Interregional compensatory mechanisms of motor functioning in progressing preclinical neurodegeneration.

Understanding brain reserve in preclinical stages of neurodegenerative disorders allows determination of which brain regions contribute to normal functioning despite accelerated neuronal loss. Besides the recruitment of additional regions, a reorganisation and shift of relevance between normally engaged regions are a suggested key mechanism. Thus, network analysis methods seem critical for investigation of changes in directed causal interactions between such candidate brain regions. To identify core compensatory regions, fifteen preclinical patients carrying the genetic mutation leading to Huntington's disease and twelve controls underwent fMRI scanning. They accomplished an auditory paced finger sequence tapping task, which challenged cognitive as well as executive aspects of motor functioning by varying speed and complexity of movements. To investigate causal interactions among brain regions a single Dynamic Causal Model (DCM) was constructed and fitted to the data from each subject. The DCM parameters were analysed using statistical methods to assess group differences in connectivity, and the relationship between connectivity patterns and predicted years to clinical onset was assessed in gene carriers. In preclinical patients, we found indications for neural reserve mechanisms predominantly driven by bilateral dorsal premotor cortex, which increasingly activated superior parietal cortices the closer individuals were to estimated clinical onset. This compensatory mechanism was restricted to complex movements characterised by high cognitive demand. Additionally, we identified task-induced connectivity changes in both groups of subjects towards pre- and caudal supplementary motor areas, which were linked to either faster or more complex task conditions. Interestingly, coupling of dorsal premotor cortex and supplementary motor area was more negative in controls compared to gene mutation carriers. Furthermore, changes in the connectivity pattern of gene carriers allowed prediction of the years to estimated disease onset in individuals. Our study characterises the connectivity pattern of core cortical regions maintaining motor function in relation to varying task demand. We identified connections of bilateral dorsal premotor cortex as critical for compensation as well as task-dependent recruitment of pre- and caudal supplementary motor area. The latter finding nicely mirrors a previously published general linear model-based analysis of the same data. Such knowledge about disease specific inter-regional effective connectivity may help identify foci for interventions based on transcranial magnetic stimulation designed to stimulate functioning and also to predict their impact on other regions in motor-associated networks

Optimizing Experimental Design for Comparing Models of Brain Function

This article presents the first attempt to formalize the optimization of experimental design with the aim of comparing models of brain function based on neuroimaging data. We demonstrate our approach in the context of Dynamic Causal Modelling (DCM), which relates experimental manipulations to observed network dynamics (via hidden neuronal states) and provides an inference framework for selecting among candidate models. Here, we show how to optimize the sensitivity of model selection by choosing among experimental designs according to their respective model selection accuracy. Using Bayesian decision theory, we (i) derive the Laplace-Chernoff risk for model selection, (ii) disclose its relationship with classical design optimality criteria and (iii) assess its sensitivity to basic modelling assumptions. We then evaluate the approach when identifying brain networks using DCM. Monte-Carlo simulations and empirical analyses of fMRI data from a simple bimanual motor task in humans serve to demonstrate the relationship between network identification and the optimal experimental design. For example, we show that deciding whether there is a feedback connection requires shorter epoch durations, relative to asking whether there is experimentally induced change in a connection that is known to be present. Finally, we discuss limitations and potential extensions of this work

Transcranial Magnetic Stimulation Intensities in Cognitive Paradigms

BACKGROUND: Transcranial magnetic stimulation (TMS) has become an important experimental tool for exploring the brain's functional anatomy. As TMS interferes with neural activity, the hypothetical function of the stimulated area can thus be tested. One unresolved methodological issue in TMS experiments is the question of how to adequately calibrate stimulation intensities. The motor threshold (MT) is often taken as a reference for individually adapted stimulation intensities in TMS experiments, even if they do not involve the motor system. The aim of the present study was to evaluate whether it is reasonable to adjust stimulation intensities in each subject to the individual MT if prefrontal regions are stimulated prior to the performance of a cognitive paradigm. METHODS AND FINDINGS: Repetitive TMS (rTMS) was applied prior to a working memory task, either at the 'fixed' intensity of 40% maximum stimulator output (MSO), or individually adapted at 90% of the subject's MT. Stimulation was applied to a target region in the left posterior middle frontal gyrus (pMFG), as indicated by a functional magnetic resonance imaging (fMRI) localizer acquired beforehand, or to a control site (vertex). Results show that MT predicted the effect size after stimulating subjects with the fixed intensity (i.e., subjects with a low MT showed a greater behavioral effect). Nevertheless, the individual adaptation of intensities did not lead to stable effects. CONCLUSION: Therefore, we suggest assessing MT and account for it as a measure for general cortical TMS susceptibility, even if TMS is applied outside the motor domain

