Can Blood Oxygenation Level Dependent Functional Magnetic Resonance Imaging Be Used Accurately to Compare Older and Younger Populations? A Mini Literature Review

A wealth of research has investigated the aging brain using blood oxygenation level dependent functional MRI [Blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI)]. However, many studies do not consider the aging of the cerebrovascular system, which can influence the BOLD signal independently from neural activity, limiting what can be inferred when comparing age groups. Here, we discuss the ways in which the aging neurovascular system can impact BOLD fMRI, the consequences for age-group comparisons and possible strategies for mitigation. While BOLD fMRI is a valuable tool in this context, this review highlights the importance of consideration of vascular confounds

Multi-Vendor and Multisite Evaluation of Cerebrovascular Reactivity Mapping Using Hypercapnia Challenge

Cerebrovascular reactivity (CVR), which measures the ability of cerebral blood vessels to dilate or constrict in response to vasoactive stimuli such as CO2 inhalation, is an important index of the brain\u27s vascular health. Quantification of CVR using BOLD MRI with hypercapnia challenge has shown great promises in research and clinical studies. However, in order for it to be used as a potential imaging biomarker in large-scale and multi-site studies, the reliability of CO2-CVR quantification across different MRI acquisition platforms and researchers/raters must be examined. The goal of this report from the MarkVCID small vessel disease biomarkers consortium is to evaluate the reliability of CO2-CVR quantification in three studies. First, the inter-rater reliability of CO2-CVR data processing was evaluated by having raters from 5 MarkVCID sites process the same 30 CVR datasets using a cloud-based CVR data processing pipeline. Second, the inter-scanner reproducibility of CO2-CVR quantification was assessed in 10 young subjects across two scanners of different vendors. Third, test-retest repeatability was evaluated in 20 elderly subjects from 4 sites with a scan interval of less than 2 weeks. In all studies, the CO2 CVR measurements were performed using the fixed inspiration method, where the subjects wore a nose clip and a mouthpiece and breathed room air and 5% CO2 air contained in a Douglas bag alternatively through their mouth. The results showed that the inter-rater CoV of CVR processing was 0.08 ± 0.08% for whole-brain CVR values and ranged from 0.16% to 0.88% in major brain regions, with ICC of absolute agreement above 0.9959 for all brain regions. Inter-scanner CoV was found to be 6.90 ± 5.08% for whole-brain CVR values, and ranged from 4.69% to 12.71% in major brain regions, which are comparable to intra-session CoVs obtained from the same scanners on the same day. ICC of consistency between the two scanners was 0.8498 for whole-brain CVR and ranged from 0.8052 to 0.9185 across major brain regions. In the test-retest evaluation, test-retest CoV across different days was found to be 18.29 ± 17.12% for whole-brain CVR values, and ranged from 16.58% to 19.52% in major brain regions, with ICC of absolute agreement ranged from 0.6480 to 0.7785. These results demonstrated good inter-rater, inter-scanner, and test-retest reliability in healthy volunteers, and suggested that CO2-CVR has suitable instrumental properties for use as an imaging biomarker of cerebrovascular function in multi-site and longitudinal observational studies and clinical trials

Investigating the Blood Oxygenation Level-Dependent Functional MRI Response to a Verbal Fluency Task in Early Stroke before and after Hemodynamic Scaling

