Neural Correlates of Self-Regulatory Fatigue and the Role of High Affinity Striatal Dopaminergic Receptors in Tourette Syndrome and Healthy Subjects

NEURAL CORRELATES OF SELF-REGULATORY FATIGUE AND THE ROLE OF HIGH AFFINITY STRIATAL DOPAMINERGIC RECEPTORS IN TOURETTE SYNDROME AND HEALTHY SUBJECTS

Elia Abi-Jaoude, BSc, MSc, MD, FRCPC

A thesis submitted in conformity with

the requirements for the degree of

Doctor of Philosophy

Graduate Department of the Institute of Medical Science, Faculty of Medicine University of Toronto

Neural Correlates of Self-Regulatory Fatigue and the Role of High Affinity Striatal Dopaminergic Receptors in Tourette Syndrome and Healthy Subjects

Elia Abi-Jaoude

Doctor of Philosophy

Institute of Medical Science, Faculty of Medicine University of Toronto

2020

Abstract

Tourette syndrome (TS) is a developmental neuropsychiatric condition characterized by motor and vocal tics. Tics are semi-voluntary movements or vocalizations that are stereotyped, repetitive and non-rhythmic. They usually occur in response to a premonitory urge, and can be suppressed temporarily. TS typically involves multiple comorbidities, in particular obsessive- compulsive disorder, attention deficit/hyperactivity disorder, and emotional dysregulation.

Given the clinical phenomenology, TS has been conceptualized as a syndrome of inhibitory deficits involving motor, cognitive, emotional and behavioral domains. Neuroimaging studies have implicated the cortico-striato-thalamo-cortical circuitry, in particular the striatal dopamine system, and cortical control areas. However, despite numerous studies, findings have been mixed, and a definitive explanation of the neurobiology underlying TS has remained elusive.

The objective of this body of work was to utilize novel neuroimaging approaches in an attempt to identify neural mechanisms that could contribute to the manifestation of TS. In a positron emission tomography (PET) imaging study of the striatum, I investigated striatal D2/3 dopamine

ii receptors in TS using the radioligands [11C]raclopride and [11C]-(+)-PHNO, an agonist that binds preferentially to D3 receptors, thus allowing higher sensitivity and measurement of receptors in a high affinity state. Eleven adults with TS and 11 matched healthy control (HC) participants underwent [11C]raclopride and [11C]-(+)-PHNO PET scans. There were no significant group differences between TS and HC participant binding potentials (BPND) in ventral, motor and associative striatum. In a functional magnetic resonance imaging (fMRI) study of self-regulatory fatigability using an eye blink inhibition paradigm, high-performing HC participants had relatively higher activation in known prefrontal cortex (PFC) control areas – inferior frontal gyrus (IFG), dorsolateral prefrontal cortex (DLPFC), and supplemental motor area (SMA) – whereas self-regulatory fatigability was associated with relatively higher activation in ventromedial PFC, rostroventral anterior cingulate cortex (ACC), and orbitofrontal cortex (OFC). Based on these findings, I carried out a region of interest (ROI) analysis comparing 19 HC and 12 TS participants. There was substantially less percent signal change in the DLPFC/IFG and SMA ROIs in the TS group in comparison to the HC group. These findings suggests that self-regulatory deficits in TS arise from fatigability in cortical control.

iii

Acknowledgments and Contributions

First and foremost, I would like to thank my PhD supervisor and mentor, Dr. Paul Sandor, for being so supportive over the years that I have known him. He introduced me to the field of

Tourette syndrome when I met him initially as a medical student in 2003, and since then I have benefitted from working with him clinically and academically during my residency, fellowship, and since. His openness and support has allowed me to pursue various different projects, in the process gaining broad and rich experiences in various aspects of the field of Tourette syndrome and beyond. As well, I would like to thank my committee members, Dr. Mary Pat McAndrews and Dr. Tomáš Paus, for their invaluable feedback and guidance in developing my project, and support and encouragement throughout the process.

In addition, I am grateful to the many friends and colleagues whom I have consulted both formally and informally, and those who have contributed to various aspects of this work, including: Drs. David Kideckel, Adrian Crawley, David Mikulis, Jane Lawrence-Dewar, Donna

Stewart, Daniel Gorman, Aaron Kucyi, Karen Davis, Conny McCormick, Rostom Mabrouk,

Robyn Stephens, Barbara Segura, Sang Soo Cho, Antonio Strafella, Ignacio Obeso, Sylvain

Houle, Anthony Lang, Pablo Rusjan, Romina Mizrahi, Ariel Graff, Kelly Aminian, Lei Chen,

Patrina Cheung, Ms. Zhe (Ann) Feng, and Ms. Tracy Bhikram. I would also like to thank Mr.

Keith Ta, Mr. Eugen Hlasny, Ms. Alvina Ng, Ms. Laura Nguyen, and Ms. Anusha Ravichandran for technical help with scanning in my studies.

I am deeply indebted to all the individuals who participated in my studies, to my patients from whom I get the most rewarding of interactions and who drive me to continue doing what I do, and from the Tourette syndrome community at large.

I would like to thank the many friends, colleagues, and family members who have been an ongoing source of encouragement and moral support, and who will be pleased with the completion of this thesis. They are too numerous to list here, but as I write this they are definitely in my thoughts. My wife, Dr. Myriam Lafreniere-Roula, has been a constant and valuable sounding board, with her insight, wisdom, love and support since two decades, and my two daughters, Luiza and Chloe, are the joy and light in my life – they make me the fortunate human being that I am. My aunt, Dr. Siham Abu-Jawdeh, valued higher education and the pursuit of knowledge, and encouraged me to pursue my PhD. Unfortunately, she will not be able to fully appreciate the completion of my thesis given her current level of dementia. This thesis is dedicated to you, Siham.

Last but not least, I would like to acknowledge the following sources of funding support that I have had: the University Health Network Department of Psychiatry Research Training

Fellowship, Ontario Mental Health Foundation Research Studentship Award, Ontario Graduate

Scholarship in Science and Technology, University of Toronto School of Graduate Studies

Conference Grant, and the University of Toronto Institute of Medical Science Open Award.

Table of Contents

Acknowledgments and Contributions ...... iv

Table of Contents ...... vi

List of Abbreviations ...... ix

List of Tables ...... xiii

List of Figures ...... xiv

List of Appendices ...... xv

Chapter 1 ...... 1

Introduction and Rationale ...... 1

Chapter 2 ...... 4

Literature Review...... 4

2.1 Introduction to Tourette Syndrome ...... 6

2.2 Clinical Assessment ...... 7

2.2.1 Diagnostic Criteria ...... 7

2.2.2 Screening for Co-morbid Disorders and Behaviors ...... 8

2.2.3 Investigations ...... 9

2.2.4 Patient and Parent Information and Resources ...... 10

2.2.5 Quality of Life...... 11

2.3 PANDAS ...... 12

2.4 Treatment of Tourette Syndrome...... 15

2.4.1 Psychosocial and Behavioural Treatments ...... 17

2.4.2 Pharmacological Treatment ...... 21

2.4.3 Treating Comorbidities ...... 40

2.5 Integrated Clinical Practice ...... 42

2.6 Tourette Syndrome Pathophysiology ...... 44

2.6.1 Dopamine Receptor Imaging ...... 46

2.6.2 Structural Magnetic Resonance Imaging ...... 49

2.6.3 Functional Imaging ...... 50

2.6.4 Summary ...... 63

Chapter 3 ...... 66

Aims and Hypotheses ...... 66

3.1 Striatal D2/D3 Dopamine Receptors in Adults with Tourette Syndrome compared to Healthy Controls: A [11C]-(+)-PHNO and [11C]Raclopride Positron Emission...... 66

3.2 The Neural Correlates of Self-Regulatory Fatigability During Inhibitory Control of Eye Blinking ...... 67

3.3 Activation of Prefrontal Cortical Regions Associated with Self-Regulatory Control in Tourette Syndrome Relative to Healthy Controls ...... 68

Chapter 4 ...... 70

Striatal D2/D3 Dopamine Receptors in Adults with Tourette Syndrome compared to Healthy Controls: A [11C]-(+)-PHNO and [11C]Raclopride Positron Emission Tomography Imaging Study ...... 70

4.1 Chapter Summary ...... 71

4.2 Introduction ...... 72

4.3 Methods ...... 74

4.4 Results ...... 78

4.5 Discussion...... 90

Chapter 5 ...... 93

The Neural Correlates of Self-Regulatory Fatigability During Inhibitory Control of Eye Blinking ...... 93

5.1 Chapter Summary ...... 94

5.2 Introduction ...... 95

5.3 Methods ...... 99

vii

5.4 Results ...... 102

5.5 Discussion...... 108

Chapter 6 ...... 114

Activation of Prefrontal Cortical Regions Associated with Self-Regulatory Control in Tourette Syndrome Relative to Healthy Controls...... 114

6.1 Chapter Summary ...... 115

6.2 Introduction ...... 116

6.3 Methods ...... 121

6.4 Results ...... 125

6.5 Discussion...... 129

Chapter 7 ...... 133

General Discussion ...... 133

7.1 Summary of Findings and Interpretations ...... 134

7.2 Future Directions ...... 147

7.3 Concluding Remarks ...... 150

References ...... 152

Appendices ...... 216

viii

List of Abbreviations

activation likelihood estimation ALE anterior cingulate cortex ACC attention deficit/hyperactivity disorder ADHD

[11C]-(+)-Propyl-Hexahydro-Naphtho-Oxazin [11C]- (+)-PHNO cannabidiol CBD centromedian and parafascicularis complex CMPf

Clinical Global Impression CGI computed tomography CT deep brain stimulation DBS

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition DSM-IV

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, DSM-IV-TR

Text Revision

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition DSM-5 dopamine D2 receptor D2R dorsal anterior cingulate cortex dACC

dorsolateral prefrontal cortex DLPFC double-blind trial DBT family-wise error FWE

F-18 fluoro-deoxyglucose FDG full width at half-maximum FWHM functional magnetic resonance imaging fMRI globus pallidus internus GPi healthy control HC

[123I]iodobenzamide [123I]-IBZM inferior frontal gyrus IFG intravenous immunoglobulins IVIG magnetic resonance imaging MRI

Montreal Neurological Institute MNI near-infrared spectroscopy NIRS

non-displaceable parametric binding potentials BPND obsessive-compulsive disorder OCD

orbitofrontal cortex OFC

Pediatric Autoimmune Neuropsychiatric Disorders Associated with PANDAS

Streptococcal Infections prefrontal cortex PFC positron emission tomography PET quality of life QOL region of interest ROI regional cerebral blood flow rCBF standardized mean difference SMD single-photon emission computed tomography SPECT supplementary motor area SMA delta-9-tetrahydrocannabinol THC

Tourette syndrome TS

Tourette Syndrome Symptom List TSSL transcranial magnetic stimulation TMS ventromedial prefrontal cortex vmPFC

voxel-based morphometry VBM

Yale-Brown Obsessive Compulsive Scale Y-BOCS

Yale Global Tic Severity Scale YGTSS

Yale Global Tic Severity Scale – Total Tic Score YGTSS-TTS

xii

List of Tables

Table 4-1. Demographic and clinical characteristics for Tourette syndrome participants

11 11 Table 4-2. [ C]raclopride and [ C]-(+)-PHNO BPND for TS and HC subjects, with group difference 95% confidence intervals across striatum subregions

Table 6-1. Demographic and Clinical Characteristics of Participants with Tourette Syndrome

Table 6-2. Region of Interest Percent Signal Change in Healthy Control and Tourette Syndrome Participants

xiii

List of Figures

Figure 4-1. HC (N=11) and TS (N=11) group [11C]raclopride (transverse view) and [11C]-(+)- PHNO (coronal view) mean BP images.

Figure 4-2. Individual participant and group average (green horizontal bar) [11C]raclopride 11 (black) and [ C]-(+)-PHNO (red) BPND for HC (circles, N=11) and TS (triangles, N=11) across striatal subregions.

Figure 4-3. Radioligand striatal subregion BPND correlations with YGTSS-TTS

Figure 4-4. Transverse brain slices of statistical parametric map of radioligand main effect with 11 ANOVA (2 x 2, repeated measures): Areas with higher [ C]raclopride BPND are shown in cool 11 colors, and those with higher [ C]-(+)-PHNO BPND in warm colors (FWE-corrected p-value > 0.05).

Figure 5-1. Increase in escape blinks across eye blink inhibition blocks

Figure 5-2. Prefrontal cortical control areas & regions involved in urges and interoceptive processing activated by effortful eye blink control

Figure 5-3. Increase in escape blinks is associated with activity in left OFC and DLPFC

Figure 5-4. High performers (n = 7) show activity in frontal control areas (red), in contrast to activity in interoceptive and likely compensatory frontal areas (blue-green) with low performers (n = 7).

Figure 6-1. Region of Interest Percent Signal Change in Healthy Control (blue) and Tourette Syndrome (red) Participants (excluding one outlier with Tourette syndrome)

xiv

List of Appendices

Yale Global Tic Severity Scale

Yale-Brown Obsessive Compulsive Scale

Chapter 1

Introduction and Rationale

Tourette syndrome (TS) is a developmental neuropsychiatric condition characterized by motor and vocal tics(Martino & Mink, 2013; Mary M. Robertson et al., 2017). Tics are semi-voluntary movements or vocalizations that are stereotyped, repetitive and non-rhythmic. They usually occur in response to a premonitory urge, and can be suppressed temporarily. TS typically involves multiple comorbidities, in particular obsessive-compulsive disorder, attention deficit/hyperactivity disorder, and emotional dysregulation(Martino & Mink, 2013; Mary M.

Robertson et al., 2017). Given the clinical phenomenology, findings from neuropsychological and from neurophysiological studies, TS has been conceptualized as a syndrome of inhibitory deficits involving motor, cognitive, emotional and behavioral domains(Stern et al., 2008a).

Neuroimaging studies have implicated the cortico-striato-thalamo-cortical circuitry, in particular the striatal dopamine system, and cortical control areas(Ganos et al., 2013a). However, despite numerous studies, findings have been mixed, and a definitive explanation of the neurobiology underlying TS has remained elusive(Ganos et al., 2013a). The aim of this dissertation was to utilize novel and more sensitive neuroimaging approaches in an attempt to identify neural mechanisms that could contribute to the manifestation of TS. Specifically, I carried out a positron emission tomography (PET) imaging study of the striatum utilizing an agonist ligand that binds preferentially to D3 receptors, thus allowing higher sensitivity and measurement of receptors in a high affinity state. In addition, I carried out a functional magnetic resonance imaging (fMRI) study investigating neural mechanisms involved in self-regulatory fatigability,

1 2 thus allowing investigation of prefrontal cortical control under conditions sensitive to inhibitory failure.

Striatal dopamine receptors have long been considered as involved in the pathophysiology of TS due to pharmacological and anatomical evidence(Buse et al., 2013; Hugh Rickards, 2009; Segura

& Strafella, 2013). As such, the dopamine system has been by far the main focus of nuclear imaging studies. However, human PET studies in patients with TS have yielded inconsistent results(Buse et al., 2013; Hugh Rickards, 2009; Segura & Strafella, 2013). Further, positive studies have often involved confounders such as age differences between comparison groups, medication effects, small sample sizes, or multiple comparisons without adequate statistical correction.

Receptor nuclear imaging studies in TS have typically focused on D2 dopamine receptors, and have utilized dopamine receptor antagonists such as the ligand [11C]raclopride. A more recently developed ligand, [11C]- (+)-Propyl-Hexahydro-Naphtho-Oxazin ([11C]- (+)-PHNO), is an agonist with preferential binding to D3 dopamine receptors. It thus allows for the evaluation of differences in D2 versus D3 receptors. Furthermore, since [11C]- (+)-PHNO is an agonist, it can allow the measurement of dopamine receptors in their high affinity state, thus providing an opportunity to investigate whether striatal dopamine receptor affinity is involved in the pathophysiology of TS(Ginovart et al., 2006; Sibley et al., 1982; Willeit et al., 2006). Thus, I carried out a PET study in TS using the ligands [11C]raclopride and [11C]- (+)-PHNO.

Cortical control regions have been found to be implicated in TS, though there are several inconsistent and even contradictory findings(Ganos et al., 2013a; Georgina M. Jackson et al.,

2015; Polyanska et al., 2017; Stern et al., 2008a; Worbe, Lehericy, et al., 2015). These divergent findings may be a result of a multitude of variables that differ across studies including participant demographic and clinical characteristics, study design, and data analysis. Further complications come from considerations around interpretations of study results. In particular, it can be difficult to judge whether brain findings are causally related to clinical symptoms on the one hand, or if they are the result of compensatory or adaptive changes.

A particularly interesting question relates to the capacity of patients with TS to sustain self- regulatory control in the face of ongoing demands, and the corresponding neural correlates.

Behavioral studies show evidence that self-regulatory capacity has limited reserve, leading to fatigue and decreased performance(Baumeister & Heatherton, 1996; Hagger et al., 2010). As such, initial efforts are followed by a shift in motivation, emotion, and attention to more immediately rewarding action(Inzlicht et al., 2014). This may be particularly relevant in TS, since patients are often exerting effort to suppress tic symptoms, and this may impact resources available for other self-regulatory demands. In addition, the multiple comorbidities in TS, including OCD, ADHD, and emotional dysregulation, likely further contribute to self-control exigencies. As such, patients with TS may be particularly susceptible to self-regulatory fatigability, and evaluating this during self-control tasks may help shed light on executive capacity and related neural mechanisms in TS. Thus, I carried out an fMRI study of self- regulatory fatigability using an eye blink inhibition paradigm in HC and TS participants.

Chapter 2

Literature Review

Sections 2.1 to 2.5 of this chapter are edited excerpts from a published book chapter titled,

“Tourette Syndrome: A Model of Integration”, in Handbook of Integrative Clinical Psychology,

Psychiatry and Behavioral Medicine: Perspectives, Practices and Research, Springer Publishing, with co-authors David Kideckel, Robyn Stephens, Myriam Lafreniere-Roula, and Paul

Sandor(Abi-Jaoude et al., 2009). Copyright permissions have been granted.

Section 2.4.2.3 of this chapter is an edited excerpt from a study titled, “Preliminary Evidence on

Cannabis Effectiveness and Tolerability for Adults With Tourette Syndrome”, which has been published in The Journal of Neuropsychiatry and Clinical Neurosciences, with co-authors Lei

Chen, Patrina Cheung, Tracy Bhikram, and Paul Sandor(Abi-Jaoude et al., 2017). Copyright permissions have been granted.

The introductory part of section 2.6 of this chapter is an edited excerpt from an article titled,

“Uncovering the Complexity of Tourette Syndrome, Little by Little”, which has been published

5 in The British Journal of Psychiatry, with co-author Daniel Gorman(Gorman & Abi-Jaoude,

2014). Copyright permissions have been granted.

Section 2.6.1 of this chapter is an excerpt from a study titled “Similar Striatal D2/D3 Dopamine

Receptor Availability in Adults with Tourette Syndrome compared to Healthy Controls: A [11C]-

(+)-PHNO and [11C]Raclopride Positron Emission Tomography Imaging Study” has been published in Human Brain Mapping, with co-authors Barbara Segura, Ignacio Obeso, Sang Soo

Cho, Sylvain Houle, Anthony Lang, Pablo Rusjan, Paul Sandor, and Antonio Strafella(Abi-

Jaoude et al., 2015). Copyright permissions have been granted.

2.1 Introduction to Tourette Syndrome

Tourette Syndrome (TS) is a familial neurodevelopmental disorder with childhood onset that manifests with tics. Tics are semi-voluntary movements or vocalizations that are stereotyped, repetitive and non-rhythmic. They usually occur in response to a premonitory urge, and can be suppressed temporarily. The first case was reported by Itard(Itard, 2006) and the first series of cases was published by George Gilles de la Tourette in 1865(Gilles de la Tourette, 1885), prompting his mentor Charcot to give the disorder its eponymous name. This complex disorder presents with a combination of involuntary behaviours in the context of otherwise normal neurological examination. Although not considered a part of the core symptoms a variety of psychiatric and psychological symptoms such as attention deficit/hyperactivity disorder

(ADHD), obsessive-compulsive disorder (OCD), anxiety, anger control problems and learning disabilities are frequently associated with TS. The clinical impact of TS typically extends beyond the patient and symptoms may affect the relationships with family and influence the educational and work milieu. This is more often the case in the presence of one or more comorbid conditions. Ideally, a multidisciplinary approach is necessary in order to provide an appropriate assessment and intervention for the more complex patients. Margaret Mahler’s formulation of TS, written in 1943 is still accurate: “While we believe we are dealing with an underlying organic pathology of the central nervous system, this somatic nucleus is acted upon and activated by psychodynamic forces…”(Mahler, 1949). The evidence accumulated since then has supported this view in ever greater detail. Until recently, TS was considered a rare disorder, however we now know that an average high school population includes 1 to 3 % of children with

TS, as reviewed by Robertson(M.M. Robertson, 2003). It is therefore clear that physicians and

7 psychologists encounter a significant number of patients with TS, although they often do not present with tics as the first, or even the main complaint.

2.2 Clinical Assessment

TS manifests with semi-voluntary movements and sounds, which are in principle detectable in an office setting during interview and examination. One needs to be aware that patients have the ability to suppress tics to a variable extent, sometimes for a few minutes, but often for much longer. The examiner needs to employ peripheral vision, since patients commonly suppress tics until the examiner in not looking at them directly e.g. while the examiner is taking notes.

Similarly, the examiner needs to be alert to signs of suggestibility; in other words, when asking about specific tics, one should note whether the patient exhibits the tic shortly after it was mentioned. It is useful to employ one of the tic severity rating instruments e.g. the Yale Global

Tic Severity Scale (YGTSS)(Leckman et al., 1989; McGuire et al., 2018; Eric A. Storch et al.,

2005) that can serve both as a semi-structured guide to the assessment of tics and provide a means of recording the severity. There are several other tic severity rating scales, but none is as widely used as YGTSS. The advantages and shortcomings of the various scales have been reviewed by various groups(Martino et al., 2017; Walkup et al., 1992).

2.2.1 Diagnostic Criteria

Following are the diagnostic criteria for TS, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition(Diagnostic and Statistical Manual of Mental Disorders, Fifth

Edition (DSM-5) by American Psychiatric Association (2013) Paperback, n.d.):

A. Both multiple motor and one or more vocal tics have been present at some time during the

illness, although not necessarily concurrently.

B. The tics may wax and wane in frequency but have persisted for more than 1 year since first

tic onset.

C. The onset is before age 18 years.

D. The disturbance is not due to the direct physiological effects of a substance (e.g., cocaine) or

another medical condition (e.g., Huntington's disease, postviral encephalitis).

Differential diagnosis for TS include motor stereotypies, chorea, dystonia, ataxia, seizure disorder, tardive dyskinesia, and conversion disorder.

2.2.2 Screening for Co-morbid Disorders and Behaviors

Although many cases of TS do not come to medical attention, the ones that present in the medical office often struggle with additional behavioural problems. The data from the general practice setting is not available, however Freedman et al. published observations regarding 3500

9 cases in various specialty clinic across the globe(Freeman et al., 2000). Approximately 60% of the sample met diagnostic criteria for ADHD and 30% met criteria for OCD. Anger control problems were present in about one third of the cases. Sleep problems and anxiety were each a complicating factor in 25% of cases. Clinical assessment must include screening for the common behavioural disorders. In addition, learning disorders, fine and/or gross motor coordination problems and speech abnormalities are present with increased frequency and must therefore be included in the screening process. Expertise from several disciplines including psychology, speech pathology and occupational therapy must complement a medical and psychiatric assessment if all of the above potential problems are to be detected, diagnosed and addressed with appropriate interventions.

2.2.3 Investigations

A typical presentation which includes a typical gradual onset of simple motor tics usually around the face, head and neck with phonic simple tics following some months or years later requires no investigations. Sudden onset of severe, simple and complex tics, especially if accompanied by history of simultaneous onset of obsessive compulsive symptoms starting in the pre-pubertal period raises the possibility of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS; discussed in section2.3). This is not an easy diagnosis to make. One needs to obtain evidence of documented streptococcal infection within a few weeks prior to onset of symptoms i.e. a positive throat culture combined with an appropriate antibody profile based on serial antibody titers.

2.2.3.1 Medication-related

Baseline investigations that include liver enzyme profile, glucose, lipid profile, haematology and electrocardiogram are recommended before commencing pharmacological treatment. It is also necessary to monitor weight and height in order to detect early any departure from normal (or baseline) body mass index.

2.2.3.2 Learning-related

When learning disabilities are suspected based on uneven performance in different subjects, a psychoeducational, or more comprehensive neuropsychological testing is recommended to determine the specific profile of strengths and weakness. Such information is invaluable in developing an individualized education plan and can also be very useful when selecting an appropriate psychotherapeutic intervention.

2.2.4 Patient and Parent Information and Resources

Once the diagnosis has been made, educating patients about the nature of their disorder is the next and often the most important intervention. Advice offered in the office is often condensed and overwhelming to the patients and their families. Written materials provide opportunity to read and absorb the information at an individualized pace. Reliable web-based information can be found on the websites of Tourette Canada http://www.tourette.ca/ and Tourette Association of

America http://www.tourette.org/ with regard to diagnosis, treatment and research. There is also assistance in locating professionals in various communities who are willing and interested in seeing TS patients. These websites also offer a wealth of advice on how to deal with the education system, workplace and insurance in various jurisdictions.

2.2.5 Quality of Life

There have been a few studies attempting to examine how TS patients cope. It appears that tics are perceived as diminishing the on quality of life (QOL) by only a minority of patients with pure TS. The presence of OCD, ADHD and other behavioural or learning problems has a much greater impact on the QOL than tics(Bawden et al., 1998; Stokes et al., 1991; Thibert et al.,

1995). Storch et al measured the functional impairment due to tics and non-tic causes separately in a group of patients with TS(E.A. Storch, Lack, et al., 2007). About 70% of the patients were noted to have functional impairment due to non-tic causes. There was a moderate inverse relationship between QOL and self-reported tic severity in this group of children(Price et al.,

1985; E.A. Storch, Merlo, et al., 2007).

2.3 PANDAS

The concept of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal

Infections (PANDAS) has been discussed in numerous reviews(Dale, 2005; D.L. Gilbert, 2009;

Lombroso & Scahill, 2008; Moretti et al., 2008; Muller, 2007; Nielsen et al., 2019; Scahill et al.,

2006a; H.S. Singer & Loiselle, 2003; Snider & Swedo, 2004; SWAIN et al., 2007; Wilbur et al.,

2019). Although the possibility of links between infections and symptoms of TS and OCD had been raised in the late 1800s, most of the attention devoted to this has been in the past 25 years.

After noticing a significant rise in both streptococcal infections and children presenting with new onset tics, Kiessling and colleagues found a several-fold increase in anti-neuronal antibodies, reacting with frozen human caudate head sections, in children with obsessive-compulsive symptoms, TS and other movement disorders(Kiessling et al., 1993, 1994).

Swedo and colleagues described a series of 50 clinical cases of PANDAS and they proposed the following five diagnostic criteria based on their clinical observations(Swedo et al., 1998):

Presence of OCD and/or tic disorder – the patient must meet lifetime diagnostic criteria for OCD or tic disorder; Pediatric onset – symptoms first evident between ages 3 and onset of puberty;

Episodic course of symptom severity – clinical course consists of abrupt onset psychiatric symptoms or dramatic symptom exacerbation; Association with GABHS (Group A beta- hemolytic streptococcus) infection – lifetime pattern of symptom exacerbation must be temporally related to GABHS infection; Association with neurological abnormalities – i.e. abnormal neurological exam, e.g. choreiform movements during exacerbation.

The presumptive pathophysiology of PANDAS involves ‘molecular mimicry’, whereby, in predisposed individuals, antibodies developed by the immune system in response to infection with group A β-hemolytic streptococci cross-react with neurons in the basal ganglia, resulting in movement disorders, including symptoms of TS. However, there have been mixed results from studies of serum titers of anti-streptococcal antibodies(SWAIN et al., 2007). There have been some intriguing experiments in which tic-like movements developed in rats that the brains of which were infused with sera of TS patients having high autoantibody titers, though, here again, there have been some inconsistent results(Scahill et al., 2006a).

Strong epidemiological evidence in support of PANDAS came from a case-control study that found an increased likelihood of prior streptococcal infection in children newly diagnosed with

TS, tic disorder or OCD(Mell et al., 2005). The risk of TS was found to be 13.6 times higher in those with multiple group A β-hemolytic streptococcal infections in the preceding year. This was later replicated by another group using a larger sample, although the associations were not as strong (odds ratio 1.54)(Leslie et al., 2008). Of note, the more recent study also found a positive association between prior streptococcal infection and diagnoses of ADHD and major depressive disorder. Thus, given the lack of negative controls, the specificity of these associations is brought into question.

Two interesting prospective studies by the TS Study Group yielded mixed results(Kurlan et al.,

2008; H.S. Singer et al., 2008). In the prospective case-control study, patients meeting criteria

14 for PANDAS were found to have a higher rate of symptom exacerbation periods, and although there was a temporal association between streptococcal infection and these, most exacerbation periods did not have such a temporal relationship(Kurlan et al., 2008). In the prospective cohort study, there was no correlation found between clinical exacerbation episodes and an array of immune markers in cases of PANDAS(H.S. Singer et al., 2008).

There have been a number of attempts to treat cases of PANDAS. In the first such study, 37 children meeting criteria for PANDAS were randomized to prophylactic penicillin or placebo in an 8-month double-blind trial(Garvey et al., 1999). There was no difference between penicillin and placebo in obsessive-compulsive or tic symptoms, but this could have been related to the lack of the antibiotic prophylaxis on the occurrence of infections. In a later double-blind trial, 23 children randomized to either penicillin or azithromycin prophylaxis had lower rates of streptococcal infection and neuropsychiatric exacerbation episodes compared to their baselines during the year prior to the study(Snider et al., 2005). An important limitation is the lack of a placebo arm in this study.

Other studies have attempted plasma exchange and intravenous immunoglobulins (IVIG) in cases of PANDAS. In the first double-blind trial, 30 children with PANDAS were randomized to a single course of either plasma exchange, IVIG, or sham IVIG(Perlmutter et al., 1999). Both plasma exchange and IVIG resulted in significant improvements in obsessive-compulsive and tic symptoms after one month, and these improvements were maintained at one-year follow-up. A subsequent 14-week double-blind trial involving 30 patients with tic disorders not meeting

15 criteria for PANDAS found no improvement of tic severity with IVIG relative to placebo(Hoekstra et al., 2004).

In summary, PANDAS remains a controversial diagnosis at this time. Although it is possible that immune factors may play a role in a small proportion of cases of TS, there is limited evidence to support routine PANDAS-related investigations or treatment at this time.

Unfortunately, a study has suggested that prophylactic antibiotics have been inappropriately used in the community in the treatment of cases falling short of the full PANDAS criteria(Gabbay et al., 2008). Until further research establishes more clearly this as a diagnostic entity and appropriate treatments, it would likely be prudent to refer suspected cases of PANDAS to specialty clinics.

2.4 Treatment of Tourette Syndrome

TS is often mild and therefore no treatment is required. In general terms, one needs to initiate treatment when the symptoms are distressing and/or when symptoms interfere with function. The tolerance for symptoms varies greatly among individuals and much depends on the underlying personality, the family attitude and social context. Hence, there can be no absolute rules about severity of symptoms that require treatment. This very personal decision will be made by each patient/family, using the advice from his health professional after considering the specific factors in each situation at that given time. Since in the majority of patients TS symptoms improve

16 substantially by early adulthood, often providing a clear diagnosis and information about etiology, prognosis and treatment options is reassuring and may be the only intervention required.

In many patients with TS, the main difficulties may arise not so much from the tics themselves but from comorbid conditions, namely OCD, ADHD and learning difficulties. In fact, for many patients with TS, no specific treatment for tics is required beyond thorough psychoeducation and reassurance for patient and family, as well as linking to community resources for those interested(T. K. Murphy et al., 2013; C. Verdellen et al., 2011). Active treatment of tics may be considered when these are impairing due to a number of different reasons. This may be related to the particular types of tics, as well as to the number, frequency, intensity and complexity of the tics. Problematic tics may interfere with a person’s ability to function, for example, frequent head-jerking or forceful blinking may interfere with a child’s ability to read. Another potential consequence may be pain or tissue damage resulting from tics (accidental or self-inflicted), such as headaches or repetitive strain injury resulting from very frequent or intense head-jerking. In addition, certain tics can be socially impairing and this can occur in social settings that are not practically amenable to psychoeducation. When used judiciously, the different treatment options for tics can be quite beneficial for patients. In general, the least invasive of the treatments should be offered first where feasible and available, keeping more invasive interventions only when really necessary and after careful consideration of the potential risks and benefits. Another important consideration is that of the waxing and waning course of tics, which should be taken into account when trying to decide if a certain intervention was really helpful or if the improvement was just coincidental with the treatment.

2.4.1 Psychosocial and Behavioural Treatments

When a parent receives a diagnosis of Tourette Syndrome for their child, the response often ranges from relief (having an understanding and explanation of why their child has been displaying unusual and uncontrollable sounds and motor movements), to disbelief or denial

(parents are sometimes oblivious of their child’s tics and will strive to explain or justify the behaviours within the normal spectrum of childhood), to anger or resentment (looking to

“blame” the genetic disposition of TS on one spouse or the other). There are also families that have exhausted multiple medical pathways prior to arriving at the diagnosis that are coming to the clinic overwhelmed with prior potential explanations, discouraged at the lack of benefit or improvements they have observed, and frustrated with the daily difficulties and challenges they have encountered with their child at school, socially and within their own home and family relationships. Thus, providing good empirically based, comprehensive psychoeducation for patients with TS is imperative, and is a necessary component of treatment, with the intention of engaging the whole family and those outside the family that are involved with the patient’s well- being, with factual knowledge including the natural course of TS (how tics can wax and wane over time, developmental expectations), an understanding of the possible comorbid disorders, how the symptoms could be demonstrated in the patient’s daily life, and how important it is to adapt a flexible approach to the patient’s needs. Importantly, the clinician can help provide understanding, constructive strategies and treatment solutions that will endeavor to improve different spheres of the patient’s world, including balancing, improving or sometimes repairing intra-family relationships(A. L. Peterson & Azrin, 1992; B. S. Peterson, 1996). Indeed,

18 psychoeducation is often all that is needed at the time for tic symptoms. Patients and families can be reassured that children will usually outgrow their tics as they mature. Those around the patients should also encouraged to ignore the tics, which can alleviate much stress from a parent repeatedly insisting that a patient stop ticking. Further, it can be helpful for psychoeducation to be provided in the school setting, to teachers and students, in order to increase awareness, understanding and tolerance of tics.

Since the early studies in TS, behavioural treatments have focused on the reduction or elimination of unwanted or interfering motor and vocal tics, while including a strong component of supportive psychoeducational therapy for both the child and their families aimed at understanding the nature, course and range of tics and tic-like behaviours. The most consistently reported approaches are habit reversal training and exposure and response prevention.

2.4.1.1 Habit Reversal Training

Habit reversal training is the most widely-studied behavioral intervention for tic disorders and

TS, and it represents the most extensive body of research and with the highest level of consistently positive results for successful reduction of both motor and vocal tics, both as an adjunctive therapy to improve the efficacy of medication, and as an alternative treatment to pharmaceuticals for those unwilling or unable to tolerate medication. Comprehensive behavioral intervention for tics, based on habit reversal training, has demonstrated efficacy in two well-

19 designed, large, randomized controlled trials(Piacentini et al., 2010; Wilhelm et al., 2012). Of the five components comprising habit reversal intervention (awareness training, relaxation training, competing response training, contingency management and generalization training), it is commonly the competing response procedure that is most effectively applied in the TS population. Competing response in therapy would consist of intentional isometric tensing of muscles in the opposite direction of the target tic.

2.4.1.2 Exposure and Response Prevention

Habituation has been reported as a strategy that can effectively decrease tic frequency and severity in individuals with TS through exposure to premonitory sensations and response prevention of tics(Hoogduin et al., 1997; Leckman et al., 1993; C. W. Verdellen et al., 2008,

2004). The focus of the therapy is aimed at increasing personal awareness of premonitory urges associated with tics, and initiating suppression of the sensations or urges to tic, for as long as possible.

2.4.1.3 Social Risks and Interventions

While not all children and adolescents with TS have difficulties in the realm of establishing and maintaining friendships, in peer relationships and with maladaptive social behaviour, there are

20 some who struggle to have positive social experiences throughout their developmental years.

The acceptance and understanding of tics among the classmates and peers of the child with TS is not always automatic, and unfortunately as the child with tics reaches their mid elementary years, when tics tend to increase, and fellow students developmentally become increasingly aware of individual differences among themselves, there is the heightened risk of peer rejection, avoidance from other students, and increased emotional stress on the child with TS. A broad range of studies have described children with TS as being less socially accepted by their peers than other students, however there remains uncertainty whether the negative social implications are directly related to the tics themselves, or whether problems with peer relations are equally a reflection of the child’s negative self-perceptions and the additional behavioral risks associated with commonly comorbid psychiatric disorders, such as ADHD, OCD, anxiety, learning disabilities, and rages and sleep disorders(Stokes et al., 1991). Most commonly, children with TS and comorbid ADHD present with the highest prevalence of behavioral and social problems, and tend to represent the greatest risk group for poor social adaptation compared to those with TS alone(Bawden et al., 1998).

Providing educational in-services and educational materials to the child’s school and classmates has been shown to be beneficial to elevating or improving the acceptance of a child’s tics among their peers and teachers, particularly when there is an emphasis on providing an understanding of the involuntary nature of tics, and the otherwise “normal” or positive attributes of the child with

TS. In addition to focusing on the tics in TS, it is also important to clearly identify any comorbid psychiatric disorders and to address the specific symptomatology that may present in the classroom or within peer related situations, in an effort to reduce potentially negative impact of

21 impulsivity, irritability, “short fused temper”, hyperactivity, perfectionism, compulsive or obsessive behaviours, which could be detrimental to the child’s acceptance and interactions with their peers.

Many psychosocial therapies, including counseling and psychoeducation for families, have been shown to provide positive alternative and adjunctive treatment interventions to psychopharmachology, with the focus on understanding the condition, improving the child’s self-esteem and social functioning, and reduction of interfering tics or maladaptive behaviours, however there remains a paucity of studies demonstrating objective data to support direct improvement in peer acceptance following peer education programs. Engagement of the parents, siblings, extended family, teachers and support workers in the educational process as well as eliciting support and understanding for ongoing therapies is essential, and provides the most promising likelihood of a positive accepting environment for the child across multiple spheres.

The family who has the benefit of working with a multidisciplinary team will be well-prepared to work with their child across all aspects of their daily functioning, with an enriched experience gained from each professional and the opportunity to develop an extensive understanding of the complexities entailing a diagnosis of TS.

2.4.2 Pharmacological Treatment

As discussed, receiving a clear diagnosis and an explanation about the etiology and prognosis of this condition is usually reassuring to patients and their families. Although there is good evidence that comprehensive behavioral intervention for tics based on habit reversal training is a safe and efficacious approach to reducing tic frequency and intensity in children(Piacentini et al.,

2010) and adults(Wilhelm et al., 2012), it does not work for all patients. As well, in most areas there is presently a shortage or a complete lack of trained therapists capable of administering the treatment. When psychosocial intervention or behavioural therapy do not seem to be sufficient, or are not readily available, one has to consider pharmacological intervention. A cost benefit analysis is necessary in order to decide when to introduce medications. The hoped-for benefits and potential adverse effects of each medication are well-known and documented. Unfortunately, the potential consequences of not treating symptoms that have a significant impact on the functioning and quality of life of patients with TS are often not fully appreciated. This is particularly important when treating children or adolescents who are in their formative years.

The untreated symptoms may attract unwanted attention, teasing, ridicule even ostracism and undermine the self-image and self-confidence of the patient. Further complications may include impaired relationships not only with peers, but also teachers, parents and siblings. As well, tics can be severe enough such that they interfere with function, cause pain, or even tissue injury.

Only about 15% of the clinical TS population presents with uncomplicated TS, while over half of patients deal with co-morbid ADHD and approximately a third have co-morbid OCD. In addition, sleep problems, anger control problems and anxiety are present in about 25%, 30% and

25% of clinic patients respectively. Often, several of these require pharmacotherapy; hence multiple medications may sometimes be needed. Naturally, potential adverse effects, drug-drug

23 interactions and detrimental effects on the TS symptoms must be considered when deciding which medications to use.

Numerous different psychopharmacological approaches have been used in TS, but the mainstay medication treatments of tics have been the dopamine antagonists, also known as antipsychotics, as well as the α2-agonists. The evidence for these two classes of medications is reviewed here, with emphasis on double-blind and controlled trials. Other, less commonly-used medications for tics are reviewed subsequently.

2.4.2.1 Dopamine antagonists

The dopamine antagonists comprise a large class of medications that are highly variable with respect to their receptor binding profiles. These medications are known as antipsychotics because of their common effect of decreasing hallucinations and delusions in psychotic disorders via their D2-antagonist effects. The high potency antipsychotics, that is, those that bind relatively strongly to the post-synaptic D2 receptor, have been found to be most effective in the treatment of tics.

The first published case of using a dopamine antagonist in TS was a 1961 paper by Seignot(H.

Rickards et al., 1997), a French psychiatrist who had a dramatically successful result with a trial

24 of haloperidol in a patient with very severe tics who had undergone numerous prior treatments including a lobotomy. This generated much interest in using haloperidol and other dopamine antagonists in TS. In an early double-blind trial (DBT) on four adolescent patients who had failed prior treatments, haloperidol reduced tic significantly in comparison to diazepam(Connell et al., 1967). Another small double-blind controlled trial of nine patients with TS found both haloperidol and pimozide significantly reduced tics compared to placebo, and improvements could be maintained up to 20 months later in most patients(Ross & Moldofsky, 1978). A subsequent placebo-controlled crossover DBT involving twenty young adult patients showed a significant improvement of tics with pimozide(A. K. Shapiro & Shapiro, 1984). A retrospective review(H.S. Singer et al., 1985) and a long-term uncontrolled study(Goetz et al., 1984) identified fluphenazine as another high potency antipsychotic effective against tics. In a small placebo- controlled crossover DBT involving 10 subjects, fluphenazine, trifluoperazine and haloperidol were all equally efficacious(Borison et al., 1982). In contrast, a small DBT of clozapine, a low- potency antipsychotic failed to show any therapeutic benefit in TS subjects(Caine et al., 1979).

A placebo-controlled study involving 57 patients with TS showed both haloperidol and pimozide to be superior to placebo(E. Shapiro et al., 1989), with haloperidol being slightly more effective.

However, a later placebo-controlled cross-over DBT of 22 child and adolescent TS subjects surprisingly showed effectiveness of pimozide but not haloperidol, which was limited by side- effects(F. R. Sallee et al., 1997). The lack of efficacy of haloperidol in this trial conflicts with previous trials involving haloperidol and with a large body of clinical experience supporting the efficacy of haloperidol in tic suppression.

As newer antipsychotics became available, there was interest in using these in TS in an attempt to avoid known side effects, especially dystonia, akathisia and parkinsonism(Kendall, 2011). A small controlled crossover trial involving only four subjects with severe TS favored olanzapine over pimozide(Onofrj et al., 2000), but this has yet to be replicated in a larger study. Otherwise, there have been only open label studies with olanzapine since then(C.L. Budman et al., 2001;

McCracken et al., 2008; Stamenkovic et al., 2000; Stephens et al., 2004). Two 8-week controlled DBTs, one involving 48 subjects(Dion et al., 2002) and the other involving 34 subjects(Scahill et al., 2003) with wide age ranges, demonstrated effectiveness of risperidone as compared to placebo. Risperidone was also shown to be at least as effective as pimozide in a 12- week DBT of 50 adolescent and adult patients(Bruggeman, 2001), as well as an 8-week crossover DBT of 19 child and adolescent patients(Donald L Gilbert et al., 2004). A single-blind study also showed similar effectiveness of riperidone to clonidine(Gaffney et al., 2002). A 56- day placebo-controlled pilot DBT of ziprasidone in 28 child and adolescent patients showed effectiveness in treating tics(F. R. Sallee et al., 2000). Otherwise, only case reports have been published for quetiapine(Chan-Ob et al., 2001; de Jonge et al., 2007; Mukaddes & Abali,

2003)(Chan-Ob et al., 2001; de Jonge et al., 2007; Mukaddes & Abali, 2003). Finally, there have been two DBTs showing efficacy of aripiprazole for tics(F. Sallee et al., 2017; Yoo et al., 2013).

Other, less-commonly used dopamine antagonists have also been studied in TS. Metoclopramide is typically used as an antiemetic and gastrointestinal prokinetic(Albibi & McCallum, 1983).

After initial open label trials(Acosta & Castellanos, 2004), an 8-week randomized placebo- controlled DBT in 27 children and young adolescents, metoclopramide was effective in reducing tics(Nicolson et al., 2005). Tiapride, an antipsychotic not available in North America, was found

26 to be superior to placebo in a 6-week trial involving 27 children(Eggers et al., 1988), replicating a similar earlier finding in TS patients in a DBT involving a mix of patients with various movement disorders(Chouza et al., 1982). Sulpiride is another antipsychotic not available in

North America but widely used for treatment of TS in UK and Europe. Its efficacy is supported only by a retrospective review(M.M. Robertson et al., 1990). Tetrabenazine, a dopamine antagonist that also depletes presynaptic monoamines, has been the subject of an extensive review(Porta et al., 2008). It was initially tried in TS some 35 years ago(Sweet et al., 1974), and has later shown positive results in long-term follow-up studies(J. Jankovic & Beach, 1997; J. M.

