Low-frequency transcranial magnetic stimulation over left dorsal premotor cortex improves the dynamic control of visuospatially cued actions.

Left rostral dorsal premotor cortex (rPMd) and supramarginal gyrus (SMG) have been implicated in the dynamic control of actions. In 12 right-handed healthy individuals, we applied 30 min of low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) over left rPMd to investigate the involvement of left rPMd and SMG in the rapid adjustment of actions guided by visuospatial cues. After rTMS, subjects underwent functional magnetic resonance imaging while making spatially congruent button presses with the right or left index finger in response to a left- or right-sided target. Subjects were asked to covertly prepare motor responses as indicated by a directional cue presented 1 s before the target. On 20% of trials, the cue was invalid, requiring subjects to readjust their motor plan according to the target location. Compared with sham rTMS, real rTMS increased the number of correct responses in invalidly cued trials. After real rTMS, task-related activity of the stimulated left rPMd showed increased task-related coupling with activity in ipsilateral SMG and the adjacent anterior intraparietal area (AIP). Individuals who showed a stronger increase in left-hemispheric premotor-parietal connectivity also made fewer errors on invalidly cued trials after rTMS. The results suggest that rTMS over left rPMd improved the ability to dynamically adjust visuospatial response mapping by strengthening left-hemispheric connectivity between rPMd and the SMG-AIP region. These results support the notion that left rPMd and SMG-AIP contribute toward dynamic control of actions and demonstrate that low-frequency rTMS can enhance functional coupling between task-relevant brain regions and improve some aspects of motor performance.

Neural correlates of affordance competition in dorsal premotor cortex

Le travail présenté dans cette thèse porte sur le rôle du cortex prémoteur dorsal (PMd) au sujet de la prise de décision (sélection d’une action parmis nombreux choix) et l'orientation visuelle des mouvements du bras. L’ouvrage décrit des expériences électrophysiologiques chez le singe éveillé (Macaca mulatta) permettant d’adresser une fraction importante des prédictions proposées par l'hypothèse des affordances concurrentes (Cisek, 2006; Cisek, 2007a). Cette hypothèse suggère que le choix de toute action est l’issue d'une concurrence entre les représentations internes des exigences et des atouts de chacune des options présentées (affordances; Gibson, 1979). Un intérêt particulier est donné au traitement de l'information spatiale et la valeur des options (expected value, EV) dans la prise de décisions. La première étude (article 1) explore la façon dont PMd reflète ces deux paramètres dans la période délai ainsi que de leur intéraction. La deuxième étude (article 2) explore le mécanisme de décision de façon plus détaillée et étend les résultats au cortex prémoteur ventral (PMv). Cette étude porte également sur la représentation spatiale et l’EV dans une perspective d'apprentissage. Dans un environnement nouveau les paramètres spatiaux des actions semblent être présents en tout temps dans PMd, malgré que la représentation de l’EV apparaît uniquement lorsque les animaux commencent à prendre des décisions éclairées au sujet de la valeur des options disponibles. La troisième étude (article 3) explore la façon dont PMd est impliqué aux “changements d'esprit“ dans un procès de décision. Cette étude décrit comment la sélection d’une action est mise à jour à la suite d'une instruction de mouvement (GO signal). I II Les résultats principaux des études sont reproduits par un modèle computationnel (Cisek, 2006) suggérant que la prise de décision entre plusieurs actions alternatives peux se faire par voie d’un mécanisme de concurrence (biased competition) qui aurait lieu dans la même région qui spécifie les actions.

Premotor and occipital theta asymmetries as discriminators of memory- and stimulus-guided tasks

The saccadic paradigm has been used to investigate specific cortical networks involving visuospatial attention. We examined whether asymmetry in theta and beta band differentiates the role of the hemispheres during the execution of two different prosacadic conditions: a fixed condition, where the stimulus was presented at the same location; and a random condition, where the stimulus was unpredictable. Twelve healthy volunteers (3 male; mean age: 26.25) performed the task while their brain activity pattern was recorded using quantitative electroencephalography. We did not find any significant difference for beta, slow- and fast-alpha frequencies for the pairs of electrodes analyzed. The results for theta band showed a superiority of the left hemisphere in the frontal region when responding to the random condition on the right, which is related to the planning and selection of responses, and also a greater activation of the right hemisphere during the random condition, in the occipital region, related to the identification and recognition of patterns. These results indicate that asymmetries in the premotor area and the occipital cortex differentiate memory- and stimulus-driven tasks. (C) 2011 Elsevier Inc. All rights reserved.

