NeuroImage: Clinical 18 (2018) 443–455

Contents lists available at ScienceDirect

NeuroImage: Clinical
journal homepage: www.elsevier.com/locate/ynicl

Network connectivity of motor control in the ageing brain T

a,b a,c d,e f d,e a,d
Michely J. , Volz L.J. , Hoffstaedter F. , Tittgemeyer M. , Eickhoff S.B. , Fink G.R. ,
⁎
Grefkes C.a,d,
a
Department of Neurology, University Hospital Cologne, 50937 Cologne, Germany
b
Wellcome Trust Centre for Neuroimaging, University College London, London WC1N 3BG, United Kingdom
c
Department of Psychological and Brain Sciences and UCSB Brain Imaging Center, University of California, 93106 Santa Barbara, USA
d
Institute of Neuroscience and Medicine (INM-1, INM-3), Research Centre Jülich, 52428 Jülich, Germany
e
Institute for Systems Neuroscience, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
f
Max Planck Institute for Metabolism Research, 50931 Cologne, Germany

A R T I C L E I N F O A B S T R A C T

Keywords: Older individuals typically display stronger regional brain activity than younger subjects during motor perfor-
fMRI mance. However, knowledge regarding age-related changes of motor network interactions between brain regions
Ageing remains scarce. We here investigated the impact of ageing on the interaction of cortical areas during movement
Motor control selection and initiation using dynamic causal modelling (DCM). We found that age-related psychomotor slowing
Effective connectivity
was accompanied by increases in both regional activity and effective connectivity, especially for ‘core’ motor
coupling targeting primary motor cortex (M1). Interestingly, younger participants within the older group
showed strongest connectivity targeting M1, which steadily decreased with advancing age. Conversely, pre-
frontal influences on the motor system increased with advancing age, and were inversely correlated with re-
duced parietal influences and core motor coupling. Interestingly, higher net coupling within the prefrontal-
premotor-M1 axis predicted faster psychomotor speed in ageing. Hence, as opposed to a uniform age-related
decline, our findings are compatible with the idea of different age-related compensatory mechanisms, with an
important role of the prefrontal cortex compensating for reduced coupling within the core motor network.

1. Introduction stronger recruitment of brain activity is beneficial for motor perfor-

mance in ageing (Mattay et al., 2002; Naccarato et al., 2006; Wu and
Ageing is associated with decline of various cognitive functions Hallett, 2005). However, from a systems-level perspective, enhanced
(Grady, 2012). Moreover, older people often display deterioration of regional activity could as well depict a compensatory mechanism to
motor performance such as psychomotor slowing or reduced fine motor account for age-related reduction in network connectivity, similar to
skills (Salthouse, 2000; Seidler et al., 2010). One important factor what has been observed in neurodegenerative diseases such as Par-
contributing to age-related performance decline is neurodegeneration kinson's disease or in stroke (Grefkes et al., 2008; Rowe et al., 2002).
as represented by, e.g., grey matter atrophy (Draganski et al., 2013). Here, studies of resting-state functional connectivity revealed that re-
However, functional neuroimaging studies revealed substantial evi- duced motor performance in older individuals is associated with both
dence for adaptive plasticity paralleling structural decline. increased and diminished interregional coupling within the motor
Typically, older subjects display both enhanced and more wide- network (Langan et al., 2010; Seidler et al., 2015; Solesio-Jofre et al.,
spread brain activation than their younger counterparts during motor 2014). However, resting-state analyses do not allow direct conclusions
performance (Mattay et al., 2002; Rowe et al., 2006). Notwithstanding, about how brain areas interact during a given task, thereby limiting
the exact functional role of increased regional brain activity for motor insights into the relationship between network changes underlying a
control in older individuals remains poorly understood. On the one specific behaviour and age-related performance decline (Rehme et al.,
hand, non-selective recruitment of brain activity could reflect a loss of 2013; Sala-Llonch et al., 2015). Nevertheless, the wealth of studies
neural specificity or efficiency in the ageing brain, i.e., dedifferentiation demonstrating age-related motor deficits is contrasted by the dearth of
(Li and Lindenberger, 1999; Logan et al., 2002; Riecker et al., 2006). On studies that addressed the question of how brain areas interact in the
the other hand, numerous studies point to a compensatory role in that ageing brain during motor performance. The evidence thus far available

⁎
Corresponding author at: Department of Neurology, University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
E-mail address: [email protected] (C. Grefkes).

https://doi.org/10.1016/j.nicl.2018.02.001
Received 9 October 2017; Received in revised form 19 January 2018; Accepted 1 February 2018
Available online 03 February 2018
2213-1582/ © 2018 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
J. Michely et al. NeuroImage: Clinical 18 (2018) 443–455

