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Neurobiology of Schizophrenia

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Harsh Garekar

on 16 October 2014

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Transcript of Neurobiology of Schizophrenia

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Cellular and molecular neuropathology
Molecular brain imaging and theories of Schizophrenia
Neurobiology of Schizophrenia
Neuropathology
Structural/Functional Brain Imaging
Molecular imaging
Neurophysiology
Genetics
Post mortem tissue research
Morphometric studies
Cytoarchitectural changes
Neurotransmitter system
Molecular techniques - microarray, DNA chip array, immunochemistry, Western blotting, PCR
Morphometric studies and cytoarchitectural changes
Most consistent observation- normal macroscopic appearance
Metaanalysis - small (2%), reduction in brain weight
1976 landmark study- reported ventricular dilatation
Replicated by other studies
20-75% enlargement of third and lateral ventricles
Lacks diagnostic specificity
Found in unaffected relatives
Hippocampal Formation
Metaanalysis - hippocamapal volume reduction ( 4%)
Left-right hippocampal asymmetry
Recent studies - anteroposterior gradient
Cellular level - no change in neuronal density, smaller pyramidal neurons in the hippocampus
Prefrontal cortex
Volume deficit primarily due to grey matter changes
3 to 12% smaller than controls
No change in neuron number
Region specific increased neuronal density; Broadmann area 9, 46
tighter packing, shorter distance
Reduced neuropil theory- quantitative deficit in neural connections
Neuropil/neuropile, is a region between neuronal cell bodies in the gray matter of the brain and spinal cord consisting of a dense tangle of axon terminals, dendrites and glial cell processes. It is where synaptic connections are formed between branches of axons and dendrites

White matter, which is mostly composed of axons and glial cells, is generally not considered to be a part of the neuropil
White matter changes
comprises of axons and myelin sheaths
Accumulating evidence for white matter pathology
DNA microarray studies - downregulated gene expression in prefrontal and temporal cortices
components of myelin (MAG, MBP)
markers of oligodendrocyte differentiation( MOG)
Erb B3, a tyrosine kinase receptor with high affinity for neuregulin (product of NRG1)
Subtle ultrastructural changes - myelin compaction and lamellar arrangement - Altered glutamate homeostasis?
Synaptic Pathology
SNAREs are small, abundant and mostly plasma membrane-bound proteins
Mediate and support the trafficking cycle of neurotransmitter packaging, release and binding
SNAP (Soluble NSF Attachment Protein) REceptor
The core SNARE complex is formed by four -helices contributed by synaptobrevin, syntaxin and SNAP-25, synaptotagmin
Existing literature is divergent , inconsistent
Brain derived neurotrophic factor
Involved in neuronal differentiation, survival and neuroplasticity
Alteration in BDNF and its receptor Trk B
reduced in prefrontal cortex, increased/ decreased in hippocampus
Supporting the developmental hypothesis
Determines which neurons survive the pruning process - BDNF , known to promote survival of dopaminergic neurons
Needs replication studies
Neurotransmitter systems
Dopamine receptor hypothesis (1960’s): Hyper-dopaminergic activity → positive symptoms (supported by animal models, effects of reserpine and amphetamines on psychosis)
crystallized in 1970s - efficacy of antipsychotic related to D2 receptor occupancy
Post mortem studies -
no evidence of dopaminergic dysfunction
normal dopamine and metabolites in CSF
D1, D2, D3, D4 expression studies all negative
Increased D2 receptors, medication effect
Dopamine
Glutamate
Major excitatory amino acid
Psychotic symptoms produced and exacerbated by NMDA antagonists like PCP and Ketamine
Major connections between prefrontal cortex, hippocampus and thalamus are glutaminergic

Acetyl Choline
upregulation in nicotine seen in normal smokers is not seen in Schizophrenia
decreased nicotinic and muscarinic receptors in hippocampus frontal cortex, thalamus and striatum
Reduced expression of
alpha 7 nicotinic eceptor in the frontal cortex
alpha4 beta2 in the hippocampus
1976 - first CT study by Johnsone et al
showed enlarged lateral ventricles

