Neuroplasticity and major depression,the role of modern antidepressant drugs

The pathophysiology of depression has been traditionally attributed to a chemical imbalance and critical interactions between genetic and environmental risk factors, and antidepressant drugs suggested to act predominantly amplifying monoaminergic neurotransmission. This conceptualization may be currently considered reductive. The current literature about the pathophysiological mechanisms underlying depression, stress-related disorders and antidepressant treatment was examined. In order to provide a critical overview about neuroplasticity, depression and antidepressant drugs, a detailed Pubmed/Medline, Scopus, PsycLit, and PsycInfo search to identify all papers and book chapters during the period between 1980 and 2011 was performed. Pathological stress and depression determine relevant brain changes such as loss of dendritic spines and synapses, dendritic atrophy as well as reduction of glial cells (both in number and size) in specific areas such as the hippocampus and prefrontal cortex. An increased dendritic arborisation and synaptogenesis may instead be observed in the amygdala as a consequence of depression and stress-related disorders. While hippocampal and prefrontal functioning was impaired, amygdala functioning was abnormally amplified. Most of molecular abnormalities and biological changes of aberrant neuroplasticity may be explained by the action of glutamate. Antidepressant treatment is associated with neurogenesis, gliogenesis, dendritic arborisation, new synapse formation and cell survival both in the hippocampus and prefrontal cortex. Antidepressants (ADs) induce neuroplasticity mechanisms reversing the pathological effects of depression and stress-related disorders. The neuroplasticity hypothesis may explain the therapeutic and prophylactic action of ADs representing a new innovative approach to the pathophysiology of depression and stress-related disorders.     

Neuroplasticity and Parkinson's disease

Emerging concept, to date, neuroplasticity becomes a concrete reality in the adult central nervous system (CNS), particularly in a so-called neurodegenerative disease as idiopathic Parkinson's disease (IPD). After a brief survey of some general aspects of plasticity in the CNS, the present tutorial review illustrates with recent data from the literature the modes of plastic changes during the course of IPD, either resulting from dopaminergic denervation (hyperactivity of remaining dopaminergic neurons with increase of their excitatory cholinergic innervation in the substantia nigra, enhancement of the corticostriatal glutamatergic synaptic activity at the striatal level) or due to dopaminergic treatment (change in phosphorylation state of the striatal glutamate receptors, internalization of D1 Dopamine receptors). Neuroplasticity in Parkinson's disease could represent a rational basis for forthcoming therapeutic issues     

Neuroplasticity and schizophrenia.

This article's title is also the name of a workshop sponsored by the International Congress on Schizophrenia Research that was focused on an appraisal of the potential role of neuroplastic processes in the etiology or course of schizophrenia. The workshop brought together clinical investigators of schizophrenia and basic scientists who study various aspects of neuroplasticity, including central nervous system (CNS) development, learning and memory, and drug action. The goal was to identify special opportunities to advance knowledge and understanding of schizophrenia pathology, treatment, or prevention by applying neuroplasticity concepts as a framework to theories of the illness. Although the focus of this workshop was schizophrenia, the phenomena considered are pertinent to other disorders, such as depression and drug abuse.     

Neuroplasticity and impulse control disorders

Impulse control disorders (ICDs) represent an important medical challenge. The authors of the present paper restricted themselves to present an overview of the neurocircuitry that is involved in ICDs and to present information about the mechanisms of neuroplasticity that are the substrate of the ICDs. Understanding the networks involved in ICDs at the level of the cellular and molecular mechanisms of neural and synaptic plasticity may facilitate the understanding of the ways in which various conditions favour the habit formation and compulsivity that are associated with neurological disorders. The psychological, sociological and forensic dimensions of ICDs are beyond the scope of this paper.     

Neuroplasticity in addictive disorders

Compulsive drug-taking behavior develops in vulnerable individuals who ingest substances that activate the reward system. This intense activation produces learned associations to cues that predict drug availability. With repetition the reward system becomes reflexively activated by cues alone, leading to a drive toward drug-taking. The central nervous system changes underlying this conditioned behavior are just beginning to be understood. New treatments aimed at this neuroplasticity are being tested in animal models. The clinical significance of these brain changes is that addiction, once established, becomes a chronic illness with relapses and remissions, it therefore requires chronic treatment with medications and behavioral therapies based on an understanding of the fundamental nature of these changes in the brain.     

Neuroplasticity in Alzheimer's disease

Ramon y Cajal proclaimed in 1928 that "once development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably. In the adult centers the nerve paths are something fixed, ended and immutable. Everything must die, nothing may be regenerated. It is for the science of the future to change, if possible, this harsh decree." (Ramon y Cajal, 1928). In large part, despite the extensive knowledge gained since then, the latter directive has not yet been achieved by 'modern' science. Although we know now that Ramon y Cajal's observation on CNS plasticity is largely true (for lower brain and primary cortical structures), there are mechanisms for recovery from CNS injury. These mechanisms, however, may contribute to the vulnerability to neurodegenerative disease. They may also be exploited therapeutically to help alleviate the suffering from neurodegenerative conditions.     

