Healthy aging is marked by declines in a variety of cognitive and motor abilities. A better understanding of the aging brain may aid in elucidating the neural substrates of these behavioral effects. Investigations of resting state functional brain connectivity have provided insights into pathology, and to some degree, healthy aging. Given the role of the cerebellum in both motor and cognitive behaviors, as well as its known volumetric declines with age, investigating cerebellar networks may shed light on the neural bases of age-related functional declines. We mapped the resting state networks of the lobules of the right hemisphere and the vermis of the cerebellum in a group of healthy older adults and compared them to those of young adults. We report disrupted cortico-cerebellar resting state network connectivity in older adults. These results remain even when controlling for cerebellar volume, signal-to-noise ratio, and signal-to-fluctuation noise ratio. Specifically, there was consistent disruption of cerebellar connectivity with both the striatum and the medial temporal lobe. Associations between connectivity strength and both sensorimotor and cognitive task performance indicate that cerebellar engagement with the default mode network and striatal pathways is associated with better performance for older adults. These results extend our understanding of the resting state networks of the aging brain to include cortico-cerebellar networks, and indicate that age differences in network connectivity strength are important for behavior.
cerebellum; aging; fcMRI; striatum; medial temporal lobe; working memory; sensorimotor performance
Recent studies have demonstrated neuroanatomically selective relationships between white matter tract microstructure, physiological function and task performance. Such findings suggest that the microstructure of transcallosal motor fibers may reflect the capacity for interhemispheric inhibition between the primary motor cortices, although full characterization of the transcallosal inhibitory sensorimotor network is lacking. Thus, the goal of the current study was to provide a comprehensive description of transcallosal fibers connecting homologous sensorimotor cortical regions and to identify the relationship(s) between fiber tract microstructure and interhemispheric inhibition during voluntary cortical activity. To this end, we assessed microstructure of fiber tracts connecting homologous sensorimotor regions of the cortex with diffusion tensor imaging. We also assessed interhemispheric inhibition by eliciting the ipsilateral silent period (iSP) within the same participants. We mapped mutually exclusive transcallosal connections between homologous sensorimotor regions and computed quantitative metrics of each fiber tract. Paralleling work in non-human primates we found the densest interhemispheric sensorimotor connections to be between the medial motor areas. Additionally, we provide a mid-sagittal callosal atlas in normalized MNI space for future studies to use when investigating callosal fiber tracts connecting primary and secondary sensorimotor cortices. Finally, we report a strong, positive relationship (r = 0.76) between strength of interhemispheric inhibition (iSP) and microstructure of interhemispheric fibers that is specific to tracts connecting the primary motor cortices. Thus, increased fiber microstructure in young adults predicts interhemispheric inhibitory capacity.
Corpus Callosum; Diffusion Tensor Imaging; Ipsilateral Silent Period; Interhemispheric Inhibition; Tractography
We introduced haptic cues to the serial reaction time (SRT) sequence learning task alongside the standard visual cues to assess the relative contributions of visual and haptic stimuli to the formation of motor and perceptual memories. We used motorized keys to deliver brief pulse-like displacements to the resting fingers, expecting that the proximity and similarity of these cues to the subsequent response motor actions (finger-activated key-presses) would strengthen the motor memory trace in particular. We adopted the experimental protocol developed by Willingham (1999) to explore whether haptic cues contribute differently than visual cues to the balance of motor and perceptual learning. We found that sequence learning occurs with haptic stimuli as well as with visual stimuli and we found that irrespective of the stimuli (visual or haptic) the SRT task leads to a greater amount of motor learning than perceptual learning.
sequence learning; haptic cue; motor memory; serial reaction time task
Researchers have begun to delineate the precise nature and neural correlates of the cognitive processes that contribute to motor skill learning. Here, we review recent work from our laboratory designed to further understand the neurocognitive mechanisms of skill acquisition. We have demonstrated an important role for spatial working memory in two different types of motor skill learning, sensorimotor adaptation and motor sequence learning. We have shown that individual differences in spatial working memory capacity predict the rate of motor learning for both sensorimotor adaptation and motor sequence learning. We have also reported neural overlap between a spatial working memory task and the early, but not late, stages of adaptation, particularly in the right dorsolateral prefrontal cortex and bilateral inferior parietal lobules. We propose that spatial working memory is relied upon for processing motor error information to update motor control for subsequent actions. Further, we suggest that working memory is relied upon during learning new action sequences for chunking individual action elements together.
