The Modulating Role of Stress in the Onset and Course of Tourette’s Syndrome

Abstract

Accumulating data indicate a common occurrence of tic exacerbations and periods of psychosocial stress. Patients with Tourette’s syndrome (TS) also exhibit aberrant markers of hypothalamic-pituitary-adrenal (HPA) axis activation. Based on these findings, a functional relationship between stress and tic disorders has been suggested, but the underlying mechanism of how stress may affect tic pathology remains to be elucidated. We suggest that dopaminergic and noradrenergic neurotransmission as well as immunology play a crucial role in mediating this relationship. Two possibilities of causal direction might be assumed: (a) psychosocial stress might lead to an exacerbation of tics via activation of HPA axis and subsequent changes in neurotransmission or immunology and (b) TS-related abnormalities in neurotransmission or immunology result in a higher vulnerability of affected patients to respond to psychosocial stress with a strong activation of the HPA axis. It may also be the case that both assumptions hold true and interact with each other.

Keywords

Tourette’s syndrome stress tics HPA axis cortisol immunology dopamine

Introduction

Tourette’s syndrome (TS) usually has a waxing and waning course with periods of tic exacerbation and periods of decreased tic severity (Leckman, 2002). Tics arise in bouts over the course of a day, and these episodes change in frequency and severity over weeks and months. The underlying factors of this waxing and waning are unclear. However, these symptom fluctuations might be due not only to internal physiological processes, but may also be influenced by various contextual factors (see Conelea & Woods, 2008, and Hoekstra, Dietrich, Edwards, Elamin, & Martino, 2013, for review). Among the contextual factors suspected to have an influence on tics, the main focus of attention has been on stress. This is reflected by the implication of stress as an influential contextual factor in the majority of reviews on TS (e.g., Du et al., 2010; Leckman, 2002; Leung & Fagan, 1989; Martino & Leckman, 2013; Swain & Leckman, 2005).

To date, there is no uniform consensus definition of “stress.” Since Walter Cannon first introduced the term in 1915, many different theories have adopted and subsequently broadened it, by describing somewhat different aspects of the phenomenon. In a narrow biological sense of the word, “stress” describes a condition of the body that includes the activation of the sympathetic nervous system, the release of catecholamine hormones, such as adrenaline or noradrenaline, the acceleration of heart and lung action as well as the dilation of the blood vessels in the muscles. The evolutionary purpose of this state was to prepare animals for fight or flight in the face of danger. The first important stress theory was developed by Hans Selye (1950) who described stress as being a general adaptive reaction to various pleasant or unpleasant stimuli. According to his theory, unspecific stressors elicit an activation of the hypothalamic-pituitary-adrenal (HPA) axis. It is assumed that the physiological stress response of HPA axis activation can be evoked by infections and injuries as well as by psychosocial stress. Psychosocial stress is referred to as the exposure to certain life events (Holmes & Rahe, 1967; Rahe, Biersner, Ryman, & Arthur, 1972; Rahe, Mahan, & Arthur, 1970) or the subjective appraisal of such events considering the individual’s resources and abilities to cope with them (Lazarus & Folkman, 1984).

In the following, we will systematically review studies on the relationship between psychosocial stress and (a) the onset of tic disorders, (b) tic exacerbations due to stressful life events, and (c) short-time fluctuations of tic frequency due to experimental manipulations. Subsequently, we will discuss which pathways of the physiological stress response to psychosocial stressors might mediate an exacerbation of tics. We suggest that these pathways include dopaminergic and noradrenergic neurotransmission as well as neuroimmunology.

To identify relevant articles, a literature search was conducted using the databases PsychIINFO, Pubmed, and MEDline. The search terms included tic or Tourette plus stress, life events, cortisol, and HPA axis. In addition, the reference lists of the identified articles were scrutinized for further articles of interest. The literature search was limited to empirical research in the English language.

Association Between Psychosocial Stress and Tics

It has been assumed that the onset of tics might frequently be preceded by stressful life events, but this supposition is not supported by the literature. However, accumulating data indicate that tic exacerbations often coincide with periods of psychosocial stress. Other studies report the onset of tics to be frequently preceded by stressful life events. A few other studies also experimentally manipulated stress under controlled conditions, to investigate the effects on short-term fluctuations of tic frequency. In the following, we will refer to “tic frequency” in the context of short-term fluctuation of tics and to “tic severity” or “tic exacerbations” in the context of long-term fluctuation of tics. The terms tic severity and, tic exacerbations may additionally involve changes in severity, complexity, and interference of tics.

Effect of Psychosocial Stress on the Onset of TS

In a large survey consisting of 763 TS patients, Bornstein, Stefl, and Hammond (1990) identified several events that had commonly occurred within the year before tic onset, including fever, operations requiring general anesthesia and other events that are usually accompanied by emotional tension such as the divorce of parents or moving to a new home.

Horesh, Zimmerman, Steinberg, Yagan, and Apter (2008) investigated the relationship between stressful life events, personality, and onset of TS and Obsessive-Compulsive Disorder (OCD) in 93 patients. Unexpectedly, the TS patients had not experienced a greater number of stressful life events in comparison with the healthy controls, neither during their entire lifetime nor in the year before tic onset. The authors concluded that the onset of tics is apparently not related to stressful life events, even though the waxing and waning of tics might be.

Overall, the available literature does not support the assumption that psychosocial stress might trigger the first onset of tics. However, the number of studies on this topic is very limited and the stress assessment had been restricted to stressful life events. To comprehensively answer the question about the association between psychosocial stress and tic onset, substantially more research including other measures of stress is needed. Also, prospective studies would be desirable.

Effect of Psychosocial Stress on Tic Exacerbations

In a large survey by Bornstein and colleagues (1990), worsening of tics due to psychosocial stress or anxiety was reported by 96.8% of the patients. In a study on the influence of 29 environmental factors on tic expression in 14 TS patients, the most commonly reported situations related to tic exacerbation were those associated with psychosocial stress, such as starting a new school year, waiting for test results, moving to a new location, and family arguments (Silva, Munoz, Barickman, & Friedhoff, 1995). An evaluation of global measures for the assessment of psychosocial stress in children and adolescents with TS determined that there was no correlation between tic severity and global stress level, but tic severity was correlated with daily life stressors. Also, the number of stressful life events and the level of perceived stress were higher in patients with TS compared with unaffected controls (Findley et al., 2003). In a 12-week study by Hoekstra, Steenhuis, Kallenberg, and Minderaa (2004), 25 children with TS and 32 TS-affected adults were asked to rate the severity of their tics on a weekly basis and to indicate how often an undesirable life event had occurred during the preceding week. Only a small minority of patients (21% in the pediatric and 18% in the adult TS sample) showed a significant association between tic severity and psychosocial stress due to small life events in the same or in the preceding week, although a weak but significant correlation between tic severity and negative small life events during the same week was found in the adult sample. Both minor and major life events and their effect on tic severity were investigated in a recent study including a sample of 60 children and adolescents with TS. The Yale Global Tic Severity Scale (YGTSS) motor tics score was associated with the quantity of positive and negative major life events. In addition, the YGTSS motor tics score and the YGTSS total score were significantly correlated with the quantity of negative minor life events (Steinberg, Shmuel-Baruch, Horesh, & Apter, 2012).

A longitudinal study by Lin et al. (2007) assessed stress levels and tic severity in 45 children with TS and/or OCD and 41 healthy controls over 2 years. Overall, levels of psychosocial stress were elevated in TS patients compared with controls and current levels of psychosocial stress were found to be a significant predictor for future tic, OCD, and depressive symptom severity 4 months in the future. In other words, those who had higher levels of psychosocial stress were more prone to having a more severe and complicated course.

In addition to the systematic studies on the role of stress in TS, there are also several case reports describing the onset of tics or worsening of the symptoms due to stressful life events (Hayes, Weber, Gallagher, & Drouillard, 2009; Surwillo, Shafii, & Barrett, 1978; Tijssen, Brown, Morris, & Lees, 1999; Witzum, Bar-On, Dolberg, & Kotler, 1996).

Maternal psychosocial stress during pregnancy has also been considered as an influencing factor for the occurrence of TS. In a study on 31 pediatric patients, it was one of three significant predictors of current tic severity (Leckman et al., 1990). In line with this finding, another study reported higher rates of psychosocial stress during pregnancy in mothers of TS patients with comorbid ADHD compared with mothers of healthy children (Motlagh et al., 2010).

In summary, the existing literature on the influence of stress on tic exacerbations is much larger than the body of research concerning the association between psychosocial stress and the onset of tics. Most of the available studies, including several retrospective and one prospective study, support the assumption that stressful life events are associated with the exacerbation of tics.

Effect of Psychosocial Stress on Short-Time Fluctuations of Tic Frequency

Only little experimental work has been done on the topic of tic fluctuations over the course of the day, although many tic patients report that the frequency of their tics is highly situation-specific. One case study by Lombroso, Mack, Scahill, King, and Leckman (1991) showed a marked situational increase in the frequency of tics in response to a physiological stressor, namely, thermal stress. This study prompted the conduct of a larger study involving 78 adults with TS of which 24% reported an increase in tic frequency on exposure to heat (Scahill et al., 2001). Ten subjects of the total sample were subjected to a thermal challenge under well-controlled circumstances (i.e., their core body temperature was increased either passively or through physical exercise). Fifty percent of them displayed a strong positive correlation between tic frequency and their local sweat rate that is thought to be mediated by dopaminergic inputs into the hypothalamus.

O’Connor and colleagues (O’Connor, Brisebois, Brault, Robillard, & Loiselle, 2003; O’Connor, Gareau, & Blowers, 1993; 1994) identified situations in which tics or habits were likely to appear and situations in which tics were weak or even absent by using Kelly’s repertory grid technique. Socializing was the most frequently named high-risk activity, while studying was most frequently named as low-risk activity. High-risk activities were commonly appraised as creating feelings of tension. That is, tense states were associated with an enhanced frequency of tics (O’Connor et al., 2003).

Another experimental study on short-term fluctuation of tic frequency included four TS patients who watched emotional scenes from a movie including scenes eliciting fear, anger, sadness, and happiness as well as a separation scene and a family scene. At baseline, patients were videotaped while waiting for the movie to begin and while actually watching the movie, to allow for an objective rating of tic frequency. Tic frequency was lowest during happy and anger scenes and moderate during scenes provoking sadness and fear. Tic severity was highest during periods of anticipation, resolution of emotional changes, and lower levels of concentration. Interestingly, when later asked about emotional triggers for their tics, the patients reported that being happy was the only emotion which resulted in the improvement of the tics (Wood et al., 2003). A disparity to the objective ratings of tic severity confirms the assumption that self-reports are not comprehensive and underlines the need for experimental studies using objective measures for tic frequency as well as stress (i.e., physiological stress parameters).

