Age-dependent changes in the neural correlates of force modulation: an fMRI study

Functional imaging studies in humans have demonstrated widespread age-related changes in cortical motor networks. However, the relative contribution of cortical regions during motor performance varies not only with age but with task parameters. In this study, we investigated whether motor system activity during a task involving increasingly forceful hand grips was influenced by age. Forty right-handed volunteers underwent functional magnetic brain imaging whilst performing repetitive isometric hand grips with either hand in separate sessions. We found no age-related changes in the average size and shape of the task-related blood oxygen level dependent (BOLD) signal in contralateral primary motor cortex (M1), but did observe reduced ipsilateral M1 deactivation in older subjects (both hands). Furthermore, task-related activity co-varied positively with force output in a number of brain regions, but was less prominent with advancing age in contralateral M1, cingulate sulcus (both hands), sensory and premotor cortices (right hand). These results indicate that a reduced ability to modulate activity in appropriate motor networks when required may contribute to age-related decline in motor performance.     

Executive functions and neurocognitive aging: dissociable patterns of brain activity

Studies of neurocognitive aging report altered patterns of brain activity in older versus younger adults performing executive function tasks. We review the extant literature, using activation likelihood estimation meta-analytic methods, to compare age-related differences in the pattern of brain activity across studies examining 2 categories of tasks associated with executive control processing: working memory and inhibition. In a direct contrast of young and older adult activations, older adults engaged bilateral regions of dorsolateral prefrontal cortex as well as supplementary motor cortex and left inferior parietal lobule during working memory. In contrast, age-related changes during inhibitory control were observed in right inferior frontal gyrus and presupplementary motor area. Additionally, when we examined task-related differences within each age group we observed the predicted pattern of differentiated neural response in the younger subjects: lateral prefrontal cortex activity associated with working memory versus right anterior insula/frontal opercular activity associated with inhibition. This separation was largely maintained in older subjects. These data provide the first quantitative meta-analytic evidence that age-related patterns of functional brain change during executive functioning depend on the specific control process being challenged.     

Impact of changed positive and negative task-related brain activity on word-retrieval in aging

Previous functional imaging studies that compared activity patterns in older and younger adults during nonlinguistic tasks found evidence for 2 phenomena: older participants usually show more pronounced task-related positive activity in the brain hemisphere that is not dominant for the task and less pronounced negative task-related activity in temporo-parietal and midline brain regions. The combined effects of these phenomena and the impact on word retrieval, however, have not yet been assessed. We used functional magnetic resonance imaging to explore task-related positive (active task > baseline) and negative activity (baseline > active task) during semantic and phonemic verbal fluency tasks. Increased right frontal positive activity during the semantic task and reduced negative activity in the right hemisphere during both tasks was associated with reduced performance in older subjects. No substantial relationship between changes in positive and negative activity was observed in the older participants, pointing toward 2 partially independent but potentially co-occurring processes. Underlying causes of the observed functional network inefficiency during word retrieval in older adults need to be determined in the future.     

Differential relationships between transcallosal structural and functional connectivity in young and older adults

Numerous studies have identified age differences in brain structure and function that correlate with declines in motor performance. While these investigations have typically focused on activity in isolated regions of the brain, resting state functional connectivity magnetic resonance imaging (MRI) and diffusion tensor imaging allow for more integrative assessments of spatially disparate neural networks. The novel contribution of the current study is to combine both resting state functional connectivity and diffusion tensor imaging to examine motor corticocortical circuits in young and older adults. We find that relatively greater functional connectivity between the primary motor cortices was strongly associated with decreased structural connectivity and poorer motor performance solely in older adults. We suggest that greater functional connectivity in older adults may be reflective of a release from the normally predominantly inhibitory interhemispheric communication associated with the primary motor cortices.     

