Patient scenario: A 53-year-old woman with hypoactive sexual desire disorder

Objective

To provide an expert review of the clinical management of hypoactive sexual desire disorder.

Method

The importance of diagnosing and providing therapeutic management for hypoactive sexual desire disorder will be explained with a case scenario which is resolved by drawing on original trial publications and meta-analyses published in English.

Results

Hypoactive sexual desire disorder (HSDD) is highly prevalent (9–16%) and has a strong impact on the quality of life of both women and their partners. Medical and sexual history, physical and laboratory examinations as well as validated questionnaires will help us make an accurate diagnosis. Treatment should begin by focusing on lifestyle and psychosexual therapy. Women randomized to oestrogen–testosterone transdermal patch combination or testosterone transdermal patch alone reported significantly increased frequency of satisfying sexual activity (p < 0.05). Hormonal treatment with oestrogen and testosterone or with testosterone alone should be personalised, as should follow-up.

Conclusions

Guidelines for the medical management of hypoactive sexual desire disorder are now available and this starts by understanding the importance of this disorder and knowing that accurate diagnosis and treatment options exist.     

Role of testosterone in the treatment of hypoactive sexual desire disorder

Hypoactive sexual desire disorder (HSDD) is a common clinical problem that may have a very negative impact on a woman's quality of life. Diagnosis and treatment is challenging, as one must keep in mind the complex web of factors influencing sexual functioning alone or in concert. Data suggest that androgens are significant independent factors affecting sexual desire, sexual activity and satisfaction, as well as other components of women's health such as mood and energy. For decades, physicians used various androgen preparations to improve sexual function in women, based on the results of smaller clinical trials and personal clinical observations when taking care of patients. Today, there is substantial body of evidence from randomized placebo-controlled trials that low-dose testosterone treatment is efficacious in women with HSDD who have an established cause of androgen deficiency such as surgical menopause. Recent data support the hypotheses that androgens may also be beneficial in naturally menopausal women or in premenopausal women with low circulating testosterone levels and a decrease in satisfying sexual activity. No single testosterone level has been found to be predictive for low female sexual function, even though women suffering from HSDD commonly have low testosterone levels. The most frequently reported side effects of testosterone treatment are mild hirsutism or acne. Long-term safety is not yet established. Several clinical trials are in progress to further investigate potential benefits and risks of androgen treatment in women with sexual dysfunction.     

The role of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women

At least 16 million women over the age of 50 currently experience low sexual desire, with approximately 4 million women exhibiting hypoactive sexual desire disorder (HSDD). Although early research established that testosterone therapy improves sexual desire in postmenopausal women, safer and more efficacious administration routes were explored. Large randomized, double-blinded placebo-controlled studies demonstrate that transdermal testosterone improves sexual function and activity in postmenopausal women with HSDD. Large multi-center Phase III trials further confirm the positive effects of the testosterone patch in the treatment of HSDD. More recent studies are exploring the utility of testosterone gels. Based upon data from two recent clinical relevance studies, physicians can be reassured that postmenopausal women with HSDD report a meaningful benefit with testosterone therapy, and further, women will only continue therapy if they experience a meaningful benefit. Although most trials combined testosterone with estrogen/progesterone therapy, the recent APHRODITE trial examined testosterone alone, showing increased sexual desire with mild adverse events. Concerns regarding the long-term safety profile of transdermal testosterone must be addressed before the FDA will approve a testosterone product for women. Although some fear an increased risk of breast cancer with exogenous testosterone administration, recent studies support the idea that androgens can play a role in suppressing the proliferative effects of estrogen and progesterone. Long-term safety data is now being collected and analyzed and Phase III trials focusing on long-term risks are underway. In the meantime, transdermal testosterone appears to be a safe and effective therapy for postmenopausal women with HSDD [Swanson S, DeRogatis L, Snabes M, Simes S, Zborowski J. Treatment of HSDD in surgically menopausal women: a newly initiated Phase III, randomized, double-blind, placebo-controlled, multi-center study of the safety and efficacy of LibiGel. Presented at the Annual Meeting of the International Society for the Study of Women's Sexual Health, February 22–25, Orlando, FL; 2007].     

Female sexual dysfunctions: Definitions and classification

Female sexuality is complex and a variety of schemes have evolved to attempt the definition and categorization of the various kinds of female sexual dysfunction. This paper reviews some of the current systems of classification and describes how understanding these systems can help the physician in evaluating the individual patient, who may present with overlapping features of several co-morbid sexual dysfunctions.     

