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By U. Eusebio. Wesleyan College.

Any neuron/silicon interface must be designed to be consistent with the cytoarchitectural constraints of the target tissue purchase cialis jelly 20mg online. Finally discount 20mg cialis jelly fast delivery, the issue of long-term viability refers to the obvious problems of maintaining e¤ective func- tional interactions between a microchip and brain tissue on a time scale of years be- cause periodic replacement of an implant is not likely to be feasible. Density and Specificity With regard to density and specificity, one can either attempt to integrate these de- sign considerations into the computational component of the prosthesis, or separate the computational and interface functions into di¤erent domains of the device and thus deal with the design constraints of each domain independently. We have chosen the latter strategy, developing silicon-based multisite electrode arrays with the ca- pability to electrophysiologically record and stimulate living neural tissue. The fun- damental technologies required for multichannel, bidirectional communication with brain tissue already exist commercially and are being developed further at a rapid rate (Egert et al. Silicon-based, 64- and 128-electrode site recording and stimulating arrays having spatial scales consistent with the hippo- campus of a mammalian animal brain (which is much smaller than that of a human) are now routinely used in our laboratory and several others (Gross et al. The circuit design also includes one additional processing unit as part of the output layer that provides feedback to the dynamic synapses. Berger and colleagues A Neural Prosthesis for Hippocampal Memory Function 267 Wheeler and Novak, 1986; Stoppini et al. In the near future, electrode densities su‰cient to influence most of the neurons in a two-dimensional plane of a targeted brain region will be operational. Most commercially available multisite electrode arrays have a uniform geometry, however, leaving the issue of specificity unresolved. For this reason, we have focused the greater part our research with respect to neural/silicon interfaces on designing multisite arrays in which the spatial distribution of electrode sites conforms to the cytoarchitecture of the target brain region, that is, array geometries specific to the hippocampus (Soussou et al. For example, one multisite electrode array that we have fabricated and tested was designed for CA3 inputs to the CA1 region of the rat hippocampus. Two rectangular arrays were constructed using silicon nitride and indium tin oxide (ITO): one 2 Â 8 array of electrodes was oriented to stimulate CA3 axons that course through the dendritic region of CA1, and a second 4 Â 12 array was positioned and oriented to record CA1 dendritic and cell body responses evoked as a consequence of stimulation through the first array (figure 12. This particular conformal probe had sixty-four 40 Â 40-mm stimulating-recording pads and a 60-mm center-to-center interelectrode distance within each array. The silicon nitride layer was deposited over the ITO electrodes, providing insulation both between the various electrodes and between each electrode and the hippocampal tissue. The layers were patterned to provide apertures only at the elec- trode tips. Silicon nitride films approximately 1500 A˚ thick were deposited using the plasma-enhanced chemical vapor deposition (PECVD) technique. Electrical char- acterization using a VLSI electronic probing station showed excellent insulation ca- pability and electrical isolation, with less than a 1. Experimental testing with acutely prepared rat hippocampal slices consistently demonstrated evoked extracellular field potentials with signal-to-noise ratios greater than 10:1. Additional mask designs that incorporate several key modifications have been suc- cessfully completed and fabricated. Berger and colleagues resized to 30-mm diameters, a size approaching the diameter of a single neuron cell body. Combined with smaller center-to-center distances between pads, the smaller pad size will allow higher density arrays for greater spatial resolution when interfac- ing with a given brain region, and thus better monitoring and control of that region. Second, several new layouts have included di¤erent distributions of stimulation- recording pads that geometrically map several subregions of the hippocampus (figure 12. This represents the beginnings of a group of interface devices that will o¤er monitoring and control capabilities with respect to di¤erent subregions of the hippo- campus, and ultimately other brain structures as well. In addition, more recent de- signs have utilized gold as the stimulation-recording electrode material to allow higher injection current densities during stimulation. Electrical characterization of the most recent generation of conformal neural probe arrays indicates, despite the higher density of electrodes, less than a 4. Biocompatibility and Long-Term Viability Many of the problems with respect to biocompatibility and long-term viability can- not be fully identified until the working prototypes of multielectrode arrays described earlier have been developed to the point that they can be tested through long-term implantation in animals. Nonetheless, we have begun to consider these issues and to develop research strategies to address them. One of the key obstacles will be main- taining close contact between the electrode sites of the interface device and the target neurons over time. 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. 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, redevelop processes, 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.