sequence learning; sensorimotor adaptation; working memory
Our recent work has shown that older adults are disproportionately impaired at bimanual tasks when the two hands are moving out of phase with each other [Bangert, A. S., Reuter-Lorenz, P. A., Walsh, C. M., Schachter, A. B., & Seidler, R. D. Bimanual coordination and aging: Neurobehavioral implications. Neuropsychologia, 48, 1165–1170, 2010]. Interhemispheric interactions play a key role during such bimanual movements to prevent interference from the opposite hemisphere. Declines in corpus callosum (CC) size and microstructure with advancing age have been well documented, but their contributions to age deficits in bimanual function have not been identified. In the current study, we used structural magnetic resonance and diffusion tensor imaging to investigate age-related changes in the relationships between callosal macrostructure, microstructure, and motor performance on tapping tasks requiring differing degrees of interhemispheric interaction. We found that older adults demonstrated disproportionately poorer performance on out-of-phase bimanual control, replicating our previous results. In addition, older adults had smaller anterior CC size and poorer white matter integrity in the callosal midbody than their younger counterparts. Surprisingly, larger CC size and better integrity of callosal microstructure in regions connecting sensorimotor cortices were associated with poorer motor performance on tasks requiring high levels of interhemispheric interaction in young adults. Conversely, in older adults, better performance on these tasks was associated with larger size and better CC microstructure integrity within the same callosal regions. These findings implicate age-related declines in callosal size and integrity as a key contributor to bimanual control deficits. Further, the differential age-related involvement of transcallosal pathways reported here raises new questions about the role of the CC in bimanual control.
We have recently demonstrated that visuospatial working memory performance predicts the rate of motor skill learning, particularly during the early phase of visuomotor adaptation. Here, we follow up these correlational findings with direct manipulations of working memory resources to determine the impact on visuomotor adaptation, a form of motor learning. We conducted two separate experiments. In the first one, we used a resource depletion strategy to investigate whether the rate of early visuomotor adaptation would be negatively affected by fatigue of spatial working memory resources. In the second study, we employed a dual n-back task training paradigm that has been shown to result in transfer effects  over five weeks to determine whether training-related improvements would boost the rate of early visuomotor adaptation. The depletion of spatial working memory resources negatively affected the rate of early visuomotor adaptation. However, enhancing working memory capacity via training did not lead to improved rates of visuomotor adaptation, suggesting that working memory capacity may not be the factor limiting maximal rate of visuomotor adaptation in young adults. These findings are discussed from a resource limitation / capacity framework with respect to current views of motor learning.
working memory; visuomotor adaptation; resource depletion; cognitive training
Throughout our life span we encounter challenges that require us to adapt to the demands of our changing environment; this entails learning new skills. Two primary components of motor skill learning are motor acquisition, the initial process of learning the skill, and motor transfer, when learning a new skill is benefitted by the overlap with a previously learned one. Older adults typically exhibit declines in motor acquisition compared to young adults, but remarkably, do not demonstrate deficits in motor transfer (Seidler, 2007). Our recent work demonstrates that a failure to engage spatial working memory (SWM) is associated with skill learning deficits in older adults (Anguera et al., 2011). Here, we investigate the role that SWM plays in both motor learning and transfer in young and older adults. Both age groups exhibited performance savings, or positive transfer, at transfer of learning for some performance variables. Measures of spatial working memory performance and reaction time correlated with both motor learning and transfer for young adults. Young adults recruited overlapping brain regions in prefrontal, premotor, parietal and occipital cortex for performance of a SWM and a visuomotor adaptation task, most notably during motor learning, replicating our prior findings (Anguera et al., 2010). Neural overlap between the SWM task and visuomotor adaptation for the older adults was limited to parietal cortex, with minimal changes from motor learning to transfer. Combined, these results suggest that age differences in engagement of cognitive strategies have a differential impact on motor learning and transfer.
