Neural adaptation to the eye's optics through phase compensation.

How does the brain achieve a seemingly veridical and 'in-focus' perception of the world, knowing how severely corrupted visual information is by the eye's optics? Optical blur degrades retinal image quality by reducing the contrast and disrupting the phase of transmitted signals. Neural adaptation can attenuate the impact of blur on image contrast, yet vision rather relies on perceptually-relevant information contained within the phase structure of natural images. Here we show that neural adaptation can compensate for the impact of optical aberrations on phase congruency. We used adaptive optics to fully control optical factors and test the impact of specific optical aberrations on the perceived phase of compound gratings. We assessed blur-induced changes in perceived phase over three distinct exposure spans. Under brief blur exposure, perceived phase shifts matched optical theory predictions. During short-term (~1h) exposure, we found a reduction in blur-induced phase shifts over time, followed by after-effects in the opposite direction-a hallmark of adaptation. Finally, patients with chronic exposure to poor optical quality showed altered phase perception when tested under fully-corrected optical quality, suggesting long-term neural compensatory adjustments to phase spectra. These findings reveal that neural adaptation to optical aberrations compensates for alterations in phase congruency, helping restore perceptual quality over time.

Sex-dependent alterations in hippocampal connectivity are linked to cerebrovascular and amyloid pathologies in normal aging.

INTRODUCTION: Compared to males, females have an accelerated trajectory of cognitive decline in Alzheimer's disease (AD). The neurobiological factors underlying the more rapid cognitive decline in AD in females remain unclear. This study explored how sex-dependent alterations in hippocampal connectivity over 2 years are associated with cerebrovascular and amyloid pathologies in normal aging. METHODS: Thirty-three females and 21 males 65 to 93 years of age with no cognitive impairment performed a face-name associative memory functional magnetic resonance imaging (fMRI) task with a 2-year follow-up. We acquired baseline carbon 11-labeled Pittsburgh compound B ([11 C]PiB) positron emission tomography (PET) and T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) MRI to quantify amyloid ß (Aß) burden and white matter hyperintensity (WMH) volume, respectively. RESULTS: Males had increased hippocampal-prefrontal connectivity over 2 years, associated with greater Aß burden. Females had increased bilateral hippocampal functional connectivity, associated with greater WMH volume. DISCUSSION: These findings suggest sex-dependent compensatory mechanisms in the memory network in the presence of cerebrovascular and AD pathologies and may explain the accelerated trajectory of cognitive decline in females.

Trajectories and contributing factors of neural compensation in healthy and pathological aging.

Neural degeneration is a hallmark of healthy aging and can be associated with specific cognitive impairments. However, neural degeneration per se is not matched by unremitting declines in cognitive abilities. Instead, middle-aged and older adults typically maintain surprisingly high levels of cognitive functioning, suggesting that the human brain can adapt to structural degeneration by neural compensation. Here, we summarize prevailing theories and recent empirical studies on neural compensation with a focus on often neglected contributing factors, such as lifestyle, metabolism and neural plasticity. We suggest that these factors moderate the relationship between structural integrity and neural compensation, maintaining psychological well-being and behavioral functioning. Finally, we discuss that a breakdown in neural compensation may pose a tipping point that distinguishes the trajectories of healthy vs pathological aging, but conjoint support from psychology and cognitive neuroscience for this alluring view is still scarce. Therefore, future experiments that target the concomitant processes of neural compensation and associated behavior will foster a comprehensive understanding of both healthy and pathological aging.

Latent trajectories of recent and delayed memory and their predictors: evidence from SHARE.

OBJECTIVES: Cognitive decline is common in the old age, but some evidence suggests it may already occur during adulthood. Previous studies have linked age, gender, educational attainment, depression, physical activity, and social engagement to better cognitive performance over time. However, most studies have used global measures of cognition, which could mask subtle changes in specific cognitive domains. The aim of this study is to examine trajectories of recent and delayed memory recall from a variable-centered perspective, in order to elucidate the impact of age, gender, educational attainment, depression, physical activity, and social engagement on recent and delayed memory both at initial time and across a 10-year period. DESIGN AND PARTICIPANTS: The sample was formed by 56,616 adults and older adults that participated in waves 4 to 8 of the Survey of Health, Aging and Retirement in Europe (SHARE). ANALYSES: We used latent growth modeling to establish latent recent and delayed memory trajectories, and then tested the effects of the aforementioned covariates on the latent intercept and slopes. RESULTS: Results showed that both recent and delayed recall display a quadratic trajectory of decline. All covariates significantly explained initial levels of immediate and delayed recall, but only a few had statistically significant effects on the slope terms. CONCLUSIONS: We discuss differences between present results and those previously reported in studies using a person-centered approach. This study provides evidence of memory decline during adulthood and old adulthood. Further, results provide support for the neural compensation reserve theory.

