Shared and distinct prefrontal cortex activation between genders in depression individuals during verbal fluency task: evidence from one large sample of fNIRS studies

Shared and distinct prefrontal cortex activation between genders in depression individuals during verbal fluency task: evidence from one large sample of fNIRS studies | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Shared and distinct prefrontal cortex activation between genders in depression individuals during verbal fluency task: evidence from one large sample of fNIRS studies Yan Zhang, Minxiao Zheng, Nian Xiang, Min Qiu, Hui Da, Qiang Xiao, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4591244/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Cognitive impairment is a key characteristic of depression. While sex differences in various aspects of depression have been well-documented, fewer studies investigated gender differences in abnormal brain region activation during specific cognitive tasks. This study aimed to explore sex differences in cognitive deficits using fNIRS technology, providing neurobiological evidence for gender-specific therapy approaches. Methods 853 young adults participated in the study, 422 healthy individuals (224 male, 198 female) and 431 individuals with depression (233 male, 198 female). The average oxyhemoglobin levels in the prefrontal cortex were measured using a 53-channel fNIRS imaging device. Results Compared to male healthy controls, lower oxyhemoglobin activation was observed in the male depression group in the frontopolar cortex, Broca's area, and left and right dorsolateral prefrontal cortex. Similarly, lower oxyhemoglobin activation was found in the female depression group in the right BA, FPC, and left dlPFC compared to female healthy controls. Additionally, a significant difference in oxyhemoglobin activation was noted between male and female depression groups in the left and right dlPFC. Conclusion Females and males had similar but unique prefrontal brain activations. FPC and BA may be the shared neural basis, whereas dlPFC may be distinct underlying physiological mechanisms for depression between genders. depression gender verbal fluency task fNIRS Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Highlights 1 Females and males had similar but unique prefrontal brain activations. 2 FPC and BA may be the shared neural basis for depression between genders. 3 dlPFC may be a significant component of distinct underlying physiological mechanisms for depression between genders at neural level. 1 Introduction Depression is a major human blight, a severe mental illness with high prevalence and recurrence rate. It is clinically characterized by persistent and pervasive depressed mood, loss of interest or pleasure, feelings of guilt and worthlessness, decreased appetite, weight changes, and sleep disturbances(Caroleo et al., 2019 ; McCarter, 2008 ; Y. Yang et al., 2022 ). Collectively, these long-term conditions result in a substantial rise in healthcare expenses, a decline in life quality, and in the worst situations, the possibility of suicide(Hoobehfekr et al., 2021 ). This places a heavy burden of illness on families and society as a whole, posing a major social and financial challenge to public health(Vos et al., 2017 ). It was the third leading source of disease burden globally in 2008, and by 2030, according to some researchers, it would be the leading causes of disease burden worldwide(Lépine & Briley, 2011 ). Depression is a common condition that often goes undiagnosed and untreated due to stigma and a lack of effective therapies. Empirical investigations over a period of more than 20 years have demonstrated that gender is one of the many factors that can affect a diagnosis of depression, even though symptoms are more likely to be recognized today than in previous decades(Krivoy et al., 2015 ; Sramek & Cutler, 2011 ). According to a noteworthy phenomenon, women are more likely than men to experience depression. This was first noted by Myrna Weissman in the 1970s, when she observed that, among adults in clinical and community samples, about twice as many women as men experience depression(Weissman & Klerman, 1977 ). A multitude of studies, including the majority of epidemiological reports and a representative nationwide sample of children, adolescents, and adults, also reported up to three times after the publication of this seminal article(Kessler et al., 2003 ; Kendler, Gatz, Gardner, & Pedersen, 2006 ; Holsen et al., 2011 ; Black, Roberts, & Li-Leng, 2012 ; Bromet et al., 2011 ). Nevertheless, this gender disparity did not continue during the course of growth(H. Zheng & Jia, 2022 ). There was no gender difference in the prevalence of depression found in childhood. Prepubescent males exhibit a higher propensity than females to satisfy the diagnostic criteria for depression. A significant transition takes place during adolescence: from 11 to 13 years of age, this pattern of declining depression rates is inverted, with a greater prevalence of depressed mood and depressive disorders among females compared to boys(Hankin et al., 1998 ;Wichstrøm, 1999 ;Twenge & Nolen-Hoeksema, 2002 ; Earls, 1984 ). A significant transition takes place during adolescence: from 11 to 13 years of age, this pattern of declining depression rates is inverted, with a greater prevalence of depressed mood and depressive disorders among females compared to boys. This gender gap in prevalence peaked during adolescence between the ages of 15 and 18(Cavanagh et al., 2017 ; Wade et al., 2002 ), and then gradually tend to stabilize until adulthood(Kessler, Chiu, Demler, Merikangas, & Walters, 2005 ; Oksuzyan et al., 2010 ; Salk, Hyde, & Abramson, 2017 ). Furthermore, research suggests that the way the two sexes present the symptoms of depression differs as well. Men who are depressed are more likely than women to report symptoms that are not included in the accepted diagnostic criteria, which could result in an under or incorrect diagnosis of depression in men(Cavanagh, Wilson, Caputi, & Kavanagh, 2016 ). According to studies(Newman, Fuqua, Gray, & Simpson, 2006 ; Parker & Brotchie, 2010 ; Winkler, Pjrek, & Kasper, 2005 ), male depression patients presenting more irritability, were more likely to overreact to small irritations, experienced anger attacks (sudden spells of anger and aggression with physical features similar to panic attacks), had lower impulse control, and displayed greater substance use. Finally, male depression patients were more likely to adopt avoidance behaviors, such as excessive involvement at work and high sexual activity in the form of extramarital affairs or a series of limited sexual encounters(Ogrodniczuk & Oliffe, 2011 ), whereas female depression patients typically exhibit symptoms of mood disturbance, appetite disturbance/weight change, and sleep disturbance more frequently and intensely(Martin, Neighbors, & Griffith, 2013 ; Romans, Tyas, Cohen, & Silverstone, 2007 ). In contrast to male, females experiencing depression are more likely to experience depressive episodes more frequently and exhibit atypical depressive symptoms like anxiety, somatization, excessive fatigue, overeating, and oversleeping(Angst & Dobler-Mikola, 1984 ; Carter, Joyce, Mulder, Luty, & McKenzie, 2000 ; Scheibe, Preuschhof, Cristi, & Bagby, 2003 ; Smith et al., 2008 ). Furthermore, decades of research have shown that gender may also be a significant factor in explaining the diversity in antidepressant therapy response. Even after accounting for potential differences in antidepressant type and usage patterns, including compliance, male depression patients showed a significantly greater therapeutic response to imipramine, a tricyclic antidepressant (TCA), than female patients(Frank, Carpenter, & Kupfer, 1988 ; Kornstein et al., 2000 ). However, a number of studies indicate that women might benefit from selective serotonin reuptake inhibitors (SSRIs) more than men do(Baca, Garcia-Garcia, & Porras-Chavarino, 2004 ; Berlanga & Flores-Ramos, 2006 ; Khan, Brodhead, Schwartz, Kolts, & Brown, 2005 ; Sramek, Murphy, & Cutler, 2016 ; S.-J. Yang et al., 2011 ). Overall, the studies mentioned above show that gender has a significant impact on the mechanisms underlying depression, which can affect a variety of clinical aspects of the illness. However, fewer studies have focused on how gender affects cognitive function during specific cognitive tasks, which has been identified as a major clinical symptom of major depression(Zuckerman et al., 2018 ). This impairment is seen in a number of cognitive domains, including verbal memory, working memory, psychomotor speed, selective attention, and especially executive function, which has been specifically linked to decreased ability in these aspects(Porter & Douglas, 2019 ; Rock, Roiser, Riedel, & Blackwell, 2014 ; Semkovska et al., 2019 ; Snyder, 2013 ). According to certain studies, cognitive function typically deteriorates with each depressive episode and gets worse with subsequent episodes. It can also exist prior to the onset of the episode and persist even after mood symptoms have subsided(Culpepper, 2015 ; Wagner, Müller, Helmreich, Huss, & Tadić, 2015 ). Wagner stated that these deficiencies impair a patient's capacity to assess, organize, prioritize, schedule, commence, and complete an activity in a timely manner(Wagner et al., 2015 ), which is a predictor of poor academic, occupational, and daily functioning and is related with poor treatment response. So far, the relationship between depression and cognitive function has always been a research hotspot. Some studies have found that structural abnormalities in the prefrontal cortex (PFC) are thought to be underlying these cognitive impairments(Fitzgerald et al., 2006 ; Pizzagalli & Roberts, 2022 ; Quaresima, Giosue, Roncone, Casacchia, & Ferrari, 2009 ). According to one assessment of structural MRI findings in adults with depression, changes in prefrontal brain regions are related with the ailment, and they are generally more visible in people with more severe or persistent forms of the illness(Lorenzetti, Allen, Fornito, & Yücel, 2009 ). Additional neuroimaging studies have also reported this phenomenon, such as studies using functional near-infrared spectroscopy (fNIRS) and functional magnetic resonance imaging(fMRI) (Boggio et al., 2007 ; Fales et al., 2009 ; Fitzgerald et al., 2006 ; Shen et al., 2015 ; Struckmann, Boden, Gingnell, Fallmar, & Persson, 2022 ; Yang et al., 2022 ; T. Yang et al., 2023 ; M. Zheng et al., 2023 ). Overall, considering the preliminary evidence of cognitive impairments in the PFC in depressed patients, gender differences in the aberrant activity of the prefrontal cortex when identifying whether cognitive impairment exists when doing certain cognitive tasks require additional investigation. If there are sex-dependent differences in the patterns and/or severity of cognitive impairment, therapy measures to improve cognitive performance and affective symptoms should be tailored accordingly. Functional near-infrared spectroscopy (fNIRS), a recently discovered optical neuroimaging technology, has been presented as a potential diagnostic tool for depression. It is relatively inexpensive, portable, straightforward to set up, and may give temporal resolution involving neither ionising radiation nor loud noise(Ho et al., 2020; Scholkmann et al., 2014 ), which utilize light sources between a spectral window of 650–1000 nm to penetrate organic tissue spectroscopy, and allows subjects to monitor brain hemodynamic changes in a natural state and is less sensitive to motion artifacts, which is suitable for psychiatric and depressed patients(Ho et al., 2020; Irani, Platek, Bunce, Ruocco, & Chute, 2007 ; Scarapicchia, Brown, Mayo, & Gawryluk, 2017 ; Scholkmann et al., 2014 ). The verbal fluency task (VFT) is a typical executive function task that tests neuropsychological abilities such as verbal recall, retrieval, working memory, and attention(Whiteside et al., 2016 ). As a result, the fNIRS-VFT paradigm is frequently employed in research to elicit various anomalies relevant to each diagnostic category of major mental diseases(Zanelli et al., 2010 ), providing a promising approach for investigating the underlying brain mechanisms of depression across genders. Taking into account the aforementioned factors, the current study attempted to demonstrate the difference hemodynamic response in the prefrontal cortex between genders during the VFT task using fNIRS, in order to provide neurobiological evidence for gender-specific therapeutic interventions. 2 Material and Methods 2.1 Participants Our study included 853 participants: 431 with depression (233 male, 198 female), and 422 with good health (224 male, 198 female). Participants were recruited from the psychiatry department of one Hospital between September 2020 and October 2022. All of these depressed individuals are between the ages of 18 and 45, right-handed, and were diagnosed by three senior psychiatrists using the DSM-5 criteria. In addition, we also recruited 422 healthy individuals as a control group. Prior to fNIRS monitoring, all participants were evaluated to see whether they met the criteria for depression and health controls using the Hospital Anxiety and Depression Scale (HADS) and the Mini International Neuropsychiatric Interview (MINI-Chinese version). The following were the exclusion criteria: 1) Previous experience with another mental illness; 2) Brain trauma or other biological brain diseases; 3) Addiction or substance abuse problems; 4) A substantial medical illness in the past; 5) Women who are pregnant or nursing; 6) People who have received electrical shock therapy (ECT) in the last six months; 7) People who are unable to finish the cognitive activities. All 853 participants spoke Chinese as their first language. All procedures were carried out in accordance with the principles outlined in the Declaration of Helsinki, and participants' informed consent was obtained before the study began. The study was approved by the ethics committee of Huazhong University of Science and Technology (20200130). 2.2 Measures The HADS is a 14-item self-report questionnaire that consists of 7 items measuring anxiety and 7 items constituting a subscale for depression(Zigmond & Snaith, 1983 ). Every item has a four-point rating system, where a higher symptom frequency is indicated by a rating of 3. Each subscale has a total score between 0 and 21, with the categories being normal (0–7) and diagnosed (11–21). In front of the interviewer, participants read the questions and provided their responses. The "D" and "A" scale results for anxiety and depression were analyzed. 2.3 Activation task (Verbal fluency task, VFT) Each participant was given a verbal fluency test (VFT) that required them to generate as many words as rapidly and accurately as possible after hearing a specific Chinese character (such as "上," "时," "说," and "家").The participants were asked to sit in front of a monitor. In this study, a block experimental design was used, with a 30-second pre-task break in which participants were asked to repeatedly count '1, 2, 3, 4, 5' until the task began, followed by a 60-second task consisting of four studies in which participants were asked to say as many 2-character words or 4-character idioms as possible on cue, and finally a 60-second post-task break in which subjects continued counting from 1 to the end of the experiment for a total of 60 seconds. Figure 1 depicted the task design. Figure 1 Experiment Procedure INSERT FIGURE 1 HERE 2.4 fNIRS measurement A 53-channel fNIRS device (BS-7000, Wuhan Znion Technology Co., Ltd., China) was used to measure three types of relative concentration changes of Oxy-Hb, Deoxy-Hb, and Total-Hb using near-infrared light at a specified wavelength. The apparatus contains 16 pairs of emission and detector probes. The wavelengths of light emitted are 760nm and 850nm, at a frequency of 15.625 Hz. The distance between the emitter and detector is 2.9–3.1 cm. A channel separates the emitter and detector probes. Each probe was placed on the scalp of the forehead. Figure 2 depicts the optode layout, which is based on the 10/20 System of Electrode Placement approach utilized in EEGs(Okamoto et al., 2004 ). Figure 2 Optode arrangement INSERT FIGURE 2 HERE 2.5 Statistical Analysis SPSS 25.0 was utilized for all statistical analyses. We compared the continuous variables for age and education years between the depression group and the health controls using one-way analyses of variance (ANOVA). To compare gender frequency between groups, χ 2 tests were used. The statistical significance was set at p < 0.05. Independent-samples t-test was used to determine the sex difference in the mean activation in Oxy-Hb. Prior to this, the data passed the Shapiro-Wilk test for normalcy. Since Oxy-Hb has a better signal-to-noise ratio than Deoxy-Hb and can more directly reflect task-related cortical activation, we concentrated on Oxy-Hb variations in the fNIRS data(Huppert, Hoge, Diamond, Franceschini, & Boas, 2006 ; Strangman, Culver, Thompson, & Boas, 2002 ). Therefore, by calculating the difference in mean Oxy-Hb levels between the task and pre-task periods, we were able to compute the mean activation of Oxy-Hb in the 53-channels. The Homer2 software processed the fNIRS data in two steps: (1) First, motion artifacts are corrected via strip-sample interpolation. To remove physiological noise, a bandpass filter operating at a frequency of 0.01-0.10Hz was employed (such as respiration, cardiac activity, and low-frequency signal drift). (2) The optical density is converted to the fluctuation of Oxy-Hb and Deoxy-Hb concentrations by applying the revised Beer-Lambert law in order to account for the differential pathlength (DP) caused by photon scattering in an inhomogeneous medium. 3 Results 3.1 Demographic characteristics and clinical scale assessments The demographic and clinical scale assessments of the various groups were completed. We discovered no significant intergroup difference in age (t = -1.799, p = 0.073) between the depressive and healthy groups. The HADS score of depression was comparable between the two groups (t = 58.346, p = 0.000). Compared to the healthy group, the depression score was was higher in depression group ( p < 0.001). 