Tourette’s Disorder

1. Tourette’sDisorder

2. DSM-V Categorization:Neurodevelopmental motor Disorder: Tic Disorders • Characterized with an onset in the developmental period, usually early in development • Symptoms of excess as well as deficits/ milestone delays • Deficits produce impairments including academic, personal, occupational and social functioning • Frequent co-occurrence with other disorders

3. DSM-V Tic Disorders • Based on the presence of motor and or vocal tics • Duration of symptoms • Age at onset • Absence of any other cause (substance use or medical condition) • Hierarchical rank: Tourette’s disorder Persistent motor or vocal tic disorder Provisional tic disorder Specified and unspecified tic disorder

4. DSM-V TicsTic: sudden, rapid, recurrent, nonrhythmic motor movement or vocalization (DSM-V) Motor Tic Simple motor tics Complex motor tics Vocal Tic Simple vocal tics Complex vocal tics Coprolalia- obscene inappropriate words or phrases Echolalia- repeating others’ words Palilalia- repeating own words Video

5. DSM-V TS Development/ Course • 4-6 average onset • Severity around 10-12 then a decline in adolescence (small percentage worsen in adulthood) • Across lifespan tic symptoms manifest/ wax and wane idea • Muscle groups and vocalizations change over time • With age comes a premonitory desire [somatic sensation] followed by a feeling of relief after expressing the tic • Particular pattern of tics, desire to express “just right” • Vulnerable to co-occurring conditions during “age of risk” and then followed by decline

6. Meeting DSM-V Diagnostic Criteria for TS • 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. Onset is before age 18 years. • D. The disturbance is not attributable to the physiological effects of a substance or another medical condition.

7. DSM-V Prevalence/Cultural influences • Childhood onset is common, but tics are usually transient • 3 to 8 per 1,000 school aged children • Males > females (2:1 to 4:1), no gender differences in kinds of tics • African Americans and Hispanic Americans < identified cases • Race, ethnicity, and culture: no varying clinical characteristics, but instead may influence perception and management of disorder (choice of treatment)

8. CHARACTERISTICS OF TICS • Mild, moderate or severe- dependent on: frequency, forcefulness, complexity and daily life impairment • Frequency does not equal impairment: eye blinking 20-30 per minute vs. loud barking several times an hour • Most individuals experience oscillations in severity over weeks and months (waxing and waning) • Involuntary but some report “semi-voluntary” based on suppression ability • Premonitory urges followed by satisfaction after tic is completed • Individuals may disguise tics as purposeful: arm jerk –comb hair

9. DSM-V Risk and Prognostic Factors Temperamental: • Tics are worsened by anxious, excited and exhausted emotions • Tics are better when individual experiences calmness and is focused Environmental: • Observation of a gesture/sound may result in individual with tic disorder to imitate (can be perceived incorrectly/purposeful) • Hinders interaction with authority figures Genetic/Physiological: • Expression and severity influenced • Risk alleles and rare genetic variants have been identified • Obstetrical complications/older paternal age/maternal smoking during pregnancy and lower birth weight associated with tic severity

10. DSM-V Functional Consequences • Many individuals do not experience impairment with their tics and may even be unaware of their tics • More severe cases usually result in daily living impairments (not definitive, some severe cases may function just fine) • Co-occurring conditions can lead to greater impairment • Less often tics lead to social isolation, interpersonal conflict, peer victimization, inability to work/attend school, poor quality of life • Rare complications include: physical injury, orthopedic injury and neurological injury

11. COMORBIDITY • In addition to tics, many experience co-occurring psychiatric and or neuropsychological difficulties • Most frequent: ADHD (50%), related learning disorders, OCD (20-60%), anxiety disorders, affective disorders, sensory integration dysfunction and explosive aggressive behaviors • Not necessarily etiological, many influences possible

12. Genetic/ Physiological Mechanisms Comorbidity: ADHD/OCD Age Tic severity Environment <18 onset of motor/vocal tics Secondary Features: Neurological, orthopedic, physical injury Functional impairment Problems with teachers, parents and law enforcement Temperament

13. DO WE HAVE EVIDENCE IN RESEARCH?

14. PERSPECTIVE IS KEY • Some researchers view TS as a discrete single entity with accompanying syndromes • Others view TS with common causes and varying manifestations more like a spectrum disorder • When reviewing research regarding TS critical to understand population requirements for TS groups

15. ADHD • More than 50% with TS who come to the attention of physician – ADHD • 30% with TS experience school difficulties/learning disabilities • Special care to be taken in medication-stimulants may worsen behaviors/tics • Relationship between ADHD/TS less understood (O’Rourke et al., 2011) • Suggested overlapping neurobiology: ADHD/OCD/TS (O’Rourke et al., 2011)

