Neurobiology of OCD, Etiology of OCD

1. Neurobiology of OCD.
Dr. Cijo Alex.

2. Overview
1) Overview of OCD.
2) Basic Neuroanatomy.
3) Basic neurophysiology.
4) Etiology and pathophysiology of OCD.
- Neurobiology
5) Conclusion

3. Overview of OCD

4. Definition and Diagnostic Features
Obsessive–compulsive disorder (OCD) is an intriguing
and often debilitating syndrome characterized by the
presence of two distinct phenomena:
obsessions and compulsions.
Obsessions are intrusive, recurrent, unwanted ideas,
thoughts, or impulses that are difficult to dismiss despite
their disturbing nature.
Compulsions are repetitive behaviors, either observable or
mental, that are intended to reduce the anxiety
engendered by obsessions.

5. OCD usually has its onset during puberty, although
it may begin as early as age 2 years and
infrequently begins after age 35 years.
Women develop OCD slightly more often than men.
Studies found that the course of OCD is usually
chronic, with symptom severity waxing and
waning over time.

6. Several large studies have found that the most
common obsession is contamination, and the
most common compulsion is checking.
However, most individuals with this disorder have
multiple obsessions and compulsions over time.
A number of psychiatric disorders co-occur with
OCD, major depressive disorder being most
frequent. Comorbidity with tic disorders is well
established.

9. Management of OCD
YBOCS

10. Basic Neuroanatomy

11. Basal ganglia
Group of nuclei that have been grouped
together on the basis of their interconnections
which play roles in movements and cognition.
Structures of BG include
G.PALLIDUS ,STRIATUM (C.Nucleus + Putamen), S.NIGRA
and SUBTHAMALIC NUCLEI.

13. Functional circuits
Major Afferents
The striatum is the major recipient of the inputs
to the basal ganglia.
Major pathways : corticostriatal, nigrostriatal,
and thalamostriatal afferents.

15. The Prefrontal Cortex
Prefrontal cortex is the most dorsal portion of
the frontal lobe, characterized as being
involved in cognitive and emotional brain
functions.
• DLPFC
• OFC
• VMPFC

16. Thalamus
The thalamus is part of the diencephalon;
It is a bilateral structure, subdivided into
multiple nuclei;It is a relay center, through
which all information about the outside world,
except olfaction, passes before reaching the
neocortex, striatum, and amygdala

18. The Limbic Sytem
Commonly included areas of Limbic system are
-Limbic Cortex.
Cingulate Gyrus
Parahippocampal Gyrus
-Hippocampal Formation & assosiated areas
-Septal Area
-Hypothalamus

20. Basic neurophysiology

21. The Serotonergic system
A monoamine neurotransmitter derived from
tryptophan.
Roles in mood, appetite, sleep and cognition.
Serotonergic neurons are clustered in midline
raphe nuclei of brain stem.

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

24. Etiology and pathophysiology of
OCD

25. Although our understanding of what causes this
disorder has continued to grow, there is still
much to learn. It is likely that OCD is caused by
a complex interaction of factors rather than a
single defect.
However, for the purpose of clarity, these factors
are described separately.
• Genetic Factors
• Psychological and Environmental Factors
• Phylogenetic Model
• Neurobiological Factors

26. Neurobiological Factors
Neuroanatomical aspects
Neurochemical aspects
Neurogenetical aspects
Neuroimmunology

27. Numerous studies have now been done with both
structural imaging—CT and MRI and functional
imaging—PET , SPECT, fMRI , and MRS and most
recently, diffusion tensor imaging.
These techniques have demonstrated abnormalities in
OCD patients (Saxena et al.1998 ). These abnormalities
occur at rest and with symptom provocation (Baxter et
al. 1992 , Rauch et al. 1994 ), and they are
“normalized” with effective treatment (Saxena et al.
2002 , Nakao et al. 2005 ).

