Neuroimaging of Mobility in Aging: A Targeted Review

Abstract

Background.

The relationship between mobility and cognition in aging is well established, but the relationship between mobility and the structure and function of the aging brain is relatively unknown. This, in part, is attributed to the technological limitations of most neuroimaging procedures, which require the individual to be immobile or in a supine position. Herein, we provide a targeted review of neuroimaging studies of mobility in aging to promote (i) a better understanding of this relationship, (ii) future research in this area, and (iii) development of applications for improving mobility.

Methods.

A systematic search of peer-reviewed studies was performed using PubMed. Search terms included (i) aging, older adults, or elderly; (ii) gait, walking, balance, or mobility; and (iii) magnetic resonance imaging, voxel-based morphometry, fluid-attenuated inversion recovery, diffusion tensor imaging, positron emission tomography, functional magnetic resonance imaging, electroencephalography, event-related potential, and functional near-infrared spectroscopy.

Results.

Poor mobility outcomes were reliably associated with reduced gray and white matter volume. Fewer studies examined the relationship between changes in task-related brain activation and mobility performance. Extant findings, however, showed that activation patterns in the cerebellum, basal ganglia, parietal and frontal cortices were related to mobility. Increased involvement of the prefrontal cortex was evident in both imagined walking conditions and conditions where the cognitive demands of locomotion were increased.

Conclusions.

Cortical control of gait in aging is bilateral, widespread, and dependent on the integrity of both gray and white matter.

Mobility impairments and limitations are common among older adults, have detrimental impact on the affected individuals and their families and constitute a major public health challenge to society (1,2). Hence, identifying modifiable risk factors for and mechanisms of mobility impairments and disability in aging is paramount. Converging evidence points to the important role cognitive processes, attention and executive functions in particular, have in explaining variance in mobility performance in healthy, frail and demented older adults (3–5). However, less is known about brain structures and functional regions that are directly involved in mobility performance and decline in the elderly (see Rosso et al. (6) for review). This, in part, is attributed to methodological limitations of most traditional neuroimaging procedures, which require the individual to be in a supine position and immobile during the scanning procedures. Nonetheless, traditional and more recent innovative neuroimaging methods have begun to shed light on brain structures, regions, and functional networks that are involved in mobility. Herein, we provide a targeted review of neuroimaging studies of mobility to provide a better understanding of the relationship between mobility and the structure and function of the aging brain.

Methods

Selection of Studies

PubMed was used to systematically identify studies investigating functional and structural neural correlates of mobility in aging. The search strategy was restricted to original studies published in English up to June 30, 2013. Only studies that examined healthy older adults (60 years of age and older) were included. Search terms included (i) aging, older adults, or elderly; (ii) gait, walking, balance, or mobility; and (iii) magnetic resonance imaging (MRI), voxel-based morphometry, fluid-attenuated inversion recovery (FLAIR), diffusion tensor imaging, positron emission tomography (PET or FDG-PET), functional MRI (fMRI), electroencephalography, event-related potential, and functional near-infrared spectroscopy (fNIR). The identified studies were screened (N.E. and H.M.B.) for content to assure compliance with the aforementioned inclusion/exclusion criteria. Disease-specific (eg, stroke) studies were included only when a healthy older control group was available. A total of 86 studies were included in the current review.

Findings by Neuroimaging Procedure

Structural MRI Studies

Voxel-based morphometry is a common neuroimaging analysis approach that involves segmenting a structural image of the brain into gray matter (GM), white matter (WM), and cerebrospinal fluid. These segmented images can then be used to perform voxel-based comparisons between groups or correlations with behavioral measures. Another common approach is to compute GM and WM volumes of particular brain structure or structures (eg, prefrontal cortices) and then compare them between groups or correlate them with behavioral measures. Finally, structural images can be used to quantify WM hyperintensities (WMH) and small vessel disease. Several cross-sectional and longitudinal studies of cognitively healthy older adults have linked increased WMH burden with poor gait performance (7–10) and balance (11) (Table 1).

Specifically, WM disease, small vessel disease, and subclinical stroke have been associated with poor quantitative gait markers, mobility decline, and increased risk for physical disability (16,17,23). Relationships between GM volume and mobility have also been identified using voxel-based morphometry procedures. Brain atrophy was associated with decreased trunk stability during walking while talking (26), while GM volume of the primary sensorimotor and medial temporal areas was associated with bradykinesia and gait disturbance (19,29). GM volume in the left cerebellum, basal ganglia, and left prefrontal regions was strongly associated with mobility (18,27,28). Furthermore, subcortical hyperintensities were linked to slower gait velocity in Alzheimer’s disease patients and healthy controls (21). Reciprocally, physical activity has also been shown to predict greater volumes of frontal, occipital, entorhinal, and hippocampal regions (22). In summary, substantial research demonstrates that both WMH burden and cortical volume are related to mobility outcomes in aging.