Semantic cognition in healthy ageing: Neural signatures of representation and control mechanisms in naming typical and atypical objects.

Effective use of conceptual knowledge engages semantic representation and control processes to access information in a goal-driven manner. Neuropsychological findings of patients presenting either degraded knowledge (e.g., semantic dementia) or disrupted control (e.g., semantic aphasia) converge with neuroimaging evidence from young adults, and delineate the neural segregation of representation and control mechanisms. However, there is still scarce research on the neurofunctional underpinnings of such mechanisms in healthy ageing. To address this, we conducted an fMRI study, wherein young and older adults performed a covert naming task of typical and atypical objects. Three main age-related differences were found. As shown by age group and typicality interactions, older adults exhibited overactivation during naming of atypical (e.g., avocado) relative to typical concepts in brain regions associated to semantic representation, including anterior and medial portions of left temporal lobe (respectively, ATL and MTG). This provides evidence for the reorganization of neural activity in these brain regions contingent to the enrichment of semantic repositories in older ages. The medial orbitofrontal gyrus was also overactivated, indicating that the processing of atypical concepts (relative to typical items) taxes additional control resources in the elderly. Increased activation in the inferior frontal gyrus (IFG) was observed in naming typical items (relative to atypical ones), but only for young adults. This suggests that naming typical items (e.g., strawberry) taxes more on control processes in younger ages, presumably due to the semantic competition set by other items that share multiple features with the target (e.g., raspberry, blackberry, cherry). Together, these results reveal the dynamic nature of semantic control interplaying with conceptual representations as people grow older, by indicating that distinct neural bases uphold semantic performance from young to older ages. These findings may be explained by neural compensation mechanisms coming into play to support neurocognitive changes in healthy ageing.

Vestibulo-ocular reflex gain improvements at peak head acceleration and velocity following onset of unilateral vestibular neuritis: Insights into neural compensation mechanisms.

BACKGROUND AND AIMS: An acute unilateral peripheral vestibular deficit (aUPVD) due to vestibular neuritis causes deficient yaw axis vestibular ocular reflex (VOR) gains. Using video head impulse tests (vHITs), we examined phasic and tonic velocity gains of the VOR over time to determine if these differed at onset and during subsequent improvement. METHODS: The VOR responses of 61 patients were examined within 5 days of aUPVD onset, and 3 and 7 weeks later using vHIT with mean peak yaw angular velocities of 177°/s (sd 45°/s) and mean peak accelerations of 3660°/s2 (sd 1300°/s2). The phasic velocity or acceleration gain (aG) was computed as the ratio of eye to head velocity around peak head acceleration, and the tonic velocity gain (vG) was calculated as the same ratio around peak head velocity. RESULTS: aG increased ipsi-deficit from 0.45 at onset to 0.67 at 3 weeks and 7 weeks later, and vG increased ipsi-deficit from 0.29 to 0.51 and 0.53, respectively, yielding a significant time effect (p < 0.001). Deficit side aG was significantly greater (p < 0.001) than vG at all time points. Deficit side gain improvements in aG and vG were similar. Contra-deficit aG increased from 0.86 to 0.95 and 0.94 at 3 weeks and 7 weeks, and vG contra-deficit increased from 0.84, to 0.89 and 0.87, respectively, also yielding a significant time effect (p = 0.004). Contra-deficit aG and vG were normal at 3 weeks. Mean canal paresis values improved from 91% to 67% over the 7 weeks. CONCLUSIONS: Acceleration and velocity VOR gains on the deficit side are reduced by aUPVD and improve most in the first 3 weeks after aUPVD onset. Deficit side aG is consistently higher than deficit side vG following an aUPVD, suggesting that acceleration rather than velocity sensitive compensatory neural mechanisms are predominant during the compensation process for aUPVD.

Mitigating the negative impacts of aging on cognitive function; modifiable factors associated with increasing cognitive reserve.

