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Striatal dopamine denervation and sensory integration for balance in middle-aged and older adults.

UNLABELLED: The dopaminergic system of the basal ganglia has been implicated in the integration of sensory information important for balance based on studies in patients with Parkinson's disease. Striatal dopaminergic activity decreases with normal aging. OBJECTIVE: To investigate the relationship between regional striatal dopaminergic denervation and sensory information integration important for balance in middle-aged and older adults. METHODS: Community-dwelling subjects (N=35; age 41-83) with no clinical diagnoses of conditions affecting balance underwent dynamic posturography testing (Sensory Organization Test/SOT) and C-11-beta-CFT dopamine transporter positron emission tomography. RESULTS: Reduced ventral striatal dopamine was significantly correlated with increased anterior-posterior sway in three SOT conditions. Specifically, during quiet standing (SOT Conditions #1, 2) and when repeatedly to sway-referenced visual environments (SOT Condition #3, Trial #3), pre-synaptic dopaminergic denervation in the anteroventral striatum explained over 20-25% of the variability in sway magnitude above and beyond that explained by age (p<or=0.01). Striatal dopaminergic denervation did not impact balance in sway-referenced floor conditions. CONCLUSIONS: The SOT Condition #3 findings suggest that, in normal aging, the central ability to inhibit balance destabilizing vision-related postural control processes depends at least partially on striatal dopaminergic pathways. In contrast, striatal dopaminergic denervation does not appear to impair the ability to disengage destabilizing proprioceptive inputs and to trigger the vestibular control system during challenging sensory perturbations (SOT Conditions #4-6). Finally, quiet standing results (SOT Conditions #1, 2) justify the need to further investigate the impact of striatal dopaminergic denervation on the ability to tune muscle tone in healthy adults.

Accidental Falls↗

Extrinsic denervation alters postprandial absorption of glucose and glutamine in the ileum: implications for small bowel transplantation.

In the postprandial period, augmentation of absorption of water, electrolytes, and taurocholate is believed to occur in the ileum. The role of extrinsic innervation in this postprandial augmentation has not been well studied and may be an important concept in small bowel transplantation. Our aim was to investigate extrinsic neural mechanisms mediating postprandial absorptive patterns. The study hypothesis was that postprandial augmentation of absorption in the ileum is blunted in transplanted (extrinsically denervated) bowel. Ileal absorption was studied in six dogs with an 80-cm in situ ileal segment via a triple-lumen perfusion technique using an iso-osmolar, ileal-like electrolyte solution alone and containing either glucose 2.5 mM, glutamine 2.5 mM, oleic acid 5 mM, or taurocholate 5 mM. Net absorptive fluxes of each substrate, as well as water and electrolytes, were measured in both the fasted state and after a 400-Kcal mixed meal before and at 2 and 12 weeks after our validated model of complete extrinsic denervation of the jejunoileum. At baseline, there were no differences in absorption of water, electrolytes, or any nutrient postprandially compared with the fasted state. Two weeks after extrinsic denervation, absorption of glucose at both 1 and 2 hours postprandially was decreased compared with absorption during fasting. Glutamine absorption was also decreased at 2 hours postprandially. At 12 weeks after extrinsic denervation, net postprandial absorption of glucose and glutamine returned toward normal and was not different from fasting absorption. No differences were noted in postprandial absorption of oleic acid or taurocholate at any time point. Decreases in absorption of nutrients postprandially after extrinsic denervation (which is necessitated by small bowel transplantation) may play an important role in post-transplant enteric absorptive dysfunction. The previously described postprandial augmentation in net absorption may be a function of enterically isolated gut and does not appear to occur in the in situ ileum.

Animals↗

Long-term follow-up evaluation of denervation of the wrist.

