited based on the NSSI diagnostic criteria, clinical characteristics such as the onset of self-injurious behavior and duration of illness at the time of admission were diverse, resulting in high clinical heterogeneity. If future studies consider these clinical characteristics in the analysis process, they will be able to control these characteristics or find correlations according to clinical characteristics.

Despite these limitations, this study is significant because it contributes to the limited body of brain imaging research specifically focused on NSSI. Notably, it is the first of its kind to compare cortical thickness in a large sample size. Furthermore, in the Korean research context, there is a paucity of studies investigating the neurobiological mechanisms of NSSI in adolescents through brain imaging. Therefore, this study’s findings are expected to provide valuable insights and augment the existing evidence on the neurobiological underpinnings of NSSI.

This study analyzed the cortical thickness differences between NSSI patients and HCs, revealing a significant reduction in cortical thickness in the right cingulate cortex of the NSSI group. These findings suggest that alterations in the right cingulate cortex may be a potential neurobiological correlate of NSSI, possibly reflecting difficulties in emotion regulation in female youth. Given the considerable prevalence and severity of NSSI in adolescents, it is necessary to pursue further research with more extensive samples and rigorously controlled clinical factors to ascertain the structural differences in the brains of patients with NSSI.