ANDROLOGY
ISSN: 2047-2919
ORIGINAL ARTICLE
Correspondence: Degui Chang, The Urology and Andrology Department, The 1st Teaching Hospital, Chengdu University of Traditional Chinese Medicine, 41#, Shierqiao Road, Chengdu, Sichuan 610072, China E-mail: [email protected] or cdg998@sina. com
White matter microstructural changes in psychogenic erectile dysfunction patients 1
Keywords: diffusion tensor imaging, erectile dysfunction, tract-based spatial statistics, white matter Received: 4-Aug-2013 Revised: 1-Jan-2014 Accepted: 13-Jan-2014
1
P. Zhang, 2J. Liu, 1G. Li, 3J. Pan, 4Z. Li, 4Q. Liu, 2W. Qin, 2M. Dong, 2J. Sun, X. Huang, 1T. Wu and 1,5D. Chang
1 The Urology and Andrology Department, The 1st Teaching Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 2Life Sciences Research Center, School of Life Sciences and Technology, Xidian University, Xi’an, Shaanxi, 3The Urology and Andrology Department, Traditional Chinese Medicine Hospital of Meishan City, Meishan, 4The 3rd Teaching Hospital, Chengdu University of Traditional Chinese Medicine, and 5The Andrology Department, The 2nd Teaching Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
doi: 10.1111/j.2047-2927.2014.00191.x
SUMMARY Brain dysfunction in erectile dysfunction (ED) has been identified by multiple neuroimaging studies. A recent MRI study indicated grey matter alterations in ED patients. This study aims to investigate the microstructural changes of cerebral white matter (WM) in psychological ED patients and their possible correlations with clinical variables. Twenty-seven psychological ED patients and 27 healthy subjects (HS) were included and underwent a magnetic resonance (MR) diffusion tensor imaging (DTI) scan. The tract-based spatial statistics were employed to identify the WM structure alterations in psychological ED patients. The multiple DTI-derived indices′ [fractional anisotropy (FA), axial diffusivity (AD) and mean diffusivity (MD)] correlations with the symptoms and their durations, respectively, were analysed. The IIEF-5, quality of erection questionnaire (QEQ) and the self-esteem and relationship (SEAR) questionnaire were used to assess the symptoms of psychological ED patients. Compared with HS, the psychological ED patients showed increased FA values, reduced MD values and reduced AD values in multiple WM tracts including the corpus callosum (genu, body and splenium), corticospinal tract, internal capsule, corona radiata, external capsule and superior longitudinal fasciculus (p < 0.05, threshold-free cluster enhancement corrected). Both of the IIEF scores and QEQ scores of ED patients showed a significantly negative correlation with the average FA values, and positive correlation with average AD values and MD values in the splenium of the corpus callosum (p < 0.05). The results provided preliminary evidence of WM microstructural changes in patients with psychological ED. The morphological alterations in the splenium of the corpus callosum were related to the symptom severity.
INTRODUCTION Erectile dysfunction (ED) or impotence is a sexual dysfunction characterized by the inability to attain or maintain a penile erection sufficient for successful vaginal intercourse. ED has been an important health care and social problem because of its high prevalence, great influence on the quality of life (QOL) and association with multiple vascular diseases. It is reported that 12% in men younger than 59 years suffered from this condition, 22% in those 60–69 years of age and 30% in those older than 69 years. It was estimated that ED will affect 322 million individuals worldwide by the year 2025 (Bacon et al., 2003). As a most common sexual disorder in men, ED not only affects a man’s sexual life, but serves as a significant detriment to the QOL and overall psychological well-being of both members of a couple (Guest & Das Gupta, © 2014 American Society of Andrology and European Academy of Andrology
2002). Furthermore, ED is not only an evidence of diffuse atherosclerosis but also an early predictor of future cardiovascular events and coronary artery disease (Vicenzini et al., 2008). Studies show that 64% of men hospitalized for myocardial infarction had previous ED (Zusman, 1999) and 57% of men who had bypass surgery had previous ED (Feldman et al., 1994). Normal erectile function is an integrated response under the control of the central nervous system (CNS) and involves the supraspinal centres, the spinal cord and peripheral nerves. Basic science research on erectile physiology has been devoted to investigating the pathogenesis of ED and has led to the conclusion that ED is predominately a disease of vascular origin, neurogenic dysfunction, or both. In the last decade, exploring the role of CNS in sexual arousal by functional neuroimaging Andrology, 2014, 2, 379–385
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techniques attracts many researchers. People found that many regions of the human brain can be considered candidates for supraspinal control of penile erection including the cingulate cortex, insula, orbitofrontal cortex, caudate nucleus, putamen, thalamus, amygdala and hypothalamus (Arnow et al., 2002; Mouras et al., 2003; Kim et al., 2006; Georgiadis et al., 2010; Seo et al., 2010; Oh et al., 2012), which were involved in visually driven sexual arousal. However, the majority of these studies focused on the cerebral functional changes to visual erotic and/ or non-erotic stimulations in healthy men or ED patients, hence scant attention was paid to the cerebral structural alterations in male sexual dysfunction. In 2011, Nicoletta Cera and his coinvestigators (Cera et al., 2012) found that, compared to healthy subjects (HS), psychological ED patients showed significant grey matter atrophy in the left medial-anterior and posterior portion of the accumbens, and that the left nucleus accumbens volumes in patients correlated with low erectile function as measured by the International Index of Erectile Function 5 (IIEF-5). This study showed that although psychological ED pertained to functional disorder, it was associated with structural changes in cerebral grey matter, and that the cerebral structural alterations involved in the pathology of ED. Recently, the role of cerebral white matter (WM) in learning, information processing and neurological and psychological disorders has attracted increasing attention (Stegemann et al., 2006; Huston & Field, 2013). Using magnetic resonance (MR) diffusion tensor imaging (DTI), people found that WM microstructural abnormalities were involved in the pathogenesis of many diseases such as multiple sclerosis (Sbardella et al., 2013), Alzheimer’s disease (Kljajevic et al., 2013), internet addiction (Yuan et al., 2011), functional dyspepsia(Zhou et al., 2013), etc. Whether there is WM microstructural damage in ED remains undiscovered and worthy of investigation. Therefore, this study aimed to (i) compare the cerebral WM microstructural differences between the psychological ED patients and HS by DTI and the tract-based spatial statistics (TBSS) with a relatively large and tightly screened sample, and (ii) investigate the correlations of WM changes with clinical variables.