Research suggests that social, physical, and cognitively challenging activities during lifetime, could mitigate the negative effects of aging on cognitive function. This effect is explained by the increased cognitive reserve (CR) resulting from such factors; in fact, such activities, by altering structural and functional properties of the human brain, equip one with more effective compensatory mechanisms to resist brain damage before the presentation of severe clinical symptoms. Therefore, applying appropriate modifications in one's lifestyle and activities may be effective in lowering the risk of developing dementia and cognitive dysfunction in old age, especially in brain areas that are susceptible to aging. In this paper, we are going to review relevant studies discussing the association between important modifiable factors, known as CR proxies (i.e., educational attainment, occupational complexity, physical activity, social engagement, bilingualism, leisure activities, and Mediterranean diet), and different domains of cognitive function, which are affected either in the process of healthy aging or neurodegenerative diseases.

Functional reallocation of sensory processing resources caused by long-term neural adaptation to altered optics.

The eye's optics are a major determinant of visual perception. Elucidating how long-term exposure to optical defects affects visual processing is key to understanding the capacity for, and limits of, sensory plasticity. Here, we show evidence of functional reallocation of sensory processing resources following long-term exposure to poor optical quality. Using adaptive optics to bypass all optical defects, we assessed visual processing in neurotypically-developed adults with healthy eyes and with keratoconus - a corneal disease causing severe optical aberrations. Under fully-corrected optical conditions, keratoconus patients showed altered contrast sensitivity, with impaired sensitivity for fine spatial details and better-than-typical sensitivity for coarse spatial details. Both gains and losses in sensitivity were more pronounced in patients experiencing poorer optical quality in their daily life and mediated by changes in signal enhancement mechanisms. These findings show that adult neural processing adapts to better match the changes in sensory inputs caused by long-term exposure to altered optics.

Investigating Age-Related Neural Compensation During Emotion Perception Using Electroencephalography.

Previous research suggests declines in emotion perception in older as compared to younger adults, but the underlying neural mechanisms remain unclear. Here, we address this by investigating how "face-age" and "face emotion intensity" affect both younger and older participants' behavioural and neural responses using event-related potentials (ERPs). Sixteen young and fifteen older adults viewed and judged the emotion type of facial images with old or young face-age and with high- or low- emotion intensities while EEG was recorded. The ERP results revealed that young and older participants exhibited significant ERP differences in two neural clusters: the left frontal and centromedial regions (100-200 ms stimulus onset) and frontal region (250-900 ms) when perceiving neutral faces. Older participants also exhibited significantly higher ERPs within these two neural clusters during anger and happiness emotion perceptual tasks. However, while this pattern of activity supported neutral emotion processing, it was not sufficient to support the effective processing of facial expressions of anger and happiness as older adults showed reductions in performance when perceiving these emotions. These age-related changes are consistent with theoretical models of age-related changes in neurocognitive abilities and may reflect a general age-related cognitive neural compensation in older adults, rather than a specific emotion-processing neural compensation.

Plasticity in brain activity dynamics after task-shifting training in older adults.

Cognitive control is supported by a dynamic interplay of transient (i.e., trial-related) brain activation across fronto-parietal networks and sustained (i.e., block-related) activation across fronto-striatal networks. Older adults show disturbances in this dynamic functional recruitment. There is evidence suggesting that cognitive-control training may enable older adults to redistribute their brain activation across cortical and subcortical networks, which in turn can limit behavioral impairments. However, previous studies have only focused on spatial rather than on temporal aspects of changes in brain activation. In the present study, we examined training-related functional plasticity in old age by applying a hybrid fMRI design that sensitively tracks the spatio-temporal interactions underlying brain-activation changes. Fifty healthy seniors were assigned to a task-shifting training or an active-control group and their pretest/posttest activation-change maps were compared against 25 untrained younger adults. After training, older adults showed the same performance as untrained young adults. Compared to the control group, task-shifting training promoted proactive (i.e., early, cue-related) changes in transient mechanisms supporting the maintenance and top-down biasing of task-set representations in a specific prefrontal circuitry; reactive (i.e., late, probe-related) changes in transient mechanisms supporting response-selection processes in dissociable fronto-parietal networks; overall reductions of sustained activation in striatal circuits. Results highlight the importance of spatio-temporal interactions in training-induced neural changes in age.

Age-related differences in brain activations during spatial memory formation in a well-learned virtual Morris water maze (vMWM) task.

