This study protocol has been approved by the Institutional Review Board of the Hospital of Chengdu University of TCM (Approval No. 2018KL–064), the Sichuan Integrative Medicine Hospital (Approval No. 2017KY-02) and has been registered under the identifier No. ChiCTR-IOR-1800018301 on the Chinese Clinical Trial Registry. Any modifications to the research protocol will be notified to this Human Research Ethics Committee. Informed consent will be obtained from each participant prior to enrollment. The study bases on the principles of the Declaration of Helsinki and Good Clinical Practice guidelines.
A total 135 Chinese patients who fulfill the criteria will be recruited at the Hospital of Chengdu University of Traditional Chinese Medicine (TCM) and Sichuan Integrative Medicine Hospital.
All psychogenic ED patients are recruited at the outpatient department in the Hospital of Chengdu University of Traditional Chinese Medicine (TCM) and Sichuan Integrative Medicine Hospital via advertisements in newspapers and via the Internet from November 2018 to January 2019.
All patients must be in a stable sexual relationship for at least 1 year, and must be estimated by as follows:
- 1. a detailed history asking, including psychosocial history (paying more attention to the patient's expectation of his own sexual performance and his general attitude and knowledge about sex, etc) and interviewing the patient's partner, medical history, mainly about relevant drug history (including tobacco, alcohol, or illicit drug use and so on), and surgical history;
- 2. a careful and detailed physical examination, especially the urology and andrology examination and rectify any misconceptions the patient might have about the relationship between penile length, masculinity, and erection;
- 3. a basic laboratory test, containing a nocturnal penile tumescence (NPT) test, a penile duplex Doppler ultrasonography (DUS) with peak systolic velocity (PSV), end-diastolic velocity (EDV) and resistant index (RI) measurements before and after intracavernous injection (ICI) of prostaglandin, as well as routine blood examinations, thyroid-stimulating hormone, serum prostatic specific antigen (PSA), and the serum sexual hormone level (sexual hormone binding globulin, free or\and total testosterone, follicle-stimulating hormone, luteinizing hormone, estrogen, and prolactin);
- 4. a psychophysical condition evaluated by 2 separate experienced psychologists, and
- 5. a series of questionnaires, mainly concerning about the International Index of Erectile Function 5 (IIEF-5), a self-esteem and relationship questionnaire (SEAR), the erection hardness score (EHS), the erection quality questionnaires (QEQ), the 14-item Hamilton Rating Scale for Anxiety (HAMA-14) and the 17-item Hamilton Rating Scale for Depression (HAMD-17). All of the above must be by checked before being enrolled in this study.
2.4 Sample size
Due to the lack of reference on the expected effect size of using CHSGS to treat erectile dysfunction evaluated in this study, we did not estimate the sample size based on a power calculation. According to previous studies, International Index of Erectile Function 5 (IIEF-5) scores of ED patients increased 6.0–7.1 after tadalafil.[13,15] Therefore, we predicted ascension of IIEF-5 score by 6.5 points after oral tadalafil or CHSGS capsule, a reduction by 2.5 points after placebo. According to the calculation with PASS software (Version 11.0, NCSS, LLC. Kaysville, UT, USA) in a 1:1:1 ratio, when α = 0.05, 1-β = 0.8 with the standard deviation to be 3.8, the effect size is 0.2550 of 41 participants in each group. Considering a dropout rate of 10% and according to our previous study, a sample size of 135 patients at baseline will be planned in this study.
According to the sample size of previous BOLD-fMRI, TDI, and fMRI studies, 12 to 15 subjects is the very reasonable sample size with stable statistical effect.[29,30] Considering the dropout rate and loss of data as to head motion during MRI scans. Among 45 patients in each group, 15 participants will be selected randomly to undergo MRI scans in this study.
Qualified participants will be randomly assigned to either the tadalafil group, the placebo group or the CHSGS capsule group in a ratio of 1: 1:1. Random numbers will be generated by a random number generator in the SPSS statistical software package (Version 22.0, SAS Institute Inc), which will be operated by a third party who is uninvolved with the treatment and data collection. The drawn letters (A or B or C) will be placed into opaque envelopes labeled with sequential numbers. The envelopes will be sealed and remain in numerical order in a safe place till the completion of this study. The same researcher (not involved in the study) will prepare the envelopes.
