The Contribution Of The Brain Response To Ketamine To Understanding The Glutamatergic System And Its Role In Human Cognition

Student thesis: Doctoral ThesisDoctor of Philosophy


A high degree of interest continues in studying the central effects of ketamine, an NMDA receptor (NMDAR) antagonist, due to its potential relevance to schizophrenia, antidepressant efficacy and analgesia. This thesis investigates the brain response to ketamine to (1) determine whether it is a valuable pharmacological tool to investigate glutamatergic dysfunction and (2) further our knowledge on the role of the glutamatergic system in human cognition.
The administration of low-dose ketamine to healthy volunteers was combined with arterial spin labelling (ASL) and blood oxygen level dependent (BOLD) imaging in both resting state and cognitive task conditions. The test-retest reliability of the ketamine response was assessed together with its effects on working memory (N-BACK) and paired associative learning (PAL) task networks. Modulatory effects of lamotrigine and risperidone, treatments thought to reduce ketamine-induced glutamate release, were also evaluated.
Ketamine induced robust and reliable effects in predicted cerebral networks with ASL and BOLD. However, risperidone and lamotrigine only attenuated the BOLD changes. Ketamine altered the load-response profile during the N-Back within the dorsolateral prefrontal cortex and subtly decreased activation in brain areas including the cingulate and thalamus. A trend towards ketamine-induced attenuation of learning-related increases in activation was found in the PAL task. Pretreatments had differential effects depending on the cognitive task, with risperidone having a more prominent role in working memory and lamotrigine in associative learning. Finally, ketamine altered associative learning-related changes in fronto-temporal connectivity.
Results suggest (1) the resting brain response to ketamine is a suitable tool to test and validate pharmacological interventions; (2) fMRI demonstrates that the function of NMDARs is implicated in both region-specific and inter-regional brain communication in working memory and associative learning contexts respectively and (3) the distinct downstream neural substrates of NMDAR antagonism are evidenced by the context-dependent reversal of its effects. The findings have implications for future ketamine-related research and its use as a model of glutamatergic dysfunction relevant to psychiatric disorders.
Date of Award2013
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorMitul Mehta (Supervisor) & Owen O'Daly (Supervisor)

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