Neuroimaging deviations in bipolar disorder: genetic liability

Neuroimaging deviations in bipolar disorder: genetic liability

Neuroimaging deviations in bipolar
disorder: genetic liability and
structural disconnectivity
Colm McDonald
National University of Ireland, Galway
Schizophrenia - distributed grey and white matter deficits
Meta-analysis of 8327
medicated and 771
antipsychotic naïve scz
patients
Haijma et al, Scz Bulletin
2013
Meta-analysis of voxel
based morphometry studies
of 1195 patients with
schizophrenia and 1262
healthy volunteers
Glahn et al, Biological Psychiatry
2008
GM increased in patients
when proportion using lithium
increased
VBM meta-analysis of
660 bip patients and 770
controls
Bora et al, Biol Psych 2010
Heterogeneity of neuroimaging results in casecontrol studies of bipolar disorder
• clinical heterogeneity
• illness course/episodes of mood exacerbation
• psychotropic medications
- lithium associated with increased GM, especially limbic
system (Hafeman et al, Bipolar Disorders, 2012)
• genetic liability/environmental risk factors
• Individual regional volumetric data on 321 patients with
bipolar disorder and 442 healthy volunteers
• Enlarged right lateral ventricle and left temporal lobe in
patients with bipolar disorder
• Those patients on lithium had larger cerebral volume,
temporal lobe, hippocampus, amygdala
Mega-analysis of ROI studies of bipolar 1 disorder – effect of lithium
7.5
p=0.002
p<0.001
7.0
Total Hippocampal Volume (ml)
p=0.04
6.5
6.0
5.5
5.0
Healthy Comparison (n = 298)
Bipolar not on lithium(n = 68)
Bipolar on lithium(n = 94)
Hallahan et al, Biol Psych, 2011
Galway Bipolar Disorder Study – 60 euthymic bipolar disorder
patients vs individually matched controls
Reduced global white matter in
bipolar patients (F=5.742, p=0.018)
*
Reduction in hippocampal volume in
bipolar patients (F=4.07, p=0.046)
Excess lateral temporal grey matter in
patients taking lithium, cluster-level
corrected p<0.002
Emsell et al, Bipolar Disorders 2013
Diffusion tensor imaging
Fractional Anisotropy (FA) is a marker of WM microstructural integrity.
Ranging from 1 (perfectly anisotropic) to 0 (perfectly isotropic)
Diffusivity – overall degree of diffusion (mean, axial, radial)
FA reductions in distributed commissural, association and
projection tracts; meta-analysis identified reduced FA in left
cingulate, right posterior temporoparietal regions
GBS - 35 euthymic bipolar 1 disorder compared with 44 controls
A
Fractional anisotropy
B
Corpus callosum
(splenium)
Cingulum
C
D
Radial diffusivity
Emsell et al, Bipolar Disorders, 2013
constrained spherical deconvolution
tensor based tractography
Neuroanatomical connectivity - network analyses
through graph theory based metrics
- Characteristic path length (CPL) is calculated by
averaging the graph distances of shortest paths
between all pairs of nodes
- Global efficiency calculates the average inverse
shortest length between all pairs of nodes
- Clustering Coefficient (CC) is equivalent to the fraction
of the node’s neighbours that are also neighbours of
each other
0 .3 5
5 .0
p = 0 .0 1 7
E g lo b a l
p = 0 .0 1 5
CPL
4 .5
0 .3 0
0 .2 5
4 .0
B
C
H
D
B
C
H
D
0 .2 0
3 .5
D ia g n o s is
D ia g n o s is
0 .2 8
p = 0 .0 4 7
Euthymic bipolar patients:
 characteristic path length
0 .2 6
0 .2 4
CC
 global efficiency
0 .2 2
 clustering coefficient
0 .2 0
D
B
H
C
0 .1 8
D ia g n o s is
O’ Donoghue et al, in preparation
Genetic liability for bipolar disorder associated with white
matter abnormalities
- white matter volume and FA are heritable - twin and sib
studies
- twin studies shows high genetic liability associated with
reduced white matter volume (Hulshoff Pol, Arch Gen Psych 2012)
- distributed reduced FA in high risk unaffected relatives of
bipolar disorder patients (Sprooten et al, Biol Psych 2011) and
siblings (Sprooten et al, Am J Psych 2013)
- reduced FA in left posterior corona radiata and genu in
relatives of psychotic bipolar disorder patients (Skudlarski et al, Am
J Psych 2013)
Reduced fractional anisotropy with increasing genetic liability for bipolar
disorder in patients with bipolar disorder and their unaffected relatives
inferior longitudinal fasciculus
genu
cerebellar
peduncle
uncinate
fasciculus
internal
capsule
Chaddock et al, BJPsych 2009
corpus callosum
superior longitudinal fasciculus
Emsell et al, Psychological Medicine, in press
Increased genetic liability associated with reduced fractional anisotropy
in left uncinate fasciculus/superior longitudinal fasciculus
Emsell et al, Psychological Medicine, in press
Conclusions
• Bipolar disorder associated with heterogenous grey matter
abnormalities – grey matter preserved/deficit reversed by lithium
• White matter disorganisation of longitudinal, commissural and
anterior limbic system tracts are trait abnormalities of bipolar
disorder
• Genetic liability linked to white matter disorganisation in
distributed tracts
• Bipolar disorder – a heritable disorder of neuroanatomical
dysconnectivity
Acknowledgements
NUIG
Dara Cannon
Louise Emsell
Camilla Langan
Cathy Scanlon
Peter McCarthy
Brian Hallahan
Natalie Forde
Stefani O’Donoghue
IoP
Chris Chaddock
Robin Murray
Gareth Barker
Muriel Walshe
Elvira Bramon
International
Alexander Leemans
Ben Jeurissen
www.clinicalneuroimaginglaboratory.com
Funding sources:
Brain and Behaviour Research Foundation
(NARSAD)
Medical Research Council (UK)