Dynamic Changes of Intrinsic Brain Activity and Neurotransmitter Defect Profile in Patients with Lifelong Premature Ejaculation

doi:10.21203/rs.3.rs-4015150/v1

Lifelong premature ejaculation (LPE) is a vexing male sexual disorder potentially linked to brain dysfunctions, although the precise mechanisms remain unclear. Data of resting state functional magnetic resonance imaging was acquired from 46 LPE patients and 35 male healthy controls. We firstly investigated altered temporal variability of spontaneous brain activity fluctuations of LPE patients using sliding-window approach. Secondly, the correlation analysis was performed between brain areas with abnormal brain dynamics and clinical characteristics. Finally, the relationship between brain dynamic abnormalities and the impairments of specific neurotransmitter systems in LPE patients was assessed using JuSpace. Dynamic analysis revealed that LPE patients had decreased dynamic regional homogeneity (dReHo) in the precentral gyrus, supplementary motor area (SMA), frontal gyrus, rolandic operculum and increased dReHo in the lingual gyrus (LING), precuneus, calcarine cortex, fusiform gyrus. While analysis also revealed that LPE patients had decreased dynamic amplitude of low-frequency fluctuations (dALFF) in the LING gyrus, occipital cortex, and increased dALFF in the cuneus, postcentral gyrus. Correlation analysis exhibited the mean dReHo of left SMA was positive associated with the ejaculation latency time (IELT) scores. Moreover, aberrant brain dynamic was significantly associated with the spatial distribution of serotonin and endogenous opioid peptide pathways. Our study indicates LPE patients brain dynamic abnormality involved in multiple brain networks, and suggests that the LPE pathophysiology may be involved in neurotransmitter system imbalances. We hope our findings may offer fresh insights into the mechanisms of LPE and potential avenues for treatment in future.

lifelong premature ejaculations

brain dynamics

magnetic resonance imaging

neurotransmitters

Premature ejaculation (PE), an irritating and frustrating male sexual disorder, accounts for a considerable proportion of sex-related diseases all around the world. In the light of definitions proposed by numerous professional organizations and professionals, PE can be generally divided into lifelong premature ejaculation (LPE) and acquired premature ejaculation (APE). LPE is typified by ejaculation that invariably occurs prior to or within 1 minute or 2 minutes after vaginal penetration based on the International Society for Sexual Medicine (ISSM) guideline(1) and the American Urological Association (AUA) guideline in 2020(2), separately. The incapacity to retard ejaculation on whole vaginal penetrations and negative personal emotions such as annoyance, distress and fear of intimacy(3). However, the pathophysiological mechanisms underlying LPE remain elusive.

The development of magnetic resonance imaging (MRI) technology provides a reliable and non-invasive means of investigating brain abnormalities in relation to certain disorders. Resting-state functional MRI (r-fMRI) has been extensively applied to provide evidence linking LPE with changes of brain functions. Recent studies(4) have shown that LPE patients exhibit higher amplitude of low-frequency fluctuations (ALFF) values in the inferior frontal gyrus, fusiform gyrus, lingual gyrus as well as insula and lower ALFF values in the posterior cingulate cortex, hippocampus and thalamus compared with healthy controls (HCs). LPE patients have been reported to have increased fractional ALFF (fALFF) values in the inferior and middle frontal gyrus(5). Significant differences of regional homogeneity (ReHo) have been noted within the default mode network (DMN) and auditory network (AUD) in LPE patients compared to HCs(6). There also exist alterations of degree centrality (DC) in the orbitofrontal cortex and anterior cingulate cortex(7). Additionally, changes of functional connectivity (FC) are observed within the intrinsic networks, related to the frontal cortex, temporal cortex, parts of the basal ganglia and limbic system when compared LPE patients to HCs(8). These studies have revealed that changed brain functions of LPE patients are crucial as they may lay a solid foundation for potential biomarkers and the exploitation of new treatment targets for this disease. However, we still need to do further researches to explore the relationship between altered brain functions and possible pathophysiological mechanism of LPE.

