Neuroendocrine aspects of Tourette syndrome.

CHAPTER NINE

Neuroendocrine Aspects of Tourette Syndrome Davide Martino*,†,{, Antonella Macerollo}, James F. Leckman}

*Queen Elizabeth Hospital, Woolwich, London, United Kingdom † Centre for Neuroscience and Trauma, Queen Mary University of London, London, United Kingdom { King’s College Hospital, London, United Kingdom } Sobell Department of Motor Neuroscience and Movement Disorders, National Hospital of Neurology and Neurosurgery, Institute of Neurology, University College London, London, United Kingdom } Child Study Center, Yale University, New Haven, Connecticut, USA

Contents 1. Introduction 2. Sex Steroid Hormones and TS 2.1 Physiology of the HPG axis and its activity in TS 2.2 The organizational/activational theory of gonadal hormone effects over neurobehavioral development 2.3 Sex-related differences in behavior and personality traits in TS 2.4 Sex-related differences in cognitive and motor abilities in TS 2.5 Sex-related differences in brain functional anatomy in TS 2.6 Gonadal hormones and TS during postnatal life: An as yet unexplored relationship 3. The Stress Response in TS 4. Neurohypophysial Peptides: Possible Players in the Complex Pathophysiology of TS? 5. Conclusions References

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Abstract There is sparse evidence suggesting the participation of neuroendocrine mechanisms, mainly involving sex and stress steroid hormones, to the pathophysiology of neurodevelopmental disorders such as Tourette syndrome (TS) and obsessive–compulsive disorder (OCD). Patients with TS exhibit a sex-specific variability in gender distribution (male/female ratio ¼ 3-4/1) and in its natural history, with a severity peak in the period around puberty. The administration of exogenous androgens may worsen tics in males with TS, whereas drugs counteracting the action of testosterone might show some antitic efficacy. This suggests a higher susceptibility of patients with TS to androgen steroids. There are insufficient data on the regulation of the hypothalamic–pituitary– gonadal (HPG) axis in TS. However, preliminary evidence suggests that a subgroup of

International Review of Neurobiology, Volume 112 ISSN 0074-7742 http://dx.doi.org/10.1016/B978-0-12-411546-0.00009-3

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women with TS might be more sensitive to the premenstrual trough of estrogen levels. Patients with TS exhibit differences in a number of behavioral, cognitive, and anatomical traits that appear to be sex related. There is a body of evidence supporting, albeit indirectly, the hypothesis of an increased exposure to androgenic steroids during the very early phases of neural development. Animal models in rodents suggest a complex role of gonadal hormones upon the modulation of anxiety-related and stereotyped behaviors during adult life. Patients with TS exhibit an enhanced reactivity of the hypothalamic–pituitary–adrenal axis to external stressors, despite a preserved diurnal cortisol rhythm and a normal restoration of the baseline activity of the axis following the acute stress response. Preliminary evidence suggests the possible implication of oxytocin (OT) in disorders related to the TS spectrum, especially non-tic-related OCD. The injection of OT in the amygdala of rodents was shown to be able to induce hypergrooming, suggesting the possible involvement of this neuropeptide in the pathophysiology of complex, stereotyped behaviors. In contrast, there is anecdotal clinical evidence that tics improve following periods of affectionate touch and sexual intercourse.

1. INTRODUCTION Contemporary research shows that the development of behavioral patterns leading to personality traits, cognitive abilities, and effective social interaction results from a complex interplay of genes, hormones, and environmental exposures related to experience. The pathophysiology of complex neurodevelopmental disorders like Tourette syndrome (TS) is therefore likely to be influenced also by changes in the functioning of endocrine regulatory systems during prenatal life as well as throughout the different postnatal developmental stages. Very general features of TS, such as gender distribution or worsening of tic severity during socially challenging stressful periods, point to a possible interplay between the development and activity of circuitries responsible for tic generation and the functioning of complex endocrine regulatory pathways, such as the hypothalamic–pituitary–gonadal (HPG) and the hypothalamic–pituitary–adrenal (HPA) axes. However, the details of this interaction have been understudied to date. This chapter critically reviews the available evidence on endocrine function in TS and contextualizes these hormonal effects with genetic, social, and cognitive influences on the mechanisms of disease in this condition. It also comments on possible theoretical models of the neuroendocrine interplay in this illness, with suggestions for possible future research.

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2. SEX STEROID HORMONES AND TS A relationship between TS and sex steroid hormones is suggested by sex-related differences in the demographic features and natural history of this condition. The most obvious feature that suggests an implication of gonadal steroids in the disease mechanisms of TS is the 3-4/1 male/female ratio, consistently reported by the vast majority of clinic- and population-based studies (Jin et al., 2005; Khalifa & von Knorring, 2003; Kraft et al., 2012). Sexspecific variability in the presentation of the clinical spectrum of TS applies also to comorbidities: for example, females are more likely than males to present with comorbid obsessive–compulsive disorder (OCD). The period of worst ever tic severity usually falls between 7 and 15 years of age. Leckman et al. (1998) reported in a birth-year cohort of 42 patients that the mean age at the peak of tic severity was 10 (standard deviation, 2.4) years, that is, very close to the age period corresponding to the hormonal surge of puberty. Additional evidence supporting this link comes from clinical anecdotal and pharmacological studies. Leckman and Scahill (1990) have described two male athletes with TS whose symptoms worsened in young adulthood following an abuse of high doses of parenterally administered anabolic steroids with a heavy androgenic component; both improved after withdrawal of the exogenous androgens. Peterson, Zhang, Anderson, and Leckman (1998) conducted a 3-week, double blind, placebo-controlled, crossover trial of flutamide (a selective androgen receptor antagonist) in 13 adult TS patients (10 males). This drug significantly reduced the severity of motor tics, although not that of phonic tics, and modestly improved obsessive–compulsive symptoms. However, serum-free testosterone levels increased following treatment with flutamide, possibly as a physiological compensation for androgen receptor blockade, and the beneficial effect over tics was short-lived. Muroni, Paba, Puligheddu, Marrosu, and Bortolato (2010) documented the effects of an 18-week regimen of finasteride 5 mg daily in 10 male adult TS patients. This drug is a 5-a-reductase inhibitor, which decreases the conversion of testosterone into its potent androgenic metabolite, 5-a-dihydrotestosterone. More recently, finasteride infusions in the ventral striatum of rats prevented the dopamine receptor agonistinduced deficits of prepulse inhibition of the acoustic startle reflex (Devoto et al., 2012), a marker of sensorimotor gating previously found altered also in patients with TS (Swerdlow et al., 2001). In the study by Muroni et al., TS patients treated with finasteride manifested a

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time-dependent decline in the severity of total, motor and phonic tics, as well as in total and compulsion, but not obsession, scores. The treatment was well tolerated, with only minor complaints of reduction in libido in two patients. Overall, this preliminary body of evidence suggests that tics may be worsened by increased exposure to, or enhanced activity of, androgenic steroids.

2.1. Physiology of the HPG axis and its activity in TS The synthesis and secretion of sex hormones is dependent on the activity of the HPG axis. The main gonadal hormones in humans are estradiol and testosterone, present in both sexes to varying degrees and both originating from cholesterol. The Leydig cells of the testes are the primary source of testosterone, which can also be secreted by the adrenal glands (Goy, Bercovitch, & McBrair, 1988; Scott, Mason, & Sharpe, 2009). Estradiol is synthesized in two steps by the theca and granulosa cells of the ovaries and is derived from the aromatization of testosterone. Men and postmenopausal women may also produce estradiol in the brain, fat tissue, vascular endothelium, smooth muscle cells, osteoblasts, and chondrocytes (Simpson, 2003). Figure 9.1 summarizes the basic feedback mechanisms regulating the HPG axis. Early reports suggest basally reduced activity of the HPG axis in TS patients. Sandyk, Bamford, Binkiewicz, and Finley (1988) measured plasma baseline levels of gonadotropins and gonadal hormones in 17 patients with TS (14 males, age range 5–69 years) and administered synthetic gonadotropin-releasing hormone (GnRH) to test the reactivity of the axis in 7 of these patients. Overall, there were low luteinizing hormone (LH) levels in all patients, with milder reductions also of follicle-stimulating hormones (FSH) levels; a marked rise of LH was also observed following GnRH stimulation. Although these authors underline the presence of reduced baseline gonadotropin concentrations in TS patients, possibly secondary to hypothalamic deficiency, patients’ hormonal levels were compared to normative values from a historical population and not to a real control group. Another report from the same group (Sandyk, 1987) suggested an improvement of tics with clomiphene citrate in two men with TS. This molecule may stimulate GnRH secretion, but may also exert antiestrogen effects. Given the complex pharmacodynamic effects of this drug, the very small numbers and the lack of follow-up or replication in subsequent studies, this finding is difficult to interpret.

