Modulation of task-related cortical connectivity in the acute and subacute phase after stroke.

The functional relevance of cortical reorganization post-stroke is still not well understood. In this study, we investigated task-specific modulation of cortical connectivity between neural oscillations in key motor regions during the early phase after stroke. EEG and EMG recordings were examined from 15 patients and 18 controls during a precision grip task using the affected hand. Each patient attended two sessions in the acute and subacute phase (median of 3 and 34 days) post-stroke. Dynamic causal modelling (DCM) for induced responses was used to investigate task-specific modulations of oscillatory couplings in a bilateral network comprising supplementary motor area (SMA), dorsal premotor cortex (PMd) and primary motor cortex (M1). Fourteen models were constructed for each subject, and the input induced by the experimental manipulation (task) was set to inferior parietal lobule (IPL). Bayesian model selection favoured a fully connected model. A reduced coupling from SMA and intact M1 in the γ-band (31-48 Hz) to lesioned M1 in the ß-band (15-30 Hz) was observed in patients in the acute phase compared to controls. Behavioural performance improved significantly in the subacute phase, while an increased positive coupling from intact PMd to lesioned M1 and a less negative modulation from lesioned M1 to intact M1 were observed for patients compared to controls both from the γ-band to the ß-band. We infer that the observed differences in cross-frequency cortical interactions are important for functional recovery.

Changes in corticospinal drive to spinal motoneurones following tablet-based practice of manual dexterity.

The use of touch screens, which require a high level of manual dexterity, has exploded since the development of smartphone and tablet technology. Manual dexterity relies on effective corticospinal control of finger muscles, and we therefore hypothesized that corticospinal drive to finger muscles can be optimized by tablet-based motor practice. To investigate this, sixteen able-bodied females practiced a tablet-based game (3 × 10 min) with their nondominant hand requiring incrementally fast and precise pinching movements involving the thumb and index fingers. The study was designed as a semirandomized crossover study where the participants attended one practice- and one control session. Before and after each session electrophysiological recordings were obtained during three blocks of 50 precision pinch movements in a standardized setup resembling the practiced task. Data recorded during movements included electroencephalographic (EEG) activity from primary motor cortex and electromyographic (EMG) activity from first dorsal interosseous (FDI) and abductor pollicis brevis (APB) muscles. Changes in the corticospinal drive were evaluated from coupling in the frequency domain (coherence) between EEG-EMG and EMG-EMG activity. Following motor practice performance improved significantly and a significant increase in EEG-EMGAPB and EMGAPB-EMGFDI coherence in the beta band (15-30 Hz) was observed. No changes were observed after the control session. Our results show that tablet-based motor practice is associated with changes in the common corticospinal drive to spinal motoneurons involved in manual dexterity. Tablet-based motor practice may be a motivating training tool for stroke patients who struggle with loss of dexterity.

Abnormal dopaminergic modulation of striato-cortical networks underlies levodopa-induced dyskinesias in humans.

Dopaminergic signalling in the striatum contributes to reinforcement of actions and motivational enhancement of motor vigour. Parkinson's disease leads to progressive dopaminergic denervation of the striatum, impairing the function of cortico-basal ganglia networks. While levodopa therapy alleviates basal ganglia dysfunction in Parkinson's disease, it often elicits involuntary movements, referred to as levodopa-induced peak-of-dose dyskinesias. Here, we used a novel pharmacodynamic neuroimaging approach to identify the changes in cortico-basal ganglia connectivity that herald the emergence of levodopa-induced dyskinesias. Twenty-six patients with Parkinson's disease (age range: 51-84 years; 11 females) received a single dose of levodopa and then performed a task in which they had to produce or suppress a movement in response to visual cues. Task-related activity was continuously mapped with functional magnetic resonance imaging. Dynamic causal modelling was applied to assess levodopa-induced modulation of effective connectivity between the pre-supplementary motor area, primary motor cortex and putamen when patients suppressed a motor response. Bayesian model selection revealed that patients who later developed levodopa-induced dyskinesias, but not patients without dyskinesias, showed a linear increase in connectivity between the putamen and primary motor cortex after levodopa intake during movement suppression. Individual dyskinesia severity was predicted by levodopa-induced modulation of striato-cortical feedback connections from putamen to the pre-supplementary motor area (Pcorrected = 0.020) and primary motor cortex (Pcorrected = 0.044), but not feed-forward connections from the cortex to the putamen. Our results identify for the first time, aberrant dopaminergic modulation of striatal-cortical connectivity as a neural signature of levodopa-induced dyskinesias in humans. We argue that excessive striato-cortical connectivity in response to levodopa produces an aberrant reinforcement signal producing an abnormal motor drive that ultimately triggers involuntary movements.

