Neuroprotection and stroke rehabilitation: modulation and enhancement of recovery

Recent advances in research are modifying our view of recovery after nervous system damage. New findings are changing previously held concepts and providing promising avenues for treatment of patients after stroke. This review discusses mechanisms of neuronal injury after brain ischemia and the attempts to study neuroprotection options based on such mechanisms. It also considers measures available at present to improve outcome after stroke and presents new areas of research, particularly stimulation techniques, neurogenesis and trophic factors to enhance recovery. In order to improve outcomes, medications that may be detrimental to recovery should be avoided, while symptomatic therapy of problems such as depression, pain syndromes and spasticity may contribute to better results. Continued surveillance and early treatment of complications associated with acute stroke, along with supportive care remain the mainstay of treatment for stroke patients in the recovery phase. Present research on limiting brain damage and improving recovery and plasticity enhance the prospects for better clinical treatments to improve recovery after stroke.     

A model for narcolepsy.

A model for narcolepsy is developed on the basis of data obtained from brains collected at post mortem from three patients with narcolepsy. The concentration of dopamine, noradrenaline, and serotonin and their metabolites was measured in many brain regions. The number and affinity of the 3-H-spiperone and 3-H-prazocin binding sites was also measured in many of these regions to characterize the D-2 dopamine and alpha-1-noradrenergic receptors, respectively. Evidence for significantly increased serotonin levels and serotonin turnover was found in many brain regions. Noradrenaline turnover was increased in the frontal cortex. DOPAC/DA was significantly reduced in the striatum. The number of D-2 dopamine receptors, however, was markedly increased in this region. The number of alpha-1-noradrenergic receptors was significantly decreased in the frontal cortex and amygdala. Our neurochemical data demonstrating increased NA and 5-HT turnover suggest that locus coeruleus noradrenergic neurones and raphe serotonergic neurones are overactive in narcolepsy. Current evidence posits that increased activity in these neurones depresses the activity of cholinergic pedunculopontine (PP) REM sleep effector neurones. PP neurones project to and stimulate the dopaminergic substantia nigra compacta neurones. Decreased PP activity in narcolepsy, thus, could lead to pontine cholinergic supersensitivity and could also reduce the firing rates of dopaminergic neurones, as the low striatal ratio of DOPAC/DA suggests. An increase in the number of D-2 dopamine receptors in the striatum may result. The reason for the increased activity of the noradrenergic and serotonergic neurones remains to be determined, but immune inactivation of alpha-1-noradrenergic receptors may be the initiating event. Low alpha-1-noradrenergic receptor numbers may account for the chronic drowsiness of narcolepsy. The repeated entry into sleep, and into REM sleep in particular, may represent a homeostatic response to increase these receptor numbers and, thus, to increase alertness. Some therapeutic implications of this model are presented in the discussion.     

Synaptic plasticity and the organization of behaviour after early and late brain injury.

Hebb proposed that synaptic change underlies behavioural and cognitive plasticity. When applied to recovery from brain injury, the general hypothesis is that if there is recovery following brain injury, then there ought to be a correlated synaptic change, which is presumed to be responsible for recovery. In contrast, if recovery fails to occur, or expected recovery is blocked in some manner, then the synaptic change will likely not be present. Systematic study of functional recovery and synaptic change following brain injury at different ages supports these predictions. Good recovery is always correlated with enhanced connectivity whereas poor recovery is always correlated with an absence of reorganized connectivity. Furthermore, factors that stimulate recovery, such as neurotrophins or experience, stimulate synaptic change and functional recovery. Factors that retard recovery, such as depletion of neuromodulators, also block synaptic change. These results thus support Hebb's general idea that synaptic plasticity is related to behavioural change.     

Neuropsychology and the emotional component of religion

Religiosity may be seen as both a rational and an emotional phenomenon. Recent technological advances have allowed neuroscientists to relate emotional perception and expression to distinct neurological substrates. When these are rendered dysfunctional through a stroke or other brain injury or disease, the victim's religiosity may change in specific ways. These changes are detailed through case study material in this article. Factors involved in recovery are delineated and guidelines for pastoral care of these patient/parishioners are offered.     