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Figure 9.1 The hypothalamus–pituitary–gonadal (HPG) axis regulates the secretion of gonadal hormones in a variable way throughout the lifespan. GnRH is synthesized by the hypothalamus to induce the synthesis of the two gonadotropins, follicle-stimulating hormone (FSH) and LH, by the anterior pituitary. In males, FSH induces spermatogenesis in testicular Sertoli cells and LH induces the synthesis of testosterone by Leydig cells. Testosterone regulates the activity of the HPG axis by a negative feedback mechanism active on the hypothalamic and pituitary levels of the axis. In females, the regulation of the HPG axis is cycle dependent. Estradiol is primarily secreted by ovarian follicular cells, which are induced by gonadotropins only during the cycle’s follicular phase. When estradiol concentration exceeds a critical level, it exerts a positive feedback over the axis, which leads to the FSH/LH surge around ovulation (midcycle). Finally, during the luteal phase, gonadotropins induce the secretion of progesterone, whereas estrogen production is markedly reduced. Blue arrows indicate facilitatory effects; red arrows indicate inhibitory effects.

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A few reports explored the relationship between phases of the menstrual cycle and tic severity in women with TS. This was prompted by anecdotal reports (Sandyk & Bamford, 1987; Schwabe & Konkol, 1992) and one questionnaire-based study (Lees, Robertson, Trimble, & Murray, 1984) that observed a premenstrual increase in tics, hypothesized as secondary to the trough in estrogen levels. Kompoliti, Goetz, Leurgans, Raman, and Comella (2001) addressed this issue more directly, correlating estrogen and progesterone levels to video-based and rating scale-based tic measurement throughout a full menstrual cycle in eight women with TS. All participants exhibited typical menstrual cycles with regard to hormonal level fluctuations, but there was no correlation between these and tic measures. Only one of the eight women reported a subjective worsening of tics in the week before menses, which continued until the beginning of menstruations, showing an inverse correlation of tic count with estrogen levels. Overall, this study suggests that, in general, women with tics do not exhibit menstrual-related fluctuations of tic severity. However, a subgroup might perceive a premenstrual worsening of tics, associated with the estrogen trough, and in these patients estrogens might be protective against tics. This hypothesis needs to be verified.

2.2. The organizational/activational theory of gonadal hormone effects over neurobehavioral development In order to discuss the possible implications of gonadal hormones in the pathogenesis of tics and related behaviors, it is necessary to summarize current views on the neural effects exerted by these hormones throughout development and adult life. A difference in exposure to gonadal hormones between the two sexes starts during prenatal life. The male fetus is more exposed to testosterone than the female one because fetal Leydig cells start producing testosterone already from the 8th week of gestation, with a peak between the 11th and 14th week and a tapering period before birth (Wilson, George, & Griffin, 1981). Testosterone levels in the male fetus are three to eight times higher than in the female between week 12 and 20, whereas there are no differences in blood testosterone levels between the male and the female fetus at the term of gestation (Scott et al., 2009). In contrast to events in the testes, masculinization of the brain occurs late in gestation in primates and perinatally in rodents (Arnold & Gorski, 1984; Goy et al., 1988; McCarthy & Konkle, 2005). Differences between sexes in the magnitude and timing of fetal testosterone surges cause differences in neurobehavioral development, thanks to the powerful modulatory effect of this hormone

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over gene expression. These differences translate into a morphological and functional sex-related dimorphism during postnatal life, involving several brain regions (Bramen et al., 2012; McCarthy, De Vries, & Forger, 2009; Raznahan et al., 2011). This dimorphism ultimately might lead to sexrelated behavioral and cognitive traits, as well as to sex-related differential predisposition to various neurodevelopmental illnesses, including TS and related disorders. Examples of changes in sex-related behaviors secondary to different testosterone levels during prenatal life come from primate and rodent models. In rhesus monkeys, behavioral masculinization consists of five major traits: when compared to juvenile females, juvenile males exhibit more mother mounting, more peer mounting, more rough play with peers, preference for male partners, and less grooming of mothers. Prenatal transplacental administration of testosterone determines behavioral masculine traits in juvenile females which have separable critical periods, with early androgenized females exhibiting, apart from genital virilization, more mother and peer mounting and less grooming of mothers; and late androgenized females exhibiting more peer mounting and rough play (Goy et al., 1988). The administration of an aromatase inhibitor, which blocks the synthesis of estradiol from testosterone, to female rats during the last third of pregnancy results in increases in anxiety and emotionality in offspring at one month of age as well as during adult life, whereas intergender differences between control male offspring and experimental female offspring in terms of behavioral measures in the novel environment such as motor activity, duration of freezing, and grooming reactions are abolished (Ordyan, Pivina, & Akulova, 2007). Overall, it is important to point out that rodent models bear greater limitations than primate models in reproducing the masculinization process in humans, due to larger interspecies differences in steroidogenesis regulation. Masculinization is driven by testosterone production by the fetal testis within a specific “masculinization programming window” that is also modulated by environmental exposure and maternal lifestyle. Regulatory differences between human and rodent fetal testis include the fact that testosterone production during the “masculinization programming window” is LH receptor independent in rodents, but is highly influenced by LH receptor modulation in humans (Scott et al., 2009). The influences of early testosterone exposure on neurobehavioral development are broadly explained by the still valid organizational/activational hypothesis (Arnold, 2009). Prenatal exposure to testosterone may cause early, and permanent, effects that are called organizational because they are

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thought to reflect changes in the organization and development of neural systems. Postnatal effects, particularly those occurring during the puberty surge, are called activational because they reflect transient activation of the previously organized systems. In the light of this theoretical construct, the link between tic disorders and androgen exposure suggested by the clinical evidence summarized earlier has driven the hypothesis that patients with TS are exposed to higher concentrations of androgens already in the intrauterine environment (Kurlan, 1992; Peterson et al., 1992). This hypothesis is even today very difficult to test directly, given the retrospective nature of the data involved and the obvious ethical limitations of manipulating gonadal hormones in humans during early development (Hines, 2011). However, based on the organizational/activational theory, an increased exposure to androgens in utero might produce permanent effects leading to behavioral, cognitive, and morphological “hypermasculine” traits, which could be interpreted as indirect evidence of a “hyperandrogenic” prenatal environment (Auyeung et al., 2009; 2012); their relationship to TS are reviewed below. In addition to the direct role of steroids on neural development, there are important sex differences in the expression of genes involved in neural pathway formation and synaptic functioning. The recent outstanding advances in genome-wide exon-level studies of gene expression (Kang et al., 2011; Pennisi, 2012) have clearly demonstrated that gene expression and exon usage during the various stages of development and across different brain regions are sex biased. The majority of spatiotemporal differences in brain gene expression occur before birth with an increase in similarity among gene expression across different brain regions over the course of postnatal life. Sex-biased gene expression involved a higher number of genes during prenatal development than in postnatal life (Kang et al., 2011). The largest number was attributable to the Y chromosome, but also other X-linked and autosomal genes were involved, including genes linked to depression (e.g., S100A10) and cognitive function (e.g., IGF2). Sex-biased exon usage was also observed in one or multiple brain regions, with a male bias for, among others, KCNH2 (linked to schizophrenia) and NLGN4X (an X-related gene linked to synapse function and associated with autistic spectrum disorders and moderate intellectual disability).

