Modulation of Excitation/Inhibition Balance in Autism Spectrum Disorder

Student thesis: Doctoral ThesisDoctor of Philosophy


Autism Spectrum Disorder (ASD) is a pervasive, neurodevelopmental disorder characterised by impairment in reciprocal social communication, and restricted, repetitive patterns of behaviours or interests. The presence of co-occurring conditions such as anxiety and depression are common and impart additional functional impairment. However, there are no validated screening tools for co-occurring conditions in ASD and no consensus guidelines for the diagnosis and treatment of core and co-occurring conditions. Therefore, in the first part of this thesis (Study 1), I conducted a pilot investigation to examine the validity and reliability of the Strengths and Difficulties Questionnaire (SDQ). My results suggest that the SDQ is a valid and reliable instrument for assessing co-occurring conditions in ASD. Next, I worked with a multidisciplinary team, established by the British Association of Psychopharmacology, to conduct a systematic review and co-author consensus guidelines on the assessment, treatment and research for ASD and its most common co-occurring conditions (Study 2).

The high co-occurrence of anxiety and depression in ASD may indicate a shared neurobiological underpinning of ‘co-occurring and ‘core’ symptoms in this condition. One such candidate is the (im)balance between excitatory (E) glutamate and inhibitory (I) gamma-aminobutyric acid (GABA), but this has yet to be investigated directly in the living human brain. Therefore, I conducted a pharmacological MRI study to investigate the relationship between E-I and both core and co-occurring symptoms and to investigate whether E-I can be ‘shifted’ acutely by targeting the serotonergic system and/or μ-opioid receptor (Studies 3-5). To do this, I administered citalopram (a selective serotonin re-uptake inhibitor) and tianeptine (a μ-opioid receptor agonist) to adult males with and without ASD. I used two neuroimaging approaches to examine E-I at two different levels, namely, i) [1H]MRS to assess ‘bulk’ levels of glutamate+glutamine (Glx) and GABA in a pre-defined region of interest and ii) regional homogeneity (ReHo) analysis of whole-brain resting-state fMRI to quantify regional synchrony of BOLD signals, as a proxy measure of E-I influence on brain activity.

In Study 3, I found that core symptoms and symptoms of anxiety and depression were respectively related to Glx and GABA levels in individuals with ASD. I also found that Glx response to citalopram was significantly different between ASD and controls. Glx decreased in controls but was unchanged in ASD. However, in both groups, there was marked individual variation in [1H]MRS response to citalopram. Individual variation in [1H]MRS response was also found for tianeptine (Study 4), and there were no main effects of group or drug or interactions. Finally, in the ReHo analyses reported in Study 5, I found that citalopram increased ReHo in the left occipital middle lobe in ASD but not in controls; tianeptine had no significant impact on this measure.

My results suggest that E-I systems are related to core ASD symptoms and symptoms of co-occurring anxiety and depression. I found evidence that E-I could be modulated using citalopram and tianeptine; but that this response may differ between ASD and controls. The considerable individual variation in pharmacological response in men with and without ASD evident across the studies carried out here suggests future work to examine whether these responsivity differences are predicative of treatment response.
Date of Award1 Apr 2019
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorGrainne McAlonan (Supervisor) & Declan Murphy (Supervisor)

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