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.
1. Alzheimer's Association. Alzheimer's disease facts and figures. Alzheimers Dement. 2008;4:110–133.
2. Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol (Berl). 1991;82:239–259.
3. Suva D, Favre I, Kraftsik R, Esteban M, Lobrinus A, Miklossy J. Primary motor cortex involvement in Alzheimer disease. J Neuropathol Exp Neurol. 1999;58:1125–1134.
4. Kluger A, Gianutsos JG, Golomb J, et al. Patterns of motor impairment in normal aging, mild cognitive decline, and early Alzheimer's disease. J Gerontol B Psychol Sci Soc Sci. 1997;52:P28–P39.
5. Ghilardi MF, Alberoni M, Rossi M, Franceschi M, Mariani C, Fazio F. Visual feedback has differential effects on reaching movements in Parkinson's and Alzheimer's disease. Brain Res. 2000;876:112–123.
6. Willingham DB, Peterson EW, Manning C, Brashear HR. Patients with Alzheimer's disease who cannot perform some motor skills show normal learning of other motor skills. Neuropsychology. 1997;11:261–271.
7. Della Sala S, Spinnler H, Venneri A. Walking difficulties in patients with Alzheimer's disease might originate from gait apraxia. J Neurol Neurosurg Psychiatry. 2004;75:196–201.
8. Thomas VS, Vandenberg EV, Potter JF. Non-neurological factors are implicated in impairments in gait and mobility among patients in a clinical dementia referral population. Int J Geriatr Psychiatry. 2002;17:128–133.
9. Alexander NB, Mollo JM, Giordani B, et al. Maintenance of balance, gait patterns, and obstacle clearance in Alzheimer's disease. Neurology. 1995;45:908–914.
10. Manckoundia P, Mourey F, Pfitzenmeyer P, Papaxanthis C. Comparison of motor strategies in sit-to-stand and back-to-sit motions between healthy and Alzheimer's disease elderly subjects. Neuroscience. 2006;137:385–392.
11. Agosta F, Rocca MA, Pagani E, et al. Sensorimotor network rewiring in mild cognitive impairment and Alzheimer's disease. Hum Brain Mapp. 2010;31:515–525.
12. Camarda R, Camarda C, Monastero R, et al. Movements execution in amnestic mild cognitive impairment and Alzheimer's disease. Behav Neurol. 2007;18:135–142.
13. Babiloni C, Miniussi C, Moretti DV, et al. Cortical networks generating movement-related EEG rhythms in Alzheimer's disease: an EEG coherence study. Behav Neurosci. 2004;118:698–706.
14. Babiloni C, Ferri R, Binetti G, et al. Fronto-parietal coupling of brain rhythms in mild cognitive impairment: a multicentric EEG study. Brain Res Bull. 2006;69:63–73.
15. Rosano C, Aizenstein HJ, Cochran JL, et al. Event-related functional magnetic resonance imaging investigation of executive control in very old individuals with mild cognitive impairment. Biol Psychiatry. 2005;57:761–767.
16. Dick MB, Shankle RW, Beth RE, Dick-Muehlke C, Cotman CW, Kean ML. Acquisition and long-term retention of a gross motor skill in Alzheimer's disease patients under constant and varied practice conditions. J Gerontol B Psychol Sci Soc Sci. 1996;51:P103–P111.
17. Dick MB, Hsieh S, Dick-Muehlke C, Davis DS, Cotman CW. The variability of practice hypothesis in motor learning: does it apply to Alzheimer's disease? Brain Cogn. 2000;44:470–489.
18. Bellgrove MA, Phillips JG, Bradshaw JL, Hall KA, Presnell I, Hecht H. Response programming in dementia of the Alzheimer type: a kinematic analysis. Neuropsychologia. 1997;35:229–240.
19. Vidoni ED, Honea RA, Burns JM. Neural correlates of impaired functional independence in early Alzheimer's disease. J Alzheimers Dis. 2010;19:517–527.
20. Howieson DB, Dame A, Camicioli R, Sexton G, Payami H, Kaye JA. Cognitive markers preceding Alzheimer's dementia in the healthy oldest old. J Am Geriatr Soc. 1997;45:584–589.
21. Fennema-Notestine C, Hagler DJ Jr, McEvoy LK, et al. Structural MRI biomarkers for preclinical and mild Alzheimer's disease. Hum Brain Mapp. 2009;30:3238–3253.
22. Toepper M, Beblo T, Thomas C, Driessen M. Early detection of Alzheimer's disease: a new working memory paradigm. Int J Geriatr Psychiatry. 2008;23:272–278.
23. Diamond EL, Miller S, Dickerson BC, et al. Relationship of fMRI activation to clinical trial memory measures in Alzheimer disease. Neurology. 2007;69:1331–1341.
24. Sorg C, Riedl V, Perneczky R, Kurz A, Wohlschlager AM. Impact of Alzheimer's disease on the functional connectivity of spontaneous brain activity. Curr Alzheimer Res. 2009;6:541–553.
25. Zhang HY, Wang SJ, Xing J, et al. Detection of PCC functional connectivity characteristics in resting-state fMRI in mild Alzheimer's disease. Behav Brain Res. J2009;197:103–108.
26. Zhou Y, Dougherty JH Jr, Hubner KF, Bai B, Cannon RL, Hutson RK. Abnormal connectivity in the posterior cingulate and hippocampus in early Alzheimer's disease and mild cognitive impairment. Alzheimers Dement. 2008;4:265–270.
27. Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A. 2004;101:4637–4642.