from task-based studies suggests that interregional connectivity is en- range 52–74). The underlying rationale for the inclusion of subjects
hanced in older as compared to young subjects, especially coupling with this particular age range was two-fold: First, we wanted to assess
among ‘core’ motor regions like premotor cortex and primary motor general ageing effects by comparing two distinct age groups, i.e., young
cortex (M1) (Boudrias et al., 2012; Heitger et al., 2013; Rowe et al., and older subjects. Second, we aimed to characterize how changes in
2006). Furthermore, interindividual variability in premotor-M1 cou- neural coupling relate to progressive structural atrophy and beha-
pling has been shown to predict motor performance in older individuals vioural performance in advancing age, i.e., within our older subgroup
(Stewart et al., 2014). between 52 and 74 years of age.
Nevertheless, motor actions do not only depend on such core motor All participants underwent a comprehensive clinical interview to
regions, but also on activity in anterior/prefrontal and posterior/par- exclude a history of any neurological or psychiatric disease or other
ietal brain regions, i.e., areas which typically show increased activity in chronic disabling medical problem. According to the Edinburg hand-
older subjects even in simple motor tasks (Heuninckx et al., 2005, 2008; edness inventory (Oldfield, 1971), all subjects were right-handed (mean
Mattay et al., 2002). Particularly enhanced prefrontal activity has 81.0 ± 20.2). In order to exclude cognitive deficits in older partici-
consistently been shown in older subjects during motor performance pants, subjects were additionally tested by the means of a compre-
(Heuninckx et al., 2005, 2008; Wu and Hallett, 2005). This is at first hensive cognitive test battery, assessing executive functions, working
sight at odds with the frontal lobe hypothesis stating that age-related memory, attention, and visuospatial functions, i.e., the Parkinson
behavioural deficits are primarily due to the structural and functional Neuropsychometric Dementia Assessment (Kalbe et al., 2008). Im-
deterioration of frontal parts of the ageing brain (Moscovitch and portantly, all subjects scored well above the cut-off score for cognitive
Winocur, 1992; West, 1996). Yet paradoxically, multiple neuroimaging impairment, hence, there was no indication of cognitive impairment in
studies have linked increased activity in anterior brain regions asso- our older participants (mean score 25.6 ± 3.7, range 20–30, cut-off
ciated with higher-order cognitive demands to better behavioural per- score < 18). FMRI data of the older subjects was previously used as
formance in ageing individuals across multiple cognitive domains healthy control data in a study on Parkinson's disease (Michely et al.,
(Cabeza et al., 2002; Grady et al., 2005; Reuter-Lorenz et al., 2000). 2015). However, all analyses, models and results in the present study
Intriguingly, this enhancement of top-down modulation seems to are new, hence, there is no overlap with previously presented results.
compensate for dysfunctional sensory-driven bottom-up processing in The study was in accordance with the Declaration of Helsinki and ap-
posterior brain regions of ageing individuals, a phenomenon termed the proved by the local ethics committee.
‘Posterior to Anterior Shift in Ageing’ (PASA; Davis et al., 2008).
To date, it remains, however, to be elucidated how the PASA theory 2.2. FMRI paradigm
relates to motor network connectivity, i.e., how anterior and posterior
brain regions change their influence on the core motor system. It is The experimental paradigm (Fig. 1) was equivalent to our previous
currently poorly understood how the balance between top-down in- studies on motor control in healthy subjects (Hoffstaedter et al., 2013),
fluences from regions anterior to and bottom-up influences from re- patients suffering from Parkinson's disease (Michely et al., 2012, 2015)
gions posterior to core motor regions affects motor performance in and major depression (Hoffstaedter et al., 2012). The task comprised
ageing individuals. To address this question, we assessed effective three conditions and an imbedded functional localizer. Subjects re-
connectivity in an extended cortical motor network underlying psy- sponded via button presses on a MRI compatible response device using
chomotor processes in young and older subjects using functional mag- the right or left index finger. Visual stimuli were generated using the
netic resonance imaging (fMRI) and dynamic causal modelling (DCM; ‘Presentation’ software package (Version 10.3, Neurobehavioral Sys-
Friston et al., 2003). We used a reaction paradigm that enabled us to tems Inc., Albany, CA). Each condition was presented in blocks of 20 s
study the neural mechanisms of both basic motor aspects such as duration separated by resting baselines of 16 s during which subjects
movement initiation as well as higher-order movement preparation, watched a blank screen. Each block was introduced by a one-word in-
selection and visuomotor integration within the same experimental struction presented for 2.5 s, informing the subject about which of the
setting (Hoffstaedter et al., 2013; Michely et al., 2015). Moreover, such four conditions followed next.
psychomotor processes, that are typically slowed in ageing individuals,
strongly rely on the integrity of neural coupling between both top-down 2.2.1. Condition ‘Free’: self-timed movement selection
modulation from anterior/prefrontal and bottom-up modulation from In the ‘Free’- condition, subjects were instructed to press either the
posterior/parietal brain regions onto the core motor system (Berchicci left or right button at any self-chosen time. Hence, subjects were free in
et al., 2012; Stewart et al., 2014; Vallesi et al., 2011). We expected that terms of both movement lateralization and timing. Every response was
ageing is associated not only with changes in interregional coupling followed by an immediate visual feedback consisting of an arrow
within the core motor network, but also with differences in the influ- pointing to the side of the button-press (duration: 400 ms; Fig. 1). By
ence that prefrontal and parietal areas exert onto (pre)motor regions. In providing a feedback arrow, we kept this condition comparable to the
line with the PASA theory, we hypothesized that age-related reduction reactive ones in terms of visual input and display delays. Moreover,
in bottom-up modulation from posterior/parietal regions might be during feedback, no further response was allowed to prevent repetitive
compensated by increasing top-down modulation from anterior/pre- finger tapping. Since subjects were not allowed to press any button
frontal regions onto the core motor system. Finally, in order to address whilst the feedback arrow was presented, response times in the ‘Free’-
this compensation theory, we tested whether age-related coupling condition reflect the interval between the end of the presentation of the
changes related to the PASA theory are linked to behavioural para- feedback arrow and the next self-initiated button press. Subjects were
meters of psychomotor speed in ageing individuals. instructed to roughly balance between left and right button presses, and
to avoid extensive periods of rest between button presses.
2. Materials and methods
2.2.2. Condition ‘Intern’: reaction to a non-informative cue
2.1. Subjects Subjects were asked to respond to a double-headed arrow, i.e., non-
informative cue (displayed for 400 ms; Fig. 1) with a button press of
Twenty-four healthy male subjects participated in the study after either their left or right index finger. Since subjects were prompted to
providing informed written consent (12 younger subjects, mean age press the right or left button as fast as possible, they were restricted
27.4 ± 4.2, range 21–35; 12 older subjects, mean age 62.1 ± 6.3, with regard to the timing of movement execution, but free in terms of

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Fig. 1. FMRI paradigm.

Each block of trials started with the presentation of a fixation cross. ‘Free’- condition: Upon appearance of the fixation cross, subjects were instructed to press the left or right button with
the respective index finger at any self-chosen time. Every response was followed by a visual feedback pointing to the side of the button-press. Thereafter, the fixation cross re-appeared
until the next response was given by the subject. Thus, subjects were free in terms of both movement lateralization and timing. ‘Intern’- condition: Subjects were instructed to react as fast
as possible and press the left or right button upon appearance of a double-headed arrow pointing to both sides. Hence, subjects were restricted with re. to the timing of movement
initiation but free in terms of movement lateralization. The fixation cross re-appeared for the time between stimuli. ‘Extern’- condition: Subjects were instructed to react as fast as possible
and press the left button upon appearance of an arrow pointing to the left or the right button upon appearance of an arrow pointing to the right. Thus, subjects were restricted with re. to
both timing and movement lateralization.