PURPOSE: To evaluate the indications and results of complete wrist denervation and to focus on the correlation between results and length of follow-up evaluation. METHODS: A retrospective review was performed of 71 complete denervations of the wrist joint in 70 patients with an average follow-up period of 9.6 years (range, 1-23 y) using the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. The denervations were performed according to the description by Wilhelm. All patients were asked to provide a DASH score. The indications for surgery were degenerative changes caused by scaphoid nonunions (25), distal radius fracture (11), Kienböck's disease (11), primary degenerative arthritis (9), scapholunate dissociation (8), and others (7). RESULTS: The average DASH score was 26 (range, 0-88). Thirty-nine patients (40 wrists) reported considerable improvement, 8 reported little improvement, and 10 reported temporary improvement after surgery. Seven experienced no change and 6 experienced worsening after surgery. Twenty-two patients were completely free of pain and 13 (14 wrists) had little, 20 had moderate, 11 had considerable, and 4 had severe pain. Forty-eight patients (49 wrists) stated that they would repeat the denervation and 61 (62 wrists) were able to keep their former occupations. There was a trend toward lower (improved) DASH scores in patients with longer follow-up periods but this did not reach statistical significance. The best results were achieved in patients with scapholunate dissociations and the worst results occurred in old distal radius fractures. Patient age did not influence the results. Nine patients with unsatisfactory results needed a second procedure. CONCLUSIONS: Complete wrist denervation resulted in subjective long-term improvement in two thirds and in a complete or marked pain relief in half of the patients. Patients with longer postoperative time and younger age did not affect the results adversely. This procedure is simple and fast, does not decrease range of motion, and leaves all other surgical options open. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic, Level IV.

Adult↗

Communication between functional and denervated muscles using radiofrequency.

OBJECTIVE: This article focuses on establishing communication between a functional muscle and a denervated muscle using a radiofrequency communications link. The ultimate objective of the project is to restore the eye blink in patients with facial nerve paralysis. STUDY DESIGN AND SETTING: Two sets of experiments were conducted using the gastrocnemius leg muscles of Sprague-Dawley rats. In the initial tests, varying magnitudes of voltages ranging from 0.85 to 2.5 V were applied directly to a denervated muscle to determine the voltage required to produce visible contraction. The second set of experiments was then conducted to determine the voltage output from an in vivo muscle contraction that could be sensed and used to coordinate a signal for actuation of a muscle in a separate limb. After designing the appropriate external communication circuitry, a third experiment was performed to verify that a signal between a functional and a denervated muscle can be generated and used as a stimulus. RESULTS: Voltages below 2 V at a 10-millisecond pulse width elicited a gentle, controlled contraction of the denervated muscle in vivo. It was also observed that with longer pulse widths, higher stimulation voltages were required to produce sufficient contractions. CONCLUSION: It is possible to detect contraction of a muscle, use this to generate a signal to an external base station, and subsequently cause a separate, denervated muscle to contract in response to the signal. SIGNIFICANCE: This demonstration in vivo of a signaling system for pacing of electrical stimulation of 1 muscle to spontaneous contraction of another, separate muscle, using radiofrequency communication without direct connection, may be used in numerous ways to overcome nerve damage.

Animals↗

Lack of effect of ovarian denervation on ovulation and pregnancy in the rabbit.

Following unilateral ovarian denervation by ovarian artery stripping in female rabbits, ovulation and pregnancy were achieved within 3 days of denervation. Three weeks later, at repeat laparotomy, ovarian dimensions and the numbers of corpora lutea and pregnancies were noted. Fluorescent histochemical studies confirmed complete adrenergic denervation in five of the rabbits' ovaries. There was no significant difference in ovarian dimensions, numbers of corpora lutea and pregnancies, or the excess of corpora lutea over implantations when the intact control side was compared with the denervated side. The control ovaries demonstrated an average of 5 corpora lutea/ovary and an average of 3.4 conceptuses in the adjacent uterine horn, while the numbers on the denervated side were 5 and 3.2, respectively. Although these findings demonstrate that central neural efferent control is not essential for the occurrence of pregnancy after mating in the rabbit, the potential significance of ovarian neuromuscular mechanisms in these functions is discussed, and future studies are suggested.

Animals↗

Involvement of dopamine D1 and D2 receptors in Fos immunoreactivity induced by stepholidine in both intact and denervated striatum of lesioned rats.