Situational psychosocial stress might influence tic frequency by reducing the ability to suppress tics. Ten TS patients underwent four different experimental conditions: a free-to-tic baseline, a reinforced tic suppression condition, a stress induction (mental math) task, and a condition combining the reinforced tic suppression condition and the stress induction task. Tic frequency was ascertained from video recordings and in covert observation through a one-way observation mirror. Interestingly, tic frequency did not differ between the baseline and the stress induction condition. However, stress was found to disrupt tic suppression, as indicated by higher tic frequencies in the combined stress and tic suppression condition, in comparison with the only tic suppression condition (Conelea, Woods, & Brandt, 2011).

These results indicate that psychosocial stress does not influence tic frequency per se, but that stress mainly reduces the ability to suppress tics. Therefore, stress particularly influences tic frequency in situations in which TS patients usually try not to tic. Conceivably, stressful situations (like the mental math task used to induce stress in the study by Conelea et al., 2011) require attentional resources which are thus not available for tic suppression. In addition, cortex excitability might be increased by stressful events (Rollnik, Schubert, & Dengler, 2000), whereby motor control—required for tic suppression—is compromised (Conelea & Woods, 2008).

In summary, a few experimental studies showed that psychosocial stress does not only influence long-term tic exacerbations but might also increase short-term tic frequency. Interestingly, there is also evidence that stress might influence tic frequency by reducing the ability to suppress tics.

Limitations of Existing Research and Future Perspectives

There is only very little evidence supporting the assumption that stressful life events might trigger the first onset of tics. Nonetheless, many of the studies examining the influence of psychosocial stress on tic fluctuations support the assumption that stressful life events as well as experimentally induced stress are associated with the exacerbation of tics. These findings, however, are not uniform and most likely depend on the study design and the means of subject selection, as well as how tic severity and stress levels were assessed. Most of these studies use a cross-sectional retrospective self-report design, which is susceptible to recall bias, and only include small numbers of patients. More compelling data could be derived from prospective, multisite, longitudinal studies.

Another weakness of the available studies can be found in the inclusion of only clinically referred cases. Especially when discussing psychosocial stress as a potential trigger for the onset of tics, population-based studies using epidemiological samples would be ideal and birth cohort and registry studies would be the way forward. Discordance between the results from different studies may also derive from dissimilar sample characteristics, such as age, co-morbidities, and treatment history. In addition, a lot of variance might stem from the different measures used to assess stress and tic exacerbations. As pointed out above, there is not one definition of “stress” and the findings on stress and TS may well vary depending on the method used to assess stress.

In the case of assessing psychosocial stress in patients with TS, a major limitation of most stress self-reports might be that they have been developed to assess psychosocial stress or exposure to stressful life events in the general population. They might, therefore, not be specific enough for the assessment of tic-related stress in TS. To overcome this shortcoming, a rating scale has been designed especially to measure psychosocial stress in children with TS: the Stress Index for Children and Adolescents With Tourette’s Syndrome (SICATS). The questionnaire was developed and can be obtained from Chao et al. (2010). The SICATS is a self-administered tool including subscales to assess psychosocial stress directly related to TS: (a) unfairly treated stress (punishment by teachers or parents and unfair treatment by classmates), (b) psychological stress (difficulties in interacting with other people), (c) symptom control stress (interference of tics with daily life), and (d) future concern stress (worries about academic achievement or finding a job in the future). In our opinion, it will be very beneficial to include this measure of symptom-related stress in future studies on stress in TS.

One major problem regarding the assessment of tic exacerbations can be found in the fact that the measures differ with regard to their degree of objectivity—(a) self- or parental report, (b) expert ratings, and (c) observed number of tics—and also in respect to the covered time span (minutes, hours, weeks, and month). Self- or parental ratings are frequently employed. They are, however, susceptible to retrospective bias. The studies by Wood et al. (2003) and Scahill et al. (2001) demonstrate that there can be some discordance between objective ratings of stress-associated increase of tic frequency (i.e., tic counts from videotape) and self-reports. In addition, in light of the study by Conelea et al. (2011), it is questionable whether tic exacerbations, as described by the patients, result from an increased urge to tic or if they derive from increased difficulties in suppressing the tics.

In summary, some caution is warranted when interpreting studies based only on findings acquired through self-report measurements. Future studies should overcome these limitations by additionally including assessments of physiological stress parameters, for example, cortisol concentrations and electrodermal activity. Most of those measures are well suited for assessing physiological stress responsivity by means of short-time fluctuations of skin conductance or cortisol secretion determined from blood, salivary, or urinary samples. For a long-term assessment of physiological stress, the measurement of cortisol concentration in a hair sample offers a promising approach (Meyer & Novak, 2012; Stalder & Kirschbaum, 2012; Staufenbiel, Penninx, Spijker, Elzinga, & van Rossum, 2013). Hair cortisol concentrations are assumed to provide a retrospective assessment of integrated cortisol secretion over periods of several months. With this method, aberrant hair cortisol concentrations have been found in patients with different psychiatric disorders and under socially or physically demanding conditions (Dettenborn et al., 2012; Dettenborn, Tietze, Bruckner, & Kirschbaum, 2010; Kirschbaum, Tietze, Skoluda, & Dettenborn, 2009; Manenschijn, van Kruysbergen, de Jong, Koper, & van Rossum, 2011; Skoluda, Dettenborn, Stalder, & Kirschbaum, 2012; Stalder et al., 2010; Steudte et al., 2013; Van Uum et al., 2008). To the best of our knowledge, there is still a lack of studies on patients with TS assessing hair cortisol concentration to determine long-term physiological stress. Studies on physiological stress responsivity of patients with TS measuring cortisol concentration in blood, saliva, urine, or cerebrospinal fluid, will be reviewed in the next section.

In summary, although several studies were able to show that long- and short-term fluctuation of tics is associated with psychosocial stress, the available body of research suffers from some methodological limitations. To investigate the issue more comprehensively, prospective studies are needed which should apply biological measures of stress (i.e., cortisol concentration in hair or saliva) and include self- and expert-rated stress scales specifically designed to assess stress in patients with tics (Table 1).

Table 1.

Overview of Studies on the Association of Stress With TS.

Author	Study design	Number of subjects	Age of subjects in years	Main findings
Surwillo, Shafii, and Barrett (1978)	CR	1 TS	10	Stressful life events have an impact on tic severity
Bornstein, Stefl, and Hammond (1990)	C-S,	763 TS	4-76	Exacerbation of tics due to stress or anxiety reported by 96.8%
Leckman et al. (1990)	C-S,	31 mothers of TS patients	7-17	Tic severity could partly be predicted by prenatal stress
Lombroso, Mack, Scahill, King, and Leckman (1991)	CR	1 TS	Not available	Marked increase in the frequency of tics in response to thermal stress
Chappell et al. (1994)	C-S	13 TS 10 healthy	17-41	Plasma ACTH level significantly higher in TS patients than in controls
Leckman et al. (1995)	C-S	33 TS 39 OCD 44 controls	31.1-63.1	TS patients exhibit higher level of cerebrospinal norepinephrine than controls
Silva, Munoz, Barickman, and Friedhoff (1995)	C-S	14 TS	6.6-14.5	Exacerbation of tics in situations making the patient upset or anxious
Chappell et al. (1996)	C-S	21 TS 20 OCD 29 controls	13-61	TS patients exhibit enhanced levels of CRF in the cerebrospinal fluid
Witzum, Bar-On, Dolberg, and Kotler (1996)	CR	1 TS		Mild TS that became severe after intense traumatic war experience
Tijssen, Brown, Morris, and Lees (1999)	CR	3 TS	25-33	Tics developed after physical trauma and emotional stress
Scahill et al. (2001)	C-S	Study 1: 78 TS Study 2: 10 TS	Study 1: 18-60 Study 2: 20-39	Study 1: 24% of TS patients report increased tic on exposure to heat Study 2: Increased tics on exposure to thermal stress in 50% of patients
Findley et al. (2003)	P-L	33 TS and/or OCD 25 controls	7-17	TS and OCD patients experience higher levels of psychosocial stress and report more major life events and daily life stress
O’Connor, Brisebois, Brault, Robillard, and Loiselle (2003)	P-L	76 tic or habit disorder	18-62	Tense states, like socialization were associated with the worsening of tics
Wood et al. (2003)	C-S	4 TS	8-14	Tic severity consistently lower during happy and anger video scenes
Hoekstra, Steenhuis, et al. (2004)	P-L	25 children with TS 32 adults with TS	Children: 7-16 Adults: 18-64	Only a small minority of patients showed a significant association between tic severity and frequency of small life events
Lin et al. (2007)	P-L	45 TS and OCD 41 controls	7-17	Current stress levels are a powerful predictor of future tic, OCD and depressive symptom severity
Corbett, Mendoza, Baym, Bunge, and Levine (2008)	P-L	20 TS 16 controls	7-13	TS patients exhibited higher levels of salivary cortisol when exposed to the MRI environment
Horesh, Zimmerman, Steinberg, Yagan, and Apter (2008)	C-S	41 TS 28 OCD 24 controls	7-18	TS patients had not experienced more stressful life events than healthy controls, neither in lifetime nor in the last year before tic onset.
Hayes, Weber, Gallagher, and Drouillard (2009)	CR	1	22	Correlation between occurrence of tics and symptoms of PTSD
Lin et al. (2010)	P-L	45 TS and OCD 41 controls	7-17	Especially the combined influence of psychosocial stress and infection with beta-hemolytic streptococcus leads to an exacerbation of tics
Motlagh et al. (2010)	C-S	157 mothers of patients with 52 ADHD 60 TS + ADHD 45 TS 65 controls	7-18	Mothers of patients exhibited higher psychosocial stress than mothers of control children
Conelea, Woods, and Brandt (2011)	C-S	10 TS	9-10	Tic frequency significantly higher in the condition with combined tic suppression and stress induction as compared with the stress induction condition alone → stress might reduce the ability to suppress tics
Steinberg, Shmuel-Baruch, Horesh, and Apter (2012)	C-S	60 TS	7-17	Correlation between tic severity and negative minor life events

Note. TS = Tourette’s Syndrome; OCD = Obsessive-Compulsive Syndrome; C-S = cross-sectional study; P-L = prospective longitudinal study; CR = case report; ACTH = adrenocorticotropic hormone; CRF = corticotrophin-releasing factor; PTSD = Posttraumatic Stress Disorder.

