Lecture 1: Panic Disorder and OCD Flashcards

1
Q

Anxiety Disorder and Obsessive-Compulsive Disorder

How much do we know?

A

*The answer for MDD is shit, BPD is shitter
and anxiety, and OCD are even worse. We
do not know what happens in the brain or
what causes it! The biochemistry, cognitive,
and neuroscience is abysmal, but we have
an okay psychological understanding of its
behavioural manifestation.

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2
Q

Anxiety Disorder definition

A

• Anxiety disorders share symptoms of
feelings of excessive fear, anxiety, and
changes in behavior
• fear = the emotional response to real or
perceived imminent threat” (both illicit the
same level of fear; physiological symptoms
of fear such as increased heart rate,
adrenaline, sweating, hard to breath etc.
during presentation and when see a lion
are the same)
• anxiety = anticipation of future threat

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3
Q

8 Anxiety Disorder Types

A

• Separation anxiety disorder (anxiety when
separated from loved one)
• Selective mutism
• Specific phobia (spider, clowns, snakes,
heights, hole s – irrational fear to things that
rationally could cause harm)
• Social anxiety disorder (i.e., fear of being
judged, not worthy, crowds etc.)
• Panic disorder & OCD (today’s lecture)
• Agoraphobia (don’t leave home)
• GAD (generalized anxiety disorder, anxious
about everything)
• Substance/medication-induced anxiety
disorder
• Anxiety disorders are distinguished by
developmental factors as well as the
situations that induce fear, anxiety, and
avoidant behaviors

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4
Q

Does Worrying Affect Mortality Risk?

A

• Gale et al. (date) examined the association
between neuroticism & mortality, and the
moderating influence of self-rated health.
• Neuroticism – the tendency to experience
negative emotions.
• Results revealed:
o higher neuroticism was associated with 6%
increase in mortality risk
o neuroticism scores tended to be lower with
increasing age
o neuroticism scores were positively
correlated with smoking and drinking
alcohol daily or nearly daily
o among people who rated their health as
poor or fair, higher neuroticism was
associated with a reduced mortality from
all causes, but such effect was not
observed in participants with excellent self-
rated health.
• Therefore, certain personality facets of
neuroticism may actually serve as a
protective factor against death
• Does Excessive Worrying Affect Mortality
Risk?
o Yes and no. it depends on your neuroticism
(high/low, what it’s linked to)
o If you are neurotic about your appearance
or body weight it can have beneficial
impacts and healthy lifestyles. Other forms
can negatively impact, psychological fear
creates physiological stress on heart/lungs
etc. which led to increased mortality risk.

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5
Q

Panic Disorder is characterized by… peaks within.. for these symptoms

A

• Characterized by the presence of recurrent
and unexpected panic attacks
(distinguishing feature)
• Panic attack is “an abrupt surge of intense
fear or intense discomfort that reaches a
peak within minutes and during which time
four or more additional symptoms occur”
• Additional symptoms include:
o Increased heart rate or palpitations
o Sweating
o Trembling (legs, hands, body)
o Chest discomfort (tightness, trouble
breathing, hyperventilating)
o Dizziness
o Fear of losing control
o Fear of dying
• Individuals with panic disorder worry about
additional panic attacks occurring and
substantially alter their behaviour to try to
avoid experiencing another panic attack.
• The frequency and severity of panic attacks
vary widely among individuals.
• Panic attacks hit you like a freight train, the
uncontrollable fear is debilitating, people
feel like they’re dying and pass out.
• No trigger required
• In most cases, the adaptive response to a
fearful stimulus (i.e., snake) would be to
away from it (flight response). A panic attack
is somewhere in between a fight or flight
response, if you have a panic attack in class
(in his example I don’t fully agree with) you
wouldn’t leave or attack the snake, you will
freeze and collapse in fear

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6
Q

Panic Disorder Stats

A

• In the United States the rate is between 2-
3%
• The disorder occurs more often in females
than males with a ratio of approximately 2:1
• Higher rates are found among
postmenopausal women
• Median age of onset between 20 and 24
years (i.e., between adolescence and
adulthood)

*hints to the role of hormones in panic
disorder

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7
Q

Multicultural Findings

A

• African Americans, Latinos, and Asian
Americans have reported lower rates of
panic disorder compared to non-Latino
whites
• Higher rates of panic disorder among gay,
lesbian, and bisexual adults in the United
States (i.e., similar to MDD where
environmental factors of bullying)
• European countries report similar prevalence
rates as the USA, while lower rates have
been reported in Latin America, Asia, Africa,
and India

*Again, we see that the prevalence is lower in
ethnic minorities than whites. Is this
biological, low ses or cultural differences in
presentation/understanding of disease, or
access to health care?
*Cultural, genetic, environmental factors!

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8
Q

Comorbidity

Panic disorder

A
• Commonly cooccurs with other 
  clinical/psychiatric:
o	GAD
o	Simple phobias
o	Social phobia
o	Substance abuse (drink to cope with 
        anxiety)
o	Major depressive disorder
o	Bipolar disorder 
• Commonly cooccurs with chronic medical 
   conditions:
o	Cardiovascular disease
o	Hypertension
o	Pulmonary disease
o	Lipid disorders
o	Asthma

*Panic attacks rarely occur in isolation. They
are usually tied to another condition.
*Psychological disorders associated with
panic attacks and their negative
physiological issues.

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9
Q

(3) Genetic Study Types

A

• Genetic linkage studies search for
chromosomal locations (“marker loci”)
where disease genes may be found. Aim to
determine whether specific chromosomal
regions in individuals with disease have
specific DNA markers relative to those
without the disorder.
• Candidate gene studies then explore how
specific genes and mutation(s) may be
involved in the etiology of clinical disorder
• Genome-wide association studies (GWAS)
use a specific statistical approach to scan
complete sets of DNA (genomes) of
thousands of people across all
chromosomes simultaneously to find
genetic variations associated with clinical
disorder

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10
Q

Heritability: Family and Twin Findings

Panic disorder

A

• Heritability estimates in female twins
between 20-30%
• 20 monozygotic and 29 dizygotic twins
o Panic disorder in monozygotic twins
relative to dizygotic twins is 2:1
• Population-based lifetime rates of panic
disorder range from 1.2 - 2.4 (out of 100),
while lifetime rates for first-degree relatives
of those with panic disorder were
substantially higher 7.7 – 20.5 (out of 100)
• Genetic factors likely contribute to the
development of panic disorder (highly
genetic; 0.48)

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11
Q

Linkage Studies and Candidate Genes

A

• Genetic linkage studies search for
chromosomal locations (“marker loci”)
where disease genes may be found. Aim to
determine whether specific chromosomal
regions in individuals with disease have
specific DNA markers relative to those
without the disorder.
• Susceptibility genes involve chromosomes
2, 4, 7, 10, 13, 15, 17, and 18
• Mixed findings, those that found no link
between single nucleotide polymorphisms
(SNPs) suggest that linkage studies are not
sensitive enough to capture the small
genetic effects which underlie complex
disorders like panic disorder.
• To date, linkage studies have not supported
main effects of and particular gene or
combination of genes on the development
of panic disorder. However, given that
heritability data do suggest that genetic
factors are involved it is likely that genetic
contributions to the disorder are complex.

*We know genes are involved but we have
not identified one anxiety gene, multiple are
involved and likely interact

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12
Q

Candidate Genes (try to identify specific genes) and Genome-Wide Association Studies

A

• Candidate gene studies then explore how
specific genes, polymorphisms and
mutation(s) may be involved in the etiology
of panic disorder. Identify genes piori that
may be linked to PD and compare patients
to healthy controls to see if they are
present.
• Candidate gene studies have focused on
genes involved in neurotransmission.
Specifically, genes that play a role in the:
o Production of enzymes that breakdown
neurotransmitters, particularly
catecholamines
o Functioning of pre- and postsynaptic
neurotransmitter receptors (e.g., serotonin,
norepinephrine, dopamine; release or
binding to receptors)
o Production and functioning of
neuromodulators, all have been the target
of candidate gene studies

*Abnormal release or binding of
neurotransmitters between pre to post-synaptic neuron create neurotransmitter
imbalances and result in mental disorders.
*We can look at the genes linked to the
production of, receptors they bind to or
enzymes that break them down of serotonin,
norepinephrine, dopamine
neurotransmitters. We know to look at these
specific molecules because treatments of
antipsychotics or SSRIs which target
them have successfully treated panic
disorders.
*Look at genes to find the answer, best
approach we have. The problem with this
logic is that the process of neurotransmitter
release/reuptake is not a linear system; a
small change in neurotransmitter can have a
large effect on adrenaline, we will never
fully. Understand each piece of the puzzle,
just a wider picture of what is happens. We
can treat with medication but do not
understand the biochemistry or
consequences of it in the brain.