Stepholidine (SPD), a natural product, has been demonstrated in previous studies as a D1 agonist and D2 antagonist. In this work SPD-induced Fos immunoreactivity was examined. In the normal rats, Fos was induced in the striatum by SPD (1-20 mg/kg, i.p.) dose-dependently. The distribution of Fos-positive cells induced by SPD showed a rostral-caudal decline, matching the distribution of D2 dopamine receptors. The Fos-positive cells were mainly found in striatal neurons retrogradely labeled with horseradish peroxidase (HRP) from GP but not from SN, and could be abolished by the pretreatment of a D2 agonist LY171555 (2 mg/kg, i.p.), suggesting that the Fos expression in normal rats was due to the D2 antagonistic action of SPD. In the unilateral 6-hydroxydopamine-lesioned rats, SPD (4 mg/kg, i.p.) induced Fos expression in intact and denervated side of the striatum with different characteristics. Similar to that of normal rats, the Fos expression in intact side possessed the rostral-caudal gradient and could be abolished by the pretreatment of LY171555. However, in the denervated side, the Fos positive cells were widely distributed, and mainly found in striatal neurons retrogradely labeled from SN but not from GP. Furthermore, this expression was prevented by the pretreatment of SCH23390 (0.2 mg/kg, i.p.) but not LY171555, suggesting that the Fos expression in denervated side was due to the D1 agonistic action of SPD. Therefore, we concluded that the Fos expression induced by SPD in intact and denervated striatum was mediated via D2 and D1 receptor respectively, supporting the previous standpoint that SPD possesses the dual action, i.e antagonist to D2 and agonist to D1 receptors. Furthermore, it is suggested that the contralateral turning behavior induced by SPD may result from the D1-mediated excitation of striatonigral neurons of the denervated side of the lesioned rats.

Animals↗

The effect of denervation on leukocyte function in soft tissue infection.

BACKGROUND: The present study was undertaken to investigate the effect of denervation on leukocyte function in soft-tissue infection in an isolated in vivo ovine flap model. METHODS: Fifteen adult ewes were divided into three groups. An island pedicle flap was raised on the right buttock. In group I (no denervation), the cutaneous nerve remained intact, whereas in group II (acute denervation) the nerve was divided acutely. In group III (prolonged denervation) the nerve was divided 7 days before flap elevation. All flaps received intradermal inoculation of 10(7) Staphylococcus aureus, and the animals were observed for 96 hours. RESULTS: In both groups II and III, the leukocyte chemiluminescence and chemotaxis were significantly decreased when compared with group I. Furthermore, there was profound impairment of leukocyte functions in group III compared with group II. Group III also had significantly higher bacterial counts, larger septic foci, lower viable leukocyte ratios, and decreased bacterial killing compared with group I. CONCLUSIONS: Denervation, particularly over a period of time, results in increased bacterial growth of soft-tissue septic foci. This appears to be due to decreased leukocyte function resulting in diminished bacterial killing.

Animals↗

Fibroblast growth factor-2 expression is up-regulated after denervation in rat lung tissue.

To understand the role of fibroblast growth factor-2 (FGF-2) during the denervation-reinnervation processes which occur after lung transplantation, we studied FGF-2 gene expression in a rat lung denervation model. The temporal profile of FGF-2 mRNA in denervated rat lungs was quantitatively assessed by competitive reverse transcription polymerase chain reaction (RT-PCR) method. The level of FGF-2 mRNA was consistently higher in denervated lungs, showing a peak value on the 5th post-operative day. Immunohistochemical analysis with an anti-FGF-2 monoclonal antibody disclosed immunoreactivity in Schwann cells at the distal severed end of the nerve fascicle located at the lung hilus, 1 week post-surgery. This study indicates that FGF-2 gene expression is up-regulated following denervation and suggests possible roles of FGF-2 in the reinnervation process of lung tissue.

Animals↗

Wrist denervation. Surgical considerations.

We have analyzed the results of 22 total wrist denervations following Wilhelm's technique and a series of 30 patients treated with denervation of the posterior interosseous nerve alone. Results of denervation have been classified depending on the pain (visual analogue scale) as other parameters (mobility and strength) have not been found to have any statistical significance. Results after partial denervation are worse than results achieved by total denervation.

Adult↗

Extrinsic surgical denervation inhibits Clostridium difficile toxin A-induced enteritis in rats.

