Using fMRI to assess patterns of brain activity associated with a simple visuomotor response behavior, that is, power-grip hand squeeze, we were able to compare patterns of activation related to movements between those with and without AD. Although both groups activated some brain regions in common, conventional and PPI analyses were able to detect differences between groups in connectivity with motor cortex, most notably in visual and motor association pathways. Specifically, using PPI, we were able to capture a broader map of regions in AD that were correlated with the moment-to-moment activation of M1 as a function of the experimental task, rather than the generally increased activation of the conventional block design analysis. Although the absence of behavioral data limits interpretation of the results, these findings fit the growing literature that neuromotor activity supporting movement is altered in early-stage AD. These differences may not have been detected if we had employed a resting-state analysis or a priori model of motor cortex connectivity.
We found that while the groups shared some motor-related activation in left primary motor cortex, right cerebellum, left middle cingulate, left precentral gyrus and insula, and right postcentral and supramarginal gyri when assessed separately, the groups exhibit differences in activation when directly compared. Specifically, participants without dementia demonstrated greater activation in supplementary motor area and premotor cortex, commonly associated with motor preparation and planning,42 although this may also have been a result of variability in grip force43 or perhaps attentional differences.44 The reduced activity in these regions by the group with AD relative to their peers without dementia suggests either a failing motor planning system or an alternative strategy for informing motor response. Although it remains unclear what functional ramification this might have, the failure to sufficiently recruit motor planning regions during a motor task could be a neural substrate for loss of independence with activities ranging from self-care to driving.
In contrast to the conventional fMRI analysis, PPI identified a generally broader pattern of brain activation in the group with AD associated with M1 activity. In effect, individuals with AD showed more regions functionally integrated with M1 during visuomotor response. Importantly, these regions were not primarily associated with the task alone, but more specifically with M1 activation. This distinction is important because it allows for an assessment of coactivation with M1 specific to the changing task, in effect providing a picture of the moment-to-moment network of regions functionally integrated with M1. Furthermore, unlike the motor region-restricted connectivity model of Agosta et al,11 our whole brain analysis not only identified similarities with that work, including increased integration of middle cingulate activation, but also revealed an extended network of higher-order processing and association regions in the AD participants.
Specifically, our results suggest that individuals with early-stage AD exhibit integrated activity of M1 and visual association areas that subserve object recognition and visual memory.45 Greater activation of certain visually related cortices, such as left fusiform gyrus and cuneus, was observed in those with AD compared with those without dementia and specifically in relation to recruitment of M1. Our data are consistent with previous reports of increased engagement of fusiform cortex by those with cognitive impairment during a visual encoding task.46 In addition, multiple motor association and execution areas including broader activation of left sensorimotor cortex, beyond the hand region, and bilateral anterior cerebellum exhibited functional integration with M1 in the group with AD.
These results support and extend prior studies that show a widespread and perhaps nonspecific network of activation supplements cognitive control of motor action.11,47 Given that both groups exhibit typical activation of the primary motor execution network (contralateral M1, ipsilateral cerebellum), the pattern of both visual association and motor control region recruitment in association with M1 suggests that these regions are inefficiently activated during a simple motor task. In this study, individuals with AD activated multiple visual and motor accessory pathways in closely connected manner with M1 in a simple motor task compared with individuals without dementia. That these regions were functionally connected in a task-specific manner suggests inefficiency and absence of selectivity in recruited networks in early-stage AD, perhaps as a consequence of disease. Neurofibrillary pathology and Aβ deposition are abundant in visual association cortices (BA 19).48 Recruitment of these pathologically burdened regions during simple visuomotor tasks may explain visuospatial and visual memory abnormalities frequently reported in the literature and underlie the deficits in performance of more complex activities in AD.15,20,49,50
Alternatively, the findings may reflect an emergent part of a compensatory visuomotor network in AD to maintain performance despite disease-related dysfunction. Indeed, individuals without dementia showed increased activation in motor preparation and planning regions, premotor cortex, and supplementary motor area. Individuals without dementia may generate and rely on a preplanned response set requiring lower vigilance to complete successfully, whereas each stimulus is evaluated and executed separately in the group with AD. This is not to suggest that visual pathways regions are unnecessary for individuals without dementia to perform the task, but that a fundamental change occurs as a consequence of the disease process that results in altered brain activity during performance of the task.
Whatever the cause, the apparently altered neural activity may underlie the well-characterized decline in dual-task performance for those with AD. Studies on dual-task performance in AD demonstrate significant impairments to both tasks when two cognitive tasks,51 or a cognitive and a motor task,49,50 are performed simultaneously. Expanded recruitment of visual and motor pathways during a single task would limit available cognitive resources for a concomitant cognitive or motor task. Although the precise mechanisms of dual-task deficits are still unclear, dementia often results in a failure of executive mechanisms, including set maintenance and switching, working memory, and attention, that underlie the ability to perform multiple simultaneous tasks. Deficits in cognitive coordination mechanisms have been postulated to explain poor dual-task performance in AD.52 As an example, if a simple visuomotor task such as picking out a specific item from a grocery shelf requires close coactivation of M1 and visual processing pathways, the multitude of other visual stimuli on the shelf, or a passing shopper, could interfere with appropriate selection of a motor plan.
The focus of this investigation was on characterizing differences in the cortical coactivation patterns during performance of a simple motor task. We did not assess how identified differences in cortical activation might influence performance of simple or complex motor tasks.
Our study suggests that, in persons with early-stage AD, performance of a simple visuomotor task activates an extended network of motor and visual processing cortices. Altered connectivity with M1 in early-stage AD may be explained by functional and pathological changes in the motor network as a result of disease. This hypothesis is in line with previous reports of global network dysfunction during movement in AD.55 The present results support previous work identifying functional change in brain networks traditionally considered to be spared in early-stage AD.11 It is possible that even simple motor tasks activate an extended network of regions in interaction with M1, including visual and motor pathways that are not engaged to the same degree or in the same closely integrated manner in individuals without dementia.
The reliance on an extended and integrated network of cortical areas for the performance of motor behaviors in persons with early-state AD has implications for the rehabilitation professionals who work with them to improve motor function. Performance during functional activities that require set-switching or parallel information processing such as meal preparation, grocery shopping, or driving could be impaired as cognitive resources would already be engaged for more simple tasks. If further study determines that broad networks of activation are detrimental to performance, then clinicians could choose to focus on challenging the motor and attentional systems of individuals with early-stage AD to help train patients to handle multiple parallel tasks. Alternatively, the clinician could choose to educate caregivers on simplifying the environment to minimize allocation of limited cognitive resources and thereby promote successful performance of functional tasks. Future work should explore the inefficiency in the cognitive aspects of motor performance that may underlie reported motor control change occurring in AD before clinically relevant symptoms manifest.4,56,57
We thank Phyllis Switzer, Pat Laubinger, MPA, BSN, and JoAnn Lierman, RNC, ARNP, PhD for their assistance, and the participants who so willingly gave their time and trust.
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