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We have begun investigating organic compounds that could be used to coat the surface of the interface device to increase its biocompatibility and thus promote outgrowth of neuronal processes from the host tissue and increase their adhesion to the interface materials discount 100 mg lady era free shipping. Poly-d-lysine and laminin are known to be particularly e¤ective in promoting ad- hesion of dissociated neuron cultures (cultures prepared from neonatal brain; neu- rons are prepared as a suspension and then allowed to adhere purchase lady era 100 mg on-line, redevelop processes generic lady era 100 mg fast delivery, and reconnect into a network) onto inorganic materials (Stenger et al. Poly-d-lysine and laminin were applied to the surface of the conformal arrays shown in figure 12. When dissociated hippocampal neurons were prepared on the surface of the array, the adhesion of cells and the extension of their processes were restricted to the treated regions; that is, hippocampal neurons were attracted, attached, and proliferated synaptic connections almost exclusively in parallel, linear tracks over the columns of electrodes (see chapter 11). Although this represents only an initial step in addressing the issues of biocompatibility, it is A Neural Prosthesis for Hippocampal Memory Function 269 Figure 12. Berger and colleagues through approaches such as these that we anticipate finding solutions to biocompati- bility problems. Although much of the electrophysiological testing of interfaces to date has been completed using acutely prepared hippocampal slices (which remain physiologically viable for 12–18 hr), we also have begun using hippocampal slice cultures to test the long-term viability of the neuron/silicon interface (Gholmieh et al. 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 incu- bator (Stoppini et al. Slice cultures can be prepared directly onto multisite electrode arrays, which then can be taken out the incubator and tested periodically to examine the robustness of the electrophysiological interaction with the hippocam- pal tissue. Preliminary findings have revealed that bidirectional communication re- mains viable for at least several weeks, although we have yet to systematically test long-term functionality. The main point to be made here is that novel preparations like the slice culture will provide highly useful platforms for identifying and resolving viability issues. Conclusions The goal of this chapter was to bring into focus what we believe will be one of the premier thrusts of the emerging field of neural engineering: to develop implantable neural prostheses that can coexist and bidirectionally communicate with living brain tissue and thus substitute for a cognitive function lost as a result of damage and/or disease (figure 12. Because of progress in neuroscience, molecular biology, bio- medical engineering, computer science, electrical engineering, and materials science, it is now reasonable to begin defining the combined theoretical and experimental pathways required to achieve this end. We have described here major progress on four of the essential requirements for an implantable neural prosthesis, achieved through a series of experimental and modeling studies using the hippocampus: bio- logically realistic neuron models that can e¤ectively replace the functional properties of hippocampal cells, the concatenation of the neuron model dynamics into neural networks that can solve a pattern recognition problem of cognitive and neurological relevance, the implementation of biologically realistic neural network models in VLSI for miniaturization, and the development of silicon-based multisite electrode arrays that provide bidirectional communication with living neural tissue. This progress does not constitute a set of final solutions to these four requirements. Additional work is needed on nonlinear models of neuron dynamics, both with re- spect to characterization of higher-order nonlinearities and particularly cross-input nonlinearities. All neurons receive inputs from more than one other source, and interactions among separate inputs most likely result in nonlinearities specific to A Neural Prosthesis for Hippocampal Memory Function 271 Figure 12. The concept is illustrated here using a prosthesis substituting for a portion of the hippocampus. Likewise, the dynamic synapse neural network models must be expanded both in terms of number of processing elements and numbers of network layers to begin approaching the complexity and mass action of brain subsystems for which a neural prosthesis will substitute. VLSI implementations of neural network models must be scaled up as well, and better incorporate e‰cient and novel interchip transmission technologies to achieve the high densities required for intracranial implantation. A critical factor is that future generations of biomimetic devices will require low-power designs to be compatible with the many temperature-sensitive biological mechanisms of the brain, an issue that our program has yet to address. Finally, there remains much concerning organic–inorganic interactions that needs to be investigated for long-term compatibility between silicon-based technology and 272 Theodore W. Although these problems are formidable, the rapid advances now occurring in the biological and engineering sciences promise equally rapid progress on elements of the global problem of intracranial implantable neural prostheses, par- ticularly given the synergy that should emerge from cooperative e¤orts between the two sets of disciplines. Acknowledgments The authors gratefully acknowledge postdoctoral fellows and graduate students who made fundamental contributions to the theoretical and experimental work described here, most notably, Choi Choi, Sunil Dalal, Alireza Dibazar, Sageev George, Ghas- san Gholmieh, Martin Han, T. Patrick Harty, Hassan Heidarin, Patrick Nasiatka, Walid Soussou, Dong Song, Jim Tai, Richard Tsai, Zhuo Wang, Xiaping Xie, and Mark Yeckel. This research was supported by the Defense Advanced Research Projects Agency (DARPA) Brain Machine Interface Program (N66001-02-C-8057), Controlled Bio- logical and Biomimetic Systems Program (grant N0001-14-98-1-0646), the DARPA Tissue-Based Biosensors Program (grant N0001-14-98-1-0825), the U. O‰ce of Naval Research (grant N0001-14-98-1-0258), the National Centers for Research Resources (grant P44-RR01861), and the National Institute of Mental Health (grants MH51722 and MH00343). In Proceedings of the Fourth Joint Symposium on Neural Computation 7 pp. To first order, the computational complexity in a neural prosthesis will scale with the number of neuron units that can be instantiated within a given physical layer, the number of physical layers that can be intercon- nected, and the degree of fan-out and fan-in that can be incorporated between pairs of such physical layers.