The current study applied a rodent-based virtual Morris water maze (vMWM) protocol to an investigation of differences in search performance and brain activations between young and older male human adults. All participants completed in-lab practice and testing before performing the task in the fMRI scanner. Behavioral performance during fMRI scanning - measured in terms of corrected cumulative proximity (CCProx) to the goal - showed that a subgroup of older good performers attained comparable levels of search accuracy to the young while another subgroup of older poor performers exhibited consistently lower levels of search accuracy than both older good performers and the young. With regard to brain activations, young adults exhibited greater activations in the cerebellum and cuneus than all older adults, as well as older poor performers. Older good performers exhibited higher activation than older poor performers in the orbitofrontal cortex (BA 10/11), as well as in the cuneus and cerebellum. Brain-behavior correlations further showed that activations in regions involved in visuomotor control (cerebellum, lingual gyrus) and egocentric spatial processing (premotor cortex, precuneus) correlated positively with search accuracy (i.e., closer proximity to goal) in all participants. Notably, activations in the anterior hippocampus correlated positively with search accuracy (CCProx inversed) in the young but not in the old. Taken together, these findings implicated the orbitofrontal cortex and the cerebellum as playing crucial roles in executive and visuospatial processing in older adults, supporting the proposal of an age-related compensatory shift in spatial memory functions away from the hippocampus toward the prefrontal cortex.

Amyloid deposition is associated with different patterns of hippocampal connectivity in men versus women.

Compared to men, women are disproportionally affected by Alzheimer's disease (AD) and have an accelerated trajectory of cognitive decline and disease progression. Neurobiological factors underlying gender differences in AD remain unclear. This study investigated brain beta-amyloid (Aß)-related neural system differences in cognitively normal older men and women (N = 61; 41 females, 65-93 years old). We found that men and women showed different associations between Aß load and hippocampal functional connectivity. During associative memory encoding, in men greater Aß burden was accompanied by greater hippocampus-prefrontal connectivity (i.e., more synchronized activities), whereas in women hippocampal connectivity did not vary by Aß burden. For resting-state data, the interaction of gender × Aß on hippocampal connectivity did not survive multiple comparison in the whole-brain analyses. In the region of interest-based analyses, resting-state hippocampal-prefrontal connectivity was positively correlated with Aß load in men and was negatively correlated with Aß load in women. The observed Aß-related neural differences may explain the accelerated trajectory of cognitive decline and AD progression in women.

Activity-Induced Amyloid-ß Oligomers Drive Compensatory Synaptic Rearrangements in Brain Circuits Controlling Memory of Presymptomatic Alzheimer's Disease Mice.

BACKGROUND: A consistent proportion of individuals at risk for Alzheimer's disease show intact cognition regardless of the extensive accumulation of amyloid-ß (Aß) peptide in their brain. Several pieces of evidence indicate that overactivation of brain regions negative for Aß can compensate for the underactivation of Aß-positive ones to preserve cognition, but the underlying synaptic changes are still unexplored. METHODS: Using Golgi staining, we investigate how dendritic spines rearrange following contextual fear conditioning (CFC) in the hippocampus and amygdala of presymptomatic Tg2576 mice, a genetic model for Aß accumulation. A molecular biology approach combined with intrahippocampal injection of a γ-secretase inhibitor evaluates the impact of Aß fluctuations on spine rearrangements. RESULTS: Encoding of CFC increases Aß oligomerization in the hippocampus but not in the amygdala of Tg2576 mice. The presence of Aß oligomers predicts vulnerability to network dysfunctions, as low c-Fos activation and spine maturation are detected in the hippocampus of Tg2576 mice upon recall of CFC memory. Rather, enhanced c-Fos activation and new spines are evident in the amygdala of Tg2576 mice compared with wild-type control mice. Preventing Aß increase in the hippocampus of Tg2576 mice restores CFC-associated spine changes to wild-type levels in both the hippocampus and amygdala. CONCLUSIONS: Our study provides the first evidence of neural compensation consisting of enhanced synaptic activity in brain regions spared by Aß load. Furthermore, it unravels an activity-mediated feedback loop through which neuronal activation during CFC encoding favors Aß oligomerization in the hippocampus and prevents synaptic rearrangements in this region.

Physical exercise increases involvement of motor networks as a compensatory mechanism during a cognitively challenging task.