Norepinephrine and brain damage: alpha noradrenergic pharmacology alters functional recovery after cortical trauma

The goal of these experiments was to evaluate the effects of some drugs affecting noradrenergic (NE) synaptic transmission, commonly prescribed following stroke or traumatic brain injury, on functional recovery. Measurement of recovery from a transient hemiplegia produced by a traumatic unilateral focal contusion in sensorimotor cortex (SMCX) of rats was used to assess the effects of chronic haloperidol (HAL) treatment begun early (1 day) or late (18 days to recovered animals) after injury. Additionally, using the same model, the effects of a single administration of drugs with selective action at NE receptors were also evaluated early or late (30 days) after injury. These drugs were: phenoxybenzamine (PBZ), an alpha 1-NE antagonist; prazosin (PRAZ), an alpha 1-NE antagonist; yohimbine (YOH), an alpha 2-NE antagonist; propranolol (PROP), a beta 1- and 2-NE receptor antagonist; methoxymine (METHOX), an alpha 1-NE agonist; and clonidine (CLON), an alpha 2-NE agonist. The data indicate that drugs with antagonistic effects at alpha 1 NE receptors, including HAL and PRAZ but not PROP, administered early after SMCX contusion retard locomotor recovery. Beneficial effects of enhancing NE transmission by METHOX or YOH were not observed. In animals recovered from beam walk (BW) deficits, a single administration of PBZ or PRAZ (alpha 1 NE antagonists) or CLON (alpha 2 NE agonist) transiently reinstated hemiplegic symptoms. The nonspecific beta NE receptor antagonist PROP had no effect in recovered animals. A single dose of HAL had no effect in recovered animals, but a BW deficit transiently developed in some animals following chronic treatment. The data are discussed with reference to drug contraindications noted in clinical studies of recovery from poststroke aphasia and cognition in demented patients with degenerative brain disease.     

Neuroimaging studies in eating disorders

The understanding of the eating disorders (EDs) anorexia (AN) and bulimia nervosa (BN) has undergone remarkable advancements in the past decade. Most studies that have been done in AN show brain gray and white matter volume loss during the ill state that, at least in part, remit with recovery. Similar patterns occur for brain phospholipids assessed using magnet resonance spectroscopy (MRS). Imaging studies have been used to provide functional information regarding serotonin neuroreceptor dynamics, regional cerebral blood flow, or cerebral glucose metabolism. Such studies have implicated cingulate, frontal, temporal, and parietal regions in AN. Investigators have found that challenges such as food and body image distortions may activate some of these regions, raising the possibility that such studies may shed light on puzzling AN symptoms, such as body image distortions or extremes of appetitive behaviors. Emerging data suggest these disturbances persist after recovery from AN, suggesting the possibility that these are traits that may create a vulnerability to develop an ED. While fewer studies have been done in BN or binge eating disorder, there may be disturbances of serotonin metabolism in similar brain regions. Taken together, these findings give promise for future investigations with the hope of delineating brain pathways that contribute to the etiology of EDs     

心理理论的遗传基础初探

心理理论在社会交往中起着关键作用,其认知过程包括对自我和他人的心理状态进行推断及预测下一步行为.心理理论在不同个体间具有差异,这种差异可能部分归因于与心理理论相关的神经化学物质如多巴胺、五羟色胺、催产素、血管加压素等.来自不同群体的研究结果还发现,与这些神经化学物质有关的基因多态性,如儿茶酚胺氧位甲基转移酶、多巴胺D4受体基因、5-羟色胺受体基因、催产素受体基因等都与心理理论的表现有关.     

Functional Neuroimaging Studies of Cognitive Recovery After Acquired Brain Damage in Adults

The first two decades of cognitive neuroimaging research have provided a constant increase of the knowledge about the neural organization of cognitive processes. Many cognitive functions (e.g.working memory) can now be associated with particular neural structures, and ongoing research promises to clarify this picture further, providing a new mapping between cognitive and neural function. The main goal of this paper is to outline conceptual issues that are particularly important in the context of imaging changes in neural function through recovery process. This review focuses primarily on studies made in stroke and traumatic brain injury patients, but most of the issues raised here are also relevant to studies using other acquired brain damages. Finally, we summarize aset of methodological issues related to functional neuroimaging that are relevant for the study ofneural plasticity and recovery after rehabilitation. Deceased     

Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack: reduction by a selective serotonin reuptake inhibitor