Jankovic et al., 1984; J. Jankovic & Orman, 1988) and retrospective chart reviews(Kenney et al.,

2007; Paleacu et al., 2004), but there has not been a report of a controlled study with tetrabenazine in TS to date.

Dopamine receptor antagonists are associated with a number of different adverse effects, though much of the knowledge about these comes from their use in populations with psychotic disorders(Correll, 2008; Stroup et al., 2006). Of particular concern has been the group of neurological side effects known as extrapyramidal symptoms (EPS). These include akathesia, dystonic reactions, parkinsonism, and dyskinesia, which can occur as tardive dyskinesia, a result of long-term dopamine antagonism, which occasionally may not be reversible. Further possible effects include cognitive dulling, depression, and anxiety. Tetrabenazine acts by depleting dopamine from the presynaptic vesicles hence it can precipitate pronounced depression in vulnerable patients. It is also associated with EPS. All of the above agents have been associated with neuroleptic malignant syndrome, which is an uncommon but serious neurological side effect that can be fatal if untreated.

Another important group of potential adverse effects due to dopamine receptor anatagonists are metabolic side effects, which include weight gain, diabetes, dyslipidemia, and potential vascular consequences if exposure is of long duration (month and years). It is to be noted that tetrabenazine does not increase appetite, nor is it associated with metabolic abnormalities.

Changes in cardiac electrical conduction leading to prolongation of the QTc interval, with the risk of sudden cardiac death, is another concern, particularly for higher doses of pimozide and ziprasidone. A retrospective cohort study found a dose-related increased relative risk of sudden cardiac death among users of dopamine receptor antagonists(Ray et al., 2009; Schneeweiss &

Avorn, 2009). Other possible side effects, particularly for lower potency antipsychotics, include sedation due to antihistaminic effects, hypotension caused by alpha-2 blockade, as well as peripheral anticholinergic effects such as dry mouth, blurry vision, and constipation.

In addition, dopamine receptor blockade in the hypothalamus can result in hyperprolactinemia, the consequences of which may include sexual dysfunction, amenorrhea, galactorrhea and gynecomastia. High potency antipsychotics, particularly ripseridone and pimozide, are especially likely to cause hyperprolactinemia. Of interest, in a double-blind placebo-controlled double crossover study involving 26 children and adolescents with TS, prolactin elevation was found to be associated with response to pimozide(Schneider et al., 2006). Subjects who developed EPS were also found to have elevated prolactin levels in both haloperidol and pimozide, though much more so with the latter.

There were numerous early claims favoring the newer dopamine antagonist drugs, the so-called atypical antipsychotics, in terms of tolerability and safety, among other things. However, an early systematic review and meta-analysis found that there was no advantage in tolerability when medication dose was taken into account(Geddes et al., 2000). Further, a number of more recent large-scale well-designed non-industry funded studies in primary psychosis populations have demonstrated a lack of advantage of the newer drugs over the older ones(Jones et al., 2006;

Kendall, 2011; Miller et al., 2008; Sikich et al., 2008).

The receptor binding profiles of antipsychotics is highly varied, precluding attempts to group them based on any single hypothesis. It is likely that anti-tic effects of antipsychotics are largely mediated via their blockade of striatal D2 receptors(H.S. Singer & Wendlandt, 2001). These receptors are also what mediate EPS(Kapur et al., 2000). This supports the findings that high potency antipsychotics, that is, those with a high affinity to D2 receptors, such are haloperidol, pimozide and risperidone, are effective in treatment of tics but also more likely to produce EPS.

On the other hand, low potency antipsychotics, that is, those that require higher doses to bind to

D2 receptors to a clinically adequate extent, bind to many other, non-intended, receptors, thus resulting in the other kinds of adverse effects. Even this general guide is an oversimplification, and one needs to consider the unique properties of each different dopamine antagonist, and, most importantly, the effects in the particular patient at hand(Correll, 2008).

2.4.2.2 α2-agonists

Clonidine is an antihypertensive medication that decreases noradrenergic transmission by stimulating presynaptic α2 receptor. Early trials of clonidine in TS yielded mixed results(Borison et al., 1982; Goetz et al., 1987; Leckman et al., 1985). This included a 6-month placebo- controlled crossover DBT involving 30 patients, with a rigorous primary outcome measure based on evaluation of one-minute video-clips of subjects that yielded negative results(Goetz et al.,

1987). Clonidine outperformed placebo in a 12-week DBT involving 47 subjects with a wide age range(Leckman et al., 1991), and it was found to be equivalent to risperidone in an 8-week

DBT with 21 children and adolescents(Gaffney et al., 2002). Clonidine has also been shown to be effective at reducing tics in children with a chronic tic disorder and ADHD in a multi-center randomized 16-week DBT 136 subjects by the TS Study Group(Kurlan et al., 2002). The tansdermal clonidine patch has been studied in a recent large DBT(Du et al., 2008), after it previously yielded negative results in a small pilot DBT(Gancher et al., 1990). In the more recent study, 326 child and adolescent subjects with different tic disorders, around half of which had TS, were administered active treatment with a weekly clonidine transdermal patch, while

111 were in the control group(Du et al., 2008). There was a statistically significant improvement in the active treatment group compared to the placebo group after 4 weeks, but the difference in final mean total YGTSS scores was quite small. Guanfacine, another α2-agonist, showed some benefit for tics in an 8-week placebo-controlled DBT of 44 youth with tic disorders and

ADHD(Scahill et al., 2001). However, in a subsequent 4-week DBT designed to assess neuropsychiatric effects of guanfacine using a total sample of 24 children and adolescents with mild TS, there was no improvement in YGTSS scores over placebo(Cummings et al., 2002).

Finally, a systematic review and meta-analysis found that while the overall effect size of α2- agonists for tics is small, the effectiveness of this class of agents for tics may be much greater in the presence of comorbid ADHD(Weisman et al., 2013).

In terms of side effects, α2-agonists can cause sedation, which can be quite common and significant as the dose is increased. Other side effects may include headaches, dizziness, hypotension, dry mouth, constipation, irritability, mood lability, insomnia, and impotence(Goetz,

1992). Often such adverse effects occur within the first two weeks of treatment or after a dose increase and then abate. Considering this, doses should be increased gradually in order to avoid significant decreases in pulse rate and blood pressure. Of particular importance is the awareness of rebound in tics, increase in pulse rate and blood pressure, as well as anxiety, with abrupt withdrawal(Leckman et al., 1986). Further, concern has been raised about guanfacine inducing mania in vulnerable children(Horrigan & Jarrett, 1999) or hallucinations(Boreman & Arnold,

2003). Although true prevalence is not known, this appears to be a rather rare adverse effect.

2.4.2.3 Cannabis

Cannabinoids have been explored as a treatment for TS since the 1980s(Moss et al., 1989;

Kirsten R. Müller-Vahl, 2013; Sandyk & Awerbuch, 1988). Delta-9-tetrahydrocannabinol

(THC), a major psychoactive ingredient of cannabis is thought to account for many of the pharmacological actions of cannabis. In recent years, there has also been interest in cannabidiol

(CBD), a primary cannabinoid in cannabis, which has been found to have antiemetic, anticonvulsant, neuro-protective, and anti-inflammatory properties(Grotenhermen & Müller-Vahl,

2012). The earliest case series reported on inhaled cannabis resulting in improvement in tics and comorbid symptoms in three TS patients(Sandyk & Awerbuch, 1988).

Subsequently, a survey of TS patients found that 17 out of 64 consecutive respondents had used cannabis and the majority of these (82%) reported that cannabis was effective in reducing tics, premonitory urges and comorbidities(K. R. Müller-Vahl et al., 1998). Later, several open uncontrolled studies with THC showed similar results(Kirsten R. Müller-Vahl, 2013). Two controlled trials have been reported to date, both of which investigated the effect of oral THC in

TS patients. In a randomized double-blind placebo-controlled crossover single-dose trial with 12 adult patients, a significant global tic improvement was observed with the self-rating scale TS

Symptom List (TSSL) after treatment with oral THC compared with placebo(K R Müller-Vahl et al., 2002). In another randomized double-blind parallel group placebo-controlled study over six- weeks with 24 adult patients, a significant difference was found in the TSSL between the THC and placebo groups after 10 treatment days(Kirsten R Müller-Vahl et al., 2003). No serious side effects occurred during the study. These two studies are limited by small sample sizes and short treatment duration. Of note, the improvements seen in THC trials were not as large as those described in the case series with cannabis. Given this limited evidence, several systematic reviews have concluded that there is currently insufficient evidence to support the use of cannabinoids for tics(Curtis et al., 2009; Koppel et al., 2014; Whiting et al., 2015; Wilkinson et al., 2016).

We conducted a retrospective study of cannabis effectiveness and tolerability in adult patients with Tourette syndrome by interviewing eligible patients in our Clinic. Of the 21 patients who were contacted, 19 participated in the study, for a response rate of 90%. These patients had moderate to severe symptoms overall, based on the baseline severity scores of their tic and comorbid symptoms, their baseline Clinical Global Impression (CGI) – severity scale ratings, and their complex medication histories. Based on our two primary outcome measures, the patients appear to have had striking improvements in symptoms, with an average 60% reduction in YGTSS – Total Tic Score (30.5 ±7.2 to 12.2 ±8.6, p<0.001), and 18 of the 19 participants

(94.7%) being rated as ‘very much improved’ or ‘much improved’ based on the CGI –

Improvement scale ratings. In addition, there were substantial improvements in comorbid symptomatology.

Medical cannabis was generally well tolerated by this group of patients, all of whom were using cannabis for at least two years. The short version of the Marijuana Effect Expectancy

Questionnaire did not suggest ongoing adverse effects overall, and the structured clinical interview for DSM-IV Axis I disorders, with psychotic screen, Patient Edition, was negative for psychotic disorders. Nevertheless, on open ended questioning, most patients did report one or more adverse effect, including feeling ‘high’, cognitive effects, and anxiety. One patient had to temporarily discontinue treatment due to difficulties with irritability.

Overall, the study participants experienced substantial improvements in their symptoms. This is particularly striking given that almost all participants had failed at least one anti-tic medication trial. Our findings are consistent with those of Müller-Vahl and colleagues, who found that most patients in their case series had reported at least a moderate improvement in their tic symptoms(K. R. Müller-Vahl et al., 1998). Of note, the improvements reported in that study, as

33 well as those described in ours, are much larger than what was seen in the trials with oral THC(K

R Müller-Vahl et al., 2002; Kirsten R Müller-Vahl et al., 2003). This may be due to the uncontrolled nature of the observational studies. Nevertheless, it is interesting to note that our patients appear to have had much greater improvement in their symptoms using inhaled cannabis than using pure oral THC, THC/CBD oromucosal spray, or the oral cannabinoid nabilone. Thus, one wonders whether inhaled medical cannabis is more effective for tics, possibly due to the impact of one or more of the various different compounds that it contains in addition to THC and

CBD, and perhaps enhanced by a route that avoids first-pass hepatic metabolism. It is also worth considering the issue of dosing. There is little information on comparing oral and inhaled doses of cannabinoids, and the limited information available is specific to THC. If one accepts various assumptions, a conversion factor of 2.5 can be used to estimate oral THC equivalent of a certain quantity of inhaled cannabis(Government of Canada, 2013; Zuurman et al., 2009). If we further assume that the average percentage THC in the cannabis used by our participants to be 10%, their median total daily amount of 1 gram of cannabis would entail 100 mg of THC. Multiplying

100 mg by the conversion factor of 2.5 would yield 250 mg equivalent of oral THC. This would be much higher than the up to 10 mg used in the previous trials with oral THC.

Nevertheless, it is important to highlight the limitations of our retrospective observational study.

There is likely a selection bias, as patients who would have tried cannabis and found it to be ineffective or intolerable, would be unlikely to remain on it for long, or may not be receptive to this as a treatment option. Such patients would not have been eligible for our study. On the other hand, according to the case series of consecutively interviewed patients by Müller-Vahl and colleagues, 82% of patients who had tried cannabis had experienced improvement in symptoms(K. R. Müller-Vahl et al., 1998). Another limitation in our study is the potential for recall bias given the retrospective nature of the baseline assessments. These assessments

34 included reviewing the patient charts for supporting clinical notes, including objective clinical examinations at various clinical visits. Still, this cannot completely eliminate the effect of recall bias in the assessments for the present study. An additional limitation of an observational study is the lack of a control. Thus, it is possible that some of the improvement, perhaps in our younger adult patients, is related to the natural history of tics, which typically improve by early adulthood for most patients. However, this is unlikely to account for the improvements seen in older patients, most of which had tried on multiple other treatments with limited benefit. Still, there could be a regression to the mean effect, especially given the known waxing and waning nature of tics. In addition, there could be an enhanced placebo effect at play with inhaled cannabis, especially given the sociocultural issues surrounding the use of medical cannabis, the administrative process to obtain it, and the ritualized procedure to utilize it. It is noteworthy, though, that 8 of our patients had discovered the use of cannabis for tics only serendipitously when they personally experienced notable reduction in their tics after using cannabis recreationally. Nevertheless, to adequately address this issue and other limitations raised here, one would need to conduct a randomized trial that is properly controlled and blinded for inhaled cannabis.

In conclusion, cannabis seems to be a promising treatment option for tics and associated symptoms. Nevertheless, despite the substantial improvements reported our study, some patients continued to take other medications in addition to cannabis. Moreover, while cannabis appears to be generally well tolerated, side effects were common. Importantly, the strength of any conclusions is limited by the retrospective nature of our study. Thus, to better characterize the benefits and risks of medical cannabis in TS, including the roles of various cannabinoid compounds, there is a need for well-designed prospective, well-controlled studies.

2.4.2.4 Dopamine agonists

Although TS has been viewed as a hyperdopaminergic condition, a number of rationales have been used to try dopamine agonists in TS. One such trial, based loosely on findings from animal models, the experimental D-1 dopamine receptor agonist, SKF 38393, showed no benefit in a

DBT of patients with different movement disorders, including two subjects with TS(A. Braun et al., 1989). It has also been suggested that stimulating presynaptic autoregulatory dopamine receptors with dopamine agonists may decrease dopamine transmission and ameliorate tic symptoms, based initially on response to apomorphine in a study of two TS subjects(Feinberg &

Carroll, 1979). Talipexole, a dopamine agonist with preferential affinity for presynaptic autoregulatory dopamine receptors, failed both in efficacy and in tolerability in a DBT of 13 adult male subjects with TS(Goetz et al., 1994). In two open trials, pergolide, a mixed

D1/D2/D3 dopamine receptor agonist with higher affinity for presynaptic vs postsynaptic D2 receptors, showed benefit in a retrospective chart review(Griesemer, 1997) and in an open label study(Lipinski et al., 1997). Sunsequently it was studied in two DBTs(D.L. Gilbert et al., 2003,

2000). In the first controlled study, 24 children and adolescents with TS were randomized to either placebo or pergolide for 6 weeks, followed by a crossover after a 2-week placebo washout(D.L. Gilbert et al., 2000). Although YGTSS scores clearly improved in the second arm of the study, this was not the case in the first arm of the study, and secondary outcome measures based on clinician assessment and parent ratings did not separate from placebo(D.L. Gilbert et al., 2000). In the subsequent larger placebo-controlled DBT involving 57 children and adolescents with TS, pergolide resulted in a modest decrease in YGTSS scores after 8 weeks, but

36 here again, the secondary outcomes based on clinician assessments and parent ratings failed to separate from placebo(D.L. Gilbert et al., 2003). Finally, a single dose of levodopa under single- blind conditions in 6 adults with TS resulted in improvement of tics(Black & Mink, 2000). This is intriguing as it cannot be explained by presynaptic inhibition, and the authors argue that previous positive findings with dopamine agonists may have all been through direct postsynaptic dopaminergic effects, possibly through effects on different aspects of the tic generation process than those pertaining to response to dopamine antagonists(Black & Mink, 2000). Overall, there is little evidence for clinical use of dopamine agonists other than pergolide, and even there the evidence is limited. Importantly, although pergolide has been generally well-tolerated in trials, there have been reports of serious adverse effects including pleural, retroperitoneal and pericardial fibrosis, cardiotoxicity and vasospasm(Scahill et al., 2006b). Non-ergot dopamine agonists such as pramipexol, or ropinorol safer however there is no data as to their efficacy in treatment of tics.

2.4.2.5 Botulinum toxin

Botulinum toxin is a potent poison that causes muscle paralysis by interfering with the release of neurotransmitter acetylcholine from nerve terminals. Locally injected in minute amounts it has been used in the treatment of dystonias, among other things. An early open study in 10 TS patients with disabling focal dystonic tics found botulinum toxin to be effective in all subjects(J.

Jankovic, 1994). Interestingly, patients noted a marked decrease in premonitory urges. This was noted again in a case report of a boy with severe coprolalia who received botulinum toxin

37 injection in the vocal cord with significant improvement in his coprolalia and marked reduction of premonitory urges associated with his vocal tics(Scott et al., 1996). A smaller proportion of subjects with different motor and vocal tics had benefit from botulinum toxin in a large open study(Awaad, 1999). In two other open studies, most patients had improvement in tics, as well as premonitory urges(Kwak et al., 2000; Porta et al., 2004). In the only controlled DBT to date, most of the 18 subjects who completed the study experienced significant reduction in the targeted tics as well as premonitory urges with botulinum toxin relative to placebo.

Unfortunately patients did not feel that the treatment reduced their tics overall(Marras et al.,

2001). In a case report, botulinum toxin in addition to antipsychotic treatment resulted in resolution of violent dystonic neck tics in a patient with TS(Aguirregomozcorta et al., 2008).

Indeed, botulinum toxin may be more useful in significant focal dystonic tics. The main adverse effects include weakness of the injected muscle, decreased voice volume when the vocal cords are treated, as well as transient soreness at the injection site(Scahill et al., 2006b).

2.4.2.6 GABA agonists

Diazepam, a benzodiazepine, was not found to be helpful for tics in an early placebo-controlled

DBT with 4 adolescents(Connell et al., 1967). Clonazepam, another benzodiazepine, was found to show some benefit in an open trial(Gonce & Barbeau, 1977), and two chart reviews(Steingard et al., 1994; Troung et al., 1988). One of the chart reviews involved children with a tic disorder and comorbid ADHD, with clonazepam being used as an adjunctive treatment to clonidine(Steingard et al., 1994). An interesting study of 20 TS patients found that those with

38 higher red blood cell-to-plasma choline ratios were more likely to respond to clonazepam than to haloperidol(Merikangas et al., 1985), but this has yet to be replicated. Clonazepam has not been studied in a controlled DBT. Clinical experience suggests that in severe cases of TS it may augment the effects of neuroleptics on tics. Progabide, a GABA-receptor agonist, showed some tic reduction in two TS patients during an open label study(Mondrup et al., 1985), but it has never been the subject of a DBT in TS. Baclofen, a GABAB receptor agonist, showed benefit in a large open trial(Awaad, 1999), but it did not significantly decrease tics in a placebo-controlled crossover DBT trial of 9 youth with TS(H.S. Singer et al., 2001). Overall, there is inadequate evidence for the use of GABA agonists to reduce tics in TS.

2.4.2.7 Nicotine

Initial positive reports using nicotine gum as an adjunct to haloperidol under open label(Sanberg et al., 1988, 1989) and single blind conditions(McConville et al., 1992), led to similar findings using the nicotine patch(Shytle et al., 1996; Silver & Sanberg, 1993; Silver et al., 1996) as an adjunct to haloperidol or as monotherapy(Dursun et al., 1994). Subsequently a 33-day placebo- controlled DBT studied the nicotine patch as an adjunct to haloperidol in 70 children with

TS(Silver et al., 2001). The nicotine patch adjunct was better than placebo in clinician- and parent-rated global improvement but not in YGTSS scores(Silver et al., 2001). A significant proportion of patients experienced side effects that included nausea (71%), vomiting (40%) and pruritis (57%). The high prevalence of side effects, as well as the equivocal benefit on tics preclude clinical use of nicotine in TS.

2.4.2.8 Other

A number of other drugs have been explored in TS but there is no good evidence from rigorous controlled DBTs to support their use. Studies with opioid agonists and antagonists have shown mixed results(Chappell, 1994; Chappell et al., 1993; Kurlan et al., 1991; van Wattum et al.,

2000). Interestingly, acute naloxone infusion decreased tics at low dose but significantly increased tics at the a higher dose(van Wattum et al., 2000). The anticonvulsant levetiracetam has shown positive results in an open label study(Awaad et al., 2005) and in an extension entailing 4 years of monotherapy in 70 TS children and adolescents(Awaad et al., 2007).

Topiramate, another anticonvulsant, showed initial effectiveness in a chart review of 39 cases(Nelson et al., 2007). It has since been evaluated in several controlled trials, but a systematic review concluded the quality of the studies was poor and the evidence was not sufficient to support its routine use in TS(Yang et al., 2013). Donepezil has shown positive effects in two case reports(Hoopes, 1999; Niederhofer, 2006) and in an open trial(Cubo et al.,

2008), but it has not subjected to a controlled study. The antiandrogen flutamide showed inconsistent results in a case series(B. S. Peterson et al., 1994) and a DBT(B. S. Peterson, Zhang, et al., 1998). There are reports that some calcium channel antagonists may reduce tics in TS patients(Micheli et al., 1990; Walsh et al., 1986), but there have not been any DBTs to subject these to rigorous study.

2.4.2.9 Summary

In summary, when, after careful consideration, a decision is made to treat tics with pharmaceutical agents, the two main classes of drugs to consider are the dopamine antagonists and the α2-agonists. The dopamine antagonists haloperidol, pimozide and risperidone have larger effect sizes and more empiric support as compared to other agents. Nevertheless, many groups recommend starting with an α2-agonist e.g. clonidine, or guanfacine, where we also have good empirical evidence of efficacy and a generally more favorable side effect profile(Pringsheim et al., 2012; SWAIN et al., 2007). These medications need to be titrated judiciously, with ongoing regular monitoring of potential side effects. Currently available medications are palliative, not curative. Given the known natural course of tics in TS, namely the observation that tics usually improve towards the end of teen years, it is prudent to gradually taper and discontinue the medication when tics have been mild or not present at all for a significant period of time (6 to 12 months).

2.4.3 Treating Comorbidities

Given the high comorbidity between ADHD and TS, children with TS are often exposed to stimulant medications. The issue of stimulant medication potentially increasing or even resulting in new onset tics has received much attention in the literature. Despite, earlier concerns that stimulants cause or exacerbate tics(Borcherding et al., 1990; Castellanos et al., 1997; Feinberg &

Carroll, 1979; Handen et al., 1991; Lipkin et al., 1994; Sverd et al., 1989), the extent of this relationship was brought into question by subsequent DBTs(Gadow, Nolan, et al., 1995; Gadow et al., 2007, 1999; Gadow, Sverd, Sprafkin, & Nolan, 1995; Gadow, Sverd, Sprafkin, Nolan, et al., 1995; Kurlan et al., 2002; Law & Schachar, 1999), and in a subsequent systematic review(Osland et al., 2018). In the largest of the trials, a landmark 16-week multicenter DBT from The Tourette’s Syndrome Study Group, 136 children with ADHD and a chronic tic disorder

(the majority being TS) were randomized to either of clonidine, the stimulant methylphenidate, the combination of these, or placebo(Kurlan et al., 2002). One of the secondary outcome findings was that the proportion of subjects reporting worsening of their tics was not higher in the methylphenidate group compared to the placebo and other groups. Of note, tic severity was found to be improved in the methylphenidate group compared to the placebo group(Kurlan et al.,

2002). Nevertheless, more individuals reported tics as a dose-limiting side effect of methylphenidate, and the pooled data may not uncover a proportion of individuals whose tics do increase with methylphenidate. Moreover, as is suggested by the authors, there may have been a selection bias against children who had previously experienced tic exacerbation on methylphenidate(Kurlan et al., 2002). Further, the study does not address potential long-term or dose related effects of methylphenidate on tics(Goldberg, 2002). Thus, although these findings have made it more likely for stimulants to be considered in the treatment of ADHD comorbid with TS, one should still consider that stimulants may exacerbate tics in certain patients(Michael

H. Bloch et al., 2012; Erenberg, 2005; Osland et al., 2018; Poncin et al., 2007).

OCD is another condition that is highly comorbid with TS. Furthermore, it has been suggested that OCD in the presence of a tic disorder represents a distinct category of OCD(Leckman et al.,

2007). Indeed, the presence of tics has been suggested to make OCD less responsive to selective serotonin reuptake inhibitors(McDougle et al., 1993; Shetti et al., 2005), as well as to predict poorer long-term outcome in OCD(Leonard et al., 1993). An early DBT demonstrated that adding haloperidol decreases OCD symptoms in fluvoxamine-refractory patients with comorbid tics but not in those without tics(McDougle et al., 1994). A later study showed that low-dose risperidone to be effective as an adjunct in OCD patients refractory to SSRI monotherapy, but the presence of a tic disorder was not a moderating factor(McDougle et al., 2000). A systematic review and meta-analysis found that the presence of a comorbid tic disorder was associated with a beneficial response to dopamine antagonist augmentation to SSRI in the treatment of

OCD(M.H. Bloch et al., 2006), but this was not the case in another meta-analysis(Skapinakis et al., 2007). A secondary analysis of the landmark Pediatric OCD Treatment Study found that the

SSRI sertraline did not separate from placebo in children with comorbid tic disorders, but there was no such effect in the arms receiving cognitive behavioral therapy(March et al., 2007).

Finally, although less of an issue compared to stimulants, one should be aware of the possibility that tic exacerbation may occur as a side effect of SSRIs(Lee et al., 2008). Overall, while cognitive behavioral therapy and SSRIs should still be considered as first-line treatments in the treatment of OCD comorbid with TS, it appears that the presence of TS can decrease the likelihood of response to SSRIs, and a proportion of patients refractory to these may respond to augmentation with haloperidol or risperidone.

2.5 Integrated Clinical Practice

Patients with TS have a wide range of presentation in terms of severity and comorbidity, among others. Uncomplicated cases of TS can often be managed by frontline care providers such as family practicioners, pediatricians, community psychiatrists, neurologists, and clinical psychologists. However, for more severe and/or complex cases, the potential treatments are highly varied and are best delivered in an individualized manner in the context of an integrated multidisciplinary clinic. Though not yet commonly the case, such clinics should be staffed by mental health care providers that trained in the different psychological and behavioral treatments for TS, particularly the HRT. These could be carried out by psychologists, psychiatrists or social workers. Neuropsychologists and psychometricians can regularly provide psychological assessments when needed. Social workers can be invaluable in dealing with parenting and other family issues, as well as advocating in patient schools and communities. Speech language pathologists can help with common phonological problems, stuttering, as well as social communication difficulties. Occupational therapists can provide help for subjects with sensory hypersensitivities, and such challenges as getting thoughts into writing, as well as fine motor difficulties that may affect handwriting. Psychiatrists should be able to integrate the complex care these patients require, and may treat tics or related difficulties with medication when required. Such clinics also benefit from readily available general practicioners, pediatricians and neurologists to act as consultants for relevant physical problems. Finally, when it is impractical to have all these care providers in the same physical space, as is often the case in community settings, ‘virtual’ integrated TS clinics can be a means to deliver the necessary care by having open and ongoing communication and collaboration among practicioners from different fields with the training, experience and availability to assess and treat TS patients.

2.6 Tourette Syndrome Pathophysiology

ADHD, and emotional dysregulation. Tics are considered “semi-compulsory”, in that they are temporarily suppressible, until the premonitory urge is such that they can no longer be contained.

This is similar to the case of compulsions in OCD. The high comorbidity with ADHD is particularly indicative of problems with inhibitory control(Martino & Mink, 2013; T. Murphy &

Muter, 2012). As well, TS is associated with emotional dysregulation in the form of rage outbursts(Baym et al., 2008; C. L. Budman et al., 2000; Cathy L. Budman et al., 2003; Chen et al., 2013; Wright et al., 2012).

On executive functioning tests, patients with TS typically show deficits that are specific to inhibitory function, such as with the Hayling test(Channon, Crawford, et al., 2003; Channon,

Pratt, et al., 2003; Channon et al., 2004; Clare Margaret Eddy et al., 2012; Yaniv et al., 2017).

While some have argued that most cognitive deficits are attributable to comorbid OCD or

ADHD(Greimel et al., 2011; Lin et al., 2012; Sukhodolsky et al., 2010), others have found that executive deficits in TS are independent of comorbidity(Channon et al., 2004; Clare M. Eddy &

Cavanna, 2017; Clare Margaret Eddy et al., 2012; Hovik et al., 2017; Jeter et al., 2015; Morand-

Beaulieu et al., 2017; Wylie et al., 2016; Yaniv et al., 2017). Regardless, given that comorbidity

45 is present in the vast majority of patients with TS, it is clear that the condition is associated with deficits in inhibitory control.

Further evidence for reduced inhibitory control comes from transcranial magnetic stimulation

(TMS) studies, which have consistently found TS subjects to have reduced measures of cortical inhibition compared to healthy controls (reviewed by Ganos and colleagues(Ganos et al.,

2013b)). In a more recent TMS study of 14 adults with TS, voluntary tic suppression was associated with reduced corticospinal excitability, though there were no changes in other cortical excitability measures(Ganos et al., 2018).

Neuroimaging studies have yielded some promising results, suggesting that reduced caudate volume and thinning of motor and sensorimotor cortices reflect the neurological predisposition to tics(Ganos et al., 2013a; Georgina M. Jackson et al., 2015; Polyanska et al., 2017; Stern et al.,

2008a; Worbe, Lehericy, et al., 2015). In addition, hypertrophy of cortical (dorsolateral prefrontal, orbitofrontal, and parietal) and limbic (amygdala and hippocampus) regions and a smaller corpus callosum are thought to reflect compensatory neuroplastic changes. Almost all these studies have been cross-sectional, however, making it difficult to tease out underlying cause from compensatory response. Conflicting findings have also been reported, likely as a result of differences in sample size, demographic characteristics, tic severity, comorbid conditions, medication use, techniques for the acquisition and processing of images, and methods for data analysis. Nevertheless, the neuroimaging literature does suggest that tic formation results from a disordered striatum and related dysfunction in cortico-striato-thalamo-cortical

46 circuits, in particular the striatal dopamine system, and cortical control areas(Ganos et al., 2013a;

Georgina M. Jackson et al., 2015; Polyanska et al., 2017; Stern et al., 2008a; Worbe, Lehericy, et al., 2015). This notion is further supported by neuropathologic studies showing reduced number and altered distribution of inhibitory GABAergic neurons in the sensorimotor areas of the striatum(Kalanithi et al., 2005; Kataoka et al., 2010).

2.6.1 Dopamine Receptor Imaging

There has been much interest in the role of dopamine in TS(Buse et al., 2013; Hugh Rickards,

2009; Segura & Strafella, 2013). Over half a century ago, high potency dopamine D2 receptor

(D2R) blockers were found to be effective in reducing tics(Abi-Jaoude et al., 2009), and these remain as the agents with the most evidence for efficacy in the pharmacological treatment of tics(Pringsheim et al., 2012). Further, cerebrospinal fluid analysis and human postmortem studies have implicated the dopamine system in TS(Buse et al., 2013). In addition, striatal dopamine is known to play a role in habit formation(Graybiel, 2008), and in animal models of

TS(Macrì et al., 2013). Finally, dopamine is involved in other movement disorders, such as

Parkinson’s Disease and Huntingon’s Chorea(Buse et al., 2013). It is thus not surprising that the first and most widely studied ligands in receptor nuclear imaging studies in TS have targeted the dopamine system(Hugh Rickards, 2009).

However, human receptor nuclear imaging studies in TS patients have been far from conclusive(Buse et al., 2013; Hugh Rickards, 2009; Segura & Strafella, 2013; Steeves et al.,

2010). Such studies have investigated striatal dopamine innervation, dopamine release, presynaptic and postsynaptic dopamine receptors, but these have yielded inconsistent results.

Striatal dopamine receptors are of particular interest, based on their role in habit formation, as well as evidence implicating the striatum in TS(Ganos et al., 2013a).

Four single-photon emission computed tomography (SPECT) studies have investigated striatal

D2 receptors in TS using the D2 receptor antagonist [123I]iodobenzamide ([123I]-IBZM). In the first of these, investigators found decreased ligand binding in the basal ganglia of the 7 medicated but no difference in the 8 unmedicated TS subjects in comparison to 6 controls(George et al., 1994). These findings are consistent with those from another [123I]-

IBZM SPECT study which found reduced striatal ligand binding in the 7 medicated compared to the 10 unmedicated patients and to the 7 healthy controls, but no difference between the unmedicated patients and the controls(K. R. Müller-Vahl et al., 2000). The most recent TS report using [123I]-IBZM found no difference in ligand uptake between TS patients and controls(Hwang et al., 2008). Finally, an interesting [123I]-IBZM SPECT investigation in 5 monozygotic twin pairs with TS found higher binding in the caudate of the more severely affected twin; further, the within pair difference in binding correlated positively with within pair differences in tic severity(Wolf et al., 1996).

Several studies investigating striatal dopamine receptors in TS have used positron emission tomography (PET) imaging, which has higher spatial resolution compared to SPECT. In most of these studies, subjects were medication free when they were scanned. An early small PET study using the D2 and D3 receptor antagonist [11C]raclopride in 5 adult patients with TS found no differences in comparison to healthy controls(Turjanski et al., 1994). A larger study of 29 subjects focusing specifically on the caudate and using the D2 receptor antagonist

[11C]methylspiperone did not find differences compared to controls(Wong et al., 1997). A subsequent study with [11C]raclopride in 7 TS patients again showed no baseline difference in

D2/D3 striatal receptor availability(Harvey S. Singer et al., 2002). A more recent study investigating various neurotransmitter measures found no baseline differences in [11C]raclopride binding potential (BP) between the 12 TS subjects and 3 healthy controls with complete data(Wong et al., 2008). Interestingly, using high- and low-specific activity [11C]raclopride scans, the investigators estimated D2 receptor affinity to be higher in the anterior putamen in TS subjects relative to the controls. Of note, dopamine receptor “supersensitivity” has been hypothesized to play a role in TS in a biochemical study over 35 years ago(H. S. Singer et al.,

1982). Finally, in the most recent PET study of its kind, using the radioligand [11C]raclopride,

Denys and colleagues found lower D2/D3 striatal receptor availability in the putamen of 12 TS participants compared to 12 healthy controls(Denys et al., 2013).

Altogether, the findings regarding striatal dopamine receptors in TS have been inconsistent.

Moreover, the literature has been characterized by several limitations, including small sample sizes, confounders such as age differences between comparison groups, medication effects, and low spatial resolution in the case of SPECT studies. Furthermore, while dopamine receptor

“supersensitivity” has been hypothesized as an underlying pathophysiological mechanism in

TS(Buse et al., 2013; Segura & Strafella, 2013; H. S. Singer et al., 1982), only one group has actually investigated this question(Wong et al., 2008).

2.6.2 Structural Magnetic Resonance Imaging

The brain areas that have been found to be affected in TS consistently involve regions known to have a role in self-control(Ganos et al., 2013b; Georgina M. Jackson et al., 2015; Stern et al.,

2008b; Worbe, Lehericy, et al., 2015). In a structural magnetic resonance imaging (MRI) study of 155 subjects with TS and 131 healthy controls, Peterson and colleagues found that the dorsolateral prefrontal cortex (DLPFC) region was increased in volume in children but not adults with TS(B. S. Peterson et al., 2001). Further, there was an inverse correlation between this increase in DLPFC volumes and tic symptom severity(B. S. Peterson et al., 2001). The speculation is that these findings represent compensatory changes associated with tic control in children; in contrast, adults had a relative decrease in DLPFC volumes, which may be related to persistence of tics in adulthood. In the same study, orbitofrontal cortex (OFC) volumes were found to have an inverse correlation with tic symptom severity, particularly in adults(B. S.

Peterson et al., 2001). An MRI study measuring cortical thickness found sensorimotor cortex and DLPFC thinning in children with TS (n=25) relative to age- and sex-matched controls

(n=35), and this correlated to tic symptom severity(Sowell et al., 2008). In another structural

MRI study, voxel-based morphometry (VBM) showed decreases in gray matter volumes in various prefrontal areas including the anterior cingulate cortex (ACC), as well as decreases in

50 white matter volumes in the right inferior frontal gyrus (IFG) and left superior frontal gyrus in 19 adults with TS compared to 20 age- and sex-matched controls(Kirsten R. Müller-Vahl et al.,

2009). In an MRI study of cortical thickness, children and youth with TS showed sensorimotor and right OFC thinning relative to controls(Fahim et al., 2010). In a similar study this time in adults, 60 TS participants had reduced thickness relative to 30 controls in the left motor cortex, left postero-lateral superior frontal and posterior part of the middle frontal gyrus (these latter two overlapping with DLPFC), right IFG and lateral OFC(Worbe et al., 2010). Tic severity correlated negatively with cortical thickness in several regions including OFC and IFG. In yet another cortical thickness MRI study, 40 adults with TS had reductions in thickness relative to 40 age- and gender-matched controls controls in OFC, ACC, and ventrolateral prefrontal cortex

(PFC), and the reductions correlated negatively with tic severity(Draganski et al., 2010). In a subsequent VBM MRI study, 29 adults with TS were found to have decreased left IFG volume relative to 24 controls(Wittfoth et al., 2012). In an MRI probabilistic tractography study, relative to 28 age- and gender-matched controls, 49 adult patients with TS had increased thalamus and striatum structural connectivity to multiple cortical areas including sensorimotor, SMA, OFC and

IFG, and decreased connectivity to ACC(Worbe, Marrakchi-Kacem, et al., 2015). A subsequent multi-center MRI VBM study found that 103 children with TS had lower white matter volume in the OFC and medial PFC relative to 103 controls participants matched for age, sex and handedness(Greene et al., 2016).

2.6.3 Functional Imaging

2.6.3.1 Tic Suppression and Tic Generation

Similar brain regions have been implicated in functional MRI (fMRI) studies. In an early study in 22 adults with TS, Peterson and colleagues found that, in comparison to a resting state, tic suppression involved increased activity in right midfrontal cortex and right ventral cortex, both of which correlated positively to each other, and inversely with activity in the putamen, globus pallidus and thalamus(B. S. Peterson, Skudlarski, et al., 1998). This is consistent with the

DLPFC being involved in suppressing tics, via excitatory projections to the caudate, which in turn sends inhibitory projections to the putamen(Stern et al., 2008b). In an event-related fMRI study, ACC, supplementary motor area (SMA) and pre-motor areas were found to be activated 2 seconds prior to and at tic onset in 10 adult TS participants(Bohlhalter et al., 2006). A subsequent study in 16 adults with TS investigated correlations of brain areas to tic-related primary motor areas and found that SMA had broader cross-correlation during tics in comparison to intentional imitation of tics by 16 matched controls(Hampson et al., 2009). In another study comparing spontaneous tics by 13 adult participants with TS to voluntary imitation of tics by 21 controls, activity during the former was relatively increased in somatosensory and posterior parietal cortices and putamen(Z. Wang et al., 2011). The TS group also had increased activity in the sensorimotor cortex, putamen, pallidum and substantia nigra relative to controls; on the other hand, activity in the anterior cingulate and caudate was weaker in the TS group. Both the increase and decrease in activity in comparison the controls correlated with tic severity. The authors conclude that tics arise from a combination of “excessive activity in motor pathways and reduced activation in control portions of cortico-striato-thalamo-cortical circuits”(Z. Wang et al.,

2011). Researchers from the same group carried out an investigation using an eye blink

52 inhibition task and found that the TS group (n=51) showed more activations in the middle frontal gyrus and dorsal ACC (dACC), and deactivations in the superior frontal gyrus relative to controls (n=69)(L. Mazzone et al., 2010). Activations in the left middle frontal gyrus and left caudate correlated positively with tic severity. On the other hand, activation in the right inferolateral PFC, left IFG and right putamen correlated negatively with tic severity(L. Mazzone et al., 2010).

The left IFG was also implicated in a resting state fMRI study in which it had increased regional homogeneity during tic suppression in comparison to the free ticking state in 14 adults with

TS(Ganos, Kahl, et al., 2014). In another resting state fMRI study, in which tic onset times were used as regressors to investigate brain activations prior to tic onset in 10 adults with TS, ACC and SMA were activated at two seconds and at 1 seconds prior to tic onset(Neuner et al., 2014).

In an interesting fMRI study design, brain activations in 11 adult participants with TS who were asked to suppress ocular tics but not eye blinks, were compared to brain activations in 19 control participants who were asked to suppress eye blinks in a block design(van der Salm et al., 2018).

Suppression of tics in the participants with TS was associated with increased activity in right anterior and dorsal anterior PFC, bilateral frontal eye fields, and right DLPFC. Suppression of eye blinks in the control participants was associated with activations in the bilateral premotor cortex, bilateral SMA, right IFG, right anterior PFC, insula bilaterally, left caudate and putamen.

Compared to controls, participants with TS had higher activations in the right anterior PFC, right

ACC, right DLPFC, left premotor cortex and frontal eye fields; in contrast, controls had higher activations in bilateral SMA, bilateral IFG and insula, and right putamen(van der Salm et al.,

2018). These contrast analyses need to be interpreted bearing in mind that the two groups of participants performed different tasks.

2.6.3.2 Cognitive Control

In a task-based fMRI study, investigators evaluated the effects of age on brain activations during performance of the Stroop task in 66 participants with Tourette syndrome (children and adults) and 70 controls(Marsh et al., 2007). In contrast to healthy controls, TS participants did not have greater deactivations with age in the mesial PFC and ventral ACC, nor increased activations with age in the right inferolateral PFC. In addition, activations in the inferolateral PFC, mesial frontal gyrus, and DLPFC correlated inversely with task performance in the TS group, while activations in the right inferolateral PFC correlated positively with performance in the healthy controls; as well, activation in the ventromedial PFC (vmPFC) correlated positively with task performance in the TS group, and negatively in the control group. Finally, the magnitude of DLPFC activation correlated positively with tic symptom severity(Marsh et al., 2007). In an event-related fMRI study using a cognitive control task, 18 children with TS exhibited greater left DLPFC activations in comparison to age-matched 19 healthy controls(Baym et al., 2008). Moreover, activations in premotor cortex, superior frontal gyrus and right IFG correlated with tic severity(Baym et al., 2008). In another cognitive control study, investigators used the Simon task to compare activations in 42 participants with TS and 37 controls in both children and adults(Raz et al., 2009). There was greater PFC activation in TS compared to healthy controls, and this was even more so in adults. In the TS group, activations in SMA and middle frontal

54 gyrus, among others, correlated inversely with task performance. Activations in the left inferior prefrontal regions correlated with tic severity. Of interest, in the group of adults with TS, activations in the midfrontal gyrus following an incongruent stimulus were delayed relative to controls(Raz et al., 2009).

A study of cognitive control based on “task-maintenance” and “adaptive control” using a semantic task showed activity differences across multiple brain regions in 27 adolescents with

TS and 27 controls(Church et al., 2009). In particular, activations associated with “adaptive control” were lower in a number of brain regions in the TS group, including in the middle frontal gyrus. Activations in several regions in the TS group, including a dorsal medial frontal region, appeared similar to adolescent participants in the control group. Activations associated with

“task-maintenance” were higher in the TS compared to the control group in multiple regions, including the middle frontal gyrus, which had similar activation to child participants from a

“developmental” dataset of typically-developing children and adults. According to the authors, these findings suggest “functional immaturity” of the control networks in TS(Church et al.,

2009). In an investigation of neural responses using a reinforcement learning task, there was no difference in SMA activation between the 60 adults with TS and 50 healthy controls(Worbe et al., 2011). Of note, the TS participants with comorbid OCD and those that were receiving a dopamine antagonist medication had decreased activations in the vmPFC as well as poorer performance on the learning task(Worbe et al., 2011). Using near-infrared spectroscopy (NIRS), a study investigated prefrontal hemodynamic response during the Stroop color-word task and found that 10 children with TS had lower PFC activation in the DLPFC area compared to 10 age- and sex-matched control participants(Yamamuro et al., 2015).

2.6.3.3 Motor Task Switching

In an interesting multi-modal imaging study, 13 child participants with TS had faster response times compared to 13 age- and gender-matched controls in a manual task-switching paradigm(S.

R. Jackson et al., 2011). This enhanced control over motor output in the participants with TS correlated inversely with tic severity. On diffusion-weighted imaging, there were differences between the TS (n=14) and control (n=14) group in the corpus callosum and forceps minor.

White matter fractional anisotropy and mean diffusivity measures in these areas correlated with tic severity. In the control but not the TS group, corpus callosum fractional anisotropy was negatively correlated with task response times. In the TS but not the control group, forceps minor fractional anisotropy was negatively correlated with task response times. Finally, task- switching associated fMRI BOLD response in a PFC region of interest (ROI) immediately adjacent to the vicinity of the right forceps minor was increased in 10 TS participants relative to

15 controls; in the TS but not the control group, activation in this area was negatively correlated with task performance(S. R. Jackson et al., 2011). In another fMRI study by the same group using the same task, 10 children with TS had less ROI activations compared to 10 controls in the

SMA, ACC and inferolateral cortex(Jeyoung Jung et al., 2013). In this study, there was no significant difference in task performance between the TS and control groups. Of interest, activations in the SMA, ACC and inferior frontal cortex ROIs was positively correlated with performance in terms of response time (though this was not statistically significant); in the TS group only, activations in these ROIs were strongly correlated with the task-switching effect

(‘switch costs’), and these activations also correlated with tic severity (though this was not statistically significant)(Jeyoung Jung et al., 2013).

