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The relationship between SV2A levels, neural activity, and cognitive function in healthy humans

Poster No:

2445

Submission Type:

Abstract Submission

Authors:

Ekaterina Shatalina¹, Ellis Chika Onwordi¹, Thomas Whitehurst², Alexander Whittington³, Ayla Mansur³, Tiago Reis Marques¹, Roger Gunn³, Sridhar Natesan¹, Matthew Nour⁴, Eugenii Rabiner³, Matthew Wall³, Oliver Howes¹

Institutions:

¹Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom, ²Imperial College London, London, United Kingdom, ³Invicro, London, United Kingdom, ⁴Departement of Psychiatry, Oxford University, Oxford, United Kingdom

First Author:

Ekaterina Shatalina
Institute of Psychiatry, Psychology and Neuroscience, King's College London
London, United Kingdom

Co-Author(s):

Ellis Chika Onwordi
Institute of Psychiatry, Psychology and Neuroscience, King's College London
London, United Kingdom

Thomas Whitehurst
Imperial College London
London, United Kingdom

Alexander Whittington
Invicro
London, United Kingdom

Ayla Mansur
Invicro
London, United Kingdom

Tiago Reis Marques
Institute of Psychiatry, Psychology and Neuroscience, King's College London
London, United Kingdom

Roger Gunn
Invicro
London, United Kingdom

Sridhar Natesan
Institute of Psychiatry, Psychology and Neuroscience, King's College London
London, United Kingdom

Matthew Nour
Departement of Psychiatry, Oxford University
Oxford, United Kingdom

Eugenii Rabiner
Invicro
London, United Kingdom

Matthew Wall
Invicro
London, United Kingdom

Oliver Howes
Institute of Psychiatry, Psychology and Neuroscience, King's College London
London, United Kingdom

Introduction:

Synapses are key sites of neuronal activity and are thought to be central to cognitive performance. [11C]UCB-J Positron Emission Tomography (PET) provides an index of synaptic terminal density, which has been linked with cognition in neurological and psychiatric populations. However, the link between synaptic terminal density and cognitive function has never been explored in healthy humans. We set out to investigate this and whether synaptic density is also positively associated with task-induced neural activity, measured by functional Magnetic Resonance Imaging (fMRI) of executive function.

Methods:

Twenty-five healthy adults (22M,3F; mean age±SD 35.36±12.46) underwent a [11C]UCB-J PET and a fMRI scan where they performed an N-back working memory task and a task switching exercise (n=23). The N-back included two working memory conditions (1-back, 2-back) and an attentional control (0-back), a 1&2back>0back contrast was computed to model effects of working memory. Mean 1&2back accuracy was used as the main performance measure. The switching task had an event-related design, where participants responded to number-letter pairs appearing either in blue or green. Depending on the stimulus colour, they indicated if the number was odd/even or if the letter was a vowel/consonant. Trials where the colour changed were defined as switch trials and a switch>no-switch contrast was computed to model the effect of switching. Switch cost, defined as the difference in reaction time between switch and no-switch trials, was the main task performance measure. Voxel-wise kinetic modelling of [11C]UCB-J was carried out using a one-tissue compartment model to produce volume of distribution values. The centrum semiovale was then used as a reference region to produce a mean distribution volume ratio (DVRcs) for task-relevant predefined regions of interest (ROIs).

A partial least squares (PLS) canonical analysis (CA) was used to test relationships between [11C]UCB-J PET DVRcs and task-induced neural activity across 6 ROIs selected for each task. PLS-regression (PLS-R) was applied to test the relationship between [11C]UCB-J PET DVRcs and task performance. Exploratory Pearson's correlations were carried out to test relationships in individual regions.

Results:

[11C]UCB-J PET DVRcs was significantly positively related to task-induced neural activity during task switching (PLS-CA second canonical component, r=0.63, p=0.043, figure 1), with the thalamus-putamen data positively contributing to this relationship (PLS-CA loading 0.679, exploratory Pearson's correlation r=0.42, p=0.044). [11C]UCB-J DVRcs was significantly predictive of behavioural switch cost (PLS-R, R2=0.45, RMSE=0.06, p=0.022, figure 2), with exploratory analyses showing significant negative correlations between switch cost and [11C]UCB-J DVRcs in the insula (r=–0.45, p=0.034), dorsolateral prefrontal cortex (r=–0.52, p=0.013), parietal-precuneus (r=–0.59, p=0.004), posterior frontal cortex (r=–0.56, p=0.007) and anterior cingulate cortex (r=–0.42, p=0.049). There were no relationships between [11C]UCB-J DVRcs and N-back working memory task-induced neural activity or task performance measures.

·Partial Least Squares Canonical Analysis (PLS-CA) showing a strong positive correlation between [11C]UCB-J DVRcs and task switching related neural activity in the second canonical component (B)

·Partial-least-squares regression results showing switch cost (s) is significantly predicted by [11C]UCB-J DVRcs values across six task-switching relevant regions of interest

Conclusions:

Interindividual differences in synaptic terminal density may be related to differences in switch cost and switching-related neural activity but not with working memory task performance or neural activity. Our results suggest some cognitive functions may be more closely related to synaptic terminal density which has implications for conditions associated with synaptic loss, as these functions may be more vulnerable to impairment.

Higher Cognitive Functions:

Executive Function, Cognitive Control and Decision Making

Novel Imaging Acquisition Methods:

BOLD fMRI ²

Multi-Modal Imaging

PET ¹

Keywords:

Cognition

FUNCTIONAL MRI

Positron Emission Tomography (PET)

^1|2Indicates the priority used for review