Multimodal (EEG-fMRI) functional connectivity study of levodopa effect in Parkinson’s disease

Aim: To assess if the intake of levodopa in patients with Parkinson’s Disease (PD) changes cerebral connectivity, as revealed by simultaneous recording of hemodynamic (functional MRI, or fMRI) and electric (electroencephalogram, EEG) signals. Particularly, we hypothesize that the strongest changes in FC will involve the motor network, which is the most impaired in PD. Methods: Eight patients with diagnosis of PD “probable”, therapy with levodopa exclusively, normal cognitive and affective status, were included. Exclusion criteria were: moderate-severe rest tremor, levodopa induced dyskinesia, evidence of gray or white matter abnormalities on structural MRI. Scalp EEG (64 channels) were acquired inside the scanner (1.5 Tesla) before and after the intake of levodopa. fMRI functional connectivity was computed from four regions of interest: right and left supplementary motor area (SMA) and right and left precentral gyrus (primary motor cortex). Weighted partial directed coherence (w-PDC) was computed in the inverse space after the removal of EEG gradient and cardioballistic artifacts. Results and discussion: fMRI group analysis shows that the intake of levodopa increases hemodynamic functional connectivity among the SMAs / primary motor cortex and: sensory-motor network itself, attention network and default mode network. w-PDC analysis shows that EEG connectivity among regions of the motor network has the tendency to decrease after the intake the levodopa; furthermore, regions belonging to the DMN have the tendency to increase their outflow toward the rest of the brain. These findings, even if in a small sample of patients, suggest that other resting state physiological functional networks, beyond the motor one, are affected in patients with PD. The behavioral and cognitive tasks corresponding to the affected networks could benefit from the intake of levodopa.

Methods for the estimation of the cortical activity and connectivity during cognitive tasks in humans

The research activity characterizing the present thesis was mainly centered on the design, development and validation of methodologies for the estimation of stationary and time-varying connectivity between different regions of the human brain during specific complex cognitive tasks. Such activity involved two main aspects: i) the development of a stable, consistent and reproducible procedure for functional connectivity estimation with a high impact on neuroscience field and ii) its application to real data from healthy volunteers eliciting specific cognitive processes (attention and memory). In particular the methodological issues addressed in the present thesis consisted in finding out an approach to be applied in neuroscience field able to: i) include all the cerebral sources in connectivity estimation process; ii) to accurately describe the temporal evolution of connectivity networks; iii) to assess the significance of connectivity patterns; iv) to consistently describe relevant properties of brain networks. The advancement provided in this thesis allowed finding out quantifiable descriptors of cognitive processes during a high resolution EEG experiment involving subjects performing complex cognitive tasks.

The future in action: neurophysiological and behavioral evidence of anticipatory motor simulation.

The motor system can no longer be considered as a mere passive executive system of motor commands generated elsewhere in the brain. On the contrary, it is deeply involved in perceptual and cognitive functions and acts as an “anticipation device”. The present thesis investigates the anticipatory motor mechanisms occurring in two particular instances: i) when processing sensory events occurring within the peripersonal space (PPS); and ii) when perceiving and predicting others’actions. The first study provides evidence that PPS representation in humans modulates neural activity within the motor system, while the second demonstrates that the motor mapping of sensory events occurring within the PPS critically relies on the activity of the premotor cortex. The third study provides direct evidence that the anticipatory motor simulation of others’ actions critically relies on the activity of the anterior node of the action observation network (AON), namely the inferior frontal cortex (IFC). The fourth study, sheds light on the pivotal role of the left IFC in predicting the future end state of observed right-hand actions. Finally, the fifth study examines how the ability to predict others’ actions could be influenced by a reduction of sensorimotor experience due to the traumatic or congenital loss of a limb. Overall, the present work provides new insights on: i) the anticipatory mechanisms of the basic reactivity of the motor system when processing sensory events occurring within the PPS, and the same anticipatory motor mechanisms when perceiving others’ implied actions; ii) the functional connectivity and plasticity of premotor-motor circuits both during the motor mapping of sensory events occurring within the PPS and when perceiving others’ actions; and iii) the anticipatory mechanisms related to others’ actions prediction.

Pharmacological Rescue of Dendritic Pathology in the Ts65Dn Mouse Model of Down Syndrome

Down syndrome (DS) is a genetic pathology characterized by brain hypotrophy and severe cognitive disability. Although defective neurogenesis is an important determinant of cognitive impairment, a severe dendritic pathology appears to be an equally important factor. It is well established that serotonin plays a pivotal role both on neurogenesis and dendritic maturation. Since the serotonergic system is profoundly altered in the DS brain, we wondered whether defects in the hippocampal development can be rescued by treatment with fluoxetine, a selective serotonin reuptake inhibitor and a widely used antidepressant drug. A previous study of our group showed that fluoxetine fully restores neurogenesis in the Ts65Dn mouse model of DS and that this effect is accompanied by a recovery of memory functions. The goal of the current study was to establish whether fluoxetine also restores dendritic development and maturation. In mice aged 45 days, treated with fluoxetine in the postnatal period P3-P15, we examined the dendritic arbor of newborn and mature granule cells of the dentate gyrus (DG). The granule cells of trisomic mice had a severely hypotrophic dendritic arbor, fewer spines and a reduced innervation than euploid mice. Treatment with fluoxetine fully restored all these defects. Moreover the impairment of excitatory and inhibitory inputs to CA3 pyramidal neurons was fully normalized in treated trisomic mice, indicating that fluoxetine can rescue functional connectivity between the DG and CA3. The widespread beneficial effects of fluoxetine on the hippocampal formation suggest that early treatment with fluoxetine can be a suitable therapy, possibly usable in humans, to restore the physiology of the hippocampal networks and, hence, memory functions. These findings may open the way for future clinical trials in children and adolescents with DS.

Residual function, spontaneous reorganisation and treatment plasticity in homonymous visual field defects

This thesis will focus on the residual function and visual and attentional deficits in human patients, which accompany damage to the visual cortex or its thalamic afferents, and plastic changes, which follow it. In particular, I will focus on homonymous visual field defects, which comprise a broad set of central disorders of vision. I will present experimental evidence that when the primary visual pathway is completely damaged, the only signal that can be implicitly processed via subcortical visual networks is fear. I will also present data showing that in a patient with relative deafferentation of visual cortex, changes in the spatial tuning and response gain of the contralesional and ipsilesional cortex are observed, which are accompanied by changes in functional connectivity with regions belonging to the dorsal attentional network and the default mode network. I will also discuss how cortical plasticity might be harnessed to improve recovery through novel treatments. Moreover, I will show how treatment interventions aimed at recruiting spared subcortical pathway supporting multisensory orienting can drive network level change.