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13
Q

Catechol-O-methyltransferase (COMT) Gene

A

• Genes involved in the regulation of the
catecholaminergic system have been
investigated because the somatic
symptoms of anxiety are closely linked to
the activation of the sympathetic nervous
system and release of catecholamines (i.e.,
COMT polymorphisms like Val158Met).
• Enzyme that breaks down catecholamines
and, if over or underactive, can lead to
dysfunction of neurotransmitter systems
such as dopamine, norepinephrine, and
serotonin
• Implicated in panic disorder
• Mixed findings in Val158Met (i.e., some
show it is increased in women with PD and
not men, found in 19.6% of those with PD
and 2.2% of HCs, found no association
between Val158Met and PD, Val158Met
only linked to PD in Caucasian females
only)
• COMT Val158Met polymorphism may be a
vulnerability factor in select populations
only.
• It has been postulated that COMT
Val158Met polymorphism is linked to PD is
that it affects dopaminergic functioning in
the limbic and prefrontal regions resulting
in increased activation in response to
unpleasant stimuli
• COMT Val158Met polymorphism has been
implicated in other clinical disorders such
as ADHD, OCD, Schizophrenia, Bipolar
Disorder, and Substance Use Disorder.
COMT Val158Met polymorphism has shown
to vary by gender and ethnicity.

Reduce dopamine in pfc and amygdala

*the role of COMT Val158Met polymorphism
in Panic Disorder remains uncertain.

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14
Q

Serotonin Transporter Gene and Serotonin Receptor Gene

A

• Serotonin transporter (5-HTT) is encoded
by the SLC6A4 gene which effects the
availability of the serotonin transporter
protein.
• SLC6A4 mutations effect the level of
serotonin available in the extracellular fluid
• No significant difference in frequencies of
the SLC6A4 gene PD patients
• However, preliminary findings show
decreased 5-HT1A binding in untreated PD
patients and 5-HT1A polymorphisms and
PD. 5-HT1A polymorphisms have also been
linked to other clinical disorders.

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15
Q

Adenosine 2A receptor gene (ADORA2A - variant of Adenosine 2A receptor gene)

Panic Disorder

A

• Adenosine are released by neurons and
glial cells and serves as a neuromodulation
that increases neuronal inhibition, and
activate neurons in pathways involved in
anxiety
• Overrepresentation of a particular
polymorphism of the ADORA2A gene in
patients with panic disorder (rs5751876)
• ADORA2A polymorphisms also linked to
personality traits such as harm avoidance in
PD relative to controls.
• Adenosine gene variants and are not
unique to panic disorder, also linked to ASD
• Adenosine – i.e., increases inhibition
meaning it has a calming effect, better able
to control emotions and stop panic attack.
Doing studies with mice to see if modifying
receptor genes, mutating ADORA2A gene
to induce anxiety symptoms in mice and
show its role in PD.

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16
Q

Additional Candidate Genes

A

• Other candidate genes researched include:
BDNF, dopamine transporters, dopamine
receptors, cholecystokinin receptors, and
norepinephrine transporters and receptors.
• Only a few of the polymorphisms were
associated with panic disorder in a
subgroup of the population.
• Meta-analysis showed only three gene
variants were associated with panic
disorder indicating it “likely involves genetic
variation in a multitude of biological
pathways that is diverse among
populations”
• Despite evidence that panic disorder has a
strong family heredity component the
genetic factors remained obscure.
• Genome-wide studies looking at nucleotide
polymorphisms found no significant
relationship with panic disorder.
• likely due to methodological variables,
sample size, comorbidity, severity of
symptoms, heterogeneity of symptoms, low
statistical power, and not including
environmental-gene interactions all linked
to inconsistent findings.

*Not a single gene, mixed findings on which
genes are involved, multiple and interactive
effects = it’s complicated and we don’t know
*Gene-environment interaction as well *We know this drug works, not sure why, but
still use it

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17
Q

Can Panic Attacks Be Provoked?

A

• Due to panic attacks spontaneous nature it
is hard to study them as they naturally
occur.
• Research indicates that substances can
induce panic-like symptoms, including
recreational drugs such as cocaine and
ecstasy and medications such as asthma
medications and prescription stimulants
• The synthetic neuropeptide (CCK-4) and
CCK receptor agonists (Pentagastrin) can
provoke anxiety symptoms in humans that
closely resemble spontaneously occurring
panic attacks
• CCK is a neuropeptide that plays a critical
role in anxiety-related behaviours in PD
• CCk-4 induced panic in majority of PD
patients and not HCs
• Panic attacks have been observed during
fMRI, revealing increased activation in the
amygdala, and left temporal gyrus
• rsFC changes in HCs as a result of
chemically induced panic attacks linked to
increased rsFC in the limbic system, anterior
cingulate gyrus, the claustrum-insular-
amygdala region, and the cerebella vermis
with concomitant reductions in blood flow in
the frontal regions.
• Collectively, these findings support that
distinct physiologic changes occur during
panic episodes and support involvement of
limbic and prefrontal regions

*Still genes but more into biochemistry. Can
panic attacks be induced/triggered by
drugs? This would allow us to do
neuroimaging during one to see what
happens, before, during and after in the
brain. Very useful information but it has an
impact on physiology outside the
brain (breathing and heart rate). This can
bias the findings if the neuroimaging method
uses a voltage signal (i.e., fMRI).
*Increasing heart rate confounds and makes
neuroimaging study findings useless if it
measure voltage
*So far, genes are a complicated approach,
giving drugs and measuring brain activity is
not going to work, the last approach is
environmental by putting someone in an
fMRI and show scary images then measure
brain activity (best controlled measure of PD)

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18
Q

Brain structures involved in PD

A
  • Hippocampus
  • Amygdala
  • Temporal gyrus
  • Anterior cingulate
  • Cerebellum
  • Frontal and temporal lobes
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19
Q

Structure

A

• Reduced volume (~9%) of the temporal
lobes (most common but the specific
structure in the temporal lobe linked to PD
remain unknown)
• Smaller amygdala volume (emotion
regulation and threat detection)
• Volume reductions in the insula (automatic
sympathetic nervous system function) and
basal ganglia (motor control, executive
functioning, emotion)
• Additional research is needed!

reading: some studies show enlarged ventricles in patients with PD relative to controls, but this is not specific to PD it is also seen in other clinical disorders.

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20
Q

Gray and White Matter Findings

A

• Differences in gray matter volume in limbic
structures including the
o Amygdala
o Hippocampus
o Basal ganglia
o Pituitary
o Frontal, cingulate and temporal cortical
areas
o Midbrain and pons
• Gray matter reductions in the right inferior
frontal gyrus and right insula in participants
with panic disorder (studied could
differentiate between PD and MDD to by
different gray matter reduction patterns)

Reading: Na et al. (2013) found gray matter reduction in the orbital frontal region in PD patients with and without agoraphobia to healthy controls and found reduced volume of orbital frontal gyrus in only in in PD patients with agoraphobia. Shang et al. (2014) compared PD with other anxiety disorders and found reduced volume in the right anterior cingulate and left frontal gyrus which is consistent with neuroanatomical models of physiological fear responses. These findings support the role of the anterior cingulate and prefrontal cortex in mediating anxiety symptoms, but the specific pathways remain unclear. similar gray matter reductions have been found in conduct disorder and autism.

*This describes most of the brain. How is this
helpful? Is the whole brain broken? How can
I fix it with this shit, too complex needs to be
simplified.
*Grey–cell bodies

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21
Q

White Matter Findings

Panic Disorder

A

• Significant volumetric reductions in
widespread white matter regions including
fronto-limbic, thalamo-cortical, and
cerebellar pathways
• The degree of white matter alterations is
associated with self-reported anxiety
sensitivity and avoidance behaviours in PD
relative to HCs
• more research is needed with larger sample
sizes, HCs and clinical comparisons.
• white matter volume reduction in temporal
lobe and hippocampus is linked to other
clinical disorders (BD & PTSD) and aging.