3.2 Changes in oxy-Hb concentration during VFT We performed an independent samples t-test comparing several groups using SPSS.Male depression individuals were found to have a lower level of Oxy-Hb activation in the right broca's area (BA) (t=-2.708, p = 0.007), frontal polar cortex (FPC) (t=-2.478, p = 0.014), left dorsolateral prefrontal cortex (dlPFC) (t=-2.092, p = 0.037), and right dorsolateral prefrontal cortex (dlPFC) (t=-1.973, p = 0.049), as illustrated in Fig. 3 . In contrast, female depression individuals were found to have a lower level of Oxy-Hb activation in the right BA (t=-2.413, p = 0.016), FPC (t=-434, p = 0.015), and left dlPFC (t=-2.591, p = 0.010), as Fig. 4 . As shown in Fig. 5 , there was a significant difference in Oxy-Hb activation between the male and female depression groups in the left and right dlPFCs (t = 2.496, p = 0.013 and t = 2.903, p = 0.004), with female depression group having lower Oxy-Hb activation compared to male depression group. Figure 3 INSERT FIGURE 3 HERE Figure 4 INSERT FIGURE 4 HERE Figure 5 INSERT FIGURE 5 HERE 4 Discussion In the current study, we investigated the share and distinct aberrant prefrontal activation between genders in a large sample of male and female young adults with and without depression using fNIRS during a VFT task. The findings indicate that the male depression group had reduced Oxy-Hb activation in the right BA, left and right dlPFC, and FPC as compared to the male healthy control group. In contrast, the female depression group showed reduced Oxy-Hb activity in the right BA, left dlPFC, and FPC when compared to the female HC, suggesting that depressed people may have cognitive impairments. Then, in left and right dlPFC, a substantial difference in Oxy-Hb activation was discovered between the male and female depression groups, suggesting that the female depression group possessed more severe cognitive deficits than the male depression group. In other words, the male depression group exhibited lower activation than the healthy control group, while the female and male depression groups had equal activity in the right BA and FPC with the female. In the meantime, the left and right dlPFCs showed different activation in male and female depression, with female depression grouping being lower than male depression. According to the current study, female and male depression groups had lower activation than healthy controls, indicating that there were some deficits in right BA and FPC, which mean that there were some deficits in right BA and FPC in depressed male and female participants, which is consistent with earlier research. For instance, a meta-analysis of prior fNIRS studies found that individuals with serious depression had a substantial decrease in activity at particular frontotemporal regions when executing the VFT task(Yeung & Lin, 2021 ). Furthermore, a recent fNIRS study found that in prefrontal regions such as the front polar cortex (FPC) and right Broca's area(BA), confirmed depressive individuals had significantly lower hemodynamic activation than the healthy control and suspected depression group(Wu, Lu, Zhang, & Li, 2024).Meanwhile, a different study showed that there were significant differences in the activation in the frontal cortex (FPC) between depressions with and without anxiety. This study used functional neuroimaging reconstitution scoring (fNIRS) to separate patients with anxious and non-anxious depression based on variations in hemodynamic changes in the right prefrontal cortex during verbal fluency task(Wu et al., 2022 ). In addition, the similar functional brain activity pattern was reported between bipolar depression and unipolar depression in FPC and BA(Zhu et al., 2018 ), as well as the bipolar depression group with healthy control in FPC(Chen et al., 2021 ). On the other hand, from an opposing perspective, an intervention study on depression using intermittent Theta burst stimulation (iTBS) revealed that the hemodynamics of depressed patients in the FPC and BA following iTBS treatment were significantly better than those prior to treatment, indicating a significant negative correlation between the severity of depressive symptoms and the hemodynamic activation of BA(Yan et al., 2023). Together with these results, we conclude that the FPC and BA may be special prefrontal regions linked to varying degrees of depressive symptoms. These regions may serve as a biomarker to differentiate between the groups of healthy controls and the depression groups or the subgroups of depression like anxious and bipolar depression. In this study, this biomarker was used to distinguish the female depression group with the female healthy control group, and separate male depression group from male healthy control. In this study, the aberrant activity in FPC and BA may be the s common neural basis for depression in both men and women. Furthermore, a significant difference in Oxy-Hb activation was found between male and female depression groups in both left and right dlPFC, indicating that female depression patients had more severe cognitive deficits than male depression patients, which was consistent with previous findings that the dysfunction in dlPFC would cause different cognitive and executive functioning in MDD patients of different genders(Caldirola et al., 2017 ).A study indicated that female patients with first-diagnosed, drug-naïve depression had more severe cognitive impairment in the visuospatial and constructional categories than did male patients(Caldirola et al., 2017 ; Wang et al., 2020 ). While a study pertinent to the gender variations in cortical thickness demonstrated that considerable localised cortical thickening in women was identified throughout, including in the superior frontal gyrus, where white matter contains fibres of the dlPFC(Im et al., 2006 ). Furthermore, amplitude of low-frequency fluctuation (ALFF) differences between males and females with MDD was discovered in some brain regions of the frontoparietal network, attention network (left superior temporal pole, left inferior parietal lobule), cerebellum network, and auditory network in a resting-state functional magnetic resonance imaging (fMRI) study. This finding is linked to the varying prevalence rates among the genders(Sun et al., 2022 ).Another study discovered that the male MDD exhibited lower ALFF of the bilateral caudate nucleus and posterior cingulate gyrus than the female MDD, indicating that the functional brain activity in MDD may differ between the sexes (Yao et al., 2014 ). Besides, for different severity of depression subtypes, compared with bipolar depression, region-specific fNIR leads show unipolar depression patients had significant lower hemodynamic activation in ventrolateral prefrontal cortex (VLPFC)(Feng et al., 2021 ). Compared to MDD patients without insomnia, those with insomnia had lower scores on the Repeatable Battery for the Assessment of Neuropsychological Status total and immediate memory, visuospatial/constructional, and delayed memory subscales, as well as lower oxy-Hb concentrations in the bilateral dorsolateral prefrontal cortex (dlPFC) and bilateral medial prefrontal cortex (mPFC)(Xu et al., 2023 ). Within the treatment-resistant depression and non- treatment-resistant depression groups, the activation of oxy-Hb changes in dorsomedial PFC in treatment-resistant depression patients was significantly lower than non- treatment-resistant depression patients. In addition, activation of oxy-Hb change in right dlPFC was negatively correlated with the severity of depressive symptoms in depression patients. On the whole, we infer that dlPFC may play an important part in prefrontal regions for the severities of depressive symptoms, which differentiate between various groups of serious depression subtypes or subtypes of depression with and without other medical or psychological disorders, such as treatment-resistant depression and non-treatment-resistant depression, depression with insomnia and without insomnia. According to this study, dlPFC may play a significant role in the neural mechanisms underpinning various gender-specific depression severities, which could potentially influence depression’s pathogenesis, including the prevalence rates, the presentation of depressive symptoms, and the response to antidepressant treatment. Overall, the current work used fNIRS to evaluate the shared and different prefrontal brain activation between genders during VFT tasks.There may be a shared neural basis for depression in both men and women. The FPC and BA may be a shared neural basis differentiating healthy control groups from depression groups or the subgroups of depression such as anxious and bipolar depression.Thee dlPFC may play a significant role in the underlying distinct physiological mechanisms for depression in men and women at the neural level which could have an impact on the pathophysiology of depression, including prevalence rates, the manifestation of depressive symptoms, and the response to antidepressant treatment. 5 Limitations This study has room for improvement and areas that need to be addressed. In this study, the researchers did not measure the VFT group word volume index to validate the relationship between brain activation and behavioral performance of the subjects. However, this presents an opportunity for future research to explore this connection and potentially uncover exciting findings. Additionally, the majority of the people who took part in the research were young adults, it would be beneficial to validate the findings of the study across different age groups, such as adolescents and the elderly, in order to gain a more comprehensive understanding. Finally,the current study is a cross-sectional study. After the depressed symptoms have been alleviated, it is still uncertain whether the aberrant activation in the prefrontal cortex still exists. Therefore, it is possible that in the future, additional longitudinal research will be considered. 