The studies mentioned above all utilize a "static" approach to analyze fMRI signals under abnormal brain activity. The premise of this approach is that blood-oxygen-level dependent (BOLD) signals remain stable throughout the whole resting-state fMRI scanning and that brain activity and connections are static during this period. However, recent studies have shown that functional activity and connection patterns of brain may change dynamically over a time scale of a few seconds to minutes(9). Brain dynamics have been paid more attention to. Applying the sliding window approach to the entire fMRI data produces a series of time windows, the dynamic ReHo (dReHo) and the dynamic ALFF (dALFF) methods are applied characterizes temporal variability and flexibility of brain activities(10), which have been preliminarily used to assess brain dysfunctions of certain diseases(11). Thereby, further dynamic analysis of brain functions may be helpful in better indicating the pathological mechanisms of LPE, facilitating the identification of reliable neural markers, and ultimately improving its diagnosis and treatment.

In the late 20th century, the 5-hydroxytryptamine (5-HT) system was found to be in the regulatory circuitry governing ejaculation in rats(12). Since then, the modulatory capacity of 5-HT in the human brain over ejaculation responses has been of particular interest. Prior to this, selective serotonin reuptake inhibitors (SSRIs) were extensively employed as antidepressant agents. However, patients using these medications exhibited long-term drug side effects, including ejaculation delay(13). Building upon these findings, subsequent research was conducted, ultimately culminating in the registration of the first medication for PE (dapoxetine)(14). This, in turn, indirectly confirmed the intricate relationship between the neurotransmitter system in the human brain and ejaculation control. Presently, various neurotransmitter systems, including γ-aminobutyric acid (GABA), 5-HT, oxytocin, and mµ-opioid neurotransmitters, have been identified to be associated with the pathogenesis of PE based on animal mode (15). However, our researches of neurotransmitter systems in f LPE patients remains limited. Exploring the pathways of neurotransmitter signal transmission implicated in LPE could offer a more comprehension of LPE.

In this study, we therefore tried to utilize sliding window analysis to calculate dReHo and dALFF to capture different temporal variability of spontaneous activity fluctuations in LPE patients compared to HCs. We also employed the JuSpace toolbox to evaluate the patterns of neurotransmitter defects in LPE patients based on imaging differences between the two groups. Here, we postulated that: (i) that LPE patients could exhibit distinct dynamic brain activity patterns compared to HCs, and (ii) these imaging differences showing dynamic characteristics might be potentially associated with clinical characteristics and aberrant neurotransmitter system in LPE patients.

Subjects

A total of 81 right-handed men were enrolled in the study, including 46 individuals with LPE and 35 HCs. The diagnosis of LPE was based on the guidelines provided by the International Society for Sexual Medicine (ISSM), the details of inclusion criteria for all participants were showed in the Supplementary materials.

Magnetic resonance imaging data acquisition

The imaging data used in this study were collected using a 3.0 T MRI scanner (Excite, General Electric) and a standard birdcage head coil obtained from a local hospital. The brain fMRI images and T1 images were acquired with specific parameters showed in the Supplementary materials. During the resting state scanning, participants were instructed to keep their eyes open and avoid engaging in any specific thoughts.

Image Preprocessing

The functional data underwent pre-processing using Data Processing Assistant for Resting-State fMRI 6.2 (DPARSF v6.2 http://www.rfmri.org/dpabi) toolbox in accordance with standard protocols. For details in the Supplementary materials.

Analysis of dReHo and dALFF

For the dReHo and dALFF analysis, the preprocessed global BOLD signals were divided into a series of consecutive time windows segments by sliding Humming window. Determining the size of the sliding window is a critical factor as the window size should be large enough to ensure robustness and high signal-to-noise ratio of the dynamic fluctuations estimation, and also small enough to ensure sensitivity in detecting transient events of interest. According In the study, a window size of 30TR (60s) with a step size of 1TR, which divided the BOLD signal time series into 181 windows, was selected to evaluate brain analysis because prior researches reported that a window size of 30 to 60 seconds is conducive to robust and meaningful results(16). The dynamic ALFF and ReHo maps were computed, and the specific steps were shown in the Supplementary materials. Subsequently, we implemented z-normalization within a gray matter mask and smoothed the dALFF and dReHo maps using a 6 mm full-width at half-maximum (FWHM) Gaussian kernel. The coefficient of variation for dReHo and dALFF is computed to assess the temporal variability of brain activity.

