Title: PSYCHOSIS%20Neuro-Imaging%20(Schizophrenia%20and%20Bipolar%20disorder)%20What%20we%20know%20and%20what%20we%20could%20know
1PSYCHOSIS Neuro-Imaging(Schizophrenia and
Bipolar disorder)What we know and what we could
know
2Why 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
3Lesion 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.
4What 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
5Quantitative sMRI in schizophrenia
6Original 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
7sMRI 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).
8Key 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?
9sMRI 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)
10Baseline 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)
11sMRI 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
12Magnetic 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
13Diffusion 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)
14The 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
15Functional 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
16Pouratian et al TINS May 2003, 26(5) Pages
277-282
17Potential 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
18(No Transcript)
19- 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.
20Functional 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
21Prefrontal cortex dysfunction during working
memory performance in schizophrenia reconciling
discrepant findings (Manoach Schizo Res,2003
60 285-298)
- Schizophrenics show increased DLPFC activation in
high load condition (five targets). - 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. - If WM load was increased, one would expect
relative hypofrontality in schizophrenia. - If the WM capacity of controls were exceeded,
they might show reduced activation.
22SPECT 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)
23Trends 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
24PET 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)
25Other 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)
26Functional 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
27fMRI 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)
28COMT 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
29Bipolar Disorder Schizophrenia
No biological parameter defines either illness
30Bipolar 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
31Overall 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)
32(No Transcript)