GABAB receptor modulation of visual sensory processing in adults with and without autism spectrum disorder
Inhibition and visual processing in ASD
Alterations in γ-aminobutyric acid (GABA)–related pathways have been shown to occur in patients with autism spectrum disorder (ASD). However, the role of GABA signaling modulation on sensory processing remains unclear. Now, Huang et al. show that visual processing, altered in patients with ASD, could be restored, promoting GABAB receptor activation using arbaclofen. The results suggest that GABA signaling alterations in ASD play a critical role in determining visual sensory responses and suggest that interventions promoting GABAergic activity might ameliorate sensory impairments in ASD.
Abstract
Sensory atypicalities in autism spectrum disorder (ASD) are thought to arise at least partly from differences in γ-aminobutyric acid (GABA) receptor function. However, the evidence to date has been indirect, arising from correlational studies in patients and preclinical models. Here, we evaluated the role of GABA receptor directly, in 44 adults (n = 19 ASD). Baseline concentration of occipital lobe GABA+ (GABA plus coedited macromolecules) was measured using proton magnetic resonance spectroscopy (1H-MRS). Steady-state visual evoked potential (SSVEP) elicited by a passive visual surround suppression paradigm was compared after double-blind randomized oral administration of placebo or 15 to 30 mg of arbaclofen (STX209), a GABA type B (GABAB) receptor agonist. In the placebo condition, the neurotypical SSVEP response was affected by both the foreground stimuli contrast and background interference (suppression). In ASD, however, all stimuli conditions had equal salience and background suppression of the foreground response was weaker. In the placebo condition, although there was no difference in GABA+ between groups, GABA+ concentration positively correlated with response to maximum foreground contrast during maximum background interference in neurotypicals, but not ASD. In neurotypicals, sensitivity to visual stimuli was disrupted by 30 mg of arbaclofen, whereas in ASD, it was made more “typical” and visual processing differences were abolished. Hence, differences in GABAergic function are fundamental to autistic (visual) sensory neurobiology and are modulated by GABAB activity.
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REFERENCES AND NOTES
1
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, ed. 5 2013).
2
S. Dakin, U. Frith, Vagaries of visual perception in autism. Neuron 48, 497–507 (2005).
3
D. R. Simmons, A. E. Robertson, L. S. McKay, E. Toal, P. McAleer, F. E. Pollick, Vision in autism spectrum disorders. Vision Res. 49, 2705–2739 (2009).
4
C. E. Robertson, D. J. Kravitz, J. Freyberg, S. Baron-Cohen, C. I. Baker, Slower rate of binocular rivalry in autism. J. Neurosci. 33, 16983–16991 (2013).
5
J. H. Foss-Feig, D. Tadin, K. B. Schauder, C. J. Cascio, A substantial and unexpected enhancement of motion perception in autism. J. Neurosci. 33, 8243–8249 (2013).
6
C. E. Robertson, C. Thomas, D. J. Kravitz, G. L. Wallace, S. Baron-Cohen, A. Martin, C. I. Baker, Global motion perception deficits in autism are reflected as early as primary visual cortex. Brain 137, 2588–2599 (2014).
7
J. Horder, M. Andersson, M. A. Mendez, N. Singh, Ä. Tangen, J. Lundberg, A. Gee, C. Halldin, M. Veronese, S. Bölte, L. Farde, T. Sementa, D. Cash, K. Higgins, D. Spain, F. Turkheimer, I. Mick, S. Selvaraj, D. J. Nutt, A. Lingford-Hughes, O. D. Howes, D. G. Murphy, J. Borg, GABAA receptor availability is not altered in adults with autism spectrum disorder or in mouse models. Sci. Transl. Med. 10, eaam8434 (2018).
8
M.-P. Schallmo, T. Kolodny, A. M. Kale, R. Millin, A. V. Flevaris, R. A. Edden, J. Gerdts, R. A. Bernier, S. O. Murray, Weaker neural suppression in autism. Nat. Commun. 11, 2675 (2020).
