Beneficial effect of clonidine on spasticity antagonized by baclofen in a stroke patient.

Although Clonidine has recently been described as a useful antispasticity agent, to our knowledge there has not been a previous report of clonidine's antispasticity effect antagonized by baclofen. Using a 0-5 Modified Ashworth Scale to evaluate the right knee extensor tone in a 74-year-old man 5 months following a left middle cerebral artery stroke, tone improved from 3 to 1 on Clonidine 0.6 mg daily in divided doses. The day after addition of baclofen at 15 mg daily in divided doses, tone increased to 4. Baclofen was withdrawn with a decrease in tone to 2. Baclofen alone at the above dose resulted in tone comparable to the clonidine-free baseline. Treatment with Clonidine alone was resumed, and the expected reduction in hypertonicity was again observed. Possible mechanisms of action for baclofen antagonizing the beneficial effect of Clonidine on spasticity after stroke are presented and discussed.

Sparing of motor function after cortical injury. A new perspective on underlying mechanisms.

Historically, many theories have been offered to explain recovery of function following permanent brain injury. Because specific functional deficits often occur after injury to certain neuroanatomical locations, it has been tempting to suggest that within the brain, structure equals function (this interpretation, of course, has its roots in "phrenology", the 19th-century practice of detecting mental and behavioral traits by examining the skull's shape). Views that were common until recently emphasized structural and functional rigidity in the brain, which would seem to provide little opportunity for the occurrence of compensation. However, the observation that a considerable amount of spontaneous functional recovery occurs after many permanent brain lesions requires some explanation for the recovery that involves modification of intact portions of the brain. Recent research has provided data that reveal several forms of brain plasticity, including changes in neurotransmitter sensitivity, collateral sprouting, and diaschisis. Evidence supporting claims that beneficial behavioral recovery occurs through such physiological modifications in the brain are abundant in the literature, although, in general, there has not been any empirical establishment of causality.

Comparative effects of fluoxetine, amitriptyline and serotonin on functional motor recovery after sensorimotor cortex injury.

A recent investigation of the effects of the antidepressants desipramine and trazodone on behavioral recovery in brain-injured animals suggested that antidepressants, which act to increase noradrenergic activity in the brain, may facilitate the rate of recovery, whereas those that act to increase serotonergic (5-HT) activity may hinder recovery and reinstate deficits in recovered animals. The present study was designed to evaluate these findings further by assessing the effect of a single intraperitoneal injection of fluoxetine (a relatively pure 5-HT reuptake blocker), amitriptyline (a mixed 5-HT and noradrenergic reuptake blocker with alpha 1-adrenergic receptor blocking activity) or a single intraventricular infusion of 5-HT on recovery of beam-walking ability in animals with a unilateral sensorimotor cortex injury. None of the drugs significantly affected the rate of recovery. Although fluoxetine was ineffective in reinstating the motor deficit in recovered animals, amitriptyline reinstated the deficit in a dose-dependent fashion. Infusion of 5-HT resulted in an extremely transient reinstatement of the deficit, which was largely attributable to its short-term sedative properties. These results suggest that 5-HT may be less involved in functional recovery than previously thought. They also add further support to previous findings that indicate that drugs which act to antagonize alpha 1-adrenergic activity (e.g., phenoxybenzamine) may interfere with motor recovery after sensorimotor cortex injury. An appreciation of the potential impact of certain antidepressants on functional recovery in brain-injured patients appears warranted.

Effects of trazodone and desipramine on motor recovery in brain-injured rats.

Rats pretrained to walk a narrow balance beam received unilateral sensorimotor cortex lesions, resulting in a contralateral transient paresis that lasted 14 days. In a dose-dependent manner, a single injection of the antidepressant trazodone given 24 hours after injury transiently slowed motor recovery compared with injured controls. After final recovery level of motor function, a reinjection of trazodone reinstated the hemiparesis for up to 6 hours. In other animals, a single injection of the antidepressant desipramine significantly facilitated motor performance when compared with injured controls. Desipramine had no deleterious motor effect when administered to animals that had recovered on the beam-walking task. These findings would suggest that the predominantly noradrenergic neurotransmitter effects of desipramine may facilitate, and those of the predominantly serotonergic trazodone may hinder, the recovery of locomotor performance after cortical injury in rats. Further studies appear indicated, including applying these findings to the clinical setting.

Unilateral locus coeruleus lesions facilitate motor recovery from cortical injury through supersensitivity mechanisms.