movement lateralization. Twelve to 14 stimuli were presented per block order was pseudorandomized yet equal for all subjects to account for
with varying stimulus onset asynchrony (ranging from 800 to 2600 ms), ordering effects and to maintain comparability.
thereby minimizing anticipation of the cue. As in the ‘Free’- condition,
subjects were instructed to roughly balance between left- and right- 2.3. Statistical analysis of behavioural data
sided responses.
In the RT conditions, i.e., ‘Intern’ and ‘Extern’, we first eliminated
2.2.3. Condition ‘Extern’: reaction to an informative cue outliers which were unlikely to represent physiologically interpretable
In the ‘Extern’-condition, subjects were instructed to respond as fast reactions to the visual stimuli: RTs longer than 1000 ms and shorter
as possible to a single-headed arrow (displayed for 400 ms; Fig. 1), than 150 ms were regarded as random or anticipatory responses.
pointing either to the left or right side. Hence, movements were purely Furthermore, for each subject, all RTs exceeding the individual mean
reactive, and thus restricted with regard to both timing and later- RT by more than three standard deviations were excluded from further
alization. As in the ‘Intern’- condition, 12–14 cues with varying sti- analysis. Together, these steps removed 1.5% ± 0.7 in young and
mulus onset asynchrony were presented per block. 1.4% ± 1.0 of the data in older participants with no between-group
differences (p = 0.728). Moreover, we defined error responses when
2.2.4. Condition ‘Tapping’: repetitive finger tapping (functional localizer) subjects pressed more than one, the wrong, or no button. The percen-
In the ‘Tapping’- condition, subjects were asked to perform vertical tage error rate, i.e., the ratio between error responses and presented
tapping movements at maximum speed using the right or left index stimuli was calculated as a measure of task accuracy. Subsequently, we
finger. A white arrow presented in the centre of a black screen pointed computed the mean individual RT for all subjects for the ‘Extern’ and
to the left or right and thereby indicated which finger to use. This cue ‘Intern’ condition as a measure of psychomotor speed. Independent two-
was presented throughout the entire tapping period. As in earlier stu- sample t-tests were used to compare performance differences between
dies (Michely et al., 2015; Wang et al., 2011), we used short finger young and older subjects regarding error rates and psychomotor speed.
tapping periods of 3 s followed by a 2.5 s break instead of continuous
tapping throughout the entire 20 s block in order to prevent fatigue. In 2.4. FMRI image acquisition and preprocessing
each block, four tapping periods had to be performed with fingers ba-
lanced, i.e., two right, two left. Functional MR images were acquired using a Siemens Trio 3 T
The ‘Tapping’- condition served as functional localizer to identify scanner (Siemens Medical Solutions) We employed a gradient echo
‘core’ (pre)motor areas for the connectivity analyses at the single sub- planar imaging (EPI) sequence with the following blood oxygenation
ject level. The other three conditions probed different aspects of higher level-dependent (BOLD) imaging parameters: repetition time
motor control such as movement preparation, selection and initiation. (TR) = 2200 ms, echo time (TE) = 30 ms, field of view
In contrast to the ‘Free’-condition where subjects were not reacting to (FOV) = 200 mm, 33 axial slices, slice thickness = 3.1 mm, voxel
any external cue, conditions ‘Extern’ and ‘Intern’ constituted externally size = 3.1 mm isotropic, flip angle = 90°, distance factor = 20%. The
and internally triggered choice reaction time (RT) tasks (Jahanshahi slices covered the whole brain from the vertex to lower parts of the
et al., 1992). Prior to scanning, subjects were trained outside and inside cerebellum. Each fMRI time series consisted of 574 images preceded by
the scanner to warrant stable task performance. A single fMRI run four dummy images allowing tissue magnetization to reach a steady
lasted 21 min including 8 repetitions of each condition. The four con- state. In addition, high-resolution T1-weighted structural images
ditions were presented consecutively in blocks, within these blocks the were acquired (MPRAGE-sequence, TR = 2250 ms, TE = 3.93 ms,