6 Conclusion Based on our understanding, this study utilized a large sample of fNIRS data to examine the activation of the prefrontal cortex in males and females during a VFT task. The findings offer valuable neuroimaging evidence that can inform the development of personalized therapeutic interventions for different genders. Lower Oxy-Hb activation was observed in the male and female depression groups in BA and FPC, respectively, compared to the male and female HC group. This finding suggests that aberrant activation in FPC and BA may serve as the shared neurological foundation for depression in both sexes. Meanwhile, a significant difference in Oxy-Hb activation was found between male and female depression groups in left dlPFC and right dlPFC, implying that dlPFC may be an important part of the underlying distinct physiological mechanisms for depression in men and women at the neural level. In a nutshell, the study gives fresh light on the critical role of functional alterations in the prefrontal cortex in the brain pathophysiology of depression across genders, offering insights into how to personalize treatment interventions. Declarations Declaration of competing interest This manuscript has not been published or presented elsewhere in part or in entirety. All study participants provided informed consent, and the study design was approved by the appropriate ethics review boards. All the authors have approved the manuscript and agree with submission to your esteemed journal. There are no conflicts of interest to declare. Author Statement Acknowledgements The study was designed in accordance with the tenets of the Declaration of Helsinki. Approval was granted by the Research Ethics Committee of the School of Educational Sciences, Huazhong University of Science and Technology, China (IRB NO.20200130). Each participant signed an informed consent before the procedure was fully explained. All authors should thank all the university students who participated in this study, the Foundation for its support, and the editor-in-chief and reviewers for their valuable revisions. CRediT authorship contribution statement Under supervision by Yan Zhang and Hui Shi. Nian Xiang, Min Qiu, Hui Da, Qiang Wei, Shanzhi Ke and Qiang Xiao performed experiment design and data analysis. Minxiao Zheng and Dongmei Zhu has made important contributions in Writing – original draft, Writing – review & editing. Yan Zhang and Hui Shi have made important contributions in Conceptualization, Data curation, Formal analysis and Methodology. All authors approved the final manuscript for publication. Data availability statement The data that support the findings of this study are available from the corresponding authors upon request. Ethics Approval and Consent to Participate All procedures performed in studies involving human participants were with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from the study participants prior to study commencement. Approval was granted by the Research Ethics Committee of the School of Educational Sciences, Huazhong University of Science and Technology, China NO.20200130). Funding This study was supported and granted by the fundamental Research Funds for the Central Universities, HUST: (2023WKFZZX109) and HUST Overseas training program for outstanding young teachers. References Angst, J., & Dobler-Mikola, A. (1984). Do the diagnostic criteria determine the sex ratio in depression? Journal of Affective Disorders , 7 (3), 189–198. Baca, E., Garcia-Garcia, M., & Porras-Chavarino, A. (2004). Gender differences in treatment response to sertraline versus imipramine in patients with nonmelancholic depressive disorders. Progress in Neuro-Psychopharmacology & Biological Psychiatry , 28 (1), 57–65. Berlanga, C., & Flores-Ramos, M. (2006). Different gender response to serotonergic and noradrenergic antidepressants. A comparative study of the efficacy of citalopram and reboxetine. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4591244","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":318242571,"identity":"d50ddb18-dee8-479a-8fd3-3b12d3e318fe","order_by":0,"name":"Yan Zhang","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Zhang","suffix":""},{"id":318242572,"identity":"e93672fb-ec75-4a42-99d2-ad1fd0b55aff","order_by":1,"name":"Minxiao Zheng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYBACfmb+hw8S/9nI2bc3EKlFsp2H2eADW5qxAc8BIrUY9POwSc5gO5y4QSKBWC3MvMekeXjSjM0lH2+8wVBjE01QizkzX7I1j4SNnOXstGILhmNpuQ2EtFg2Mxje5jFIM2a4nWMmwdhwmLAWg8MMBtI8CYcTG26eIVoLj5HkjANA79/gIVKLZDNbssHHhjRjyR6gXxKI8Qs//+GDDxIbbOT42Q9vvPGhxoawFhRHEh01SFpI1TEKRsEoGAUjAwAAIIs946Db4a0AAAAASUVORK5CYII=","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":true,"prefix":"","firstName":"Minxiao","middleName":"","lastName":"Zheng","suffix":""},{"id":318242573,"identity":"de404485-9c62-4995-bd84-55a48fb67b3f","order_by":2,"name":"Nian Xiang","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Nian","middleName":"","lastName":"Xiang","suffix":""},{"id":318242575,"identity":"faaec695-01a1-431a-a3be-596911ac16fd","order_by":3,"name":"Min Qiu","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"","lastName":"Qiu","suffix":""},{"id":318242576,"identity":"1d75bab3-020e-4868-ba0d-5808215eb383","order_by":4,"name":"Hui Da","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Da","suffix":""},{"id":318242577,"identity":"6ab73ac0-4c2f-4861-8686-8cba6a0caf49","order_by":5,"name":"Qiang Xiao","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Qiang","middleName":"","lastName":"Xiao","suffix":""},{"id":318242579,"identity":"9123d59d-b259-4281-973a-d5ca612b257a","order_by":6,"name":"Qiang Wei","email":"","orcid":"","institution":"Jianghan University","correspondingAuthor":false,"prefix":"","firstName":"Qiang","middleName":"","lastName":"Wei","suffix":""},{"id":318242580,"identity":"daad61f0-f4ac-4622-8c49-c17869316e10","order_by":7,"name":"Shanzhi Ke","email":"","orcid":"","institution":"Wujiashan NO.2 Middle School","correspondingAuthor":false,"prefix":"","firstName":"Shanzhi","middleName":"","lastName":"Ke","suffix":""},{"id":318242582,"identity":"75667004-dc1a-4370-b123-fbc8f4757890","order_by":8,"name":"Dongmei Zhu","email":"","orcid":"","institution":"Jianghan University","correspondingAuthor":false,"prefix":"","firstName":"Dongmei","middleName":"","lastName":"Zhu","suffix":""},{"id":318242585,"identity":"28143585-5e22-4828-93a8-2d2be2b3573f","order_by":9,"name":"Hui Shi","email":"","orcid":"","institution":"Beijing Chao-Yang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Shi","suffix":""}],"badges":[],"createdAt":"2024-06-17 02:02:01","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4591244/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4591244/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60599616,"identity":"ac0ae212-9d9e-4abf-9355-7b8a99c1b44c","added_by":"auto","created_at":"2024-07-18 15:58:59","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":22422,"visible":true,"origin":"","legend":"\u003cp\u003eExperiment Procedure\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4591244/v1/bfe2dbdc7322175bfb57aac1.jpg"},{"id":60599614,"identity":"60e1d274-68bd-4fa3-bcfd-118d14b8cafa","added_by":"auto","created_at":"2024-07-18 15:58:59","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":54030,"visible":true,"origin":"","legend":"\u003cp\u003eOptode arrangement\u003c/p\u003e\n\u003cp\u003eThere are a total of 16 pairs of optodes and 53 channels. The numbers represent remitter probes, with the letters representing detector probes.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4591244/v1/20c87431cde2e9b6ace85d61.jpg"},{"id":60602389,"identity":"e599f9d4-b0fb-4e37-b537-d0b1d5ffc91d","added_by":"auto","created_at":"2024-07-18 16:14:59","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":77604,"visible":true,"origin":"","legend":"\u003cp\u003e(A)Haemodynamic changes in the prefrontal cortex among male healthy control and depression group during verbal fluency task. (B)Histogram of the distribution of the average oxyhemoglobin of male healthy control and depression group in right broca cotex(rBA), left dorsolateral prefrontal cortex(ldlPFC), right dorsolateral prefrontal cortex(rdlPFC), frontal polar cortex(FPC).\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4591244/v1/d20ff5aa0c7cfa39cb996c5f.jpg"},{"id":60601824,"identity":"7abaccd7-5282-488d-a28d-df2cd74d6de7","added_by":"auto","created_at":"2024-07-18 16:06:59","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":87449,"visible":true,"origin":"","legend":"\u003cp\u003e(A)Haemodynamic changes in the prefrontal cortex among female healthy control and depression group durin verbal fluency task. (B)Histogram of the distribution of the average oxyhemoglobin of male healthy control and depression group in right broca cotex(rBA), left dorsolateral prefrontal cortex(ldlPFC), frontal polar cortex(FPC).\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4591244/v1/1d1c70c8f13b6bb319cf5e4e.jpg"},{"id":60599618,"identity":"ff3a5856-b4c5-4db3-bd10-59ad70f97706","added_by":"auto","created_at":"2024-07-18 15:58:59","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":84492,"visible":true,"origin":"","legend":"\u003cp\u003e(A)Haemodynamic changes in the dorsolateral prefrontal cortexamong female healthy control and depression group durin verbal fluency task. (B)Histogram of the distribution of the average oxyhemoglobin of male healthy control and depression group in right dorsolateral prefrontal cortex(rdlPFC), left dorsolateral prefrontal cortex(ldlPFC).\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4591244/v1/dc0eab45d3bb2d89e310c7e9.jpg"},{"id":62307120,"identity":"72ca9670-8442-4e31-b9dd-84f972615060","added_by":"auto","created_at":"2024-08-12 18:46:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":913788,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4591244/v1/d2e46682-1b8d-4e14-808e-9dbcae77f98a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eShared and distinct prefrontal cortex activation between genders in depression individuals during verbal fluency task: evidence from one large sample of fNIRS studies\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Highlights","content":"\u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e Females and males had similar but unique prefrontal brain activations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e FPC and BA may be the shared neural basis for depression between genders.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3\u0026nbsp;\u003c/strong\u003edlPFC may be a significant component of distinct underlying physiological mechanisms for depression between genders at neural level.