By K. Rathgar. Western Michigan University.
The surface area of the brain of a ischemia discount 200 mcg synthroid with visa, as described in Experimental Case mouse is 1/1000th that of the human brain 100 mcg synthroid for sale. The milieu for mechanisms of re- Studies of axonal regeneration in rats and mice pair will differ as well with the type of lesion consider an extension of axons for a few mil- induced generic synthroid 200 mcg on line. A cortical infarct will not elicit the limeters to a centimeter as exuberant growth buy 25mcg synthroid. Axons in human brain to moderate cortical injury that resolves in sev- or spinal cord may have to grow from several eral days. A human injury may include contu- centimeters to over a meter to reach targets. These differences in pathology and the Signaling molecules that fashioned the CNS persistence of injury-induced cascades in hu- during embryogenesis and development never mans make interventions for neuroprotection had to manage such long distance tours. Very different fective dose-response curve for biologic inter- mechanisms and outcomes may unfold in hu- ventions in man? A repair intervention in mice mans over time as molecular cascades interact. Since humans will need to produce complex behav- the injury model was originally developed to iors such as goal-directed walking and manip- 132 Neuroscientific Foundations for Rehabilitation pair intervention in the rat or mouse and the timing of the same intervention in patients? Medications may have con- founding effects on an intervention for repair. The need for immunosuppressants after a transplant of cells may have adverse effects on regenerative capacity. In addition, animals do not take drugs for hypertension, diabetes, pain, seizures, and other ailments. How will adjunct drugs and associated diseases affect the human equivalent of an animal intervention, especially over the weeks and months needed for some types of repair? Adjuncts may alter the ab- sorption or metabolism or bioavailability of the experimental intervention. Also, an interven- tion in a rodent model is derived from dose- response curves for serious toxicity such as death. Human trials almost invari- man brain compared to a whole brain and spinal cord from ably use doses of drugs that are far lower than a rat and the even smaller CNS of a mouse. The differ- what worked in the animal, to avoid lesser tox- ences in size carry over to the magnitudes of difference in icities such as confusion, agitation, somno- the distance a regenerating axon or migrating neuronal precursor would have to travel to reach a target location. Inverted U-shaped dose- As another comparison, human neocortex is approximately response curves are not uncommon, in which 100 times larger than that of the commonly studied squir- low doses and high doses fail to work and in- rel monkey. A dose that is most likely resentation for the forearm 12 mm2 in the monkey com- pared to approximately 1100 mm2 in humans. If the drug intervention developed in an an- imal model must pass the human blood-brain ulation of objects. The number of fibroblasts barrier, will penetration in humans be enough that secrete a neurotrophin or the number of to give the same effect as in the rodent? Neu- implanted stem cells that must migrate and rotrophins that worked in rodents had no ap- reintegrate will very likely be far greater for tri- parent effect when given subcutaneously to treat als with human subjects. The delivery tive simplicity of structures that mediate the of cells and substances into the region of inter- modest cognitive functions of rodents makes est poses far more invasive and injurious poten- any anatomical reconstruction for a simple- tial to humans than to rodents. Better delivery minded behavior in the rodent of unclear ap- vehicles will be needed for patients. What were the measures of efficacy in ro- executive function impairments. Is the timing of an intervention after in- relevant to outcomes in patients? In the rodent, rather pair intervention for patients may start in a bed limited behaviors are tested; physiologic, his- of injury-induced molecules and tattered ar- tologic, and molecular measures take prece- chitecture that differs from the state of affairs dence.