Spatial Working Memory; Aging; Visuomotor Adaptation; Skill Acquisition; Transfer
In many cases bilateral cortical activation in older adults has been associated with better task performance, suggesting that a greater reliance on interhemispheric interactions aids performance. Interhemispheric communication is primarily mediated via the corpus callosum (CC), however with advancing age the anterior half of the CC undergoes significant atrophy. Here we determine whether there are age differences in the relationship between cross-sectional area of the CC and performance on cognitive tests of psychomotor processing speed and working memory. We found that older adults had significantly smaller callosal area in the anterior and mid-body of the CC than young adults. Furthermore, older adults with larger size in these callosal areas performed better on assessments of working memory and processing speed. Our results indicate that older adults with larger size of the anterior half of the CC exhibit better cognitive function, although their performance was still poorer than young adults with similar CC size. Thus, while the capability for interhemispheric interactions, as inferred from callosal size, may provide performance benefits for older adults, this capacity alone does not assure protection from general performance decline.
Corpus callosum; aging; working memory; processing speed
Although connections between cognitive deficits and age-associated brain differences have been elucidated, relationships with motor performance are less well understood. Here, we broadly review age-related brain differences and motor deficits in older adults in addition to cognition-action theories. Age-related atrophy of the motor cortical regions and corpus callosum may precipitate or coincide with motor declines such as balance and gait deficits, coordination deficits, and movement slowing. Correspondingly, degeneration of neurotransmitter systems—primarily the dopaminergic system—may contribute to age-related gross and fine motor declines, as well as to higher cognitive deficits. In general, older adults exhibit involvement of more widespread brain regions for motor control than young adults, particularly the prefrontal cortex and basal ganglia networks. Unfortunately these same regions are the most vulnerable to age-related effects, resulting in an imbalance of “supply and demand”. Existing exercise, pharmaceutical, and motor training interventions may ameliorate motor deficits in older adults.
Aging; Motor Performance; fMRI; Dopamine; Cognition; Plasticity; Exercise; Rehabilitation
We investigate whether aging leads to global declines in discrete and continuous bimanual coordination tasks thought to rely on different control mechanisms for temporal coupling of the limbs. All conditions of continuous bimanual circle drawing were associated with age-equivalent temporal control. This was also true for discrete simultaneous tapping. Older adults’ between-hand coordination deficits were specific to discrete tapping conditions requiring asynchronous intermanual timing and were associated with self-reported executive dysfunction on the Dysexecutive (DEX) questionnaire. Also, older adults exclusively showed a relationship between the most difficult bimanual circling condition and a measure of working memory. Thus, age-related changes in bimanual coordination are specific to task conditions that place complex timing demands on left and right hand movements and are, therefore, likely to require executive control.
Executive Control; Motor Control; Bimanual Coordination; Aging
Older adults show less lateralized task-related brain activity than young adults. One potential mechanism of this increased activation is that age-related degeneration of the corpus callosum (CC) may alter the balance of inhibition between the two hemispheres. To determine whether age differences in interhemispheric connectivity affect functional brain activity in older adults, we used magnetic resonance imaging (MRI) to assess resting functional connectivity and functional activation during a simple motor task. We found that older adults had smaller CC area compared to young adults. Older adults exhibited greater recruitment of ipsilateral primary motor cortex (M1), which was associated with longer reaction times. Additionally, recruitment of ipsilateral M1 in older adults was correlated with reduced resting interhemispheric connectivity and a larger CC. We suggest that reduced interhemispheric connectivity reflects a loss of the ability to inhibit the non-dominant hemisphere during motor task performance for older adults, which has a negative impact on performance.