\u003c/p\u003e"},{"header":"1 Introduction","content":"\u003cp\u003eDepression is a major human blight, a severe mental illness with high prevalence and recurrence rate. It is clinically characterized by persistent and pervasive depressed mood, loss of interest or pleasure, feelings of guilt and worthlessness, decreased appetite, weight changes, and sleep disturbances(Caroleo et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; McCarter, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Y. Yang et al., \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Collectively, these long-term conditions result in a substantial rise in healthcare expenses, a decline in life quality, and in the worst situations, the possibility of suicide(Hoobehfekr et al., \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). This places a heavy burden of illness on families and society as a whole, posing a major social and financial challenge to public health(Vos et al., \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). It was the third leading source of disease burden globally in 2008, and by 2030, according to some researchers, it would be the leading causes of disease burden worldwide(L\u0026eacute;pine \u0026amp; Briley, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). Depression is a common condition that often goes undiagnosed and untreated due to stigma and a lack of effective therapies. Empirical investigations over a period of more than 20 years have demonstrated that gender is one of the many factors that can affect a diagnosis of depression, even though symptoms are more likely to be recognized today than in previous decades(Krivoy et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Sramek \u0026amp; Cutler, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2011\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAccording to a noteworthy phenomenon, women are more likely than men to experience depression. This was first noted by Myrna Weissman in the 1970s, when she observed that, among adults in clinical and community samples, about twice as many women as men experience depression(Weissman \u0026amp; Klerman, \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e1977\u003c/span\u003e). A multitude of studies, including the majority of epidemiological reports and a representative nationwide sample of children, adolescents, and adults, also reported up to three times after the publication of this seminal article(Kessler et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2003\u003c/span\u003e; Kendler, Gatz, Gardner, \u0026amp; Pedersen, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Holsen et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Black, Roberts, \u0026amp; Li-Leng, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Bromet et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). Nevertheless, this gender disparity did not continue during the course of growth(H. Zheng \u0026amp; Jia, \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). There was no gender difference in the prevalence of depression found in childhood. Prepubescent males exhibit a higher propensity than females to satisfy the diagnostic criteria for depression. A significant transition takes place during adolescence: from 11 to 13 years of age, this pattern of declining depression rates is inverted, with a greater prevalence of depressed mood and depressive disorders among females compared to boys(Hankin et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e1998\u003c/span\u003e;Wichstr\u0026oslash;m, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e1999\u003c/span\u003e;Twenge \u0026amp; Nolen-Hoeksema, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; Earls, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e1984\u003c/span\u003e). A significant transition takes place during adolescence: from 11 to 13 years of age, this pattern of declining depression rates is inverted, with a greater prevalence of depressed mood and depressive disorders among females compared to boys. This gender gap in prevalence peaked during adolescence between the ages of 15 and 18(Cavanagh et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Wade et al., \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e2002\u003c/span\u003e), and then gradually tend to stabilize until adulthood(Kessler, Chiu, Demler, Merikangas, \u0026amp; Walters, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2005\u003c/span\u003e; Oksuzyan et al., \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Salk, Hyde, \u0026amp; Abramson, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2017\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFurthermore, research suggests that the way the two sexes present the symptoms of depression differs as well. Men who are depressed are more likely than women to report symptoms that are not included in the accepted diagnostic criteria, which could result in an under or incorrect diagnosis of depression in men(Cavanagh, Wilson, Caputi, \u0026amp; Kavanagh, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). According to studies(Newman, Fuqua, Gray, \u0026amp; Simpson, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Parker \u0026amp; Brotchie, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Winkler, Pjrek, \u0026amp; Kasper, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e2005\u003c/span\u003e), male depression patients presenting more irritability, were more likely to overreact to small irritations, experienced anger attacks (sudden spells of anger and aggression with physical features similar to panic attacks), had lower impulse control, and displayed greater substance use. Finally, male depression patients were more likely to adopt avoidance behaviors, such as excessive involvement at work and high sexual activity in the form of extramarital affairs or a series of limited sexual encounters(Ogrodniczuk \u0026amp; Oliffe, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2011\u003c/span\u003e), whereas female depression patients typically exhibit symptoms of mood disturbance, appetite disturbance/weight change, and sleep disturbance more frequently and intensely(Martin, Neighbors, \u0026amp; Griffith, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Romans, Tyas, Cohen, \u0026amp; Silverstone, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2007\u003c/span\u003e). In contrast to male, females experiencing depression are more likely to experience depressive episodes more frequently and exhibit atypical depressive symptoms like anxiety, somatization, excessive fatigue, overeating, and oversleeping(Angst \u0026amp; Dobler-Mikola, \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1984\u003c/span\u003e; Carter, Joyce, Mulder, Luty, \u0026amp; McKenzie, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2000\u003c/span\u003e; Scheibe, Preuschhof, Cristi, \u0026amp; Bagby, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2003\u003c/span\u003e; Smith et al., \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). Furthermore, decades of research have shown that gender may also be a significant factor in explaining the diversity in antidepressant therapy response. Even after accounting for potential differences in antidepressant type and usage patterns, including compliance, male depression patients showed a significantly greater therapeutic response to imipramine, a tricyclic antidepressant (TCA), than female patients(Frank, Carpenter, \u0026amp; Kupfer, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e1988\u003c/span\u003e; Kornstein et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2000\u003c/span\u003e). However, a number of studies indicate that women might benefit from selective serotonin reuptake inhibitors (SSRIs) more than men do(Baca, Garcia-Garcia, \u0026amp; Porras-Chavarino, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Berlanga \u0026amp; Flores-Ramos, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Khan, Brodhead, Schwartz, Kolts, \u0026amp; Brown, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2005\u003c/span\u003e; Sramek, Murphy, \u0026amp; Cutler, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; S.-J. Yang et al., \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e2011\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOverall, the studies mentioned above show that gender has a significant impact on the mechanisms underlying depression, which can affect a variety of clinical aspects of the illness. However, fewer studies have focused on how gender affects cognitive function during specific cognitive tasks, which has been identified as a major clinical symptom of major depression(Zuckerman et al., \u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). This impairment is seen in a number of cognitive domains, including verbal memory, working memory, psychomotor speed, selective attention, and especially executive function, which has been specifically linked to decreased ability in these aspects(Porter \u0026amp; Douglas, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Rock, Roiser, Riedel, \u0026amp; Blackwell, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Semkovska et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Snyder, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). According to certain studies, cognitive function typically deteriorates with each depressive episode and gets worse with subsequent episodes. It can also exist prior to the onset of the episode and persist even after mood symptoms have subsided(Culpepper, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Wagner, M\u0026uuml;ller, Helmreich, Huss, \u0026amp; Tadić, \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Wagner stated that these deficiencies impair a patient's capacity to assess, organize, prioritize, schedule, commence, and complete an activity in a timely manner(Wagner et al., \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), which is a predictor of poor academic, occupational, and daily functioning and is related with poor treatment response. So far, the relationship between