MATERIALS AND METHODS Participant selection ED patients The ED patients were recruited at the outpatient department in the 1st Teaching Hospital of Chengdu University of Traditional Chinese Medicine from May 2012 to Dec 2012. A total of 169 ED patients were screened and 27 were subsequently included. Each patient underwent a detailed history taking. It included a psychosocial history (which focusing on the patient’s assessment of his own sexual performance and his general attitude and knowledge about sex, etc.), a medical history, a relevant drug history (including alcohol, tobacco, or illicit drug use) and surgical disorders, etc. They also received careful physical examination and basic laboratory tests which included a urology and andrology exam, a penile duplex doppler ultrasonography (DUS), a Nocturnal Penile Tumescence (NPT) test, an electrocardiogram exam and other laboratory 380
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ANDROLOGY tests. The laboratory tests included routine blood exams (including fasting serum glucose level, cholesterol, triglycerides and complete blood count), thyroid-stimulating hormone level, prostate-specific antigen and the serum sexual hormone status (free/total testosterone, sexual hormone-binding globulin, follicle-stimulating hormone, luteinizing hormone, oestrogen and prolactin). To meet the inclusion criteria, patients should: (i) be right handed, and 18–45 in age, and (ii) have experienced impotence more than 6 months according to National Institutes of Health criteria (National Institutes of Health Consensus Development Panel on impotence: NIH consensus conference: impotence, 1993), and (iii) be diagnosed as psychological ED rather than an organic disorder and (iv) be in a stable heterosexual relationship for at least 1 year. The following participants were screened out if they: (i) were diagnosed as having organic ED, or (ii) had a history of urological surgery or head trauma with loss of consciousness, or (iii) had been using medication affecting sexual function for over 2 weeks before enrolment, or (iv) had suffered from serious psychiatric, neurological, cardiovascular, respiratory, gastrointestinal or renal illnesses, or (v) were drug or alcohol users and smokers, or (vi) participated in other current clinical trials, or (vii) had any contraindications to a DTI scan. Healthy subjects Twenty-seven right-handed healthy volunteers, free from any urosexual symptoms or signs, were enrolled in this study by advertisement. The same clinical examinations were performed on all HS. Ethics statement This study was performed according to the principles of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Chengdu University of Traditional Chinese Medicine. All participants provided written informed consent before participating in the study. Symptom assessments This study selected IIEF-5, quality of erection questionnaire (QEQ), the erection hardness score (EHS) and the self-esteem and relationship (SEAR) questionnaire to assess symptoms of the ED patients. The IIEF is a widely used, multidimensional self-report instrument for the evaluation of male sexual function (Rosen et al., 1997). It has been recommended as a primary endpoint for clinical trials of ED and as a diagnostic evaluation of ED severity (Rosen et al., 2002). The QEQ is a six-question, patient-reported outcome measure for comprehensively evaluating satisfaction with the quality of erections in terms of hardness, onset and duration (Porst et al., 2007; Hvidsten et al., 2010). The single-item EHS is a validated instrument used to measure erection hardness and ability for penetration (Mulhall et al., 2007). The 14-item SEAR is a brief, self-administered and disease-specific scale for assessing the relevant psychosocial manifestations of ED, specifically, patient-reported outcomes of self-esteem, confidence and relationships (Althof et al., 2003; Cappelleri et al., 2004). Furthermore, the psychophysical statuses of the participants were assessed by two independent psychologists using the 14-item Hamilton Anxiety Rating Scale (HAMA) (Hamilton, © 2014 American Society of Andrology and European Academy of Andrology
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1960) and 17-item Hamilton Depression Rating Scale (HAMD) (Hamilton, 1959). DTI scan The DTI data were acquired on a 3.0T Siemens scanner (Allegra, Siemens Medical System, Erlangen, Germany) at the Huaxi MR Research Center, West China Hospital of Sichuan University, Chengdu, China. Diffusion-weighted sequences with single-shot echo planar imaging in alignment with the anterior–posterior commissural plane were acquired with the following parameters: field of view = 240 9 240 mm2, repetition time/echo time = 6800/93 ms, matrix = 128 9 128, slice thickness = 3 mm, 45 continuous axial slices with no gap. Two diffusion-weighted sequences were acquired using gradient values b = 0 and b = 1000 s/mm2 with the diffusion-sensitizing gradients applied along 30 non-linear directions. Data analysis Clinical variables All of the physiological measures were analysed using SPSS 17.0 (SPSS Inc., Chicago, IL, USA) by two blinded evaluators. All the data in this article were presented as mean standard deviation (SD). An independent samples t-test was used on numerical variables and a two-sided test was applied on all available data. p value < 0.05 was considered statistically significant. TBSS analysis Voxelwise statistical analysis of the fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) values was carried out using TBSS (Smith et al., 2006), part of FSL (Smith et al., 2004). First, FA images were created by fitting a tensor model to the raw diffusion data using FDT, and then brain extracted using BET (Smith, 2002). All subjects’ FA data were then aligned into a common space using the non-linear registration tool FNIRT (Andersson et al., 2007a,b), which used a b-spline representation of the registration warp field (Rueckert et al., 1999). Next, the mean FA image was created and thinned to create a mean FA skeleton which represented the centres of all tracts common to the group. Each subject’s aligned FA data were then projected onto this skeleton and the resulting data fed into voxelwise cross-subject statistics. The MD, AD and RD images were also aligned into MNI space and projected onto the mean FA skeleton using the protocol of non-FA images in TBSS. Finally, the permutation-based non-parametric inferences were used to detect the between-group differences in our study (5000 random permutations). For multiple comparison corrections, the threshold-free cluster enhancement (TFCE) with the familywise error correction was employed.
RESULTS Clinical variables There were no significant differences in the demographics including age, weight and height between the ED patients and HS (p > 0.05). There were significant differences in the IIEF-5 Score. EHS, SEAR Score and QEQ Score between the ED patients and HS (p < 0.01) are shown in Table 1. Among the ED patients, the mean duration of symptoms was 32.44 27.43 months. © 2014 American Society of Andrology and European Academy of Andrology
Table 1 Comparisons in demographic data and clinical variables between the erectile dysfunction (ED) patients and the healthy subjects Items
ED patients N = 27
Age (years), mean SD Weight (kg), mean SD Height (cm), mean SD IIEF-5 Score (0–25), mean SD EHS (1–4), mean SD SEAR score (0–80), mean SD QEQ score (0–100), mean SD
33.22 65.11 171.67 13.56 2.70 32.38 33.63
5.92 6.66 3.98 3.61 0.54 11.14 15.44
Healthy subjects N = 27 31.41 66.52 171.41 22.26 3.93 68.36 80.04
5.82 9.47 4.37 0.95 0.27 4.96 7.20
p value
0.261 0.530 0.821 0.000 0.000 0.000 0.000
SD, standard deviation; IIEF-5, International Index of Erectile Function; QEQ, quality of erection questionnaire; EHS, erection hardness score; SEAR, self-esteem and relationship.
TBSS findings The WM structural alterations in ED patients Between-group comparisons showed that, compared to HS, the psychological ED patients exhibited significantly increased FA values, and reduced MD and AD values in multiple WM regions (p < 0.05, TFCE corrected) (shown in Fig. 1 and Table 2). None of the significantly reduced FA values, increased MD values, increased AD values and altered RD values were found in psychological ED patients (p < 0.05, TFCE corrected). The overlapping regions of the changed FA, MD and AD values The overlapping regions among the increased FA, reduced MD and reduced AD included the CC (body and splenium) and left anterior corona radiata. The overlapping regions of the reduced
Figure 1 Differences in white matter microstructures between erectile dysfunction (ED) patients and healthy subjects. Compared with healthy subjects, ED patients showed significantly increased fractional anisotropy (FA) (A), decreased mean diffusivity (MD) (B) and decreased axial diffusivity (AD) (C) in multiple brain regions (p < 0.05, TFCE corrected), whereas no difference in radial diffusivity (RD) was observed.
(A)
(B)
(C)
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P. Zhang et al. Table 2 The microstructural alternations in white matter tracts in erectile dysfunction (ED) patients White matter tracts
Side
Increased FA
Reduced MD
Reduced AD
Overlaps FA & MD & AD
Middle cerebellar peduncle Genu of Corpus callosum Body of corpus callosum Splenium of corpus callosum Corticospinal tract Medial lemniscus Inferior cerebellar peduncle Cerebral peduncle Anterior limb of internal capsule Posterior limb of internal capsule Retrolenticular part of internal capsule Anterior corona radiate Superior corona radiate Posterior corona radiate Posterior thalamic radiation Sagittal stratum External capsule Cingulum Fornix Superior longitudinal fasciculus
L R L L L R L R L R L R L R L R L R L R L R L R L R L R L
√ √ √ √ √ √ √
√ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √
√ √ √
√ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √
√ √ √ √ √ √
√ √ √ √ √ √ √ √ √ √ √ √ √
√ √
FA & MD-AD
√ √
√
MD & AD-FA √ √ √ √ √
√ √
√
√
√ √ √ √
√ √
√ √
√ √ √ √ √ √
√
√
√ √
L, left; R, right; B, bilateral; FA, fractional anisotropy; AD, axial diffusivity; MD, mean diffusivity; p < 0.05, corrected.
MD and reduced AD without increased FA included the CC (body and Splenium), left anterior limb of internal capsule, right retrolenticular part of the internal capsule, bilateral posterior corona radiate, bilateral posterior thalamic radiation and right superior longitudinal fasciculus (SLF). The overlapping regions of the increased FA and reduced MD without reduced AD included the middle cerebellar peduncle, CC (genu, body and splenium), left corticospinal tract, left internal capsule (anterior limb, posterior limb and retrolenticular part of the internal capsule), bilateral anterior corona radiate, bilateral superior corona radiata, left posterior corona radiata, left external capsule and SLF (shown in Fig. 2 and Table 2). No overlapping region with increased FA and reduced AD without reduced MD was found.
