Elsevier

NeuroImage

Volume 55, Issue 1, 1 March 2011, Pages 194-203
NeuroImage

Age-related changes of the functional architecture of the cortico-basal ganglia circuitry during motor task execution

https://doi.org/10.1016/j.neuroimage.2010.12.030Get rights and content

Abstract

Normal human aging is associated with declining motor control and function. It is thought that dysfunction of the cortico-basal ganglia circuitry may contribute to age-related sensorimotor impairment, however the underlying mechanisms are poorly characterized. The aim of this study was to enhance our understanding of age-related changes in the functional architecture of these circuits. Fifty-nine subjects, consisting of a young, middle and old group, were studied using functional MRI and a motor activation paradigm. Functional connectivity analyses and examination of correlations of connectivity strength with performance on the activation task as well as neurocognitive tasks completed outside of magnet were conducted. Results indicated that increasing age is associated with changes in the functional architecture of the cortico-basal ganglia circuitry. Connectivity strength increased between subcortical nuclei and cortical motor and sensory regions but no changes were found between subcortical components of the circuitry. Further, increased connectivity was correlated with poorer performance on a neurocognitive task independently of age. This result suggests that increased connectivity reflects a decline in brain function rather than a compensatory process. These findings advance our understanding of the normal aging process. Further, the methods employed will likely be useful for future studies aimed at disambiguating age-related versus illness progression changes associated with neuropsychiatric disorders that involve the cortico-basal ganglia circuitry.

Research Highlights

► Functional changes of the basal ganglia circuitry occur during normal aging. ► Functional connectivity increases between some cortical and subcortical regions. ► Increased connectivity reflects a decline in brain function. ► Connectivity changes likely contribute to age-related loss of motor function.

Introduction

Advanced age is associated with declining sensorimotor control and functioning. Fine motor control deficits as well as gait and balance impairments limit the ability of older adults to perform activities of daily living and function independently. Motor performance impairment associated with advancing age is thought to arise as a result of central nervous system, peripheral nervous system and neuromuscular system dysfunction (Seidler et al., 2010).

In the human central nervous system, many changes occur related to age that could contribute to motor performance deficits. These include loss of cortical gray matter (Good et al., 2001) particularly in prefrontal regions (Jernigan et al., 2001, Resnick et al., 2003), reductions of white matter (Ge et al., 2002, Ota et al., 2006) and volume reductions in the basal ganglia (Langenecker et al., 2007). Neurochemical changes occur as well; for example altered serotonin transmission has been associated with motor dysfunction in mice (Sibille et al., 2007). Further, decreased striatal dopamine (DA) signaling is associated with age (Haycock et al., 2003) as well as alterations of DA receptors (Suhara et al., 1991) and the dopamine transporter (DAT) (Troiano et al., 2010). Age-related altered basal ganglia response to dopamine has been demonstrated in non-human primates (Zhang et al., 2001) and there is evidence that changes in striatal DA transmission is associated with motor deficits (Cham et al., 2007, Cham et al., 2008).

While the cortico-basal ganglia circuits (Fig. 1) have been implicated in age-associated motor deficits, the exact underlying mechanisms remain to be elucidated. Functional MRI (fMRI) studies have demonstrated age-related changes in basal ganglia activation (Langenecker et al., 2007) and functional connectivity (Taniwaki et al., 2007). Other functional connectivity analyses have been successfully used to enhance our understanding of the cortico-basal ganglia circuitry, for example Barnes et al. (2010), Doron and Goelman (2010), Postuma and Dagher (2006), Taniwaki et al. (2006), Williams et al. (2002), Ystad et al. (2010), and Zhang et al. (2008). In the present study, we further extend prior functional connectivity work by also examining correlation of connectivity strength with performance on (a) the activation paradigm comprising a simple motor output and (b) motor and executive function tasks conducted outside of magnet. A similar approach has been used to correlate connectivity in the basal ganglia with performance on the California Verbal Learning Test (Ystad et al., 2010) and correlate corticostriatal connectivity with symptom severity scores for Obsessive Compulsive Disorder (Harrison et al., 2009). Functional imaging studies have also demonstrated age-related increased cortical recruitment during motor behavior (Calautti et al., 2001, Heuninckx et al., 2005, Heuninckx et al., 2008) and have found relationships between activation and motor performance (Harada et al., 2009, Heuninckx et al., 2008, Mattay et al., 2002, Ward and Frackowiak, 2003). Therefore, we reasoned that fMRI using a motor activation paradigm would be likely to reveal aberrant connectivity involving both cortical–subcortical and subcortical–subcortical regions.

