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

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Abnormalities In Subcortical Glutamate/Glutamine,
But Not GABA, In Adults With An ASDA 1HMRS
Study

• M. Andreina Mendez, Jamie Horder, Nicola Gillan,
  Suzanne Coghlan, Declan Murphy

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Background - General

• GABA / glutamate balance implicated in ASD?

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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)

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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)

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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)

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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)

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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)
• But PET cant measure neurotransmitters

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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?

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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
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Participants

• n 22 adult males with a diagnosis of ASD and
  IQgt70 and 27 control males matched on verbal,
  performance and full-scale IQ (t-test, all pgt0.4,
  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.

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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.

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(Previous Findings
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Discussion 1 MRS fMRI

• Might a reduction in striatal Glx have functional
  implications?
• We used resting state fMRI to examine the
  correlation between 1HMRS Glx signal and the
  functional connectivity to/from the basal ganglia
  region (putamen) as a seed (seed-voxel
  correlations)

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Results 2 MRS-fMRI association in all
participants (n42)
A significant (p lt 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.
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Results 3 Glx vs. Connectivity HV vs. ASD

• The correlation between left basal ganglia Glx
  and left putamen connectivity was stronger
  (plt0.05 whole brain corrected) for healthy
  controls than for ASD patients in two regions
• Medial prefrontal cortex
• Lateral temporal lobe including STG and MTG.

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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?

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Detailed Methods

• fMRI
• 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.

• MRS
• J-edited MEGAPRESS 1HMRS at 3T was used, TE
  68 ms.
• Unsuppressed water signal was acquired and used
  for absolute quantitation
• 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).

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Acknowledgements

• Prof Gareth Barker
• Christine Ecker
• Richard Edden
• Grainne McAlonan
• Ruth OGorman
• 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_at_kcl.ac.uk