Physiological Approaches to the Interaction of Stress and TS—The Modulating Role of Dopamine and Noradrenaline

Physiological stress is basically manifested in an activation of the HPA axis. Within this multi-step biochemical pathway, several brain regions, including the prefrontal cortex and the amygdala, pass information about environmental stressors on to the paraventricular nucleus of the hypothalamus, which, in turn, releases the corticotropin-releasing hormone (CRH) which interacts with receptors of corticotropic cells in the pituitary gland. Subsequently, adrenocorticotropic hormone (ACTH) is secreted into the blood. ACTH binds to the cortex of the adrenal glands and causes the secretion of the steroid hormone cortisol, the final key messenger in the cascade. Glucocorticoids (cortisol in humans and corticosterone in rodents) can permeate the cellular membranes and interact with neurons via binding to steroid hormone receptors. Thereby glucocorticoids are able to influence the regulation of signaling pathways and the long-term remodeling of dendrites and synapses particularly in the prefrontal cortex, the amygdala, and the hippocampus (McEwen, 2007, 2010). In this way, glucocorticoids can also affect the transcription of multiple genes (de Kloet, Fitzsimons, Datson, Meijer, & Vreugdenhil, 2009; Zalachoras, Houtman, & Meijer, 2013) and—depending on the nature of the target cell—take influence on the metabolism, the immune system, and cognitive processes such as attention and memory (Kirschbaum, Wolf, May, Wippich, & Hellhammer, 1996; Vedhara, Hyde, Gilchrist, Tytherleigh, & Plummer, 2000; Wolf, 2009).

There is compelling evidence that TS patients exhibit stronger activation of the HPA axis, leading to enhanced levels of cortisol secretion when exposed to psychosocial stress.

When exposed to the magnetic resonance imaging (MRI) environment during a mock scan session, children with TS showed higher levels of salivary cortisol compared with healthy controls, while both groups of children exhibited the normal diurnal cortisol rhythm, with the physiological sharp rise of the cortisol levels in the morning (cortisol awakening response) and lower levels in the evening. However, there was a trend toward lower evening cortisol levels in the TS group, which might be the result of chronic daily stress (Corbett, Mendoza, Baym, Bunge, & Levine, 2008).

Chappell and colleagues (1994) obtained blood samples to measure the level of plasma ACTH, plasma cortisol, and urinary catecholamines in medication-free TS patients and healthy controls at several points in time before and after lumbar puncture. The ACTH level was significantly higher in TS patients compared with controls, before as well as after the procedure, indicating a stronger responsivity of the HPA axis in TS patients, which is in line with the findings reported by Corbett and colleagues (2008). Inconsistent with the findings on the plasma ACTH levels was the result regarding the plasma cortisol levels, which were similar in both groups. The authors, however, considered it possible that the difference between both groups might have been masked by the circadian rise of plasma cortisol levels, as the study took place rather early in the day. In another study, in which blood samples were taken during the morning, there were also no differences between patients with tic disorders and healthy subjects in regard to plasma cortisol concentration (Hoekstra, Anderson, Troost, Kallenberg, & Minderaa, 2007). In a subsequent study, Chappell et al. (1996) measured the levels of CRH in the cerebrospinal fluid of the same patient groups. Compared with both healthy controls and OCD patients, the mean levels of CRH were enhanced in TS patients by about 28% (TS vs. controls) and 31% (TS vs. OCD), respectively.

In summary, the reported findings suggest that patients with TS exhibit higher levels of cortisol, ACTH, and CRH, indicating that TS is associated with a stronger responsivity of the HPA axis.

The complex neurochemical pathways by which biochemical stress responses might influence tic expression are still unclear, but there is a lot of evidence suggesting that activation of the HPA axis may have a negative impact on the normal physiology of the dopaminergic system (Pani, Porcella, & Gessa, 2000), which plays a pivotal role in the pathophysiology of TS (Buse, Schoenefeld, Münchau, & Roessner, 2012; Leckman, Bloch, Smith, Larabi, & Hampson, 2010; Singer, 2013).

There is broad evidence supporting the influence of the stress response on the dopaminergic system. As early as 1989, Thind and Goldsmith found that CRH neuronal efferents synaptically activate A14 dopamine neurons in the primate periventricular nucleus and parvocellular paraventricular nucleus. Studies on rodents have shown that exposure to stressors effects the extracellular dopamine concentration in many regions of the brain (Mora, Segovia, Del Arco, de Blas, & Garrido, 2012), namely, the prefrontal cortex (Del Arco & Mora, 2001; Del Arco, Segovia, Garrido, de Blas, & Mora, 2007; Del Arco, Segovia, & Mora, 2001; Feenstra, Botterblom, & Mastenbroek, 2000; Segovia, Del Arco, de Blas, Garrido, & Mora, 2008), the amygdala (Inglis & Moghaddam, 1999), the hippocampus (Yamato et al., 2002), and the nucleus accumbens (Feenstra, Botterblom, & van Uum, 1998; Imperato, Angelucci, Casolini, Zocchi, & Puglisi-Allegra, 1992). Administering ovine CRH to rats had stimulatory effects on dopaminergic neuron terminals in the nucleus accumbens, hypothalamic periventricular nucleus and the paraventricular nucleus and intermediate pituitary lobe, as measured by means of 3,4-Dihydroxyphenylacetic acid (DOPAC), a major metabolite of dopamine (Pan, Lookingland, & Moore, 1995). The relationship between stress and dopamine release has also been demonstrated in humans. In a Positron emission tomography (PET) study on healthy students, psychosocial stressors were found to cause dopamine release in the ventral striatum (Pruessner, Champagne, Meaney, & Dagher, 2004).

Dopaminergic neurotransmission in the cortico-striato-thalamocortical circuits has an important influence on the etiology and course of tic disorders (Ganos, Roessner, & Münchau, 2013; Leckman et al., 2010). The firing rate of the GABAergic projection neurons in the striatum is modulated by dopamine receptors. The D1-dominant cells predominantly send inhibitory projections to the substantia nigra pars reticulate (SNr) (direct pathway), while the D2-dominant cells of the striatum send inhibitory projections to the globus pallidus (indirect pathway), which in turn send inhibitory projections to the subthalamic nucleus and the SNr. These GABAergic cells in turn send tonic inhibitory output to their targets in the thalamus and brainstem (DeLong & Wichmann, 2007). The selection of movement takes place across the direct pathway, while the inhibition of ongoing movement is regulated across the indirect pathway via disinhibition of the SNr (Humphries, Stewart, & Gurney, 2006). Both pathways play an essential role in the etiology and course of tic disorders. The balance between direct and indirect pathways is regulated by the differential actions of dopamine on striatal neurons (DeLong & Wichmann, 2007). Taking the above into consideration, it becomes clear how enhanced dopamine activity, for example, through stress, can lead to a dysbalance in the motor circuit, which in turn potentially might result in motor disorders, such as tics.

Stress-induced enhancement of dopamine release in the human prefrontal cortex has also been observed and was associated with the subjectively rated experiences of psychosocial stress (Lataster et al., 2011). Finlay and Zigmond (1997) noted, that the response of dopamine neurons is highly heterogeneous with the largest increase of extracellular dopamine in response to acute stress being observed in the prefrontal cortex. Stress-induced abnormalities in prefrontal areas are especially interesting in light of the observation that stress might challenge the ability to control or suppress tics instead of enhancing the urge to tic.

The previous paragraphs have aimed to provide an explanation of how the biochemical stress response might influence dopaminergic neurotransmission which might, in turn, cause an exacerbation of tics. In general, the stress-induced exacerbation of tics might be understood to be the result of additional demands placed on an already compromised population of dopamine neurons (Finlay & Zigmond, 1997). However, the interaction between physiological stress response and the dopaminergic system can also be looked on from another perspective. That is, TS pathology, for example, altered dopaminergic neurotransmission, might also influence the physiological stress response. This assumption derives from the findings that patients with TS exhibit enhanced physiological responses to stress-inducing stimuli (Chappell et al., 1996; Chappell et al., 1994; Corbett et al., 2008), but because studies which directly assess the neurobiological relationship between altered dopamine levels and stress responsivity in patients with TS are still missing, this assumption has to remain unproved.

However, there are some animal studies showing that dopaminergic neurotransmission influences the secretion of biological stress parameter (Borowsky & Kuhn, 1992; Cheung, Ballew, Moore, & Lookingland, 1998; Eaton, Cheung, Moore, & Lookingland, 1996; Liposits & Paull, 1989; Wagner, Eaton, Moore, & Lookingland, 1995).

In summary, the physiological mechanisms of stress seem to be closely related to changes in dopaminergic neurotransmission which plays a major role in TS. Although the exact interplay among stress, DA, and tics is still unclear, two causal models can be proposed: (a) psychosocial stress activates dopaminergic neurotransmission which then initiates or exacerbates tics and (b) an overactive or imbalanced dopaminergic neurotransmission underlying TS leads to an elevated physiological stress response. It may also be the case that both assumptions hold true and interact with each other, with increased baseline dopamine levels resulting in TS patients being susceptible to an enhanced physiological stress response which again enhances dopamine release even more, in turn exacerbating tics.

In addition to ACTH, CRH, and cortisol, levels of norepinephrine in the urine (Chappell et al., 1994) and in the cerebrospinal fluid (Leckman et al., 1995) were found to be enhanced in TS patients. This finding is of particular interest as noradrenaline is not only part of the acute stress response but also plays an important role in the pathophysiology of TS (Leckman et al., 2010). Alpha-2 agonists, such as clonidine and guanfacine, have proven to be efficient in reducing tics (Bloch, Panza, Landeros-Weisenberger, & Leckman, 2009; Pringsheim et al., 2012). These agents reduce the firing rate and the release of noradrenaline from noradrenergic neurons via negative feedback through binding to receptors on presynaptic sites. In this regard, the noradrenergic pathway might also be a mechanism by which stressors may influence tic severity (Leckman et al., 2010). It might be speculated that part of the benefits of alpha-2 agonists in the treatment of tics derives from their modulating influence on the physiological stress response.

Immunopathogenic Mechanisms in TS and the Modulating Role of Stress

It has been suggested that the influence of stress on tic expression is entangled with the influence of immunology on tic expression. One possible means of interaction of both mechanisms might be the modulation of dopaminergic neurotransmission.