aging; corpus callosum; fMRI; functional connectivity; motor cortex
Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by dopamine depletion in the striatum. One consistent pathophysiological hallmark of PD is an increase in spontaneous oscillatory activity in the basal ganglia thalamocortical networks. We evaluated these effects using resting state functional connectivity MRI in mild to moderate stage Parkinson's patients on and off l-DOPA and age-matched controls using six different striatal seed regions. We observed an overall increase in the strength of cortico-striatal functional connectivity in PD patients off l-DOPA compared to controls. This enhanced connectivity was down-regulated by l-DOPA as shown by an overall decrease in connectivity strength, particularly within motor cortical regions. We also performed a frequency content analysis of the BOLD signal time course extracted from the six striatal seed regions. PD off l-DOPA exhibited increased power in the frequency band 0.02–0.05 Hz compared to controls and to PD on l-DOPA. The l-DOPA associated decrease in the power of this frequency range modulated the l-DOPA associated decrease in connectivity strength between striatal seeds and the thalamus. In addition, the l-DOPA associated decrease in power in this frequency band correlated with the l-DOPA associated improvement in cognitive performance. Our results demonstrate that PD and l-DOPA modulate striatal resting state BOLD signal oscillations and cortico-striatal network coherence.
dopamine; Parkinson's disease; fMRI; functional connectivity; striatum; neural oscillation
Many studies have demonstrated that aging is associated with declines in skill acquisition. In the current study, we tested whether older adults could acquire general, transferable knowledge about skill learning processes. Older adult participants learned five different motor tasks. Two older adult control groups performed the same number of trials, but learned only one task. The experimental group exhibited faster learning than that seen in the control groups. These data demonstrate that older adults can learn to learn new motor skills.
The basal ganglia are thought to play a critical role in duration perception and production. However, experimental evidence for impaired temporal processing in Parkinson’s disease (PD) patients is mixed. This study examined the association between striatal dopaminergic denervation in PD patients and sensorimotor synchronization. Twenty-eight mild-to-moderate stage PD patients synchronized finger taps to tone sequences of either 500 ms, 1000 ms or 1500 ms time intervals while ON levodopa (L-DOPA) or placebo pill (on separate test days) with the index finger of their more and less affected hands. We measured the accuracy and variability of synchronization. In a separate session, patients underwent 11C-dihydrotetrabenazine (11C-DTBZ) PET scanning to measure in vivo striatal dopaminergic denervation. Patients were less accurate synchronizing to the 500 ms target time interval, compared to the 1000 and 1500 ms time intervals, but neither medication state nor hand affected accuracy; medication state, hand nor the target time interval affected synchronization variability. Regression analyses revealed no strong relationships between synchronization accuracy or variability and striatal dopaminergic denervation. We performed a cluster analysis on the degree of dopaminergic denervation to determine whether patient subgroup differences underlie our results. Three patient subgroups showed behavioral differences in synchronization accuracy, but not variability, paralleling their pattern of denervation. These findings provide further evidence for the role of the basal ganglia and dopamine in duration production and suggest that the degree of striatal dopaminergic denervation may explain the heterogeneity of performance between PD patients on the sensorimotor synchronization task.
Positron emission tomography; Dopaminergic denervation; Parkinson’s disease; Basal ganglia; Paced finger tapping; Duration production
The cerebellum has been implicated in both sensorimotor and cognitive function, but is known to undergo volumetric declines with advanced age. Individual differences in regional cerebellar volume may therefore provide insight into performance variability across the lifespan, as has been shown with other brain structures and behaviors. Here, we investigated whether there are regional age differences in cerebellar volume in young and older adults, and whether these volumes explain, in part, individual differences in sensorimotor and cognitive task performance. We found that older adults had smaller cerebellar volume than young adults; specifically, lobules in the anterior cerebellum were more impacted by age. Multiple regression analyses for both age groups revealed associations between sensorimotor task performance in several domains (balance, choice reaction time, and timing) and regional cerebellar volume. There were also relationships with working memory, but none with measures of general cognitive or executive function. Follow-up analyses revealed several differential relationships with age between regional volume and sensorimotor performance. These relationships were predominantly selective to cerebellar regions that have been implicated in cognitive functions. Therefore, it may be the cognitive aspects of sensorimotor task performance that are best explained by individual differences in regional cerebellar volumes. In sum, our results demonstrate the importance of regional cerebellar volume with respect to both sensorimotor and cognitive performance, and we provide additional insight into the role of the cerebellum in age-related performance declines.
