SCHIZOPRENIA 3: SUBSTRATES
A confused field, with conflicts. Need to explain both positive symptoms and
• Traditional: Not much discussed these days!
o schizophrenia = left temporal focus?
Recall: chronic temporal lobe epilepsy can lead to schizophrenia and a
tonic-clonic seizure can cause forced-normalization (a temporary period
of being normal after tonic-clonic seizure)
o Whereas depression = right temporal focus?
Query: Exactly what is wrong in schizophrenics? Is there an anatomical “site” of
abnormality? Perhaps two or more.
• Bio ψ – perspective (an odd grab bag of symptoms) so we probably won’t
just find ONE anatomical sites, probably many.
For example: its not isolated like too much anxiety, too much depression,
too much voluntary movement or too little voluntary movement like the
next topics we’ll discuss
o Delusions – a limbic mistake? (delusions not open to logical
o Hallucinations – cortical? (but not like epileptic hallucinations – not
open to discussion)
o Feelings of threat (amygdala?)
o Feelings of grandeur (?)
o Thought disorder (s).
Not easy to explain like “anxiety syndrome = neuropathic anxiety).
Could there be multiple sites? Possibly. There are in Huntington’s chorea.
***************** What anatomical sites could be affected in schizophrenia?
Cell loss studies suggest that there is widespread cell loss in schizophrenia, and
that a number of sites could be involved.
Carlson shows pictures of the brains of schizophrenic and non-schizophrenic twins.
The schizophrenic twin shows a number of sites in the cortex that are smalled and
enlarged ventricles are enlarged, indicating cell loss.
Below shows enlarged lateral ventricles (suggesting cell loss)
Which two sites actually cause the symptoms?
Carlson: nucleus accumbens and prefrontal cortex 1) The Nucleus Accumbens: (nucleus accumbens septi)
o Is one some ways related to the amygdala (receives dopaminergic
projection from the ventral tegmental area – VTA). They have the
same supply of dopaminergic neurons!
What is the Nucleus accumbens (n. acc.)?
• It is in the subcortical forebrain (telencephalon) and is next to the septal area
–not blantantly limbic or BG; sometimes both (classically defined)
o The septal area is found in front of the thalamus, near the basal ganglia. They
provide cholinergic and GABAergic input to the hippocampus – thought to be the
wakeup for the hippocampus (particularly the cholinergic input)
o The nucleus accumbens is small, so do testing in the caudate nucleus (dorsal
striatum) – both have strong dopaminergic projections. It differs from the n. acc
because the abnormalities associated with it are often blatantly motor (basal
• A part of the “ventral striatum” (which also contains the olfactory tubercle –
sometimes classified as part of the BG)
• Target or dopaminergic axons from the VTA (floor of the mesencephalon
and right next to the substantia nigra; mesolimbic pathway)
o Carlson: VTA → N. Acc + Amyg + frontal cortex
VTA n. acc + amyg is the mesolimbic pathway (subcortical)
VTA cortex is the mesocortical pathway
Note: The amygdala might produce feelings of threat that give rise to the delusions
of persecution. –Fibiger
Puzzle of the N. Accumbens?
“Reward” (site of reinforcement)? Anxiety? Schizophrenia?
• Carlson tries to tie the development of delusions of persecution to an
overactive reinforcement. So basically, an overactive nucleus accumbens is
accidently reinforcing ideas of grandeur and persecution.
Support for the nucleus accumbens: dopamine hypothesis (below) 2) The Prefrontal Neocortex
Another Postulated Site of Abnormality
What is the Prefrontal Neocortex?
• Frontal lobe: contains a variety of limbic cortices plus neocortex
• Prefrontal neocortex = premotor = anterior association area = planning and
strategy (imaging non-present things) = dlPFC
Support for the Prefrontal Cortex: Carlson argues that schizophrenics
resemble people with prefrontal brain damage
Recent papers have identified the hippocampus as being another structure
that is abnormal
• Are these structures overactive or underactive? According to Carlson, the
positive symptoms relate to the nucleus accumbens and perhaps amygdala
(overactive?) and negative symptoms relate to the prefrontal cortex
• Positive symptoms
o Excess activity in DA circuits that connects to the n. acc.
don’t know if hyper- or hypofunctional; implication is hyperfunctional
o In other words, excess activity in mesolimbic paths, leading to the
Projecting to the n.acc and amygdala
o Model – discuss later
o Query: Is the n. acc. overactive therefore? Not clear.
Would depend on the receptors. When dealing with the motor systems
(caudate nucleus of striatum), they have both D1 and D2 receptors.
• D1 are excitatory and D2 are inhibitory
o receptors in the striatum are D2 family: they are inhibitory • Negative Symptoms
o Carlson relates these to hypofunction in the prefrontal cortex
He postulates prenatal brain damage which makes the child somewhat
abnormal from birth: this seems to cause behavioral abnormalities in pre-
Symptoms of children with this prenatal brain damage (Seen in several brain
damage syndromes though)
o catatonia, facial dyskinesia, too much or too little blinking, poor
visual pursuit, etc.
After puberty, further cell loss occurs (pruning; loss of axons) which leads to
severe PFC hypofunction and the onset of negative and then positive
Query: If there is widespread cell loss, why is the prefrontal cortex especially
affected? We don’t know.
Query: HPC? Another Strucure. Some theorists now postulate that the HPC is
overactive in Schiz and that that causes excess DA release in the N. Acc. NEUROCHEMISTRY
Background Review (Dr. Mitchell’s lecture)
The striatum is one structure in lower animals.
o Becomes caudate + putamen in higher.
VTA and substantia nigra lie in the floor of the midbrain.
• DA Paths:
o SN (substantia nigra) → Striatum (C/PU)
o VTA (mesolimbic, mesocortical) → N. Acc Amyg, Cx (cortex), etc
DA Receptors: al