Previous research has indicated that noradrenergic infusions into the cerebellum contralateral to a sensorimotor cortex injury facilitate recovery of motor function. In the present study, the locus coeruleus was lesioned at 2 weeks prior to, 1 week prior to, or simultaneous with a right sensorimotor cortex injury, and functional recovery in response to noradrenergic cerebellar infusions was measured using the beam-walk task. When the locus coeruleus lesion was separated from the sensorimotor cortex lesion by 1 week or more, noradrenergic-induced facilitation of functional recovery occurred with the greater effects observed at the 2-week interval. Simultaneous locus coeruleus and sensorimotor cortex injury with cerebellar noradrenergic infusions revealed no difference in functional recovery. The results suggest that denervation supersensitivity and/or sprouting developed in the cerebellum following the locus coeruleus lesions if a sufficient amount of time elapsed before the sensorimotor cortex injury. The heightened sensitivity to noradrenergic infusions in the contralateral cerebellum suggests that noradrenergic changes in this structure underlie the acceleration of functional recovery from the cortical injury.

Neuroplasticity in the smooth muscle of the myenterically and extrinsically denervated rat jejunum.

The objective of this study was to examine the effects of two different denervation procedures on the distribution of nerve fibers and neurotransmitter levels in the rat jejunum. Extrinsic nerves were eliminated by crushing the mesenteric pedicle to a segment of jejunum. The myenteric plexus and extrinsic nerves were eliminated by serosal application of the cationic surfactant benzyldimethyltetradecylammonium chloride (BAC). The effects of these two denervation procedures were evaluated at 15 and 45 days. The level of norepinephrine in whole segments of jejunum was initially reduced by more than 76% after both denervation procedures, but by 45 days the level of norepinephrine was the same as in control tissue. Tyrosine hydroxylase (noradrenergic nerve marker) immunostaining was absent at 15 days, but returned by 45 days. However, the pattern of noradrenergic innervating axons was altered in the segment deprived of myenteric neurons. Immunohistochemical studies showed protein gene product 9.5 (PGP 9.5)-immunoreactive fibers in whole-mount preparations of the circular smooth muscle in the absence of the myenteric plexus and extrinsic nerves. At 45 days, the number of nerve fibers in the circular smooth muscle increased. Vasoactive intestinal polypeptide (VIP)-immunoreactive fibers, a subset of the PGP 9.5 nerve fibers, were present in the circular smooth muscle at both time points examined. Choline acetyltransferase (CAT) activity and VIP and leucine enkephalin levels were measured in separated smooth muscle and submucosa-mucosal layers of the denervated jejunum. VIP and leucine-enkephalin levels were no different from control in tissue that was extrinsically denervated alone. However, the levels of these peptides were elevated two-fold in the smooth muscle 15 and 45 days after myenteric and extrinsic denervation. In the submucosa-mucosa, VIP and leucine enkephalin levels also were elevated two-fold at 15 days, but comparable to control at 45 days. CAT activity was equal to control in the smooth muscle but elevated two-fold in the submucosa-mucosa at both times. These results provide evidence for innervation of the circular smooth muscle by the submucosal plexus. Moreover, these nerve fibers originating from the submucosal plexus proliferate in the absence of the myenteric plexus. Furthermore, the myenteric neurons appear to be essential for normal innervation of the smooth muscle by the sympathetic nerve fibers. It is speculated that the sprouting of the submucosal plexus induced by myenteric plexus ablation is mediated by increased production of trophic factors in the hyperplastic smooth muscle.

Reinstatement of motor deficits in recovered brain-injured animals: the role of cerebellar norepinephrine.

Previous research has indicated that antagonists of locus ceruleus functioning, when administered during the acute phase of an injury, slow recovery of motor function following unilateral sensorimotor cortex injury. Following a recovery plateau in animals, it is possible to pharmacologically reinstate unilateral motor deficits in recovered animals with similar acting drugs given intraperitoneally. The present study was designed to localize the brain systems responsible for the reinstatement of the deficit after recovery from the cortical injury. The results indicate that maintaining functional recovery after injury is modulated by NE in the cerebellum contralateral to the injury, since microinfusions of phenoxybenzamine into this structure reinstate motor deficits. Additionally, removal of the noradrenergic projection to contralateral cerebellum through unilateral lesions of the locus ceruleus reinstate unilateral deficits more severely than the drug administration.

Biochemical and behavioral effects of a sensorimotor cortex injury in rats pretreated with the noradrenergic neurotoxin DSP-4.

The role of the noradrenergic (NE) system in recovery of motor function after sensorimotor cortex (SMCX) injury was investigated. After training on a beam-walking task to assess changes in motor function, animals were given DSP-4 or saline and tested for 2 weeks; both groups then received unilateral SMCX suction ablations. Animals that received DSP-4 were significantly retarded in motor recovery compared with the saline group. At 24 days after injury (after motor recovery), the animals' deficits were significantly reinstated with NE-blocking drugs. DSP-4 significantly depressed NE levels in the hippocampus and cerebellum. A Timm histochemical analysis revealed glutamatergic sprouting in the hippocampus of animals that were pretreated with DSP-4, which suggests the possibility that similar glutamatergic plasticity in other pathways may occur and that excitotoxicity might also play a role after the DSP-4 induced NE deafferentation.