Double blind and double simulated tests will used in this study protocol to guarantee the blinding, we will made sham tadalafil and sham CHSGS capsule. The medicine will be specially handled and labeled by the Pharmacy Department in the Hospital of Chengdu University of TCM to guarantee that the patients and the practitioners included in the study will maintain completely blinded as to the identity of the treatment administered. Besides, the all practitioner will be prohibited to communicate with participants about the information of this trail.
2.7 Eligibility criteria
2.7.1 Inclusion criteria
Patients must meet the following diagnostic criteria from the current guidelines, including:
- 1. men be right-handed and the age ranged from 20 to 40,
- 2. men be diagnosed as psychogenic ED (DSM-5),
- 3. men must be in a stable sexual relationship for at least 1 year with his regular sexual partner,
- 4. penile erection can occur in the circumstance of masturbation or audiovisual stimulation,
- 5. men who meet the TCM diagnosisof stagnation of liver-qi”,
- 6. men who agree to complete all demand during the study period,
- 7. sign an informed consent form.
2.7.2 Exclusion criteria
Exclusion criteria for the forthcoming study are as follows:
- 1. be diagnosed as organic ED rather than psychogenic disorder,
- 2. a current diagnosis or history of drug or alcohol dependence;
- 3. use of any medication that might impact sexual function during the previous 30 days before enrolled in this study;
- 4. any physical illness as assessed by personal history and laboratory analysis finding any history of serious psychiatric, neurological, cardiovascular, respiratory, gastrointestinal or renal diseases or hepatic disorders or significant physical disorders;
- 5. participated in any other current clinical trials;
- 6. had any contraindications for MRI scan.
2.8 Test drugs
Test drugs are tadalafil, CHSGS capsule and placebo, provided by the Hospital of Chengdu University of TCM. The three drugs had the same shape, size, color, smell, package, and Lot number.
3.1 CHSGS group
Patients will be provided three-daily treatment with 5 g CHSGS added to the 5 capsule each time until 4 weeks.
The CHSGS preparation contained the gathering of the following components: 6 g Bupleurum Chinese root, 4.5 g Rhizoma Chuanxiong, 4.5 g Fructus Aurantii, 6 g Pericarpium CitriReticulatae, 4.5 g Paeonia, 1.5 g Glycyrrhizaeuralensis root and 5 g Cyperusrotundus. All CHSGS herbal components were obtained from the Hospital of Chengdu University of TCM. The herbal components were identified by an expert in order to fulfill the quality requirements of the Pharmacopoeia of the People's Republic of China (2015 edition). CHSGS and its components were individually decocted in boiling water for 30 minutes, concentrated and vacuum-dried to form a paste, and were subsequently combined into a paste containing 8 g crude extracts per gram. Starch powder was mixed into a container. Stir it well and make it into capsule.
3.2 Tadalafil group
Patients will be provided a once-daily treatment with 5 mg tadalafil added to the capsule until 4 weeks.
According to the current guidelines, the therapeutic interventions for ED are basic treatment, drug treatment, physical treatment and surgical treatment. Drugs are phosphodiesterase type 5 inhibitors such as tadalafil, sildenafil, vardenafil, avanafil, which have been regarded as the first-line oral pharmacotherapy for ED.[17,18] Some previous clinical research have confirmed that patients and partners prefer tadalafil to sildenafil in the treatment of ED.[11,13–16,43,44] Therefore, we selected tadalafil as the positive control group as well as the treatment group. Smashed tadalafil will be mixed with starch powder and stir well into a container in order to be made into capsule.
3.3 Placebo group
Patients will be provided three-daily treatment with the 5 g mixed starch powder added to the 5 capsule each time until 4 weeks.
It is known that placebos are the best comparison between clinical controlled trials. Therefore, we adopted this placebo and standardized its performance. The placebo components were obtained from the Hospital of Chengdu University of TCM. The standard operating procedures (SOP) are listed as follows:
- 1. the materials are starch,
- 2. add the liquid base: place the mixed starch powder into a container, add honey and stir well to make it into capsule. The above materials made shared the same character with the CHSGS capsule in terms of appearance, weight and taste.