Figure 2 The overlapped brain regions with abnormal diffusion tensor imaging properties in erectile dysfunction (ED) patients. The abnormal white matter tracts with increased fractional anisotropy (FA), decreased mean diffusivity (MD) and axial diffusivity (AD) are shown in red including the corpus callosum (body and splenium) and left anterior corona radiata. The tracts with decreased AD and MD without changes in other indices are shown in green. The tracts with increased FA and decreased MD without changes in other indices are shown in yellow. No overlapping region with increased FA and decreased AD without lower AD was found.
The correlation analysis between the TBSS findings and clinical variables The IIEF scores of ED patients showed a significantly negative correlation with the average FA values, and positive correlation with average AD values and MD values in the splenium of the CC (p < 0.05) (shown in Fig. 3A). The QEQ scores of ED patients exhibited a significantly negative correlation with the average FA values, and positive correlation with average AD values and MD values in the splenium of the CC (p < 0.05) (shown in Fig. 3B). The duration of ED showed negative correlation with the average 382
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Figure 3 The correlation between the morphological alterations in the splenium part of the corpus callosum and the IIEF scores (A). The correlation between the morphological alterations in the splenium part of the corpus callosum and the QEQ scores (B). The correlation between the morphological alterations in the splenium part of the corpus callosum and the duration (C).
(A)
(B)
(C)
MD values in the splenium of the CC (p < 0.05) (shown in Fig. 3C).
DISCUSSION This study revealed the WM integrity changes in ED patient for the first time. We found that multiple WM regions in ED patients exhibited altered FA, MD and AD values compared with those in HS, and the alterations of the splenium of the CC were significantly correlated with symptom severity. The differences in the WM microstructure between ED patients and HS In this study, multiple DTI-derived indices including the FA, MD, AD and RD values were calculated to measure the microstructural alterations in WM tracts. Compared with HS, ED patients showed increased FA values, reduced MD values and reduced AD values in multiple WM tracts including the CC (genu, body and splenium), corticospinal tract, internal capsule (anterior limb and posterior limb), corona radiata, external © 2014 American Society of Andrology and European Academy of Andrology
capsule and SLF (shown in Fig. 1 and Table 2). FA is an accepted measure of WM structural integrity. It reflects the structure of axonal cell membranes and myelin sheaths (Alexander et al., 2007). A high FA suggests a myelination process, an increased number of myelinated fibres and an increased ratio between longitudinal vs. oblique aligned myelinated fibres (Versace et al., 2008). AD and RD measure the diffusion of water parallel to and perpendicular to WM fibres respectively. A reduced AD value may suggest axonal loss or loss of bundle coherence (Alexander et al., 2007). MD gives a measurement of the average molecular motion independent of the direction of uz et al., 2013). In this study, increased myelinadiffusion (Og tion in these tracts might implicate increased structural connectivity between connected brain regions (Rouw & Scholte, 2007), which were likely to suggest functional connectivity abnormalities in ED patients. The speculation could be supported by the notion that myelin changes might alter the conduction velocity and synchronization of neural signals (Fields, 2008; Scholz et al., 2009). Andrology, 2014, 2, 379–385
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In this study, the microstructural changes in WM tracts might be the consequence of brain dysfunction induced by the disease. As we know, the tracts such as the CC, corticospinal tract, internal capsule (IC), corona radiata, external capsule and SLF have rich interconnections with cortical and subcortical regions. For example, the CC connects with lateral aspects of the prefrontal cortex (PFC) as well as medially with the rostral anterior cingulate cortex (rACC) together with the insula (Schmahmann & Pandya, 2006). The IC consists of axonal fibres that run between the cerebral cortex and the subcortical brain structures such as the basal ganglia, thalamus and brainstem (Axer & Keyserlingk, 2000). The SLF, connecting the front and the back of the cerebrum, are closely related to the frontal, occipital, parietal and temporal lobes (Makris et al., 2005). Recently, number of neuroimaging studies (Hagemann et al., 2003; Montorsi et al., 2003a, 2003b) had reported that, compared to the healthy male, ED patients showed abnormal activities in multiple brain regions including the PFC, ACC, insula, hypothalamus, basal ganglia, occipital, parietal and temporal lobes. Thus, we predicted that the microstructural changes in the CC, corticospinal tract, IC, corona radiata, external capsule and SLF might relate to the dysfunction of these grey matter regions mentioned above.
investigate the cerebral structural changes of multiple organic ED by comparing with their primary disorders (e.g. diabetic ED vs. diabetes, hypertensive ED vs. hypertension) in the future. In summary, this study demonstrated the WM’s morphometric alterations in the psychogenic ED patient and the correlation of WM tract abnormalities and symptom severity for the first time. We hoped that our work will enhance our understandings of ED and provide a new approach in future studies and new therapy development.
The morphological alterations in the corpus callosum The CC is the largest commissure in the human brain, connecting neocortical regions of the two hemispheres and playing a primary role in the sensory and cognitive integration of information (Henze et al., 2012). In this study, the changes of FA, MD and AD values in the CC (genu, body and splenium) have been found in ED patients (shown in Fig. 2). It suggested that the CC plays an important role in the etiopathogenesis of ED. Furthermore, our results demonstrated that the splenium part of the CC is the overlapping region with increased FA, reduced MD and AD values, and that the average FA, MD and AD values in the splenium of the CC were significantly correlated with the IIEF scores and QEQ scores of ED patients, respectively, and that the average MD values in the splenium of the CC were negatively correlated with the duration (shown in Fig. 3). The results indicated that the abnormalities in the multiple DTI-derived indices in the splenium of the CC might be more severe with more severe symptoms and longer duration of ED. As we know, the splenium fibres of the CC connect occipital and parietal cortices, as well as inferior and medial temporal regions (including the posterior cingulate) (Knyazeva, 2013), and are involved in the somatosensory information communication and visual signal conduction. The activity changes in the inferior temporal gyrus, occipital cortex, parietal cortex and posterior cingulate had been highly reproducible in neuroimaging studies on sexual arousal (Montorsi et al., 2003a, 2003b; Mouras et al., 2003; Kim et al., 2006; Hu et al., 2008). Hence, we predicted that the increased myelination in the splenium of the CC might relate to the abnormal sexual arousal in ED.
FINANCIAL DISCLOSURE
Limitations and future direction The main limitation of this study lied in that it was not a longitudinal design, so it could not explain the causality between the symptoms, psychological factors, duration and altered cerebral structures. This study provided the basis for further investigation of cerebral structure changes in organic ED, so we plan to 384
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ACKNOWLEDGEMENTS This study was supported by the Scientific Research Fund of Sichuan Provincial Education Department (NO.12ZB034). We thank Shuwu Zhang and Jiuyuan Wang for assistance in patient recruitment of this study.
AUTHOR CONTRIBUTIONS P.Z., W.Q., M.D., D.C. contributed to study protocol and design; P.Z., J.P., G.L., X.H., Q.L. acquired the data; J.L., Z.L., J.S. analysed and/or interpreted the data; P.Z., J.L. drafted the manuscript; D.C., J.P., G.L., Z.L., Q.L., W.Q., M.D., J.S., X.H., T.W. revised the manuscript.
No conflicts of interest exist.