Clostridium difficile enteritis is caused by toxin A (TA) which stimulates substance P release and subsequent receptor activation. This receptor stimulation results in secretion, inflammation, and structural damage. However, it is unclear as to which subset of neurons is required to initiate substance P release following toxin stimulation. Five centimeter ileal segments were surgically denervated. After 10 days, three ileal loops were constructed in each rat: the denervated loop was injected intraluminally with 5 microg of TA and two intact loops were injected with TA or vehicle, respectively. Ileal secretion, myeloperoxidase activity, and histology were then assessed. Denervated ileal loops injected with TA had a 75% reduction in ileal secretion (P < 0.001), 92% reduction in myeloperoxidase activity (P < 0.01) and 96% reduction in histologic damage (P < 0.001) compared to innervated loops. There were no significant differences between the denervated loops injected with TA and those injected with vehicle. Extrinsic surgical denervation results in protection of ileal loops from TA enteritis. Furthermore, these results exclude the participation of intrinsic enteric nerves in TA-induced ileal damage. Finally, this suggests that extrinsic primary sensory neurons mediate the effects of intraluminal TA in the ileum.

Animals↗

Adrenoceptor involvement in the cardiovascular responses to B-HT 920 in sinoaortic denervated rats.

1. A study was made relating the involvement of alpha-adrenoceptors in the cardiovascular responses to intracerebroventricular (i.c.v.) injection of B-HT 920, a clonidine-type drug, in conscious sham-operated and sinoaortic-denervated rats. 2. Wistar rats were used, 7 days after the sham operation or sinoaortic denervation. For i.c.v. injection of drugs, a guide cannula had been previously implanted in the left lateral ventricle. 3. In sham-operated rats, cardiovascular responses to B-HT 920 (10-60 microg) were increased blood pressure and bradycardia; but, in sinoaortic-denervated rats, after the pressor response, a decrease in blood pressure also was seen. The responses to this agent were greater in sinoaortic-denervated rats than in sham-operated animals. Treatment with the alpha2-adrenoceptor antagonist yohimbine (30 microg), the imidazoline receptor antagonist idazoxan (15 microg) and the alpha1A-adrenoceptor antagonist 5-methylurapidil (15 microg) blocked the responses to B-HT 920 (30 microg). The alpha1-adrenoceptor antagonist prazosin (15 microg) and the alpha1B-adrenoceptor antagonist chloroethylclonidine (100 microg) did not modify the responses to agonist. 4. Sinoaortic denervation enhances the cardiovascular responses to B-HT 920. Moreover, the effects of i.c.v. administration of B-HT 920 could be mediated by several types of brain receptors: imidazoline receptors and alpha1A- and alpha2-adrenoceptors.

Adrenergic alpha-Agonists↗

Motoneurons innervating partially denervated rat hindlimb muscles remain susceptible to axotomy-induced cell death.

Tibialis anterior and extensor digitorum longus muscles were partially denervated by cutting the L4 spinal nerve in three-day-old rats. The ultrastructure of the intact axons to these muscles in the L5 spinal nerve was examined in nine-day-old rats. In the control L5 spinal nerve, myelinated and unmyelinated axons were intermingled throughout the cross-section of the nerve, while on the operated side the nerve contained areas with predominantly small unmyelinated immature axons. The number of motoneurons innervating the partially denervated muscles was established by retrograde labelling with Diamidino Yellow. In nine- and 21-day-old rats, the number of labelled motoneurons on the partially denervated side, expressed as a percentage of the control side, was 26.1 +/- 5.5% and 20.7 +/- 3.0%, respectively. The response of these uninjured motoneurons to axotomy was tested. The axons of the motoneurons to the partially denervated muscles were crushed at nine days and the numbers of labelled motoneurons in the spinal cord of these rats counted at 21 days of age. Only 4.9 +/- 2.0% labelled motoneurons were seen on the operated side, as opposed to 20.7 +/- 3.0% present in animals without sciatic nerve injury. In normal animals, nerve injury at nine days does not cause motoneuron death. Thus, motoneurons to partially denervated muscles (i) have axons with several immature features and (ii) remain susceptible to axotomy-induced death for much longer than normal.

Animals↗

Repeated stimuli for axonal growth causes motoneuron death in adult rats: the effect of botulinum toxin followed by partial denervation.

