Sven C. Mueller

Long‐Term Evaluation of Cross‐Sex Hormone Treatment in Transsexual Persons

INTRODUCTION Long-term effects and side effects of cross-sex hormone treatment in transsexual persons are not well known. AIM The aim of this study is to describe the effects and side effects of cross-sex hormone therapy in both transsexual men and women. MAIN OUTCOME MEASURES Hormone levels were measured by immunoassays. Physical health was assessed by physical examination and questionnaires on general health and specific side effects, areal bone parameters by dual energy X-ray absorptiometry. METHODS Single center cross-sectional study in 100 transsexual persons post-sex reassignment surgery and on average 10 years on cross-sex hormone therapy. RESULTS Transsexual men did not experience important side effects such as cardiovascular events, hormone-related cancers, or osteoporosis. In contrast, a quarter of the transsexual women had osteoporosis at the lumbar spine and radius. Moreover, 6% of transsexual women experienced a thromboembolic event and another 6% experienced other cardiovascular problems after on average 11.3 hormone treatment years. None of the transsexual women experienced a hormone-related cancer during treatment. CONCLUSION Cross-sex hormone treatment appears to be safe in transsexual men. On the other hand, a substantial number of transsexual women suffered from osteoporosis at the lumbar spine and distal arm. Twelve percent of transsexual women experienced thromboembolic and/or other cardiovascular events during hormone treatment, possibly related to older age, estrogen treatment, and lifestyle factors. In order to decrease cardiovascular morbidity, more attention should be paid to decrease cardiovascular risk factors during hormone therapy management.

Enhanced cognitive control in young people with Tourette's syndrome.

Tourettes syndrome (TS) is a neurodevelopmental disorder characterized by the presence of chronic vocal and motor tics. Tics are sudden, highly stereotyped, movements that can be simple or complex in appearance. Since patients with TS have difficulties preventing unwanted movements, one might expect that their ability to voluntarily control goal-directed movements would be similarly poor. Indeed, it has been suggested that TS sufferers are impaired at inhibiting reflexively triggered movements and in rapidly selecting or switching between different motor sets. This idea is consistent with current views on the neurological basis of TS that posit a dysfunction of the neural circuits linking the frontal lobes and the striatum. These circuits are known to be involved in the voluntary control of action. By using an oculomotor switching task, we show for the first time that young people with TS exhibit paradoxically greater levels of cognitive control over their movements than their age-matched controls. This finding is consistent with an increased need to monitor and control movements and may indicate a subcortical locus for the triggering of tics. It also suggests that the constant need to suppress tics could have resulted in an enhancement of the executive processes involved in inhibitory control.

Early androgen exposure modulates spatial cognition in congenital adrenal hyperplasia (CAH)

Major questions remain about the exact role of hormones in cognition. Furthermore, the extent to which early perturbation in steroid function affects human brain development continues to be a wide open area of research. Congenital adrenal hyperplasia (CAH), a genetic disorder of steroid dysfunction characterized in part by in utero over-production of testosterone, was used as a natural model for addressing this question. Here, CAH (n=54, mean age=17.53, 31 female) patients were compared to healthy age- and sex-matched individuals (n=55, mean age=19.02, 22 female) on a virtual equivalent of the Morris Water Maze task [Morris, R., 1984. Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 11, 47-60], an established measure of sex differences in spatial cognition in rodents. Findings revealed that females with CAH with the most severe form of the disease and expected highest level of in utero exposure to androgens were found to perform similarly to both healthy males and CAH males, whereas strong sex differences were apparent in milder forms of the disorder and in controls. Moreover, advanced bone age, an indicator of long-term childhood exposure to testosterone was correlated with improved performance. The results indicate that individuals exposed to both excess androgens prenatally and prolonged exposure during childhood may manifest long-lasting changes in cognitive function. Such finding suggests a pivotal role of hormonal function on brain development in humans, mirroring results from the animal literature.

