Neurobiological understanding of anxiety disorder

1. NEUROBIOLOGICAL UNDERSTANDING OF
ANXIETY DISORDER: AN UPDATE
Devashish Konar MD Consultant Psychiatrist
Mental Health Care Centre,
Burdwan & Kolkata, W.B.
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2. INTRODUCTION
• Last century witnessed remarkable change in almost all
spheres of life. Whether you like or not, whether you are able
to take the change or not, life is ever changing.
• Demands of life is exponentially increasing.
• Personal aspiration, family support, the environment, the way
we work, the way we communicate, the way we travel, the way
we love or hate each other and everything else is changing all
the time.
• As we approach future the pace of change is going to be faster.
Changes are for good and also for bad.
• Changes are good for those who can accommodate and take
things into command and bad for those who lose control and
are victim of its adverse consequences, anxiety being one.
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3. INTRODUCTION
• Adapting is not easy, there has to be conscious effort on part of human
beings.
• One such endeavor is to have neurobiological understanding of anxiety so
that we know what goes wrong and what we need to do.
• Anxiety/fear is a normal reaction to threatening situations and it represents a
physiologically protective function.
• Anxiety/fear is often manifested as avoidance and is also characterized by
overt sympathetic reactions.
• Pathological anxiety is a level of anxiety that is disproportionate to the threat
and can be manifested even in the absence of threat.
• In clinical practice, categorical systems set the boundary at which a particular
level of anxiety becomes an anxiety disorder.
(Toth & Zupan, 2007)
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4. NEUROANATOMY AND CIRCUITRY
• Recent years have witnessed an explosion of interest focused on
the interplay of emotion and cognition.
• Anxiety Disorders involve prominent disturbances of both
cognition and emotion, suggesting that they can be
conceptualized as disorders of the emotional-cognitive brain.
• The amygdala and Pre Frontal Cortex are key components of
human fear neurocircuitry.
• The amygdala and PFC are interconnected with the PFC
modulating amygdala responses.
• In Anxiety Disorders the fear production system is too strong and
the fear regulation system is too weak.
(Blackford & Pine 2012)
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5. AMYGDALA IS AN INTEGRAL PART OF CIRCUITRY
MAINTAINING MEMORIES FOR AVERSIVE EVENTS
Amygdala
Hypothalamus
Pituitary
Adrenal
Cortisol 5

6. AMYGDALA AT THE CENTRE-STAGE
• The amygdala is a well-known epicenter for the
emotional "understanding" of stimuli.
• In other words, the amygdala helps the brain to
remember the averseness of otherwise neutral stimuli.
• Therefore, the amygdala is an integral part of the
circuitry maintaining memories for aversive events.
• Clinical studies based on animal data consistently point
to amygdala hyperactivity in anxiety disorders.
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7. THIS IS HOW THE CLASSICAL STRESS HORMONE
CORTISOL WORKS:
Cortisol
Norepinehprine & Adrenaline
Palpitation, Tremor, Slow
Digestion & Psychological Fear and Apprehention
(Vergne 2014)
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8. EXTRAHYPOTHALAMIC STRESS AXIS
• The extrahypothalamic stress axis is another way in which brain
uses norepinephrine through the amygdala, bypassing pituitary
and adrenal cortisol.
• The amygdala has received substantial attention as a core
component of fear circuitry; however, other brain regions are
also involved in fear and anxiety.
• For example, the bed nucleus of the stria terminalas (BNST) – a
part of the “extended amygdala”- is involved in sustained fear
reactions (in contrast to short-term or phasic fear responses) in
rodents.
• These sustained reactions, which are elicited by less specific and
less predictable threats, are maintained over time and are
considered akin to anxiety in humans.
(Blackford & Pine 2012)
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9. THE PREFRONTAL CORTEX CONNECTION
• And then comes the role of prefrontal cortex which connects to the amygdala
through multiple regions.
• However, interest focuses primarily on GABA ( aminobutyric acid)-ergic
neurons, emphasizing an inhibitory role for the PFC over amygdala function.
• At least in some contexts, neuroimaging studies in humans show an inverse
relationship between the amygdala and multiple PFC regions including
vmPFC, vIPFC, dmPFC, and dlPFC.
• Particularly for the vlPFC and vmPFC, these findings suggest inhibitory input.
(Blackford & Pine 2012)
• In anxiety disorder there is abnormal effective top down or cognitive
modulation of anxious states and that makes it very difficult for the thinking
brain to shut down the irrational anxiety.
(Vergne 2014)
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10. AETIOLOGY: EVOLUTION
• Appreciation of the differences that have evolved is how organisms
successfully use a behavioral state, anxiety, in avoiding threats to their
survival.
• As soon as animals evolved, more than one kind of response to danger
came into picture and more kinds of receptor came into play that could
detect cues before the imminent injury.
