Abnormalities In Subcortical Glutamate/Glutamine,
But Not GABA, In Adults With An ASD
A [1H]MRS Study
M. Andreina Mendez, Jamie Horder, Nicola Gillan, Suzanne
Coghlan, Declan Murphy
Background - General
● GABA / glutamate balance implicated in ASD?
Background - General
● GABA / glutamate balance implicated in ASD?
• Rodent models
• e.g. reduced GABA-A receptors, increased
glutamate mGluR receptors (subtype-specific) (Selby
et al 2007)
Background - General
● GABA / glutamate balance implicated in ASD?
• Rodent models
• e.g. reduced GABA-A receptors, increased
glutamate mGluR receptors (subtype-specific) (Selby
et al 2007)
• Human Postmortem Studies (Blatt & Fatemi 2011)
Background - General
● GABA / glutamate balance implicated in ASD?
• Rodent models
• e.g. reduced GABA-A receptors, increased
glutamate mGluR receptors (subtype-specific) (Selby
et al 2007)
• Human Postmortem Studies (Blatt & Fatemi 2011)
• Genetics – ASD CNVs include GABA-A receptors e.g.
15q11-13 (Urraca et al 2013)
Background - General
● GABA / glutamate balance implicated in ASD?
• Rodent models
• e.g. reduced GABA-A receptors, increased
glutamate mGluR receptors (subtype-specific) (Selby
et al 2007)
• Human Postmortem Studies (Blatt & Fatemi 2011)
• Genetics – ASD CNVs include GABA-A receptors e.g.
15q11-13 (Urraca et al 2013)
• Comorbidities – epilepsy common in ASD (20% vs
2% in non-ASD) (Kohane et al 2012)
Background - PET
• Positron Emission Tomography (PET) can measure GABA-A
receptor density
• We showed preliminary evidence of reduced GABA-A alpha5
(Mendez et al 2013)
[11C]Ro154513 VT parametric
images, averages of 3 healthy
adult males and 3 ASD males.
This view illustrates lower
average binding in the nucleus
accumbens, and other regions
HEALTHY
0
ASD
4
8
VT
12
16
• But PET can’t measure neurotransmitters…
Background - MRS
● Proton magnetic resonance spectroscopy (MRS) can
measure GABA, glutamate and glutamine (Glx)
● Previous studies have found evidence of
glutamate/glutamine (Glx) abnormalities….
But how about GABA?
Methods - GABA/Glx MRS
Left striatum
35 x 30 x 25 mm
Function: action and movement
control
Bilateral midline dorsal ACC
25 x 40 x 30 mm
Function: cognitive control, error
monitoring, executive
Participants
● n = 22 adult males with a diagnosis of ASD and IQ>70 and 27
control males matched on verbal, performance and full-scale IQ (ttest, all p>0.4, mean FSIQ 119 vs. 116.
● Diagnosis by expert clinical judgement using ICD-10-R criteria
based on ADOS Module IV + ADI-R (where possible)
● Exclusion criteria included:
•
•
•
•
•
Epilepsy
Genetic disorder
Psychosis
Substance dependence.
Any psychoactive medication at the time of scanning, within previous six
weeks minimum.
Results #1 – MRS
We found a significant reduction in Glx in
the left striatum (p = 0.033 two-tailed).
However, no differences were seen in Glx in
the DMPFC, or in GABA in either voxel.
Therefore, replicating previous findings
using PRESS MRS (Horder et al 2013), we
showed reduced Glx in the basal ganglia
region in adults with ASD.
(Previous Findings
Discussion #1: MRS – fMRI
● Might a reduction in striatal Glx have functional implications?
● We used resting state fMRI to examine the correlation between
[1H]MRS Glx signal and the functional connectivity to/from the
basal ganglia region (putamen) as a seed (seed-voxel correlations):
Results #2: MRS-fMRI association in all
participants (n=42)
A significant (p < 0.05, whole-brain cluster corrected) effect of striatal Glx on the
pattern of connectivity with the left putamen was found. Areas of significant
differences included the anterior cingulate cortex.
Inspection of the scatterplot revealed that this effect was not driven by outliers.
Results #3: Glx vs. Connectivity: HV vs.
ASD
The correlation between left
basal ganglia Glx and left
putamen connectivity was
stronger (p<0.05 whole brain
corrected) for healthy controls
than for ASD patients in two
regions:
• Medial prefrontal cortex
• Lateral temporal lobe
including STG and MTG.
Conclusions
● Subcortical (striatum) glutamate/glutamine is reduced in
adults with ASD
● However, we found no differences in GABA in either the
cortex or the subcortex
● Contrasts with prior evidence and theory?
● Or understandable in terms of multiple ‘pools’ of brain
GABA, only some of which may be abnormal?
Detailed Methods
MRS
fMRI
●
J-edited MEGAPRESS [1H]MRS at 3T
was used, TE = 68 ms.
●
Unsuppressed
acquired and
quantitation
water
used
signal was
for absolute
●
Voxel grey, white and CSF composition
was calculated from T1 structural MRI.
Water-scaled metabolite concentrations
were corrected for CSF.
●
Data analysed in LCModel software.
Unedited spectra were used to quantify
Glx while J-edited ON/OFF subtraction
spectra were analysed to measure
“GABA+” (GABA + macromolecules).
●
Instructions were to remain awake with
eyes open and fixate on a static cross
on a dark background
●
256 volumes, TR = 2000 ms. Analysed
in FSL v 4.18. Preprocessing:
MCFLIRT
motion
correction;
registration and normalization to MNI
2mm; 5 mm smoothing.
●
EVs of no interest: 6 motion parameters
+ pulse and breathing (recorded in
scan) + mean signal over all grey,
white, and CSF voxels.
Acknowledgements
Prof Gareth Barker
Christine Ecker
Richard Edden
Grainne McAlonan
Ruth O’Gorman
Prof Steve Williams
Eileen Daly
Dave Lythgoe
Ellie Wilson
Jessica Faulkner
EU-AIMS Consortium
Medical Research Council (MRC)
National Institute for Health Research (NIHR)
Wellcome Trust
For more information, please contact: maria.mendez@kcl.ac.uk