Enhanced cognitive control in Tourette Syndrome during task uncertainty

Tourette Syndrome (TS) is a developmental neurological condition that is characterised by the presence of multiple motor and one or more vocal tics. Tics are highly stereotyped repetitive behaviours that fluctuate in type, complexity and severity. TS has been linked to impaired cognitive control processes, however, a recent study (Mueller et al. in Curr Biol 16:570–573, 2006) demonstrated that young people with TS, although exhibiting chronic motor and vocal tics, nevertheless performed significantly better than a group of age-matched controls on a task that required extremely high levels of cognitive control (i.e., predictably shifting between executing pro-saccade and anti-saccade responses to a visual stimulus). As predictable task sequences allow task-related cognitive processes to commence prior to the presentation of target stimuli we examined whether the superior performance of the TS group could be replicated when task sequences were varied unpredictably. Our results confirmed that both the TS group and an age-matched control group benefited, by the same extent, when the saccade task (pro-saccade vs. anti-saccade) was pre-cued. In contrast, while the control group showed a significant decrease in performance on task switch trials relative to task repetition trials—the TS group exhibited no significant ‘costs’ of switching task. While task performance was modulated by response and target location shifts in the control group, these factors had less impact on the TS group’s performance on task switch trials. These results confirm and extend the previous demonstration that individuals with TS exhibit paradoxically greater levels of cognitive control than healthy controls.

The adolescent brain: Insights from functional neuroimaging research

With the development of functional neuroimaging tools, the past two decades have witnessed an explosion of work examining functional brain maps, mostly in the adult brain. Against this backdrop of work in adults, developmental research begins to gather a substantial body of knowledge about brain maturation. The purpose of this review is to present some of these findings from the perspective of functional neuroimaging. First, a brief survey of available neuroimaging techniques (i.e., fMRI, MRS, MEG, PET, SPECT, and infrared techniques) is provided. Next, the key cognitive, emotional, and social changes taking place during adolescence are outlined. The third section gives examples of how these behavioral changes can be understood from a neuroscience perspective. The conclusion places this functional neuroimaging research in relation to clinical and molecular work, and shows how answers will ultimately come from the combined efforts of these disciplines.

Inhibitory control in anxious and healthy adolescents is modulated by incentive and incidental affective stimuli

BACKGROUND Anxiety disorders are characterized by elevated, sustained responses to threat, that manifest as threat attention biases. Recent evidence also suggests exaggerated responses to incentives. How these characteristics influence cognitive control is under debate and is the focus of the present study. METHODS Twenty-five healthy adolescents and 25 adolescents meeting DSM-IV diagnostic criteria for an anxiety disorder were compared on a task of response inhibition. Inhibitory control was assayed with an antisaccade task that included both incentive (monetary reward) and incidental emotion (facial expression) cues presented prior to the execution of inhibitory behavior. RESULTS Inhibitory control was enhanced following exposure to threat cues (fear faces) only in adolescent patients, and following exposure to positive cues (happy faces) only in healthy adolescents. Results also revealed a robust performance improvement associated with monetary incentives. This incentive effect did not differ by group. No interaction between incentives and emotional cues was detected. CONCLUSIONS These findings suggest that biased processing of threat in anxious adolescents affects inhibitory control, perhaps by raising arousal prior to behavioral performance. The absence of normalization of performance in anxious adolescents following exposure to positive emotional cues is a novel finding and will require additional exploration. Future studies will need to more specifically examine how perturbations in positive emotion processes contribute to the symptomatology and the pathogenesis of anxiety disorders.

Gray Matter Volume in Adolescent Anxiety: An Impact of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism?

OBJECTIVE Minimal research links anxiety disorders in adolescents to regional gray matter volume (GMV) abnormalities and their modulation by genetic factors. Prior research suggests that a brain-derived neurotrophic factor (BNDF) Val(66)Met polymorphism may modulate such brain morphometry profiles. METHOD Using voxel-based morphometry and magnetic resonance imaging, associations of BDNF and clinical anxiety with regional GMVs of anterior cingulate cortex, insula, amygdala, and hippocampus were examined in 39 affected (17 Met allele carriers, 22 Val/Val homozygotes) and 63 nonaffected adolescents (27 [corrected] Met allele carriers, 36 [corrected] Val/Val homozygotes). RESULTS Amygdala and anterior hippocampal GMVs were significantly smaller in patients than in healthy comparison adolescents, with a reverse pattern for the insula. Post-hoc regression analyses indicated a specific contribution of social phobia to the GMV reductions in the amygdala and hippocampus. In addition, insula and dorsal-anterior cingulate cortex (ACC) GMVs were modulated by BDNF genotype. In both regions, and GMVs were larger in the Val/Val homozygote patients than in individuals carrying the Met allele. CONCLUSIONS These results implicate reduced GMV in the amygdala and hippocampus in pediatric anxiety, particularly social phobia. In addition, the data suggest that genetic factors may modulate differences in the insula and dorsal ACC.

