Transcript SKZ Hx Ebefrenia Catatonia Demenza paranoide Demenza precox

SKZ
Hx
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Ebefrenia
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Catatonia
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Demenza paranoide
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Demenza precox
Malattia maniacodepressiva
?
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paranoid
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disorganized
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catatonic
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undifferentiated
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residual
evidence
Brain structures
Nervous tissue architecture
Cell properties
↓
Hypotheses
models
Background
http://www.schizophrenia.com/research/schiz.brain.htm
http://www.loni.ucla.edu/
Grey matter loss (red)
n=96
SKZ
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Interplay between biological and psychosocial
factors
New conception of schizophrenia as a brain
disorder (last 20 years)
Not to dismiss environmental stressors, but
rather to put these in the perspective of a brain
disorder in evolution
SKZ
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Behavioral aberrations → diffuse abnormality in
several brain systems
Frontal and temporal lobes
Reduced volume was reported in multiple
regions including the superior temporal gyrus,
hippocampus, and thalamus.
Preimaging era
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Persistent negative symptoms have been
observed as a neurobehavioral sequela of
frontal lobe damage
Productive positive symptoms of hallucinations
and delusions have been related to the
temporolimbic system
SKZ
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The exception is basal ganglia regions ↑ volume
→ related to the effects of dopamine receptor
antagonists ?
Blood flow
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Patients did not show the normal pattern of
more anterior than posterior flow.
Decreased frontal metabolic activity has been
associated with duration of illness and negative
symptoms
Improvement in clinical status correlated with a
shift toward lower left hemispheric metabolism
relative to that in the right hemisphere
Metabolism and blood flow
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PET described abnormal cerebral blood flow in
the parahippocampal gyrus, associated with
positive symptoms.
SPECT blood flow changes in the
hippocampus, parahippocampus, and amygdala
→ Hallucinations
Symmetrical temporal lobe perfusion (lower in
the left than the right) in patients with auditory
hallucinations (inconsistencies).
Activation studies
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Healthy controls showed the expected greater
left hemispheric increase for the verbal task and
greater right hemispheric increase for the
spatial task.
Patients with schizophrenia had a bilaterally
symmetrical activation for the verbal task and
greater left hemispheric activation for the spatial
task.
Conclusion 1
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SKZ is a multifactorial brain disease
Neurodevelopment is crucial to the disease
and sensitive to external stimula
Front lobes and the limbic system are central
to SKZ but results from nimg did not yeald
comprehensive results
Thus → go into into further details, propose
and check models
Specificity of symptoms ?
Role of interneurons
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Higher order cognitive processes → θ and γ
oscillations (synchronized activity of networks of
pyramidal neurons at 4–7 and 30–80 Hz)
Normal → Power of θ and γ synchrony ↑ when
working memory load ↑
SKZ → ↓cortical θ and γ band power and
working memory performance
CCK-immunoreactive cell bodies → layers 2–
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Cortical θ and γ oscillations require strong
inhibition provided by GABAergic inputs to the
perisomatic region of pyramidal cells
Perisomatic inhibitory inputs to pyramidal
neurons are furnished primarily by GABAergic
basket cells that contain calcium-binding protein
PV (PVb cells) or neuropeptide cholecystokinin
(CCKb cells)
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↓ PV-immunoreactive
axon might reflect
fewer PVb terminals.
∼50% of PV neurons
lack detectable levels
of GAD67
↑ μOR PFC → ↓ PV
activity
↓ GABAA receptor α1
subunit → ↑ activity of
pyramidal cells
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CB1R ↓ PFC
statistically significant
in layers deep 3–4
and 6
That results in ↓
GABAergic
transmission
Is GABA that central ?
