1. CONTENT
1.OCD brief introduction
2.Neuroanatomical basis
3.Relevant neural pathways
4. Neurochemicals involved
5. Brain changes in OCD
6.Neurogenetics and
neuroimmunology

2. Introduction:
An obsession is a thought that persists and dominates an individual’s thinking despite the individual’s
awareness that the thought is either entirely without purpose or else has persisted and dominated their
thinking beyond the point of relevance or usefulness.
Causes sufferer great anxiety or even guilt.
Compulsions are obsessional motor acts.

3. Introduction
Cognitive and Neuropsychological studies of OCD reveal:
 impairments in executive functions
Cognitive inflexibility
Motor impulsivity
Excessive habit formation (consistent with hypothesis that OCD
represents impaired control of automated, habitual behaviour)
Another group of studies show:
Change in affective and reward processing in OCD

4. Neuroanatomical basis:
Brain regions primarily involved –
Anterior cingulate
Orbitofrontal cortex
Striatum
Other regions also have important role

5. Brain circuits involved in OCD:
 The cortico-striatal-thalamic-cortical loop (CSTC) is
considered the critical brain circuit involved in the
phenomenology of OCD.
 The CSTC circuits modulate several specific functions.
 In addition, the frontoparietal and fronto limbic network also
plays a role in the pathophysiology of OCD.

6. 1. Sensorimotor CSTC circuit
 Supplementary motor area to putamen to the thalamus
 Stimulus-response-based habitual behaviour (S-R)
Treatments that target this circuit:
rTMS
Repetattive transcranial
Magnetic stimulation
tDCS
Transcranial direct current
stimulation

7. 2. Dorsal Cognitive CSTC circuit
Dorsolateral Prefrontal Cortex (DLPFC) and Dorsomedial Prefrontal Cortex (DMPFC) to caudate(dorsal) to
thalamus
Involved in working memory, planning and emotional regulation
Treatments that target this circuit:
Cognitive therapy
rTMS
tDCS

8. 3. Ventral cognitive CSTC circuit
Inferior frontal gyrus (IFG) and Ventrolateral Prefrontal cortex (VLPFC) to ventral caudate to thalamus
Involved in response inhibition

9. 4. Ventral Motivational/ Reward CSTC Circuit
Orbitofrontal Cortex (OFC) to Nucleus Accumbens (NAc) to the Thalamus
Involved in Stimulus Outcome based motivational behaviour i.e. Stimulus – outcome (S –O)
Treatments that target this circuit:
DBS
Deep brain
stimulation
Capsulotomy
Cingulotomy

10. 5. Frontoparietal network Frontal cortex to the thalamus and parietal cortex
Coordination of cognitive control
Part of the alerting network

11. 6. Frontolimbic circuit VMPFC to amygdala to thalamus
Role in fear extinction
Alterations in the Amygdala were most pronounced in unmedicated OCD patients
Treatments that target this cicuit:
ERP
SRIs

12. 7. Frontal CSTC and Cerebellar Circuit
The cerebellum plays an important role in motor control and cognition.
OCD patients showed abnormal spontaneous cerebellar activity and weakened functional connectivity between
the cerebellum and the CSTC circuit.
Decreased functional connectivity may result in an inability of the striatum to effectively inhibit the thalamus.
Excitation of the thalamus leads to hyperactivation of the direct excitatory CSTC. [Zhang et al, 2019]

13. The CSTC consists of a direct excitatory and indirect inhibitory loop.
Direct Excitatory CSTC Loop
Parts – Orbitofrontal cortex, Striatum and Thalamus
OFC is a part of direct excitatory CSTC loop
The orbitofrontal CSTC loop is implicated in motor response to emotional stimuli
Overexcitation of the excitatory direct pathway drives the compulsive and ritualistic features typical of OCD.
Indirect inhibitory CSTC loop
Parts – Dorsolateral prefrontal cortex, Striatum, caudate, globus pallidus interna, Thalamus
Hypoactivity of this circuit (i.e. overactivation of indirect pathway) may contribute to the inability to switch between
tasks that is characteristic of OCD

16.  In the normally functioning cortico-striato-thalamo-cortical circuit, direct and
indirect pathways lead to increased or decreased inhibition of the thalamus,
respectively, in a balanced manner.
 According to Saxena et al., who proposed the model [Saxena et al. 1998] : OCD is
mediated by an imbalance between the direct (excitatory, OFC-striatum globus
pallidus-thalamus-cortical) and indirect (inhibitory, DLPFC-striatum globus pallidus-
subthalamic nucleus-cortical) pathways within this circuit, which causes a brain lock
in the caudate nucleus and a mutual hyperactivation between the OFC and
thalamus.
 Whereas the CTSC hypothesis provides a useful framework, it doesn’t
comprehensively explain the pathophysiology of OCD.

19. Imbalance of Goal-directed vs Habit areas:
Studies are increasingly focusing on the role of the goal-directed and habit areas of the brain in OCD.
[Lipton et al, 2019]
Proposed two-stage pathophysiology of OCD
Patients with OCD show hyperactivation of the caudate nucleus which is associated with increased habit
formation and this hyperactivity is remediated when treatments are successful [Gillan et al, 2016]

20. Brain activity in OCD during emotional processing vs cognitive processing
Functional neuroimaging studies have shown increased activation in the areas of
basal ganglia (predominantly head of caudate), anterior cingulate, and orbitofrontal
orbitofrontal cortex (areas involved in emotional and cognitive processing) in OCD
patients as compared to healthy controls. [Parmar & Sarkar, 2016], [Nakao et al,
2014]
OCD is characterised by dysfunctions in affective and cognitive processing. This
cognitive affective dysfunction is a feature of many psychiatric disorders and may
lack specificity. [Stein et al, 2019]

21. Neurotransmitters involved:
Serotonin
Glutamate
Dopamine
GABA
The neurotransmitter model of OCD postulates
Dopaminergic and glutamatergic overactivity in frontostriatal pathways
Diminished serotonergic and GABAergic neurotransmission in frontolimbic systems.
These neurotransmitter imbalances may explain frontostriatal hyperactivity and impaired frontolimbic
emotion regulation.