3.4 MRI scan
The MRI scanning of the brain will be executed on a 3.0-T GE MRI scanner (General Electric Company, America) at the Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China, including the magnetic resonance (MR) diffusion tensor imaging (DTI), T1-weighted, a resting-state blood oxygenation level dependent MRI (BOLD-MRI) data of all participants in this study.
T1-weighted structure images in 3D Magnetization-Prepared Rapid-Gradient-Echo (MPRAGE) Images will be firstly collected before resting-state scanning with the following sequence parameters: field of view (FOV) = 240 × 240 mm2, repetition time (TR) = 1900 ms, echo time (TE) = 2.26ms, and matrix = 256 × 256.
DTI will be applied along 63 non-linear directions (b value = 1000 s/mm2) together with an acquisition without diffusion weighting (b value = 0 s/mm2), and the scanning parameters are as follows: FOV = 230 × 230 mm2, TR = 8900 ms, TE = 84 ms, and matrix = 256 × 256.
The resting-state BOLD-MRI will be obtained by using Gradient-Recalled Echo-Planer Imaging (GER-EPI) with the following sequence parameters: TR = 2000 ms, TE = 30 ms, inverse angler (IA) = 90°, number of slice = 32, slice thickness (ST) = 5 mm, FOV = 240 × 240 mm2, matrix = 64 × 64, and total volumes = 400.
3.5 Outcome assessment
The following outcomes will be assessed by independent assessors, who had been trained before participating in this study and blinded to the randomization. All outcome data for participants whether completed or withdrawn during the study will be collected and recorded in the case report form (CRF).
3.5.1 Primary outcome
Based on various clinical studies, all the patients, including the primary symptoms of the ED patients will be assessed on mean changes from baseline (the day that the patient begin protocol) to end of observation (the day of end of protocol) in the brain MRI and International Index of Erectile Function 5 (IIEF-5) total scores,[45,46] which has been widely used and recommended as a primary outcome for clinical trials of ED. Furthermore, the quality of erection questionnaire (QEQ)[47–49] and the erection hardness score (EHS) total scores will also be included in this study.[47,50]
3.5.2 Secondary outcome
In terms of the assessment of symptom severity of erectile function for all the participants in this study, the secondary outcome will be based on the self-esteem and relationship (SEAR) questionnaire. As to the level of anxiety and depression of all the participants in this study, it will be evaluated by two independent psychologists within the questionnaires of the 14-item Hamilton Anxiety Rating Scale (HAMA-14) and the 17-item Hamilton Depression Rating Scale (HAMD-17).[52,53]
3.6 Adverse events
Adverse events (AEs) related to tadalafil treatment such as myalgia, back pain and flushing will be appropriately estimated and recorded by the observers during the trial. AEs will be managed by a specialized practitioner (do not participate in clinical data analysis) within 24 hours. The principal researcher (PH Zhang) will make the final decision to terminate the trial if severe AEs occurs. All data for participants during the study and details of related and unexpected AEs (the time of occurrence, severity of AE, and suspected causes) will be collected and recorded in the case report form (CRF). Measures may vary from symptomatic treatment to case submission to the Research Ethics Committee within 48 hours depending on the severity of AEs.
3.7 Quality control and Data collection
Due to the fact that any nonstandard or bias input of clinical data can dominate the bias of results, two practitioners (to estimate the effect of treatment and the data authenticity) will independently gather the data with case report forms and original cerebrum MRI. The collected data will be input into a dedicated computer. The above process will maximize the reliability and safety of the all data. In order to guarantee the quality of the study, all practitioners will be required to have an official license for at least 2 years of protocol study and clinical experience.
3.8 Data analysis
3.8.1 Clinical variables analysis
The clinical data will be analyzed with the help of SPSS22.0 (SPSS Inc., Chicago, IL) by 2 blinded evaluators. The missing data analysis will be based on the intention-to-treat (ITT) principle regarding baseline characteristics. The clinical scores of the subjects (including the pED severity and duration, the sum scores of IIEF-5, SEAR, EHS, QEQ, HAMD-17 and HAMA-14) will be examined by means of the Pearson correlation analysis. All the clinical data in this study will be presented as follows:
- 1. a continuous measurement data being presented as the mean±standard deviation (SD), the mean, SD, median and interquartile range.