*White – myeline, interneuron connectivity,
transduction of signal
*Structural changes in PD: gray matter
reduction In most brain regions and
reduced brain region interconnectivity
(white matter)

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22
Q

Functional Findings

A

• Unprovoked panic attacks often occur at
random and are therefore difficult to
capture
• Provocation of panic attacks often leads to
hyperventilation and vasoconstriction,
which may obfuscate blood flow changes in
the brain
• patients with PD may be more sensitive to
panic inducing substances
• the experience of being in a scanner may
influence glucose metabolism, blood flow,
and medication effects the brain
• reduced cerebral blood flow in temporal
regions in patients with PD was negatively
correlated with severity and duration of
illness.
• compared to patients with OCD, patients
with PD did not have reduced cerebral
blood flow in caudate.
• Thus, functional neuroimaging studies of
panic disorder are difficult and findings
should be interpreted with these
methodological issues in mind.

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23
Q

Resting States

PD

A

• At rest, those with panic disorder tend to
display increased activation in the
hippocampal and frontal regions relative to
control participants and decreased
activation in the anterior cingulate gyrus,
amygdala, parietal, and temporal lobe
regions
• These findings suggest differential patterns
of brain activation may exist in patients with
panic disorder compared to healthy
controls

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24
Q

Activity States During Cognitive Tasks

A

• Looking at functional differences while
exposed to visual images (i.e., neutral vs
emotional/threatening) or during cognitive,
motor or sensory tasks.
• Activations patterns of patients with and
without panic disorder in response to neutral
and disorder-related (threatening) visual
images
o Participants with panic disorder display
greater activation to disorder-related
images compared to neutral scenes in
several brain regions, including the brain
stem, insula, thalamus amygdala, and
cingulate cortex; most studies reports
differences in patterns of activation in some
but not all of these structures.
o Together these studies suggest that
patients with panic disorder have a
heightened sensitivity to anxiety-provoking
stimuli that is characterized by increased
neuronal activity in subcortical, limbic, and
frontal regions
• PD’s have heightened awareness of
emotion-specific stimuli and interoceptive
stimuli (i.e., internal bodily sensations)
• Participants with panic disorder, specific
phobia or PTSD have the same activation
patterns in response to fearful stimuli with
greater activation in the left amygdala and
reduced activation in the ventromedial
prefrontal cortex but these are characteristic
of all anxiety disorders and not just panic
disorder.