2.3. Sex-related differences in behavior and personality traits in TS An important sex-related behavioral difference occurring early in life applies to children’s play preferences. Girls and boys differ in their toy, playmate,

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and play style preferences (Hines, 2010). Studies from primate species and humans show that males’ toys and females’ toys differ in shape and color, and these sex differences are already present in very young infants (Alexander & Saenz, 2012; Jadva, Golombok, & Hines, 2010). Additionally, object preferences are independent from shape and color preferences, with males, including nonhuman primates, preferring toys that can be moved in space, for example, vehicles. This preference could be related to prenatal androgen exposure increasing interest in watching things move in space, possibly by modulating visual system development (Alexander, 2003). As suggested by primate models (Goy et al., 1988), play preferences may also affect the choice of the playmate, usually chosen among individuals of the same sex, and of the play style, with males being more interested than females in playing patterns characterized by overall body contact or playful aggression, for example, the “rough-and-tumble play” (Hines, 2011). The relevance of intrauterine androgen exposure to play preferences is confirmed by the observation that girls suffering from congenital adrenal hyperplasia (CAH), a genetic disorder that causes increased adrenal androgen production beginning prenatally, show increased male-typical play and reduced female-typical play (Pasterski et al., 2005). Play preferences of TS patients have been explored in a seminal work by Alexander and Peterson (2004). These authors administered the Recalled Childhood Gender Identity Scale, a 23-item questionnaire yielding two summary measures (Gender-Typical Play and Gender Dysphoria), to 21 patients with TS only (12 males), 19 with OCD only (10 males), 19 with TS þ OCD (11 males), and 49 unaffected individuals (28 males). All subjects were older than 13 years and were asked to report on the play preferences they had when they were 10 years old. The presence of a tic disorder in both males and females was associated with stronger preferences for masculine play (p < 0.01), indicated by a preference of male playmates and of maletypical toys and play styles. In addition, preferences for masculine play positively correlated with the severity of motor and phonic tics (rs ¼ 0.68 and 0.61, respectively, ps < 0.01) among male patients. Play preferences are tightly connected to gender identification; sexual orientation and core gender identity also appear to be influenced by prenatal testosterone exposure. Women with CAH show reduced heterosexual orientation and increased gender dysphoria as adults (Meyer-Bahlburg, Dolezal, Baker, & New, 2008). Although sexual orientation has not been studied systematically in TS patients, the patients studied by Alexander and Peterson (2004) showed that a diagnosis of OCD was associated with

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a greater number of undifferentiated responses on the Gender Dysphoria items, more so for males with the disorder. Moreover, the presence of a tic disorder in females, but not in males, was associated with greater gender dysphoria, and this was not influenced by age. In the same study, gender group identification was explored using the Draw-A-Person Task in 33 patients with TS only (22 males), 24 with OCD only (12 males), 32 with TS þ OCD (21 males), and 67 unaffected subjects (36 males). When asked to draw a person, both children and adults draw a figure that they later identify as belonging to their own gender group; subjects with high gender dysphoria scores tend to draw figures representing the opposite gender. Alexander and Peterson (2004) showed that females with a diagnosis of OCD were less likely than other groups to draw a figure of the same gender, suggesting less consolidated gender identification. Apart from gender identification, other personality traits might also exhibit sex-related differences. Tendencies toward physical aggression are higher in males and correlate positively to prenatal testosterone exposure (Hines, 2011). Children exposed to androgenic progestins in utero show increased physical aggression (Reinisch, 1981). Up to 40% of TS patients manifest difficulties in anger management and rage outbursts (Kano, Ohta, Nagai, Spector, & Budman, 2008), which seem associated with different contributing factors (Chen et al., 2013). However, there was no effect of diagnosis in the patients studied by Alexander and Peterson (2004) following administration of the Reinisch aggression inventory, an instrument measuring the potential for responding to interpersonal conflict with aggressive behavior. Another personality dimension showing sex-related differences is dominance/assertiveness, whereas empathy, which is higher on average in females, seems to be reduced by prenatal testosterone exposure (Hines, 2011), with females with CAH showing reduced empathy than healthy control subjects (Mathews, Fane, Conway, Brook, & Hines, 2009). This seems not consistent to the hypothesis of increased prenatal androgen exposure in TS, in that a higher degree of somatic empathy in these subjects has been hypothesized. New studies addressing personality characteristics are needed to define in more depth the potential link of patients with TS to an abnormally testosterone-enriched intrauterine environment. Interestingly, studies correlating fetal testosterone levels measured in amniotic fluid to behavioral measures identified significant correlations to quantitative autistic traits (Auyeung, Ahluwalia, et al., 2012; Auyeung, Knickmeyer, et al., 2012), as well as to behavioral decisions based on emotionally salient, rewardmediated external cues, in the offspring (Lombardo et al., 2012).

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2.4. Sex-related differences in cognitive and motor abilities in TS A few cognitive abilities also seem to be influenced by prenatal testosterone exposure, mainly related to visuospatial processing (Auyeung, Ahluwalia, et al., 2012; Auyeung, Knickmeyer, et al., 2012; Hines, 2010). Particularly, females with CAH showed enhanced performance on mental rotation tasks, although not consistently throughout studies, whereas males with CAH were impaired (Hines, 2011). A correlation with testosterone levels in amniotic or other biological fluids could not be demonstrated for any of the explored cognitive abilities. Abnormal performance on tasks tapping on visuospatial domains has been reported in a number of studies on patients with TS (Bornstein, King, & Carroll, 1983; Randolph, Hyde, Gold, Goldberg, & Weinberger, 1993; Sheppard, Bradshaw, & Mattingley, 2002). In their study focusing on the prenatal hormone hypothesis, Alexander and Peterson (2004) employed two tasks of spatial ability, the Two-Dimensional Mental Rotation Task and the Object Location Memory Task of Silverman and Eals. Whereas the former of the two focuses on mental rotation of figures perceived at different spatial orientations, the latter measures memory for identity and location of objects perceived within a spatial array of common objects. In some interesting analogy to subjects with CAH (Hines et al., 2003), mental rotation ability in individuals with tic symptoms was impaired in males and enhanced in females. On the Object Location Memory Task, females with a chronic tic disorder showed a pattern of response which was reduced for object locations in each visual hemispace, differently from normal subjects of the same gender, who were more accurate in the location of objects in the right hemispace than in the left hemispace, thus demonstrating a pattern which was closer to that of normal males (Hines, 2011). Performance on fine motor tasks and its degree of lateralization are also thought to differ between sexes, probably in the form of reduced degree of lateralization among males compared to females. Yazgan, Peterson, Wexler, and Leckman (1995) conducted the first study to report lack of normal functional asymmetries on a battery of lateralizing neuropsychological measures in 11 adult TS patients who lacked the normal asymmetry in the lenticular nucleus volume. Interestingly, these neuropsychological measures accounted for a relevant proportion of the variance in tic severity in these patients. Alexander and Peterson (2004) found a reduced prevalence of right-handedness in females with tics, whereas there is evidence showing

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that in the general population more men than women are left-handed, and men more often show less consistent right-handed preferences across a variety of manual tasks (Hines & Gorski, 1985). This finding also points to a more “masculine” trait of females with tics. Finally, Avanzino et al. (2011) have shown, by means of a sensor-engineered glove, that children with TS presented less asymmetry than healthy peers in terms of movement accuracy between the two hands during the execution of bimanual sequential finger movements, which also points to reduced lateralization of motor control in these subjects.

2.5. Sex-related differences in brain functional anatomy in TS The organizational effects of early testosterone exposure may lead to sexrelated differences in brain structure and function. For example, total brain volume, like body size, is larger in males than females (Hines, 2011). Recent findings obtained using a new “surface-based” morphometry approach showed that sex is a major determinant of the differences in the tempo of developmental change in cortical volume and surface area, which vary with radial brain size (Raznahan et al., 2011; Bramen et al., 2012). The amygdala is larger in males, and the hippocampus is larger in females (Goldstein et al., 2001; Uematsu et al., 2012). Cortical thickness and gyrification are greater in women in many regions, especially within the frontal and parietal lobes, probably as a compensation for the smaller volume (Luders et al., 2006). Interestingly, Peterson et al. (2007) have shown, on anatomical magnetic resonance imaging (MRI), larger volumes of the amygdala, mainly of the dorsal and ventral surfaces over its basolateral and central nuclei, and of the hippocampus, mainly of the head and medial surface over the length of the dentate gyrus, comparing 154 TS patients to 128 control individuals of different ages. The finding on hippocampal volumes is not consistent with a more “masculine” trait, but the finding on amygdala volumes is suggestive of such a trait. Subsequent studies have, however, warned against the possible effect of comorbidities on amygdala volume in TS patients (Ludolph et al., 2008). Neuner et al. (2010) used functional MRI to show that TS patients activate amygdala to a larger degree than control subjects when asked to discriminate among different emotional facial expressions; in another study, the same group (Werner et al., 2010) demonstrated increased functional connectivity of amygdala during a simple motor task in 15 adults with TS (11 males) compared to 15 age- and sex-matched normal individuals. Also, reduced cortical thickness has been repeatedly demonstrated in

