Download The neuroscience of depression: why does it matter?

The neuroscience of
depression: why does it
matter?
Dr Susan Mizen
Exeter
Mark Solms and the Freudian
Brain
Neuroscience and the clinical
features of depression
Clinical features
Neural correlates
and decreased drive
Anhedonia
Highly simplified.
The SEEKING system
Reduced energy
The HPA axis
Memory problems
Hippocampus dysfunction
Attention and cognitive
impairment
Hippocampus, prefrontal cortex
and anterior cingulate
Anxiety
Amygdala and related regions
Immune dysfunction
HPA dysregulation implicated.
Brain regions implicated in depression
dorsolateral PFC
(DLPFC)
orbital PFC (OFC)
ventrolateral PFC (VLPFC)
anterior cingulate
amygdala
hippocampus
from Davidson et al 2002
One overarching system ties many regional disruptions together:
HPA axis and the stress response
immediate response (seconds)
adrenaline (norepinephrine):
blood from viscera to muscles
increase fuel availability
increase attention
decrease pain perception
longer-term response (min-hr)
cortisol:
increase glucose formation
increase cardiac contractility
suppresses inflammation and
other immune activity (prevents
genes from being replicated)
supports memory formation
(sensitizes amygdala and
hippocampus)
Findings linking stress and depression
Depressed patients have:
• high levels of circulating cortisol
• impaired negative feedback (suppression test)
• elevated levels of CRF in CSF
• increased number of CRF-secreting neurons
• CRF binding sites reduced in frontal cortex
• dysregulated circadian cortisol patterns
• reduced hippocampal volume
• increased amygdala sensitivity
Dysregulation caused by early life stress
Maternal separation and similar protocols (in rats)
associated with:
• increased CRF mRNA
• sensitization of CRF neurons
• hippocampal atrophy
• decreased glucocorticoid receptor density in HC and PFC
• increased locus coeruleus (NA) activity
• decreased GABA/BZ binding
• decreased oxytocin binding
Early life stress and depression
Dep.
ELS
Not all depressed people have a history of ELS
Not all people with history of ELS are depressed
However, HPA dysregulation is clearly linked to ELS and
ELS clearly linked to depression
SEEKING system
• evidence that DA modulates appetitive
positive affect
• “High” associated with DA activity in ventral striatum
• “High” attenuated by DA antagonism
• DAT polymorphism associated with diminished high
• Extroversion associated with DA functioning
• Dysphoria of DA antagonists associated with DA binding
• Drugs of abuse increase DA in Nacc
• Depression associated with dysregulation
of DA/SEEKING system and, of course, reduced
motivation.
The value cycle
Amygdala = Reward encoding
 Overall Function: Adjusts reward/punishment expectations
according to evolving contingencies
 Mobilizes autonomic nervous system
 Balleine (2006) Trends Neurosci 29 272
OFC = Improved Amygdala
 Learns associations between primary and secondary
reinforcers. Idealization/Devaluation is likely implicated here.
 Primary reinforcers (taste, touch) encoded in posterior
regions; more abstract (secondary) reinforcers (attachment
figures) encoded in anterior regions; hierarchical processing.
 OFC encodes pleasure
DLPFC = Control
 DLPFC: Control functions
 OFC: Reward (and punishment) encoding
 Euthymia: When control is on and punishment is off.
 Depression: When punishment is on and control is off
Mayberg (1999) Reciprocal limbic-cortical function and negative mood:
Converging PET findings in depression and normal sadness. Am J Psych
156:5 675-682
Both transient sadness & depression have increased ACC and
decreased DLPFC activity simultaneously; this reverses in neutral
mood and remission respectively.
ACC = Conflict Detection
 ACC is itself subdivided:
 - Dorsal ‘Cognitive’ division (red)
- Ventral ‘Affective’ division (blue);
“Activated in conflict between
incompatible streams of information.
Following conflict detection, the
lateral prefrontal cortices… are
engaged to resolve the conflict.”
(Van Veen and Carter, 2002)
- May also be involved in post hoc
error detection
- Can function consciously and
unconsciously
ACC activation in social exclusion
ACC is active -- and subjective distress reported -- when we think we
have been purposely neglected by others, but not when we think their
neglect is inadvertent.
Eisenberger (2003) Does Rejection Hurt? An fMRI study of social exclusion. Science 302: 290-292
The PANIC system
The PANIC system
Putting it all together
Control
DLPFC
OFC
Reward
Conflict & Advertising
+
ACC
Amygdala
Reward
VTA/NA
Putting it all together
Anterior Cingulate
DLPFC
Suppression
Abstract pl. /
unpl./ guilt
OFC
+
Conflict /
discrepancy
from ideal
Pleasure/
Unpleasure
Amygdala
Libido
Key NTs in MDD
•
•
•
•
•
•
Nestler (2002) Neuron
34 13-25
Locus Ceruleus (LC)
produces
Norepinephrine (NE)
Ventral Tegmental Area
(VTA) produces
dopamine (DA)
Dorsal Raphe Nuclei
(DRN) produce
serotonin (5-hydroxy
tryptophan or 5-HT)
GABA: inhibitory
interneurons
Glutamate: excitatory
NT from pyramidal cells
GABA
 Major inhibitory NT in mammalian brain;
40% of all neurons produce GABA!