Age-related differences of saccade induced cortical activation

Recent functional MRI (fMRI) studies have described the increased task-related brain activation in older subjects during motor, cognitive and perceptual tasks. Age affects the ability to control saccadic eye movements. To investigate the age-related changes of oculomotor control, we studied the representation of saccades in 11 young (median age 29 years) and 11 older (median age 62 years) healthy individuals using fMRI. Brain activation was measured during a visually guided prosaccade trial. Differences in activation between rest and saccades as well as between younger and older subjects were assessed with statistical parametric mapping (SPM). In both age groups, activation of a frontoparietal network was observed. Older subjects showed increased activation compared to younger subjects with overactivation in bilateral parietal eye fields, the right frontal eye field, as well as in the right extrastriate cortex. We conclude that older adults increase activation in an extended oculomotor and visual network to maintain performance during simple prosaccades. This observation also underlines the importance of using appropriate age-matched control groups in fMRI studies after brain lesions.     

Age-related dedifferentiation and compensatory changes in the functional network underlying face processing

Recent evidence has shown that older adults fail to show adaptation in the right fusiform gyrus (FG) to the same face presented repeatedly, despite accurate detection of the previously presented face. We used functional magnetic resonance imaging to investigate whether this phenomenon is associated with age-related reductions in face specificity in brain activity and whether older adults compensate for these face-processing deficiencies by increasing activity in other areas within the face-processing network, or outside this network. A comparison of brain activity across multiple stimulus categories showed that, unlike young adults who engaged a number of brain regions specific to face processing, older adults generalized these patterns of activity to objects and houses. Also, young adults showed functional connectivity between the right FG and its homologous region during face processing, whereas older adults did not engage the left FG but showed a functional connection between the right FG and left orbitofrontal cortex. Finally, this frontotemporal functional connection was activated more strongly in older adults who performed better on a face-matching task (done outside of the scanner), suggesting increased involvement of this functional link for successful face recognition with increasing age. These findings suggest that 2 neural mechanisms, dedifferentiation and compensatory neural recruitment, underlie age differences in face processing.     

Age-related alterations in default mode network: impact on working memory performance

The default mode network (DMN) is a set of functionally connected brain regions which shows deactivation (task-induced deactivation, TID) during a cognitive task. Evidence shows an age-related decline in task-load-related modulation of the activity within the DMN during cognitive tasks. However, the effect of age on the functional coupling within the DMN and their relation to cognitive performance has hitherto been unexplored. Using functional magnetic resonance imaging, we investigated functional connectivity within the DMN in older and younger subjects during a working memory task with increasing task load. Older adults showed decreased connectivity and ability to suppress low frequency oscillations of the DMN. Additionally, the strength of the functional coupling of posterior cingulate (pCC) with medial prefrontal cortex (PFC) correlated positively with performance and was lower in older adults. pCC was also negatively coupled with task-related regions, namely the dorsolateral PFC and cingulate regions. Our results show that in addition to changes in canonical task-related brain regions, normal aging is also associated with alterations in the activity and connectivity of brain regions within the DMN. These changes may be a reflection of a deficit in cognitive control associated with advancing age that results in deficient resource allocation to the task at hand.     

Aberrant brain activation following motor skill learning in schizophrenic patients as shown by functional magnetic resonance imaging

BACKGROUND: Motor skill learning may be impaired in schizophrenia. While functional brain imaging studies have shown reduced activation during motor task performance in schizophrenic patients, brain activity changes with motor skill learning in these patients have not been studied by functional imaging. METHODS: A sequential complex motor task involving the right hand was performed by nine medicated schizophrenic patients and 10 age-matched healthy controls. Functional magnetic resonance images were obtained using a gradient echo, echoplanar imaging (EPI) pulse sequence before and after 1 week of training in performing the task. RESULTS: Bilaterally, patients showed significantly less blood oxygenation level-dependent (BOLD) signal response in the premotor area (PMA) before beginning motor training than controls. BOLD signal response increased in the left PMA of schizophrenic patients after 1 week of motor training; in contrast, the signal decreased in the left PMA of control subjects. Training effects concerning the number of finger movement sequences achieved did not differ between groups. Daily neuroleptic dose did not significantly affect changes with training in BOLD signal response in the PMA. CONCLUSIONS: These preliminary results suggest that schizophrenic patients have dysfunction of neural networks in areas including the PMA that are involved in executing a complex motor task. In terms of brain activity, motor learning may be less efficient or slower in the patients than in healthy subjects.     

