Universität zu Köln

Pool, Eva-Maria (2015). Systems Biology Determinants of Motor Behavior in Humans. PhD thesis, Universität zu Köln.

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Abstract

Motor skills are mediated by a dynamic and finely regulated interplay of the primary motor cortex (M1) with various cortical and subcortical regions engaged in movement preparation and execution. Several neuroimaging studies already demonstrated that increasing motor performance in simple motor tasks is associated with higher activation levels in the motor system. Additional to the extrinsic modulation of motor performance, neural activity is also influenced by intrinsic factors such as handedness. Handedness – defined as the preference to use one hand over the other – is associated with differences in activation levels in various motor tasks performed with the dominant or non-dominant hand. However, motor actions are implemented in a distributed network of motor regions rather than a single cortical area. For that reason, it is important to consider the neural processes underlying motor behavior from a network perspective that is offered by connectivity analyses. Models of effective connectivity allow the estimation of the influence that areas exert over each other while functional connectivity is defined as temporal coherence between remote, segregated neurophysiological events. The present thesis aimed to investigate how the dynamic modulation of motor performance and connectivity is mediated by extrinsic and intrinsic factors in the human motor system. In the first study, we used functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) to investigate effective connectivity of key motor areas at different movement frequencies performed by right-handed subjects (n=36) with the left or right hand. The network of interest consisted of motor regions in both hemispheres including M1, supplementary motor area (SMA), ventral premotor cortex (PMv), motor putamen, and motor cerebellum. The connectivity analysis showed that performing hand movements at higher frequencies was associated with a linear increase in neural coupling strength from premotor areas (SMA, PMv) contralateral to the moving hand and ipsilateral cerebellum towards contralateral, active M1. In addition, we found hemispheric differences in the amount by which the coupling of premotor areas and M1 was modulated, depending on which hand was moved. Other connections were not modulated by changes in motor performance. The results suggest that a stronger coupling, especially between contralateral premotor areas and M1, enables increased motor performance of simple unilateral hand movements. In the second study, we used fMRI and DCM to investigate effective connectivity between key motor areas during fist closures of the dominant or non-dominant hand performed by 18 right- and 18 left-handers. Handedness was assessed employing the Edinburgh-Handedness-Inventory (EHI). The network of interest consisted of key motor regions in both hemispheres including M1, SMA, PMv, motor putamen and motor cerebellum. The connectivity analysis revealed that in right-handed subjects movements of the dominant hand were associated with significantly stronger coupling of contralateral (left, i.e., dominant) SMA with ipsilateral SMA, ipsilateral PMv, contralateral motor putamen and contralateral M1 compared to equivalent connections in left-handers. The degree of handedness as indexed by the individual EHI scores also correlated with coupling parameters of these connections. In contrast, we found no differences between right- and left-handers when testing for the effect of movement speed on effective connectivity. In conclusion, the data show that handedness is associated with differences in effective connectivity within the human motor network with a prominent role of SMA in right-handers. Left-handers featured less asymmetry in effective connectivity implying different hemispheric mechanisms underlying hand motor control compared to right-handers. However, differences in task performance are inherent putative confounds for all task based fMRI studies. For example, performing a standard motor task might be less demanding when using the dominant hand compared to the non-dominant hand, which may also affect neural activation levels, e.g., in frontoparietal areas. Thus, resting-state fMRI seems an attractive approach to overcome these putative confounds as it allows investigating networks independent from performance. In the third study, we, therefore, scanned 18 right- and 18 left-handers with resting-state fMRI. Handedness was assessed by the EHI. We computed whole-brain functional connectivity maps of the left and right M1. To test for the effect of handedness, we computed differential contrasts and regression analyses including EHI as a covariate. We further used a multivariate linear support vector machine (SVM) classifier algorithm to reveal the individual specificity of brain regions showing differences between the resting-state maps of right- and left-handers. Using left M1 as a seed region revealed stronger interhemispheric functional connectivity between M1 and dorsolateral premotor cortex (PMd) in right-handers as compared to left-handers. Furthermore, this individual cluster in right PMd classified right- and left-handers with 86.2% accuracy. Control analyses using non-motor resting-state networks, including the (Broca) speech and the visual network, revealed no significant differences in functional connectivity related to handedness. Higher connectivity in right-handers might, therefore, reflect a systematic impact of handedness on an intrinsic functional level and might explain the observation that right-handedness is usually more lateralised than left-handedness. Furthermore, enhanced connectivity between M1 and PMd serves as an individual marker / endophenotype of handedness. In summary, the present thesis demonstrates that the dynamic modulation of the motor system during motor performance is mediated by a specific set of brain regions in both rightand left-handers. Furthermore, the results indicate that differences in coupling strength between right- and left-handers reflect the impact of handedness on both functional and effective connectivity.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Pool, Eva-Maria e.pool@fz-juelich.de UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-59689
Date:	January 2015
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > Forschungszentrum Jülich Faculty of Mathematics and Natural Sciences > Department of Biology > Zoologisches Institut
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language Movement frequency; Handedness; Motor asymmetry; Premotor cortex; Motor putamen; Cerebellum; Dynamic causal modeling; Effective connectivity; Functional connectivity; Support vector machine English
Date of oral exam:	14 January 2015
Referee:	Name Academic Title Büschges, Ansgar Prof. Dr. rer. nat. Grefkes, Christian Prof. Dr. med.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/5968