Functional Brain Activation Associated with Inhibitory Control Deficits in Older Adults.

In young adults, canceling an initiated action depends on the right inferior frontal cortex (IFC), presupplementary motor area (preSMA), and the basal ganglia. Older adults show response inhibition deficits, but how this relates to functional brain activation remains unclear. Using event-related functional magnetic resonance imaging, we tested whether older adults (N = 20) exhibit overactivation during stop-signal inhibition as shown for attentional control tasks, or reduced activity compared with young adults (N = 20). We used a modified stop-signal task involving coupled bimanual responses and manipulated whether both or just one hand was cued to stop. Stop-task difficulty was matched across groups. We found a group by condition interaction in supramarginal gyrus, anterior insula, rIFC, and preSMA, with activation increasing for successful Stop versus Go trials in the young adults only. Comparing the groups on Stop trials revealed preSMA and striatum hypoactivity for older adults. White matter tracts connecting rIFC, preSMA, and the subthalamic nuclei were associated with stronger activation of preSMA in older adults, suggesting that maintenance of the brain's structure has positive implications for brain function.

8-prenylnaringenin and tamoxifen inhibit the shedding of irradiated epithelial cells and increase the latency period of radiation-induced oral mucositis : cell culture and murine model.

PURPOSE: The major component in the pathogenesis of oral radiation-induced mucositis is progressive epithelial hypoplasia and eventual ulceration. Irradiation inhibits cell proliferation, while cell loss at the surface continues. We conceived to slow down this desquamation by increasing intercellular adhesion, regulated by the E-cadherin/catenin complex. We investigated if 8-prenylnaringenin (8-PN) or tamoxifen (TAM) decrease the shedding of irradiated human buccal epithelial cells in vitro and thus delay the ulcerative phase of radiation-induced mucositis in vivo. MATERIALS AND METHODS: In vitro, aggregates of buccal epithelial cells were irradiated and cultured in suspension for 11 days. 8-PN or TAM were investigated regarding their effect on cell shedding. In vivo, the lower tongue surface of mice was irradiated with graded single doses of 25 kV X-rays. The incidence, latency, and duration of the resulting mucosal ulcerations were analyzed after topical treatment with 8-PN, TAM or solvent. RESULTS: 8-PN or TAM prevented the volume reduction of the irradiated cell aggregates during the incubation period. This was the result of a higher residual cell number in the treated versus the untreated irradiated aggregates. In vivo, topical treatment with 8-PN or TAM significantly increased the latency of mucositis from 10.9 to 12.1 and 12.4 days respectively, while the ulcer incidence was unchanged. CONCLUSION: 8-PN and TAM prevent volume reduction of irradiated cell aggregates in suspension culture. In the tongues of mice, these compounds increase the latency period. This suggests a role for these compounds for the amelioration of radiation-induced mucositis in the treatment of head and neck tumors.

Aging and inhibitory control of action: cortico-subthalamic connection strength predicts stopping performance.

Diffusion weighted imaging (DWI) studies in humans have shown that seniors exhibit reduced white matter integrity compared with young adults, with the most pronounced change occurring in frontal white matter. It is generally assumed that this structural deterioration underlies inhibitory control deficits in old age, but specific evidence from a structural neuroscience perspective is lacking. Cognitive action control is thought to rely on an interconnected network consisting of right inferior frontal cortex (r-IFC), pre-supplementary motor area (preSMA), and the subthalamic nucleus (STN). Here we performed probabilistic DWI tractography to delineate this cognitive control network and had the same individuals (20 young, 20 older adults) perform a task probing both response inhibition and action reprogramming. We hypothesized that structural integrity (fractional anisotropy) and connection strength within this network would be predictive of individual and age-related differences in task performance. We show that the integrity of r-IFC white matter is an age-independent predictor of stop-signal reaction time (SSRT). We further provide evidence that the integrity of white matter projecting to STN predicts both outright stopping (SSRT) and transient braking of response initiation to buy time for action reprogramming (stopping interference effects). These associations remain even after controlling for Go task performance, demonstrating specificity to the Stop component of this task. Finally, a multiple regression analysis reveals bilateral preSMA-STN tract strength as a significant predictor of SSRT in older adults. Our data link age-related decline in inhibitory control with structural decline of STN projections.

Brain activity during ankle proprioceptive stimulation predicts balance performance in young and older adults.