There is ample evidence pointing toward immunopathogenic mechanisms playing a role in TS (Elamin, Edwards, & Martino, 2013; Hoekstra, Anderson, et al., 2004; Hoekstra, Kallenberg, Korf, & Minderaa, 2002; Hoekstra et al., 2007; Murphy, Kurlan, & Leckman, 2010, for review, see Hoekstra et al., 2013). Various alterations of the immune response have been observed in TS patients, for instance, overexpression of D8/17B lymphocyte surface marker (Hoekstra, Anderson, et al., 2004; Murphy et al., 1997), increased levels of tumor necrosis factor alpha (Leckman et al., 2005), reduced percentages of regulatory T-cells (Kawikova et al., 2007), elevated levels of IL-12 plasma cytokines (Gabbay et al., 2009), elevated levels of memory T-cells (Hsieh et al., 2010), decreased levels of lgA (Kawikova et al., 2010), pathological oligoclonal bands in the corticotrophin-releasing factor (CRF) (Wenzel, Wurster, & Müller-Vahl, 2011), decreased serum lg3 (Bos-Veneman et al., 2011), elevated anti-streptolysin O (ASO) titers (Martino et al., 2011), altered autoantibody positivity, antistreptolysin, and several plasma cytokines (Cheng et al., 2012).

Altered immune response regulation in TS has been intensively discussed, especially in the context with Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections (PANDAS; Kurlan, 1998; Kurlan & Kaplan, 2004; Leslie et al., 2008; Martino et al., 2011; Martino, Dale, Gilbert, Giovannoni, & Leckman, 2009; Singer, Gause, Morris, Lopez, & Tourette’s Syndrome Study Group, 2008; Swedo et al., 1998). PANDAS refers to the onset of tic or OCD symptoms after an infection with Group A streptococcus (GAS; Swedo et al., 1998). In children with PANDAS, a positive correlation between antineuronal antibodies and severity of tics was found (Pavone et al., 2004). However, the PANDAS hypothesis remains a very controversial issue (Hoekstra et al., 2013), especially because two recent studies of high methodological quality reported negative results (Kurlan, Johnson, & Kaplan, 2008; Leckman et al., 2011).

Martino et al. (2009) developed a pathophysiological model describing how an enhanced autoimmune response (i.e., to GAS infection) might contribute to the onset or worsening of tics via dopaminergic neurotransmission. According to this model, antineuronal antibodies in the central nervous system (CNS) increase calcium-calmodulin-dependent (CaM) kinase II and tyrosine hydroxylase (TH) activity which in turn increase dopamine release in central synapses. In the periphery, the infections elicit inflammatory responses by up-regulating natural killer cells, cytotoxic T-lymphocytes, and the synthesis of cytokines. This, in turn, enhances dopamine release from sympathetic nervous system fibers, resulting in high levels of dopamine in the periphery. Dopamine modulates immunology by activating D1/D5 dopamine receptors on the lymphocyte cell surface (Ferrari et al., 2008). The stimulation of the dopamine receptors modifies the differentiation of t-cells in favor of autoimmunology (Pacheco, Prado, Barrientos, & Bernales, 2009). An enhanced autoimmune response might, in turn, contribute to the onset and/or worsening of tics via the CNS pathway described above (Martino et al., 2009). According to Martino’s pathophysiological model (Martino et al., 2009), psychosocial stress may contribute to the increase of dopamine release from the sympathetic nervous system leading to an enhanced autoimmune response. Consistent with this, several studies reported that the level of plasma DA, the primary source of dopamine for t-cells, is increased in the pathophysiological state of stress (for a review, see Pacheco et al., 2009).

The relevance of the interplay between stress and immunology in TS is underpinned by a longitudinal study on 45 children with TS and/or OCD and 41 healthy controls. Structural equation modeling indicated that these newly diagnosed GAS infections were predictive of modest increases in future tic and OCD symptom severity. The inclusion of GAS infections in the model also greatly enhanced the predictive power of psychosocial stress. Thus, the prediction of future tic and OCD symptoms was most accurate when both GAS infections as well as psychosocial stress were included in the model (Lin et al., 2010).

It is a well-known fact that the activation of the HPA axis has a powerful effect on the immune system, in terms of cortisol suppressing the inflammatory response to avoid deleterious effects (Pittman, 2011). The complex HPA axis response to inflammation is mediated my cytokines, including IL-1, IL-6, and leukemia inhibitory factor (LIF) . During inflammation, these cytokines stimulate the HPA axis and thereby antagonize their own peripheral pro-inflammatory action (Chesnokova & Melmed, 2002). Thus, concurrent with the pro-inflammatory response, an anti-inflammatory response is activated (Pittman, 2011). With regard to this mechanism, the increased activation of HPA axis observed in TS patients might possibly also be considered to be a consequence of elevated inflammatory response, for example, to GAS infection.

Stress Reduction in the Treatment of TS

With regard to the outlined relevance of psychosocial stress and the pathophysiological stress response for tics, stress reduction might be an important component in the treatment of TS. It might be particularly beneficial for those patients, who report suffering from stress-related tic exacerbations.

Various stress reduction techniques are available that produce common, general as well as specific positive effects (Lehrer, Carr, Sargunaraj, & Woolfolk, 1994). In TS, where muscular activity is abnormal, “muscle-oriented” methods such as muscle relaxation and/or electromyography (EMG) biofeedback might be most promising. A review showed that progressive muscle relaxation had moderate overall effects when used as an intervention for psychophysiological and stress-related disorders (Carlson & Hoyle, 1993). There is evidence that progressive muscle relaxation training also reduces saliva cortisol and enhances levels of immunoglobulin A (Jasnoski & Kugler, 1987; Pawlow & Jones, 2002, 2005). To the best of our knowledge, there is only one study on the effects of progressive muscle relaxation training in the treatment of tics, reporting a tic reduction by 32% (Peterson & Azrin, 1992). A study on the effectiveness of a relaxation therapy comprised of awareness training, diaphragmatic breathing, behavioral relaxation training, and biofeedback failed to show significant improvement of tics (Bergin, Waranch, Brown, Carson, & Singer, 1998). However, in both studies only a small number of patients were included in the relaxation training group (6 and 7), therefore reducing the validity of these results.

The European clinical guidelines for TS and tic disorders suggest relaxation training as a second-line behavioral treatment or add-on treatment to other behavioral techniques (Verdellen, van de Griendt, Hartmann, Murphy, & ESSTS Guidelines Group, 2011), while habit reversal training, which is also the most extensively researched behavioral treatment for tics, is considered to be first choice (Frank & Cavanna, 2013; Piacentini et al., 2010; Scahill et al., 2013; Verdellen et al., 2011; Wile & Pringsheim, 2013; Wilhelm et al., 2012).

Many programs for habit reversal include a relaxation component (O’Connor et al., 2001; O’Connor et al., 2009; Rowe, Yuen, & Dure, 2013; Verdellen et al., 2011), such as the comprehensive behavioral intervention for tics (CBIT) program that has proven to be very efficient in reducing the number of tic expressions, tic severity, and level of distress associated with tics (Rowe et al., 2013). Habit reversal training usually includes awareness exercises that comprise the identification of high-risk situations associated with enhanced tic activity, for example, situations in which a person experiences mainly psychosocial stress (O’Connor et al., 2001; O’Connor et al., 2003). It is important to be able to foresee such high-risk situations, if habit reversal shall be applied successfully by the patients in their daily life. It is also an important component of the habit reversal training to identify cognitive factors (e.g., catastrophic anticipations/unrealistic expectations) associated with the stressful situations and to modify them to reduce stress (O’Connor et al., 2001).

Furthermore, biofeedback has been used as a method for stress management, for example, in the treatment of heart disease (Moravec & McKee, 2011). One study determined that relaxation biofeedback on galvanic skin response was successful in reducing tic frequency (Nagai, Cavanna, & Critchley, 2009).

There are also various alternative therapies that might help in reducing stress. For instance, yoga has been found to be a beneficial intervention for stress. However, the evidence is not entirely clear because controlled trials of high methodological quality are missing (Li & Goldsmith, 2012; McCall, Ward, Roberts, & Heneghan, 2013). There is one report about self-hypnosis techniques helping children with TS to reduce the frequency of their tics (Kohen, 1995). In addition, mindfulness-based stress reduction (MBSR) programs have received a substantial amount of attention in recent years. These programs aim at enhancing awareness of moment-to-moment experiences in which thoughts, feelings, and/or sensations that arise in the attentional field are to be acknowledged and accepted non-judgmentally. A meta-analysis including 20 studies of acceptable quality on both clinical and non-clinical samples supports the positive effect of MBSR (Grossman, Niemann, Schmidt, & Walach, 2004). There is also accumulating evidence indicating that activation of the HPA axis, indicated by cortisol levels, decreased after participation in an MBSR program (Matousek, Dobkin, & Pruessner, 2010). To the best of our knowledge, there are no reports about MBSR in TS patients so far, but a trial testing a modified form of MBSR in combination with habit reversal training for the treatment of TS, that was founded by the international TS association, was initiated in 2011 (http://tsa-usa.org/aResearch/gran/2011_rees.html).

Pharmacological treatment with D2 dopamine receptor blockers has shown to be very effective in treating tic disorders. In particular, the blockade of striatal D2 dopamine receptors is thought to lead to a reduction of tics (Roessner et al., 2011). As stress effects the dopamine neurotransmission, for example, in the ventral striatum (Pruessner et al., 2004), D2 receptor antagonists might not only be successful because they regulate a substantial tic-related dysfunction of the dopamine system but also because they might regulate stress-induced increase of dopamine.

In addition, alpha-2 agonists, such as clonidine and guanfacine, which reduce the release of noradrenaline, have proven to be efficient in reducing tics (Bloch et al., 2009; Pringsheim et al., 2012). Because the release of noradrenaline is a core part of the physiological stress response and stress is associated with an increase of tics, it might be speculated, that one part of the benefits of alpha-2 agonists in the treatment of tics derives from their ability to reduce the effects of stress. In light of the finding that the ability to suppress tics may be reduced under the condition of psychosocial stress (Conelea et al., 2011), it is interesting to note that stress-related noradrenaline release effects functioning of the prefrontal cortex (Arnsten, 2009), which is in turn involved in the voluntary suppression of tics. It has been found that stress-induced cognitive deficits can be prevented by administration of α1-receptor antagonists in the prefrontal cortex and that stimulation of postsynaptic α2A-receptors in the prefrontal cortex improves working memory performance (Arnsten, 2009). In light of this, it might be assumed that administration of alpha-2 agonists could improve the ability to suppress tics even when experiencing psychosocial stress.

