This research project will provide novel and unique approach and data on spinal functional topography, structural and functional organization of the spinal motor output and spinal cord rhythmogenesis in individuals with hereditary spastic paraplegia (HSP) and its progression, thus providing spinal biomarkers of this genetic disease.
Originally considered to be caused by damage to the CNS, the potential involvement of the spinal cord circuitry impairment in HSP genesis has received little attention, even though a part of sensorimotor abnormalities is attributable to the impaired state of the spinal circuitry. The rationale and novelty of this project is the following: if the state of the spinal cord is impaired, it should be controlled differently by the descending pathways, which in turn would enhance the reorganization and involvement of the supraspinal structures to compensate for these abnormalities. These reciprocal spinal-supraspinal compensatory mechanisms create a risk of irreversible plastic changes in the state of locomotor circuitry during progression of the disease. Therefore, a better
knowledge about what happens in HSP at the spinal level is critical for both gait and motor function evaluation and rehabilitation.
Specific gait impairments in HSP is an essential concern. We will test whether locomotor impairments are associated with impairment in the rhythmogenesis capacity of the spinal circuitry and segmental spinal reflexes, that we will assess by the proposed methodology and correlate them with genotype. The knowledge collected in
the project has true chances of becoming a landmark in the field of spinal motor impairments in HSP as well as a significant contribution to the understanding the spinal cord mechanisms and connectivity in this genetic disease. This project has immediate clinical outcomes as a new method for evaluation and prognosis of gait disturbances in individuals with HSP, as well as for gait rehabilitation
The project is based on an innovative clinical research approach with a viable technique for uncovering spinal functional biomarkers of this genetic disease, for decoding the spinal locomotor output and documenting the spatiotemporal spinal maps of MN activity in HSP, with considerable diagnostic and rehabilitation relevance.
Spinal cord imaging and assessment of the spatiotemporal EMG and kinematic patterns, as predictive indicators of motor function, have become an essential tool for investigating the function of pattern generation networks in the spinal cord (Yakovenko et al. 2002; Ivanenko et al. 2006, 2013; O¿Donovan et al. 2008; Monaco et al. 2010;
Warp et al. 2012; Stroman et al. 2014; Capogrosso et al. 2016). In recent years, many researchers put significant efforts into understanding and assessing the functional state of the spinal locomotor circuits in humans (Ivanenko et al. 2017). The spinal cord does not simply transmit information to and from the brain and its physiologic state determines reflex, postural and locomotor control. An abnormal spatiotemporal integration of activity in specific spinal segments may result in a risk for failure or abnormalities in gait recovery. Furthermore, it is important to investigate various locomotor tasks given a differential involvement of spinal motoneuronal and
interneuronal circuits in these tasks (Ivanenko et al. 2008; Merkulyeva et al. 2018). This new information is much needed in the context of locomotor impairments in HSP and it will provide a reference for clinical studies to investigate the relative efficacy of different therapeutic interventions. We expect to identify differential changes in segmental reflexes (AIM 3), correlate them with spinal functional topography (AIM 1,2) and with genotype (SPG4, SPG3A, SPG5, SPG7). This will provide a unified approach for looking for spinal functional biomarkers of this genetic disease.