Unilateral, but not bilateral, locus coeruleus lesions facilitate recovery from sensorimotor cortex injury.

This study investigates the role of the locus coeruleus in recovery from sensorimotor cortex injury. Unilateral locus coeruleus lesions given 2 weeks prior to unilateral sensorimotor cortex injury facilitate subsequent motor recovery compared to animals with only a sensorimotor cortex injury, while bilateral locus coeruleus lesions severely retard motor recovery. The results suggest that recovery of function from the cortical injury is facilitated as long as a sufficient amount of the noradrenergic system remains intact, perhaps to provide a basis for compensatory sprouting. The results also suggest that recovery does occur in the absence of the locus coeruleus, indicating that the noradrenergic system is not necessary for recovery to occur after the cortical injury.

Cerebellar norepinephrine infusions facilitate recovery after sensorimotor cortex injury.

This study reports the effects of norepinephrine infusions into cerebellum after unilateral sensorimotor cortex injury. The results demonstrate an immediate and permanent acceleration in motor recovery in awake rats infused with 150 micrograms norepinephrine into the cerebellum contralateral to a right sensorimotor cortex ablation. A vehicle infusion or infusion of norepinephrine into the ipsilateral cerebellum produced no beneficial effects on functional recovery.

Cortical microstimulation thresholds adjacent to sensorimotor cortex injury.

The initial severe contralateral impairment of motor function after unilateral damage to a portion of sensorimotor (SM) cortex lessens within a few weeks after injury. In this study, two hypotheses proposed to explain recovery of behavioral function after cortical injury were tested: (1) Intact cortex adjacent to the injury reorganizes to take over the function of the destroyed area. (2) Intact SM cortex adjacent or connected to the injured area undergoes a transient shock (diaschisis), and as this dissipates, some behavioral recovery occurs. Using microstimulation of the cortex of the adult rat, movements evoked from areas near cortical injuries were studied at various times after undercut laceration, contusion, or suction ablation of an area of SM cortex. Stimulation areas were compared to those obtained from uninjured control animals and to the contralateral uninjured hemisphere. No evidence was obtained for any reorganization of stimulated motor responses in the injured hemisphere even in animals followed for as long as 475 days postinjury, suggesting other mechanisms underlying functional recovery. In intact cortex at some distance from contusion and laceration injuries, there was a marked elevation of thresholds to evoke movements that returned to normal by 9-15 days postinjury. Some intact hindlimb responses were observed after contusion injury that were absent in animals after 15 days postinjury, indicating a slow-growing lesion after this type of trauma. Surprisingly, no elevation in thresholds was noted for ablation injuries up to the edge of the cavity at any time postinjury, indicating that threshold changes near the boundary may be uncorrelated with functional recovery.

Adverse effects of catecholaminergic drugs following unilateral cerebellar ablations.

The following experiment was designed to examine the effects of unilateral cerebellar cortex lesions and pharmacological postinjury treatments with catecholamine drugs on recovery of beam walking ability in rats. Rats trained on a beam walking task were initially given either amphetamine, haloperidol, or a combination of the drugs at 24 h after injury, and tested at various intervals after drug administration. Six total doses were given to animals at 5d intervals during recovery. All drugs retarded recovery of function on the beam walking task compared to saline controls. Animals with cortical lesions that involved the deep cerebellar nuclei showed no recovery on the beam, regardless of group assignment. Phenoxybenzamine and propranalol were both ineffective in reinstating the beam walking deficit in those animals that demonstrated recovery on the beam walking task. The results indicate that the cerebellum plays a particularly important role in recovery of beam walking ability, and may contribute to beam walking recovery commonly observed after sensorimotor cortex ablations.

Intraventricular norepinephrine facilitates motor recovery following sensorimotor cortex injury.

Intraventricular norepinephrine, dopamine, or vehicle was administered to rats 24 hours after a unilateral sensorimotor cortex ablation to determine their potential roles in acceleration of motor recovery as measured by the beam-walking task. Norepinephrine was found to be the critical neurotransmitter in facilitating motor recovery. Blocking norepinephrine synthesis by dopamine-beta-hydroxylase inhibition coupled with dopamine administration failed to accelerate recovery, indicating a more important role for norepinephrine compared to its precursor dopamine in motor recovery after sensorimotor cortex injury.

The effect of seizures on recovery of function following cortical contusion in the rat.