Axons of motoneurons to tibialis anterior and extensor digitorum longus muscles of adult rats were induced to sprout by injecting botulinum toxin into them, by partial denervation or by a combination of the two procedures. Ten weeks later, the number of motoneurons innervating the control and operated tibialis anterior and extensor digitorum longus muscles was established by retrograde labelling with horseradish peroxidase. In the same preparations, the motoneurons were also stained with a Nissl stain (gallocyanin) to reveal motoneurons in the sciatic pool. Examination of the spinal cords from animals treated with botulinum toxin showed that the number of retrogradely labelled cells and those stained with gallocyanin in the ventral horn on the treated compared to the control side was unchanged. In rats that had their L4 spinal nerve sectioned on one side, the number of retrogradely labelled cells on the operated side was 48+/-3% (n = 5) of that present in the control unoperated ventral horn. Thus, just over half the innervation was removed by cutting the L4 spinal nerve. Counts made from gallocyanin-stained sections showed that 94+/-4% (n = 5) of motoneurons were present in the ventral horn on the operated side. Thus, section of the L4 spinal nerve did not lead to any death of motoneurons. In rats that had their muscles injected with botulinum toxin three weeks prior to partial denervation, the number of retrogradely labelled cells was reduced from 48+/-3% (n = 5) to 35+/-4% (n = 5). Moreover, only 67+/-5% (n = 5) of motoneurons stained with gallocyanin, suggesting that a proportion of motoneurons died after this combined procedure. This result was supported by experiments in which motor unit numbers in extensor digitorum longus muscles were determined by measurements of stepwise increments of force in response to stimulation of the motor nerve with increasing stimulus intensity. In partially denervated extensor digitorum longus muscles, 16.6+/-0.7 (n = 5) motor units could be identified, and in animals treated with botulinum toxin prior to partial denervation only 13.3+/-0.9 (n = 3) motor units were present. Taken together, these results show that treatment with botulinum toxin followed by partial denervation causes motoneuron death in adult rats.

Animals↗

[Selective microsurgical denervation in spastic paralysis].

Denervation, provosed at the turn of the century and abandoned because of inconstant results, has again been taken up in principle, but with a notable change in technique. It is necessary to do a careful examination of the muscles that are to be denervated (of the median and ulnar nerves) and to determine the nature of the spasticity. The incision, longer than in the original technique, allows a better view of the median and ulnar nerves. The nerve branches to each muscle are thus easily identified, and by electric stimulation during the operation one judges how much denervation to subject the muscles to while taking into account the phenomenon of the take-over of the denervated muscles by the remaining nerve fibers. Part of the nerve branches are then sectioned under microscopic control near the muscle, taking care to cauterize the proximal stump. It may be necessary to do associated tenotomies or capsulotomies. This method gives good results if the technique and the contraindications, (athetosis, chorea and cerebral deficits) are respected. It must be emphasized that the results depend on the degree of denervation, which is hardly quantifiable, and is subject to the operator's experience.

Arm↗

Fibrillation potential amplitude to quantitatively assess denervation muscle atrophy.

Denervated muscle fibers exhibit spontaneous, repetitive single muscle fiber discharges and display fibrillation potentials detectable by electromyography. To explore the changing pattern of fibrillation potential amplitude after peripheral nerve injury and its relationship to the degree of muscle atrophy, fibrillation potential amplitudes were recorded on completely denervated biceps brachii of 173 patients with brachial plexus injury. Biceps brachii biopsies were taken at the same sites as the electromyogram recordings in 63 patients. The biopsies were analyzed by ATPase staining and the cross-sectional areas of fast and slow-twitch fibers were calculated. We found that the fibrillation potential amplitude and the cross-sectional areas of denervated muscle decay over time (P < 0.05), and both correlate negatively with denervation time (P < 0.01-0.05) within the first 15 months. The fibrillation potential amplitude correlates positively with both type I and II fiber cross-sectional areas (P < 0.0005-0.01). Our results show that fibrillation potential amplitude is closely correlated with muscle fiber size during the first 15 months after nerve injury, and it may therefore serve as a convenient index to evaluate quantitatively the degree of atrophy of denervated muscles. Electromyographic studies thus may help in designing treatment strategies.

Adolescent↗

Differential adrenergic response to extrinsic denervation in canine longitudinal jejunal and ileal smooth muscle.