注意缺陷多动障碍儿童动态功能连接的功能磁共振成像研究

目的:探索注意缺陷多动障碍儿童静态以及动态功能连接的异常。方法:收集智商高于80的6～16岁符合DSM-IV诊断的注意缺陷多动障碍儿童97例(男78例,女19例)和年龄匹配的正常对照儿童74例(男45例,女29例)的静息态功能磁共振成像数据,比较两组全脑静态功能连接和动态功能连接指标。结果:注意缺陷多动障碍组的静态功能连接与正常对照组的差异无统计学意义(P>0.05),注意缺陷多动障碍组腹外侧前额叶与全脑其他脑区功能连接的模式变异性大于正常对照组[(0.65±0.07)%vs.(0.60±0.08)%,P<0.01]。结论:动态分析提示腹外侧前额叶是注意缺陷多动障碍的关键脑区,为理解疾病的脑机制提供可能的新视角。     

强迫症患者脑岛功能连接异常磁共振成像研究

目的:探讨静息态下强迫症患者脑岛的功能连接特点。方法:纳入符合DSM-IV强迫症诊断标准的患者32例及性别、年龄、教育年限相匹配的正常对照37例,采用Y-BOCS量表评定强迫思维、强迫行为严重程度,应用3.0T磁共振成像系统进行静息态数据扫描。以双侧脑岛为感兴趣区(ROI)进行全脑功能连接(FC)分析,比较强迫症组与正常对照组之间的功能连接差异,并分析差异脑区功能连接强度与临床症状之间的关系。结果:与正常对照组相比,强迫症患者组的左侧脑岛与右侧缘上回、右侧顶下回、右侧顶上回的功能连接增强(FDR校正,P<0.01);右侧脑岛与右侧岛盖部额下回、左侧缘上回、右侧缘上回、右侧中央后回的功能连接增强(FDR校正,P<0.05);进一步分析发现,右侧脑岛与右侧中央后回的功能连接强度与强迫行为得分呈负相关(r=-0.35,P<0.05)。结论:强迫症患者脑岛的功能连接网络模式可能存在异常。     

Olfactory-induced brain activity in Parkinson's disease relates to the expression of event-related potentials: a functional magnetic resonance imaging study

Olfactory disorders are common in patients with idiopathic Parkinson's disease (IPD). In IPD patients with hyposmia olfactory event-related potentials (ERPs) are typically found to be delayed or absent. Altered ERPs in IPD patients may also be consistent with reduced neuronal activity in the medial temporal lobe following olfactory stimulation, as demonstrated by functional magnetic resonance imaging (fMRI). We analyzed ERPs and fMRI scans of hyposmic IPD patients (n=18) to gain further insight about the brain regions involved in generation of olfactory ERPs. Patients were separated into two groups (n=9 per group), based on the detectability (+) or non-detectability (−) of ERPs. Central activation during olfactory stimulation was examined using fMRI. Both ERP+ and ERP− patients showed activity in brain areas relevant to olfactory processing, such as the amygdala, parahippocampal regions, and temporal regions (BA 37, 21/22). Comparison of both groups revealed higher activation in ERP+ patients, especially in the amygdala, parahippocampal cortex, inferior frontal gyrus (BA 47), insula, cingulate gyrus, striatum, and inferior temporal gyrus. The relationship between the expression of olfactory ERPs and cortical activation patterns seen during olfactory stimulation in fMRI in IPD patients supports the idea that ERPs are a sensitive marker of neurodegeneration in olfactory regions. In accordance with current neuropathological staging concepts, olfactory ERPs may be reflecting pathological changes in olfactory regions, independent of the typically observed nigro-striatal degeneration in IPD. Reduced activation of primary olfactory areas in the ERP-group may reflect a severe disruption of olfactory processing in these patients.     

Valuating other people's emotional face expression: a combined functional magnetic resonance imaging and electroencephalography study

Reading the facial expression of other people is a fundamental skill for social interaction. Human facial expressions of emotions are readily recognized but may also evoke the same experiential emotional state in the observer. We used event-related functional magnetic resonance imaging and multi-channel electroencephalography to determine in 14 right-handed healthy volunteers (29+/-6 years) which brain structures mediate the perception of such a shared experiential emotional state. Statistical parametric mapping showed that an area in the dorsal medial frontal cortex was specifically activated during the perception of emotions that reflected the seen happy and sad emotional face expressions. This area mapped to the pre-supplementary motor area which plays a central role in control of behavior. Low resolution brain electromagnetic tomography-based analysis of the encephalographic data revealed that the activation was detected 100 ms after face presentation onset lasting until 740 ms. Our observation substantiates recently emerging evidence suggesting that the subjective perception of an experiential emotional state-empathy-is mediated by the involvement of the dorsal medial frontal cortex.     

