Fmri

Viviano and Damoiseaux Alzheimer's Research & Therapy (2020) 12:23
https://doi.org/10.1186/s13195-020-00591-9
REVIEW Open Access
Functional neuroimaging in subjective

cognitive decline: current status and a
research path forward
Raymond P. Viviano1,2 and Jessica S. Damoiseaux1,2*
Abstract
Subjective cognitive decline is a putative precursor to dementia marked by perceived worsening of cognitive
function without overt performance issues on neuropsychological assessment. Although healthy older adults
with subjective cognitive decline may function normally, perceived worsening may indicate incipient dementia
and predict future deterioration. Therefore, the experience of decline represents a possible entry point for
clinical intervention. However, intervention requires a physical manifestation of neuroabnormality to both
corroborate incipient dementia and to target clinically. While some individuals with subjective cognitive
decline may harbor pathophysiology for specific neurodegenerative disorders, many do not display clear
indicators. Thus, disorder-agnostic brain measures could be useful to track the trajectory of decline, and
functional neuroimaging in particular may be sensitive to detect incipient dementia and have the ability to
track disease-related change when the underlying disease etiology remains unclear. Therefore, in this review,
we discuss functional neuroimaging studies of subjective cognitive decline and possible reconciliations to
inconsistent findings. We conclude by proposing a functional model where noisy signal propagation and
inefficient signal processing across whole-brain networks may lead to the subjective experience of decline
and discuss future research directions guided by this model.
Keywords: Subjective cognitive decline, Functional neuroimaging, Connectivity
Introduction function. For example, an individual with anosognosia