2.6.3.4 Inhibitory Control

In a study using the stop-signal task, the group of 14 adults with TS showed greater activation compared to 15 controls in the dorsal premotor cortex during the ‘go’ versus the ‘successful- stop’ condition, a pattern that was opposite to that seen in the healthy controls(Ganos, Kühn, et al., 2014). On exploratory correlation analyses, activations in the SMA during the ‘successful- stop’ versus ‘go’ conditions correlated positively with motor tic frequency(Ganos, Kühn, et al.,

2014). In another fMRI study using the stop-signal task, in adults with TS (n=18), OCD (n=18) and healthy controls (n=20), there were no differences identified in PFC with three-group whole brain analysis(Fan et al., 2017). ROI analysis of activity during error processing showed higher activation in the TS relative to the other groups in the SMA(Fan et al., 2017). In an go/no-go fMRI study, 15 adults with TS had lower activations compared to 15 control participants during the ‘go’ condition in the left dorsal premotor cortex and SMA(Thomalla et al., 2014).

In an earlier fMRI go/no-go study, investigators used the task with and without an infusion of levodopa to study the role of dopamine in modulating task performance-related brain activity(Hershey et al., 2004); they found no differences between 8 adults with TS and 10 matched healthy control participants(Hershey et al., 2004). In a task-based fMRI study in 39

57 children with TS and 39 controls, Debes and colleagues found no significant differences in activation between the TS and control participant groups during performance of the Stroop, go/no-go and finger tapping tasks(Debes et al., 2011a).

2.6.3.5 Finger Tapping

In another finger-tapping study, 19 children with TS showed higher activations relative to 16 controls in the right medial frontal gyrus and left caudate but relatively lower activations in the right middle frontal gyrus and left precentral gyrus (SMA area)(Roessner et al., 2012). In a subsequent publication by the same group, 22 children with TS had less activations in left middle frontal gyrus and caudate relative to 22 controls during a finger tapping task with the dominant

(right) hand, but greater activations in medial, superior frontal and precentral gyri, pre-SMA,

DLPFC and ACC during finger tapping with the non-dominant (left) hand(Roessner et al., 2013).

In yet another finger-tapping investigation, 19 adult participants with TS showed increased left

PFC activations relative to 18 controls during finger tapping with the non-dominant (left) hand and during bimanual tapping(Werner et al., 2011). In addition, whereas control participants activated the ACC only during the bimanual tapping, the TS group recruited the area similarly in the dominant, non-dominant, and bimanual finger tapping conditions(Werner et al., 2011). An investigation during a finger opposition motor task found the group of 24 adults with TS to have greater activations in superior and middle frontal gyri, and IFG relative to 24 controls during task execution, and in the superior and middle frontal gyri during imagination of the task(Zapparoli et al., 2016).

2.6.3.6 Prepulse Inhibition

In an fMRI study of prepulse inhibition (PPI), 17 adult participants with TS had a reduced startle response relative to 16 healthy controls, and lower activations in multiple regions including the

OFC, ventral lateral prefrontal cortex/anterior insula, and caudate (Zebardast et al., 2013). In the

TS group, task-related activity in the caudate and in the OFC correlated positively with tic and obsessive-compulsive symptom severity scores, respectively(Zebardast et al., 2013). A combined electromyography/fMRI study also using PPI by Buse and colleagues found that the startle response was reduced in 22 adolescent participants with TS relative to 22 controls, as was activity in the middle frontal gyrus and caudate(Buse et al., 2016). In another paper by the same group, 17 adolescents with TS had more activation relative to 23 controls in the ACC in response to harmonic versus disharmonic musical chords, in contrast to healthy controls, who showed the opposite pattern(Buse et al., 2017). Further, activation during the harmonic chord sequence in the TS participants correlated with tic severity. In addition, the control participants had greater premotor cortex activation in the disharmonic versus the harmonic chords, whereas there was no such difference in the TS group(Buse et al., 2017).

2.6.3.7 Emotion and Theory of Mind

In an event-related fMRI study of neural responses to emotional faces, 19 adults with Tourette syndrome exhibited increased activation relative to 19 age- and sex-matched controls in the medial and dorsolateral aspects of the superior frontal gyrus, the IFG, and the anterior, middle and posterior cingulum, as well as the amygdala in response to any emotional facial expression(Neuner et al., 2010). An fMRI investigation compared 24 participants with TS and

24 age- and gender-matched healthy controls during performance of a theory of mind task(Clare

M. Eddy et al., 2016). TS participants had lower activations compared to controls in the temporoparietal junction (TPJ), posterior cingulate cortex (PCC), and superior frontal gyrus(Clare M. Eddy et al., 2016). In another investigation from the same study, this time using an emotion recognition task, the authors found that relative to the controls, the TS participants had increased activation in the TPJ, PCC and OFC(C. M. Eddy et al., 2017). In an interesting fMRI study, 21 adults with TS and 21 control participants were exposed to images of neutral and angry faces(Rae et al., 2018). TS participants had increased activation in IFG, and in the anterior insula, which showed task-related functional connectivity with middle frontal gyrus, ACC, pre-

SMA, premotor cortex, primary motor cortex and putamen. Furthermore, insula connectivity with globus pallidus and thalamus correlated with tic severity, and connectivity with SMA correlated with premonitory sensations(Rae et al., 2018).

2.6.3.8 Behavioural Therapy

An fMRI study compared 8 adult patients with TS before and after Comprehensive Behavioral

Intervention for Tics (CBIT), to 8 control participants matched for age, gender, education and

60 handedness before and after a 10 week waiting period, using the visuospatial priming task(Deckersbach et al., 2014). The authors use selective ROIs, and they do not elaborate on their choices. There were no prime-specific condition differences identified. The investigators resorted to comparing a concatenation of all visuospatial priming task conditions (negative, positive, and neutral) contrasted to a fixation cross condition. However, given the disparate conditions of the task, it is not clear what the meaning is of such an analysis and related findings.

Furthermore, such a contrast does not allow for the subtraction of nonspecific motor response effects. Bearing that in mind, the authors found an interaction between group and time, whereby there was a decrease in activation in the putamen from pre- to post-CBIT. The investigators carried out multiple correlations – changes in and pre-treatment scores for several symptom rating scales with task-related activation changes from pre- to post-CBIT. They found a significant negative correlation between changes in tic severity score and changes in activation in the IFG(Deckersbach et al., 2014).

2.6.3.9 Deep Brain Stimulation

In an interesting study, 5 adult patients with severe medically refractory TS undergoing centromedian and parafascicularis complex (CMPf) thalamic deep brain stimulation (DBS) had intraoperative fMRI scans done (while under general anesthesia) with and without stimulation in a block paradigm(Jo et al., 2018). Simulation was associated with widespread BOLD signal changes, including decreased activity in the ACC, OFC, medial PFC, caudate, nucleus accumbens and amygdala, increased activity in primary motor and parietal regions, and both

61 increased and decreased activity in the insula. BOLD signal changes in multiple areas correlated with reduction in tics, including ACC, OFC, insula, thalamus, amygdala and accumbens. The investigators also looked at BOLD signal changes and correlations based on tic type, i.e., vocal or motor. There were multiple such correlations across a wide range of brain regions. The authors argued that there were distinct BOLD signal changes and correlations for motor and vocal tics(Jo et al., 2018). Different results were obtained from a prior DBS study in which 5 adult patients with severe medically refractory TS underwent SPECT scanning at baseline and postoperatively (all under general anesthesia), as did 6 control participants (while awake)(Haense et al., 2016). The postoperative scans were carried out three months after either CMPf thalamus, globus pallidus internus (GPi), or sham stimulation. At baseline, regional cerebral blood flow

(rCBF) was decreased in the SMA and middle frontal cortex in the TS patients in comparison to controls. Relative to baseline, sham stimulation was followed by increase in SMA rCBF, and decrease in ACC, inferior, middle and superior frontal cortex, and striatum. GPi stimulation was associated with decrease in rCBF in inferior frontal cortex, striatum, and insula relative to baseline, and decrease in OFC, insula and striatum, and increase in superior and middle frontal cortex relative to sham stimulation. Thalamus CMPf stimulation was associated with rCBF decrease in inferior frontal cortex and increase in middle frontal cortex relative to baseline, and increase in SMA, middle and superior frontal cortex relative to sham stimulation. The authors suggest that the decreased rCBF in frontal regions in TS relative to controls could be reversed with DBS. It should be noted, however, that DBS in this study did not result in statistically significant improvement in tic symptoms relative to sham stimulation(Haense et al., 2016).

2.6.3.10 Cerebral Blood Flow and Metabolism

Besides MRI, functional neuroimaging studies using other modalities also point to the PFC as being involved in TS. In an early F-18 fluoro-deoxyglucose positron emission tomography

(FDG-PET) study, 16 adult patients with TS had decreased metabolic activity relative to 16 age- and sex-matched controls in ventral prefrontal cortex, in particular OFC, and ventral striatum, and increased metabolism in the SMA and lateral premotor cortices(A. R. Braun et al., 1993); in addition, cerebral metabolic rate in the OFC was positively associated compulsive and impulsive behavioral symptoms in the TS patients(A. R. Braun et al., 1995). In a SPECT study, 38 children with TS had lower regional cerebral perfusion than 18 control participants in the

DLPFC, OFC, cingulum and caudate(Diler et al., 2002). In an FDG-PET study of glucose metabolism across participant groups using principal components analyses, 12 adults with TS showed a pattern of resting metabolic activity that was decreased in the OFC and striatum and increased in the premotor cortex relative to 12 age- (but not sex-) matched controls(Pourfar et al.,

2011). Additional analysis within the TS group showed that the 6 participants considered to have clinically significant OCD symptoms had a metabolic activity pattern that was relatively decreased in the ACC and DLPFC and increased in the primary motor cortex(Pourfar et al.,

15 2011). In a H2 O PET study in which participants were shown pictures with asymmetrically ordered objects, 14 patients with TS and symmetry behavior had larger increase in rCBF in the

ACC relative to 10 controls, who had larger increase in dorsomedial PFC(de Vries et al., 2013).

The participants with TS reported higher urge to correct the asymmetry relative to controls; the ratings correlated with OFC activity in the TS group, whereas they correlated negatively with

DLPFC activation in the control group(de Vries et al., 2013).

2.6.3.11 Activation Likelihood Estimation

An activation likelihood estimation (ALE) meta-analysis included 14 task-based neuroimaging studies that compared participants with TS to controls, entailing 25 experiments and 651 child and adult participants(Polyanska et al., 2017). Differences between TS and control participants were identified in lateral PFC, including IFG, middle, and superior frontal gyri, ACC, lateral premotor cortex and SMA. In addition, correlation with tic severity were analyzed across 7 studies comprising 378 participants and 8 experiments. Tic severity in participants with TS was found to correlate with activations in the SMA, lateral premotor cortex, and lateral PFC (middle frontal gyrus).

2.6.4 Summary

Thus, cortical control regions have been found to be implicated in TS, though there are several inconsistent and even contradictory findings. In addition, multiple studies have not identified any differences between TS and control participants. A structural MRI VBM study did not find any differences between 38 boys with TS and 38 healthy boys matched for age and IQ(Roessner et al., 2009). A later study did not find any differences in gray or white matter between 24 children with TS and 18 controls using several methods including VBM, tract-based spatial- statistics analysis, fractional anisotropy, and apparent diffusion coefficient(Jeppesen et al., 2014).

An earlier study using large deformation high dimensional brain mapping to study basal ganglia structure did not identify any differences between 15 adult TS and 15 control participants matched for age, gender, and handedness(L. Wang et al., 2007). In terms of fMRI studies, as described earlier, an investigation using the Stroop, go/no-go and finger tapping tasks in 39 children with TS and 39 controls did not identify an brain differences between the groups(Debes et al., 2011a). Similarly, an earlier fMRI study in which adult participants were administered levodopa during the go/no-go task did not show any differences between 8 participants with TS and 10 controls(Hershey et al., 2004). These divergent findings may be a result of a multitude of variables that differ across studies including sample size, demographic characteristics, tic characteristics including severity, illness duration, comorbid conditions, medication use, consideration of online tics, extent of control participant matching, study task, image acquisition and processing techniques, methods for data analysis, and scanner hardware factors.

Further complications come from considerations around interpretations of study results. In particular, it can be difficult to judge whether brain findings are causally related to clinical symptoms on the one hand, or if they are the result of compensatory or adaptive changes.

Indeed, there are a number of studies in which participants with TS outperform healthy participants on measures of behavioral control(Valerie C. Brandt et al., 2017; Valerie Cathérine

Brandt et al., 2017; Hovik et al., 2016; G. M. Jackson et al., 2007; S. R. Jackson et al., 2011;

JeYoung Jung et al., 2015; Mueller et al., 2006; Tajik-Parvinchi & Sandor, 2011, 2012). For example, in a study described earlier, 13 children with TS had shorter reaction times than 13 gender- and age-matched controls during mixed trials of a manual task-switching paradigm(S. R.

Jackson et al., 2011). Subsequent neuroimaging showed widespread differences between the two

65 groups in the white matter microstructure, in particular the forceps minor, and the TS group had higher task-related fMRI BOLD signal in a right PFC ROI adjacent to the forceps minor(S. R.

Jackson et al., 2011). The suggestion from these studies is that chronic efforts at tic symptom suppression may contribute to an enhanced capacity with certain control tasks.

Nevertheless, a meta-analysis that included 61 studies of neuropsychological tasks found that overall TS patients exhibited inhibitory deficits compared to control participants(Morand-

Beaulieu et al., 2017). And, as per the ALE meta-analysis described above, evidence from task- based functional neuroimaging studies in TS implicate PFC control regions(Polyanska et al.,

2017). Based on a body of literature including post-mortem neuropathologic studies in patients with TS, as well as animal models of TS, it is believed that the basal ganglia, subcortical structures known for their role in habit formation and movement, are involved in the generation of tic symptoms (reviewed by Ganos and colleagues(Ganos et al., 2013b)). Thus, the overall picture suggests that TS involves a deficit in frontal cortical inhibition of aberrant basal ganglia output(Ganos et al., 2013b; Georgina M. Jackson et al., 2015; Stern et al., 2008b; Worbe,

Lehericy, et al., 2015).

Chapter 3

Aims and Hypotheses

The general aims of this thesis are to elucidate the pathophysiology of TS. The body of evidence to date suggests that TS involves a deficit in frontal cortical inhibition of aberrant basal ganglia output. However, findings from neuroimaging studies in TS have been mixed, and a definitive explanation of the neurobiology underlying TS has remained elusive. The objective of this thesis was to use novel approaches to investigate striatal D2/D3 dopamine receptors and cortical control regions. In a PET study, I used a novel radioligand with the aim of measuring striatal

D2/D3 dopamine receptor availability with higher sensitivity. In a separate fMRI study, I used an eye blink inhibition paradigm to investigate cortical control regions involved in self- regulatory fatigability in healthy subjects and participants with TS.

3.1 Striatal D2/D3 Dopamine Receptors in Adults with

Tourette Syndrome compared to Healthy Controls: A

[11C]-(+)-PHNO and [11C]Raclopride Positron Emission

Pharmacological and anatomical evidence implicates striatal dopamine receptors in Tourette syndrome (TS). Nevertheless, results of PET studies of the dopamine system in TS have been

67 inconsistent. I investigated striatal D2/3 dopamine receptors in TS using the radioligands

[11C]raclopride and [11C]-(+)-PHNO, an agonist that binds preferentially to D3 receptors, thus allowing higher sensitivity and measurement of receptors in a high affinity state.

Hypotheses:

1. Consistent with known distribution of D2 and D3 dopamine receptors, in all participants

[11C]-(+)-PHNO binding will be higher in ventral striatum, whereas [11C]raclopride

binding will be higher in motor and associative striatum.

2. TS participants will have higher [11C]-(+)-PHNO binding and [11C]raclopride binding

relative to healthy controls.

3. [11C]-(+)-PHNO binding and [11C]raclopride binding will correlate with tic and

comorbid symptom measures in TS participants.

3.2 The Neural Correlates of Self-Regulatory Fatigability

During Inhibitory Control of Eye Blinking

68 self-regulatory fatigability. Functional MRI was used to detect brain activations in healthy participants during inhibition of eye blinking.

Hypotheses:

1. Repeated effortful eye blink inhibition will show evidence of self-regulatory fatigability

manifesting as an increase in the number of eye blinks escaping inhibitory control.

2. Inhibition of blinking will invoke known cortical frontal control areas as well as regions

involved in experience of urge and interoceptive processing.

3. Self-regulatory fatigability will involve altered activity in PFC subregions involved in

self-regulatory control including the DLPFC, IFG and ACC, and interoceptive processing

areas such as the ventral PFC and parietal cortex.

3.3 Activation of Prefrontal Cortical Regions Associated

with Self-Regulatory Control in Tourette Syndrome

Relative to Healthy Controls

Given the ongoing need to manage multiple symptoms, patients with TS may be particularly susceptible to self-regulatory failure. Thus, using a paradigm that induces self-regulatory

69 fatigability can help elucidate differences in cortical control in TS participants relative to healthy controls.

Hypotheses:

1. Participants with TS will be more likely to manifest self-regulatory fatigability.

2. Relative to the healthy controls, participants with TS will have lower activation of IFG,

DLPFC, and SMA, and higher activation of OFC and ventromedial PFC.

Chapter 4

Striatal D2/D3 Dopamine Receptors in Adults with

Tourette Syndrome compared to Healthy Controls:

A [11C]-(+)-PHNO and [11C]Raclopride Positron

Emission Tomography Imaging Study

This study, titled “Similar Striatal D2/D3 Dopamine Receptor Availability in Adults with

Tourette Syndrome compared to Healthy Controls: A [11C]-(+)-PHNO and [11C]Raclopride

Positron Emission Tomography Imaging Study” has been published in Human Brain Mapping, with co-authors Barbara Segura, Ignacio Obeso, Sang Soo Cho, Sylvain Houle, Anthony Lang,

Pablo Rusjan, Paul Sandor, and Antonio Strafella(Abi-Jaoude et al., 2015). Copyright permissions have been granted.

4.1 Chapter Summary

Pharmacological and anatomical evidence implicates striatal dopamine receptors in Tourette syndrome (TS). Nevertheless, results of positron emission tomography (PET) studies of the dopamine system in TS have been inconsistent. I investigated striatal D2/3 dopamine receptors in TS using the radioligands [11C]raclopride and [11C]-(+)-PHNO, an agonist that binds preferentially to D3 receptors, thus allowing higher sensitivity and measurement of receptors in a high affinity state. Eleven adults with TS and eleven matched healthy control (HCs) participants underwent [11C]raclopride and [11C]-(+)-PHNO PET scans. General linear model was used for voxelwise contrasts of striatal binding potentials (BPND) between TS and HC participants.

Analysis of variance was carried out to investigate main effect of radioligand. In addition, BPND values were extracted for ventral, motor and associative striatum. Finally, we examined the relationship between BPND measures and symptom severity in TS participants. Main effects analyses showed that [11C]-(+)-PHNO BPND was higher in ventral striatum, whereas

[11C]raclopride BPND was higher in motor and associative striatum. There were no significant group differences between TS and HC. Furthermore, TS and HC participants had similar [11C]-

(+)-PHNO and [11C]raclopride BPND in the three striatal subregions. Moreover, there was no significant correlation between BPND and symptom severity. TS and HC participants had similar striatal D2/3 receptor availability measures. These results challenge the assumption that striatal dopamine receptors have a major role in the pathophysiology of TS. Consistent with previous findings, [11C]-(+)-PHNO localized preferentially to ventral striatal, D3 receptor-rich regions, in contrast to [11C]raclopride, which localized preferentially in the dorsal striatum.

4.2 Introduction

As described in the Literature Review section 2.6.1, there has been longstanding interest in the role of dopamine in TS(Buse et al., 2013; Hugh Rickards, 2009; Segura & Strafella, 2013).

Indeed, the first and most widely studied ligands in receptor nuclear imaging studies in TS have targeted the dopamine system(Hugh Rickards, 2009). Striatal dopamine receptors are of particular interest given their role in habit formation, and evidence implicating the striatum in

TS(Ganos et al., 2013a).

Two single-photon emission computed tomography (SPECT) studies that investigated striatal D2 receptors in TS using the D2 receptor antagonist [123I]iodobenzamide ([123I]-IBZM) both found decreased ligand binding in the basal ganglia of medicated patients with TS but no difference in unmedicated TS subjects in comparison to controls(George et al., 1994; K. R.

Müller-Vahl et al., 2000). The most recent TS report using [123I]-IBZM found no difference in ligand uptake between TS patients and controls(Hwang et al., 2008). An interesting earlier

[123I]-IBZM SPECT investigation in 5 monozygotic twin pairs with TS found higher binding in the caudate of the more severely affected twin; further, the within pair difference in binding correlated positively with within pair differences in tic severity(Wolf et al., 1996).

An early small PET study using the D2 and D3 receptor antagonist [11C]raclopride found no differences in 5 TS participants in comparison to healthy controls(Turjanski et al., 1994). A larger study focusing specifically on the caudate and using the D2 receptor antagonist

[11C]methylspiperone did not find differences in TS participants compared to controls(Wong et al., 1997). A subsequent study with [11C]raclopride in 7 TS patients again showed no baseline difference in D2/D3 striatal receptor availability(Harvey S. Singer et al., 2002). A study investigating various neurotransmitter measures found no baseline differences in [11C]raclopride binding potential (BP) between the 12 TS subjects and 3 healthy controls with complete data(Wong et al., 2008). Interestingly, using high- and low-specific activity [11C]raclopride scans, the investigators estimated D2 receptor affinity to be higher in the anterior putamen in TS subjects relative to the controls. In the most recent PET study of its kind, using the radioligand

[11C]raclopride, Denys and colleagues found lower D2/D3 striatal receptor availability in the putamen of 12 TS participants compared to 12 healthy controls(Denys et al., 2013).

Thus, the findings from striatal dopamine receptors studies in TS have been inconsistent.

“supersensitivity” has been hypothesized as an underlying pathophysiological mechanism in

TS(Buse et al., 2013; Segura & Strafella, 2013; H. S. Singer et al., 1982), only one group has actually investigated this question(Wong et al., 2008).

In this study, I investigate striatal dopamine receptors in TS using two different ligands, the D2/3 receptor antagonist [11C]raclopride, as well as [11C]- (+)-Propyl-Hexahydro-Naphtho-Oxazin

([11C]- (+)-PHNO), an agonist with preferential binding to D3 dopamine receptors. This unique binding profile allows the evaluation of differences in D2 versus D3 receptors, which would not be possible with [11C]raclopride alone. Furthermore, because [11C]- (+)-PHNO is an agonist, it can permit the measurement of dopamine receptors in their high affinity state, thus providing an opportunity to interrogate whether striatal dopamine receptor affinity is involved in the pathophysiology of TS(Ginovart et al., 2006; Sibley et al., 1982; Willeit et al., 2006). To my knowledge, this is the first study using the [11C]- (+)-PHNO ligand in TS.

4.3 Methods

Participants

A total of 22 adult subjects, 11 with TS and 11 matched healthy controls (HCs) participated in the study. The participants with TS were recruited through the Tourette Syndrome

Neurodevelopmental Clinic at the Toronto Western Hospital, Toronto, Canada. HC participants were recruited through postings and web advertisements. The groups were matched for age and sex. The group mean age and standard deviation was 34.0 ± 7.9 for the HC, and 32.2 ± 10.1 for the TS subjects.

The subject assessments, neuroimaging scans and data analysis were carried out at the PET

Center, Research Imaging Center at the Center for Addiction and Mental Health, Toronto,

Canada. The study was approved by the relevant institutional research ethics boards. The study was conducted in compliance with the Code of Ethics of the World Medical Association

(Declaration of Helsinki) and the standards established by the relevant Institutional Review

Board and granting agencies. All participants received financial reimbursement. After complete description of the study to the subjects, written informed consent was obtained from all study participants prior to any procedures.

Clinical Measures

I carried out a neuropsychiatric assessment on all study participants. Diagnoses of TS and other comorbidities including obsessive-compulsive disorder (OCD) and attention deficit/hyperactivity disorder (ADHD) were made according to criteria in the Diagnostic and Statistical Manual of

Mental Disorders, 4th edition, Text Revision (DSM-IV-TR; American Psychiatric Association,

2000). Tic severity scores were measured with the Yale Global Tic Severity Scale – Total Tic

Score (YGTSS-TTS; Leckman et al. 1989), and obsessive-compulsive symptoms were measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS; Goodman, Price, Rasmussen,

Mazure, Fleischmann, et al. 1989; Goodman, Price, Rasmussen, Mazure, Delgado, et al. 1989).

A detailed medication history was obtained from patient interview and chart review.

Image Acquisition

Each study subject underwent two PET scans on separate days, and one magnetic resonance imaging (MRI) scan. PET scans were carried out with a high-resolution PET / Computed tomography (CT), Siemens-Biograph HiRez XVI (Siemens Molecular Imaging, Knoxville, TN,

USA) operating in 3D mode with an intrinsic in-plane resolution of ∼ 4.6 mm full width at half- maximum (FWHM). To minimize head motion, subjects were fitted with a custom-made thermoplastic facemask that was secured to the scanner platform (Tru-Scan Imaging, Annapolis).

Prior to each emission scan, a scout view was used to verify accurate subject head positioning, and a low dose (0.2 mSv) CT scan was acquired to correct for attenuation.

Radioligands were injected into the left antecubital vein. [11C]raclopride (mean ± standard deviation; mean dose 10.0 ± 0.7 mCi; specific activity 1924 ± 582 mCi/µmol; mass 2.0 ± 0.6 µg) emission data were acquired over 60 minutes and subsequently redefined into 28 frames of progressively increasing duration (five 1-minute frames, 20 2-minute frames, and three 5-minute frames). [11C]- (+)-PHNO (mean dose 9.6 ± 1.4 mCi; specific activity 1286 ± 388 mCi/µmol; mass 2.0 ± 0.4 µg) emission data were acquired over 90 minutes and subsequently redefined into

30 frames of progressively increasing duration (fifteen 1-minute frames and fifteen 5-minute frames). The radiosynthesis of [11C]- (+)-PHNO has been described in detail elsewhere(Wilson et al., 2005). For each 3D sinogram, data was normalized for attenuation and scatter corrected before applying fourier rebinning to convert the 3D sinograms into 2D sinograms. The 2D sinograms were then reconstructed into image space using a 2D filtered back projection

77 algorithm, with a ramp filter at Nyquist cut-off frequency. After reconstruction, a Gaussian filter with a 5 mm FWHM was applied.

MRI scans were done to rule out structural brain abnormalities and to provide anatomical reference for the image analyses. A T1-weighted MRI image was obtained for each subject using a high-resolution MRI (GE Discovery MR750 3T, T1-weighted images, FSPGR with repletion time = 6.7 ms, echo time = 3.0 ms, flip angle = 8 mm, slice thickness = 1 mm, NEX =

1, matrix size = 256×192).

Image Analysis

PET imaging analysis was carried out in MATLAB version 7.4 (Mathworks Inc., Natick, Mass.,

USA) using an in-house image analysis platform(Gunn et al., 1997; Lammertsma & Hume,

1996). After frame realignment for motion correction in SPM2 (Wellcome Department of

Imaging Neuroscience, London, UK; http://www.fil.ion.ucl.ac.uk/spm), motion-corrected PET frames were summed, coregistered to the corresponding MRI and transformed into Montreal

Neurological Institute (MNI) standardized stereotaxic space(Collins et al., 1994) using the transformation parameters of the individual structural MRIs. Voxelwise non-displaceable parametric binding potentials (BPND) were calculated using a simplified reference tissue

(cerebellum) method(Gunn et al., 1997). Subsequent to calculation of BPND, parametric BPND images were smoothed in SPM8 (Wellcome Department of Imaging Neuroscience, London, UK;

78 http://www.fil.ion.ucl.ac.uk/spm) with a Gaussian function at 4 mm FWHM. Statistical parametric analysis was carried out in SPM8 to obtain voxelwise general linear model contrasts

11 11 comparing striatal BPND between the TS and HC groups for [ C]raclopride and [ C]- (+)-

PHNO. In addition, a 2 x 2 repeated measures analysis of variance (ANOVA), with radioligand

([11C]raclopride and [11C]- (+)-PHNO) and group (HC and TS) included as factors was carried out to obtain a main effect of radioligand. Statistical map thresholds were set at p < 0.05, family- wise error-corrected, with an extent threshold k = 5 voxels. Furthermore, we conducted region of interest (ROI) analysis using probabilistic ROI masks, created manually as previously described(Martinez et al., 2003; Mawlawi et al., 2001), using a histologically-based basal ganglia brain atlas(Chakravarty et al., 2006). BPND values were extracted for ventral, motor and associative striatum for each subject with the MarsBaR ROI toolbox(Brett et al., 2002). We then used SPSS (Version 16.0) to compare the extracted BP values between HC and TS for each of the striatal regions, using 2-tailed student t-tests and a p-value threshold of 0.05. Moreover,

Pearson correlation coefficients were calculated between [11C]raclopride and [11C]- (+)-PHNO

BPND on the one hand, and YGTSS-TTS and Y-BOCS severity rating total scores on the other.

Mean BP images were visualized using MRIcro(Rorden & Brett, 2000), and BPND voxelwise contrasts were visualized using the xjView toolbox (http://www.alivelearn.net/xjview).

4.4 Results

Demographic and Clinical Characteristics

Table 4-1 shows demographic and clinical characteristics of TS study participants. Six of the TS subjects had no comorbidities. Three TS subjects had OCD, four had ADHD, and two had a past history of substance abuse. Of the three patients with comorbid OCD, one was female, two had a past history of substance abuse, and their mean age 31.7 years (± 5.5), which was not significantly different from that of the rest of the TS participants, or the HC group. Based on

YGTSS-TTS, tic symptoms ranged from mild to severe. With the exception of one TS subject who had started a low dose of clonidine one month prior to participating, none of the subjects were on psychotropic medication when they took part in the study. Three patients had been on medication up to 3 months prior to their participation in the study: dextroamphetamine/amphetamine for 3 months (discontinued 3 months prior to scanning); clonidine for 1 year (discontinued 3 months prior to scanning); SSRI for 3 weeks (discontinued 4 months prior to scanning). For three other patients that had been on psychotropic medication, these had been discontinued at least 6 months prior: antipsychotic for 1 month (discontinued 6 months prior to scanning); antipsychotic (discontinued 10 months prior to scanning); remote brief trial of methylphenidate (16 years prior to the study). Four of the 11 TS participants were medication naïve. Further, six of the TS participants were naïve to dopaminergic medication, seven if the participant with a brief remote trial of methylphenidate is included. As detailed above, one patient had been on dextroamphetamine/amphetamine up to 3 months prior to scanning, and three had been on dopamine antagonist and/or agonist medication at least 6 months prior to scanning (see Table 4-1 for further details). The mean age of participants in the

TS group was 32.2 years (standard deviation ± 10.1), and in the HC group 34.0 years (± 7.9).

There were 2 females and 9 males in each of the TS and HC groups. The HC and TS groups each received similar amounts of radioligand for the [11C]raclopride (mean ± standard deviation;

HC: mean dose 10.1 ± 0.5 mCi, specific activity 1843 ± 480 mCi/µmol, mass 2.0 ± 0.6 µg; TS: mean dose 9.9 ± 0.9 mCi, specific activity 2004 ± 684 mCi/µmol, mass 1.9 ± 0.6 µg; p>0.5) and for the [11C]- (+)-PHNO (HC: mean dose 9.4 ± 1.5 mCi, specific activity 1262 ± 373 mCi/µmol, mass 2.0 ± 0.4 µg; TS: mean dose 9.7 ± 1.5 mCi, specific activity 1310 ± 419 mCi/µmol, mass

2.0 ± 0.5 µg; p>0.5) scans.

Striatal dopamine receptor radioligand binding

Mean striatal BP images are displayed in Figure 4-1, which shows similar radioligand binding for the TS and HC groups. Statistical parametric maps of voxelwise contrasts comparing BPND in the TS and HC groups showed no significant voxels with either [11C]raclopride or [11C]- (+)-

PHNO. Individual participant BPND for each of the ligands, across motor, associative and ventral subregions of the striatum are shown in Figure 4-2. There were no group differences in BPND in any of the striatal subregions with either radioligand, nor was there a trend in either direction. I

11 11 also extracted group mean [ C]raclopride and [ C]- (+)-PHNO BPND values separately for right and left striatal subregions, and calculated group difference 95% confidence intervals. There were no notable trends and most confidence intervals were fairly symmetrical with respect to zero and showed good precision (Table 4-2). Secondary analyses comparing the three patients with comorbid OCD to the HC group did not reveal any significant differences in BPND in any of the striatal subregions with either of the radioligands. I also tested the correlations between

11 11 BPND of striatal subregions and YGTSS-TTS for [ C]raclopride (Figure 4-3A) and [ C]- (+)-

PHNO BPND (Figure 4-3B) in TS participants. While there was a positive correlation between

11 [ C]raclopride BPND and YGTSS-TTS in the ventral striatum (r = 0.62, p-value = 0.044), this would not survive a correction for multiple comparisons. Otherwise, none of the correlations were significant. Likewise, there were no significant correlations between either radioligand

BPND and Y-BOCS severity rating total scores (data not shown). Radioligand main effects

11 analysis from the ANOVA showed that [ C]- (+)-PHNO BPND was higher in ventral striatum,

11 whereas [ C]raclopride BPND was higher in motor and associative striatum (Figure 4-4; see also

Figure 4-2).

Table 4-1. Demographic and clinical characteristics for Tourette syndrome participants

Past Medications (listed Participant Comorbid YGTSS- Medications at in reverse chronological number Age Sex Education diagnoses TTS Y-BOCS time of scan order)

6 months prior to scan, 1 month trial of aripiprazole 4 mg daily; > 3 years prior to scan: clonazepam, ziprasidone, 1 28 M College none 30 12 nil tetrabenazine, ropinirole, pergolide, risperidone, carbidopa/levodopa, clonidine, buproprion, donepezil, quetiapine, pimozide, haloperidol, nitrazepam

2 43 M University none, OCS 13 13 nil nil

10 months prior to scan: ziprasidone, High OCS, 3 29 M 38 12 nil aripiprazole, buproprion, School ADHD methylphenidate, haloperidol

4 33 F University none 8 0 nil nil

5 55 M University none 26 6 nil nil

ADHD, methylphenidate brief 23 M University 9 11 nil 6 LD trial at age 7

clonidine x 1 year, 7 18 M University none 31 0 nil discontinued 3 months prior to scan

OCD, ADHD, clonidine 0.15 mg daily, 38 M College substance 9 19 clonidine started 1 month prior to abuse scan 8 (past)

none, mild 9 30 M University 16 0 nil nil OCS

OCD, dextroamphetamine/amp MDD hetamine 20 mg for 3 (past), months, discontinued 3 29 M University 23 19 nil substance months prior to scan; abuse paroxetine > 2 years 10 (past) prior to scan

4 months prior to scan: OCD, escitalopram 10 mg x 3 ADHD, albuterol, weeks; prior to this: High asthma, fluticasone, 11 28 F 16 26 sertraline, mirtazapine, School subclinical acetaminophen melatonin, clonidine, hyperthyro /codeine methylphenidate, idism carbidopa/levodopa,

trazodone, zopiclone, domperidone, imipramine, risperidone

M=male; F=female; OCS=obsessive-compulsive symptoms; ADHD=attention deficit/hyperactivity disorder; LD=learning disability; OCD=obsessive-compulsive disorder; MDD=major depressive disorder; YGTSS-TTS=Yale Global Tic Severity Scale – Total Tic Score; Y-BOCS=Yale-Brown Obsessive Compulsive Scale

11 11 Table 4-2. [ C]raclopride and [ C]-(+)-PHNO BPND for TS and HC subjects, with group difference 95% confidence intervals across striatum subregions.

[11C]raclopride [11C]-(+)-PHNO

HC TS HC TS

N=11 N=11 N=11 N=11

2.35 2.40 1.71 1.77 Left (-0.26, 0.16) (-0.21, 0.08) Motor Striatum 2.48 2.54 1.72 1.79 Right (-0.31, 0.19) (-0.23, 0.10)

2.18 2.10 1.61 1.57 Left (-0.17, 0.34) (-0.16, 0.25) Associative Striatum 2.04 2.04 1.45 1.45 Right (-0.27, 0.26) (-0.20, 0.21)

2.24 2.16 2.96 2.90 Left (-0.16, 0.32) (-0.19, 0.32) Ventral Striatum 2.31 2.31 2.81 2.69 Right (-0.23, 0.24) (-0.14, 0.38)

Figure 4-1. HC (N=11) and TS (N=11) group [11C]raclopride (transverse view) and [11C]- (+)-PHNO (coronal view) mean BP images.

HC=healthy controls; TS=Tourette syndrome; BP=binding potential

Figure 4-2. Individual participant and group average (green horizontal bar) 11 11 [ C]raclopride (black) and [ C]-(+)-PHNO (red) BPND for HC (circles, N=11) and TS (triangles, N=11) across striatal subregions.

BPND=Non-displaceable binding potential; HC=healthy control; TS=Tourette syndrome

Figure 4-3. Radioligand striatal subregion BPND correlations with YGTSS-TTS

BPND=Non-displaceable binding potential; YGTSS-TTS=Yale Global Tic Severity Scale – Total Tic Score

Figure 4-4. Transverse brain slices of statistical parametric map of radioligand main effect 11 with ANOVA (2 x 2, repeated measures): Areas with higher [ C]raclopride BPND are 11 shown in cool colors, and those with higher [ C]-(+)-PHNO BPND in warm colors (FWE- corrected p-value > 0.05).

BPND=Non-displaceable binding potential; FWE=family-wise error

4.5 Discussion

This is the first study using [11C]- (+)-PHNO to investigate D2/3 receptors in TS. Consistent

11 with previous findings, I showed that [ C]- (+)-PHNO BPND was higher in ventral striatum, and

11 [ C]raclopride BPND was higher in motor and associative striatum. However, I did not find any

11 11 differences in [ C]- (+)-PHNO or [ C]raclopride BPND between TS and HC groups. Further, there was no relationship between symptom severity scores and BPND for either radioligand. In addition, I found no significant differences in the three patients with comorbid OCD, though this is limited by the small number of participants in this subgroup. The TS and HC groups were well-matched, and most of the TS participants did not have a history of significant exposure to medications that directly influence dopamine transmission. Moreover, the TS participants are a good representation of the TS population in terms of comorbidities and range of symptom severity. These findings do not support a role for changes in striatal D2 or D3 receptor availability or affinity in the pathophysiology of TS.

A number of possible explanations should be considered in interpreting my findings.

Radioligand binding in vivo is influenced by the number of available receptors, endogenous dopamine levels, and receptor affinity. It is thus conceivable that opposing processes – for example, increased dopamine receptor affinity but also increased binding competition from endogenous dopamine – may cancel out each other’s effects on radioligand binding such that overall receptor availability as measured by BPND remains unchanged. Since I do not have an estimate of endogenous dopamine levels, I cannot rule out this possibility with this study.

Moreover, it is possible that striatal dopamine changes in TS are limited to specific micro areas

91 that are beyond the reach of the spatial resolution of current in vivo imaging. In addition, it is likely that the pathophysiology of TS is variable across individuals, and as such, it is possible that striatal dopamine receptors are involved in only a subset of TS patients. Such a possibility cannot be tested in a reliable fashion with typical sample sizes of most PET studies, including mine. One might wonder whether increasing my sample size could result in significant differences between TS and HC groups; however, the data do not suggest any trend, in either direction. Indeed, the effect sizes were all fairly small; further, the confidence intervals were almost all symmetrical around the null (see Table 4-2), and were fairly narrow, comparable to the standard deviations. The sample size of 11 HC and 11 TS participants was larger or comparable to that of other studies of striatal dopamine receptors in TS. Importantly, based on the effect sizes, p-values and confidence intervals, there is no trend in the data to suggest that increasing sample size would result in a positive finding. This is most clearly illustrated by the individual participant BPND values plotted in Figure 4-2.

While striatal dopamine receptors have been believed to be involved in the pathophysiology of

TS (Buse et al. 2013), the literature is far from consistent, and studies reported as positive are often limited by methodological issues. The [123I]-IBZM SPECT studies reviewed in the

Literature Review section 2.6.1 found decreased binding only in medicated patients(George et al., 1994; K. R. Müller-Vahl et al., 2000). This is likely the result of competitive dopamine receptor binding by antipsychotic medications. In one study, 5 unmedicated patients with a disease duration of 15 years and greater had lower binding compared to the controls, and there was an inverse relationship between ligand uptake and disease duration in the 10 unmedicated patients(K. R. Müller-Vahl et al., 2000); however, this finding did not adequately account for

92 age, which differed between the groups and was also inversely related to ligand uptake.

Furthermore, there was no relationship between ligand uptake and symptom severity(K. R.

Müller-Vahl et al., 2000). The study showing higher [123I]-IBZM caudate binding in the more severely affected twin among 5 twin pairs with TS(Wolf et al., 1996) is interesting but has not been replicated in a larger sample. Initial PET investigations did not identify differences in striatal dopamine receptor availability between TS and HC participants(H.S. Singer et al., 2002;

Turjanski et al., 1994; Wong et al., 1997). The study by Wong and colleagues(Wong et al.,

1997) estimated D2 receptor affinity to be higher in the anterior putamen in 12 TS subjects; however, the control group was comprised of only the 3 subjects with complete data. Moreover, despite numerous tests in that study, there was no correction for multiple comparisons. Of note, consistent with our findings, there were no group differences in their primary outcome measure of striatal D2/3 receptor binding potential. The [11C]raclopride study by Denys and colleagues found lower D2/D3 striatal receptor availability in the putamen of 12 TS participants, most of whom were medication naive(Denys et al., 2013). The discrepant results relative to our findings may be related to one or more of the following factors in that study: the groups were not matched for gender; there were higher depression and anxiety scores in the TS group; there was no information about comorbid ADHD.

In conclusion, I have shown similar striatal D2/D3 dopamine receptor availability in adults with

TS compared to HC using the radioligands [11C]- (+)-PHNO and [11C]raclopride. My results challenge the widely assumed role of striatal dopamine receptors in the pathophysiology of TS.

While dopamine has long been believed to underlie the pathophysiology of TS, decades of investigation have yielded inconsistent results.

Chapter 5

The Neural Correlates of Self-Regulatory Fatigability

During Inhibitory Control of Eye Blinking

This study, titled “The Neural Correlates of Self-Regulatory Fatigue During Inhibitory Control of Eye Blinking” has been published in The Journal of Neuropsychiatry and Clinical

Neurosciences, with co-authors Barbara Segura, Sang Soo Cho, Adrian Crawley, and Paul

Sandor(Abi-Jaoude et al., 2018a). Copyright permissions have been granted.

5.1 Chapter Summary

The capacity to regulate urges is an important human characteristic associated with a range of social and health outcomes. Self-regulatory capacity has been postulated to have a limited reserve, which, when depleted, leads to failure. I set out to investigate the neural correlates of self-regulatory fatigability. Functional MRI was used to detect brain activations in 19 right- handed healthy participants during inhibition of eye blinking, in a block design. The increase in number of blinks during blink inhibition from the first to the last block was used as covariate of interest. There was an increase in the number of eye blinks escaping inhibitory control across blink inhibition blocks, whereas there was no change in the number of eye blinks occurring during rest blocks. Inhibition of blinking activated a wide network bilaterally including inferior frontal gyrus, dorsolateral prefrontal cortex, dorsal anterior cingulate cortex, supplementary motor area, and caudate. Deteriorating performance was associated with activity in orbitofrontal cortex, ventromedial prefrontal cortex, rostroventral anterior cingulate cortex, precuneus, somatosensory and parietal areas. As anticipated, effortful eye blink control resulted in activation of prefrontal control areas and regions involved in urge and interoceptive processing.

Worsening performance was associated with activations in brain areas involved in urge, as well as regions involved in motivational evaluation. My findings suggest that self-regulatory fatigability is associated with relatively less recruitment of prefrontal cortical regions involved in executive control.

5.2 Introduction

The capacity to regulate urges is an important human characteristic associated with a range of academic, financial, legal, physical and mental health outcomes(Francis & Susman, 2009;

Kubzansky et al., 2009; W. Mischel et al., 1989; Walter Mischel et al., 2011; Moffitt et al., 2011;

Poulton et al., 2015; Seeyave et al., 2009). Early experiments that started in the 1960s by Walter

Mischel and colleagues found that preschoolers’ ability to delay gratification was predictive of better performance based on various social, psychological and health measures even 40 years later(W. Mischel et al., 1989; Walter Mischel et al., 2011). A series of follow-up studies showed that the number of seconds preschoolers were able to wait for a delayed reward correlated with higher sense of self-worth and self-esteem, better distress tolerance, less interpersonal difficulties, and less substance abuse(Walter Mischel et al., 2011). In another long-term follow- up investigation, ability to delay gratification at age 4 years was found to be associated with increased likelihood of being overweight at age 11 years(Seeyave et al., 2009), with similar findings obtained in yet another such study(Francis & Susman, 2009). Similar results have been obtained from the Dunedin Multidisciplinary Health and Development Study, in which measures of self-control in childhood predicted better health and functional outcomes in adulthood(Moffitt et al., 2011; Poulton et al., 2015),. These findings underscore the important role of self- regulatory capacity in mental health, physical health and psychosocial functioning.