REFERENCES Alexander AL, Lee JE, Lazar M & Field AS. (2007) Diffusion tensor imaging of the brain. Neurotherapeutics 4, 316–329. Althof SE, Cappelleri JC, Shpilsky A, Stecher V, Diuguid C, Sweeney M et al. (2003) Treatment responsiveness of the Self-Esteem And Relationship questionnaire in erectile dysfunction. Urology 61, 888– 892. Andersson JLR, Jenkinson M & Smith S. (2007a) Non-linear optimisation. FMRIB technical report TR07JA1 from www.fmrib.ox.ac.uk/analysis/ techrep. Andersson JLR, Jenkinson M & Smith S. (2007b). Non-linear registration, aka Spatial normalisation. FMRIB technical report TR07JA2 from www.fmrib.ox.ac.uk/analysis/techrep. Arnow BA, Desmond JE, Banner LL, Glover GH, Solomon A, Polan ML et al. (2002) Brain activation and sexual arousal in healthy, heterosexual males. Brain 125, 1014–1023. Axer H & Keyserlingk DG. (2000) Mapping of fiber orientation in human internal capsule by means of polarized light and confocal scanning laser microscopy. J Neurosci Methods 94, 165–175. Bacon CG, Mittleman MA, Kawachi I, Giovannucci E, Glasser DB & Rimm EB. (2003) Sexual function in men older than 50 years of age: results from the health professionals follow-up study. Ann Intern Med 139, 161–168. Cappelleri JC, Althof SE, Siegel RL, Shpilsky A, Bell SS & Duttagupta S. (2004) Development and validation of the Self-Esteem And Relationship (SEAR) questionnaire in erectile dysfunction. Int J Impot Res 16, 30–38. Cera N, Delli Pizzi S, Di Pierro ED, Gambi F, Tartaro A, Vicentini C et al. (2012) Macrostructural alterations of subcortical grey matter in psychogenic erectile dysfunction. PLoS ONE 7, e39118. Feldman H, Goldstein I, Hatzichristou DG, Krane RJ & McKinlay JB. (1994) Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 151, 54–61. Fields RD. (2008) White matter in learning, cognition and psychiatric disorders. Trends Neurosci 31, 361–370. Georgiadis JR, Farrell MJ, Boessen R, Denton DA, Gavrilescu M, Kortekaas R et al. (2010) Dynamic subcortical blood flow during male © 2014 American Society of Andrology and European Academy of Andrology
WHITE MATTER STRUCTURE CHANGES IN ED PATIENT sexual activity with ecological validity: a perfusion fMRI study. Neuroimage 50, 208–216. Guest JF & Das Gupta R. (2002) Health-related quality of life in a UK-based population of men with erectile dysfunction. Pharmacoeconomics 20, 109–117. Hagemann JH, Berding G, Bergh S, Sleep DJ, Knapp WH, Jonas U et al. (2003) Effects of visual sexual stimuli and apomorphine SL on cerebral activity in men with erectile dysfunction. Eur Urol 43, 412–420. Hamilton M. (1959) The assessment of anxiety states by rating. Br J Med Psychol 32, 50–55. Hamilton M. (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23, 56–62. Henze R, Brunner R, Thiemann U, Parzer P, Klein J, Resch F et al. (2012) White matter alterations in the corpus callosum of adolescents with first-admission schizophrenia. Neurosci Lett 513, 178–182. Hu SH, Wei N, Wang QD, Yan LQ, Wei EQ, Zhang MM et al. (2008) Patterns of brain activation during visually evoked sexual arousal differ between homosexual and heterosexual men. AJNR Am J Neuroradiol 29, 1890–1896. Huston JM & Field AS. (2013) Clinical applications of diffusion tensor imaging. Magn Reson Imaging Clin N Am 21, 279–298. Hvidsten K, Carlsson M, Stecher VJ, Symonds T & Levinson I. (2010) Clinically meaningful improvement on the quality of erection questionnaire in men with erectile dysfunction. Int J Impot Res 22, 45–50. Kim SW, Sohn DW, Cho YH, Yang WS, Lee KU, Juh R et al. (2006) Brain activation by visual erotic stimuli in healthy middle aged males. Int J Impot Res 18, 452–457. Kljajevic V, Meyer P, Holzmann C, Dyrba M, Kasper E, Bokde AL et al. (2013) The e4 genotype of apolipoprotein E and white matter integrity in Alzheimer’s disease. Alzheimers Dement. doi: 10.1016/j.jalz.2013.02. 008. Knyazeva MG. (2013) Splenium of corpus callosum: patterns of interhemispheric interaction in children and adults. Neural Plast 2013, 639430. doi: 10.1155/2013/639430 Makris N, Kennedy DN, McInerney S, Sorensen AG, Wang R, Caviness VS Jr et al. (2005) Segmentation of subcomponents within the superior longitudinal fascicle in humans: a quantitative, in vivo, DT-MRI Study. Cereb Cortex 15, 854–869. Montorsi F, Perani D, Anchisi D, Salonia A, Scifo P, Rigiroli P et al. (2003a) Brain activation patterns during video sexual stimulation following the administration of apomorphine: results of a placebo-controlled study. Eur Urol 43, 405–411. Montorsi F, Perani D, Anchisi D, Salonia A, Scifo P, Rigiroli P et al. (2003b) Apomorphine-induced brain modulation during sexual stimulation: a new look at central phenomena related to erectile dysfunction. Int J Impot Res 15, 203–209. ru S, Bittoun J, Glutron D, Pe l e grini-Issac M, Paradis AL Mouras H, Stole et al. (2003) Brain processing of visual sexual stimuli in healthy men: a functional magnetic resonance imaging study. Neuroimage 20, 855– 869. Mulhall JP, Goldstein I, Bushmakin AG, Cappelleri JC & Hvidsten K. (2007) Validation of the erection hardness score. J Sex Med 4, 1626– 1634. uz KK, Sanverdi E, Has A, Temucßin C € rk S & Doerschner K. (2013) Og ß , Tu Tract-based spatial statistics of diffusion tensor imaging in hereditary spastic paraplegia with thin corpus callosum reveals widespread white matter changes. Diagn Interv Radiol 19, 181–186. Oh SK, Kim GW, Yang JC, Kim SK, Kang HK & Jeong GW. (2012) Brain activation in response to visually evoked sexual arousal in
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ANDROLOGY male-to-female transsexuals: 3.0 tesla functional magnetic resonance imaging. Korean J Radiol 13, 257–264. Porst H, Gilbert C, Collins S, Huang X, Symonds T, Stecher V et al. (2007) Development and validation of the quality of erection questionnaire. J Sex Med 4, 372–381. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J & Mishra A. (1997) The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 49, 822–830. Rosen RC, Cappelleri JC & Gendrano N. (2002) The International Index of Erectile Function (IIEF): a state-of-the-science review. Int J Impotence Res 14, 226–244. Rouw R & Scholte HS. (2007) Increased structural connectivity in grapheme-color synesthesia. Nat Neurosci 10, 792–797. Rueckert D, Sonoda LI, Hayes C, Hill DL, Leach MO & Hawkes DJ. (1999) Non-rigid registration using free-form deformations: application to breast MR images. IEEE Trans Med Imaging 18, 712–721. Sbardella E, Petsas N, Tona F, Prosperini L, Raz E, Pace G et al. (2013) Assessing the correlation between grey and white matter damage with motor and cognitive impairment in multiple sclerosis patients. PLoS ONE 8, e63250. Schmahmann JD & Pandya DN. (2006) Fiber Pathways of the Brain. Oxford University Press, New York. Scholz J, Klein MC, Behrens TEJ & Johansen-Berg H. (2009) Training induces changes in white matter architecture. Nat Neurosci 12, 1370– 1371. Seo Y, Jeong B, Kim JW & Choi J. (2010) The relationship between age and brain response to visual erotic stimuli in healthy heterosexual males. Int J Impot Res 22, 234–239. Smith SM. (2002) Fast robust automated brain extraction. Hum Brain Mapp 17, 143–155. Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H et al. (2004) Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage 23, 208–219. Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE et al. (2006) Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. NeuroImage 31, 1487–1505. € sterhus P & Schulte-Markwort M. (2006) Stegemann T, Heimann M, Du Diffusion tensor imaging (DTI) and its importance for exploration of normal or pathological brain development. Fortschr Neurol Psychiatr 74, 136–148. Versace A, Almeida JRC, Hassel S, Walsh ND, Novelli M, Klein CR et al. (2008) Elevated left and reduced right orbitomedial prefrontal fractional anisotropy in adults with bipolar disorder revealed by tract-based spatial statistics. Arch Gen Psychiatry 65, 1041–1052. Vicenzini E, Altieri M, Michetti PM, Ricciardi MC, Ciccariello M, Shahabadi H et al. (2008) Cerebral vasomotor reactivity is reduced in patients with erectile dysfunction. Eur Neurol 60, 85–88. National Institutes of Health Consensus Development Panel on impotence: NIH consensus conference: impotence. (1993) JAMA 270, 83–90. Yuan K, Qin W, Wang G, Zeng F, Zhao L, Yang X et al. (2011) Microstructure abnormalities in adolescents with internet addiction disorder. PLoS ONE 6, e20708. Zhou G, Qin W, Zeng F, Liu P, Yang X, von Deneen KM et al. (2013) White-matter microstructural changes in functional dyspepsia: a diffusion tensor imaging study. Am J Gastroenterol 108, 260–269. Zusman RM. (1999) Cardiovascular data on sildenafil citrate: introduction. Am J Cardiol 83, 1C–2C.
