Depression Flashcards
(21 cards)
Depression prevalence
Lifetime prevalence 8-12%, 12-month prevalence 6.7%, of which 30.4% are classified as “severe”
Prevalence for women is about twice that for men, Adolescents and young adults as at-risk populations (elevated depressive symptoms in 37% of 10-19 yrs olds)
What’s Major Depressive Disorder?
Heterogeneous syndrome (specifiers based on symptomatic differences, e.g., melancholic, atypical,
anxious). Highly heritable: 40-50% of risk is genetic. Genetic predisposition interacts with environmental factors (stress). ~80% of patients improve (partial response) with treatment; only ~50% remit completely. The pathogenesis of depressive disorder remains largely unknown
Which functions are dysregulated in depression?
➢ mood regulation
➢ emotional expression
➢ reward processing
➢ attention
➢ motivation
➢ stress responses
➢ neurovegetative functions (sleep, appetite, energy, libido)
The functional neuroanatomy of depression
The pathophysiology of depression implicates dysfunction within two extended cortical systems
associated with the orbital and medial PFC:
• Orbital prefrontal network: primarily connects central and lateral OFC with primary and
association sensory cortices. It functions as a system of both multi-modal sensory integration
and coding of the affective characteristics of stimuli and relative value
• Medial prefrontal Network: comprises prominent connections between the medial PFC and
anterior OFC, limbic structures (e.g., amygdala, striatum), structures that modulate visceral
function (nucleus tractus solitarius, PAG, hypothalamus), and a specific set of other cortical
regions (posterior cingulate, dlPFC, parahippocampal cortex, superior temporal gyrus);
does not have substantial sensory connections. The Medial Prefrontal Network is a
visceromotor network, involved in the coordination of affective (introspection, mood and
emotion), cognitive, behavioral, neuroendocrine, and visceral/somatomotor responses to
stress-related, reward-related, and aversive stimuli
Individuals with depression show abnormalities in both the Orbital prefrontal Network and the
Medial prefrontal Network during fMRI studies involving emotional processing tasks, although
the Medial Network and related structures are more specifically related to mood dysfunction
The Medial Prefrontal Network and the default mode network
The Medial Prefrontal Network is part of the system that has been defined in humans as the default mode network, a set of interconnected areas that are coherently more active in resting
(default) conditions, but become deactivated during extrinsic, externally-oriented sensory-motor tasks.
Default-mode activity is viewed as an “intrinsic”, self-referential activity, including
self-representations, episodic autobiographic memory, mind wandering, imagination,
“day-dreaming” and stimulus-independent thoughts.
Hyperactivity of the default mode network in depression might explain self-absorption and
perseveration on negative, self-referential thoughts
Different depression subtypes and symptom profiles may be mediated by dysfunctions of different nature (e.g., increased/reduced), localized to specific brain areas and/or imbalances in synaptic interactions within and between particular subcomponents of the circuitry.
Deriving quantitative measures based on coherent neurobiological dysfunctions or ‘biotypes’
enable stratification of patients with depression and anxiety
Structural brain abnormalities in depression
The magnitude and prevalence of morphological abnormalities depend partly on sex, age-at-onset, presence of mania or psychosis, presence of familial aggregation of illness
1) Reduced grey matter of subgenual ACC (20-50%), observed:
- early in the course of illness
- in young adults at high familial risk
- in both males and females
Persists despite successful treatment with antidepressants
2) Reduced volume of OFC and vlPFC (~30%)
3) Reduced volume of the hippocampus (8-19%) => glucocorticoid neurotoxicity
- possibly reversed by antidepressant treatment and electroconvulsive therapy through neurogenesis stimulation (increase in levels of brain-derived neurotrophic factor, BDNF)
4) Reduced volume of the caudate, putamen, and NAc
5) Reduced volume of the amygdala? (inconsistent)
Functional brain abnormalities in depression
Basal activity is increased in Depressed vs Controls and in Currently depressed vs Remitted in the vlPFC (inferior frontal cortex), sgACC, medial orbital cortex and the amygdala
How is hyperactivation of these brain structures related to depression symptoms?