depression and cognitive function has always been a research hotspot. Some studies have found that structural abnormalities in the prefrontal cortex (PFC) are thought to be underlying these cognitive impairments(Fitzgerald et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Pizzagalli \u0026amp; Roberts, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Quaresima, Giosue, Roncone, Casacchia, \u0026amp; Ferrari, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). According to one assessment of structural MRI findings in adults with depression, changes in prefrontal brain regions are related with the ailment, and they are generally more visible in people with more severe or persistent forms of the illness(Lorenzetti, Allen, Fornito, \u0026amp; Y\u0026uuml;cel, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). Additional neuroimaging studies have also reported this phenomenon, such as studies using functional near-infrared spectroscopy (fNIRS) and functional magnetic resonance imaging(fMRI) (Boggio et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Fales et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Fitzgerald et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Shen et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Struckmann, Boden, Gingnell, Fallmar, \u0026amp; Persson, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Yang et al., \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; T. Yang et al., \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; M. Zheng et al., \u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOverall, considering the preliminary evidence of cognitive impairments in the PFC in depressed patients, gender differences in the aberrant activity of the prefrontal cortex when identifying whether cognitive impairment exists when doing certain cognitive tasks require additional investigation. If there are sex-dependent differences in the patterns and/or severity of cognitive impairment, therapy measures to improve cognitive performance and affective symptoms should be tailored accordingly. Functional near-infrared spectroscopy (fNIRS), a recently discovered optical neuroimaging technology, has been presented as a potential diagnostic tool for depression. It is relatively inexpensive, portable, straightforward to set up, and may give temporal resolution involving neither ionising radiation nor loud noise(Ho et al., 2020; Scholkmann et al., \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2014\u003c/span\u003e), which utilize light sources between a spectral window of 650\u0026ndash;1000 nm to penetrate organic tissue spectroscopy, and allows subjects to monitor brain hemodynamic changes in a natural state and is less sensitive to motion artifacts, which is suitable for psychiatric and depressed patients(Ho et al., 2020; Irani, Platek, Bunce, Ruocco, \u0026amp; Chute, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Scarapicchia, Brown, Mayo, \u0026amp; Gawryluk, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Scholkmann et al., \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). The verbal fluency task (VFT) is a typical executive function task that tests neuropsychological abilities such as verbal recall, retrieval, working memory, and attention(Whiteside et al., \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). As a result, the fNIRS-VFT paradigm is frequently employed in research to elicit various anomalies relevant to each diagnostic category of major mental diseases(Zanelli et al., \u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e2010\u003c/span\u003e), providing a promising approach for investigating the underlying brain mechanisms of depression across genders. Taking into account the aforementioned factors, the current study attempted to demonstrate the difference hemodynamic response in the prefrontal cortex between genders during the VFT task using fNIRS, in order to provide neurobiological evidence for gender-specific therapeutic interventions.\u003c/p\u003e"},{"header":"2 Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Participants\u003c/h2\u003e \u003cp\u003eOur study included 853 participants: 431 with depression (233 male, 198 female), and 422 with good health (224 male, 198 female). Participants were recruited from the psychiatry department of one Hospital between September 2020 and October 2022. All of these depressed individuals are between the ages of 18 and 45, right-handed, and were diagnosed by three senior psychiatrists using the DSM-5 criteria. In addition, we also recruited 422 healthy individuals as a control group.\u003c/p\u003e \u003cp\u003ePrior to fNIRS monitoring, all participants were evaluated to see whether they met the criteria for depression and health controls using the Hospital Anxiety and Depression Scale (HADS) and the Mini International Neuropsychiatric Interview (MINI-Chinese version). The following were the exclusion criteria: 1) Previous experience with another mental illness; 2) Brain trauma or other biological brain diseases; 3) Addiction or substance abuse problems; 4) A substantial medical illness in the past; 5) Women who are pregnant or nursing; 6) People who have received electrical shock therapy (ECT) in the last six months; 7) People who are unable to finish the cognitive activities. All 853 participants spoke Chinese as their first language. All procedures were carried out in accordance with the principles outlined in the Declaration of Helsinki, and participants' informed consent was obtained before the study began. The study was approved by the ethics committee of Huazhong University of Science and Technology (20200130).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Measures\u003c/h2\u003e \u003cp\u003eThe HADS is a 14-item self-report questionnaire that consists of 7 items measuring anxiety and 7 items constituting a subscale for depression(Zigmond \u0026amp; Snaith, \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e1983\u003c/span\u003e). Every item has a four-point rating system, where a higher symptom frequency is indicated by a rating of 3. Each subscale has a total score between 0 and 21, with the categories being normal (0\u0026ndash;7) and diagnosed (11\u0026ndash;21). In front of the interviewer, participants read the questions and provided their responses. The \"D\" and \"A\" scale results for anxiety and depression were analyzed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e\u003cb\u003e2.3 Activation task\u003c/b\u003e (Verbal fluency task, VFT)\u003c/h2\u003e \u003cp\u003e Each participant was given a verbal fluency test (VFT) that required them to generate as many words as rapidly and accurately as possible after hearing a specific Chinese character (such as \"上,\" \"时,\" \"说,\" and \"家\").The participants were asked to sit in front of a monitor. In this study, a block experimental design was used, with a 30-second pre-task break in which participants were asked to repeatedly count '1, 2, 3, 4, 5' until the task began, followed by a 60-second task consisting of four studies in which participants were asked to say as many 2-character words or 4-character idioms as possible on cue, and finally a 60-second post-task break in which subjects continued counting from 1 to the end of the experiment for a total of 60 seconds. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e depicted the task design.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e Experiment Procedure\u003c/p\u003e \u003cp\u003eINSERT FIGURE \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e HERE\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 fNIRS measurement\u003c/h2\u003e \u003cp\u003eA 53-channel fNIRS device (BS-7000, Wuhan Znion Technology Co., Ltd., China) was used to measure three types of relative concentration changes of Oxy-Hb, Deoxy-Hb, and Total-Hb using near-infrared light at a specified wavelength. The apparatus contains 16 pairs of emission and detector probes. The wavelengths of light emitted are 760nm and 850nm, at a frequency of 15.625 Hz. The distance between the emitter and detector is 2.9\u0026ndash;3.1 cm. A channel separates the emitter and detector probes. Each probe was placed on the scalp of the forehead. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e depicts the optode layout, which is based on the 10/20 System of Electrode Placement approach utilized in EEGs(Okamoto et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2004\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e Optode arrangement\u003c/p\u003e \u003cp\u003eINSERT FIGURE \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e HERE\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Statistical Analysis\u003c/h2\u003e \u003cp\u003eSPSS 25.0 was utilized for all statistical analyses. We compared the continuous variables for age and education years between the depression group and the health controls using one-way analyses of variance (ANOVA). To compare gender frequency between groups, χ\u003csup\u003e2\u003c/sup\u003e tests were used. The statistical significance was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Independent-samples t-test was used to determine the sex difference in the mean activation in Oxy-Hb. Prior to this, the data passed the Shapiro-Wilk test for normalcy. Since Oxy-Hb has a better signal-to-noise ratio than Deoxy-Hb and can more directly reflect task-related cortical activation, we concentrated on Oxy-Hb variations in the fNIRS data(Huppert, Hoge, Diamond, Franceschini, \u0026amp; Boas, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Strangman, Culver, Thompson, \u0026amp; Boas, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2002\u003c/span\u003e). Therefore, by calculating the difference in mean Oxy-Hb levels between the task and pre-task periods, we were able to compute the mean activation of Oxy-Hb in the 53-channels. The Homer2 software processed the fNIRS data in two steps: (1) First, motion artifacts are corrected via strip-sample interpolation. To remove physiological noise, a bandpass filter operating at a frequency of 0.01-0.10Hz was employed (such as respiration, cardiac activity, and low-frequency signal drift). (2) The optical density is converted to the fluctuation of Oxy-Hb and Deoxy-Hb concentrations by applying the revised Beer-Lambert law in order to account for the differential pathlength (DP) caused by photon scattering in an inhomogeneous medium.