Probing Context-Dependent Modulations of Ipsilateral Premotor-Motor Connectivity in Relapsing-Remitting Multiple Sclerosis

Objective: We employed dual-site TMS to test whether ipsilateral functional premotor-motor connectivity is altered in relapsing-remitting Multiple Sclerosis (RR-MS) and is related to central fatigue. Methods: Twelve patients with RR-MS and 12 healthy controls performed a visually cued Pinch-NoPinch task with their right hand. During the reaction time (RT) period of Pinch and No-Pinch trials, single-site TMS was applied to the left primary motor cortex (M1) or dual-site TMS was applied to the ipsilateral dorsal premotor cortex (PMd) and to M1. We traced context-dependent changes of corticospinal excitability and premotor-motor connectivity by measuring Motor-Evoked Potentials (MEPs) in the right first dorsal interosseus muscle. Central fatigue was evaluated with the Fatigue Scale for Motor and Cognitive Functions (FSMS). Results: In both groups, single-pulse TMS revealed a consistent increase in mean MEP amplitude during the Reaction Time (RT) period relative to a resting condition. Task-related corticospinal facilitation increased toward the end of the RT period in Pinch trials, while it decreased in No-Pinch trials. Again, this modulation of MEP facilitation by trial type was comparable in patients and controls. Dual-site TMS showed no significant effect of a conditioning PMd pulse on ipsilateral corticospinal excitability during the RT period in either group. However, patients showed a trend toward a relative attenuation in functional PMd-M1 connectivity at the end of the RT period in No-Pinch trials, which correlated positively with the severity of motor fatigue (r = 0.69; p = 0.007). Conclusions: Dynamic regulation of corticospinal excitability and ipsilateral PMd-M1 connectivity is preserved in patients with RR-MS. MS-related fatigue scales positively with an attenuation of premotor-to-motor functional connectivity during cued motor inhibition. Significance: The temporal, context-dependent modulation of ipsilateral premotor-motor connectivity, as revealed by dual-site TMS of ipsilateral PMd and M1, constitutes a promising neurophysiological marker of fatigue in MS.

Unraveling neural and behavioral mechanisms of cognitive self-attenuation and alienation

Giedre Stripeikyte

The present thesis aimed at investigating behavioral and neural underpinnings of the mechanisms related to the different aspects of self-monitoring. The first aim was to study functional connectivity alterations related to the mechanisms accounting for the alienation in psychotic patients and those at high-risk to develop it. The second aim was to extend the fundamental knowledge of whether higher-level cognitive processes beyond sensorimotor involvement are subject to attenuation and whether it is affected in psychotic patients with thought insertion. In Part I of the thesis, I have studied whether the neural mechanisms (PH-network) accounting for the presence hallucination (PH), the experience that someone is here when no one is around, could also be relevant to understand alienation experienced in psychotic patients. In Study 1, I have investigated psychotic patients with passivity experiences where one's own actions, thoughts and emotions are perceived as not self-generated and caused by an external entity. In Study 2, individuals with 22q11 deletion syndrome who are at high-risk for psychosis development were investigated. In both populations, reduced functional connectivity between fronto-temporal connections within the PH-network was revealed. Taken together, these studies show that PH-network is affected not only when psychosis manifests but also in individuals prone to develop psychosis. The current findings strengthen the relevance of PH mechanisms to explain the occurrence of psychotic symptoms, specifically the alienation, and potentially could provide a biomarker for the disease development. In Part II of the thesis, I have investigated self-attenuation, an important aspect for the sense of agency, during the cognitive function of numerosity estimations in healthy individuals and psychotic patients with thought insertion. In Study 3, a novel fMRI task was designed, allowing a controlled comparison of numerosity estimations for self and externally generated words in healthy volunteers. For the first time, self-attenuation during cognitive function beyond sensorimotor processing was reported. It was linked to the functional network involving intraparietal sulcus (key numerosity region) and extended areas more generally associated with attenuation processes. This work was continued in Study 4, where psychotic patients with thought insertion were studied. I showed that cognitive self-attenuation during numerosity estimations can be observed in patients with thought insertion and is related to altered executive functioning. Importantly, increased functional connectivity within the network related to attenuation processing during numerosity estimations was found in patients with thought insertion suggesting insufficient attenuation at the neural level. Lastly, I found the association between the altered functional connectivity within the PH-network and cognitive self-attenuation, providing a link between two different aspects related to the self-monitoring in patients with thought insertion. To summarize, I present new insights into the different mechanisms related to self-monitoring, which would help to understand the manifestation of psychotic symptoms and develop prevention strategies.

EPFL2020

The role of the inferior parietal lobule in writer's cramp

Traian Popa

Humans have a distinguishing ability for fine motor control that is subserved by a highly evolved cortico-motor neuronal network. The acquisition of a particular motor skill involves a long series of practice movements, trial and error, adjustment and refinement. At the cortical level, this acquisition begins in the parieto-temporal sensory regions and is subsequently consolidated and stratified in the premotor-motor cortex. Task-specific dystonia can be viewed as a corruption or loss of motor control confined to a single motor skill. Using a multimodal experimental approach combining neuroimaging and non-invasive brain stimulation, we explored interactions between the principal nodes of the fine motor control network in patients with writer's cramp and healthy matched controls. Patients and healthy volunteers underwent clinical assessment, diffusion-weighted MRI for tractography, and functional MRI during a finger tapping task. Activation maps from the task-functional MRI scans were used for target selection and neuronavigation of the transcranial magnetic stimulation. Single- and double-pulse TMS evaluation included measurement of the input-output recruitment curve, cortical silent period, and amplitude of the motor evoked potentials conditioned by cortico-cortical interactions between premotor ventral (PMv)-motor cortex (M1), anterior inferior parietal lobule (aIPL)-M1, and dorsal inferior parietal lobule (dIPL)-M1 before and after inducing a long term depression-like plastic change to dIPL node with continuous thetaburst transcranial magnetic stimulation in a randomized, sham-controlled design. Baseline dIPL-M1 and aIPL-M1 cortico-cortical interactions were facilitatory and inhibitory, respectively, in healthy volunteers, whereas the interactions were converse and significantly different in writer's cramp. Baseline PMv-M1 interactions were inhibitory and similar between the groups. The dIPL-PMv resting state functional connectivity was increased in patients compared to controls, but no differences in structural connectivity between the nodes were observed. Cortical silent period was significantly prolonged in writer's cramp. Making a long term depression-like plastic change to dIPL node transformed the aIPL-M1 interaction to inhibitory (similar to healthy volunteers) and cancelled the PMv-M1 inhibition only in the writer's cramp group. These findings suggest that the parietal multimodal sensory association region could have an aberrant downstream influence on the fine motor control network in writer's cramp, which could be artificially restored to its normal function.

OXFORD UNIV PRESS2020

The role of the inferior parietal lobule in writer's cramp

Traian Popa

OXFORD UNIV PRESS2020

Unraveling neural and behavioral mechanisms of cognitive self-attenuation and alienation

Giedre Stripeikyte

EPFL2020