Self-regulatory capacity has been postulated to involve limited reserve, which, when depleted, leads to failure(Baumeister & Heatherton, 1996; Hagger et al., 2010). An alternative explanation

96 to this resource depletion model is that self-regulatory failure after initial effort is mediated by a shift in motivation, emotion and attention towards more inherently rewarding action(Dang et al.,

2017; Inzlicht et al., 2014). These models may not be mutually exclusive, and may in fact be complementary. Fatigue can be seen as a cost/benefit calculation and may be caused by increased cost of continued effort, decreased value of reward, and depleted internal resources(Boksem & Tops, 2008). Thus, continued effort in an activity without a commensurate reward can result in an unfavorable cost/benefit evaluation and a shift in motivation towards activity that is more rewarding. Self-regulatory fatigability has been postulated as a process through which efforts to resist cravings in addiction can fail(Levy, 2006). Indeed, several studies have implicated self-regulatory fatigability in substance abuse and addiction(Dvorak & Simons,

2009; Gauggel et al., 2010; Hagger et al., 2013; Hofmann et al., 2012; Moeller et al., 2012). In addition, deficits in sustained attention, recognized as a feature of attention deficit/hyperactivity disorder (ADHD)(Barkley, 1997; Gmehlin et al., 2016; Tucha et al., 2017), can also be conceptualized as a form of self-regulatory fatigability(Thomson et al., 2015). Interestingly, subjective perception of mental effort during attention tasks correlates with extent of reported

ADHD symptoms(Hsu et al., 2017; Panetta et al., 2016). Self-regulatory fatigability may also be involved in other psychiatric conditions that are known to entail deficits in self-regulation, including Tourette syndrome, obsessive-compulsive disorder (OCD), behavioral addictions

(pathological gambling, video game addition, sex/pornography addiction), bulimia nervosa, and sleep deprivation. Of note, frontal control neural systems have been found to be implicated in these conditions.

The neural basis of self-regulation is believed to involve prefrontal cortical executive control, particularly the dorsal, lateral, and medial regions of the prefrontal cortex (PFC)(Goldstein &

Volkow, 2011; Kelley et al., 2015). There have been few studies that investigated the neural basis of the phenomenon of self-regulatory fatigability. These have used a variety of different self-regulatory tasks, including emotion suppression, cognitive control, and impulse control. An early study found that white volunteers performed more poorly on the Stroop task following interaction with black individuals; the degree of worsening in Stroop performance correlated highly with racial bias scores on the implicit association test, an unobtrusive behavioral measure of racial bias(Richeson et al., 2003). The rationale is that white volunteers with higher racial bias scores required more self-regulatory effort during interaction with black individuals, which resulted in more self-regulatory fatigability during their Stroop performance. In a separate session, functional magnetic resonance imaging (fMRI) showed that activity in the right dorsolateral prefrontal cortex (DLPFC) in response to viewing black faces predicted the Stroop interference that followed the interracial interaction(Richeson et al., 2003). A later study by

Inzlicht and Gutsell (2007) found that after a self-control activity in which subjects were required to suppress their emotions while watching an emotional movie, subsequent performance on the

Stroop task was worse compared to that of subjects who watched the movie normally; moreover, electroencephalographic recordings during the Stroop task showed that the worsened performance was mediated by a weaker dorsal anterior cingulate (dACC)-associated error-related negativity signal(Inzlicht & Gutsell, 2007). This was later replicated by another group(Y. Wang et al., 2014). Of interest, in the more recent replication, when subjects were instructed to regulate their emotions by reappraisal rather than suppression, there was no worsening of performance on the subsequent Stroop task, nor weakening of the error-related negativity signal(Y. Wang et al., 2014). In an fMRI study, following an attention control task that involved

98 having to pay attention to a film while ignoring distracting words appearing on screen, participants showed increased activity in the amygdala when shown negative emotional scenes, as well as decreased functional connectivity between the left amygdala and the ventromedial

PFC(Wagner & Heatherton, 2013). The same attention control task was used by the same group with chronic dieter participants, who subsequently had greater food-cue-related activity in the orbitofrontal cortex (OFC), and decreased functional connectivity between the OFC and the inferior frontal gyrus (IFG), in comparison to chronic dieter participants not exposed to the attention control task(Wagner et al., 2013). In another fMRI study, participants who suppressed their emotions while viewing images that included negatively valenced pictures subsequently had worse performance on the Stroop task, with decreased activity in the right DLPFC compared with control participants(Friese et al., 2013). A particularly interesting fMRI study recruited individuals who had taken part in the original preschooler gratification delay studies 40 years earlier to perform a go/no-go task; those individuals who had been identified as “high delayers”

(i.e., those that were better able to delay gratification) showed significantly greater right IFG activation in the nogo versus the go trials, in comparison to the participants identified as “low delayers”(Casey et al., 2011). Finally, another, more recent fMRI study with participants from the original preschooler gratification delay studies suggested that the “high delayers” recruited a network of brain areas including IFG, ACC/superior frontal gyrus more efficiently in comparison to the “low delayers” during a working memory task(M. G. Berman et al., 2013). Overall, studies investigating the neural basis of self-regulatory fatigability have implicated the PFC, in particular, dorsal, lateral, and medial regions.

Here, I contribute to this emerging literature with an fMRI investigation of the neural mechanisms of the phenomenon of self-regulatory fatigability via an eye blink inhibitory control paradigm. I hypothesized that: repeated effortful eye blink inhibition will show evidence of self- regulatory fatigability manifesting as an increase in the number of eye blinks escaping inhibitory control; inhibition of blinking will invoke known cortical frontal control areas as well as regions involved in experience of urge and interoceptive processing; self-regulatory fatigability will involve altered activity in PFC subregions involved in self-regulatory control including the

DLPFC, IFG and ACC, and interoceptive processing areas such as the ventral PFC and parietal cortex.

5.3 Methods

Participants

A total of 20 right-handed adult subjects participated in the study. Participants were recruited through postings at local university hospitals and the university campus. I carried out psychiatric assessments on all study participants to rule out any psychiatric or other health condition. One of the subjects was found to have had a history of cerebral palsy and was excluded. The group mean age was 32 years, ranging from 20 to 49. There were 14 male and 5 female participants.

The subject assessments, neuroimaging scans and data analysis were carried out at the Toronto

Western Hospital – University Health Network, Toronto, Canada. The study was approved by

100 the relevant institutional research ethics board. The study was conducted in compliance with the

Code of Ethics of the World Medical Association (Declaration of Helsinki) and the standards established by the relevant Institutional Review Board and granting agencies. All participants received financial reimbursement. After complete description of the study to the subjects, written informed consent was obtained from all study participants prior to any procedures.

Behavioral Task

The task, carried out in a block design, consisted of one-minute ‘no blink’ blocks of effortful inhibition of eye blinking, alternating with one-minute ‘blink’ blocks without such inhibition.

There were two runs, 6 minutes each. Participants were given visual prompts for each block type, delivered via goggles: a horizontal oval to indicate the blocks for keeping the eyes open; a horizontal line to indicate that subjects could blink. Escape blinks, i.e., blinks that occurred during ‘no blink’ blocks, were monitored via an infrared camera attached to the participants’ goggles, and were manually recorded. There was a 5-minute break between runs, during which the participants viewed images of water (for a separate study). Participants were told how many runs to expect.

Image Acquisition

101

Images were acquired with a 3.0 T GE clinical scanner (GE Medical Systems, Milwaukee,

Wisconsin, USA), using an 8-channel head coil. T1-weighted image parameters were as follows: repetition time 12.0 s, echo time 5.1-15.0 ms, flip angle 20°, slice thickness 1.5 mm, number of

2 * slices 106, field of view 20x20 cm , and a matrix size of 256x256. T2 -weighted image parameters were: repetition time 2.0 s, echo time 30 ms, flip angle 85°, slice thickness 4.5 mm, number of slices 30, field of view 24x24 cm2, and matrix size 64x64.

Image Analysis

Image analysis was carried out in SPM8 (Wellcome Department of Imaging Neuroscience,

London, UK; http://www.fil.ion.ucl.ac.uk/spm). Images underwent standard preprocessing that included: slice timing correction, motion correction, normalization to the Montreal Neurological

Institute (MNI) EPI template, followed by spatial smoothing with a Gaussian function at 8 mm full width at half-maximum (FWHM). Subsequently, voxelwise statistical parametric analysis was carried out to obtain general linear model contrasts between the ‘no blink’ and the ‘blink’ blocks. The latter 40 seconds of each one-minute block was used for analyses in order to maximize the capture of effort and fatigue. Following this, the increase in number of escape blinks was used as a covariate of interest. Finally, the top performers, i.e., those that had the least increase in escape blinks, were contrasted with the worst performers, i.e., those that had the most increase in escape blinks. For the behavioral measures, statistical significance was defined at a p value threshold of 0.05. For the imaging data, the main effects analyses (‘no blink’ and

‘blink’ block contrasts) significance was set at 0.05, Family Wise Error-corrected. Due to

102 decreased power, in the subsequent analyses p value correction was done via extent thresholding.

For the analyses involving escape blinks as a covariate, significance was set at 0.01, with extent thresholding k = 25 voxels. For the comparison of the subjects based on performance, significance was set at 0.05, with extent thresholding k = 50 voxels. Voxelwise contrast images were visualized using the xjView toolbox (http://www.alivelearn.net/xjview).

5.4 Results

There was an increase in the number of eye blinks escaping inhibitory control across blink inhibition blocks, from an average (± standard deviation) of 4.2 (± 5.9) escape blinks in the first

‘no blink’ block to 6.8 (± 8.4) in the sixth ‘no blink’ block (Figure 5-1). Thus, there was an average increase of 2.6 (± 3.8) escape blinks from the first to the last ‘no blink’ blocks (p =

0.01). In contrast, there was no significant change in rest blink rates from baseline, with 27.8 (±

13.6) and 28.5 (± 19.0) blinks in the first and last ‘blink’ blocks, respectively (p = 0.82).

Contrasting the ‘no blink’ and ‘blink’ blocks revealed that inhibition of blinking activated a wide network bilaterally including IFG, DLPFC, dACC, frontal eye fields, supplementary motor area, and caudate (Family Wise Error-corrected p < 0.05; Figure 5-2). There were also bilateral activations in inferior parietal, anterior insula, precuneus, and sensory association areas (p <

0.05, Family Wise Error-corrected).

103

Areas positively correlated with increase in escape blinks, identified by using the increase in number of escape blinks as a covariate of interest in the ‘no blink’ vs ‘blink’ block contrast analysis, included left OFC, bilateral supplementary motor area, cuneus, precuneus, mid- cingulate, and bilateral somatosensory areas (p < 0.01 uncorrected, extent thresholding k = 25 voxels; Figure 5-3). Finally, the top performers (n = 7), i.e., those that had the least increase in escape blinks, were contrasted with the worst performers (n = 7), i.e., those that had the most increase in escape blinks. The top performers showed relatively higher task-related activity in frontal control areas including left DLPFC, left IFG, and bilateral supplementary motor areas (p

< 0.05 uncorrected, extent thresholding k = 50 voxels; Figure 5-4). In contrast, the worst performers had relatively higher task-related activity in the left OFC, ventral ACC, right inferior parietal lobule, and bilateral somatosensory cortex.

104

Figure 5-1. Increase in escape blinks across eye blink inhibition blocks

10 9 8 7 6 5

4 Escape Blinks Escape 3 2 1 0 1 2 3 4 5 6

Blink Inhibition Block

105

Figure 5-2. Prefrontal cortical control areas & regions involved in urges and interoceptive processing activated by effortful eye blink control

106

Figure 5-3. Increase in escape blinks is associated with activity in left OFC and DLPFC

107

Figure 4. High performers (n = 7) show activity in frontal control areas (red), in contrast to activity in interoceptive and likely compensatory frontal areas (blue-green) with low performers (n = 7).

108

5.5 Discussion

In this study, I demonstrated behavioral evidence of self-regulatory fatigability in an eye blink inhibition task. There was a progressive, significant increase in escape eye blinks across blink inhibition blocks (Figure 5-1). In contrast, there was no significant change in blink rates during rest blocks. As anticipated, inhibition of blinking activated PFC control areas, including

DLPFC, IFG, dACC, supplementary motor areas, as well as areas involved in interoceptive processing including anterior insula, inferior parietal lobule, and sensory association areas

(Figure 5-2). This is consistent with prior studies of self-control using suppression of bodily urges including eye blink inhibition(B. D. Berman et al., 2012; Lerner et al., 2009), cough suppression(S. B. Mazzone et al., 2011), breath holding(McKay et al., 2008), urinary bladder control(Kuhtz-Buschbeck et al., 2009; Seseke et al., 2006), and control over the urge to scratch an itch(Mochizuki et al., 2014). Worsening performance was associated with activity in overlapping areas, including cuneus, precuneus, and SMA, as well as OFC, mid-cingulate, and somatosensory areas (Figure 5-3). The cuneus has been implicated in inhibitory control in bipolar depressed patients(Haldane et al., 2008) and, along with the precuneus, in differential activation between pathological gamblers and controls in response to visual gambling cues(Crockford et al., 2005). Further, given its functional connectivity to motor cortex, dorsomedial prefrontal cortex, and DLPFC, the precuneus is believed to be involved in sensorimotor and cognitive functions related to these regions(Margulies et al., 2009). The mid- cingulate cortex has been involved in itch relief(Mochizuki et al., 2014; Papoiu et al., 2013) and other sensory processing functions(Kleckner et al., 2017; Vogt, 2016). The OFC has been associated with subjective sensations of fatigue with prolonged performance of the trail-making task(Tajima et al., 2010), and craving in response to visual cues in cocaine abusers (see

109 below)(Volkow et al., 2010). More generally, the OFC is known to have an evaluative role with regards to the rewarding or aversive consequences of actions(Boksem & Tops, 2008). The positive correlation between escape blinks and SMA and premotor areas may be a compensatory response to fatigue(C. Wang et al., 2016). Contrasting the top performers with those that most demonstrated the phenomenon of self-regulatory fatigability showed a particularly interesting pattern: while the former had relatively higher activation in known PFC control areas – IFG,

DLPFC, SMA – the latter had relatively higher activation in ventromedial PFC, rostroventral

ACC, and OFC (Figure 5-4), areas more related to response to hedonic impulses(Goldstein &

Volkow, 2011). Self-regulatory fatigability was also associated with relatively higher activation of sensory areas and the inferior parietal lobule.

These findings are consistent with a model of response inhibition and salience attribution that has been used to explain emotional, cognitive, and behavioral changes seen in addiction(Goldstein &

Volkow, 2011). According to this model, higher order control, or ‘cold’ processes, are subserved by dorsal and lateral subregions of the PFC. On the other hand, automatic, emotion- laden, or ‘hot’ processes, are associated with ventral subregions of the PFC. Thus, the activations in the high performers suggest that the urge to blink remains controlled by the control subregions of the PFC. In contrast, self-regulatory fatigue was associated with activations in ventral subregions of the PFC, suggesting reduced self-control, with emotion and attentional resources directed to craving. Interestingly, this group also showed relatively higher activation of somatosensory and interoceptive processing areas, including the inferior parietal lobule, which has been found to be involved in the experience of urges. In a 2-deoxy-2[18F]fluoro-D-glucose

PET study by Volkow and colleagues, instructions for cocaine abusers to suppress their craving

110 when watching a cocaine-cue video resulted in decreased activity in the rostroventral ACC, insula, and OFC, with associated activation in right inferior frontal areas(Volkow et al., 2010).

In an fMRI study, tobacco dependent smokers shown cigarette cues with instruction to resist craving showed increased activity in dorsal ACC and superior frontal gyrus, and decreased activity in sensory areas(Brody et al., 2007). A similar study by another group showed that control of craving in smokers to be associated with activity in dorsomedial PFC, DLPFC, and ventrolateral PFC, and decreased activity in OFC and subgenual cingulate(Kober et al., 2010).

Further, in a particularly interesting fMRI and ecological study, increased right IFG and SMA activation during a go/no-go task was associated in a weakening of the link between cravings and subsequent smoking(Berkman et al., 2011). These findings overlap with those from another fMRI and ecological study that found that the IFG mediated the effect of resistance to giving in to temptation to eat(Lopez et al., 2014).

Based on this model, when alcohol addicts(Gauggel et al., 2010), cocaine abusers(Moeller et al.,

2012), or smokers(Hagger et al., 2013) are exposed to the relevant cues from the relevant substance, subsequent performance in self-control tasks deteriorates as ‘hot processes’, subserved by ventral PFC regions, become relatively more active. Of more general clinical significance, resources used for symptom suppression may result in self-regulatory fatigability and difficulty in maintaining executive control. In Tourette syndrome, which is known to involve multiple comorbidities, in particular OCD and ADHD, sustained efforts at tic suppression may exacerbate difficulties with attention and impact school performance; in addition, tics and comorbid symptoms are known to be worse with fatigue, which may be a reason why tics tend to generally be worse at the end of the day(Cohen et al., 2013). In ADHD,

111 deficits in sustained self control(Barkley, 1997; Gmehlin et al., 2016; Tucha et al., 2017) may help explain the high comorbidity with substance abuse(Levy, 2006; Zulauf et al., 2014). In fact, the deficits in delayed gratification in ADHD(Solanto et al., 2001) can be conceptualized as a form of executive fatigability. Interestingly, subjective perception of mental effort during attention tasks correlates with extent of reported ADHD symptoms(Hsu et al., 2017; Panetta et al., 2016). It thus makes sense that environmental interventions that decrease executive demand, such as having a predictable structure, planned frequent breaks, and decreasing undue stress, can be helpful in ADHD.

While this study cannot settle the debate regarding the processes leading to the phenomenon of self-regulatory fatigability, i.e., the resource depletion model versus the more recent non- resource-based competing model, the findings do show distinct dorsal and lateral PFC subregions associated with consistent self-control, in contrast to ventral PFC and other somatosensory urge-related brain areas that are associated with self-regulatory fatigability. A possible explanation – which would encompass both models as complementary – is that depletion of resources required to maintain a certain level of activity in dorsal and lateral PFC control regions results in a relative shift towards ventral PFC regions, with concomitant deterioration of performance. Accordingly, resource depletion would be accompanied by a shift in motivation, emotion and attention towards giving in to the urge to blink. Of note, in the original delay of gratification in preschoolers studies, attentional control away from the immediate reward was found to play an important role in their ability to maintain self-control(W.

Mischel et al., 1989). This appears to fit with my findings, as well as the competing model to explain the phenomenon of self-regulatory fatigability(Inzlicht et al., 2014). Also of interest, in

112 the original delay of gratification studies cognitive reappraisal was another successful self- control strategy(Walter Mischel et al., 2011). This is consistent with findings from the more recent neuroimaging research which found that while suppression of emotions impairs subsequent executive function(Friese et al., 2013; Inzlicht & Gutsell, 2007; Y. Wang et al.,

2014), task performance was not adversely impacted when reappraisal was used as the emotional regulation strategy(Y. Wang et al., 2014). In fact, distraction and environmental modification are recognized strategies for self-control in substance abuse, dieting, and daily life situation(Duckworth et al., 2016). Such strategies involve activation of dorsal and lateral PFC self-control regions(Jasinska et al., 2014) and may function by helping to ensure that attention, motivation, and emotion resources are not directed towards hedonic, immediate-reward cues.

There are a number of limitations to consider in my study. First, while the total sample size is comparable to that of other fMRI studies, the analysis comparing the subjects based on performance entailed a smaller number of subjects. It is for this reason that p value correction was done via extent thresholding, as opposed to consistently via family wise error. Another limitation was that I did not assess for motivation, nor did I have an online rating for urge and discomfort during the task – all of these are factors that could influence performance. Further, I did not control for time of day, smoking, caffeine intake, or medication, all of which could affect the results, for example through effects on arousal. Finally, my task design did not entail a longitudinal analysis that could presumably show a shift of brain area activations with self- regulatory fatigability. As such, I am unable to uncover potential compensatory changes in response to increasing fatigue.

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In conclusion, I demonstrated behavioral evidence of self-regulatory fatigability in an eye blink inhibition task. As anticipated, effortful eye blink control resulted in activation of prefrontal control areas and regions involved in urge and interoceptive processing. Worsening performance was associated with activation in regions involved in affective salience attribution and craving.

In contrast, high performers showed relatively more activation in prefrontal cortical control areas, including those involved in attentional control. My findings suggest that the phenomenon of self-regulatory fatigability is associated with relatively less recruitment of prefrontal cortical control regions. My study has a number of limitations, including the sample size. Future larger studies that include analyses of brain activation changes over time during task performance are warranted. Furthermore, investigation of changes in effective connectivity in relation to task performance could help elucidate the neural dynamics that mediate self-regulatory fatigability.

In addition, there are many opportunities for more research of self-regulatory fatigability in clinical conditions, such as substance abuse, ADHD, and Tourette syndrome, among others.

Finally, improved knowledge in this field promises to help in the development of interventions to improve executive functions in young children(Diamond & Ling, 2016; Tang & Posner, 2009), which has the potential to have a significant positive impact on long-term outcomes.

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Chapter 6

Activation of Prefrontal Cortical Regions

Associated with Self-Regulatory Control in

Tourette Syndrome Relative to Healthy Controls

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6.1 Chapter Summary

The capacity to regulate urge is associated with a range of academic, financial, legal, physical and mental health outcomes. The neural substrates of self-regulation are believed to entail a balance between prefrontal cortical control regions and limbic and affective areas. Using an eye- blink inhibitory control paradigm, I have shown that self-regulatory failure in healthy subjects was associated with decreased activation of prefrontal cortical regions associated with self- regulatory control(Abi-Jaoude et al., 2018b). I set out to investigate differences in activation of these regions in Tourette syndrome (TS) relative to healthy controls (HC) during the same self- regulatory control task. I used BOLD fMRI to detect brain activations in 19 HC subjects during inhibition of eye blinking in a block design. This entailed one-minute blocks of effortful inhibition of eye blinking, alternating with one-minute blocks without such inhibition (2 runs, 6 minutes each). I identified regions showing activation changes associated with self-regulatory failure, defined as an increased number of blinks during blink inhibition blocks. From these, I selected prefrontal cortical regions known to be involved in self-regulatory control, such that I obtained the following three regions of interest (ROIs): left dorsolateral prefrontal cortex / inferior frontal gyrus (DLPFC/IFG), supplementary motor area (SMA), and ventromedial prefrontal cortex / left orbitofrontal cortex (vmPFC/OFC). Subsequently, percent signal change in these areas was compared between the HC and 12 TS participants carrying out the same blink inhibition task. On initial analysis, while there was increased signal change in the DLPFC/IFG and SMA ROIs in HC relative to TS, this was not statistically significant. However, one TS participant was a clear outlier, with percent signal change values of at least 3.5 standard deviations in comparison to the rest of the study participants. Upon exclusion of this participant, there emerged a clear difference between the two groups, such that there was substantially less

116 percent signal change in the DLPFC/IFG (standardized mean difference (SMD)=-0.74, p=0.041) and SMA (SMD=-0.91, p=0.036) ROIs in the TS group in comparison to the HC group. There was no group difference in activation changes in the vmPFC/OFC ROI (SMD=0.06, p=0.87).

During a motor self-regulatory control task, subjects with TS had significantly lower activation of ROIs encompassing the DLPFC/IFG and SMA, which are prefrontal cortical regions known to be involved in self-regulatory control. On the other hand, there was no difference in activation in vmPFC/OFC, considered hedonic areas given their involvement in immediate reward. This suggests that self-regulatory deficits in TS arise from aberrant control rather than increased hedonic drive.

6.2 Introduction

TS has been conceptualized as a syndrome of inhibitory deficits involving motor, cognitive, emotional and behavioral domains(Mink, 2001; Stern et al., 2008b). Phenomenologically, this would be consistent with the “semi-compulsory” nature of tics, as well as the high comorbidity with OCD, ADHD(Martino & Mink, 2013; T. Murphy & Muter, 2012), and emotional dysregulation(Baym et al., 2008; C. L. Budman et al., 2000; Cathy L. Budman et al., 2003; Chen et al., 2013; Wright et al., 2012). On executive functioning tests, patients with TS typically show deficits that are specific to inhibitory function, whether related to comorbid OCD or

ADHD(Greimel et al., 2011; Lin et al., 2012; Sukhodolsky et al., 2010), or independent of comorbidity(Channon et al., 2004; Clare M. Eddy & Cavanna, 2017; Clare Margaret Eddy et al.,

2012; Hovik et al., 2017; Jeter et al., 2015; Morand-Beaulieu et al., 2017; Wylie et al., 2016;

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Yaniv et al., 2017). A meta-analysis that included 61 studies of neuropsychological tasks found that overall TS patients exhibited inhibitory deficits compared to control participants(Morand-

Beaulieu et al., 2017).

Further evidence for reduced inhibitory control come from transcranial magnetic stimulation

(TMS) studies, which have consistently found TS subjects to have reduced measures of cortical inhibition compared to healthy controls (reviewed by Ganos and colleagues(Ganos et al.,

2013b)).

In addition, the brain areas that have been found to be affected in TS involve regions known to have a role in self-control(Ganos et al., 2013b; Georgina M. Jackson et al., 2015; Stern et al.,

2008b; Worbe, Lehericy, et al., 2015). In particular, PFC regions are consistently involved in functional neuroimaging studies of tic suppression(Ganos, Kahl, et al., 2014; B. S. Peterson,

Skudlarski, et al., 1998; van der Salm et al., 2018), tic generation(Bohlhalter et al., 2006;

Hampson et al., 2009; Neuner et al., 2014; Z. Wang et al., 2011), cognitive control(Baym et al.,

2008; Church et al., 2009; Marsh et al., 2007; Raz et al., 2009; Yamamuro et al., 2015), and inhibitory control(Debes et al., 2011b; Fan et al., 2017; Ganos, Kühn, et al., 2014; Hershey et al.,

2004; Thomalla et al., 2014). As well, PFC regions have been consistently implicated in cerebral blood flow and metabolism studies in TS(A. R. Braun et al., 1995, 1993; de Vries et al., 2013;

Diler et al., 2002; Pourfar et al., 2011).

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In a study comparing spontaneous tics by 13 adult participants with TS to voluntary imitation of tics by 21 controls, activity during the former was relatively increased in somatosensory and posterior parietal cortices and putamen(Z. Wang et al., 2011). The TS group also had increased activity in the sensorimotor cortex, putamen, pallidum and substantia nigra relative to controls; on the other hand, activity in the anterior cingulate and caudate was weaker in the TS group.

Both the increase and decrease in activity in comparison the controls correlated with tic severity.

The authors conclude that tics arise from a combination of “excessive activity in motor pathways and reduced activation in control portions of cortico-striato-thalamo-cortical circuits”(Z. Wang et al., 2011). Researchers from the same group carried out an investigation using an eye blink inhibition task and found that the TS group (n=51) showed more activations in the middle frontal gyrus and dorsal ACC (dACC), and deactivations in the superior frontal gyrus relative to controls (n=69)(L. Mazzone et al., 2010). Activations in the left middle frontal gyrus and left caudate correlated positively with tic severity. On the other hand, activation in the right inferolateral PFC, left IFG and right putamen correlated negatively with tic severity(L. Mazzone et al., 2010). In an interesting fMRI study design, brain activations in 11 adult participants with

TS who were asked to suppress ocular tics but not eye blinks, were compared to brain activations in 19 control participants who were asked to suppress eye blinks in a block design(van der Salm et al., 2018). Suppression of tics in the participants with TS was associated with increased activity in right anterior and dorsal anterior PFC, bilateral frontal eye fields, and right DLPFC.

Suppression of eye blinks in the control participants was associated with activations in the bilateral premotor cortex, bilateral SMA, right IFG, right anterior PFC, insula bilaterally, left caudate and putamen. Compared to controls, participants with TS had higher activations in the right anterior PFC, right ACC, right DLPFC, left premotor cortex and frontal eye fields; in

119 contrast, controls had higher activations in bilateral SMA, bilateral IFG and insula, and right putamen(van der Salm et al., 2018).

However, the neuroimaging literature in TS entails several inconsistent and even contradictory findings, and multiple studies have not identified any differences between TS and control participants(Debes et al., 2011b; Hershey et al., 2004; Jeppesen et al., 2014; Roessner et al.,

2009; L. Wang et al., 2007). This may be a result of a multitude of variables including sample size, demographic characteristics, tic characteristics including severity, illness duration, comorbid conditions, medication use, consideration of online tics, extent of control participant matching, study task, scanner hardware factors, image acquisition and processing techniques, methods for data analysis, and interpretation of results. Nevertheless, an activation likelihood estimation meta-analysis of task-based functional neuroimaging studies in TS implicated PFC control regions(Polyanska et al., 2017). Given the known evidence, including post-mortem neuropathologic studies in patients with TS, as well as animal models of TS, implicating the basal ganglia in TS (reviewed by Ganos and colleagues(Ganos et al., 2013b)), the overall picture suggests that TS involves a deficit in frontal cortical inhibition of aberrant basal ganglia output(Ganos et al., 2013b; Georgina M. Jackson et al., 2015; Stern et al., 2008b; Worbe,

Lehericy, et al., 2015).

A particularly interesting question relates to the capacity of patients with TS to sustain self- regulatory control in the face of ongoing demands, and the corresponding neural correlates.

Behavioral studies show evidence that self-regulatory capacity has limited reserve, leading to

120 fatigue and decreased performance(Baumeister & Heatherton, 1996; Hagger et al., 2010). As such, initial efforts are followed by a shift in motivation, emotion, and attention to more immediately rewarding action(Inzlicht et al., 2014). This may be particularly relevant in TS, since patients are often exerting effort to suppress tic symptoms, and this may impact resources available for other self-regulatory demands. In addition, the multiple comorbidities in TS, including OCD, ADHD, and emotional dysregulation, likely further contribute to self-control exigencies. In fact, the various symptoms can often interact and exacerbate each other. For example, repeated efforts to suppress tic symptoms can adversely impact the ability to focus in school. In addition, tic and other symptoms in TS are often worse with fatigue, which may explain why they are prone to be worse towards the end of the day(Cohen et al., 2013). Thus, patients with TS may be particularly susceptible to self-regulatory fatigability, and evaluating this during self-control tasks may help shed light on executive capacity in TS both from behavioral and neural perspectives.

I have previously investigated the neural correlates of self-regulatory fatigability in healthy subjects in an fMRI study(Abi-Jaoude et al., 2018b). While participants performed an eye blink inhibition task in a block design, there was an increase in the average number of eye blinks escaping inhibitory control across blocks of blink inhibition. Contrasting the worst and top performing participants, those who had the most self-regulatory fatigability had relatively higher activity in the ventromedial PFC (vmPFC), rostroventral ACC, and OFC. In contrast, those participants that were best able to maintain performance in self-regulatory control had relatively higher activity in the IFG, DLPFC, and SMA(Abi-Jaoude et al., 2018b). The PFC areas involved are consistent with those in a model of self-control in the context of addiction, whereby higher-

121 order control is subserved by dorsal and lateral PFC regions, in contrast to hedonic/automatic processes, which are subserved by ventral regions of the PFC(Goldstein & Volkow, 2011).

Accordingly, exposure to cues related to the substance of addiction can result in eventual failure in self-control as ventral regions of the PFC become more active relative to dorsal and lateral regions(Abi-Jaoude et al., 2018b). Investigating self-regulatory fatigability in TS is particularly salient given the ongoing need to manage multiple symptoms.

In this study, I investigate self-regulatory fatigability in TS, using the eye blink suppression paradigm in the fMRI scanner. I utilize the PFC regions we previously identified to be involved in maintaining self-regulatory performance versus self-regulatory fatigability(Abi-Jaoude et al.,

2018b). I hypothesized that, given continual demands to control symptoms, patients with TS will be more likely to manifest self-regulatory fatigability, and that relative to healthy controls, the activation pattern of their PFC control regions will be consistent with what I previously identified in self-regulatory fatigability. Specifically, I anticipated that relative to the healthy controls, participants with TS will have lower activation of IFG, DLPFC, and SMA, and higher activation of OFC and ventromedial PFC.

6.3 Methods

Participants

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Participants with TS were recruited through postings at a specialized TS clinic at a quaternary care center, and through a national TS patient organization. A total of 12 adults with TS

(average age 36 years, range 20-52; 9 males and 3 females) participated in the study.

Demographic data, comorbid psychiatric diagnoses and psychiatric medications by TS participants at the time of the scan are shown in Table 6-1. Eight TS participants had psychiatric comorbidities, including OCD (3 participants), ADHD (3 participants), learning disability (2 participants), anxiety (2 participants), and substance abuse (1 participant). Four participants had no comorbidities. Five TS participants were taking psychiatric medications at the time of the scan, including selective serotonin reuptake inhibitors (3 participants), benzodiazepine (2 participants), stimulant (1 participant), and dopamine antagonist (1 participant). Seven participants were not taking any medication. The control group was comprised of 19 healthy adults (average age 32 years, range 20-49; 14 males and 5 females) with no psychiatric diagnoses. I carried out psychiatric assessments on all study participants.

All participant assessments, neuroimaging scans and data analysis were carried out at the

Toronto Western Hospital – University Health Network, Toronto, Canada. The study was approved by the University Health Network institutional research ethics board. The study was conducted in compliance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) and the standards established by the relevant Institutional Review Board and granting agencies. All participants received financial reimbursement. After complete description of the study to participants, written informed consent was obtained from all study participants prior to any procedures.

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Behavioral Task

The task, which was carried out in a block design, consisted of one-minute ‘no blink’ blocks of effortful inhibition of eye blinking, alternating with one-minute ‘blink’ blocks without such inhibition. There were two runs, 6 minutes each. Participants were given the following visual prompts for each block type, delivered via goggles: a horizontal oval to indicate the blocks for keeping the eyes open; a horizontal line to indicate that subjects could blink. Escape blinks, i.e., blinks that occurred during ‘no blink’ blocks, were monitored via an infrared camera attached to the participants’ goggles, and were manually recorded. Unfortunately, due to a technical problem that was undetected prior to data analysis, the escape blinks from the TS participants were not recorded.

Image Acquisition

Images were acquired with a 3.0 T GE clinical scanner (GE Medical Systems, Milwaukee,

Wisconsin, USA), using an 8-channel head coil. T1-weighted image parameters were: repetition time 12.0 s, echo time 5.1-15.0 ms, flip angle 20°, slice thickness 1.5 mm, number of slices 106,

2 * field of view 20x20 cm , and a matrix size of 256x256. T2 -weighted image parameters were as follows: repetition time 2.0 s, echo time 30 ms, flip angle 85°, slice thickness 4.5 mm, number of slices 30, field of view 24x24 cm2, and matrix size 64x64.

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Image Analysis

Image analysis was carried out in SPM8 (Wellcome Department of Imaging Neuroscience,

London, UK; http://www.fil.ion.ucl.ac.uk/spm). Images underwent standard preprocessing as follows: slice timing correction, motion correction, normalization to the Montreal Neurological

Institute (MNI) EPI template, followed by spatial smoothing with a Guassian function at 8 mm full width at half-maximum (FWHM). Voxelwise statistical parametric analysis was carried out to obtain general linear model contrasts between the ‘no blink’ and the ‘blink’ blocks. In my previous study with healthy participants(Abi-Jaoude et al., 2018b), covered in Chapter 5, the top performers, i.e., those that had the least increase in escape blinks, were contrasted with the worst performers, i.e., those that had the most increase in escape blinks. The top performers had relatively higher activity in the IFG, DLPFC, and SMA, while the worst performers had relatively higher activity in the ventromedial PFC, rostroventral ACC, and OFC (see Figure 5-4).

From these activation regions, I used the MarsBaR (MARSeille Boîte À Région d’Intérêt) ROI toolbox for SPM(Brett et al., 2002) to construct the following ROI masks: DLPFC/IFG, SMA, and vmPFC/OFC. Subsequently, I extracted percent signal change in each of these ROIs from each healthy control and TS participant using the REX toolkit(Duff et al., 2007). Finally, the percent signal change was compared across both groups using using two-tailed t tests. A threshold value of p<0.05 was used for statistical significance.

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6.4 Results

Both groups showed task-related increase in brain activity in all the ROIs (Table 6-2). On initial analysis, while there was increased signal change in the DLPFC/IFG and SMA ROIs in HC relative to TS, this was not statistically significant. However, one TS participant (participant number 3 in Table 6-1) was a clear outlier, with percent signal change values of at least 3.5 standard deviations in comparison to the rest of the study participants. Specifically, this participant’s percent signal change values were 1.58, 2.86, and 2.66, in comparison to 0.33, 0.52, and 0.34 for all the other study participants (average of HC and TS combined), for the

DLPFC/IFG, SMA, and vmPFC/OFC ROIs, respectively. Upon exclusion of this participant, there emerged a clear difference between the two groups, such that there was substantially less percent signal change in the DLPFC/IFG (standardized mean difference (SMD)=-0.74, p=0.041) and SMA (SMD=-0.91, p=0.036) ROIs in the TS group in comparison to the HC group (Table 6-

2, Figure 6-1). There was no group difference in activation changes in the vmPFC/OFC ROI

(SMD=0.06, p=0.87).

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Table 1. Demographic and Clinical Characteristics of Participants with Tourette Syndrome

ADHD, attention deficit/hyperactivity disorder; OCD, obsessive-compulsive disorder; LD, learning disability

Other Psychiatric Subject Number Age Gender Current Psychiatric Medication Diagnosis

1 32 M ADHD, substance abuse clonazepam

2 43 M ADHD, OCD MPH

3 25 M none none

4 38 F OCD none

5 52 M none none

6 20 F ADHD none

7 40 M none none

8 21 M LD fluoxetine

9 35 M none none

10 49 F anxiety venlafaxine

11 52 M anxiety pimozide, escitalopram, clonazepam

12 22 M OCD, LD none

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Table 2. Region of Interest Percent Signal Change in Healthy Control and Tourette Syndrome Participants

HC, healthy controls; TS, Tourette syndrome; SD, standard deviation; L_DLPFC/L_IFG, left dorsolateral prefrontal cortex/left inferior frontal gyrus; SMA, supplementary motor area; vmPFC/L_OFC, ventromedial prefrontal cortex/left orbitofrontal cortex

Percent Signal Change

L_DLPFC/L_IFG SMA vmPFC/L_OFC

HC 0.44 0.69 0.32

SD 0.45 0.46 0.74

TS all 0.26 0.44 0.56

SD 0.51 0.95 1.02 p-value (all participants) 0.33 0.40 0.49

TS outlier 1.58 2.86 2.66

TS excluding outlier 0.14 0.22 0.37

SD 0.31 0.60 0.81 p-value (excluding TS 0.04 0.04 0.87 outlier)

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Figure 1. Region of Interest Percent Signal Change in Healthy Control (blue) and Tourette Syndrome (red) Participants (excluding one outlier with Tourette syndrome)

L_DLPFC/L_IFG, left dorsolateral prefrontal cortex/left inferior frontal gyrus; SMA, supplementary motor area; vmPFC/L_OFC, ventromedial prefrontal cortex/left orbitofrontal cortex

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6.5 Discussion

In this study, during an eye blink suppression task, after exclusion of a clear outlier, participants with TS had less task-related percent signal change relative to healthy control participants in

DLPFC/IFG and SMA ROIs (Table 6-2, Figure 6-1). These areas are known to be involved in self-control and movement control. In contrast, there was no difference between the HC and TS groups in the vmPFC/OFC ROI, which comprise regions known to be involved in emotional regulation and decision making. The ROIs were selected based on my prior analyses showing them to be involved in self-regulatory fatigability during the eye blink suppression task(Abi-

Jaoude et al., 2018b). All of my ROIs have been implicated in prior studies in TS, albeit in different directions(Ganos et al., 2013b; Georgina M. Jackson et al., 2015; Polyanska et al.,

2017; Worbe, Lehericy, et al., 2015).

A number of functional neuroimaging studies using cognitive control paradigms show differences between TS and control participants in PFC control regions(Baym et al., 2008;

Church et al., 2009; Marsh et al., 2007; L. Mazzone et al., 2010; Raz et al., 2009; van der Salm et al., 2018; Yamamuro et al., 2015). Of particular interest, an fMRI study using an eye blink suppression task in children and adults found activity in the middle frontal gyrus and dorsal ACC to be higher in the TS group relative to controls(L. Mazzone et al., 2010). Furthermore, activity in this area correlated positively with tic severity, whereas activity in the IFG correlated negatively with tic severity(L. Mazzone et al., 2010). An fMRI study compared suppression of ocular tics in adults with TS to suppression of eye blinks in healthy controls(van der Salm et al.,

2018). The TS group had relatively increased activity in the DLPFC, but, similar to our findings,

130 decreased activity in the IFG and SMA. It is noteworthy that, in contrast to my findings, in both of these studies(L. Mazzone et al., 2010; van der Salm et al., 2018), the TS participants had increased DLPFC activity relative to the controls. In fact, in contrast to my study, increased activity in PFC control areas in TS participants is a common finding across a number of the studies described here(Baym et al., 2008; Fan et al., 2017; Neuner et al., 2010; Rae et al., 2018;

Raz et al., 2009; Roessner et al., 2013; Zapparoli et al., 2016). The general explanations for such findings is that these increases represent compensatory mechanisms in the TS group, particularly since in some cases they correlate negatively with task performance(Baym et al., 2008; Marsh et al., 2007), and positively with symptom severity(Ganos, Kühn, et al., 2014; Marsh et al., 2007;

L. Mazzone et al., 2010; Rae et al., 2018; Raz et al., 2009). In this regard, it is instructive to consider the details of the task designs. Whereas in the study by Mazzone and colleagues the task entailed two runs consisting of 4 blocks each lasting 40 seconds (L. Mazzone et al., 2010), my task design included two runs consisting of 6 blocks each lasting 60 seconds. The task design in my study is thus much more taxing, and, indeed, has been shown to result in self- regulatory fatigability(Abi-Jaoude et al., 2018b). As such, while participants with TS might be able to maintain performance via compensatory mechanisms, such processes may fail in the face of increasing demands. In the case of the study by van der Salm and colleagues, the design consisted of a “performance adapted fMRI analysis”, whereby the suppression block ended at the first blink (in the case of controls) or tic detected(van der Salm et al., 2018). Such a design would essentially circumvent the occurrence of fatigability.

Thus, tasks that elicit self-regulatory fatigability may help to highlight and clarify deficits in inhibitory control in TS. Of note, other studies have found that, similar to my results, PFC

131 control areas in TS to have decreased activity relative to control participants(Buse et al., 2016;

Jeyoung Jung et al., 2013; Roessner et al., 2012; Thomalla et al., 2014; Yamamuro et al., 2015).

The vmPFC and OFC also show variability across fMRI studies in TS, though perhaps less so than the other regions described above(C. M. Eddy et al., 2017; Jo et al., 2018; Marsh et al.,

2007; Worbe et al., 2011; Zebardast et al., 2013). However, the vmPFC and OFC do not feature as frequently in functional neuroimaging studies of TS relative to the SMA, IFG, and

DLPFC(Polyanska et al., 2017), and may be more related to comorbid OCD(Worbe et al., 2011;

Zebardast et al., 2013). In my study, I did not find a difference in the vmPFC/OFC ROI between the TS and HC groups. My sample size precluded exploratory analyses of the effects of comorbidity such as OCD.

There are several important limitations in my study that should be noted. While my TS participants are representative of the TS population in terms of demographic and clinical characteristics, the sample size is modest. My findings became significant only after exclusion of an outlier, though it was clear that this participant was an outlier. Unfortunately, due to technical difficulties, I did not get escape blink data from my TS participants. Thus, behavioral studies are warranted to verify whether TS patients are truly more susceptible to self-regulatory fatigability in comparison to healthy controls. In addition, my ROI selection was based on activations from control participants, which will have likely introduced bias when using these for the TS group. Future studies should investigate these ROIs in independent samples. Moreover, while I restricted my ROIs to the PFC, future studies should include other brain areas,

132 particularly regions commonly implicated in TS, including basal ganglia (especially the striatum) and insula. Further, due to sample size limitations, I was unable to explore the role of comorbidities – in particular ADHD and OCD – and medications. Finally, a longitudinal analysis could be particularly interesting to investigate the possibility that initial compensatory mechanisms in TS could eventually fail in the context of self-regulatory fatigue. In particular, investigation of changes in effective connectivity in relation to task performance could shed light on neural dynamics mediating self-regulatory fatigue in TS in comparison to healthy controls.

In conclusion, using an eye blink suppression paradigm that I have previously shown to induce self-regulatory fatigability(Abi-Jaoude et al., 2018b), I found that relative to a healthy control group, TS participants had less task-related BOLD signal change in DLPFC/IFG and SMA ROIs, but no difference in the vmPFC/OFC ROI. The decreased task-related activation in these PFC control areas is consistent with the view that, while patients with TS may be able to initially engage compensatory processes to meet self-regulatory demands, the ongoing requirements for multiple symptom control may make them more vulnerable to self-regulatory fatigability. Well- designed and well-powered future studies, ideally with a longitudinal design, are called for to confirm my findings and further explore these hypotheses, including the role of comorbidity.

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Chapter 7

General Discussion

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7.1 Summary of Findings and Interpretations

In my investigation of striatal D2/3 dopamine receptors in TS, there were no differences in [11C]-

11 (+)-PHNO or [ C]raclopride BPND between TS and HC groups, nor was there any relationship

11 between symptom severity scores and BPND for either radioligand. As expected, [ C]- (+)-

11 PHNO BPND was higher in ventral striatum, and [ C]raclopride BPND was higher in motor and associative striatum. My groups were well-matched, and the TS participants are a good representation of the TS population in terms of comorbidities and range of symptom severity.

My negative findings are not consistent with what was hypothesized, and do not support a role for changes in striatal D2 or D3 receptor availability or affinity in the pathophysiology of TS.