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25
``` Motor control (basal ganglia) Panic Disorder ```
• Basal ganglia studied due to increase in bilateral and reduced cortical activation in healthy controls in response to fearful stimuli. • During motor tasks PD patients show reduced activation of the putamen (part of the basal ganglia) during motor tasks • Basal ganglia transform incoming sensory information into motor movement. • Deep brain stimulation of the basal ganglia triggers panic attacks in patients without panic disorder
26
Sensory Processing | Panic Disorder
• Auditory task: o Participants with panic disorder showed reduced glucose metabolism (activity decreases) in the left parietal lobe and Increases in the orbital frontal cortex • Word fluency production (cognitive task): o Participants with panic disorder show reduced activation of the prefrontal cortex • Olfaction task: o Participants with PD show different activation patterns in the amygdala, thalamus, prefrontal regions, and anterior cingulate. • Collectively, findings from motor and sensory tasks support differences in activation responses in participants with panic disorder relative to controls
27
Summary
• Differential activation patterns at rest and during cognitive, sensory, and motor tasks • Reduced gray matter • Altered white matter connectivity • Decreased and increased neuronal activation in pathways extending from the amygdala and hippocampal regions to the frontal cortex • These findings support theoretical models of panic disorder and anxiety models *All correlational findings, and mixed, we still do not know the cause of PD! *Findings do not reveal the cause of the functional differences between those with and without panic
28
Anxiety Models
A single, universally accepted structural and functional theory explaining panic disorder DOES NOT exist. However, some models have been proposed
29
Model #1
• Emphasises the role of the “fear network”: prefrontal cortex, brain stem, amygdala, hippocampus, thalamus, hypothalamus, periaqueductal gray, and locus cerulues in anxiety disorders. • Panic occurs due to deficit exists in “relay and coordination of upstream (cortical) and downstream (brain stem) sensory information, which results in heightened amygdala activity with resultant behavioral, autonomic, and neuroendocrine activation (nervous system controling heart rate etc. and stress hormones) o Participants with PD have a lower threshold for activating the “fear network”, this hyperactive activation leads to stimulation of the autonomic and neuroendocrine systems (projection from the amygdala to the brain stem and hypothalamus). Stimulation of the automatic sympathetic nervous system and neuroendocrine systems result in physiological symptoms. § Heart rate § Stress hormones § Release of norepinephrine § Increased blood pressure o Meanwhile, the prefrontal cortex receives this sensory input from the limbic system and processes it. Faulty processing results in the interoceptive (bodily sensations) being misinterpreted and excitatory projections being sent to the amygdala and other limbic structures heightening the fear response = panic. Reading: patients with panic disorder have heightened elevated plasma levels of norepinephrine. Panic disorder is highly familial and environmental factors, such as early childhood trauma and disruptions in parent-infant attachment, increase the risk of developing the disorder. Specifically, PD patients inherit a CNS which is overly sensitive to fear, the degree of sensitivity will vary among people. This model doesn’t address the HPA axis.
30
Model #2
• Hypo-thalamic-pituitary-adrenal axis (HPA) o The HPA axis is involved in the stress response and the release of stress-related hormones such as corticotropin-releasing factor (CRF) § CRF increases the release of norepinephrine as well as other peptides and steroids • Antidepressants are hypothesized to normalize functioning of a hyperactive hypothalamic-pituitary-adrenal system in panic disorder • The symptoms of panic disorder are similar to those with hyperthyroidism, there is a high rate of comorbidity between hyperthyroidism and anxiety.
31
Summary
• Theoretical models of anxiety emphasise the role of the brain stem, cortex, and subcortical structures in the pathophysiology of anxiety disorder. • At the level of the brain stem and subcortical structures: o Physiologic alterations result in a hyperactive “fear network” that triggers stimulation of sympathetic nervous system and neuroendocrine systems • At the level of the cortex: o Misinterpretation of interoceptive signals leads to misperceptions of danger that further stimulates the “fear network” leading to physiologic symptoms of panic *Communication between neurons and pathways between the subcortical and cortical regions of the brain occur via neurotransmission.
32
Neurotransmitters
``` • Most major neurotransmitter systems have been implicated in panic disorder o Serotonin o GABA o Dopamine o Norepinephrine o Glutamate ```
33
Serotonin | Panic Disorder
Serotonin • Implicated in panic disorder due to the efficacy of antidepressants in reducing anxiety symptoms o Tricyclics o Monoamine oxidase inhibitors o SSRIs (most efficient – reduce anxiety symptoms without dependency, and have limited side effects) o SNRIs Serotonin • Brain serotonin turnover is increased approximately fourfold in subcortical brain regions and in the cerebral cortex in participants with panic disorder • Serotonin turnover is highest in participants with the most severe symptoms and significantly reduced with treatment of SSRIs. • Lower rCBF have been found in women with PD In the temporal cortex, and increased significant following treatment with a serotonin agonist. • These findings show that serotonin increases may modulate an underlying functional pathology of the serotonergic system in patients with panic disorder • SSRIs (serotonin agonists) showed a dramatic reduction in panic attack frequency but no difference was fund with serotonin antagonists. Serotonin • The specific role that serotonin plays in panic disorder is unclear, possibly the serotonin pre and postsynaptic receptors (5-HT1A) are implicated o Lower density of serotonin receptors in several brain regions § Anterior and posterior cingulate cortex § Orbitofrontal cortex § Temporal cortex § Amygdala § Raphe nuclei Serotonin • Decreased binding of the serotonin transporter in the thalamus and hippocampus, and increased serotonin transporter (SERT) binding in the rephe nuclei and several other cortical areas in patients with PD. • Gender differences in SERT are present with women having higher levels of serotonin transporter (SERT) binding than males in several brain regions, including the hippocampus • Differences in serotonin receptor expression and functioning exists between healthy males and females, and may also be implicated in the higher rate of panic disorder among females than males
34
Dopamine and Norepinephrine
Dopamine and Norepinephrine • Dopamine has been studied in PD because: o Norepinephrine is biosynthesized from dopamine o Dopamine agonists have been found to produce panic symptoms o Dopamine antagonists have been found to extinguish conditioned fear responses in mice o Plasma dopamine levels tend to be higher in patients prior to antidepressant treatment and may normalize following treatment • However, norepinephrine typically is the primary focus Dopamine and Norepinephrine • Norepinephrine is focused on in PD due to its known effects on the nervous system “fight or flight” response that results in increased arousal, vigilance, heart rate, and blood pressure • Serotonin and norepinephrine systems function interactively (abnormality in their interaction may result in anxiety pathology i.e., serotonergic neurons project from the raphe nuclei to the locus coeruleus and have an inhibitory effect on neurons. The locus coeruleus is rich in norepinephrine- releasing neurons which project into the midbrain and forebrain to modulate fear and anxiety responses. They can have an excitatory effect resulting in increased heart rate and blood pressure) • Consequently, factors that disrupt the homeostasis of the serotonin system can affect norepinephrine neurotransmitter system and result in symptomatic behaviour such as panic.
35
SSRIs | Panic Disoder
• SSRIs alter both serotonin and norepinephrine cerebral spinal fluid metabolite levels and lead to symptom improvement o When serotonin activity and availability is increased by SSRIs, norepinephrine receptors activity decreases § Symptoms of panic disorder are decreased • SSRIs decrease the release of stress- related hormones (cortisol) from the hypothalamus and adrenal gland, thereby decreasing heart rate, blood pressure, … • SSRIs modulate the effects of glutamate, by decreasing their excitatory effects in the amygdala, hypothalamus and brain stem to mitigate anxiety symptoms.
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GABA
• The locus coeruleus contains cells which also release neuropeptides and other neurotransmitters such as GABA. • Benzodiazepines, which act on GABA receptors, improve anxiety symptoms and are used in the treatment of panic disorder o In a study, individuals who experienced panic attacks and were being treated for alcohol or drug abuse, used alcohol—a GABA agonist—to self-medicate their attacks, described this method as effective at reducing or preventing panic attacks • Benzodiazepines are also effective at reducing panic symptoms by enhancing GABA transmission
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Pharmacological Intervention
• The primary treatment approach for anxiety disorders is pharmacological o SSRIs (Prozac, Paxil, Zoloft) ----- Preferred treatment o SNRIs (Venlafaxine, Effexor) o Tricyclic antidepressants (Anafranil, Tofranil) o MAOIs (Marplan, Nardil) o Benzodiazepines (Valium, Xanax, klonopin; are used short-term due to high risk of dependence/withdrawl and can be used in conjunction with SSRIs for severe cases) • Reading: o BuSpar is a non-sedating anxiolytic serotonin agonist that is also used to treat PD, as are beta-blockers. Beta-Blockers are prescribed to enhance heart rhythm and are used off label to treat PD. o Note the drugs prescribed by clinicians do not always follow clinical guidelines. That Is, beta-blockers and benzodiazepines are prescribed more than tricyclic antidepressants. o The mode of action between the most prescribed medications are very different. SSRIs are serotonin agonists and benzodiazepines are GABA agonists (bind to GABA receptor to modulate the effects of GABA by allowing lower concentrations to open -Cl channel and facilitates neural inhibition). Patients with PD have lower GABA receptors in hippocampus, left temporal lobe, prefrontal cortex and global reduction in benzodiazepine binding throughout the brain. This is also seen in alcoholics and patients with PTSD. o Due to mixed findings the role of GABA transmission in PD remain unclear.
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Pharmacological Intervention
``` Pharmacological Intervention • Temporary use of benzodiazepines in conjunction with SSRIs is recommended in severe cases o The mode of action of benzodiazepines and SSRIs is substantially different § SSRIs are serotonin agonists § Benzodiazepines are GABA agonists ``` Pharmacological Intervention • Long-term treatment of panic disorder typically involves medication in conjunction with cognitive-behavioral therapy to improve treatment response (due to methodological issues it is hard to determine if there is additive effects) • Some researchers have argued that cognitive-behavioral therapy is preferable to pharmacological interventions o Others advocate for the management of panic disorder with short-term use of benzodiazepines and long-term use of SSRIs
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Alternative Interventions | Panic Disorder
