PSYCHOSIS%20Neuro-Imaging%20(Schizophrenia%20and%20Bipolar%20disorder)%20What%20we%20know%20and%20what%20we%20could%20know

1
PSYCHOSIS Neuro-Imaging(Schizophrenia and
Bipolar disorder)What we know and what we could
know

• Stephen Lawrie
• Edinburgh

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Why brain scan in psychosis?

• Some current clinical utility
• To improve understanding of pathophysiology
• To refine (endo)phenotype definition
• ? (early) Diagnostic aids
• ? Predicting treatment response and/or prognosis

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Lesion detection qualitative analyses of
structural imaging

• Lawrie et al, Schizo Res, 1997
• gross lesions (e.g. AVMs, cysts, tumours) in 0-5
• atrophy in 4-52 c.f. 2-19 controls
• HIS foci in 5-38 c.f. 3-19 controls
• Usually of little clinical importance
• i.e. CT/sMRI only indicated in atypical
  presentations
• Albon et al, HTA, 2008
• In MRI studies, approximately 5 of patients had
  findings that would influence clinical
  management, whereas in the CT studies,
  approximately 0.5 of patients had these
  findings.
• The strategy of neuroimaging for all psychosis is
  either cost-incurring or cost-saving (dependent
  upon whether MRI or CT is used) if the prevalence
  of organic causes is around 1.

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What did CT tell us?

• - Ventriculomegaly (corr. hospitalisation) and
  cerebral atrophy (Raz, Psychol Bull 1990, 108
  93-108)
• VBR not bimodally distributed (Daniel, Biol
  Psych 1991, 30 887-903)
• VBR related to duration Dx criteria (van
  Horn, Br J Psych 1992, 160 687-97)
• VBR not related to treatment response
  (Friedman, J Psychiatri Neurosci 1992, 17
  42-54)
• i.e. not much more than pneumo-encephalography

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Quantitative sMRI in schizophrenia
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Original T1 image
Segment images (GM, WM CSF) remove
extra-cerebral voxels
Normalise GM seg. to template to obtain norm.
parameters
Voxel Based Morphometry
Apply norm. parameters to original images
Segment normalised images remove extra-cerebral
voxels
Smooth final images
unmodulated
modulated
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sMRI systematic reviews in schizophrenia

• reduced whole brain volume (by 3 Ward, Schiz
  Res 1996197-213)
• corpus callosum similarly (Woodruff, JNNP 1995
  58 457-61)
• reduced hippocampal and amygdala volume (by about
  4 each Nelson, Arch Gen Psych 1998 55 433-40)
• reduced pre-frontal medial temporal lobe (MTL)
  volumes (Lawrie Abukmeil, Br J Psych 1998172
  110-120)
• reduced superior temporal gyrus (STG) increased
  globus pallidus volumes (Wright, Am J Psych 2000
  157 16-25)
• reduced thalamus (Konick Friedman, Biol Psych
  2001 49 28-38)
• reduced anterior cingulate (Baiano, Schizo Res
  2007)
• Similar changes also seen in first episode cases
  (Vita et al, 2005 Steen et al, 2006)
• Also, 15 VBM studies consistently find reduced
  grey matter (GM) in MTL and STG (Honea et al, Am
  J Psych 2005 162 2233-45)
• An ALE analysis of 27 articles found GM decreases
  in the thalamus, the left uncus/amygdala region,
  the insula bilaterally, and the anterior
  cingulate both first-episode schizophrenia (FES)
  and chronic schizophrenia. Comparing patient
  groups, decreases in GM were detected in FES in
  the caudate head bilaterally, while decreases
  were more widespread in cortical regions in
  chronic schizophrenia (Ellison-Wright et al, Am J
  Psych 2008).

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Key unresolved questions

• When and how do the abnormalities arise?
• What is their neuropathology?
• How is the anatomical phenotype related to the
  clinical and cognitive features?
• Does it progress after onset?
• Do antipsychotic drugs ameliorate or exacerbate
  these abnormalities?