OBJECTIVE: Neuroimaging studies suggest that older adults may compensate for declines in cognitive function through neural compensation and reorganization of neural resources. While neural compensation as a key component of cognitive reserve is an important factor that mediates cognitive decline, the field lacks a quantitative measure of neural compensatory ability, and little is known about factors that may modify compensation, such as physical exercise. METHODS: Twenty-five healthy older adults participated in a 6-week dance training exercise program. Gait speed, cognitive function, and functional magnetic resonance imaging during a challenging memory task were measured before and after the exercise program. In this study, we used a newly proposed data-driven independent component analysis approach to measure neural compensatory ability and tested the effect of physical exercise on neural compensation through a longitudinal study. RESULTS: After the exercise program, participants showed significantly improved memory performance in Logical Memory Test (WMS(LM)) (P < .001) and Rey Auditory Verbal Learning Test (P = .001) and increased gait speed measured by the 6-minute walking test (P = .01). Among all identified neural networks, only the motor cortices and cerebellum showed greater involvement during the memory task after exercise. Importantly, subjects who activated the motor network only after exercise (but not before exercise) showed WMS(LM) increases. CONCLUSIONS: We conclude that physical exercise improved gait speed, cognitive function, and compensatory ability through increased involvement of motor-related networks.

A New Measure for Neural Compensation Is Positively Correlated With Working Memory and Gait Speed.

Neuroimaging studies suggest that older adults may compensate for declines in brain function and cognition through reorganization of neural resources. A limitation of prior research is reliance on between-group comparisons of neural activation (e.g., younger vs. older), which cannot be used to assess compensatory ability quantitatively. It is also unclear about the relationship between compensatory ability with cognitive function or how other factors such as physical exercise modulates compensatory ability. Here, we proposed a data-driven method to semi-quantitatively measure neural compensation under a challenging cognitive task, and we then explored connections between neural compensation to cognitive engagement and cognitive reserve (CR). Functional and structural magnetic resonance imaging scans were acquired for 26 healthy older adults during a face-name memory task. Spatial independent component analysis (ICA) identified visual, attentional and left executive as core networks. Results show that the smaller the volumes of the gray matter (GM) structures within core networks, the more networks were needed to conduct the task (r = -0.408, p = 0.035). Therefore, the number of task-activated networks controlling for the GM volume within core networks was defined as a measure of neural compensatory ability. We found that compensatory ability correlated with working memory performance (r = 0.528, p = 0.035). Among subjects with good memory task performance, those with higher CR used fewer networks than subjects with lower CR. Among poor-performance subjects, those using more networks had higher CR. Our results indicated that using a high cognitive-demanding task to measure the number of activated neural networks could be a useful and sensitive measure of neural compensation in older adults.

A critical review of brain and cognitive reserve in Huntington's disease.

The 'reserve' hypothesis posits that the brain undergoes structural and functional reorganisation to actively cope with brain damage or disease. Consistent with passive and active components of 'reserve', the brain moderates its biological substrates (brain reserve) and differentially changes the level of neural activity in tasks-specific networks and/or by recruiting additional non-task related brain regions (cognitive reserve) to optimise behavioural performance. How the 'reserve' hypothesis applies in neurodegenerative disorders such as Huntington's disease (HD) remains unknown. We postulate that unless the 'reserve' hypothesis is tested empirically, it is impossible to draw firm conclusions about how task-related neural activity is providing a neuroplastic change in HD and possibly other neurodegenerative disorders. We conclude that there is a pressing need to operationalise cognitive reserve, as well as incorporate different biological substrates into a model of 'reserve'. We suggest that it is important to identify and embed potential neuroprotective modulating factors of 'reserve' in randomised controlled multi-domain non-pharmaceutical interventions to potentially enhance 'reserve' and thus preserve cognitive and psychosocial functioning in HD patients.

Damage of the temporal lobe and APOE status determine neural compensation in mild cognitive impairment.

In mild cognitive impairment (MCI), the APOE4 genotype is associated with accelerated memory decline, likely due to the impact of neuropathology on main cerebral networks required for successful memory retrieval and/or to decreased capacity for recruiting secondary networks that might compensate for that brain damage. Here, we tested this hypothesis in twenty-six healthy older adults and thirty-four MCI patients, of which sixteen were APOE4 carriers. Compared to controls, MCI showed hippocampal volume reduction, cortical thinning in frontal, temporal and parietal regions, and dysfunctional EEG oscillations across fronto-temporal networks. But importantly, APOE4 status was the critical factor in determining the impact of temporal lobe degeneration on memory in MCI individuals. Specifically, path analyses revealed that hippocampal damage in MCI was responsible for memory deterioration in APOE4 carriers, a relationship mediated by the serial intervention of three related factors in noncarriers. Temporal cortical thickness (first mediator) accounted for activation of functional networks through synchronized theta activity across temporal regions (second mediator), which, in turn, coordinated memory reactivation through desynchronized alpha/beta activity across sensorimotor areas (third mediator). Results revealed that, contrary to APOE4-carrier patients, noncarriers are successful in recruiting secondary cortical networks to improve memory performance as long as the integrity and functionality of the temporal lobe is preserved, a fact primarily dependent on hippocampal degeneration.