cerebellum; volume; sensorimotor performance; individual differences
Physical activity has been linked to better cognitive function in older adults, especially for executive control processes. Researchers have suggested that temporal processing of durations less than 1 second is automatic and engages motor processes, while timing of longer durations engages executive processes. The purpose of this study was to determine whether a higher level of physical activity is associated with better reproduction performance in older adults, especially for durations in the “cognitive” range (i.e. longer than 1 s). Older right-handed adults completed a temporal reproduction task with five target durations (300, 650, 1000, 1350, and 1700 ms). Physical activity level was assessed via estimation of VO2 peak using a self-report activity scale. Results indicated that higher physical activity level was associated with better timing accuracy and that this effect was dependent on target duration. Namely, the relationship between physical activity and timing accuracy was strongest at the longest durations. Therefore, greater physical activity in older adults may have specific benefits linked to better executive functions.
Temporal reproduction; Physical Activity; Cognition; Older Adults; Neuro-protection
Long duration spaceflight (i.e., 22 days or longer) has been associated with changes in sensorimotor systems, resulting in difficulties that astronauts experience with posture control, locomotion, and manual control. The microgravity environment is an important causal factor for spaceflight induced sensorimotor changes. Whether spaceflight also affects other central nervous system functions such as cognition is yet largely unknown, but of importance in consideration of the health and performance of crewmembers both in- and post-flight. We are therefore conducting a controlled prospective longitudinal study to investigate the effects of spaceflight on the extent, longevity and neural bases of sensorimotor and cognitive performance changes. Here we present the protocol of our study.
This study includes three groups (astronauts, bed rest subjects, ground-based control subjects) for which each the design is single group with repeated measures. The effects of spaceflight on the brain will be investigated in astronauts who will be assessed at two time points pre-, at three time points during-, and at four time points following a spaceflight mission of six months. To parse out the effect of microgravity from the overall effects of spaceflight, we investigate the effects of seventy days head-down tilted bed rest. Bed rest subjects will be assessed at two time points before-, two time points during-, and three time points post-bed rest. A third group of ground based controls will be measured at four time points to assess reliability of our measures over time. For all participants and at all time points, except in flight, measures of neurocognitive performance, fine motor control, gait, balance, structural MRI (T1, DTI), task fMRI, and functional connectivity MRI will be obtained. In flight, astronauts will complete some of the tasks that they complete pre- and post flight, including tasks measuring spatial working memory, sensorimotor adaptation, and fine motor performance. Potential changes over time and associations between cognition, motor-behavior, and brain structure and function will be analyzed.
This study explores how spaceflight induced brain changes impact functional performance. This understanding could aid in the design of targeted countermeasures to mitigate the negative effects of long-duration spaceflight.
Space flight; Astronauts; Microgravity; Sensorimotor feedback; Cognition; Neuroimaging; MRI; Longitudinal studies; Bed rest
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 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 cortico-cortical 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.
Older adults (OA) show more diffuse brain activity than young adults (YA) during the performance of cognitive, motor, and perceptual tasks. It is unclear whether this over-activation reflects compensation or dedifferentiation. Typically, these investigations have not evaluated the organization of the resting brain, which can help to determine whether more diffuse representations reflect physiological or task- dependent effects. In the present study we used transcranial magnetic stimulation (TMS) to determine whether there are differences in motor cortex organization of both brain hemispheres in YA and OA. We measured resting motor threshold, motor evoked potential (MEP) latency and amplitude, and extent of first dorsal interosseous representations, in addition to a computerized measure of reaction time. There was no significant age difference in motor threshold, but we did find that OA had larger contralateral MEP amplitudes and a longer contralateral MEP latency. Furthermore, the spatial extent of motor representations in OA was larger. We found that larger dominant hemisphere motor representations in OA were associated with higher reaction times, suggesting dedifferentiation rather than compensation effects.
