Understanding affective disorders Flashcards
What does the principle of neurobiological timescales refer to?
Different neurobiological events and pathological processes have different timescales
What is the timescale of ionic and ligand processes?
Micro-seconds to milliseconds
What is the timescale of synaptic events?
Milliseconds to seconds
What is the timescale of neural circuit processes?
Seconds to minutes
What is the timescale of cellular synthetic processes?
Hours to days
What is the timescale of disease state-specific processes?
Days to weeks
What is the timescale of environmental, preclinical and sense trait-specific processes?
Weeks, months to years
What is the timescale of genetic processes?
Decades
What is the key feature of regulated physiological systems?
Regulated systems exhibit Adaptive Gain Control
-> output is constant over the regulated range
What is the key feature of non-regulated physiological systems?
Output is always proportional to input
What is the key feature of dysregulated physiological systems?
Output never proportional to input
What is the state of the physical regulation in affective disorders?
Dysregulated system
-> outputs are unpredictable or deviate from the (regulated) norm = symptoms
What are the biological factors in depressive disorder?
- Heritability: 40-50%
- Gene polymorphisms: 5-HTTLPR, BDNF
- Increased HPA axis reactivity
- Increased inflammation
- Dysregulated brain circuitry
What are the biological factors in bipolar disorder?
- Heritability: 80-90%
- Gene polymorphisms: ANK3, CACNA1C
- Increased HPA axis reactivity
- Increased inflammation
- Dysregulated brain circuitry
What are the psychological factors in depressive disorder?
- Negative cognitive bias
- Low self-esteem
What are the psychological factors in bipolar disorder?
Childhood anxiety
What are the social factors in depressive disorder?
- Life events
- Childhood adversity
- Vulnerability by lack of support
What are the social factors in bipolar disorder?
Life events
Why is there little room for interaction of non-genetic factors in bipolar disorder?
High heritability: 80-90%
What is the role of genetics in affective disorders?
Genetics are a major contribution to depression and bipolar disorder
What is the male-female ratio in depression?
2:3
What is the male-female ratio in bipolar disorder?
1:1
What is the heritability in depression?
40-50%
What is the heritability in bipolar disorder?
80-90%
What makes depression and bipolar disorder polygenetic disorders?
Familial transmission does not follow simple Mendelian patterns of inheritance
-> no single gene of major effect
=> polygenetic: many genes of minor but interacting effects are implicated in both conditions
What are the candidate genes in depressive disorder?
> SLC6A4: serotonin transporter gene polymorphism
> 5-HTTLPR: serotonin transporter-linked promoter region
> BDNF gene
What are the candidate genes in bipolar disorder?
> ANK3
> CACNA1C
What is the action of the serotonin transporter gene (SLC6A4) and transporter-linked promoter region (5-HTTLPR)?
Facilitates serotonin reuptake
What he serotonin transporter gene (SLC6A4) and transporter-linked promoter region (5-HTTLPR) polymorphisms associated with?
Amygdala activity in response to fearful stimuli
- may cause developmental reduction in amygdala volume
NOT reduction in transporter availability
With which psychosocial factor do the serotonin transporter gene (SLC6A4) and transporter-linked promoter region (5-HTTLPR) interact with?
May interact with childhood adversity, to produce chronic course of adult depression
- does not appear to contribute to onset of depression following severe life events
What is the action of the BDNF gene Val66Met polymorphism?
Neurotrophic factor: actions on many site
- reduced amygdala volume
- increased HPA axis dysregulation
- mediates onset of depression following recent severe life event
What is the role of the ANK3 gene?
Ankyrin G scaffold protein
- formation and maintenance of neuron axon initial segment
- production and propagation of action potentials
- links voltage-gated sodium and potassium channels to the cytoskeleton
What is the action of the ANK3 gene in bipolar disorder?
In Hippocampal dentate gyrus:
- modulates anxiety-like behaviours and risk-taking
What is the role of the CACNA1C gene?
α-1 subunit of voltage-gated calcium channel
- NT release and neuron excitability
What is the action of the CACNA1C gene in bipolar disorder?
- Modulates anxiety-like behaviours and risk-taking
- Affects NT release and neuron excitability
- Modifies effect of synaptic activity on cell survival, synaptic plasticity, gene expression
How is the number of previous depressive episodes associated to the contribution of life events in precipitating depression?
Succession of depressive episodes lowers contribution of stressful life events precipitating later episodes of depression
How is the number of previous depressive episodes associated to the risk of depression onset?
Risk of depression onset increases after each subsequent episode
(succession increases risk of recurrence)
To which environmental factor does the 5-HTTLPR gene polymorphism interact with in the causation of depression?
Childhood maltreatment
To which environmental factor does the BDNF gene polymorphism interact with in the causation of depression?
Severe life events
What is the contribution of the negative cognitive bias to depression?
Fuels depressive thinking, hoeplessness and pessimism
What is the mechanism of the negative cognitive bias in depression?
Person more likely to:
- interpret ambiguous information as negative
- remember negative information
- focus on negative stimuli (salience)
Effect of low self-esteem on depression
> effect of depression on self-esteem
What are the brain structures mediating negative cognitive bias?
> Limbic and subcortical (emotion)
- over activity in processing immediate emotional stimuli
> Hippocampal (memory)
> Dorsolateral prefrontal cortex (expectancy)
- reduced control of strategic emotional planning
- > increased response to negative stimuli
- > reduced response to positive stimuli
What characterises amygdala activity in depression?