Subjective cognitive decline (SCD) is a putative precur- may not notice worsening cognitive ability but perform
sor to dementia marked by professed worsening of cog- poorly on assessment, while an individual with percep-
nitive functioning, in any domain, without explicit tion of decline may perform within a normal range [2].
performance issues on neuropsychological assessment. Although not a concurrent indicator of objective decline,
Precise definition and labeling of the concept have evidence suggests SCD can predict future cognitive de-
evolved over the past decades, with an international terioration and may demarcate incipient dementia [3–7].
working group recently coming to a consensus to help The term “cognitive” implies that perceived worsening
spur data consistency [1]. Briefly, “subjective” denotes may apply to any domain, not just memory function.
personal experience and can be orthogonal to objective This ensures that research efforts capture trajectories
from SCD to dementia when initial symptoms are unre-
lated to memory. Many earlier definitions focused on
* Correspondence: damoiseaux@wayne.edu
1
Department of Psychology, Wayne State University, 5057 Woodward Ave.
perceived memory impairment [8]; however, cognitive is
7th Floor Suite 7908, Detroit, MI 48201, USA a more beneficial label than memory as individuals may
2
Institute of Gerontology, Wayne State University, 87 E. Ferry St., Detroit, MI misreport problems in other cognitive domains as
48202, USA
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Viviano and Damoiseaux Alzheimer's Research & Therapy (2020) 12:23 Page 2 of 18
memory problems. Finally, decline reflects a progressive Therefore, here, we review the functional neuroimaging
experience of cognitive worsening rather than an acutely literature in SCD, propose a functional model of SCD
caused stable impairment. On an individual basis, de- where differences in signal processing across whole-
cline may relate to healthy or pathological aging; regard- brain networks may lead to the experience of cognitive
less, the consensus label has shifted to decline from decline, and suggest future research efforts to test the
impairment to reflect a progressive nature—possibly due model. This model refers to individuals who experience
to underlying neurodegeneration. SCD more likely due to nascent neurodegeneration than
The memory component of SCD has been the domin- other causes and are at greater risk of developing de-
ant focal point of prior research, and early data collec- mentia rather than individuals who exhibit cognitive
tion efforts emphasized memory deficit by determining maintenance or for whom SCD is a temporary event.
SCD through a single question or a set of questions
about perceived memory [8]. In addition, earlier defini- Search and review methodology
tions placed SCD as a stage directly before mild cogni- We searched the PubMed and Web of Science Core da-
tive impairment on the healthy aging to Alzheimer’s tabases for articles evaluating functional characteristics
disease (AD) continuum [9]. However, SCD has multiple of the brain in SCD. Title, keyword, and abstract search
etiologies and potential outcomes [1]; therefore, classifi- terms included either subjective cognitive decline, sub-
cation as a symptom or risk factor of incipient dementia jective executive decline, subjective memory impairment,
may be more appropriate. Nevertheless, many reports subjective cognitive impairment, subjective cognitive
discuss SCD within an AD framework. According to the concerns, or subjective memory concerns. We then nar-
modern research definition by the National Institute on rowed the results of the pooled broad searches with
Aging and the Alzheimer’s Association [10], Alzheimer’s functional, connectivity, activity, magnetic resonance
disease is a designation for individuals who exhibit (fMRI), infrared spectroscopy, electroencephalography
pathological amyloid-β and tau deposits, determined ei- (EEG), and magnetoencephalography (MEG) as add-
ther through positron emission tomography or cerebro- itional terms. After sifting through titles and abstracts,
spinal fluid evaluation. Although discussion of SCD we identified 38 relevant articles. Table 1 provides an
biases towards a precursor to AD, and SCD associates overview of the methods and sample characteristics for
with future dementia development [1, 3], associations these prior analyses; it also provides more comprehen-
between SCD and amyloid-β and tau burden are mixed sive overviews of specific results than we address in the
[11–18]; thus, an Alzheimer’s-centric approach could body of the text. We excluded articles involving an inter-
misguide interpretation of SCD data. Although AD may vention (e.g., diet or resveratrol), where SCD was a con-
be the most common dementia etiology [19], and indi- tinuous variable measured within a patient population
viduals with SCD may receive an AD diagnosis over (e.g., subjective decline in Parkinson’s disease), where
time, SCD possibly serves more accurately as a branch- SCD was unrelated to aging (e.g., cancer, fatigue, mul-
ing point between cognitively intact aging and a myriad tiple sclerosis), where there was no control group with-
of potential outcomes, including various dementias but out cognitive concerns or no continuous measure of
also, commonly, recovery to a subjectively unimpaired SCD, and when the methods did not include functional
state. Indeed, for many, SCD may be a temporary event. imaging.
As there is no one-to-one mapping between SCD and As mentioned previously, SCD outcomes are varied,
preclinical AD, amyloid-β and tau burden evaluation with some individuals reverting to a subjectively un-
alone are not the optimal strategies to characterize SCD. impaired state while others may develop dementia.
Furthermore, prior analyses and models propose that Furthermore, there are additional factors that could
functional brain network communication may break influence perception and report of perceived cognitive
down prior to amyloid-β accumulation [20, 21], suggest- decline, such as personality or depression [62–68].
ing that functional brain alterations are sensitive metrics However, for the analyses considered in this review,
for early change. Therefore, measures that are non- many research groups recruited samples from mem-
specific to disease outcome may be more appropriate to ory clinics, adhered to guidelines proposed by an
evaluate SCD than disease-specific indicators and could international working group [1], and accounted for
identify patterns of brain structure or function that dis- potential confounds either in recruitment or during
criminate between individuals who remain cognitively data analysis. Therefore, we are confident that a syn-
unimpaired from individuals who develop dementia at a thesis of this literature reflects functional brain char-
later time. Furthermore, functional neuroimaging may acteristics of SCD for individuals who may harbor
be a viable method for tracking change in SCD as evi- incipient neurodegeneration and are at greater risk of
denced by previous longitudinal work showing change developing dementia, and thus interpret the results
related to aging and neurodegenerative disease [22–24]. within that assumption.
Table 1 Results from various functional neuroimaging analyses in subjective cognitive decline
Authors Year Citation Mod Task/Rest Methodology Operationalization Participants Results Pattern
Alexander 2006 [25] EEG Eyes open and Average power spectra over 4 s periods Participants with SCD recruited from 79 SCD, 79 Greater α band power, increased Increase
et al. closed resting. during resting state. Measure of phase general population with complaint control frontal θ power, and increased
Visual working synchrony during task. of memory problems increasing over spatiotemporal wave activity during
memory task time and informant confirmation. working memory in SCD. Greater α
Controls age and gender matched. power and wave activity related to
lower verbal memory performance
and reaction time, and greater
reverse digit span performance.
Rodda et al. 2009 [26] fMRI Verbal episodic Voxelwise task contrasts. Group Participants with SCD had persistent 10 SCD, 10 Greater left prefrontal cortex Increase
memory task comparison with ANOVA. Cluster memory concerns and were control activation in SCD during encoding.
correction. recruited from a memory clinic. No differences in recognition rate.
Controls were recruited from a prior
study and were similar to SCD in age
and education.
Maestu et al. 2011 [27] MEG Sternberg’s MEG source reconstruction. Participants with SCD recruited from 12 SCD, 18 Greater task-related activation within Increase
letter-probe task Nonparametric permutation testing to memory clinic with memory control 200–900 ms after stimulus onset in
Viviano and Damoiseaux Alzheimer's Research & Therapy
identify spatio-temporal clusters that deterioration confirmed by SCD in parietal, temporal, occipital,
distinguish the groups. informant. Participants scored below motor/premotor, and dorsal pre-
9 on the Geriatric Depression Scale frontal regions.
and greater than 13 on the Memory
Failures of Everyday test. Healthy
elderly control participants recruited
from university educational courses.
(2020) 12:23
Rodda et al. 2011 [28] fMRI Divided Voxelwise task contrasts. Group Participants with SCD had persistent 11 SCD, 10 Greater thalamus, caudate, posterior Increase
attention task comparison with ANOVA. Cluster perceived decline from prior control cingulate, hippocampus, and
with visual correction. memory performance and were parahippocampus task-related activa-
letters and recruited from a memory clinic. tion in SCD. No differences on
auditory Controls were recruited as part of a performance.
numbers prior study.
Dumas et al. 2013 [29] fMRI N-back working Voxelwise analysis. Group comparisons Healthy, older, post-menopausal 12 SCD, 11 Greater working memory task-related Increase
memory task with random effects ANOVA (group by women recruited from general control activity in precuneus, midfrontal, and
working memory load). Cluster-level population. Participants identified as cingulate gyri in SCD.
correction. SCD if they endorsed > 20% of the
items of the Cognitive Complaint
Index and as control otherwise.
Hafkemeijer 2013 [30] fMRI Eyes closed Independent components analysis and Participants with SCD recruited from 25 SCD, 29 Greater DMN and medial temporal Increase
et al. resting state dual regression. memory outpatient clinic. control connectivity in SCD.
Dillen et al. 2016 [31] fMRI Eyes open Functional seed-based correlation Participants with SCD recruited from 27 SCD, 25 Greater functional connectivity Increase
resting state analysis. outpatient memory clinic. Healthy control between retrosplenial cortex and
controls recruited from general ventromedial prefrontal cortex in
population through advertisements. SCD.
Participants with SCD had memory
complaint scores > 24 and normal
cognitive test results.
Sun et al. 2016 [32] fMRI Eyes closed Voxelwise amplitude of low-frequency Participants with SCD recruited from 25 SCD, 61 Greater low-frequency signal ampli- Increase
resting state fluctuation analysis. Group differences a memory clinic. Participants with control tude in superior temporal, cerebellar,
Page 3 of 18
evaluated with voxelwise general linear SCD reported persistent decline in occipital, and inferior parietal cortex
Table 1 Results from various functional neuroimaging analyses in subjective cognitive decline (Continued)
model analysis. memory corroborated by an in SCD. Greater low-frequency ampli-
informant. Healthy controls recruited tude associated with poor verbal
from the general population and did learning within the SCD group.
not harbor cognitive concerns.
Cespon 2018 [33] EEG Simon task Evaluation of P300 latency and Participants recruited from general 18 low-SCD, Greater medial prefrontal negativity Increase
et al. amplitude during executive control population and split into low-SCD 16 high- during task associated with greater
processes. and high-SCD groups based on SCD degree of subjective cognitive
scores of a memory complaints decline.
questionnaire.
Lazarou 2018 [34] EEG Administration N170 event-related potential Participants recruited from a 14 SCD, 12 Greater N170 (negative) amplitude in Increase
et al. of pictures of evaluation. memory clinic. SCD status based on control response to faces expressing fear.
facial affect SCD international working group
during EEG suggestions.
Verfaillie 2018 [35] fMRI Resting state Parcellation-based functional Healthy older adults recruited from 68 SCD, 56 Greater connectivity between Increase
et al. connectivity analysis. Linear regression general population if they had a control posterior DMN and medial temporal
evaluated strength of association family history of Alzheimer’s disease. regions, in SCD.
between SCD and connectivity Participants subsequently classified

strength. as SCD if they responded “Yes” to
the question “Do you think your
memory is becoming worse?”
Kawagoe 2019 [36] fMRI Eyes closed Principle component multivariate Participants recruited from the 155 Greater connectivity between lingual Increase
et al. resting state pattern analysis for functional general population. Subjective participants gyrus and cuneus, lingual gyrus and
(2020) 12:23
connectivity. memory score measured as a with SCD as precuneus, superior parietal lobe and
continuous variable. a postcentral gyrus, and between
continuous cuneus and many occipital and
variable association areas in SCD.
Bajo et al. 2012 [37] MEG Sternberg’s Functional connectivity patterns, via Participants with SCD recruited from 12 SCD, 25 Diffuse lower synchronization Decrease
letter-probe synchronization likelihood, evaluated memory clinic with memory control between electrode pairs in α and β
task. for task hits. deterioration confirmed by bands in SCD.
informant. Participants scored below
9 on the Geriatric Depression Scale
and greater than 13 on the Memory
Failures of Everyday test. Healthy
elderly control participants recruited
from university educational courses.
Wang et al. 2013 [38] fMRI Eyes closed Independent components analysis and Participants recruited through 23 SCD, 16 Lower connectivity between right Decrease
resting state dual regression. advertisements and through referrals control hippocampus and the DMN in SCD.
from medical centers. Group
classification then based on results
of neuropsychological assessment,
self-, and informant-report. All partici-
pants classified by clinical consensus
panel.
Yasuno et al. 2015 [18] fMRI Eyes closed Region-of-interest based Pearson’s Participants with and without SCD 23 SCD, 30 Lower functional connectivity Decrease
resting state correlation functional connectivity recruited from hospital psychiatry control between retrosplenial cortex and
analysis. unit. SCD classification based on dorsomedial prefrontal cortex, and
Page 4 of 18
Reisberg criteria. between retrosplenial and anterior