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FOV = 256 mm, 176 sagittal slices, voxel size = 1.0 mm3, flip matrix represents the direct experimental input to the system that
angle = 9°). FMRI data were analyzed using Statistical Parametric drives regional activity. Note that DCM models also accounted for
Mapping (SPM8; Wellcome Trust Centre for Neuroimaging, London, temporal differences in image acquisition, i.e., slice-timing.
UK, http://www.fil.ion.ucl.ac.uk). After discarding the dummy images, For our connectivity models, regions were selected based on dif-
the EPI volumes were realigned to the mean image of each time series. ferent criteria. Besides generating a model that is biologically plausible,
The structural T1-weighted image was co-registered to the mean EPI we selected brain regions that were significantly activated by all tasks
image. Spatial normalization of all images into the space of the whilst also considering between-group differences in in brain activation
Montreal Neurological Institute (MNI) was achieved via the unified (cf. Fig. 2). Moreover, the selected regions are known to be crucially
segmentation approach using the individual mean EPI image involved in movement selection and initiation as well as visuomotor
(Ashburner and Friston, 2005). After spatial normalization, the voxel transformation processes. Note that the number of ROIs for DCM is
size was resampled to 1.5 mm3. Finally, data were smoothed using an limited to prevent dramatic increase of the number of free parameters
isotropic Gaussian kernel of 8-mm full-width at half-maximum to sup- requiring more stringent shrinkage priors to ensure system stability,
press noise and effects due to residual interindividual differences in and hence result in a reduction of the conditional precision for any of
functional and gyral anatomy. the estimated parameters. We tried to overcome this issue by focusing
our analysis on an extended cortical motor system in accordance with
2.5. FMRI statistical analysis the network suggested by the GLM group analysis yielding strongest
activity at the cortical level. Dorsal premotor cortex (PMC), supple-
Statistical analysis was performed within the framework of the mentary motor area (SMA) and primary motor cortex (M1) feature core
general linear model. The four experimental conditions and the in- regions of the motor system and were hence included in the con-
structions were separately modelled using boxcar stimulus functions nectivity models (Boudrias et al., 2012; Grefkes et al., 2008). Further-
convolved with a canonical hemodynamic response function. The time more, the intraparietal sulcus (IPS) as part of the dorsal visual stream is
series in each voxel were high-pass filtered at 1/128 Hz. The six head an important region for the integration of visuospatial information into
motion parameters, as assessed by the realignment algorithm, were motor plans, i.e., ‘bottom-up’ processes (Cieslik et al., 2011; Grefkes
treated as covariates to remove movement-related variance from the et al., 2004; Rushworth et al., 2003) and was therefore included into
image time series. We computed a full factorial ANOVA second level the models. Moreover, a prefrontal region was included in the con-
analysis. Main effects for each condition were computed by contrasting nectivity matrix. Specifically the prefrontal ROI represents the dorso-
task-related activity (‘Free’/‘Intern’/‘Extern’; ‘Tapping’ as functional lateral prefrontal cortex, given its crucial role in executive control over
localizer) with the resting baselines for each subject. Moreover, we motor output and movement preparation, i.e., in ‘top-down’ processes
compared contrasts for all three higher motor control conditions be- (Nishitani and Hari, 2000; Rowe et al., 2010) and the strong activation
tween young and older subjects. of the dorsolateral prefrontal cortex in our task (see Fig. 2). For sim-
plification, we use the abbreviation PFC for this region throughout the
2.6. Dynamic causal modelling manuscript. We extracted the first eigenvariate of the effects-of-interest
adjusted time series for all nodes using 4-mm radius spheres centred on
Deterministic, bilinear DCM as implemented in SPM8 models the subject-specific individual activation maxima (p < 0.05) in the
changes in neuronal states over time as respective region based on functional and anatomical criteria. The
group maximum MNI coordinate was set as origin to search for the
m
dx ⎛ ⎞ closest local maximum in the individual SPM maps. The mean number
dt
= A+
⎜ ∑ uj B (j) ⎟ x + Cu of voxels per ROI was 78.9 ± 6.8 across all subjects. The anatomical
⎝ j=1 ⎠
landmarks used for region identification and coordinates of all ROIs are
where x is the state vector, A represents the endogenous (intrinsic) provided in the Supplementary data.
connectivity, B(j) represents the modulatory influence of the experi- The model space used for DCM constitutes a set of network hy-
mental manipulation u(j) onto the endogenous connections among the potheses that are considered plausible explanations for the observed
network nodes, and C denotes the influence of direct inputs to the regional responses. For each model, we assumed a network based on
system. Deterministic DCM requires the definition of an external known anatomical connectivity among the ROIs as derived from in-
driving input that modulates activity of a given area (DCM-C matrix) vasive tract-tracing studies in primates. Firstly, we constructed two
and propagates within the entire system. In the DCM formula, the different sets (families) of models. For our first set of models (Family 1),
driving input is represented by ‘u’ (which is either 0 at baseline or 1 for we constructed an endogenous connectivity matrix (DCM-A) between
the presence of a given condition). Note that due to the block design of IPS/PFC and premotor regions (Bates and Goldman-Rakic, 1993;
the present study, the input function u is not locked to single events but Cavada and Goldman-Rakic, 1989; Lu et al., 1994; Miyachi et al., 2005;
covers visual cues, motor responses and also the cognitive state induced Tanji and Hoshi, 2008) as well as premotor regions (PMC/SMA) and M1
by the instruction of a current condition during the blocks. It is im- (Rouiller et al., 1994). Moreover, we assumed interhemispheric trans-
portant to note that the definition of the DCM-A coupling values have callosal connections between homologous regions (Leichnetz, 1986;
changed across different DCM versions. As used here in DCM within Marconi et al., 2003; McGuire et al., 1991; Padberg et al., 2005;
SPM8, endogenous connectivity (DCM-A) is always present during the Rouiller et al., 1994). The second set (Family 2) was similarly con-
experiment and reflects the context-independent (i.e., constant) com- structed, yet with the difference that we omitted endogenous con-
ponent of interregional coupling across the entire experimental setting. nectivity between PFC and premotor regions, but instead assumed
Hence, it is not equivalent to the resting-conditions only but also con- connectivity between PFC and IPS. Hence, in this family, only IPS was
siders coupling values that were consistent during the movement con- assumed to directly modulate activity in premotor regions, whilst ac-
ditions (see also Rehme et al., 2013). The context-dependent modula- tivity in PFC merely modulated premotor regions indirectly via IPS.
tions are represented in DCM-B and reflect changes in interregional Note, however, that although we constructed our network on anato-
coupling evoked by a particular higher motor control condition asses- mical plausible connections as informed by primate studies, con-
sing psychomotor speed (‘Free’/‘Intern’/‘Extern’). The tapping condi- nectivity parameters in DCM do to necessarily reflect monosynaptic
tion was not included into the DCM analysis as this condition served as anatomical connections but rather the net effect a region exerts on
independent functional localizer for (pre)motor regions. The DCM-C activity of other regions. This can theoretically be transmitted via direct