1984 - first MRI study by RC Smith et al

1998 - Diffuse tensor imaging, Buchsbaum et al
Diffuse tensor imaging
MRI structural brain abnormalities
In a 2001 review 193 MRI studies were examined
atleast 10 subjects, use of quantitative measures
Findings
1. Enlarged lateral ventricles (80% of 55 studies)
2. Medical temporal lobe volume reduction (74% of 49 studies) - among the medical temporal lobe structure( amygdala, hippocampus, neocortical region) , the Superior temporal gyrus - 100% studies showed volume reduction
3. Third ventricle enlargement
"MRI findings now confirm structural brain abnormalities in Schizophrenia"
Since 2001....
574 publications
Questions have changed
What sort of disease is it?
Are changes present early in the course?
Do abnormalities change over time?
Do changes indicate a developmental lesion or are they neurodeenerative (as postulated by Kraepelin)
Chronic patients, First episode psychosis, prodrome studies, Family studies
DTI
White matter appears uniform and homogenous on MRIs
DTI quantifies white matter abnormalities through indirect measure of molecular motion of water in brain tissue
Fiber density, fiber diameter, thickness of myelin sheaths and direction of fibers affect diffusion of water molecules
Higher anisotropic diffusion = greater integrity of fiber tracts
Lower anisotropic diffusion = lower integrity
Example of fiber tracking. Voxels within fiber bundles are color coded according to their FA values (i.e., blue, low anisotropy; and red, high anisotropy).
80 published studies
Most consistent finding - Decreased FA within prefrontal and temporal lobes, as well as abnormalities within the fiber bundles connecting these regions (including uncinate fasciculus, cingulum bundle and arcuate fasciculus)
Other brain regions implicated- corpus callosum, anterior limb of internal capsule, fornix
Still early days, needs more standardized procedures
DTI Tractography - a promising new method introduced in 2005- the whole fiber bundle, instead of just a fragment, can be evaluated
Visulaization of in vivo brain chemistry using radiolabeled ligands with PET, SPECT, MRS
Arvid Carlsson's dopamine theory of schizophrenia
Serotonin hypothesis
Glutamate hypothesis
Response to drugs and new drug development
Cerebral blood flow and cerebral metabolism
Xe- 133, and radioactive water, FDG PET
reduced blood flow in frontal cortex, anterior cingulate, cerebellum and thalamus in left hemisphere
possibly increased compensatory increase in the right
FDG PET - hypofrontality in patients with Schizophrenia
Molecular imaging of dopamine
Binding Dopamine D2 like receptors
Absolute Dopamine D2 like receptor density
Dopamine percursor estimates
Intrasynaptic dopamine
Extrastriatal dopamine like receptors

One unifying theory by Anthony Grace -
Two states - phasic tonic dopamine theory

Tonic state- resting, basal, unstimulated state
Phasic state - maximal arousal, episodic, probably associated with symptomatology

Intrasynaptic dopamine -
abnormally reduced in tonic state
abnormally elevated in phasic states
Other receptors
lack of selective D1, D3 radiotracers
Serotonin -
decreased 5HT2a binding in the prefrontal cortex
increased 5HT1a in cortical areas
no difference in Serotonin transporter density found yet
Acetylcholine -
Muscarinic - marked decrease in muscarinic receptos (one study, consistent with post mortem studies)
Nicotinic - studies proceeding
Glutamate

Radiotracers binding to NMDA receptor channel , PCP site ( thalamus and other brain regions)
This binding was 1. reduced by ketamine (NMDA antagonist) 2. Clozapine reduces this binding 3. Increase in negative symptoms
Hypothesis - reduction of glutamate in the brain led to negative symptoms
Glutamate hypothesis- hypoglutaminergic state in frontal cortical regions leads to hyperdopaminergic states in the striatum
Linking abnormalities with phenomenology:

STG - hallucinations
STG, posterior temporal lobe - FTD
Fusiform gyrus and amygdala - face recognition
Anterior cingulate gyrus - impairment in social recognition
Frontal lobe - insight
Cingulum - error detection
Medial temporal lobe - language disturbances
Prefrontal cortex - deficit schizophrenia
Medial orbitofrontal cortex -negative symptoms
Functional imaging studies
fMRI, explosion of such studies n the last 5 years
BOLD Imaging - magnetic susceptibility effects of deoxyhemoglobin --> increase in image intensity = local decrease in hemoglobin--> increase in blood flow--> regional brain activation
abnormalities in activation patterns with deficits in performance
Confounding variables - Sample, medications, symptom severity, performance
Consistent findings -

Abnormal activation of ventro- medial and superior temporal lobe, prefrontal cortices and limbic structures with memory and executive tasks

Learning difficulty in schizophrenia → decreased activation of the frontal cortex, especially inferior prefrontal region; concomitant hippocampal dysfunction → suggesting disrupted fronto-temporal connectivity

Verbal memory (Healthy controls: activation of prefrontal regions and deactivation of STG) → less deactivation of STG in schizophrenia

