Max O. Krucoff

Extracting kinetic information from human motor cortical signals

Brain machine interfaces (BMIs) have the potential to provide intuitive control of neuroprostheses to restore grasp to patients with paralyzed or amputated upper limbs. For these neuroprostheses to function, the ability to accurately control grasp force is critical. Grasp force can be decoded from neuronal spikes in monkeys, and hand kinematics can be decoded using electrocorticogram (ECoG) signals recorded from the surface of the human motor cortex. We hypothesized that kinetic information about grasping could also be extracted from ECoG, and sought to decode continuously-graded grasp force. In this study, we decoded isometric pinch force with high accuracy from ECoG in 10 human subjects. The predicted signals explained from 22% to 88% (60 ± 6%, mean ± SE) of the variance in the actual force generated. We also decoded muscle activity in the finger flexors, with similar accuracy to force decoding. We found that high gamma band and time domain features of the ECoG signal were most informative about kinetics, similar to our previous findings with intracortical LFPs. In addition, we found that peak cortical representations of force applied by the index and little fingers were separated by only about 4mm. Thus, ECoG can be used to decode not only kinematics, but also kinetics of movement. This is an important step toward restoring intuitively-controlled grasp to impaired patients.

Motor cortical prediction of EMG: evidence that a kinetic brain-machine interface may be robust across altered movement dynamics

During typical movements, signals related to both the kinematics and kinetics of movement are mutually correlated, and each is correlated to some extent with the discharge of neurons in the primary motor cortex (M1). However, it is well known, if not always appreciated, that causality cannot be inferred from correlations. Although these mutual correlations persist, their nature changes with changing postural or dynamical conditions. Under changing conditions, only signals directly controlled by M1 can be expected to maintain a stable relationship with its discharge. If one were to rely on noncausal correlations for a brain-machine interface, its generalization across conditions would likely suffer. We examined this effect, using multielectrode recordings in M1 as input to linear decoders of both end point kinematics (position and velocity) and proximal limb myoelectric signals (EMG) during reaching. We tested these decoders across tasks that altered either the posture of the limb or the end point forces encountered during movement. Within any given task, the accuracy of the kinematic predictions tended to be somewhat better than the EMG predictions. However, when we used the decoders developed under one task condition to predict the signals recorded under different postural or dynamical conditions, only the EMG decoders consistently generalized well. Our results support the view that M1 discharge is more closely related to kinetic variables like EMG than it is to limb kinematics. These results suggest that brain-machine interface applications using M1 to control kinetic variables may prove to be more successful than the more standard kinematic approach.

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

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.

Rates and predictors of success and failure in repeat epilepsy surgery: A meta‐analysis and systematic review

Medically refractory epilepsy is a debilitating disorder that is particularly challenging to treat in patients who have already failed a surgical resection. Evidence regarding outcomes of further epilepsy surgery is limited to small case series and reviews. Therefore, our group performed the first quantitative meta‐analysis of the literature from the past 30 years to assess for rates and predictors of successful reoperations.

A novel paraplegia model in awake behaving macaques

Lower limb paralysis from spinal cord injury (SCI) or neurological disease carries a poor prognosis for recovery and remains a large societal burden. Neurophysiological and neuroprosthetic research have the potential to improve quality of life for these patients; however, the lack of an ethical and sustainable nonhuman primate model for paraplegia hinders their advancement. Therefore, our multidisciplinary team developed a way to induce temporary paralysis in awake behaving macaques by creating a fully implantable lumbar epidural catheter-subcutaneous port system that enables easy and reliable targeted drug delivery for sensorimotor blockade. During treadmill walking, aliquots of 1.5% lidocaine with 1:200,000 epinephrine were percutaneously injected into the ports of three rhesus macaques while surface electromyography (EMG) recorded muscle activity from their quadriceps and gastrocnemii. Diminution of EMG amplitude, loss of voluntary leg movement, and inability to bear weight were achieved for 60-90 min in each animal, followed by a complete recovery of function. The monkeys remained alert and cooperative during the paralysis trials and continued to take food rewards, and the ports remained functional after several months. This technique will enable recording from the cortex and/or spinal cord in awake behaving nonhuman primates during the onset, maintenance, and resolution of paraplegia for the first time, thus opening the door to answering basic neurophysiological questions about the acute neurological response to spinal cord injury and recovery. It will also negate the need to permanently injure otherwise high-value research animals for certain experimental paradigms aimed at developing and testing neural interface decoding algorithms for patients with lower extremity dysfunction.NEW & NOTEWORTHY A novel implantable lumbar epidural catheter-subcutaneous port system enables targeted drug delivery and induction of temporary paraplegia in awake, behaving nonhuman primates. Three macaques displayed loss of voluntary leg movement for 60-90 min after injection of lidocaine with epinephrine, followed by a full recovery. This technique for the first time will enable ethical live recording from the proximal central nervous system during the acute onset, maintenance, and resolution of paraplegia.