Since the brain neurotransmitter changes characterising panic disorder remain uncertain, we quantified brain noradrenaline and serotonin turnover in patients with panic disorder, in the absence of a panic attack. Thirty-four untreated patients with panic disorder and 24 matched healthy volunteers were studied. A novel method utilising internal jugular venous sampling, with thermodilution measurement of jugular blood flow, was used to directly quantify brain monoamine turnover, by measuring the overflow of noradrenaline and serotonin metabolites from the brain. Radiographic depiction of brain venous sinuses allowed differential venous sampling from cortical and subcortical regions. The relation of brain serotonin turnover to serotonin transporter genotype and panic disorder severity were evaluated, and the influence of an SSRI drug, citalopram, on serotonin turnover investigated. Brain noradrenaline turnover in panic disorder patients was similar to that in healthy subjects. In contrast, brain serotonin turnover, estimated from jugular venous overflow of the metabolite, 5-hydroxyindole acetic acid, was increased approximately 4-fold in subcortical brain regions and in the cerebral cortex (P < 0.01). Serotonin turnover was highest in patients with the most severe disease, was unrelated to serotonin transporter genotype, and was reduced by citalopram (P < 0.01). Normal brain noradrenaline turnover in panic disorder patients argues against primary importance of the locus coeruleus in this condition. The marked increase in serotonin turnover, in the absence of a panic attack, possibly represents an important underlying neurotransmitter substrate for the disorder, although this point remains uncertain. Support for this interpretation comes from the direct relationship which existed between serotonin turnover and illness severity, and the finding that SSRI administration reduced serotonin turnover. Serotonin transporter genotyping suggested that increased whole brain serotonin turnover most likely derived not from impaired serotonin reuptake, but from increased firing in serotonergic midbrain raphe neurons projecting to both subcortical brain regions and the cerebral cortex.     

A proposed regional hierarchy in recovery of post-stroke aphasia

Activation studies in patients with aphasia due to stroke or tumours in the dominant hemisphere have revealed effects of disinhibition in ipsilateral perilesional and in contralateral homotopic cortical regions, referred to as collateral and transcallosal disinhibition. These findings were supported by studies with selective disturbance of cortical areas by repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers and in patients with focal brain lesions. Both, collateral as well as transcallosal disinhibition might be relevant for the compensation of lesions within a functional network. From these data a hierarchical organization of recovery of aphasia after stroke and of compensation of language defects due to brain tumours can be deduced, by which the reactivation of undamaged network areas of the ipsilateral hemisphere usually lead to better outcome than the involvement of homotopic contra-lateral regions. rTMS can be used to identify areas relevant for speech production and might play a role in treatment strategies targeted at modulating the activity of contralateral homotopic areas of the functional network which might interfere with language recovery.     

Alcohol,head injury,and neuropsychological function

Evidence is reviewed indicating that the extent of alcohol abuse alone cannot account for the neuropsychological deficits observed in alcoholics, and that alcohol abuse and head injury may interact in some patients to influence neuropsychological status. Alcohol abuse both increases the risk for head trauma and potentiates the resulting brain injury, which can lead to negative neuropsychological consequences. Clinicians involved in the treatment of addiction should assess patients for history of head injury, and neuropsychological deficits consequent to both head injury and ethanol. These deficits may limit patient ability to comply with addiction rehabilitation programs. Conversely, clinicians in acute care and rehabilitation of the sequelae of head trauma should routinely assess their patients for substance abuse, because such abuse can have a significant impact on recovery from brain injury.     

The Use of Non-invasive Brain Stimulation Techniques to Facilitate Recovery from Post-stroke Aphasia

Aphasia is a common symptom after left hemispheric stroke. Neuroimaging techniques over the last 10–15 years have described two general trends: Patients with small left hemisphere strokes tend to recruit perilesional areas, while patients with large left hemisphere lesions recruit mainly homotopic regions in the right hemisphere. Non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have been employed to facilitate recovery by stimulating lesional and contralesional regions. The majority of these brain stimulation studies have attempted to block homotopic regions in the right posterior inferior frontal gyrus (IFG) to affect a presumed disinhibited right IFG (triangular portion). Other studies have used anodal or excitatory tDCS to stimulate the contralesional (right) fronto-temporal region or parts of the intact left IFG and perilesional regions to improve speech-motor output. It remains unclear whether the interhemispheric disinhibition model, which is the basis for motor cortex stimulation studies, also applies to the language system. Future studies could address a number of issues, including: the effect of lesion location on current density distribution, timing of the intervention with regard to stroke onset, whether brain stimulation should be combined with behavioral therapy, and whether multiple brain sites should be stimulated. A better understanding of the predictors of recovery from natural outcome studies would also help to inform study design, and the selection of clinically meaningful outcome measures in future studies.     