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ISSN: 2047-2919
ORIGINAL ARTICLE
Correspondence: Degui Chang, The Urology and Andrology Department, The 1st Teaching Hospital, Chengdu University of Traditional Chinese Medicine, 41#, Shierqiao Road, Chengdu, Sichuan 610072, China E-mail: [email protected] or cdg998@sina. com
White matter microstructural changes in psychogenic erectile dysfunction patients 1
Keywords: diffusion tensor imaging, erectile dysfunction, tract-based spatial statistics, white matter Received: 4-Aug-2013 Revised: 1-Jan-2014 Accepted: 13-Jan-2014
1
P. Zhang, 2J. Liu, 1G. Li, 3J. Pan, 4Z. Li, 4Q. Liu, 2W. Qin, 2M. Dong, 2J. Sun, X. Huang, 1T. Wu and 1,5D. Chang
1 The Urology and Andrology Department, The 1st Teaching Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 2Life Sciences Research Center, School of Life Sciences and Technology, Xidian University, Xi’an, Shaanxi, 3The Urology and Andrology Department, Traditional Chinese Medicine Hospital of Meishan City, Meishan, 4The 3rd Teaching Hospital, Chengdu University of Traditional Chinese Medicine, and 5The Andrology Department, The 2nd Teaching Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
doi: 10.1111/j.2047-2927.2014.00191.x
SUMMARY Brain dysfunction in erectile dysfunction (ED) has been identified by multiple neuroimaging studies. A recent MRI study indicated grey matter alterations in ED patients. This study aims to investigate the microstructural changes of cerebral white matter (WM) in psychological ED patients and their possible correlations with clinical variables. Twenty-seven psychological ED patients and 27 healthy subjects (HS) were included and underwent a magnetic resonance (MR) diffusion tensor imaging (DTI) scan. The tract-based spatial statistics were employed to identify the WM structure alterations in psychological ED patients. The multiple DTI-derived indices′ [fractional anisotropy (FA), axial diffusivity (AD) and mean diffusivity (MD)] correlations with the symptoms and their durations, respectively, were analysed. The IIEF-5, quality of erection questionnaire (QEQ) and the self-esteem and relationship (SEAR) questionnaire were used to assess the symptoms of psychological ED patients. Compared with HS, the psychological ED patients showed increased FA values, reduced MD values and reduced AD values in multiple WM tracts including the corpus callosum (genu, body and splenium), corticospinal tract, internal capsule, corona radiata, external capsule and superior longitudinal fasciculus (p < 0.05, threshold-free cluster enhancement corrected). Both of the IIEF scores and QEQ scores of ED patients showed a significantly negative correlation with the average FA values, and positive correlation with average AD values and MD values in the splenium of the corpus callosum (p < 0.05). The results provided preliminary evidence of WM microstructural changes in patients with psychological ED. The morphological alterations in the splenium of the corpus callosum were related to the symptom severity.
INTRODUCTION Erectile dysfunction (ED) or impotence is a sexual dysfunction characterized by the inability to attain or maintain a penile erection sufficient for successful vaginal intercourse. ED has been an important health care and social problem because of its high prevalence, great influence on the quality of life (QOL) and association with multiple vascular diseases. It is reported that 12% in men younger than 59 years suffered from this condition, 22% in those 60–69 years of age and 30% in those older than 69 years. It was estimated that ED will affect 322 million individuals worldwide by the year 2025 (Bacon et al., 2003). As a most common sexual disorder in men, ED not only affects a man’s sexual life, but serves as a significant detriment to the QOL and overall psychological well-being of both members of a couple (Guest & Das Gupta, © 2014 American Society of Andrology and European Academy of Andrology
2002). Furthermore, ED is not only an evidence of diffuse atherosclerosis but also an early predictor of future cardiovascular events and coronary artery disease (Vicenzini et al., 2008). Studies show that 64% of men hospitalized for myocardial infarction had previous ED (Zusman, 1999) and 57% of men who had bypass surgery had previous ED (Feldman et al., 1994). Normal erectile function is an integrated response under the control of the central nervous system (CNS) and involves the supraspinal centres, the spinal cord and peripheral nerves. Basic science research on erectile physiology has been devoted to investigating the pathogenesis of ED and has led to the conclusion that ED is predominately a disease of vascular origin, neurogenic dysfunction, or both. In the last decade, exploring the role of CNS in sexual arousal by functional neuroimaging Andrology, 2014, 2, 379–385
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techniques attracts many researchers. People found that many regions of the human brain can be considered candidates for supraspinal control of penile erection including the cingulate cortex, insula, orbitofrontal cortex, caudate nucleus, putamen, thalamus, amygdala and hypothalamus (Arnow et al., 2002; Mouras et al., 2003; Kim et al., 2006; Georgiadis et al., 2010; Seo et al., 2010; Oh et al., 2012), which were involved in visually driven sexual arousal. However, the majority of these studies focused on the cerebral functional changes to visual erotic and/ or non-erotic stimulations in healthy men or ED patients, hence scant attention was paid to the cerebral structural alterations in male sexual dysfunction. In 2011, Nicoletta Cera and his coinvestigators (Cera et al., 2012) found that, compared to healthy subjects (HS), psychological ED patients showed significant grey matter atrophy in the left medial-anterior and posterior portion of the accumbens, and that the left nucleus accumbens volumes in patients correlated with low erectile function as measured by the International Index of Erectile Function 5 (IIEF-5). This study showed that although psychological ED pertained to functional disorder, it was associated with structural changes in cerebral grey matter, and that the cerebral structural alterations involved in the pathology of ED. Recently, the role of cerebral white matter (WM) in learning, information processing and neurological and psychological disorders has attracted increasing attention (Stegemann et al., 2006; Huston & Field, 2013). Using magnetic resonance (MR) diffusion tensor imaging (DTI), people found that WM microstructural abnormalities were involved in the pathogenesis of many diseases such as multiple sclerosis (Sbardella et al., 2013), Alzheimer’s disease (Kljajevic et al., 2013), internet addiction (Yuan et al., 2011), functional dyspepsia(Zhou et al., 2013), etc. Whether there is WM microstructural damage in ED remains undiscovered and worthy of investigation. Therefore, this study aimed to (i) compare the cerebral WM microstructural differences between the psychological ED patients and HS by DTI and the tract-based spatial statistics (TBSS) with a relatively large and tightly screened sample, and (ii) investigate the correlations of WM changes with clinical variables.