cingulate cortex in SCD. No
differences between groups in
amyloidopathy.
Lopez-Sanz 2016 [39] MEG Eyes closed MEG source reconstruction and Participants recruited from a hospital 39 SCD, 41 Diffuse lower relative α power in Decrease
et al. resting state spectral analysis. Groups differences neurology department, a center for control SCD. No differences in α peak
assessed with ANCOVA. the prevention of cognitive frequency slowing.
impairment, and a senior center.
Cognitive concerns self-reported and
SCD status determined by multidis-
ciplinary panel.
Contreras 2017 [40] fMRI Eyes closed Independent components analysis Participants with SCD had cognitive 16 SCD, 13 Greater functional connectivity Decrease
et al. resting state resting-state network analysis. concerns but tested normally on control within all resting-state networks
cognitive tests. Controls had no negatively associated with the cogni-
significant cognitive concerns. tive complaint index.
Dillen et al. 2017 [41] fMRI Resting state Region-of-interest based temporal Participants with SCD recruited from 28 SCD, 25 Decreased functional connectivity Decrease
network modeling. outpatient memory clinic. Healthy control between hippocampus and posterior
controls recruited from general DMN in SCD. Retrosplenial cortex

population through advertisements. mediated connectivity between
Participants with SCD had memory hippocampus and DMN in controls
complaint scores > 24 and normal but not SCD.
cognitive test results.
Hayes et al. 2017 [42] fMRI Event-related Voxelwise contrasts based on Participants with and without SCD 23 SCD, 41 Weaker task-related activity related to Decrease
(2020) 12:23
visual memory subsequently remembered items. recruited from general population. control successful encoding in occipital, su-
encoding task Higher level analysis carried out with However, participants with SCD saw perior parietal, and cingulate cortex
FMRIB’s Local Analysis of Mixed Effects. a medical professional regarding in SCD. No differences in retrieval
their complaints prior to performance.
participation.
Hu et al. 2017 [43] fMRI Intertemporal Voxelwise task contrasts for choice Participants with SCD recruited from 20 SCD, 24 Poor temporal reward decision- Decrease
decision task process and subjective valuation memory clinic and reported decline control making related to reduced hippo-
with an episodic components of task. Group level in memory with onset in the past campal engagement in SCD. Lower
imagination task factorial designs. 5 years. Control participants recruited insulae activation during task-
embedded from the general population and switching in SCD.
within reported no cognitive concerns.
Mazzon 2018 [44] EEG Eyes closed Kruskal-Wallis and Wilcoxon rank sum Participants recruited from a 8 SCD, 7 Lower parietal β and γ band power Decrease
et al. resting state tests compared groups on regional memory center. Inclusion criteria for control in SCD during a memorization task.
and Rey’s relative band power. SCD included persistent memory
Auditory Verbal complaints within the past 5 years,
Learning task normal cognitive performance, and
no psychiatric disease.
Yang et al. 2018 [45] fMRI Eyes closed Amplitude of low-frequency fluctuation Participants with SCD recruited from 44 SCD, 57 Lower amplitude and fraction Decrease
resting state evaluation. Support vector machine a memory clinic. Healthy controls control amplitude of low-frequency fluctua-
evaluation of ALFF for group recruited from general population. tions in precuneus, anterior cingu-
discrimination. SCD determination based on the lum, and cerebellum in SCD.
SCD international working group
definition and made by experienced
neurologists.
Page 5 of 18
Lopez-Sanz 2019 [46] MEG Eyes closed Source power spectra estimation and Participants recruited from a hospital 91 SCD, 70 Lower relative α band power, Decrease
et al. resting state group classification based on source neurology department, a center for control predominantly in frontal regions,
power analysis with regularized logistic the prevention of cognitive associated with SCD.
regression with the Least Absolute impairment, and a senior center.
Shrinkage and Selection Operator. Cognitive concerns self-reported and
ciplinary panel.
Viviano et al. 2019 [47] fMRI Eyes closed Region-of-interest based functional Participants with and without SCD 35 SCD, 48 Lower functional connectivity Decrease
resting state connectivity analysis. recruited from general population. control between retrosplenial cortex and
However, participants with SCD saw precuneus in SCD.
a medical professional regarding
their complaints prior to
participation.
Wang et al. 2019 [48] fMRI Eyes closed Vertex-based functional connectivity Participants with SCD recruited from 32 SCD, 40 Lower subgraph centrality in Decrease
resting state analysis and graph-theoretic ap- memory clinic and status control occipital and paracentral regions in
proaches to the functional determined by two psychiatrists SCD.
connectome. according to the international