16. OCD/anxiety OCD: • Many with TS may also have obsessive-compulsive symptoms (OCS) • Disruptive to life and to tics • Need to “even things up”, “feel right”, touching forbidden objects (hot frying pan) • Complex tic or compulsion • Special care to be taken in medication: antipsychotic vs. SSRI Anxiety: • Unknown if genetically related to TS • Avoidance behavior common: reluctance to go to school or other activities (sleepovers)

17. TEMPERAMENTAL INFLUENCES • Individuals with TS- higher levels of aggression, hostility and personality disorder (Robertson et al., 1997) • Tics have been “associated” with increased neuroticism/ additional OCD diagnosis also showed low extraversion (Cath et al., 2001) • Comorbid ADHD “associated” with emotional instability • Severe OCD symptoms-emotional hypercontrol (Balottin et al., 2009) • Schizotypical personality traits-more common in TS population (Cavanna, Robertonson, & Critchley, 2007; Comings & Comings, 1987) • TS has been “associated” with significant differences in QofL aspects (home, peer and family interactions) (Eddy, Rizzo, Gulisano, Agodi, Parchitta, Cali, et al., 2011) • 88% of individuals with TS report tics having an effect on their life-potential to influence perceptions of abilities and feelings about themselves (Eddy, Rickard, Critchley & Cavanna)

18. EXPLOSIVE/AGGRESSIVE BEHAIVOR • 25-70% of patients with TS report outbursts and anger issues (factor analysis accounting for 62.5% of variance) (Budman, Rockmore, Stokes, & Sossin, 2003) • Kicking, screaming, threatening others, biting, hitting, fits of anger/rage, punching holes in walls • Individuals typically afraid of their own behavior • “Run it’s course” nature • Thin barrier between outward expression and impulses/thoughts • Causes problems with teachers, families, and patients themselves

19. Personality Influenced • 25 adult outpatients, TS clinic, all fulfilled DSM-IV-TR criteria for TS • Comprehensive clinical interviews- National Hospital Interview Schedule for TS • Participants completed: Ten Item Personality Index, Beck Depression Inventory, Positive and Negative Affect Schedule, & Yale Global Tic Severity Scale • Group scores were compared: TS patients vs. controls, between-group analysis subgroup of ‘pure TS’ to controls • Results: No significant differences on: BDI, PANAS positive or negative subscales, or the TIPI agreeableness scores • Significant difference between groups for four other TIPI scores (extraversion: MWU = 170.5, p = 0.005; conscientiousness: MWU = 204, p = 0.033; emotional stability: MWU = 130.5, p<0.001; openness: MWU = 196.5, p = 0.022) • Correlations: significance for emotional stability scores negatively related to BDI (SR= -0.501, p = 0.011, PANAS negative subscale scores (SR = -0.482, p = 0.015) and positively related to PANAS positive subscale scores (Sr = 0.682, p<0.001). TIPI emotional stability negatively related to BDI scores (Sr = -0.891, p<0.001) and positively related to PANAS positive subscale scores (Sr = 0.619, p = 0.014)

21. Behavioral Influences • Self-Injurious Behaviors (deliberate/repetitive infliction of self-harm) • Skin/scab picking, hair pulling, pinching oneself, self-biting • Study focused on the relationship between SIB and other behavioral features that commonly co-occur with TS (Mathews et al., 2004) ~300 subjects with TS participating in three genetic studies • Analyzed SIB, obsessions, compulsions, tic severity, attention deficit hyperactivity disorder related impulsivity, risk taking behaviors, and rages

24. Stress Related INFLUENCES • Life events are commonly used for the purpose of measuring stress • Stressful life events and TS relationship is unclear • Tic expression may be involved (Meidinger et al., 2005; Woods & Himle, 2004) • Impact of stressful life events and tic severity is best predicted by parental report (Lin et al., 2007) • Comorbid OCD: more stressful life events than controls (Findley et al., 2003)

25. ENVIRONMENTAL INFLUENCES • Literature review • Antecedent vs. Consequence Factors • Fatigue and social activities- exacerbate tics • Concentration, studying, relaxation- attenuate tics • Limited to applying these findings to population or even other clinical samples because of self-report issues and reported in aggregate form • Negative consequences reported to have negative or neutral outcomes • Positive consequences resulting in positive outcomes • Consequences were parent reported • Generalizability unclear, overall however, stressful frustrating or anxiety provoking events reported to exacerbate tics

29. ENVIRONMENTAL INFLUENCES • ‘tic-talk’ condition found to increase frequency of vocal but not motor tics (Woods, Watson, Wolfe, Twohig, & Friman, 2001) • Tics found to increase in presence of certain people (teacher, custodian, father, mother, examiner) (Malatesta, 1990) • Videotaping of children watching emotional video- most severe tics at specific emotional states, least severe in anger/happiness

30. LIMITATIONS IN UNDERSTANDING CONTEXTUFAL FACTORS • The studies reviewed examined the relationship in experimental settings • Isolating certain variables would be most helpful in applying these findings to treatment interventions • Little information about the premonitory ‘urge’ in the development of the disorders • Most interesting but still unknown: Is it tics themselves that are impacted by contextual factors or is it the suppression/inhibitory behaviors that are being changed?