9
J. Rubenstein, M. M. Merzenich, Model of autism: Increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003).
10
O. Yizhar, L. E. Fenno, M. Prigge, F. Schneider, T. J. Davidson, D. J. O’shea, V. S. Sohal, I. Goshen, J. Finkelstein, J. T. Paz, K. Stehfest, R. Fudim, C. Ramakrishnan, J. R. Huguenard, P. Hegemann, K. Deisseroth, Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477, 171–178 (2011).
11
J. H. Foss-Feig, B. D. Adkinson, J. L. Ji, G. Yang, V. H. Srihari, J. C. McPartland, J. H. Krystal, J. D. Murray, A. Anticevic, Searching for cross-diagnostic convergence: Neural mechanisms governing excitation and inhibition balance in schizophrenia and autism spectrum disorders. Biol. Psychiatry 81, 848–861 (2017).
12
S. H. Fatemi, T. J. Reutiman, T. D. Folsom, P. D. Thuras, GABAA receptor downregulation in brains of subjects with autism. J. Autism Dev. Disord. 39, 223–230 (2009).
13
H.-T. Chao, H. Chen, R. C. Samaco, M. Xue, M. Chahrour, J. Yoo, J. L. Neul, S. Gong, H.-C. Lu, N. Heintz, M. Ekker, J. R. Rubenstein, J. L. Noebles, C. Rosenmund, H. Y. Zoghbi, Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468, 263–269 (2010).
14
R. Pizzarelli, E. Cherubini, Alterations of GABAergic signaling in autism spectrum disorders. Neural Plast. 2011, 1–12 (2011).
15
S. Han, C. Tai, R. E. Westenbroek, H. Y. Frank, C. S. Cheah, G. B. Potter, J. L. Rubenstein, T. Scheuer, O. Horacio, W. A. Catterall, Autistic-like behaviour in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission. Nature 489, 385–390 (2012).
16
N. A. Puts, E. L. Wodka, A. D. Harris, D. Crocetti, M. Tommerdahl, S. H. Mostofsky, R. A. Edden, Reduced GABA and altered somatosensory function in children with autism spectrum disorder. Autism Res. 10, 608–619 (2017).
17
W. Gaetz, L. Bloy, D. Wang, R. G. Port, L. Blaskey, S. Levy, T. P. Roberts, GABA estimation in the brains of children on the autism spectrum: Measurement precision and regional cortical variation. Neuroimage 86, 1–9 (2014).
18
G. S. Drenthen, E. M. Barendse, A. P. Aldenkamp, T. M. van Veenendaal, N. A. Puts, R. A. Edden, S. Zinger, G. Thoonen, M. P. Hendriks, R. P. Kessels, J. A. Jansen, Altered neurotransmitter metabolism in adolescents with high-functioning autism. Psychiatry Res. Neuroimaging 256, 44–49 (2016).
19
D. A. Edmondson, P. Xia, R. McNally Keehn, U. Dydak, B. Keehn, A magnetic resonance spectroscopy study of superior visual search abilities in children with autism spectrum disorder. Autism Res. 13, 550–562 (2020).
20
T. Kolodny, M. P. Schallmo, J. Gerdts, R. A. Edden, R. A. Bernier, S. O. Murray, Concentrations of cortical GABA and glutamate in young adults with autism spectrum disorder. Autism Res. 13, 1111–1129 (2020).
21
C. E. Robertson, E.-M. Ratai, N. Kanwisher, Reduced GABAergic action in the autistic brain. Curr. Biol. 26, 80–85 (2016).
22
R. G. Port, W. Gaetz, L. Bloy, D. J. Wang, L. Blaskey, E. S. Kuschner, S. E. Levy, E. S. Brodkin, T. P. Roberts, Exploring the relationship between cortical GABA concentrations, auditory gamma-band responses and development in ASD: Evidence for an altered maturational trajectory in ASD. Autism Res. 10, 593–607 (2017).