• It became advantageous for them to enter into an intervening state
between stimulus and response.
• The evolution of the limbic system of the brain has made possible an
enormous amplification of the kinds of possible intervening emotional
states, creating a variety of qualitatively different anxieties.
• The evolution of the cerebral cortex has vastly expanded capabilities for
learning and memory so that long –past experiences, as well as recent
ones, play important roles in eliciting anxiety and in shaping the
information processing during the state.
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11. AETIOLOGY: EVOLUTION
• The extent of parallel processing that has become possible in the primate brain
has increased the extent of self-regulation within the system to the point that
self-awareness and what we call consciousness has emerged.
• This creates a whole new order of response to anxiety-namely, the inner
subjective experience of it.
• Finally, the advent of symbolic communication in language has made it possible
for us to communicate that experience to one another.
• This, in turn, has led to a wealth of verbal interactions that can alleviate or
perpetuate anxiety and can avoid or create new dangers.
• Insights into the evolution of anxiety can be clinically useful. This
understanding can provide the basis for a variety of psychotherapeutic
interventions.
(Stein 2002)
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12. EARLY LIFE STRESS
• Early life stress in the form of maternal deprivation or neglect has
provided a model for the study of susceptibility to
neuropsychiatric disorders.
• Much work on the genetic and epigenetic consequences of early
life stress has yielded important clues about their effects on
neurotransmitter systems that sub serve emotional tone.
• Corticotropin-releasing factor is a key system for understanding
the long-term effects of early life stress on emotional regulation.
• For example, a blunted cortisol response to psychosocial stress is
common in individuals who have experienced early life stress,
whereas a comparison cohort shows a normal response.
• A blunted cortisol response points to impaired hypothalamus-
pituitary-adrenal (HPA) axis reactivity, which is seen in victims of
trauma and has been correlated with PTSD and anxiety disorders.
(Vergne 2014)
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13. DEVELOPMENTAL STAGES AND ANXIETY
• In children different anxiety disorders appear at different
developmental stages.
• To some extent they are normal.
• If excessive, they may get a diagnostic tag.
• Stranger anxiety appear around 8 to 12 months of age.
• Separation anxiety is typically evident around 10 to 18 months.
• Social phobia typically arises in adolescence.
(Blackford & Pine 2012)
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14. EXCITOTOXICITY :
CELL DEATH FROM EXCESSIVE OXIDATION
• In the hippocampus, models of early life stress show down-regulation
of corticotropin-releasing factor receptors.
• This has been linked to excessive glutamate neurotransmission and
hippocampal cell death owing to glutamate-mediated excitotoxicity
(cell death from excessive oxidation).
• In other words, adaptive responses to trauma can become
maladaptive, at least in part as a result of genetic and molecular
changes.
• These changes lead to alterations in receptor pharmacology that
perpetuate the deleterious physiologic and psychological effects of
trauma.
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15. DEVELOPMENTAL STAGES AND ANXIETY
• Early life trauma in the form of abuse and neglect has repeatedly
shown a tendency for an overactive HPA stress-response axis.
• Effect of trauma on the methylation of glucocorticoid receptors
explain the hyper reactive stress response of individuals with PTSD.
• In other words, it is not necessarily all about the serotonin receptor
genotype, but about the combination of epigenetic (methylation)
and environmental factors.
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16. GENETIC STUDIES
• There is definitive evidence that at least some genetic component
contributes to the development of anxiety disorder.
• Panic Disorder is thought to be the most heritable of the anxiety
disorders.
• First-degree relatives of proband patients who have Panic
Disorder have a sevenfold increased likelihood for Panic Disorder
and also have an increased risk for phobic disorders.
• Twin studies suggest that 30% to 40% of the variance in
vulnerability for Panic Disorder is derived from genetic factors
and the remainder from individual-specific, but not shared,
environment/life experiences.
(Martin et al. 2009)
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17. GENETIC STUDIES
• The figures for other anxiety disorders, although not as high,
also indicate a higher frequency of the illness in first-degree
relatives of affected patients than in the relatives of nonaffected
persons.
• Clearly a linkage exists between genetics and anxiety disorders,
but no anxiety disorder is likely to result from a simple
Mandelian abnormality.
• One report has attributed about 4 percent of the intrinsic
variability of anxiety within the general population to a
polymorphic variant of the gene for the serotonin transporter,
which is the site of action of many serotonergic drugs.
• Persons with the variant produce less transporter and have
higher levels of anxiety.
(Sadock et. al 2015)
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18. GENETIC STUDIES
• Corticolimbic connectivity, in the context of genetic
polymorphisms has been studied.
• SLC6A4 is the gene coding for the serotonin transporter, the
protein that picks up serotonin from the synaptic cleft after
neurotransmission.