28. Wang L, Zang Y, He Y, et al. Changes in hippocampal connectivity in the early stages of Alzheimer's disease: evidence from resting state fMRI. Neuroimage. 2006;31:496–504.
29. Sorg C, Riedl V, Muhlau M, et al. Selective changes of resting-state networks in individuals at risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2007;104:18760–18765.
30. Petrella JR, Sheldon FC, Prince SE, Calhoun VD, Doraiswamy PM. Default mode network connectivity in stable vs progressive mild cognitive impairment. Neurology. 2011;76:511–517.
31. Dickerson BC, Sperling RA. Large-scale functional brain network abnormalities in Alzheimer's disease: insights from functional neuroimaging. Behav Neurol. 2009;21:63–75.
32. Egner T, Hirsch J. The neural correlates and functional integration of cognitive control in a Stroop task. Neuroimage. 2005;24:539–547.
33. Burns JM, Cronk BB, Anderson HS, et al. Cardiorespiratory fitness and brain atrophy in early Alzheimer disease. Neurology. 2008;71:210–216.
34. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43:2412b–2414b.
35. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology. 1984;34:939–944.
36. Pfeffer RI, Kurosaki TT, Harrah CH Jr, Chance JM, Filos S. Measurement of functional activities in older adults in the community. J Gerontol. 1982;37:323–329.
37. Rosen WG, Terry RD, Fuld PA, Katzman R, Peck A. Pathological verification of ischemic score in differentiation of dementias. Ann Neurol. 1980;7:486–488.
38. Momenan R, Rawlings R, Fong G, Knutson B, Hommer D. Voxel-based homogeneity probability maps of gray matter in groups: assessing the reliability of functional effects. Neuroimage. 2004;21:965–972.
39. Lancaster JL, Rainey LH, Summerlin JL, et al. Automated labeling of the human brain: a preliminary report on the development and evaluation of a forward-transform method. Hum Brain Mapp. 1997;5:238–242.
40. Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH. An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage. 2003;19:1233–1239.
41. Price CJ, Friston KJ. Cognitive conjunction: a new approach to brain activation experiments. Neuroimage. 1997;5:261–270.
42. Krakauer J, Ghez C. Voluntary movement. In: Kandel ER, Schwartz JH, Jessell TM, eds. Principles of Neural Science. 4th ed. New York: McGraw-Hill; 2000:756–781.
43. Cramer SC, Weisskoff RM, Schaechter JD, et al. Motor cortex activation is related to force of squeezing. Hum Brain Mapp. 2002;16:197–205.
44. Keisker B, Hepp-Reymond MC, Blickenstorfer A, Meyer M, Kollias SS. Differential force scaling of fine-graded power grip force in the sensorimotor network. Hum Brain Mapp. 2009;30:2453–2465.
45. Vaidya CJ, Zhao M, Desmond JE, Gabrieli JD. Evidence for cortical encoding specificity in episodic memory: memory-induced re-activation of picture processing areas. Neuropsychologia. 2002;40:2136–2143.
46. Hamalainen A, Pihlajamaki M, Tanila H, et al. Increased fMRI responses during encoding in mild cognitive impairment. Neurobiol Aging. 2007;28:1889–1903.
47. Ferreri F, Pauri F, Pasqualetti P, Fini R, Dal Forno G, Rossini PM. Motor cortex excitability in Alzheimer's disease: a transcranial magnetic stimulation study. Ann Neurol. 2003;53:102–108.
48. McKee AC, Au R, Cabral HJ, et al. Visual association pathology in preclinical Alzheimer disease. J Neuropathol Exp Neurol. 2006;65:621–630.
49. Cocchini G, Della Sala S, Logie RH, Pagani R, Sacco L, Spinnler H. Dual task effects of walking when talking in Alzheimer's disease. Rev Neurol (Paris). 2004;160:74–80.
50. Della Sala S, Cocchini G, Logie RH, Allerhand M, Macpherson SE. Dual task during encoding, maintenance, and retrieval in Alzheimer's disease. J Alzheimers Dis. 2010;19(2):503–515.
51. MacPherson SE, Della Sala S, Logie RH, Wilcock GK. Specific AD impairment in concurrent performance of two memory tasks. Cortex. 2007;43:858–865.
52. Kaschel R, Logie RH, Kazen M, Della Sala S. Alzheimer's disease, but not ageing or depression, affects dual-tasking. J Neurol. 2009;256:1860–1868.
53. Thiyagesh SN, Farrow TF, Parks RW, et al. Treatment effects of therapeutic cholinesterase inhibitors on visuospatial processing in Alzheimer's disease: a longitudinal functional MRI study. Dement Geriatr Cogn Disord. 2010;29:176–188.
54. Gorbet DJ, Sergio LE. Preliminary sex differences in human cortical BOLD fMRI activity during the preparation of increasingly complex visually guided movements. Eur J Neurosci. 2007;25:1228–1239.
55. Babiloni C, Babiloni F, Carducci F, et al. Movement-related electroencephalographic reactivity in Alzheimer disease. Neuroimage. 2000;12:139–146.
56. Gillain S, Warzee E, Lekeu F, et al. The value of instrumental gait analysis in elderly healthy, MCI or Alzheimer's disease subjects and a comparison with journal clinical tests used in single and dual-task conditions. Ann Phys Rehabil Med. 2009;52:453–474.
57. O'Bryant SE, Waring SC, Cullum CM, et al. Staging dementia using Clinical Dementia Rating Scale Sum of Boxes scores: a Texas Alzheimer's research consortium study. Arch Neurol. 2008;65:1091–1095.
dementia; dual-task performance; functional connectivity; motor control; visuomotor response