23
Q. Chen, C. A. Deister, X. Gao, B. Guo, T. Lynn-Jones, N. Chen, M. F. Wells, R. Liu, M. J. Goard, J. Dimidschstein, Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD. Nat. Neurosci. 23, 520–532 (2020).
24
D. C. Rojas, D. Singel, S. Steinmetz, S. Hepburn, M. S. Brown, Decreased left perisylvian GABA concentration in children with autism and unaffected siblings. Neuroimage 86, 28–34 (2014).
25
C. E. Robertson, S. Baron-Cohen, Sensory perception in autism. Nat. Rev. Neurosci. 18, 671–684 (2017).
26
M. Farrant, Z. Nusser, Variations on an inhibitory theme: Phasic and tonic activation of GABA A receptors. Nat. Rev. Neurosci. 6, 215–229 (2005).
27
M. T. Craig, C. J. McBain, The emerging role of GABAB receptors as regulators of network dynamics: Fast actions from a ‘slow’ receptor? Curr. Opin. Neurobiol. 26, 15–21 (2014).
28
W. M. Connelly, S. J. Fyson, A. C. Errington, C. P. McCafferty, D. W. Cope, G. Di Giovanni, V. Crunelli, GABAB receptors regulate extrasynaptic GABAA receptors. J. Neurosci. 33, 3780–3785 (2013).
29
J. Mentch, A. Spiegel, C. Ricciardi, C. E. Robertson, GABAergic inhibition gates perceptual awareness during binocular rivalry. J. Neurosci. 39, 8398–8407 (2019).
30
N. Langer, E. J. Ho, L. M. Alexander, H. Y. Xu, R. K. Jozanovic, S. Henin, A. Petroni, S. Cohen, E. T. Marcelle, L. C. Parra, A resource for assessing information processing in the developing brain using EEG and eye tracking. Sci. Data 4, 170040 (2017).
31
T. Z. Lauritzen, J. M. Ales, A. R. Wade, The effects of visuospatial attention measured across visual cortex using source-imaged, steady-state EEG. J. Vis. 10, 39–39 (2010).
32
M. I. Vanegas, A. Blangero, S. P. Kelly, Electrophysiological indices of surround suppression in humans. J. Neurophysiol. 113, 1100–1109 (2015).
33
C. A. Erickson, J. M. Veenstra-Vanderweele, R. D. Melmed, J. T. McCracken, L. D. Ginsberg, L. Sikich, L. Scahill, M. Cherubini, P. Zarevics, K. Walton-Bowen, R. L. Carpenter, M. F. Bear, P. P. Wang, B. H. King, STX209 (arbaclofen) for autism spectrum disorders: An 8-week open-label study. J. Autism Dev. Disord. 44, 958–964 (2014).
34
J. Veenstra-VanderWeele, E. H. Cook, B. H. King, P. Zarevics, M. Cherubini, K. Walton-Bowen, M. F. Bear, P. P. Wang, R. L. Carpenter, Arbaclofen in children and adolescents with autism spectrum disorder: A randomized, controlled, phase 2 trial. Neuropsychopharmacology 42, 1390–1398 (2017).
35
M. G. Saleh, G. Oeltzschner, K. L. Chan, N. A. Puts, M. Mikkelsen, M. Schär, A. D. Harris, R. A. Edden, Simultaneous edited MRS of GABA and glutathione. Neuroimage 142, 576–582 (2016).
36
P. G. Henry, C. Dautry, P. Hantraye, G. Bloch, Brain GABA editing without macromolecule contamination. Magn. Reson. Med. 45, 517–520 (2001).
37
P. G. Mullins, D. J. McGonigle, R. L. O'Gorman, N. A. Puts, R. Vidyasagar, C. J. Evans; Cardiff Symposium on MRS of GABA, R. A. Edden, Current practice in the use of MEGA-PRESS spectroscopy for the detection of GABA. Neuroimage 86, 43–52 (2014).