Differential activation of the lateral premotor cortex during action observation

Background Action observation leads to neural activation of the human premotor cortex. This study examined how the level of motor expertise (expert vs. novice) in ballroom dancing and the visual viewpoint (internal vs. external viewpoint) influence this activation within different parts of this area of the brain. Results Sixteen dance experts and 16 novices observed ballroom dance videos from internal or external viewpoints while lying in a functional magnetic resonance imaging scanner. A conjunction analysis of all observation conditions showed that action observation activated distinct networks of premotor, parietal, and cerebellar structures. Experts revealed increased activation in the ventral premotor cortex compared to novices. An internal viewpoint led to higher activation of the dorsal premotor cortex. Conclusions The present results suggest that the ventral and dorsal premotor cortex adopt differential roles during action observation depending on the level of motor expertise and the viewpoint.

Activation of the parieto-premotor network is associated with vivid motor imagery - a parametric FMRI study

The present study examined the neural basis of vivid motor imagery with parametrical functional magnetic resonance imaging. 22 participants performed motor imagery (MI) of six different right-hand movements that differed in terms of pointing accuracy needs and object involvement, i.e., either none, two big or two small squares had to be pointed at in alternation either with or without an object grasped with the fingers. After each imagery trial, they rated the perceived vividness of motor imagery on a 7-point scale. Results showed that increased perceived imagery vividness was parametrically associated with increasing neural activation within the left putamen, the left premotor cortex (PMC), the posterior parietal cortex of the left hemisphere, the left primary motor cortex, the left somatosensory cortex, and the left cerebellum. Within the right hemisphere, activation was found within the right cerebellum, the right putamen, and the right PMC. It is concluded that the perceived vividness of MI is parametrically associated with neural activity within sensorimotor areas. The results corroborate the hypothesis that MI is an outcome of neural computations based on movement representations located within motor areas.

Premotor Mechanisms for Orofacial Coordination

The mouth, throat, and face contain numerous muscles that participate in a large variety of orofacial behaviors. The jaw and tongue can move independently, and thus require a high degree of coordination among the muscles that move them to prevent self-injury. However, different orofacial behaviors require distinct patterns of coordination between these muscles. The method through which motor control circuitry might coordinate this activity has yet to be determined. Electrophysiological, immunohistochemical, and retrograde tracing studies have attempted to identify populations of premotor neurons which directly send information to orofacial motoneurons in an effort to identify sources of coordination. Yet these studies have not provided a complete picture of the population of neurons which monosynaptically connect to jaw and tongue motoneurons. Additionally, while many of these studies have suggested that premotor neurons projecting to multiple motor pools may play a role in coordination of orofacial muscles, no clear functional roles for these neurons in the coordination of natural orofacial movements has been identified.

In this dissertation, I took advantage of the recently developed monosynaptic rabies virus to trace the premotor circuits for the jaw-closing masseter muscle and tongue-protruding genioglossus muscle in the neonatal mouse, uncovering novel premotor inputs in the brainstem. Furthermore, these studies identified a set of neurons which form boutons onto motor neurons in multiple motor pools, providing a premotor substrate for orofacial coordination. I then combined a retrogradely traveling lentivirus with a split-intein mediated split-Cre recombinase system to isolate and manipulate a population of neurons which project to both left and right jaw-closing motor nuclei. I found that these bilaterally projecting neurons also innervate multiple other orofacial motor nuclei, premotor regions, and midbrain regions implicated in motor control. I anatomically and physiologically characterized these neurons and used optogenetic and chemicogenetic approaches to assess their role in natural jaw-closing behavior, specifically with reference to bilateral masseter muscle electromyogram (EMG) activity. These studies identified a population of bilaterally projecting neurons in the supratrigeminal nucleus as essential for maintenance of an appropriate level of masseter activation during natural chewing behavior in the freely moving mouse. Moreover, these studies uncovered two distinct roles of supratrigeminal bilaterally projecting neurons in bilaterally synchronized activation of masseter muscles, and active balancing of bilateral masseter muscle tone against an excitatory input. Together, these studies identify neurons which project to multiple motor nuclei as a mechanism by which the brain coordinates orofacial muscles during natural behavior.