One possibility is that opposing processes affecting radioligand binding in vivo – for example, increased dopamine receptor affinity but also increased binding competition from endogenous dopamine – may cancel out each other’s effects on radioligand binding such that overall receptor availability as measured by BPND remains unchanged. Since I do not have an estimate of endogenous dopamine levels, I cannot rule out this possibility with this study. Another possibility is that striatal dopamine changes in TS are beyond what can be detected with the spatial resolution of current in vivo imaging. In addition, it is likely that the pathophysiology of

TS is variable across individuals, and as such, it is possible that striatal dopamine receptors are involved in only a subset of TS patients. Regardless, it is unlikely that increasing my sample size would result in a positive finding of significant differences between TS and HC groups, since my data do not suggest any trend, in either direction (see Table 4-2 and Figure 4-2).

135

My hypothesis that TS participants will have higher striatal dopamine receptor availability relative to healthy controls was based on prior neuroimaging studies in the field. However, a more critical review of this literature shows that findings are inconsistent, and studies reported as positive are often limited by methodological issues. The [123I]-IBZM SPECT studies found decreased binding only in medicated patients(George et al., 1994; K. R. Müller-Vahl et al.,

2000). This is likely the result of competitive dopamine receptor binding by antipsychotic medications. Initial PET investigations did not identify differences in striatal dopamine receptor availability between TS and HC participants(H.S. Singer et al., 2002; Turjanski et al., 1994;

Wong et al., 1997). The study by Wong and colleagues(Wong et al., 1997) estimated D2 receptor affinity to be higher in the anterior putamen in 12 TS subjects; however, the control group was comprised of only the 3 subjects with complete data. Moreover, despite numerous tests in that study, there was no correction for multiple comparisons. Of note, consistent with our findings, there were no group differences in their primary outcome measure of striatal D2/3 receptor binding potential. The [11C]raclopride study by Denys and colleagues found lower

D2/D3 striatal receptor availability in the putamen of 12 TS participants, most of whom were medication naive(Denys et al., 2013). The discrepant results relative to our findings may be related to one or more of the following factors in that study: the groups were not matched for gender; there were higher depression and anxiety scores in the TS group; there was no information about comorbid ADHD.

Some authors have suggested that disturbances in the dopamine system in TS may be more related to changes in striatal dopamine innervation or dopamine release rather than dysfunction

136 of dopamine receptors(Buse et al., 2013; Segura & Strafella, 2013). In the [11C]raclopride study by Singer and colleagues(H.S. Singer et al., 2002), there was no baseline difference in D2/D3 striatal receptor availability, but an amphetamine challenge resulted in increased dopamine release in TS subjects in the putamen relative to controls. However, while the result was statistically significant (p-value = 0.04), there were four tests carried out (two regions and two analytical methods) without correction, and the study included only 7 TS and 5 HC participants(H.S. Singer et al., 2002). In the study by Wong and colleagues(Wong et al., 2008), there was a robust increase in amphetamine-induced dopamine release in the right ventral striatum in the TS group relative to the HC group. However, this result should be interpreted bearing in mind the numerous uncorrected tests in that study including: 10 striatum subdivisions,

7 ligand measures, 2 analysis methods, and various neuropsychiatric and neuropsychological measures used for correlations (only two of which were reported, neither related to tic symptom severity measures). Moreover, the groups were not matched for gender. Showing the opposite effect, the recent study by Denys and colleagues found amphetamine-induced striatal dopamine release to be decreased in 12 TS participants relative to HC subjects (though the differences disappeared after the investigators controlled for baseline binding)(Denys et al., 2013). On the other hand, a study of extrastriatal cortical and subcortical D2/3 receptors using the radiotracer

[11C]FLB 457 found differences in amphetamine-induced dopamine release between 8 medication naïve TS and 8 HC participants, with some areas being significantly increased in TS, while the opposite was seen for other areas(Steeves et al., 2010). There has not been another study of extrastriatal cortical and subcortical amphetamine-induced dopamine release in TS.

Overall, neuroimaging investigations of dopamine in TS have resulted in a heterogeneous literature.

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In my investigation of the neural correlates of self-regulatory fatigability, the findings were essentially consistent with my anticipated hypotheses. I demonstrated behavioral evidence of self-regulatory fatigability in healthy participants, whereby there was a progressive increase in eye blinks escaping inhibitory control across blink inhibition blocks (see Figure 5-1). Inhibition of blinking invoked known cortical frontal control areas, including DLPFC, IFG, dACC, as well as regions involved in experience of urge and interoceptive processing, including anterior insula, inferior parietal lobule, and sensory association areas (Figure 5-2). These findings are consistent with prior studies of self-control using suppression of bodily urges including eye blink inhibition(B. D. Berman et al., 2012; Lerner et al., 2009), cough suppression(S. B. Mazzone et al., 2011), breath holding(McKay et al., 2008), urinary bladder control(Kuhtz-Buschbeck et al.,

2009; Seseke et al., 2006), and control over the urge to scratch an itch(Mochizuki et al., 2014).

Further, self-regulatory fatigability involved altered activity in PFC subregions involved in self- regulatory control including the DLPFC, IFG and ACC, and interoceptive processing areas such as the ventral PFC and parietal cortex. Specifically, worsening performance was associated with activity in the cuneus, precuneus, and SMA, as well as OFC, mid-cingulate, and somatosensory areas (Figure 5-3). The cuneus has been implicated in inhibitory control in bipolar depressed patients(Haldane et al., 2008) and, along with the precuneus, in differential activation between pathological gamblers and controls in response to visual gambling cues(Crockford et al., 2005).

Further, given its functional connectivity to motor cortex, dorsomedial prefrontal cortex, and

DLPFC, the precuneus is believed to be involved in sensorimotor and cognitive functions related to these regions(Margulies et al., 2009). The mid-cingulate cortex has been involved in itch relief(Mochizuki et al., 2014; Papoiu et al., 2013) and other sensory processing functions(Kleckner et al., 2017; Vogt, 2016). The OFC has been associated with subjective sensations of fatigue with prolonged performance of the trail-making task(Tajima et al., 2010),

138 and craving in response to visual cues in cocaine abusers (see below)(Volkow et al., 2010).

More generally, the OFC is known to have an evaluative role with regards to the rewarding or aversive consequences of actions(Boksem & Tops, 2008). The positive correlation between escape blinks and SMA and premotor areas may be a compensatory response to fatigue(C. Wang et al., 2016). Contrasting the top performers with those that most demonstrated self-regulatory fatigability showed a particularly interesting pattern: while the former had relatively higher activation in known PFC control areas – IFG, DLPFC, SMA – the latter had relatively higher activation in ventromedial PFC, rostroventral ACC, and OFC (Figure 5-4), areas more related to response to hedonic impulses(Goldstein & Volkow, 2011). Self-regulatory fatigability was also associated with relatively higher activation of sensory areas and the inferior parietal lobule.

These findings are consistent with a model of response inhibition and salience attribution that has been used to explain emotional, cognitive, and behavioral changes seen in addiction(Goldstein &

139 suppress their craving when watching a cocaine-cue(Volkow et al., 2010), fMRI studies in which tobacco dependent smokers were instructed to resist craving while being shown cigarette cues(Brody et al., 2007; Kober et al., 2010), and fMRI and ecological studies of the link between cravings and subsequent smoking(Berkman et al., 2011; Lopez et al., 2014). Thus, when alcohol addicts(Gauggel et al., 2010), cocaine abusers(Moeller et al., 2012), or smokers(Hagger et al., 2013) are exposed to the relevant cues from the relevant substance, subsequent performance in self-control tasks deteriorates as ‘hot processes’, subserved by ventral

PFC regions, become relatively more active. Of more general clinical significance, resources used for symptom suppression may result in self-regulatory fatigability and difficulty in maintaining executive control. In Tourette syndrome, which is known to involve multiple comorbidities, in particular OCD and ADHD, sustained efforts at tic suppression may exacerbate difficulties with attention and impact school performance; in addition, tics and comorbid symptoms are known to be worse with fatigue, which may be a reason why tics tend to generally be worse at the end of the day(Cohen et al., 2013).

Using this paradigm to investigate PFC control in TS, I found that, after exclusion of a clear outlier, consistent with part of my hypothesis, participants with TS had less task-related activity increase relative to healthy control participants in DLPFC/IFG and SMA ROIs (Table 6-2,

Figure 6-1). These areas are known to be involved in self-control and movement control. In contrast, there was no difference between the HC and TS groups in the vmPFC/OFC ROI, which comprise regions known to be involved in emotional regulation and decision making. Due to technical difficulties, I did not get escape blink data from my TS participants and thus could not get confirmation of my hypothesis that they would be more likely to manifest self-regulatory

140 fatigability. All of my ROIs have been implicated in prior studies in TS, albeit in different directions(Ganos et al., 2013b; Georgina M. Jackson et al., 2015; Polyanska et al., 2017; Worbe,

Lehericy, et al., 2015).

The DLPFC, IFG, and the SMA have been implicated in an ALE meta-analysis of task-based neuroimaging studies compared TS to control participants(Polyanska et al., 2017). Moreover, activations in the SMA and lateral PFC/middle frontal gyrus(Polyanska et al., 2017). The IFG has been involved in tic suppression, during which it had increased regional homogeneity compared to free ticking states(Ganos, Kahl, et al., 2014). An fMRI study of neural response to emotional faces showed the IFG to have increased activation in adult TS participants relative to controls(Neuner et al., 2010). In another such study in adults, TS participants had increased IFG and insula activation when viewing images of neutral and angry faces; moreover, insula connectivity with SMA correlated with premonitory sensations(Rae et al., 2018). In an fMRI study using a motor task-switching paradigm, IFG and SMA activation was decreased in children with TS compared to controls; in the TS group only, activations in these regions strongly correlated with task-switching costs(Jeyoung Jung et al., 2013). The SMA has been involved in fMRI studies of tic release(Bohlhalter et al., 2006; Hampson et al., 2009; Neuner et al., 2014). In a go/no-go fMRI study, SMA activation was lower in adult TS participants relative to controls(Thomalla et al., 2014). In an fMRI study using the stop-signal task, SMA activity during error processing was higher in adult TS participants in comparison to the OCD and control groups(Fan et al., 2017). In another stop-signal task fMRI study in adult participants,

SMA activation during the ‘successful-stop’ versus ‘go’ conditions correlated positively with motor tic frequency(Ganos, Kühn, et al., 2014). A finger tapping fMRI study found the SMA to

141 be decreased in children with TS compared to controls(Roessner et al., 2012); the children with

TS also had decreased middle frontal gyrus activation when finger tapping with the dominant hand, whereas doing the task with the non-dominant hand involved increased activation of the

DLPFC relative to controls(Roessner et al., 2013). In a finger opposition fMRI study in adults,

TS participants had increased middle frontal gyrus and IFG activation relative to controls(Zapparoli et al., 2016). In a study using PPI in adults, the TS group had decreased activation relative to controls in the ventral lateral PFC and OFC(Zebardast et al., 2013). In a

PPI combined electromyography/fMRI study, middle frontal gyrus activity was decreased in adolescents with TS relative to control participants(Buse et al., 2016).

A number of functional neuroimaging studies using cognitive control paradigms show differences between TS and control participants in PFC control regions. In an fMRI study of the

Stroop task in both children and adults, in contrast to controls, the TS group did not have greater deactivations with age in the vmPFC and ventral ACC, nor increased activations with age in the inferolateral PFC(Marsh et al., 2007). Further, activations in the inferolateral PFC and DLPFC correlated negatively with task performance in the TS group, while activations in the inferolateral PFC correlated positively with performance in the control group; moreover, activation in the vmPFC correlated positively with task performance in the TS group, and negatively in the control group. In addition, DLPFC activation correlated with tic symptom severity(Marsh et al., 2007). In another fMRI study using a cognitive control task, children with

TS had increased DLPFC activity in comparison to controls; in addition, activation in the IFG correlated with tic severity(Baym et al., 2008). A study using the Simon task found that TS participants (children and adults) had higher PFC activation relative to controls; further, in the

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TS group, activity in the middle frontal gyrus and SMA correlated inversely with task performance(Raz et al., 2009). An fMRI study using a semantic task in adolescents showed that in comparison to controls, middle frontal gyrus activity in the TS group was lower during adaptive control, and higher during task maintenance(Church et al., 2009). In a NIRS study using the Stroop task, children with TS had lower PFC activity in the DLPFC area compared to the control group(Yamamuro et al., 2015).

In the fMRI study comparing TS adults before and after CBIT to control participants, there was a negative correlation between changes in tic severity and changes in activation in the

IFG(Deckersbach et al., 2014). While the authors present their findings as related to CBIT, a more apt comparison group for this would have been TS subjects participating in the control arm

(psychoeducation and supportive therapy) of the CBIT trial. This could have related the specificity of any brain changes to CBIT, as opposed to any therapy in general, or even to the well-known phenomenon of natural fluctuation in tic severity. As it stands, the findings may be more related to performing the task under conditions of different tic severity.

There is no clear explanation for the contrasting findings across the studies. There is much heterogeneity across studies, including around demographic and clinical characteristics, study design, and data analysis, among other factors. It should also be noted that there is wide variability in the control areas (DLPFC, IFG, SMA, others), aspects of the task (for ex. the ‘go’ condition, the ‘no-go’ condition, or contrast between the two), and symptoms severity measures

143

(motor, vocal, total, current, worst ever, other) used in the correlational analyses – this may have contributed to findings of uncertain reliability.

Of particular interest, an fMRI study using an eye blink suppression task in children and adults found activity in the middle frontal gyrus and dorsal ACC to be higher in the TS group relative to controls(L. Mazzone et al., 2010). Furthermore, activity in this area correlated positively with tic severity, whereas activity in the IFG correlated negatively with tic severity(L. Mazzone et al.,

2010). An fMRI study compared suppression of ocular tics in adults with TS to suppression of eye blinks in healthy controls(van der Salm et al., 2018). The TS group had relatively increased activity in the DLPFC, but, similar to our findings, decreased activity in the IFG and SMA. It is noteworthy that, in contrast to my findings, in both of these studies(L. Mazzone et al., 2010; van der Salm et al., 2018), the TS participants had increased DLPFC activity relative to the controls.

In fact, in contrast to my study, increased activity in PFC control areas in TS participants is a common finding across a number of the studies described here(Baym et al., 2008; Fan et al.,

2017; Neuner et al., 2010; Rae et al., 2018; Raz et al., 2009; Roessner et al., 2013; Zapparoli et al., 2016). The general explanations for such findings is that these increases represent compensatory mechanisms in the TS group, particularly since in some cases they correlate negatively with task performance(Baym et al., 2008; Marsh et al., 2007), and positively with symptom severity(Ganos, Kühn, et al., 2014; Marsh et al., 2007; L. Mazzone et al., 2010; Rae et al., 2018; Raz et al., 2009). In this regard, it is instructive to consider the details of the task designs. Whereas in the study by Mazzone and colleagues the task entailed two runs consisting of 4 blocks each lasting 40 seconds (L. Mazzone et al., 2010), my task design included two runs consisting of 6 blocks each lasting 60 seconds. The task design in my study is thus much more

144 taxing, and, indeed, has been shown to result in self-regulatory fatigability(Abi-Jaoude et al.,

2018b). As such, while participants with TS might be able to maintain performance via compensatory mechanisms, such processes may fail in the face of increasing demands. In the case of the study by van der Salm and colleagues, the design consisted of a “performance adapted fMRI analysis”, whereby the suppression block ended at the first blink (in the case of controls) or tic detected(van der Salm et al., 2018). Such a design would essentially circumvent the occurrence of fatigability.

Thus, tasks that elicit self-regulatory fatigability may help to highlight and clarify deficits in inhibitory control in TS. Of note, other studies have found that, similar to my results, PFC control areas in TS to have decreased activity relative to control participants(Buse et al., 2016;

Jeyoung Jung et al., 2013; Roessner et al., 2012; Thomalla et al., 2014; Yamamuro et al., 2015).

The vmPFC and OFC also show variability across fMRI studies in TS, though perhaps less so than the other regions described above. In the PPI study described earlier, adults with TS had decreased activation in the OFC relative to controls(Zebardast et al., 2013); moreover, OFC activation correlated positively with obsessive-compulsive symptom severity(Zebardast et al.,

2013). In the Stroop study, the TS group did not have greater deactivations with age in the vmPFC and ventral ACC, in contrast to controls(Marsh et al., 2007); further, activation in the vmPFC correlated positively with task performance in the TS group, and negatively in the control group(Marsh et al., 2007). In a study of reinforcement learning, adults with TS and comorbid OCD had decreased vmPFC and poorer task performance relative to controls(Worbe et

145 al., 2011). In a study of emotion recognition, adults with TS had decreased OFC activation relative to controls (C. M. Eddy et al., 2017). In a DBS study, thalamic stimulation in adult patients with TS was associated with decreased activity in the medial PFC and OFC, with BOLD signal changes in the latter being associated with reduction in tics(Jo et al., 2018). Overall, the vmPFC and OFC do not feature as frequently in functional neuroimaging studies of TS relative to the SMA, IFG, and DLPFC(Polyanska et al., 2017), and may be more related to comorbid

OCD(Worbe et al., 2011; Zebardast et al., 2013). In my study, I did not find a difference in the vmPFC/OFC ROI between the TS and HC groups. My sample size precluded exploratory analyses of the effects of comorbidity such as OCD.

Interestingly, findings from nuclear imaging studies appear to be more consistent, with a tendency for decreased activity in TS in the PFC regions considered. Regional cerebral perfusion was found to be decreased in the DLPFC and OFC in a SPECT study of children with

TS(Diler et al., 2002). In an FDG-PET study, adults with TS had resting metabolic activity patterns that was decreased in the OFC(Pourfar et al., 2011). In the same study, those with comorbid OCD had activity patterns that was decreased in the DLPFC(Pourfar et al., 2011). An earlier FDG-PET study in adults with TS found decreased metabolic activity the ventral PFC and

OFC, but increased activity in the SMA(A. R. Braun et al., 1993). Furthermore, metabolic rate in the OFC correlated positively with compulsive and behavioral symptoms(A. R. Braun et al.,

15 1995). In an H2 O-PET study, obsessive-compulsive symmetry symptom provocation correlated positively with OFC rCBF in adults with TS, whereas in the control group they correlated negatively with the DLPFC(de Vries et al., 2013). In a SPECT study of patients undergoing DBS, adults with TS at baseline had lower rCBF compared to controls in the SMA

146 and middle frontal cortex(Haense et al., 2016). GPi stimulation was associated with decrease in rCBF in OFC and increase rCBF in middle frontal cortex relative to sham stimulation(Haense et al., 2016). Thalamic stimulation was associated with rCBF increase in SMA and middle and frontal cortex relative to sham stimulation(Haense et al., 2016).

Overall, it is clear that key control areas of the PFC are implicated in TS, though in task-based functional imaging studies, the variability in the findings may be related to multiple factors, including the possible role of compensatory mechanisms. In my blink suppression task, which I have shown to result in self-regulatory fatigability(Abi-Jaoude et al., 2018b) and thus overcome potential compensatory effects, I found that TS participants had less task-related activity changes relative to controls in the DLPFC/IFG ROI (Table 6-2, Figure 6-1). This is consistent with my hypothesis that, given continual demands to control symptoms, patients with TS will be more prone to self-regulatory fatigability and that the activation pattern of their PFC control regions will be consistent with what I previously identified as self-regulatory fatigability(Abi-Jaoude et al., 2018b). The findings are also consistent with the known comorbidity between TS and

ADHD, a condition which can be conceptualized as a model of self-regulatory fatigability given its known deficits in delayed gratification(Abi-Jaoude et al., 2018b; Jiang et al., 2018; Solanto et al., 2001). Moreover, neuroimaging studies implicate PFC control regions in both ADHD and

TS(Plessen et al., 2007). The finding of less task-related activity change relative to controls in our SMA ROI may also be related to tonic GABA inhibition in this region(Georgina M. Jackson et al., 2015). SMA GABA is increased in TS and this correlates negatively with cortico-spinal excitability and BOLD signal, and positively with tic severity(Draper et al., 2014). Indeed, this has been hypothesized to mediate tic control by TS patients(Georgina M. Jackson et al., 2015).

147

Yet another factor may be the result of voluntary tic suppression during scanning by the TS participants, which has been associated with reduced corticospinal excitability(Ganos et al.,

2018). Finally, there was no difference between our HC and TS groups in the vmPFC/OFC ROI

(Table 6-2, Figure 6-1), contrary to my hypothesis that it would be increased in the TS group.

One can only speculate as to the reasons for this. One possibility is that there were two opposing phenomena at play – since these regions have often been shown to be less active in TS relative to controls(A. R. Braun et al., 1993; Diler et al., 2002; C. M. Eddy et al., 2017; Pourfar et al., 2011;

Worbe et al., 2011; Zebardast et al., 2013), this may have obviated a manifestation of activity increase in the context of self-regulatory fatigability. Clearly, this would need to be clarified in future investigations.

7.2 Future Directions

I have shown similar striatal D2/D3 dopamine receptor availability in adults with TS compared to HC using the radioligands [11C]- (+)-PHNO and [11C]raclopride. My results challenge the widely assumed role of striatal dopamine receptors in the pathophysiology of TS. While dopamine has long been believed to underlie the pathophysiology of TS, decades of investigation have yielded inconsistent results. Interestingly, in a case series of four patients with comorbid

TS and Parkinson’s disease, there was improvement in parkinsonism without worsening of tics with treatment with levodopa, and there was a lack of a consistent relationship between “on” and

“off” states and tic symptom severity(Kumar & Lang, 1997). As an alternative avenue of research, the γ-aminobutyric acid-ergic system has been implicated in TS based on two post-

148 mortem histologic studies(Kalanithi et al., 2005; Kataoka et al., 2010), a PET study(Lerner et al.,

2012), a magnetic resonance spectroscopy/magnetoencephalography investigation(Tinaz et al.,

2014), and a basal ganglia transcriptome analysis(Lennington et al., 2016). These suggest new avenues that are worth pursuing further as part of investigations to elucidate the underlying pathophysiology of TS.

As well, given the evidence that cannabinoids can improve tics and comorbid symptoms in patients with TS, and that endocannabinoids (eCBs) modulate dopaminergic motor circuits, the role of the endocannabinoid system in the pathophysiology of TS warrants investigation. The basal ganglia are rich in cannabinoid 1 receptors (CB1), a primary site of action of THC, which can help explain the effect of cannabis on motor activity. In addition, eCBs are known to modulate dopamine transmission both directly and indirectly. Hence, pharmacological and neuroanatomical evidence suggests that the eCB system may be implicated in the pathophysiology of TS. N-arachidonlylethanolamine (anandamide, AEA), an endogenous endocannabinoid that interacts with cannabinoid 1 receptors (CB1), is metabolized by the enzyme fatty Acid Amide Hydrolase (FAAH), which thus sets the tone of the eCB system.

FAAH is the enzyme responsible for the metabolism of the eCB AEA, thus setting the tone of the eCB system. [11C]CURB, a carbon-11-labelled form of the potent irreversible FAAH inhibitor URB694, has recently been synthesized. Animal and human studies have demonstrated that [11C]CURB presents excellent radioligand properties: high brain uptake consistent with known levels of FAAH and selectivity. This presents an opportunity to use [11C]CURB in a

PET imaging study to investigate FAAH, the enzyme responsible to set eCB tone, in TS. The primary hypothesis would be that [11C]CURB binding in the striatum and prefrontal cortex will

149 be significantly lower in TS as compared to healthy control participants. Exploratory aims would examine the relation between regional FAAH levels, indexed as [11C]CURB binding, and tic and associated symptom severity.

In addition, the phenomenon of self-regulatory fatigability in TS deserves further investigation.

Future larger studies that include analyses of brain activation changes over time during task performance are warranted. Furthermore, investigation of changes in effective connectivity in relation to task performance could help elucidate the neural dynamics that mediate self- regulatory fatigability. In addition, there are many opportunities for more research of self- regulatory fatigability in clinical conditions, such as substance abuse, ADHD, and Tourette syndrome, among others.

Nevertheless, it is likely that the causes and neural mechanisms involved in TS are complex, varied, and may involve interactions among different systems. As such, the field would benefit from concerted efforts and collaborations to carry out multimodal studies with large samples and longitudinal design. Future projects that I intend to pursue include using the large dataset from the Province of Ontario Neurodevelopmental Disorders Network to further investigate the neurobiology and phenomenology of Tourette syndrome, study the model of self-regulatory fatigability in clinical populations, and further investigate chronic cannabis in Tourette syndrome and its effects on neuropsychological and neurobiological markers.

150

7.3 Concluding Remarks

The general aims of this thesis have been to elucidate the pathophysiology of TS. The body of evidence to date suggests that TS involves a deficit in frontal cortical inhibition of aberrant basal ganglia output. However, findings from neuroimaging studies in TS have been mixed, and a definitive explanation of the neurobiology underlying TS has remained elusive. In a PET study,

I used a novel radioligand with the aim of measuring striatal D2/D3 dopamine receptor availability with higher sensitivity, and I found similar striatal D2/D3 dopamine receptor availability in adults with TS compared to HC. My results challenge the widely assumed role of striatal dopamine receptors in the pathophysiology of TS. In a separate fMRI study, using an eye blink inhibition paradigm, I showed that the neural correlates of self-regulatory fatigability are consistent with a model whereby dorsal and lateral PFC control areas, including DLPFC and

IFG, are active in self-regulatory control, whereas activity in ventromedial PFC, rostroventral

ACC, and OFC areas is related to response to hedonic impulses. Applying this paradigm in TS, I found that relative to a healthy control group, TS participants had less task-related BOLD signal change in DLPFC/IFG and SMA ROIs, but no difference in the vmPFC/OFC ROI. The decreased task-related activation in these PFC control areas is consistent with the view that, while patients with TS may be able to initially engage compensatory processes to meet self- regulatory demands, the ongoing requirements for multiple symptom control may make them more vulnerable to self-regulatory fatigability. Well-designed and well-powered future studies, ideally with a longitudinal design, are called for to confirm my findings and further explore these hypotheses, including the role of comorbidity. Improved knowledge in this field promises to help in the development of interventions to improve executive functions in young

151 children(Diamond & Ling, 2016; Tang & Posner, 2009), which has the potential to have a significant positive impact on long-term outcomes.

152

References

Abi-Jaoude, E., Chen, L., Cheung, P., Bhikram, T., & Sandor, P. (2017). Preliminary Evidence

on Cannabis Effectiveness and Tolerability for Adults With Tourette Syndrome. The

Journal of Neuropsychiatry and Clinical Neurosciences, appineuropsych16110310.

https://doi.org/10.1176/appi.neuropsych.16110310

Abi-Jaoude, E., Kideckel, D., Stephens, R., Lafreniere-Roula, M., Deutsch, J., & Sandor, P.

(2009). Tourette syndrome: A model of integration. In R. Carlstedt (Ed.), Handbook of

Integrative Clinical Psychology, Psychiatry and Behavioral Medicine: Perspectives,

Practices and Research (pp. 549–588). Springer Publishing Company.

Abi-Jaoude, E., Segura, B., Cho, S. S., Crawley, A., & Sandor, P. (2018a). The Neural Correlates

of Self-Regulatory Fatigability During Inhibitory Control of Eye Blinking. The Journal of

Neuropsychiatry and Clinical Neurosciences, appineuropsych17070140.

https://doi.org/10.1176/appi.neuropsych.17070140

Abi-Jaoude, E., Segura, B., Cho, S. S., Crawley, A., & Sandor, P. (2018b). The Neural

Correlates of Self-Regulatory Fatigability During Inhibitory Control of Eye Blinking. The

Journal of Neuropsychiatry and Clinical Neurosciences, appineuropsych17070140.

https://doi.org/10.1176/appi.neuropsych.17070140

Abi-Jaoude, E., Segura, B., Obeso, I., Cho, S. S., Houle, S., Lang, A. E., Rusjan, P., Sandor, P.,

& Strafella, A. P. (2015). Similar striatal D2/D3 dopamine receptor availability in adults

with Tourette syndrome compared with healthy controls: A [(11) C]-(+)-PHNO and [(11)

153

C]raclopride positron emission tomography imaging study. Human Brain Mapping,

36(7), 2592–2601. https://doi.org/10.1002/hbm.22793

Acosta, M. T., & Castellanos, F. X. (2004). Use of the “inverse neuroleptic” metoclopramide in

Tourette syndrome: An open case series. J Child Adolesc.Psychopharmacol, 14, 123–

128.

Aguirregomozcorta, M., Pagonabarraga, J., az-Manera, J., Pascual-Sedano, B., Gironell, A., &

Kulisevsky, J. (2008). Efficacy of botulinum toxin in severe Tourette syndrome with

dystonic tics involving the neck. Parkinsonism and. Related Disorders.14(5)()(Pp,

443(445), 2008.Date.

Albibi, R., & McCallum, R. W. (1983). Metoclopramide: Pharmacology and clinical application.

Ann.Intern.Med, 98, 86–95.

Awaad, Y. (1999). Tics in Tourette syndrome: New treatment options.[see comment]. Journal of

Child Neurology, 14, 316–319.

Awaad, Y., Michon, A. M., & Minarik, S. (2005). Use of levetiracetam to treat tics in children

and adolescents with Tourette syndrome. Movement Disorders, 20, 714–718.

Awaad, Y., Michon, A. M., & Minarik, S. (2007). Long-term use of levetiracetam to treat tics in

children and adolescents with Tourette syndrome. Journal of Pediatric

Neurology.5(3)()(Pp, 209(214), 2007.Date.

Barkley, R. A. (1997). Behavioral inhibition, sustained attention, and executive functions:

Constructing a unifying theory of ADHD. Psychological Bulletin, 121(1), 65–94.

154

Baumeister, R. F., & Heatherton, T. F. (1996). Self-Regulation Failure: An Overview.

Psychological Inquiry, 7(1), 1–15. https://doi.org/10.1207/s15327965pli0701_1

Bawden, H. N., Stokes, A., Camfield, C. S., Camfield, P. R., & Salisbury, S. (1998). Peer

relationship problems in children with Tourette’s disorder or diabetes mellitus. J.Child

Psychol.Psychiatry, 39, 663–668.

Baym, C. L., Corbett, B. A., Wright, S. B., & Bunge, S. A. (2008). Neural correlates of tic

severity and cognitive control in children with Tourette syndrome. Brain: A Journal of

Neurology, 131(Pt 1), 165–179. https://doi.org/10.1093/brain/awm278

Berkman, E. T., Falk, E. B., & Lieberman, M. D. (2011). In the trenches of real-world self-

control: Neural correlates of breaking the link between craving and smoking.

Psychological Science, 22(4), 498–506. https://doi.org/10.1177/0956797611400918

Berman, B. D., Horovitz, S. G., Morel, B., & Hallett, M. (2012). Neural correlates of blink

suppression and the buildup of a natural bodily urge. NeuroImage, 59(2), 1441–1450.

https://doi.org/10.1016/j.neuroimage.2011.08.050

Berman, M. G., Yourganov, G., Askren, M. K., Ayduk, O., Casey, B. J., Gotlib, I. H., Kross, E.,

McIntosh, A. R., Strother, S., Wilson, N. L., Zayas, V., Mischel, W., Shoda, Y., &

Jonides, J. (2013). Dimensionality of brain networks linked to life-long individual

differences in self-control. Nature Communications, 4, 1373.

https://doi.org/10.1038/ncomms2374

Black, K. J., & Mink, J. W. (2000). Response to levodopa challenge in Tourette syndrome.

Movement Disorders, 15, 1194–1198.

155

Bloch, M.H., Landeros-Weisenberger, A., Kelmendi, B., Coric, V., Bracken, M. B., & Leckman,

J. F. (2006). A systematic review: Antipsychotic augmentation with treatment refractory

obsessive-compulsive disorder.[see comment][erratum appears in Mol Psychiatry.

Aug;11(8):795]. [Review] [49 Refs]. Molecular Psychiatry, 11, 622–632.

Bloch, Michael H., Gorman, D. A., & Abi-Jaoude, E. (2012). Commentaries on

‘Pharmacological treatment for Attention Deficit Hyperactivity Disorder (ADHD) in

children with comorbid tic disorders.’ Evidence-Based Child Health: A Cochrane Review

Journal, 7(4), 1231–1234. https://doi.org/10.1002/ebch.1862

Bohlhalter, S., Goldfine, A., Matteson, S., Garraux, G., Hanakawa, T., Kansaku, K., Wurzman,

R., & Hallett, M. (2006). Neural correlates of tic generation in Tourette syndrome: An

event-related functional MRI study. Brain: A Journal of Neurology, 129(Pt 8), 2029–

2037. https://doi.org/10.1093/brain/awl050

Boksem, M. A. S., & Tops, M. (2008). Mental fatigue: Costs and benefits. Brain Research

Reviews, 59(1), 125–139. https://doi.org/10.1016/j.brainresrev.2008.07.001

Borcherding, B. G., Keysor, C. S., Rapoport, J. L., Elia, J., & Amass, J. (1990). Motor/vocal tics

and compulsive behaviors on stimulant drugs: Is there a common vulnerability?

Psychiatry Research.33(1)()(Pp, 83(94), 1990.Date.

Boreman, C. D., & Arnold, L. E. (2003). Hallucinations associated with initiation of guanfacine.

J Am Acad.Child Adolesc.Psychiatry, 42.

156

Borison, R. L., Ang, L., Chang, S., Dysken, M., Comaty, J. E., & Davis, J. M. (1982). New

pharmacological approaches in the treatment of Tourette syndrome. Adv.Neurol, 35, 377–

382.

Brandt, Valerie C., Stock, A.-K., Münchau, A., & Beste, C. (2017). Evidence for enhanced

multi-component behaviour in Tourette syndrome—An EEG study. Scientific Reports,

7(1), 7722. https://doi.org/10.1038/s41598-017-08158-9

Brandt, Valerie Cathérine, Moczydlowski, A., Jonas, M., Boelmans, K., Bäumer, T., Brass, M.,

& Münchau, A. (2017). Imitation inhibition in children with Tourette syndrome. Journal

of Neuropsychology. https://doi.org/10.1111/jnp.12132

Braun, A., Mouradian, M. M., Mohr, E., Fabbrini, G., & Chase, T. N. (1989). Selective D-1

dopamine receptor agonist effects in hyperkinetic extrapyramidal disorders. Journal of

Neurology, Neurosurgery & Psychiatry, 52, 631–635.

Braun, A. R., Randolph, C., Stoetter, B., Mohr, E., Cox, C., Vladar, K., Sexton, R., Carson, R.

E., Herscovitch, P., & Chase, T. N. (1995). The functional neuroanatomy of Tourette’s

syndrome: An FDG-PET Study. II: Relationships between regional cerebral metabolism

and associated behavioral and cognitive features of the illness.

Neuropsychopharmacology: Official Publication of the American College of

Neuropsychopharmacology, 13(2), 151–168. https://doi.org/10.1016/0893-

133X(95)00052-F

Braun, A. R., Stoetter, B., Randolph, C., Hsiao, J. K., Vladar, K., Gernert, J., Carson, R. E.,

Herscovitch, P., & Chase, T. N. (1993). The functional neuroanatomy of Tourette’s

syndrome: An FDG-PET study. I. Regional changes in cerebral glucose metabolism

157

differentiating patients and controls. Neuropsychopharmacology: Official Publication of

the American College of Neuropsychopharmacology, 9(4), 277–291.

https://doi.org/10.1038/npp.1993.64

Brett, M., anton, Jean-Luc, Valabregue, R., & Poline, J.-B. (2002). Region of interest analysis

using an SPM toolbox [abstract]. NeuroImage, 16.

Brody, A. L., Mandelkern, M. A., Olmstead, R. E., Jou, J., Tiongson, E., Allen, V., Scheibal, D.,

London, E. D., Monterosso, J. R., Tiffany, S. T., Korb, A., Gan, J. J., & Cohen, M. S.

(2007). Neural substrates of resisting craving during cigarette cue exposure. Biological

Psychiatry, 62(6), 642–651. https://doi.org/10.1016/j.biopsych.2006.10.026

Bruggeman, R. (2001). Risperidone versus pimozide in Tourette’s disorder: A comparative

double-blind parallel-group study. Journal of Clinical Psychiatry, 62, 50–56.

Budman, C. L., Bruun, R. D., Park, K. S., Lesser, M., & Olson, M. (2000). Explosive outbursts

in children with Tourette’s disorder. Journal of the American Academy of Child and

Adolescent Psychiatry, 39(10), 1270–1276. https://doi.org/10.1097/00004583-

200010000-00014

Budman, Cathy L., Rockmore, L., Stokes, J., & Sossin, M. (2003). Clinical phenomenology of

episodic rage in children with Tourette syndrome. Journal of Psychosomatic Research,

55(1), 59–65.

Budman, C.L., Gayer, A., Lesser, M., Shi, Q., & Bruun, R. D. (2001). An open-label study of the

treatment efficacy of olanzapine for Tourette’s disorder. Journal of Clinical Psychiatry,

62, 290–294.

158

Buse, J., Beste, C., Herrmann, E., & Roessner, V. (2016). Neural correlates of altered

sensorimotor gating in boys with Tourette Syndrome: A combined EMG/fMRI study. The

World Journal of Biological Psychiatry: The Official Journal of the World Federation of

Societies of Biological Psychiatry, 17(3), 187–197.

https://doi.org/10.3109/15622975.2015.1112033

Buse, J., Beste, C., & Roessner, V. (2017). Neural correlates of prediction violations in boys with

Tourette syndrome: Evidence from harmonic expectancy. The World Journal of

Biological Psychiatry: The Official Journal of the World Federation of Societies of

Biological Psychiatry, 1–12. https://doi.org/10.1080/15622975.2016.1274052

Buse, J., Schoenefeld, K., Münchau, A., & Roessner, V. (2013). Neuromodulation in Tourette

syndrome: Dopamine and beyond. Neuroscience and Biobehavioral Reviews, 37(6),

1069–1084. https://doi.org/10.1016/j.neubiorev.2012.10.004

Caine, E. D., Polinsky, R. J., Kartzinel, R., & Ebert, M. H. (1979). The trial use of clozapine for

abnormal involuntary movement disorders. American Journal of Psychiatry, 136, 317–

320.

Casey, B. J., Somerville, L. H., Gotlib, I. H., Ayduk, O., Franklin, N. T., Askren, M. K., Jonides,

J., Berman, M. G., Wilson, N. L., Teslovich, T., Glover, G., Zayas, V., Mischel, W., &

Shoda, Y. (2011). Behavioral and neural correlates of delay of gratification 40 years later.

Proceedings of the National Academy of Sciences of the United States of America,

108(36), 14998–15003. https://doi.org/10.1073/pnas.1108561108

Castellanos, F. X., Giedd, J. N., Elia, J., Marsh, W. L., Ritchie, G. F., & Hamburger, S. D.

(1997). Controlled stimulant treatment of ADHD and comorbid Tourette’s syndrome:

159

Effects of stimulant and dose. Journal of the American Academy of Child & Adolescent

Psychiatry, 36, 589–596.

Chakravarty, M. M., Bertrand, G., Hodge, C. P., Sadikot, A. F., & Collins, D. L. (2006). The

creation of a brain atlas for image guided neurosurgery using serial histological data.

NeuroImage, 30(2), 359–376. https://doi.org/10.1016/j.neuroimage.2005.09.041

Channon, S., Crawford, S., Vakili, K., & Robertson, M. M. (2003). Real-life-type problem

solving in Tourette syndrome. Cognitive and Behavioral Neurology: Official Journal of

the Society for Behavioral and Cognitive Neurology, 16(1), 3–15.

Channon, S., Pratt, P., & Robertson, M. M. (2003). Executive function, memory, and learning in

Tourette’s syndrome. Neuropsychology, 17(2), 247–254.

Channon, S., Sinclair, E., Waller, D., Healey, L., & Robertson, M. M. (2004). Social cognition in

Tourette’s syndrome: Intact theory of mind and impaired inhibitory functioning. Journal

of Autism and Developmental Disorders, 34(6), 669–677.

Chan-Ob, T., Kuntawongse, N., & Boonyanaruthee, V. (2001). Quetiapine for tic disorder: A

case report. Journal of the Medical Association of Thailand.84(11)()(Pp, 1624(1628),

2001.Date.

Chappell, P. B. (1994). Sequential use of opioid antagonists and agonists in Tourette’s syndrome.

Lancet.343(8897)()(pp, 556, 556.

Chappell, P. B., Leckman, J. F., Scahill, L. D., Hardin, M. T., Anderson, G., & Cohen, D. J.

(1993). Neuroendocrine and behavioral effects of the selective kappa agonist spiradoline

in Tourette’s syndrome: A pilot study. Psychiatry Research, 47, 267–280.

160

Chen, K., Budman, C. L., Diego Herrera, L., Witkin, J. E., Weiss, N. T., Lowe, T. L., Freimer,

N. B., Reus, V. I., & Mathews, C. A. (2013). Prevalence and clinical correlates of

explosive outbursts in Tourette syndrome. Psychiatry Research, 205(3), 269–275.

https://doi.org/10.1016/j.psychres.2012.09.029

Chouza, C., Romero, S., Lorenzo, J., Camano, J. L., Fontana, A. P., & Alterwain, P. (1982).

[Clinical trial of tiapride in patients with dyskinesia (author’s transl)]. [French]. Semaine

Des Hopitaux, 58, 725–733.

Church, J. A., Wenger, K. K., Dosenbach, N. U. F., Miezin, F. M., Petersen, S. E., & Schlaggar,

B. L. (2009). Task control signals in pediatric tourette syndrome show evidence of

immature and anomalous functional activity. Frontiers in Human Neuroscience, 3, 38.

https://doi.org/10.3389/neuro.09.038.2009

Cohen, S. C., Leckman, J. F., & Bloch, M. H. (2013). Clinical assessment of Tourette syndrome

and tic disorders. Neuroscience & Biobehavioral Reviews, 37(6), 997–1007.

https://doi.org/10.1016/j.neubiorev.2012.11.013

Collins, D. L., Neelin, P., Peters, T. M., & Evans, A. C. (1994). Automatic 3D intersubject

registration of MR volumetric data in standardized Talairach space. Journal of Computer

Assisted Tomography, 18(2), 192–205.

Connell, P. H., Corbett, J. A., Horne, D. J., & Mathews, A. M. (1967). Drug treatment of

adolescent tiqueurs. A double-blind trial of Diazepam and. Haloperidol. British Journal

of Psychiatry, 113, 375–381.

161

Correll, C. U. (2008). Antipsychotic use in children and adolescents: Minimizing adverse effects

to maximize outcomes. Journal of the American Academy of Child and Adolescent

Psychiatry.47(1)()(Pp, 9(20), 2008.Date.

Crockford, D. N., Goodyear, B., Edwards, J., Quickfall, J., & el-Guebaly, N. (2005). Cue-

induced brain activity in pathological gamblers. Biological Psychiatry, 58(10), 787–795.

https://doi.org/10.1016/j.biopsych.2005.04.037

Cubo, E., Fernndez, J. A., Moreno, C., Anaya, B., Gonzlez, M., & Kompoliti, K. (2008).

Donepezil use in children and adolescents with tics and attention-deficit/hyperactivity

disorder: An 18-week, single-center, dose-escalating, prospective, open-label study.

Clinical Therapeutics.30(1)()(Pp, 182(189), 2008.Date.

Cummings, D. D., Singer, H. S., Krieger, M., Miller, T. L., & Mahone, E. M. (2002).

Neuropsychiatric effects of guanfacine in children with mild tourette syndrome: A pilot

study. Clinical Neuropharmacology, 25, 325–332.

Curtis, A., Clarke, C. E., & Rickards, H. E. (2009). Cannabinoids for Tourette’s Syndrome. The

Cochrane Database of Systematic Reviews, 4, CD006565.

https://doi.org/10.1002/14651858.CD006565.pub2

Dale, R. C. (2005). Post-streptococcal autoimmune disorders of the central nervous system.

Dev.Med Child Neurol, 47, 785–791.

Dang, J., Björklund, F., & Bäckström, M. (2017). Self-control depletion impairs goal

maintenance: A meta-analysis. Scandinavian Journal of Psychology.

https://doi.org/10.1111/sjop.12371

162 de Jonge, J. L., Cath, D. C., & van Balkom, A. J. (2007). Quetiapine in patients with Tourette’s

disorder: An open-label, flexible-dose study. Journal of Clinical Psychiatry, 68, 1148–

1150. de Vries, F. E., van den Heuvel, O. A., Cath, D. C., Groenewegen, H. J., van Balkom, A. J. L.

M., Boellaard, R., Lammertsma, A. A., & Veltman, D. J. (2013). Limbic and motor

circuits involved in symmetry behavior in Tourette’s syndrome. CNS Spectrums, 18(1),

34–42. https://doi.org/10.1017/S1092852912000703

Debes, N. M. M. M., Hansen, A., Skov, L., & Larsson, H. (2011a). A functional magnetic

resonance imaging study of a large clinical cohort of children with Tourette syndrome.

Journal of Child Neurology, 26(5), 560–569. https://doi.org/10.1177/0883073810387928

Debes, N. M. M. M., Hansen, A., Skov, L., & Larsson, H. (2011b). A Functional Magnetic

Resonance Imaging Study of a Large Clinical Cohort of Children With Tourette

Syndrome. Journal of Child Neurology, 26(5), 560–569.

https://doi.org/10.1177/0883073810387928

Deckersbach, T., Chou, T., Britton, J. C., Carlson, L. E., Reese, H. E., Siev, J., Scahill, L.,

Piacentini, J. C., Woods, D. W., Walkup, J. T., Peterson, A. L., Dougherty, D. D., &

Wilhelm, S. (2014). Neural correlates of behavior therapy for Tourette’s disorder.