MATERIALS AND METHODS Participant selection ED patients The ED patients were recruited at the outpatient department in the 1st Teaching Hospital of Chengdu University of Traditional Chinese Medicine from May 2012 to Dec 2012. A total of 169 ED patients were screened and 27 were subsequently included. Each patient underwent a detailed history taking. It included a psychosocial history (which focusing on the patient’s assessment of his own sexual performance and his general attitude and knowledge about sex, etc.), a medical history, a relevant drug history (including alcohol, tobacco, or illicit drug use) and surgical disorders, etc. They also received careful physical examination and basic laboratory tests which included a urology and andrology exam, a penile duplex doppler ultrasonography (DUS), a Nocturnal Penile Tumescence (NPT) test, an electrocardiogram exam and other laboratory 380
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ANDROLOGY tests. The laboratory tests included routine blood exams (including fasting serum glucose level, cholesterol, triglycerides and complete blood count), thyroid-stimulating hormone level, prostate-specific antigen and the serum sexual hormone status (free/total testosterone, sexual hormone-binding globulin, follicle-stimulating hormone, luteinizing hormone, oestrogen and prolactin). To meet the inclusion criteria, patients should: (i) be right handed, and 18–45 in age, and (ii) have experienced impotence more than 6 months according to National Institutes of Health criteria (National Institutes of Health Consensus Development Panel on impotence: NIH consensus conference: impotence, 1993), and (iii) be diagnosed as psychological ED rather than an organic disorder and (iv) be in a stable heterosexual relationship for at least 1 year. The following participants were screened out if they: (i) were diagnosed as having organic ED, or (ii) had a history of urological surgery or head trauma with loss of consciousness, or (iii) had been using medication affecting sexual function for over 2 weeks before enrolment, or (iv) had suffered from serious psychiatric, neurological, cardiovascular, respiratory, gastrointestinal or renal illnesses, or (v) were drug or alcohol users and smokers, or (vi) participated in other current clinical trials, or (vii) had any contraindications to a DTI scan. Healthy subjects Twenty-seven right-handed healthy volunteers, free from any urosexual symptoms or signs, were enrolled in this study by advertisement. The same clinical examinations were performed on all HS. Ethics statement This study was performed according to the principles of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Chengdu University of Traditional Chinese Medicine. All participants provided written informed consent before participating in the study. Symptom assessments This study selected IIEF-5, quality of erection questionnaire (QEQ), the erection hardness score (EHS) and the self-esteem and relationship (SEAR) questionnaire to assess symptoms of the ED patients. The IIEF is a widely used, multidimensional self-report instrument for the evaluation of male sexual function (Rosen et al., 1997). It has been recommended as a primary endpoint for clinical trials of ED and as a diagnostic evaluation of ED severity (Rosen et al., 2002). The QEQ is a six-question, patient-reported outcome measure for comprehensively evaluating satisfaction with the quality of erections in terms of hardness, onset and duration (Porst et al., 2007; Hvidsten et al., 2010). The single-item EHS is a validated instrument used to measure erection hardness and ability for penetration (Mulhall et al., 2007). The 14-item SEAR is a brief, self-administered and disease-specific scale for assessing the relevant psychosocial manifestations of ED, specifically, patient-reported outcomes of self-esteem, confidence and relationships (Althof et al., 2003; Cappelleri et al., 2004). Furthermore, the psychophysical statuses of the participants were assessed by two independent psychologists using the 14-item Hamilton Anxiety Rating Scale (HAMA) (Hamilton, © 2014 American Society of Andrology and European Academy of Andrology
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1960) and 17-item Hamilton Depression Rating Scale (HAMD) (Hamilton, 1959). DTI scan The DTI data were acquired on a 3.0T Siemens scanner (Allegra, Siemens Medical System, Erlangen, Germany) at the Huaxi MR Research Center, West China Hospital of Sichuan University, Chengdu, China. Diffusion-weighted sequences with single-shot echo planar imaging in alignment with the anterior–posterior commissural plane were acquired with the following parameters: field of view = 240 9 240 mm2, repetition time/echo time = 6800/93 ms, matrix = 128 9 128, slice thickness = 3 mm, 45 continuous axial slices with no gap. Two diffusion-weighted sequences were acquired using gradient values b = 0 and b = 1000 s/mm2 with the diffusion-sensitizing gradients applied along 30 non-linear directions. Data analysis Clinical variables All of the physiological measures were analysed using SPSS 17.0 (SPSS Inc., Chicago, IL, USA) by two blinded evaluators. All the data in this article were presented as mean standard deviation (SD). An independent samples t-test was used on numerical variables and a two-sided test was applied on all available data. p value < 0.05 was considered statistically significant. TBSS analysis Voxelwise statistical analysis of the fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) values was carried out using TBSS (Smith et al., 2006), part of FSL (Smith et al., 2004). First, FA images were created by fitting a tensor model to the raw diffusion data using FDT, and then brain extracted using BET (Smith, 2002). All subjects’ FA data were then aligned into a common space using the non-linear registration tool FNIRT (Andersson et al., 2007a,b), which used a b-spline representation of the registration warp field (Rueckert et al., 1999). Next, the mean FA image was created and thinned to create a mean FA skeleton which represented the centres of all tracts common to the group. Each subject’s aligned FA data were then projected onto this skeleton and the resulting data fed into voxelwise cross-subject statistics. The MD, AD and RD images were also aligned into MNI space and projected onto the mean FA skeleton using the protocol of non-FA images in TBSS. Finally, the permutation-based non-parametric inferences were used to detect the between-group differences in our study (5000 random permutations). For multiple comparison corrections, the threshold-free cluster enhancement (TFCE) with the familywise error correction was employed.
RESULTS Clinical variables There were no significant differences in the demographics including age, weight and height between the ED patients and HS (p > 0.05). There were significant differences in the IIEF-5 Score. EHS, SEAR Score and QEQ Score between the ED patients and HS (p < 0.01) are shown in Table 1. Among the ED patients, the mean duration of symptoms was 32.44 27.43 months. © 2014 American Society of Andrology and European Academy of Andrology
Table 1 Comparisons in demographic data and clinical variables between the erectile dysfunction (ED) patients and the healthy subjects Items
ED patients N = 27
Age (years), mean SD Weight (kg), mean SD Height (cm), mean SD IIEF-5 Score (0–25), mean SD EHS (1–4), mean SD SEAR score (0–80), mean SD QEQ score (0–100), mean SD
33.22 65.11 171.67 13.56 2.70 32.38 33.63
5.92 6.66 3.98 3.61 0.54 11.14 15.44
Healthy subjects N = 27 31.41 66.52 171.41 22.26 3.93 68.36 80.04
5.82 9.47 4.37 0.95 0.27 4.96 7.20
p value
0.261 0.530 0.821 0.000 0.000 0.000 0.000
SD, standard deviation; IIEF-5, International Index of Erectile Function; QEQ, quality of erection questionnaire; EHS, erection hardness score; SEAR, self-esteem and relationship.
TBSS findings The WM structural alterations in ED patients Between-group comparisons showed that, compared to HS, the psychological ED patients exhibited significantly increased FA values, and reduced MD and AD values in multiple WM regions (p < 0.05, TFCE corrected) (shown in Fig. 1 and Table 2). None of the significantly reduced FA values, increased MD values, increased AD values and altered RD values were found in psychological ED patients (p < 0.05, TFCE corrected). The overlapping regions of the changed FA, MD and AD values The overlapping regions among the increased FA, reduced MD and reduced AD included the CC (body and splenium) and left anterior corona radiata. The overlapping regions of the reduced
Figure 1 Differences in white matter microstructures between erectile dysfunction (ED) patients and healthy subjects. Compared with healthy subjects, ED patients showed significantly increased fractional anisotropy (FA) (A), decreased mean diffusivity (MD) (B) and decreased axial diffusivity (AD) (C) in multiple brain regions (p < 0.05, TFCE corrected), whereas no difference in radial diffusivity (RD) was observed.
(A)
(B)
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P. Zhang et al. Table 2 The microstructural alternations in white matter tracts in erectile dysfunction (ED) patients White matter tracts
Side
Increased FA
Reduced MD
Reduced AD
Overlaps FA & MD & AD
Middle cerebellar peduncle Genu of Corpus callosum Body of corpus callosum Splenium of corpus callosum Corticospinal tract Medial lemniscus Inferior cerebellar peduncle Cerebral peduncle Anterior limb of internal capsule Posterior limb of internal capsule Retrolenticular part of internal capsule Anterior corona radiate Superior corona radiate Posterior corona radiate Posterior thalamic radiation Sagittal stratum External capsule Cingulum Fornix Superior longitudinal fasciculus
L R L L L R L R L R L R L R L R L R L R L R L R L R L R L
√ √ √ √ √ √ √
√ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √
√ √ √
√ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √
√ √ √ √ √ √
√ √ √ √ √ √ √ √ √ √ √ √ √
√ √
FA & MD-AD
√ √
√
MD & AD-FA √ √ √ √ √
√ √
√
√
√ √ √ √
√ √
√ √
√ √ √ √ √ √
√
√
√ √
L, left; R, right; B, bilateral; FA, fractional anisotropy; AD, axial diffusivity; MD, mean diffusivity; p < 0.05, corrected.
MD and reduced AD without increased FA included the CC (body and Splenium), left anterior limb of internal capsule, right retrolenticular part of the internal capsule, bilateral posterior corona radiate, bilateral posterior thalamic radiation and right superior longitudinal fasciculus (SLF). The overlapping regions of the increased FA and reduced MD without reduced AD included the middle cerebellar peduncle, CC (genu, body and splenium), left corticospinal tract, left internal capsule (anterior limb, posterior limb and retrolenticular part of the internal capsule), bilateral anterior corona radiate, bilateral superior corona radiata, left posterior corona radiata, left external capsule and SLF (shown in Fig. 2 and Table 2). No overlapping region with increased FA and reduced AD without reduced MD was found.
Figure 2 The overlapped brain regions with abnormal diffusion tensor imaging properties in erectile dysfunction (ED) patients. The abnormal white matter tracts with increased fractional anisotropy (FA), decreased mean diffusivity (MD) and axial diffusivity (AD) are shown in red including the corpus callosum (body and splenium) and left anterior corona radiata. The tracts with decreased AD and MD without changes in other indices are shown in green. The tracts with increased FA and decreased MD without changes in other indices are shown in yellow. No overlapping region with increased FA and decreased AD without lower AD was found.