Genetic polymorphisms of the dopamine and serotonin systems modulate the neurophysiological response to feedback and risk taking in healthy humans

Genetic differences in the dopamine and serotonin systems have been suggested as potential factors underlying interindividual variability in risk taking and in brain activation during the processing of feedback. Here, we studied the effects of dopaminergic (dopamine transporter [DAT1], catecholamine-O-methyltransferase val158met [COMT]) and serotonergic (serotonin transporter [5HTTLPR]) polymorphisms on risk taking and brain responses following feedback in 60 healthy female subjects. The subjects completed a well-established experimental gambling paradigm while an electroencephalogram was recorded. During the task, risk-taking behavior and prefrontal brain responses (feedback-related negativity [FRN]) following monetary gains and losses were assessed. FRN amplitudes were enhanced for nine-repeat-allele carriers of the DAT1 and short-allele carriers of 5HTTLPR, which are both presumably linked to less transporter activity and higher neurotransmitter levels. Moreover, nine-repeat DAT1 carriers displayed a trend toward increased risk taking in general, whereas 5HTTLPR short-allele carriers showed decreased risk taking following gains. COMT val158met genotype was unrelated to FRN amplitude and average risk taking. However, COMT met/met carriers showed a pronounced feedback P3 amplitude independent of valence, and a gradual increase in risk taking during the gambling task. In sum, the present findings underline the importance of genetic variability in the dopamine and serotonin systems regarding the neurophysiology of feedback processing.     

The case against memory consolidation in REM sleep

We present evidence disputing the hypothesis that memories are processed or consolidated in REM sleep. A review of REM deprivation (REMD) studies in animals shows these reports to be about equally divided in showing that REMD does, or does not, disrupt learning/memory. The studies supporting a relationship between REM sleep and memory have been strongly criticized for the confounding effects of very stressful REM deprivation techniques. The three major classes of antidepressant drugs, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), and selective serotonin reuptake inhibitors (SSRIs), profoundly suppress REM sleep. The MAOIs virtually abolish REM sleep, and the TCAs and SSRIs have been shown to produce immediate (40-85%) and sustained (30-50%) reductions in REM sleep. Despite marked suppression of REM sleep, these classes of antidepressants on the whole do not disrupt learning/memory. There have been a few reports of patients who have survived bilateral lesions of the pons with few lingering complications. Although these lesions essentially abolished REM sleep, the patients reportedly led normal lives. Recent functional imaging studies in humans have revealed patterns of brain activity in REM sleep that are consistent with dream processes but not with memory consolidation. We propose that the primary function of REM sleep is to provide periodic endogenous stimulation to the brain which serves to maintain requisite levels of central nervous system (CNS) activity throughout sleep. REM is the mechanism used by the brain to promote recovery from sleep. We believe that the cumulative evidence indicates that REM sleep serves no role in the processing or consolidation of memory.     

Cathodal transcranial direct current stimulation of the right Wernicke's area improves comprehension in subacute stroke patients

Previous studies have shown the appearance of right-sided language-related brain activity in right-handed patients after a stroke. Non-invasive brain stimulation such as transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) have been shown to modulate excitability in the brain. Moreover, rTMS and tDCS have been found to improve naming in non-fluent post-stroke aphasic patients. Here, we investigated the effect of tDCS on the comprehension of aphasic patients with subacute stroke. We hypothesized that tDCS applied to the left superior temporal gyrus (Wernicke’s area) or the right Wernicke’s area might be associated with recovery of comprehension ability in aphasic patients with subacute stroke. Participants included right-handed subacute stroke patients with global aphasia due to ischemic infarct of the left M1 or M2 middle cerebral artery. Patients were randomly divided into three groups: patients who received anodal tDCS applied to the left superior temporal gyrus, patients who received cathodal tDCS applied to the right superior temporal gyrus, and patients who received sham tDCS. All patients received conventional speech and language therapy during each period of tDCS application. The Korean-Western Aphasia Battery (K-WAB) was used to assess all patients before and after tDCS sessions. After intervention, all patients had significant improvements in aphasia quotients, spontaneous speech, and auditory verbal comprehension. However, auditory verbal comprehension improved significantly more in patients treated with a cathode, as compared to patients in the other groups. These results are consistent with the role of Wernicke’s area in language comprehension and the therapeutic effect that cathodal tDCS has on aphasia patients with subacute stroke, suggesting that tDCS may be an adjuvant treatment approach for aphasia rehabilitation therapy in patients in an early stage of stroke.     