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Planning/Goals Overall generic lady era 100mg mastercard, both consumers and health care professionals seem to underestimate the risks of taking this herbal supple- The client will: ment cheap lady era 100 mg with visa. If present order 100 mg lady era fast delivery, avoid the herb during pregnancy, because effects are un- caretakers will implement safety measures. Severe or prolonged ill- relieving pain or insomnia, scheduling rest periods, and ness, impaired interpersonal relationships, inability to increasing or decreasing socialization. Criteria for choosing bupropion, mirtazapine, nefa- • When signs and symptoms of depression are observed, ini- zodone, and venlafaxine are not clearly defined. Institute pion does not cause orthostatic hypotension or sexual suicide precautions for clients at risk. Mirtazapine decreases anxiety, agitation, volve close observation, often on a one-to-one basis, and migraines, and insomnia, as well as depression. For dition, it does not cause sexual dysfunction or clini- clients hospitalized on medical-surgical units, transfer to cally significant drug–drug interactions. However, it has been associated with liver • Interview regarding feelings and mood. In addition, serum • Observe and interview regarding suicidal thoughts and nefazodone levels are increased in clients with cir- behaviors. Venlafaxine has stimulant effects, increases blood pressure, and causes sexual dysfunction, but does not cause signif- icant drug–drug interactions PRINCIPLES OF THERAPY 5. For clients with cardiovascular disorders, most antide- pressants can cause hypotension, but the SSRIs, bupro- Drug Selection pion, nefazodone, and venlafaxine are rarely associated with cardiac dysrhythmias. Venlafaxine and MAOIs Because the available drugs seem similarly effective, the can increase blood pressure. Cost also needs MAOIs, and desipramine are less likely to cause seizures. For clients with diabetes mellitus, SSRIs may have a sive than the TCAs. However, they may be more cost ef- hypoglycemic effect and bupropion and venlafaxine fective overall because TCAs are more likely to cause have little effect on blood sugar levels. Lithium is the drug of choice for clients with bipolar dis- drug levels and ECGs, and clients are more likely to stop order. Additional guidelines for choosing a drug in- controlling mania in 65% to 80% of clients. When used clude the following: prophylactically, the drug decreases the frequency and 1. Carbamazepine (Tegretol), an effective and usually produce fewer and milder adverse anticonvulsant, may be as effective as lithium as a effects than other drugs. It is often used in clients who do SSRI over another have not been established. For example, if a client (or a close family mem- ber) responded well to a particular drug in the past, that Dosage and Administration is probably the drug of choice for repeated episodes of depression. The response of family members to indi- Dosage of antidepressant drugs should be individualized ac- vidual drugs may be significant because there is a strong cording to clinical response. Antidepressant drug therapy is genetic component to depression and drug response. If usually initiated with small, divided doses that are gradually therapeutic effects do not occur within 4 weeks, the increased until therapeutic or adverse effects occur. Specific TCA probably should be discontinued or changed, guidelines for dosage include the following: because some clients tolerate or respond better to one 1. With SSRIs, nefazodone, and venlafaxine, therapy is TCA than to another. MAOIs are third-line drugs for the treatment of de- With nefazodone, an optimal response may require pression because of their potential interactions with 300 mg to 500 mg daily. An MAOI is most likely smaller doses may be indicated in older adults and to be prescribed when the client does not respond to clients taking multiple medications. Do not alter doses ✔ Counseling, support groups, relaxation techniques, and when symptoms subside. Antidepressants are usually other nonmedication treatments are recommended along given for several months, perhaps years; lithium therapy with drug therapy.

