1. Obsessive-compulsive disorder (OCD)
BCS 246
Spring 2017

2. Obsessive-compulsive disorder (OCD)
One of the 10 leading causes of disability
Considered a major medical condition
The obsession/ worry neural circuitry

3. OCD
30 to 50% of OCD patients have childhood onset, frequently before the age of 10
early-onset more prevalent in boys; associated w/ motor tic disorders, autism, ADHD
age of onset ranges from <10 to adulthood
adult onset OCD peaks in the 20’s & affects more females
unclear whether childhood OCD is a distinct disorder
main treatment for OCD: SSRIs, cognitive behavioral therapy (CBT)

4. Heredity of OCD
50-80% incidence of OCD in monozygotic twins; 20-40% incidence in dizygotic (fraternal) twins
Increased incidence of OCD in relatives
Higher incidence of OCD in 1st degree relatives of patients with Tourette’s syndrome (Stein et al, 2002)

5. Obsessive symptom frequencies observed in OCD patients

6. Compulsive symptom frequencies observed in OCD patients

7. OCD spectrum disorders
Tourette’s syndrome: compulsive movements & utterances; linked to BG dysfunction; treated w/ anti-DA antipsychotics
trichotillomania: hair pulling
body dysmorphic disorder: obsession with one’s appearance
PANDAS (Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections): rare type of OCD occurring in childhood as an autoimmune response to infection

8. Increased glucose consumption in the orbitofrontal cortex in OCD
*frontal lobe activity: involved in directing attention
-Increased activity also observed in the caudate nuclei in OCD
from the National Institute of Mental Health

9. Increased volume in the putamen (BG) in OCD, unlike other anxiety disorders
*decreased vol in ant cingulate gyrus in OCD, PD, & PTSD
Radua et al, 2010

10. Basal ganglia functions
-control of voluntary movements
-procedural learning
-routine behaviors
-action selection: which behavior to perform

11. The theoretical basis for obsessive-compulsive disorder
Figure 1 | The theoretical basis of OCD. An individual with obsessive–compulsive disorder experiences exaggerated concerns about danger, hygiene or harm that result in persistent conscious attention to the perceived threat or threats; in other words, they result in obsessions. In response to the distress and/or anxiety associated with these obsessions, the person acts (that is, performs a behaviour) to neutralize the distress and/or anxiety, which provides temporary relief from the anxiety associated with the obsession. However, this relief leads to reinforcement of the behaviours, leading to repetitive, compulsive behaviour when obsessions recur.
*attempts to neutralize the anxiety ritualistic behavior  relief from anxiety reinforces the behavior
Pauls et al, Nat Rev Neurosci 2014; 15:

12. A working model for OCD: significant gene-environment interaction affecting Glu, 5-HT, & DA
Figure3|Anintegrativemodelofgenetics,environmentandneurobiologyfortheexpressionofOCD. Individuals Nature Reviews | Neuroscience
with obsessive–compulsive disorder (OCD) may be genetically vulnerable to the impact of environmental factors that may trigger modification of the expression of glutamate-, serotonin- and dopamine-system-related genes through epigenetic mechanisms. In turn, neuroanatomical expression of these modifications results in an OCD-specific imbalance between the direct and indirect loops of the cortico–striato–thalamo–cortical (CSTC) circuit. Aberrant activation along the CSTC loop is associated with phenotypic presentation of OCD phenomenology. Although OCD is clinically heterogeneous, it is generally and universally characterized by obsessive concerns about threats or danger and subsequent engagement in rituals to neutralize the threats and/or distress that accompany obsessions. This negative reinforcement cycle, when left untreated, perpetuates OCD psychopathology.
*CSTC loop (Cx-Str-Thal-Cx) imbalance in direct vs. indirect pathways
Pauls et al, Nat Rev Neurosci 2014; 15:

13. Hyperactivity/deregulation in the direct pathway vs
Hyperactivity/deregulation in the direct pathway vs. the indirect pathway in thalamocortical signaling (CSTC loop) in OCD
Figure 2 | The cortico–striato–thalamo–cortical circuitry. dashed lines depict GABAergic (inhibitory) pathways. a | In the normally functioning cortico–striato–thalamo–cortical circuit, glutamatergic signals from the frontal cortex (specifically, the orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC)) lead to excitation in the striatum. Through the so-called direct pathway, striatal activation increases inhibitory GABA signals to the globus pallidus interna (GPi) and the substantia nigra (SNr). This decreases the inhibitory GABA output from the GPi and SNr to the thalamus, resulting in excitatory glutamatergic output from the thalamus to the frontal cortex. This direct pathway is a positive-feedback loop. In an indirect, external loop, the striatum inhibits the globus pallidus externa (GPe), which decreases its inhibition of the subthalamic nucleus (STN). The STN is then free to excite the GPi and SNr and thereby inhibit the thalamus. b | In patients with obsessive– compulsive disorder (OCD), an imbalance between the direct and indirect pathways results in excess tone in the former over the latter.
Pauls et al, Nat Rev Neurosci 2014; 15:

14. In the basal ganglia:
Direct pathway excites Cx,
Indirect pathway inhibits Cx
2) SNc DA projections to STM excite the direct pathway & inhibit the indirect pathway

15. Putative neural circuits of obsessive-compulsive disorder
-reduced 5HT input from raphe nuclei + increased Glu, DA activity  creates
positive feedback loops betw. BG, Thal, & OFC
-feedback loops maintain compulsions
Linden Chapter 13