Fluid Attenuated Inversion Recovery

FLAIR is a structural MRI sequence that is particularly suitable for detecting WMH because it masks the cerebrospinal fluid that cloud other structural MRI sequences (eg, T2-weighted images) (30). Several studies that have used a FLAIR sequence in cognitively healthy older adults implicated increased WMH burden in poor gait performance (31–35) and increased risk for falls (36,37) (Table 2).

WMH in prefrontal regions (32,46) and the splenium (and other corpus callosum regions) (41,47–49) appear to be specifically detrimental to gait performance. This is presumably because these regions coordinate the processing of visuospatial information during walking (44,48,49) and play an essential role in executive functions (37,44). In fact, executive functions have been shown to be more affected by WMH than memory or language functions (44). Several reliable and valid manual, semi- and fully automated methods for quantifying WMH in FLAIR sequences exist (51–54). The Age-Related White Matter Changes (ARWMC) (51) scale, a manual ratings scale, is comparable to semiautomated methods for detecting associations between WMH and gait (39) and simpler scales (see Fazekas (53)) may be sufficient for clinical settings (38).

Diffusion Tensor Imaging

Diffusion tensor imaging is a reliable method for evaluation of WM integrity (WMI) that is capable of detecting abnormalities in the WM that appear normal on conventional MRI (55,56). To date, only a small number of studies have thoroughly investigated the relationship of WMI and mobility outcomes in aging (Table 3).

Specifically, findings reveal that WMI is associated with gait disturbances (46,59,61) and that WMI in the corpus callosum is a critical marker of gait impairments in aging (58). In studies examining relationships between gait, balance, and postural stability, evidence for greater age-related microstructural deterioration was reported in frontal brain regions (32,57,62). Studies examining the function of the pedunculopontine nucleus in healthy and impaired older adults have revealed the importance of intact connectivity from pedunculopontine nucleus to locomotion centers, including cerebellum, for independent walking (60,63,65). Thus, there is evidence to support the notion that specific patterns of WM abnormalities in aging are related to various mobility outcomes including gait, balance, and fall risk.

Positron Emission Tomography

PET is an invasive neuroimaging technique that can be used to track glucose utilization after injection of a radioactive tracer such as fludeoxyglucose-18 (FDG). PET studies have shown that in healthy older adults gait, balance, and sensory integration are related to striatal pathways of the dopaminergic system of the basal ganglia (66–69) (Table 4).

These pathways, which tend to denervate in normal aging, are also implicated in the executive control of gait when balance is challenged (68,75). Thus, dopaminergic physiology may relate to certain aspects of gait, independent of age-related changes, and may partially explain recurrent falls in older adults (71). “In-vivo” locomotion studies, where patients are injected with FDG, walk on a treadmill, and then undergo a static PET scan, reveal that “real” locomotion uses a direct pathway via the primary motor cortex. Conversely, imagined locomotion (as measured via fMRI) uses an indirect pathway via the supplementary motor cortex and basal ganglia loop implicating the primary sensorimotor area, prefrontal area, and temporal lobe in more cognitively demanding gait protocols (74,76).

Functional Magnetic Resonance Imaging

fMRI is a noninvasive but stationary neuroimaging technique that provides a blood-oxygen-level-dependent signal of neural activity (79). Actual gait cannot be studied with fMRI, but imagined gait studies provide a window into the functional correlates of actual gait in the elderly (74,80–82) (Table 5).

Older adults activate supplementary motor areas (SMA), caudate, visual, and cerebellar regions to the same extent as younger adults during imagined walk relative to imagined stance (80). Older adults also activate primary motor, SMA, parietal, thalamic, and caudate regions during imagined walk backward to a greater extent than imagined walk forward (82). Moreover, highly fit individuals activate primary motor cortices to a greater extent during imagined walk backward than forward while less fit individuals activate prefrontal regions a greater extent during imagined walk backward than forward (82). SMA are also activated to a greater extent in older than younger adults during imagined stepping over obstacle and terminating gait (81). Finally, SMA and other prefrontal regions are activated to a greater extent during imagined walking-while-talking relative to imagined walking or talking alone (85). Taken together, imagined gait fMRI studies suggest that gait engages SMA, pre-SMA, posterior parietal and cerebellar regions, and that older adults (particularly less fit older adults) engage SMA and other prefrontal regions during gait—presumably because locomotion necessitates executive functions. The results of these fMRI studies are comparable to FDG-PET studies of actual gait (74).