Summary

Based on clinical experience, stress has been assumed to play a role in the onset and course of TS for a long time. In recent years, a number of studies have pointed toward the association between psychosocial stress and fluctuations in tic severity. Initial studies of the physiological stress response in terms of the activation of the HPA axis suggest that it may be dysregulated in TS. We suggest that dopaminergic and noradrenergic neurotransmission as well as immunology play a crucial role in mediating the relationship between stress and tic exacerbations. Stress can have an impact on dopamine activity in the cortico-striato-thalamocortical circuits, which play a crucial role in the selection and inhibition of movements and are dysfunctional in patients with tic disorders. By influencing dopamine activity in the striatum, stress might also impact tic expression.

An enhanced autoimmune response (e.g., to GAS infection) might also contribute to the onset or worsening of tics via dopaminergic neurotransmission. With growing awareness concerning the important role of stress on the course of TS, stress reduction techniques might become an important component in its treatment. Well-established programs for habit reversal training in patients with TS, such as the CBIT, already include a relaxation component, but detailed research on specific stress reduction techniques, like progressive muscle relaxation training or MBSR, is still lacking.

Future Research Directions

The review emphasizes the need for more research on the relationship between stress and TS. On one hand, further studies with longitudinal designs are needed that are not susceptible to retrospective bias and able to capture both long-term fluctuations in psychosocial stress level as well as tic severity. On the other hand, more studies using experimentally controlled stress paradigms are needed to investigate the relation between situational stress and short-term changes in tic frequency. To overcome limitations associated with the use of patients or parents’ self-reports, future studies should include more objective measures of tic exacerbation and researchers in this field might want to work toward a common definition of tic exacerbations. In addition, we assume that the inclusion of different physiological measures of stress would add a lot to our understanding of the precise mechanisms underlying the relationship between stress and tic exacerbations.

The ongoing European Multicentre Tics Study (EMTICS) project, which comprises 27 centers in 11 European countries, is a promising opportunity to further investigate the functional relationship among stress, immunological processes, and tics. EMTICS continuously records immunological parameters, psychosocial stress and exacerbation or onset of tics in a total of 500 children with a high risk to develop tics and 700 children already exhibiting tics over a time span of 3 years. All of these children will be assessed with the same measures of stress, including self- and parent reports as well as biological parameters (i.e., cortisol concentration in hair). Tic severity will be rated by clinicians, who had received the identical kind of training, and tic exacerbations will be classified on the basis of a joint definition. Because—parallel to the assessment of tics and stress—many immunological parameters will be determined from regularly taken blood samples, the project will be of particular value in elucidating the modulating role of the immune system.

We assume that stress might impact tic expression via influencing dopamine activity in the striatum. However, this assumption is derived from the aggregated knowledge of three different kinds of studies: (a) studies assessing the relationship between stress and tic disorders, (b) studies assessing the relationship between stress and the dopamine neurotransmission, and (c) studies assessing the relationship between the dopamine system and tic disorders. To get a deeper understanding of the precise underlying biological mechanisms, studies are needed that integrate all three approaches in one. Conceivably mouse models mimicking tic disorders might offer a good opportunity for broadening the knowledge in this field. One question that is still unresolved is whether stress-related fluctuations in tic expression that occur on a long-term basis have the same underlying biological mechanism as stress-related fluctuations in tic expression that occur on a short-term basis. Both may perhaps differ with respect to the impact they have on tonic versus phasic dopamine neurotransmission. However, so far, this is subject of speculation, and would rather be an interesting question in future studies.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no external financial support for the research, authorship, and/or publication of this article. The preparation of the manuscript was funded by intramural resources.

Authors’ Biographies

Judith Buse, Dipl-Psych, is a doctoral researcher at the Department of Child and Adolescent Psychiatry at the University Medical Center Dresden. Her research focuses on neurophysiological correlates of sensory phenomena in Tourette’s syndrome and obsessive-compulsive disorder, and on the contribution of stress to the onset and severity of tics.

Clemens Kirschbaum is head of the Institute for Biopsychology at the Technical University of Dresden. His research focuses on (neuro)cognitive, clinical, endocrinological, immunological, and genetic aspects of stress in humans.

James F. Leckman, MD, is the Neison Harris Professor of Child Psychiatry, Psychiatry, Psychology, and Pediatrics at Yale and the director of the Yale Child Study Center. He is a widely recognized clinician and highly cited researcher in the field of Tourette’s syndrome and early onset obsessive-compulsive disorder.

Alexander Münchau is the head of the Department of Paediatric and Adult Movement Disorders and Neuropsychiatry in the Institute of Neurogenetics at the University of Lübeck. From 2003 to 2013, he was consultant neurologist and head of the movement disorders unit in the Neurological Department at the University Medical Center Hamburg.

Veit Roessner is head of the Department of Child and Adolescent Psychiatry at the University Medical Center Dresden. He published important work on the pathophysiology of Tourette’s syndrome, ADHD, and obsessive-compulsive symptoms, and edited the European clinical guidelines for the diagnosis and treatment of tic disorders.

References

Arnsten

A. F. T.

(2009). Stress signalling pathways that impair prefrontal cortex structure and function. Nature Reviews Neuroscience, 10, 410-422. doi:10.1038/nrn2648

Bergin

Waranch

H. R.

Brown

Carson

Singer

H. S.

(1998). Relaxation therapy in Tourette syndrome: A pilot study. Pediatric Neurology, 18, 136-142.

Bloch

M. H.

Panza

K. E.

Landeros-Weisenberger

Leckman

J. F.

(2009). Meta-analysis: Treatment of attention-deficit/hyperactivity disorder in children with comorbid tic disorders. Journal of the American Academy of Child & Adolescent Psychiatry, 48, 884-893. doi:10.1097/CHI.0b013e3181b26e9f

Bornstein

R. A.

Stefl

M. E.

Hammond

(1990). A survey of Tourette syndrome patients and their families: The 1987 Ohio Tourette Survey. The Journal of Neuropsychiatry and Clinical Neurosciences, 2, 275-281.

Borowsky

Kuhn

C. M.

(1992). D1 and D2 dopamine receptors stimulate hypothalamo-pituitary-adrenal activity in rats. Neuropharmacology, 31, 671-678.

Bos-Veneman

N. G. P.

Olieman

Tobiasova

Hoekstra

P. J.

Katsovitch

Bothwell

A. L. M.

. . .Kawikova

(2011). Altered immunoglobulin profiles in children with Tourette syndrome. Brain, Behavior, and Immunity, 25, 532-538. doi:10.1016/j.bbi.2010.12.003

Buse

Schoenefeld

Münchau

Roessner

(2012). Neuromodulation in Tourette syndrome: Dopamine and beyond. Neuroscience & Biobehavioral Reviews, 37, 1069-1084. doi:10.1016/j.neubiorev.2012.10.004

Cannon

W. B.

(1915). Bodily changes in pain, hunger, fear and rage: An account of recent researches into the function of emotional excitement. New York, NY: Appleton.

Carlson

C. R.

Hoyle

R. H.

(1993). Efficacy of abbreviated progressive muscle relaxation training: A quantitative review of behavioral medicine research. Journal of Consulting and Clinical Psychology, 61, 1059-1067.

10.

Chao

K.-Y.

Wang

H.-S.

Chang

H.-L.

Wang

Y.-W.

See

L.-C.

(2010). Establishment of the reliability and validity of the Stress Index for Children or Adolescents with Tourette Syndrome (SICATS). Journal of Clinical Nursing, 19, 332-340. doi:10.1111/j.1365-2702.2009.03061.x

11.

Chappell

Leckman

Goodman

Bissette

Pauls

Anderson

. . .Cohen

(1996). Elevated cerebrospinal fluid corticotropin-releasing factor in Tourette’s syndrome: Comparison to obsessive compulsive disorder and normal controls. Biological Psychiatry, 39, 776-783.

12.

Chappell

Riddle

Anderson

Scahill

Hardin

Walker

. . .Leckman

(1994). Enhanced stress responsivity of Tourette syndrome patients undergoing lumbar puncture. Biological Psychiatry, 36, 35-43.

13.

Cheng

Zheng

Yang

Wang

. . .Chen

(2012). Detection of autoantibodies and increased concentrations of interleukins in plasma from patients with Tourette’s syndrome. Journal of Molecular Neuroscience, 48, 219-224. doi:10.1007/s12031-012-9811-8

14.

Chesnokova

Melmed

(2002). Minireview: Neuro-immuno-endocrine modulation of the hypothalamic-pituitary-adrenal (HPA) axis by gp130 signaling molecules. Endocrinology, 143, 1571-1574.

15.

Cheung

Ballew

J. R.

Moore

K. E.

Lookingland

K. J.

(1998). Contribution of dopamine neurons in the medial zona incerta to the innervation of the central nucleus of the amygdala, horizontal diagonal band of Broca and hypothalamic paraventricular nucleus. Brain Research, 808, 174-181.

16.

Conelea

C. A.

Woods

D. W.

(2008). The influence of contextual factors on tic expression in Tourette’s syndrome: A review. Journal of Psychosomatic Research, 65, 487-496. doi:10.1016/j.jpsychores.2008.04.010

17.

Conelea

C. A.

Woods

D. W.

Brandt

B. C.

(2011). The impact of a stress induction task on tic frequencies in youth with Tourette syndrome. Behaviour Research and Therapy, 49, 492-497. doi:10.1016/j.brat.2011.05.006

18.

Corbett

B. A.

Mendoza

S. P.

Baym

C. L.

Bunge

S. A.

Levine

(2008). Examining cortisol rhythmicity and responsivity to stress in children with Tourette syndrome. Psychoneuroendocrinology, 33, 810-820. doi:10.1016/j.psyneuen.2008.03.014

19.

De Kloet

E. R.

Fitzsimons

C. P.

Datson

N. A.

Meijer

O. C.

Vreugdenhil

(2009). Glucocorticoid signaling and stress-related limbic susceptibility pathway: About receptors, transcription machinery and microRNA. Brain Research, 1293, 129-141. doi:10.1016/j.brainres.2009.03.039

20.

Del Arco

Mora

(2001). Dopamine release in the prefrontal cortex during stress is reduced by the local activation of glutamate receptors. Brain Research Bulletin, 56, 125-130.

21.

Del Arco

Segovia

Garrido

de Blas

Mora

(2007). Stress, prefrontal cortex and environmental enrichment: Studies on dopamine and acetylcholine release and working memory performance in rats. Behavioural Brain Research, 176, 267-273. doi:10.1016/j.bbr.2006.10.006

22.