Induction of Hebbian associative plasticity through paired non-invasive brain stimulation of premotor-motor areas to elucidate the network's functional role

The ventral premotor cortex (PMv) is believed to play a pivotal role in a multitude of visuomotor behaviors, such as sensory-guided goal-directed visuomotor transformations, arbitrary visuomotor mapping, and hyper-learnt visuomotor associations underlying automatic imitative tendencies. All these functions are likely carried out through the copious projections connecting PMv to the primary motor cortex (M1). Yet, causal evidence investigating the functional relevance of the PMv-M1 network remains elusive and scarce. In the studies reported in this thesis we addressed this issue using a transcranial magnetic stimulation (TMS) protocol called cortico-cortical paired associative stimulation (ccPAS), which relies on multisite stimulation to induce Hebbian spike-timing dependent plasticity (STDP) by repeatedly stimulating the pathway connecting two target areas to manipulate their connectivity. Firstly, we show that ccPAS protocols informed by both short- and long-latency PMv-M1 interactions effectively modulate connectivity between the two nodes. Then, by pre-activating the network to apply ccPAS in a state-dependent manner, we were able to selectively target specific functional visuo-motor pathways, demonstrating the relevance of PMv-M1 connectivity to arbitrary visuomotor mapping. Subsequently, we addressed the PMv-to-M1 role in automatic imitation, and demonstrated that its connectivity manipulation has a corresponding impact on automatic imitative tendencies. Finally, by combining dual-coil TMS connectivity assessments and ccPAS in young and elderly individuals, we traced effective connectivity of premotor-motor networks and tested their plasticity and relevance to manual dexterity and force in healthy ageing. Our findings provide unprecedent causal evidence of the functional role of the PMv-to-M1 network in young and elderly individuals. The studies presented in this thesis suggest that ccPAS can effectively modulate the strength of connectivity between targeted areas, and coherently manipulate a networks’ behavioral output. Results open new research prospects into the causal role of cortico-cortical connectivity, and provide necessary information to the development of clinical interventions based on connectivity manipulation.

Relationships between movement initiation times and movement-related cortical potentials in Parkinson's disease

Movement-related cortical potentials recorded from the scalp reveal increasing cortical activity occurring prior to voluntary movement. Studies of set-related cortical activity recorded from single neurones within premotor and supplementary motor areas in monkeys suggest that such premovement activity may act to prime activity of appropriate motor units in readiness to move, thereby facilitating the movement response. Such a role of early stage premovement activity in movement-related cortical potentials was investigated by examining the relationship between premovement cortical activity and movement initiation or reaction times. Parkinson's disease and control subjects performed a simple button-pressing reaction time task and individual movement-related potentials were averaged for responses with short compared with long reaction times. For Parkinson's disease subjects but not for the control subjects, early stage premovement cortical activity was significantly increased in amplitude for faster reaction times, indicating that there is indeed a relationship between premovement cortical activity amplitude and movement initiation or reaction times. In support of studies of set-related cortical activity in monkeys, it is therefore suggested that early stage premovement activity reflects the priming of appropriate motor units of primary motor cortex, thereby reducing movement initiation or reaction times. (C) 1999 Elsevier Science B.V. All rights reserved.

Bimanual co-ordination in Huntington's disease

The ability of Huntington's disease patients to co-ordinate their two hands with and without external cueing was investigated. Twelve Huntington's disease patients and sex- and age-matched controls performed a bimanual cranking task at two speeds (0.5 Hz, 1.5 Hz) and phase relationships (in-phase, anti-phase), with and without an external metronome cue. Data were sampled at 200 Hz, and raw displacement data for each hand, mean and standard deviation measures of the relative positions of the two hands and their velocities were then calculated. All participants could perform the in-phase movement, at both speeds; however, the Huntington's disease patients were more variable and less accurate than the control participants, particularly at the fast speed. While controls could perform the anti-phase movement, in which rotation of the cranks differed by 180 degrees at both speeds, Huntington's disease patients were unable to do so at either speed, reverting to the in-phase movement at the slow speed. An external metronome cue did not improve the performance of the Huntington's disease patients, which differentiated this group from patients suffering from Parkinson's disease. The Huntington's disease patients' inability to perform the anti-phase movement may be due to damage to the basal ganglia and its output regions.