working group standard proposed
by Jessen et al. Participants without
SCD recruited from general
population.
Babiloni 2010 [49] EEG Eyes closed Spectral and cortical source analysis of Participants with SCD recruited from 53 SCD, 79 Greater frontal δ band amplitude, Complex
(2020) 12:23
et al. resting. EEG data. outpatient clinics with memory control lower parietal and occipital θ and α1
centers. Participants with SCD had z- (8–10.5 Hz) amplitude, and greater
scores > − 1.5 on cognitive battery. occipital α2 (10.5–13 Hz) amplitude
Controls also recruited from the in SCD.
clinics, but without and neurologic
or psychiatric disease, and without
social limitations.
Erk et al. 2011 [50] fMRI Visual memory Voxelwise task contrasts. Group Participants with SCD recruited from 19 SCD, 20 Lower posterior hippocampal Complex
encoding, recall, comparison with ANOVA (full-factorial memory clinic and had informant control activation and greater right
and recognition design). Family-wise error correction corroboration. Healthy controls dorsolateral prefrontal cortex
tasks. N-Back across whole brain at p < .05, or across without complain recruited from the activation during recall in SCD. No
working mem- a-prior hippocampal and dorsolateral general population. All participants differences in task performance or
ory task prefrontal regions of interest. scored within 1.5 standard deviations task-related activity during memory
on all subtests of the Consortium to encoding. No group differences in N-
Establish a Registry for Alzheimer’s back task.
Disease.
Vega et al. 2016 [51] fMRI Resting state Voxelwise seed-based functional con- Healthy, older, post-menopausal 31 SCD Greater within executive control Complex
nectivity. Second-level regression ana- women recruited from general (continuous) network and within middle temporal
lysis associated cognitive complaint population. Participants identified as gyrus connectivity, and lower frontal
index with voxelwise connectivity. SCD if they endorsed > 20% of the cortex functional connectivity in SCD.
items of the Cognitive Complaint
Index and as control otherwise. Cog-
nitive complaints evaluated as a con-
tinuous variable.
Lopez-Sanz 2017 [52] MEG Eyes closed Source reconstruction and phase Participants recruited from a hospital 41 SCD, 39 Increased α-band connectivity Complex
Page 6 of 18
et al. resting state synchronization functional connectivity neurology department, a center for control between anterior regions and de-
analysis. the prevention of cognitive creased α-band connectivity be-
impairment, and a senior center. tween posterior regions in SCD.
Cognitive concerns self-reported and
ciplinary panel.
Jiang et al. 2018 [53] fMRI Eyes closed Vertex-based functional connectivity Participants with SCD recruited from 42 SCD, 54 Lower vertex-wise index of functional Complex
resting state analysis. memory clinic and status control criticality (a measure of signal stand-
determined by two psychiatrists ard deviation, within cluster correl-
according to the international ation, and correlation with
working group standard proposed components outside a cluster) in the
by Jessen et al., [1]. Participants inferior temporal gyri and frontal
without SCD recruited from general poles, and greater criticality in precu-
population. neus, cingulate, parietal, and ventro-
medial prefrontal cortices in SCD.
Li et al. 2018 [54] fMRI Eyes open Whole-brain Pearson’s correlations and Participants with SCD and healthy 44 SCD, 40 Participants with SCD exhibited Complex
resting state graph-theoretic methods to evaluate controls pulled from the Alzheimer’s controls greater degree centrality in
functional connectivity differences be- Disease Neuroimaging Initiative hippocampus, and fusiform gyrus,
tween groups. (ADNI) database. and lower inferior parietal degree
centrality. No differences between
groups in eigen centrality. No
differences between groups in
amyloidopathy or tauopathy.
(2020) 12:23
Xie et al. 2019 [55] fMRI Eyes closed Static and dynamic functional Participants with SCD recruited from 40 SCD, 53 Centrality frequency (proportion of Complex
resting state connectivity based on connectivity a memory clinic. Healthy controls control time a degree centrality hub region
matrices derived from the Automated recruited from general population. appeared in a dynamic functional
Anatomical Labeling atlas. SCD determination based on the connectivity analysis) differed
SCD international working group between SCD and controls. Lower
definition and made by experienced gyrus rectus and cingulum, and
neurologists. greater hippocampus, calcarine,
lingual, and occipital centrality
frequency in SCD.
Yan et al. 2019 [56] fMRI Eyes closed Multimodal (functional connectome Participants with SCD recruited from 39 SCD, 45 Classification accuracy for Complex
resting state and structural connectome via a memory clinic. Healthy controls control distinguishing SCD from controls
diffusion imaging) classifier training. recruited from general population. ranged from 72 to 77% over a set of
SCD determination based on the classifiers trained on connectome
SCD international working group data. Important regions for
definition and made by experienced classification included frontal,
neurologists. parietal, temporal, and hippocampal
regions.
Dierks et al. 1997 [57] EEG Eyes closed EEG segmented into microstates based Participants with SCD recruited from 31 SCD, 21 Duration of microstates, distinct No
resting. on the locations of centroids of memory clinic, did not exhibit control spatial patterns of electrical activity, difference
electrical activity during spikes in difficulties in everyday living, and reduced in dementia. No difference
spatial variance. performed less than one standard between controls and SCD.
deviation below age reference
average on cognitive tasks. Control
subjects did not harbor memory
Page 7 of 18
complaints and came from the