Spatial correlation with neurotransmitter density map

The JuSpace toolkit (version 1.4) was employed to investigate whether changes of dReHo and dALFF exhibited associations with specific neurotransmitter systems in LPE patients compared to the HCs(17). We focused on evaluating the serotonin, dopamine, and endogenous opioid systems, considering the following neurotransmitter components: 5-HT1a receptor, 5-HT1b receptor, 5-HT2a receptor, 5-HT4a receptor, serotonin transporter (SERT), dopamine receptor D1, dopamine receptor D2, dopamine transporter (DAT), mµ receptor, cannabinoid receptor 1 (CB1), CBF, FDOPA, GABAa Receptor, vesicular acetylcholine transporter (VAChT), metabotropic glutamate receptor 5 (mGLUR5), and norepinephrine transporter (NAT).

The neuromorphometric map was derived using the automatic Anatomy Marker (AAL) map employed by JuSpace developers. We extracted the average regional values of dReHo and dALFF for all the LPE patients. Subsequently, we calculated the Spearman correlation coefficient (Fisher's Z transform) between the Z-transformed dReHo and dALFF maps of patients and the spatial distribution of neurotransmitter maps in the JuSpace toolbox.

To determine the significance, we employed exact permutation-based p-values included in JuSpace (with 10,00 permutations randomly assigning group labels using orthogonal permutations). This allowed us to assess whether the observed Fisher's Z-transformed individual correlation coefficients differed significantly from zero while correcting for the number of neurotransmitter maps using FDR correction. The Spearman correlation coefficients were calculated between the spatial distributions of the Z-transformed dReHo and dALFF maps and their respective neurotransmitter maps. Negative correlations (and the resulting negative Fisher's Z values) indicate that patients exhibit the most substantial decline in dReHo or dALFF in areas where the healthy population originally demonstrated high availability of the respective neurotransmitter, suggesting increased vulnerability in those regions.

Statistical analysis

Statistical analysis was performed using SPSS version 20.0 (IBM, Armonk, NY, USA). Key demographic information and clinical characteristics were compared between LPE patients and HCs. Statistical results were presented as mean ± standard deviation. To assess differences of dReHo and dALFF between two groups, two-sample t-test was conducted with a significance level P < 0.005 at voxal level and P < 0.05 false discovery rate (FDR) at cluster level. In order to investigate the correlation between patients' brain dynamic abnormalities and clinical indicators, the dReHo and dALFF in abnormal brain areas were analyzed in relation to IELT and PEDT clinical scores using Pearson correlation analysis. Bonferroni correction was used to adjust for multiple hypotheses in this analysis.

Demographic and clinical characteristics

The study included 46 LPE patients and 35 HCs. Table 1 summarizes the clinical characteristics of both the LPE and HC groups. There was no significant difference observed in age and IIEF-5 score between the LPE patients and the HCs (P < 0.05). However, as expected, the LPE patients exhibited higher PEDT scores (indicating higher levels of premature ejaculation symptoms), lower IELT duration scores (indicating shorter intravaginal ejaculatory latency time), as well as higher anxiety and depression scores compared to HCs.

Dynamic ALFF and dynamic ReHo differences in LPE patients

Compared to HCs, LPE patients exhibited significant temporal variability of dReHo and dALFF values in a range of brain regions. It was illustrated in Figure 1, Figure 2, Table 2 and Table 3. LPE patients displayed decreased dReHo in the right precentral gyrus (preCG), left supplementary motor area (SMA), left inferior temporal gyrus (ITG), bilateral middle frontal gyrus (MFG), right superior frontal gyrus (SFG), and Rolandic Operculum (ROL), and significant increased dReHo in the bilateral lingual gyrus (LING), right precuneus (preCUN), bilateral calcarine cortex (CAL), and left fusiform gyrus (FFG) (Figure 1 and Table 2).

In terms of dALFF, LPE patients showed significant decreased dALFF in the right LING gyrus as well as right inferior occipital cortex (IOC), and increased dALFF in the bilateral CUN and right postcentral gyrus (poCG) (Figure 2 and Table 3).