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Demographic characteristics and clinical scale assessments\u003c/h2\u003e \u003cp\u003eThe demographic and clinical scale assessments of the various groups were completed. We discovered no significant intergroup difference in age (t = -1.799, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.073) between the depressive and healthy groups. The HADS score of depression was comparable between the two groups (t\u0026thinsp;=\u0026thinsp;58.346, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000). Compared to the healthy group, the depression score was was higher in depression group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Changes in oxy-Hb concentration during VFT\u003c/h2\u003e \u003cp\u003eWe performed an independent samples t-test comparing several groups using SPSS.Male depression individuals were found to have a lower level of Oxy-Hb activation in the right broca's area (BA) (t=-2.708, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007), frontal polar cortex (FPC) (t=-2.478, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014), left dorsolateral prefrontal cortex (dlPFC) (t=-2.092, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.037), and right dorsolateral prefrontal cortex (dlPFC) (t=-1.973, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.049), as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. In contrast, female depression individuals were found to have a lower level of Oxy-Hb activation in the right BA (t=-2.413, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016), FPC (t=-434, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015), and left dlPFC (t=-2.591, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010), as Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, there was a significant difference in Oxy-Hb activation between the male and female depression groups in the left and right dlPFCs (t\u0026thinsp;=\u0026thinsp;2.496, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013 and t\u0026thinsp;=\u0026thinsp;2.903, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004), with female depression group having lower Oxy-Hb activation compared to male depression group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003c/p\u003e \u003cp\u003eINSERT FIGURE \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e HERE\u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003c/p\u003e \u003cp\u003eINSERT FIGURE \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e HERE\u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u003c/p\u003e \u003cp\u003eINSERT FIGURE \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e HERE\u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eIn the current study, we investigated the share and distinct aberrant prefrontal activation between genders in a large sample of male and female young adults with and without depression using fNIRS during a VFT task. The findings indicate that the male depression group had reduced Oxy-Hb activation in the right BA, left and right dlPFC, and FPC as compared to the male healthy control group. In contrast, the female depression group showed reduced Oxy-Hb activity in the right BA, left dlPFC, and FPC when compared to the female HC, suggesting that depressed people may have cognitive impairments. Then, in left and right dlPFC, a substantial difference in Oxy-Hb activation was discovered between the male and female depression groups, suggesting that the female depression group possessed more severe cognitive deficits than the male depression group. In other words, the male depression group exhibited lower activation than the healthy control group, while the female and male depression groups had equal activity in the right BA and FPC with the female. In the meantime, the left and right dlPFCs showed different activation in male and female depression, with female depression grouping being lower than male depression.\u003c/p\u003e \u003cp\u003eAccording to the current study, female and male depression groups had lower activation than healthy controls, indicating that there were some deficits in right BA and FPC, which mean that there were some deficits in right BA and FPC in depressed male and female participants, which is consistent with earlier research. For instance, a meta-analysis of prior fNIRS studies found that individuals with serious depression had a substantial decrease in activity at particular frontotemporal regions when executing the VFT task(Yeung \u0026amp; Lin, \u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Furthermore, a recent fNIRS study found that in prefrontal regions such as the front polar cortex (FPC) and right Broca's area(BA), confirmed depressive individuals had significantly lower hemodynamic activation than the healthy control and suspected depression group(Wu, Lu, Zhang, \u0026amp; Li, 2024).Meanwhile, a different study showed that there were significant differences in the activation in the frontal cortex (FPC) between depressions with and without anxiety. This study used functional neuroimaging reconstitution scoring (fNIRS) to separate patients with anxious and non-anxious depression based on variations in hemodynamic changes in the right prefrontal cortex during verbal fluency task(Wu et al., \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). In addition, the similar functional brain activity pattern was reported between bipolar depression and unipolar depression in FPC and BA(Zhu et al., \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2018\u003c/span\u003e), as well as the bipolar depression group with healthy control in FPC(Chen et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). On the other hand, from an opposing perspective, an intervention study on depression using intermittent Theta burst stimulation (iTBS) revealed that the hemodynamics of depressed patients in the FPC and BA following iTBS treatment were significantly better than those prior to treatment, indicating a significant negative correlation between the severity of depressive symptoms and the hemodynamic activation of BA(Yan et al., 2023). Together with these results, we conclude that the FPC and BA may be special prefrontal regions linked to varying degrees of depressive symptoms. These regions may serve as a biomarker to differentiate between the groups of healthy controls and the depression groups or the subgroups of depression like anxious and bipolar depression. In this study, this biomarker was used to distinguish the female depression group with the female healthy control group, and separate male depression group from male healthy control. In this study, the aberrant activity in FPC and BA may be the s common neural basis for depression in both men and women.\u003c/p\u003e \u003cp\u003eFurthermore, a significant difference in Oxy-Hb activation was found between male and female depression groups in both left and right dlPFC, indicating that female depression patients had more severe cognitive deficits than male depression patients, which was consistent with previous findings that the dysfunction in dlPFC would cause different cognitive and executive functioning in MDD patients of different genders(Caldirola et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2017\u003c/span\u003e).A study indicated that female patients with first-diagnosed, drug-na\u0026iuml;ve depression had more severe cognitive impairment in the visuospatial and constructional categories than did male patients(Caldirola et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Wang et al., \u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). While a study pertinent to the gender variations in cortical thickness demonstrated that considerable localised cortical thickening in women was identified throughout, including in the superior frontal gyrus, where white matter contains fibres of the dlPFC(Im et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). Furthermore, amplitude of low-frequency fluctuation (ALFF) differences between males and females with MDD was discovered in some brain regions of the frontoparietal network, attention network (left superior temporal pole, left inferior parietal lobule), cerebellum network, and auditory network in a resting-state functional magnetic resonance imaging (fMRI) study. This finding is linked to the varying prevalence rates among the genders(Sun et al., \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).Another study discovered that the male MDD exhibited lower ALFF of the bilateral caudate nucleus and posterior cingulate gyrus than the female MDD, indicating that the functional brain activity in MDD may differ between the sexes (Yao et al., \u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). Besides, for different severity of depression subtypes, compared with bipolar depression, region-specific fNIR leads show unipolar depression patients had significant lower hemodynamic activation in ventrolateral prefrontal cortex (VLPFC)(Feng et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Compared to MDD patients without insomnia, those with insomnia had lower scores on the Repeatable Battery for the Assessment of Neuropsychological Status total and immediate memory, visuospatial/constructional, and delayed memory subscales, as well as lower oxy-Hb concentrations in the bilateral dorsolateral prefrontal cortex (dlPFC) and bilateral medial prefrontal cortex (mPFC)(Xu et al., \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Within the treatment-resistant depression and non- treatment-resistant depression groups, the activation of oxy-Hb changes in dorsomedial PFC in treatment-resistant depression patients was significantly lower than non- treatment-resistant depression patients. In addition, activation of oxy-Hb change in right dlPFC was negatively correlated with the severity of depressive symptoms in depression patients. On the whole, we infer that dlPFC may play an important part in prefrontal regions for the severities of depressive symptoms, which differentiate between various groups of serious depression subtypes or subtypes of depression with and without other medical or psychological disorders, such as treatment-resistant depression and non-treatment-resistant depression, depression with insomnia and without insomnia. According to this study, dlPFC may play a significant role in the neural mechanisms underpinning various gender-specific depression severities, which could potentially influence depression\u0026rsquo;s pathogenesis, including the prevalence rates, the presentation of depressive symptoms, and the response to antidepressant treatment.