- 2. a categorical data being presented as case and percentages. Analysis tools include: the Cochran-Mantel-Haenszel (CMH) test or nonparametric test, an independent samples t-test, and a two-sided test. Also, analysis of covariance, covariance analysis or generalized estimating equations, χ2 and Linear regression will be applied on all available and suitable data (P value <.05 is considered to be statistically significant).
3.8.2 MRI data analysis
The fMRI scan data will be preprocessed and analyzed by SPM12 software (http://www.fil.ion.ucl.ac.uk/spm/) performed on MATLAB 2015b (MathWorks, Inc, Natick, MA). Two-sample t tests will be used to evaluate possible cerebral responses in each group by within-group analysis (post-treatment minus pre-treatment). We will use between-group analysis to compare the difference in cerebral response changes. Correlation analysis will be conducted to investigate changes between fMRI image data and corresponding clinical data in each group. Based on our previous research's methods and acquisition of the brain MRI data, MRI data will be firstly preprocessed and analyzed by SPM12 software performing on MATLAB 8.6 (Math works, Inc., Natick, MA, USA), Brain Voyager QXsoftware (Brain Innovation, The Netherlands). And then, for accurately investigate the different cerebral responses, including regional homogeneity (ReHo), tract-based spatial statistics (TBSS),[56,57] amplitude of low-frequency fluctuation (ALFF), and functional connectivity (FC) will be used in this study. Finally, correlation analysis will be processed between clinical data and MRI image data.
Figure 3 illustrates the data access and the analysis of the brain MRI data as well as the analysis methods of the primary and secondary outcomes.
In this protocol study, the qualified participants are asked to maintain their current living habits and sexual performances, especially their diet, exercise and the quality of sleep. Meanwhile, they are required to fill out relevant questionnaires throughout the full observational process. To satisfy the requirements of the Rule of Ethics and reduce the bias caused by performance, the rest of the all clinical procedures maintain the same.
Seen from the current records and recent RCT results, tadalafil has an enduring effect and was the best-marched choice between patients and their partner for treating psychogenic ED. However, its central mechanism remains unclear. Considering the importance of the brain for the psychogenic ED, we have designed the randomized controlled MRI trial to reveal the central mechanism of the psychogenic ED treated by tadalafil. In this study, we will compare the changes in brain function after administration of 2 interventions: the tadalafil and the CHSGS capsule.
Many regions of the human brain have been found to play a very important role in human sexual arousal as well as penile erection, emotion, and cognition. Over the last 15 years, MRI science has been widely used to disclose the cerebral mechanism of human sexual arousal especially the penile erection and investigate the brain function alteration in psychogenic ED and healthy subjects. Erection is known to be one of the most convincing and mischievous signs of the sexual response cycle. Relatively, ED not only can be conceptualized as an impairment in the arousal phase of sexual response, but also can be seen as a central and spinal center reflex, which can be sponsored by recruitment of penile afferents, both somatic and autonomic, and the changes of visual, imaginary stimuli, and olfactory. Several central transmitters play a crucial role in erectile control and the main regions that control of male sexual arousal are summarized in Figure 4. Previous DTI studies showed that psychogenic ED had decreased or increased white matter microstructures in multiple brain regions. Besides, brain networks neuro-imaging studies also had showed that psychogenic ED had increased the small-worldness and modules in the left prefrontal cortex and limbic system including the right superior parietal gyrus, and the superior parietal gyrus.[23–25]These brain networks were absolutely believed to be closely related to the brain sexual arousal of the psychogenic ED.[60–63]
In order to guarantee the reliability of the result of this study, we adopt the quality key point control as follows:
- 1. patient in this study restricts the subjects to age between 20 to 40 and being right-handed for baseline homogeneity;
- 2. sample size to obtain stable statistical power; 135 patients will be included in each group for clinical evaluation and 15 patients will be included in each group for the central mechanism study and receive MRI scans; and
- 3. MRI scans; each scan will be performed in the afternoon with the same scanner and operator. During the scanning period, all participants will be asked to remain relaxed, keep their eyes closed and wear a birdcage head coil filled with sponge material and to stay still to reduce the effects of head movement. The scanning room maintains the noise less than 150 dB and the temperature between 18 and 22°C, with humidity higher than 60%.