The correlation analysis between the TBSS findings and clinical variables The IIEF scores of ED patients showed a significantly negative correlation with the average FA values, and positive correlation with average AD values and MD values in the splenium of the CC (p < 0.05) (shown in Fig. 3A). The QEQ scores of ED patients exhibited a significantly negative correlation with the average FA values, and positive correlation with average AD values and MD values in the splenium of the CC (p < 0.05) (shown in Fig. 3B). The duration of ED showed negative correlation with the average 382
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Figure 3 The correlation between the morphological alterations in the splenium part of the corpus callosum and the IIEF scores (A). The correlation between the morphological alterations in the splenium part of the corpus callosum and the QEQ scores (B). The correlation between the morphological alterations in the splenium part of the corpus callosum and the duration (C).
(A)
(B)
(C)
MD values in the splenium of the CC (p < 0.05) (shown in Fig. 3C).
DISCUSSION This study revealed the WM integrity changes in ED patient for the first time. We found that multiple WM regions in ED patients exhibited altered FA, MD and AD values compared with those in HS, and the alterations of the splenium of the CC were significantly correlated with symptom severity. The differences in the WM microstructure between ED patients and HS In this study, multiple DTI-derived indices including the FA, MD, AD and RD values were calculated to measure the microstructural alterations in WM tracts. Compared with HS, ED patients showed increased FA values, reduced MD values and reduced AD values in multiple WM tracts including the CC (genu, body and splenium), corticospinal tract, internal capsule (anterior limb and posterior limb), corona radiata, external © 2014 American Society of Andrology and European Academy of Andrology
capsule and SLF (shown in Fig. 1 and Table 2). FA is an accepted measure of WM structural integrity. It reflects the structure of axonal cell membranes and myelin sheaths (Alexander et al., 2007). A high FA suggests a myelination process, an increased number of myelinated fibres and an increased ratio between longitudinal vs. oblique aligned myelinated fibres (Versace et al., 2008). AD and RD measure the diffusion of water parallel to and perpendicular to WM fibres respectively. A reduced AD value may suggest axonal loss or loss of bundle coherence (Alexander et al., 2007). MD gives a measurement of the average molecular motion independent of the direction of uz et al., 2013). In this study, increased myelinadiffusion (Og tion in these tracts might implicate increased structural connectivity between connected brain regions (Rouw & Scholte, 2007), which were likely to suggest functional connectivity abnormalities in ED patients. The speculation could be supported by the notion that myelin changes might alter the conduction velocity and synchronization of neural signals (Fields, 2008; Scholz et al., 2009). Andrology, 2014, 2, 379–385
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In this study, the microstructural changes in WM tracts might be the consequence of brain dysfunction induced by the disease. As we know, the tracts such as the CC, corticospinal tract, internal capsule (IC), corona radiata, external capsule and SLF have rich interconnections with cortical and subcortical regions. For example, the CC connects with lateral aspects of the prefrontal cortex (PFC) as well as medially with the rostral anterior cingulate cortex (rACC) together with the insula (Schmahmann & Pandya, 2006). The IC consists of axonal fibres that run between the cerebral cortex and the subcortical brain structures such as the basal ganglia, thalamus and brainstem (Axer & Keyserlingk, 2000). The SLF, connecting the front and the back of the cerebrum, are closely related to the frontal, occipital, parietal and temporal lobes (Makris et al., 2005). Recently, number of neuroimaging studies (Hagemann et al., 2003; Montorsi et al., 2003a, 2003b) had reported that, compared to the healthy male, ED patients showed abnormal activities in multiple brain regions including the PFC, ACC, insula, hypothalamus, basal ganglia, occipital, parietal and temporal lobes. Thus, we predicted that the microstructural changes in the CC, corticospinal tract, IC, corona radiata, external capsule and SLF might relate to the dysfunction of these grey matter regions mentioned above.
investigate the cerebral structural changes of multiple organic ED by comparing with their primary disorders (e.g. diabetic ED vs. diabetes, hypertensive ED vs. hypertension) in the future. In summary, this study demonstrated the WM’s morphometric alterations in the psychogenic ED patient and the correlation of WM tract abnormalities and symptom severity for the first time. We hoped that our work will enhance our understandings of ED and provide a new approach in future studies and new therapy development.
The morphological alterations in the corpus callosum The CC is the largest commissure in the human brain, connecting neocortical regions of the two hemispheres and playing a primary role in the sensory and cognitive integration of information (Henze et al., 2012). In this study, the changes of FA, MD and AD values in the CC (genu, body and splenium) have been found in ED patients (shown in Fig. 2). It suggested that the CC plays an important role in the etiopathogenesis of ED. Furthermore, our results demonstrated that the splenium part of the CC is the overlapping region with increased FA, reduced MD and AD values, and that the average FA, MD and AD values in the splenium of the CC were significantly correlated with the IIEF scores and QEQ scores of ED patients, respectively, and that the average MD values in the splenium of the CC were negatively correlated with the duration (shown in Fig. 3). The results indicated that the abnormalities in the multiple DTI-derived indices in the splenium of the CC might be more severe with more severe symptoms and longer duration of ED. As we know, the splenium fibres of the CC connect occipital and parietal cortices, as well as inferior and medial temporal regions (including the posterior cingulate) (Knyazeva, 2013), and are involved in the somatosensory information communication and visual signal conduction. The activity changes in the inferior temporal gyrus, occipital cortex, parietal cortex and posterior cingulate had been highly reproducible in neuroimaging studies on sexual arousal (Montorsi et al., 2003a, 2003b; Mouras et al., 2003; Kim et al., 2006; Hu et al., 2008). Hence, we predicted that the increased myelination in the splenium of the CC might relate to the abnormal sexual arousal in ED.
FINANCIAL DISCLOSURE
Limitations and future direction The main limitation of this study lied in that it was not a longitudinal design, so it could not explain the causality between the symptoms, psychological factors, duration and altered cerebral structures. This study provided the basis for further investigation of cerebral structure changes in organic ED, so we plan to 384
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ACKNOWLEDGEMENTS This study was supported by the Scientific Research Fund of Sichuan Provincial Education Department (NO.12ZB034). We thank Shuwu Zhang and Jiuyuan Wang for assistance in patient recruitment of this study.
AUTHOR CONTRIBUTIONS P.Z., W.Q., M.D., D.C. contributed to study protocol and design; P.Z., J.P., G.L., X.H., Q.L. acquired the data; J.L., Z.L., J.S. analysed and/or interpreted the data; P.Z., J.L. drafted the manuscript; D.C., J.P., G.L., Z.L., Q.L., W.Q., M.D., J.S., X.H., T.W. revised the manuscript.
No conflicts of interest exist.