Amygdala hyperarousal
- current patients with major depressions show higher responses (arousal states) to sad facial expression
- AND this persists in recovered patients who had major depressions, even if responses are lower compared to current patients
What are the inflammatory changes in affective disorders?
- Increased HPA axis activity
- Elevated sympathetic tone
What are the consequences of the inflammatory changes in affective disorders?
- Increased release of cortisol circulating from adrenal cortex
- Loss of glucocorticoid circadian rhythm
What are the raised markers of clinical inflammation in patients with depression?
- Activation of macrophages in blood
AND - Activation of microglia in brain
-> increased blood and brain pro-inflammatory cytokines
What is the most important consequence of increased inflammation observed in affective disorders?
Glucocorticoid receptor insensitivity/resistance
- loss of negative feedback
-> Elevated cortisol concentration
AND
-> Increased inflammation in both cerebral spinal fluid and peripheral blood
What are the structural abnormalities observed in both depressive and bipolar disorder?
- Enlargement of ventricular volume
- Hyperintensities of subcortical grey matter
- Reduction of hippocampal volume
- Small reduction (depressive) or subtle changes (bipolar) of prefrontal cortex volume
- Reduction of anterior cingulate cortex volume
Which structural abnormality is specific to depressive disorder?
Reduction of basal ganglia volume
Which structural abnormalities are specific to bipolar disorder?
- Vascular hyperintensities of white matter
- Reduction of corpus callosum area
Which areas of the brain have increased metabolic activation in depression?
- Amygdala
- Habenual
- Anterior cingulate cortex
- Hippocampus
Which areas of the brain have increased metabolic activation in bipolar depression?
- Limbic
- Thalamus
Which areas of the brain have increased metabolic activation in mania?
- Striatum
- Amygdala (more or less)
Which areas of the brain have decreased metabolic activation in depression?
- Nucleus accumbens
- Dorsolateral prefrontal cortex
- Medial prefrontal cortex
Which areas of the brain have decreased metabolic activation in bipolar depression?
- Dorsolateral prefrontal cortex
- Anterior cingulate cortex
Which areas of the brain have decreased metabolic activation in mania?
- Orbitofrontal cortex
- Anterior cingulate cortex (more or less)
- Posterior cingulate cortex
What is the pattern for the areas of increased metabolic activation in depression and bipolar depression?
Increased metabolic activation in emotion processing areas of the limbic system
What is the pattern for the areas of decreased metabolic activation in depression and bipolar depression?
Decreased metabolic activation in cortical areas that exert control over limbic emotional processing
What is the “kindling effect” observed in depression?
The more previous episodes of depression, the higher the risk of future episodes
What is the consequence of the enduring changes in brain activity and connectivity that occur in both depressive and bipolar disorders?
Increase the attention allocated to mood-congruent cues
What is the altered corticolimbic connectivity in affective disorders?
> Decreased connectivity from anterior cingulate cortex to
- thalamus and striatum in depression and bipolar
- left amygdala in bipolar mania
- right amygdala in bipolar depression
> Unstable connectivity in bipolar disorder
- decreased and increased connectivity reported during euthymic phase
-> instability is trait-dependent
(does not depend on the state of the illness)
Which cortical areas constitute the autobiographical memory network?
- PFC
- Anterior and posterior cingulate cortex
- Hippocampal formation
- Parietal regions
What is the other name for the autobiographical memory network?
Default mode network
What are the functions of the autobiographical memory (default mode) network?
- Autobiographic memory
- Autonoetic consciousness
- Daydreaming
- Mind-wandering
- Introspection
What is the autonomic consciousness?
Capacity to put oneself in another place and time while maintaining a sense of self
Which cortical areas constitute the cognitive control network?
> Bilateral circuit of front-cingulate structures
- dorsolateral prefrontal cortex
- anterior cingulate cortex
> Medial temporal lobe
> Intra-parietal regions
What are the functions of the cognitive control network?
- Goal-directed behaviours
- Working memory
- Selective attention to relevant tasks - inhibition
- Flexibility in task-switching
Which cortical areas constitute the affective network?
- Bilateral portions of cingulate cortex
- Ventromedial PFC
- Connected to amygdala, hypothalamus, striatum, midbrain, nucleus accumbens
What are the functions of the affective network?
- Arousal
- Appetite
- Libido
- Sleep
- Diurnal variation
- Vigilance
What is the correlation between the autobiographical memory (default mode) network and the cognitive control network?
They are anti-correlated:
- activation of one unactivates the other
During a goal-directed behaviour in a healthy state, what is the activity of the autobiographical memory, cognitive control and affective networks?
- “Task-positive” cognitive control network highly activated
- Autobiographical memory (default mode) network deactivated
- Affective (mood regulating) network suppressed
During a goal-directed behaviour in a depressed state, what is the activity of the autobiographical memory, cognitive control and affective networks?
- “Task-positive” cognitive control network highly deactivated
- Autobiographical memory (default mode) network hyperactivated
- Affective (mood regulating) network activated
During a goal-directed behaviour in a bipolar manic state, what is the activity of the autobiographical memory, cognitive control and affective networks?
- “Task-positive” cognitive control network highly activated
- Autobiographical memory (default mode) network disrupted
- Affective (mood regulating) network dysregulated
What happens during a goal-directed behaviour in a depressed state?
Focus shifts from cognitive task to introspective and emotion-laden thought processing
-> Patients express increased rumination and distractibility
What happens during a goal-directed behaviour in a bipolar manic state?
Instability in information between affective (mood-regulating) network and autobiographical memory (default mode) network
- > Decreased attention to internal mental processes
- > Dysfunctional attention to external stimuli
- > Dysregulation of mood-regulating network
