Patients with spinal cord injury lack the connections between brain and spinal cord circuits essential for voluntary movement. Clinical systems that achieve muscle contraction through functional electrical stimulation (FES) have proven to be effective in allowing patients with tetraplegia to regain control of hand movement and to achieve a greater measure of independence in activities of daily living 1,2. In typical systems, the patient uses residual proximal limb movements to trigger pre-programmed stimulation that causes the paralyzed muscles to contract, allowing use of one or two basic grasps. Instead, we have developed, in primates, an FES system that is controlled by recordings made from microelectrodes permanently implanted in the brain. We simulated some of the effects of the paralysis caused by C5-C6 spinal cord injury 3 by injecting a local anesthetic to block the median and ulnar nerves at the elbow. Then, using recordings from approximately 100 neurons in the motor cortex, we predicted the intended activity of several of the paralyzed muscles, and used these predictions to control the intensity of stimulation of the same muscles. This process essentially bypassed the spinal cord, restoring to the monkeys voluntary control of their paralyzed muscles. This achievement represents a major advance toward similar restoration of hand function in human patients through brain-controlled FES. We anticipate that in human patients, this neuroprosthesis would allow much more flexible and dexterous use of the hand than is possible with existing FES systems.

Summary:During the past several years, there has been increasing interest in the role of the blood-brain barrier (BBB) in epilepsy. Advances in neuroradiology have enhanced our ability to image and study the human cerebrovasculature, and further developments in the research of metabolic deficiencies linked to seizure disorders (e.g., GLUT1 deficiency), neuroinflammation, and multiple drug resistance to antiepileptic drugs (AEDs) have amplified the significance of the BBB's relationship to epilepsy.Prior to 1986, BBB research in epilepsy focused on three main areas: ultrastructural studies, brain glucose availability and transport, and clinical uses of AEDs. However, contrast-based imaging techniques and medical procedures such as BBB disruption provided a framework that demonstrated that the BBB could be reversibly disrupted by pathologic or iatrogenic manipulations, with important implications in terms of CNS drug delivery to "multiple drug resistant" brain. This concept of BBB breakdown for therapeutic purposes has also unveiled a previously unrecognized role for BBB failure as a possible etiologic mechanism in epileptogenesis. Finally, a growing body of evidence has shown that inflammatory mechanisms may participate in the pathological changes observed in epileptic brain, with increasing awareness that blood-borne cells or signals may participate in epileptogenesis by virtue of a leaky BBB. In this article we will review the relationships between BBB function and epilepsy. In particular, we will illustrate consensus and divergence between clinical reality and animal studies. Key Words: Antiepileptic drugs-Membrane transport proteins-Monosaccharide transport proteins-Epileptogenesis-Cerebral blood flow.Historically, the convergence between studies of bloodbrain barrier (BBB) and clinical investigation of the epilepsies has been limited to interactions between putative antiepileptic drugs (AED) and the endothelium (for a review of the original BBB studies in epilepsy see (Cornford and Oldendorf, 1986)). These studies were based on the observation that many promising antiepileptic drugs are excluded by the BBB and are thus clinically unusable in spite of significant potency and selectivity, as revealed by in vitro screening or animal models. More recently, it has become apparent that multiple drug resistance is only one of the aspects in BBB research that may impact how we define, prevent and treat seizure disorders. The following paragraphs will summarize recent findings and knowledge within a historical perspective of BBB relevance in the field of epilepsy research (see Fig. 1). Fig. 2 shows the proposed links between BBB and epilepsy. Drug resistance affecting approximately 30%

Behavior is driven by coordinated activity across a population of neurons. Learning requires the brain to change the neural population activity produced to achieve a given behavioral goal. How does population activity reorganize during learning? We studied intracortical population activity in the primary motor cortex of rhesus macaques during short-term learning in a brain-computer interface (BCI) task. In a BCI, the mapping between neural activity and behavior is exactly known, enabling us to rigorously define hypotheses about neural reorganization during learning. We found that changes in population activity followed a suboptimal neural strategy of Reassociation: animals relied on a fixed repertoire of activity patterns and associated those patterns with different movements after learning. These results indicate that the activity patterns that a neural population can generate are even more constrained than previously thought and might explain why it is often difficult to quickly learn to a high level of proficiency.

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Learning has been associated with changes in the brain at every level of organization. However, it remains difficult to establish a causal link between specific changes in the brain and new behavioral abilities. We establish that new neural activity patterns emerge with learning. We demonstrate that these new neural activity patterns cause the new behavior. Thus, the formation of new patterns of neural population activity can underlie the learning of new skills.

Summary:Objectives: A common experimental model of status epilepticus (SE) utilizes intraperitoneal administration of the cholinergic agonist pilocarpine preceded by methylscopolamine treatment. Currently, activation of cholinergic neurons is recognized as the only factor triggering pilocarpine SE. However, cholinergic receptors are also widely distributed systemically and pretreatment with methyl-scopolamine may not be sufficient to counteract the effects of systemically injected pilocarpine. The extent of such peripheral events and the contribution to SE are unknown and the possibility that pilocarpine also induces SE by peripheral actions is yet untested.Methods: We measured in vivo at onset of SE: brain and blood pilocarpine levels, blood-brain barrier (BBB) permeability, Tlymphocyte activation and serum levels of IL-1β and TNF-α. The effects of pilocarpine on neuronal excitability was assessed in vitro on hippocampal slices or whole guinea pig brain preparations in presence of physiologic or elevated [K + ] out .Results: Pilocarpine blood and brain levels at SE were 1400 ± 200 µM and 200 ± 80 µM, respectively. In vivo, after pilocarpine injection, increased serum IL-1β, decreased CD4:CD8 T-lymphocyte ratios and focal BBB leakage were observed. In vitro, pilocarpine failed to exert significant synchronized epileptiform activity when applied at concentrations identical or higher to levels measured in vivo. Intense electrographic seizure-like events occurred only in the copresence of levels of K + (6 mM) mimicking BBB leakage.Conclusions: Early systemic events increasing BBB permeability may promote entry of cofactors (e. g. K + ) into the brain leading to pilocarpine-induced SE. Disturbance of brain homeostasis represents an etiological factor contributing to pilocarpine seizures.

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B.M.Y. designed the experiments and interpreted the results. A.D.D. performed the experiments with input from W.E.B. W.E.B. and B.M.Y. designed the stabilization method. A.D.D. and W.E.B. developed the realtime implementation of the stabilized BCI. A.D.D. and W.E.B. performed the analyses and wrote the manuscript. E.R.O., E.C.T.-K. and A.D.D. implanted the electrode arrays used for the experiments. All authors provided feedback on the manuscript.