Hyperactivity in the sgACC may account for:
- exaggerated feeling of sadness;
- increased sensitivity to affective conflict (e.g., mood vs. contextual demands);
- excessive/dysregulated visceral and autonomic responses to stressful and emotional events;
- anhedonia (through dysregulated influence over the ventral striatum)
Subgenual ACC
In healthy individuals, experimentally-induced transient sadness increases activity in subgenual ACC. Activity in subgenual ACC decreases with chronic fluoxetine treatment
Hyperactivity in the vlPFC/OFC may reflect:
- endogenous (unsuccessful) attempts to interrupt or inhibit unreinforced maladaptive emotional,
cognitive and behavioral responses → perseverative responses to stressors, poor flexibility in adapting behavior to changing reinforcement contingencies - exaggerated sensitivity to mistakes, negative feedback and failures (in individuals with depression, greater vlPFC activity correlates with higher amygdala activity and stronger sympathetic responses!)
Hyperactivity in the amygdala may account for:
- dysregulation of autonomic and neuroendocrine functions through excessive stimulation of subcortical and brainstem structures, e.g.
• hypothalamus→ excessive response to stress
• locus coeruleus and PAG→ excessive autonomic arousal - anxiety symptoms (and high comorbidity with anxiety disorders);
- “seeing the bad side of everything”: enhanced (and sustained) processing of negative stimuli, rumination, facilitated access to negative memories, negative interpretation of neutral or ambiguous stimuli
The PFC in depression: distinct roles for ventromedial and dorsolateral PFC
- vmPFC, Projections to hypothalamus, PAG, ventral striatum, amygdala = Affective functions
- dlPFC, Afferences from sensory cortices, reciprocal connections to premotor areas, frontal eye fields, parietal cortex= Cognitive/executive functions
Depression is associated with opposite activity profiles (imbalance) in vmPFC/vlPFC and dlPFC:
• basal resting-state activity in depressed patients as compared with non-depressed individuals is
abnormally high in the vmPFC and abnormally low in the dlPFC
• recovery from depressive episode is associated with increased activity in the dlPFC, and decreased activity in the vmPFC
How is the function of each PFC subregion related to depression?
A hyperactive vmPFC may be related to:
- the generation of enhanced negative emotion (in healthy individuals, resting vmPFC activity correlates with self-reported negative affect)
- increased self-awareness and self-reflection (vmPFC lesions are associated with loss of self-insight and reduction of negative self-referential emotions, e.g., shame, guilt, regret, sadness, self- depreciation)
- impaired modulation of emotion-related physiological components (projections to PAG, hypothalamus, amygdala)
A hypoactive dlPFC may be related to:
- impaired cognitive-executive functioning (attentional control, working memory, goal-directed
action, planning, decision-making, and abstract reasoning)
- poor emotion regulation (through reappraisal/suppression)
Is abnormal activity in vmPFC/dlPFC a cause or a correlate of depression?