Schizophrenic patients → difficulty in perceiving the affect displayed in facial expressions and non-vocal communication. Patients failed to adequately activate limbic regions during emotional valence discrimination as compared to healthy controls

Specificity - unclear, Heritability - preliminary data

Neurophysiological measures
recorded using standard EEG techniques
well suited for use as biomarkers
objective indices of cognitive dysfunction
time-locked to sensory events (for example, auditory or visual stimuli)
high heritability
P50 event-related potential (P50 ERP)
P300 event-related potential (P300 ERP)
Mismatch negativity (MMN)
Prepulse inhibition (PPI)
Neural synchronization
Eye movements
Neurophysiological markers
Event related potential occurring approximately 50 ms after the presentation of a stimulus, usually an auditory click

Used to measure sensory gating

Using paired click test

Localization of P50 – frontal lobe, hippocampus


P50 ERP
Sensory gating describes neurological processes of filtering out redundant or unnecessary stimuli in the brain from all possible environmental stimuli.

Prevents an overload of irrelevant information in the higher cortical centers of the brain
one auditory click sound will be presented
followed by a second click approximately 200 ms after the first one
The second sound is considered redundant
a typical control showing normal sensory gating will produce a reduced response (in wave amplitude) to the second click.
controls show an approximately 80% decrease to the second stimulus
Schizophrenia - reduction of only 10-20%
Paired click test
Auditory P300 ERP
earliest and best studied cognitive ERP abnormality in schizophrenia
elicited in the context of the
auditory oddball paradigm
subjects are instructed to attend to the sequence of tones, and either count the deviants or press a button in response to the deviants
P300 occurs approximately 300 ms following deviant tone presentation
reduction of P300 amplitude of approximately one standard deviation relative to healthy subjects
Seen in BPAD, other non-schizophrenic psychosis
Mismatch negativity (MMN)
reflect a pre-attentive stage of auditory information processing
elicited by unattended, as well as attended, deviants within an auditory oddball task
deficits in MMN generation - extensively replicated in schizophrenia
relatively selective for schizophrenia
Prepulse inhibition
pre-attentive state of information processing
a weaker prestimulus (prepulse) inhibits the reaction to a subsequent strong startling stimulus
Abnormal in chronic as well as first episode schizophrenia
Can be induced by NMDA antagonists like Ketamine
State dependent (reversible by clozapine)
Neural synchronization
examines naturally arising brain rhythms that occur while the brain performs specific sensory, cognitive or motor operations
Using advanced computing (Fourier transform or wavelet analysis)
Neural synchronization deficits have been reported in schizophrenia
Major focus of research - specifically on gamma oscillations
Neurons in different parts of the visual cortex fire at nearly the same time (i.e., in phase) during a cycle of gamma frequency oscillations to convey different attributes of the scenery and to help form a unified representation
Abnormality and reduced synchrony of gamma band correlated with positive symptoms, FTD, attention deficits
Eye movements
Smooth pursuit movements are impaired, with abnormal ‘catch-up’ saccades
Affected by anti-psychotic medications
Seen in unaffected relatives
In a sibling pair study, heritability of abnormal pursuit movements was reported to be 90%
decreased activation in multiple brain regions including the medio-superior temporal cortex, the frontal eye fields and the secondary eye fields


Ernst Rudin (1916): first family study - relatives of patients of dementia praecox have a greater risk of developing the same
Family Studies prior to 1980: criticized (lack of control group, lack of blinding in making diagnosis, lack of use of operational diagnostic criteria)
Later studies: confirmed schizophrenia runs in families
Higher risk in sibling and children- morbidity risk similar to older studies
Limitations:
higher risk could be due to genetic or environmental factors

Twin studies: concordance in MZ > DZ twins
Adoption studies: Children of schizophrenia patients have a risk of developing schizophrenia, schizoaffective disorder, other schizophrenia spectrum disorders, even when they are adopted away soon after birth
Familial aggregation - more genetic then environmental

Current approach

Association studies
Linkage studies
Copy number variants
SNP studies
Genome-wide Association studies

Potential candidate genes:
Disrupted-in-schizophrenia 1 (DISC1)
Dystrobrevin-binding protein 1 (DTNBP1)
Neuregulin 1 (NRG1)
Catecholamine-O-methyl transferase (COMT)
Regulator of G-protein signalling-4 (RGS4)
CHRNA7
Metabotropic glutamate receptor-3 (mGlu3)
Proline dehydrogenase (PRODH2)
D-Amino oxidase (DAAO) and G72
Catecholamine-O-methyl transferase (COMT)