Sense of agency is related to gamma band coupling in an inferior parietal-preSMA circuitry.

In the present study we tested whether sense of agency (SoA) is reflected by changes in coupling between right medio-frontal/supplementary motor area (SMA) and inferior parietal cortex (IPC). Twelve healthy adult volunteers participated in the study. They performed a variation of a line-drawing task (Nielsen, 1963; Fourneret and Jeannerod, 1998), in which they moved a cursor on a digital tablet with their right hand without seeing the hand. Visual feedback displayed on a computer monitor was either in correspondence with or deviated from the actual movement. This made participants uncertain as to the agent of the movement and they reported SoA in approximately 50% of trials when the movement was computer-generated. We tested whether IPC-preSMA coupling was associated with SoA, using dynamic causal modeling (DCM) for induced responses (Chen et al., 2008; Herz et al., 2012). Nine different DCMs were constructed for the early and late phases of the task, respectively. All models included two regions: a superior medial gyrus (preSMA) region and a right supramarginal gyrus (IPC) region. Bayesian models selection (Stephan et al., 2009) favored a model with input to IPC and modulation of the forward connection to SMA in the late task phase, and a model with input to preSMA and modulation of the backward connection was favored for the early task phase. The analysis shows that IPC source activity in the 50-60 Hz range modulated preSMA source activity in the 40-70 Hz range in the presence of SoA compared with no SoA in the late task phase, but the test of the early task phase did not reveal any differences between presence and absence of SoA. We show that SoA is associated with a directionally specific between frequencies coupling from IPC to preSMA in the higher gamma (É£) band in the late task phase. This suggests that SoA is a retrospective perception, which is highly dependent on interpretation of the outcome of the performed action.

10 Hz rTMS over right parietal cortex alters sense of agency during self-controlled movements.

A large body of fMRI and lesion-literature has provided evidence that the Inferior Parietal Cortex (IPC) is important for sensorimotor integration and sense of agency (SoA). We used repetitive transcranial magnetic stimulation (rTMS) to explore the role of the IPC during a validated SoA detection task. 12 healthy, right-handed adults were included. The effects of rTMS on subjects' SoA during self-controlled movements were explored. The experiment consisted of 1/3 self-controlled movements and (2)/3 computer manipulated movements that introduced uncertainty as to whether the subjects were agents of an observed movement. Subjects completed three sessions, in which subjects received online rTMS over the right IPC (active condition), over the vertex (CZ) (sham condition) or no TMS but a sound-matched control. We found that rTMS over right IPC significantly altered SoA of the non-perturbed movements. Following IPC stimulation subjects were more likely to experience self-controlled movements as being externally perturbed compared to the control site (P = 0.002) and the stimulation-free control (P = 0.042). The data support the importance of IPC activation during sensorimotor comparison in order to correctly determine the agent of movements.

The acute brain response to levodopa heralds dyskinesias in Parkinson disease.

OBJECTIVE: In Parkinson disease (PD), long-term treatment with the dopamine precursor levodopa gradually induces involuntary "dyskinesia" movements. The neural mechanisms underlying the emergence of levodopa-induced dyskinesias in vivo are still poorly understood. Here, we applied functional magnetic resonance imaging (fMRI) to map the emergence of peak-of-dose dyskinesias in patients with PD. METHODS: Thirteen PD patients with dyskinesias and 13 PD patients without dyskinesias received 200mg fast-acting oral levodopa following prolonged withdrawal from their normal dopaminergic medication. Immediately before and after levodopa intake, we performed fMRI, while patients produced a mouse click with the right or left hand or no action (No-Go) contingent on 3 arbitrary cues. The scan was continued for 45 minutes after levodopa intake or until dyskinesias emerged. RESULTS: During No-Go trials, PD patients who would later develop dyskinesias showed an abnormal gradual increase of activity in the presupplementary motor area (preSMA) and the bilateral putamen. This hyperactivity emerged during the first 20 minutes after levodopa intake. At the individual level, the excessive No-Go activity in the predyskinesia period predicted whether an individual patient would subsequently develop dyskinesias (p < 0.001) as well as severity of their day-to-day symptomatic dyskinesias (p < 0.001). INTERPRETATION: PD patients with dyskinesias display an immediate hypersensitivity of preSMA and putamen to levodopa, which heralds the failure of neural networks to suppress involuntary dyskinetic movements.

Motivational tuning of fronto-subthalamic connectivity facilitates control of action impulses.

