Implanting electrical devices in the nervous system to treat neural diseases is becoming very common. The success of these brain-machine interfaces depends on the electrodes that come into contact with the neural tissue. Here we show that conventional tungsten and stainless steel wire electrodes can be coated with carbon nanotubes using electrochemical techniques under ambient conditions. The carbon nanotube coating enhanced both recording and electrical stimulation of neurons in culture, rats and monkeys by decreasing the electrode impedance and increasing charge transfer. Carbon nanotube-coated electrodes are expected to improve current electrophysiological techniques and to facilitate the development of long-lasting brain-machine interface devices.

The mechanisms that trigger or contribute to loss of dopaminergic (DA) neurons in Parkinson's disease (PD) remain unclear and controversial. Elevated levels of tumor necrosis factor (TNF) in CSF and postmortem brains of PD patients and animal models of PD implicate this proinflammatory cytokine in the pathophysiology of the disease; but a role for TNF in mediating loss of DA neurons in PD has not been clearly demonstrated. Here, we report that neutralization of soluble TNF (solTNF) in vivo with the engineered dominantnegative TNF compound XENP345 (a PEGylated version of the TNF variant A145R/I97T) reduced by 50% the retrograde nigral degeneration induced by a striatal injection of the oxidative neurotoxin 6-hydroxydopamine (6-OHDA). XENP345 was neuroprotective only when infused into the nigra, not the striatum. XENP345/6-OHDA rats displayed attenuated amphetamine-induced rotational behavior, indicating preservation of striatal dopamine levels. Similar protective effects were observed with chronic in vivo coinfusion of XENP345 with bacterial lipopolysaccharide (LPS) into the substantia nigra, confirming a role for solTNF-dependent neuroinflammation in nigral degeneration. In embryonic rat midbrain neuron/glia cell cultures exposed to LPS, even delayed administration of XENP345 prevented selective degeneration of DA neurons despite sustained microglia activation and secretion of solTNF. XENP345 also attenuated 6-OHDAinduced DA neuron toxicity in vitro. Collectively, our data demonstrate a role for TNF in vitro and in vivo in two models of PD, and raise the possibility that delaying the progressive degeneration of the nigrostriatal pathway in humans is therapeutically feasible with agents capable of blocking solTNF in early stages of PD.

Adult adipose contains stromal progenitor cells with neurogenic potential. However, the stability of neuronal phenotypes adopted by Adipose-Derived Adult Stromal (ADAS) cells and whether terminal neuronal differentiation is required for their consideration as alternatives in cell replacement strategies to treat neurological disorders is largely unknown. We investigated whether in vitro neural induction of ADAS cells determined their ability to neuroprotect or restore function in a lesioned dopaminergic pathway. In vitro-expanded naïve or differentiated ADAS cells were autologously transplanted into substantia nigra 1-week after an intrastriatal 6-hydroxydopamine injection. Neurochemical and behavioral measures demonstrated neuroprotective effects of both ADAS grafts against 6-hydroxydopamine-induced dopaminergic neuron death, suggesting that pre-transplantation differentiation of the cells does not determine their ability to survive or neuroprotect in vivo. Therefore, we investigated whether equivalent protection by naïve and neurally-induced ADAS grafts resulted from robust in situ differentiation of both graft types into dopaminergic fates. Immunohistological analyses revealed that ADAS cells did not adopt dopaminergic cell fates in situ, consistent with the limited ability of these cells to undergo terminal differentiation into electrically active neurons in vitro. Moreover, re-exposure of neurally-differentiated ADAS cells to serum-containing medium in vitro confirmed ADAS cell phenotypic instability (plasticity). Lastly, given that gene expression analyses of in vitro-expanded ADAS cells revealed that both naïve and differentiated ADAS cells express potent dopaminergic survival factors, ADAS transplants may have exerted neuroprotective effects by production of trophic factors at the lesion site. ADAS cells may be ideal for ex vivo gene transfer therapies in Parkinson's disease treatment.

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The pressor reflex evoked by muscular contraction (exercise pressor reflex) is one important model of cardiovascular adjustments during static exercise. The central nervous system (CNS) structures mediating this reflex have remained largely obscure. Therefore, we examined the contribution of selected levels of the neuraxis in mediating the pressor reflex evoked by muscular contraction from stimulation of ventral roots. Decerebrate cats exhibited larger pressor reflexes than those found in intact alpha-chloralose-anesthetized cats, a difference more apparent at low (5 Hz or repeated twitch) rather than at high (50 Hz or tetanic) stimulus frequencies. Although a depressor response to 5-Hz stimulation was observed in the intact anesthetized cats, it appeared to be primarily due to anesthetic level, since a depressor response was not observed in decerebrate animals (nonanesthetized). Cerebellectomy produced no changes in the reflexes of the decerebrate animal. Further transection of the neuraxis (caudal to the midcollicular level) attenuated the exercise pressor reflex. The spinal cat demonstrated slight evidence of exercise pressor reflex activity. These results provide clarification as to representation of this pressor reflex within the CNS and establish the reflex's characteristics at several levels of neuraxis integration.

The effect of evoked muscle tension, active muscle mass, and fiber-type composition on the pressor reflex evoked by muscular contraction was examined in decerebrate and anesthetized cats. Muscular contraction was induced by stimulating the L7 and S1 ventral roots with 0.1-ms duration pulses three times motor threshold at various frequencies. The experiments were designed to isolate the variable under study as much as possible and included the use of selectively denervated preparations to limit contractions to specific muscles. It was found that altering the evoked tension by varying the resting muscle length had commensurate effects on the pressor reflex (greater evoked tension caused a larger reflex). In addition it was found that changing the amount of active muscle mass caused similar changes in the reflex (the smaller the muscle mass, the smaller the reflex). Finally, it was found that contrary to other accounts, pressor reflexes could be evoked by activation of the slow-twitch muscle soleus, composed exclusively of red (type I) fibers.

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Single motor units of the flexor carpi radialis (FCR) muscle were activated with a series of constant-rate stimulus trains to study the relation between the frequency of activation and isometric tension development (F-T relation). The tension produced by each stimulus train was expressed as a percentage of the maximum tension-time area (Amax) found for a given unit. Between 25 and 75% Amax a clear separation was seen in the rates needed to produce the same relative tension for the F-T curves of slow-twitch (type S) and fast-twitch (type F) units. Over the steepest portion of the F-T curve (25-50% Amax), where tension output was most sensitive to changes in activation rate, type F units required substantially higher stimulation rates (30 pps) to achieve the same relative tension output as type S units. Furthermore, the frequency range that corresponded to the steep portion of the curve was 2.3 times greater for type F units. For both type S and F units, twitch duration was deemed to be an important determinant of the F-T curve, as has been shown previously. A direct continuous relation was seen between the integrated twitch time (ITT) and the stimulus interval needed to produce 50% Amax (r = 0.94, P less than 0.001). Thus, units that had relatively brief twitches required higher activation rates to achieve the same relative percentage of Amax. Comparison of F-T curves from FCR with those derived by other investigators for cat hindlimb units (medial gastrocnemius and peroneus longus) revealed that significant differences in activation rates were needed to produce the same percentage of Amax throughout the midrange of the F-T curve. At 50% Amax, type F units in FCR required activation rates approximately 20 pps higher than type F units in the hindlimb. Type S units in FCR required only slightly higher rates (approximately equal to 5 pps). Based on a number of well-founded assumptions, F-T curves derived from FCR units were used to estimate the potential contribution of rate coding to total muscle tension by type S and F units. This analysis leads to the conclusion that rate modulation is a potentially important factor in the gradation of tension for the FCR muscle.