MGluR5 binding changes during a mismatch negativity task in a multimodal protocol with [11C]ABP688 PET/MR-EEG

Cláudia Régio Brambilla ,Nibal Yahya Khudeish,Christine Wyss,Hasan Sbaihat,Shukti Ramkiran,Karl‐Josef Langen ,Ravichandran Rajkumar,Jörg Mauler ,Bernd Neumaier,N Jon Shah,Christoph Lerche ,Andrej Ruch,Elena Rota Kops,Lutz Tellmann,Hans Herzog,Tanja Veselinović ,Markus Lang,J Scheins ,Karsten Heekeren,Wolfram Kawohl,Stefan Stüsgen ,Nicolas Kaulen,Linda Orth,Andreas Matusch,Frank Boers,Irene Neuner

doi:10.1038/s41398-021-01763-3

Cláudia Régio Brambilla , Nibal Yahya Khudeish + Show 24 more

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https://doi.org/10.1038/s41398-021-01763-3

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Currently, the metabotropic glutamate receptor 5 (mGluR5) is the subject of several lines of research in the context of neurology and is of high interest as a target for positron-emission tomography (PET). Here, we assessed the feasibility of using [11C]ABP688, a specific antagonist radiotracer for an allosteric site on the mGluR5, to evaluate changes in glutamatergic neurotransmission through a mismatch-negativity (MMN) task as a part of a simultaneous and synchronized multimodal PET/MR-EEG study. We analyzed the effect of MMN by comparing the changes in nondisplaceable binding potential (BPND) prior to (baseline) and during the task in 17 healthy subjects by applying a bolus/infusion protocol. Anatomical and functional regions were analyzed. A small change in BPND was observed in anatomical regions (posterior cingulate cortex and thalamus) and in a functional network (precuneus) after the start of the task. The effect size was quantified using Kendall’s W value and was 0.3. The motor cortex was used as a control region for the task and did not show any significant BPND changes. There was a significant ΔBPND between acquisition conditions. On average, the reductions in binding across the regions were - 8.6 ± 3.2% in anatomical and - 6.4 ± 0.5% in the functional network (p ≤ 0.001). Correlations between ΔBPND and EEG latency for both anatomical (p = 0.008) and functional (p = 0.022) regions were found. Exploratory analyses suggest that the MMN task played a role in the glutamatergic neurotransmission, and mGluR5 may be indirectly modulated by these changes.

Highlights

Glutamate is generally acknowledged as the most important excitatory neurotransmitter for normal brain function
We investigated the feasibility of simultaneous positron-emission tomography (PET)/ MRI–EEG acquisition using [11C]ABP688 to assess changes in glutamatergic neurotransmission through an MMN task
This study describes the effect of the MMN paradigm on the BPND, and for regions that may show significant task effects, it presents correlations between the binding changes and the EEG-latency times represented by the time range from the onset of stimuli until the MMN

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Introduction

Glutamate is generally acknowledged as the most important excitatory neurotransmitter for normal brain function. Most excitatory neurons and over half of all brain synapses in the central nervous system are glutamatergic [1]. An increasing number of studies have confirmed abnormal glutamatergic neurotransmission in several mental disorders such as schizophrenia, depression, mood disorders, sleep deprivation, and addiction [2,3,4,5,6]. Interventions aimed at targeting the glutamate system are currently under development [7]. Prior to 2006, it was not possible to measure fluctuations in endogenous glutamate in vivo due to the lack of radiotracers for assessing the sensitivity of glutamate receptors to changed glutamate levels induced by a drug or stimuli tasks [8].

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