Nanopolymeric substrates for cyto-regulatory gene program interrogation

Functionalized block copolymers that possess nanoscale thicknesses represent an important class of biomimetic materials with potential applications in drug delivery, membrane/protein-based devices, as well as cellular interrogation platforms for basic science studies. A key element that serves as the foundation for the translational applicability of this material is represented by the examination of its effects upon cyto-regulatory gene programs that govern processes such as cellular stress and inflammation. With a better understanding of the cellular response to these materials, improved design principles can be examined towards the utilization of these polymers for biomedical applications in vivo. Here we present a comprehensive assessment of the basal levels of secretion for a spectrum of inflammatory cytokines/molecules including tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6), interleukin-12 (IL-12), as well as inducible nitric oxide synthase (iNOS). In addition, we examine the effects of cellular incubation with the triblock copolymer in solution upon morphology as well as growth capabilities in vitro. The foundational information gleaned from this study will provide an important glimpse into the internal cellular response to foreign material contact towards the forging of devices fabricated at the interface of biology and artificial materials.

Integrating Molecular, Cellular, and Systems Approaches to Repairing the Brain After Stroke

A stroke implies a sudden and spontaneous onset of neurological symptoms due to a vascular insult. Despite the brain’s inherent capacity for plasticity and spontaneous improvement, strokes still leave many patients with devastating deficits that can permanently affect independence and quality of life. This chapter focuses on ways to help restore the functionality of the central nervous system (CNS) after this type of injury. Understanding how neurons interact on both individual (i.e. cellular and molecular) and population (i.e. synapses and circuits) levels is crucial to developing successful restorative strategies, as is appreciating how these interactions change over the injury-recovery timeline. The CNS has several characteristics that make its restitution exceptionally difficult; beyond even its incredible intricacy, its parenchymal cells, or neurons, do not regenerate well after injury, and this damaged neuronal substrate embodies a consciousness system that must be engaged in its own recovery. In fact, there is now data suggesting that conscious intention, often invoked through goal-oriented rehabilitation, plays a crucial role in facilitating functional plasticity and long-range axonal sprouting. To capitalize on this principle, neural interfaces and electrical stimulation strategies are being integrated into rehabilitation paradigms to provide critically-timed feedback that can reinvigorate injured circuits. Combining these approaches with interventions at the cellular and molecular level (e.g. immunological or genetic modulations aimed at promoting neuronal outgrowth, or stem cells that can replace damaged parenchyma) has the chance to improve neurological recovery to back toward baseline levels. Ultimately, because cells of the CNS do not regrow on their own, and because regrowth and synapse formation does not necessarily ensure restoration of function, harmonious application of synergistic approaches at both the micro- and macroscopic levels will be needed to establish long-lasting functional plasticity and meaningful recovery.

Toward Functional Restoration of the Central Nervous System: A Review of Translational Neuroscience Principles

Injury to the central nervous system (CNS) can leave patients with devastating neurological deficits that may permanently impair independence and diminish quality of life. Recent insights into how the CNS responds to injury and reacts to critically timed interventions are being translated into clinical applications that have the capacity to drastically improve outcomes for patients suffering from permanent neurological deficits due to spinal cord injury, stroke, or other CNS disorders. The translation of such knowledge into practical and impactful treatments involves the strategic collaboration between neurosurgeons, clinicians, therapists, scientists, and industry. Therefore, a common understanding of key neuroscientific principles is crucial. Conceptually, current approaches to CNS revitalization can be divided by scale into macroscopic (systems-circuitry) and microscopic (cellular-molecular). Here we review both emerging and well-established tenets that are being utilized to enhance CNS recovery on both levels, and we explore the role of neurosurgeons in developing therapies moving forward. Key principles include plasticity-driven functional recovery, cellular signaling mechanisms in axonal sprouting, critical timing for recovery after injury, and mechanisms of action underlying cellular replacement strategies. We then discuss integrative approaches aimed at synergizing interventions across scales, and we make recommendations for the basis of future clinical trial design. Ultimately, we argue that strategic modulation of microscopic cellular behavior within a macroscopic framework of functional circuitry re-establishment should provide the foundation for most neural restoration strategies, and the early involvement of neurosurgeons in the process will be crucial to successful clinical translation.

Multitherapeutic hybrid material platforms for nanoengineered medicine

The realization of optimized therapeutic delivery is often challenged by the inability for localized drug activity and systemic cytotoxicity which can contribute to patient treatment complications. Here we demonstrate the block copolymer-mediated deposition of LXRalpha/beta agonist 3-((4-Methoxyphenyl)amino)-4-phenyl-1-(phenylmethyl)-1H-pyrrole-2,5-dione (LXRa) and doxorubicin hydrochloride (Dox) at the air-water interface via Langmuir-Blodgett deposition, as well as copolymer-mediated potent drug elution toward the Raw 264.7 murine macrophage cell line. Confirmation of drug functionality was confirmed via suppression of the interleukin 6 (II-6) and tumor necrosis factor alpha (TNFalpha) inflammatory cytokines (LXRa), as well as DNA fragmentation analysis (Dox). Furthermore, the fragmentation assays demonstrated the innate biocompatibility of the copolymeric material at the genetic level via the confirmed absence of material-induced apoptosis. This modality enables layer-by-layer control of agonist and chemotherapeutic functionalization at the nanoscale for the fine tuning of drug dosage, while simultaneously utilizing the copolymer platform as an anchoring mechanism for drug sequestering, all with an innate material thickness of 4 nm per layer, which is orders of magnitude thinner than existing commercial technologies. Furthermore, these studies comprehensively confirmed the potential translational applicability of copolymeric nanomaterials as localized multi-therapeutic thin film platforms.