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sMRI studies of relatives

• Relatives have smaller MTLs than controls
  (Keshavan 1997 2002 Lawrie 1999 2001
  Schreiber 1999 Seidman 1997 1999)
• Schizophrenics have smaller MTLs than relatives
  (Lawrie 1999 2001O'Driscoll 2001Steel 2002
  but see Staal 2000)
• Best evidence for hippocampal differences on ROI
  (Waldo 1994Harris 2002Seidman 2002van Erp 2002
  but see Schulze 2003).
• Best evidence for pre-frontal differences on VBM
  (Job 2003).
• Supported by twin studies (Suddath 1990 Baare
  2001 Cannon/Narr 2002 van Erp 2004)
• and g-e risk factor studies (DeLisi 1988
  Stefanis 1999 McNeil 2000)
• Boos et al meta-analysis (Archives 2007) of
  relatives ROI finds hippocampal reductions in
  relatives Vs controls (ES 0.3) and additional
  difference in relatives Vs patients (ES 0.5)

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Baseline prediction of conversion- studies of
relatives or ultra-high risk

• Hippocampus volume is a best a weak and
  inconsistent predictor (Lawrie, Archives 2007)
• No prediction (Job, 2005 Johnstone, 2005
  Velakoulis, 2006)
• Small hippocampus predicts (Pantelis 2003)
• Large hippocampus predicts (!) (Phillips 2002
  Bogwardt 2007)
• Anterior cingulate and Superior temporal gyrus
  volumes may however predict (PACE studies)
• Gyral folding may predict (EHRS Harris et al,
  2007)

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sMRI studies of pre-psychosis progression from
the PACE clinic the EHRS

• Pantelis et al (2003) reductions in grey
• matter in the left parahippocampal,
• fusiform, orbitofrontal and cerebellar
• cortices, and the cingulate gyri.

Job et al (2005) reductions in grey matter in the
left (para)hippocampal uncus and fusiform gyrus,
and right cerebellar cortex
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Magnetic Resonance Spectroscopy (MRS)

• Initial resolution problems solved
• Whole brain acquisitions still impractical
• Incredibly consistent literature reductions in
  frontal and temporal NAA which are not volume /
  medication artefacts
• (see Steen et al 2005 Neuropsychopharmacology 30
  1949-62)
• 3-4T systems give good enough resolution for
  reliable estimation of Glu, Gln, GABA and a-ATP,
  ß-ATP and ?-ATP moieties
• Interpretation difficulties - ? a structural or
  functional index of integrity / viability

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Diffusion Tensor Imaging (DTI)

• Can assess the structural integrity of white
  matter tracts
• Inconsistency of the literature in schizophrenia
  overplayed, but inconsistency of methods usefully
  highlighted, in a recent review (Kanaan et al
  2005, Biol Psychiatry 58 921-9)
• ROI and VBM analysis giving way to TBSS and
  tractography analyses
• Also, Magnetisation Transfer Imaging (MTI)

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The future of structural imaging in schizophrenia

• Increasingly sophisticated automated analyses
  DBM and TBM
• The anatomical basis of disconnectivity e.g.
  GI, DTI
• More high resolution studies e.g. 3T of CA3, ?Cx
  layers
• The use of pattern classification methods to use
  more information to e.g. make diagnostic
  classifications
• Automated extraction of regional volumes, to
  avoid brain averaging
• Multi-centre studies
• Integration with other techniques in multi-modal
  imaging

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Functional imaging techniques

• Electrophysiology
• EEG
• ERPs
• MEG
• NIRS
• LORETA

• rCBF studies
• SPE(C)T
• PET
• fMRI
• in conditions
• Rest
• Active vs Rest
• Active Vs Active
• receptor ligands
• pharmacological manipulation

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Pouratian et al TINS May 2003, 26(5) Pages
277-282
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Potential confounders of functional imaging
abnormalities

• IQ
• Reaction time
• Distraction by positive symptoms
• Motivation
• Medication
• Alcohol and other drugs
• Structural brain abnormalities
• Causative versus effect modifying genes

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• Statistical maps of regional cerebral blood flow
• Conjunction analysis showing voxels with
  significantly (p lt 0.01, voxel level) higher rCBF
  during the task than the control task.
• Wisconsin Card Sorting Test stimuli.
• (c) Voxels showing significantly (p lt 0.05)
  higher rCBF in the task-minus-control contrast in
  the frontal lobes of controls as compared to
  patients.