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anatomical connections, a single relay region or more complex network connections displaying significant differences between young and older
loops. Moreover, condition-specific modulations of interregional cou- subjects, and for coupling parameters showing significant correlations
pling may not necessarily affect all intrinsic anatomical connections. with advancing age, connectivity analyses were repeated including in-
We, therefore, constructed several alternative models (similar for both dividual grey matter parameters of the particular two ROIs for a con-
families) with varying complexity representing plausible hypotheses on nection as covariates of no interest.
interregional coupling (Supplementary data). First, we omitted inter-
hemispheric coupling between homologous areas for both families 2.9. Regional BOLD activity
(A–E). Moreover, for family 1, we removed modulatory effects between
PFC and premotor areas (F), and modulatory effects between PFC and The main focus of this study was to assess age-related network ef-
IPS (F), for family 2 respectively. Moreover, for both families, we re- fects. However, in addition to our whole-brain BOLD analysis, we also
moved modulatory effects between IPS and premotor areas (G). As al- assessed regional differences in brain activity for the 9 regions used for
ternative, we excluded modulatory effects of premotor areas onto M1 the DCM analysis using the MarsBar toolbox (Brett et al., 2002). Similar
(H). Finally, modulatory effects of task conditions were allowed to to our connectivity analysis, we used grey matter parameters to control
modulate all intrinsic connections (I) for both families. Next, we used for the effect of structural atrophy.
random-effects Bayesian model selection first to compare model evi-
dence between the two families, and then to determine the model 3. Results
providing the best trade-off between accuracy and generalizability/
complexity (Penny et al., 2004; Stephan et al., 2009). Following earlier 3.1. Behavioural data
DCM studies, we assumed that activity across conditions was driven and
propagated to other regions by the PFC and IPS due to their roles in There were strong between-group differences with respect to RT in
‘top-down’ and ‘bottom-up’ control over motor output and core motor both internally and externally cued responses, with a significant
network activity (DCM-C; Cieslik et al., 2011; Grefkes et al., 2010; slowing of psychomotor speed in older compared to young subjects
Rowe et al., 2010; Wang et al., 2010). (‘Extern’: young 309.1 ms ± 21.2, old 353.9 ms ± 36.3, p = 0.001;
‘Intern’: young 243.7 ms ± 17.5, old 281.2 ± 37.7, p = 0.005). In
2.7. Statistical analysis of connectivity data contrast, performance accuracy as assessed by error rates was only
marginally different between groups in the reaction conditions
To test for general effects of ageing on neural coupling, i.e., differ- (‘Extern’: young 6.4% ± 3.2, old 9.8% ± 6.2, p = 0.109; ‘Intern’:
ences between young and older subjects, coupling estimates of all young 1.8% ± 1.4, old 3.8% ± 3.2, p = 0.059). Notably, there was no
connections were compared using independent two-sample t-tests, se- correlation between psychomotor speed (RTs) and accuracy (error
parately for endogenous connections (DCM-A) and condition-specific rates) in older participants (‘Extern’: r = −0.381, p = 0.222; ‘Intern’:
coupling for the three task conditions (DCM-B for ‘Free’/‘Intern’/ r = −0.279, p = 0.381). Moreover, there was no correlation with
‘Extern’). Due to the significant age gape between groups and the scores from the cognitive test battery and RTs in the older group
missing “middle-aged” subjects in our sample, we did not compute (Extern: r = 0.134, p = 0.678; Extern: r = 0.044, p = 0.892). In the
linear correlation with age across the entire sample. However, to in- ‘Free’ condition, subjects on average pressed a button 15.4 times per
vestigate the effects of advancing age on neural coupling and to further block, i.e., participants performed a slightly higher number of executed
differentiate whether putative group differences were further in- movements as in the reaction conditions in which they were forced by
creasing or diminishing with older age, we additionally computed the cues to perform on average 13 button presses per block.
Pearson's correlations between age and coupling strength for all con- Importantly, the two groups showed a comparable timing with re. to
nections in the older group only. The false discovery rate (FDR, initiating a button press in the ‘Free’ condition (young 858.3 ms ±
Benjamini and Hochberg, 1995) approach was used to correct for 262.0, old 956.3 ms ± 269.2, p = 0.376). Hence, there was no sig-
multiple comparisons, both for group comparisons and correlation nificant between-group difference for the number of self-initiated motor
analyses. responses. Moreover, there was no significant between-group difference
for the distribution of right- and left-handed responses in the conditions
2.8. Confound removal: structural atrophy with self-chosen response lateralization, i.e., ‘Free’ and ‘Intern’ (pro-
portion of right-handed responses out of all responses: ‘Free’: young
As also healthy ageing is associated with regional grey matter 0.514 ± 0.025, old 0.523 ± 0.046, p = 0.545; ‘Intern’: young
atrophy, which in turn may contribute to changes in effective con- 0.520 ± 0.045, old 0.510 ± 0.065, p = 0.644).
nectivity, we performed additional analyses of age-related structural
changes using voxel-based morphometry (VBM). The structural ana- 3.2. Structural atrophy
lyses were conducted using the VBM8 toolbox (dbm.neuro.uni-jena.de/
vbm.html) within SPM8 with standard settings for bias-field correction, Older subjects displayed a significant reduction of total grey matter
segmentation of grey matter, white matter and cortico-spinal fluid, volume, adjusted for individual intracranial volume, compared to
partial volume effect adjustment and spatial normalization into MNI- young subjects (young 50.8% ± 1.3, old 46.5% ± 1.8, p < 0.001).
space within a unified segmentation model (Ashburner and Friston, Additionally, within the group of older subjects, i.e., between 52 and
2005). The segmented images were non-linearly modulated for nor- 74 years in our sample, grey matter volume displayed a significant
malization to the group mean template. The resulting voxel-wise negative correlation with advancing age (r = −0.79, p = 0.002).
amount of expansion or contraction was used to estimate grey matter Hence, as expected, grey matter volume was significantly reduced in
volume for all ROIs as identified from the functional analysis in all older as compared to young subjects.
subjects. Thereby, regionally specified grey matter volume was cor-
rected for individual brain size as it represents the non-linear modula- 3.3. BOLD activation pattern
tion of the grey matter of each individual brain in relation to the group
template. The structural parameters obtained with VBM were subse- Fig. 2 depicts the neural activation pattern evoked by the three
quently used to control for the influence of atrophy on age-related motor control conditions. All regions included in the connectivity
functional changes as observed in our connectivity analysis. Hence, for model were significantly activated by all three conditions of interest

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Fig. 2. BOLD activation pattern and between-group activity differences.

(I) Conjunction analysis of the neural networks activated by all three higher motor control conditions (‘Free’/‘Intern’/‘Extern’) across all subjects, i.e., n = 24. ROIs used for DCM analysis
are highlighted. PFC = prefrontal cortex, PMC = premotor cortex, SMA = supplementary motor area, M1 = primary motor cortex, IPS = intraparietal sulcus. (II) Activity for young
(n = 12) and old (n = 12) subjects for each condition separately. (III) Between-group activity differences. Significantly enhanced BOLD activity in old as compared to young individuals
for each condition separately. All p < 0.05, family-wise error (FWE) corrected at the cluster level.

across the entire sample of subjects. Note that differences in brain ac- modulate premotor regions (Family 2). Moreover, the model selection
tivity at the subcortical level between young and older individuals were showed that out of all models tested model ‘I’ was the most likely one
most pronounced in the thalamus, especially for the ‘Extern’ condition, given the data. This was true when testing across all 24 subjects as well
which strongly relies on sensory input. In contrast, between-group as when testing for each group separately, i.e., young and older subjects
differences were considerably weaker -if not absent- in the basal ganglia (Supplementary data). The winning model assumed modulatory effects
(Supplementary data). At the cortical level, older participants displayed from both PFC and IPS onto premotor regions as well as interhemi-
widespread enhancement of activity (Fig. 2). Here, the BOLD analysis spheric connectivity between homologous areas.
confirmed findings from earlier studies showing that older subjects
feature enhanced activity not only in core motor regions but also in 3.5. Endogenous connectivity (DCM-A)
parietal and prefrontal cortex. As expected from the results of the
whole-brain analyses, there were strong increases in BOLD activity for We first analyzed interregional coupling that was constant across all
our regions of interest in older subjects for all three conditions three tasks of interest, i.e., ‘Intern’, ‘Extern’ and ‘Free’. Here, older
(p < 0.05, corrected, Supplementary data). Notably, differences in subjects showed significantly stronger coupling for several connections
regional BOLD activity for our regions of interest persisted when cor- compared to young subjects (all p < 0.05, corrected, Fig. 3). Excitatory
recting for grey matter atrophy in the respective regions. Moreover, influences from PMC and SMA targeting M1 were significantly en-
there was a positive correlation with advancing age for right prefrontal hanced in the older group in both hemispheres. Moreover, we found
cortex activation in the ‘Extern’ condition (p < 0.05, corrected; increases in interhemispheric coupling between both homologous PMC
r = 0.777). However this prefrontal overactivation did not correlate and M1. Thus, especially coupling between core motor regions was
with behavioural performance in older participants. Therefore, the key significantly enhanced in the older group. In addition, there was a
question of the present study was to investigate whether and to what stronger excitatory influence exerted by right-hemispheric PFC upon
degree changes in activity found within this extended cortical motor PMC in older subjects. When using the individual GM parameters of the
network can be explained by changes in network connectivity using particular ROIs as covariates to control for putative effects of regional
DCM. atrophy on effective connectivity, all previously reported differences
between groups remained significant.
3.4. Bayesian model selection We next tested whether coupling strengths correlated with higher
age in the group of older subjects. That is, whether connectivity in the
Firstly, the random-effects Bayesian model selection revealed that extended motor network of interest further changes with advancing
the set of models involving connections from both PFC and IPS onto age, i.e., between 52 and 74 in our subjects sample. Interestingly, only
premotor regions (Family 1) clearly outperformed the set of models right-hemispheric connections (PFC-PMC, IPS-PMC, SMA-M1, PMC-
involving connections between PFC and IPS but only assuming IPS to M1) and interhemispheric connectivity between homologous regions

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Fig. 3. Between-group connectivity differences.