The primary aim of this work was to expand our understanding of age-related changes in the functional architecture of the cortico-basal ganglia circuitry as well determine whether such changes might play a direct role in the decline of motor function associated with normal aging. A motor activation paradigm involving hand function was utilized because normal aging is associated with loss of hand motor function (Ranganathan et al., 2001) and because there is a close relationship between hand motor function and the ability to function independently among the elderly (Scherder et al., 2008).

A secondary goal of this study was to better characterize a functional MRI motor activation task we have previously found to have robust activation (Marchand et al., 2008) and excellent group reliability (Lee et al., 2010). We have reported that motor paradigms are effective probes of cortico-basal ganglia function in some mood and anxiety disorders (Marchand et al., 2009, Marchand et al., 2007a, Marchand et al., 2007b) and therefore anticipate using this task in future studies of neuropsychiatric conditions. To that end, we wanted to define how age might impact activation and functional connectivity associated with this paradigm. This information is critical for planned studies of illness progression as well as investigations of geriatric mood and anxiety disorders.

Section snippets

Subjects

Participants were 59 females recruited from three age groups. The age ranges of the cohorts were 18–22, 25–35 and 65–75 for “young,” “middle” and “old” groups respectively. The age ranges for the three groups were selected specifically to allow us to examine and compare activation and connectivity patterns of groups representing: (a) a healthy adult brain (the middle group); (b) the period prior to the completion of brain maturation (the young group) and (c) the period after brain functions

Behavioral results

Group performances on behavioral variables are presented in Table 3. Group differences were evident on most variables. Bonferroni post hoc analyses showed that the young group performed better than the middle and old groups on the activation task (Bonferroni p values = 0.030 and .031, respectively; Cohen's d = 0.80 and 0.79); the old group performed more poorly than the young and the middle groups on PTT accuracy and the AS task (all Bonferroni p values < 0.002, Cohen's d ranging from 1.21 to 1.53),

Between-group comparison of whole brain activation maps

There were no significant differences between the middle and young groups at the threshold utilized (voxel-wise 0.05 corrected for multiple comparisons with FWE). Further, comparisons of the young to middle, young to old and middle to old groups revealed no greater activation of a younger group relative to an older group. In contrast, the same comparisons demonstrated greater activation of the old group relative to both the middle and young group. Areas of greater activation for the old group

Correlation of behavioral and imaging data

To determine whether age-related changes in connectivity could explain age-related decrements in performance, we selected those connectivity pairs on which age-related changes were evident (i.e., M1–caudate, M1–VA, S1–caudate, and S1–VA, S1–putamen) and correlated them with the behavioral variables on which age-related changes were apparent (i.e., the AS task, PTT errors, and PTT motor planning). The results are presented in Table 7. As can be seen from the table, greater connectivity values on

Discussion

The primary aim of this study was to enhance our understanding of both the nature of age-related functional changes in cortico-basal ganglia circuitry and the impact of these alterations on motor task performance. Advancing age is known to be associated with changes in the basal ganglia nuclei. These changes include volume reduction, iron accumulation in the striatum and changes in DA signaling (Haycock et al., 2003, Langenecker et al., 2007, Suhara et al., 1991, Troiano et al., 2010). There is

Conclusions

It has been thought that age-related changes in cortico-basal ganglia circuitry contribute to motor deficits among the elderly. However, changes in functional architecture accompanying advancing age have been incompletely characterized. The findings reported herein expand our understanding of these changes. Our novel finding that increased cortical–subcortical connectivity contributes to the decline of motor function provides the first evidence of how circuit functional architecture changes

Acknowledgments

This work was supported by a University of Utah Faculty Incentive Seed grant and a Department of Veterans Affairs Career Development Award (Marchand). Additional support was provided by the resources and the use of facilities at the VA Salt Lake City Health Care System.

References (78)

  • C. Hammond et al.

    Pathological synchronization in Parkinson's disease: networks, models and treatments

    Trends Neurosci.

    (2007)
  • T.L. Jernigan et al.

    Effects of age on tissues and regions of the cerebrum and cerebellum

    Neurobiol. Aging

    (2001)
  • S.A. Langenecker et al.