38
A. L. Oblak, T. T. Gibbs, G. J. Blatt, Decreased GABA(B) receptors in the cingulate cortex and fusiform gyrus in autism. J. Neurochem. 114, 1414–1423 (2010).
39
G. Bonanna, A. Fassio, G. Schmid, P. Severi, R. Sala, M. Raiteri, Pharmacologically distinct GABAB receptors that mediate inhibition of GABA and glutamate release in human neocortex. Br. J. Pharmacol. 120, 60–64 (1997).
40
M. Gassmann, B. Bettler, Regulation of neuronal GABAB receptor functions by subunit composition. Nat. Rev. Neurosci. 13, 380–394 (2012).
41
M. S. Perkinton, T. S. Sihra, Presynaptic GABAB receptor modulation of glutamate exocytosis from rat cerebrocortical nerve terminals: Receptor decoupling by protein kinase C. J. Neurochem. 70, 1513–1522 (1998).
42
S. E. Thompson, G. Ayman, G. L. Woodhall, R. S. Jones, Depression of glutamate and GABA release by presynaptic GABAB receptors in the entorhinal cortex in normal and chronically epileptic rats. Neurosignals 15, 202–215 (2006).
43
S. Kantamneni, Cross-talk and regulation between glutamate and GABAB receptors. Front. Cell. Neurosci. 9, 135 (2015).
44
A. E. Purcell, O. H. Jeon, A. W. Zimmerman, M. E. Blue, J. Pevsner, Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology 57, 1618–1628 (2001).
45
S. H. Fatemi, D. F. Wong, J. R. Brašić, H. Kuwabara, A. Mathur, T. D. Folsom, S. Jacob, G. M. Realmuto, J. V. Pardo, S. Lee, Metabotropic glutamate receptor 5 tracer [18F]-FPEB displays increased binding potential in postcentral gyrus and cerebellum of male individuals with autism: A pilot PET study. Cerebellum Ataxias 5, 3 (2018).
46
S. B. Nelson, V. Valakh, Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron 87, 684–698 (2015).
47
F. H. Marshall, in Inhibitory Regulation of Excitatory Neurotransmission (Springer, 2007), pp. 87–98.
48
J. Ciarrusta, R. Dimitrova, G. McAlonan, Early maturation of the social brain: How brain development provides a platform for the acquisition of social-cognitive competence. Prog. Brain Res. 254, 49–70 (2020).
49
N. Gogolla, A. E. Takesian, G. Feng, M. Fagiolini, T. K. Hensch, Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron 83, 894–905 (2014).
50
J. Ciarrusta, R. Dimitrova, D. Batalle, J. O’Muircheartaigh, L. Cordero-Grande, A. Price, E. Hughes, J. Kangas, E. Perry, A. Javed, J. Demilew, J. Hajnal, A. D. Edwards, D. Murphy, T. Arichi, G. McAlonan, Emerging functional connectivity differences in newborn infants vulnerable to autism spectrum disorders. Transl. Psychiatry 10, 131 (2020).
51
V. Tatavarty, A. T. Pacheco, C. G. Kuhnle, H. Lin, P. Koundinya, N. J. Miska, K. B. Hengen, F. F. Wagner, S. D. Van Hooser, G. G. Turrigiano, Autism-associated Shank3 is essential for homeostatic compensation in rodent V1. Neuron 106, 769–777.e4 (2020).
52
T. Gliga, R. Bedford, T. Charman, M. H. Johnson; BASIS Team, Enhanced visual search in infancy predicts emerging autism symptoms. Curr. Biol. 25, 1727–1730 (2015).
53
C. L. Hilton, J. D. Harper, R. H. Kueker, A. R. Lang, A. M. Abbacchi, A. Todorov, P. D. LaVesser, Sensory responsiveness as a predictor of social severity in children with high functioning autism spectrum disorders. J. Autism Dev. Disord. 40, 937–945 (2010).