Early postoperative complications after small bowel transplantation (SBT) are likely mediated, at least in part, by dysmotility caused by the obligate disruption of extrinsic and enteric nerves in the graft. Adrenergic hypersensitivity of gut smooth muscle has been observed in some (but not all) segments of intestine in various experimental models of SBT, highlighting regional and species variability in response to denervation. Little is known about changes in canine longitudinal muscle after extrinsic denervation. Six dogs each underwent either complete extrinsic denervation of the jejunoileum or a control operation (transection and reanastomosis of the proximal jejunum and distal ileum). In vitro contractile response of longitudinal muscle strips to norepinephrine was evaluated at the time of the operation, and 2 weeks and 8 weeks later. After extrinsic denervation, the jejunal response to norepinephrine was preserved at all time points; however, the ileum displayed a decreased sensitivity to norepinephrine, an effect unmasked after intramural neural blockade with tetrodotoxin. These data support a potential for neurally mediated dysmotility after SBT and reinforce the differences in responses to extrinsic denervation between species, as well as differences within different regions and between anatomic segments of small intestine in the same species.

Adrenergic Fibers↗

Analysis for transcript expression of meltrin alpha in normal, regenerating, and denervated rat muscle.

Meltrin alpha (a disintegrin and metalloprotease (ADAM) 12) is a recently discovered molecule of the metalloprotease-disintegrin family which has been shown to participate in myotube formation in vitro and in myogenesis in vivo. In this study we investigated meltrin alpha in regenerating rat muscle, which is a condition where satellite cells (SC) contribute to myofiber growth by fusing with one another and with myotubes or muscle fibers. We studied meltrin alpha mRNA expression by RT-PCR and in situ-hybridization in normal adult muscle, in soleus muscle regenerating for 2, 5, or 10 days, and in muscle which had been denervated 1 week, 4 weeks, or 6 months previously. SC do not fuse after denervation. They detach from the principal muscle fiber. Immunohistochemistry using an antibody against M-cadherin was performed in parallel in order to identify SC. Messenger RNA as revealed by RT-PCR was absent in normal adult muscle, but present in regenerating and also in denervated muscle. Meltrin alpha transcript detected by in situ-hybridization was present in regenerating muscle only, not in normal or denervated muscle. It was localized to SC. Taken together, meltrin alpha is absent in normal muscle, and localized to SC in fusing conditions. After denervation, the transcript is upregulated. However, it is so lowly abundant that it fails to be detected by in situ-hybridization. This expression profile suggests a role for meltrin alpha in the fusion of SC with myotubes or muscle fibers, but not in SC adhesion to the adjacent myofiber in normal adult muscle.

ADAM Proteins↗

Acute denervation alters the epithelial response to adrenoceptor activation through an increase in alpha1-adrenoceptor expression on villus enterocytes.

Loss of sympathetic input due to intestinal denervation results in hypersensitivity and increased intestinal secretion. It is unknown whether denervation-induced alterations in intestinal epithelial physiology are the result of changes in adrenoceptors on enterocytes (ENTs). The purpose of this study was to examine adrenoceptor distribution and pharmacology on small intestinal ENTs following acute intestinal denervation. Lewis rats underwent small bowel transplantation (SBT) or sham operation and proximal small intestinal segments were harvested 1, 2 and 4 weeks postoperatively. Intestinal electrolyte movement was assessed using short-circuit current (Isc) measurements of stripped epithelial sheets following stimulation with phenylephrine (PE), an alpha(1)-adrenoceptor agonist. The presence of adrenoceptor subtypes on separated villus and crypt ENTs was assessed using flow cytometry. Alpha(1)-adrenoceptors were found on approximately 27% of jejunal villus ENTs, but not crypt ENTs, following acute extrinsic denervation. ENTs from the Lewis rat have few beta-adrenoceptors. Alpha(1)-adrenoceptor stimulation of acutely denervated intestinal epithelial sheets decreased Isc by -13.45%. This effect was mediated by a reduction in chloride (Cl(-)) secretion; the absence of Cl(-) reversed the Isc to +13.79%. In conclusion, loss of sympathetic innervation to the gastrointestinal epithelium causes acute upregulation of alpha(1)-adrenoceptors on villus ENTs, leading to inhibition of Cl(-) secretion at the villus tip. The increase in adrenoceptors may reflect a compensatory mechanism to combat the increased secretory state of the bowel due to the loss of the sympathetic innervation and tonic control over intestinal secretion.

Animals↗