Background and objectiveBlood oxygenation level-dependent (BOLD) functional MRI (fMRI) has been extensively used as a marker of brain dysfunction and subsequent recovery following stroke. However, growing evidence suggests that straightforward interpretation of BOLD fMRI changes with aging and disease is challenging. In this study, we investigated the effect of calibrating task fMRI data by applying a hemodynamic calibration method using the resting-state fluctuation amplitude (RSFA). Task fMRI responses were obtained during a covert verbal fluency task in a group of early stage stroke patients and matched healthy normal controls.MethodsFifteen acute left hemisphere stroke patients (less than 7 days from stroke; aged 44–84 years, average ~64 years) and 21 healthy controls (aged 55–77 years, average ~61 years) were prospectively studied. All subjects completed a 3-min covert verbal fluency task, and a 10-min eyes-closed resting-state fMRI scan, from which the calibration factor (RSFA) was computed. A behavioral measure on the verbal fluency task was also collected outside the scanner. Whole brain activation volumes and region-of-interest (ROI)-wise percent signal change and activation volumes before and after calibration were computed.ResultsBetween-group differences in whole brain activation volumes, although statistically significant before calibration failed to be significant after calibration. There were significant within-group differences before and after calibration with RSFA. Statistically significant between-group differences on ROI-wise measures before calibration also significantly reduced after calibration. Exploratory brain-behavior correlations revealed a similar pattern: significant correlations before calibration failed to survive after calibration.Discussion and conclusionBOLD fMRI changes with aging and disease is confounded by changes in neurofunctional coupling leading to challenges in the straightforward interpretation of task fMRI results. Application of the hemodynamic calibration using the RSFA technique in the current study appeared to mitigate any differences between stroke and age-matched healthy controls. Our study indicates that estimating neural activity after applying hemodynamic scaling is important for studies of aging and for studies tracking post-stroke changes. We recommend that further investigation of hemodynamic calibration with RSFA in healthy subjects and in stroke in larger samples is necessary

Effects of age on prestimulus neural activity predictive of successful memory encoding: An fMRI study

Prestimulus subsequent memory effects (SMEs)-differences in neural activity preceding the onset of study items that are predictive of later memory performance-have consistently been reported in young adults. The present functional magnetic resonance imaging experiment investigated potential age-related differences in prestimulus SMEs. During study, healthy young and older participants made one of two semantic judgments on images, with the judgment signaled by a preceding cue. In test phase, participants first made an item recognition judgment and, for each item judged old, a source memory judgment. Age-invariant prestimulus SMEs were observed in left dorsomedial prefrontal cortex, left hippocampus, and right subgenual cortex. In each case, the effects reflected lower blood oxygen level dependent signal for later recognized items, regardless of source accuracy, than for unrecognized items. A similar age-invariant pattern was observed in left orbitofrontal cortex, but this effect was specific to items attracting a correct source response compared to unrecognized items. In contrast, the left angular gyrus and fusiform cortex demonstrated negative prestimulus SMEs that were exclusive to young participants. The findings indicate that age differences in prestimulus SMEs are regionally specific and suggest that prestimulus SMEs reflect multiple cognitive processes, only some of which are vulnerable to advancing age

Divided attention at retrieval does not influence neural correlates of recollection in young or older adults

Age-related decline in episodic memory has been partially attributed to older adults’ reduced domain general processing resources. In the present study, we examined the effects of divided attention (DA) - a manipulation assumed to further deplete the already limited processing resources of older adults - on the neural correlates of recollection in young and older adults. Participants underwent fMRI scanning while they performed an associative recognition test in single and dual (tone detection) task conditions. Recollection effects were operationalized as greater BOLD activity elicited by test pairs correctly endorsed as ‘intact’ than pairs correctly or incorrectly endorsed as ‘rearranged’. Detrimental effects of DA on associative recognition performance were identified in older but not young adults. The magnitudes of recollection effects did not differ between the single and dual (tone detection) tasks in either age group. Across the task conditions, age-invariant recollection effects were evident in most members of the core recollection network. However, while young adults demonstrated robust recollection effects in left angular gyrus, angular gyrus effects were undetectable in the older adults in either task condition. With the possible exception of this result, the findings suggest that DA did not influence processes supporting the retrieval and representation of associative information in either young or older adults, and converge with prior behavioral findings to suggest that episodic retrieval operations are little affected by DA