54
F. E. Howe, S. D. Stagg, How sensory experiences affect adolescents with an autistic spectrum condition within the classroom. J. Autism Dev. Disord. 46, 1656–1668 (2016).
55
M. D. Thye, H. M. Bednarz, A. J. Herringshaw, E. B. Sartin, R. K. Kana, The impact of atypical sensory processing on social impairments in autism spectrum disorder. Dev. Cogn. Neurosci. 29, 151–167 (2018).
56
O. Bogdashina, Sensory Perceptual Issues in Autism and Asperger Syndrome: Different Sensory Experiences-Different Perceptual Worlds (Jessica Kingsley Publishers, 2016).
57
E. Giarelli, R. Nocera, R. Turchi, T. L. Hardie, R. Pagano, C. Yuan, Sensory stimuli as obstacles to emergency care for children with autism spectrum disorder. Adv. Emerg. Nurs. J. 36, 145–163 (2014).
58
B. A. Boyd, M. McBee, T. Holtzclaw, G. T. Baranek, J. W. Bodfish, Relationships among repetitive behaviors, sensory features, and executive functions in high functioning autism. Res. Autism Spectr. Disord. 3, 959–966 (2009).
59
C. D. Rae, A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra. Neurochem. Res. 39, 1–36 (2014).
60
J. L. Silverman, M. Pride, J. Hayes, K. Puhger, H. Butler-Struben, S. Baker, J. Crawley, GABAB receptor agonist R-baclofen reverses social deficits and reduces repetitive behavior in Two mouse models of autism. Neuropsychopharmacology 40, 2228–2239 (2015).
61
E. Berry-Kravis, R. Hagerman, J. Visootsak, D. Budimirovic, W. E. Kaufmann, M. Cherubini, P. Zarevics, K. Walton-Bowen, P. Wang, M. F. Bear, Arbaclofen in fragile X syndrome: Results of phase 3 trials. J. Neurodevelop. Dis. 9, 3 (2017).
62
O. D. Howes, M. Rogdaki, J. L. Findon, R. H. Wichers, T. Charman, B. H. King, E. Loth, G. M. McAlonan, J. T. McCracken, J. R. Parr, C. Povey, P. Santosh, S. Wallace, E. Simonoff, D. G. Murphy, Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J. Psychopharmacol. 32, 3–29 (2018).
63
R. Sanchez-Ponce, L.-Q. Wang, W. Lu, J. Von Hehn, M. Cherubini, R. Rush, Metabolic and pharmacokinetic differentiation of STX209 and racemic baclofen in humans. Metabolites 2, 596–613 (2012).
64
C. Lord, M. Rutter, A. Le Couteur, Autism Diagnostic Interview-Revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J. Autism Dev. Disord. 24, 659–685 (1994).
65
C. Lord, S. Risi, L. Lambrecht, E. H. Cook Jr., B. L. Leventhal, P. C. DiLavore, A. Pickles, M. Rutter, The Autism Diagnostic Observation Schedule—Generic: A standard measure of social and communication deficits associated with the spectrum of autism. J. Autism Dev. Disord. 30, 205–223 (2000).
66
S. Baron-Cohen, S. Wheelwright, R. Skinner, J. Martin, E. Clubley, The autism-spectrum quotient (AQ): Evidence from asperger syndrome/high-functioning autism, malesand females, scientists and mathematicians. J. Autism Dev. Disord. 31, 5–17 (2001).
67
D. Wechsler, Wechsler Abbreviated Scale of Intelligence Second Edition (WASI-II) (Pearson, 2011).
68
R. Simpson, G. A. Devenyi, P. Jezzard, T. J. Hennessy, J. Near, Advanced processing and simulation of MRS data using the FID appliance (FID-A)—An open source, MATLAB-based toolkit. Magn. Reson. Med. 77, 23–33 (2017).