Subsequent investigations revealed significant correlations between the IELT score and dReHo in specific brain regions of LPE patients. Specifically, there was a positive correlation between the IELT score and dReHo time variability in the left SMA (r = 0.32, P = 0.03) (Figure 3). On the other hand, no significant correlation was observed between the clinical characteristics of PE (PEDT and IELT scale) and dALFF value.

Neurotransmitters profile in LPE patients

In comparison to HCs, a significant relationship between the dReHo temporal variability and spatial distribution of the 5-HT4 receptor (r = -0.09, P < 0.01) and mμ receptor (r = -0.10, P < 0.05) (Figure 4).

In this study, we used the dReHo and dALFF methods to assess more accurate neural markers of LPE between the LPE patients and HCs. Compared to HCs, LPE patients showed significantly decreased dReHo in the SMA, preCG, MFG, SFG, ITG, and increased dReHo in the LING, preCUN, and CAL. While, the significantly decreased dALFF in the LING, IOC as well as increased dALFF in the poCG and CUN were observed in LPE patients. Additionally, there was a positive correlation between the time variability of dReHo in the SMA and IELT score. Furthermore, utilizing the JuSpace tool introduced by Dukart et al. ^[40], which allows our research to establish a direct connection between LPE neuroimaging and abnormal levels of neurotransmitters in the central nervous system, we detected that the function of 5-HT4 and mµ receptors in the central nervous system of LPE patients was impaired compared to HCs.

Altered dynamic ReHo and dynamic ALFF in LPE patients

We found that compared to HCs, LPE patients had significantly decreased dReHo in the SMA and preCG, which are crucial components of the sensorimotor network (SMN) responsible for motor planning and execution control(18). SMA is highly implicated in motor activation and action control(19), and is activated not only during physical movement but also during the inhibition of imaginative behavior (behavior occurs in imagination, but not in practice(20). preCG belongs to the SMN cortex and is related to motor control(21). Abnormal functions of the SMA and preCG in LPE were reported(22). A positive correlation was also found between the dReHo in the lift SMA and IELT scores. Thereby, we speculate that the decreased dReHo in the SMA and preCG in LPE patients may be related to the difficulty in controlling their own rapid ejaculation.

We observed significantly decreased dReHo in the bilateral MFG, right SFG, and left ITG in LPE patients compared to HCs. These brain regions are integral components of the executive control network (ECN), responsible for executing cognitive control functions and carrying out instructions from the executive centers of the brain(23). The MFG and SFG are considered to be crucial parts of the ECN and are associated with reward circuits and cognitive complexities(24). Previous neurosurgical investigations have implicated the involvement of the frontal and temporal lobes in the inhibitory functions during male ejaculation(25), and functional impairments in the frontal and temporal lobes have been reported in individuals with LPE(26). Therefore, our study provides further evidence that the ECN may be involved in the pathophysiology of PE, and ECN-related abnormalities may be closely associated with the inability of patients to delay ejaculation, leading to impaired control over ejaculation behavior.

In comparison to HCs, LPE patients had a significantly increased dReHo in the right preCUN within the DMN in our study. Extensive neuroimaging investigations have highlighted the crucial role of the DMN in advanced functions such as introspection, memory, and emotional processing(27). The preCUN, considered a key hub of the DMN(28), is implicated in complex cognitive functions such as reward circuitry, emotional processing, and visual-spatial imagination(29). Studies on LPE have indicated that visual stimuli induces a decreased preCUN activity in healthy males while increasing preCUN activity in LPE patients(30). Consequently, we hypothesize that the heightened responsiveness of the DMN during sexual activity in LPE patients may be related to the dysregulation of emotional processing and reward mechanisms, potentially underpinning the abnormal aspects of the condition.

Our study revealed LPE patients showed the increased dReHo in the bilateral LING and lift CAL regions compared to HCs. These regions are parts of the visual network (VN) and are associated with visual processing and anxiety-related emotions(31). The elevated dReHo in these brain regions may be related to emotional factors such as anxiety that PE patients may experience.