In conclusion, this study is conducted in the purpose of supporting the concept of brain MRI alteration in psychogenic ED with tadalafil or CHSGS capsule. We expect that the results of this trial can provide both an evidence-based treatment option for patients suffering from ED, an enhanced level of evidence on which central mechanism research and to provide an innovation of the clinical treatment in psychogenic ED.
FR, ZM, PZ, DC, YS and ZL have put forward the conception and design of the Trial and planned for the analysis of the data. FR, PZ, YS and DC agreed in drafting this manuscript. FR, ZM, XY, YY, DC, and GL, standing in the data Collection, ZL standing in the data analysis, and were in the charge of recruitment and treatment of patients. Authors discussed, read, revised the manuscript, and approved the final manuscript.
. Glina S, Cohen DJ, Vieira M. Diagnosis of erectile dysfunction. Curr Opin Psychiatry 2014;27:394–9.
. Rajkumar RP. The impact of disrupted childhood attachment on the presentation of psychogenic erectile dysfunction
: an exploratory study. J Sex Med 2015;12:798–803.
. Bacon CG, Mittleman MA, Kawachi I, et al. Sexual function in men older than 50 years of age: results from the health professionals follow-up study. Ann Intern Med 2003;139:161–8.
. Capogrosso P, Montorsi F, Salonia A. Erectile dysfunction in young patients is a proxy of overall men's health status. Curr Opin Urol 2016;26:140–5.
. Zusman RM. Cardiovascular data on sildenafil citrate: introduction. Am J Cardiol 1999;83:1c–2c.
. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts male aging study. J Urol 1994;151:54–61.
. Vicenzini E, Altieri M, Michetti PM, et al. Cerebral vasomotor reactivity is reduced in patients with erectile dysfunction. Eur Neurol 2008;60:85–8.
. Shamloul R, Ghanem H. Erectile dysfunction. Lancet 2013;381:153–65.
. Yuan J, Zhang R, Yang Z, et al. Comparative effectiveness and safety of oral phosphodiesterase type 5 inhibitors for erectile dysfunction: a systematic review and network meta-analysis. Eur Urol 2013;63:902–12.
. Kim SC, Lee YS, Seo KK, et al. Reasons and predictive factors for discontinuation of PDE-5 inhibitors despite successful intercourse in erectile dysfunction patients. Int J Impot Res 2014;26:87–93.
. Gong B, Ma M, Xie W, et al. Direct comparison of tadalafil
with sildenafil for the treatment of erectile dysfunction: a systematic review and meta-analysis. Int Urol Nephrol 2017;49:1731–40.
. Hatzimouratidis K, Amar E, Eardley I, et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol 2010;57:804–14.
. Hatzichristou D, d’Anzeo G, Porst H, et al. Tadalafil
5 mg once daily for the treatment of erectile dysfunction during a 6-month observational study (EDATE): impact of patient characteristics and comorbidities. BMC Urol 2015;15:111.
. Bai WJ, Li HJ, Dai YT, et al. An open-label, multicenter, randomized, crossover study comparing sildenafil citrate and tadalafil
for treating erectile dysfunction in Chinese men naive to phosphodiesterase 5 inhibitor therapy. Asian J Androl 2015;17:61–7.
. Brock G, Ni X, Oelke M, et al. Efficacy of continuous dosing of tadalafil
once daily vs tadalafil
on demand in clinical subgroups of men with erectile dysfunction: a descriptive comparison using the integrated tadalafil
databases. J Sex Med 2016;13:860–75.
. Buvat J, Buttner H, Hatzimouratidis K, et al. Adherence to initial PDE-5 inhibitor treatment: randomized open-label study comparing tadalafil
once a day, tadalafil
on demand, and sildenafil on demand in patients with erectile dysfunction. J Sex Med 2013;10:1592–602.
. Andersson KE. Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction. Pharmacol Rev 2011;63:811–59.