The ontogeny of defensive reactions in the rat: Influence of the monoamine transmission systems

The effects of neonatal treatment of rats with the neurotoxins 5,7-dihydroxytryptamine and 6-hydroxydopamine on the ontogeny of the ultra sound vocalization and the immobility response were studied. The 5,7-dihydroxytryptamine treated rats showed reduced strength of both reactions indicating involvement of the serotonin system in their ontogeny. This hypothesis was supported by experiments with depletion of serotonin by para-chlorophenylalanine followed by replenishment with 5-hydroxytryptophan. The 6-hydroxydopamine treated rats showed normal defensive reactions, but displayed hyperactivity from their second week of age. The role of the dopamine system in the defensive reactions was studied by variations of the dopamine activity level by traditional tools: depletion by α-methyl-tyrosin followed by replenishment by l -DOPA; stimulation or inhibition of the dopamine receptors by apomorphine or haloperidol. The results suggested an inhibitory function of the dopamine system in both defensive reactions, antagonistic to that of the serotonin system.     

Prenatal dopamine and neonatal behavior and biochemistry

Depressed pregnant women (N=126) were divided into high and low prenatal maternal dopamine (HVA) groups based on a tertile split on their dopamine levels at 20 weeks gestation. The high versus the low dopamine group had lower Center for Epidemiological Studies-Depression Scale (CES-D) scores, higher norepinephrine levels at the 20-week gestational age visit and higher dopamine and serotonin levels at both the 20- and the 32-week gestational age visits. The neonates of the mothers with high versus low prenatal dopamine levels also had higher dopamine and serotonin levels as well as lower cortisol levels. Finally, the neonates in the high dopamine group had better autonomic stability and excitability scores on the Brazelton Neonatal Behavior Assessment Scale. Thus, prenatal maternal dopamine levels appear to be negatively related to prenatal depression scores and positively related to neonatal dopamine and behavioral regulation, although these effects are confounded by elevated serotonin levels.     

Alcohol, neurotransmitter systems, and behavior

Alcohol affects several neurotransmitter systems within the brain. In this article, the author describes its effects on 5 major ones: glutamate, gamma-amino-butyric acid (GABA), dopamine, serotonin, and opioid systems. The author also notes the interactions and interdependencies of these transmitters, and provides details on both immediate effects and long-term adaptations. Last, the author explains several psychopharmacological treatments for alcoholism and the effects of these treatments on transmitters, and draws conclusions.     

Aphasic patients exhibit a reversal of hemispheric asymmetries in categorical color discrimination

Patients with left hemisphere (LH) or right hemisphere (RH) brain injury due to stroke were tested on a speeded, color discrimination task in which two factors were manipulated: (1) the categorical relationship between the target and the distracters and (2) the visual field in which the target was presented. Similar to controls, the RH patients were faster in detecting targets in the right visual field when the target and distracters had different color names compared to when their names were the same. This effect was absent in the LH patients, consistent with the hypothesis that injury to the left hemisphere handicaps the automatic activation of lexical codes. Moreover, the LH patients showed a reversed effect, such that the advantage of different target-distracter names was now evident for targets in the left visual field. This reversal may suggest a reorganization of the color lexicon in the right hemisphere following left hemisphere brain injury and/or the unmasking of a heightened right hemisphere sensitivity to color categories.     

Emotion-based dispositions to rash action: positive and negative urgency

Under heightened emotional states, individuals are more inclined to engage in ill-considered or rash actions than at other times. The authors present evidence for the existence of 2 related traits called positive and negative urgency. The traits refer to individual differences in the disposition to engage in rash action when experiencing extreme positive and negative affect, respectively. The authors provide evidence that these traits are distinct from other dispositions toward rash action and that they play distinct roles in predicting problem levels of involvement in behaviors such as alcohol consumption, binge eating, drug use, and risky sexual behavior. The authors identify facilitative conditions for the emergence of the urgency traits from neuroscience. Certain gene polymorphisms are associated with low levels of serotonin and high levels of dopamine; that pattern of neurotransmitter activity in a brain system linking the orbitofrontal cortex and the amygdala appears to facilitate the development of positive and negative urgency. The authors discuss the implications of this theory.