Psychiatry Research, 224(3), 269–274. https://doi.org/10.1016/j.pscychresns.2014.09.003

Denys, D., de Vries, F., Cath, D., Figee, M., Vulink, N., Veltman, D. J., van der Doef, T. F.,

Boellaard, R., Westenberg, H., van Balkom, A., Lammertsma, A. A., & van Berckel, B.

N. M. (2013). Dopaminergic activity in Tourette syndrome and obsessive-compulsive

disorder. European Neuropsychopharmacology: The Journal of the European College of

163

Neuropsychopharmacology, 23(11), 1423–1431.

https://doi.org/10.1016/j.euroneuro.2013.05.012

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) by American

Psychiatric Association (2013) Paperback. (n.d.).

Diamond, A., & Ling, D. S. (2016). Conclusions about interventions, programs, and approaches

for improving executive functions that appear justified and those that, despite much hype,

do not. Developmental Cognitive Neuroscience, 18, 34–48.

https://doi.org/10.1016/j.dcn.2015.11.005

Diler, R. S., Reyhanli, M., Toros, F., Kibar, M., & Avci, A. (2002). Tc-99m-ECD SPECT brain

imaging in children with Tourette’s syndrome. Yonsei Medical Journal, 43(4), 403–410.

https://doi.org/10.3349/ymj.2002.43.4.403

Dion, Y., Annable, L., Sandor, P., & Chouinard, G. (2002). Risperidone in the treatment of

tourette syndrome: A double-blind, placebo-controlled trial. Journal of Clinical

Psychopharmacology, 22, 31–39.

Draganski, B., Martino, D., Cavanna, A. E., Hutton, C., Orth, M., Robertson, M. M., Critchley,

H. D., & Frackowiak, R. S. (2010). Multispectral brain morphometry in Tourette

syndrome persisting into adulthood. Brain: A Journal of Neurology, 133(Pt 12), 3661–

3675. https://doi.org/10.1093/brain/awq300

Draper, A., Stephenson, M. C., Jackson, G. M., Pépés, S., Morgan, P. S., Morris, P. G., &

Jackson, S. R. (2014). Increased GABA Contributes to Enhanced Control over Motor

164

Excitability in Tourette Syndrome. Current Biology, 24(19), 2343–2347.

https://doi.org/10.1016/j.cub.2014.08.038

Du, Y.-S., Li, H.-F., Vance, A., Zhong, Y.-Q., Jiao, F.-Y., & Wang, H.-M. (2008). Randomized

double-blind multicentre placebo-controlled clinical trial of the clonidine adhesive patch

for the treatment of tic disorders. Australian and New Zealand Journal of

Psychiatry.42(9)()(Pp, 807(813), 2008.Date.

Duckworth, A. L., Gendler, T. S., & Gross, J. J. (2016). Situational Strategies for Self-Control.

Perspectives on Psychological Science: A Journal of the Association for Psychological

Science, 11(1), 35–55. https://doi.org/10.1177/1745691615623247

Duff, E. P., Cunnington, R., & Egan, G. F. (2007). REX: Response exploration for neuroimaging

datasets. Neuroinformatics, 5(4), 223–234. https://doi.org/10.1007/s12021-007-9001-y

Dursun, S. M., Reveley, M. A., Bird, R., & Stirton, F. (1994). Longlasting improvement of

Tourette’s syndrome with transdermal nicotine. Lancet.344(8936)()(Pp, 1577.

Dvorak, R. D., & Simons, J. S. (2009). Moderation of resource depletion in the self-control

strength model: Differing effects of two modes of self-control. Personality & Social

Psychology Bulletin, 35(5), 572–583. https://doi.org/10.1177/0146167208330855

Eddy, C. M., Cavanna, A. E., & Hansen, P. C. (2017). Empathy and aversion: The neural

signature of mentalizing in Tourette syndrome. Psychological Medicine, 47(3), 507–517.

https://doi.org/10.1017/S0033291716002725

165

Eddy, Clare M., & Cavanna, A. E. (2017). Set-Shifting Deficits: A Possible Neurocognitive

Endophenotype for Tourette Syndrome Without ADHD. Journal of Attention Disorders,

21(10), 824–834. https://doi.org/10.1177/1087054714545536

Eddy, Clare M., Cavanna, A. E., Rickards, H. E., & Hansen, P. C. (2016). Temporo-parietal

dysfunction in Tourette syndrome: Insights from an fMRI study of Theory of Mind.

Journal of Psychiatric Research, 81, 102–111.

https://doi.org/10.1016/j.jpsychires.2016.07.002

Eddy, Clare Margaret, Rickards, H. E., & Cavanna, A. E. (2012). Executive functions in

uncomplicated Tourette syndrome. Psychiatry Research, 200(1), 46–48.

https://doi.org/10.1016/j.psychres.2012.05.023

Eggers, C., Rothenberger, A., & Berghaus, U. (1988). Clinical and neurobiological findings in

children suffering from tic disease following treatment with tiapride. European Archives

of Psychiatry & Neurological Sciences, 237, 223–229.

Erenberg, G. (2005). The Relationship Between Tourette Syndrome, Attention Deficit

Hyperactivity Disorder, and Stimulant Medication: A Critical Review. In Seminars in

Pediatric Neurology.12(4)()(pp (Vol. 217, p. 2005.Date). of Publication.

Fahim, C., Yoon, U., Das, S., Lyttelton, O., Chen, J., Arnaoutelis, R., Rouleau, G., Sandor, P.,

Frey, K., Brandner, C., & Evans, A. C. (2010). Somatosensory-motor bodily

representation cortical thinning in Tourette: Effects of tic severity, age and gender.

Cortex; a Journal Devoted to the Study of the Nervous System and Behavior, 46(6), 750–

760. https://doi.org/10.1016/j.cortex.2009.06.008

166

Fan, S., Cath, D. C., van der Werf, Y. D., de Wit, S., Veltman, D. J., & van den Heuvel, O. A.

(2017). Trans-diagnostic comparison of response inhibition in Tourette’s disorder and

obsessive-compulsive disorder. The World Journal of Biological Psychiatry: The Official

Journal of the World Federation of Societies of Biological Psychiatry, 1–11.

https://doi.org/10.1080/15622975.2017.1347711

Feinberg, M., & Carroll, B. J. (1979). Effects of dopamine agonists and antagonists in Tourette’s

disease. Archives of General Psychiatry, 36, 979–985.

Francis, L. A., & Susman, E. J. (2009). Self-regulation and rapid weight gain in children from

age 3 to 12 years. Archives of Pediatrics & Adolescent Medicine, 163(4), 297–302.

https://doi.org/10.1001/archpediatrics.2008.579

Freeman, R. D., Fast, D. K., Burd, L., Kerbeshian, J., Robertson, M. M., & Sandor, P. (2000). An

international perspective on Tourette syndrome: Selected findings from 3,500 individuals

in 22 countries. Dev.Med.Child Neurol, 42, 436–447.

Friese, M., Binder, J., Luechinger, R., Boesiger, P., & Rasch, B. (2013). Suppressing Emotions

Impairs Subsequent Stroop Performance and Reduces Prefrontal Brain Activation. PLOS

ONE, 8(4), e60385. https://doi.org/10.1371/journal.pone.0060385

Gabbay, V., Coffey, B. J., Babb, J. S., Meyer, L., Wachtel, C., & Anam, S. (2008). Pediatric

autoimmune neuropsychiatric disorders associated with streptococcus: Comparison of

diagnosis and treatment in the community and at a specialty clinic. Pediatrics, 122, 273–

278.

167

Gadow, K. D., Nolan, E., Sprafkin, J., & Sverd, J. (1995). School observations of children with

attention-deficit hyperactivity disorder and comorbid tic disorder: Effects of

methylphenidate treatment. Journal of Developmental & Behavioral Pediatrics, 16, 167–

176.

Gadow, K. D., Sverd, J., Nolan, E. E., Sprafkin, J., & Schneider, J. (2007). Immediate-release

methylphenidate for ADHD in children with comorbid chronic multiple tic disorder.

Journal of the American Academy of Child & Adolescent Psychiatry, 46, 840–848.

Gadow, K. D., Sverd, J., Sprafkin, J., & Nolan, E. E. (1995). “Efficacy of methylphenidate for

attention-deficit hyperactivity disorder in children with tic disorder”: Correction.

Archives of General Psychiatry, 52, 836.

Gadow, K. D., Sverd, J., Sprafkin, J., Nolan, E. E., & Ezor, S. N. (1995). Efficacy of

methylphenidate for attention-deficit hyperactivity disorder in children with tic

disorder.[erratum appears in Arch Gen. Psychiatry, 52, 444–455.

Gadow, K. D., Sverd, J., Sprafkin, J., Nolan, E. E., & Grossman, S. (1999). Long-term

methylphenidate therapy in children with comorbid attention-deficit hyperactivity

disorder and chronic multiple tic disorder.[see comment]. Archives of General

Psychiatry, 56, 330–336.

Gaffney, G. R., Perry, P. J., Lund, B. C., Bever-Stille, K. A., Arndt, S., & Kuperman, S. (2002).

Risperidone versus clonidine in the treatment of children and adolescents with Tourette’s

syndrome. Journal of the American Academy of Child and Adolescent Psychiatry, 41(3),

330–336. https://doi.org/10.1097/00004583-200203000-00013

168

Gancher, S., Conant-Norville, D., & Angell, R. (1990). Treatment of Tourette’s syndrome with

transdermal clonidine: A pilot study. Journal of Neuropsychiatry & Clinical

Neurosciences, 2, 66–69.

Ganos, C., Kahl, U., Brandt, V., Schunke, O., Bäumer, T., Thomalla, G., Roessner, V., Haggard,

P., Münchau, A., & Kühn, S. (2014). The neural correlates of tic inhibition in Gilles de la

Tourette syndrome. Neuropsychologia, 65, 297–301.

https://doi.org/10.1016/j.neuropsychologia.2014.08.007

Ganos, C., Kühn, S., Kahl, U., Schunke, O., Feldheim, J., Gerloff, C., Roessner, V., Bäumer, T.,

Thomalla, G., Haggard, P., & Münchau, A. (2014). Action inhibition in Tourette

syndrome. Movement Disorders: Official Journal of the Movement Disorder Society,

29(12), 1532–1538. https://doi.org/10.1002/mds.25944

Ganos, C., Rocchi, L., Latorre, A., Hockey, L., Palmer, C., Joyce, E. M., Bhatia, K. P., Haggard,

P., & Rothwell, J. (2018). Motor cortical excitability during voluntary inhibition of

involuntary tic movements. Movement Disorders: Official Journal of the Movement

Disorder Society, 33(11), 1804–1809. https://doi.org/10.1002/mds.27479

Ganos, C., Roessner, V., & Münchau, A. (2013a). The functional anatomy of Gilles de la

Tourette syndrome. Neuroscience and Biobehavioral Reviews, 37(6), 1050–1062.

https://doi.org/10.1016/j.neubiorev.2012.11.004

Ganos, C., Roessner, V., & Münchau, A. (2013b). The functional anatomy of Gilles de la

Tourette syndrome. Neuroscience and Biobehavioral Reviews, 37(6), 1050–1062.

https://doi.org/10.1016/j.neubiorev.2012.11.004

169

Garvey, M. A., Perlmutter, S. J., Allen, A. J., Hamburger, S., Lougee, L., & Leonard, H. L.

(1999). A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations

triggered by streptococcal infections. Biol.Psychiatry, 45, 1564–1571.

Gauggel, S., Heusinger, A., Forkmann, T., Boecker, M., Lindenmeyer, J., Cox, W. M., &

Staedtgen, M. (2010). Effects of alcohol cue exposure on response inhibition in

detoxified alcohol-dependent patients. Alcoholism, Clinical and Experimental Research,

34(9), 1584–1589. https://doi.org/10.1111/j.1530-0277.2010.01243.x

Geddes, J., Freemantle, N., Harrison, P., & Bebbington, P. (2000). Atypical antipsychotics in the

treatment of schizophrenia: Systematic overview and meta-regression analysis. BMJ, 321,

1371–1376.

George, M. S., Robertson, M. M., Costa, D. C., Ell, P. J., Trimble, M. R., Pilowsky, L., &

Verhoeff, N. P. (1994). Dopamine receptor availability in Tourette’s syndrome.

Psychiatry Research, 55(4), 193–203. https://doi.org/10.1016/0165-1781(95)91245-9

Gilbert, D.L. (2009). Inflammation in Tic Disorders and Obsessive-Compulsive Disorder: Are

PANS and PANDAS a Path Forward? - Donald L. Gilbert,. https://journals-sagepub-

com.myaccess.library.utoronto.ca/doi/full/10.1177/0883073819848635

Gilbert, D.L., Dure, L., Sethuraman, G., Raab, D., Lane, J., & Sallee, F. R. (2003). Tic reduction

with pergolide in a randomized controlled trial in children. Neurology, 60, 606–611.

Gilbert, D.L., Sethuraman, G., Sine, L., Peters, S., & Sallee, F. R. (2000). Tourette’s syndrome

improvement with pergolide in a randomized, double-blind, crossover trial. Neurology,

54, 1310–1315.

170

Gilbert, Donald L, Batterson, J. R., Sethuraman, G., & Sallee, F. R. (2004). Tic reduction with

risperidone versus pimozide in a randomized, double-blind, crossover trial. Journal of the

American Academy of Child and Adolescent Psychiatry, 43(2), 206–214.

https://doi.org/10.1097/00004583-200402000-00017

Gilles de la Tourette, G. (1885). Etude sur nerveus caracterisee par de l"incoordination motrice

accompagnee d"echolalie et coprolalie. Arch.Neurol, 9, 158–200.

Ginovart, N., Galineau, L., Willeit, M., Mizrahi, R., Bloomfield, P. M., Seeman, P., Houle, S.,

Kapur, S., & Wilson, A. A. (2006). Binding characteristics and sensitivity to endogenous

dopamine of [11C]-(+)-PHNO, a new agonist radiotracer for imaging the high-affinity

state of D2 receptors in vivo using positron emission tomography. Journal of

Neurochemistry, 97(4), 1089–1103. https://doi.org/10.1111/j.1471-4159.2006.03840.x

Gmehlin, D., Fuermaier, A. B. M., Walther, S., Tucha, L., Koerts, J., Lange, K. W., Tucha, O.,

Weisbrod, M., & Aschenbrenner, S. (2016). Attentional Lapses of Adults with Attention

Deficit Hyperactivity Disorder in Tasks of Sustained Attention. Archives of Clinical

Neuropsychology: The Official Journal of the National Academy of Neuropsychologists,

31(4), 343–357. https://doi.org/10.1093/arclin/acw016

Goetz, C. G. (1992). Clonidine and clonazepam in Tourette syndrome. Adv.Neurol, 58, 245–251.

Goetz, C. G., Stebbins, G. T., & Thelen, J. A. (1994). Talipexole and adult Gilles de la

Tourette’s syndrome: Double-blind, placebo-controlled clinical trial. Movement

Disorders, 9, 315–317.

171

Goetz, C. G., Tanner, C. M., & Klawans, H. L. (1984). Fluphenazine and multifocal tic

disorders. Arch.Neurol, 41, 271–272.

Goetz, C. G., Tanner, C. M., Wilson, R. S., Carroll, V. S., Como, P. G., & Shannon, K. M.

(1987). Clonidine and Gilles de la Tourette’s syndrome: Double-blind study using

objective rating methods. Annals of Neurology, 21, 307–310.

Goldberg, J. (2002). Clonidine and methylphenidate were effective for attention deficit

hyperactivity disorder in children with comorbid tics. Evid.Based Ment.Health, 5, 122.

Goldstein, R. Z., & Volkow, N. D. (2011). Dysfunction of the prefrontal cortex in addiction:

Neuroimaging findings and clinical implications. Nature Reviews. Neuroscience, 12(11),

652–669. https://doi.org/10.1038/nrn3119

Gonce, M., & Barbeau, A. (1977). Seven cases of Gilles de la tourette’s syndrome: Partial relief

with clonazepam: A pilot study. Canadian Journal of Neurological Sciences, 4, 279–283.

Gorman, D. A., & Abi-Jaoude, E. (2014). Uncovering the complexity of Tourette syndrome,

little by little. The British Journal of Psychiatry: The Journal of Mental Science, 204(1),

6–8. https://doi.org/10.1192/bjp.bp.113.135996

Government of Canada, H. C. (2013, June 12). Information for Health Care Professionals:

Cannabis (marihuana, marijuana) and the cannabinoids [Health Canada, 2013].

http://www.hc-sc.gc.ca/dhp-mps/marihuana/med/infoprof-eng.php

Graybiel, A. M. (2008). Habits, rituals, and the evaluative brain. Annual Review of Neuroscience,

31, 359–387. https://doi.org/10.1146/annurev.neuro.29.051605.112851

172

Greene, D. J., Williams Iii, A. C., Koller, J. M., Schlaggar, B. L., & Black, K. J. (2016). Brain

structure in pediatric Tourette syndrome. Molecular Psychiatry.

https://doi.org/10.1038/mp.2016.194

Greimel, E., Wanderer, S., Rothenberger, A., Herpertz-Dahlmann, B., Konrad, K., & Roessner,

V. (2011). Attentional performance in children and adolescents with tic disorder and co-

occurring attention-deficit/hyperactivity disorder: New insights from a 2 × 2 factorial

design study. Journal of Abnormal Child Psychology, 39(6), 819–828.

https://doi.org/10.1007/s10802-011-9493-7

Griesemer, D. A. (1997). Pergolide in the management of Tourette syndrome. Journal of Child

Neurology.12(6)()(pp, 402(403), 1997.Date.

Grotenhermen, F., & Müller-Vahl, K. (2012). The Therapeutic Potential of Cannabis and

Cannabinoids. Deutsches Ärzteblatt International, 109(29–30), 495–501.

https://doi.org/10.3238/arztebl.2012.0495

Gunn, R. N., Lammertsma, A. A., Hume, S. P., & Cunningham, V. J. (1997). Parametric imaging

of ligand-receptor binding in PET using a simplified reference region model.

NeuroImage, 6(4), 279–287. https://doi.org/10.1006/nimg.1997.0303

Haense, C., Müller-Vahl, K. R., Wilke, F., Schrader, C., Capelle, H. H., Geworski, L., Bengel, F.

M., Krauss, J. K., & Berding, G. (2016). Effect of Deep Brain Stimulation on Regional

Cerebral Blood Flow in Patients with Medically Refractory Tourette Syndrome.

Frontiers in Psychiatry, 7. https://doi.org/10.3389/fpsyt.2016.00118

173

Hagger, M. S., Leaver, E., Esser, K., Leung, C.-M., Te Pas, N., Keatley, D. A., Chan, D. K.-C.,

& Chatzisarantis, N. L. D. (2013). Cue-induced smoking urges deplete cigarette smokers’

self-control resources. Annals of Behavioral Medicine: A Publication of the Society of

Behavioral Medicine, 46(3), 394–400. https://doi.org/10.1007/s12160-013-9520-8

Hagger, M. S., Wood, C., Stiff, C., & Chatzisarantis, N. L. D. (2010). Ego depletion and the

strength model of self-control: A meta-analysis. Psychological Bulletin, 136(4), 495–525.

https://doi.org/10.1037/a0019486

Haldane, M., Cunningham, G., Androutsos, C., & Frangou, S. (2008). Structural brain correlates

of response inhibition in Bipolar Disorder I. Journal of Psychopharmacology (Oxford,

England), 22(2), 138–143. https://doi.org/10.1177/0269881107082955

Hampson, M., Tokoglu, F., King, R. A., Constable, R. T., & Leckman, J. F. (2009). Brain areas

coactivating with motor cortex during chronic motor tics and intentional movements.

Biological Psychiatry, 65(7), 594–599. https://doi.org/10.1016/j.biopsych.2008.11.012

Handen, B. L., Feldman, H., Gosling, A., Breaux, A. M., & McAuliffe, S. (1991). Adverse side

effects of methylphenidate among mentally retarded children with ADHD. Journal of the

American Academy of Child & Adolescent Psychiatry, 30, 241–245.

Hershey, T., Black, K. J., Hartlein, J., Braver, T. S., Barch, D. M., Carl, J. L., & Perlmutter, J. S.

(2004). Dopaminergic modulation of response inhibition: An fMRI study. Brain

Research. Cognitive Brain Research, 20(3), 438–448.

https://doi.org/10.1016/j.cogbrainres.2004.03.018

174

Hoekstra, P. J., Minderaa, R. B., & Kallenberg, C. G. (2004). Lack of effect of intravenous

immunoglobulins on tics: A double-blind placebo-controlled study. J Clin.Psychiatry, 65,

537–542.

Hofmann, W., Vohs, K. D., & Baumeister, R. F. (2012). What people desire, feel conflicted

about, and try to resist in everyday life. Psychological Science, 23(6), 582–588.

https://doi.org/10.1177/0956797612437426

Hoogduin, K., Verdellen, C., & Cath, D. (1997). Exposure and response prevention in the

treatment of Gilles de la Tourette’s syndrome: Four case studies. Clinical Psychology and

Psychotherapy, 125–137.

Hoopes, S. P. (1999). Donepezil for Tourette’s disorder and ADHD. Journal of Clinical

Psychopharmacology, 19, 381–382.

Horrigan, J. P., & Jarrett, B. L. (1999). Guanfacine and secondary mania in children. Journal of

Affective Disorders.54(3)()(Pp, 309(314), 1999.Date.

Hovik, K. T., Egeland, J., Isquith, P. K., Gioia, G., Skogli, E. W., Andersen, P. N., & Øie, M.

(2017). Distinct Patterns of Everyday Executive Function Problems Distinguish Children

With Tourette Syndrome From Children With ADHD or Autism Spectrum Disorders.

Journal of Attention Disorders, 21(10), 811–823.

https://doi.org/10.1177/1087054714550336

Hovik, K. T., Plessen, K. J., Skogli, E. W., Andersen, P. N., & Øie, M. (2016). Dissociable

Response Inhibition in Children With Tourette’s Syndrome Compared With Children

175

With ADHD. Journal of Attention Disorders, 20(10), 825–835.

https://doi.org/10.1177/1087054713512371

Hsu, C.-F., Eastwood, J. D., & Toplak, M. E. (2017). Differences in Perceived Mental Effort

Required and Discomfort during a Working Memory Task between Individuals At-risk

And Not At-risk for ADHD. Frontiers in Psychology, 8.

https://doi.org/10.3389/fpsyg.2017.00407

Hwang, W.-J., Yao, W.-J., Fu, Y.-K., & Yang, A.-S. (2008). [99mTc]TRODAT-1/[123I]IBZM

SPECT studies of the dopaminergic system in Tourette syndrome. Psychiatry Research:

Neuroimaging, 162(2), 159–166. https://doi.org/10.1016/j.pscychresns.2007.04.006

Inzlicht, M., & Gutsell, J. N. (2007). Running on empty: Neural signals for self-control failure.

Psychological Science, 18(11), 933–937. https://doi.org/10.1111/j.1467-

9280.2007.02004.x

Inzlicht, M., Schmeichel, B. J., & Macrae, C. N. (2014). Why self-control seems (but may not

be) limited. Trends in Cognitive Sciences, 18(3), 127–133.

https://doi.org/10.1016/j.tics.2013.12.009

Itard, J. M. (2006). Study of several involuntary functions of the apparatus of movement,

gripping, and voice. 1825. Hist Psychiatry, 17, 339–351.

Jackson, G. M., Mueller, S. C., Hambleton, K., & Hollis, C. P. (2007). Enhanced cognitive

control in Tourette Syndrome during task uncertainty. Experimental Brain Research,

182(3), 357–364. https://doi.org/10.1007/s00221-007-0999-8

176

Jackson, Georgina M., Draper, A., Dyke, K., Pépés, S. E., & Jackson, S. R. (2015). Inhibition,

Disinhibition, and the Control of Action in Tourette Syndrome. Trends in Cognitive

Sciences, 19(11), 655–665. https://doi.org/10.1016/j.tics.2015.08.006

Jackson, S. R., Parkinson, A., Jung, J., Ryan, S. E., Morgan, P. S., Hollis, C., & Jackson, G. M.

(2011). Compensatory neural reorganization in Tourette syndrome. Current Biology: CB,

21(7), 580–585. https://doi.org/10.1016/j.cub.2011.02.047

Jankovic, J. (1994). Botulinum toxin in the treatment of dystonic tics. Mov Disord, 9, 347–349.

Jankovic, J., & Beach, J. (1997). Long-term effects of tetrabenazine in hyperkinetic movement

disorders. Neurology, 48, 358–362.

Jankovic, J. M., Glaze, D. G. M., & Frost, J. D. J. (1984). Effect of tetrabenazine on tics and

sleep of Gilles de la Tourette’s syndrome. [Miscellaneous]. Neurology, 34, 688–692.

Jankovic, J., & Orman, J. (1988). Tetrabenazine therapy of dystonia, chorea, tics, and other

dyskinesias (Vol. 38).

Jasinska, A. J., Stein, E. A., Kaiser, J., Naumer, M. J., & Yalachkov, Y. (2014). Factors

modulating neural reactivity to drug cues in addiction: A survey of human neuroimaging

studies. Neuroscience and Biobehavioral Reviews, 38, 1–16.

https://doi.org/10.1016/j.neubiorev.2013.10.013

Jeppesen, S. S., Debes, N. M., Simonsen, H. J., Rostrup, E., Larsson, H. B. W., & Skov, L.

(2014). Study of medication-free children with Tourette syndrome do not show imaging

abnormalities. Movement Disorders: Official Journal of the Movement Disorder Society,

29(9), 1212–1216. https://doi.org/10.1002/mds.25858

177

Jeter, C. B., Patel, S. S., Morris, J. S., Chuang, A. Z., Butler, I. J., & Sereno, A. B. (2015).

Oculomotor executive function abnormalities with increased tic severity in Tourette

syndrome. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 56(2),

193–202. https://doi.org/10.1111/jcpp.12298

Jiang, X., Liu, L., Ji, H., & Zhu, Y. (2018). Association of Affected Neurocircuitry With Deficit

of Response Inhibition and Delayed Gratification in Attention Deficit Hyperactivity

Disorder: A Narrative Review. Frontiers in Human Neuroscience, 12.

https://doi.org/10.3389/fnhum.2018.00506

Jo, H. J., McCairn, K. W., Gibson, W. S., Testini, P., Zhao, C. Z., Gorny, K. R., Felmlee, J. P.,

Welker, K. M., Blaha, C. D., Klassen, B. T., Min, H.-K., & Lee, K. H. (2018). Global

network modulation during thalamic stimulation for Tourette syndrome. NeuroImage:

Clinical, 18, 502–509. https://doi.org/10.1016/j.nicl.2018.02.018

Jones, P. B., Barnes, T. R., Davies, L., Dunn, G., Lloyd, H., & Hayhurst, K. P. (2006).

Randomized controlled trial of the effect on Quality of Life of second- vs first-generation

antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in

Schizophrenia Study (CUtLASS 1). Arch.Gen.Psychiatry, 63, 1079–1087.

Jung, JeYoung, Jackson, S. R., Nam, K., Hollis, C., & Jackson, G. M. (2015). Enhanced saccadic

control in young people with Tourette syndrome despite slowed pro-saccades. Journal of

Neuropsychology, 9(2), 172–183. https://doi.org/10.1111/jnp.12044

Jung, Jeyoung, Jackson, S. R., Parkinson, A., & Jackson, G. M. (2013). Cognitive control over

motor output in Tourette syndrome. Neuroscience and Biobehavioral Reviews, 37(6),

1016–1025. https://doi.org/10.1016/j.neubiorev.2012.08.009

178

Kalanithi, P. S. A., Zheng, W., Kataoka, Y., DiFiglia, M., Grantz, H., Saper, C. B., Schwartz, M.

L., Leckman, J. F., & Vaccarino, F. M. (2005). Altered parvalbumin-positive neuron

distribution in basal ganglia of individuals with Tourette syndrome. Proceedings of the

National Academy of Sciences of the United States of America, 102(37), 13307–13312.

https://doi.org/10.1073/pnas.0502624102

Kapur, S., Zipursky, R., Jones, C., Remington, G., & Houle, S. (2000). Relationship between

dopamine D(2) occupancy, clinical response, and side effects: A double-blind PET study

of first-episode schizophrenia. American Journal of Psychiatry, 157, 514–520.

Kataoka, Y., Kalanithi, P. S. A., Grantz, H., Schwartz, M. L., Saper, C., Leckman, J. F., &

Vaccarino, F. M. (2010). Decreased number of parvalbumin and cholinergic interneurons

in the striatum of individuals with Tourette syndrome. The Journal of Comparative

Neurology, 518(3), 277–291. https://doi.org/10.1002/cne.22206

Kelley, W. M., Wagner, D. D., & Heatherton, T. F. (2015). In search of a human self-regulation

system. Annual Review of Neuroscience, 38, 389–411. https://doi.org/10.1146/annurev-

neuro-071013-014243

Kendall, T. (2011). The rise and fall of the atypical antipsychotics. The British Journal of

Psychiatry: The Journal of Mental Science, 199(4), 266–268.

Kenney, C. J., Hunter, C. B., Mejia, N. I., & Jankovic, J. (2007). Tetrabenazine in the treatment

of Tourette syndrome. Journal of Pediatric Neurology, 5, 9–13.

Kiessling, L. S., Marcotte, A. C., & Culpepper, L. (1993). Antineuronal Antibodies in Movement

Disorders. Pediatrics, 92, 39–43.

179

Kiessling, L. S., Marcotte, A. C., & Culpepper, L. (1994). Antineuronal antibodies: Tics and

obsessive-compulsive symptoms. Journal of Developmental & Behavioral Pediatrics, 15,

421–425.

Kleckner, I. R., Zhang, J., Touroutoglou, A., Chanes, L., Xia, C., Simmons, W. K., Quigley, K.

S., Dickerson, B. C., & Barrett, L. F. (2017). Evidence for a Large-Scale Brain System

Supporting Allostasis and Interoception in Humans. Nature Human Behaviour, 1.

https://doi.org/10.1038/s41562-017-0069

Kober, H., Mende-Siedlecki, P., Kross, E. F., Weber, J., Mischel, W., Hart, C. L., & Ochsner, K.

N. (2010). Prefrontal-striatal pathway underlies cognitive regulation of craving.

Proceedings of the National Academy of Sciences of the United States of America,

107(33), 14811–14816. https://doi.org/10.1073/pnas.1007779107

Koppel, B. S., Brust, J. C. M., Fife, T., Bronstein, J., Youssof, S., Gronseth, G., & Gloss, D.

(2014). Systematic review: Efficacy and safety of medical marijuana in selected

neurologic disorders: report of the Guideline Development Subcommittee of the

American Academy of Neurology. Neurology, 82(17), 1556–1563.

https://doi.org/10.1212/WNL.0000000000000363

Kubzansky, L. D., Martin, L. T., & Buka, S. L. (2009). Early manifestations of personality and

adult health: A life course perspective. Health Psychology: Official Journal of the

Division of Health Psychology, American Psychological Association, 28(3), 364–372.

https://doi.org/10.1037/a0014428

Kuhtz-Buschbeck, J. P., Gilster, R., van der Horst, C., Hamann, M., Wolff, S., & Jansen, O.

(2009). Control of bladder sensations: An fMRI study of brain activity and effective

180

connectivity. NeuroImage, 47(1), 18–27.

https://doi.org/10.1016/j.neuroimage.2009.04.020

Kumar, R., & Lang, A. E. (1997). Coexistence of tics and parkinsonism: Evidence for non-

dopaminergic mechanisms in tic pathogenesis. Neurology, 49(6), 1699–1701.

Kurlan, R., Goetz, C. G., McDermott, M. P., Plumb, S., Singer, H., & Dure, L. (2002). Treatment

of ADHD in children with tics: A randomized controlled trial. Neurology.58(4)()(Pp,

527(536), 2002.Date.

Kurlan, R., Johnson, D., & Kaplan, E. L. (2008). Streptococcal infection and exacerbations of

childhood tics and obsessive-compulsive symptoms: A prospective blinded cohort study.

Pediatrics, 121, 1188–1197.

Kurlan, R., Majumdar, L., Deeley, C., Mudholkar, G. S., Plumb, S., & Como, P. G. (1991). A

controlled trial of propoxyphene and naltrexone in patients with Tourette’s syndrome.[see

comment]. Annals of Neurology, 30, 19–23.

Kwak, C. H., Hanna, P. A., & Jankovic, J. (2000). Botulinum toxin in the treatment of tics.

Archives of Neurology, 57, 1190–1193.

Lammertsma, A. A., & Hume, S. P. (1996). Simplified reference tissue model for PET receptor

studies. NeuroImage, 4(3 Pt 1), 153–158. https://doi.org/10.1006/nimg.1996.0066

Law, S. F., & Schachar, R. J. (1999). Do typical clinical doses of methylphenidate cause tics in

children treated for attention-deficit hyperactivity disorder? Journal of the American

Academy of Child & Adolescent Psychiatry, 38, 944–951.

181

Leckman, J. F., Detlor, J., Harcherik, D. F., Ort, S., Shaywitz, B. A., & Cohen, D. J. (1985).

Short- and long-term treatment of Tourette’s syndrome with clonidine: A clinical

perspective. Neurology, 35, 343–351.

Leckman, J. F., Hardin, M. T., Riddle, M. A., Stevenson, J., Ort, S. I., & Cohen, D. J. (1991).

Clonidine treatment of Gilles de la Tourette’s syndrome. Archives of General Psychiatry,

48, 324–328.

Leckman, J. F., Ort, S., Caruso, K. A., Anderson, G. M., Riddle, M. A., & Cohen, D. J. (1986).

Rebound phenomena in Tourette’s syndrome after abrupt withdrawal of clonidine.

Behavioral, cardiovascular, and neurochemical effects. Archives of General Psychiatry,

43, 1168–1176.

Leckman, J. F., Rauch, S. L., & Mataix-Cols, D. (2007). Symptom dimensions in obsessive-

compulsive disorder: Implications for the DSM-V. CNS Spectrums.12(5)()(Pp, 376(387),

2007.Date.

Leckman, J. F., Riddle, M. A., Hardin, M. T., Ort, S. I., Swartz, K. L., Stevenson, J., & Cohen,

D. J. (1989). The Yale Global Tic Severity Scale: Initial testing of a clinician-rated scale

of tic severity. Journal of the American Academy of Child and Adolescent Psychiatry,

28(4), 566–573. https://doi.org/10.1097/00004583-198907000-00015

Leckman, J. F., Walker, D. E., & Cohen, D. J. (1993). Premonitory urges in Tourette’s

syndrome. Am.J.Psychiatry, 150, 98–102.

182

Lee, M. S., Lee, H. Y., & Kim, S. H. (2008). Relapse of tic symptoms in a patient diagnosed

with obssesive-compulsive disorder and treated with high-dose paroxetine. [References].

Journal of Child and Adolescent Psychopharmacology, 18, 305–306.

Lennington, J. B., Coppola, G., Kataoka-Sasaki, Y., Fernandez, T. V., Palejev, D., Li, Y.,

Huttner, A., Pletikos, M., Sestan, N., Leckman, J. F., & Vaccarino, F. M. (2016).

Transcriptome Analysis of the Human Striatum in Tourette Syndrome. Biological

Psychiatry, 79(5), 372–382. https://doi.org/10.1016/j.biopsych.2014.07.018

Leonard, H. L., Swedo, S. E., Lenane, M. C., Rettew, D. C., Hamburger, S. D., & Bartko, J. J.

(1993). A 2- to 7-year follow-up study of 54 obsessive-compulsive children and

adolescents. Archives of General Psychiatry, 50, 429–439.

Lerner, A., Bagic, A., Hanakawa, T., Boudreau, E. A., Pagan, F., Mari, Z., Bara-Jimenez, W.,

Aksu, M., Sato, S., Murphy, D. L., & Hallett, M. (2009). Involvement of insula and

cingulate cortices in control and suppression of natural urges. Cerebral Cortex (New

York, N.Y.: 1991), 19(1), 218–223. https://doi.org/10.1093/cercor/bhn074

Lerner, A., Bagic, A., Simmons, J. M., Mari, Z., Bonne, O., Xu, B., Kazuba, D., Herscovitch, P.,

Carson, R. E., Murphy, D. L., Drevets, W. C., & Hallett, M. (2012). Widespread

abnormality of the γ-aminobutyric acid-ergic system in Tourette syndrome. Brain: A

Journal of Neurology, 135(Pt 6), 1926–1936. https://doi.org/10.1093/brain/aws104

Leslie, D. L., Kozma, L., Martin, A., Landeros, A., Katsovich, L., & King, R. A. (2008).

Neuropsychiatric Disorders Associated With Streptococcal Infection: A Case-Control

Study Among Privately. Insured Children. J Am Acad.Child Adolesc.Psychiatry.

183

Levy, N. (2006). Addiction, autonomy and ego-depletion: A response to Bennett Foddy and

Julian Savulescu. Bioethics, 20(1), 16–20.

Lin, Y.-J., Lai, M.-C., & Gau, S. S.-F. (2012). Youths with ADHD with and without tic

disorders: Comorbid psychopathology, executive function and social adjustment.

Research in Developmental Disabilities, 33(3), 951–963.

https://doi.org/10.1016/j.ridd.2012.01.001

Lipinski, J. F., Sallee, F. R., Jackson, C., & Sethuraman, G. (1997). Dopamine agonist treatment

of Tourette disorder in children: Results of an open-label trial of pergolide. Mov Disord,

12, 402–407.

Lipkin, P. H., Goldstein, I. J., & Adesman, A. R. (1994). Tics and dyskinesias associated with

stimulant treatment in attention-deficit hyperactivity disorder. Archives of Pediatrics &

Adolescent Medicine, 148, 859–861.

Lombroso, P. J., & Scahill, L. (2008). Tourette syndrome and obsessive-compulsive disorder.

Brain Dev, 30, 231–237.

Lopez, R. B., Hofmann, W., Wagner, D. D., Kelley, W. M., & Heatherton, T. F. (2014). Neural

predictors of giving in to temptation in daily life. Psychological Science, 25(7), 1337–

1344. https://doi.org/10.1177/0956797614531492

Macrì, S., Onori, M. P., Roessner, V., & Laviola, G. (2013). Animal models recapitulating the

multifactorial origin of Tourette syndrome. International Review of Neurobiology, 112,

211–237. https://doi.org/10.1016/B978-0-12-411546-0.00008-1

184

Mahler, M. S. (1949). Psychoanalytic evaluation of tics: A sign and synptom in

psychopathology. Psychoanal Study Child, 34, 279.

March, J. S., Franklin, M. E., Leonard, H., Garcia, A., Moore, P., Freeman, J., & Foa, E. (2007).

Tics moderate treatment outcome with sertraline but not cognitive-behavior therapy in

pediatric obsessive-compulsive disorder. Biological Psychiatry, 61(3), 344–347.

https://doi.org/10.1016/j.biopsych.2006.09.035

Margulies, D. S., Vincent, J. L., Kelly, C., Lohmann, G., Uddin, L. Q., Biswal, B. B., Villringer,

A., Castellanos, F. X., Milham, M. P., & Petrides, M. (2009). Precuneus shares intrinsic

functional architecture in humans and monkeys. Proceedings of the National Academy of

Sciences of the United States of America, 106(47), 20069–20074.

https://doi.org/10.1073/pnas.0905314106

Marras, C., Andrews, D., Sime, E., & Lang, A. E. (2001). Botulinum toxin for simple motor tics:

A randomized, double-blind, controlled clinical trial.[see comment]. Neurology, 56, 605–

610.

Marsh, R., Zhu, H., Wang, Z., Skudlarski, P., & Peterson, B. S. (2007). A developmental fMRI

study of self-regulatory control in Tourette’s syndrome. The American Journal of

Psychiatry, 164(6), 955–966. https://doi.org/10.1176/ajp.2007.164.6.955

Martinez, D., Slifstein, M., Broft, A., Mawlawi, O., Hwang, D.-R., Huang, Y., Cooper, T.,

Kegeles, L., Zarahn, E., Abi-Dargham, A., Haber, S. N., & Laruelle, M. (2003). Imaging

human mesolimbic dopamine transmission with positron emission tomography. Part II:

Amphetamine-induced dopamine release in the functional subdivisions of the striatum.

185

Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International

Society of Cerebral Blood Flow and Metabolism, 23(3), 285–300.

Martino, D., & Mink, J. W. (2013). Tic disorders. Continuum (Minneapolis, Minn.), 19(5

Movement Disorders), 1287–1311.

https://doi.org/10.1212/01.CON.0000436157.31662.af

Martino, D., Pringsheim, T. M., Cavanna, A. E., Colosimo, C., Hartmann, A., Leckman, J. F.,

Luo, S., Munchau, A., Goetz, C. G., Stebbins, G. T., Martinez-Martin, P., & Members of

the MDS Committee on Rating Scales Development. (2017). Systematic review of

severity scales and screening instruments for tics: Critique and recommendations.

Movement Disorders: Official Journal of the Movement Disorder Society, 32(3), 467–

473. https://doi.org/10.1002/mds.26891

Mawlawi, O., Martinez, D., Slifstein, M., Broft, A., Chatterjee, R., Hwang, D. R., Huang, Y.,

Simpson, N., Ngo, K., Van Heertum, R., & Laruelle, M. (2001). Imaging human

mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and

precision of D(2) receptor parameter measurements in ventral striatum. Journal of

Cerebral Blood Flow and Metabolism: Official Journal of the International Society of

Cerebral Blood Flow and Metabolism, 21(9), 1034–1057.

https://doi.org/10.1097/00004647-200109000-00002

Mazzone, L., Yu, S., Blair, C., Gunter, B. C., Wang, Z., Marsh, R., & Peterson, B. S. (2010). An

FMRI study of frontostriatal circuits during the inhibition of eye blinking in persons with

Tourette syndrome. The American Journal of Psychiatry, 167(3), 341–349.

https://doi.org/10.1176/appi.ajp.2009.08121831

186

Mazzone, S. B., Cole, L. J., Ando, A., Egan, G. F., & Farrell, M. J. (2011). Investigation of the

neural control of cough and cough suppression in humans using functional brain imaging.

The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 31(8),

2948–2958. https://doi.org/10.1523/JNEUROSCI.4597-10.2011

McConville, B. J., Sanberg, P. R., Fogelson, M. H., King, J., Cirino, P., Parker, K. W., &

Norman, A. B. (1992). The effects of nicotine plus haloperidol compared to nicotine only

and placebo nicotine only in reducing tic severity and frequency in Tourette’s disorder.

Biological Psychiatry, 31(8), 832–840.

McCracken, J. T., Suddath, R., Chang, S., Thakur, S., & Piacentini, J. (2008). Effectiveness and

tolerability of open label olanzapine in children and adolescents with Tourette syndrome.

[References]. Journal of Child and Adolescent Psychopharmacology, 18, 501–508.

McDougle, C. J., Epperson, C. N., Pelton, G. H., Wasylink, S., & Price, L. H. (2000). A double-

blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-

refractory obsessive-compulsive disorder.[see comment]. Archives of General Psychiatry,

57, 794–801.

McDougle, C. J., Goodman, W. K., Leckman, J. F., Barr, L. C., Heninger, G. R., & Price, L. H.

(1993). The efficacy of fluvoxamine in obsessive-compulsive disorder: Effects of

comorbid chronic tic disorder. Journal of Clinical Psychopharmacology, 13, 354–358.

McDougle, C. J., Goodman, W. K., Leckman, J. F., Lee, N. C., Heninger, G. R., & Price, L. H.

(1994). Haloperidol addition in fluvoxamine-refractory obsessive-compulsive disorder. A

double-blind, placebo-controlled study in patients with and without tics. Archives of

General Psychiatry, 51, 302–308.

187

McGuire, J. F., Piacentini, J., Storch, E. A., Murphy, T. K., Ricketts, E. J., Woods, D. W.,

Walkup, J. W., Peterson, A. L., Wilhelm, S., Lewin, A. B., McCracken, J. T., Leckman,

J. F., & Scahill, L. (2018). A multicenter examination and strategic revisions of the Yale

Global Tic Severity Scale. Neurology, 90(19), e1711–e1719.

https://doi.org/10.1212/WNL.0000000000005474

McKay, L. C., Adams, L., Frackowiak, R. S. J., & Corfield, D. R. (2008). A bilateral cortico-

bulbar network associated with breath holding in humans, determined by functional

magnetic resonance imaging. NeuroImage, 40(4), 1824–1832.

https://doi.org/10.1016/j.neuroimage.2008.01.058

Mell, L. K., Davis, R. L., & Owens, D. (2005). Association between streptococcal infection and

obsessive-compulsive disorder, Tourette’s syndrome, and tic disorder. Pediatrics, 116,

56–60.

Merikangas, J. R., Merikangas, K. R., Kopp, U., & Hanin, I. (1985). Blood choline and response

to clonazepam and haloperidol in Tourette’s syndrome. Acta Psychiatrica Scandinavica,

72, 395–399.

Micheli, F., Gatto, M., Lekhuniec, E., Mangone, C., Fernandez, P. M., & Pikielny, R. (1990).

Treatment of Tourette’s syndrome with calcium antagonists. Clinical

Neuropharmacology, 13, 77–83.

Miller, D. D., Caroff, S. N., Davis, S. M., Rosenheck, R. A., McEvoy, J. P., & Saltz, B. L.

(2008). Extrapyramidal side-effects of antipsychotics in a randomised trial. The British

Journal of Psychiatry, 193, 279–288.

188

Mink, J. W. (2001). Neurobiology of basal ganglia circuits in Tourette syndrome: Faulty

inhibition of unwanted motor patterns? Advances in Neurology, 85, 113–122.

Mischel, W., Shoda, Y., & Rodriguez, M. I. (1989). Delay of gratification in children. Science

(New York, N.Y.), 244(4907), 933–938.