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Regardless of this unre- during voluntary contractions solved issue buy cialis jelly 20mg mastercard, similar changes in heteronymous recur- Heteronymous recurrent inhibition of quadriceps rent inhibition to voluntarily activated motoneu- motoneurones due to a soleus motor discharge has rones have been observed using a method in which been assessed with the quadriceps H reflex during the test reflex did not undergo the AHP following the tonic voluntary contractions of the quadriceps (Iles conditioning reflex discharge (Iles & Pardoe generic cialis jelly 20mg without prescription, 1999; &Pardoe, 1999). Because this finding was observed with a declined with the strength of the contraction, and method independent of changes in AHP, it confirms fell to zero at ∼35% of MVC. This resembles the inhi- that recurrent inhibition is decreased during strong bition of soleus-coupled Renshaw cells described contractions. By exclusion, the inhibition of Renshaw cells account for the lesser decrease in homonymous is likely to be of supraspinal origin, and this con- than in heteronymous recurrent inhibition of the Motor tasks – physiological implications 179 motoneurones involved in voluntary contractions: when the same force is developed in a tonic con- (i) as discussed above, the decrease in homony- traction (Fig. This particular control prob- mous recurrent inhibition is underestimated with ablyoccursbecauseeffectivereciprocalIainhibition the paired H reflex technique, given the lesser sensi- of the antagonistic muscle is required during phasic tivity of H to excitatory inputs, and the summation contractions (Pierrot-Deseilligny, Katz & Hultborn, of the AHPs; (ii) if homonymous and heteronymous 1983). Descending inhibition of Renshaw cells The gain hypothesis The decreased recurrent inhibition occurs because The facilitation of Renshaw cells during weak con- Renshaw cells receive potent descending inhibition tractions would be explained if recurrent inhibi- whichislikelytobecorticospinalinorigin. The reduction of recurrent inhi- reduce the slope (the gain) of the input–output bition of motoneurones during strong contractions relation for the motoneurone pool. This reduction ensures a high input–output gain for the motoneu- will be maximal when Renshaw cells are facilitated, rone pool, and this would favour large tension out- as occurs during weak contractions. During sustained long-lasting contractions, the low gain for the motoneurone pool would allow absence of recurrent inhibition of silent homony- supraspinal centres to operate over a large part of mous motoneurones would facilitate their recruit- their working range and cause only small changes in ment, thus helping overcome fatigue. As a result, a facilitated recurrent path- waywouldimproveresolutioninthecontrolofmotor Inhibition of Renshaw cells favours output. In contrast, an inhibited recurrent pathway reciprocal Ia inhibition wouldgiverisetoahighoutputgainallowingthecen- It has been a general feature that, for a given level tral command to generate larger forces for a given of force reached towards the end of phasic ramp drive, despite the strong motor discharge reaching contractions, Renshaw cells are more inhibited than Renshaw cells via recurrent collaterals. Any discharging motoneurones would inhibit other motoneurones The paired H reflex technique has been used to and thus curtail the stretch reflex. B ecause Recurrent inhibition of antagonistic of the AHP, the H test reflex is less sensitive than muscles involved in co-contraction the reference H reflex to the inhibitory inputs related to the antagonistic contraction (see p. During the ramp phase of aramp-and-hold voluntary dorsiflexion, the H test In soleus, the H reflex is depressed during weak reflexcontinuouslydecreases,whereasthereference and facilitated during strong plantar flexion (cf. Interestingly, heteronymous recurrent of H when there is relative facilitation of the ref- inhibition to quadriceps motoneurones, assessed erence H reflex indicates an increase in recurrent with a method independent of possible changes inhibition. During a ramp contraction, the refer- It was suggested that the increased recurrent inhibi- ence H reflex was facilitated with respect to its rest tion of soleus motoneurones during voluntary con- value in both types of contraction, but H underwent traction of antagonistic pretibial flexors was due to a different changes: continuous increase throughout descending facilitation of soleus-coupled Renshaw the ramp plantar flexion with complete suppression cells (Katz & Pierrot-Deseilligny, 1984). Motor tasks – physiological implications 181 Specific control during co-contraction such as the maintenance of upright stance, recur- rent inhibition of soleus motoneurones has been It is unlikely that the control of soleus-coupled Ren- compared when standing with and without support shaw cells during co-contraction is the sum of the (Pierrot-Deseilligny et al. The H test reflex opposite effects observed