Dennis M. Feeney

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.

α-Noradrenergic agonists and antagonists affect recovery and maintenance of beam-walking ability after sensorimotor cortex ablation in the rat.

Rats trained to traverse a narrow elevated beam were given a single intraperitoneal injection of either D-amphetamine, clonidine, L-phenylephrine, prazosin, yohimbine, or saline 24 h after ablation of the right sensorimotor cortex and tested for recovery of beam-walking (BW) ability to day 16 postsurgery. Clonidine, prazosin and L-phenylephrine did not significantly affect BW recovery. A 10 mg/kg dose of yohimbine significantly accelerated BW recovery, as did D-amphetamine (2 mg/kg). Since D-amphetamine and yohimbine both increase norepinephrine (NE) release and prior research has implicated NE but not dopamine in BW recovery, these data support the hypothesis that increased NE release benefits functional recovery in this model of cortical injury. However, a possible role of dopaminergic or serotonergic influences of D-amphetamine or yohimbine treatment cannot be ruled out. To investigate the role of the NE system in maintenance of recovery, animals recovered from BW deficits 18 days after injury were administered clonidine, prazosin, or yohimbine and retested on the BW task. Both the α1-NE antagonist prazosin (2 or 4 mg/kg) and the α2-NE agonist clonidine (0.1 or 0.4 mg/kg) produced a dose-dependent, transient worsening of BW performance. This reinstatement of deficits in recovered rats suggests that integrity of the α-NE system is necessary for maintaining functional recovery.

Reinstatement of binocular depth perception by amphetamine and visual experience after visual cortex ablation

In adult cats with bilateral visual cortex ablation the complete deficit in binocular depth perception, as measured on a visual cliff, was reversed by 4 doses of amphetamine. The amphetamine-induced recovery endured after the amphetamine treatment was discontinued. This enduring recovery of function was not obtained if the animals were housed in the dark during drug intoxication. Therefore, both amphetamine intoxication and visual experience are simultaneously required for recovery of binocular depth perception after visual cortex ablation.

The locus coeruleus and cerebral metabolism: Recovery of function after cortical injury

Cerebral metabolic effects of locus coeruleus (LC) lesion or drugs affecting LC were investigated after unilateral injury of sensorimotor cortex in rats. Sensoriomotor cortex ablation produced a widespread depression of cerebral 14C-2-deoxyglucose utilization which was reversed by amphetamine (AMP, 2 mg/kg) and worsened by haloperidol (HAL, 0.4 mg/kg). Lesion of LC alone did not affect cerebral oxidative metabolism, measured by a stain for the enzyme alpha-glycerophosphate dehydrogenase (α-GPDH). Lesion of LC prior to undercut laceration of motor cortex shortened time to onset of α-GPDH cortical paling. Treatment with AMP (2 mg/kg) blocked cortical paling of the enzyme stain at 4 days postinjury, an effect prevented by concomitant HAL (0.3 or 0.6 mg/kg). Apomorphine (1 mg/kg) did not block cortical paling. These data parallel effects of these drugs on recovery of function. The results suggest that a metabolic “remote functional depression” (RFD) is alleviated by catecholamine activation after cortical injury, whereas onset of RFD is accelerated by LC lesions and exacerbated by catecholamine blockade.

Amphetamine accelerates recovery of locomotor function following bilateral frontal cortex ablation in cats

Prior work has demonstrated that d-amphetamine hastens recovery of beam-walking ability following unilateral sensorimotor or frontal cortex ablation (Hovda & Feeney, 1984). In this study, after bilateral frontal cortex ablation, cats given injections of d-amphetamine showed an enduring acceleration of recovery of beam-walking ability relative to saline controls. In general, rates of spontaneous and drug-induced recovery in cats with bilateral lesions were similar to those previously reported for cats with unilateral ablations. These results indicate that the bilateral corticostriate and corticothalamic projections from the contralateral homotopic cortex do not mediate the beneficial effects of d-amphetamine on locomotor recovery after unilateral cortical ablation.

Amphetamine and apomorphine restore tactile placing after motor cortex injury in the cat

Unilateral motor cortex injury in the cat results in a prolonged loss of tactile placing in the forelimb contralateral to the injury. Amphetamine (5 mg/kg) temporarily reverses this tactile placing deficit as early as 4 days following the injury. Racemic amphetamine was found to produce a significantly more prolonged restoration of placing than the d isomer, which was significantly more effective than the l isomer. Haloperidol (0.4 mg/kg) blocked the amphetamineinduced recovery of placing responses and also blocked placing in nondrugged cats showing partial spontaneous recovery. This dosage of haloperidol had no effect on tactile placing in normal cats. Apomorphine at moderate dosages (0.25 and 0.5 mg/kg) produced a weak restoration of tactile placing in motor cortex-injured animals. These pharmacological data suggest that the loss of tactile placing after motor cortex injury is due to a depression of catecholaminergic function, which is temporarily reversible by catecholaminergic stimulation.