general population.
Lopez-Sanz 2017 [58] MEG Eyes closed Source reconstruction and region-of- Participants recruited from a hospital 55 SCD, 63 Decreased small-world characteristics No
et al. resting state interest based functional connectivity neurology department, a center for control of mild cognitive impairment brains difference
analysis. Graph theoretic approaches the prevention of cognitive compared to healthy controls in θ
utilized. impairment, and a senior center. and β bands. Individuals with SCD
Cognitive concerns self-reported and exhibited a similar pattern, though
SCD status determined by multidis- not significantly different from
ciplinary panel. controls.
Teipel et al. 2018 [59] fMRI Resting state Pearson’s correlation based functional Participants recruited from the 90 SCD, 80 Functional connectivity did not reach No
connectivity. Amplitude of low- general population and grouped as controls significant discrimination accuracy difference
frequency fluctuation evaluation. Evalu- SCD if they answered “Yes” to the for distinguishing SCD from controls.
ation of functional connectivity to dis- questions “Are you complaining
tinguish SCD via cross-validated about your memory?” and “Is it a
discrimination accuracy based on pe- regular complaint that lasts more
nalized logistic regression. than 6 months?”
Contreras 2019 [60] fMRI Eyes closed Within- and between-network func- Participants drawn from two cohorts. 27 SCD, 31 No significant difference between No
et al. resting state tional connectivity based on whole- Participants with SCD had cognitive control controls and SCD. difference
brain parcellation. concerns but tested normally on
cognitive tests. Controls had no
significant cognitive concerns.
Scarapicchia 2019 [61] fMRI Eyes open Association between resting-state vox- Participants drawn from ADNI 19 SCD, 19 No significant difference between No
et al. resting state elwise BOLD variability and white mat- database. SCD status determined by control controls and SCD in blood-oxygen- difference
(2020) 12:23
ter hyperintensities older adults with ADNI investigators. Participants self- level dependent variability. Higher
and without SCD. reported cognitive concerns and white matter hyperintensity burden
scored > 15 on the first 12 items of associated with greater variability in
the Cognitive Change Index. Control temporal regions for controls only.
participants had no significant cogni-
tive concerns.
Page 8 of 18
Functional neuroimaging in subjective cognitive working memory, attention, and other executive func-
decline tions [70, 71]. Lower insula activation during task
Task-related brain activity in subjective cognitive decline switching [43], however, suggests that SCD may relate to
Previous fMRI analyses that examined memory pro- inefficient salience network functioning, as the insulae
cessing in older adults have observed lower hippo- are part of a network observed to send control signals to
campal and greater dorsolateral prefrontal cortex the default mode and executive control regions to
task-related activity during memory retrieval, as well modulate their engagement relative to internal and ex-
as greater task-related activity in dorsolateral pre- ternal task demands [72]. Thus, it is possible that the
frontal cortex and lower activity in superior parietal, circuitry involved in memory and executive functions
cingulate, and occipital cortex during memory encod- may operate efficiently in some individuals with SCD,
ing in individuals with SCD [26, 42, 50]. These results but the ability to properly recruit different circuits at ap-
suggest that SCD may arise from processing aberra- propriate times diminishes.
tions underlying either memory encoding or retrieval. Overall, tasked-based analyses suggest that cognitive
As different analyses uncovered encoding or retrieval processing alterations exist in individuals with SCD,
group differences, the ability to efficiently access but precise and accurate synthesis of the results re-
stored information may diminish first for some while mains difficult. Lower hippocampal task-related activ-
the ability to efficiently encode information may ity during retrieval [50] and decreased occipital and
deteriorate earliest for others. This suggests that epi- default mode network task-related activity during
sodic memory encoding and retrieval processing alter- encoding [42] could either indicate local processing
ations are independently sufficient for the subjective inefficiencies in the observed regions or indicate de-
experience of decline, but neither are necessary. creased network signaling to those regions during
In addition to episodic memory, fMRI analyses have memory processing in SCD. This interpretation is
also identified group differences in functional activity based on multimodal imaging research that indicates
during working memory and other executive functions that neuronal contributions to the blood-oxygen-level
in SCD. Prior analyses suggest greater working memory- dependent (BOLD) response reflect metabolic de-
related activity in precuneus, middle frontal gyrus, and mands of synaptic activity [73], which suggests that
cingulate gyrus [29], and greater divided attention- regional signal reflects local computation and process-
related activity in thalamus, caudate, posterior cingulate, ing of distal afferent input. This interpretation of the
hippocampus, and parahippocampus [28] in individuals BOLD response also contextualizes observations of
with SCD. Moreover, greater EEG alpha band power greater task-related activity in frontal regions during
across electrodes, greater frontal theta power, and encoding or retrieval [26, 50], which could reflect ei-
greater spatiotemporal wave activity during working ther greater processing within regional microcircuits,
memory have been observed in older adults with SCD, or greater processing of afferent input to frontal re-
with greater alpha power and wave activity relating to gions. Greater processing of afferent input could re-
lower verbal memory performance and reaction time, flect functional compensation [74]. Here, the
and greater reverse digit span performance [25]. Finally, neurocognitive Scaffolding Theory of Aging and Cog-
greater MEG post-stimulus-related activity has been nition would posit that cognitive ability remains rela-
noted in older adults with SCD in parietal, temporal, oc- tively stable through aging despite neuronal declines,
cipital, motor, and dorsal prefrontal during a working and the continuous recruitment of additional neur-
memory task [27]. Overall, these analyses provide evi- onal circuits, which may manifest as functional activ-
dence that neural information processing disruptions in ity increases via neuroimaging analysis, may be
SCD do not just relate to memory but may also extend responsible for stable cognitive ability through healthy
to executive functions. aging and early disease states. Thus, functional activ-
Though many analyses have evaluated functional brain ity increases in frontal regions in SCD could repre-
aberrations related to memory and executive functions, sent compensatory recruitment (more processing of
these processing disturbances may not be the sole afferent input) to aide processing deficiencies in cir-
drivers of SCD. Previously observed lower insula activa- cuits with neural insults. Greater executive task-
tion in individuals with SCD during a task that involved related activity and greater alpha band power in indi-
switching between imagination and temporal decision- viduals with SCD [25, 27–29] could also indicate ex-
making suggests decreased ability to control engagement plicit strategy use in response to self-knowledge of
of the default mode and executive control networks in decline, rather than compensatory regional recruit-
SCD [43]. The default mode network is involved in epi- ment outside of cognitive control. Though, greater
sodic memory, theory of mind, and future planning [69], alpha band power in older adults with SCD under
while the executive control network is involved in cognitive load could also reflect more automatic
compensatory processing to nascent decline, an inter- Brain network functional connectivity in subjective
pretation supported by increased band power relating cognitive decline at wakeful rest
to better executive performance [25]. Variability and inconsistencies across the resting-state
However, another valid interpretation of greater re- functional connectivity literature in SCD have resulted
gional task-related activity in SCD could be that compu- in a challenging picture to decipher. Some groups
tational failure in a circuit leads to a shifting of have reported greater connectivity, mainly within and
processing loads and computation to other regions. between default mode network and medial temporal
While the distinction between compensatory recruit- regions, in older adults with SCD [30, 31, 35, 36].
ment and shifting processing load is subtle, this refram- However, many groups have also observed lower con-
ing of interpretation would fit the Cascading Network nectivity between these regions in individuals with
Failure model of AD [20]. Furthermore, although com- SCD [18, 76–79]. Others have reported no difference
pensatory processing is a common chorus across discus- from control [60], or intricate patterns of greater and
sion sections, increased task-related activity could also lower functional connectivity in individuals with SCD
reflect inefficient processing. Briefly, decreased network [51–55], suggesting that a complex reorganization of
segregation or age-related functional dedifferentiation processing responsibilities across network nodes may
[75, 76], which could reflect less economical neural occur. Multifaceted patterns of increased and de-
function in aging where maintenance of cognitive abil- creased connectivity between regions could reflect
ities may require greater BOLD signal [77, 78], could be breakdown in processing within a subnetwork that