COMT catalyses the methylation of catechols
val158met polymorphism is being extensively investigated
Val allele was associated with higher tyrosine hydroxylase expression, especially in neurons projecting to the striatum and amygdala ,indirectly leads to increased mesencephalic dopamine activity
val allele has been associated with poorer executive cognition, cortical processing inefficiency, abnormal P300
Neuregulin 1 (NRG1)


NRG1 is a member of the neuregulin family, comprising of four isoforms from NRG1-4
Mapped to chromosome 8p12-21
NRG1 mRNA and protein has been shown to be present in developing human brain especially the hippocampus, neocortex and cerebellum
Possible role schizophrenia → neuronal migration, axon guidance, synaptogenesis, glial differentiation, myelination, action of GABA and NMDA

Disrupted-in-schizophrenia 1 (DISC1)

First identified in an extended pedigree from Scotland
Chromosomal abnormality is a balanced translocation (1,11) affecting the Ch 1q42 → disrupts two genes: DISC1 and DISC2
Associated with cytoskeletal proteins, membrane trafficking of receptors, ribosomal and mitochondrial function
DISC1 polymorphisms - decreased hippocampal volume
Dystrophin binding protein1/Dysbindin (DTNBP1)

Identified in 2001 and mapped to chromosome 6p24-22
The expressed protein is the binding partner of A and B dystrobrevin that is part of the dystrophin associated protein complexes in the NM junctions and brain respectively
Involved in post-synaptic trafficking and tethering of NMDA, nicotinic and GABA receptors
Expressed in pyramidal cells of DLPFC, hippocampus

Currently, about 700 genes have been implicated in schizophrenia with more than 7000 polymorphisms,
Only few have demonstrated, at best, a modest association with schizophrenia in population based studies
Schizophrenia - currently cannot be explained with a single gene effect
Polygenic models where the effects of multiple risk genes acting additively or multiplicatively may provide the best explanatory fit

EPIGENETICS
Epigenetic modification refers to reversible modification of DNA through chromatin remodeling, rather than the inherited variability within the DNA sequences
dynamically regulated by histones
methylation, acetylation, phosphorylation
multiple genes could be modulated through a common pathway
Environmental factors - maternal malnutrition, intrauterine, viral infections can influence epigenetic change
Many neurochemicals are implicated, but dopamine is still considered to have central role
No single gene/ factor which can be believed to be causative for schizophrenia
Multiple genes , epigenetic and environmental factors, each contributing a small but significant risk for the disease process
Anatomical/physiological/functional changes identified till date→ No specificity to be considered as biomarkers

A Brief History
Both Kraepelin and Bleuler- believed that brain abnormalities would be linked to Schizophrenia

Neurochemical abnormality hypothesis - Dopaminergic overactivity
Serotonergic overactivity
Glutaminergic hypoactivity
alpha adrenergic overactivity
GABA hypoactivity

The neurodevelopmental hypothesis

The disconnection hypothesis

Social theories - The schizophrenogenic mother

Abnormality of information processing (Braff 1993)

Problem of working memory (Goldman-Racik 1994)
Cognitive dysmetria (Andreassen 1994)

Neurodegenerative disorder (Weiberger and McClure, 2002)

Disorder of Language (Berlim and Crow 2003)

Abnormal neural migration and DISC1 gene (Johnstone et al 2011)
Purpose of Seminar
To discuss the neurobiological basis of the aeteological theories of Schizophrenia
Increased presynaptic striatal dopamine synthesis - single most widely replicated brain dopaminergic abnormality in schizophrenia (effect size is moderate to large)
Increased dopamine release in the striatum (effect size is moderate to large)

Serotonin
Earlier basis: hallucinogenic effect of LSD mediated through 5HT2A receptors
Atypical antipsychotics that block 5HT receptors have clinical advantages over pure DA antagonists
Clozapine and Aripiprazole also antagonize 5HT2A and are partial 5HT1A agonists
5HT2A - tonic inhibition of DA neurons, which is antagonized by atypical antipsychotics
DTI findings
Conclusions
Ionotropic receptors -
AMPA, Kainite(KA), NMDA receptors
Decrease in AMPA recceptor mRNA and protein expression in hippocampus
Downregualtion of NMDA in the temporal cortex


Metabotropic glutamate receptors - mGluRs
Group II mGluRs - implicated in Schizophrenia using animal and human models
pre-treatment with mGluR agonists reverses the effets of NMDA antagonists ( phase II clinical trials, LY354740 (also known as Eglumegad, an mGlu2/3 agonist))
Interest in NAAG - N acetylaspartylglutamate, an endogenous neurotransmitter, weak agonist at NMDA, potent agonist at mGluR3
Full transcript