Intermanual transfer of sensorimotor memory for grip force when lifting objects: the role of wrist angulation

To investigate the mechanisms underlying the intermanual transfer of sensorimotor memory when lifting an object.Twenty healthy subjects grasped and lifted an object with constant mechanical properties with the right hand (RH) first and then with the left hand (LH). Ten of the subjects lifted the object with the RH in a regular wrist angulation (WA), followed by lifts with the LH in a regular WA. The remaining 10 subjects lifted the object with the RH in a hyper-flexed WA, followed by lifts with the LH in a regular WA.Subjects generated greater peak grip force (GF) rates, grip and lift forces when lifting the object with the wrist in a regular WA compared to lifts with the wrist in hyper-flexion. Importantly, subjects transferred the predictive scaling of GF from the RH to the LH, regardless of the WA.Biomechanical properties of the object do not seem to be used by the CNS as a first line information to evaluate GF when handling an object or transferring information about the grasp to the opposite hemisphere.The predictive scaling of GF rather reflects an internal sense of effort than an internal representation of the mechanical object properties

1Hz rTMS preconditioned by tDCS over the primary motor cortex in Parkinson's disease: Absence of effect on arm lift and hand grip force control

© 2012 Human Kinetics, Inc

1Hz rTMS über dem primärmotorischen Kortex der nicht betroffenen Hemisphäre steigt die Effizienz eines motorischen Handtrainings in der Rehabilitation von Handfunktionsstörungen nach Schlaganfall

Podubecka J, Theilig S, Bösl K, Sarfeld A-S, Nowak D-A. 1Hz rTMS über dem primärmotorischen Kortex der nicht betroffenen Hemisphäre steigt die Effizienz eines motorischen Handtrainings in der Rehabilitation von Handfunktionsstörungen nach Schlaganfall. Neurologie und Rehabilitation . 2010;16(6):322

Sensorimotor processing in the grip-lift task: The impact of maximum wrist flexion / extension on force scaling

To evaluate the effect of wrist angulation on the grip force (GF) scaling in healthy subjects.The first experiment investigated if hyperflexion or hyperextension of the wrist affects the scaling of GF. Subjects performed sets of 10 lifts with the wrist positioned in (i) a self-chosen, regular, slightly extended angulation, (ii) a hyperextended angulation and (iii) a hyperflexed angulation. The second experiment tested if wrist angulation applied during a preceding lift influenced GF scaling when lifting the object with a predefined wrist angulation.Compared with the regular and hyperflexed wrist angulations, subjects generated an overshoot of GF when lifting the object with the wrist hyperextended. Irrespective of the wrist angulation applied in the preceding lift, subjects generated an overshoot of GF when lifting the object with the wrist hyperextended, but not during lifts with the wrist in a regular or hyperflexed angulation.We demonstrate that a change in the horizontal angulation of the wrist of the grasping hand interferes with the scaling of GF.We interpret these data to reflect a very basic strategic response of the motor system to changes in the geometry of the hand in order to ensure grasp stability

Arbitrary visuomotor mapping in the grip-lift task: Dissociation of performance deficits in right and left middle cerebral artery stroke

The ability to rapidly establish a memory link between arbitrary sensory cues and goal-directed movements is part of our daily motor repertoire. It is unknown if this ability is affected by middle cerebral artery stroke. Eighteen right-handed subjects with a first unilateral middle cerebral artery stroke were studied while performing a precision grip to lift objects of different weights. In a "no cue" condition, a noninformative neutral visual stimulus was presented before each lift, thereby not allowing any judgment about the object weight. In a "cue" condition arbitrary color cues provided advance information about the weight to be lifted in the subsequent trial. Subjects performed both conditions with either hand. During "no cue" trials subjects scaled their grip force according to the weight of the preceding lift, irrespective of the hand performing the lift or the hemisphere affected. The presentation of color cues allowed patients with right hemispheric stroke, but not those with left hemispheric stroke, to scale their grip force according to the weight in the upcoming lift when lifting the weight with the unaffected hand. Color cues did not allow for a predictive scaling of grip force according to the weight of the object to be lifted when lifting with the affected hand, irrespective of the affected hemisphere. These data imply that the ability of visuomotor mapping in the grip-lift task is selectively impaired in the affected hand after right middle cerebral artery stroke, but in both hands after left middle cerebral artery stroke