Title : Intrathecal baclofen (ITB) combined with locomotor exercise provides better therapeutic outcome in reducing spasticity, improving anxiety, cognitive and activity performance, and no adverse effect on balance performance in a traumatic brain injury (TBI) r
Abstract:
Spasticity is a major health problem for patients with moderate to severe TBI. Progressive development of spasticity following TBI often represents a significant barrier for practical re-entry of TBI patients into the community. This preclinical study evaluated the safety and efficacy of acute ITB treatments and treadmill locomotor training (Tm), individually and as combined therapy. We employed a comprehensive series of long-term quantitative outcome measures to compare new versus standard of care with ITB treatment following TBI, where this combination therapy appears to potentially represent a paradigm shift in rehabilitation therapy. In these studies, ITB (Lioresal® baclofen injection; 0.8µg/hr) and Tm were initiated at one week after injury in a clinically relevant rodent TBI model where we observed enduring spasticity, balance, anxiety and cognitive deficits (Bose et al. 2013; Hou et al. 2017) (Marmarou model; 450g/1.5 m). Spasticity, anxiety-like behavior, balance, cognitive, and home cage activity performances were measured using velocity-dependent ankle torque, an elevated plus maze (EPM), rotorod, Morris water maze (MWM), and Noldus Phenotyper, respectively. One month of ITB and Tm combined treatment completely blocked early onset spasticity and also positive impacts on cognitive, balance, anxiety and activity recoveries. More importantly, this significant therapeutic benefit persisted even after cessation of ITB therapy. The combined therapy group exhibited significantly reduced MWM latency at the fourth day of testing, and significantly less anxiety-like behavior in the EPM. Twelve hour video-tracked activity monitoring data (recorded 6pm - 6am) revealed that compared with non-treated TBI animals, the ITB+Tm group exhibited home caged behavioral patterns that were most similar to normal animals. These observations indicated that initiating ITB in combination with a Tm produced a robust rehabilitation that was more effective than either therapy implemented individually. This improved spasticity outcome was accompanied by marked up-regulation of GABA/GABAb, norepinephrine and BDNF expression in the spinal cord tissue. These data will be compared and discussed with a data set derived from another study where ITB treatment alone initiated at a chronic time point (post-TBI 1 month) showed less attenuation of spasticity, and it adversely affected balance performance. This broad spectrum of comprehensive data supports confidence in the safety, feasibility, and efficacy of early intervention ITB treatments for TBI using with locomotor and ITB therapy for TBI-spasticity. Supported by Medtronic, PLC. and VA Merit Review B6570R.