aging; transcranial magnetic stimulation; motor cortex
Interhemispheric communication consists of a complex balance of facilitation and inhibition that is modulated in a task-dependent manner. However, it remains unclear how individual differences in interhemispheric interactions relate to motor performance. To assess interhemispheric inhibition, we utilized the ipsilateral silent period technique (iSP; evoked by suprathreshold transcranial magnetic stimulation), which elicits inhibition of volitional motor activity. Participants performed three force production tasks: 1) unimanual (right hand) constant force, 2) bimanual constant force, (bimanual simultaneous) and 3) bimanual with right hand constant force and left hand sine wave tracking (bimanual independent). We found that individuals with greater IHI capacity demonstrated reduced mirror EMG activity in the left hand during unimanual right hand contraction. However, these same individuals demonstrated the poorest performance during the bimanual independent force production task. We suggest that a high capacity for IHI from one motor cortex to another can effectively prevent “motor overflow” during unimanual tasks, but it can also limit interhemispheric cooperation during independently controlled bimanual tasks.
ipsilateral silent period; force production; motor overflow
Cerebellar contributions to motor learning are well-documented. For example, under some conditions, patients with cerebellar damage are impaired at visuomotor adaptation and at acquiring new action sequences. Moreover, cerebellar activation has been observed in functional MRI (fMRI) investigations of various motor learning tasks. The early phases of motor learning are cognitively demanding, relying on processes such as working memory, which have been linked to the cerebellum as well. Here, we investigated cerebellar contributions to motor learning using activation likelihood estimation (ALE) meta-analysis. This allowed us to determine, across studies and tasks, whether or not the location of cerebellar activation is constant across differing motor learning tasks, and whether or not cerebellar activation in early learning overlaps with that observed for working memory. We found that different regions of the anterior cerebellum are engaged for implicit and explicit sequence learning and visuomotor adaptation, providing additional evidence for the modularity of cerebellar function. Furthermore, we found that lobule VI of the cerebellum, which has been implicated in working memory, is activated during the early stages of explicit motor sequence learning. This provides evidence for a potential role for the cerebellum in the cognitive processing associated with motor learning. However, though lobule VI was activated across both early explicit sequence learning and working memory studies, there was no spatial overlap between these two regions. Together, our results support the idea of modularity in the formation of internal representations of new motor tasks in the cerebellum, and highlight the cognitive processing relied upon during the early phases of motor skill learning.
cerebellum; sequence learning; visuomotor adaptation; working memory; meta-analysis
Conventional neuroimaging techniques provide information about condition-related changes of the BOLD (blood-oxygen-level dependent) signal, indicating only where and when the underlying cognitive processes occur. Recently, with the help of a new approach called “model-based” functional neuroimaging (fMRI), researchers are able to visualize changes in the internal variables of a time varying learning process, such as the reward prediction error or the predicted reward value of a conditional stimulus. However, despite being extremely beneficial to the imaging community in understanding the neural correlates of decision variables, a model-based approach to brain imaging data is also methodologically challenging due to the multicollinearity problem in statistical analysis. There are multiple sources of multicollinearity in functional neuroimaging including investigations of closely related variables and/or experimental designs that do not account for this. The source of multicollinearity discussed in this paper occurs due to correlation between different subjective variables that are calculated very close in time. Here, we review methodological approaches to analyzing such data by discussing the special case of separating the reward prediction error signal from reward outcomes.
prediction error; model comparison; dopamine; predicted value; fMRI
motor learning; sensorimotor adaptation; sequence learning; motor cortex; consolidation
Older adults exhibit more bilateral motor cortical activity during unimanual task performance than young adults. Interestingly, a similar pattern is seen in young adults with reduced hand dominance. However, older adults report stronger hand dominance than young adults, making it unclear how handedness is manifested in the aging motor cortex. Here, we investigated age differences in the relationships between handedness, motor cortical organization, and interhemispheric communication speed. We hypothesized that relationships between these variables would differ for young and older adults, consistent with our recent proposal of an age-related shift in interhemispheric interactions. We mapped motor cortical representations of the right and left first dorsal interosseous muscles using transcranial magnetic stimulation (TMS) in young and older adults recruited to represent a broad range of the handedness spectrum. We also measured interhemispheric communication speed and bimanual coordination. We observed that more strongly handed older adults exhibited more ipsilateral motor activity in response to TMS; this effect was not present in young adults. Furthermore, we found opposing relationships between interhemispheric communication speed and bimanual performance in the two age groups. Thus, handedness manifests itself differently in the motor cortices of young and older adults and has interactive effects with age.