28. Methods
Structural imaging
Functional imaging studies
• PET
• SPECT
• fMRI
Interpretation
• Comparing pts. with controls in baseline state
• Pts. before and after treatment- cerebral activity changes
corresponding to treatment
• Symptom provocation studies
• Activation studies – during performance of a cognitive task

29. While not all results are in agreement, a majority of
these studies have implicated abnormalities in
Anterior cingulate cortex,
Orbitofrontal cortex,
Basal ganglia and
Thalamus.
These structures are proposed to be linked in
neuroanatomical circuits of OCD
(Baxter1992 ).

30. Cingulate Cortex
• Szeszeko et al, 2004 [MRI]- ↑ Gray matter in
ACG
• Busatto et al, 2000 [SPECT]- ↓ Lt. ACC
• Ebert et al, 1997 [MRS]- ↓ Vol of CC
• Perani et al, 1995 [PET]- b/l ↑ ant, middle and
post CC

31. Alterations in the anterior cingulate and globus pallidus
Szeszko et al., Am J Psychiatry 2004

32. Anterior cingulotomy – Upto 50% success in
refractory cases of OCD.
Anterior capsulotomy- the anterior limb of the
internal capsule

33. Basal Ganglia
• Szeszeko et al, 2004 [MRI]- ↓ volumes of the globus
pallidus; Pt and healthy control did not differ in volumes of
caudate nucleus and putamen
• Bartha et al, 1998 [MRS]- Caudate nucleus volume of pt =
healthy control
• Rosenberg et al, 1997 [MRI]- Smaller putamen
• Lucey et al, 1997 [SPECT]- Decreased rt. caudate vol.
• Jenike et al, 1996 and Aylward et al, 1996 [MRI]- No
difference in caudate vol.
• Robinson et al, 1995 [MRI]- ↓ b/l caudate vol
• Perani et al, 1995 [PET]- ↑ pallidum/ putamen complex

34. Early studies of caudate nucleus morphometry in OCD

35. Further indirect evidence implicating a role for
basal ganglia dysfunction in OCD lies in the
clinical relationship between neurological
insults to the basal ganglia and the
subsequent development of obsessions and
compulsions.

36. Injury-induced OCD
Chako et al., 2004

37. Thalamus
• Smith et al, 2003 [MRS]- ↑ b/l medial thalamic choline
conc in OCD compared to MDD and control
• Lacerda et al, 2003 [ SPECT]- ↑ b/l thalamus
• Kim et al, 2001 [MRI]- ↑ gray matter density in
thalamus
• Alptekin et al, 2001 [SPECT]- ↑ Rt. thalamus
• Fitzgerald et al, 2000 [MRS]- ↓ NAA b/l medial
thalamus
• Rosenberg et al, 1997 [MRI]- large 3rd ventricle
• Perani et al, 1995 [PET]- ↑ thalamus

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

39. Prefrontal Cortex
• Kang et al, 2004 [MRI]- ↓ Lt. OFC
• Lacerda et al, 2003 [SPECT]- ↑ Inf FC
• Kim et al, 2001 [MRI]- ↑ grey matter density
in Lt. OFC
• Alptekin et al, 2001 [SPECT]- ↑ b/l OFC
• Busatto et al, 2000 [SPECT]- ↓ Rt. OFC
• Rosenberg et al, 1998 [MRI]- ↑ Ventral PFC
vol

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

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

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

43. Successful treatment of OCD symptoms may
lead to normalization of frontal cortical
activation (Saxena et al. 2002 , Nakao et al.
2005 ).

44. Circuits to explain OCD
(Proposed integration of findings)

45. All these evidence point towards involvement of
basal ganglia and frontostraiatal connections
Cortico-Strito-Thalamo-Cortical circuit
dysfunction
One well-articulated model by Saxena et al. ( 1998 )
proposes that OCD symptoms are mediated by
hyperactivity in orbitofrontal–subcortical circuits
(Saxena et al. 1998 , Lacerda et al.2003 , Szeszko et al. 2005 )

47. Direct and Indirect pathways of CSTC
The direct system ( Accelerator) involves direct projections
from striatum to Globus Pallidus interna. And it uses
substance P as neurotransmitter with net effect of
Excitation on Thalamus.
The indirect system (Brake)uses indirect projections from
Striatum to GPi via Gpe using Enkephalin as transmitter
with net effect of Inhibition on Thalamus

