Abnormalities In Subcortical GlutamateGlutamine But Not GABA In

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Abnormalities In Subcortical Glutamate/Glutamine, But Not GABA, In Adults With An ASD A [1

Abnormalities In Subcortical Glutamate/Glutamine, But Not GABA, In Adults With An ASD A [1 H]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?

Background - General ● GABA / glutamate balance implicated in ASD? • Rodent models

Background - General ● GABA / glutamate balance implicated in ASD? • Rodent models • e. g. reduced GABA-A receptors, increased glutamate m. Glu. R receptors (subtype-specific) (Selby et al 2007)

Background - General ● GABA / glutamate balance implicated in ASD? • Rodent models

Background - General ● GABA / glutamate balance implicated in ASD? • Rodent models • e. g. reduced GABA-A receptors, increased glutamate m. Glu. R receptors (subtype-specific) (Selby et al 2007) • Human Postmortem Studies (Blatt & Fatemi 2011)

Background - General ● GABA / glutamate balance implicated in ASD? • Rodent models

Background - General ● GABA / glutamate balance implicated in ASD? • Rodent models • e. g. reduced GABA-A receptors, increased glutamate m. Glu. R receptors (subtype-specific) (Selby et al 2007) • Human Postmortem Studies (Blatt & Fatemi 2011) • Genetics – ASD CNVs include GABA-A receptors e. g. 15 q 11 -13 (Urraca et al 2013)

Background - General ● GABA / glutamate balance implicated in ASD? • Rodent models

Background - General ● GABA / glutamate balance implicated in ASD? • Rodent models • e. g. reduced GABA-A receptors, increased glutamate m. Glu. R receptors (subtype-specific) (Selby et al 2007) • Human Postmortem Studies (Blatt & Fatemi 2011) • Genetics – ASD CNVs include GABA-A receptors e. g. 15 q 11 -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 •

Background - PET • Positron Emission Tomography (PET) can measure GABA-A receptor density • We showed preliminary evidence of reduced GABA-A alpha 5 (Mendez et al 2013) [11 C]Ro 154513 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

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

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

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

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

(Previous Findings

Discussion #1: MRS – f. MRI ● Might a reduction in striatal Glx have

Discussion #1: MRS – f. MRI ● Might a reduction in striatal Glx have functional implications? ● We used resting state f. MRI to examine the correlation between [1 H]MRS Glx signal and the functional connectivity to/from the basal ganglia region (putamen) as a seed (seed-voxel correlations):

Results #2: MRS-f. MRI association in all participants (n=42) A significant (p < 0.

Results #2: MRS-f. MRI 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

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

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 ● J-edited MEGAPRESS [1 H]MRS at 3 T was used, TE

Detailed Methods MRS ● J-edited MEGAPRESS [1 H]MRS at 3 T was used, TE = 68 ms. ● Unsuppressed acquired and quantitation water signal was used for absolute ● Voxel grey, white and CSF composition was calculated from T 1 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). f. MRI ● 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 2 mm; 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 Mc. Alonan Ruth O’Gorman Prof

Acknowledgements Prof Gareth Barker Christine Ecker Richard Edden Grainne Mc. Alonan 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. [email protected] ac. uk