Compared to HCs, LPE patients also exhibited the significantly increased dALFF in the bilateral CUN and decreased dALFF in the right LING and right IOC in this study. The regions showing dALFF group differences were closely related to visual processing(32), suggesting a potential association with abnormal visual processing in LPE patients.

Furthermore, LPE patients exhibited the increased dALFF in the poCG. The postcentral gyrus is a crucial region of the SMN, which is regarded as a physiological indicator of penile erection. However, the specific role of the postcentral gyrus in sexual behavior remains unclear.

Altered neurotransmitters profile in LPE patients

Our findings revealed the close association between the abnormal brain dynamics in PE patients and impairment of the 5-HT system and the mµ system. There is several physiological and biological evidence supporting the link between neurotransmitters and LPE(33), Waldinger proposed that LPE was influenced by complex interactions between the central nervous system, peripheral nervous system, and endocrine system, exhibiting decreased release and transmission of 5-HT, along with dysfunctional 5-HT receptor subtypes in patient group. The serotonergic system is currently considered to be closely linked to the pathogenesis of LPE, with various subtypes of 5-HT receptors involved in the regulation of dopamine release mediated by endogenous monoamine neurotransmitter 5-HT(34). Furthermore, the close relationship has been reported between mµ receptor and the occurrence of LPE, the opioid analgesic tramadol has been proved to be an effective drug for the treatment of LPE (activator of mµ receptor)(35). The imbalance in the 5-HT and mµ neurotransmitter system we found in this study might disrupt the regulation of erection duration in men. Our findings provide further evidence support aberrant impact of neurotransmitter system on LPE through the lens of imaging and physiological mechanisms.

There are several limitations to acknowledge in this study. Firstly, the lack of a longitudinal design prevents further clinical validation of our hypotheses. Additionally, the relatively small sample size restricts the generalizability of our conclusions. Furthermore, our use of default brain parcellation templates and neurotransmitter maps in the JuSpace toolbox may benefit from more precise conditions to achieve optimal results. Lastly, although we conduct investigations on different window sizes, we cannot guarantee whether the chosen window size is optimal, necessitating further research.

In this study, we observed alterations in dReHo and dALFF within certain brain regions encompassed by the SMN, ECN, DMN, and VN in LPE patients. These findings suggest that the difficulties of LPE patients experience in controlling rapid ejaculation may be linked to abnormalities in their motor execution control, emotional processing, and visual processing. And we speculate that dysregulation in two neurotransmitter systems may contribute to the pathophysiological basis of LPE. The changes of dynamic brain activity and associated neurotransmitter system in patients will enhance our understanding of the neuropathology and physiology of LPE and will potentially offer new insights and strategies for the diagnosis and treatment of this condition.

Acknowledgements

I would like to express my heartfelt gratitude to Professor Gao Ming, Professor Gao Junjun, and Professor Liu Peng for their invaluable data and theoretical support in the successful execution of this research. I also extend my thanks to Professor Liu Peng, Senior Colleague Liu Chengxiang, and all the fellow colleagues in the research group for their unwavering support throughout the process of writing this paper.

Ethics statement

The procedures of the study were approved by the Ethical Committee of the local hospital and were conducted in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). Each subject signed a written informed consent before study participation.

Consent to participate

All participants volunteered to participate in the present study with informed consents.

Consent to publish

All the authors agreed to publish this study in this journal.

Competing interests

We declare that we have no conflict of interest.

Authors’ contributions

Ming Gao was responsible for the study concept and design as well as drafted the manuscript; Jiarui Yuan and Dingxin Nie assisted with data analysis and interpretation of findings and drafted the manuscript; Chengxiang Liu, Pinxiao Wang, Wanxiang Zheng, Jianyong Feng, Yuntao Zhang, Yanzhu Wang, Junjun Gao and Peng Liu contributed to acquisition of MRI data and study design; Dingxin Nie contributed to data analysis and interpretation of findings. All authors critically reviewed the content and approved the final version for publication.