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MRI reports from TS adults, although the distribution of reduced cortical thickness was region selective and correlated nicely to clinical measures (Sowell et al., 2008). There is a documented sexual dimorphism also in the developmental trajectories of subcortical nuclei. The caudate nucleus peaks around age 10.5 in females and around age 14 in males (Lenroot et al., 2007). Interestingly, caudate volumes in children with TS correlate inversely with the severity of tic and obsessive–compulsive symptoms in early adulthood (Bloch, Leckman, Zhu, & Peterson, 2005); this suggests that a slower maturation of this subcortical nucleus during childhood, which potentially could represent a “masculine” trait, increases the likelihood of persistence of symptoms in adulthood. Another region that shows sexrelated differences and was found to be structurally different in TS patients compared to healthy subjects is the corpus callosum, which might account for part of the different degree of hemispheric lateralization hypothesized in these patients (Avanzino et al., 2011). Other structures and circuitries should be analyzed ad hoc in TS include areas and networks related to language lateralization and to navigational performance, which also bear relevant sexrelated differences (Hines, 2011).

2.6. Gonadal hormones and TS during postnatal life: An as yet unexplored relationship Postnatal levels of gonadal hormones might also play a role in differentiating TS patients from typically developing/developed subjects in a number of functional and structural features. Some of these effects might be exerted during the developmental period (i.e., from the neonatal period to late adolescence), whereas others may pertain to the different stages of adult life (Leckman & Peterson, 1993; Leckman & Scahill, 1990). The different visuospatial abilities and the abnormalities of core gender identity could also be explained by a reduced exposure to the so-called mini-puberty, that is, the testosterone surge occurring in boys and the estrogen surge occurring in girls during the neonatal period. This surge is crucial for human brain development, particularly cortical development, and modulates its progression and reactivity to experience throughout the first two years of life. As an example, spatial abilities are impaired in men without a normal testosterone surge after birth, such as those with anorchia (Poomthavorn, Stargatt, & Zacharin, 2009) or with idiopathic hypogonadotropic hypogonadism (Hier & Crowley, 1982). Another very important time window in respect to hormonal surge and brain development is puberty. Male-typical brain development, particularly

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of white matter structures, and testosterone levels correlate during puberty in different ways, according to the efficiency of the androgen receptor subtype expressed (Perrin et al., 2008). It would be interesting to assess the progression of structural and functional brain development during the restricted time frame around puberty also in TS patients and measure the impact of androgen receptor subtype upon maturation trajectories in these patients.

3. THE STRESS RESPONSE IN TS Contextual factors that increase physical and emotional stress levels have a negative effect on the severity of tics and related symptoms, which has been repeatedly demonstrated by a number of clinical studies over the last 25 years (Bornstein, Stefl, & Hammond, 1990; Conelea & Woods, 2008; Lombroso, Mack, Scahill, King, & Leckman, 1991; Nelson, 1993; Shapiro, Shapiro, Young, & Feinberg, 1988). Among the different forms of physical stress, there are preliminary data showing abnormal response to thermal stress in patients with TS. Nineteen of 78 (24%) adults with TS (62 men) reported increases of tic severity following heat exposure (Scahill et al., 2001). Subjects exhibiting this response did not differ from the rest of the clinical sample in gender, age, and characteristics of the course of illness. This finding was consistent with a previous report that found a similar result in 23% of investigated patients (Bornstein et al., 1990). Ten subjects from the same clinical sample were also involved in a passive thermal challenge during which the room temperature was raised from 22 C to 35 C under climate controlled conditions. On a background of normal thermoregulatory responses in all these subjects, the heat-affected subjects (5 out of 10) showed higher peak sweat rate, suggesting an enhanced thermoregulatory response in a subgroup of TS patients. A possible interpretation of these preliminary findings includes dysfunction of hypothalamic subregions implicated in thermoregulation, which is also regulated by monoaminergic transmission, with a direct influence of dopamine in modulating response to heat. Heat loss generated by thermal dispersion in response to increased environmental temperature may be generated by intracerebroventricular administration of dopamine agonists or amphetamine (Lee, Mora, & Myers, 1985). The study by Scahill et al., despite limitations such as the limited sample size, lack of consecutive enrolment in the study with potential self-selection bias, and lack of control condition for the thermal challenge, provides initial evidence to the broad concept that

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abnormal dopamine release within the hypothalamus of TS patients could explain abnormal responses of endocrine pathways to external stimuli. Stress responses induced by the emotional context have been explored in greater detail in TS. Earlier reports have documented that the first appearance of tics could be preceded by emotionally traumatic events (Carney, 1977), leading to the need for more aggressive pharmacological treatment (Surwillo, Shafti, & Barrett, 1978). Life stressors need to be taken into account in order to assess the response to treatment in patients with tics. However, the worsening of tics following exposure to intense emotional stress (e.g., watching a film with an age-appropriate emotionally intense content) may not directly depend on autonomic changes induced by the stressful situation (e.g., changes in cardiac or respiratory rate, Wood et al., 2003). Negative life events might influence tic severity at least in part through an increase in depression, anxiety, and compulsions symptoms (Steinberg, Shmuel-Baruch, Horesh, & Apter, 2012). Clinical studies with a longitudinal design are the most appropriate to explore the short-term effect of life stressors on the severity of tics and related symptoms. A preliminary uncontrolled study that used questionnaires on small life events on 24 children/adolescents (age range 7–16) and 28 adults with TS showed a small positive correlation between negative events and self-rated tic severity only in the adult group (Hoekstra, Steenhuis, Kallenberg, & Minderaa, 2004); however, no specific measure of psychosocial stress was used in this study. Lin et al. (2007) obtained consecutive ratings for 2 years of tic (Yale Global Tic Severity Scale), obsessive–compulsive (Children’s Yale–Brown Obsessive Compulsive Scale), and depressive symptom severity (Children’s Depression Rating Scale-Revised) from 45 children/adolescents with TS and/or OCD and 41 healthy subjects. Psychosocial stress was measured monthly through parent report, patient report, and long-term contextual threat using Parent Perceived Stress Scale (PSS-P), Daily Life Stressors Scale, and Yale children’s Global Stress Index (YCGSI), respectively, and the effect of time interval between observations was taken into account using a latent time-varying stress construct in the analysis. Scores on the three psychosocial stress measures correlated significantly in both patients and healthy subjects. On the YCGSI, 47% (21 of 45) of the patients exhibited a high-moderate or severe level of contextual threat stress on 38 occasions as opposed to 20% (8 of 41) of the healthy subjects on 17 occasions; this difference was statistically significant. Current psychosocial stress and depression levels independently predicted future tic severity, whereas current tic severity did not predict psychosocial stress or depressive

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symptoms. There was a stronger short-term predictive effect of current psychosocial stress on obsessive–compulsive and depression severity, with PSS-P scores proving to be the strongest predictors. Only depression levels had a small predictive effect on short-term future psychosocial stress levels. Following up on this study, Lin et al. (2010) showed in a subsequent study that a new diagnosis of group A streptococcal infection (both when Definite and when Definite or Possible) increased the predictive power of the stress construct upon short-term future tic and obsessive–compulsive severity by a factor of about 3. It is important to point out that these infections had a strong predictive effect on psychosocial stress levels, suggesting that, at least in part, streptococcal infections might modulate the risk of worsening of tics and related symptoms acting as a stress-inducing factor. Psychosocial stress was therefore confirmed as an important modulating factor of tics, obsessive–compulsive symptoms, and related depression in TS patients, whereas more work is needed to clarify the type of interaction between stress and infections in altering the course of these symptoms. There is even more limited evidence on the role of maternal life stressors during pregnancy in the pathogenesis of tics. Motlagh et al. (2010) compared the exposure to different pre and perinatal risk factors among 45 patients with isolated TS, 52 with isolated ADHD, 60 with TSþ ADHD, and 65 without major neuropsychiatric disorders. Similar to other maternal pregnancy-related exposures (e.g., cigarette smoking), higher levels of severe maternal psychosocial stress (i.e., disrupting existing family life patterns, like unemployment, death or serious injury, separation) were strongly associated with isolated ADHD, showing only a trend for association with TS with or without comorbid ADHD. This isolated study is limited by the sample size and the retrospective data collection, and more data are necessary to explore this aspect. Stress responses are primarily modulated by the HPA axis, which is also engaged in a complex crosstalk with other regulatory systems, thus modulating basal metabolism, immune responses, digestion and absorption of nutrients, emotional control, and sexual behavior (Dallman, Bhatnagar, & Viau, 2000). The structural organization of the HPA axis is shown in Fig. 9.2. Of note, the HPA axis is directly conditioned by external sensory inputs associated with threat and fear generation through the basolateral and central nuclei of the amygdala. These inputs activate an alarm reaction consisting of acute cortisol release, after which negative feedback mechanisms, involving also structures outside of the HPA axis such as the hippocampus (Cirulli & Alleva, 2009), intervene to facilitate adaptation and the activation of mechanisms counteracting these external threats (Jankord & Herman, 2008).