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Functional imaging (brain mapping) systematic
reviews

• Delayed and reduced P300
• Increased P300 peak latency (Ebmeier, Biol Psych
  1991 29 1156-60)
• Reduced P300 amplitude too (Jeon Polich Psych
  Res 2001 104 61-74 Psychophysiol 2003 40
  684-701 also Bramon et al 2004 Sch Res 70
  315-29 PSES0.6 0.8)
• Hypo- and Hyper- frontality
• 21 resting PET studies ES 0.64 (95CI 0.91 to
  0.38) 9 activated studies overall ES 1.13
  (1.53 to 0.73) (Zakzanis Heinrichs, JINS
  1999 5 556-66 see also Davidson Heinrichs
  Psych Res 2003 122 69-87 and Hill et al Acta
  Psychiatr Scand. 2004 110243-56.)
• Glahn et al (Hum Brain Mapp 2005 25 60-9)
  reviewed 12 N-back studies to find DLPFC
  hypofrontality and hyper-frontality in Ant.
  Cing. (L) frontal pole
• Hyper- and Hypo- temporality
• 13 SPECT studies show effect sizes from 0.25
  (superior) to 2.0 (inferior) 6 PET studies show
  effect sizes from 0.14 (right) to 1.3 (superior)
  (Zakzanis, Psychol Med 2000 30 491-504)
• Achim Lepage (Br J Psych 2005 187 500-9)
  examined 18 episodic memory studies and found
  consistent (L) IPFC and (Bi) MTL reductions in
  activation

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Prefrontal cortex dysfunction during working
memory performance in schizophrenia reconciling
discrepant findings (Manoach Schizo Res,2003
60 285-298)

1. Schizophrenics show increased DLPFC activation in
   high load condition (five targets).
2. When task performance is matched by comparing
   schizophrenics in low load condition (two
   targets) to controls in high load condition (five
   targets), DLPFC activation does not differ.
3. If WM load was increased, one would expect
   relative hypofrontality in schizophrenia.
4. If the WM capacity of controls were exceeded,
   they might show reduced activation.

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SPECT PET dopamine - ligand studies

• Dopamine D2 receptor numbers are increased
• effect size 1.47 in 17 PM PET studies
  (Zakzanis, Schizo Res 1998 32 201-6)
• by 12 in 13 imaging studies (Laruelle, QJ Nucl
  Med 1998 42 211-21)
• with moderate increases in both DA D2 density
  (Bmax) and affinity (Kd) (Kestler et al Behav
  Pharmacol 2001 12 355-71)
• Presynaptic dopaminergic function increased in
  striatum
• with greater amphet. DA release and DOPA decarb.
  activity (Laruelle, QJ Nucl Med 1998 42 211-21)
• Striatal F-DOPA uptake and DOPA decarb. activity
  is increased in schizophrenia (e.g.
  Meyer-Lindenberg et al. 2002, replicates four
  previous reports)

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Trends in functional imaging of schizophrenia

• Testing the dis-connectivity hypothesis
• Examining relatives and genetic / symptomatic
  high risk subjects
• Genetic imaging
• Computational modelling
• Testing more specific hypotheses in activation
  studies e.g. fearful face processing, associative
  learning
• Default mode resting studies
• Biomarkers and other Translational studies

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PET and/or fMRI replicated pre-frontal
functional disconnectivity

• Less DLPFC reduction of (left) STG metabolism
  during verbal fluency on PET (Frith, 1995, Br J
  Psychiatry) and fMRI (Yurgulun-Todd et al, 1996)
• Abnormal anterior cingulate dopaminergic
  modulation of STG activity on PET (Dolan, Nature
  1996 378180-2 Fletcher, 1996 1998 1999)
• Reduced (left) DLPFC-STG functional connectivity
  correlates with auditory hallucinations on fMRI
• (Lawrie, Biol Psychiatry 2002 Shergill, 2003)
• Widespread disconectivities at rest and on
  activation including reduced fronto-temporal and
  fronto-parietal connectivities with both PET and
  fMRI (Meyer-Lindenburg, 2001 2005 Kim et al
  2003 Foucher, 2005)

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Other replicated disconnectivities

• 1. Reduced EEG coherence
• Including reduced fronto-temporal coherence and
  hallucinations (Norman 1997 Ford 2002)
• 2. Effective connectivity on PET/fMRI
• Different AC-fronto-temporal interactions on PET
  (Jennings 1998)
• Disease and medication related changes in
  Fronto-fronto/-parietal/-thalamo-cerebellar
  networks on fMRI (Schlosser, 2003 Schizo Res)
• PET D2 binding path connections reduced in AC to
  frontal, parietal and thalamus regions with no
  Papez connectviity (Yasuno, 2005 PRNI)
• 3. Increased weirdness on fMRI (Welchew 2002)
  and signal variability on EEG (Winterer 2000) and
  MEG (Ioannides 2004)
• 4. Reduced (shortened) EEG microstates
  (spontaneous concatenations) at rest (Koenig
  1999 Lehmann 2005)
• 5. Abnormal gamma-band oscillation and
  synchronisation (Spencer 20034 Symond 2005)