Green arrows indicate significantly enhanced endogenous
connectivity (DCM-A) between two regions in old as com-
pared to young individuals. Note that all differences be-
tween groups remained significant when controlling for
structural atrophy as informed by the VBM analysis.
PFC = prefrontal cortex, PMC = premotor cortex,
SMA = supplementary motor area, M1 = primary motor
cortex, IPS = intraparietal sulcus. R = right-hemispheric,
L = left-hemispheric. p < 0.05, FDR-corrected for multiple
comparisons. Bars represent coupling strength in 1/s. Error
bars: SEM.

from the left targeting the right hemisphere (M1, PFC) showed a re- other connections displaying a relationship with advancing age in older
lationship with advancing age (all p < 0.05, corrected). Except for subjects (as informed by the results shown in Fig. 4). Indeed, consistent
interhemispheric PFC coupling, correlations with age persisted when with our hypothesis, we found a significant negative correlation be-
correcting for grey matter atrophy in the respective regions (p < 0.05, tween prefrontal-premotor connectivity and parietal-premotor and
range of r = 0.66–0.89). Hence, age-related changes in connectivity premotor-M1 coupling (all p < 0.05, corrected, Fig. 5). Hence, older
occurred independent of the degree of structural atrophy. Accordingly, subjects featuring the lowest parietal-premotor-M1 coupling showed
we identified three patterns of differential connectivity changes (Fig. 4): the strongest increase in prefrontal-premotor connectivity. Thus, pre-
First, parietal-premotor connectivity showed no group difference, yet a frontal influences on the motor system increase as parietal influences
negative correlation with age in older subjects. Second, connectivity and coupling within the core motor system decreases with advancing
targeting M1 was increased in older subjects at the group level, but age.
featured a negative correlation with advancing age in the group of older
subjects. Hence, group difference seemed to be driven by younger 3.7. Association between prefrontal coupling and performance
subjects within the older group. As this connectivity pattern was com-
patible with an inverted U-shaped association with age, we specifically In the next step, we tested whether age-related connectivity changes
tested this relationship. Indeed, for all three tested connections, there as informed by the previous analyses (cf. Fig. 4) were related to be-
was a significant, negative quadratic association between coupling havioural performance, i.e., psychomotor speed. However, there was no
parameters and age across the entire subject sample (PMC-M1: correlation with individual RT for the five connections tested, also
r = −0.68, p = 0.002; SMA-M1: r = −0.79, p ≤0.001; interhemi- when correcting for grey matter atrophy. Hence, there was no one-to-
spheric M1: r = −0.77, p < 0.001). Third, prefrontal-premotor cou- one mapping between RTs and single coupling parameters.
pling showed an increase in older as compared to young subjects at the However, in line with the PASA theory, we expected prefrontal
group level, and in addition featured a positive correlation with ad- coupling to be positively correlated with good performance. Moreover,
vancing age in the group of older subjects. Hence, in contrast to cou- as there were differential changes with advancing age, i.e., both in-
pling targeting M1 the group difference was driven by the older subjects creases and decreases of connectivity, we tested for a net effect of dif-
within the older group. ferent connections that showed the aforementioned changes with ad-
vancing age. Interestingly, we found a significant negative correlation
3.6. Association between prefrontal coupling and other connections between RTs in both the ‘Intern’ and ‘Extern’ condition and the sum of
PFC-PMC and SMA-M1 coupling (p < 0.05, corrected for multiple
In line with the PASA theory, we hypothesized that anterior/pre- comparisons and grey matter atrophy, Fig. 6). Hence, older subjects
frontal connectivity increases alongside age-related reduction of pos- with stronger positive coupling within the prefrontal-premotor-M1 axis,
terior/parietal connectivity and core motor connectivity. To specifically i.e., strong increase of PFC-PMC coupling accompanied by less pro-
address this hypothesis, we tested whether the aforementioned age- nounced decrease of SMA-M1 coupling, displayed faster RT, i.e., better
related increase in PFC-PMC coupling correlated with a decrease in the behavioural performance. Other combinations of connectivity did not

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Fig. 4. Network changes with advancing age.

Correlations between advancing age and coupling parameters (DCM-A) in old individuals. Coupling parameters of young subjects are indicated by grey diamonds and shown for
illustrative purposes to underline between-group differences for the respective connections. Coupling parameters for older subjects are indicated by red circles for connections displaying
a negative correlation with age, and by green circles for connections showing a positive correlation with age. Three different patterns of differential connectivity changes emerged: (I) IPS-
PMC: no group difference between young and old subjects, negative correlation with age in old subjects. (II) Coupling targeting M1: enhanced connectivity in older individuals at the
group level, negative correlation with age in old subjects. (III) PFC-PMC: enhanced connectivity in older individuals at the group level, positive correlation with age in older subjects. Note
that all correlations shown remained significant when controlling for structural atrophy as informed by the VBM analysis. PFC = prefrontal cortex, PMC = premotor cortex,
SMA = supplementary motor area, M1 = primary motor cortex, IPS = intraparietal sulcus. *p < 0.05, FDR-corrected for multiple comparisons; n.s. = not significant. Coupling strength
in 1/s.

correlate with behavioural measures. Importantly, there was no such subjects. In the ‘Free’ condition, older subjects displayed enhanced
relationship between connectivity and performance accuracy as in- coupling between PMC and M1 in both hemispheres, as well as stronger
dexed by error rates. interhemispheric connectivity from left M1 targeting right M1 (all
p < 0.05, corrected). No such effects were found for the ‘Extern’ and
3.8. Condition-specific connectivity (DCM-B) ‘Intern’ condition. In contrast to changes in endogenous connectivity,
there were no significant correlations with advancing age in the older
We next tested whether condition-specific connectivity (‘Intern’, group. Moreover, there were no significant correlations between cou-
‘Extern’, ‘Free’) showed differential effects between young and older pling parameters and behavioural measures.