accelerated in SCD and reflect inefficient information shifts processing load to more intact components of
processing and noisy signal propagation across brain the broader network. Diffuse and frontally localized
networks. Synaptic disruption, supported by observa- MEG alpha band power reductions have also been
tions of structural atrophy in SCD [79–86], could also noted in older adults with SCD [39, 46], without
result in unrefined noisy signal. Therefore, it could be group differences in the small world properties of
that the increased task-related activity and alpha band theta and beta bands [58]. Moreover, lower subgraph
power during executive functions reflects increased pro- centrality (a measure of weighted, closed walks start-
cessing demands in individuals with SCD, possibly from ing and ending at a node, representing mid-scale con-
inefficient signal processing and system noise, rather nectivity) has been observed in occipital and
than compensatory mechanisms. For example, increased paracentral regions in older adults with SCD [48].
spatiotemporal wave activity [25] could indicate lower Though the functional connectivity results appear in-
stability of distinct states of information processing, and congruous, they do suggest that connectivity abnormal-
greater alpha band power could indicate increased pro- ities occur in SCD that could represent information
cessing demands of attention without necessarily offer- processing inefficiencies and could demarcate incipient
ing a compensatory advantage. Negative associations of dementia. The implications of elevated functional con-
alpha band power with verbal memory performance and nectivity in SCD [30, 31, 35] are unclear but could re-
reaction time [25] could support this interpretation. flect compensatory intrinsic signaling resulting from
Overall, the exact interpretations of complex patterns gray matter atrophy or other neural insult. This could
of increased and decreased task-related neural activity reflect a neurocognitive scaffolding mechanism for
remain up for debate. However, existing theories and maintaining stable internal mentation and memory func-
models of cognitively unimpaired aging and dementia tioning [74]. However, increased connectivity does not
development, e.g., the Scaffolding Theory of Aging and always confer greater cognitive performance and may re-
Cognition [74], the Dedifferentiation Theory of Aging flect a shift in network properties that underlies poor
[76], or the Cascading Network Failure Model of AD memory performance [87]. Increased processing de-
[20], offer valid interpretations for comparing the func- mands for internal mentation and memory at rest could
tional brains of older adults with and without SCD. arise due to noisier information traveling through mem-
There is also room for a general model that unifies con- ory systems [77]. Increasing regional metabolic demands
cepts across these theories and models to explain func- from processing noisy information could serve as a
tional alterations of the brain in SCD. Compensatory mechanism that induces further neurodegenerative de-
neural recruitment, non-compensatory network dediffer- cline. Eventually, this neurodegenerative pressure could
entiation, cascading network failures and processing load shift elevated functional connectivity early in SCD to de-
shifts, noisy signal propagation, and inefficient network creased functional connectivity later in SCD.
signal processing could all occur in the same brain; one Lower functional connectivity between default mode
mechanism could influence observed neural activity in and medial temporal structures in SCD [18, 37, 38, 41,
one region while a different mechanism affects the activ- 47] could either reflect cohort differences compared to
ity in another region. analyses noting greater functional connectivity in SCD
[30, 31, 35, 36] or represent a later phase of SCD close Time since onset of SCD may be an important meas-
to mild cognitive impairment conversion marked by de- ure for both researchers and clinicians if brain change
creased signaling capability between regions. While in- trajectories over the progression of SCD to objective de-
volved in episodic memory, cortical midline regions of cline are nonlinear. This suggests a possible reconcili-
the default mode network also mediate self-referential ation to the discrepancies of previous connectivity
processing [69, 88]. Therefore, reduced connectivity research in SCD. The results may not disprove each
could indicate either decreased computation related to other, but rather, they may capture different stages of
self-awareness of memory processing or decreased mem- SCD; high or low network connectivity could reflect dif-
ory processing directly. Furthermore, as cortical midline ferent phases of the underlying mechanisms responsible
structures, hippocampus, and parahippocampus com- for the experience. Though speculative, and requiring
pose a memory system import for accessing episodic longitudinal evaluation for verification, we propose that
memories [89], and as decreased posterior hippocampal elevated network functional connectivity characterizes
activation during memory recall has been noted in older early SCD, which transitions to lower functional con-
adults with SCD [50], the aforementioned task and nectivity with time (see Fig. 1). Though, the time course
resting-state results together provide parallel evidence of this nonlinear trajectory may emerge in some regions
that issues in memory access processing are either a earlier than other, e.g., in regions most susceptible to
common or a sufficient component of SCD. early neurodegenerative change like the transentorhinal
The confounding variables responsible for discrep- areas in AD [91]. This concept of elevated connectivity
ancies in the results remain unclear; however, a few transitioning to lower connectivity is not novel, and re-
differences across samples could help explain the re- views of dementia research have proposed this concept
sults. For example, [18] found lower fractional anisot- before [92]. However, here, we suggest that this trajec-
ropy in the superior longitudinal fasciculus and tory reflects the underlying neurodegenerative process of
higher fractional anisotropy in the parahippocampal the transition between cognitively unimpaired aging and
cingulum in individuals with SCD that significantly dementia, and that SCD is the experience of this
associated with the functional connectivity of cortical process.
midline structures. Aberrant diffusion characteristics Due to potential nonlinearities, the existence of inflec-
involving physical connections between memory and tion points in the trajectory of brain changes related to
self-referential regions may distinguish this sample pathology could reduce differences between healthy
from the others and may reflect a mechanism for older adults with and without SCD in cross-sectional
lower functional connectivity unrelated to mecha- analyses. This may not be the case for protein aggregates
nisms underlying increased connectivity [30, 31, 35]. as they may not spontaneously clear. But for brain mea-
Group differences in diffusion metrics do not explain sures, such as functional integration, where either a posi-
the group differences in [47] though as there were no tive or negative association with SCD could be
differences between the groups in neurite orientation meaningful, and where a change in the direction of asso-
dispersion and density [90] throughout the cingulum ciation may be equally or more meaningful, the omission
fiber tract. However, lower working memory perform- of variables related to length of time that participants
ance for the SCD participants in that sample may have experienced SCD may pose a fundamental problem
have related to decreased connectivity. for data analyses. Because of possible nonlinearities in
Inconsistent results of increased and decreased brain changes or other changes related to SCD, longitu-
functional connectivity may also reflect unmeasured dinal analysis must drive the discussion regarding poten-
confounds. The confounds are unlikely to relate to tial neurodegenerative-related brain changes in this
age as the average sample ages do not appear to drive population. Furthermore, ongoing longitudinal data col-
the differences; they averaged between the mid-sixties lection efforts should retroactively gather years-since-
to early seventies without a clear pattern of younger onset information when possible, and new projects
or older samples corresponding to particular group should collect this information from the start.
differences. Thus, the underlying reason for differ- Although a nonlinear trajectory for functional con-
ences in cross-sectional results could reflect an im- nectivity change makes cross-sectional analysis difficult
portant unmeasured variable. Though aforementioned to interpret, there may be an unseen benefit to this po-
sample differences in structural and cognitive mea- tential change trajectory. Evaluation of an individual
sures may have accounted for some of the connectiv- over multiple timepoints could help determine their pro-
ity variability across studies, there is one commonly gression though SCD, regardless of initial measurement
unreported variable which may capture a substantial values. For example, an individual at an early phase of
portion of connectivity variance in SCD: time since SCD might exhibit increasing functional connectivity
the onset of perceived cognitive worsening. over time while an individual on the cusp of converting
Fig. 1 Possible trajectory of resting-state functional connectivity changes in subjective cognitive decline for default mode network and medial
temporal regions based on cross-sectional analyses. Observations of both greater and lower functional connectivity in SCD could suggest a
nonlinear change trajectory over the progression from subjective to objective impairment, highlighting the need for longitudinal analysis. Early
