Increased glutamate/GABA+ ratio in a shared autistic and schizotypal trait phenotype termed Social Disorganisation

Ford, Talitha C.; Nibbs, Richard; Crewther, DP

doi:10.1016/j.nicl.2017.07.009

Cited by 35 publications

(40 citation statements)

References 61 publications

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“…[ 24 41 108 164 ] Yet, a growing literature strongly suggest a link to abnormalities in glutamate and/or GluR function as major players in ASDs, which includes children, high functioning autism, and adults with autism. [ 80 223 224 282 ]…”

Section: Integration Of Immune Dysfunction Glutamate Receptor Changementioning

confidence: 99%

Immunoexcitotoxicity as the central mechanism of etiopathology and treatment of autism spectrum disorders: A possible role of fluoride and aluminum

Blaylock¹,

Patočka

Strunecký

2018

Surg Neurol Int

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Our review suggests that most autism spectrum disorder (ASD) risk factors are connected, either directly or indirectly, to immunoexcitotoxicity. Chronic brain inflammation is known to enhance the sensitivity of glutamate receptors and interfere with glutamate removal from the extraneuronal space, where it can trigger excitotoxicity over a prolonged period. Neuroscience studies have clearly shown that sequential systemic immune stimulation can activate the brain's immune system, microglia, and astrocytes, and that with initial immune stimulation, there occurs CNS microglial priming. Children are exposed to such sequential immune stimulation via a growing number of environmental excitotoxins, vaccines, and persistent viral infections. We demonstrate that fluoride and aluminum (Al3+) can exacerbate the pathological problems by worsening excitotoxicity and inflammation. While Al3+ appears among the key suspicious factors of ASD, fluoride is rarely recognized as a causative culprit. A long-term burden of these ubiquitous toxins has several health effects with a striking resemblance to the symptoms of ASD. In addition, their synergistic action in molecules of aluminofluoride complexes can affect cell signaling, neurodevelopment, and CNS functions at several times lower concentrations than either Al3+ or fluoride acting alone. Our review opens the door to a number of new treatment modes that naturally reduce excitotoxicity and microglial priming.

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Section: Integration Of Immune Dysfunction Glutamate Receptor Changementioning

confidence: 99%

Immunoexcitotoxicity as the central mechanism of etiopathology and treatment of autism spectrum disorders: A possible role of fluoride and aluminum

Blaylock¹,

Patočka

Strunecký

2018

Surg Neurol Int

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“…Participant recruitment and experimental procedures have been reported previously (Ford & Crewther, 2014;Ford et al, 2017b). Briefly, 38 non-clinical participants (18 males, 20 females; mean age [SD] = 23.22 [5.52]) were recruited for the 1 H-MRS component of a much larger study of 1,678 young adults aged 18-40 years (Ford et al, 2017b) based on their scores on a questionnaire of pseudo-randomized Autism-Spectrum Quotient (AQ) and Schizotypal Personality Questionnaire (SPQ) items (Ford & Crewther, 2014). Participants were recruited for the larger study via social media and on-campus advertising and were invited to complete the online questionnaire.…”

Section: Participantsmentioning

confidence: 99%

“…The edit-on A D B C E F spectrum was subtracted from the edit-off spectrum to expose GABA+ concentration (institutional units [IU]) at 3.0ppm relative to the water spectra (Mullins et al, 2014). All GABA+ spectra were adequate, see Ford et al (2017b) for fit details. Glutamate and GABA+ concentrations were corrected for individual variation in grey matter, white matter and cerebrospinal fluid using the formula provided in Harris, Puts, and Edden (2015).…”

Section: H-mrs Analysismentioning

confidence: 99%

Psychosocial deficits across autism and schizotypal spectra are interactively modulated by excitatory and inhibitory neurotransmission

Ford

Crewther

Abu‐Akel

2019

Autism

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behavior Excitation-inhibition and psychosocial deficits 2 Psychosocial deficits across autism and schizotypal spectra are interactively modulated by excitatory and inhibitory neurotransmission Abstract Background: Continued human and animal research has strengthened evidence for aberrant excitatory-inhibitory neural processes underlying autism and schizophrenia spectrum disorder psychopathology, particularly psychosocial functioning, in clinical and nonclinical populations. We investigated the extent to which autistic traits and schizotypal dimensions were modulated by the interactive relationship between excitatory glutamate and inhibitory GABA neurotransmitter concentrations in the social processing area of the superior temporal cortex (STC) using proton magnetic resonance spectroscopy ( 1 H-MRS). Methods: 38 non-clinical participants (20 female; age range = 18-35, mean[SD] = 23.22 [5.52]) completed the autism spectrum quotient and schizotypal personality questionnaire, and underwent 1 H-MRS to quantify glutamate and GABA concentrations in the right and left STC.Results: Regression analyses revealed that glutamate and GABA interactively modulated autistic social skills and schizotypal interpersonal features (pcorr < .05), such that those with high right STC glutamate but low GABA concentrations exhibited poorer social and interpersonal skills.Conclusions: These findings evidence an excitation-inhibition imbalance that is specific to psychosocial features across the autism and schizophrenia spectra.