Alternative Interventions • Transcranial magnetic stimulation (TMS) has been studied but has not yet been approved by the FDA for treating anxiety disorders • Systematic review of the use of TMS in the treatment of anxiety disorders concluded that TMS has a significant effect, but in some studies, the effect is small and short lived Neurosurgery • Used in rare cases of treatment-resistant anxiety disorders o Study (bilateral lesioning of the internal capsule - capsulotomy): § 5 with social phobia § 13 with GAD § 8 with panic disorder • 67% responded favorably to the procedure but seven of the 26 demonstrated neuropsychological impairment on executive function tasks and emotional apathy (i.e., adverse side effects) Exercise • Several studies have reported that regular, high intensity exercise is associated with significant improvement in symptoms of panic disorder but appears to be less effective than treatment with an antidepressant • Acupuncture, autogenic training, and biofeedback are often recommended, however, only a few methodologically sound studies are currently available
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Summary of Panic Disorder:
- higher rates in females than men at all ages - high genetic component but no single gene has been identified - serotonin, norepinephrine and GABA are neurotransmitters linked to PD - Acute treatment of panic disorder involved benzodiazepines, and a combination of SSRIs or SNRIs, and CBT is recommended for long-term management.
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Obsessive-Compulsive Disorder (OCD) Is it an Anxiety Disorder? What is OCD? Does OCD always present with obsessions and compulsions?
• No longer classified as an anxiety disorder; now it is classified under “OCD and related disorders” Obsessive-Compulsive Disorder (OCD) • Recurrent obsessions and/or compulsions that are time consuming or cause significant distress and impairment in daily living o Obsessions are persistent ideas, impulses, thoughts, or images that are intrusive and unwanted o Compulsions are repetitive overt or mental acts that an individual feels compelled to perform *whilst developmental differences have been found, they do not belong to a specific age group *Two components of OCD obsession/compulsion. Most OCD patients have both.
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Common obsessions and compulsions
Common obsessions • Contamination (dirty/sick/unclean; found in 45- 60% of OCD cases) • Doubts (worried didn’t lock door, turn stove off etc.) • Symmetry or exactness (colour coding) • Somatic fears (hyperfocus on • Sexual thoughts • Thoughts of harm • Contamination is the most common obsession, 45–60% of OCD patients suffer from this. obsession ``` Common compulsions • Cleaning • Checking • Counting • Ordering ``` Common compulsions • Most patients with OCD have obsessions and compulsions o OCD symptoms fall into distinct subtypes (classification) § Symmetry/repeating/ordering/counting § Forbidden thoughts/checking § Contamination/washing § Hoarding • Obsessions tend to be highly idiosyncratic and are often connected with “magical” or implausible beliefs • OCD/MDD is not linked to intellect! Uncontrollable thoughts due to anatomical and neurological changes in the brain.
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Prevalence, Cross-Cultural, Diversity | OCD
``` • In the United States the prevalence of OCD is approximately 1.2% • Similar rates have been reported in other countries • Italy ~3% of adolescents reported significant OCD symptoms • 0.25% of British children aged 5–15 reported significant OCD symptoms • Native Hawaiians have a twofold higher risk for OCD than other ethnicities • OCD is less common among black than non-Hispanic white respondents • More common in black than whites (genetic/cultural component) ```
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Religiosity and OCD
• OCD symptoms and the course of the disorder can be shaped by cultural, ethnic, and religious experiences o Study: Most common obsessions in patients from Bali, Indonesia, included the need-to- know information about passersby, somatic obsessions (i.e., body image, touching body part over and over again), and obsessions concerning witchcraft and spirits o Study: Most common obsessions in 90 patients with OCD attending an outpatient clinic in Cairo, Egypt, were religious and contamination obsessions (disease/cleanliness), and the most common compulsion was repeating rituals *Expression of OCD is highly correlated with religious beliefs. Meaning that cultural ideologies shape what obsessions and compulsion you form. Religious beliefs do not cause OCD. • Study: 42% of a sample of 45 patients with OCD had religious obsessions • Study: A group of college students that self- reported highly devout participants (Catholics, Protestants) scored higher on religious obsessive compulsive symptoms than less religious participants (more religious you are the more likely your OCD obsessions will be expressed religiously) • Study: Reported that religious symptoms were found in 13 of 19 ultraorthodox Jewish patients with OCD but only 1 of 15 non- ultraorthodox Jewish patients with OCD • These studies suggest that OCD may be expressed in religious practices but is not a determinant of the disorder *Do not have to be religious to have OCD but if you are religious and have OCD than it’s highly likely your obsessions will be expressed religiously. *Culture, ethnic and religious experiences shape progression and symptoms of OCD
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Diversity (prevalence)
• Equally common in adults of both sexes but more common in boys during childhood (gender distribution equal) • Begins in adolescence or adulthood (late teens or early 20s) o Males have an earlier onset than females • More likely to occur in males with tic or other anxiety disorders such as phobias (more prevalent in males with comorbidities) • Females are more likely to have an acute onset of OCD symptoms • In majority of OCD cases, it is a chronic condition with periods of diminishing symptoms (waxing and waning). • Childhood onset of OCD is associated with continuation of symptoms into adulthood in majority of cases.
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Comorbidity | OCD
``` • Depression (most common comorbid condition) • Eating psychotic (not a spelling mistake; term used in textbook) • Tic disorders • Tourette’s disorder ``` *OCD rarely occurs on its own
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Differences in OCD symptoms based comorbid condition
• Participants with comorbid OCD and Tourette’s disorder have more sexual, violent, and symmetrical obsessions as well as counting, blinking, and touching compulsions • Those with only OCD have more contamination obsessions and cleaning compulsions • Patients with OCD and comorbid tic disorder have significantly more rubbing, touching, tapping, blinking, and staring compulsions (but didn't differ in obsessions) • Patients with comorbid bipolar disorder have a higher rate of sexual obsessions and fewer ordering compulsions than those with OCD alone • Touching, tapping, rubbing, hoarding, ordering, and self-mutilating behaviors are more common in patients with autistic disorder. More contamination, sexual, aggressive, and religious obsessions with comorbid autism. • Patients with anorexia and OCD have a higher need for symmetry and ordering than those with OCD alone • Patients with schizophrenia and comorbid OCD have a poorer prognosis and treatment outcome *behavioral differences reflect differential neurophysiological underpinnings of OCD relative to OCD with a comorbid condition
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Genetics Heritability OCD
• It is important to recognise that increased familial transmission of OCD can be due to either shared genetic or environmental factors • No environmental risk factors have convincingly been associated with OCD (if not environment than it must be genetic; may still be involved but no specific factors found yet) • 20% of patients with OCD have a family history of OCD (strong genetic component) • Fourfold increase in the likelihood of developing OCD in first-degree relatives of adult patients with the disorder • Relatives of patients with early onset OCD have a tenfold increase of developing the disorder • Familial studies support a heritability component to OCD
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Twin Studies | OCD
• Study: 1,054 female twins exhibited a heritability estimate of 33% for obsessions and 26% for compulsions • Meta-analysis of twin studies suggests the heritability estimate of OCD is 40% • concordance of OCD between twins ranges between .63 -.87 but for every 10 monozygotic pairs in concordance with OCD, 4 or so are discordant. Thus, showing non-genetic factors also plat an important role in the development of OCD.
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Linkage studies identifying chromosome locations
• No firm conclusions • Studies continue to explore variants of a number of susceptibility genes particularly those involved in the serotonergic and dopaminergic neurotransmitter systems Reading: • Linkage studies found susceptibility genes in chromosome locations 1q, 1p21, 1p36, 2p14, 3q27-28, 5q13, 6p25, 6q, 9p24, 10p13, 15q11-13, 15q14, 16q24, 17p12, and 22q11. However, these studies have been inconsistent, and no firm conclusions can be drawn.
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Serotonin Genes | OCD
Serotonin Genes • Reasons for investigation of serotonin genes in OCD: o Serotonin agonists including antidepressants such as SSRIs (Prozac) and tricyclics (clomipramine) are effective at reducing OCD symptoms o Serotonin antagonists can trigger or worsen OCD symptoms o Some recreational drugs that are serotonin agonists (LSD, ecstasy, psilocybin) have been found to improve OCD symptoms Serotonin Candidate Genes • The serotonin transporter gene (SLC6A4) has been extensively investigated in OCD given that serotonin reuptake inhibitors block the serotonin transporter and reduce OCD symptoms • Specific polymorphisms in the SLC6A4 gene are associated with OCD (5-HTTLPR, controversial) Serotonin Receptor Genes • Polymorphisms of the serotonin receptor gene HTR2A is associated with OCD • The HTR2A gene is located on chromosome 13 and encodes the serotonin receptor 5-HT2A • Interestingly, this receptor has been found to down-regulate with the chronic administration of SSRIs • 5HT3A receptor gene polymorphisms also have been linked to OCD. Their activation in the insula of mice is associated with disgust response and may be linked to contamination concerns and hand washing. *meta-analysis indicates that 5HTTLPR and receptor HTR2A polymorphisms (rs6311/rs6313) are most consistently linked to OCD
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Dopamine Genes
``` Dopamine Genes • Reasons for investigations: o Dopamine agonists such as amphetamine induce or worsen OCD symptoms o Dopamine antagonists such as antipsychotic medications improve OCD symptoms o Neuroimaging and brain stimulation studies support involvement of the dopaminergic systems ``` Dopamine Transporter Genes • The dopamine transporter gene (SLC6A3, DAT1) is located on chromosome 5 and is a candidate gene in OCD • A specific polymorphism (VNTR) of the dopamine transporter gene has been found to increase susceptibility to Tourette’s disorder that is often comorbid with OCD (controversial) Dopamine Receptor Genes • Polymorphisms of the dopamine postsynaptic receptor gene (DRD4) is lower in patients with OCD. • The DRD4 gene encodes the dopamine receptor (D4) and antipsychotic medications such as clozapine (serotonin antagonist) have a high affinity for the D4 receptor
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Glutamate Genes | OCD