Electroencephalography

Electroencephalography is a noninvasive method of measuring complex neural activity where brain responses to specific events are recorded. This electrical activity consists of positive (P) and negative (N) components or voltage deflections that occur at specific latencies. To date, there is a paucity of studies investigating the relationship of neural activation and mobility outcomes in aging; nevertheless, significant age-related differences in amplitude and latency have been reported (Table 6).

One study examined whether age-related changes in WM function were associated with mobility impairments using stance perturbation evoked potentials and found delayed onset of the first P component (P1) for older adults, as well as smaller and later activation of the first negative component (N1) for frail elders (87). In other aging studies examining neural oscillations, increased asymmetrical alpha- and theta-band activity were reported, with significant associations between frontocortical right activation and perceived level of physical health/fitness (88) and central activation with neural relaxation (86). Lastly, one study reported significantly greater amplitude of initial componentry at Cz for healthy youngs compared with healthy older adults during a gait initiation task (89). Electroencephalography can be used to identify neural mechanisms of specific mobility outcomes but at present these data are very limited.

Functional Near-Infrared Spectroscopy

fNIR is a relatively new noninvasive neuroimaging technique that provides information about changes in cortical brain oxygenation levels using the light–tissue interaction properties of light within the near infrared range (90–97). fNIR has been validated against traditional neuroimaging methods and is less prone to movement artifacts (98–107). A limited number of recent studies began to utilize fNIR to assess cortical control of mobility in real, as opposed to imagined conditions (Table 7).

In those studies the number of participants was small and the populations under investigation limited to young and older adult samples (108,109,111–116), though stroke patients were also assessed (110). While the mobility tasks and fNIR devices varied across studies (see Supplementary Appendix 1), consistent increases in task-related oxygenation levels in prefrontal cortex, premotor cortex, and SMA were observed. The involvement of these brain regions was increased in response to anticipation of and acceleration during tasks (109–112) and when locomotion became more cognitively demanding (113–116). Furthermore, cortical responses to task demands were moderated by disease status (110), age (113), and walking capacity (112). fNIR can augment traditional neuroimaging methods by establishing associations between brain activation and mobility performance when assessed simultaneously in real time.

Discussion

Although the neuroimaging literature of mobility in aging has been relatively scarce, consistent and complementary findings across different imaging modalities were observed. Structural MRI was most commonly used followed by FLAIR and diffusion tensor imaging. Fewer studies utilized methods that examined the relationship between changes in task-related brain activation and mobility performance. Especially noted is the paucity of studies that aim to determine task-related changes in brain activation during actual mobility.

Models of cortical and brainstem control of gait and posture have been previously described (117), implicating the basal ganglia (118), cerebellum (119), frontal and parietal cortices (120), in the planning and execution of purposeful locomotion. The neuroimaging studies reviewed reveal consistencies with these aforementioned models and provide important insights into the neural substrates of mobility in aging. Cortical control of locomotion is widespread in aging. Damage and reduced volume in multiple regions of GM and WM and worse functional integrity of the latter were related to poor mobility outcomes as evidenced by different neuroimaging methods. These findings support the notion of age-related increases in the size and number of brain regions and networks that are correlated with motor and cognitive functions (121). Widespread involvement of WM in mobility further suggests that among older adults locomotion is dependent on the integrity and communication of multiple tracks across both hemispheres. However, the degree of damage and method used to assess WMI, as well as the type of mobility outcome determine the extent of their relationship (122).

Consistent with existing models of locomotion, the neuroimaging findings revealed that the cerebellum, basal ganglia, parietal and frontal cortices were related to mobility outcomes. Moreover, increased involvement of frontal cortical regions was evident in imagined walking conditions and when cognitive demands of locomotion increased. The involvement of frontal and prefrontal circuits in cognitively demanding locomotion tasks affirms robust behavioral literature that implicates cognitive processes, notably the executive functions, in mobility (3,5,123,124). Building on existing theories of cognitive and brain reserve (125), future research should aim to determine the functional relevance of specific brain regions and networks that might represent compensation, inefficiency, or di-differentiation (cf, Holtzer et al. (126) for further details regarding these models) vis-à-vis purposeful locomotion in aging.

While beyond the scope of this article determining shared and distinct brain regions and functional networks of mobility in normal and pathological aging is of interest (for instance, see two recent reviews on the neural substrates of gait in Parkinson’s disease, refs (127,128)). Future studies should also focus on integrating different neuroimaging methods to determine how brain structures, WM, functional networks, and biochemical pathways jointly subserve mobility outcomes in healthy and pathological aging.

References

Author notes