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“…A more recent combined schizophrenia and bipolar study 121 reported that increased frontal and right temporal duration MMN was associated 122 with higher anterior cingulate glutamate/creatine ratios for schizophrenia patients 123 only, while reduced MMN peak amplitude at frontal and temporal sites was 124 associated with increased hippocampal glutamate/creatine, albeit not significantly 125 (Kaur et al, 2019). It is important to note that these studies did not report on 126 Participant recruitment and data collection procedures for this study have been described 158 previously (Ford et al, 2017a(Ford et al, , 2017dFord and Crewther, 2014). Initially, 1,678 adults aged 159 18 to 40 years (428 male, 1250 female) were recruited to complete an online questionnaire 160 consisting of the autism-spectrum quotient (AQ) and the schizotypal personality 161 questionnaire (SPQ).…”

mentioning

confidence: 99%

Cortical excitation-inhibition ratio mediates the effect of pre-attentive auditory processing deficits on interpersonal difficulties

Ford

Woods

Enticott

et al. 2019

Preprint

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23Several lines of evidence identify aberrant excitatory-inhibitory neural processes across 24 autism and schizophrenia spectrum disorders, particularly within the psychosocial domain. 25 Such neural processes include increased excitatory glutamate and reduced inhibitory GABA 26 concentrations, which may affect auditory pre-attentive processing as indexed by the 27 mismatch negativity (MMN); thus, an excitation-inhibition imbalance might lead to aberrant 28 MMN, which might in turn drive the relationship between the MMN and psychosocial 29 difficulties. This research has the potential to enhance the neurochemical understanding of 30 the relationship between electrophysiology (MMN) and behavioural/clinical measures 31 (psychosocial difficulties). 32 Thirty-eight adults (18 male, 18-40 years) completed the Schizotypal 33 Personality Questionnaire (SPQ) and Autism-Spectrum Quotient (AQ). Glutamate 34 and GABA concentrations in bilateral superior temporal cortex (STC) were quantified 35 using proton magnetic resonance spectroscopy (1H-MRS) while auditory MMN to a 36 duration deviant was measured with magnetoencephalography. Spearman 37 correlations probed the relationships between STC glutamate/GABA ratios, MMN 38 amplitude and latency, and AQ and SPQ dimensions. Mediation effects of 39 glutamate/GABA ratios on the relationship between MMN and AQ-SPQ dimensions 40 were probed using causal mediation analysis. 41 Only SPQ-interpersonal and AQ-communication were significantly correlated 42 with right hemisphere glutamate/GABA ratios and MMN latency (ps<.05), which 43 were themselves correlated (p=.038). Two mediation models were investigated, with 44 right MMN latency as predictor and SPQ-interpersonal and AQ-communication as 45 outcome variables. Right STC glutamate/GABA ratios significantly mediated the 46 relationship between MMN latency and SPQ-interpersonal scores (ß=86.6, p=.033), 47 but only partially mediated the relationship between MMN latency and AQ-48 communication scores (ß=21.0, p=.093). 49 These findings support the growing body of literature pointing toward an 50 excitation-inhibition imbalance that is central to psychosocial functioning across 51 multi-dimensional spectrum disorders, such as autism and schizophrenia, and 52 provides neurochemical indicators of the processes that underlie psychosocial 53 dysfunction. 54 3 55

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Increased glutamate/GABA+ ratio in a shared autistic and schizotypal trait phenotype termed Social Disorganisation

Cited by 35 publications

References 61 publications

Immunoexcitotoxicity as the central mechanism of etiopathology and treatment of autism spectrum disorders: A possible role of fluoride and aluminum

Immunoexcitotoxicity as the central mechanism of etiopathology and treatment of autism spectrum disorders: A possible role of fluoride and aluminum

Psychosocial deficits across autism and schizotypal spectra are interactively modulated by excitatory and inhibitory neurotransmission

Cortical excitation-inhibition ratio mediates the effect of pre-attentive auditory processing deficits on interpersonal difficulties

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