If vmPFC and dlPFC are causally involved in the pathogenesis of depression, then damage to either
area would presumably affect the development of depression, but with opposite effects→ vmPFC lesions would confer resistance to depression (impairment of self-insight or self-reflection), whereas dlPFC lesions would confer vulnerability to depression (impaired regulation of negative emotion)
Clinical cases of PFC damage
Patients with bilateral vmPFC lesions have significantly lower levels of depression, whereas
patients with bilateral dlPFC lesions have significantly higher levels of depression as compared with patients with non-PFC brain lesions
A depressed patient who attempted suicide by a gunshot and destroyed most of the ventral PFC
(including vmPFC) while leaving intact most of the dorsal PFC => Depression markedly diminished following ventral PFC injury, and the patient reported a complete absence of sadness or suicidal
ideation
Transcranial magnetic stimulation and Deep brain stimulation
- Transcranial magnetic stimulation: Stimulation of left dlPFC is effective in treating refractory depression
- Deep brain stimulation: Inhibition of vmPFC is effective in treating refractory depression
Kindling hypothesis
‘Kindling hypothesis’: depressive episodes become more easily triggered over time
Kindling can be described as a process which occurs by a lowering of the threshold for the impact of stressful life events (i.e., sensitisation to minor events) or by an increase in spontaneous dysregulation, both of which could indicate progressive effects of MDD
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in depression
Activation of the HPA axis is a prominent mechanism by which the brain responds to acute and chronic stress:
In stress conditions, the paraventricular nucleus (PVN) of the hypothalamus releases
corticotropin releasing factor (CRF), which stimulates the synthesis and release of adrenocorticotropin hormone (ACTH) from the anterior pituitary and ultimately leads to
the release of glucocorticoids (cortisol) from the adrenal glands. Circulating cortisol provides negative feedback effects by binding to glucocorticoids receptors in the pituitary, hypothalamus and hippocampus
The negative feedback loop is deficient in depression despite high levels of circulating cortisol, leading to excessive activity of the HPA axis. Altered function of the HPA axis has consistently been found in individuals with major depression and anxiety (about 50% of cases); corrected by antidepressants
Acutely depressed, unmedicated subjects show an exaggerated release of cortisol in saliva upon
awakening as compared with controls
Euthymic, medication-free individuals with a past history of recurrent depression, and
asymptomatic individuals at genetic risk of depression have similarly increased cortisol levels after
waking→ cortisol hypersecretion might be a biological marker of depression vulnerability, not just an illness marker
HPA axis hyper-reactivity may mediate the higher rate of depression as a function of exposure to stressful life events in genetically predisposed individuals. The patterns of stress reactivity
vary as a function of genotype: individuals who are homozygous for the short allele (s/s) in the
promoter region of the serotonin transporter gene (5-HTTLPR) exhibit greater and prolonged
cortisol production in response to a laboratory stressor than individuals who have one or two
copies of the long allele→ lower serotonergic activity (serotonin enhances the negative feedback
control of cortisol)
It is still unknown whether HPA axis dysfunction is a primary pathophysiological disturbance in depression, or it is secondary to dysfunction in other brain system(s)
It is likely that dysfunction of the HPA axis is a core feature of depression (endophenotype), or at least that a considerable proportion of individuals who develop depression have exaggerated stress sensitivity (early life stress, e.g., abuse, neglect, traumatic events) and subsequent HPA axis sensitization (increasingly minor stressors maintain the disorder than were required to
trigger its initial onset)
The mesolimbic dopamine reward circuit in depression
Anhedonia (lack of positive affect in response to pleasant stimuli), reduced motivation, decreased
energy and psychomotor slowing have led to the hypothesis that mesolimbic dopaminergic dysfunction is involved in the pathophysiology and (possibly) etiology of depression
The mesolimbic dopamine system plays a critical role in mediating responses to rewarding stimuli (food, sex, social interactions, etc.), in motivation and psychomotor speed.
VTA-NAcc pathway may be also involved in mood regulation → antidepressant treatment alters
dopaminergic activity in the VTA and related target areas; experimental manipulation of dopaminergic transmission in the pathway can regulate depression-like behavior in animal models
Major depressive disorder is associated with opposing abnormalities in the reward circuit:
hypo-responses in the ventral striatum and hyper-responses in the orbitofrontal cortex
OFC hyperactivity may reflect enhanced inhibitory control over subcortical regions underlying reward-related behavior, leading to anhedonia
Dysregulated corticostriatal connectivity may underlie reward-processing abnormalities in major depressive disorder
Subprocesses and subdomains implicated in reward processing
- Reward-related cue
- Reward association
- Interest
- Anticipation
- Motivation
- Compute action plan
- Feedback integration
- Pleasure/ liking
- Expend effort
- Effort Computation
Specific anhedonic behaviors may be chiefly associated with disruption in one of several of these subdomains
