Neurobiology of OCD.Dr. Cijo Alex.

Overview

1) Overview of OCD.

2) Basic Neuroanatomy.

3) Basic neurophysiology.

4) Etiology and pathophysiology of OCD.

- Neurobiology

5) Conclusion

Overview of OCD

Definition and Diagnostic Features

Obsessive–compulsive disorder (OCD) is an intriguingand 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.

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.

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.

Management of OCDYBOCS

Basic Neuroanatomy

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.

Functional circuitsMajor Afferents

The striatum is the major recipient of the inputs to the basal ganglia.

Major pathways : corticostriatal, nigrostriatal, and thalamostriatal afferents.

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

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

The Limbic Sytem

Commonly included areas of Limbic system are

-Limbic Cortex.Cingulate GyrusParahippocampal Gyrus

-Hippocampal Formation & assosiated areas

-Septal Area

-Hypothalamus

Basic neurophysiology

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.

Serotonin modulates the prefrontal cortex, striatum, and thalamus

Etiology and pathophysiology of OCD

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

Neurobiological Factors

Neuroanatomical aspects

Neurochemical aspects

Neurogenetical aspects

Neuroimmunology

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 ).

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

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 ).

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

Alterations in the anterior cingulate and globus pallidusSzeszko et al., Am J Psychiatry 2004

Anterior cingulotomy – Upto 50% success in refractory cases of OCD.

Anterior capsulotomy- the anterior limb of the internal capsule

Basal Ganglia

• Szeszeko et al, 2004 [MRI]- ↓ volumes of the globuspallidus; 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

Early studies of caudate nucleus morphometry in OCD

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.

Injury-induced OCDChako et al., 2004

Thalamus

• Smith et al, 2003 [MRS]- ↑ b/l medial thalamic cholineconc 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

Increased activity in the thalamusSaxena et al., Biol Psychiatry, 2001

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

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

Activation in the orbitofrontal cortex and amygdala during symptom provocation

Patients with OCD had significantly reduced

bilateral orbital frontal and amygdalavolumes compared with healthy comparison subjects

Successful treatment of OCD symptoms may lead to normalization of frontal cortical

activation (Saxena et al. 2002 , Nakao et al. 2005 ).

Circuits to explain OCD

(Proposed integration of findings)

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 )

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

• 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)

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

Neurochemical Aspects

• Role of neurotransmitters in OCD

– Serotonin

– Dopamine

– Glutamate

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

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).

Reduced 5-HT transporters in midbrainStengler-Wenzke et al.,

Eur Arch Psychiatr Clin Neurosci, 2004

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

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

Neurogenetics

• 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

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

Neuroimmunology

• 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

controlsMurphy et al, 2006

• Immune parameters in Pts of OCD- Antibasalganglia 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

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.

Thank You