\u003c/p\u003e \u003cp\u003eOverall, the current work used fNIRS to evaluate the shared and different prefrontal brain activation between genders during VFT tasks.There may be a shared neural basis for depression in both men and women. The FPC and BA may be a shared neural basis differentiating healthy control groups from depression groups or the subgroups of depression such as anxious and bipolar depression.Thee dlPFC may play a significant role in the underlying distinct physiological mechanisms for depression in men and women at the neural level which could have an impact on the pathophysiology of depression, including prevalence rates, the manifestation of depressive symptoms, and the response to antidepressant treatment.\u003c/p\u003e"},{"header":"5 Limitations","content":"\u003cp\u003eThis study has room for improvement and areas that need to be addressed. In this study, the researchers did not measure the VFT group word volume index to validate the relationship between brain activation and behavioral performance of the subjects. However, this presents an opportunity for future research to explore this connection and potentially uncover exciting findings. Additionally, the majority of the people who took part in the research were young adults, it would be beneficial to validate the findings of the study across different age groups, such as adolescents and the elderly, in order to gain a more comprehensive understanding. Finally,the current study is a cross-sectional study. After the depressed symptoms have been alleviated, it is still uncertain whether the aberrant activation in the prefrontal cortex still exists. Therefore, it is possible that in the future, additional longitudinal research will be considered.\u003c/p\u003e"},{"header":"6 Conclusion","content":"\u003cp\u003eBased on our understanding, this study utilized a large sample of fNIRS data to examine the activation of the prefrontal cortex in males and females during a VFT task. The findings offer valuable neuroimaging evidence that can inform the development of personalized therapeutic interventions for different genders. Lower Oxy-Hb activation was observed in the male and female depression groups in BA and FPC, respectively, compared to the male and female HC group. This finding suggests that aberrant activation in FPC and BA may serve as the shared neurological foundation for depression in both sexes. Meanwhile, a significant difference in Oxy-Hb activation was found between male and female depression groups in left dlPFC and right dlPFC, implying that dlPFC may be an important part of the underlying distinct physiological mechanisms for depression in men and women at the neural level. In a nutshell, the study gives fresh light on the critical role of functional alterations in the prefrontal cortex in the brain pathophysiology of depression across genders, offering insights into how to personalize treatment interventions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDeclaration of competing interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis manuscript has not been published or presented elsewhere in part or in entirety. All study participants provided informed consent, and the study design was approved by the appropriate ethics review boards. All the authors have approved the manuscript and agree with submission to your esteemed journal. There are no conflicts of interest to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was designed in accordance with the tenets of the Declaration of Helsinki. Approval was granted by the Research Ethics Committee of the School of Educational Sciences, Huazhong University of Science and Technology, China (IRB NO.20200130). Each participant signed an informed consent before the procedure was fully explained.\u0026nbsp;All authors should thank all the university students who participated in this study, the Foundation for its support, and the editor-in-chief and reviewers for their valuable revisions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRediT authorship contribution statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUnder supervision by\u0026nbsp;Yan Zhang\u0026nbsp;and\u0026nbsp;Hui Shi.\u0026nbsp;Nian Xiang,\u0026nbsp;Min Qiu,\u0026nbsp;Hui\u0026nbsp;Da, Qiang Wei, Shanzhi Ke and Qiang Xiao\u0026nbsp;performed experiment design and data analysis.\u0026nbsp;Minxiao Zheng and Dongmei Zhu\u0026nbsp;has\u0026nbsp;made important contributions in Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing.\u0026nbsp;Yan Zhang\u0026nbsp;and\u0026nbsp;Hui Shi\u0026nbsp;have\u0026nbsp;made important\u0026nbsp;contributions in Conceptualization, Data curation, Formal analysis and Methodology.\u0026nbsp;All authors approved the final manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding authors upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in studies involving human participants were with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.\u0026nbsp;Informed consent was obtained from the study participants prior to study commencement.\u0026nbsp;Approval was granted by the Research Ethics Committee of the School of Educational Sciences, Huazhong University of Science and Technology, China NO.20200130).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported and granted by the\u0026nbsp;fundamental Research Funds for\u0026nbsp;the\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Central Universities, HUST: (2023WKFZZX109) and HUST Overseas training program for outstanding young teachers.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAngst, J., \u0026amp; Dobler-Mikola, A. 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S., Iacobucci, M., et al. (2018). Recognition and Treatment of Cognitive Dysfunction in Major Depressive Disorder. \u003cem\u003eFrontiers in Psychiatry\u003c/em\u003e, \u003cem\u003e9\u003c/em\u003e, 655.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"depression, gender, verbal fluency task, fNIRS","lastPublishedDoi":"10.21203/rs.3.rs-4591244/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4591244/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eCognitive impairment is a key characteristic of depression. While sex differences in various aspects of depression have been well-documented, fewer studies investigated gender differences in abnormal brain region activation during specific cognitive tasks. This study aimed to explore sex differences in cognitive deficits using fNIRS technology, providing neurobiological evidence for gender-specific therapy approaches.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003e853 young adults participated in the study, 422 healthy individuals (224 male, 198 female) and 431 individuals with depression (233 male, 198 female). The average oxyhemoglobin levels in the prefrontal cortex were measured using a 53-channel fNIRS imaging device.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eCompared to male healthy controls, lower oxyhemoglobin activation was observed in the male depression group in the frontopolar cortex, Broca's area, and left and right dorsolateral prefrontal cortex. Similarly, lower oxyhemoglobin activation was found in the female depression group in the right BA, FPC, and left dlPFC compared to female healthy controls. Additionally, a significant difference in oxyhemoglobin activation was noted between male and female depression groups in the left and right dlPFC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion \u003c/strong\u003eFemales and males had similar but unique prefrontal brain activations. FPC and BA may be the shared neural basis, whereas dlPFC may be distinct underlying physiological mechanisms for depression between genders.\u003c/p\u003e","manuscriptTitle":"Shared and distinct prefrontal cortex activation between genders in depression individuals during verbal fluency task: evidence from one large sample of fNIRS studies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 15:58:54","doi":"10.21203/rs.3.rs-4591244/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7eff2ba9-6c7b-4fc4-9a6a-9ce9867e8950","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-12T18:38:32+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-18 15:58:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4591244","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4591244","identity":"rs-4591244","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}