Effects of cognitive reserve depend on executive and semantic demands of the task.

BACKGROUND: Cognitive reserve (CR) is one factor that helps to maintain cognitive function in patients with Alzheimer's disease (AD). Whether the effects of CR depend on the semantic/executive components of the task remains unknown. METHODS: 470 patients (138 with AD, 332 with mild cognitive impairment (MCI)) were selected from the Alzheimer's Disease Neuroimaging Initiative database. Linear regression models were used to determine the effects of CR (years of education) on cognitive performance after controlling for demographic factors and regional cortical atrophy. First, we assessed memory tasks with low (Auditory Verbal Learning Test (AVLT) discriminability), moderate (AVLT delayed recall) and high (Logical Memory Test (LMT) delayed recall) executive/semantic components. Next, we assessed tasks with lower (digit span forward, Trails A) or higher (digit span backwards, Trails B) executive demands, and lower (figure copying) or higher (naming, semantic fluency) semantic demands. RESULTS: High CR was significantly associated with performance on the LMT delayed recall, approached significance in the AVLT delayed recall and was not significantly associated with performance on AVLT discriminability. High CR was significantly associated with performance on the Trails B and digit span backwards, mildly associated with Trails A performance and was not associated with performance on digit span forwards. High CR was associated with performance on semantic but not visuospatial tasks. High CR was associated with semantic tasks in patients with both MCI and AD, but was only associated with executive functions in patients with MCI. CONCLUSION: CR may relate to executive functioning and semantic knowledge, leading to preserved cognitive performance in patients with AD pathology.

Neural impact of low-level alcohol use on response inhibition: An fMRI investigation in young adults.

It is widely known that alcohol consumption adversely affects human health, particularly in the immature developing brains of adolescents and young adults, which may also have a long-lasting impact on executive functioning. The present study investigated the neural activity of 28 young adults from the Ottawa Prenatal Prospective Study (OPPS) using functional magnetic resonance imaging (fMRI). The purpose of this study was to discover the impact of regular low-level alcohol consumption on response inhibition as the participants performed a Go/No-Go task. Results indicated that, despite a lack of performance differences, young adults who use alcohol on a regular basis differ significantly from those who do not use alcohol regularly (if at all) with respect to their neural activity as the circuitry engaged in response inhibition is being challenged. Specifically, areas that showed significantly more activation in users compared to controls included the left hippocampus, parahippocampal gyrus, superior frontal gyrus, precentral gyrus, right superior parietal lobule, and the cerebellum. These results suggest that even in low amounts, regular consumption of alcohol may have a significant impact on neurophysiological functioning during response inhibition in the developing brain of youth.

Age differences in the motor control of speech: An fMRI study of healthy aging.

Healthy aging is associated with a decline in cognitive, executive, and motor processes that are concomitant with changes in brain activation patterns, particularly at high complexity levels. While speech production relies on all these processes, and is known to decline with age, the mechanisms that underlie these changes remain poorly understood, despite the importance of communication on everyday life. In this cross-sectional group study, we investigated age differences in the neuromotor control of speech production by combining behavioral and functional magnetic resonance imaging (fMRI) data. Twenty-seven healthy adults underwent fMRI while performing a speech production task consisting in the articulation of nonwords of different sequential and motor complexity. Results demonstrate strong age differences in movement time (MT), with longer and more variable MT in older adults. The fMRI results revealed extensive age differences in the relationship between BOLD signal and MT, within and outside the sensorimotor system. Moreover, age differences were also found in relation to sequential complexity within the motor and attentional systems, reflecting both compensatory and de-differentiation mechanisms. At very high complexity level (high motor complexity and high sequence complexity), age differences were found in both MT data and BOLD response, which increased in several sensorimotor and executive control areas. Together, these results suggest that aging of motor and executive control mechanisms may contribute to age differences in speech production. These findings highlight the importance of studying functionally relevant behavior such as speech to understand the mechanisms of human brain aging. Hum Brain Mapp 38:2751-2771, 2017. © 2017 Wiley Periodicals, Inc.