Noradrenergic Pharmacotherapy, Intracerebral Infusion and Adrenal Transplantation Promote Functional Recovery After Cortical Damage

The research described in this review briefly summarizes evidence that short term pharmacological enhancement of noradrenergic (NA) synaptic activity, combined with symptom relevant experience (SRE), promotes functional recovery of some symptoms of cortical damage in rat, cat and human beings even when treatment is initiated from days to weeks after injury. A summary is provided of the numerous drugs tested in rodent cortical injury models which have been proven useful for predicting beneficial or harmful effects on behavioral outcome in human stroke. The pattern of drug effects indicates a central role for NA in functional recovery. Additionally, studies of the effects of direct intraventricular infusion of monoamine neurotransmitters are reviewed and further support the hypothesized role of NA in recovery from some symptoms of cortical injury. The site of NA/SRE interaction to promote recovery from hemiplegia apparently involves the cerebellar hemisphere contralateral to the cortical injury. Microinfusions of NA into the contra- but not ipsilaterai cerebellar hemisphere dramatically enhance recovery. Furthermore, like its systemic action, microinfusion of the α1- NA receptor antagonist, phenoxybenzamine, reinstates hemiplegia. A “permanent” symptom of motor cortex injury in the cat is the complete loss of tactile placing contralateral to the injury which does not spontaneously recover for as long as seven years after ablation. This posturai reflex is temporarily restored for 8-12 hours following amphetamine administration. However, this permanently lost reflex can be enduringly restored by transplanting catecholamine secreting adrenal tissue into the wound cavity. The experiment is reviewed in detail and involves chromaffin cell autografts into the frontal cortex ablation wound cavity producing a restoration of tactile placing for the 7-10 month duration of the study. This enduring restoration of tactile placing is considered a result of the release of catecholamines into the CNS from the grafted chromaffin cells found, by histochemical methods, surviving 7-10 months after transplant. Lastly, we attribute these delayed treatment effects to an attenuation of a diaschisis, or remote functional depression, in morphologically intact areas anatomically connected to the area of injury. The widespread reduction of glycolytic and oxidative metabolism, produced by focal cortical injury, is normalized by the same treatment which alleviates symptoms and is worsened by drugs which exacerbate deficits. These data support the hypothesis that providing SRE during a period of enhanced NA synaptic activity produces an enduring functional recovery after cortical injury by attenuating remote functional depression. This treatment for enhancing recovery is especially attractive since it is effective even when begun weeks after cortical damage.

Sensory neglect after lesions of substantia nigra or lateral hypothalamus: Differential severity and recovery of function

Sensory neglect was studied in cats after unilateral lesions of: lateral hypothalamus (LH); internal capsule (IC) adjacent to the LH; substantia nigra (SN) or the ventromedial hypothalamus (VMH). Special behavioral tests were employed to yield quantifiable data and also to exclude any confounding due to simple movement deficits. Lesions of SN or IC produced severe and enduring contralateral visual and somesthetic deficits and a facilitation of ipsilateral visual responsiveness. In contrast, LH lesions sparing the adjacent IC produced only weak and transient deficits and VMH lesions had no effects on sensory function. This suggests that lesions of the SN or its forebrain connections are important for producing sensory neglect and that sensory deficits after LH lesions are due to infringement on fibers of passage to or from the SN. Lesions which produced neglect often suppressed the amplitude of flash evoked responses in the ipsilateral caudate nucleus and visual and association cortex. However, these evoked potential effects were transient. There was no effect on the spontaneous EEG and this fails to support the hypothesis of a lack of hemispheric arousal in sensory neglect. The results are discussed in relation to nigrotectal projections and the process of attention. This lesion-behavior model is suggested for studies of recovery of function.

Decrease and recovery of N-acetylaspartate/creatine in rat brain remote from focal injury

Magnetic resonance spectroscopy (MRS) studies on traumatic brain injury (TBI) have shown that the neuronal metabolite N-acetylaspartate (NAA) may be reduced in regions of brain remote from sites of focal injury. Such reductions have generally been attributed to diffuse axonal injury (DAI) or neuron death. The aim of the present study was to investigate the contribution of metabolic depression, in the absence of DAI or cell death, to remote NAA reduction after TBI. The right sensorimotor cortices of adult rats were injured by weight drop. Two and six days later, tissue slices from the ipsilateral occipital cortex, or from the same region in uninjured rats, were superfused and examined by 1H-MRS. The occipital cortex has been shown to have negligible DAI or cell death but marked transient metabolic depression in this model of TBI. Two days after injury, the ratio of the NAA peak height to the total creatine peak height (NAA/TCr) was 14% lower than in control samples. Six days after injury, NAA/TCr recovered to within 7% of the control value. The time course of NAA/TCr decrease and recovery was similar to the time courses of widespread depression and recovery of 2-deoxyglucose uptake and mitochondrial alpha-glycerophosphate dehydrogenase activity measured previously in this model of TBI. Together, these results suggest that at least one component of remote NAA depression after TBI may be associated with a widespread and reversible metabolic depression that is unrelated to either DAI or cell death.

Amphetamine-induced recovery of visual cliff performance after bilateral visual cortex ablation in cats: measurements of depth perception thresholds

After bilateral visual cortex ablation, cats exhibit a loss of depth perception as measured on a visual cliff, which recovers following administration of d-amphetamine. In this Study, 3 amphetamine-treated cats with visual cortex ablations showed a rapid and enduring recovery, with 2 of these animals obtaining levels of performance seen only with binocular vision, suggesting a restoration of binocular depth perception. Cats with asymmetrical lesions showed only a transient improvement during amphetamine treatment, and some animals not displaying autonomic signs of amphetamine intoxication did not improve. Saline-treated cats showed no signs of improvement, and the effect of amphetamine was blocked by the catecholaminergic antagonist haloperidol. These results indicate that amphetamine can induce an enduring recovery from a behavioral deficit after brain injury, which if left untreated would not spontaneously recover.