Proprioceptive information from the foot/ankle provides important information regarding body sway for balance control, especially in situations where visual information is degraded or absent. Given known increases in catastrophic injury due to falls with older age, understanding the neural basis of proprioceptive processing for balance control is particularly important for older adults. In the present study, we linked neural activity in response to stimulation of key foot proprioceptors (i.e., muscle spindles) with balance ability across the lifespan. Twenty young and 20 older human adults underwent proprioceptive mapping; foot tendon vibration was compared with vibration of a nearby bone in an fMRI environment to determine regions of the brain that were active in response to muscle spindle stimulation. Several body sway metrics were also calculated for the same participants on an eyes-closed balance task. Based on regression analyses, multiple clusters of voxels were identified showing a significant relationship between muscle spindle stimulation-induced neural activity and maximum center of pressure excursion in the anterior-posterior direction. In this case, increased activation was associated with greater balance performance in parietal, frontal, and insular cortical areas, as well as structures within the basal ganglia. These correlated regions were age- and foot-stimulation side-independent and largely localized to right-sided areas of the brain thought to be involved in monitoring stimulus-driven shifts of attention. These findings support the notion that, beyond fundamental peripheral reflex mechanisms, central processing of proprioceptive signals from the foot is critical for balance control.

Split-belt walking: adaptation differences between young and older adults.

Human walking is highly adaptable, which allows us to walk under different circumstances. With aging, the probability of falling increases, which may partially be due to a decreased ability of older adults to adapt the gait pattern to the needs of the environment. The literature on visuomotor adaptations during reaching suggests, however, that older adults have little problems in adapting their motor behavior. Nevertheless, it may be that adaptation during a more complex task like gait is compromised by aging. In this study, we investigated the ability of young (n = 8) and older (n = 12) adults to adapt their gait pattern to novel constraints with a split-belt paradigm. Findings revealed that older adults adapted less and more slowly to split-belt walking and showed fewer aftereffects than young adults. While young adults showed a fast adjustment of the relative time spent in swing for each leg older adults failed to do so, but instead they were very fast in manipulating swing speed differences between the two legs. We suggest that these changes in adaptability of gait due to aging stem from a mild degradation of cortico-cerebellar pathways (reduced adaptability) and cerebral structures (decreased ability to change gait cycle timing). However, an alternative interpretation may be that the observed reduced adaptation is a compensatory strategy in view of the instability induced by the split-belt paradigm.

The neural basis of central proprioceptive processing in older versus younger adults: an important sensory role for right putamen.

Our sense of body position and movement independent of vision (i.e., proprioception) relies on muscle spindle feedback and is vital for performing motor acts. In this study, we first sought to elucidate age-related differences in the central processing of proprioceptive information by stimulating foot muscle spindles and by measuring neural activation with functional magnetic resonance imaging. We found that healthy older adults activated a similar, distributed network of primary somatosensory and secondary-associative cortical brain regions as young individuals during the vibration-induced muscle spindle stimulation. A significant decrease in neural activity was also found in a cluster of right putamen voxels for the older age group when compared with the younger age group. Given these differences, we performed two additional analyses within each group that quantified the degree to which age-dependent activity was related to (1) brain structure and (2) a behavioral measure of proprioceptive ability. Using diffusion tensor imaging, older (but not younger) adults with higher mean fractional anisotropy were found to have increased right putamen neural activity. Age-dependent right putamen activity seen during tendon vibration was also correlated with a behavioral test of proprioceptive ability measuring ankle joint position sense in both young and old age groups. Partial correlation tests determined that the relationship between elderly joint position sense and neural activity in right putamen was mediated by brain structure, but not vice versa. These results suggest that structural differences within the right putamen are related to reduced activation in the elderly and potentially serve as biomarker of proprioceptive sensibility in older adults.

Reduced basal ganglia function when elderly switch between coordinated movement patterns.

Structural and neurochemical changes in frontostriatal circuits are thought to underlie age-related behavioral deficits on cognitive tasks. Here, we test the hypothesis that age-related motor switching deficits are associated with reduced basal ganglia (BG) function. Right-handed volunteers (15 Old, and 15 Young) made spatially and temporally coupled bimanual circular motions during event-related FMRI. A visual cue signaled the right hand to Switch or Continue its circling direction. Switching from mirror symmetric to asymmetric (SW¼ASYMM) took longer and resulted in more contralateral (left-) hand disruptions than vice versa. These effects were more pronounced in the elderly, showing that the ability to suppress and flexibly adapt motor behavior (agility) declines with age. For both groups, switching activated the BG and a typical network for task-set implementation, including dorsal anterior cingulate cortex/supplementary motor area (pre-SMA, SMA-proper) and anterior insula/inferior frontal gyrus. A region of interest analysis revealed significantly reduced SW¼ASYMM activation in bilateral subthalamic nucleus and right globus pallidus, only in the elderly. Age-related behavioral deficits may be related to inefficient recruitment of cortico-BG loops to suppress undesired movements. The elderly may use an alternative strategy to select the required movement pattern as indicated by increased activation of prefrontal cortex.

The neural control of bimanual movements in the elderly: Brain regions exhibiting age-related increases in activity, frequency-induced neural modulation, and task-specific compensatory recruitment.