Cognitive deficits are present and progressive
years before the onset of psychosis
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the degree of cognitive impairment is the best
predictor of long-term functional outcome
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gamma frequency (30–80 Hz) oscillations in
DLPFC neural networks are thought to be a key
neural substrate for cognition
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↓ GABA in DLPFC → ∆ gamma frequency
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GAD65 and GAD67 drive the synthesis of
GABA in the brain
GAD67 mRNA and protein have been found
consistently to be lower in the DLPFC of
subjects with schizophrenia
frontal lobe GABA levels tended to be
correlated with working memory performance in
subjects with early-stage schizophrenia
Conclusion 2
GABAergic transmission in the mPFC could be
a main biological target for explaining the
cognitive deficits in SKZ
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▲ in the GABAergic transmission would result
in ↓ efficacy of the mPFC functioning
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Thus → check in other regions, find common
pathways
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SKZ KEY MAP POINTS
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PFC
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NACC
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HIPPOCAMPUS/AMYGDALA
PFC
1936 Jacobsen → monkeys with dlPFC lesions are example
of “out of sight, out of mind”
1979 Brozoski → depletion of cathecolamines from dlPFC
was detrimental as ablating the dlPFC itself
1992 Liddle → hyperactivity of the hippocampus in SKZ
2006 Lewis and Moghaddam → ↓ parvalbumin interneurons
in SKZ
2010 Arnsten → neuromodulators ∆ dlPFC network firing
(sec) through impacts on ion channels → dynamic network
connectivity (DNC)
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1987 Goldman Rakic → dlPFC receives visual
feature, auditory feature or auditory spatial
inputs, thus extending parallel sensory
processing into the dlPFC
1991 Goldman Rakic → dlPFC networks are
already observed in utero and in very early life
so they do not require experience to establish
connections
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Maier 2008 → A large portion of neurons in the
principal sulcal dlPFC show spatially tuned,
persistent firing across the delay period
Thus, neurons in dlPFC can represent visual
space in the absence of sensory stimulation
Goldman Rakic, 1996 → behavioural inhibition
and cognitive control depend on these
mechanisms
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Seo and lee, 2009 → emotions reward,
changing rules and goals require the activation
of the PFC
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Nearby neurons with similar spatial tuning
excite each other via connections on spines to
maintain firing without the need for bottom-up
regulatory stimulation
This persistent firing is highly dependent on
NMDA receptors, including those with NR2B
subunits (slow kinetics)
AMPA receptors are involved in the activity of
GABA interneurons
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Schizophrenia → ↓ GABAergic
action, with loss of spines and
neuropil in layer III
There is evidence of ↓
parvalbumin-containing neurons
in schizophrenic patients
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Layer V neurons also exhibit alterations in
schizophrenia
They project to the striatum and engage in
cortico-cortical connections
Lidow, 1998 → Some delay cells and most
response cells reside in layer V, they are
selectively influenced by D2 receptors and D2
receptor mRNA is enriched in layer V
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Ford 2002 → alterations in discharge feedback
from PFC may contribute to hallucinations
Corlett, 2007 → errors in feedback may also
play a role in delusions
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Working memory
A momentary ever
changing pattern of
recurrent activation of
relative stable
architectural networks
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Long term memory
It is associated with
structural changes in
synapses obtained
through:
Rapid ∆ n AMPA and
NMDA receptors
leading to structural
changes of the spine
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Long term memory
Requires Ca++ and cAMP which are facilitated
by neuromodulators and lead to trascriptional
events in the nucleus (Barco, 2003)
In this way the cortex is thought to accumulate
a lifetime of experience in remote memory
storage
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Working memory
↑ cAMP → ↓ working
memory
↑ NE stimulation of α1
receptors → ↓ working
memory
U shaped influence of
catecolamines
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Long term memory
↑ cAMP → ↑ long term
memory
↑ NE stimulation of α1
receptors → ↑ long term
memory
PKA activation may uncouple the α2R
that normally serve to inhibit cAMP
signaling
Ca++ can build up in spines through
a number of mechanisms:
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NMDA
IP3
NE α1R and mGluR
This process is further increased
through phosphorylation of IP3
receptors
Ca++ opens a variety of channels,
including the SK channels that
provide negative feedback to
NMDA receptors and reduce PFC
firing thus impairing working
memory
cAMP signaling also influences the
open state of a variety of ion
channels:
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↑ the open state of HCN channels
↑ the open state of KCNQ
channels, also called M channels
as they are activated by muscarinic
receptor stimulation. They are also
sensitive to
endocannabanoid/arachidonic adic
signaling
The phosphodiesterase PDE4A (kept
in the right place by DISC1) is
commonly found in the spine neck
and in the spine head near HCN
channels, it regulates the amount of
cAMP and thus the degree of HCN
channel opening.