BOLD signal physiology: Models and applications

The BOLD contrast mechanism has a complex relationship with functional brain activity, oxygen metabolism, and neurovascular factors. Accurate interpretation of the BOLD signal for neuroscience and clinical applications necessitates a clear understanding of the sources of BOLD contrast and its relationship to underlying physiology. This review describes the physiological components that contribute to the BOLD signal and the steady-state calibrated BOLD models that enable quantification of functional changes with a separate challenge paradigm. The principles derived from these biophysical models are then used to interpret BOLD measurements in different neurological disorders in the presence of confounding vascular factors related to disease

Recollection-related hippocampal fMRI effects predict longitudinal memory change in healthy older adults

Prior fMRI studies have reported relationships between memory-related activity in the hippocampus and in-scanner memory performance, but whether such activity is predictive of longitudinal memory change remains unclear. Here, we administered a neuropsychological test battery to a sample of cognitively healthy older adults on three occasions, the second and third sessions occurring one month and three years after the first session. Structural and functional MRI data were acquired between the first two sessions. The fMRI data were derived from an associative recognition procedure and allowed estimation of hippocampal effects associated with both successful associative encoding and successful associative recognition (recollection). Baseline memory performance and memory change were evaluated using memory component scores derived from a principal components analysis of the neuropsychological test scores. Across participants, right hippocampal encoding effects correlated significantly with baseline memory performance after controlling for chronological age. Additionally, both left and right hippocampal associative recognition effects correlated negatively with longitudinal memory decline after controlling for age, and the relationship with the left hippocampal effect remained after also controlling for left hippocampal volume. Thus, in cognitively healthy older adults, the magnitude of hippocampal recollection effects appears to be a robust predictor of future memory change

Effects of age on goal-dependent modulation of episodic memory retrieval

Retrieval gating refers to the ability to modulate the retrieval of features of a single memory episode according to behavioral goals. Recent findings demonstrate that younger adults engage retrieval gating by attenuating the representation of task-irrelevant features of an episode. Here, we examine whether retrieval gating varies with age. Younger and older adults incidentally encoded words superimposed over scenes or scrambled backgrounds that were displayed in one of three spatial locations. Participants subsequently underwent fMRI as they completed two memory tasks: the background task, which tested memory for the word's background, and the location task, testing memory for the word's location. Employing univariate and multivariate approaches, we demonstrated that younger, but not older adults, exhibited attenuated reinstatement of scene information when it was goal-irrelevant (during the location task). Additionally, in younger adults only, the strength of scene reinstatement in the parahippocampal place area during the background task was related to item and source memory performance. Together, these findings point to an age-related decline in the ability to engage retrieval gating

Separating vascular and neuronal effects of age on fMRI BOLD signals.

Accurate identification of brain function is necessary to understand the neurobiology of cognitive ageing, and thereby promote well-being across the lifespan. A common tool used to investigate neurocognitive ageing is functional magnetic resonance imaging (fMRI). However, although fMRI data are often interpreted in terms of neuronal activity, the blood oxygenation level-dependent (BOLD) signal measured by fMRI includes contributions of both vascular and neuronal factors, which change differentially with age. While some studies investigate vascular ageing factors, the results of these studies are not well known within the field of neurocognitive ageing and therefore vascular confounds in neurocognitive fMRI studies are common. Despite over 10 000 BOLD-fMRI papers on ageing, fewer than 20 have applied techniques to correct for vascular effects. However, neurovascular ageing is not only a confound in fMRI, but an important feature in its own right, to be assessed alongside measures of neuronal ageing. We review current approaches to dissociate neuronal and vascular components of BOLD-fMRI of regional activity and functional connectivity. We highlight emerging evidence that vascular mechanisms in the brain do not simply control blood flow to support the metabolic needs of neurons, but form complex neurovascular interactions that influence neuronal function in health and disease. This article is part of the theme issue 'Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity'.This work is supported by the British Academy (PF160048), the Guarantors of Brain (G101149), the Wellcome Trust (103838), the Medical Research Council (SUAG/051 G101400; and SUAG/046 G101400), European Union’s Horizon 2020 (732592) and the Cambridge NIHR Biomedical Research Centre