Coordinated hand use is an essential component of many activities of daily living. Although previous studies have demonstrated age-related behavioral deficits in bimanual tasks, studies that assessed the neural basis underlying such declines in function do not exist. In this fMRI study, 16 old and 16 young healthy adults performed bimanual movements varying in coordination complexity (i.e., in-phase, antiphase) and movement frequency (i.e., 45, 60, 75, 90% of critical antiphase speed) demands. Difficulty was normalized on an individual subject basis leading to group performances (measured by phase accuracy/stability) that were matched for young and old subjects. Despite lower overall movement frequency, the old group "overactivated" brain areas compared with the young adults. These regions included the supplementary motor area, higher order feedback processing areas, and regions typically ascribed to cognitive functions (e.g., inferior parietal cortex/dorsolateral prefrontal cortex). Further, age-related increases in activity in the supplementary motor area and left secondary somatosensory cortex showed positive correlations with coordinative ability in the more complex antiphase task, suggesting a compensation mechanism. Lastly, for both old and young subjects, similar modulation of neural activity was seen with increased movement frequency. Overall, these findings demonstrate for the first time that bimanual movements require greater neural resources for old adults in order to match the level of performance seen in younger subjects. Nevertheless, this increase in neural activity does not preclude frequency-induced neural modulations as a function of increased task demand in the elderly.

Proprioceptive sensibility in the elderly: degeneration, functional consequences and plastic-adaptive processes.

As the percentage of individuals over the age of 60 years continues to rise, determining the extent and functional significance of age-related declines in sensorimotor performance is of increasing importance. This review examines the specific contribution of proprioceptive feedback to sensorimotor performance in older adults. First, a global perspective of proprioceptive acuity is provided assimilating information from studies where only one of several aspects of proprioceptive function (e.g. sense of position, motion or dynamic position) was quantified, and/or a single joint or limb segment tested. Second, the consequences of proprioceptive deficits are established with particular emphasis placed on postural control. Lastly, the potential for plastic changes in the aging proprioceptive system is highlighted, including studies which relate physical activity to enhanced proprioceptive abilities in older adults. Overall, this review provides a foundation for future studies regarding the proprioceptive feedback abilities of elderly individuals. Such studies may lead to greater advances in the treatment and prevention of the sensorimotor deficits typically associated with the aging process.

Ipsilateral coordination at preferred rate: effects of age, body side and task complexity.

Functional imaging studies have shown that elderly individuals activate widespread additional brain networks, compared to young subjects, when performing motor tasks. However, the parameters that effect this unique neural activation, including the spatial distribution of this activation across hemispheres, are still largely unknown. Here, we examined the effect of task complexity and body side on activation differences between older and younger adults while performing cyclical flexion-extension movements of the ipsilateral hand and foot. In particular, easy (isodirectional) and more difficult (non-isodirectional) coordination patterns were performed with either the left or right body side at a self-selected, comfortable rate. Even in the absence of imposed pacing the older group activated a larger brain network, suggestive of increased attentional deployment for monitoring the spatial relationships between the simultaneously moving segments and enhanced sensory processing and integration. Evidence of age-dependent underactivation was also found in contralateral M1, SMA and bilateral putamen, possibly reflecting a functional decline of the basal ganglia-mesial cortex pathway in the older group. An ANOVA model revealed significant main effects of task complexity and body side. However the interaction of these factors with age did not reach significance. Consequently, we conclude that under self-paced conditions, task complexity and body side did not have a modulatory effect on age-related brain activation.

White matter microstructural organization and gait stability in older adults.

Understanding age-related decline in gait stability and the role of alterations in brain structure is crucial. Here, we studied the relationship between white matter microstructural organization using Diffusion Tensor Imaging (DTI) and advanced gait stability measures in 15 healthy young adults (range 18-30 years) and 25 healthy older adults (range 62-82 years). Among the different gait stability measures, only stride time and the maximum Lyapunov exponent (which quantifies how well participants are able to attenuate small perturbations) were found to decline with age. White matter microstructural organization (FA) was lower throughout the brain in older adults. We found a strong correlation between FA in the left anterior thalamic radiation and left corticospinal tract on the one hand, and step width and safety margin (indicative of how close participants are to falling over) on the other. These findings suggest that white matter FA in tracts connecting subcortical and prefrontal areas is associated with the implementation of an effective stabilization strategy during gait.

White matter fractional anisotropy predicts balance performance in older adults.

Aging is characterized by brain structural changes that may compromise motor functions. In the context of postural control, white matter integrity is crucial for the efficient transfer of visual, proprioceptive and vestibular feedback in the brain. To determine the role of age-related white matter decline as a function of the sensory feedback necessary to correct posture, we acquired diffusion weighted images in young and old subjects. A force platform was used to measure changes in body posture under conditions of compromised proprioceptive and/or visual feedback. In the young group, no significant brain structure-balance relations were found. In the elderly however, the integrity of a cluster in the frontal forceps explained 21% of the variance in postural control when proprioceptive information was compromised. Additionally, when only the vestibular system supplied reliable information, the occipital forceps was the best predictor of balance performance (42%). Age-related white matter decline may thus be predictive of balance performance in the elderly when sensory systems start to degrade.