Glutamate Genes • Study: Mice genetically engineered to lack the SAPAP3 gene o SAPAP3 encodes proteins expressed in the striatum and important in glutamate signaling o Mice groomed themselves compulsively and exhibited additional anxiety behaviors • When the mice were treated with an SSRI the OCD-like behaviors improved, and when the gene was reinserted, the behaviors were prevented Glutamate Transporter Genes • The glutamate transporter gene, SLC1A1, located on chromosome 9, encodes glutamate transporters. • Polymorphisms of this gene have been implicated in OCD. • These gene variants are believed to alter the retrieval of glutamate from the synaptic cleft and transporting it across the plasma membrane Glutamate Receptor Genes (NMDA) • Polymorphisms (rs1019385) and variants of NMDA receptor genes (GRIN2A GRIN2B) have been consistently linked to OCD • Located in the fronto-parietal-temporal cortex, amygdala, and basal ganglia
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Additional Candidate Genes
Genes which encode monoamine oxidase, catechol-o-methyltransferase, BDNF, and others have been mixed but are more common in women suggesting that gender differences of the susceptibility of OCD.
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Genetic Summary
• Collectively, family and twin studies support a heritability component to OCD • Over 100 genetic association studies involving over 200 polymorphisms and gene variants • OCD is likely to be associated with multiple genes with most having small to modest effects, and their main effects remain largely unknown. • The heterogeneity of OCD, as well as methodological challenges, increases the difficulty of elucidating the complex relationships among genetic and other factors
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Structural Findings | OCD
• Meta-analysis revealed reductions in cortical and subcortical brain regions in patients with OCD: o Smaller hippocampal volumes (adults; larger in medicated adults) o Larger pallidum volumes (adults; larger in medicated adults) o Larger thalamic volumes (medication naïve children) o Reduced hippocampal volumes (adults) o Severity of OCD symptoms tends to be negatively correlated with hippocampal size
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Decreased cortical thickness
* Superior and inferior frontal regions * Posterior cingulate * Temporal lobe * Inferior parietal lobe * Precuneus gyri *Cortical thinning linked with increased age and medication response *Small change makes a big difference *Widespread structural abnormalities contribute to the vulnerability of OCD and not just cortical thinning
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Gray Matter
``` • Changes in gray matter in participants with OCD: o Frontal o Striatal o Thalamus (hand washing severity negatively correlated with gray matter volume) o Parietal o Cerebellar o Frontal eye fields o Medial frontal gyrus o Anterior cingulate cortex o Basal ganglia (increased/reduced/no difference; some speculate that increases basal ganglia size is a neuroplastic change that results from chronic compulsive behaviour) ``` *Highly variable *OCD involves many pathways, more than the traditional orbitofrontal region! *Too many structures and pathways are identified for the information to be useful
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White Matter
• Both reduced and increased density of white matter has been reported • Studies in the corpus callosum (inconclusive results) • Changes in lateral frontal and parietal regions and pathways linking areas of the prefrontal cortex to posterior parietal and occipital association cortices • Inconsistent findings in reductions of white matter volume in the corpus callosum. • Additional research is needed to further explore white matter density in participants with OCD *Mixed findings, debate *Reduced and increased white matter density in different regions of the brain
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Amygdala
• Amygdala volume is smaller in participants with OCD (controversial) • Other studies which found that the left amygdala was significantly larger in patients with OCD (controversial)
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Summary of Structural Differences
• Findings are not consistent among studies o Findings likely reflects differences among participants with OCD, such as age of onset, comorbid disorders, ethnicity, family history of OCD, medication history, as well as methodological characteristics of the studies *Correlational findings, no causal findings!
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Functional Findings
• Pathways from subcortical structures to the prefrontal cortex and back again (cortico- striatal-thalamic loop) o Glucose metabolic rates are higher in the cortico-striatal-thalamic loop in OCD (specifically. in the left orbital gyrus and bilateral caudate nuclei) • Different patterns of activation during rest conditions as well as during cognitive, memory, executive function, and emotional tasks that illicit emotions of fear, disgust, guilt, and shame *Take home message for OCD and Anxiety is that there are emotional reactions caused by a stimulus. If the stimulus and the prefrontal cortex do not align well then individuals can have intense uncontrollable reactions to real/perceived stimulus because the executive control function is not effectively regulating their emotions or behaviour
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Beyond the Cortico-Striatal-Thalamic Loop
• Studies now implicate limbic structures, temporal cortex, parietal cortex, pallidum, anterior cingulate cortex, angular gyrus, and cerebellum in OCD o Increased activation in cortico-cerebellar regions of participants with OCD with hand- washing rituals o Patients with checking rituals show decreased activation in the left caudate and left anterior cingulate cortex compared to healthy controls • Advocates for a more neurobiological model of OCD. o evidence of increased activation in the anterior cingulate cortex, insula, caudate head, and putamen during affective tasks with OCD. These structural changes linked to salience, arousal and habitual responding which are problematic in OCD. They showed decreased activity in medial, prefrontal cortex and posterior caudate which are implicated in cognitive and behavioural control. o during non-affective tasks OCD patients there is a pattern of increased activation in structures linked to self-referential processing (precuneus, posterior cingulate) and decreased activation in the subcortical regions involved in goal-directed behaviour and motor control (pallidum, ventral anterior thalamus, posterior caudate). o overall, this indicates increased affective and self-referential processing, habitual responding, and blunted cognitive control in participants with OCD
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What Happens in the Brain When OCD Symptoms Are Provoked?
• While in an fRMI scanner, participants with OCD are shown visual images of scenes that trigger OCD symptoms (dirty door knobs, food crusted dishes, messy clothing, crooked paintings, pet hair) • While viewing the images patients have consistently shown increased activation of the cortico-striatal-thalamic loop as well as temporal and parietal cortices and subcortical structures (anterior cingulate cortex, globus pallidus, hippocampus, uncus) • Increased activity in the orbitofrontal regions contributes to evaluation of the occurrence of negative consequences following an action, which in turn leads to the generation of obsessive thoughts • In order to prevent the imagined negative consequences, and or anxiety, repetitive or ritualistic behaviors are performed • These obsessive thoughts and compulsive behaviors are mediated by complex pathways within the cortico-striatal-thalamic loop, temporal and parietal cortices, cerebellum, and subcortical structures, including the anterior cingulate cortex, amygdala, basal ganglia and limbic structures • This theory is circular in nature because neuroimaging data is only correlational
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Functional Findings and Medication
• Higher rCBF in caudate cingulate, and dorsolateral prefrontal region of medication naïve patients with OCD relative to controls. Following treatment with SSRIs these regions have showed significant reductions in rCBF. • Increased activation in the cortico-striatal- thalamic loop has been associated with increased severity of OCD symptoms • SSRI treatment generates changes in glucose metabolism changes in the putamen, cerebellum, and hippocampus that are associated with improved performance on neuropsychological tasks • Pathophysiology of OCD may differ with age at which OCD symptoms began. for example, prior to age 10 and after age 12 both groups showed decreased rCBF in the right orbitofrontal regions. However, participants with early onset show reduced rCBF in the left anterior cingulate and increased rCBF in right cerebellum compared to controls. In addition, early onset showed reduced rCBF in the right thalamus. • Children with OCD had larger thalamus volumes, but they returned to healthy leaves following 12-week treatment of SSRIs. Contrary to expectations, CBT was not linked to thalamus volumes (i.e., pharmacology linked to neuroplasticity changes and not CBT).
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Summary
• Functional studies implicate cortico-striatal- thalamic pathways • Treatment with SSRIs has been found to decrease activity within these regions • Inconsistencies likely reflect participant characteristics • Cortico-striatal-thalamic pathways are implicated in other disorders (ADHD, Tourette’s disorder) • Neuroimaging data is correlational in nature, no causal pathways have been identified. • A disorder-specific structural pathophysiology of OCD is far from identified!
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Does Strep Throat Cause OCD?
• Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) has been used to describe children and in some cases adults who have abrupt onset of OCD or tics following streptococcal infections. o Increased basal ganglia volumes that corresponded with severity of abrupt OCD or tic symptoms due to the increased antibodies within the basal ganglia in reaction to the streptococcal infection • Mixed findings on whether antibodies are helpful in preventing or decreasing PANDAS-related OCD symptoms. It may be that people who develop OCD from streptococcal infections are genetically susceptible to OCD. • The clinical implications of PANDAS remains hotly debated!
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Neurotransmitters | Neurotransmitters: Serotonin
``` • Serotonin agonists, including antidepressants such as SSRIs and tricyclics reduce OCD symptoms • Serotonin antagonists trigger OCD symptoms • Recreational drugs that are serotonin agonists (LSD, ecstacy, psilocybin) improve OCD • Unmedicated individuals with OCD have 25% higher serotonin transporter binding in the midbrain and pons regions relative to controls and binding is highest in individuals with early onset OCD. ``` • Reading: o No significant difference in serotonin transporter binding in the striatum. (Controversial because other studies found reduced or no difference in serotonin transporter availability this is due to two confounding factors: Medication history and age of onset). o A study to address these concerns found significantly higher serotonin transporter availability in the putamen of early onset participants, not in other structures, and was not associated with symptom severity. Indicating there are structural binding differences between early and late onset OCD in the putamen and persist with SSRIs treatment (do not know if this is due to increased capacity for serotonin reuptake or higher density of serotonin transporters to compensate for low serotonin levels remains unclear) o Serotonin receptors: some studies found no differences between OCD and HCs serotonin receptor binding. Others found reduced serotonin receptor 5-HT2A in frontal, dorsolateral, and medial frontal cortex, parietal and temporal cortex in OCD patients relative to HCs. Another found receptor availability in the orbitofrontal and dorsolateral frontal cortex was linked to OCD symptom severity. No difference in 5-HT1B receptors between OCD and HCs. o The role of serotonin receptors in OCD is inconclusive and remains unknown.