Del Arco

Segovia

Mora

(2001). Dopamine release during stress in the prefrontal cortex of the rat decreases with age. Neuroreport, 12, 4019-4022.

23.

DeLong

M. R.

Wichmann

(2007). Circuits and circuit disorders of the basal ganglia. Archives of Neurology, 64, 20-24. doi:10.1001/archneur.64.1.20

24.

Dettenborn

Muhtz

Skoluda

Stalder

Steudte

Hinkelmann

. . .Otte

(2012). Introducing a novel method to assess cumulative steroid concentrations: Increased hair cortisol concentrations over 6 months in medicated patients with depression. Stress, 15, 348-353. doi:10.3109/10253890.2011.619239

25.

Dettenborn

Tietze

Bruckner

Kirschbaum

(2010). Higher cortisol content in hair among long-term unemployed individuals compared to controls. Psychoneuroendocrinology, 35, 1404-1409. doi:10.1016/j.psyneuen.2010.04.006

26.

J.-C.

Chiu

T.-F.

Lee

K.-M.

H.-L.

Yang

Y.-C.

Hsu

S.-Y.

. . .Leckman

J. F.

(2010). Tourette syndrome in children: An updated review. Pediatrics and Neonatology, 51, 255-264.

27.

Eaton

M. J.

Cheung

Moore

K. E.

Lookingland

K. J.

(1996). Dopamine receptor-mediated regulation of corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus. Brain Research, 738, 60-66.

28.

Elamin

Edwards

M. J.

Martino

(2013). Immune dysfunction in Tourette syndrome. Behavioural Neurology, 27, 23-32. doi:10.3233/BEN-120295

29.

Feenstra

M. G.

Botterblom

M. H.

Mastenbroek

(2000). Dopamine and noradrenaline efflux in the prefrontal cortex in the light and dark period: Effects of novelty and handling and comparison to the nucleus accumbens. Neuroscience, 100, 741-748.

30.

Feenstra

M. G.

Botterblom

M. H.

van Uum

J. F.

(1998). Local activation of metabotropic glutamate receptors inhibits the handling-induced increased release of dopamine in the nucleus accumbens but not that of dopamine or noradrenaline in the prefrontal cortex: Comparison with inhibition of ionotropic receptors. Journal of Neurochemistry, 70, 1104-1113.

31.

Ferrari

Termine

Franciotta

Castiglioni

Pagani

Lanzi

. . .Balottin

(2008). Dopaminergic receptor D5 mRNA expression is increased in circulating lymphocytes of Tourette syndrome patients. Journal of Psychiatric Research, 43, 24-29. doi:10.1016/j.jpsychires.2008.01.014

32.

Findley

D. B.

Leckman

J. F.

Katsovich

Lin

Zhang

Grantz

. . .King

R. A.

(2003). Development of the Yale Children’s Global Stress Index (YCGSI) and its application in children and adolescents with Tourette’s syndrome and obsessive-compulsive disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 42, 450-457. doi:10.1097/01.CHI.0000046816.95464.EF

33.

Finlay

J. M.

Zigmond

M. J.

(1997). The effects of stress on central dopaminergic neurons: Possible clinical implications. Neurochemical Research, 22, 1387-1394.

34.

Frank

Cavanna

A. E.

(2013). Behavioural treatments for Tourette syndrome: An evidence-based review. Behavioural Neurology, 27, 105-117. doi:10.3233/BEN-120309

35.

Gabbay

Coffey

B. J.

Guttman

L. E.

Gottlieb

Katz

Babb

J. S.

. . .Gonzalez

C. J.

(2009). A cytokine study in children and adolescents with Tourette’s disorder. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 33, 967-971. doi:10.1016/j.pnpbp.2009.05.001

36.

Ganos

Roessner

Münchau

(2013). The functional anatomy of Gilles de la Tourette syndrome. Neuroscience & Biobehavioral Reviews, 37, 1050-1062. doi:10.1016/j.neubiorev.2012.11.004

37.

Grossman

Niemann

Schmidt

Walach

(2004). Mindfulness-based stress reduction and health benefits. A meta-analysis. Journal of Psychosomatic Research, 57, 35-43. doi:10.1016/S0022-3999(03)00573-7

38.

Hayes

P. C.

Weber

C. L.

Gallagher

M. B.

Drouillard

G. J.

(2009). Attenuation of apparent new-onset ocular tics with successful treatment of PTSD. CNS Spectrums, 14, 214-220.

39.

Hoekstra

P. J.

Anderson

G. M.

Limburg

P. C.

Korf

Kallenberg

C. G. M.

Minderaa

R. B.

(2004). Neurobiology and neuroimmunology of Tourette’s syndrome: An update. Cellular and Molecular Life Sciences, 61, 886-898. doi:10.1007/s00018-003-3320-4

40.

Hoekstra

P. J.

Anderson

G. M.

Troost

P. W.

Kallenberg

C. G. M.

Minderaa

R. B.

(2007). Plasma kynurenine and related measures in tic disorder patients. European Child & Adolescent Psychiatry, 16(Suppl. 1), 71-77. doi:10.1007/s00787-007-1009-1

41.

Hoekstra

P. J.

Dietrich

Edwards

M. J.

Elamin

Martino

(2013). Environmental factors in Tourette syndrome. Neuroscience & Biobehavioral Reviews, 37(6), 1040-1049. doi:10.1016/j.neubiorev.2012.10.010

42.

Hoekstra

P. J.

Kallenberg

C. G. M.

Korf

Minderaa

R. B.

(2002). Is Tourette’s syndrome an autoimmune disease? Molecular Psychiatry, 7, 437-445. doi:10.1038/sj.mp.4000972

43.

Hoekstra

P. J.

Steenhuis

M.-P.

Kallenberg

C. G. M.

Minderaa

R. B.

(2004). Association of small life events with self reports of tic severity in pediatric and adult tic disorder patients: A prospective longitudinal study. The Journal of Clinical Psychiatry, 65, 426-431.

44.

Holmes

T. H.

Rahe

R. H.

(1967). The Social Readjustment Rating Scale. Journal of Psychosomatic Research, 11, 213-218.

45.

Horesh

Zimmerman

Steinberg

Yagan

Apter

(2008). Is onset of Tourette syndrome influenced by life events? Journal of Neural Transmission, 115, 787-793. doi:10.1007/s00702-007-0014-3

46.

Hsieh

M.-Y.

Lee

W.-I.

Lin

K.-L.

Hung

P.-C.

Chou

M.-L.

Chang

M.-Y.

. . .Wang

H.-S.

(2010). Immunologic analysis and serum heavy metal levels in exacerbated Tourette syndrome. Pediatric Allergy and Immunology, 21(4, Pt. 2), e764-e771. doi:10.1111/j.1399-3038.2010.01009.x

47.

Humphries

M. D.

Stewart

R. D.

Gurney

K. N.

(2006). A physiologically plausible model of action selection and oscillatory activity in the basal ganglia. The Journal of Neuroscience, 26, 12921-12942. doi:10.1523/JNEUROSCI.3486-06.2006

48.

Imperato

Angelucci

Casolini

Zocchi

Puglisi-Allegra

(1992). Repeated stressful experiences differently affect limbic dopamine release during and following stress. Brain Research, 577, 194-199. doi:10.1016/0006-8993(92)90274-D

49.

Inglis

F. M.

Moghaddam

(1999). Dopaminergic innervation of the amygdala is highly responsive to stress. Journal of Neurochemistry, 72, 1088-1094.

50.

Jasnoski

M. L.

Kugler

(1987). Relaxation, imagery, and neuroimmunomodulation. Annals of the New York Academy of Sciences, 496, 722-730.

51.

Kawikova

Grady

B. P. X.

Tobiasova

Zhang

Vojdani

Katsovich

. . .Leckman

J. F.

(2010). Children with Tourette’s syndrome may suffer immunoglobulin A dysgammaglobulinemia: Preliminary report. Biological Psychiatry, 67, 679-683. doi:10.1016/j.biopsych.2009.09.034

52.

Kawikova

Leckman

J. F.

Kronig

Katsovich

Bessen

D. E.

Ghebremichael

Bothwell

A. L. M.

(2007). Decreased numbers of regulatory T cells suggest impaired immune tolerance in children with Tourette syndrome: A preliminary study. Biological Psychiatry, 61, 273-278. doi:10.1016/j.biopsych.2006.06.012

53.

Kirschbaum

Tietze

Skoluda

Dettenborn

(2009). Hair as a retrospective calendar of cortisol production—Increased cortisol incorporation into hair in the third trimester of pregnancy. Psychoneuroendocrinology, 34, 32-37. doi:10.1016/j.psyneuen.2008.08.024

54.

Kirschbaum

Wolf

May

M. T.

Wippich

Hellhammer

D. H.

(1996). Stress- and treatment-induced elevations of cortisol levels associated with impaired declarative memory in healthy adults. Life Sciences, 58, 1475-1483.

55.

Kohen

D. P.

(1995). Coping with the stress of Tourette syndrome in children and adolescents: Use of self-hypnosis techniques. Australian Journal of Clinical & Experimental Hypnosis, 23, 145-157.

56.

Kurlan

(1998). Tourette’s syndrome and “PANDAS”: Will the relation bear out? Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Neurology, 50, 1530-1534.

57.

Kurlan

Johnson

Kaplan

E. L.

(2008). Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: A prospective blinded cohort study. Pediatrics, 121, 1188-1197. doi:10.1542/peds.2007-2657

58.

Kurlan

Kaplan

E. L.

(2004). The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) etiology for tics and obsessive-compulsive symptoms: Hypothesis or entity? Practical considerations for the clinician. Pediatrics, 113, 883-886.

59.

Lataster

Collip

Ceccarini

Haas

Booij

van Os

. . .Myin-Germeys

(2011). Psychosocial stress is associated with in vivo dopamine release in human ventromedial prefrontal cortex: A positron emission tomography study using [18F]fallypride. NeuroImage, 58, 1081-1089. doi:10.1016/j.neuroimage.2011.07.030

60.

Lazarus

R. S.

Folkman

(1984). Stress, appraisal, and coping. New York, NY: Springer.

61.

Leckman

J. F.

(2002). Tourette’s syndrome. Lancet, 360, 1577-1586. doi:10.1016/S0140-6736(02)11526-1

62.