cAMP levels are also reduced by α2A
receptors which inhibit cAMP
generation
α2 R colocalize with HCN channels in
layer III near the spines and spine
neck
Stimulation of α2R increases firing for
the neuron's preferred direction, thus
enhancing mental representation
Ach also plays a relevant role in
enhancing the activity of PFC
(nicotine receptor α7)
↑ nicotinc α2R agonism → ↑ delay
neurons firing rate in layer III
↑ muscarinic receptors → ↓ KCNQ
channels increasing neuron
excitability
The CA U shaped effect
The effect of age
Skz
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Atrophy in layer III of dlPFC
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Loss of neuropil, dendritic spines
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Weakened GABAergic lateral inhibition
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Atrophy in layer V dlPFC
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↓cortical DA and ↑ subcortical DA
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COMT genotype
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CA++ signaling
RGS4 normally serves to inhibit Gq signaling and it is markedly reduced from
the dlPFC of patients with schizophrenia
Schizophrenia is associated with the increased expression of receptors that
promote ca++ cAMP signling (↑ expression of mGluR1α → ↑ Ca++ internal
release and D1R expression)
Conclusion 3
Dendrite activity in the mPFC is central to
representation of stimuli before reaction and after their
termination
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These events may be the basis for delusional thoughts
and hallucinations
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The Ca++ homeostasis and PKA activation in dendrites
of layer III in mPFC is central to the correct firing rate
during delay period
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Thus → check more in delay period and
representation, check other parts of the brain
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NAc
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The central structure for integration of
contextual stimuli processed in the
hippocampus and executive functions from
the PFC
This system is modulated by the DA in the
ventral tegmental area to control goal directed
behavior
→ Latent inhibition
NAc
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Latent inhibition → proactive interference of
non-reinforced stimulus pre-exposure on the
subsequent performance of a learning task
involving this stimulus (Lubow 1973)
↓ the attention for that stimulus but does not
affect the association strength (Wagner and
Rescorla 1972)
NAc
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Latent inhbition → stimulus that are not
associated with any particular event are
actively ignored in their affective counterparts
→ SKZ ?
NAc
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1919 Kraepelin → disorder of attention” is
“conspicuously developed” in patients with
dementia praecox
1911 Bleuler → schizophrenia as the loss of
“selectivity [...] among the sensory
impressions”
NAc
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Normal rat + low doses of amphetamine → ↓
LI, reversed by AP
Normal rat + high doses of amphetamine →
normal LI
Normal rat + haloperidol → ↑ LI
The effect of drugs is only visible when the LI
is to be recalled, not when it is formed
NAc
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LI … conditioning … ↓ LI → affective
association with the stimulus
{LI + (hal | cloz)} … conditioning … ↓ LI →
affective association with the stimulus
LI … {conditioning + (hal | cloz)} … ≈ LI → no
affective association with the stimulus (Peters
and Joseph 1993)
→ the DA system is not involved in the
acquisition of LI but in it recovery when the
same stimulus is given
NAc
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The target of LI disruption by amphetamines is
the NAc (Solomon and Staton,1982)
↑ DA in NAc → ↓ LI → switch to the actual
association
↓ DA in NAc → ↑ LI →| switch to the actual
association
NAc
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Not involved in the LI formation but activated in
the conditioning stage, when the previously
non-reinforced stimulus is followed by
reinforcement
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Shell → promotes LI ↓
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Core → promotes LI ↑
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→ a shell lesion will destroy LI, a large NAc
lesion will promote perseveration
Hippocampus
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SKZ → ↑ activity in hippocampal structures (↓
parvalbumin interneurons in the PFC?)
This is correlated with positive symptoms
(Liddle, 1992)
Hyperactivity in the hippocampus is thought to
impair the Nac responses and leads to
hyperactivity of the DA pathway (O'Donnel
1999)
Hippocampus
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Intact hippocampus is necessary for LI
But destruction of fornix-fimbria does not alter
LI, while toxic effect of muscimole on
hippocampus impairs LI switch
H prevents of LI expression when conditioning
takes place in a different context
H has no role in LI extension when
conditioning takes place in the same context
Other relevant regions
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Disruption of the ehtorhinal cortex → ↓ LI
This event is reverted by hal → disruption of LI
in the NAc after lesion to the cortex is
mediated by an ↑ DA in the Nac
Lesions of the PFC or BLA do not affect LI