The neural correlates of reward-related processing in major depressive disorder: A meta-analysis of functional magnetic resonance imaging studies

Background

A growing number of functional magnetic resonance imaging (fMRI) studies have been conducted in major depressive disorder (MDD) to elucidate reward-related brain functions. The aim of this meta-analysis was to examine the common reward network in the MDD brain and to further distinguish the brain activation patterns between positive stimuli and monetary rewards as well as reward anticipation and outcome.

Methods

A series of activation likelihood estimation (ALE) meta-analyses were performed across 22 fMRI studies that examined reward-related processing, with a total of 341 MDD patients and 367 healthy controls.

Results

We observed several frontostriatal regions that participated in reward processing in MDD. The common reward network in MDD was characterized by decreased subcortical and limbic areas activity and an increased cortical response. In addition, the cerebellum, lingual gyrus, parahippocampal gyrus and fusiform gyrus preferentially responded to positive stimuli in MDD, while the insula, precuneus, cuneus, PFC and inferior parietal lobule selectively responded to monetary rewards. Our results indicated a reduced caudate response during both monetary anticipation and outcome stages as well as increased activation in the middle frontal gyrus and dorsal anterior cingulate during reward anticipation in MDD.

Limitations

The reward-related tasks and mood states of patients included in our analysis were heterogeneous.

Conclusions

Our current findings suggest that there exist emotional or motivational pathway dysfunctions in MDD during reward-related processing. Future studies may be strengthened by paying careful attention to the types of reward used as well as the different components of reward processing examined.     

Sleep stabilizes visuomotor adaptation memory: a functional magnetic resonance imaging study

The beneficial effect of sleep on motor memory consolidation is well known for motor sequence memory, but remains unsettled for visuomotor adaptation in humans. The aim of this study was to characterize more clearly the influence of sleep on consolidation of visuomotor adaptation using a between‐subjects functional magnetic resonance imaging (fMRI) design contrasting sleep to total sleep deprivation. Our behavioural results, based on seven different parameters, show that sleep stabilizes performance whereas sleep deprivation deteriorates it. During training, while a set of cerebellar, striatal and cortical areas is activated in proportion to performance improvement, the recruitment of the hippocampus and frontal cortex protects motor memory against the detrimental effects of sleep deprivation. During retest after sleep loss a cerebello–cortical network, usually involved in the earliest stage of learning, was recruited to perform the task. In contrast, no changes in cerebral activity were observed after sleep, suggesting that it may only support the stabilization of the visuomotor adaptation memory trace.     

Error-related processing following severe traumatic brain injury: An event-related functional magnetic resonance imaging (fMRI) study

Continuous monitoring of one's performance is invaluable for guiding behavior towards successful goal attainment by identifying deficits and strategically adjusting responses when performance is inadequate. In the present study, we exploited the advantages of event-related functional magnetic resonance imaging (fMRI) to examine brain activity associated with error-related processing after severe traumatic brain injury (sTBI). fMRI and behavioral data were acquired while 10 sTBI participants and 12 neurologically-healthy controls performed a task-switching cued-Stroop task. fMRI data were analyzed using a random-effects whole-brain voxel-wise general linear model and planned linear contrasts. Behaviorally, sTBI patients showed greater error-rate interference than neurologically-normal controls. fMRI data revealed that, compared to controls, sTBI patients showed greater magnitude error-related activation in the anterior cingulate cortex (ACC) and an increase in the overall spatial extent of error-related activation across cortical and subcortical regions. Implications for future research and potential limitations in conducting fMRI research in neurologically-impaired populations are discussed, as well as some potential benefits of employing multimodal imaging (e.g., fMRI and event-related potentials) of cognitive control processes in TBI.     

重性抑郁症首发未用药患者的枕叶GABA波谱研究

在中枢神经系统中,γ-氨基丁酸(GABA)是主要的抑制性神经递质。由于GABA在普通磁共振波谱(MRS)上为低谱峰信号,且与其他物质的波峰重叠,因此难以准确得出其在脑内感兴趣区的含量。为观察抑制性神经递质GABA在首发未用药重性抑郁症(MDD)患者枕叶的含量改变,本研究采用了J-耦合编辑点分辨波谱(MEGA-PRESS)技术检测18例首发未用药重性MDD(17项HAMD评分>18分)患者和23名健康对照被试枕叶皮层的GABA含量。采用双样本t检验及相关分析进行统计学处理。结果表明,病例组枕叶GABA含量(11.35±3.26)显著低于对照组(27.30±8.87),P<0.001。病例组枕叶GABA含量与汉密尔顿抑郁量表及贝克抑郁自评量表相关性均不显著。首发未用药重性MDD患者的枕叶GABA含量降低,可能导致其视觉功能下降。     

