Enhancing Nervous System Recovery through Neurobiologics, Neural Interface Training, and Neurorehabilitation

Ok, lay out a strategy to accomplish and deliver it to the stroke leader that will follow thru. Oh well, NO LEADERS IN STROKE, nothing will happen.  And look at all those references that nothing will be done with. There really in no point in doing ANY STROKE RESEARCH until we get survivors in charge. It is a complete waste of time until that occurs.

Enhancing Nervous System Recovery through Neurobiologics, Neural Interface Training, and Neurorehabilitation

Max O. Krucoff^1*, Shervin Rahimpour¹, Marc W. Slutzky^2,3, V. Reggie Edgerton⁴ and Dennis A. Turner^1,5,6

• ¹Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA
• ²Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
• ³Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
• ⁴Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA
• ⁵Department of Neurobiology, Duke University Medical Center, Durham, NC, USA
• ⁶Research and Surgery Services, Durham Veterans Affairs Medical Center, Durham, NC, USA

After an initial period of recovery, human neurological injury has long been thought to be static. In order to improve quality of life for those suffering from stroke, spinal cord injury, or traumatic brain injury, researchers have been working to restore the nervous system and reduce neurological deficits through a number of mechanisms. For example, neurobiologists have been identifying and manipulating components of the intra- and extracellular milieu to alter the regenerative potential of neurons, neuro-engineers have been producing brain-machine and neural interfaces that circumvent lesions to restore functionality, and neurorehabilitation experts have been developing new ways to revitalize the nervous system even in chronic disease. While each of these areas holds promise, their individual paths to clinical relevance remain difficult. Nonetheless, these methods are now able to synergistically enhance recovery of native motor function to levels which were previously believed to be impossible. Furthermore, such recovery can even persist after training, and for the first time there is evidence of functional axonal regrowth and rewiring in the central nervous system of animal models. To attain this type of regeneration, rehabilitation paradigms that pair cortically-based intent with activation of affected circuits and positive neurofeedback appear to be required—a phenomenon which raises new and far reaching questions about the underlying relationship between conscious action and neural repair. For this reason, we argue that multi-modal therapy will be necessary to facilitate a truly robust recovery, and that the success of investigational microscopic techniques may depend on their integration into macroscopic frameworks that include task-based neurorehabilitation. We further identify critical components of future neural repair strategies and explore the most updated knowledge, progress, and challenges in the fields of cellular neuronal repair, neural interfacing, and neurorehabilitation, all with the goal of better understanding neurological injury and how to improve recovery.

Introduction

Historically, for patients suffering from spinal cord injury (SCI), stroke, or traumatic brain injury (TBI), the prognosis for recovery has been poor, and patients with more complete and chronic injuries have shown the least potential for improvement (Jennett et al., 1976; Waters et al., 1992, 1996; Curt et al., 2008; Perel et al., 2008; Steyerberg et al., 2008; Lloyd-Jones et al., 2010). Researchers have been dedicated to improving the quality of life for these patients in several ways, e.g., (1) biological manipulation of the cellular milieu to encourage neuronal repair and regeneration (Magavi et al., 2000; Chen et al., 2002; Lee et al., 2004; Freund et al., 2006; Benowitz and Yin, 2007; Park et al., 2008; Maier et al., 2009; de Lima et al., 2012b; Dachir et al., 2014; Li et al., 2015; Omura et al., 2015), (2) creation of neural- or brain-machine interfaces designed to circumvent lesions and restore functionality (Wolpaw and McFarland, 1994; Kennedy and Bakay, 1998; Leuthardt et al., 2004; Monfils et al., 2004; Hochberg et al., 2006, 2012; Moritz et al., 2008; O'Doherty et al., 2009; Ethier et al., 2012; Collinger et al., 2013; Guggenmos et al., 2013; Ifft et al., 2013; Memberg et al., 2014; Zimmermann and Jackson, 2014; Grahn et al., 2015; Jarosiewicz et al., 2015; Soekadar et al., 2015; Bouton et al., 2016; Capogrosso et al., 2016; Donati et al., 2016; Hotson et al., 2016; Rajangam et al., 2016; Vansteensel et al., 2016), and (3) new rehabilitation techniques that include electrical stimulation and pharmacological enhancement of spinal circuitry to stimulate recovery (Carhart et al., 2004; Levy et al., 2008, 2016; Dy et al., 2010; Harkema et al., 2011, 2012; Dominici et al., 2012; van den Brand et al., 2012; Gad et al., 2013b, 2015; Angeli et al., 2014; Gharabaghi et al., 2014a,c; Wahl et al., 2014; Gerasimenko et al., 2015b). Unfortunately, the path to clinical relevance for these individual approaches remains long, and each field tends to operate largely in its own sphere of influence. Nonetheless, there is now emerging evidence that these methods may synergistically enhance recovery of native motor function that can persist even after the training period and is beyond what was previously thought possible (van den Brand et al., 2012; Guggenmos et al., 2013; Angeli et al., 2014; Wahl et al., 2014; Gad et al., 2015; García-Alías et al., 2015). Some animal models are even displaying functional axonal regrowth, sprouting, and rewiring never seen before in the central nervous system (CNS) of mammals (Bregman et al., 1995; Chen et al., 2002; Liebscher et al., 2005; Freund et al., 2006; Maier et al., 2009; van den Brand et al., 2012; Wahl et al., 2014; García-Alías et al., 2015). Throughout much of this work, evidence is emerging that combinatorial therapy across fields may actually be necessary to achieve significant and lasting neurological repair (Wahl et al., 2014; Gad et al., 2015). This paper explores the state of the art in each of these disciplines, identifies essential components of rehabilitation strategies, and argues why synthesizing approaches across specialties will be essential to realizing clinical applicability.