Mischel, Walter, Ayduk, O., Berman, M. G., Casey, B. J., Gotlib, I. H., Jonides, J., Kross, E.,

Teslovich, T., Wilson, N. L., Zayas, V., & Shoda, Y. (2011). “Willpower” over the life

span: Decomposing self-regulation. Social Cognitive and Affective Neuroscience, 6(2),

252–256. https://doi.org/10.1093/scan/nsq081

Mochizuki, H., Papoiu, A. D. P., & Yosipovitch, G. (2014). Brain Processing of Itch and

Scratching. In E. Carstens & T. Akiyama (Eds.), Itch: Mechanisms and Treatment. CRC

Press/Taylor & Francis. http://www.ncbi.nlm.nih.gov/books/NBK200933/

Moeller, S. J., Tomasi, D., Honorio, J., Volkow, N. D., & Goldstein, R. Z. (2012). Dopaminergic

involvement during mental fatigue in health and cocaine addiction. Translational

Psychiatry, 2, e176. https://doi.org/10.1038/tp.2012.110

Moffitt, T. E., Arseneault, L., Belsky, D., Dickson, N., Hancox, R. J., Harrington, H., Houts, R.,

Poulton, R., Roberts, B. W., Ross, S., Sears, M. R., Thomson, W. M., & Caspi, A.

(2011). A gradient of childhood self-control predicts health, wealth, and public safety.

Proceedings of the National Academy of Sciences of the United States of America,

108(7), 2693–2698. https://doi.org/10.1073/pnas.1010076108

Mondrup, K., Dupont, E., & Braendgaard, H. (1985). Progabide in the treatment of hyperkinetic

extrapyramidal movement disorders. Acta Neurol.Scand, 72, 341–343.

189

Morand-Beaulieu, S., Grot, S., Lavoie, J., Leclerc, J. B., Luck, D., & Lavoie, M. E. (2017). The

puzzling question of inhibitory control in Tourette syndrome: A meta-analysis.

Neuroscience and Biobehavioral Reviews, 80, 240–262.

https://doi.org/10.1016/j.neubiorev.2017.05.006

Moretti, G., Pasquini, M., Mandarelli, G., Tarsitani, L., & Biondi, M. (2008). What every

psychiatrist should know about PANDAS: a review. Clin.Pract.Epidemol.Ment.Health, 4,

13.

Moss, D. E., Manderscheid, P. Z., Montgomery, S. P., Norman, A. B., & Sanberg, P. R. (1989).

Nicotine and cannabinoids as adjuncts to neuroleptics in the treatment of Tourette

syndrome and other motor disorders. Life Sciences, 44(21), 1521–1525.

Mueller, S. C., Jackson, G. M., Dhalla, R., Datsopoulos, S., & Hollis, C. P. (2006). Enhanced

cognitive control in young people with Tourette’s syndrome. Current Biology: CB, 16(6),

570–573. https://doi.org/10.1016/j.cub.2006.01.064

Mukaddes, N. M., & Abali, O. (2003). Quetiapine Treatment of Children and Adolescents with

Tourette’s Disorder. Journal of Child and Adolescent Psychopharmacology.13(3)()(Pp,

295(299), 2003.Date.

Muller, N. (2007). Tourette’s syndrome: Clinical features, pathophysiology, and therapeutic

approaches. Dialogues.Clin.Neurosci, 9, 161–171.

Müller-Vahl, K. R., Berding, G., Kolbe, H., Meyer, G. J., Hundeshagen, H., Dengler, R., Knapp,

W. H., & Emrich, H. M. (2000). Dopamine D2 receptor imaging inGilles de la Tourette

190

syndrome. Acta Neurologica Scandinavica, 101(3), 165–171.

https://doi.org/10.1034/j.1600-0404.2000.101003165.x

Müller-Vahl, K. R., Kolbe, H., Schneider, U., & Emrich, H. M. (1998). Cannabinoids: Possible

role in patho-physiology and therapy of Gilles de la Tourette syndrome. Acta

Psychiatrica Scandinavica, 98(6), 502–506.

Müller-Vahl, K R, Schneider, U., Koblenz, A., Jöbges, M., Kolbe, H., Daldrup, T., & Emrich, H.

M. (2002). Treatment of Tourette’s syndrome with Delta 9-tetrahydrocannabinol (THC):

A randomized crossover trial. Pharmacopsychiatry, 35(2), 57–61.

https://doi.org/10.1055/s-2002-25028

Müller-Vahl, Kirsten R. (2013). Treatment of Tourette syndrome with cannabinoids.

Behavioural Neurology, 27(1), 119–124. https://doi.org/10.3233/BEN-120276

Müller-Vahl, Kirsten R., Kaufmann, J., Grosskreutz, J., Dengler, R., Emrich, H. M., & Peschel,

T. (2009). Prefrontal and anterior cingulate cortex abnormalities in Tourette Syndrome:

Evidence from voxel-based morphometry and magnetization transfer imaging. BMC

Neuroscience, 10, 47. https://doi.org/10.1186/1471-2202-10-47

Müller-Vahl, Kirsten R, Schneider, U., Prevedel, H., Theloe, K., Kolbe, H., Daldrup, T., &

Emrich, H. M. (2003). Delta 9-tetrahydrocannabinol (THC) is effective in the treatment

of tics in Tourette syndrome: A 6-week randomized trial. The Journal of Clinical

Psychiatry, 64(4), 459–465.

Murphy, T. K., Lewin, A. B., Storch, E. A., Stock, S., & American Academy of Child and

Adolescent Psychiatry (AACAP) Committee on Quality Issues (CQI). (2013). Practice

191

parameter for the assessment and treatment of children and adolescents with tic disorders.

Journal of the American Academy of Child and Adolescent Psychiatry, 52(12), 1341–

1359. https://doi.org/10.1016/j.jaac.2013.09.015

Murphy, T., & Muter, V. (2012). Risk factors for comorbidity in ADHD and GTS: Looking

beyond a single-deficit model. Applied Neuropsychology. Child, 1(2), 129–136.

https://doi.org/10.1080/21622965.2012.703889

Neuner, I., Kellermann, T., Stöcker, T., Kircher, T., Habel, U., Shah, J. N., & Schneider, F.

(2010). Amygdala hypersensitivity in response to emotional faces in Tourette’s patients.

The World Journal of Biological Psychiatry: The Official Journal of the World

Federation of Societies of Biological Psychiatry, 11(7), 858–872.

https://doi.org/10.3109/15622975.2010.480984

Neuner, I., Werner, C. J., Arrubla, J., Stöcker, T., Ehlen, C., Wegener, H. P., Schneider, F., &

Shah, N. J. (2014). Imaging the where and when of tic generation and resting state

networks in adult Tourette patients. Frontiers in Human Neuroscience, 8.

https://doi.org/10.3389/fnhum.2014.00362

Nicolson, R., Craven-Thuss, B., Smith, J., McKinlay, B. D., & Castellanos, F. X. (2005). A

randomized, double-blind, placebo-controlled trial of metoclopramide for the treatment

of Tourette’s disorder. Journal of the American Academy of Child & Adolescent

Psychiatry, 44, 640–646.

Niederhofer, H. (2006). Donepezil also effective in the treatment of Tourette’s syndrome?

Movement Disorders: Official Journal of the Movement Disorder Society, 21(11), 2027.

https://doi.org/10.1002/mds.21053

192

Nielsen, M. Ø., Köhler-Forsberg, O., Hjorthøj, C., Benros, M. E., Nordentoft, M., & Orlovska-

Waast, S. (2019). Streptococcal Infections and Exacerbations in PANDAS: A Systematic

Review and Meta-analysis. The Pediatric Infectious Disease Journal, 38(2), 189–194.

https://doi.org/10.1097/INF.0000000000002218

Onofrj, M., Paci, C., D’Andreamatteo, G., & Toma, L. (2000). Olanzapine in severe Gilles de la

Tourette syndrome: A 52-week double-blind cross-over study vs. Low-dose pimozide.

Journal of Neurology, 247, 443–446.

Osland, S. T., Steeves, T. D., & Pringsheim, T. (2018). Pharmacological treatment for attention

deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders. The

Cochrane Database of Systematic Reviews, 6, CD007990.

https://doi.org/10.1002/14651858.CD007990.pub3

Paleacu, D., Giladi, N., Moore, O., Stern, A., Honigman, S., & Badarny, S. (2004).

Tetrabenazine treatment in movement disorders. Clinical Neuropharmacology, 27, 230–

233.

Panetta, L., Phinnemore, R., Eastwood, J., & Toplak, M. (2016). The experience of mental effort

during a sustained attention task in individuals with self-reported attention problems.

Personality and Individual Differences, 101, 503.

https://doi.org/10.1016/j.paid.2016.05.246

Papoiu, A. D. P., Nattkemper, L. A., Sanders, K. M., Kraft, R. A., Chan, Y.-H., Coghill, R. C., &

Yosipovitch, G. (2013). Brain’s Reward Circuits Mediate Itch Relief. A Functional MRI

Study of Active Scratching. PLOS ONE, 8(12), e82389.

https://doi.org/10.1371/journal.pone.0082389

193

Perlmutter, S. J., Leitman, S. F., Garvey, M. A., Hamburger, S., Feldman, E., & Leonard, H. L.

(1999). Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-

compulsive disorder and tic disorders in childhood. Lancet, 354, 1153–1158.

Peterson, A. L., & Azrin, N. H. (1992). An evaluation of behavioral treatments for Tourette

syndrome. Behav.Res.Ther, 30, 167–174.

Peterson, B. S. (1996). Considerations of natural history and pathophysiology in the

psychopharmacology of Tourette’s syndrome. The Journal of Clinical Psychiatry, 57

Suppl 9, 24–34.

Peterson, B. S., Leckman, J. F., Scahill, L., Naftolin, F., Keefe, D., & Charest, N. J. (1994).

Steroid hormones and Tourette’s syndrome: Early experience with antiandrogen therapy.

Journal of Clinical Psychopharmacology, 14, 131–135.

Peterson, B. S., Skudlarski, P., Anderson, A. W., Zhang, H., Gatenby, J. C., Lacadie, C. M.,

Leckman, J. F., & Gore, J. C. (1998). A functional magnetic resonance imaging study of

tic suppression in Tourette syndrome. Archives of General Psychiatry, 55(4), 326–333.

Peterson, B. S., Staib, L., Scahill, L., Zhang, H., Anderson, C., Leckman, J. F., Cohen, D. J.,

Gore, J. C., Albert, J., & Webster, R. (2001). Regional brain and ventricular volumes in

Tourette syndrome. Archives of General Psychiatry, 58(5), 427–440.

Peterson, B. S., Zhang, H., Anderson, G. M., & Leckman, J. F. (1998). A double-blind, placebo-

controlled, crossover trial of an antiandrogen in the treatment of Tourette’s syndrome.

Journal of Clinical Psychopharmacology, 18, 324–331.

194

Piacentini, J., Woods, D. W., Scahill, L., Wilhelm, S., Peterson, A. L., Chang, S., Ginsburg, G.

S., Deckersbach, T., Dziura, J., Levi-Pearl, S., & Walkup, J. T. (2010). Behavior therapy

for children with Tourette disorder: A randomized controlled trial. JAMA, 303(19), 1929–

1937. https://doi.org/10.1001/jama.2010.607

Plessen, K. J., Royal, J. M., & Peterson, B. S. (2007). Neuroimaging of tic disorders with co-

existing attention-deficit/hyperactivity disorder. European Child & Adolescent

Psychiatry, 16 Suppl 1, 60–70. https://doi.org/10.1007/s00787-007-1008-2

Polyanska, L., Critchley, H. D., & Rae, C. L. (2017). Centrality of prefrontal and motor

preparation cortices to Tourette Syndrome revealed by meta-analysis of task-based

neuroimaging studies. NeuroImage. Clinical, 16, 257–267.

https://doi.org/10.1016/j.nicl.2017.08.004

Poncin, Y., Sukhodolsky, D. G., McGuire, J., & Scahill, L. (2007). Drug and non-drug

treatments of children with ADHD and tic disorders. 2007.Date of Publication: Jul,

78(88), 78–88.

Porta, M., Maggioni, G., Ottaviani, F., & Schindler, A. (2004). Treatment of phonic tics in

patients with Tourette’s syndrome using botulinum toxin type A. Neurological Sciences,

24, 420–423.

Porta, M., Sassi, M., Cavallazzi, M., Fornari, M., Brambilla, A., & Servello, D. (2008).

Tourette’s syndrome and role of tetrabenazine: Review and personal experience. Clinical

Drug Investigation.28(7)()(pp, 443(459), 2008.Date.

195

Poulton, R., Moffitt, T. E., & Silva, P. A. (2015). The Dunedin Multidisciplinary Health and

Development Study: Overview of the first 40 years, with an eye to the future. Social

Psychiatry and Psychiatric Epidemiology, 50(5), 679–693.

https://doi.org/10.1007/s00127-015-1048-8

Pourfar, M., Feigin, A., Tang, C. C., Carbon-Correll, M., Bussa, M., Budman, C., Dhawan, V., &

Eidelberg, D. (2011). Abnormal metabolic brain networks in Tourette syndrome.

Neurology, 76(11), 944–952. https://doi.org/10.1212/WNL.0b013e3182104106

Price, R. A., Kidd, K. K., Cohen, D. J., Pauls, D. L., & Leckman, J. F. (1985). A twin study of

Tourette syndrome. Arch.Gen.Psychiatry, 42, 815–820.

Pringsheim, T., Doja, A., Gorman, D., McKinlay, D., Day, L., Billinghurst, L., Carroll, A., Dion,

Y., Luscombe, S., Steeves, T., & Sandor, P. (2012). Canadian guidelines for the

evidence-based treatment of tic disorders: Pharmacotherapy. Canadian Journal of

Psychiatry. Revue Canadienne De Psychiatrie, 57(3), 133–143.

https://doi.org/10.1177/070674371205700302

Rae, C. L., Polyanska, L., Gould van Praag, C. D., Parkinson, J., Bouyagoub, S., Nagai, Y., Seth,

A. K., Harrison, N. A., Garfinkel, S. N., & Critchley, H. D. (2018). Face perception

enhances insula and motor network reactivity in Tourette syndrome. Brain, 141(11),

3249–3261. https://doi.org/10.1093/brain/awy254

Ray, W. A., Chung, C. P., Murray, K. T., Hall, K., & Stein, C. M. (2009). Atypical

Antipsychotic Drugs and the Risk of Sudden Cardiac Death. New England Journal of

Medicine, 360(3), 225–235. https://doi.org/10.1056/NEJMoa0806994

196

Raz, A., Zhu, H., Yu, S., Bansal, R., Wang, Z., Alexander, G. M., Royal, J., & Peterson, B. S.

(2009). Neural substrates of self-regulatory control in children and adults with Tourette

syndrome. Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie, 54(9),

579–588.

Richeson, J. A., Baird, A. A., Gordon, H. L., Heatherton, T. F., Wyland, C. L., Trawalter, S., &

Shelton, J. N. (2003). An fMRI investigation of the impact of interracial contact on

executive function. Nature Neuroscience, 6(12), 1323–1328.

https://doi.org/10.1038/nn1156

Rickards, H., Hartley, N., & Robertson, M. M. (1997). Seignot’s paper on the treatment of

Tourette’s syndrome with haloperidol. Classic Text. Hist Psychiatry, 31, 433–436.

Rickards, Hugh. (2009). Functional neuroimaging in Tourette syndrome. Journal of

Psychosomatic Research, 67(6), 575–584.

https://doi.org/10.1016/j.jpsychores.2009.07.024

Robertson, Mary M., Eapen, V., Singer, H. S., Martino, D., Scharf, J. M., Paschou, P., Roessner,

V., Woods, D. W., Hariz, M., Mathews, C. A., Črnčec, R., & Leckman, J. F. (2017).

Gilles de la Tourette syndrome. Nature Reviews. Disease Primers, 3, 16097.

https://doi.org/10.1038/nrdp.2016.97

Robertson, M.M. (2003). Diagnosing Tourette syndrome: Is it a common disorder?

Robertson, M.M., Schnieden, V., & Lees, A. J. (1990). Management of Gilles de la Tourette

syndrome using sulpiride. Clin.Neuropharmacol, 13, 229–235.

197

Roessner, V., Overlack, S., Baudewig, J., Dechent, P., Rothenberger, A., & Helms, G. (2009).

No brain structure abnormalities in boys with Tourette’s syndrome: A voxel-based

morphometry study. Movement Disorders: Official Journal of the Movement Disorder

Society, 24(16), 2398–2403. https://doi.org/10.1002/mds.22847

Roessner, V., Wittfoth, M., August, J. M., Rothenberger, A., Baudewig, J., & Dechent, P.

(2013). Finger tapping-related activation differences in treatment-naïve pediatric Tourette

syndrome: A comparison of the preferred and nonpreferred hand. Journal of Child

Psychology and Psychiatry, and Allied Disciplines, 54(3), 273–279.

https://doi.org/10.1111/j.1469-7610.2012.02584.x

Roessner, V., Wittfoth, M., Schmidt-Samoa, C., Rothenberger, A., Dechent, P., & Baudewig, J.

(2012). Altered motor network recruitment during finger tapping in boys with Tourette

syndrome. Human Brain Mapping, 33(3), 666–675. https://doi.org/10.1002/hbm.21240

Rorden, C., & Brett, M. (2000). Stereotaxic display of brain lesions. Behavioural Neurology,

12(4), 191–200.

Ross, M. S., & Moldofsky, H. (1978). A comparison of pimozide and haloperidol in the

treatment of Gilles de la Tourette’s syndrome. American Journal of Psychiatry, 135,

585–587.

Sallee, F., Kohegyi, E., Zhao, J., McQuade, R., Cox, K., Sanchez, R., van Beek, A., Nyilas, M.,

Carson, W., & Kurlan, R. (2017). Randomized, Double-Blind, Placebo-Controlled Trial

Demonstrates the Efficacy and Safety of Oral Aripiprazole for the Treatment of

Tourette’s Disorder in Children and Adolescents. Journal of Child and Adolescent

Psychopharmacology, 27(9), 771–781. https://doi.org/10.1089/cap.2016.0026

198

Sallee, F. R., Kurlan, R., Goetz, C. G., Singer, H., Scahill, L., & Law, G. (2000). Ziprasidone

treatment of children and adolescents with Tourette’s syndrome: A pilot study. Journal of

the American Academy of Child & Adolescent Psychiatry, 39, 292–299.

Sallee, F. R., Nesbitt, L., Jackson, C., Sine, L., & Sethuraman, G. (1997). Relative efficacy of

haloperidol and pimozide in children and adolescents with Tourette’s disorder.[see

comment]. American Journal of Psychiatry, 154, 1057–1062.

Sanberg, P. R., Fogelson, H. M., Manderscheid, P. Z., Parker, K. W., Norman, A. B., &

McConville, B. J. (1988). Nicotine gum and haloperidol in Tourette’s syndrome. Lancet,

1, 592.

Sanberg, P. R., McConville, B. J., Fogelson, H. M., Manderscheid, P. Z., Parker, K. W., &

Blythe, M. M. (1989). Nicotine potentiates the effects of haloperidol in animals and in

patients with Tourette syndrome. Biomed.Pharmacother, 43, 19–23.

Sandyk, R., & Awerbuch, G. (1988). Marijuana and Tourette’s syndrome. Journal of Clinical

Psychopharmacology, 8(6), 444–445.

Scahill, L., Chappell, P. B., Kim, Y. S., Schultz, R. T., Katsovich, L., & Shepherd, E. (2001). A

placebo-controlled study of guanfacine in the treatment of children with tic disorders and

attention deficit hyperactivity disorder. American Journal of Psychiatry, 158, 1067–1074.

Scahill, L., Erenberg, G., Berlin, C. M., Jr., Budman, C., Coffey, B. J., & Jankovic, J. (2006a).

Contemporary assessment and pharmacotherapy of Tourette syndrome. NeuroRx, 3, 192–

206.

199

Scahill, L., Erenberg, G., Berlin, C. M., Jr., Budman, C., Coffey, B. J., & Jankovic, J. (2006b).

Contemporary assessment and pharmacotherapy of Tourette syndrome. NeuroRx, 3, 192–

206.

Scahill, L., Leckman, J. F., Schultz, R. T., Katsovich, L., & Peterson, B. S. (2003). A placebo-

controlled trial of risperidone in Tourette syndrome. Neurology, 60, 1130–1135.

Schneeweiss, S., & Avorn, J. (2009). Antipsychotic Agents and Sudden Cardiac Death – How

Should We Manage the Risk? The New England Journal of Medicine, 360, 294–296.

Schneider, L. S., Tariot, P. N., Dagerman, K. S., Davis, S. M., Hsiao, J. K., Ismail, M. S.,

Lebowitz, B. D., Lyketsos, C. G., Ryan, J. M., Stroup, T. S., Sultzer, D. L., Weintraub,

D., Lieberman, J. A., & CATIE-AD Study Group. (2006). Effectiveness of atypical

antipsychotic drugs in patients with Alzheimer’s disease. The New England Journal of

Medicine, 355(15), 1525–1538. https://doi.org/10.1056/NEJMoa061240

Scott, B. L., Jankovic, J., & Donovan, D. T. (1996). Botulinum toxin injection into vocal cord in

the treatment of malignant coprolalia associated with Tourette’s syndrome. Mov Disord,

11, 431–433.

Seeyave, D. M., Coleman, S., Appugliese, D., Corwyn, R. F., Bradley, R. H., Davidson, N. S.,

Kaciroti, N., & Lumeng, J. C. (2009). Ability to delay gratification at age 4 years and risk

of overweight at age 11 years. Archives of Pediatrics & Adolescent Medicine, 163(4),

303–308. https://doi.org/10.1001/archpediatrics.2009.12

200

Segura, B., & Strafella, A. P. (2013). Functional imaging of dopaminergic neurotransmission in

Tourette syndrome. International Review of Neurobiology, 112, 73–93.

https://doi.org/10.1016/B978-0-12-411546-0.00003-2

Seseke, S., Baudewig, J., Kallenberg, K., Ringert, R.-H., Seseke, F., & Dechent, P. (2006).

Voluntary pelvic floor muscle control—An fMRI study. NeuroImage, 31(4), 1399–1407.

https://doi.org/10.1016/j.neuroimage.2006.02.012

Shapiro, A. K., & Shapiro, E. (1984). Controlled study of pimozide vs. Placebo in Tourette’s

syndrome. Journal of the American Academy of Child Psychiatry, 23, 161–173.

Shapiro, E., Shapiro, A. K., Fulop, G., Hubbard, M., Mandeli, J., & Nordlie, J. (1989).

Controlled study of haloperidol, pimozide and placebo for the treatment of Gilles de la

Tourette’s syndrome. Archives of General Psychiatry, 46, 722–730.

Shetti, C. N., Reddy, Y. C. J., Kandavel, T., Kashyap, K., Singisetti, S., & Hiremath, A. S.

(2005). Clinical predictors of drug nonresponse in obsessive-compulsive disorder.

Journal of Clinical Psychiatry.66(12)()(Pp, 1517(1523), 2005.Date.

Shytle, R. D., Silver, A. A., Philipp, M. K., McConville, B. J., & Sanberg, P. R. (1996).

Transdermal nicotine for Tourette’s syndrome. Drug Development Research.38(3-

4)()(Pp, 290(298), 1996.Date.

Sibley, D. R., De Lean, A., & Creese, I. (1982). Anterior pituitary dopamine receptors.

Demonstration of interconvertible high and low affinity states of the D-2 dopamine

receptor. The Journal of Biological Chemistry, 257(11), 6351–6361.

201

Sikich, L., Frazier, J. A., McClellan, J., Findling, R. L., Vitiello, B., & Ritz, L. (2008). Double-

Blind Comparison of First- and Second-Generation Antipsychotics in Early-Onset

Schizophrenia and Schizo-affective Disorder: Findings From the Treatment of Early-

Onset Schizophrenia Spectrum Disorders (TEOSS) Study. American Journal of

Psychiatry, 165, 1420–1431.

Silver, A. A., & Sanberg, P. R. (1993). Transdermal nicotine patch and potentiation of

haloperidol in Tourette’s syndrome. Lancet, 342, 182.

Silver, A. A., Shytle, R. D., Philipp, M. K., & Sanberg, P. R. (1996). Case study: Long-term

potentiation of neuroleptics with transdermal nicotine in Tourette’s syndrome. Journal of

the American Academy of Child and Adolescent Psychiatry.35(12)()(Pp, 1631(1636),

1631–1636.

Silver, A. A., Shytle, R. D., Philipp, M. K., Wilkinson, B. J., McConville, B., & Sanberg, P. R.

(2001). Transdermal nicotine and haloperidol in Tourette’s disorder: A double-blind

placebo-controlled study.[see comment]. Journal of Clinical Psychiatry, 62, 707–714.

Singer, H. S., Butler, I. J., Tune, L. E., Seifert, W. E., & Coyle, J. T. (1982). Dopaminergic

dsyfunction in Tourette syndrome. Annals of Neurology, 12(4), 361–366.

https://doi.org/10.1002/ana.410120408

Singer, Harvey S., Szymanski, S., Giuliano, J., Yokoi, F., Dogan, A. S., Brasic, J. R., Zhou, Y.,

Grace, A. A., & Wong, D. F. (2002). Elevated intrasynaptic dopamine release in

Tourette’s syndrome measured by PET. The American Journal of Psychiatry, 159(8),

1329–1336.

202

Singer, H.S., Gammon, K., & Quaskey, S. (1985). Haloperidol, fluphenazine and clonidine in

Tourette syndrome: Controversies in treatment. Pediatr.Neurosci, 12, 71–74.

Singer, H.S., Gause, C., Morris, C., & Lopez, P. (2008). Serial immune markers do not correlate

with clinical exacerbations in pediatric autoimmune neuropsychiatric disorders associated

with streptococcal infections. Pediatrics, 121, 1198–1205.

Singer, H.S., & Loiselle, C. (2003). PANDAS: a commentary. J Psychosom.Res, 55, 31–39.

Singer, H.S., Szymanski, S., Giuliano, J., Yokoi, F., Dogan, A. S., & Brasic, J. R. (2002).

Elevated intrasynaptic dopamine release in Tourette’s syndrome measured by. PET. Am J

Psychiatry, 159, 1329–1336.

Singer, H.S., Wendlandt, J., Krieger, M., & Giuliano, J. (2001). Baclofen treatment in Tourette

syndrome: A double-blind, placebo-controlled, crossover trial.[see comment]. Neurology,

56, 599–604.

Singer, H.S., & Wendlandt, J. T. (2001). Neurochemistry and synaptic neurotransmission in

Tourette syndrome. Adv.Neurol, 85, 163–178.

Skapinakis, P., Papatheodorou, T., & Mavreas, V. (2007). Antipsychotic augmentation of

serotonergic antidepressants in treatment-resistant obsessive-compulsive disorder: A

meta-analysis of the randomized controlled trials. European

Neuropsychopharmacology.17(2)()(pp, 79(93), 2007.Date.

Snider, L. A., Lougee, L., Slattery, M., Grant, P., & Swedo, S. E. (2005). Antibiotic prophylaxis

with azithromycin or penicillin for childhood-onset neuropsychiatric disorders.

Biol.Psychiatry, 57, 788–792.

203

Snider, L. A., & Swedo, S. E. (2004). PANDAS: current status and directions for research.

Mol.Psychiatry, 9, 900–907.

Solanto, M. V., Abikoff, H., Sonuga-Barke, E., Schachar, R., Logan, G. D., Wigal, T.,

Hechtman, L., Hinshaw, S., & Turkel, E. (2001). The ecological validity of delay

aversion and response inhibition as measures of impulsivity in AD/HD: A supplement to

the NIMH multimodal treatment study of AD/HD. Journal of Abnormal Child

Psychology, 29(3), 215–228.

Sowell, E. R., Kan, E., Yoshii, J., Thompson, P. M., Bansal, R., Xu, D., Toga, A. W., &

Peterson, B. S. (2008). Thinning of sensorimotor cortices in children with Tourette

syndrome. Nature Neuroscience, 11(6), 637–639. https://doi.org/10.1038/nn.2121

Stamenkovic, M., Schindler, S. D., Aschauer, H. N., De, Z. M., Willinger, U., & Resinger, E.

(2000). Effective open-label treatment of tourette’s disorder with olanzapine.

International Clinical Psychopharmacology, 15, 23–28.

Steeves, T. D. L., Ko, J. H., Kideckel, D. M., Rusjan, P., Houle, S., Sandor, P., Lang, A. E., &

Strafella, A. P. (2010). Extrastriatal dopaminergic dysfunction in tourette syndrome.

Annals of Neurology, 67(2), 170–181. https://doi.org/10.1002/ana.21809

Steingard, R. J., Goldberg, M., Lee, D., & DeMaso, D. R. (1994). Adjunctive clonazepam

treatment of tic symptoms in children with comorbid tic disorders and. ADHD. J Am

Acad.Child Adolesc.Psychiatry, 33, 394–399.

204

Stephens, R. J., Bassel, C., & Sandor, P. (2004). Olanzapine in the treatment of aggression and

tics in children with Tourette’s syndrome–a pilot study. Journal of Child & Adolescent

Psychopharmacology, 14, 255–266.

Stern, E. R., Blair, C., & Peterson, B. S. (2008a). Inhibitory deficits in Tourette’s syndrome.

Developmental Psychobiology, 50(1), 9–18. https://doi.org/10.1002/dev.20266

Stern, E. R., Blair, C., & Peterson, B. S. (2008b). Inhibitory deficits in Tourette’s syndrome.

Developmental Psychobiology, 50(1), 9–18. https://doi.org/10.1002/dev.20266

Stokes, A., Bawden, H. N., Camfield, P. R., Backman, J. E., & Dooley, J. M. (1991). Peer

problems in Tourette’s disorder. Pediatrics, 87, 936–942.

Storch, E.A., Lack, C. W., Simons, L. E., Goodman, W. K., Murphy, T. K., & Geffken, G. R.

(2007). A measure of functional impairment in youth with Tourette’s syndrome.

J.Pediatr.Psychol, 32, 950–959.

Storch, E.A., Merlo, L. J., Lack, C., Milsom, V. A., Geffken, G. R., & Goodman, W. K. (2007).

Quality of life in youth with Tourette’s syndrome and chronic tic disorder.

Storch, Eric A., Murphy, T. K., Geffken, G. R., Sajid, M., Allen, P., Roberti, J. W., & Goodman,

W. K. (2005). Reliability and validity of the Yale Global Tic Severity Scale.

Psychological Assessment, 17(4), 486–491. https://doi.org/10.1037/1040-3590.17.4.486

Stroup, T. S., Kraus, J. E., & Marder, S. R. (2006). Pharmacotherapies. In T. S. S. J.A.Lieberman

& D. O. Perkins (Eds.), Textbook of Schizophrenia (pp. 303–325). American Psychiatric

Publishing, Inc.

205

Sukhodolsky, D. G., Landeros-Weisenberger, A., Scahill, L., Leckman, J. F., & Schultz, R. T.

(2010). Neuropsychological functioning in children with Tourette syndrome with and

without attention-deficit/hyperactivity disorder. Journal of the American Academy of

Child and Adolescent Psychiatry, 49(11), 1155–1164.

https://doi.org/10.1016/j.jaac.2010.08.008

Sverd, J., Gadow, K. D., & Paolicelli, L. M. (1989). Methylphenidate treatment of attention-

deficit hyperactivity disorder in boys with Tourette’s syndrome. Journal of the American

Academy of Child & Adolescent Psychiatry, 28, 574–579.

SWAIN, J. E. M., SCAHILL, L. M. S. N., LOMBROSO, P. J. M., KING, R. A. M., &

LECKMAN, J. F. M. (2007). Tourette Syndrome and Tic Disorders: A Decade of

Progress. [Miscellaneous Article]. Journal of the American Academy of Child &

Adolescent Psychiatry, 46, 947–968.

Swedo, S. E., Leonard, H. L., Garvey, M., Mittleman, B., Allen, A. J., & Perlmutter, S. (1998).

Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal

Infections: Clinical Description of the First 50 Cases. American Journal of Psychiatry,

155, 264–271.

Sweet, R. D., Bruun, R., Shapiro, E., & Shapiro, A. K. (1974). Presynaptic catecholamine

antagonists as treatment for Tourette syndrome. Effects of alpha methyl para tyrosine and

tetrabenazine. Archives of General Psychiatry, 31, 857–861.

Tajik-Parvinchi, D. J., & Sandor, P. (2011). Smooth pursuit and fixation ability in children with

Tourette syndrome. Cognitive and Behavioral Neurology: Official Journal of the Society

206

for Behavioral and Cognitive Neurology, 24(4), 174–186.

https://doi.org/10.1097/WNN.0b013e31823f90eb

Tajik-Parvinchi, D. J., & Sandor, P. (2012). Unique saccadic abilities associated with tourette

syndrome: Pure and comorbid groups a controlled study. Journal of Obsessive-

Compulsive and Related Disorders, 1(4), 283–293.

https://doi.org/10.1016/j.jocrd.2012.07.004

Tajima, S., Yamamoto, S., Tanaka, M., Kataoka, Y., Iwase, M., Yoshikawa, E., Okada, H.,

Onoe, H., Tsukada, H., Kuratsune, H., Ouchi, Y., & Watanabe, Y. (2010). Medial

Orbitofrontal Cortex Is Associated with Fatigue Sensation [Research article]. Neurology

Research International. https://doi.org/10.1155/2010/671421

Tang, Y.-Y., & Posner, M. I. (2009). Attention training and attention state training. Trends in

Cognitive Sciences, 13(5), 222–227. https://doi.org/10.1016/j.tics.2009.01.009

Thibert, A. L., Day, H. I., & Sandor, P. (1995). Self-concept and self-consciousness in adults

with Tourette syndrome. Can.J.Psychiatry, 40, 35–39.

Thomalla, G., Jonas, M., Bäumer, T., Siebner, H. R., Biermann-Ruben, K., Ganos, C., Orth, M.,

Hummel, F. C., Gerloff, C., Müller-Vahl, K., Schnitzler, A., & Münchau, A. (2014).

Costs of control: Decreased motor cortex engagement during a Go/NoGo task in

Tourette’s syndrome. Brain, 137(1), 122–136. https://doi.org/10.1093/brain/awt288

Thomson, D. R., Besner, D., & Smilek, D. (2015). A resource-control account of sustained

attention: Evidence from mind-wandering and vigilance paradigms. Perspectives on

207

Psychological Science: A Journal of the Association for Psychological Science, 10(1),

82–96. https://doi.org/10.1177/1745691614556681

Tinaz, S., Belluscio, B. A., Malone, P., van der Veen, J. W., Hallett, M., & Horovitz, S. G.

(2014). Role of the sensorimotor cortex in tourette syndrome using multimodal imaging.

Human Brain Mapping. https://doi.org/10.1002/hbm.22588

Troung, D. D., Bressman, S., Shale, H., & Fahn, S. (1988). Clonazepam, haloperidol, and

clonidine in tic disorders. Southern Medical Journal, 81, 1103–1105.

Tucha, L., Fuermaier, A. B. M., Koerts, J., Buggenthin, R., Aschenbrenner, S., Weisbrod, M.,

Thome, J., Lange, K. W., & Tucha, O. (2017). Sustained attention in adult ADHD: Time-

on-task effects of various measures of attention. Journal of Neural Transmission (Vienna,

Austria: 1996), 124(Suppl 1), 39–53. https://doi.org/10.1007/s00702-015-1426-0

Turjanski, N., Sawle, G. V., Playford, E. D., Weeks, R., Lammerstma, A. A., Lees, A. J., &

Brooks, D. J. (1994). PET studies of the presynaptic and postsynaptic dopaminergic

system in Tourette’s syndrome. Journal of Neurology, Neurosurgery, and Psychiatry,

57(6), 688–692. van der Salm, S. M. A., van der Meer, J. N., Cath, D. C., Groot, P. F. C., van der Werf, Y. D.,

Brouwers, E., de Wit, S. J., Coppens, J. C., Nederveen, A. J., van Rootselaar, A.-F., &

Tijssen, M. A. J. (2018). Distinctive tics suppression network in Gilles de la Tourette

syndrome distinguished from suppression of natural urges using multimodal imaging.

NeuroImage. Clinical, 20, 783–792. https://doi.org/10.1016/j.nicl.2018.09.014

208 van Wattum, P. J., Chappell, P. B., Zelterman, D., Scahill, L. D., & Leckman, J. F. (2000).

Patterns of response to acute naloxone infusion in Tourette’s syndrome. Movement

Disorders, 15, 1252–1254.

Verdellen, C., van de Griendt, J., Hartmann, A., Murphy, T., & 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(4), 197–207. https://doi.org/10.1007/s00787-011-0167-3

Verdellen, C. W., Hoogduin, C. A., Kato, B. S., Keijsers, G. P., Cath, D. C., & Hoijtink, H. B.

(2008). Habituation of premonitory sensations during exposure and response prevention

treatment in Tourette’s syndrome. Behav.Modif, 32, 215–227.

Verdellen, C. W., Keijsers, G. P., Cath, D. C., & Hoogduin, C. A. (2004). Exposure with

response prevention versus habit reversal in Tourettes’s syndrome: A controlled study.

Behav.Res.Ther, 42, 501–511.

Vogt, B. A. (2016). Midcingulate cortex: Structure, connections, homologies, functions and

diseases. Journal of Chemical Neuroanatomy, 74, 28–46.

https://doi.org/10.1016/j.jchemneu.2016.01.010

Volkow, N. D., Fowler, J. S., Wang, G.-J., Telang, F., Logan, J., Jayne, M., Ma, Y., Pradhan, K.,

Wong, C., & Swanson, J. M. (2010). Cognitive control of drug craving inhibits brain

reward regions in cocaine abusers. NeuroImage, 49(3), 2536–2543.

https://doi.org/10.1016/j.neuroimage.2009.10.088

209

Wagner, D. D., Altman, M., Boswell, R. G., Kelley, W. M., & Heatherton, T. F. (2013). Self-

regulatory depletion enhances neural responses to rewards and impairs top-down control.

Psychological Science, 24(11), 2262–2271. https://doi.org/10.1177/0956797613492985

Wagner, D. D., & Heatherton, T. F. (2013). Self-regulatory depletion increases emotional

reactivity in the amygdala. Social Cognitive and Affective Neuroscience, 8(4), 410–417.

https://doi.org/10.1093/scan/nss082

Walkup, J. T., Rosenberg, L. A., Brown, J., & Singer, H. S. (1992). The validity of instruments

measuring tic severity in Tourette’s syndrome. J.Am.Acad.Child Adolesc.Psychiatry, 31,

472–477.

Walsh, T. L., Lavenstein, B., Licamele, W. L., Bronheim, S., & O’Leary, J. (1986). Calcium

antagonists in the treatment of Tourette’s disorder. American Journal of Psychiatry, 143,

1467–1468.

Wang, C., Trongnetrpunya, A., Samuel, I. B. H., Ding, M., & Kluger, B. M. (2016).

Compensatory Neural Activity in Response to Cognitive Fatigue. Journal of

Neuroscience, 36(14), 3919–3924. https://doi.org/10.1523/JNEUROSCI.3652-15.2016

Wang, L., Lee, D. Y., Bailey, E., Hartlein, J. M., Gado, M. H., Miller, M. I., & Black, K. J.

(2007). Validity of large-deformation high dimensional brain mapping of the basal

ganglia in adults with Tourette syndrome. Psychiatry Research, 154(2), 181–190.

https://doi.org/10.1016/j.pscychresns.2006.08.006

210

Wang, Y., Yang, L., & Wang, Y. (2014). Suppression (but Not Reappraisal) Impairs Subsequent

Error Detection: An ERP Study of Emotion Regulation’s Resource-Depleting Effect.

PLOS ONE, 9(4), e96339. https://doi.org/10.1371/journal.pone.0096339

Wang, Z., Maia, T. V., Marsh, R., Colibazzi, T., Gerber, A., & Peterson, B. S. (2011). The neural

circuits that generate tics in Tourette’s syndrome. The American Journal of Psychiatry,

168(12), 1326–1337. https://doi.org/10.1176/appi.ajp.2011.09111692

Weisman, H., Qureshi, I. A., Leckman, J. F., Scahill, L., & Bloch, M. H. (2013). Systematic

review: Pharmacological treatment of tic disorders--efficacy of antipsychotic and alpha-2

adrenergic agonist agents. Neuroscience and Biobehavioral Reviews, 37(6), 1162–1171.

https://doi.org/10.1016/j.neubiorev.2012.09.008

Werner, C. J., Stöcker, T., Kellermann, T., Bath, J., Beldoch, M., Schneider, F., Wegener, H. P.,

Shah, J. N., & Neuner, I. (2011). Altered motor network activation and functional

connectivity in adult Tourette’s syndrome. Human Brain Mapping, 32(11), 2014–2026.

https://doi.org/10.1002/hbm.21175

Whiting, P. F., Wolff, R. F., Deshpande, S., Di Nisio, M., Duffy, S., Hernandez, A. V.,

Keurentjes, J. C., Lang, S., Misso, K., Ryder, S., Schmidlkofer, S., Westwood, M., &

Kleijnen, J. (2015). Cannabinoids for Medical Use: A Systematic Review and Meta-

analysis. JAMA, 313(24), 2456–2473. https://doi.org/10.1001/jama.2015.6358

Wilbur, C., Bitnun, A., Kronenberg, S., Laxer, R. M., Levy, D. M., Logan, W. J., Shouldice, M.,

& Yeh, E. A. (2019). PANDAS/PANS in childhood: Controversies and evidence.

Paediatrics & Child Health, 24(2), 85–91. https://doi.org/10.1093/pch/pxy145

211

Wilhelm, S., Peterson, A. L., Piacentini, J., Woods, D. W., Deckersbach, T., Sukhodolsky, D. G.,

Chang, S., Liu, H., Dziura, J., Walkup, J. T., & Scahill, L. (2012). Randomized trial of

behavior therapy for adults with Tourette syndrome. Archives of General Psychiatry,

69(8), 795–803. https://doi.org/10.1001/archgenpsychiatry.2011.1528

Wilkinson, S. T., Radhakrishnan, R., & D’Souza, D. C. (2016). A Systematic Review of the

Evidence for Medical Marijuana in Psychiatric Indications. The Journal of Clinical

Psychiatry, 77(8), 1050–1064. https://doi.org/10.4088/JCP.15r10036

Willeit, M., Ginovart, N., Kapur, S., Houle, S., Hussey, D., Seeman, P., & Wilson, A. A. (2006).

High-affinity states of human brain dopamine D2/3 receptors imaged by the agonist

[11C]-(+)-PHNO. Biological Psychiatry, 59(5), 389–394.

https://doi.org/10.1016/j.biopsych.2005.09.017

Wilson, A. A., McCormick, P., Kapur, S., Willeit, M., Garcia, A., Hussey, D., Houle, S.,

Seeman, P., & Ginovart, N. (2005). Radiosynthesis and evaluation of [11C]-(+)-4-propyl-

3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol as a potential radiotracer

for in vivo imaging of the dopamine D2 high-affinity state with positron emission

tomography. Journal of Medicinal Chemistry, 48(12), 4153–4160.

https://doi.org/10.1021/jm050155n

Wittfoth, M., Bornmann, S., Peschel, T., Grosskreutz, J., Glahn, A., Buddensiek, N., Becker, H.,

Dengler, R., & Müller-Vahl, K. R. (2012). Lateral frontal cortex volume reduction in

Tourette syndrome revealed by VBM. BMC Neuroscience, 13, 17.

https://doi.org/10.1186/1471-2202-13-17

212

Wolf, S. S., Jones, D. W., Knable, M. B., Gorey, J. G., & al, et. (1996). Tourette syndrome:

Prediction of phenotypic variation in monozygotic twins by caudate nucleas D2 receptor

binding. Science, 273(5279), 1225.

Wong, D. F., Brašić, J. R., Singer, H. S., Schretlen, D. J., Kuwabara, H., Zhou, Y., Nandi, A.,

Maris, M. A., Alexander, M., Ye, W., Rousset, O., Kumar, A., Szabo, Z., Gjedde, A., &

Grace, A. A. (2008). Mechanisms of Dopaminergic and Serotonergic Neurotransmission

in Tourette Syndrome: Clues from an In Vivo Neurochemistry Study with PET.

Neuropsychopharmacology, 33(6), 1239–1251. https://doi.org/10.1038/sj.npp.1301528

Wong, D. F., Singer, H. S., Brandt, J., Shaya, E., Chen, C., Brown, J., Kimball, A. W., Gjedde,

A., Dannals, R. F., Ravert, H. T., Wilson, P. D., & Wagner, H. N. (1997). D2-Like

Dopamine Receptor Density in Tourette Syndrome Measured by PET. Journal of Nuclear

Medicine, 38(8), 1243–1247.

Worbe, Y., Gerardin, E., Hartmann, A., Valabrégue, R., Chupin, M., Tremblay, L., Vidailhet,

M., Colliot, O., & Lehéricy, S. (2010). Distinct structural changes underpin clinical

phenotypes in patients with Gilles de la Tourette syndrome. Brain: A Journal of

Neurology, 133(Pt 12), 3649–3660. https://doi.org/10.1093/brain/awq293

Worbe, Y., Lehericy, S., & Hartmann, A. (2015). Neuroimaging of tic genesis: Present status and

future perspectives. Movement Disorders: Official Journal of the Movement Disorder

Society, 30(9), 1179–1183. https://doi.org/10.1002/mds.26333

Worbe, Y., Marrakchi-Kacem, L., Lecomte, S., Valabregue, R., Poupon, F., Guevara, P.,

Tucholka, A., Mangin, J.-F., Vidailhet, M., Lehericy, S., Hartmann, A., & Poupon, C.