A familial form of convulsive disorder with or without mental retardation limited to females: extension of a pedigree limits possible genetic mechanisms

An unusual pedigree of female-limited seizures with or without mental retardation is updated. The disorder was first detected in a large cohort of women whose fathers were brothers, and affected women had previously transmitted the disorder. Four brothers of affected females have now had five unaffected daughters while four affected women have had four affected and one unaffected daughters and two unaffected sons. This unusual transmission pattern is discussed in terms of germ-line imprinting, neuronal sexual differentiation, and the generally higher risk of seizures seen when the mother, rather than the father, is affected.     

Pattern of cortical reorganization in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study

Depending on individual lesion location and extent, reorganization of the human motor system has been observed with a high interindividual variability. In addition, variability of forces exerted, of motor effort, and of movement strategies complicates the interpretation of functional imaging studies. We hypothesize that a general pattern of reorganization can be identified if a homogeneous patient population is chosen and experimental conditions are controlled. Patients with amyotrophic lateral sclerosis (ALS) and healthy volunteers were trained to perform a simple finger flexion task with 10% of each individual's maximum grip force with constant movement amplitude and frequency. The activation pattern in ALS patients was distinctly different to that in healthy controls: In ALS patients, motor cortex activation was located more anteriorly, encompassing the premotor gyrus. The cluster volume within the supplementary motor area (SMA) was higher and shifted toward the pre-SMA. Contralateral inferior area 6 and bilateral parietal area 40 revealed higher cluster volumes. Our results demonstrate a general pattern of functional changes after motor neuron degeneration. They support the concept of a structurally parallel and functionally specialized organization of voluntary motor control. Degeneration of the first and second motor neurons leads to enhanced recruitment of motor areas usually involved in initiation and planning of movement. Partial compensation between functionally related motor areas seems to be a strategy to optimize performance if the most efficient pathway is unavailable.     

Depression symptoms and cognitive control of emotion cues: a functional magnetic resonance imaging study

Few studies have examined associations between depressive symptoms and alterations in neural systems that subserve cognitive control. Cognitive control was assessed with an exogenous cueing task using happy, sad, and neutral facial expressions as cues among women with mild to moderate symptoms of depression and a non-depressed control group while functional magnetic resonance imaging (fMRI) measured brain activity. Amygdala and medial/orbital prefrontal cortex (PFC) response to valid emotion cues did not differ as a function of depression symptoms. However, significant depression group differences were observed when task demands required cognitive control. Participants with elevated depression symptoms showed weaker activation in right and left lateral PFC and parietal regions when shifting attentional focus away from invalid emotion cues. No depression group differences were observed for invalid non-emotional cues. Findings suggest that mild to moderate depression symptoms are associated with altered function in brain regions that mediate cognitive control of emotional information.     

Pineal gland volume in primary insomnia and healthy controls: a magnetic resonance imaging study

Little is known about the relation between pineal volume and insomnia. Melatonin promotes sleep processes and, administered as a drug, it is suitable to improve primary and secondary sleep disorders in humans. Recent magnetic resonance imaging studies suggest that human plasma and saliva melatonin levels are partially determined by the pineal gland volume. This study compares the pineal volume in a group of patients with primary insomnia to a group of healthy people without sleep disturbance. Pineal gland volume (PGV) was measured on the basis of high‐resolution 3 Tesla MRI (T1‐magnetization prepared rapid gradient echo) in 23 patients and 27 controls, matched for age, gender and educational status. Volume measurements were performed conventionally by manual delineation of the pineal borders in multi‐planar reconstructed images. Pineal gland volume was significantly smaller (P < 0.001) in patients (48.9 ± 26.6 mm³) than in controls (79 ± 30.2 mm³). In patients PGV correlated negatively with age (r = ?0.532; P = 0.026). Adjusting for the effect of age, PGV and rapid eye movement (REM) latency showed a significant positive correlation (r_S = 0.711, P < 0.001) in patients. Pineal volume appears to be reduced in patients with primary insomnia compared to healthy controls. Further studies are needed to clarify whether low pineal volume is the basis or the consequence of functional sleep changes to elucidate the molecular pathology for the pineal volume loss in primary insomnia.     

Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T (1)H MRS imaging study

Chronic fatigue syndrome (CFS) is a controversial diagnosis because of the lack of biomarkers for the illness and its symptom overlap with neuropsychiatric, infectious, and rheumatological disorders. We compared lateral ventricular volumes derived from tissue-segmented T(1)-weighted volumetric MRI data and cerebrospinal fluid (CSF) lactate concentrations measured by proton MRS imaging ((1)H MRSI) in 16 subjects with CFS (modified US Centers for Disease Control and Prevention criteria) with those in 14 patients with generalized anxiety disorder (GAD) and in 15 healthy volunteers, matched group-wise for age, sex, body mass index, handedness, and IQ. Mean lateral ventricular lactate concentrations measured by (1)H MRSI in CFS were increased by 297% compared with those in GAD (P < 0.001) and by 348% compared with those in healthy volunteers (P < 0.001), even after controlling for ventricular volume, which did not differ significantly between the groups. Regression analysis revealed that diagnosis accounted for 43% of the variance in ventricular lactate. CFS is associated with significantly raised concentrations of ventricular lactate, potentially consistent with recent evidence of decreased cortical blood flow, secondary mitochondrial dysfunction, and/or oxidative stress abnormalities in the disorder.     

Neuronal substrates of haptic shape encoding and matching: a functional magnetic resonance imaging study

We used functional magnetic resonance imaging to differentiate cerebral areas involved in two different dimensions of haptic shape perception: encoding and matching. For this purpose, healthy right-handed subjects were asked to compare pairs of complex 2D geometrical tactile shapes presented in a sequential two-alternative forced-choice task. Shape encoding involved a large sensorimotor network including the primary (SI) and secondary (SII) somatosensory cortex, the anterior part of the intraparietal sulcus (IPA) and of the supramarginal gyrus (SMG), regions previously associated with somatosensory shape perception. Activations were also observed in posterior parietal regions (aSPL), motor and premotor regions (primary motor cortex (MI), ventral premotor cortex, dorsal premotor cortex, supplementary motor area), as well as prefrontal areas (aPFC, VLPFC), parietal-occipital cortex (POC) and cerebellum. We propose that this distributed network reflects construction and maintenance of sensorimotor traces of exploration hand movements during complex shape encoding, and subsequent transformation of these traces into a more abstract shape representation using kinesthetic imagery. Moreover, haptic shape encoding was found to activate the left lateral occipital complex (LOC), thus corroborating the implication of this extrastriate visual area in multisensory shape representation, besides its contribution to visual imagery. Furthermore, left hemisphere predominance was shown during encoding, whereas right hemisphere predominance was associated with the matching process. Activations of SI, MI, PMd and aSPL, which were predominant in the left hemisphere during the encoding, were shifted to the right hemisphere during the matching. In addition, new activations emerged (right dorsolateral pre-frontal cortex, bilateral inferior parietal lobe, right SII) suggesting their specific involvement during 2D geometrical shape matching.     

Activation of the hippocampal formation by vestibular stimulation: a functional magnetic resonance imaging study

Functional MRI (f-MRI) is a non-invasive technique developed to permit functional mapping of the brain with a better temporal and spatial resolution than that offered by PET techniques. In our study, f-MRI was performed using blood oxygenation level dependent (BOLD) contrast imaging based on the magnetic properties of hemoglobin. This method relies on changes in the blood supply to the brain that accompany sensory stimulation or changes in cognitive state. All the images were obtained at 1.5 T on a Signa GEMS without ultrafast imaging. The vestibular stimulation was cold irrigation of the external auditory meatus (caloric stimulation). A population of normal healthy volunteers without a history of vestibular dysfunction was studied. The hippocampal formation as well as the retrosplenial cortex and the subiculum were activated by vestibular stimulation, suggesting that this activation may be related to spatial disorientation and a sensation of self-rotation experienced by the subjects during vestibular stimulation. The other results are similar to those obtained using PET.     

Evidence for a dysfunctional retrosplenial cortex in patients with schizophrenia: a functional magnetic resonance imaging study with a semantic-perceptual contrast

We investigated whether the retrosplenial and the posterior cingulate cortex (RS-PCC) is functionally impaired in schizophrenia patients. Therefore, we measured functional magnetic resonance imaging (fMRI) signal changes associated with a synonym-judgment task known to activate, among other areas, the RS-PCC. Compared to 12 matched control subjects, 12 schizophrenia patients exhibited reliably weaker activations in the RS-PCC, the dorsolateral prefrontal cortex and the left orbitofrontal cortex (P < 0.05, corrected). Differences in frontal activations are in line with previous studies showing a structurally and functionally affected prefrontal cortex in schizophrenia. The impaired RS-PCC functionality in a semantic task may relate to verbal memory deficits frequently observed in schizophrenia patients, because this region is pivotal for gating information into the medial temporal lobe memory system.