69
J. Near, R. Edden, C. J. Evans, R. Paquin, A. Harris, P. Jezzard, Frequency and phase drift correction of magnetic resonance spectroscopy data by spectral registration in the time domain. Magn. Reson. Med. 73, 44–50 (2015).
70
D. H. Brainard, The psychophysics toolbox. Spat. Vis. 10, 433–436 (1997).
71
V. P. Clark, S. Fan, S. A. Hillyard, Identification of early visual evoked potential generators by retinotopic and topographic analyses. Hum. Brain Mapp. 2, 170–187 (1994).
72
F. Di Russo, S. Pitzalis, G. Spitoni, T. Aprile, F. Patria, D. Spinelli, S. A. Hillyard, Identification of the neural sources of the pattern-reversal VEP. Neuroimage 24, 874–886 (2005).
73
M. I. Vanegas, A. Blangero, S. P. Kelly, Exploiting individual primary visual cortex geometry to boost steady state visual evoked potentials. J. Neural Eng. 10, 036003 (2013).
74
H. H. Jasper, The ten-twenty electrode system of the International Federation. Electroencephalogr. Clin. Neurophysiol. 10, 371–375 (1958).
75
X. Chen, Y. Wang, M. Nakanishi, X. Gao, T.-P. Jung, S. Gao, High-speed spelling with a noninvasive brain–computer interface. Proc. Natl. Acad. Sci. 112, E6058–E6067 (2015).
76
Y. Benjamini, Y. Hochberg, Controlling the false discovery rate: A practical and powerful approach to multiple testing. J. R. Stat. Soc. B. Methodol. 57, 289–300 (1995).
77
P. H. Westfall, S. S. Young, Resampling-Based Multiple Testing: Examples and Methods for p-Value Adjustment (John Wiley & Sons, 1993), vol. 279.
78
S. W. Provencher, Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR Biomed. 14, 260–264 (2001).
79
S. W. Provencher, Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn. Reson. Med. 30, 672–679 (1993).
80
Y. Zhang, L. An, J. Shen, Fast computation of full density matrix of multispin systems for spatially localized in vivo magnetic resonance spectroscopy. Med. Phys. 44, 4169–4178 (2017).
81
D. Rotaru, D. Lythgoe, Proceedings of the 26th Annual Meeting of the ISMRM (ISMRM, 2018), pp. 3973.
82
V. Govindaraju, K. Young, A. A. Maudsley, Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed. 13, 129–153 (2000).
83
R. Kreis, C. S. Bolliger, The need for updates of spin system parameters, illustrated for the case of γ-aminobutyric acid. NMR Biomed. 25, 1401–1403 (2012).
84
R. A. Edden, N. A. Puts, A. D. Harris, P. B. Barker, C. J. Evans, Gannet: A batch-processing tool for the quantitative analysis of gamma-aminobutyric acid–edited MR spectroscopy spectra. J. Magn. Reson. Imaging 40, 1445–1452 (2014).
85
J. Ashburner, K. J. Friston, Unified segmentation. Neuroimage 26, 839–851 (2005).
86
T. Ernst, R. Kreis, B. Ross, Absolute quantitation of water and metabolites in the human brain. I. Compartments and water. J. Magn. Reson. B 102, 1–8 (1993).
87
S. W. Provencher, LCModel & LCMgui user’s manual. LCModel Version 6, (2014).
88
A. L. Peek, T. Rebbeck, N. A. Puts, J. Watson, M.-E. R. Aguila, A. M. Leaver, Brain GABA and glutamate levels across pain conditions: A systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool. Neuroimage 210, 116532 (2020).
89
R. Kreis, Issues of spectral quality in clinical 1H-magnetic resonance spectroscopy and a gallery of artifacts. NMR Biomed. 17, 361–381 (2004).