16. Gene expression in the CSTC circuit in OCD
Central role of the CSTC circuitry in obsessive–compulsive disorder in humans and compulsive–repetitive behaviors in mice. (a) Diagram of a human
brain section (coronal) illustrating a simplified CSTC loop. Right panel, zoom view of the CSTC loop illustrating the intermingled but functionally distinct
‘direct’ and ‘indirect’ projection pathways of the basal ganglia that are thought to exert opposing control over selection of motor behaviors. (b) Diagram
of a mouse brain section (sagittal) illustrating the equivalent CSTC loop in the corresponding rodent brain structures. Abbreviations: CTX, cortex; STR,
striatum; CAU, caudate; PUT, putamen; HIP, hippocampus; THAL, thalamus; STN, sub-thalamic nucleus; SNr, substantia nigra pars reticulata; GPe,
globus pallidus externa; GPi, globus pallidus interna; SC, superior colliculus; BS, brain stem; CB cerebellum. (c) Highly simplified diagram of candidate
OCD gene expression patterns throughout the mouse brain demonstrating extensive overlap of expression in brain regions composing the CSTC
circuitry.
Ting and Feng, Curr Op Neurobiol 2011, 21:842–848

17. The 5HT hypothesis of OCD
Evidence:
All antidepressants (SSRIs) that effectively treat OCD affect serotonin (Westenberg et al, 2007)
-Mechanism is unclear
2) 5HT2A receptor levels are increased in OCD caudate, and decrease after SSRI treatment (Adams et al, Int. J Neuropsychopharm 2005)
Acute depletion of Trp (5HT precursor) can increase anxiety & compulsive behaviors (Bell et al, 2001)
Decreased levels of 5HT in platelets following clomipramine treatment correlates w/ improved health (Westenberg et al, 2007)
Higher levels of 5HT in blood have been associated w/ improvement following SSRI treatment (Delorme et al, 2004)

18. Reduced 5-HT transporters in OCD patient midbrain
Stengler-Wenzke et al, Eur Arch Psych Clin Neurosci 2004

19. SSRIs, clomipramine (TCA): 5HT inhibitors for treating OCD

20. Dopamine and OCD
Approx. 40% of OCD patients do not respond to SSRI treatment
DA agonists (eg. apomorphine) can exacerbate OCD symptoms
Antipsychotics with SSRIs further reduce OCD symptoms (Stein et al, 2002)
DAT1, DRD3 may be associated with OCD (GWAS)

21. Compulsive lever-pressing in rats is diminished with SCH 23390
Rationale: D1 receptor blocker will increase the indirect pathway in the basal ganglia (which inhibits the excitatory pathway)

22. Glu and OCD
Prefrontal cortex: hyperglutamatergic state
Increased Glu in caudate, which decreases after paroxetine treatment
OCD patients have increased Glu levels in CSF (Chakrabarty et al, 2005)
SLC1A1 (EAAT3 Glu transporter) is associated with OCD (Arnold et al, 2006)

23. SLITRK5: human OCD gene regulating AMPA, NMDARs
-single-pass TM domain protein similar to Slit (axon guidance) and NTrk
-human genetic analysis identified SLITRK5 association w/ Tourette’s syndrome
-Slitrk5 -/- mice: overgroom, anxious, decreased corticostriatal transmission

24. Inactivation of the Slitrk5 gene results in excessive self-grooming and anxiety
Shmelkov et al, Nat Med 2010; 16(5):

25. Decreased levels of AMPAR, NMDAR in the striatum, decreased dendritic arbor of MSNs & lower corticostriatal transmission in Slitrk5 -/- mice
mice had decreased striatal volume, & elevated FosB (neuronal activation) levels in the OFC
Shmelkov et al, Nat Med 2010; 16(5):

26. 5HT receptor polymorphisms and OCD
Gene encoding 5HT2A receptor: alleles of promoter region (-1438 A/G) and coding region (T102C) associated w/ OCD
5HT2C receptor: Variant Cys-Ser aa 23 of N-terminal region
5HT1Dβ autoreceptor: G861C variant may affect disease severity
TPH (5HT synthesis) enzyme: TPH2 implicated in early-onset OCD (Chamberlain et al, 2005; Hemmings et al, 2006)

27. SSRI can rescue hyperactivation of the corticostriatal pathway in mice
A mouse optogenetic model stimulating OFC projections in the striatum was generated (Ahmari et al, 2013)
Mice developed excessive grooming in response to light-activated stimulation of OFC neuron terminals in the striatum
Excessive grooming, increased neural firing was suppressed by fluoxetine treatment

28. Activation of the OFC-striatal circuit triggers excessive grooming
injected AAV into the ventromedial OFC; implanted fiber-optic stimulator into ventromedial STM to stimulate terminals from OFC
Ahmari et al, Science 2013; 340:

29. SSRI inhibitor reduced excessive grooming and firing rate in OFC- ChR2 stimulated mice
Ahmari et al, Science 2013; 340:

30. Sapap3, Glu transmission, and OCD
Sapap3: postsynaptic scaffolding protein that interacts with PSD95 & Shank at excitatory synapses
Welch et al (2007) found strong expression in the striatum
Knockout mice had high levels of anxiety, and pulled out their fur due to excessive grooming (formed lesions)
Re-expression of a Sapap3 transgene in the striatum of knockouts rescued the phenotype
Administration of fluoxetine SSRI ameliorated the phenotype

31. Excessive grooming observed in Sapap3 (Dlgap3) -/- mice
Welch et al, Nature 2007; 448:

32. Sapap3-/- mice have reduction of NR2A & increased NR1, NR2B
*striatal PSD extracts
Sapap3: functions in corticostriatal pathway to maintain NMDAR
Welch et al, Nature 2007; 448:

33. Conclusions
No single model fits all aspects of OCD
CSTC loop: the primary pathology & common pathway in OCD
Genetic vulnerability to striatal damage by autoimmunity
5HT modulation is important to treatment

34. Model of neuropathology of OCD