Aging associated changes in the motor control of ankle movements in the brain

Although age-related gait changes have been well characterized, little is known regarding potential functional changes in central motor control of distal lower limb movements with age. We hypothesized that there are age-related changes in brain activity associated with the control of repetitive ankle movements, an element of gait feasible for study with functional magnetic resonance imaging. We analyzed standardized functional magnetic resonance imaging data from 102 right-foot dominant healthy participants aged 20–83 years for age-associated effects using FSL and a meta-analysis using coordinate-based activation likelihood estimation. For the first time, we have confirmed age-related changes in brain activity with this gait-related movement of the lower limb in a large population. Increasing age correlated strongly with increased movement-associated activity in the cerebellum and precuneus. Given that task performance did not vary with age, we interpret these changes as potentially compensatory for other age-related changes in the sensorimotor network responsible for control of limb function.     

Changes in diffusion path length with old age in diffuse optical tomography

Diffuse, optical near infrared imaging is increasingly being used in various neurocognitive contexts where changes in optical signals are interpreted through activation maps. Statistical population comparison of different age or clinical groups rely on the relative homogeneous distribution of measurements across subjects in order to infer changes in brain function. In the context of an increasing use of diffuse optical imaging with older adult populations, changes in tissue properties and anatomy with age adds additional confounds. Few studies investigated these changes with age. Duncan et al. measured the so-called diffusion path length factor (DPF) in a large population but did not explore beyond the age of 51 after which physiological and anatomical changes are expected to occur [Pediatr. Res. 39(5), 889-894 (1996)]. With increasing interest in studying the geriatric population with optical imaging, we studied changes in tissue properties in young and old subjects using both magnetic resonance imaging (MRI)-guided Monte-Carlo simulations and time-domain diffuse optical imaging. Our results, measured in the frontal cortex, show changes in DPF that are smaller than previously measured by Duncan et al. in a younger population. The origin of these changes are studied using simulations and experimental measures.     

Cerebellar direct current stimulation enhances motor learning in older adults

Developing novel approaches to combat age related declines in motor function is key to maintaining health and function in older adults, a subgroup of the population that is rapidly growing. Motor adaptation, a form of motor learning, has been shown to be impaired in healthy older subjects compared with their younger counterparts. Here, we tested whether excitatory anodal transcranial direct current stimulation (tDCS) over the cerebellum could enhance adaptation in older subjects. Participants performed a “center-out” reaching task, adapting to the sudden introduction of a visual cursor rotation. Older participants receiving sham tDCS (mean age 56.3 ± 6.8 years) were slower to adapt than younger participants (mean age 20.7 ± 2.1 years). In contrast, older participants who received anodal tDCS (mean age 59.6 ± 8.1 years) adapted faster, with a rate that was similar to younger subjects. We conclude that cerebellar anodal tDCS enhances motor adaptation in older individuals. Our results highlight the efficacy of the novel approach of using cerebellar tDCS to combat age related deficits in motor learning.     

Age-Related Increase in Cross-Sensory Noise in Resting and Steady-State Cerebral Perfusion

Behavioral research indicates that healthy aging is accompanied by maintenance of voluntary attentional function in many situations, suggesting older adults are able to use attention to enhance and suppress neural activity. However, other experiments show increased distractibility with age, suggesting a failure of attention. One hypothesis for these apparently conflicting findings is that older adults experience a greater sensory processing load at baseline compared to younger adults. In this situation, older adults might successfully modulate sensory cortical activity relative to a baseline referent condition, but the increased baseline load results in more activity than younger adults after attentional modulation. This hypothesis was tested by comparing average functional brain activity in auditory cortex using quantitative perfusion imaging during resting state and steady-state visual conditions. It was observed that older adults demonstrated greater processing of task-irrelevant auditory background noise than younger adults in both conditions. As expected, auditory activity was attenuated relative to rest during a visually engaging task for both older and younger participants. However, older adults continued to show greater auditory processing than their younger counterparts even after this task modulation. Furthermore, auditory activity during the visual task was predictive of cross-sensory distraction on a behavioral task in older adults. Together, these findings suggest that older adults are more distractible than younger, and the cause of this increased distractibility may lie in baseline brain functioning.     

Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T

Proton magnetic resonance spectroscopy was performed at 4 T to determine effects of age, region and gender on glutamate and glutamine in the normal human brain. Furthermore, glutamate and glutamine alterations with age were tested for correlations with other cerebral metabolites. Two 8 cm3 volumes were selected in corona radiata and mesial motor cortex in normal subjects (N = 24) between 24 and 68 years old. Older subjects had lower glutamate concentration in the motor cortex compared to younger subjects (p < 0.001). In corona radiata, older subjects demonstrated a trend in higher glutamine compared to younger subjects (p = 0.05). Glutamate in the motor cortex was positively correlated with glutamine, N-acetyl aspartate and creatine. Reduced glutamate and N-acetyl aspartate in the motor cortex is consistent with neuronal loss/shrinkage with age. In conclusion, different patterns in association with normal aging in these brain regions were detected in this study.     

Language and the aging brain: patterns of neural compensation revealed by functional brain imaging

Human aging brings with it declines in sensory function, both in vision and in hearing, as well as a general slowing in a variety of perceptual and cognitive operations. Yet in spite of these declines, language comprehension typically remains well preserved in normal aging. We review data from functional magnetic resonance imaging (fMRI) to describe a two-component model of sentence comprehension: a core sentence-processing area located in the perisylvian region of the left cerebral hemisphere and an associated network of brain regions that support the working memory and other resources needed for comprehension of long or syntactically complex sentences. We use this two-component model to describe the nature of compensatory recruitment of novel brain regions observed when healthy older adults show the same success at comprehending sentences as their younger adult counterparts. We suggest that this plasticity in neural recruitment contributes to the stability of language comprehension in the aging brain.     

Quantitative Analysis of Asymmetrical Cortical Activity Based on Power Spectrum Changes

The present study intends to quantitatively analyze power changes in blood oxygenation level-dependent (BOLD) signals, and to investigate functional asymmetry of cortical activity in motor areas during sequential finger movements. A power spectrum method was employed, mainly in contrast with the signal magnitude analysis, to investigate functional asymmetry of motor area cortical activity. Six right-handed subjects were included in the functional magnetic resonance imaging (fMRI) experiments. Both bi-handed and single-handed movements were analyzed. The power spectrum method demonstrated that right-handed subjects exhibited a larger power difference in BOLD signals between task and rest states in the right motor area than in the left motor area. These results showed that more nerve cells were evoked in the right motor area of right-handed subjects. In addition, the power spectrum method was confirmed to be a valid quantitative-analysis method for brain asymmetry analyses.     

Age-related changes in the functional neuroanatomy of overt speech production

Alterations of existing neural networks during healthy aging, resulting in behavioral deficits and changes in brain activity, have been described for cognitive, motor, and sensory functions. To investigate age-related changes in the neural circuitry underlying overt non-lexical speech production, functional MRI was performed in 14 healthy younger (21-32 years) and 14 healthy older individuals (62-84 years). The experimental task involved the acoustically cued overt production of the vowel /a/ and the polysyllabic utterance /pataka/. In younger and older individuals, overt speech production was associated with the activation of a widespread articulo-phonological network, including the primary motor cortex, the supplementary motor area, the cingulate motor areas, and the posterior superior temporal cortex, similar in the /a/ and /pataka/ condition. An analysis of variance with the factors age and condition revealed a significant main effect of age. Irrespective of the experimental condition, significantly greater activation was found in the bilateral posterior superior temporal cortex, the posterior temporal plane, and the transverse temporal gyri in younger compared to older individuals. Significantly greater activation was found in the bilateral middle temporal gyri, medial frontal gyri, middle frontal gyri, and inferior frontal gyri in older vs. younger individuals. The analysis of variance did not reveal a significant main effect of condition and no significant interaction of age and condition. These results suggest a complex reorganization of neural networks dedicated to the production of speech during healthy aging.     

Blood flow to exercising limbs varies with age, gender, and training status.