 Primarily interneurons – eg local circuits –
and particularly abundant in mood-related
regions
 Pyramidal (output) neurons: Each GABA
neuron innervates ~3,000 pyramidal cells
 Li, Depakote, gabapentin, topirimate,
lamotrigine, SSRIs all increase plasma
GABA.
 GABA density reduced in MDD, and in
plasma and CSF
 Source: Taylor et al (2003)
Psychologocial Medicine 33 387-393
Glutamate
• Major Excitatory NT of brain; caffeine works via
Glu
• Allows Na+ influx, hyperpolarizing cell (bringing
it closer to firing)
• Activates NMDA receptors (cortex, amygdala,
hippocampus, BG) involved in LTP (long term
potentiation)
• Released by Pyramidal cells of cortex (80% of
neurons of cortex!)
• Reabsorbed through active transport; recycled
and reused
• GABAergic interneurons:
40% of all neurons in cortex!
• 1 GABA: 1000 Pyramidal
(permits oscillating
coordination)
Amygdala
GABA
Pyr
Prefrontal Cortex
Hippocampus
+
• Serotonin is major
excitatory input to cortical,
amygdala, and hippocampal
GABA interneurons =
dampens activity
• In turn, pyramidal neurons
are major excitatory input to
DRN GABA interneurons =
dampens the dampening
Glutamate
+
• Negative Feedback loop
5-HT
GABA
Taylor et al (2003) Psychological Medicine 33 387-393
Dorsal Raphe Nuclei
Overview
Serotonin dampens cortical, amygdala and
hippocampal activity in pyramidal cells, via
GABA
Medications that increase GABA and 5-HT
may potentiate this inhibition
If these regions are biased towards
punishment encoding, they can provide relief
If they help to grow more neurons (via BDNF),
they can improve information processing
BDNF and neurogenesis
 Hippocampus reduces in size in MDD, regains in treatment
 BDNF (brain derived neurotrophic factor) modulates hippocampal plasticity,
and triggers both increased dendritic sprouting, synaptic creation, and
neurogenesis
 ADs are known to increase BDNF and lead to increased size of
hippocampus and frontal cortex
 Nestler (2002) Neuron
34 13-25
Overview
GABA suppresses processing in amygdala,
cortex
Serotonin potentiates GABA, therefore
suppresses processing in amygdala, cortex
Both can suppress ‘punishment’, social
pain and distress calculations
BDNF boosts neural networks
? If the brain is biased towards calculating
punishments, improving function may
mitigate this bias
S allele predisposes
to ‘exogenous’ depression
Caspi (2003) Science 301 386
S-allele Dose-dependent amygdala activity




Bertonino (2005) Biol Psych 57 1517-1525
No of s alleles: 0, 1 or 2 s-alleles
Activity on a negative emotion perception task
Amygdala activity was predicted as a fx of No s alleles!
Putting it all together
Anterior Cingulate
DLPFC
Suppression
Abstract pl. /
unpl./ guilt
OFC
+
Conflict /
discrepancy
from ideal
Pleasure/
Unpleasure
Amygdala
Libido
Depression Subtypes
Typical
Poor sleep, no appetite, low mood,
(melancholic) ruminations, anhedonic
Atypical
Rejection sensitive, hedonic, high sleep, high
appetite
Alexithymic
Hostile
Anxious
Psychotic
Profuse somatic sx (pain, HA, GI) and denial
of psychological sx
Irritable, rage attacks + depression, often
atypical
MDD + GAD, often with trembling, pacing,
obsessions, ‘lady MacBeth’
Loss of reality testing + MDD
Therapeutic implications?
Mourning and Melancholia Revisited
2008: Carhart-Harris, Mayberg, Malizia and Nutt
Panksepp’s three innovations:
Reducing pain and increasing
pleasure
 Intervening with:
 PANIC (promoting excessive sadness and grief)
 SEEKING (promoting enthusiasm)
 PLAY (promoting social joy)
 To regulate depressive affect through:
 (a) reducing PANIC, namely, “psychic pain” with buprenorphine;
 (b) facilitating enthusiasm with deep brain stimulation of SEEKING
 (c) facilitating social joy (PLAY) GLYX-13, a partial agonist of glycine
receptors) currently in successful human testing.
 Therapeutic perspective
 Centrality of loss and separation in depression
 How loss is grieved for (Mourning)or defended against (Melancholia) in the
mind. (Freud, S. 1917)
How do therapies work?
Adshead and Fonagy (2012)
Therapy
Brain Area
Cognitive Therapy
Dorsal prefrontal cortex,
medial prefrontal cortex.
Reflective Therapy
Anterior cingulate cortex,
Posterior cingulate cortex,
Precuneus and Insula.
Amygdala
Behavioural Therapy