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Fig. 5. Association between increased prefrontal coupling and decreased coupling in other parts of the network.
Negative correlations between individual PFC-PMC coupling and coupling parameters of other connections displaying a relationship with advancing age in older individuals (cf. Fig. 5).
Subjects featuring weaker parietal-premotor-M1 coupling with advancing age show the strongest increase in prefrontal-premotor connectivity. PFC = prefrontal cortex, PMC = premotor
cortex, SMA = supplementary motor area, M1 = primary motor cortex, IPS = intraparietal sulcus. *p < 0.05, FDR-corrected for multiple comparisons. Coupling strength in 1/s.

4. Discussion DCM-A; Rehme et al., 2013). The endogenous connectivity is, however,
specific for the setting of an fMRI experiment and is likely to reflect
We assessed age-related effects on grey matter volume as well as task-specific components (Friston et al., 2003). Hence, these results are
local brain activity and motor network connectivity underlying psy- indicative of global changes in the functional architecture of the ageing
chomotor processes. Behaviourally, older subjects showed significant motor network. The global nature of network changes was also re-
psychomotor slowing. However, despite pronounced structural atrophy, flected on the behavioural level: we observed behavioural slowing to
indicated by both between-group differences as well as correlations the same extent in both the ‘Extern’ and ‘Intern’ condition in older
with advancing age, older participants displayed increases in both re- participants. This conformity between behavioural and neural findings
gional activity and effective connectivity within an extended cortical supports the idea that ageing might result in a global change in the
motor network. Notably, ageing most prominently affected endogenous functional network architecture underlying psychomotor performance,
connectivity, yet not condition-specific connectivity. Importantly, en- irrespective of older subjects being internally or externally cued to se-
dogenous connectivity is not equivalent to the experimental baseline lect and initiate movement.
activity as it is estimated from the whole time-series. Indeed, we have Interestingly, we found hints for differential connectivity changes at
recently shown that resting-state functional connectivity fMRI para- different stages of the ageing process. Specifically, younger participants
meters correlated only weakly with activity-dependent connectivity within the older group showed highest coupling values for core motor
(both functional connectivity and effective connectivity as computed in connectivity targeting M1, which steadily decreased with advancing

Fig. 6. Association between increased prefrontal-premotor-M1 coupling and behavioural performance.

When controlling for grey matter atrophy as informed by the VBM analysis, increased net coupling within the prefrontal-premotor-M1 axis (PFC-PMC + SMA-M1 connectivity) negatively
correlates with RTs in both the ‘Intern’ and ‘Extern’ condition. Hence, stronger positive coupling is associated with faster RT, i.e., better behavioural performance. Note that in both
panels, data points of two subjects are very close, giving rise to the impression that the plots only contain 11 data points. However, in conformity with previous figures, all 12 data points
are displayed in both panels. PFC = prefrontal cortex, PMC = premotor cortex, SMA = supplementary motor area, M1 = primary motor cortex, IPS = intraparietal sulcus. *p < 0.05,
FDR-corrected for multiple comparisons.

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age. In contrast, prefrontal-premotor coupling increased with advan- Indeed, PFC has frequently been shown to display the greatest evidence
cing age. Notably, age-related increases of prefrontal influences on the for age-related atrophy (Driscoll et al., 2009; Raz et al., 2005), yet
motor system occurred irrespective of age-related grey matter atrophy paradoxically, PFC constitutes the part of the brain where evidence for
and were inversely correlated with parietal influences and core motor functional compensation is most consistently and most prominently
coupling. Although these findings rely on a relatively small sample observed across neuroimaging studies (Reuter-Lorenz and Cappell,
only, they are perfectly in line with the PASA theory, supporting the 2008; Cabeza and Dennis, 2012). Strikingly, we here found that pre-
validity of our findings. Interestingly, higher connectivity within the frontal-premotor coupling was inversely correlated with parietal-pre-
prefrontal-premotor-M1 axis correlated with faster psychomotor speed, motor and premotor-M1 coupling in older individuals. Hence, in line
implying that older participants with stronger neural coupling were with the PASA theory, top-down control from PFC seemingly increases
faster to select and initiate movements. in response to a functional impairment of posterior brain regions in-
volved in sensory bottom-up processing (Davis et al., 2008; Madden
4.1. Core motor connectivity in older participants et al., 2014).
Moreover, in contrast to prefrontal-premotor-M1 coupling, pos-
In line with previous studies, we found regional BOLD activity to be terior/parietal influences on premotor cortex were not enhanced in
enhanced in older subjects, especially for core (pre)motor areas older participants at the group level, rather these influences even de-
(Heuninckx et al., 2008; Mattay et al., 2002; Rowe et al., 2006; Ward creased with higher age. Thus, there seems to be no increase in parietal-
et al., 2008). Notably, older subjects also displayed stronger inter- premotor connectivity at any point of the ageing process, at least for the
hemispheric connectivity between homologous PMC and M1 compared motor tasks tested in the present study. Since parietal-premotor in-
to young subjects. Moreover, connectivity from premotor regions such formation processing is crucial for visuomotor transformation and
as SMA and PMC targeting M1 was elevated in the older group. Similar movement planning (Grefkes et al., 2010; Rushworth et al., 2003), the
DCM effects were reported by Boudrias et al., 2012 who found that age-related decrease of parietal-premotor coupling might provide a
older subjects display stronger facilitatory coupling onto M1 from neural mechanism for the reduction of perceptual motor speed in older
premotor areas and homologous contralateral M1. In a PET study, Rowe individuals. Interestingly, we found strongest correlations with advan-
et al., 2006 also showed that older individuals feature enhanced cou- cing age for right-hemispheric connections. In line with that, other
pling between PMC and M1 as compared to younger adults during studies have described that behavioural tasks, which more strongly rely
motor performance. Although subjects in the present study were con- on right-hemispheric processing are more susceptible to age-related
fronted with more complex motor demands such as visuomotor trans- deterioration (Gerhardstein et al., 1998; Lamb and Robertson, 1988),
formation, movement selection and speeded movement initiation, the supporting the notion of a right-hemispheric ageing model (Dolcos
similarity of findings between studies suggests enhanced coupling be- et al., 2002; Hellige, 1993). Notably, solely right-handed subjects par-
tween core motor regions to represent a general property of the ageing ticipated in our study. Therefore, another possible explanation for the
motor system. One interesting finding of the present study is that de- pronounced right-hemispheric effects might be that advancing age
spite a general effect of ageing as depicted as an increase of connectivity potentially impacts more strongly on the functional network archi-
targeting M1 at the group level, connectivity again decreased in the tecture of the non-dominant motor hemisphere. Previous neuroimaging
oldest participants of our study. This pattern resembles an inverted U- studies assessing age-related motor control have shown a loss of later-
shaped relationship with age. Interestingly, comparable effects have alized brain activity in ageing (Mattay et al., 2002; Ward and
already been shown for brain activity underlying memory performance Frackowiak, 2003), in line with the HAROLD model of reduced hemi-
in older subjects, increasing from healthy ageing to mild cognitive spheric asymmetry in ageing during non-motor tasks (Cabeza, 2002).
impairment, yet decreasing in the transition to manifest Alzheimer's Note that, however, due to the block design of our experiment, we were
disease (Dickerson et al., 2005; Wierenga and Bondi, 2007). Therefore, not able to distinguish between left- and right-handed responses on a
it seems reasonable to assume that similar effects might occur in the trial by trial basis. Thus, the hemispheric specificity of our findings
motor system, i.e., connectivity increases with incipient age-related could be investigated in future studies that aim at thoroughly dissecting
degeneration, but eventually decreases again when compensatory re- effects for both hands separately, and optimally include both right- and
sources are exhausted within specific parts of the network (Cabeza and left-handedness subjects (Pool et al., 2014).
Dennis, 2012; Scheller et al., 2014). However, this issue needs to be
addressed specifically in future studies including a wider age range. 4.3. Different stages of age-related compensation?

