Apomorphine has a therapeutic effect on neglect produced by unilateral dorsomedial prefrontal cortex lesions in rats

doi:10.1016/0014-4886(86)90247-5

Experimental Neurology

Volume 94, Issue 3, December 1986, Pages 683-698

https://doi.org/10.1016/0014-4886(86)90247-5 Get rights and content

Abstract

Neglect is a disorder in which the response to stimulation is diminished or absent on the side of the body contralateral to the lesion in the absence of an elemental sensory or motor defect. Most cases of neglect in humans are induced by cortical damage, but there have been no investigations of the pharmacologic basis of neglect induced by cortical damage. We examined the role of the dopamine system in polymodal neglect caused by a unilateral lesion of the medial percentral prefrontal cortex of the rat. A dose-response examination of the effect of apomorphine on neglect revealed that apomorphine, at 0.5 mg/kg, the highest dose examined, significantly improved the orientation scores of subjects in all modalities tested and significantly decreased the total number of allesthetic responses. The therapeutic effect of apomorphine was mediated by dopamine receptors as the therapeutic effect of apomorphine was blocked by prior administration of spiroperidol. These results demonstrate the important role of disruption of dopamine mechanisms in neglect induced by a lesion of medial precentral cortex.

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Previous studies evaluating the orienting movements in rats have used a variety of tasks. For example, rats held by the experimenter's hands were evaluated based on the degree of the head orientation to the visual, auditory, and tactile stimuli presented from the left and right spaces [12,17,34–38]. Recent studies evaluated the orienting movements of rats using the spatial visual attention task [39] and the clicks accumulation task [18,40].
Unilateral spatial neglect is a disorder of higher brain function that occurs after a brain injury, such as stroke, traumatic brain injury, brain tumor, and surgical procedures etc., and leads to failure to attend or respond to stimuli presented to the side contralateral to the lesioned cerebral hemisphere. Because patients with this condition often have other symptoms due to the presence of several brain lesions, it is difficult to evaluate the recovery mechanisms and effect of training on unilateral spatial neglect. In this study, a mouse model of unilateral spatial neglect was created to investigate whether the size of the lesion is related to the severity of ipsilesional spatial bias and the recovery process. Focal infarction was induced in the right medial agranular cortex (AGm) of mice via photothrombosis. After induction of cerebral infarction, ipsilesional spatial bias was evaluated for 9 consecutive days. The major findings were as follows: (1) unilateral local infarction of the AGm resulted in ipsilateral bias during internally guided decision-making; (2) the lesion size was correlated with the degree of impairment rather than slight differences in the lesion site; and (3) mice with anterior AGm lesions experienced lower recovery rates. These findings suggest that recovery from ipsilesional spatial bias requires neural plasticity within the anterior AGm. This conditional mouse model of ipsilesional spatial bias may be used to develop effective treatments for unilateral spatial neglect in humans.
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It has recently been revealed that spatial neglect can be modulated by motivational factors including anticipated monetary reward. A number of dopaminergic agents have been evaluated as treatments for neglect, but the results have been mixed, with no clear anatomical or cognitive predictors of dopaminergic responsiveness. Given that the effects of incentive motivation are mediated by dopaminergic pathways that are variably damaged in stroke, we tested the hypothesis that the modulatory influences of reward and dopaminergic drugs on neglect are themselves related.
We employed a single-dose, double-blind, crossover design to compare the effects of Co-careldopa and placebo on a modified visual cancellation task in patients with neglect secondary to right hemisphere stroke. Whilst confirming that reward improved visual search in this group, we showed that dopaminergic stimulation only enhances visual search in the absence of reward. When patients were divided into REWARD-RESPONDERs and REWARD-NON-RESPONDERs, we found an interaction, such that only REWARD-NON-RESPONDERs showed a positive response to reward after receiving Co-careldopa, whereas REWARD-RESPONDERs were not influenced by drug. At a neuroanatomical level, responsiveness to incentive motivation was most associated with intact dorsal striatum.
These findings suggest that dopaminergic modulation of neglect follows an ‘inverted U’ function, is dependent on integrity of the reward system, and can be measured as a behavioural response to anticipated reward.
Prefrontal neural dynamics in consciousness
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This cognitive availability can be attained by preserving the content of consciousness in working memory (Horst and Laubach, 2009; Hupalo and Berridge, 2016; Klaassen et al., 2014; Mottaghy et al., 2002) as a single perceptive unit (Vargo et al., 1988). Decades ago, Vargo and other researchers indicated that when you selectively injure left and right dorsomedial cortices in rats, it produces severe polymodal neglect (Corwin et al., 1986; Cowey and Bozek, 1974; Vargo et al., 1989, 1988). Similar results have been reported in more recent research (Christakou et al., 2005; Lucchetti et al., 1998).
The Prefrontal Cortex (PFC) is one of the principal brain regions studied in consciousness. Previous investigations suggest that the PFC is an important neural hub in both awareness and the manipulation of the content of consciousness. Despite a consensus in the scientific community regarding PFC function in cortico-cortical networks, there is still intense debate as to its role in the thalamocortical network and the formation of content of consciousness. The objective of this research is to provide a comprehensive review of the possible implications of PFC activity in awareness, with a focus on thalamic neural pathways that could explain perceptual alterations in the content of consciousness. We posit that the PFC and its connection with nonspecific thalamic nuclei could be responsible for the functional integration of sensory perception into a unique conscious content. This cortico-thalamocortical neural loop would denote a small closed-loop subnetwork within the thalamocortical system that organizes the flow of temporal and spatial information to maintain a subjective stream of consciousness. In particular, attentional top-down mechanisms between the PFC and the reticular thalamic nucleus could influence the formation of the content of consciousness through their capacity to regulate thalamic activity. Summarizing, the PFC acts as a dynamic and multifunctional neural hub that recalibrates global neural dynamics and regulates interactive brain processes associated with consciousness.