synaptic disruption may lead to noisy signal propagation across systems or early compensatory processes that underlie elevated functional
connectivity which may transition to lower functional connectivity as neurodegeneration progresses and objective decline become more
apparent. Furthermore, this trajectory might shift depending on the brain regions evaluated as some groups report complex patterns of both
higher and lower functional connectivity in SCD
to mild cognitive impairment or dementia may exhibit predictor of the type of functional connectivity pat-
decreasing connectivity over the time. This hypothetical tern exhibited in SCD.
trajectory requires confirmation, but nevertheless sug-
gests that functional connectivity may be a valid method Hypothetical functional model of SCD
to track the progression of incipient neurodegenerative As individuals with SCD may revert to a subjectively
disease and may be useful regardless of the magnitude of normal state, maintain cognitive performance over time,
the baseline measurement. or develop dementia, models of SCD that reflect func-
Finally, recruitment methods may also influence tional connectivity change related to progressive neuro-
functional connectivity results. Perhaps individuals degeneration implicitly refer to the latter group. While
who are concerned about their cognitive ability and SCD outcomes are heterogenous, we argue that func-
seek medical advice represent older adults with SCD tional neuroimaging has promise as a marker for incipi-
more likely to harbor incipient neurodegeneration ent neurodegeneration and for progression of cognitive
while individuals recruited from the general public decline, distinguishing between those that develop de-
may include SCD cases in an early disease phase, or mentia and those that do not. Therefore, we propose the
cases due to neuroticism, poor sleep, or transient following model to account for common features of
stressful life events. The extant literature suggests that SCD based on the aforementioned functional neuroim-
recruitment methods may indeed contribute to SCD aging results (Fig. 2).
sample characteristics, with cohorts recruited from The first node of the model represents age-related
memory clinics exhibiting poorer neuropsychological neurodegeneration; at the cellular level, synapse loss
performance, greater hippocampal atrophy, greater could occur before appreciable cell death. Thus, in early
cortical atrophy over time, and greater depression SCD, this node may not represent cell loss, but rather
than cohorts recruited from the general population physical disconnectivity. This disconnectivity could im-
that have not sought medical help [93–95]. However, pact short-range connection within a region or could
as samples that have sought medical help have exhib- impact long-range connections that mediate the signal-
ited both increased and decreased functional connect- ing between different whole-brain networks. For SCD,
ivity cross-sectionally [18, 30, 47], the impact of the we speculate that disruptions occur in the hippocampus
severity of cognitive complaint on functional metrics and surrounding medial temporal lobe through observa-
is not as clear. Future research should aim to further tions of altered task-related hippocampal activity and
clarify if recruitment methodology is an important resting connectivity [38, 43, 50] and, although not the
Fig. 2 Proposed functional model of subjective cognitive decline. a Incipient neurodegeneration and synapse loss lead to disruption in short-
and long-range functional connections within and between default mode, executive control, and salience networks. This disconnectivity may in
turn lead to information loss and noisy signal propagation that directly disrupts memory and executive functions, and indirectly disrupts those
functions though reduced ability of the salience network to modulate the activity of the default mode and executive control networks with
control signals. Disrupted memory and executive functioning in turn results in the personal experience of deteriorating cognitive ability. b Default
mode (red), executive control (blue), and salience (green) networks visualized with Neurosynth uniformity test images [110]. Search terms
included “default network,” “executive network,” and “salience network.” Z-score thresholds set at 6
focus of this review, observations of structural atrophy regional decline may differ between individuals, but all
[79–86]. As hippocampal atrophy is a common fea- processing inefficiencies may be sufficient for the experi-
ture of AD, this may help identify adults with SCD ence of SCD, and subtle objective decline that neuro-
that could develop AD specifically while other psychological tests may not be sensitive enough to
neurodegenerative patterns could indicate dementia detect. Functional neuroimaging allows for the
development due to a different cause. We also specu- visualization of these inefficiencies through observation
late that long-range connectivity alterations occur be- of network functional connectivity and task-related
tween regions of the default mode, executive control, neural activity aberrations, and continued cross-sectional
and salience networks based on diffuse task-related and longitudinal evaluation of network connectivity and
and resting functional connectivity alterations across activity can help refine this model.
studies [18, 26, 30, 31, 35, 38, 41–43, 47, 50]. While we place loss of synaptic connections as the
Altered connectivity, both at the local and global level, first node in the model and speculate that they could
presumably carries two major consequences: (1) infor- have a causal role in disrupting network signaling, it
mation loss from signal not reaching downstream targets is reasonable to order the events in reverse. Disrupted
in a global circuit, and (2) noisy signals that reach down- signaling between brain regions may affect trophic
stream targets, but arise due to inadequate processing signaling between pre- and post-synaptic neurons and
and refinement from local circuits and whole-brain net- downstream processes related to synaptic maintenance
works. Information loss and noisy signal could lead to [96, 97], thus having a causal role in neuropil loss.
processing inefficiencies in control signals from the sali- Hebb’s postulate stated colloquially: “Cells that fire
ence network that mediate memory and executive pro- together, wire together” [98]. Therefore, temporal or-
cesses, as well as direct processing inefficiencies in dering of events requires exploration, as does the pos-
memory encoding or retrieval, and executive function- sibility that a positive feedback loop exists where
ing. Specific processing inefficiencies may be highly indi- synaptic disconnectivity and gray matter atrophy
vidualized, and the ordering of component failure or through neuropil and cell loss amplify functional
signaling disruption between regions, which in turn and other networks, may occur in older adults with SCD
exacerbates cell and neuropil loss by disrupting syn- [43]. Salience network gray matter atrophy occurs at a
aptic maintenance processes. greater rate in cognitively unimpaired aging than the rest
While we emphasize that the proposed and alternative of the brain, and atrophy is even greater in mild cogni-
functional models of SCD are non-specific to neurode- tive impairment and dementia, and this atrophy may
generative etiology and outcome, AD may be the domin- occur alongside lower functional connectivity between
ant dementia etiology [19]; thus, it will be important to salience and executive control network regions and
extend this model, or create a parallel model, to account greater connectivity between salience and default mode
for individuals with SCD that specifically exhibit AD network regions [100]. If SCD indicates incipient de-
pathology. As network failure may occur before mentia, greater salience network atrophy and connectiv-
amyloid-β accumulation [20], SCD has variable associ- ity alterations could occur compared to healthy aging
ation with amyloidopathy and tauopathy [11–18], and and serve as a prognostic marker for further dementia
detection of aberrant amyloid-β and tau may precede development. In addition, subtle differences in cognitive
observable structural decline [99], we speculate that our performance between adults with and without perceived
model could fit in-between the Cascading Network Fail- cognitive decline exist [101], and salience network dis-
ure [20] and Pathological Cascade [99] models of AD for ruption may help explain these group differences, pos-
older adults with SCD that develop AD specifically. sibly through failure to effectively engage the executive
Here, network failure and complex reorganization of control networks for cognitive tasks while disengaging
processing loads across whole-brain networks could in- the default mode network. As mentioned previously,
fluence metabolic and molecular processes related to [43] found lower insula activation in individuals with
AD pathology and neurodegeneration while simultan- SCD during a task that involved switching between task
eously accounting for the experience of decline. Analyses demands handled by default mode regions and task de-
reporting functional connectivity differences between mands handled by executive control regions. Thus, there
older adults with and without SCD without finding is evidence to support exploring connectivity between
group differences in amyloid or tau deposition [18, 54] the default mode, salience, and executive control net-
suggest that functional brain alterations and perception works in SCD.
of cognitive decline could co-occur before AD pathology Furthermore, as mentioned earlier, longitudinal ana-
detection. Finally, this model could be extended to ac- lyses must drive the discussion of functional connectivity
count for disease-specific outcomes in general; however, change trajectories as some groups have observed