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Hormones and TS

Stressors Limbic system

Autonomic system CRH

(amygdala– hippocampus)

Hypothalamus Sympathetic system

Pituitary gland

Adrenal medulla Behavioral activation

Epinephrine

ACTH

Adrenal cortex

Cortisol

Figure 9.2 The hypothalamus–pituitary–adrenal (HPA) axis regulates the secretion of corticosteroid hormones. Corticotropin-releasing factor (CRF) is synthesized by the hypothalamus to induce the synthesis of adrenocorticotropic hormone (ACTH) by the anterior pituitary. ACTH induces the synthesis of cortisol and corticosterone in the cortical portion of the adrenal gland. CRF release is also deeply influenced by social and physical stressors, as well as circulating cortisol levels, which exert a negative feedback over the hypothalamus and the anterior pituitary, leading to restoration of the baseline activity of the axis. Green arrows indicate facilitatory effects; red arrows indicate inhibitory effects.

In normal subjects, HPA axis activity is influenced by the sleep/wake cycle and follows a diurnal (circadian) rhythm (Backhaus, Junghanns, & Hohagen, 2004), which is already functioning at the third month of postnatal life. Two separate peaks of cortisol release occur in the morning after awakening and in the late afternoon, with troughs during the middle of the night. Apart from the sleep/wake cycle, the release of corticotropinreleasing hormone (CRH) may be triggered by specific, potentially threatening contextual factors and is also modulated by circulating cortisol levels, which exert influence by blood levels of cortisol, which exerts a negative feedback over the paraventricular nucleus of the hypothalamus and on the anterior pituitary. Such negative feedback allows the restoration of the baseline activity of the axis. Finally, the HPA axis is modulated by monoaminergic transmission and by other hypothalamic peptides (oxytocin (OT), arginine–vasopressin (AVP)). The degree of activity of the HPA axis may

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also reflect the long-term exposure to environmental stressors, with overactive stress responses potentially facilitated by prolonged exposure to these contextual factors. Moreover, many medical and behavioral illnesses display a specific polarization of the HPA axis toward hypo- or hyperreactivity: autoimmune diseases, for instance, were found to be associated with hyporeactive responses, whereas major depression may present with a hyperactive HPA axis. HPA axis activity is usually assessed by measuring cortisol and other peptidic hormones of the axis in biological fluids from patients and healthy subjects. Usually salivary and plasmatic cortisol is measured; salivary cortisol levels show good correlation with the amount of free cortisol in blood, but only moderate correlation with total cortisol levels (i.e., cortisol bound to binding proteins in blood plus biologically active, unbound, “free” cortisol). The first research question to approach this topic is whether the circadian cortisol rhythm is maintained in TS and associated neurodevelopmental disorders. The findings of the studies that have explored this did not provide highly consistent results, particularly in respect to obsessive–compulsive and attention deficit hyperactivity disorders. A first consideration on this aspect is that TS and related disorders are not consistently associated with a reduction of the physiologic circadian oscillations of the HPA axis activity, as shown in chronic stress-related conditions like insomnia, depression, posttraumatic stress disorder, or chronic fatigue syndrome (Backhaus et al., 2004; Klaassens, Giltay, Cuijpers, van Veen, & Zitman, 2012; McHale et al., 1998; Pruessner, Hellhammer, & Kirschbaum, 1999; Stetler & Miller, 2011). The circadian pattern of cortisol secretion seems preserved in adults and children/adolescents with OCD, although these patients have higher levels of cortisol secretion than age-matched healthy individuals (Brambilla, Perna, Bussi, & Bellodi, 2000; Kluge et al., 2007; Monteleone, Catapano, Del Buono, & Maj, 1994), which do not correlate with symptom severity. Studies on adults and children with ADHD have been more inconsistent, with some authors reporting irregular diurnal activity measuring salivary cortisol (Kaneko, Hoshino, Hashimoto, Okano, & Kumashiro, 1993), other larger studies reporting normal diurnal rhythm (Hirvikoski, Lindholm, Nordenstrom, Nordstrom, & Lajic, 2009; Pesonen et al., 2011), and other documenting significantly phase delayed cortisol rhythms in adults with ADHD (Baird, Coogan, Siddiqui, Donev, & Thome, 2012). Although not without some inconsistencies across findings, patients with autistic spectrum disorders may exhibit higher variability of circadian rhythms of the HPA axis (Corbett, Mendoza, Abdullah, Wegelin, & Levine, 2006; Corbett,

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Mendoza, Wegelin, Carmean, & Levine, 2008; Nir et al., 1995; Richdale & Prior, 1992), associated with lower cortisol morning levels and higher evening levels. Corbett, Mendoza, Baym, Bunge, and Levine (2008) studied 20 unmedicated children (age range 7–13 years; 17 males) with TS and 16 age-matched healthy control subjects (11 males). The authors obtained baseline levels of salivary cortisol in the morning, mid-afternoon, and evening for three diurnal cycles. There was no between-group difference in the physiological cortisol circadian pattern, whereas a trend for lower cortisol values in the evening was observed in the TS group compared to the typical group. The latter finding may be interpreted as the consequence of chronic stress, as it is a common observation in chronic stress conditions, such as posttraumatic stress disorder. Whereas chronically active stress responses might also be the result of suffering from a chronic, potentially disabling illness, it seems unlikely that in TS this is determined exclusively, or even primarily, by tics. Nevertheless, an interesting correlation with tics and other clinical features was also detected: the first morning cortisol sample was positively correlated with the number of motor tics; evening cortisol values were negatively correlated with the number, intensity, or interference of motor tics, global impairment, and overall tic severity; and average diurnal cortisol levels were negatively correlated with Multidimensional Anxiety Scale for Children scores. More work is necessary to evaluate whether the correlation of cortisol levels at specific times during the day may be related to the diurnal fluctuations of tic severity. Many patients indeed report tics as being worse during the evening hours, possibly associated with increased fatigue and relaxed environment leading to less effective active tic suppression. A second key question is whether the extent of the acute stress response differs between TS patients and healthy subjects. This has been addressed by a few studies which used stressors related to the anticipation of a physical threat. In the first of these studies (Chappell et al., 1994), the stressor used was a lumbar puncture: plasmatic levels of HPA axis hormones were measured at several time points throughout the day, including immediately before and after a lumbar puncture, in 13 drug-free adults with TS and 10 age-matched healthy volunteers in an age range of 17–41 years. Plasma cortisol levels peaked just after the lumbar puncture in both groups, but TS patients showed constantly higher adrenocorticotropic hormone (ACTH) levels throughout the day than control subjects, without any obvious correlation with anxiety/depression symptoms. Apart from HPA axis hormones and consistent with a previous study (Leckman et al., 1995), there was also a higher excretion of noradrenaline in TS patients shortly before the lumbar