The latter preparations involve placing slices of hippocampus on a semipermeable membrane in contact with tissue culture media and maintaining them long term in a culture incubator (Gholmieh et al order synthroid 125mcg fast delivery. Slice cultures can be prepared directly on multisite electrode arrays generic synthroid 25 mcg overnight delivery, which then can be tested periodically to examine the robustness of the electrophysiological interaction with the hippocampal tissue synthroid 75 mcg mastercard. Preliminary findings have revealed that bidirectional communication remains viable for at least several weeks synthroid 75mcg line, although we have yet to systematically test long-term functionality. For e¤ective signal detection and transmission, intimate contact between neurons and electrode components of a neural prosthesis is necessary. A neural prosthesis will inevitably be sandwiched between two surfaces so that it will 232 Roberta Diaz Brinton and colleagues A B HN HN OC OC PO3 PO3 PO3 PO3 Optical microscopy image Optical microscopy image Correct orientation of Incorrect orientation of CAM (presents–DGR) CAM (presents –RGD) Good Adhesion Poor Adhesion SEM image SEM image Figure 11. TiN substrates (shown as black bars) were coated with (A) aminoalkyl-phosphonic and (B) carboxyl- phosphonic acids. The RGDS peptide (arginine-glycine-aspartate-serine) was then coupled to each surface as shown. Both optical (top) and scanning elec- trical micrographs (bottom) show string cell adhesion and growth on the amino-treated surface and no ad- hesion on the carboxyl surface. Implanted in the brain, a neural prosthesis would reconnect two disconnected regions of the brain and would have to interface between four surfaces in three-dimensions. Axons from the surviv- ing neural tissue will have to provide input to the device, with the device functioning as the postsynaptic element, whereas dendrites will have to be functionally connected to its output, with the device functioning as the presynaptic element and the dendrite as the postsynaptic element. Achieving such selective portioning of neuronal elements will require the use of ad- hesion and attraction strategies that will promote, at the very least, the attachment of neural elements to the reception and transmission electrodes of the prosthesis. In par- allel, repulsion of glial cells from the signal detection and transmission electrodes, must be achieved. However, the repulsion of glial cells will have to be very limited in order to keep glial cells in close enough proximity to promote long-term neuron survival. One potential strategy to achieve selective adhesion is to use cell adhesion molecules (CAMs) to generate adhesion or antiadhesion surfaces (see figure 11. Our approach will be to develop specific surface modifications using a combination of cell-specific adhesion The Biotic/Abiotic Interface 233 Figure 11. The background illustrates the complexity of neuroimmune signaling in the brain, whereas the foreground illus- trates the types of cells involved in the inflammatory response. Of particular importance are the microglia and resistive astrocytes that are the principal inflammatory cells of the brain. Also shown are factors that can regulate the inflammatory response, including endogenous factors such as estrogen and exogenous anti-inflammatory drugs such as rapamycin, which is both an anti-inflammatory and an antiproliferative agent. Biocompatibility and Long-Term Viability Long-term viability of the implant requires the maintenance of e¤ective functional interactions between the microchip and brain tissue on a time scale of years, as peri- odic replacement of a neural prosthetic implant is not a realistic option. While not all of the biocompatibility and long-term viability challenges can be fully appreciated until the working prototypes of implant devices have been developed, preventing or suppressing the inflammatory response to foreign objects is likely to be a problem for all implantable neural prosthetics and will be chief among the factors that will im- pede the long-term viability of a neural implant (see figure 11. In labo- ratories conducting chronic electrophysiological recordings, it has been well known for decades that the quality of electrophysiological signals generated by many stan- dard recording methods designed for long-term use in behaving animals gradually degrades over the course of weeks. However, not all electrophysiological recording methods are always subject to such degradation in signal quality over time. For ex- ample, multimicrowire recording methods using a small number of wires can record in a stable manner for many months (approaching a year). The inflammatory response begins immediately upon insertion of electrodes into the brain, reaches steady state within several weeks, and is correlated with a gradual decrease in the quality of electrophysiological signals recorded from target neurons (A. To be considered viable, any strategy for a long-term, implantable, cortical prosthetic system must overcome the inflammatory encapsulation response. For images of the encapsulation process and the contribution of astrocytes and microglia, the reader is referred to the web site of the Craighead laboratory. Astrocyte func- tion is crucial to neuron viability because astrocytes are the repository of growth fac- tors vital to neuron survival (Anderson and Swanson, 2000; Aschner, 2000; Dong and Benveniste, 2001; Gates and Dunnett, 2001; Gimenez y Ribotta et al. However, astrocyte proliferation is well known to be a principal culprit in blocking regeneration of central nervous system neurons and encapsulation of implanted de- vices (Eclancher et al. The production of the glial-derived cytokines that lead to inflammation is highly complex but, in general, activation of actrocytes and espe- cially microglia leads to the inflammatory response and ultimately to encapsulation of the device and degeneration of neurons (see figure 11. In contrast, radial glia can function as progenitor cells for neurogenesis (Yang et al. Despite their role in the inflammatory response, astrocytes also serve as sources of growth factors and nutrients and function to remove toxins from the extracellular compartment.