    An evaluation of distinct volumetric and functional MRI contributions toward understanding age and task performance: a study in the basal ganglia

    Brain Res.

    (2007)
  • J.N. Lee et al.

    Reliability of fMRI motor tasks in structures of the corticostriatal circuitry: implications for future studies and circuit function

    Neuroimage

    (2010)
  • W.R. Marchand et al.

    A functional MRI study of a paced motor activation task to evaluate frontal–subcortical circuit function in bipolar depression

    Psychiatry Res.

    (2007)
  • W.R. Marchand et al.

    A preliminary longitudinal fMRI study of frontal–subcortical circuits in bipolar disorder using a paced motor activation paradigm

    J. Affect. Disord.

    (2007)
  • W.R. Marchand et al.

    An fMRI motor activation paradigm demonstrates abnormalities of putamen activation in females with panic disorder

    J. Affect. Disord.

    (2009)
  • M. Naccarato et al.

    Does healthy aging affect the hemispheric activation balance during paced index-to-thumb opposition task? An fMRI study

    Neuroimage

    (2006)
  • R.C. Oldfield

    The assessment and analysis of handedness: the Edinburgh inventory

    Neuropsychologia

    (1971)
  • M. Ota et al.

    Age-related degeneration of corpus callosum measured with diffusion tensor imaging

    Neuroimage

    (2006)
  • W.D. Penny et al.

    Modelling functional integration: a comparison of structural equation and dynamic causal models

    Neuroimage

    (2004)
  • M.C. Petit-Taboue et al.

    Effects of healthy aging on the regional cerebral metabolic rate of glucose assessed with statistical parametric mapping

    Neuroimage

    (1998)
  • R.D. Seidler et al.

    Motor control and aging: links to age-related brain structural, functional, and biochemical effects

    Neurosci. Biobehav. Rev.

    (2010)
  • T. Taniwaki et al.

    Functional network of the basal ganglia and cerebellar motor loops in vivo: different activation patterns between self-initiated and externally triggered movements

    Neuroimage

    (2006)
  • T. Taniwaki et al.

    Age-related alterations of the functional interactions within the basal ganglia and cerebellar motor loops in vivo

    Neuroimage

    (2007)
  • M. Ystad et al.

    Subcortical functional connectivity and verbal episodic memory in healthy elderly—a resting state fMRI study

    Neuroimage

    (2010)
  • K.K. Zakzanis et al.

    An fMRI study of the Trail Making Test

    Neuropsychologia

    (2005)
  • Z. Zhang et al.

    Pharmacological MRI mapping of age-associated changes in basal ganglia circuitry of awake rhesus monkeys

    Neuroimage

    (2001)
  • G.E. Alexander et al.

    Parallel organization of functionally segregated circuits linking basal ganglia and cortex

    Annu. Rev. Neurosci.

    (1986)
  • K. Arbuthnott et al.

    Trail making test, part B as a measure of executive control: validation using a set-switching paradigm

    J. Clin. Exp. Neuropsychol.

    (2000)
  • M. Banich

    Cognitive Neuroscience and Neuropsychology

    (2004)
  • K.A. Barnes et al.

    Identifying basal ganglia divisions in individuals using resting-state functional connectivity MRI

    Front. Syst. Neurosci.

    (2010)
  • C. Calautti et al.

    Effects of age on brain activation during auditory-cued thumb-to-index opposition: a positron emission tomography study

    Stroke

    (2001)
  • R. Cham et al.

    Striatal dopaminergic denervation and gait in healthy adults

    Exp. Brain Res.

    (2008)
  • D.F. Chen et al.

    Comparison of neural activity in the supplementary motor area and in the primary motor cortex in monkeys

    Somatosens. Mot. Res.

    (1991)
  • T.P. Corporation

    Wechsler Test of Adult Reading: Manual

    (2001)
  • A. Eastvold et al.

    Test–retest reliability of an electronic alternative to the Trail Making Test

    Arch. Clin. Neuropsychol.

    (2004)
  • K.J. Friston et al.

    Assessing the significance of focal activation using their spatial extent

    Hum. Brain Mapp.

    (1993)
  • Y. Ge et al.

    Age-related total gray matter and white matter changes in normal adult brain. Part II: quantitative magnetization transfer ratio histogram analysis

    AJNR Am. J. Neuroradiol.

    (2002)
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