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NEUROBIOLOGICAL UNDERSTANDING OF ANXIETY DISORDER: AN UPDATE

Devashish Konar MD Consultant Psychiatrist Mental Health Care Centre,

Burdwan & Kolkata, W.B.

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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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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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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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AMYGDALA IS AN INTEGRAL PART OF CIRCUITRY MAINTAINING

MEMORIES FOR AVERSIVE EVENTS

Amygdala

Hypothalamus

Pituitary

Adrenal

Cortisol

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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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NEW TARGETS FOR TREATMENT OF ANXIETY DISORDERS

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GLUTAMATERGIC SYSTEM AND OTHER ACTIVE AREAS OF

RESEARCHSome 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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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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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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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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