during isolated voluntary was significantly smaller during active stance than plantar and dorsiflexions. The (i) The inhibition observed during strong co- size of the reference H reflex was the same in the contraction is greater than the sum of the strong two situations, and increased recurrent inhibition facilitation during strong plantar flexion and the of soleus motoneurones during active standing is moderate inhibition during strong dorsiflexion. The increased recurrent inhibition (ii) The strong inhibition of H observed during was not directly related to muscle contraction in the first 100 ms of voluntary dorsiflexion (Fig. Neither was it due to the cutaneous trol of recurrent inhibition during co-contraction, afferent discharge from the sole of the foot because and would be in line with previous studies which this discharge would be the same whether stance have suggested that the descending control of spinal was supported or unsupported. The main differ- segmental pathways is conveyed by different des- ence between the two positions is that when equi- cending pathways during co-contraction and dur- librium is unsteady, contractions may be required ing flexion–extension movements (see Chapter 11, in either of the antagonistic muscles operating at p. The reinforcement of recur- rent inhibition in active standing is probably due During strong contraction of the target muscle, the to a supraspinal mechanism, possibly vestibular. In decreased recurrent inhibition to active motoneu- this connection, homonymous recurrent inhibition rones probably results from corticospinal inhibition of soleus motoneurones is enhanced during static of Renshaw cells (see above). The strong recurrent backward tilt from 80◦ to 40◦ of a subject fixed to a inhibition during co-contraction could be explained tilting chair (Rossi, Mazzocchio & Scarpini, 1987). Functional implications If this were so, recurrent inhibition should paral- Renshaw cells are facilitated during co-contractions lel the on-going motor discharge. However, during of antagonistic muscles, contractions which, in the ramp co-contractions, the inhibition of the H test lower limbs, may be necessary in postural tasks. This reflex increases abruptly at the end of the ramp, is of functional interest, because: (i) transmission in and this suggests the existence of a supplementary theIainhibitorypathwaymustbedepressedtoallow descending facilitation of Renshaw cells. The arrows indicate the conditioning reflex discharges that activate Renshaw cells (RC). The size of the H test reflex of Sol (expressed as a percentage of the H1 conditioning reflex) is plotted against the size of H1 (expressed as a percentage of Mmax). Motor tasks – physiological implications 183 Heteronymous recurrent inhibition and quadriceps to soleus was reduced with respect to sit- heteronymous Ia excitation ting, whether assessed with the on-going EMG activ- ity (Fig. In recurrent inhibition may be to limit the extent situations in which the soleus contraction was not of Ia excitation has been examined by studying associated with a quadriceps contraction (standing the changes in heteronymous recurrent inhibition on tip of toes or leaning forwards during stance), during postural tasks requiring co-contraction of heteronymous recurrent inhibition from quadriceps lower-limb muscles linked in Ia synergism. Similarly, heteronymous recurrent inhibition from soleus to quadriceps was reduced during postural stance involving quadri- Methodology cepsandsoleusco-contractionwhencomparedwith similar voluntary muscle contractions when sitting Recurrent inhibition of tibialis anterior and soleus (Iles, Ali & Pardoe, 2000). Recur- cles associated with the quadriceps in postural co- rent inhibition from quadriceps was compared at contractions is probably due to descending control matched levels of background EMG activity dur- becausetheon-goingmotordischargereachingRen- ing voluntary co-contraction of quadriceps and of shaw cells via recurrent collaterals and the cuta- the relevant ankle muscle while sitting (control situ- neous activation due to the pressure of the foot sole ation) and in different postural tasks. In the reverse wouldhavebeenthesameinthecontrolandpostural paradigm(soleustoquadriceps),Renshawcellswere situations. The above results support the view that the facilita- tion of heteronymous recurrent inhibition functions to limit the extent of heteronymous Ia excitation. Decreased recurrent inhibition to As discussed in Chapter 2,prewired Ia connections motoneurones of the muscle involved in link the quadriceps to both tibialis anterior and postural co-contraction soleus operating at the ankle (and, similarly, the During postural co-contractions of quadriceps and gastrocnemius-soleustobothquadricepsandbiceps tibialis anterior, as occur when standing and lean- femoris). In functional terms this may be explained ing backwards, heteronymous recurrent inhibition by the versatile synergisms required for various from quadriceps to tibialis anterior was reduced tasks (see Chapter 2,p.

