The effect of APOE genotype and streamline density volume, on hippocampal CA1 down-regulation: a real-time fMRI virtual reality neurofeedback study

Abstract

† The complete list of collaborators of the ALFA Study can be found in the acknowledgements section *Correspondence to: jlmolinuevo@barcelonabeta.org Highlights • APOE-ε4 alleles impact hippocampal down-regulation neurofeedback performance.• Hippocampal streamline density volume is associated with decreased hippocampal down-regulation performance.• Bilaterally cohesive hippocampal activity is associated with better memory performance.• We provide a novel paradigm to investigate self-regulation and brain function. AbstractHippocampal hyperactivity is a precursor of Alzheimer's disease and more prominent in APOE-ε4 carriers. It is therefore important to investigate the processes of hippocampal self-regulation, to monitor therapeutic efficacy of preclinical interventions. We have developed a closed-loop, virtual reality neurofeedback paradigm for real-time fMRI, that provides a standardized method for quantifying processes of hippocampal self-regulation. We acquired multi-modal neuroimaging data from a sample of 53 cognitively unimpaired subjects at risk for AD and applied standard methods of structural and functional connectomics. The analyses reveal significant negative associations between hippocampal CA1 down-regulation performance and APOE-ε4 alleles, as well as hippocampal streamline density volume.Better memory performance was associated with increased, bilateral hippocampal functional connectivity during the neurofeedback task. These are the first results to link neurofeedback performance to a genetic risk factor and structural connectivity.Further, these are the first evidence that functional cohesion between the hippocampi can reflect subtle differences in memory function, in cognitively unimpaired individuals at risk for AD. We provide a novel method to assess hippocampal function in preclinical AD, and propose it can be used to derive proxies for neural reserve. IntroductionRecent fMRI studies have renewed hope for identifying subtle functional changes preceding irreversible neurodegeneration due to Alzheimer's disease (AD) [1][2][3]. In-depth literature review suggests that the hippocampus is the only brain region that is consistently and bilaterally both a) implicated in memory encoding processes, as indicated by a meta-analysis of 72 fMRI studies of subsequent memory effects [4] and b) differing in activity between AD patients and controls, as indicated by a quantitative meta-analysis of 11 fMRI studies on memory encoding [5].Moreover, recent evidence suggests hippocampal hyperactivity as a precursor of amyloid deposition [1], which is accepted as the earliest sign of preclinical AD [6].Similarly, APOE-ε4 carriers, exhibit hippocampal hyperactivity during a memory task designed to assess pattern separation [7], suggesting the possibility of a genetic mechanism linked to the concepts of neural reserve and neural efficiency [8][9].

Can we predict real‐time fMRI neurofeedback learning success from pretraining brain activity?

“…Further possible candidates for predicting neurofeedback success might be factors that have already been identified to be predictive of cognitive and behavioral training success in non‐neurofeedback studies, for example, activity in areas related to stimulus encoding and motor control has been found to be predictive of motor learning (Herholz, Coffey, Pantev, & Zatorre, 2016), and activity in the motor network has been found to predict training‐related changes in working memory (Simmonite & Polk, 2019). Finally, very recent work by Skouras et al indicates that neurofeedback learning performance can be influenced by biological factors such as genetic and anatomical predispositions (Skouras et al, 2019), thus demonstrating the complexity of the underlying processes and the need for using multimodal data sets.…”

Neurofeedback and the Aging Brain: A Systematic Review of Training Protocols for Dementia and Mild Cognitive Impairment

“…In this context we want to highlight the recent research from Skouras et al who found an association between a clinical biomarker for AD and self-regulation success (please note that the study was not included in our systematic review because the authors did not report cognitive or clinical outcome measurements). First, the authors showed that participants carrying APOE-ε4 alleles showed lower selfregulation performance during hippocampal down-regulation compared to non-carriers (Skouras et al, 2019). Second, they reported reduced eigenvector centrality (i.e., less influence based on iterative whole-brain connectomics) in the anterior cingulate cortex and primary motor cortex during hippocampus downregulation when comparing cognitively unimpaired participants who had abnormal levels of CSF amyloid-β peptide 42 with cognitively unimpaired participants with lower CSF amyloidβ peptide 42 levels (Skouras et al, 2020).…”

Distinct effects of amyloid and tau deposition on eigenvector centrality during hippocampal down-regulation: a real-time fMRI virtual reality closed-loop neurofeedback study with CSF biomarkers

“…The design of the VR paradigm was guided by the following objectives: a) we used VR to make the task immersive, engaging and entertaining; b) that in turn enabled making the task particularly long, 30 minutes, to maximize 1 st -level statistical power; c) we employed sliding-window closed-loop NF to achieve an optimal design for analysis of functional connectomics; d) we narrowed the NF target ROI to hippocampal subfield CA1, that presents atrophy in AD but not in healthy aging (Frisoni et al, 2008;Wilson et al, 2004;Yushkevich et al, 2015), while also being consistently implicated in memory encoding (Kim, 2011) and differing in activity in patients (Schwindt and Black, 2009). Prior to the acquisition of CSF biomarkers, the task was validated in a larger, partly independent sample (77% overlap), by showing that hippocampal downregulation was associated with genetic predisposition to AD, neurodevelopmental processes and bilateral cohesion of hippocampal function (Skouras et al, 2019b).…”