. Francis SH, Busch JL, Corbin JD, et al. cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev 2010;62:525–63.
. Liu Q, Zhang P, Pan J, et al. Cerebral activity changes in different traditional Chinese medicine patterns of psychogenic erectile dysfunction
patients. Evid Based Complement Alternat Med 2015;2015:503536.
. Cera N, Delli Pizzi S, Di Pierro ED, et al. Macrostructural alterations of subcortical grey matter in psychogenic erectile dysfunction
. PLoS One 2012;7:e39118.
. Zhang P, Liu J, Li G, et al. White matter microstructural changes in psychogenic erectile dysfunction
patients. Andrology 2014;2:379–85.
. Arnow BA, Desmond JE, Banner LL, et al. Brain activation and sexual arousal in healthy, heterosexual males. Brain 2002;125:1014–23.
. Chen J, Chen Y, Chen G, et al. Altered brain networks in psychogenic erectile dysfunction
: a resting-state fMRI study. Andrology 2017;5:1073–81.
. Chen J, Chen Y, Gao Q, et al. Brain structural network topological alterations of the left prefrontal and limbic cortex in psychogenic erectile dysfunction
. Int J Neurosci 2018;128:393–403.
. Chen J, Chen Y, Gao Q, et al. Impaired prefrontal-amygdala pathway, self-reported emotion, and erection in psychogenic erectile dysfunction
patients with normal nocturnal erection. Front Hum Neurosci 2018;12:157.
. Oh SK, Kim GW, Yang JC, et al. Brain activation in response to visually evoked sexual arousal in male-to-female transsexuals: 3.0 tesla functional magnetic resonance imaging. Korean J Radiol 2012;13:257–64.
. Georgiadis JR, Farrell MJ, Boessen R, et al. Dynamic subcortical blood flow during male sexual activity with ecological validity: a perfusion fMRI study. NeuroImage 2010;50:208–16.
. Seo Y, Jeong B, Kim JW, et al. The relationship between age and brain response to visual erotic stimuli in healthy heterosexual males. Int J Impot Res 2010;22:234–9.
. Hayasaka S, Peiffer AM, Hugenschmidt CE, et al. Power and sample size calculation for neuroimaging studies by non-central random field theory. NeuroImage 2007;37:721–30.
. Desmond JE, Glover GH. Estimating sample size in functional MRI (fMRI) neuroimaging studies: statistical power analyses. J Neurosci Methods 2002;118:115–28.
. Chen L, Staubli SE, Schneider MP, et al. Phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: a trade-off network meta-analysis. Eur Urol 2015;68:674–80.
. Deng Y, Zhang CH, Zhang HN. Effects of chaihu shugan powder on the behavior and expressions of BDNF and TrkB in the hippocampus, amygdala, and the frontal lobe in rat model of depression. Zhongguo Zhong Xi Yi Jie He Za Zhi 2011;31:1373–8.
. Kim SW, Sohn DW, Cho YH, et al. Brain activation by visual erotic stimuli in healthy middle aged males. Int J Impot Res 2006;18:452–7.
. Gao M, Yang X, Liu L, et al. Abnormal white matter microstructure in lifelong premature ejaculation patients identified by tract-based spatial statistical analysis. J Sex Med 2018;15:1272–9.
. Rifbjerg-Madsen S, Christensen AW, Boesen M, et al. The course of pain hypersensitivity according to painDETECT in patients with rheumatoid arthritis initiating treatment: results from the prospective FRAME-cohort study. Arthritis Res Ther 2018;20:105.
. Yin S, Chen Y, Lei D, et al. Cerebral mechanism of puncturing at He-Mu point combination for functional dyspepsia: study protocol
for a randomized controlled parallel trial. Neural Regen Res 2017;12:831–40.
. Petzke F, Jensen KB, Kosek E, et al. Using fMRI to evaluate the effects of milnacipran on central pain processing in patients with fibromyalgia. Scand J Pain 2013;4:65–74.
. Koopmann A, Bach P, Schuster R, et al. Ghrelin modulates mesolimbic reactivity to alcohol cues in alcohol-addicted subjects: a functional imaging study. Addiction biology 2019;24:1066–76.