• It may confer vulnerability or protection.
• The s allele confers vulnerability for anxiety and depression.
• The amygdala is overactive in patients carrying the s allele.
(Vergne 2014)
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19. IMPLICATION OF GENETICS IN TREATMENT
• At some point in the future, it is expected that some of these
genetic findings will be translated to clinical tests for the
presence of risk factors for anxiety and depression.
• Some evidence shows that antidepressants and psychotherapy
may revert epigenetic modifications in affected patients,
although much work still needs to be done.
• It is imperative that we understand how the environment may
interact with biology to induce illness.
(Vergne 2014)
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20. BRAIN IMAGING STUDIES
• A range of brain imaging studies, almost always conducted with a
specific anxiety disorder, has produced several possible leads in
the understanding of anxiety disorders.
• Structural studies- for example, CT and MRI occasionally show
some increase in the size of cerebral ventricles.
• In one study, the increase was correlated with the length of time
patients had been taking benzodiazepines.
• In one MRI study, a specific effect in the right temporal lobe was
noted in patients with panic disorder.
• Some type of cerebral asymmetries may be important in the
development of anxiety disorder symptoms in specific patients.
• Functional brain imaging have variously reported abnormalities
in the frontal cortex; the occipital and temporal areas; and, in a
study of panic disorder, the parahippocampal gyrus.
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21. BRAIN IMAGING STUDIES
• In posttraumatic stress disorder, fMRI studies have found increased activity in
the amygdala, a brain region associated with fear.
• In anxiety disorder there is demonstrable, functional, cerebral pathology.
(Sadock et. al. 2015)
• During adolescence amygdala function is enhanced relative to PFC function,
resulting in an over-contribution of the amygdala to adolescent emotions and
behavior.
• As PFC development catches up during early adulthood, emotions and
behavior are stabilized.
• This amygdala-PFC imbalance may contribute to the increased prevalence of
anxiety disorders during early adolescence.
• In developing phase there is imbalance between the early maturation of
subcortical regions, such as the amygdala, and late maturation of PFC
regions.
(Blackford & Pine 2012)
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22. NEW TARGETS FOR TREATMENT
OF ANXIETY DISORDERS
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23. GLUTAMATERGIC SYSTEM AND OTHER
ACTIVE AREAS OF RESEARCH
Some of the active areas of research holds promise for
expanding and improving evidence-based treatment
options for individuals suffering with clinical anxiety:
• Glutamatergic system
• Neuropeptides substance P
• Neuropeptide Y
• Oxytocin
• Orexin
• Galanin
(Sanjay et. al. 2008)
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24. NEUROPEPTIDE Y
• Neuropeptide Y (NPY) is a highly conserved 36-amino acid peptide
in mammalian brain.
• Evidence suggesting the involvement of the amygdala in the
anxiolytic effects of NPY is robust, and it probably occurs via the
NPY-Y1 receptor.
• Preliminary studies in special operations soldiers under extreme
training stress indicate that high NPY levels are associated with
better performance.
GALANIN
• Galanin is a peptide that, in human, contains 30 amino acids.
• Studies in rats have shown that galanin administered centrally
modulates anxiety-related behaviors.
(Sadock et. al. 2015)
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25. IMPLICATION OF NEUROBIOLOGY IN THE
TREATMENT OF ANXIETY DISORDERS
• Abnormalities in amygdala pathways can affect the acquisition and expression of
fear conditioning.
• Drugs such as glutamate N-methyl-D-aspartate (NMDA) antagonists, and blockers
of voltage-gated calcium channels, in the amygdala, may block these effects.
• Finally, fear extinction, which entails new learning of fear inhibition, is central to
the mechanism of effective anti-anxiety treatments.
• Several pharmacological manipulations, such as D-cycloserine, a partial NMDA
agonist, have been found to facilitate extinction.
• There is also preliminary evidence for the use of centrally acting beta-adrenergic
antagonists, like propranolol, to inhibit consolidation of traumatic memories in
PTSD.
• Combining these medication approaches with psychotherapies that promote
extinction, such as cognitive behavioral therapy (CBT), may offer patients with
anxiety disorders a rapid and robust treatment with good durability of effect.
(Garakani A et. al 2006)
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26. CONCLUSION
• Anxiety per se, and anxiety as comorbidity remains
psychiatrist’s major preoccupation.
• Both, ability to give immediate relief, as well as, ability to
correct the disorder are equally important.
• Bracing up with the knowledge of neurobiology of anxiety
and ability to translate it into clinical practice is an
important part in building up acumen for successful
psychiatric practice.
• Expecting changes in understanding of the disease and
being open to modification in your understanding and
practice in the field of anxiety will be the mantra for the
future.
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27. Thanks27