Understanding the effects of physiological aging on blood flow to active skeletal muscle and its regulation during exercise has important functional, hemodynamic, and metabolic implications for our rapidly expanding elderly population. During peak exercise involving a large muscle mass, blood flow to the legs is lower in healthy older compared to younger persons; this results from central (reduced cardiac output) and peripheral (reduced leg vascular conductance) limitations. There is considerable variability in the literature concerning age-related changes in leg blood flow during submaximal exercise, with reports of similar or reduced leg blood flow and vascular conductance in older vs. younger subjects depending on the exercise intensity and the gender and training status of the subjects. However, all the studies involving non-endurance-trained subjects are consistent in that older subjects achieve the requisite leg blood flow at higher arterial perfusion pressures than young subjects, suggesting altered local vasoregulatory mechanisms with aging. Although the nature of these age-related alterations is poorly understood, we have preliminary evidence for augmented sympathetic vasoconstrictor responsiveness in the legs of older men during exercise, and blunted leg vasodilator responsiveness in older women. Systematic research will be needed in order to define the central and local mechanisms underlying these age- and gender-specific differences in muscle vascular responsiveness. Such information will be important for designing future interventions aimed at improving muscle blood supply and functional capacity in older persons.     

Pain and emotion in the insular cortex: evidence for functional reorganization in major depression

Huntington's Disease (HD) is a neurodegenerative disease caused by a CAG triplet-repeat expansion-mutation in the Huntingtin gene. Subjects at risk for HD can be identified by genetic testing in the prodromal phase. Structural changes of basal-ganglia nuclei such as the caudate nucleus are well-replicated findings observable early in prodromal-HD subjects and may be preceded by distinct functional alterations of cortico-striatal circuits. This study aims to assess functional integrity of the motor system as a cortico-striatal circuit with particular clinical relevance in HD. Ten subjects in the prodromal phase of HD and ten matched controls were administered blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at rest (3T). Functional connectivity was measured as synchrony of BOLD activity between the caudate nucleus and thirteen cortical brain regions (seeds). Basal-ganglia volumes were assessed as established markers of disease progression in prodromal-HD. Linear regression analysis was performed to test for a relationship between structural changes and group differences in functional connectivity. Prodromal-HD subjects showed reduced BOLD synchrony between two seeds in the premotor cortex (BA6) and the caudate nucleus. While similar effect sizes could be observed for reduced basal-ganglia volumes and differences in functional connectivity, coefficients of determination indicate a moderate relationship between functional connectivity and striatal atrophy. Our data show reduced cortico-striatal functional connectivity at rest in prodromal-HD and suggest a relation to early structural brain changes. Additional longitudinal studies are necessary to elucidate the temporal relationship between functional alterations and earliest structural brain changes in prodromal-HD.     

Experimental Modeling of Functional Deficiency of the Nigrostriatal Dopaminergic System in Mice

The dopaminergic nigrostriatal system of the brain is a key component in controlling motor behavior. The bodies of dopaminergic neurons are located in the compact zone of the substantia nigra and their axons, forming the nigrostriatal tract, project to the striatum. The aim of the present work was to develop an experimental model of functional deficiency of the dopaminergic neurons of the nigrostriatal system with no impairment to motor behavior, i.e., the presymptomatic stage of parkinsonism. The model was created in mice by administration of single subcutaneous injections of low doses (12 mg/kg) of 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is converted to MPP⁺ in the brain, this being a neurotoxin for dopaminergic neurons. These experiments showed that 14 days after administration of MPTP the animals a) lacked any impairment to motor behavior; b) had no decrease in the dopamine level or any dopamine neuron degeneration in the substantia nigra; c) showed significant reductions in dopamine levels in the striatum due to degeneration of half of its dopaminergic fibers. The absence of changes in motor behavior in the presence of significant changes in dopamine metabolism and structural damage to dopaminergic axons in the striatum provides evidence for the activation of compensatory mechanisms in the brain. Thus, we have developed an experimental model of the presymptomatic stage of parkinsonism, which is characterized by degeneration of the axons of dopaminergic neurons in the striatum with no changes in the bodies of these neurons in the substantia nigra; this model will be used for further studies of compensatory mechanisms.     

Anticipation of monetary gain but not loss in healthy older adults

Although global declines in structure have been documented in the aging human brain, little is known about the functional integrity of the striatum and prefrontal cortex in older adults during incentive processing. We used event-related functional magnetic resonance imaging to determine whether younger and older adults differed in both self-reported and neural responsiveness to anticipated monetary gains and losses. The present study provides evidence for intact striatal and insular activation during gain anticipation with age, but shows a relative reduction in activation during loss anticipation. These findings suggest that there is an asymmetry in the processing of gains and losses in older adults that may have implications for decision-making.