31. GENETIC INFLUENCES • Previous studies have sought to identify several chromosomal regions associated with the susceptibility loci for TS • TS and Chronic motor tics among first-degree relatives 2.0% and 12.0% (respectively) • Morbid risk for TS among relatives: 9.8%-15% • When replicated, results typically do not hold • Difficult to extract out comorbid ADHD in findings, unable to conclude TS specific findings (< 10% of patients account for ‘pure’ TS population (Ozonoff et al., 1998; Mahone et al., 2002)

32. Neurological influences • Suggested involvement of the frontal cortex connections to subcortical regions including basal ganglia through the frontal cortico-striatal-thalamo-cortico circuits (Mink, 2001; Singer, 2005; Albin and Mink, 2006) • Suggested abnormality in brain systems that effect neural transmission from limbic to motor systems deficit in regions involved with motivation and action (Jeffries et al., 2002) • Involvement with frontal cortex including response inhibition and selective attention (Bornstein et al., 1991; Johannes et al., 2001; Channon et al., 2003)

33. GENETIC/ PHYSIOLOGICAL INFLUENCES • rs-fcMRI used to explore the possible disruption of brain systems in patients with TS (Fair et al., 2007a, 2008; Franssonet al., 2007) • Defects in neural circuits from the cerebral cortex through the structures constituting the basal ganglia and back to the cerebrum (Olson, 2004). • Cingulo-opercular network: maintenance of tasks sets across events within task period • Fronto-parietal network: rapidly adaptive online control • TD: strength of correlation coefficients ‘between’ differences in control networks seem to be stronger in children and decline with age (Fair et al., 2007) • Consideration of TS behaviors lead to theory of 3 suggested possibilities (Church et al., 2009) : • Abnormal connectivity within and between cingulo-opercular network • Altered connectivity with and within fronto-parietal network • More widespread set of differences could affect both networks and relations between them

36. GENTIC/ PHYSIOLOGICAL INFLUENCES • Largest off-curve differences found mostly in fronto-parietal network (adaptive control-/ controlling settings from one event to the next) • Immaturity in connections may be related to adaptive control network being more vulnerable to distraction while cingulo-opercular network (set-maintenance) stable and resistant

37. GENTIC/ PHYSIOLOGICAL INFLUENCES • Results for TS showed underdevelopment in 10-15 year olds, instead reflecting 7-9 year old • Groups of adolescents TD and with TS: 34 functional connections (p < 0.05) but after Benjamini and Hochberg False Discovery Rate correction, no emphasis produced • Connections examined using rs-fcMRI show weaker functional connections

40. WHAT DO These DIFFERENCES MEAN? • As mentioned, fronto-parietal network is associated with supporting online task-control while allowing for adaptive change from one event to the next (disruption here might make sense for the increase in severity in different environments that produce a change in emotion (going from calm to excitement, > frequency and severity of tics) • The fronto-parietal network has also been hypothesized as being more susceptible to distraction which would make transient control impaired • Adolescents with TS (10-15) may have less functional communication between distant areas of cortex and over communication between closer regions (similar to young children) • Lack of long range communication could explain inability to supress unwanted behaviors in TS

41. Genetic influences • 6 family studies have previously looked into familial related conditions in TS (5- US & Europe, 1-Japan) • Interviews from first degree family members • Found morbid risk of 9.8-15% among relatives • 15-20% for other tics • Age correct rates among first degree relatives 2.0-12% • More recently, researchers suggest inheritance patterns are more complex than originally thought and are seeking association and linkage studies (Pauls, 2003)

42. Problems with Genetic association/linkage studies ASSOCIATION: • Case control or family based • Limited by many irrelevant markers appearing to be disease associated • High rates of false positives • Population stratification- cases and controls differ not only with phenotype of interests but overall population genetic ancestry • Difficult to find appropriate control group