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puncture, with urinary noradrenaline levels positively correlating with tic severity scores. In a subsequent, very similar study, the same authors measured CRH levels in 21 patients with TS (13–44 years of age, 15 males), 20 patients with OCD (19–61 years of age, 8 males), and 29 healthy volunteers (19–58 years of age, 17 males). TS patients exhibited approximately 30% higher levels of CSF CRH than the other two groups (at a p of < 0.04); at difference, CRH concentration in the CSF of patients with OCD was similar to that of healthy subjects, regardless of the cooccurrence of tics. A number of clinical and demographic variables were checked for possible confounding effect, which was ruled out. Corbett, Mendoza, Baym, et al. (2008) used a milder acute environmental stressor, that is, simulated MRI followed by real MRI scanning, in their study. Simulated sessions took place between 1 and 3 PM; salivary samples were collected upon arrival, 20 and 40 min postexposure to the mock scan, immediately before real MRI, and 1 h after the beginning of real MRI. Cortisol responses were significantly higher in TS children than in normal subjects for the first four time points, and there was a trend for a similar difference also for the postreal MRI time point. Overall, despite the discrepant results on plasma cortisol levels between the Chappell et al. (1994) and the Corbett, Mendoza, Baym, et al. (2008) studies, this preliminary evidence points to increased HPA axis reactivity following acute physical stressors, which should be further verified in future research. Interestingly, the same authors obtained similar results in patients with autism challenged with the same acute environmental stressor (Corbett, Mendoza, Wegelin, et al., 2008). There is, however, notable inconsistency across studies assessing HPA reactivity to acute stressors in patients with OCD (Altemus et al., 1992; Chappell et al., 1996; Gustafsson, Gustafsson, Ivarsson, & Nelson, 2008). All studies performed in TS patients to date employed acute physical stressors; however, cognitive and social stressors are likely to be even more relevant to the natural history of tic disorders, as suggested by cohort studies (Lin et al., 2007, 2010). Children with ADHD exhibited lower poststress cortisol levels compared to healthy children when they were administered a classical social stress test, the Trier Social Stress Test for Children (Pesonen et al., 2011); other authors did not obtain the same result using a cognitive stressor (Hirvikoski et al., 2009). There is certainly a valid rationale to explore HPA reactivity to social stressors also in TS patients; it would also be particularly interesting to investigate whether stress responses differ among TS patients across different age groups, with different comorbidity profiles, as well as between medicated and unmedicated patients.

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259

Negative feedback mechanisms responsible for the restoration of the basal activity of the system have not been adequately explored in TS to date. The dexamethasone suppression test (DST) can be used to this aim. Low doses of dexamethasone, an exogenous steroid that exerts negative feedback to the pituitary but is unable to pass the blood–brain barrier and reach the hypothalamus, suppress cortisol in healthy individuals. Interestingly, a pathological nonsuppression response on the DST was found in patients with ADHD or autism (Kaneko et al., 1993). Despite the available evidence should be considered preliminary, it suggests abnormalities in HPA axis reactivity in TS, mainly in the form of hyperreactivity to acute physical stressors. It remains to be ascertained whether this is the consequence of increased exposure to stressors related to the underlying chronic illness, or, rather, a manifestation of an intrinsically dysfunctional HPA axis. The development of the HPA axis might be influenced by early environmental insults that may arise even during intrauterine life (GatzkeKopp, 2011). It has been hypothesized that maternal cortisol primes the offspring HPA axis in order to increase sensitivity to postnatal threat cues (Crespi & Denver, 2005), and it may be speculated that abnormal maternal exposure to life stressors during pregnancy might influence this priming effect (O’Donnell et al., 2012). Indirect support to this hypothesis comes from the predictive effect of high pregnancy-related stress upon the offspring risk of developing ADHD (Motlagh et al., 2010). In addition, the dopamine system is particularly sensitive to indicators of adversity via the maternal stress response system, as suggested by rodent models (McArthur, McHale, & Gillies, 2007; Son et al., 2007). It seems intriguing to hypothesize that increased maternal stress and cortisol levels during pregnancy contribute to HPA axis reactivity and dopaminergic mesolimbic system responsiveness in the offspring; this would indicate a possible common denominator for motor, behavioral, and endocrine changes in TS. The possibility that an increased intrauterine exposure to cortisol, secondary to maternal stress, might contribute to both a hypersensitive HPA axis and to a hyperresponsive dopaminergic mesolimbic system suggests a possible common denominator for motor, behavioral, and HPA-related changes in TS.

4. NEUROHYPOPHYSIAL PEPTIDES: POSSIBLE PLAYERS IN THE COMPLEX PATHOPHYSIOLOGY OF TS? The neuroanatomic distribution and neurophysiology of the OT and AVP systems (summarized in Fig. 9.3) suggests an important role of these

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OT projections AVP projections

Amygdala Lateral septum Nucleus accumbens Hippocampus Ventral tegmental area

Nucleus accumbens Ventral tegmental area

SON PVN

Hypothalamus

Posterior pituitary

OT target

Breast

Uterus

Pancreas

AVP target

Kidney

Kidney

Figure 9.3 Summary of the physiology of neurohypophysial peptides. Oxytocin (OT) and arginine vasopressin (AVP) are released from the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. Secondary central sources of OT are the bed nucleus of the stria terminalis, spinal cord, and anterior commissural nucleus. Peripherally, OT is synthesized in the heart, thymus, gastrointestinal tract, testis, prostate, pregnant intrauterin tissues, ovaries, and adrenal medulla. Secondary central sources of AVP are the suprachiasmatic nucleus, medial amygdala, bed nucleus of the stria terminalis, and brainstem areas.

261

Hormones and TS

nanopeptides in the integration of several neural and neuroendocrine regulatory pathways controlling social behaviors (Gordon, Martin, Feldman, & Leckman, 2011). The interaction of these nanopeptide systems with the salience and reward pathways, the HPG and HPA axes (Figs. 9.4 and 9.5), and with the immune system justifies some reflection on how they might be involved in the complex pathophysiology of TS and related disorders. The integrative role of OT and AVP is above all suggested by their anatomical framework. Their synthesis in the central nervous system occurs primarily in the magnocellular neurons of the supraoptic nuclei (SON) and PVN of the hypothalamus. Other central sources of OT include the spinal cord, the bed nucleus of the stria terminalis (BST), and the anterior commissural nucleus, whereas AVP can be synthesized also in the suprachiasmatic nucleus, medial amygdala, BST, and brainstem areas (Sofroniew, 1983). Importantly, oxytocinergic fibers from the hypothalamus project to several brain regions including amygdala and lateral septum, nucleus accumbens, hippocampus, and the ventral tegmental area (VTA) of the midbrain; fibers containing AVP may also project to the nucleus accumbens and VTA (De Vries & Bujis, 1983). Interestingly, the concentration of AVP in the BST and amygdala is greater in male rats than in females and appears to Testosterone

Aromatization process

Estradiol

SON PVN Breast Uterus Kidney Pancreas

AVP

¯Fear ¯Punishment sensitivity Social cognition Sensitivity for reward

OT

¯Fear Social bonding Social cognition Ingroup favorism

OT receptors

Figure 9.4 Modulation of the oxytocin (OT)/arginine vasopressin (AVP) by gonadal hormones. PVN, paraventricular nucleus of the hypothalamus; SON, supraoptic nucleus of the hypothalamus. Green arrows: facilitatory effects, red arrows: final effects.

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Figure 9.5 Interaction between the oxytocin (OT)/arginine vasopressin (AVP) system and the hypothalamus–pituitary–adrenal (HPA) axis. A potential feedback loop may be active between corticotrophin-releasing factor (CRF) and the OT/AVP system, based on reciprocal connections between CRF-containing neurons of the bed nucleus of the stria terminalis (BNST) and OT-containing neurons of paraventricular nucleus (PVN) of the hypothalamus in rats. OT reduces the activity of HPA by stimulation of GABAergic neurons connected with CRF neurons in the BNST (Dabrowska et al., 2011). AVP may increase the activity of HPA axis by stimulation of Avpr1b receptors on anterior pituitary cells (Roper, Craighead, O’Carroll, & Lolait, 2010).