Noradrenergic antagonists mitigate amphetamine-induced recovery
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An incision was made in the dura mater extending the length of the skull window to expose the underlying medial agranular cortex (AGm). Then, the AGm was removed by gentle aspiration down to the white matter with the use of a fine-gauge pipette attached to a suction pump [14,42,43]. Following hemostasis, gelfoam was gently placed into the lesion cavity.
Brain injury, including that due to stroke, leaves individuals with cognitive deficits that can disrupt daily aspect of living. As of now there are few treatments that shown limited amounts of success in improving functional outcome. The use of stimulants such as amphetamine have shown some success in improving outcome following brain injury. While the pharmacological mechanisms for amphetamine are known; the specific processes responsible for improving behavioral outcome following injury remain unknown. Understanding these mechanisms can help to refine the use of amphetamine as a potential treatment or lead to the use of other methods that share the same pharmacological properties. One proposed mechanism is amphetamine’s impact upon noradrenaline (NA). In the current, study noradrenergic antagonists were administered prior to amphetamine to pharmacologically block α- and β-adrenergic receptors. The results demonstrated that the blockade of these receptors disrupted amphetamines ability to induce recovery from hemispatial neglect using an established aspiration lesion model. This suggests that amphetamine’s ability to ameliorate neglect deficits may be due in part to noradrenaline. These results further support the role of noradrenaline in functional recovery. Finally, the development of polytherapies and combined therapeutics, while promising, may need to consider the possibility that drug interactions can negate the effectiveness of treatment.
Pharmacological Treatment of Visuospatial Neglect: A Systematic Review
2017, Journal of Stroke and Cerebrovascular Diseases
The aims of the current review were (1) to give an overview of human studies investigating pharmacotherapy to ameliorate visuospatial neglect and (2) to evaluate the quality of those studies.
A systematic literature search using PubMed, Scopus, and ResearchGate was conducted in regard to studies that evaluated pharmacological interventions aiming to ameliorate poststroke visuospatial neglect. The search was limited in the following features: species (human), adults (≥18 years of age), language (English), and type of neglect (visuospatial). Two independent authors extracted data on study content and effectiveness and evaluated the quality of studies and methods.
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Currently, cholinergic therapy might be the best option for future research. However, we must emphasize the explorative nature and the limited quality of the reviewed studies.
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Subjects were tested for the presence of neglect 4–6 h after neglect surgery and then twice a week for 8 weeks during the light phase of the light/dark cycle with the experimenter blind to the subjects’ conditions. Neglect testing was a modification of the testing procedure developed by Crowne and Pathria [12] and is described in detail in previous publications [11,40,44]. Following observation of circling behavior, subjects were taken out of their cage and placed directly on the testing platform.
Neglect is a neuropsychological disorder characterized by the failure to report or respond to stimuli presented to the side of the body opposite a brain lesion and occurs in approximately 40% of right hemisphere strokes. The need for effective therapies to treat neglect in humans has led to the development of a rodent model. Unilateral destruction of medial agranular cortex (AGm), which is part of a cortical network for directed attention, produces severe multimodal neglect with deficits similar to those seen in humans. Amphetamines have previously been investigated for inducing plasticity and recovery of function following brain damage. Amphetamine treatment has been shown to produce recovery from visual, frontal, and sensorimotor cortex damage in animals and this recovery may be the result of axonal growth originating from the opposite, unlesioned hemisphere. The purpose of this study was to investigate whether amphetamine treatment would induce recovery from neglect produced by unilateral AGm destruction, the time frame in which amphetamine must be administered in order to be effective, and the permanence of recovery following treatment. The results indicated that subjects injected with 2 mg/kg of d-amphetamine on days 0, 2, and 5 recovered in significantly fewer days than saline-treated controls, even when administration was delayed by 2 and 7 days. Additionally, these studies indicated that recovery persisted for at least 60 days suggesting that recovery is likely to be long term.

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^a: Dr. Hashimoto's present address is Department of Neuropsychiatry, Kinki University School of Medicine, Osaka 589, Japan.

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Apomorphine has a therapeutic effect on neglect produced by unilateral dorsomedial prefrontal cortex lesions in rats

Abstract

Brain Res.

Behav. Brain Res.

Behav. Brain Res.

Exp. Neurol.

Brain Res. Rev.

Brain Res.

Brain Res.

Exp. Neurol.

Brain Res.

Brain Res.

Brain Res.

Exp. Neurol.

Neurosci. Lett.

Organization of afferent input to subdivisions of area 8 in the rhesus monkey

J. Comp. Neurol.

Convergent thalamic and mesencephalic projections of the anterior medial cortex in the rat

J. Comp. Neurol.

An autoradiographic examination of corticocortical and subcortical projections of the mediodorsal-projection (prefrontal) cortex in the rat

J. Comp. Neurol.

Visual disorientation with special reference to lesions of the right cerebral hemisphere

Brain

Efferent connections of the medial precentral component of prefrontal cortex in the rat

Soc. Neurosci. Abstr.

The frontal eye fields and attention

Psychol. Bull.