It is critical for survival to quickly respond to environmental stimuli with the most appropriate action. This task becomes most challenging when response tendencies induced by relevant and irrelevant stimulus features are in conflict, and have to be resolved in real time. Inputs from the pre-supplementary motor area (pre-SMA) and inferior frontal gyrus (IFG) to the subthalamic nucleus (STN) are thought to support this function, but the connectivity and causality of these regions in calibrating motor control has not been delineated. In this study, we combined off-line noninvasive brain stimulation and functional magnetic resonance imaging, while young healthy human participants performed a modified version of the Simon task. We show that impairing pre-SMA function by noninvasive brain stimulation improved control over impulsive response tendencies, but only when participants were explicitly rewarded for fast and accurate responses. These effects were mediated by enhanced activation and connectivity of the IFG-STN pathway. These results provide causal evidence for a pivotal role of the IFG-STN pathway during action control. Additionally, they suggest a parallel rather than hierarchical organization of the pre-SMA-STN and IFG-STN pathways, since interruption of pre-SMA function can enhance IFG-STN connectivity and improve control over inappropriate responses.

Levodopa reinstates connectivity from prefrontal to premotor cortex during externally paced movement in Parkinson's disease.

Dopamine deficiency affects functional integration of activity in distributed neural regions. It has been suggested that lack of dopamine induces disruption of neural interactions between prefrontal and premotor areas, which might underlie impairment of motor control observed in patients with Parkinson's disease (PD). In this study we recorded cortical activity with high-density electroencephalography in 11 patients with PD as a pathological model of dopamine deficiency, and 13 healthy control subjects. Participants performed repetitive extension-flexion movements of their right index finger, which were externally paced at a rate of 0.5 Hz. This required participants to align their movement velocity to the slow external pace. Patients were studied after at least 12-hour withdrawal of dopaminergic medication (OFF state) and after intake of the dopamine precursor levodopa (ON state) in order to examine oscillatory coupling between prefrontal and premotor areas during respectively low and high levels of dopamine. In 10 patients and 12 control participants multiple source beamformer analysis yielded task-related activation of a contralateral cortical network comprising prefrontal cortex (PFC), lateral premotor cortex (lPM), supplementary motor area (SMA) and primary motor cortex (M1). Dynamic causal modelling was used to characterize task-related oscillatory coupling between prefrontal and premotor cortical areas. Healthy participants showed task-induced coupling from PFC to SMA, which was modulated within the γ-band. In the OFF state, PD patients did not express any frequency-specific coupling between prefrontal and premotor areas. Application of levodopa reinstated task-related coupling from PFC to SMA, which was expressed as high-ß-γ coupling. Additionally, strong within-frequency γ-coupling as well as cross-frequency θ-γ coupling was observed from PFC to lPM. Enhancement of this cross-frequency θ-γ coupling after application of levodopa was positively correlated with individual improvement in motor function. The results demonstrate that dopamine deficiency impairs the ability to establish oscillatory coupling between prefrontal and premotor areas during an externally paced motor task. Application of extrinsic dopamine in PD patients reinstates physiological prefrontal-premotor coupling and additionally induces within- and cross-frequency coupling from prefrontal to premotor areas, which is not expressed in healthy participants.

Task-specific modulation of effective connectivity during two simple unimanual motor tasks: a 122-channel EEG study.

Neural oscillations are thought to underlie coupling of spatially remote neurons and gating of information within the human sensorimotor system. Here we tested the hypothesis that different unimanual motor tasks are specifically associated with distinct patterns of oscillatory coupling in human sensorimotor cortical areas. In 13 healthy, right-handed subjects, we recorded task-induced neural activity with 122-channel electroencephalography (EEG) while subjects performed fast self-paced extension-flexion movements with the right index finger and an isometric contraction of the right forearm. Task-related modulations of inter-regional coupling within a core motor network comprising the left primary motor cortex (M1), lateral premotor cortex (lPM) and supplementary motor area (SMA) were then modeled using dynamic causal modeling (DCM). A network model postulating coupling both within and across frequencies best captured observed spectral responses according to Bayesian model selection. DCM revealed dominant coupling within the ß-band (13-30 Hz) between M1 and SMA during isometric contraction of the forearm, whereas fast repetitive finger movements were characterized by strong coupling within the γ-band (31-48 Hz) and between the θ- (4-7 Hz) and the γ-band. This coupling pattern was mainly expressed in connections from lPM to SMA and from lPM to M1. We infer that human manual motor control involves task-specific modulation of inter-regional oscillatory coupling both within and across distinct frequency bands. The results highlight the potential of DCM to characterize context-specific changes in coupling within functional brain networks.

Altered sense of Agency in children with spastic cerebral palsy.