49. • 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
Hyperactivity is exacerbated during symptom
provocation
Breiter et al (1996)

51. Summary of Neuroanatomical Studies
• Imperfect replicability
• Strong link- OFC
• Less consistent- ACG, Striatum, Thalamus
• Least- Lateral frontal and temporal cortices,
Amygdala.
Saxena et al, 2000; Whiteside et al, 2004; Remijnse et al, 2005; Mataix-cols et al, 2006

52. Neurochemical Aspects
• Role of neurotransmitters in OCD
– Serotonin
– Dopamine
– Glutamate

53. The serotonin hypothesis of OCD.
The hypothesis that OCD involves an
abnormality in the serotonin neurotransmitter
system has been called the serotonin
hypothesis.
All of the antidepressants that effectively treat
OCD affect serotonin (Westenberg et al.
2007).
Exactly how the SRIs improve OCD symptoms
remains unclear

54. Evidence of 5HT hypothesis
• 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)
• A decrease in platelet serotonin levels—an indirect
measure of neuronal reuptake—has been highly
correlated with clinical improvement with clomipramine
(Westenberg et al. 2007)
• Higher whole-blood 5-HT levels have been associated
with clinical improvement with SRIs (Delorme et al.2004).

55. Reduced 5-HT transporters in midbrain
Stengler-Wenzke et al.,
Eur Arch Psychiatr Clin Neurosci, 2004

56. Dopamine
• Up to 40% of OCD patients do not respond to SSRIs.
• Dopamine agonists can exacerbate OCD symptoms
(Apomorphine,Bromocriptine)
• Adjunctive therapy with conventional antipsychotics
add to reduction of OCD symptoms in individuals
treated with SSRIs.
Stein et al, 2002

57. Glutamate
• Hyperglutamatergic state involving prefrontal
brain regions
• Greater caudate glutamate concentrations
and significant decrease after treatment with
paroxetine.
• Significantly raised CSF glutamate levels in
OCD patients compared to normal controls.
Chakrabarty et al, 2005

58. Neurogenetics

59. • Concordance
– MZ -53%-87%
– DZ -22%-47%
• Higher rates of OCD, sub threshold OCD, tics in
relatives of probands with OCD than with controls
• Early age of onset – relatives higher risk for OCD/
Tics
• Higher rates of OCD in first degree relatives of
probands with Tourette’s syndrome
Stein et al, 2002

60. Polymorphism in 5HT Receptor
• Gene encoding 5-HT2A receptor: allele of -1438 A/G
promoter region and T102C polymorphism
• 5 HT2C receptor: Structural variant cysteine to serine
substitution at position 23 of N terminal region
• 5-HT1Dβ autoreceptor: G861C allelic variant might
contribute to disease severity
• TPH enzyme: 2 forms- TPH1 and TPH2
– TPH2 implicated in early onset OCD
Hemmings et al, 2006; Chamberlain et al, 2005

61. Neuroimmunology

62. • OCSx in Sydenham’s chorea
• OCSx ppt. or exacerbated by streptococcal
(GABHS) infection-PANDAS
• D8/17
– a B- lymphocyte antigen
– more risk for infection with GABHS.
– more in children with PANDAS and Sydenham’s
chorea than with in controls
– Childhood onset OCD or TS higher expression than
controls
Murphy et al, 2006

63. • Immune parameters in Pts of OCD- Antibasal
ganglia ab, Type 1 cytokines (IL-12, TNF-α, D
8/17), ↓ NK cell activity
• Antibrain Ab +ve: Effects functioning of BG
• ↑ level of Neoptrin (marker of cellular immune
system activation)
• Immunotherapy reduce exacerbations and
recurrences
• High prevalence of OCD: SLE and MS pts
Murphy et al, 2006

64. Conclusion
No single model can explain OCD as of now.
CSTC loop appears to be the final common pathway and
locus of primary pathology
Genetic vulnerability to autoimmune damage to striatum
Serotonergic modulation is important in treatment
Further research is needed to understand the
neurobiology of OCD.

65. Thank You