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For over 40 years, since I first obtained evidence for nonsynaptic diffusion neurotransmission (most scientists call it Volume Transmission), I have been convinced that we scientists were ignoring organizational dynamics other than the mechanistic synaptic organization of the brain. For many years it was an uneasy feeling, since I was aware there are so many avenues to explore in brain function. I have wondered how much we scientists have ignored, in our quest to understand how the brain really works, due to our efforts to "be scientific". In addition to the difficulty of understanding how the brain functions, how could we even begin to explore the human experience? In this paper I will first discuss some emerging concepts of brain function. I will then comment on the development of concepts that have been a part of my own research experience.

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Termination of motor rehabilitation is often recommended as patients with cerebrovascular accident (CVA) become more chronic and/or when they fail to respond positively to motor rehabilitation (commonly termed a "plateau"). Managed-care programs frequently reinforce this practice by restricting care to patients responding to therapy and/or to the most acute patients. When neuromuscular adaptation occurs in exercise, rather than terminating the current regimen, a variety of techniques (eg, modifying intensity, attempting different modalities) are used to facilitate neuromuscular adaptations. After presenting the concepts of the motor recovery plateau and adaptation, we similarly posit that patients with CVA adapt to therapeutic exercise but that this is not indicative of a diminished capacity for motor improvement. Instead, like traditional exercise circumstances, adaptive states can be overcome by modifying regimen aspects (eg, intensity, introducing new exercises). Findings suggesting that patients with chronic CVA can benefit from motor rehabilitation programs that apply novel or different parameters and modalities. The objectives of this commentary are to (1) to encourage practitioners to reconsider the notion of the motor recovery plateau, (2) to reconsider chronic CVA patients' ability to recover motor function, and (3) to use different modalities when accommodation is exhibited.

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Forty years ago a project to explore late brain plasticity was initiated that was to lead into a broad area of sensory substitution studies. The questions at that time were: Can a person who has never seen learn to see as an adult? Is the brain sufficiently plastic to develop an entirely new sensory system? The short answer to both questions is yes, first clearly demonstrated in 1969 ((Bach-y-Rita et al., 1969)). To reach that conclusion, it was first necessary to find a way to get visual information to the brain. That took many years and is still the most challenging aspect of the research and the development of practical sensory substitution and augmentation systems. The sensor array is not a problem: a TV camera for blind persons; an accelerometer for persons with vestibular loss; a microphone for deaf persons. These are common and fully developed devices. The problem is the brain-machine interface (BMI). In this short report, only two substitution systems are discussed, vision and vestibular substitution.

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How much surviving normal neural tissue is required for functional reorganization after a lesion? Clinical and experimental studies suggest that at little as two percent remaining tissue may be sufficient, at least in some cases, for functional reorganization. Recent sensory substitution studies with persons who have been diagnosed with total vestibular loss (e.g., due to an ototoxic reaction to an antibiotic) suggest that the persisting function after removal of the substitution system may be related to the survival of a small amount of vestibular tissue.

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Recent advances in the instrumentation technology of sensory substitution have presented new opportunities to develop systems for compensation of sensory loss. In sensory substitution (e.g. of sight or vestibular function), information from an artificial receptor is coupled to the brain via a human-machine interface. The brain is able to use this information in place of that usually transmitted from an intact sense organ. Both auditory and tactile systems show promise for practical sensory substitution interface sites. This research provides experimental tools for examining brain plasticity and has implications for perceptual and cognition studies more generally.

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Stroke-induced hemiparesis is a debilitating impairment that compromises ability to perform many activities of daily living (ADLs). Many new therapies for hemiparesis, although intriguing, require exceptional patient motivation and/or may be difficult to implement in some clinical situations. This brief report revisits a motivating, game-based rehabilitation modality reported nearly three decades ago that has heretofore been ignored. Pilot data, examining the feasibility and efficacy of the device, are presented.

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Volume transmission (VT) is the diffusion through the brain extracellular fluid of neurotransmitters released at points that may be remote from the target cells with the resulting activation of extrasynaptic receptors. VT appears to play multiple roles in the brain in normal and abnormal activity, brain plasticity and drug actions. The relevance of VT to pain perception has been explored in this review.

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This lecture highlights my career in rehabilitation research. My principal efforts in rehabilitation have been to study (1) mechanisms of brain plasticity related to reorganization of the brain and recovery of function; (2) late postacute rehabilitation; (3) sensory substitution; and (4) rehabilitation engineering. A principal goal has been to aid in the development of a strong scientific base in rehabilitation.

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Evidence has been accumulating that the brain can reorganize extensively after damage and that reorganization can be obtained even many years after the trauma with appropriate late rehabilitation. An understanding of the brain plasticity mechanisms should lead to more effective rehabilitation and neuropharmacology. In this communication, several emerging concepts with supporting experimental evidence have been presented. These include non-synaptic diffusion neurotransmission, extracellular space volume fraction, neurotransmitters, regeneration and neurogenesis and multiplexing.

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The human postural coordination mechanism is an example of a complex closed-loop control system based on multisensory integration [9,10,13,14]. In models of this process, sensory data from vestibular, visual, tactile and proprioceptive systems are integrated as linearly additive inputs that drive multiple sensory-motor loops to provide effective coordination of body movement, posture and alignment [5-8, 10, 11]. In the absence of normal vestibular (such as from a toxic drug reaction) and other inputs, unstable posture occurs. This instability may be the result of noise in a functionally open-loop control system [9]. Nonetheless, after sensory loss the brain can utilize tactile information from a sensory substitution system for functional compensation [1-4, 12]. Here we have demonstrated that head-body postural coordination can be restored by means of vestibular substitution using a head-mounted accelerometer and a brain-machine interface that employs a unique pattern of electrotactile stimulation on the tongue. Moreover, postural stability persists for a period of time after removing the vestibular substitution, after which the open-loop instability reappears.

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Shepherd I. Franz was an important figure in psychology of the last century, and historians of psychology have given recognition to much of his work. However, his experimental work with animals and his pioneer investigations in experimental and clinical neuropsychology have been largely ignored. This article reviews his conceptual, assessment, and treatment contributions, including (1) his pioneering work on the use of learned behavior as a baseline for the study of cerebral ablations, (2) his interest in brain plasticity, (3) his development of comprehensive psychological assessment methods, and (4) his work on the rehabilitation of neurological patients with techniques derived from his animal experiments. His work predated much of what is now part of the conceptual substance of the experimental and clinical neurosciences.

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Based on our results during the last 25 years, we are developing late stroke computer-assisted motivating rehabilitation (CAMR) for the upper extremity. Evidence has been accumulating that functional gains are possible even many years after the damage. However, postacute rehabilitation must be motivating and related to real-life functional activities, or it may fail to enlist active participation. With CAMR programs, such as briefly reported here, instead of exercise, the patient is engaged in a game (e.g., ping-pong); instead of concentrating on the specific movements, he/she is concentrating on the game and the movements become subconscious. Patients, even those who initially consider that they cannot accomplish the task, show interest and improvement, and functional recovery appears to be extended beyond the specific movements that are being practiced. CAMR is also suitable for late functional reorganization programs in an educational model.

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