REFERENCES Alexander AL, Lee JE, Lazar M & Field AS. (2007) Diffusion tensor imaging of the brain. Neurotherapeutics 4, 316–329. Althof SE, Cappelleri JC, Shpilsky A, Stecher V, Diuguid C, Sweeney M et al. (2003) Treatment responsiveness of the Self-Esteem And Relationship questionnaire in erectile dysfunction. Urology 61, 888– 892. Andersson JLR, Jenkinson M & Smith S. (2007a) Non-linear optimisation. FMRIB technical report TR07JA1 from www.fmrib.ox.ac.uk/analysis/ techrep. Andersson JLR, Jenkinson M & Smith S. (2007b). Non-linear registration, aka Spatial normalisation. FMRIB technical report TR07JA2 from www.fmrib.ox.ac.uk/analysis/techrep. Arnow BA, Desmond JE, Banner LL, Glover GH, Solomon A, Polan ML et al. (2002) Brain activation and sexual arousal in healthy, heterosexual males. Brain 125, 1014–1023. Axer H & Keyserlingk DG. (2000) Mapping of fiber orientation in human internal capsule by means of polarized light and confocal scanning laser microscopy. J Neurosci Methods 94, 165–175. Bacon CG, Mittleman MA, Kawachi I, Giovannucci E, Glasser DB & Rimm EB. (2003) Sexual function in men older than 50 years of age: results from the health professionals follow-up study. Ann Intern Med 139, 161–168. Cappelleri JC, Althof SE, Siegel RL, Shpilsky A, Bell SS & Duttagupta S. (2004) Development and validation of the Self-Esteem And Relationship (SEAR) questionnaire in erectile dysfunction. Int J Impot Res 16, 30–38. Cera N, Delli Pizzi S, Di Pierro ED, Gambi F, Tartaro A, Vicentini C et al. (2012) Macrostructural alterations of subcortical grey matter in psychogenic erectile dysfunction. PLoS ONE 7, e39118. Feldman H, Goldstein I, Hatzichristou DG, Krane RJ & McKinlay JB. (1994) Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 151, 54–61. Fields RD. (2008) White matter in learning, cognition and psychiatric disorders. Trends Neurosci 31, 361–370. Georgiadis JR, Farrell MJ, Boessen R, Denton DA, Gavrilescu M, Kortekaas R et al. (2010) Dynamic subcortical blood flow during male © 2014 American Society of Andrology and European Academy of Andrology
WHITE MATTER STRUCTURE CHANGES IN ED PATIENT sexual activity with ecological validity: a perfusion fMRI study. Neuroimage 50, 208–216. Guest JF & Das Gupta R. (2002) Health-related quality of life in a UK-based population of men with erectile dysfunction. Pharmacoeconomics 20, 109–117. Hagemann JH, Berding G, Bergh S, Sleep DJ, Knapp WH, Jonas U et al. (2003) Effects of visual sexual stimuli and apomorphine SL on cerebral activity in men with erectile dysfunction. Eur Urol 43, 412–420. Hamilton M. (1959) The assessment of anxiety states by rating. Br J Med Psychol 32, 50–55. Hamilton M. (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23, 56–62. Henze R, Brunner R, Thiemann U, Parzer P, Klein J, Resch F et al. (2012) White matter alterations in the corpus callosum of adolescents with first-admission schizophrenia. Neurosci Lett 513, 178–182. Hu SH, Wei N, Wang QD, Yan LQ, Wei EQ, Zhang MM et al. (2008) Patterns of brain activation during visually evoked sexual arousal differ between homosexual and heterosexual men. AJNR Am J Neuroradiol 29, 1890–1896. Huston JM & Field AS. (2013) Clinical applications of diffusion tensor imaging. Magn Reson Imaging Clin N Am 21, 279–298. Hvidsten K, Carlsson M, Stecher VJ, Symonds T & Levinson I. (2010) Clinically meaningful improvement on the quality of erection questionnaire in men with erectile dysfunction. Int J Impot Res 22, 45–50. Kim SW, Sohn DW, Cho YH, Yang WS, Lee KU, Juh R et al. (2006) Brain activation by visual erotic stimuli in healthy middle aged males. Int J Impot Res 18, 452–457. Kljajevic V, Meyer P, Holzmann C, Dyrba M, Kasper E, Bokde AL et al. (2013) The e4 genotype of apolipoprotein E and white matter integrity in Alzheimer’s disease. Alzheimers Dement. doi: 10.1016/j.jalz.2013.02. 008. Knyazeva MG. (2013) Splenium of corpus callosum: patterns of interhemispheric interaction in children and adults. Neural Plast 2013, 639430. doi: 10.1155/2013/639430 Makris N, Kennedy DN, McInerney S, Sorensen AG, Wang R, Caviness VS Jr et al. (2005) Segmentation of subcomponents within the superior longitudinal fascicle in humans: a quantitative, in vivo, DT-MRI Study. Cereb Cortex 15, 854–869. Montorsi F, Perani D, Anchisi D, Salonia A, Scifo P, Rigiroli P et al. (2003a) Brain activation patterns during video sexual stimulation following the administration of apomorphine: results of a placebo-controlled study. Eur Urol 43, 405–411. Montorsi F, Perani D, Anchisi D, Salonia A, Scifo P, Rigiroli P et al. (2003b) Apomorphine-induced brain modulation during sexual stimulation: a new look at central phenomena related to erectile dysfunction. Int J Impot Res 15, 203–209. ru S, Bittoun J, Glutron D, Pe l e grini-Issac M, Paradis AL Mouras H, Stole et al. (2003) Brain processing of visual sexual stimuli in healthy men: a functional magnetic resonance imaging study. Neuroimage 20, 855– 869. Mulhall JP, Goldstein I, Bushmakin AG, Cappelleri JC & Hvidsten K. (2007) Validation of the erection hardness score. J Sex Med 4, 1626– 1634. uz KK, Sanverdi E, Has A, Temucßin C € rk S & Doerschner K. (2013) Og ß , Tu Tract-based spatial statistics of diffusion tensor imaging in hereditary spastic paraplegia with thin corpus callosum reveals widespread white matter changes. Diagn Interv Radiol 19, 181–186. Oh SK, Kim GW, Yang JC, Kim SK, Kang HK & Jeong GW. (2012) Brain activation in response to visually evoked sexual arousal in
© 2014 American Society of Andrology and European Academy of Andrology
ANDROLOGY male-to-female transsexuals: 3.0 tesla functional magnetic resonance imaging. Korean J Radiol 13, 257–264. Porst H, Gilbert C, Collins S, Huang X, Symonds T, Stecher V et al. (2007) Development and validation of the quality of erection questionnaire. J Sex Med 4, 372–381. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J & Mishra A. (1997) The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 49, 822–830. Rosen RC, Cappelleri JC & Gendrano N. (2002) The International Index of Erectile Function (IIEF): a state-of-the-science review. Int J Impotence Res 14, 226–244. Rouw R & Scholte HS. (2007) Increased structural connectivity in grapheme-color synesthesia. Nat Neurosci 10, 792–797. Rueckert D, Sonoda LI, Hayes C, Hill DL, Leach MO & Hawkes DJ. (1999) Non-rigid registration using free-form deformations: application to breast MR images. IEEE Trans Med Imaging 18, 712–721. Sbardella E, Petsas N, Tona F, Prosperini L, Raz E, Pace G et al. (2013) Assessing the correlation between grey and white matter damage with motor and cognitive impairment in multiple sclerosis patients. PLoS ONE 8, e63250. Schmahmann JD & Pandya DN. (2006) Fiber Pathways of the Brain. Oxford University Press, New York. Scholz J, Klein MC, Behrens TEJ & Johansen-Berg H. (2009) Training induces changes in white matter architecture. Nat Neurosci 12, 1370– 1371. Seo Y, Jeong B, Kim JW & Choi J. (2010) The relationship between age and brain response to visual erotic stimuli in healthy heterosexual males. Int J Impot Res 22, 234–239. Smith SM. (2002) Fast robust automated brain extraction. Hum Brain Mapp 17, 143–155. Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H et al. (2004) Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage 23, 208–219. Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE et al. (2006) Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. NeuroImage 31, 1487–1505. € sterhus P & Schulte-Markwort M. (2006) Stegemann T, Heimann M, Du Diffusion tensor imaging (DTI) and its importance for exploration of normal or pathological brain development. Fortschr Neurol Psychiatr 74, 136–148. Versace A, Almeida JRC, Hassel S, Walsh ND, Novelli M, Klein CR et al. (2008) Elevated left and reduced right orbitomedial prefrontal fractional anisotropy in adults with bipolar disorder revealed by tract-based spatial statistics. Arch Gen Psychiatry 65, 1041–1052. Vicenzini E, Altieri M, Michetti PM, Ricciardi MC, Ciccariello M, Shahabadi H et al. (2008) Cerebral vasomotor reactivity is reduced in patients with erectile dysfunction. Eur Neurol 60, 85–88. National Institutes of Health Consensus Development Panel on impotence: NIH consensus conference: impotence. (1993) JAMA 270, 83–90. Yuan K, Qin W, Wang G, Zeng F, Zhao L, Yang X et al. (2011) Microstructure abnormalities in adolescents with internet addiction disorder. PLoS ONE 6, e20708. Zhou G, Qin W, Zeng F, Liu P, Yang X, von Deneen KM et al. (2013) White-matter microstructural changes in functional dyspepsia: a diffusion tensor imaging study. Am J Gastroenterol 108, 260–269. Zusman RM. (1999) Cardiovascular data on sildenafil citrate: introduction. Am J Cardiol 83, 1C–2C.
Andrology, 2014, 2, 379–385
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