(2015). Altered structural connectivity of cortico-striato-pallido-thalamic networks in

213

Gilles de la Tourette syndrome. Brain: A Journal of Neurology, 138(Pt 2), 472–482.

https://doi.org/10.1093/brain/awu311

Worbe, Y., Palminteri, S., Hartmann, A., Vidailhet, M., Lehéricy, S., & Pessiglione, M. (2011).

Reinforcement learning and Gilles de la Tourette syndrome: Dissociation of clinical

phenotypes and pharmacological treatments. Archives of General Psychiatry, 68(12),

1257–1266. https://doi.org/10.1001/archgenpsychiatry.2011.137

Wright, A., Rickards, H., & Cavanna, A. E. (2012). Impulse-control disorders in gilles de la

tourette syndrome. The Journal of Neuropsychiatry and Clinical Neurosciences, 24(1),

16–27. https://doi.org/10.1176/appi.neuropsych.10010013

Wylie, S. A., Claassen, D. O., Kanoff, K. E., van Wouwe, N. C., & van den Wildenberg, W. P.

M. (2016). Stopping Manual and Vocal Actions in Tourette’s Syndrome. The Journal of

Neuropsychiatry and Clinical Neurosciences, appineuropsych15110387.

https://doi.org/10.1176/appi.neuropsych.15110387

Yamamuro, K., Ota, T., Iida, J., Nakanishi, Y., Uratani, M., Matsuura, H., Kishimoto, N.,

Tanaka, S., Negoro, H., & Kishimoto, T. (2015). Prefrontal dysfunction in pediatric

Tourette’s disorder as measured by near-infrared spectroscopy. BMC Psychiatry, 15, 102.

https://doi.org/10.1186/s12888-015-0472-3

Yang, C.-S., Zhang, L.-L., Zeng, L.-N., Huang, L., & Liu, Y.-T. (2013). Topiramate for

Tourette’s syndrome in children: A meta-analysis. Pediatric Neurology, 49(5), 344–350.

https://doi.org/10.1016/j.pediatrneurol.2013.05.002

214

Yaniv, A., Benaroya-Milshtein, N., Steinberg, T., Ruhrrman, D., Apter, A., & Lavidor, M.

(2017). Specific executive control impairments in Tourette syndrome: The role of

response inhibition. Research in Developmental Disabilities, 61, 1–10.

https://doi.org/10.1016/j.ridd.2016.12.007

Yoo, H. K., Joung, Y. S., Lee, J.-S., Song, D. H., Lee, Y. S., Kim, J.-W., Kim, B.-N., & Cho, S.

C. (2013). A multicenter, randomized, double-blind, placebo-controlled study of

aripiprazole in children and adolescents with Tourette’s disorder. The Journal of Clinical

Psychiatry, 74(8), e772-780. https://doi.org/10.4088/JCP.12m08189

Zapparoli, L., Porta, M., Gandola, M., Invernizzi, P., Colajanni, V., Servello, D., Zerbi, A.,

Banfi, G., & Paulesu, E. (2016). A functional magnetic resonance imaging investigation

of motor control in Gilles de la Tourette syndrome during imagined and executed

movements. The European Journal of Neuroscience, 43(4), 494–508.

https://doi.org/10.1111/ejn.13130

Zebardast, N., Crowley, M. J., Bloch, M. H., Mayes, L. C., Wyk, B. V., Leckman, J. F.,

Pelphrey, K. A., & Swain, J. E. (2013). Brain mechanisms for prepulse inhibition in

adults with Tourette syndrome: Initial findings. Psychiatry Research, 214(1), 33–41.

https://doi.org/10.1016/j.pscychresns.2013.05.009

Zulauf, C. A., Sprich, S. E., Safren, S. A., & Wilens, T. E. (2014). The Complicated Relationship

Between Attention Deficit/Hyperactivity Disorder and Substance Use Disorders. Current

Psychiatry Reports, 16(3), 436. https://doi.org/10.1007/s11920-013-0436-6

215

Zuurman, L., Ippel, A. E., Moin, E., & van Gerven, J. M. A. (2009). Biomarkers for the effects

of cannabis and THC in healthy volunteers. British Journal of Clinical Pharmacology,

67(1), 5–21. https://doi.org/10.1111/j.1365-2125.2008.03329.x

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Appendices

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Yale Global Tic Severity Scale

ID #:

YGTS S Yale Global Tic Severity Scale

Yale Child Study Center

October 1992 version

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NAME: TODAY'S DATE : / /

RATER:

MOTOR TIC SYMPTOM CHECKLIST

Description of Motor Tic Symptoms. Motor tics usually begin in childhood and are characterized by sudden jerks or movements, such as forceful eye blinking or a rapid head jerk to one side or the other. The same tics seem to recur in bouts during the day and are worse during periods of fatigue and/or stress. Many tics occur without warning and may not even be noticed by the person doing them. Others are preceded by a subtle urge that is difficult to describe (some liken it to the urge to scratch an itch). In many cases it is possible to voluntarily hold back the tics for brief periods of time. Although any part of the body may be affected, the face, head, neck, and shoulders are the most common areas involved. Over periods of weeks to months, motor tics wax and wane and old tics may be replaced by totally new ones.

Simple motor tics can be described as a sudden, brief, "meaningless" movement that recurs in bouts (such as excessive eye blinking or squinting). Complex motor tics are sudden, stereotyped (i.e., always done in the same manner) semi-purposeful (i.e., the movement may resemble a meaningful act, but is usually involuntary and not related to what is occurring at the time) movements that involve more than one muscle group. There may often be a constellation of movements such as facial grimacing together with body movements. Some complex tics may be misunderstood by other people (i.e., as if you were shrugging to say "I don't know"). Complex tics can be difficult to distinguish from compulsions; however, it is unusual to see complex tics in the absence of simple ones. Often there is a tendency to explain away the tics with elaborate explanations (e.g., “I have hay fever that has persisted” even though it is not the right time of year). Tics are usually at their worst in childhood and may virtually disappear by early adulthood, so if you are completing this form for yourself, it may be helpful to talk to your parents, an older sibling, or a relative, as you answer the following questions.

• Age of first motor tics? ______years old

• Describe first motor tic: ______

• Was tic onset sudden or gradual? ______

• Age of worst motor tics? ______years old

Motor Tic Symptom Checklist

In the boxes on the left below, please check with a mark (x) the tics the patient

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1) has EVER experienced 2) is CURRENTLY experiencing (during the past week)

State AGE OF ONSET (in years) if patient has had that behavior.

Also, in the tic descriptions below, please circle or underline the specific tics that the patient has experienced (circle or underline the words that apply).

[In Years]

Ever Cur- Age The patient has experienced, or others have noticed, involuntary and Ver rent apparently purposeless bouts of: of

onset

-eye movements.

eye blinking, squinting, a quick turning of the eyes, rolling of the eyes to one side, or opening eyes wide very briefly.

eye gestures such as looking surprised or quizzical, or looking to one side for a brief period of time, as if s/he heard a noise.

-nose, mouth, tongue movements, or facial grimacing.

nose twitching, biting the tongue, chewing on the lip or licking the lip, lip pouting, teeth baring, or teeth grinding.

broadening the nostrils as if smelling something, smiling, or other gestures involving the mouth, holding funny expressions, or sticking out the tongue.

-head jerks/movements.

touching the shoulder with the chin or lifting the chin up.

throwing the head back, as if to get hair out of the eyes.

-shoulder jerks/movements.

jerking a shoulder.

shrugging the shoulder as if to say "I don't know."

-arm or hand movements.

quickly flexing the arms or extending them, nail biting, poking with fingers, or popping knuckles.

passing hand through the hair in a combing like fashion, or touching objects or others, pinching, or counting with fingers for no purpose, or writing tics, such as writing over and over the same letter or word, or pulling back on the pencil while writing.

-leg, foot or toe movements.

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kicking, skipping, knee-bending, flexing or extension of the ankles; shaking, stomping or tapping the foot.

taking a step forward and two steps backward, squatting, or deep knee-bending.

Ever Cur- Age The patient has experienced, or others have noticed, involuntary and Ver rent of apparently purposeless bouts of:

onset

-abdominal/trunk/pelvis movements.

tensing the abdomen, tensing the buttocks.

-other simple motor tics.

Please write example(s):

-other complex motor tics.

touching

tapping

picking

evening-up

reckless behaviors

stimulus-dependent tics (a tic which follows, for example, hearing a particular word or phrase, seeing a specific object, smelling a particular odor). Please write example(s): ______

rude/obscene gestures; obscene finger/hand gestures.

unusual postures.

bending or gyrating, such as bending over.

rotating or spinning on one foot.

copying the action of another (echopraxia)

sudden tic-like impulsive behaviors. Please describe: ______

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tic-like behaviors that could injure/mutilate others. Please describe: ______

self-injurious tic-like behavior(s). Please describe:

______

-other involuntary and apparently purposeless motor tics (that do not fit in any previous categories).

Please describe any other patterns or sequences of motor tic behaviors: ______

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Phonic (Vocal) Tics

Description of Phonic (or Vocal) Tic Symptoms Phonic tics usually begin in childhood, typically after motor tics have already started, but they can be the first tic symptoms. They are characterized by a sudden utterance of sounds such as throat clearing or sniffing. The same tics seem to recur in bouts during the day and are worse during periods of fatigue and/or stress. Many tics occur without warning and may not even be noticed by the person doing them. Others are preceded by a subtle urge that is difficult to describe (some liken it to the urge to scratch an itch). In many cases it is possible to voluntarily hold back the tics for brief periods of time. Over periods of weeks to months, phonic tics wax and wane and old tics may be replaced by totally new ones. Simple phonic tics are utterances of fast, meaningless sounds whereas complex phonic tics are involuntary, repetitive, purposeless utterances of words, phrases or statements that are out of context, such as uttering obscenities (i.e., coprolalia), or repeating over and over again what other people have said (i.e., echolalia). Complex tics can be difficult to distinguish from compulsions; however, it is unusual to see complex tics in the absence of simple ones. Often there is a tendency to explain away the tics with elaborate explanations (e.g., “I have hay fever that has persisted” even though it is not the right time of year). Tics are usually at their worst in childhood and may virtually disappear by early adulthood, so if you are completing this form for yourself, it may be helpful to talk to your parents, an older brother or sister, or older relative, as you answer the following questions.

• Age of first vocal tics? ______years old.

• Describe first vocal tic: ______

• Was tic onset sudden or gradual? ______

• Age of worst vocal tics? ______years old.

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Phonic Tic Symptom Checklist

In the boxes on the left below, please check with a mark (x) the tics the patient

1) has EVER experienced 2) is CURRENTLY experiencing (during the past week)

State AGE OF ONSET (in years) if patient has had that behavior.

Also, in the tic descriptions below, please circle or underline the specific tics that the patient has experienced (circle or underline the words that apply).

[In Years] Ever Cur- Age The patient has experienced, or others have noticed, bouts of involuntary and Ver rent apparently purposeless utterance of: of onset

-coughing.

-throat clearing.

-sniffing.

-whistling.

-animal or bird noises.

-Other simple phonic tics. Please list:

-syllables. Please list:

-words. Please list:

-rude or obscene words or phrases. Please list:

-repeating what someone else said, either sounds, single words or sentences. Perhaps repeating what’s said on TV (echolalia).

-repeating something the patient said over and over again (palilalia).

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-other tic-like speech problems, such as sudden changes in volume or pitch. Please describe:

Describe any other patterns or sequences of phonic tic behaviors:

SEVERITY RATINGS

Motor Phonic NUMBER

None   0

Single tic   1

Multiple discrete tics (2-5)   2

Multiple discrete tics (>5)   3

Multiple discrete tics plus as least one orchestrated pattern of multiple simultaneous or sequential   4 tics where it is difficult to distinguish discrete tics

Multiple discrete tics plus several (>2) orchestrated paroxysms of multiple simultaneous or   5 sequential tics that where it is difficult to distinguish discrete tics

Motor Phonic FREQUENCY

NONE No evidence of specific tic behaviors   0

RARELY Specific tic behaviors have been present during previous week. These behaviors occur   1 infrequently, often not on a daily basis. If bouts of tics occur, they are brief and uncommon.

OCCASIONALLY Specific tic behaviors are usually present on a daily basis, but there are long tic-   2 free intervals during the day. Bouts of tics may occur on occasion and are not sustained for more than a few minutes at a time.

FREQUENTLY Specific tic behaviors are present on a daily basis. tic free intervals as long as 3   3 hours are not uncommon. Bouts of tics occur regularly but may be limited to a single setting.

ALMOST ALWAYS Specific tic behaviors are present virtually every waking hour of every day, and   4 periods of sustained tic behaviors occur regularly. Bouts of tics are common and are not limited to a single setting.

ALWAYS Specific tic behaviors are present virtually all the time. Tic free intervals are difficult to   5 identify and do not last more than 5 to 10 minutes at most.

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Motor Phonic INTENSITY

ABSENT   0

MINIMAL INTENSITY Tics not visible or audible (based solely on patient's private experience) or   1 tics are less forceful than comparable voluntary actions and are typically not noticed because of their intensity.

MILD INTENSITY Tics are not more forceful than comparable voluntary actions or utterances and   2 are typically not noticed because of their intensity.

MODERATE INTENSITY Tics are more forceful than comparable voluntary actions but are not   3 outside the range of normal expression for comparable voluntary actions or utterances. They may call attention to the individual because of their forceful character.

MARKED INTENSITY Tics are more forceful than comparable voluntary actions or utterances and   4 typically have an "exaggerated" character. Such tics frequently call attention to the individual because of their forceful and exaggerated character.

SEVERE INTENSITY Tics are extremely forceful and exaggerated in expression. These tics call   5 attention to the individual and may result in risk of physical injury (accidental, provoked, or self- inflicted) because of their forceful expression.

Motor Phonic COMPLEXITY

NONE If present, all tics are clearly "simple" (sudden, brief, purposeless) in character.   0

BORDERLINE Some tics are not clearly "simple" in character.   1

MILD Some tics are clearly "complex" (purposive in appearance) and mimic brief "automatic"   2 behaviors, such as grooming, syllables, or brief meaningful utterances such as "ah huh," "hi" that could be readily camouflaged.

MODERATE Some tics are more "complex" (more purposive and sustained in appearance) and   3 may occur in orchestrated bouts that would be difficult to camouflage but could be rationalized or "explained" as normal behavior or speech (picking, tapping, saying "you bet" or "honey", brief echolalia).

MARKED Some tics are very "complex" in character and tend to occur in sustained orchestrated   4 bouts that would be difficult to camouflage and could not be easily rationalized as normal behavior or speech because of their duration and/or their unusual, inappropriate, bizarre or obscene character (a lengthy facial contortion, touching genitals, echolalia, speech atypicalities, longer bouts of saying "what do you mean" repeatedly, or saying "fu" or "sh").

SEVERE Some tics involve lengthy bouts of orchestrated behavior or speech that would be   5 impossible to camouflage or successfully rationalize as normal because of their duration and/or extremely unusual, inappropriate, bizarre or obscene character (lengthy displays or utterances often involving copropraxia, self-abusive behavior, or coprolalia).

Motor Phonic INTERFERENCE

NONE   0

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MINIMAL When tics are present, they do not interrupt the flow of behavior or speech.   1

MILD When tics are present, they occasionally interrupt the flow of behavior or speech.   2

MODERATE When tics are present, they frequently interrupt the flow of behavior or speech.   3

MARKED When tics are present, they frequently interrupt the flow of behavior or speech, and   4 they occasionally disrupt intended action or communication.

SEVERE When tics are present, they frequently disrupt intended action or communication.   5

IMPAIRMENT

NONE  0

MINIMAL Tics associated with subtle difficulties in self-esteem, family life, social acceptance, or school or  10 job functioning (infrequent upset or concern about tics vis a vis the future, periodic, slight increase in family tensions because of tics, friends or acquaintances may occasionally notice or comment about tics in an upsetting way).

MILD Tics associated with minor difficulties in self-esteem, family life, social acceptance, or school or job  20 functioning.

MODERATE Tics associated with some clear problems in self-esteem family life, social acceptance, or  30 school or job functioning (episodes of dysphoria, periodic distress and upheaval in the family, frequent teasing by peers or episodic social avoidance, periodic interference in school or job performance because of tics).

MARKED Tics associated with major difficulties in self-esteem, family life, social acceptance, or school or  40 job functioning.

SEVERE Tics associated with extreme difficulties in self-esteem, family life, social acceptance, or school or  50 job functioning (severe depression with suicidal ideation, disruption of the family (separation/divorce, residential placement), disruption of social tics - severely restricted life because of social stigma and social avoidance, removal from school or loss of job).

SCORING

Number Frequency Intensity Complexity Interference Total (0-5) (0-5) (0-5) (0-5) (0-5) (0-25) Motor Tic Severity Vocal Tic Severity

Total Tic Severity Score = Motor Tic Severity + Vocal Tic Severity (0-50)

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Total Yale Global Tic Severity Scale Score (Total Tic Severity Score +

Impairment) (0-100)

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Yale-Brown Obsessive-Compulsive Severity Scale

YALE-BROWN OBSESSIVE COMPULSIVE SCALE (Y-BOCS)

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General Instructions

This rating scale is designed to rate the severity and type of symptoms in patients with obsessive compulsive disorder (OCD). In general, the items depend on the patient's report; however, the final rating is based on the clinical judgement of the interviewer. Rate the characteristics of each item during the prior week up until and including the time of the interview. Scores should reflect the average (mean) occurrence of each item for the entire week.

This rating scale is intended for use as a semi-structured interview. The interviewer should assess the items in the listed order and use the questions provided. However, the interviewer is free to ask additional questions for purposes of clarification. If the patient volunteers information at any time during the interview, that information will be considered. Ratings should be based primarily on reports and observations gained during the interview. If you judge that the information being provided is grossly inaccurate, then the reliability of the patient is in doubt and should be noted accordingly at the cad of the interview (item 19).

Additional information supplied by others (e.g., spouse or parent) may be included in a determination of the ratings only if it is judged that (1) such information is essential to adequately assessing symptom severity and (2) consistent week-to-week reporting can be ensured by having the same informant(s) present for each rating session.

Before proceeding with the questions, define "obsessions" and "compulsions" for the patient as follows:

"OBSESSIONS are unwelcome and distressing ideas, thoughts, images or impulses that repeatedly enter your mind. They may seem to occur against your will. They may be repugnant to you, you may recognize them as senseless, and they may not fit your personality."

"COMPULSIONS, on the other hand, are behaviors or acts that you feel driven to perform although you may recognize them as senseless or excessive. At times, you may try to resist doing them but this may prove difficult. You may experience anxiety that does not diminish until the behavior is completed."

"Let me give you some examples of obsessions and compulsions."

"An example of an obsession is: the recurrent thought or impulse to do serious physical harm to your children even though you never would."

"An example of a compulsion is: the need to repeatedly check appliances, water faucets, and the lock on the front door before you can leave the house. While most compulsions are observable behaviors, some are unobservable mental acts, such as silent checking or having to recite nonsense phrases to yourself each time you have a bad thought."

"Do you have any questions about what these words mean?" [If not, proceed.]

On repeated testing it is not always necessary to re-read these definitions and examples as long as it can be established that the patient understands them. It may be sufficient to remind the patient that obsessions are the thoughts or concerns and compulsions are the things you feel driven to do, including covert mental acts.

Have the patient enumerate current obsessions and compulsions in order to generate a list of target symptoms. Use the Y-BOCS Symptom Checklist as an aid for identifying current symptoms. It is also useful to identify and be aware of past symptoms since they may re-appear during subsequent ratings. Once the current types of obsessions and compulsions are identified, organize and list them on the Target Symptoms form according to clinically convenient distinctions (e.g., divide target compulsions into checking and washing). Describe salient features of the symptoms so that they can be more easily tracked (e.g., in addition to listing checking, specify what the patient checks for). Be sure to indicate which are the most prominent symptoms; i.e., those that will be the major focus of assessment. Note, however, that the final score for each item should reflect a composite rating of all of the patient's obsessions or compulsions.

The rater must ascertain whether reported behaviors are bona fide symptoms of OCD and not symptoms of another disorder, such as Simple Phobia or a Paraphilia. The differential diagnosis between certain complex motor tics and certain compulsions (e.g., involving touching) may be difficult

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or impossible. In such cases, it is particularly important to provide explicit descriptions of the target symptoms and to be consistent in subsequent ratings. Separate assessment of tie severity with a tic rating instrument may be necessary in such cases. Some of the items listed on the Y-BOCS Symptom Checklist, such as trichotillomania, are currently classified in DSM-m-R as symptoms of an Impulse Control Disorder. It should be noted that the suitability of the Y-BOCS for use in disorders other than DSM-m-R-defined OCD has yet to be established. However, when using the Y-BOCS to rate severity of symptoms not strictly classified under OCD (e.g., trichotillomania) in a patient who otherwise meets criteria for OCD, it has been our practice to admuista the Y-BOCS twice: once for conventional obsessivecompulsive symptoms, and a second time for putative OCD-related phenomena. In this fashion separate Y-BOCS scores are generated for severity of OCD and severity of other symptoms in which the relationship to OCD is still unsettled.

On repeated testing, review and, if necessary, revise target obsessions prior to rating item I. Do likewise for compulsions prior to rating item 6.

All 19 items are rated, but only items 1-10 (excluding items lb and 6b) are used to determine the total score. The total Y-BOCS score is the sum of items 1-10 (excluding lb and 6b), whereas the obsession and compulsion subtotals are the sums of items 1-5 (excluding lb) and 10 (excluding 6b3; respectively.

Because at the time of this writing (9/89) there are limited data regarding the psychometric properties of items lb, 6b, and 11-16, these items should be considered investigational. Until adequate studies of toe reliability, validity, and sensitivity to change of those items are conducted, we must caution against placing much weight on results derived from these item scores. These important caveats aside, we believe that items lb (obsession-free interval), 6b (compulsion-free interval), and 12 (avoidance) may provide information that has bearing on the severity of obsessive-compulsive symptoms. Item 11 (insight) may also furnish useful clinical information. We are least secure about the usefulness of items 13-16.

Items 17 (global severity) and 18 (global improvement) have been adapted from the Clinical Global Impression Seale (Guy W, 1976) to provide measures of overall functional impairment associated with, but not restricted to, the presence of obsessive-compulsive symptoms. Disability produced by secondary depressive symptoms would also be considered when rating these items. Item 19, which estimates the reliability of the information reported by the patient, may assist in the interpretation of scores on other Y-BOCS items in some cases of OCD.

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Y-BOCS SYMPTOM CHECKLIST (9/89)

Check all that apply, but clearly mark the principal symptoms with a "P", (Rater must asertain whether reported behviors are bona fide symptoms of OCD, and not symptoms of another disorder such as Simple Phobia or Hypochondriasis. Items maried "*" may or may not be OCD phenomena.)

AGGRESSIVE OBSESSIONS Current Past

Fear might harm self

Fear might harm others

Violent or horrific images

Fear of blurting out obscenities or insults

Fear of doing something else embarrassing *

Fear will act on unwanted impulses (e.g. to stab friend)

Fear will steal things

Fear will harm others because not careful enough (e.g. hit/run MVA)

Fear will be responsible for something else terrible happening (e.g. fire, burglary)

Other

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CONTAMINATION OBSESSIONS Current Past

Concerns or disgust with bodily waste or secretions (e.g. urine, feces, saliva)

Concern with dirt or germs

Excessive concern with environmental contarninants (c.g. asbestos, radiation, toxic waste)

Excessive concern with household items (e.g. cleansers, solvents, )

Excessive concern with animals (e.g. insects)

Bothered by sticky substances or residues

Concerned will get ill because of contaminant

Concerned will get others ill by spreading contaminant (Aggressive)

No concern with consequences of contarnination other than how it might feel

Other

SEXUAL OBSESSIONS Current Past

Forbidden or perverse sexual thoughts, images, or impulses

Content involves children or incest

Content involves homosexuality *

Sexual behavior toward others (Aggressive)*

Other

MOARDING/SAVING OBSESSIONS Current Past

[distinguish from hobbies and concern with objects of monetary or sentimental value]

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RELIGIOUS OBSESSIONS Current Past

(Scrupulosity) Concerned with sacrilege and blasphemy

Excess concern with right/wrong, morality

Other

OBSESSION WITH NEED FOR SYMMETRY OR EXACTNESS Current Past

(Accompanied by magical thinking (c.x., concerned the mother will have accident unless things and in the right place)

Not accompanied by magical thinking

MISCELLANEOUS OBSESSIONS Current Past

Need to know or remember

Fear of saying certain things

Fear of not saying just the right thing

Fear of losing things

Intrusive (non-violent) images

Intrusive nonsense sounds, words, or music

Bothered by certain sounds/noises *

Lucky/unlucky numbers

Colors with special significance Superstitious fears

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SOMATIC OBSESSIONS Current Past

Concern with illness or disease *

Excessive concern with body part or aspect of appearance (e.g. dysmorphophobia) *

Other

CLEANING/WASHING COMPULSIONS Current Past

Excessive or rituailzed handwashing

Excessive or ritualized showering, bathing, toothbrushing, grooming, or toilet routine. Involves cleaning of household items or other inanimate objects

Other measures to prevent or remove contact with contaminants

Other

CHECKING COMPULSIONS Current Past

Checking locks, stove, appliances, etc.

Cheeking that did not/will not harm others

Checking that did not/will not harm self

Checking that nothing terrible did/will happen

Checking that did not make mistake

Checking tied to somatic obsessions

Others

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REPEATING RITUALS Current Past

Re-reading or re-writing

Need to repeat routine activities(e.g. in/out door, up/down from chair)

Other

COUNTING COMPULSIONS Current Past

ORDERING/ARRANGING COMPULSIONS Current Past

HOARDING/COLLECTING COMPULSIONS Current Past

[distinguish from hobbies and concern with objects of monetary or sentimental value (e.g.,carefulig reads junkmail, piles up old newspapers, sorts through garbage, collects useless objects)

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MISCELLANEOUS COMPULSIONS Current Past Mental rituals (other than checking/counting)

Excessive listmaking

Need to tell, ask, or confess

Need to touch, tap, or rub *

Rituals involving blinking or staring *

Measures (not checking) to prevent:

harm to self harm to others terrible consequences

Ritualized eating behaviors *

Superstitious behaviors

Trichotillomania *

Other self damaging or self-mutilating behaviors *

Other

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TARGET SYMPTOM LIST

Obsessions:

COMPULSIONS:

AVOIDANCE:

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YALE-BROWN OBSESSIVE COMPULSIVE SCALE (Y-BOCS)

"I am now going to ask several questions about your obsessive thoughts." [Make specific reference to the patient's target obsessions.]

1. TIME OCCUPED BY OBSESSIVE THOUGHTS 0 = None. 1 = Mild, less than 1 hr/day or occasional intrusion. 2 = Moderate, 1 to 3 hrs/day or frequent intrusion. 3 = Severe, greater than 3 and up to 8 hrs/day or very frequent intrusion. 4 = Extreme, greater than 8 hrs/day or near constant intrusion.

Q: How much of your time is occupied by obsessive thoughts? 0 [When obsessions occur as brief, intermittent intrusions, it may 1 be difficult to assess time occupied by them in temns of total 2 hours. In such cases, estirnate time by detesmining how 3 frequently they occur. Consider both the number of times the 4 intrusions occur and how many hours of the day are affected. Ask:1 How frequently do the obsessive thoughts occur? [Be sure to exclude ruminations and preoccupations which, unlike obsessions, are ego-syntonic and rational (but exaggerated).]

I b. OBSESSION-FREE INTERVAL (not included in total score) 0 = No symptoms. 1 = Long symptom-free interval, more than 8 consecutive hours/day symptom-free. 2 = Moderately long symptom-free interval, more than 3 and up to 8 consecutive hours/day symptom-free. 3 = Short symptom-free interval, from I to 3 consecutive hours/day symptom-free. 4 = Extremely short symptom-free interval, less than I consecutive hour/day symptom-free.

Q: On the average, what is the longest number of consecutive 0 waking hours per day that you are 1 completely free of obsessive thoughts? [If necessary, ask:1 What 2 is the longest block of time in which 3 obsessive thoughts are absent? 4

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2. INTERFERENCE DUE TO OBSESSIVE THOUGHTS 0 = None. 1 = Mild, slight interference with social or occupational activities, but overall performance not impaired. 2 = Moderate, definite interference with social or occupational performance, but still manageable. 3 = Severe, causes substantial impairment in social or occupational performance. 4 - Extreme, incapacitating.

Q: How much do your obsessive thoughts interfere with your 0 social or work (or role) functioning? Is there anything that you 1 don't do because of them? [If currently not working determine 2 how much 3 performance would be affected if patient were employed.] 4

3. DISTRESS ASSOCIATED W1TH OBSESSIVE THOUGHTS 0 = None I = Mild, not too disturbing 2 = 1doderate, disturbing, but still manageable 3 = Severe, very disturbing 4 = Extreme, near constant and disabling distress

Q: How much distress do your obsessive thoughts cause you? 0 [In most eases, distress is equated with anxiety; however, 1 patients may report that their obsessions are "disturbing" but 2 deny "anxiety." Only rate anxiety that seems triggered by 3 obsessions, not generalized anxiety or associated with other 4 conditions.]

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4. RESISTANCE AGAINST OBSESSIONS 0 = Makes an effort to always resist, or symptoms so minimal doesn't need to actively resist 1 = Tries to resist most of the time 2 = Makes some effort to resist 3 = Yields to all obsessions without attempting to control them, but does so with some reluctance 4 = Completely and willingly yields to all obsessions

Q: How much of an effort do you make to resist the obsessive 0 thoughts? How often do you try to disregard or turn your anention 1 away from these thoughts as they eater your mind? [Only rate 2 effort made to resist, not success or failure in actually controlling 3 the obsessions. How much the patient resists the obsessions may 4 or may not correlate with his/her abilig to control them. Note that this item does not direetly measure the severig of the intrusive thoughts; rather it rates a manifestation of health, i.e., the effort the patient makes to counteract the obsessions by means other than avoidance or the performance of compulsions. Thus, the more the patient tries to resist, the less impaired is this aspect of his/her functioning. There are "active" and “passive" forms of resistance. Patients in behavioral therapy may be encouraged to counteract their obsessive symptoms by not struggling against them (e.g., "just let the thoughts come; passive opposition) or by intentionally bringing on the disturbing thoughts. For the purposes of this item, consider use of these behavioral techniques as forms of resistance. If the obsessions are minimal, the patieut may not feel the need to resist them. In such cases, a rating of "0" should be given.]

5. DEGREE OP CONTROL OVER OBSESSIVE THOUGHTS 0 = Complete control. 1 = Much control, usually able to stop or divert obsessions with some effort and concentration. 2 = Moderate control, sometimes able to stop or divert obsessions. 3 = Little control, rarely successful in stopping or dismissing obsessions, can only divert attention with difficulty. 4 = No control, experienced as completely involuntary, rarely able to even momentarily alter obsessive thinking.

Q: How much control do you have over your obsessive thoughts? 0 How successful are you in stopping or diverting your obsessive 1 thinking? Can you dismiss them? [In contrast to the preceding 2 item on resistance, the ability of the patient to control his 3 obsessions is more closely related to the severity of the intrusive 4 thoughts.]

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"The next several questions are about your compulsive behaviors." [Make specific reference to the patient's target compulsions.]

6. TIME SPENT PERFORM~G COMPULSIVE BEHAVIORS 0 = None 1 = Mild (spends less than I hr/day performing compulsions), or occasional performance of compulsive behaviors. 2 = Moderate (speeds from I to 3 hrs/day performing compulsions), or frequent performance of compulsive behaviors. 3 = Severe (spends more than 3 and up to 8 hrs/day performing compulsions), or very frequent performance of compulsive behaviors. 4 = Extreme (spends more than 8 hrs/day performing compulsions), or near constant performance of compulsive behaviors (too numerous to count).

Q: How much time do you spend performing compulsive 0 behaviors? [When rituals involving activities of daily living are 1 chiefly present, ask:] How much longer than most people does it 2 take to complete routine activities because of your rituals? [When 3 compulsions occur as brief, intermittent behaviors, it may difficult 4 to assess time spent performing them in terms of total hours. In such cases, estimate time by determining how frequently they are performed. Consider both the number of times compulsions are performed and how many hours of the day are affected. Count separate occurrences of compulsive behaviors, not number of repetitions; e.g., a patient who goes into the bathroom 20 different times a day to wash his hands 5 times very quickly, performs compulsions 20 times a day, not 5 or 5 x 20 = 100. Ask:] How frequently do you perform compulsions? 1In most cases compulsions are observable behaviors(e.g., land washing), but some compulsions are covert (e.g., silent checking).]

6b. COMPULSION-FREE INTERVAL(not included in total score) 0 = No symptoms. 1 = Long symptom-free interval, more than 8 consecutive hours/day symptom-free. 2 = Moderately long symptom-free interval, more than 3 and up to 8 consecutive hours/day symptom-free. 3 = Short symptom-free interval, from I to 3 consecutive hours/day symptom-free. 4 = Extremely short symptom-free interval, less than I consecutive hour/day symptom-free.

Q: On the average, what is the longest number of consecutive 0 waking hours per day that you are completely free of compulsive 1 behavior? [If necessary, ask:] What is the longest block of time in 2 which compulsions are absent?different times a day to wash his 3 hands 5 times very quickly, performs compulsions 20 times a day, 4 not 5 or 5 x 20 = 100. Ask:] How frequently do you perform compulsions? 1In most cases compulsions are observable behaviors(e.g., land washing), but some compulsions are covert (e.g., silent checking).]

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7 INTERFERIINCE DUE TO COMPULSIVE BEHAVIQRS 0 = None 1 = Mild, slight interference with social or occupational activities, but overall performance not impaired 2 = Moderate, definite interference with social or occupational performance, but still manageable 3 = Severe, causes substantial impaiment in social or occupational performance 4 = Extreme, incapacitating

Q: How much do your compulsive behaviors interfere with your 0 social or work (or role) functioning? Is there anything that you 1 don't do because of the compulsions? [If currently not working 2 determine how much performance would be affected if patient 3 were employed.] 4

8. DISTRESS ASSOCIATED WITH COMPULSIVE BEHAVIOR 0 = None I = Mild only slightly anxious if compulsions prevented, or only slight anxiety during performance of compulsions 2 = Moderate, reports that anxioty would mount but remain manageable if compulsions prevented, or that anxiety increases but remains manageable during performance of compulsions 3 = Severe, prominent and very disturbing increase in anxiety if compulsions interrupted, or prorninent and very disturbing increase in anxiety during performance of compulsions 4 = Extreme, incapacitating anxiety from any intervention aimed at modifying activity, or incapacitating anxiety develops during performance of compulsions

Q: How would you feel if prevented from performing your 0 compulsion(s)? [Pause] How anxious would you become? [Rate 1 degree of distress patient would experience if performance of the 2 compulsion were suddenly interrupted without reassurance 3 offered. In most, but not all cases, performing compulsions 4 reduces anxiety. If, in the judgement of the interviewer, anxiety is actually reduced by preventing compulsions in the manner described above, then asked: How anxious do you get while performing compulsions until you are satisfied they are completed?

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9. RESISTANCE AGAINST COMPULSIONS 0 = Malces an effort to always resist, or symptoms so minimal doesn't need to actively resist I = Tries to resist most of the time 2 = Makes some effort to resist 3 = Yields to almost all compulsions without attempting to control them, but does so with some reluetance 4 = Completely and willingly yields to all compulsions

Q: How much of an effort do you make to resist the compulsions? 0 I Only rate effort made to resist, not success or failure in actually 1 controlling the compulsions. How much the patient resists the 2 compulsions may or may not correlate with his ability to control 3 them. Note that this item does not directly measure the severity 4 of the compulsions; rather it rates a manifestation of health, i.e., the effort the patient makes to counteract the compulsions. Thus, the more the patient tries to resist, the less impaired is this aspect of his functioning. If the compulsions are minimal, the patient may not feel the need to resist them. In such cases, a rating of "0" should be given.]

10. DEGREE OF CONTROL OVER COMULSIVE BEHAVIOR I = Much control, experiences pressure to perform the behavior but usually able to exercise voluntary control over it. 2 = Moderate control, strong pressure to perform behavior, can control it only with difficulty 3 = Little control, very strong drive to perform behavior, must be carried to completion, can only delay with difficulty 4 = No control. drive to perform behavior expericoced as completely involuntary and overpowering, rarely able to even momentarily delay activity

Q: How strong is the drive to perform the compulsive behavior? 0 [Pause] How much control do you have over the compulsions? [In 1 contrast to the preceding item on resistance, the ability of the 2 patient to control his compulsions is more closely related to the 3 severity of the compulsions.] 4

"The remaining questions are about both obsessions and compulsions. Some ask about related problems." These are investigational items not included in total Y-BOCS score but may be useful in assessing these symptoms.

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11. INSIGHT INTO OBSESSIONS AND COMPULSIONS 0 = Excellent insight, fully rational 1 = Good insight. Readily acknowledges absurdity or excessiveness of thoughts or behaviors but does not seem completely convinced that there isn't something besides anxiety to be concerned about (i.e., has lingering doubts). 2 = Fair insight. Reluctantly admits thoughts or behavior seem unreasonable or excessive, but wavers. May have some unrealistic fears, but no fixed convictions. 3 = Poor insight. Maintains that thoughts or behaviors are not unreasonable or excessive, but acknowledges validity of contrary evidence (i.e., overvalued ideas present). 4 = Lacks insight, delusional. Definitely convinced that concerns and behavior are reasonable, unresponsive to contrary evidence.

Q: Do you think your concerns or behaviors are reasonable? 0 [Pause] What do you think would happen if you did not perform 1 the compulsion(s)? Are you convinced something would really 2 happen? 1Ratc patient's insight into the senselessness or 3 excessiveness of his obsession(s) based on beliefs expressed at 4 the time of the interview.]

12. AVOIDANCE 0 = No deliberate avoidance 1 = Mild, minimal avoidance 2 = Moderate, some avoidance; clearly present 3 = Severe, much avoidance; avoidance prominent 4 = Extreme, very extensive avoidance; patient does almost everything he/she can to avoid triggering symptoms

Q: Have you been avoiding doing anything, going any place, or 0 being with anyone because of your obsessional thoughts or out of 1 concern you will perform compulsions? [If yes, then ask:] Elow 2 much do you avoid? [Rate degree to which patient deliberately 3 tries to avoid things. Sometimes compulsions are designed to 4 "avoid" contact with something that the patient fears. For example, clothes washing rituals would be designated as compulsions, not as avoidant behavior. If the patient stopped doing the laundry then this would constitute avoidance.]

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13. DEGEE OF INDECISIVENESS 0 = None 1 = Mild, some trouble making decisions about minor things 2 = Moderate, freely reports significant trouble making decisions that others would not think twice about 3 = Severe, continual weighing of pros and cons about nonessentials. 4 = Extreme, unable to make any decisions. Disabling.

Q: Do you have trouble making decisions about little things that 0 other people might not think twice about (e.g., which clothes to 1 put on in the morning; which brand of cereal to buy)? [Exclude 2 difficulty making decisions which reflect ruminative thinking. 3 Ambivalence concerning rationally-based difficult choices should 4 also be excluded.]

14. OVERVALUED SENSE OF RESPONSIBILY 0 = None I = Mild, only mentioned on questioning, slight sense of over-responsibility 2 = Moderate, ideas stated spontaneously, clearly present; patient experiences significant sense of over-responsibility for events outside his/her reasonable control 3 = Severe, ideas prominent and pervasive; deeply concerned he/she is responsible for events clearly outside his control. Self-blaming farfetched and nearly irrational 4 = Extreme, delusional sense of responsibility (e.g., if an earthquake occurs 3,000 miles away patient blames herself because she didn't perform her compulsions)

Q: Do you feel very responsible for the consequences of your 0 actions? Do you blame yourself for the outcome of events not 1 completely in your control? [Distinguish from normal feelings of 2 responsibility, feelings of worthlessness, and pathological guilt. A 3 guilt-ridden person experiences himself or his actions as bad or 4 evil.]

15. PERVASIVE SLOWNESS/ DISTURBANCE OF INERTIA 0 = None. I = Mild, occasional delay in starting or finishing. 2 = Moderate, frequent prolongation of routine activities but tasks usually completed. Frequently late. 3 = Severe, pervasive and marked difficulty initiating and completing routine tasks. Usually late. 4 = Extreme, unable to start or complete routine tasks without full assistance.

Q: Do you have difficulty starting or finishing tasks? Do many 0 routine activities take longer than they should? [Distinguish from 1 psychomotor retardation secondary to depression. Rate increased 2 time spent performing routine activities even when specific 3 obsessions cannot be identified.] 4

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16. PATHOLOGICAL DOUBTING 0 = None. 1 = Mild, only mentioned on questioning, slight pathological doubt. Examples given may be within normal range. 2 = Moderate, ideas stated spontaneously, clearly present and apparent in some of patient's behaviors, patient bothered by significant pathological doubt. Some effect on performance but still manageable. 3 = Severe, uncertainty about perceptions or ,memory prominent; pathological doubt frequently affects performance. 4 = Extreme uncertainty about perceptions constantly present; pathological doubt substantially affects almost all activities. Incapacitating (e.g., patient states "my mind doesn't trust what my eyes see").

Q: After you complete an activity do you doubt whether you 0 performed it correctly? Do you doubt whether you did it at all? 1 When carrying out routine activities do you find that you don't 2 trust your senses (i.e., what you see, hear, or touch)? 3 4

[Items 17 and 18 refer to global illness severity. The rater is required to consider global function, not just the severity of obssive-compulsive symptoms.]

17. GLOBAL SEVERITY: 0 = No illness 1 = Illness slight, doubtful, transient; no functional impairment 2 = Mild symptoms, little functional impairment 3 = Moderate symptoms, functions with effort 4 = Moderate - Severe symptoms, limited functioning 5 = Severe symptoms, functions mainly with assistance 6 = Extremely Severe symptoms, completely nonfunctional

Interviewer's judgement of the overall severity of the patient's 0 illness. Rated from O (no illness) to 6-(most severe patient seen). 1 [Consider the degree of distress reported by the patient, the 2 symptoms observed, and the functional impairment reported. 3 Your judgement is required both in averaging this data as well as 4 weighing the reliability or accuracy of the data obtained. This 5 judgement is based on information obtained during the interview.] 6

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18. GLOBAL IMPROVEMENT: 0 = Very much worse 1 = Much worse 2 = Minimal worse 3 = No change 4 = Minimally improved 5 = Much improved 6 = Very much improved

Rate total overall improvement present SINCE THE INITIAL 0 RATING whether or not, in your judgement, it is due to drug 1 treatment. 2 3 4 5 6

19. RELIABILITY: 0 = Excellent, no reason to suspect data unreliable . . 1 = Good, factor(s) present that may adversely affect reliability 2 = Fair, factorts) present that definitely reduce reliability 3 = Poor, very low reliability

Rate the overall reliability of the rating scores obtained. Factors 0 that may affect reliability include the patient's cooperativenes and 1 his/her natural ability to communicate. The type and severity of 2 obsessive-compulsive symptoms present may interfere with the 3 patient's concentration, attention, or freedom to speak spontaneously (e.g., the content of some obsessions may cause the patient to choose his words very carefully).

Items 17 and 18 arc adapted from the Clinical Global Impression Scale (Guy W: ECDEU Assessment Manual for Psychopharrnacology: Publication 76-338. Washington, D.C., U.S. Department of Health, Education, and Welfare (1976)).

Additional infomnation regarding the development, use, and psychometric properties of the Y-BOCS can be found in Goodman WK, Price LH, Rasmussen SA, et al.: The Yale-Brown Obsessive Compulsive Scaie (YBOCS): Part I. Development, use, and reliability. Arch Gen Psvchiaty (46:1006~1011, 1989). and Goodman WK, Price LH, Rasmussen SA, ct al.: The Yale-Brown Obsessive Compulsive Scale (Y- BOCS): Part II. Validity. Arch Gen Psvchiatry (46:1012-1016, 1989).

Copies of a version of the Y-BOCS modified for usc in children, the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) (Goodman WK, Rasmussen SA, Price LH, Mazure C, Rapoport JL, Heninger GR, Charney DS), is available from Dr. Goodman on request.

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Y-BOCS TOTAL(add items 1-10)

Patient Name Patient id

None Mild Moderate Severe Extreme Obsessions 0 1 2 3 4

1 TIME SPENT ON OBSESSIONS 1b Obsession-free interval (do not add to subtotal or total score)

2 INTERFERERENCE FROM OBSESSIONS

3 DISTRESS OF OBSESSIONS

4 RESISTANCE

5 CONTROL OVER OBSESSIONS

OBSESSION SUBTOTAL(add items 1-5)

None Mild Moderate Severe Extreme Compulsions 0 1 2 3 4

6 TIME SPENT ON COMPULSIONS 6b Compulsion-free interval (do not add to subtotal or total score)

7 INTERFERENCE FROM COMPULSION

8 DISTRESS FROM COMPULSIONS

9 RESISTANCE

10 CONTROL OVER COMPULSIONS

COMPULSION SUBTOTAL(add items 6-10)

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None Mild Moderate Severe Extreme 0 1 2 3 4

11 INSIGHT INTO O-C SYMPTOMS

12 AVOIDANCE

13 INDECISIVENESS

14 PATHOLOGIC RESPONSIBILITY

15 SLOWNESS

16 PATHOLOGIC DOUBTING

17 GLOBAL SEVERITY

0 1 2 3 4 5 6

17 GLOBAL SEVERITY

18 GLOBAL IMPROVEMENT

19 RELIABILITY: Excellent=0 Good=1 Fair=2 Poor=3