BACKGROUND: Children diagnosed with spastic Cerebral Palsy (CP) often show perceptual and cognitive problems, which may contribute to their functional deficit. Here we investigated if altered ability to determine whether an observed movement is performed by themselves (sense of agency) contributes to the motor deficit in children with CP. METHODS: Three groups; 1) CP children, 2) healthy peers, and 3) healthy adults produced straight drawing movements on a pen-tablet which was not visible for the subjects. The produced movement was presented as a virtual moving object on a computer screen. Subjects had to evaluate after each trial whether the movement of the object on the computer screen was generated by themselves or by a computer program which randomly manipulated the visual feedback by angling the trajectories 0, 5, 10, 15, 20 degrees away from target. RESULTS: Healthy adults executed the movements in 310 seconds, whereas healthy children and especially CP children were significantly slower (p < 0.002) (on average 456 seconds and 543 seconds respectively). There was also a statistical difference between the healthy and age matched CP children (p = 0.037). When the trajectory of the object generated by the computer corresponded to the subject's own movements all three groups reported that they were responsible for the movement of the object. When the trajectory of the object deviated by more than 10 degrees from target, healthy adults and children more frequently than CP children reported that the computer was responsible for the movement of the object. CP children consequently also attempted to compensate more frequently from the perturbation generated by the computer. CONCLUSIONS: We conclude that CP children have a reduced ability to determine whether movement of a virtual moving object is caused by themselves or an external source. We suggest that this may be related to a poor integration of their intention of movement with visual and proprioceptive information about the performed movement and that altered sense of agency may be an important functional problem in children with CP.

Tibialis anterior stretch reflex in early stance is suppressed by repetitive transcranial magnetic stimulation.

A rapid plantar flexion perturbation in the early stance phase of walking elicits a large stretch reflex in tibialis anterior (TA). In this study we use repetitive transcranial magnetic stimulation (rTMS) to test if this response is mediated through a transcortical pathway. TA stretch reflexes were elicited in the early stance phase of the step cycle during treadmill walking. Twenty minutes of 1 Hz rTMS at 115% resting motor threshold (MT(r)) significantly decreased (P < 0.05) the magnitude of the later component of the reflex at a latency of approximately 100 ms up to 25 min after the rTMS. Control experiments in which stretch reflexes were elicited during sitting showed no effect on the spinally mediated short and medium latency stretch reflexes (SLR and MLR) while the long latency stretch reflex (LLR) and the motor-evoked potential (MEP) showed a significant decrease 10 min after 115% MT(r) rTMS. This study demonstrates that 1 Hz rTMS applied to the leg area of the motor cortex can suppress the long latency TA stretch reflex during sitting and in the stance phase of walking. These results are in line with the hypothesis that the later component of the TA stretch reflex in the stance phase of walking is mediated by a transcortical pathway. An alternative explanation for the observed results is that the reflex is mediated by subcortical structures that are affected by the rTMS. This study also shows that rTMS may be used to study the neural control of walking.

Modulation of aesthetic value by semantic context: an fMRI study.

Aesthetic judgments, like most judgments, depend on context. Whether an object or image is seen in daily life or in an art gallery can significantly modulate the aesthetic value humans attach to it. We investigated the neural system supporting this modulation by presenting human subjects with artworks under different contexts whilst acquiring fMRI data. Using the same database of artworks, we randomly labelled images as being either sourced from a gallery or computer generated. Subjects' aesthetic ratings were significantly higher for stimuli viewed in the 'gallery' than 'computer' contexts. This contextual modulation correlated with activity in the medial orbitofrontal cortex and prefrontal cortex, whereas the context, independent of aesthetic value, correlated with bilateral activations of temporal pole and bilateral entorhinal cortex. This shows that prefrontal and orbitofrontal cortices recruited by aesthetic judgments are significantly biased by subjects' prior expectations about the likely hedonic value of stimuli according to their source.

An fMRI study of the neural correlates of graded visual perception.

The neural correlates of clearly perceived visual stimuli have been reported previously in contrast to unperceived stimuli, but it is uncertain whether intermediate or graded perceptual experiences correlate with different patterns of neural activity. In this study, the subjective appearance of briefly presented visual stimuli was rated individually by subjects with respect to perceptual clarity: clear, vague or no experience of a stimulus. Reports of clear experiences correlated with activation in a widespread network of brain areas, including parietal cortex, prefrontal cortex, premotor cortex, supplementary motor areas, insula and thalamus. The reports of graded perceptual clarity were reflected in graded neural activity in a network comprising the precentral gyrus, intraparietal sulcus, basal ganglia and the insula. In addition, the reports of vague experiences demonstrated unique patterns of activation. Different degrees of perceptual clarity were reflected both in the degree to which activation was found within parts of the network serving a clear conscious percept, and additional unique activation patterns for different degrees of perceptual clarity. Our findings support theories proposing the involvement of a widespread network of brain areas during conscious perception.