90
M. Wilson, O. Andronesi, P. B. Barker, R. Bartha, A. Bizzi, P. J. Bolan, K. M. Brindle, I. Y. Choi, C. Cudalbu, U. Dydak, U. E. Emir, R. G. Gonzalez, S. Gruber, R. Gruetter, R. K. Gupta, A. Heerschap, A. Henning, H. P. Hetherington, P. S. Huppi, R. E. Hurd, K. Kantarci, R. A. Kauppinen, D. W. J. Klomp, R. Kreis, M. J. Kruiskamp, M. O. Leach, A. P. Lin, P. R. Luijten, M. Marjańska, A. A. Maudsley, D. J. Meyerhoff, C. E. Mountford, P. G. Mullins, J. B. Murdoch, S. J. Nelson, R. Noeske, G. Öz, J. W. Pan, A. C. Peet, H. Poptani, S. Posse, E.-M. Ratai, N. Salibi, T. W. J. Scheenen, I. C. P. Smith, B. J. Soher, I. Tkáč, D. B. Vigneron, F. A. Howe, Methodological consensus on clinical proton MRS of the brain: Review and recommendations. Magn. Reson. Med. 82, 527–550 (2019).
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Science Translational Medicine
Volume 14 | Issue 626
January 2022
January 2022
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Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 27 January 2021
Accepted: 5 November 2021
Acknowledgments
We thank P. Graces from Roche and J. Castelhano from University of Coimbra, and J. Horder for help with the EEG task design piloting. We also thank J. Kangas, C. Carey, and B. Kowalewska for help with study logistics, as well as all the participants.
Funding: This project was funded by an Independent Investigator Award to G.M.M. from the Brain and Behaviour Research Foundation and by funding from Clinical Research Associates L.L.C. (CRA), an affiliate of the Simons Foundation (to G.M.M and D.G.M.M.). Support is also acknowledged from Autistica (to A.C.P.) and the Sackler Institute for Translational Neurodevelopment at King’s College London (to A.C.P., H.V., C.L.E., A.L., E.D., D.G.M.M., and G.M.M.) and EU-AIMS (European Autism Interventions)/EU AIMS-2-TRIALS, an Innovative Medicines Initiative Joint Undertaking under grant agreement no. 777394 (to E.D., D.G.M.M., and G.M.M.). In addition, this paper represents independent research part funded by the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King’s College London (supporting D.G.M.M., G.M.M., C.M.P., N.M.L.W., Q.H., and H.V.). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.
Author contributions: G.M.M. conceived the study and wrote the funding applications with D.G.M.M. G.M.M. obtained U.K. National Research Ethics Committee approvals. Q.H., A.C.P., H.V., J.A., G.M.M., E.D., and D.G.M.M. jointly designed the protocols for data collection. A.C.P., H.V., N.M.L.W., C.L.E, F.M.P., L.K., M.D., A.L., and C.M.P collected 1H-MRS scans and EEG data. G.I. oversaw pharmacy setup and dispensing and safety checks. D.J.L., D.R., and R.A.E.E. were responsible for physics and software for the HERMES protocol to quantify GABA+. Q.H. led the EEG analyses supported by C.L.E. and J.A. A.C.P. led the MRS analyses supported by A.L., F.M.P., and M.D. Coordinated recruitment, data acquisition, quality checking, and clinical screening and monitoring were provided by H.V., L.K., and A.L., supervised by G.M.M. and D.G.M.M. Q.H. and A.C.P. performed statistical analysis, supervised by G.M.M., E.D., and D.G.M.M. Q.H., A.C.P., D.G.M.M., and G.M.M. drafted the manuscript. All authors contributed to regular reviews of study progress, discussion, and interpretation of results and edited and approved the final draft.
Competing interests: The authors declare that they have no competing interests. Unrelated to this study, G.M.M. receives research funding from Compass Pathways Ltd. and has consulted for Greenwich (G.W.) Pharmaceuticals. D.G.M.M. is a consultant for F. Hoffmann-La Roche AG.
Data and materials availability: All the data associated with this study are present in the paper or the Supplementary Materials.
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EU-AIMS (European Autism Interventions)/EU AIMS-2-TRIALS:
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