A medial to lateral shift in pre-movement cortical activity in hemi-Parkinson's disease

Objective: Recent evidence suggests that cortical activity associated with voluntary movement is relatively shifted from medial to lateral premotor areas in Parkinson's disease. This shift occurs bilaterally even for unilateral responses. It is not clear whether the shift in processing reflects an overall change in movement strategy, thereby involving alternate cortical areas, or reflects a compensatory change whereby, given the appropriate conditions, less impaired cortical areas are able to provide a similar function in compensation for those areas which are more impaired. This issue was examined in patients with hemi-Parkinson's disease, in whom basal ganglia impairment is most pronounced in one hemisphere. Methods: Fourteen patients with hemi-Parkinson's disease and 15 age-matched control subjects performed a Go/NoGo finger movement task and the contingent negative variation (CNV) was recorded from 21 scalp positions. Results and conclusions: Maximal CNV amplitudes were found over central medial regions for control subjects, but were shifted more frontally for Parkinson's disease patients, reduced in amplitude over the midline and lateralized towards the side ipsilateral to the greatest basal ganglia impairment. This shift in cortical activity from medial to lateral areas in Parkinson's disease patients appears to reflect a compensatory mechanism operating predominantly on the side of greatest basal ganglia impairment. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

Motor imagery in Parkinson's disease: A PET study

We used positron emission tomography (PET) with O-15-labelled water to record patterns of cerebral activation in six patients with Parkinson's disease (PD), studied when clinically off and after turning on as a result of dopaminergic stimulation. They were asked to imagine a Finger opposition movement performed with their right hand. externally paced at a rate of 1 Hz. Trials alternating between motor imagery and rest were measured. A pilot study of three age-matched controls was also performed. We chose the task as a robust method of activating the supplementary motor area (SMA), defects of which have been reported in PD. The PD patients showed normal de-rees of activation of the SMA (proper) when both off and on. Significant activation with imagining movement also occurred in the ipsilateral inferior parietal cortex (both off and when on) and ipsilateral premotor cortex (when off only). The patients showed significantly greater activation of the rostral anterior cingulate and significantly less activation of the left lingual gyrus and precuneus when performing the task on compared with their performance when off. PD patients when imagining movement and off showed less activation of several sites including the right dorsolateral prefrontal cortex (DLPFC) when compared to the controls performing the same task. No significant differences from controls were present when the patients imagined when on. Our results are consistent with other studies showing deficits of pre-SMA function in PD with preserved function of the SMA proper. In addition to the areas of reduced activation (anterior cingulate, DLPFC), there were also sites of activation (ipsilateral premotor and inferior parietal cortex) previously reported as locations of compensatory overactivity for PD patients performing similar tasks. Both failure of activation and compensatory changes a-re likely to contribute to the motor deficit in PD. (C) 2001 Movement Disorder Society.

The preparation and execution of self-initiated and externally-triggered movement: A study of event-related fMRI

Studies of functional brain imaging in humans and single cell recordings in monkeys have generally shown preferential involvement of the medially located supplementary motor area (SMA) in self-initiated movement and the lateral premotor cortex in externally cued movement. Studies of event-related cortical potentials recorded during movement preparation, however, generally show increased cortical activity prior to self-initiated movements but little activity at early stages prior to movements that are externally cued at unpredictable times. In this study, the spatial location and relative timing of activation for self-initiated and externally triggered movements were examined using rapid event-related functional MRI. Twelve healthy right-handed subjects were imaged while performing a brief finger sequence movement (three rapid alternating button presses: index-middle-index finger) made either in response to an unpredictably timed auditory cue (between 8 to 24 s after the previous movement) or at self-paced irregular intervals. Both movement conditions involved similar strong activation of medial motor areas including the pre-SMA, SMA proper, and rostral cingulate cortex, as well as activation within contralateral primary motor, superior parietal, and insula cortex. Activation within the basal ganglia was found for self-initiated movements only, while externally triggered movements involved additional bilateral activation of primary auditory cortex. Although the level of SMA and cingulate cortex activation did not differ significantly between movement conditions, the timing of the hemodynamic response within the pre-SMA was significantly earlier for self-initiated compared with externally triggered movements. This clearly reflects involvement of the pre-SMA in early processes associated with the preparation for voluntary movement. (C) 2002 Elsevier Science.