22. 1. Serotonin (5-HT) Changes in serotonin levels and serotonergic genes have been implicated, but
the evidence is inconclusive.
2. The role of serotonin is implicated due to the finding that SSRIs are effective treatments for OCD.
3. Some potential therapeutic effects of serotonergic transmission in OCD are: Central serotonin
depletion is known to increase habitual responding at the expense of goal-directed behaviour.
4. Serotonergic medication remediates goal-directed deficits in OCD by increasing 5-HT activity in
OFC, facilitating a shift from automatic habitual to goal-directed behaviours. This effect again
may be mediated by 5-HT2C agonist activity. [Gillan et al, 2016], [Fineberg et al, 2018]
5. Significant pre and post-treatment (SSRI or CBT) increase in whole-brain 5-HT synthesis capacity
was associated with patients that responded.
6. Increases in global 5- HT synthesis capacity correlated with reductions in OCD symptom severity.

23. Glutamate:
Glutamate is the primary driver of the direct excitatory CSTC circuit.
Glutamatergic neurons originating in the PFC project to the striatum and
thus receive significant excitatory output from the PFC.
Glutamatergic signaling regulates neurotransmission between the
orbitofrontal cortex (OFC), anterior cingulate cortex (ACC) and striatal
structures (caudate, putamen and others).
Glutamatergic hyperactivity associated with over-activity of the direct
pathway is postulated to be one of the mechanisms in the pathophysiology
of OCD. [Karthik et al, 2020]

24. 3. Dopamine (DA)
• The direct and indirect pathway of the CSTC covered earlier consists of D1 and D2 receptors,
respectively, the imbalance of which affects the brake that controls repetition.
• D1 receptor types (D1Rs) are excitatory and D2 receptor types (D2Rs) are inhibitory. [Costa et al,
2022] Dopamine has a key role in stereotypic behaviour
• A decrease in striatal dopamine D2 receptors has been identified in patients with OCD.
• A hyperdopaminergic state is postulated to underpin OCD as evidenced by increased endogenous
DA levels at baseline due to increased phasic firing at rest. (and Tourette Syndrome which is
commonly comorbid with OCD). [Denys et al, 2013]
• Dopamine neurons are known to represent Reward Processing Error (RPE) signals that can facilitate
learning of reward predictions by the basal ganglia (striatum). [Costa et al, 2022]
• The dopaminergic neurons encode differences between rewards and expectations in the goal-
directed system and differences between the chosen and habitual actions in the habit system.
[Bogacz, 2020] This RPE processing plays an important role in action planning and decision-making.

25. Neuroimaging and changes in OCD brain:
 Both CT and MRI of untreated children and adults with OCD have revealed smaller
volumes of basal ganglia segments compared to healthy controls.
 According to a meta-analysis of Voxel based morphometry (VBM), gray matter
density in OCD patients was smaller in parieto frontal cortical regions but larger in
basal ganglia and anterior prefrontal cortex
 In children increased thalamic volume has been found
 Adult studies – hypermetabolism in CSTC network in untreated undividual
 Both medication and behavioural interventions have lead to reduction of
orbitofrontal and caudate metabolic rates in children and adults with OCD.

26. Some distinct correlates identified are as follows:[van den Heuvel OA et al, 2008], [Nakao et al, 2014
Neural correlates of symptoms:
Harm checking: Negative correlation with bilateral temporal lobes Hypoactivation in the left caudate
and left ACC
Contamination/washing: Negative correlation with bilateral caudate and right parietal region
Hyperactivation in several bilateral cortico-cerebellar regions (Washing rituals) Decreased right insula
(Contamination)
Symmetry/ordering: Negatively correlated with regional GM volume in the right motor cortex, left
insula and left parietal cortex Positively correlated with bilateral temporal GM and white matter (WM)
volume
Aggression symptoms: Symptoms were modulated by connectivity between the ventral striatum,
amygdala, and ventromedial frontal cortex. Decreased right cerebellum activity.
Sexual/religious symptoms: Ventral striatal-insular connectivity

27. Other general brain changes: [Stein et al, 2019]
A decreased volume of the hippocampus and an increased volume of the bilateral putamen in
adults with OCD are more pronounced in medicated patients.
Reductions in hippocampus volume are more pronounced in those with comorbid depression.
Increased volume of the pallidum was mainly present in the adults with OCD who had a child-
onset disease.
Medicated patients with OCD had thinner cortex in frontal, temporal, parietal, temporal and
occipital regions (adult sample) and smaller surface areas in frontal regions (pediatric sample).
In contrast, unmedicated patients with OCD did not differ from controls.
Changes in brain white matter have also been reported in patients with OCD.

28. Neurogenetics:
Genetic factor – Early onset
1st degree relatives – 10 times rate of OCD
Twin studies – Monozygotic twins [0.57] > Dizygotic [0.22] [ Concordance rates]
Genetic linkage studies – susceptibility loci on chromosomes (1q, 3q, 6q, 9p, 10p, 15p)
OCD collaborative genetic studies – Sapap3 gene a/w grooming disorders, a promising candidate for OCD
Neuroimmunology:
Infection trigerred OCD –
GABHS
PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Steptococcus)
MRI studies- Proportional relationship between size of basal ganglia and severity of OCD

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