Multifactorial motor behavior assessment for real-time evaluation of emerging therapeutics to treat neurologic impairments

Abstract

Conflict of interestThe authors declare no conflicts of interest. AcknowledgementsThe authors thanks Mr. Seungleal (Brian) Paek for surgical and experimental assistance related to the Parkinsonian model. Finally, the authors thank Mayo Clinic's Division of Engineering for their support to design and construct the multifactorial assessment system. AbstractIntegrating multiple assessment parameters of motor behavior is critical for understanding neural activity dynamics during motor control in both intact and dysfunctional nervous systems.Here, we described a novel approach (termed Multifactorial Behavioral Assessment (MfBA)) to integrate, in real-time, electrophysiological and biomechanical properties of rodent spinal sensorimotor network activity with behavioral aspects of motor task performance. Specifically, the MfBA simultaneously records limb kinematics, multi-directional forces and electrophysiological metrics, such as high-fidelity chronic intramuscular electromyography synchronized in time to spinal stimulation in order to characterize spinal cord functional motor evoked potentials (fMEPs). Additionally, we designed the MfBA to incorporate a body weight support system to allow bipedal and quadrupedal stepping on a treadmill and in an open field environment to assess function in rodent models of neurologic disorders that impact motor activity This novel approach was validated using, a neurologically intact cohort, a cohort with unilateral Parkinsonian motor deficits due to midbrain lesioning, and a cohort with complete hind limb paralysis due to T8 spinal cord transection. In the SCI cohort, lumbosacral epidural electrical stimulation (EES) was applied, with and without administration of the serotonergic agonist Quipazine, to enable hind limb motor functions following paralysis. The results presented herein demonstrate the MfBA is capable of integrating multiple metrics of motor activity in order to characterize relationships between EES inputs that modulate mono-and polysynaptic outputs from spinal circuitry which in turn, can be used to elucidate underlying electrophysiologic mechanisms of motor behavior by synchronizing these datasets to metrics of movement and behavior. These results also demonstrate that proposed MfBA is an effective tool to integrate biomechanical and electrophysiology metrics, synchronized to therapeutic inputs such as EES or pharmacology, during body weight supported treadmill or open field motor activities, to target a high range of variations in motor behavior as a result of neurological deficit at the different levels of CNS.

Newly regenerated axons through a cell-containing biomaterial scaffold promote reorganization of spinal circuitry and restoration of motor functions with epidural electrical stimulation

“…4 week time-point in this study of the combined therapy group (5.29±0.7) was similar to effect of OPF+ scaffolds with GDNF Schwann cells (3.67±0.4) 13 . Limitations of BBB 40,41 we added to the validity of these findings with electrophysiological and kinematic analysis in behavior assessment system 42 . Improvement in group with combined therapy vs. EES only, and with intermediate effect in scaffolds only group was found.…”

“…Nexus system was used to obtain threedimensional coordinates of the markers. Analysis of kinematic data was performed using method previously described 42 .…”

“…Electrophysiology: EMG activity was collected from TA and MG muscles on both legs at 4000 Hz during stepping and later high-pass filtered at 0.5 Hz to remove direct current offset. In order to determine flexor (TA) and extensor (MG) coordination, EMG signals were band pass filtered (10 Hz to 1000 Hz), rectified, normalized and plotted on X and Y axis consecutively 42 . The excitability of the spinal cord were determined by stimulating the spinal cord at S1 spinal level while spinal cord motor evoked potentials (SCMEP) were recorded from the hind-limb muscles via EMG 20 , while the rats were suspended in the body weight support system 42 .…”

“…In order to determine flexor (TA) and extensor (MG) coordination, EMG signals were band pass filtered (10 Hz to 1000 Hz), rectified, normalized and plotted on X and Y axis consecutively 42 . The excitability of the spinal cord were determined by stimulating the spinal cord at S1 spinal level while spinal cord motor evoked potentials (SCMEP) were recorded from the hind-limb muscles via EMG 20 , while the rats were suspended in the body weight support system 42 . The functional connectivity across the injury and reflexes below the injury were tested by stimulating T8 spinal level above and S1 segment below the injury, while recording SCMEP from hindlimb muscles.…”

The Translesional Spinal Network and Its Reorganization after Spinal Cord Injury

“…The absence of effective single clinical therapeutic to heal the human spinal cord following injury lead to multiple state-of-the-art combinatorial treatment paradigms that demonstrate functional gains below the level of SCI. Numerous preclinical investigations, as well as a few clinical trials, have reported beneficial outcomes from experimental treatments, such as immunomodulatory therapies (Krupa and others 2019; Machova Urdzikova and others 2015), stem cells (Islamov and others 2017; Izmailov and others 2017; Krupa and others 2018; Mukhamedshina and others 2019; Ruzicka and others 2017), trophic factors (Zhang and others 2014), electrical stimulation (ES) of the sublesional spinal cord circuits (Gerasimenko and others 2001; Gill and others 2018; Ichiyama and others 2005a; Islam and others 2019b; Lavrov and others 2015), or neuroprosthetics approaches (Frigon and others 2011; Mikhaylov and others 2020; Shah and Lavrov 2017).…”