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Event-related fMRI allows the responses to Magnetic scalp stimulation techniques apply a a single stimulus or task to be imaged purchase 20 mg cialis jelly mastercard, much transient clockwise current from a stimulating as an evoked potential is stimulated electro- coil placed on the scalp in an optimal position physiologically discount cialis jelly 20mg overnight delivery. A single experimental trial may to induce a counterclockwise current in the free the response from such difficult–to–assess brain (Fig. The brief, intense electric field matters as attention and the context in which induced by magnetic coils shaped as a figure-of- Figure 3–2. Transcranial magnetic stimulation over primary motor cor- tex causes a twitch of the finger mus- cles. When the subject contracts the extensor propius indicis slightly, this muscle is preferentially excited. This pro- cedure allows the site of maximal stimulation to be overlaid precisely on the cerebral anatomy for local- ization. Functional Neuroimaging of Recovery 157 eight is more focal, but weaker than the field in- and amplitude of an evoked muscle response, duced by circular coils. Transcranial magnetic central conduction time, the number of ex- stimulation (TMS) painlessly activates corti- citable positions on the scalp, the positions that cospinal neurons transsynaptically through their give the highest amplitude of evoked muscle horizontal afferent connections. The horizontal response, and the center of gravity, meaning projections extend only a few millimeters. The the amplitude-weighted location of the motor focal point of the stimulation is within a few mil- map. Thus, the direction and size of a change limeters of cortex and peaks around 300 ms af- in representational plasticity can be deter- ter onset of the stimulus. Thus, the investigator mined for a motor map, most commonly for an needs a good a priori hypothesis about the struc- evoked response of a single finger muscle. The ture involved and behavioral effects of a stimu- TMS-induced map can be coregistered on an lus at a focal location. Direct elec- with a 20% or less of maximum contraction trical stimulation has a history that goes back to shortens the latency by several milliseconds. Transcranial electrical stimulation tors that reflect the sum of activity of the up- (TES) bypasses cortical interneurons and stim- per and lower motoneurons. The brain stem to peak amplitude vary so much that an ab- and spinal cord can be directly stimulated over solute measure has little clinical meaning, al- the occiput and posterior spine, although this though a side-to-side difference of over 50% in may cause discomfort. The area of cortex that plasticity may not distinguish between organi- evokes a motor response can be tested over zational adaptations and changes in cortical ex- time to examine the size and location of citability. The technique can be used to stimu- changes in representational plasticity. Medial and subcortical struc- functional technique that can temporarily dis- tures are generally too deep and at a difficult rupt a pathway by inducing disorder in neu- angle for TMS activation. Motor potentials ronal firing which, in turn, creates a transient evoked from a single muscle, such as the ab- virtual lesion. For example, stimulation of the ductor pollicus brevis, are more easily elicited if primary visual cortex impaired the ability of a subject contracts the muscle slightly. The technique did not in- by pain17 and brain tumors,18 to investigate duce a seizure when rTMS trains at 20 Hz for motor system plasticity after peripheral nerve 1. Interpretation of di- during double simultaneous visual stimula- pole measures depends on the chosen mathe- tion. Analytic methods to correct for proved, suggesting disinhibition of structures motion artifact are in development, such as in the hemisphere that did not receive rTMS. In good hands, studies have tion in the network for spatial attention with revealed changes in representational plasticity dominance in the right parietal cortex (see after stroke30 and adaptations in amputees with Chapter 1). Repetitive pulse TMS may possi- phantom limb pain17 and chronic back pain. Unlike metabolic nerve was stimulated and somatosensory neuroimaging studies of cognition, which show evoked magnetic fields recorded. For rehabilita- postsynaptic potentials generated by thalamo- tion, coupling rTMS with a specific cognitive cortical afferents to layer IV pyramidal cells in or motor therapy may improve the targeted BA 3b. For example, low intensity rTMS at inhibitory postsynaptic potentials near the so- 5 Hz over the left prefrontal region led to an mata of the cells. Presumably, do so in a patient with TBI or stroke who has inhibition was reestablished in subjects who a prefrontal injury or another lesion connected had clinical improvement, although other cor- to this node of a cognitive network? This technique may be useful in monitoring somatosensory changes induced by rehabilita- Magnetoencephalography tion interventions. Optimal sensory feedback appears to be a pivotal requirement for motor Magnetoencephalography (MEG) reveals gains in hand function and walking (see Chap- changes in magneto-electrical fields with pre- ter 1). Magnetoencephalography may also help cise 3-dimensional localization of the activated researchers understand the bridge between the neuronal pool within milliseconds. Subjects sensorimotor internal dynamics of the cortex wear a helmet-shaped neuromagnetometer ar- and movement behavior. The technique records the tangential component of dipoles in the depth of gyri and sulci. The MEG is usually coregistered with sometimes referred to as EEG brain mapping MRI anatomy. An estimated 30,000 neurons or quantitative EEG, uses signal averaging and must be simultaneously activated for detection statistical approaches to assess EEG field po- of an extracranial field. High resolution EEG tentials and evoked potentials such as the P300 is often simultaneously recorded to confirm the of an event-related potential (see Chapter 4). The technique reflects the activity of cortical The procedure takes considerable time to surface dipoles. It offers high temporal resolu- Functional Neuroimaging of Recovery 159 tion, but limited spatial resolution.

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