Neurobiology of Obsessive Compulsive Disorder: focus on Neuroimaging

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Neurobiology of Obsessive Compulsive
Disorderfocus on Neuroimaging

• Prof. Antonio Vita
• University of Brescia

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Structural alterations
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Early studies of caudate nucleus morphometry in
OCD
Author Year n.pts/ctrls Results
Scarone et al 1992 20/16 Right C increase
Robinson et al 1995 26/26 Bilateral C decrease
Jenike et al 1996 10/10 Trend RgtL
Aylward et al 1997 24/21 No differences
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Patients with OCD had significantly reduced
bilateral orbital frontal and amygdala volumes
compared with healthy comparison subjects
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Reduced left orbitofrontal cortex in OCD patients
correlates with severity of symptoms
Kang, et al., 2004, J Neuropsychiatry Clin
Neurosci
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Alterations in the anterior cingulate and globus
pallidus
Drug-naïve patients
Szeszko et al., Am J Psychiatry 2004
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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
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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
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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
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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
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Altered function of the cortico-striatal-thalamo-c
ortical loop
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OCD PATIENTS HAVE INCREASED ACTIVITY IN
ORBITOFRONTAL CORTEX, CAUDATE AND ANTERIOR
CINGULATE CORTEX
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Overactivity of prefrontal-basal ganglia loops
Baxter et al., 1998
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Increased activity in the thalamus
Saxena et al., Biol Psychiatry, 2001
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Aree cerebrali coinvolte nellOCD
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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

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Hyperactivity is exacerbated during symptom
provocation Breiter 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

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Activation in the orbitofrontal cortex and
amygdala during symptom provocation
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(Shapira et al, 2003)
Iperattivazione cortico-sottocorticale rispetto a
volontari sani
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Injury-induced OCD
12-year-old female, struck by car Max et al. 1995
Chako et al., 2004
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Alterations in other cognitive/emotional processes
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Activation of the anterior cingulate when errors
are committed on a cognitive task in OCD patients
Ursu et al., Psychol Sci, 2003
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Cognitive Alterations

• Memory (working memory)
• Set shifting
• Response inhibition (more errors of commission)

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Dysfunction of inhibitory processing
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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

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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
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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

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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
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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
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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.
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Neurochemical alterations
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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

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Serotonin modulates the prefrontal cortex,
striatum, and thalamus
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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

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Reduced 5-HT transporters in midbrain
Stengler-Wenzke et al., Eur Arch Psychiatr Clin
Neurosci, 2004
No depression No psychotropic drug use for 6
months
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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 Tourettes and OCD (up to 90 of
  individuals with Tourettes have OCD)
• Adjunctive therapy with conventional
  antipsychotics add to reduction of OCD symptoms
  in individuals treated with SSRIs

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Increased striatal DA transporters in
psychotropic-naïve OCD patients
Van der Wee, et al., Am J Psychiatry 2004
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Alterations in striatal D2 receptors
Denys, et al. 2004 Biol Psychiatry
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Treatments
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Treatments

• SSRIs
• Adjunctive antipsychotics (dopamine antagonists)
• Behavior therapy
• Psychosurgery

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Normalization of orbitofrontal cortex activation
Saxena et al., 1999
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Can imaging help predict treatment efficacy?
Overactivation of right orbitofrontal cortex and
bilateral thalamus predicts effectiveness of
adjunctive neuroleptics
Overactivation of right caudate predicts
effectiveness of SSRIs
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Behavioral treatment is effective
Limitations no controls
Nakatani, et al. 2003
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PET scans of OCD patients
OCD, pre-behavior therapy
OCD, pre-drug treatment
OCD, post-behavior therapy
OCD, post-drug treatment
Behavior- or drug therapy produce similar
reductions in the activity of the basal ganglia
From Baxter et al., Arch Gen Psychiatry, 1992
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PSYCHOTHERAPHY EFFECTS IN OCD
Studies of cognitive behavioural therapy (CBT)
effects in obsessive-compulsive disorder (OCD)
were consistent in showing decreased
metabolism in the right caudate nucleus
(Linden, Mol Psychiatry 2006)
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• STUDY DESIGN
• Using functional magnetic resonance imaging
  (fMRI), brain activation to spider videos was
  measured in 28 spider phobic and 14 healthy
  control subjects
• Phobics were randomly assigned to a therapy-
  group (TG) and a waiting-list control group (WG)
• Both groups of phobics were scanned twice
• Between scanning sessions, CBT was given to the
  TG

(Straube et al., Neuroimage 2006)
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Increased activation of ACC and insula to spider
vs. control videos in phobic subjects (PS)
compared to control subjects (CS) during the
first scanning session
(Straube et al., Neuroimage 2006)
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Increased activation of ACC and insula to spider
vs. control videos in the waiting-list group
(WG) compared to the therapy group (TG) during
the second but not the first scanning session.
(Straube et al., Neuroimage 2006)
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A PROTON MRSI STUDY OF BRAIN N-ACETYLASPARTATE
LEVEL AFTER 12 WEEKS OF CITALOPRAM TREATMENT IN
DRUG-NAIVE PATIENTS WITH OBSESSIVE-COMPULSIVE
DISORDER

• MATERIALS AND METHOD
• Thirteen drug-naive OCD patients and 13 age- and
  sex-matched healthy comparison subjects were
  included in this study.
• N-acetylaspartate levels (obtained from ratios
  of N-acetylaspartate with creatine, choline, and
  creatine plus choline) in the prefrontal cortex,
  parietal cortex, anterior cingulate, posterior
  cingulate, frontal white matter, and parietal
  white matter were measured by 1H-MRSI.
• In OCD patients, measurements were taken before
  and after 12 weeks of citalopram treatment.
• Correlations between N-acetylaspartate
  concentrations in regions of interest and
  clinical measures were also assessed.

(Joon et al., Am J Psychiatry 2006)
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A PROTON MRSI STUDY OF BRAIN N-ACETYLASPARTATE
LEVEL AFTER 12 WEEKS OF CITALOPRAM TREATMENT IN
DRUG-NAIVE PATIENTS WITH OBSESSIVE-COMPULSIVE
DISORDER
aSignificant difference between patients with OCD
and comparison subjects (plt0.05) bSignificant
difference between pretreatment and posttreatment
in patients with OCD (plt0.05)
(Joon et al., Am J Psychiatry 2006)
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A PROTON MRSI STUDY OF BRAIN N-ACETYLASPARTATE
LEVEL AFTER 12 WEEKS OF CITALOPRAM TREATMENT IN
DRUG-NAIVE PATIENTS WITH OBSESSIVE-COMPULSIVE
DISORDER
N-Acetylaspartate/Creatine Ratios in the
Prefrontal Cortex and Frontal White Matter of
Patients OCD Before and After 12 Weeks of
Citalopram Treatment
(Joon et al., Am J Psychiatry 2006)
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Psychosurgeries Destroy connections between the
frontal lobe and basal ganglia/limbic structures
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Psychosurgery Success

• 27 definite improvement, 27 probably
  improvement, 46 no improvement (Baer et al,
  1995)
• 32 definite improvement, 14 partial
  improvement, 54 no improvement (Dougherty et al,
  2002)

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Psychosurgeries
Deep Brain Stimulation
1. The surgeon inserts wires through the skull
and into capsule. 2. Wires are permanent and
attached to battery pack implanted in chest. 3.
Battery produces adjustable fre- quencies that
have same effects as the other surgeries.
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