4.2. PASA in motor network connectivity As outlined above, increased prefrontal coupling in older subjects
was inversely correlated with decreased coupling between other net-
In contrast to the decrease in connectivity targeting M1 with ad- work nodes. These correlations might indicate that influences exerted
vancing age, prefrontal-premotor connectivity was not only enhanced by the PFC upon the motor system steadily increase in order to com-
in older individuals at the group level, but also steadily increased with pensate for reduced functioning in other parts of the motor network
higher age. Enhanced recruitment of prefrontal cortex in older adults (Cabeza and Dennis, 2012; Davis et al., 2008).
has frequently been shown across a variety of fMRI studies assessing However, whether or not brain activity and connectivity can be
attentional processes, working memory or executive functions (Cabeza considered compensatory, implying a causal effect is difficult to es-
et al., 2004; Gunning-Dixon and Raz, 2003; Madden et al., 1997). tablish on the basis of functional and structural imaging data alone. One
Likewise, Heuninckx et al., 2008 found PFC overactivation during a attractive way of interpreting the data is that the observed coupling
complex interlimb coordination task to positively correlate with better changes may be interpreted in terms of functional compensation oc-
motor performance in older subjects. Moreover, Berchicci et al., 2012 curring at different stages of the ageing process. In our study, group
found that older individuals engage more PFC activity during response comparisons indicated that both prefrontal-premotor and premotor-M1
preparation in a visuomotor discrimination task, enabling them to coupling was significantly enhanced in older subjects. However, addi-
reach comparable accuracy as young subjects, yet with slower response tional analyses were indicative of differential effects at different stages
speed. These results might reflect increased cognitive control and per- of the ageing process, i.e., enhanced coupling within parts of the net-
formance monitoring during movement execution (Seidler-Dobrin and work increasing during a ‘first stage’ (premotor-M1) and a ‘second
Stelmach, 1998). stage’ (prefrontal-premotor) of the ageing process. Hence, data suggest
Interestingly, in the present study, increases in prefrontal con- that core motor coupling initially ramps up, then with further ageing
nectivity occurred irrespective of the degree of grey matter atrophy. this functional mechanism breaks down and seems to be replaced by

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increasing prefrontal influences that make up for reduced functioning 5. Conclusion

of the core motor network.
This is particularly interesting as enhanced activity of brain regions, The results of our study are compatible with the idea that, as op-
and also increased connectivity between brain regions is often inter- posed to a uniform functional impairment, age-related changes within
preted as functional compensation in older individuals (Reuter-Lorenz the motor network occur with anatomical specificity and at different
and Cappell, 2008; Grady, 2012). For example, age-related ‘hyper- stages of the ageing process. One novel finding is that prefrontal in-
activity’ and ‘hyperconnectivity’ of the PFC has often been associated fluences on the motor system seem to emerge to compensate for re-
with better performance in older subjects for both motor and higher duced connectivity in other parts of the network, yet only the combi-
cognitive functions (Davis et al., 2008; Heuninckx et al., 2008; Rossi nation of this phenomenon with preserved core motor coupling is
et al., 2004). Moreover, also enhanced premotor-M1 coupling has re- associated with better motor performance in ageing individuals.
cently been associated with preserved motor performance in older Finally, our results provide plausible candidate regions within the
subjects (Stewart et al., 2014). Our data complement these findings by prefrontal-premotor-M1 axis to be targeted by means of non-invasive
revealing that increasing prefrontal influences on the motor system are brain stimulation in order to further elucidate their compensatory role
primarily associated with advancing age. However, only older in- for motor behaviour as described for PFC activity in memory function
dividuals with stronger coupling within the prefrontal-premotor-M1 (Manenti et al., 2011; Rossi et al., 2004).
axis featured faster psychomotor speed. This was indicated by the
correlation between higher net coupling within the prefrontal-pre- Acknowledgments
motor-M1 axis (PFC-PMC and SMA-M1) and faster movement initiation
in older subjects. Thus, our findings support the view of a compensatory J.M., G.R.F. and C.G. are supported by the German Research
role for the PFC in motor behaviour (Berchicci et al., 2012; Heuninckx Foundation (Clinical Research Group KFO219 ‘Basal-Ganglia-Cortex-
et al., 2008). However, only older subjects in which this compensatory Loops: Mechanisms of Pathological Interactions and Therapeutic
mechanism is flanked by preserved integrity of core motor coupling Modulation’; GR 3285/5–1). J.M. is additionally supported by a fel-
display faster psychomotor speed at the behavioural level. lowship from the German Research Foundation (MI 2158/1-1). G.R.F.
and C.G. receive additional funding from the University of Cologne
4.4. Limitations Emerging Groups Initiative (CONNECT group) implemented into the
Institutional Strategy of the University of Cologne and the German
The most important limitation of the study is the small sample size. Excellence Initiative. G.R.F. gratefully acknowledges additional support
Notably, the sample size is particularly small for the correlations with from the Marga and Walter Boll Stiftung. S.B.E. acknowledges funding
advancing age in the older group only, which certainly limits the afore- by the Helmholtz Initiative on Systems-Biology ‘The Human Brain
mentioned interpretation with regard to compensatory mechanisms. Model’ and the NIH (R01-MH074457).
However, the use of appropriate correction methods and the strong effects
for endogenous connectivity for both group differences and correlations Appendix A. Supplementary data
with advancing age underline the robustness of our findings and the fact
that the sample size is large enough to detect meaningful age-related Supplementary data to this article can be found online at https://
connectivity changes. Moreover, the between-group differences are very doi.org/10.1016/j.nicl.2018.02.001.
well in line with previous studies on motor network activity and con-
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