The input-output properties of synapses and neurons are not static generic synthroid 25mcg amex, but are altered by biological learning mechanisms to achieve an opti- mal feature set during memory formation for a new pattern cheap 100 mcg synthroid with visa. Biomimetic Models of Hippocampal Neuron Properties Quantifying Input-Output Nonlinearities of Hippocampal Neurons In order to incorporate the nonlinear dynamics of biological neurons into neuron models to develop a prosthesis discount synthroid 200mcg overnight delivery, it is first necessary to measure them accurately cheap synthroid 75 mcg amex. We have developed and applied methods for quantifying the nonlinear dynamics of hippocampal neurons (Berger et al. In this approach, properties of neurons are assessed experimentally by applying a random interval train of electrical impulses as an input and electrophysiologically recording the evoked output of the target neuron during stimulation (figure 12. The input train consists of a series of impulses (as many as 4064), with interimpulse intervals varying according to a Poisson process having a mean of 500 ms and a range of 0. Nonlinear response properties are expressed in terms of the relation between pro- gressively higher-order temporal properties of a sequence of input events and the probability of neuronal output, and are modeled as the kernels of a functional power series. In the case of a third-order estimation: yðtÞ¼G0 þ G1½h1; xðtÞ þ G2½h2; xðtÞ þ G3½h3; xðtÞþÁÁÁ; where yðtÞ is the output, ðGiÞ is a set of functionals, and ðhiÞ is a set of kernels that characterize the relationship between the input and output: G0ðtÞ¼h0 ð G1ðtÞ¼ h1ðtÞxðt À tÞ dt ðð G2ðtÞ¼2 h2ðt; t þ DÞxðt À tÞxðt À D À tÞ dD dt A Neural Prosthesis for Hippocampal Memory Function 247 Figure 12. Each arrow indicates when an electrical impulse is applied to perforant path inputs (see figure 12. Large, positive-going, unitary (action potential) events indicate when an input generated an output response from the granule cell; smaller, positive-going events (e. The time delay (la- tency) from the input event (arrow) to the granule cell response is equivalent to the parameter t in the equations in the text (all latencies are less than 10 ms); the intervals between input events are equivalent to the parameter D in the equations in the text. Berger and colleagues ððð G3ðtÞ¼6 h3ðt; t þ D1; t þ D1 þ D2Þxðt À tÞxðt À t À D1Þ Â xðt À t À D1 À D2Þ dD1 dD2 dt The train of discrete input events defined by xðtÞ is a set of d-functions. The first-, second-, and third-order kernels of the series are obtained using a variety of estima- tion procedures (Lee and Schetzen, 1965; Krausz, 1975; Marmarelis, 1990). To clarify the interpretation of the kernels in the context of results for a typical granule cell of the hippocampus, the first-order kernel, h1ðtÞ, is the average probabil- ity of an action potential output occurring (with a latency of t) to any input event in the train. The intensity of stimulation was chosen so that the first-order kernel had a probability value of 0. The second-order kernel, h2ðt; DÞ, repre- sents the modulatory e¤ect of any preceding input occurring D ms earlier on the most current impulse in the train (figure 12. Second-order nonlinearities are strong: intervals in the range of 10–30 ms result in facilitation as great as 0. The magnitude of second-order facilitation decreases as the interstimulus interval lengthens, with values of D greater than 100 ms leading to sup- pression; for example, interstimulus intervals in the range of 200–300 ms decrease the average probability of an output event by approximately 0. The third-order kernel, h3ðt; D1; D2Þ, represents the modulatory e¤ects of any two preceding input events oc- curring D1 ms and D2 ms earlier on the most current impulse that are not accounted for by the first- and second-order kernels (figure 12. The example third-order kernel shown is typical for hippocampal granule cells, and reveals that combinations of intervals less than approximately 150 ms lead to additional suppression of granule cell output by as much as 0. This third-order nonlinearity represents in part satura- tion of second-order facilitative e¤ects. Improved Kernel Estimation Methods The output of hippocampal and other cortical neurons exhibits a dependence on the input temporal pattern that is among the greatest of any class of neuron in the brain, because of a wide variety of voltage-dependent conductances found through- out their dendritic and somatic membranes. Despite this, input-output models of the type described here provide excellent predictive models of cortical neuron behavior. Depending on the circumstances, kernels to the third order, and sometimes even to the second order alone, can account for 80–90% of the variance of hippocampal neu- ron output. Until recently, high-order nonlinearities have been di‰cult to estimate accurately; traditional kernel estimation methods (e. To circumvent these problems, we have developed several novel methods for estimating nonlinearities that are signif- A Neural Prosthesis for Hippocampal Memory Function 249 icantly more e‰cient and result in substantially improved kernel estimates (Krieger et al. Several of the new methods involve the use of feedforward artificial neural networks (ANN). We have compared the Volterra-Wiener (cross-correlation) and ANN models in terms of their prediction ability on test data. The results showed two major advantages of the new-generation methodologies: (1) a significant reduc- tion in the required data length (by a factor of at least 10) to achieve similar or better levels of prediction accuracy, and (2) an ability to model higher-order nonlinearities that could not be detected using traditional kernel estimation methods. In addition, we have recently developed methods capable of estimating nonstationary processes, and demonstrated their e‰cacy with long-term forms of hippocampal cellular plasticity (Xie et al. The ability to ac- curately characterize nonstationarities provides the opportunity to extend the appli- cability of this approach to modeling adaptive properties of hippocampal and other cortical neural systems as well.