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This suggests that presynaptic but order lady era 100 mg amex, by that time generic 100 mg lady era mastercard, other mechanisms are available inhibition might effectively modulate physiological to maintain the desired trajectory and generic lady era 100 mg amex, in addition, feedback signals, without interfering with compen- the decrease in the gain is required to prevent oscil- sation for abrupt transients. Similarly, during tonic vol- untary contractions, presynaptic inhibition of Ia ter- minals on motoneurones of the contracting muscle is not decreased or is hardly so. Motor tasks and physiological implications Ia terminals on motoneurones of inactive Ia terminals on lower-limb motoneurones synergistic muscles of the lower limb involved in voluntary contraction The decreased presynaptic inhibition of homony- At the onset of a selective voluntary contraction mous Ia afferents seen at the onset of a selective of one muscle, presynaptic inhibition of Ia ter- voluntary contraction of a muscle is accompanied minals on motoneurones of the contracting mus- by increased presynaptic inhibition of the collaterals cle is decreased below its level at rest or during of these Ia afferents to inactive heteronymous mus- a tonic contraction with an equivalent level of cles. This effect is highly selec- monosynaptic Ia connections are well developed in tive and of similar magnitude on both homony- human subjects, probably to provide the more elab- mous and heteronymous Ia terminals projecting to orate reflex assistance required for bipedal stance the motoneurones responsible for the contraction and gait. The decrease in presynaptic inhibition one muscle, the Ia discharge from the contracting appears 50 ms before the onset of the movement, muscle will tend to excite motoneurones linked by persists unchanged during the first half of the ramp Ia connections. Enhanced presynaptic inhibition of Resume´ ´ 377 heteronymous Ia terminals to other motoneurone contraction resists the passive ankle dorsiflexion, pools prevents these pools from being activated. The increased pre- synapticinhibitionofthehomonymousIaexcitatory Ia afferents to antagonists feedback contributes to this. During standing with- Presynaptic inhibition is increased on Ia afferents out support, the increased presynaptic inhibition of projecting to motoneurones antagonistic to the vol- soleus Ia terminals could contribute to the depres- untarily activated motoneurone pool. This increase sion of reciprocal Ia inhibition, through presynaptic becomes significant only when PAD interneurones inhibition of the Ia input to interneurones of recip- are activated by the peripheral feedback. Methodology Studying changes in the inhibition of a test H reflex Presynaptic inhibition in the upper limb elicitedbyaheteronymoustaporanelectricalstimu- In the upper limb, there is a slight decrease in pre- lus(D1)isthesimplestandmostconvenientmethod synaptic inhibition of Ia terminals to motoneurones for clinical use. There is a progressive decrease in of the contracting muscle at the onset of a volun- the amount of femoral-induced facilitation and in tary contraction, but this decrease differs from that heteronymous inhibition of the soleus H reflex with observed in the lower limb in several respects: (i) the ageing, and this must be taken into account when decrease is quantitatively less prominent; (ii) there investigating patients. The Over-interpretation of findings using prolonged lack of specificity in this slight depression suggests vibration of the homonymous tendon reticulospinal depression. A decrease in presynaptic inhibition of Ia terminals has long been considered one of the spinal mech- Stance and gait anisms underlying the stretch reflex exaggeration characteristic of spasticity. This conclusion is, how- (i) Presynaptic inhibition of quadriceps Ia termi- ever, flawed: the method used to investigate pre- nals is decreased during standing without support synaptic inhibition was vibratory inhibition of the and in the early part of the stance phase of gait. In homonymous tendon, and the vibration-induced the early stance phase of walking, as in standing, the depression of the H reflex is then also caused quadriceps contraction may need to support much by post-activation depression and by activity- of the body weight. Thefor- bition of homonymous quadriceps Ia terminals then mer is decreased in spastic patients (see Chapter 2, observed assures that the excitatory Ia feedback is pp. During the stance phase, the triceps surae terminals in the lower limb of spastic patients with 378 Presynaptic inhibition of Ia terminals hemiplegia. In the upper limb, presynaptic inhibi- REFERENCES tion of FCR Ia terminals is consistently reduced on the affected side of hemiplegic patients. Distribution of presynaptic inhibition on type-identified Patients with spinal cord lesions motoneurones in the extensor carpi radialis pool in man. Whatever the lesion in the spinal cord (traumatic, Journal of Physiology (London), 522, 125–35. Mechanical cutaneous stimulation alters Ia pre- multiple sclerosis, amyotrophic lateral sclerosis), synapticinhibitioninhumanwristextensormuscles:asin- presynaptic inhibition of Ia terminals is decreased gle motor unit study. The´ ´ level of presynaptic inhibition of Ia terminals in nor- effectofDOPAonthespinalcord. Behavior of human muscle receptors when reliant terminals in patients with spinal cord lesions and in on proprioceptive feedback during standing. Reciprocalinhibition reflex exaggeration observed at rest or for the occur- betweenforearmmusclesinspastichemiplegia. In Progress in Clinical Neu- modulation of presynaptic inhibition of Ia terminals rophysiology,vol. Of particular interest was the finding that tion of Ia afferents during voluntary wrist flexion and in those patients who were examined on and off extension in man. Experimental Brain Research, 137, L-dopa medication, the amount of presynaptic inhi- 127–31. Inhibition of mono- synaptic extensor reflex attributable to presynaptic depo- improvement in bradykinesia and walking speed. Presynaptic and postsynaptic effects in the mono- The radial-induced D1 inhibition of the FCR H reflex synaptic reflex pathway to extensor motoneurones follow- is decreased in all types of dystonia. Archives Italiennes de the dystonia the more marked the decrease in pre- Biologie, 108, 259–94. Journal of Physiology The response of Golgi tendon organs to single motor unit (London), 210, 18P–20P. Methodological implications of the post-activation response of human muscle spindle endings to vibration of depression of the soleus H-reflex in man. Journal of Neurology, Neurosurgery the cortical command for voluntary movement in man.

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