future research must determine the patterns of func- greater functional connectivity in older adults with SCD
tional connectivity change that are sensitive enough to compared to controls while other groups have observed
predict specific outcomes before this model is extended. lower functional connectivity. These results suggest a
possible nonlinear change in brain network functional
Future directions integration across the course of SCD. However, the only
While cross-sectional analyses have evaluated default way to verify that speculation would be extensive longi-
mode and medial temporal functional connectivity, tudinal analysis.
evaluation of other brain networks that SCD may impact While we emphasize the importance of longitudinal
remains sparse. Though the medial temporal lobes and analyses to understand trajectories of functional con-
default mode network may be sensitive to distinguish nectivity change, there are important cross-sectional
SCD from unimpaired, healthy aging, some individuals analyses that could use existing data to help clarify pat-
may display connectivity aberrations in other networks, terns of functional connectivity in SCD. However, they
such as the salience or executive control networks, be- would require coordination across research groups. Cur-
fore default mode network disruption occurs. For ex- rently, a meta-analysis of the functional neuroimaging
ample, it is possible that the location of the earliest literature in SCD is infeasible due to too many methodo-
synaptic disruptions is determined by the specific cogni- logical inconsistencies (e.g., different network definitions,
tive domain of the initial complaints. Subjective decline preprocessing pipelines, type of functional connectivity
in executive and attentional processing may relate to ex- metric utilized, specific regions reported or evaluated).
ecutive and salience network synaptic disruption prior to However, if research groups interested in SCD coordi-
memory system disruption. The extant functional neuro- nated a common preprocessing and analysis pipeline to
imaging literature on SCD largely focuses on memory evaluate connectivity within and between whole-brain
complaints and does not generally address other cogni- networks, the results could be combined in a pseudo-
tive domains perceived as affected. Nevertheless, previ- meta-analytic framework.
ous research suggests that connectivity disruption within In addition to underexplored network connectivity in
the salience network, and between the salience network SCD, the full extent of functional differences during
cognitive tasks between older adults with and without structures [108, 109]; this method could resolve afore-
perceived decline remains unknown, and the field has mentioned issues and evaluate hippocampal subfield
yet to report on many detailed components of memory connectivity. Combination of structural and functional
and other cognitive domains through functional neuro- methods could uncover mechanisms underlying SCD.
imaging. For example, although the extant literature to For example, if diffeomorphic mapping finds inward de-
date has explored memory encoding and retrieval formation of cornu ammonis 1 in person with SCD that
through visual and verbal means, these tasks have lacked corresponds to decreased connectivity between cornu
explicit spatial components, and some spatial memory ammonis 1 and entorhinal cortex through submillimeter
processing occurs in the medial temporal lobes [102]. imaging, but intact communication between hippocam-
Evaluation of spatial memory encoding and retrieval pal subfields, then the results would indicate that hippo-
may be sensitive to detect hippocampal and medial tem- campal processing is largely intact but input to—and
poral alterations in SCD that may serve as markers of output from the hippocampus—may be aberrant in in-
further decline. Furthermore, continued evaluation of cipient neurodegenerative disease. Conversely, intact
memory encoding and retrieval, working memory, and communication between entorhinal cortex and hippo-
attention is necessary to understand the neural under- campal subfields, but aberrant communication between
pinnings of SCD. subfields, would indicate that hippocampal processing
Finally, although current neuroimaging resolutions disruption, rather than input or output disruption, ini-
only allow for macro-level evaluation of whole-brain net- tially occurs. Though speculative, functional neuroimag-
work integration, it is still important to speculate on ing in the future may allow for understanding
circuit-level changes that may occur in SCD as informa- connectivity disruption at the circuit level.
tion processing ultimately occurs at the synaptic level.
The circuitry of the medial temporal lobes may be im- Conclusion
portant for understanding SCD for a multitude of rea- SCD is a risk factor for dementia marked by perceived
sons, including previously mentioned connectivity worsening of cognitive ability without observable deficit.
aberrations [30, 35, 38, 47], but also because T1- The extant task-related activation and resting-state func-
weighted and diffusion-weighted imaging analyses indi- tional connectivity literature suggest that SCD relates to
cate that neuropil density and gray matter volume may functional alterations in brain regions important for mem-
be lower in entorhinal, perirhinal, parahippocampal, and ory, such as retrosplenial cortex and hippocampus.
hippocampal regions compared to controls [79–86, 103, Though, subtle disruption in memory encoding, retrieval,
104]. Aberrant functional connectivity and significant at- or other cognitive processes may all be sufficient for the
rophy within hippocampal circuitry may emerge as ap- experience of cognitive decline. Furthermore, aberrant
propriate prognostic signals for disease, and the first task-related activation during memory and executive func-
subfield to critically evaluate may be cornu ammonis 1 tioning tasks and aberrant functional connectivity in older
as many reports suggest inward deformation of the sub- adults with SCD suggest that information processing alter-
field in older adults with SCD [105–107]. Unfortunately, ations may occur in the salience, executive control, and
typical functional connectivity analyses do not have suf- default mode networks. Finally, more research must occur
ficient spatial resolution to determine which hippocam- on the functional characteristics of the brain in SCD to
pal subfields or which hippocampal and entorhinal cell understand prognostic markers for dementia, and longitu-
layers exhibit the greatest differences in connectivity be- dinal evaluation of functional brain characteristics in SCD
tween adults with and without SCD. Even with 2-mm must occur specifically to determine trajectories of change
isotropic voxels, subject movement, partial voluming, that could serve as prognostic and diagnostic markers of
and spatial smoothing during image processing could objective decline.
smear signal from different hippocampal subregions to-
Abbreviations
gether, in addition to smearing entorhinal and hippo- AD: Alzheimer’s disease; ADNI: Alzheimer’s Disease Neuroimaging Initiative;
campal signal. Thus, it is difficult to resolve whether BOLD: Blood-oxygen-level dependent; CON: Control;
disrupted communication between hippocampus and EEG: Electroencephalography; fMRI: Functional magnetic resonance imaging;
MEG: Magnetoencephalography; SCD: Subjective cognitive decline
distant cortex is a downstream result of computation
disruption within the hippocampus proper, disruption Acknowledgements
between direct hippocampus to cortex connections, or Not applicable.
disrupted connectivity between entorhinal and parahip- Authors’ contributions
pocampal cortex and other regions. Nevertheless, high- RV and JS contributed to the conceptualization and writing of the
resolution, submillimeter fMRI is undergoing active de- manuscript. The authors read and approved the final manuscript
velopment and analyses are uncovering functional Funding
organization across columnar and laminar cortical Not applicable.
Availability of data and materials 18. Yasuno F, Kazui H, Yamamoto A, Morita N, Kajimoto K, Ihara M, et al.
Not applicable. Resting-state synchrony between the retrosplenial cortex and anterior
medial cortical structures relates to memory complaints in subjective
Ethics approval and consent to participate cognitive impairment. Neurobiol Aging. 2015;36(6):2145–52.
Not applicable. 19. van der Flier WM, Scheltens P. Epidemiology and risk factors of dementia. J
Neurol Neurosurg Psychiatry. 2005;76(Suppl 5):v2–7.
20. Jones DT, Knopman DS, Gunter JL, Graff-Radford J, Vemuri P, Boeve BF, et al.
Consent for publication Cascading network failure across the Alzheimer’s disease spectrum. Brain.
Not applicable. 2016;139:547–62.
21. Sheline YI, Morris JC, Snyder AZ, Price JL, Yan Z, D'Angelo G, et al. APOE4
Competing interests allele disrupts resting state fMRI connectivity in the absence of amyloid
The authors declare that they have no competing interests. plaques or decreased CSF Abeta42. J Neurosci. 2010;30(50):17035–40.
22. Salami A, Wahlin A, Kaboodvand N, Lundquist A, Nyberg L. Longitudinal
Received: 1 November 2019 Accepted: 26 February 2020 evidence for dissociation of anterior and posterior MTL resting-state
connectivity in aging: links to perfusion and memory. Cereb Cortex. 2016;
26(10):3953–63.
23. Fjell AM, Sneve MH, Storsve AB, Grydeland H, Yendiki A, Walhovd KB. Brain
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Viviano and Damoiseaux Alzheimer's Research & Therapy (2020) 12:23

REVIEW Open Access

Functional neuroimaging in subjective

Introduction function. For example, an individual with anosognosia

between SCD and connectivity Participants subsequently classified

Reisberg criteria. between retrosplenial and anterior

controls recruited from general DMN in SCD. Retrosplenial cortex

connectome. according to the international

complaints and came from the

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