43. Problems with Genetic association/linkage studies • LINKAGE (Pauls, 2003): • Members of the Tourette Syndrome Association International Consortium on Genetics (TSAICG) conducted all initial linkage studies • 31 multigenerational families were studied • > 800 genetic marker loci were screened • No strong positive evidence found for linkage with TS • Re-conducted by TSAICG in sib-pair study of 76 families • 64 had only two affected siblings • 10 had three effected siblings • 2 had 4 and 5 affected siblings • Candidate genes such as the dopamine D4 receptor DRD4 have been suggested but fail to be replicated (Pauls, 2003)

44. Review • Temperament, environment, & genetics/physiology in relation to TS commonly produced inconclusive research findings • Tic severity may to be influenced by awareness, context, age, & comorbidity • Immature connectivity throughout neurological regions have been measured and may influence the inability to inhibit unwanted behaviors • Research findings of TS struggle to be generalizable to entire population because of high comorbidity rates • As earlier stated, perspective of disorder is important in approaching targets of treatment intervention

46. Socialization/ Peer- acceptance/ Quality of relationships Neuroanatomical/ Genetic Substrates Comorbidity ADHD/OCD Academic/ Behavioral Functioning Age Awareness of Behaviors Motor Tics/ (simple or complex) Vocal Tics Stress/Anxiety/ Fatigue/Inattention Inhibitory deficits Tic Severity Cunningham TS Model 2013 Self-Injury Inattentiveness Aggression Functional Impairment Deficits in relationships

47. REFERENCES American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing. Balottin, U., Rossi, M., Rossi, G., Vigano, L., Salini, S., Lanzi, G, et al. The rorscharch test and gilles de la tourette’s syndrome: A pilot case control study. Brain Development, 31, 657-665. Bloch, M. H., & Leckman, J. F. (2009). Clinical course of tourette syndrome. Journal of Psychosomatic Research, 67, 497-501. Brito, G. N. O. (1997). A neurobiological model for tourette syndrome centered on the nucleus accumbens. Medical Hypotheses, 49, 133-142. Budman, C. L., Rockmore, L., Stoke, J., & Sossin, M. (2003). Clinical phenomenology of episodic rage in children with tourette syndrome. Journal of Psychosomatic Research, 55, 59-65. Cath, D. C., Spinhoven, P., Landman, A. D., & van Kempen, G. M. J. (2001). Psychopathology and personality characteristics in relation to blood serotonin in tourette’ssynfrome and obsessive-compulsive disorder. Journal of Psychopharmochology, 15, 111-119. Church, J. A., Fair, D. A., Dosenbach, N. U. F., Cohen, A. L., Miezin, F. M., Peterson, S. E., & Schlaggar, B. L. (2009). Control networks in paediatrictourette syndrome show immature and anomalous patterns of functional connectivity. Brain, A Journal of Neurology, 132, 225-238. Conelea, C. A., & Woods. D. W. (2008). The influence of contextual factors on tic expression in tourette’s syndrome: A review. Journal of Psychosomatic Research, 65, 487-496.

48. Eddy, C. M., Rickards, H. E., Critchley, H. D., & Cavanna, A. E. (2013). A controlled study of personality and affect in tourette syndrome. Comprehensive Psychiatry, 54, 105-110. Findley, D. B., Leckman, J. F., Katsovich, L., Lin, H., Zhang, H., Grantz, H. et al. (2003). Development of the yale children’s global stress index (YCGSI) and its application in children and adolescents with tourette syndrome and obsessive-compulsive disorder. Journal of American Academy of Child Adolescent Psychiatry, 42, 450-457. Jeffries, K. J., Schooler, C., Schoenbach, C., Herscovitch, P., Chase, T. N., & Braun, A. R. (2002). The functional neuroanatomy of tourette’s syndrome: An fdg pet study III: Functional coupling of regional cerebral metabolic rates. Neuropsychopharmacology, 27, 92-104. Leckman, J. F. (2002). Tourette’s syndrome. The Lancet, 360, 1577-1586. Lin, H., Katsovich, L., Ghebremichael, M., Findley, D. B., Grantz, H., Lombroso, P. J., et al. (2007). Psychosocial stress predicts future symptom severities in children and adolecents with tourettesynfrome and/or obsessive compulsive disoder. Journal of Child Psychology and Psychiatry, 48, 157-166. Pauls, D. L. (2003). An update on the genetics of gilles de la tourette syndrome. Journal of Psychosomatic Research, 55, 7-12. Robertson, M. M., Banerjee, S., Hiley, P.J. F., & Tannock, C. (1997). Personality disorder and psychopathology in tourette’s syndrome: A controlled study. Br J Psychiatry, 171, 283-286. Steinberg, T., Shmuel-Baruch, S., Horesh, N., & Apter, A. (2013). Life events and tourette syndrome. Comprehensive Psychiatry, 54, 467-473.