. Lu XW, Guo H, Sun JR, et al. A shared effect of paroxetine treatment on gray matter volume in depressive patients with and without childhood maltreatment: a voxel-based morphometry study. CNS Neurosci Ther 2018;24:1073–83.
. Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining standard protocol
items for clinical trials. Ann Intern Med 2013;158:200–7.
. Schulz KF, Altman DG, Moher D, et al. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med 2010;8:18.
. Chan AW, Tetzlaff JM, Gotzsche PC, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ 2013;346:e7586.
. Bai WJ, Li HJ, Jin JJ, et al. A randomized clinical trial investigating treatment choice in Chinese men receiving sildenafil citrate and tadalafil
for treating erectile dysfunction. Asian J Androl 2017;19:500–4.
. Buvat J, Hatzichristou D, Boess FG, et al. Continuation and effectiveness of tadalafil
once daily during a 6-month observational study in erectile dysfunction: the EDATE study. Int J Clin Pract 2014;68:1087–99.
. Rosen RC, Cappelleri JC, Gendrano N 3rd. The international index of erectile function (IIEF): a state-of-the-science review. Int J Impot Res 2002;14:226–44.
. Rosen RC, Riley A, Wagner G, et al. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997;49:822–30.
. Lowy M, Collins S, Bloch M, et al. Quality of erection questionnaire correlates: change in erection quality with erectile function, hardness, and psychosocial measures in men treated with sildenafil for erectile dysfunction. J Sex Med 2007;4:83–92.
. Porst H, Gilbert C, Collins S, et al. Development and validation of the quality of erection questionnaire. J Sex Med 2007;4:372–81.
. Hvidsten K, Carlsson M, Stecher VJ, et al. Clinically meaningful improvement on the quality of erection questionnaire in men with erectile dysfunction. Int J Impot Res 2010;22:45–50.
. Mulhall JP, Goldstein I, Bushmakin AG, et al. Validation of the erection hardness score. J Sex Med 2007;4:1626–34.
. Cappelleri JC, Althof SE, Siegel RL, et al. Development and validation of the Self-Esteem And Relationship (SEAR) questionnaire in erectile dysfunction. Int J Impot Res 2004;16:30–8.
. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959;32:50–5.
. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62.
. Berntsen EM, Rasmussen IA, Samuelsen P, et al. Putting the brain in Jeopardy: a novel comprehensive and expressive language task? Acta neuropsychiatrica 2006;18:115–9.
. Hao H, Chen C, Mao W, et al. Aberrant brain regional homogeneity in first-episode drug-naive patients with major depressive disorder: a voxel-wise meta-analysis. J Affect Disord 2018;245:63–71.
. Smith SM, Jenkinson M, Johansen-Berg H, et al. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. NeuroImage 2006;31:1487–505.
. Smith SM, Jenkinson M, Woolrich MW, et al. Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage 2004;23(Suppl 1):S208–219.
. Zhao N, Yuan LX, Jia XZ, et al. Intra- and inter-scanner reliability of voxel-wise whole-brain analytic metrics for resting state fMRI. Front Neuroinform 2018;12:54.
. Burnett AL, Nehra A, Breau RH, et al. Erectile Dysfunction: AUA Guideline. J Urol 2018;200:633–41.
. Li L, Fan W, Li J, et al. Abnormal brain structure as a potential biomarker for venous erectile dysfunction: evidence from multimodal MRI and machine learning. Eur Radiol 2018;28:3789–800.
. Wang Y, Dong M, Guan M, et al. Aberrant insula-centered functional connectivity in psychogenic erectile dysfunction
patients: a resting-state fMRI study. Front Hum Neurosci 2017;11:221.
. Zhao L, Guan M, Zhang X, et al. Structural insights into aberrant cortical morphometry and network organization in psychogenic erectile dysfunction
. Hum Brain Mapp 2015;36:4469–82.
. Zhao L, Guan M, Zhu X, et al. Aberrant topological patterns of structural cortical networks in psychogenic erectile dysfunction
. Front Hum Neurosci 2015;9:675.
Keywords:Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.
Chaihu-Shugan-San capsule; protocol; psychogenic erectile dysfunction; tadalafil