Re- back pain to PD exclusively synthroid 75 mcg amex, and an- cently buy 25mcg synthroid, an increasing number of med- tipagetic medical treatment alone may ical reports have implicated osteo- be ineffective discount 200mcg synthroid mastercard. Neural element dys- porotic fractures as a cause of serious function may be attributed to com- neurological deficit and painful dis- pressive myelopathy by pagetic bone abling spinal deformities buy synthroid 50 mcg online. This has overgrowth, pagetic intraspinal soft been corroborated by the present au- tissue overgrowth, ossification of thors as well. These complications epidural fat, platybasia, spontaneous are only amenable to surgical man- bleeding, sarcomatous degeneration agement, requiring instrumentation. Instrumenting an osteoporotic spine, Neural dysfunction can also result although a challenging task, can be from spinal ischemia when blood is accomplished if certain guidelines diverted by the so-called arterial A. Tzermiadianos Neurological deficits respond equally tiveness of pharmacologic treatment School of Health Sciences, well to an anterior or posterior de- for pagetic spinal stenosis has been University of Crete, compression, provided this is coupled clearly demonstrated, surgical de- Department of Orthopaedic Surgery & Traumatology, with multisegmental fixation of the compression should only be insti- University General Hospital, construct. With the steady increase in tuted after failure of antipagetic med- PO Box 1352, the elderly population, it is antici- ical treatment. Surgery is indicated 71110 Heraklion, Crete, Greece pated that the spine surgeon will face as a primary treatment when neural Tel. With regard logic fractures, dislocations, sponta- to surgery, however, excellent correc- neous epidural hematoma, syringo- A. Hadjipavlou Division of Spine Surgery, tion of deformities can be achieved, myelia, platybasia, or sarcomatous Department of Orthopaedic Surgery, by combining anterior and posterior transformation. Tsoukas bolic disorder and the spine is the lar antipagetic drug and several Department of Endocrinology, second most commonly affected site. Montreal General Hospital, About one-third of patients with spi- McGill University School of Medicine, Montreal, Quebec, Canada nal involvement exhibit symptoms of Keywords Osteoporosis · Fractures · clinical stenosis. The overall mortality rate also appears to be equivalent The former is a very common skeletal disorder, whereas to hip fractures. This pa- lowed over 8 years, demonstrated that patients with OVCF per looks at both conditions. It first addresses principles of have a 23–34% increased mortality rate when compared surgical management of complications caused by osteo- to patients without OVCF. This study echoes the porosis of the spine (minimally invasive surgery for these findings of Cooper et al. However, in hip fractures, the excess mortality rate occurs within 6 months Osteoporosis of the fracture event, whereas in OVCF survival declines steadily after the fracture. Most common causes of Surgical treatment of osteoporosis is still not widely ac- death in patients with OVCF are pulmonary problems cepted by orthopedic surgeons, nor well known among the caused by chronic obstructive pulmonary disease (COPD) medical community at large. The first is (FVC, FEV1) is significantly decreased in patients with that more in-depth studies, which are detailed below, have thoracic and lumbar fracture. It has been estimated that shown that osteoporosis is not an innocent disease charac- one OVCF may result in 9% loss of forced vital capacity terized by minor complications and disabilities, but a seri- (FVC) [82, 121, 122]. The second OVCF are associated with back pain, which in the major- reason is the advancement of medical knowledge and tech- ity of patients is expected to subside within 2–3 months nology, which allows the use of more sophisticated instru-. However, it has been postulated that in one-third of mentation and makes it possible to operate successfully patients, this pain remains as chronic pain, with varying on high-risk patients of advanced age who no longer ac- degrees of physical disability. Several reports also in- cept physical conditions limiting their life enjoyment. Most cases of OVCF quences associated with osteoporosis are well known are wedge compression fractures (type A1), creating vary- through widely cited publications [24, 94, 112]. It is not ing degrees of kyphotic deformity of the spine, usually not the scope of this paper to review this aspect of osteoporo- associated with neurological deficit. However, it is worth highlighting some pertinent sta- manageable either conservatively (braces, corsets, anal- tistics regarding the magnitude and implications of osteo- gesics and antiresorptive osteoporotic drugs such as calci- porotic vertebral compression fractures (OVCF) in order to tonin and bisphosphonates, or parathyroid hormone, ap- emphasize the need for a more specific treatment. OVCF parently the most effective antiosteoporotic drug) [22, 70, is the most common fracture that may occur after minimal 88], or surgically by means of minimally invasive surgery trauma (e.