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263

be modulated by testosterone exposure (van Leeuwen, van Heerikhuize, van der Meulen, & Wolters, 1985). Moreover, SON and PVN neurons project to the posterior pituitary to release OT and AVP in the peripheral bloodstream, thereby leading to their peripheral effects (Fig. 9.4). Particularly, the distribution of the OT receptor system in both the brain and periphery is highly diffuse and its expression may undergo important changes during development. Finally, OT is synthesized also in the heart, thymus, gastrointestinal tract, testis, prostate, pregnant intrauterine tissues, ovaries, and adrenal medulla (Gordon et al., 2011). Although OT synthesized in the periphery cannot cross the blood–brain barrier, it is likely that peripheral levels of OT may have an impact on the central nervous system through a feedback loop involving the autonomic nervous system. Such an articulated framework serves as a backbone for a complex modulatory activity of these nanopeptides over the characterization of social behaviors in mammals, particularly in motivational aspects of speciesspecific, highly conserved interactions, such as parental behaviors and sexual behavior relevant to the formation and maintenance of adult pair bonds. Nanopeptide systems work in a highly “plastic” way, being very sensitive to changes in the external environment and the internal somatic world. Their dynamic physiology might influence their modulatory role in a number of other regulatory and nonregulatory functions, including the processing of sensory inputs, the detection of salience, reward and threat, and the functional set-up of the two main endocrine axes, the HPG and the HPA axes (Gordon et al., 2011). The possible points of connection between OT/AVP systems and mechanisms of disease in TS will be discussed below and include: the modulation of pathways linking stimulus salience and reward to the consolidation of stereotyped behaviors; the processing of stressors and threatening stimuli and organization of the stress response; anecdotal clinical observations associated with the development of sex-specific behavioral patterns, mainly related to the formation and maintenance of pair bonds; and the modulation of the immune response. The interaction of the dopaminergic system with the OT/AVP systems is mainly related to the consolidation of behavioral patterns of affiliative nature. The participation of dopamine to the shaping of these behaviors is based on the involvement of this neurotransmitter in the detection of salient stimuli, their link to the reward system, and the related selection of advantageous behavioral responses. This functional activity is controlled by the mesolimbic and mesocortical dopaminergic pathways, originating

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from the midbrain VTA. There is remarkable overlap between OT and dopamine neuron populations within both hypothalamic nuclei and areas which receive hypothalamic projections including the VTA, hippocampus, and amygdala (Baskerville & Douglas, 2010). Moreover, areas like the prefrontal cortex and the ventral striatum are rich in both oxytocinergic and dopaminergic receptors. Overall, this suggests bidirectional interaction between the two systems, and indeed dopaminergic stimulation is known to induce OT secretion, whereas there is evidence suggesting that dopaminergic activity may be OT dependent (Baskerville & Douglas, 2010). OT release may link sexual arousal during mating phases, as well as highly salient stimuli coming from pups, to, respectively, behaviors facilitating adult pair bonds and maternal behaviors, by activating the mesolimbic dopamine circuit and causing release of dopamine from the nucleus accumbens (Young & Wang, 2004). Interestingly, some of these behavioral responses are highly conserved and stereotyped, including licking– grooming behavior during pup nurturing. In addition to dopamine, salience and reward systems might also involve noradrenergic and serotonergic pathways. Finally, a body of evidence has also linked AVP to the promotion of repetitive stereotyped behaviors, some of which (e.g., grooming) related to parental behavior (Delanoy, Dunn, & Tintner, 1978) and others (e.g., flank marking) more related to setting territorial boundaries (Ferris, Rasmussen, Messenger, & Koppel, 2001), and in maintaining conditioned responses to aversive stimuli in experimental animals (De Vries & Bujis, 1983). Therefore, although neuropeptide systems are involved in the consolidation of stereotyped behaviors especially in the area of affiliative conduct, their interaction with catecholaminergic systems might play a role in the acquisition and maintenance also of different forms of behavior leading to positive reward, a mechanism enhanced in patients with TS (Palminteri et al., 2011). It would, nevertheless, be particularly interesting to explore mating and parental behavior also in these patients, as this might indirectly unveil alterations in the complex interplay between nanopeptide and catecholaminergic systems. As highlighted earlier, the PVN is a crucial structure for the synthesis of both OT and corticotropin-releasing factor, the hypothalamic hormone of the HPA stress response axis. The HPA axis and the OT system seem to be reciprocally regulated in the hypothalamus and in the BNST of rats (Dabrowska et al., 2011). This interaction may also contribute to the anxiolytic properties of OT (de Oliveira, Zuardi, Graeff, Queiroz, & Crippa,

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2012; Yoshida et al., 2009). Anecdotally, we have noted a decline in tic severity following the development of intimate interpersonal relationships in several adult patients with TS. In addition, many TS patients report a decrease in tics following sexual intercourse, which may be due in part to the release of OT (Leckman, personal observation). Consistent with these findings, OT is released during sexual activity in both men and women (Carmichael et al., 1987). Loving affectionate touch between romantic partners, such as hugs and provision of social support, are related to higher levels of OT (Grewen, Girdler, Amico, & Light, 2005; Light, Grewen, & Amico, 2005). Although complex, there seems to be a relationship between HPA axis activity and periods during which the affiliative behaviors modulated by OT are performed (see Fig. 9.5 for a summary of relevant interactions between the OT/AVP system and the HPA axis). Activation of the stress response is expected during bond formation periods (e.g., falling in love, organizing the care for newborns, etc.). OT might modulate this response by reducing the level of social anxiety in association with these events (Neumann & Landgraf, 2008). Moreover, OT is an essential modulator for stress-induced antinociception in the presence of other forms of acute stressors, and its expression was found to be upregulated in animal models of stress-induced grooming behavior, with possible modulation by the expression of a clock gene, Per1, related to the circadian pattern of the HPA axis activity (Zhang et al., 2011). The relationship between OT and grooming behavior may be influenced by brain structures involved in the modulation of emotions and stress response, such as the amygdala. OT microinjections in the central nucleus of amygdala of rodents induced hypergrooming, suggesting that this neuropeptide may be directly involved in the pathogenesis of compulsive behavioural patterns thanks to a link between amygdala and the PVN and dorsal hypothalamic area (Marroni et al., 2007). In addition, AVP is considered, together with CRH and corticosteroids, a molecular marker for stress-induced grooming behavior. AVP might play a more direct role on the acute stress response through activation of its Avpr1b receptor. Pharmacological antagonism or inactivation of Avpr1b causes a reduction in the HPA axis response, particularly ACTH, to acute restraint and forced swimming stress. Avpr1b knockout mice constitute a good model by which to study the contribution of Avpr1b to the HPA axis response to acute stressors (Roper, O’Carroll, Young, & Lolait, 2011;

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Roper et al., 2010). Given the reported enhanced response to acute stressors in TS patients, it would be interesting to explore the contribution of Avpr1b to neuroendocrine modulation in TS. Gonadal hormones (estradiol and testosterone) activate various socioemotional behavioral profiles that include reproductive behaviors and aggressive conduct. Some of these behaviors have also been linked to OT and AVP. There is a fine interplay between gonadal steroids and nanopeptides. Estradiol has a facilitatory effect over the OT system by acting on the excitability of OT-producing neurons and on the rate of expression of OT receptors, whereas testosterone potentiates the AVP system, also affecting OT via aromatization to estradiol. Therefore, it is intriguing to notice that the activation of the OT/AVP systems displays sex-related differences which may contribute to sex-related differences in the formation and consolidation of stereotyped behaviors in mammals, including subhuman primates and humans. Given the link of testosterone to AVP, it may be hypothesized that a hyperactive AVP system, and its possible behavioral consequences, could be one of the “hypermasculine” traits exhibited by TS patients; this assumption needs to be verified in future research. Apart from interacting with nanopeptides to increase the degree and efficacy of parental care, gonadal steroids may act in concert with nanopeptides to modulate behavioral patterns for the formation and maintenance of adult pair bonds. Testosterone is known to interact with AVP to reduce fear and increase sympathetic efference, amygdala output to the brainstem, and motivation to act within socially challenging contexts. Conversely, estradiol exerts opposite effects on autonomic pathways and amygdala output, facilitating OT–dopamine interactions within safe environmental contexts (Bos, Panksepp, Bluthe´, & Honk, 2012). As already suggested earlier, it is possible that the increased amygdala output and activation to aversive emotional stimuli demonstrated in TS patients might be associated to increased exposure to testosterone and to its interaction with a hyperactive AVP system. OT may also be associated with the hyperactive immune response detected in TS patients (Martino, Dale, Gilbert, Giovannoni, & Leckman, 2009). It has been suggested that OT might act as a link between the neuroendocrine and immune systems. An established effect of this peptide is that of increasing the activation of lymphocytes and their surface expression of CD25 and CD95 (Maccio` et al., 2010). Cytokine release