Funding

International Science and Technology Cooperation Program of Shaanxi Province - General Project (No.2022KW-21), Health research talent project of Xi'an Health Commission (No.2021yb61), General projects of Shaanxi Provincial Health Commission (No.2022D006), Youth Talent Program of Xi'an Talent Plan (No.XAYC211060), General Medical Research of Xi'an Science and Technology Bureau (No.2022JH-YBYJ-0399), Real World Research on Appropriate Electrophysiological Techniques Fund Projects (No.HDSL202001080), Science popularization activities of Shaanxi association for science and technology (No.2023-2-1-3).

Availability of data and materials

The datasets generated and/or analyzed during this study are available from the corresponding author on reasonable request.

Code availability Not applicable.

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Table 1. Demographic and clinical characteristics of LPE patients and HCs

Characteristics	PE (n = 46)	HCs (n = 35)	P - value
Ages (years)	30.33 ± 5.16	31.66 ± 3.02	0.178
IIEF-5 score	23.85 ± 0.84	24.26 ± 1.26	0.082
PEDT score	17.15 ± 1.87	0.91 ± 1.54	0.000***
IELT (min)	39.74 ± 14.62	652.29 ± 327.94	0.000***
Anxiety	38.70 ± 5.96	30.34 ± 1.71	0.000***
Depression	40.85 ± 3.41	30.29 ± 2.07	0.000***
Abbreviations: LPE lifelong premature ejaculation, HCs healthy controls, IIEF-5 international index of erectile function, IELT intravaginal ejaculatory latency time, PEDT premature ejaculation diagnostic tool Data are expressed as the mean ± standard deviation (SD) (range values) ***P < 0.001 by independent sample t-test

Table 2. Brain regions showing significantly dReHo alterations between the LPE patients and HCs

Regions		Peak MNI Coordinate			BA	Cluster size	T-value
Regions		X	Y	Z	BA	Cluster size	T-value
Patients < HCs
	Left SMA	-6	-15	57	6	52	-3.77
	Right preCG	63	12	18	6	63	-3.81
	Right MFG	27	36	42	9	103	-3.95
	Right SFG	15	36	51	9	116	-3.39
	Left MFG	-30	33	39	9	68	-3.9
	Left ITG	-45	-6	-39	20	249	-4.58
	Left ROL	-36	-33	15	48	56	-3.98
Patients > HCs
	Right preCUN	6	-78	-42	7	71	3.95
	Left CAL	-21	-66	9	17	68	3.57
	Left LING	-9	-66	3	18	73	3.20
	Right LING	21	-60	-3	19	86	3.54
	Right FFG	27	-51	-6	37	88	3.57
Abbreviations: LPE lifelong premature ejaculation; HCs healthy controls; dReHo, dynamic Regional Homogeneity; MNI Montreal Neurological Institute; BA Brodmann’s area; X, Y, Z, peak coordinate in the MNI space; SMA supplementary motor areas; preCG precentral gyrus; MFG middle frontal gyrus; SFG superior frontal gyrus; ITG inferior temporal gyrus; ROL rolandic operculum; preCUN precuneus lobe; CAL calcarine; LING lingual gyrus; FFG fusiform gyrus

Table 3. Brain regions showing significantly dALFF alterations between the LPE patients and HCs

Regions		Peak MNI Coordinate			BA	Cluster size	T-value
Regions		X	Y	Z	BA	Cluster size	T-value
Patients < HCs
	Right LING	27	-96	-15	18	65	-3.15
	Right IOG	30	-90	-15	18	68	-3.23
Patients > HCs
	Right poCG	63	-6	36	43	69	4.41
	Left CUN	-6	-84	42	19	102	3.57
	Right CUN	12	-87	36	19	90	3.52
Abbreviations: PE premature ejaculation; HCs healthy controls; dALFF, dynamic Amplitude of low-frequency fluctuation; MNI Montreal Neurological Institute; BA Brodmann’s area; X, Y, Z, peak coordinate in the MNI space; LING lingual gyrus; IOG inferior occipital gyrus; poCG postcentral gyrus; CUN cuneus lobe;

No competing interests reported.

Supplementarymaterials.docx

Dynamic Changes of Intrinsic Brain Activity and Neurotransmitter Defect Profile in Patients with Lifelong Premature Ejaculation

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Abstract

Figures

Introduction

Experimental procedures

Statistical analysis

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1