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Neurotransmitters: Dopamine
``` Neurotransmitters: Dopamine • Animal studies have demonstrated that dopamine agonists can induce behavior that resembles OCD behavior in humans • Dopamine antagonists can improve OCD symptoms • Dopamine agonists can trigger or worsen OCD symptoms • Studies: Compulsive behavior in mice, rats, and dogs • Rats and mice treated with dopamine receptor agonists develop checking behavior and excessive lever pressing • Dogs, cats, and rabbits often spontaneously display compulsive behaviors (licking, tail chasing, circling behavior) can be treated with antidepressants, such as clomipramine and dopamine antagonists • Dopamine antagonists have also been used in the treatment of OCD in humans who do not respond to SSRIs or to augment SSRIs ``` ``` Dopamine transporter protein (DAT) • DAT density in dogs with compulsive behaviors is either abnormally high or abnormally low in the striatum • Reduced availability of dopamine receptors in participants with OCD (controversial) o 18% decrease in striatal dopamine receptors (D2) availability in participants with OCD o an association between effectiveness of antipsychotic mediation (dopamine antagonist) and D2 and D3 receptor affinity. ```
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Parkinson’s, Tourette’s and ADHD
• Genetic, structural, and functional studies have implicated dopamine in all three of these disorders, and OCD is often comorbid with these disorders • Interestingly, amphetamines that primarily affect the dopaminergic system and are used to treat ADHD, have been found to sometimes induce OCD symptoms in children and adults • A side effect of dopamine agonists used to treat Parkinson’s disease is compulsive, repetitive behaviors
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Dopaminergic agonist (Cocaine)
• There is a relationship between cocaine use, dopamine agonist, and increased risk of OCD in adults. The intricacies of this relationship are poorly understood. • The serotonergic and dopaminergic neurotransmitter systems function interactively, and it is possible that decreased inhibitory influences of serotonin on dopaminergic neurons results in hyperactivity of dopaminergic neurons within the basal ganglia • OCD may be the consequence of dysfunctional interactive neurotransmitter systems within the basal ganglia
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Neurotransmitters: Glutamate
• 40 - 60% of patients with OCD who do not respond to antidepressants often respond to other types of medications suggests other neurotransmitter are involved in the disorder • Glutamate system directly affects dopamine-releasing neurons in the striatum, and glutamate antagonists have been found to improve OCD symptoms in treatment resistant cases • Glutamate concentrations are higher in patients with OCD but were reduced to HCs levels following antidepressant treatment (i.e., dysfunction in glutamate system in the caudate nucleus is reversible with antidepressant treatment).
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Neurotransmitters: Opioids | OCD
• The rate of OCD is four times higher in individuals addicted to opioids • Oral weekly doses of morphine reduces OCD symptoms in OCD treatment- resistant patients • Findings have been mixed regarding the effectiveness of opioid antagonists in reducing OCD symptoms.
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Interventions: Pharmacological
• Antidepressants are the most commonly used medications for treating OCD, particularly SSRIs and the tricyclic antidepressant clomipramine. o SSRIs and cognitive behavior therapy are the most effective form of treatment in both children and adults § Greatest benefits are found after 6 weeks of initiating SSRIs (symptoms are reduced not abolished – treatment responders often still show symptoms of OCD) § different forms of SSRIs show the same benefits, higher doses lead to greater symptom improvement but increases risk of side effects.
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Clomipramine (Serotonin Reuptake Inhibitor)
``` • Highly effective at reducing OCD symptomatology but is associated with more side effects and have lower compliance rates. • Side effects include: o Dry mouth o Blurred vision o Constipation o Fatigue o Tremor o Cardiac arrhythmia ```
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Augmentation
• treatment non-response to medication or CBT is not uncommon (i.e., 40-60%). It is recommended to try other SSRIs, serotonin-norepinephrine reuptake inhibitor, or CBT. • in treatment resistant cases it is also recommended to augment treatment with neuroleptics. • the combination of SSRIs and Clomipramine is more effective at reducing OCD symptoms than either drug alone.
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Neurosurgery
• Used in patients with chronically severe and treatment-resistant mental illness, including mood, anxiety disorders, and OCD • 5 types of surgeries: 1. Subcaudate tractotomy: Lesion of area under the head of the caudate nucleus to interrupt connections between subcortical and orbitofrontal regions 2. Anterior capsulotomy: Lesion of pathways connecting the thalamus and the frontal lobes 3. Anterior cingulotomy: Lesion of the anterior cingulate cortex 4. Limbic leucotomy: (a combination of anterior cingulotomy and capsulotomy) 5. Gamma ventral capsulotomy: Delivery of gamma rays through the skull. Gamma rays destroy cells on the pathways connecting the dorsomedial thalamus and ventral prefrontal cortex and destroy cells therein (does not require opening the skull)
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Neurosurgery Stats
• Neurosurgical procedures are effective at reducing intractable OCD symptoms in 35– 75% of cases, with benefits extending 6–24 months after surgery • Commonly reported negative side effects associated with these procedures include: o Memory deficits o Apathy o Urinary incontinence o Seizures • Neurosurgical treatment of OCD does not have deleterious effects on personality • Patients who show OCD symptom reduction also reported a reduction in neuroticism and an increase in extraversion, novelty seeking, and self-directedness Reading: • following a bilateral orbitomedial leucotomy revealed significant reductions of activity in the caudate, anterior cingulate, thalamus, and several frontal regions 18 days later, and sustained reduced glucose metabolism in these regions for three years. These reductions in activity were associated with improvement of symptoms and support involvement of subcortical-cortical pathways in OCD. Others found decreases in the medial frontal cortex, cingulate, and striatum. What do we do? How do we treat OCD with all these mixed findings? Their life is still impaired, and we do not know how to help. We cannot use talk therapy, surgery/stimulation, medication to “fix” them without knowing the neurochemistry behind the disorder. They know there is something wrong/irrational with them, they do not need to be told that, they seek help on how to change it.
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Beyond the Cortico-Striatal-Thalamic Loop
• Studies now implicate limbic structures, temporal cortex, parietal cortex, pallidum, anterior cingulate cortex, angular gyrus, and cerebellum in OCD o Increased activation in cortico-cerebellar regions of participants with OCD with hand- washing rituals o Patients with checking rituals show decreased activation in the left caudate and left anterior cingulate cortex compared to healthy controls • Advocates for a more neurobiological model of OCD. o evidence of increased activation in the anterior cingulate cortex, insula, caudate head, and putamen during affective tasks with OCD. These structural changes linked to salience, arousal and habitual responding which are problematic in OCD. They showed decreased activity in medial, prefrontal cortex and posterior caudate which are implicated in cognitive and behavioural control. o during non-affective tasks OCD patients there is a pattern of increased activation in structures linked to self-referential processing (precuneus, posterior cingulate) and decreased activation in the subcortical regions involved in goal-directed behaviour and motor control (pallidum, ventral anterior thalamus, posterior caudate). o overall, this indicates increased affective and self-referential processing, habitual responding, and blunted cognitive control in participants with OCD
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What Happens in the Brain When OCD Symptoms Are Provoked?
• While in an fRMI scanner, participants with OCD are shown visual images of scenes that trigger OCD symptoms (dirty door knobs, food crusted dishes, messy clothing, crooked paintings, pet hair) • While viewing the images patients have consistently shown increased activation of the cortico-striatal-thalamic loop as well as temporal and parietal cortices and subcortical structures (anterior cingulate cortex, globus pallidus, hippocampus, uncus) • Increased activity in the orbitofrontal regions contributes to evaluation of the occurrence of negative consequences following an action, which in turn leads to the generation of obsessive thoughts • In order to prevent the imagined negative consequences, and or anxiety, repetitive or ritualistic behaviors are performed • These obsessive thoughts and compulsive behaviors are mediated by complex pathways within the cortico-striatal-thalamic loop, temporal and parietal cortices, cerebellum, and subcortical structures, including the anterior cingulate cortex, amygdala, basal ganglia and limbic structures • This theory is circular in nature because neuroimaging data is only correlational
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Functional Findings and Medication
• Higher rCBF in caudate cingulate, and dorsolateral prefrontal region of medication naïve patients with OCD relative to controls. Following treatment with SSRIs these regions have showed significant reductions in rCBF. • Increased activation in the cortico-striatal- thalamic loop has been associated with increased severity of OCD symptoms • SSRI treatment generates changes in glucose metabolism changes in the putamen, cerebellum, and hippocampus that are associated with improved performance on neuropsychological tasks • Pathophysiology of OCD may differ with age at which OCD symptoms began. for example, prior to age 10 and after age 12 both groups showed decreased rCBF in the right orbitofrontal regions. However, participants with early onset show reduced rCBF in the left anterior cingulate and increased rCBF in right cerebellum compared to controls. In addition, early onset showed reduced rCBF in the right thalamus. • Children with OCD had larger thalamus volumes, but they returned to healthy leaves following 12-week treatment of SSRIs. Contrary to expectations, CBT was not linked to thalamus volumes (i.e., pharmacology linked to neuroplasticity changes and not CBT).
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Summary