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267

may be overactive in TS patients, in association with symptom exacerbations; in addition, flow cytometry studies showed increased numbers of activated T-cells, particularly of those expressing CD-95 (for a detailed review, see Martino et al., 2009). Finally, OT is produced in the thymus, where it may exert an effect in the maturation and differentiation of T-cells (Elands, Resink, & De Kloet, 1990). In addition to their potential contribution to consolidation of repetitive behaviors, abnormalities of stress response, and sex-related traits, these nanopeptides could be involved also in the generation of immunological changes observed in patients with TS and related disorders. Despite this potential link of OT/AVP systems to mechanisms of disease in TS, their role in this condition has been understudied to date. Only one study (Leckman et al., 1994) measured CSF levels of OT and AVP in 23 patients with TS (16 males, age range 13–44 years), 29 patients with OCD (12 males, age range 18–61 years), and 31 normal controls (19 males, age range 19–58 years). Whereas TS patients did not differ from normal controls in CSF nanopeptide levels, the OCD group had significantly higher (p < 0.01) CSF OT levels than the other two groups, whereas CSF AVP were not significantly different across the three groups. Importantly, the different OT levels in OCD patients were predominantly accounted for by non-tic-related OCD, whereas tic-related OCD had a mean CSF OT level similar to those of both patients with TS and normal controls. OT levels in the CSF also showed a significant positive correlation to the total Yale–Brown Obsessive–Compulsive Scale scores in OCD patients. CSF OT levels seem to reflect the amount of OT produced in the central nervous system and not of that released in the bloodstream by the posterior pituitary. However, a potential drawback of this finding is that there seems to be a caudal–rostral gradient of OT levels in the CSF, and therefore lumbar CSF might not truly reflect the OT production rate in the brain. Although the lack of difference between TS patients and healthy controls in CSF OT and AVP levels seems inconsistent with a pathophysiological role of these peptides in TS, novel studies are warranted to confirm this. Moreover, the finding of increased OT, but not AVP, CSF levels in patients with non-tic-related OCD is not clearly consistent with previous works that reported either an inverse relationship between AVP/OT ratio and OCD clinical measures (Swedo et al., 1992) or increased CSF levels of AVP among patients with OCD (Altemus et al., 1992). Part of these differences might be explained by heterogeneity across studies of

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the immunoassays used to measure the concentration of these peptides in the CSF (Leckman et al., 1994). In addition, chronic intranasal administration OT has been associated with a reduction or no change in obsessive–compulsive symptoms (Ansseau et al., 1987; den Boer & Westenberg, 1992; Epperson, McDougle, & Price, 1996). The effect of intranasal OT on tic symptoms is unknown. Given the background summarized earlier, it would be useful to explore plasma and CSF levels of OT and AVP in TS patients, ideally combining them with other measures expressing the level of activation of the other regulatory systems that interact with the nanopeptide systems. For example, another monoamine neurotransmitter, histamine, has recently been implicated in the pathophysiology of some individuals with TS (Ercan-Sencicek et al., 2010), and the intraventricular injection of histamine has been reported to increase both the amount of AVP and OT released from the posterior pituitary (Hashimoto, Noto, & Nakajima, 1988).

5. CONCLUSIONS The neural abnormalities leading to stereotyped behaviors such as human tics and compulsions are likely to depend on a highly intricate interplay between genetic susceptibility and the characteristics of the environment in which the individual is located, from prenatal life to elderly age. The other main regulatory systems of the body, the immune and the endocrine systems, process information from the environment and organize defensive/adaptive responses which increase the chances for survival of the individual in that specific environment. Neuroplastic changes throughout development are also modulated by the functioning of endocrine and immune subsystems, which might therefore contribute to a relevant extent to the network changes subduing the presentation of abnormal repetitive behaviors. The possibility that an abnormal exposure to gonadal hormones, glucocorticoids, and even neuropeptidic hormones could facilitate the onset of these abnormal behaviors is supported by a very preliminary body of intriguing evidence (summarized in Table 9.1). A great amount of work is needed to elucidate the details of such a complex interaction (see Table 9.2 for key questions for future research) and to understand better its potential implications for the diagnosis and treatment of disorders like TS and OCD.

Table 9.1 Overview of clinical studies assessing endocrinological changes in patients with TS Age Hormone(s) group Study Main findings Hypothalamic–pituitary–gonadal axis

Gonadotropin-releasing factor (GnRH)

Adults

Sandyk (1987)

This clomiphene citrate trial suggested a potential positive effect on tic severity through the stimulation of GnRH secretion

Luteinizing hormone (LH) and Follicle-stimulating hormone (FSH)

Adults, Sandyk et al. (1988) children

Measurement of plasma levels of gonadotropins at baseline and after a Gonadotropin Stimulation test, using a GnRH synthetic analog. Gonadotropin (particularly LH) baseline levels were low in all patients. GnRH stimulation was followed by a marked rise in LH levels

Androgens

Adults

Leckman and Scahill (1990)

Case report of worsening of TS symptoms after anabolic steroids administration

Androgens

Adults

Peterson et al. (1998)

This trial of flutamide (antiandrogen) showed significant reduction in motor tic severity and mild improvement of obsessive–compulsive symptoms

Androgens

Adults

Muroni et al. (2010)

Open label pharmacological study of finasteride (5-a-reductase inhibitor) showing effects on the severity of motor/ phonic tics and compulsions

Estrogens

Adults

Sandyk and Bamford (1987)

Description of tic severity fluctuations linked to menstrual activity Continued

Table 9.1 Overview of clinical studies assessing endocrinological changes in patients with TS—cont'd Age Hormone(s) group Study Main findings

Estrogens

Adults

Schwabe and Konkol (1992)

Evidence of increased tic frequency during the follicular phase of the ovarian cycle

Estrogens

Adults

Kompoliti et al. (2001)

Evidence of increased tic severity during the premenstrual phase in one of eight women with TS

Hypothalamus–pituitary–adrenal axis

Cortisol

Children Corbett, Mendoza, Wegelin, et al. (2008) TS patients showed a trend for lower cortisol levels compared to healthy subjects; no and Corbett, Mendoza, Baym, et al. (2008) differences in the circadian cortisol rhythm

ACTH and cortisol

Adults

Chappell et al. (1994)

Examination of effects of lumbar puncture (acute physical stressor) on ACTH and cortisol plasma levels. Higher ACTH secretion in TS patients before and after lumbar puncture

CRH

Teens, adults

Chappell et al. (1994)

Examination of effects of lumbar puncture (acute physical stressor) on CRF levels in CSF. Higher levels of CRF levels in TS patients

Teens, adults

Leckman et al. (1994)

No difference between TS patients and control subjects in CSF levels of OT/AVP. Lower CSF levels of OT in TS patients compared to OCD patients

Neurohypophysial peptides

Oxytocin (OT) and arginine vasopressin (AVP)

Hormones and TS

271

Table 9.2 Questions for future research

To what degree does fetal testosterone exposure contribute to the increased rates of Tourette syndrome (TS) in males? In what way do gonadal hormones influence the organization of neural systems during development to increase the vulnerability to develop tics or other stereotyped behaviors? Do activational effects exerted by androgens and estrogens play a role in the modulation of tics before, during, and after puberty? What are the relevant neural cells, systems, or structures targeted by gonadal hormones in their possible modulation of tics and other repetitive behaviors during adult life? Can pharmacological treatment targeting androgen or estrogen activity be useful to treat tics in clinical practice? Does the hypothalamus–pituitary–adrenal (HPA) axis of TS patients undergo early priming eventually leading to HPA hyperreactivity during postnatal life and enhanced acute response to stressors? Are TS patients truly more exposed to chronic stress than typically developing subjects? Is this enhanced acute response to stressors in TS detectable also with more socially challenging types of stressor? What is the role of limbic structures (hippocampus, amygdala, lateral septum) in modulating the response to acute stress in TS patients? Are TS patients exposed to increased glucocorticoids in utero, and how does this influence the development of the dopaminergic system? How do the oxytocin and arginine–vasopressin systems function in TS patients? What is their role in modulating HPA reactivity, anxiety, and immune response? How distinctive is the pattern of oxytocin and arginine/vasopressin receptors in the brains of TS patients? Would modulation of these neuroendocrine systems lead to therapeutic benefits?

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