Neurobiology of Obsessive Compulsive Disorder: focus on Neuroimaging

1. Neurobiology of Obsessive Compulsive Disorder:focus on Neuroimaging Prof. Antonio Vita University of Brescia

2. Structural alterations

3. Early studies of caudate nucleus morphometry in OCD

5. Patients with OCD had significantly reduced bilateral orbital frontal and amygdala volumes compared with healthy comparison subjects

6. Reduced left orbitofrontal cortex in OCD patients correlates with severity of symptoms Kang, et al., 2004, J Neuropsychiatry Clin Neurosci

7. Alterations in the anterior cingulate and globus pallidus Drug-naïve patients Szeszko et al., Am J Psychiatry 2004

9. Statistical parametric t map of gray matter volume reduction in obsessive-compulsive disorder in the orbitofrontal cortex, medial frontal gyrus and left insulo-opercular region

10. Statistical parametric t map showing gray matter volume increase in obsessive-compulsive disorder in the ventral part of the striatum and in the anterior cerebellum

11. Statistical parametric t map showing gray matter volume decrease in patients with prominent aggressive obsessions and checking compulsions compared with the rest of the obsessive-compulsive disorder sample Significant voxels were found in a right hemisphere region involving the amygdala

13. Fractional anisotropic reductions in patients with obsessive compulsive disorder vs healthy comparison subjects in the right and left hemisphere anterior cingulate white matter rendered onto a T1-weighted image

14. Altered function of the cortico-striatal-thalamo-cortical loop

15. OCD PATIENTS HAVE INCREASED ACTIVITY IN ORBITOFRONTAL CORTEX, CAUDATE AND ANTERIOR CINGULATE CORTEX

16. Overactivity of prefrontal-basal ganglia loops Baxter et al., 1998

17. Increased activity in the thalamus Saxena et al., Biol Psychiatry, 2001

18. Aree cerebrali coinvolte nell’OCD

19. At rest: • Increased activity of the orbitofrontal cortex • Increased activity of the cingulate cortex • Increased activity in the caudate nucleus • Increased activity in the thalamus

20. Hyperactivity is exacerbated during symptom provocationBreiter et al (1996) • fMRI • “Contaminated” items vs neutral items • Handling of contaminated items exacerbated activity in the prefrontal cortical areas (anterior cingulate, orbitofrontal), the basal ganglia, and the amygdala

21. Activation in the orbitofrontal cortex and amygdala during symptom provocation

22. (Shapira et al, 2003) Iperattivazione cortico-sottocorticale rispetto a volontari sani

23. Injury-induced OCD 12-year-old female, struck by car Max et al. 1995 Chako et al., 2004

25. Alterations in other cognitive/emotional processes

26. Activation of the anterior cingulate when errors are committed on a cognitive task in OCD patients Ursu et al., Psychol Sci, 2003

27. Cognitive Alterations • Memory (working memory) • Set shifting • Response inhibition (more errors of commission)

28. Dysfunction of inhibitory processing

31. Brain maps illustrating regions where grey matter density was most strongly correlated with latency of motor inhibitory response (SSRT) • Red/yellow regions indicate areas in which increased grey matter density is associated • with prolonged SSRT (impaired response inhibition) • Blue regions indicate areas where decreased grey matter density is associated with • prolonged SSRT

32. Red/yellow regions indicate areas in which increased grey matter density is associated with prolonged SSRT (impaired response inhibition) Blue regions indicate areas where decreased grey matter density is associated with prolonged SSRT

34. CONCLUSIONS: • Response inhibition, indexed by SSRT, is abnormal in patients with OCD and their first-degree relatives • Grey matter density in discrete brain areas is (positively or negatively) correlated with variability in stop-signal task performance • Pts with OCD and their relatives have structural abnormalities compared to healthy volunteers • Variation in brain systems correlated with inhibitory function is likely determined by familial factors in common between patients and their first-degree relative

37. Increased BOLD signal in right caudate nucleus during planning compared with baseline in control subjects compared with patients with OCD Increased BOLD signal in left DLPFC correlating with task load in control subjects compared with patients with OCD

38. Increased BOLD signal correlating with task load in patients with OCD compared to control subjects : A. in parahippocampal gyrus, B. in ventrolateral prefrontal cortex, C. in cyngulate cortex

39. RESULTS: • Behavioral results showed significant planning impairments in OCD patients compared with control subjects. • During planning, decreased frontalstriatal responsiveness was found in OCD patients, mainly in DLPFC and caudate nucleus. • OCD patients showed increased, presumably compensatory, involvement of brain areas known to play a role in performance monitoring and short-term memory processing, such as anterior cingulate, ventrolateral prefrontal, and parahippocampal cortices. CONCLUSIONS: These findings support the hypothesis that decreased dorsal prefrontal-striatal responsiveness is associated with impaired planning capacity in OCD patients.

40. Neurochemical alterations

41. Serotonin hypothesis • OCD is related to serotonin dysfunction • Pharmacological treatments for OCD • Clomipramine • Fluoxetine • Paroxetine • Sertraline • Serotonin Antagonists exacerbate symptoms • Data on serotonergic measures in OCD patients have been conflicting

42. Serotonin modulates the prefrontal cortex, striatum, and thalamus

43. Evidence of 5-HT dysfunction • Increased 5-HT2A receptors in caudate which are normalized after SSRI treatment (Adams et al., 2005, Int J Neuropsychopharmacol) • Acute trypotophan depletion can increase anxiety and compulsive urges and rituals when faced with stimuli (Bell et. al. (2001) • Not always replicated (Barr, 2003) • Alterations in serotonin transporters

44. Reduced 5-HT transporters in midbrain No depression No psychotropic drug use for 6 months Stengler-Wenzke et al., Eur Arch Psychiatr Clin Neurosci, 2004

45. Dopamine • Up to 40% of OCD patients do not respond to SSRIs. • Dopamine agonists induce stereotyped movements in humans and animals • Dopamine agonists can exacerbate OCD symptoms • Co-morbidity of Tourette’s and OCD (up to 90% of individuals with Tourette’s have OCD) • Adjunctive therapy with conventional antipsychotics add to reduction of OCD symptoms in individuals treated with SSRIs

46. Increased striatal DA transporters in psychotropic-naïve OCD patients Van der Wee, et al., Am J Psychiatry 2004

47. Alterations in striatal D2 receptors Denys, et al. 2004 Biol Psychiatry

48. Treatments

49. Treatments • SSRIs • Adjunctive antipsychotics (dopamine antagonists) • Behavior therapy • Psychosurgery

50. Normalization of orbitofrontal cortex activation Saxena et al., 1999