The influence of emotion on cognitive control: relevance for development and adolescent psychopathology

The last decade has witnessed an explosion of research into the neural mechanisms underlying emotion processing on the one hand, and cognitive control and executive function on the other hand. More recently, studies have begun to directly examine how concurrent emotion processing influences cognitive control performance but many questions remain currently unresolved. Interestingly, parallel to investigations in healthy adults, research in developmental cognitive neuroscience and developmental affective disorders has provided some intriguing findings that complement the adult literature. This review provides an overview of current research on cognitive control and emotion interactions. It integrates parallel lines of research in adulthood and development and will draw on several lines of evidence ranging from behavioral, neurophysiological, and neuroimaging work in healthy adults and extend these to work in pediatric development and patients with affective disorders. Particular emphasis is given to studies that provide information on the neurobiological underpinnings of emotional and cognitive control processes using functional magnetic resonance imaging. The findings are then summarized and discussed in relation to neurochemical processes and the dopamine hypothesis of prefrontal cortical function. Finally, open areas of research for future study are identified and discussed within the context of cognitive control emotion interactions.

Behavioural and neurophysiological correlates of bivalent and univalent responses during task switching

A hallmark of human behaviour is its flexibility. In any given circumstance there is typically a range of possible responses that could be selected. In the current study participants were presented with stimulus displays that afforded two simple cognitive tasks and were required to switch predictably between them. The judgements for each task were either uniquely mapped onto separate effectors (univalent conditions) or else mapped onto shared effectors (bivalent condition). The results demonstrated that whilst behavioural switch costs were similar across the mapping conditions, these conditions differed in the patterns of brain activity observed during task preparation and early visual processing of the target. Specifically, a cue-locked switch-related late frontal negativity was present over frontal sensors for the bivalent condition only, and a target-locked N1 over occipital sensors was larger in the bivalent condition than the univalent conditions. In contrast, a switch-related target-locked P3b component was common to all mapping conditions. These findings are discussed with respect to differences in processing demands for switching between tasks with bivalent versus univalent responses.

Attentional processing of other’s facial display of pain: An eye tracking study

&NA; Initial attention allocation and attentional maintenance to facial expressions of pain is dependent upon intensity of facial pain expressiveness and observers’ pain intensity and catastrophizing. &NA; The present study investigated the role of observer pain catastrophizing and personal pain experience as possible moderators of attention to varying levels of facial pain expression in others. Eye movements were recorded as a direct and continuous index of attention allocation in a sample of 35 undergraduate students while viewing slides presenting picture pairs consisting of a neutral face combined with either a low, moderate, or high expressive pain face. Initial orienting of attention was measured as latency and duration of first fixation to 1 of 2 target images (i.e., neutral face vs pain face). Attentional maintenance was measured by gaze duration. With respect to initial orienting to pain, findings indicated that participants reporting low catastrophizing directed their attention more quickly to pain faces than to neutral faces, with fixation becoming increasingly faster with increasing levels of facial pain expression. In comparison, participants reporting high levels of catastrophizing showed decreased tendency to initially orient to pain faces, fixating equally quickly on neutral and pain faces. Duration of the first fixation revealed no significant effects. With respect to attentional maintenance, participants reporting high catastrophizing and pain intensity demonstrated significantly longer gaze duration for all face types (neutral and pain expression), relative to low catastrophizing counterparts. Finally, independent of catastrophizing, higher reported pain intensity contributed to decreased attentional maintenance to pain faces vs neutral faces. Theoretical implications and further research directions are discussed.