Leckman

J. F.

Bloch

M. H.

Smith

M. E.

Larabi

Hampson

(2010). Neurobiological substrates of Tourette’s disorder. Journal of Child and Adolescent Psychopharmacology, 20, 237-247. doi:10.1089/cap.2009.0118

63.

Leckman

J. F.

Dolnansky

E. S.

Hardin

M. T.

Clubb

Walkup

J. T.

Stevenson

Pauls

D. L.

(1990). Perinatal factors in the expression of Tourette’s syndrome: An exploratory study. Journal of the American Academy of Child & Adolescent Psychiatry, 29, 220-226. doi:10.1097/00004583-199003000-00010

64.

Leckman

J. F.

Goodman

W. K.

Anderson

G. M.

Riddle

M. A.

Chappell

P. B.

McSwiggan-Hardin

M. T.

. . .Pauls

D. L.

(1995). Cerebrospinal fluid biogenic amines in obsessive compulsive disorder, Tourette’s syndrome, and healthy controls. Neuropsychopharmacology, 12, 73-86. doi:10.1016/0893-133X(94)00070-G

65.

Leckman

J. F.

Katsovich

Kawikova

Lin

Zhang

Krönig

. . .King

R. A.

(2005). Increased serum levels of interleukin-12 and tumor necrosis factor-alpha in Tourette’s syndrome. Biological Psychiatry, 57, 667-673. doi:10.1016/j.biopsych.2004.12.004

66.

Leckman

J. F.

King

R. A.

Gilbert

D. L.

Coffey

B. J.

Singer

H. S.

Dure

L. S.

IV . . .Kaplan

E. L.

(2011). Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: A prospective longitudinal study. Journal of the American Academy of Child & Adolescent Psychiatry, 50, 108-118.e3. doi:10.1016/j.jaac.2010.10.011

67.

Lehrer

P. M.

Carr

Sargunaraj

Woolfolk

R. L.

(1994). Stress management techniques: Are they all equivalent, or do they have specific effects? Biofeedback and Self-Regulation, 19, 353-401.

68.

Leslie

D. L.

Kozma

Martin

Landeros

Katsovich

King

R. A.

Leckman

J. F.

(2008). Neuropsychiatric disorders associated with streptococcal infection: A case-control study among privately insured children. Journal of the American Academy of Child & Adolescent Psychiatry, 47, 1166-1172. doi:10.1097/CHI.0b013e3181825a3d

69.

Leung

A. K.

Fagan

J. E.

(1989). Tic disorders in childhood (and beyond). Postgraduate Medicine, 86, 251-252, 257-261.

70.

A. W.

Goldsmith

C.-A. C. W.

(2012). The effects of yoga on anxiety and stress. Alternative Medicine Review: A Journal of Clinical Therapeutic, 17, 21-35.

71.

Lin

Katsovich

Ghebremichael

Findley

D. B.

Grantz

Lombroso

P. J.

. . .Leckman

J. F.

(2007). Psychosocial stress predicts future symptom severities in children and adolescents with Tourette syndrome and/or obsessive-compulsive disorder. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 48, 157-166. doi:10.1111/j.1469-7610.2006.01687.x

72.

Lin

Williams

K. A.

Katsovich

Findley

D. B.

Grantz

Lombroso

P. J.

. . .Leckman

J. F.

(2010). Streptococcal upper respiratory tract infections and psychosocial stress predict future tic and obsessive-compulsive symptom severity in children and adolescents with Tourette syndrome and obsessive-compulsive disorder. Biological Psychiatry, 67, 684-691. doi:10.1016/j.biopsych.2009.08.020

73.

Liposits

Paull

W. K.

(1989). Association of dopaminergic fibers with corticotropin releasing hormone (CRH)-synthesizing neurons in the paraventricular nucleus of the rat hypothalamus. Histochemistry, 93, 119-127.

74.

Lombroso

P. J.

Mack

Scahill

King

R. A.

Leckman

J. F.

(1991). Exacerbation of Gilles de la Tourette’s syndrome associated with thermal stress: A family study. Neurology, 41, 1984-1987.

75.

Manenschijn

van Kruysbergen

R. G. P.M.

de Jong

F. H.

Koper

J. W.

van Rossum

E. F. C.

(2011). Shift work at young age is associated with elevated long-term cortisol levels and body mass index. The Journal of Clinical Endocrinology & Metabolism, 96, E1862-E1865. doi:10.1210/jc.2011-1551

76.

Martino

Chiarotti

Buttiglione

Cardona

Creti

Nardocci

. . . Italian Tourette Syndrome Study Group (2011). The relationship between group A streptococcal infections and Tourette syndrome: A study on a large service-based cohort. Developmental Medicine & Child Neurology, 53, 951-957. doi:10.1111/j.1469-8749.2011.04018.x

77.

Martino

Dale

R. C.

Gilbert

D. L.

Giovannoni

Leckman

J. F.

(2009). Immunopathogenic mechanisms in Tourette syndrome: A critical review. Movement Disorders: Official Journal of the Movement Disorder Society, 24, 1267-1279. doi:10.1002/mds.22504

78.

Martino

Leckman

J. F.

(2013). Tourette syndrome. Oxford, UK: Oxford University Press.

79.

Matousek

R. H.

Dobkin

P. L.

Pruessner

(2010). Cortisol as a marker for improvement in mindfulness-based stress reduction. Complementary Therapies in Clinical Practice, 16, 13-19. doi:10.1016/j.ctcp.2009.06.004

80.

McCall

M. C.

Ward

Roberts

N. W.

Heneghan

(2013). Overview of systematic reviews: Yoga as a therapeutic intervention for adults with acute and chronic health conditions. Evidence-Based Complementary and Alternative Medicine, 2013, Article 945895. doi:10.1155/2013/945895

81.

McEwen

B. S.

(2007). Physiology and neurobiology of stress and adaptation: Central role of the brain. Physiological Reviews, 87, 873-904. doi:10.1152/physrev.00041.2006

82.

McEwen

B. S.

(2010). Stress, sex, and neural adaptation to a changing environment: Mechanisms of neuronal remodeling. Annals of the New York Academy of Sciences, 1204(Suppl. 1), E38-59. doi:10.1111/j.1749-6632.2010.05568.x

83.

Meyer

J. S.

Novak

M. A.

(2012). Minireview: Hair cortisol: A novel biomarker of hypothalamic-pituitary-adrenocortical activity. Endocrinology, 153, 4120-4127. doi:10.1210/en.2012-1226

84.

Mora

Segovia

Del Arco

de Blas

Garrido

(2012). Stress, neurotransmitters, corticosterone and body-brain integration. Brain Research, 1476, 71-85. doi:10.1016/j.brainres.2011.12.049

85.

Moravec

C. S.

McKee

M. G.

(2011). Biofeedback in the treatment of heart disease. Cleveland Clinic Journal of Medicine, 78(Suppl. 1), S20-S23. doi:10.3949/ccjm.78.s1.03

86.

Motlagh

M. G.

Katsovich

Thompson

Lin

Kim

Y.-S.

Scahill

. . .Leckman

J. F.

(2010). Severe psychosocial stress and heavy cigarette smoking during pregnancy: An examination of the pre- and perinatal risk factors associated with ADHD and Tourette syndrome. European Child & Adolescent Psychiatry, 19, 755-764. doi:10.1007/s00787-010-0115-7

87.

Murphy

T. K.

Goodman

W. K.

Fudge

M. W.

Williams

R. C.

Jr. Ayoub

E. M.

Dalal

. . .Zabriskie

J. B.

(1997). B lymphocyte antigen D8/17: A peripheral marker for childhood-onset obsessive-compulsive disorder and Tourette’s syndrome? The American Journal of Psychiatry, 154, 402-407.

88.

Murphy

T. K.

Kurlan

Leckman

(2010). The immunobiology of Tourette’s disorder, pediatric autoimmune neuropsychiatric disorders associated with Streptococcus, and related disorders: A way forward. Journal of Child and Adolescent Psychopharmacology, 20, 317-331. doi:10.1089/cap.2010.0043

89.

Nagai

Cavanna

Critchley

H. D.

(2009). Influence of sympathetic autonomic arousal on tics: Implications for a therapeutic behavioral intervention for Tourette syndrome. Journal of Psychosomatic Research, 67, 599-605. doi:10.1016/j.jpsychores.2009.06.004

90.

O’Connor

K. P.

Brault

Robillard

Loiselle

Borgeat

Stip

(2001). Evaluation of a cognitive-behavioural program for the management of chronic tic and habit disorders. Behaviour Research and Therapy, 39, 667-681.

91.

O’Connor

K. P

Brisebois

Brault

Robillard

Loiselle

(2003). Behavioral activity associated with onset in chronic tic and habit disorder. Behaviour Research and Therapy, 41, 241-249.

92.

O’Connor

K. P.

Gareau

Blowers

G. H.

(1993). Changes in construals of tic-producing situations following cognitive and behavioral therapy. Perceptual & Motor Skills, 77(3, Pt. 1), 776-778.

93.

O’Connor

K. P.

Gareau

Blowers

G. H.

(1994). Personal constructs associated with tics. British Journal of Clinical Psychology, 33, 151-158. doi:10.1111/j.2044-8260.1994.tb01106.x

94.

O’Connor

K. P.

Laverdure

Taillon

Stip

Borgeat

Lavoie

(2009). Cognitive behavioral management of Tourette’s syndrome and chronic tic disorder in medicated and unmedicated samples. Behaviour Research and Therapy, 47, 1090-1095. doi:10.1016/j.brat.2009.07.021

95.

Pacheco

Prado

C. E.

Barrientos

M. J.

Bernales

(2009). Role of dopamine in the physiology of T-cells and dendritic cells. Journal of Neuroimmunology, 216, 8-19. doi:10.1016/j.jneuroim.2009.07.018

96.

Pan

J.-T.

Lookingland

K. J.

Moore

K. E.

(1995). Differential effects of corticotropin-releasing hormone on central dopaminergic and noradrenergic neurons. Journal of Biomedical Science, 2, 50-56.

97.

Pani

Porcella

Gessa

G. L.

(2000). The role of stress in the pathophysiology of the dopaminergic system. Molecular Psychiatry, 5, 14-21.

98.

Pavone

Bianchini

Parano

Incorpora

Rizzo

Mazzone

Trifiletti

R. R.

(2004). Anti-brain antibodies in PANDAS versus uncomplicated streptococcal infection. Pediatric Neurology, 30, 107-110. doi:10.1016/S0887-8994(03)00413-2

99.

Pawlow

L. A.

Jones

G. E.

(2002). The impact of abbreviated progressive muscle relaxation on salivary cortisol. Biological Psychology, 60, 1-16.