Overall, several EEG, PET and fMRI studies find
disturbances in functional and effective
connectivity within and from pre-frontal lobes
(Stephan et al Biol Psych 2006)
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Functional imaging in relatives

• Hypo- compensatory Hyper- frontality
• Berman (1992) Sch twins hypofrontal on WCST
• Blackwood (1999) reduced L-IPFC AC at rest
• ODriscoll (1999) NS diffs in 17 relatives
• Spence (2000) NS diffs in 10 obligates
• Keshavan (2002) reduced BOLD in DLPFC IPC on
  MGS task
• Callicott (2003) (R)DLPFC increased BOLD on
  matched N-back task
• Thermenos (2004) increased BOLD in (L) DLPFC,
  AC, thalamus PHG on CPT
• Whalley (2004) increased parietal reduced
  front-thalamo-cerebellar BOLD on HSCT (etc)
• Seidman (2005) - exaggerated fMRI response in
  DLPFC on auditory WM
• Disconnectivity
• Replicated reduced fronto-frontal connectivity on
  SPET (Spence, 2000) and fMRI (Whalley, 2005)
• Electrophysiology
• Bramon (2005) pooled 472 relatives 513
  controls
• - P300 amplitude reduced (PSES 0.61, 0.30 to
  0.91)
• - P300 latency delayed (PSES -0.50 -0.88 to
  -0.13)
• In a series of studies Winterer et al (2001,
  2003, 2004) have internally replicated reduced
  EEG coherence and increased variance / reduced
  STN in relatives

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fMRI in the Edinburgh High Risk Study- results
with the Hayling sentence completion test

• Reduced fronto-thalamo-cerebellar activation in
  all at genetic high risk Increased parietal
  activation in those with psychotic symptoms
  (Whalley, Brain 2004)
• Increased fronto-thalamo-cerebellar functional
  connectivity but no alteration in fronto-temporal
  connectivity (Whalley, Brain 2005)
• Increased parietal, reduced lingual and reduced
  MTL/STG activation predicts onset of
  schizophrenia 1-15 months later (Whalley, Biol
  Psychiatry 2005)
• Individuals homozygous for the risk allele (T/T)
  of the Neuregulin 1 (SNP8NRG243177) all developed
  psychotic symptoms, had reduced NART scores and
  decreased activation of right medial PFC and
  right posterior MTG (Hall et al Nature
  Neuroscience, 2006)

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COMT Val gt Met differences for parametric contrast
High Risk subjects with the COMT Val allele also
had reduced grey matter density in anterior
cingulate cortex and a greater risk of becoming
ill (McIntosh et al, Biological Psychiatry 2007
611127-34).
19 MM 29 MV 9 VV
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Bipolar Disorder Schizophrenia
No biological parameter defines either illness
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Bipolar Disorder Schizophrenia
Structure ? ventral PFC ? amygdala
Structure ? dorsal gt ventral PFC ? amygdala / MTL
Structure ? thalamus ? HPC ? medial PFC
Function ?? dorsal PFC ?? striatum ?? amygdala
Function ?? ventral PFC ?? ventral striatum ?
amygdala
Function ?? Cingulate
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Overall Conclusions

• The gross structural neuroanatomy of
  schizophreniais evident to some extent in those
  at high risk and further MTL reductions are
  likely around onsetbut it is at least partly
  non-specific and of largely unknown cause(s)
• WE NEED
• 1 More longitudinal sMRI studies within 5 years
  of onset
• 2 Urgent harmonisation of multi-centre sMRI and
  approaches to DTI acquisition and analysis
• The functional neuroanatomy of schizophrenia
  involves hypofrontality, and dopamine modulated
  striatal abnormalities and (symptom related)
  fronto-temporal disconnectivity
• WE NEED
• 1 Functional imaging studies which examine
  performance at multiple points across the
  load-response curve, with and without
  pharmacological challenge
• 2 Harmonisation of approaches to functional and
  effective connectivity analyses, for EEG, MEG
  fMRI, with a view to integration with DTI (and
  sMRI)

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