The effect of seizures on recovery of motor function was studied in rats following unilateral contusion of the sensorimotor cortex. Animals receiving two electroconvulsive seizures (ECSs) within the first 24 hours postcontusion showed accelerated recovery of beam-walking ability, reduced volume of necrosis and less spontaneous activity compared to animals receiving only contusions. Animals receiving seven ECSs after contusion had an even smaller volume of necrosis and also reduced spontaneous activity compared to the two ECS group and to controls receiving contusions alone. However, for recovery of beam-walking ability, the seven ECS group did not differ from control rats receiving only contusions. The results are discussed in terms of the effects of seizures on catcholamines, gamma-amino butyric acid, cerebral blood flow and possible effects on remote functional depression after brain injury.

Striatal dopamine after cortical injury.

After right or left unilateral sensorimotor cortex ablation or a sham operation, dopamine concentrations were assayed in the right and left striatum of rats. In the sham-operated animals, a greater amount of dopamine was found in the left striatum compared with the right. Right or left sensorimotor cortex injury reduced dopamine in both striata. Right hemisphere lesions produced a greater loss of dopamine in the right striatum compared with the effect of a left lesion on dopamine in the left striatum. The results support the hypothesis of an asymmetric response to cortical injury.

Responses to cortical injury: I. Methodology and local effects of contusions in the rat.

In order to develop some understanding of the evolution of cortical contusions, interdisciplinary studies including behavior, morphology and histochemistry were conducted at varying intervals after standardized injuries. A method for producing graded and reproducible focal cortical contusions in the rat is described. When these impact injuries are made in the "hindpaw cortical area,' specific trauma dose dependent behavioral deficits can be readily observed in the contralateral hindlimb. While most functional recovery occurs in the first two weeks after trauma, with severe contusions, deficits persist beyond 90 days. Morphologically these injuries progress from hemorrhages in white matter directly under contused cortex during the first hours after injury to the development of a necrotic cavity by 24 hours. The cavitation appears to expand over the subsequent two weeks and by 15 days is lined with fibroblast-like elements and macrophages. Intense acid phosphatase activity is seen on the borders of the area of necrosis. This lysosomal enzyme may participate in autolysis and development of focal cavitation following cortical contusion.

Responses to cortical injury: II. Widespread depression of the activity of an enzyme in cortex remote from a focal injury.

As a part of a broader study of the reaction of the brain to injury, we report here an interesting loss of the activity of an enzyme in areas quite remote from the site of direct injury. At 36 h following a laceration or contusion injury to the hindpaw area of the motor cortex, a peculiar loss of staining for the enzyme alpha glycerophosphate dehydrogenase (alpha-GPDH) was noted. alpha-GPDH activity was markedly depressed in cortical layers II and III throughout the hemisphere on the side of the injury. The depression of alpha-GPDH activity extended far laterally across the rhinal fissure into the pyriform cortex. The decrease in alpha-GPDH staining was prominent 4 days after the injury: however, the staining pattern had returned to normal at 9 days. Enzyme changes in animals lesioned in the occipital cortex paralleled that seen in animals with a lesion in the motor cortex. Animals which had received an undercut lesion in the motor cortex 56 days earlier were contused in the occipital cortex. The old injury site presented the same sequelae of changes as seen in other lesioned animals. Additionally, a suction ablation injury involving only a small part of motor cortex resulted in the same widespread reduction of staining for alpha-GPDH in layers II and III. The derangement in energy metabolism suggests that cells in layers II and III of the cerebral cortex may be particularly vulnerable to perturbations induced by cortical trauma. These findings may be related to the diffuse and transient functional losses observed after head injury in man.

Dopaminergic agonists differentially affect open-field activity of rats with A10 lesions.

Dopaminergic systems appear to exert considerable control over locomotor activity. Although dopamine neurons are located in relatively close proximity within the mesencephalon, their axons project to more diffuse areas, perhaps reflecting some underlying heterogeneity in their function. The purpose of this study was to determine whether dopamine agonists differentially affect activity by acting upon distinct dopamine systems. Bilateral radio-frequency lesions of area A10 in rats failed to affect spontaneous open-field behavior over a 1-month postoperative period. When injected with 1 mg/kg of apomorphine, however, experimental rats more than doubled their activity as compared to the response of sham-operated controls. In contrast, no difference between the two groups of animals was observed in terms of increased activity following 3 mg/kg of either d-amphetamine or methylphenidate. These results are consistent with previous work indicating the involvement of ventromedial mesencephalic dopamine somata in the control of locomotor activity. The data suggest, however, that systems in addition to the dopaminergic mesolimbic projection are responsible, in part, for the hyperactivity elicited by d-amphetamine or methylphenidate.