100.

Pawlow

L. A.

Jones

G. E.

(2005). The impact of abbreviated progressive muscle relaxation on salivary cortisol and salivary immunoglobulin A (sIgA). Applied Psychophysiology and Biofeedback, 30, 375-387. doi:10.1007/s10484-005-8423-2

101.

Peterson

A. L.

Azrin

N. H.

(1992). An evaluation of behavioral treatments for Tourette syndrome. Behaviour Research and Therapy, 30, 167-174.

102.

Piacentini

Woods

D. W.

Scahill

Wilhelm

Peterson

A.L.

Chang

. . .Walkup

J. T.

(2010). Behavior therapy for children with Tourette disorder: A randomized controlled trial. Journal of the American Medical Association, 303, 1929-1937. doi:10.1001/jama.2010.607

103.

Pittman

D. Q. J.

(2011). A neuro-endocrine-immune symphony. Journal of Neuroendocrinology, 23, 1296-1297. doi:10.1111/j.1365-2826.2011.02176.x

104.

Pringsheim

Doja

Gorman

McKinlay

Day

Billinghurst

. . .Sandor

(2012). Canadian guidelines for the evidence-based treatment of tic disorders: Pharmacotherapy. Canadian Journal of Psychiatry/Revue Canadienne de Psychiatrie, 57, 133-143.

105.

Pruessner

J. C.

Champagne

Meaney

M. J.

Dagher

(2004). Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: A positron emission tomography study using [11C]raclopride. The Journal of Neuroscience, 24, 2825-2831. doi:10.1523/JNEUROSCI.3422-03.2004

106.

Rahe

R. H.

Biersner

R. J.

Ryman

D. H.

Arthur

R. J.

(1972). Psychosocial predictors of illness behavior and failure in stressful training. Journal of Health and Social Behavior, 13, 393-397.

107.

Rahe

R. H.

Mahan

J. L.

Jr. Arthur

R. J.

(1970). Prediction of near-future health change from subjects’ preceding life changes. Journal of Psychosomatic Research, 14, 401-406.

108.

Roessner

Plessen

K. J.

Rothenberger

Ludolph

A. G.

Rizzo

Skov

. . . ESSTS Guidelines Group (2011). European clinical guidelines for Tourette syndrome and other tic disorders. Part II: Pharmacological treatment. European Child & Adolescent Psychiatry, 20, 173-196. doi:10.1007/s00787-011-0163-7

109.

Rollnik

J. D.

Schubert

Dengler

(2000). Effects of a competitive stressor on motor cortex excitability: A pilot study. Stress Medicine, 16, 49-54. doi:10.1002/(SICI)1099-1700(200001)16:1<49::AID-SMI831>3.0.CO;2-E

110.

Rowe

Yuen

H. K.

Dure

L. S.

(2013). Comprehensive behavioral intervention to improve occupational performance in children with Tourette disorder. The American Journal of Occupational Therapy, 67, 194-200. doi:10.5014/ajot.2013.007062

111.

Scahill

Lombroso

Mack

G. J.

Van Wattum

P. J.

Zhang

Vitale

Leckman

J. F.

(2001). Thermal sensitivity in Tourette syndrome: Preliminary report. Perceptual & Motor Skills, 92, 419-432.

112.

Scahill

Woods

D. W.

Himle

M. B.

Peterson

A. L.

Wilhelm

Piacentini

J. C.

. . .Mink

J. W.

(2013). Current controversies on the role of behavior therapy in Tourette syndrome. Movement Disorders, 28, 1179-1183. doi:10.1002/mds.25488

113.

Segovia

Del Arco

de Blas

Garrido

Mora

(2008). Effects of an enriched environment on the release of dopamine in the prefrontal cortex produced by stress and on working memory during aging in the awake rat. Behavioural Brain Research, 187, 304-311. doi:10.1016/j.bbr.2007.09.024

114.

Selye

(1950). Stress and the general adaptation syndrome. British Medical Journal, 1, 1383-1392.

115.

Silva

R. R.

Munoz

D. M.

Barickman

Friedhoff

A. J.

(1995). Environmental factors and related fluctuation of symptoms in children and adolescents with Tourette’s disorder. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 36, 305-312.

116.

Singer

H. S.

Gause

Morris

Lopez

& Tourette Syndrome Study Group (2008). Serial immune markers do not correlate with clinical exacerbations in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Pediatrics, 121, 1198-1205. doi:10.1542/peds.2007-2658

117.

Singer

H. S.

(2013). The Neurochemistry of Tourette syndrome. In Martino

Leckman

(Eds.), Tourette Syndrome. New York: Oxford University Press.

118.

Skoluda

Dettenborn

Stalder

Kirschbaum

(2012). Elevated hair cortisol concentrations in endurance athletes. Psychoneuroendocrinology, 37, 611-617. doi:10.1016/j.psyneuen.2011.09.001

119.

Stalder

Kirschbaum

(2012). Analysis of cortisol in hair—State of the art and future directions. Brain, Behavior, and Immunity, 26, 1019-1029. doi:10.1016/j.bbi.2012.02.002

120.

Stalder

Kirschbaum

Heinze

Steudte

Foley

Tietze

Dettenborn

(2010). Use of hair cortisol analysis to detect hypercortisolism during active drinking phases in alcohol-dependent individuals. Biological Psychology, 85, 357-360. doi:10.1016/j.biopsycho.2010.08.005

121.

Staufenbiel

S. M.

Penninx

B. W. J. H.

Spijker

A. T.

Elzinga

B. M.

van Rossum

E. F. C.

(2013). Hair cortisol, stress exposure, and mental health in humans: A systematic review. Psychoneuroendocrinology, 38, 1220-1235. doi:10.1016/j.psyneuen.2012.11.015

122.

Steinberg

Shmuel-Baruch

Horesh

Apter

(2012). Life events and Tourette syndrome. Comprehensive Psychiatry, 54, 467-473. doi:10.1016/j.comppsych.2012.10.015

123.

Steudte

Kirschbaum

Gao

Alexander

Schönfeld

Hoyer

Stalder

(2013). Hair cortisol as a biomarker of traumatization in healthy individuals and posttraumatic stress disorder patients. Biological Psychiatry, 74, 639-646. doi:10.1016/j.biopsych.2013.03.011

124.

Surwillo

W. W.

Shafii

Barrett

C. L.

(1978). Gilles de la Tourette syndrome: A 20-month study of the effects of stressful life events and haloperidol on symptom frequency. The Journal of Nervous and Mental Disease, 166, 812-816.

125.

Swain

J. E.

Leckman

J. F.

(2005). Tourette Syndrome and Tic Disorders. Psychiatry, 2(7), 26-36.

126.

Swedo

S. E.

Leonard

H. L.

Garvey

Mittleman

Allen

A. J.

Perlmutter

. . .Dubbert

B. K.

(1998). Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: Clinical description of the first 50 cases. The American Journal of Psychiatry, 155, 264-271.

127.

Thind

K. K.

Goldsmith

P. C.

(1989). Corticotropin-releasing factor neurons innervate dopamine neurons in the periventricular hypothalamus of juvenile macaques. Synaptic evidence for a possible companion neurotransmitter. Neuroendocrinology, 50, 351-358.

128.

Tijssen

M. A.

Brown

Morris

H. R.

Lees

(1999). Late onset startle induced tics. Journal of Neurology, Neurosurgery, & Psychiatry, 67, 782-784.

129.

Van Uum

S. H. M.

Sauvé

Fraser

L. A.

Morley-Forster

Paul

T. L.

Koren

(2008). Elevated content of cortisol in hair of patients with severe chronic pain: A novel biomarker for stress. Stress, 11, 483-488. doi:10.1080/10253890801887388

130.

Vedhara

Hyde

Gilchrist

I. D.

Tytherleigh

Plummer

(2000). Acute stress, memory, attention and cortisol. Psychoneuroendocrinology, 25, 535-549.

131.

Verdellen

van

Griendt

Hartmann

Murphy

& ESSTS Guidelines Group (2011). European clinical guidelines for Tourette syndrome and other tic disorders. Part III: Behavioural and psychosocial interventions. European Child & Adolescent Psychiatry, 20, 197-207. doi:10.1007/s00787-011-0167-3

132.

Wagner

C. K.

Eaton

M. J.

Moore

K. E.

Lookingland

K. J.

(1995). Efferent projections from the region of the medial zona incerta containing A13 dopaminergic neurons: A PHA-L anterograde tract-tracing study in the rat. Brain Research, 677, 229-237.

133.

Wenzel

Wurster

Müller-Vahl

K. R.

(2011). Oligoclonal bands in cerebrospinal fluid in patients with Tourette’s syndrome. Movement Disorders: Official Journal of the Movement Disorder Society, 26, 343-346. doi:10.1002/mds.23403

134.

Wile

D. J.

Pringsheim

T. M.

(2013). Behavior therapy for Tourette syndrome: A systematic review and meta-analysis. Current Treatment Options in Neurology, 15, 385-395. doi:10.1007/s11940-013-0238-5

135.

Wilhelm

Peterson

A. L.

Piacentini

Woods

D. W.

Deckersbach

Sukhodolsky

D. G.

. . .Scahill

(2012). Randomized trial of behavior therapy for adults with Tourette syndrome. Archives of General Psychiatry, 69, 795-803. doi:10.1001/archgenpsychiatry.2011.1528

136.

Witzum

Bar-On

Dolberg

O. T.

Kotler

(1996). Traumatic war experiences affect outcome in a case of Tourette’s syndrome. Psychotherapy and Psychosomatics, 65, 106-108.

137.

Wolf

O. T.

(2009). Stress and memory in humans: Twelve years of progress? Brain Research, 1293, 142-154. doi:10.1016/j.brainres.2009.04.013

138.

Wood

B. L.

Klebba

Gbadebo

Lichter

Kurlan

Miller

(2003). Pilot study of effect of emotional stimuli on tic severity in children with Tourette’s syndrome. Movement Disorders, 18, 1392-1395. doi:10.1002/mds.10552

139.

Yamato

Yamasaki

Misumi

Kino

Obata

Aomine

(2002). Modulation of the stress response by coffee: An in vivo microdialysis study of hippocampal serotonin and dopamine levels in rat. Neuroscience Letters, 332, 87-90.

140.

Zalachoras

Houtman

Meijer

O. C.

(2013). Understanding stress-effects in the brain via transcriptional signal transduction pathways. Neuroscience, 242, 97-109. doi:10.1016/j.neuroscience.2013.03.038