• Functional studies implicate cortico-striatal- thalamic pathways • Treatment with SSRIs has been found to decrease activity within these regions • Inconsistencies likely reflect participant characteristics • Cortico-striatal-thalamic pathways are implicated in other disorders (ADHD, Tourette’s disorder) • Neuroimaging data is correlational in nature, no causal pathways have been identified. • A disorder-specific structural pathophysiology of OCD is far from identified!
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Does Strep Throat Cause OCD?
• Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) has been used to describe children and in some cases adults who have abrupt onset of OCD or tics following streptococcal infections. o Increased basal ganglia volumes that corresponded with severity of abrupt OCD or tic symptoms due to the increased antibodies within the basal ganglia in reaction to the streptococcal infection • Mixed findings on whether antibodies are helpful in preventing or decreasing PANDAS-related OCD symptoms. It may be that people who develop OCD from streptococcal infections are genetically susceptible to OCD. • The clinical implications of PANDAS remains hotly debated!
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Neurotransmitters Neurotransmitters: Serotonin OCD
``` • Serotonin agonists, including antidepressants such as SSRIs and tricyclics reduce OCD symptoms • Serotonin antagonists trigger OCD symptoms • Recreational drugs that are serotonin agonists (LSD, ecstacy, psilocybin) improve OCD • Unmedicated individuals with OCD have 25% higher serotonin transporter binding in the midbrain and pons regions relative to controls and binding is highest in individuals with early onset OCD. ``` • Reading: o No significant difference in serotonin transporter binding in the striatum. (Controversial because other studies found reduced or no difference in serotonin transporter availability this is due to two confounding factors: Medication history and age of onset). o A study to address these concerns found significantly higher serotonin transporter availability in the putamen of early onset participants, not in other structures, and was not associated with symptom severity. Indicating there are structural binding differences between early and late onset OCD in the putamen and persist with SSRIs treatment (do not know if this is due to increased capacity for serotonin reuptake or higher density of serotonin transporters to compensate for low serotonin levels remains unclear) o Serotonin receptors: some studies found no differences between OCD and HCs serotonin receptor binding. Others found reduced serotonin receptor 5-HT2A in frontal, dorsolateral, and medial frontal cortex, parietal and temporal cortex in OCD patients relative to HCs. Another found receptor availability in the orbitofrontal and dorsolateral frontal cortex was linked to OCD symptom severity. No difference in 5-HT1B receptors between OCD and HCs. o The role of serotonin receptors in OCD is inconclusive and remains unknown.
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Neurotransmitters: Dopamine | OCD
``` Neurotransmitters: Dopamine • Animal studies have demonstrated that dopamine agonists can induce behavior that resembles OCD behavior in humans • Dopamine antagonists can improve OCD symptoms • Dopamine agonists can trigger or worsen OCD symptoms • Studies: Compulsive behavior in mice, rats, and dogs • Rats and mice treated with dopamine receptor agonists develop checking behavior and excessive lever pressing • Dogs, cats, and rabbits often spontaneously display compulsive behaviors (licking, tail chasing, circling behavior) can be treated with antidepressants, such as clomipramine and dopamine antagonists • Dopamine antagonists have also been used in the treatment of OCD in humans who do not respond to SSRIs or to augment SSRIs ``` ``` Dopamine transporter protein (DAT) • DAT density in dogs with compulsive behaviors is either abnormally high or abnormally low in the striatum • Reduced availability of dopamine receptors in participants with OCD (controversial) o 18% decrease in striatal dopamine receptors (D2) availability in participants with OCD o an association between effectiveness of antipsychotic mediation (dopamine antagonist) and D2 and D3 receptor affinity. ```
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Parkinson’s, Tourette’s and ADHD
• Genetic, structural, and functional studies have implicated dopamine in all three of these disorders, and OCD is often comorbid with these disorders • Interestingly, amphetamines that primarily affect the dopaminergic system and are used to treat ADHD, have been found to sometimes induce OCD symptoms in children and adults • A side effect of dopamine agonists used to treat Parkinson’s disease is compulsive, repetitive behaviors
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``` Dopaminergic agonist (Cocaine) OCD ```
• There is a relationship between cocaine use, dopamine agonist, and increased risk of OCD in adults. The intricacies of this relationship are poorly understood. • The serotonergic and dopaminergic neurotransmitter systems function interactively, and it is possible that decreased inhibitory influences of serotonin on dopaminergic neurons results in hyperactivity of dopaminergic neurons within the basal ganglia • OCD may be the consequence of dysfunctional interactive neurotransmitter systems within the basal ganglia
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Neurotransmitters: Glutamate OCD Link to dopamine Link to treatment
* 40 - 60% of patients with OCD who do not respond to antidepressants often respond to other types of medications suggests other neurotransmitter are involved in the disorder * Glutamate system directly affects dopamine-releasing neurons in the striatum, and glutamate antagonists have been found to improve OCD symptoms in treatment resistant cases * Glutamate concentrations are higher in patients with OCD but were reduced to HCs levels following antidepressant treatment (i.e., dysfunction in glutamate system in the caudate nucleus is reversible with antidepressant treatment).
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Neurotransmitters: Opioids | OCD
• The rate of OCD is four times higher in individuals addicted to opioids * in treatment resistant ocd cased weekly oral doses of morphine (opioids) reduces OCD symptoms in OCD treatment-resistant patients * Findings have been mixed regarding the effectiveness of opioid antagonists in reducing OCD symptoms.
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Interventions: Pharmacological | OCD
• Antidepressants are the most commonly used medications for treating OCD, particularly SSRIs and the tricyclic antidepressant clomipramine. o SSRIs and cognitive behavior therapy are the most effective form of treatment in both children and adults § Greatest benefits are found after 6 weeks of initiating SSRIs (symptoms are reduced not abolished – treatment responders often still show symptoms of OCD) § different forms of SSRIs show the same benefits, higher doses lead to greater symptom improvement but increases risk of side effects.
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Clomipramine (trycilic antidepressants) | OCD
``` • Highly effective at reducing OCD symptomatology but is associated with more side effects and have lower compliance rates. • Side effects include: o Dry mouth o Blurred vision o Constipation o Fatigue o Tremor o Cardiac arrhythmia ```
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Augmentation
* treatment non-response to medication or CBT is not uncommon (i.e., 40-60%). It is recommended to try other SSRIs, serotonin-norepinephrine reuptake inhibitor, or CBT. * in treatment resistant cases it is also recommended to augment treatment with neuroleptics. * the combination of SSRIs and Clomipramine is more effective at reducing OCD symptoms than either drug alone.
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Neurosurgery | OCD
• Used in patients with chronically severe and treatment-resistant mental illness, including mood, anxiety disorders, and OCD • 5 types of surgeries: 1. Subcaudate tractotomy: Lesion of area under the head of the caudate nucleus to interrupt connections between subcortical and orbitofrontal regions 2. Anterior capsulotomy: Lesion of pathways connecting the thalamus and the frontal lobes 3. Anterior cingulotomy: Lesion of the anterior cingulate cortex 4. Limbic leucotomy: (a combination of anterior cingulotomy and capsulotomy) 5. Gamma ventral capsulotomy: Delivery of gamma rays through the skull. Gamma rays destroy cells on the pathways connecting the dorsomedial thalamus and ventral prefrontal cortex and destroy cells therein (does not require opening the skull)
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Neurosurgery Stats
• Neurosurgical procedures are effective at reducing intractable OCD symptoms in 35–75% of cases, with benefits extending 6–24 months after surgery • Commonly reported negative side effects associated with these procedures include: o Memory deficits o Apathy o Urinary incontinence o Seizures • Neurosurgical treatment of OCD does not have deleterious effects on personality • Patients who show OCD symptom reduction also reported a reduction in neuroticism and an increase in extraversion, novelty seeking, and self-directedness Reading: • following a bilateral orbitomedial leucotomy revealed significant reductions of activity in the caudate, anterior cingulate, thalamus, and several frontal regions 18 days later, and sustained reduced glucose metabolism in these regions for three years. These reductions in activity were associated with improvement of symptoms and support involvement of subcortical-cortical pathways in OCD. Others found decreases in the medial frontal cortex, cingulate, and striatum. What do we do? How do we treat OCD with all these mixed findings? Their life is still impaired, and we do not know how to help. We cannot use talk therapy, surgery/stimulation, medication to “fix” them without knowing the neurochemistry behind the disorder. They know there is something wrong/irrational with them, they do not need to be told that, they seek help on how to change it.
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Brain Stimulation Brain Stimulation Techniques: DBS OCD
Brain Stimulation Techniques: DBS • When used for OCD, DBS placement typically involves the anterior limb of the internal capsule/nucleus accumbens or thalamus/subthalamic nucleus o Difference in Unilateral vs. Bilateral stimulation benefits remains unclear (some advocate bilateral over unilateral) • Study: Two of three patients showed sustained improvement of symptoms over time (33 months) with no harmful side effects. • Empirical evidence supports the efficacy of DBS in treatment-resistant OCD with assumable side effects
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Brain Stimulation Techniques: ECT | OCD
• ECT has shown short- and long-term reduction in OCD symptoms • Study: Nearly all of 32 patients with intractable OCD benefited from ECT and that improvement was sustained over a 1- year period • A number of side effects are associated with ECT including headaches, memory impairment, nausea, and muscle aches • very controversial to use on children – most clinicians do not
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Brain Stimulation Techniques: rTMS & trans cranial direct current stimulation: tDCS
• rTMS involves he rapid delivery of brief magnetic pulses to the scalp that induce neural depolarisation (increases excitation) while low frequency pulses are thought to increase neural inhibition. • tDCS passes small electrical currents through the skull and has a modulatory effect on neurotransmission by either increasing or decreasing neural firing at the level of the cortex. • To date, compared to pharmacological interventions, relatively few studies have investigated the efficacy of these techniques at improving OCD symptoms but preliminary findings are encouraging