Neuroplasticity and cellular therapy in cerebral infarction

Stroke is the second to third most common cause of death in adults, and more than a third of people who survive a stroke will have severe disability. Therapeutic options currently centre on fibrinolytic treatment, but its limitations restrict use to a small proportion of patients. Although a wide range of neuroprotective substances has been effective in experimental models, they have repeatedly failed in clinical trials because of toxicity or loss of effectiveness. Recent strategies based on neuroplasticity and cellular therapy have shown significant efficacy in improving functional recovery in experimental models, although further study is still necessary to clarify how the brain responds to ischaemic damage and is able to reorganize itself in the long term. Although steps must still be taken to ensure the safety and feasibility of treatments based on neuroplasticity and cellular therapy, neurorepair strategies provide promising future therapeutic options for stroke.     

Neuroplasticity and the progression of Alzheimer's disease

A neurobiological hypothesis is proposed to explain the relation between the percentage cell loss in the cholinergic basal forebrain and the density of neuritic plaques in cortex, as found by Arendt et al. (1985) in Alzheimer's disease: When cells in the cholinergic basal forebrain die, their cortical synaptic target sites can be reoccupied by axonal sprouting of other neurons from the basal forebrain. This neuroplasticity hypothesis leads to equations that are consistent with the quantitative data of Arendt et al. (1985), and it makes specific predictions that can be tested experimentally. Moreover, this hypothesis suggests that the more rapid course of the presenile form of Alzheimer's disease and its more extensive pathology can be understood as a consequence of the decline in neuroplasticity with age.     

Neuroplasticity in mood disorders

Neuroimaging and neuropathological studies of major depressive disorder (MDD) and bipolar disorder (BD) have identified abnormalities of brain structure in areas of the prefrontal cortex, amygdala, striatum, hippocampus, parahippocampal gyrus, and raphe nucleus. These structural imaging abnormalities persist across illness episodes, and preliminary evidence suggests they may in some cases arise prior to the onset of depressive episodes in subjects at high familial risk for MDD. In other cases, the magnitude of abnormality is reportedly correlated with time spent depressed. Postmortem histopathological studies of these regions have shown abnormal reductions of synaptic markers and glial cells, and, in rare cases, reductions in neurons in MDD and BD. Many of the regions affected by these structural abnormalities show increased glucose metabolism during depressive episodes. Because the glucose metabolic signal is dominated by glutamatergic transmission, these data support other evidence that excitatory amino acid transmission is elevated in limbic-cortical-striatal-pallidal-thalamic circuits during depression. Some of the subject samples in which these metabolic abnormalities have been demonstrated were also shown to manifest abnormally elevated stressed plasma cortisol levels. The co-occurrence of increased glutamatergic transmission and Cortisol hypersecretion raises the possibility that the gray matter volumetric reductions in these depressed subjects are partly accounted for by processes homologous to the dendritic atrophy induced by chronic stress in adult rodents, which depends upon interactions between elevated glucocorticoid secretion and N-meihyl-D-aspartate (NMDA)-glutamate receptor stimulation. Some mood-stabilizing and antidepressant drugs that exert neurotrophic effects in rodents appear to reverse or attenuate the gray matter volume abnormalities in humans with mood disorders. These neurotrophic effects may be integrally related to the therapeutic effects of such agents, because the regions affected by structural abnormalities in mood disorders are known to play major roles in modulating the endocrine, autonomic, behavioral, and emotional experiential responses to stressors.     

Neuroplasticity and cellular resilience in mood disorders

Although mood disorders have traditionally been regarded as good prognosis diseases, a growing body of data suggests that the long-term outcome for many patients is often much less favorable than previously thought. Recent morphometric studies have been investigating potential structural brain changes in mood disorders, and there is now evidence from a variety of sources demonstrating significant reductions in regional CNS volume, as well as regional reductions in the numbers and/or sizes of glia and neurons. Furthermore, results from recent clinical and preclinical studies investigating the molecular and cellular targets of mood stabilizers and antidepressants suggest that a reconceptualization about the pathophysiology and optimal long-term treatment of recurrent mood disorders may be warranted. It is proposed that impairments of neuroplasticity and cellular resilience may underlie the pathophysiology of mood disorders, and further that optimal long-term treatment for these severe illnesses may only be achieved by the early and aggressive use of agents with neurotrophic/neuroprotective effects. It is noteworthy that lithium, valproate and antidepressants indirectly regulate a number of factors involved in cell survival pathways including CREB, BDNF, bcl-2 and MAP kinases, and may thus bring about some of their delayed long-term beneficial effects via underappreciated neurotrophic effects. The development of novel treatments which more directly target molecules involved in critical CNS cell survival and cell death pathways have the potential to enhance neuroplasticity and cellular resilience, and thereby modulate the long-term course and trajectory of these devastating illnesses.     

Neuroplasticity and cellular resilience in bipolar disorder

Manji HK, Zhou R, Chen G. Neuroplasticity and cellular resilience in bipolar disorder. Bipolar Disord 2002: 4(Suppl. 1): 56–57. © Blackwell Munksgaard, 2002     

Neuroplasticity,limbic neuroblastosis and neuro-regenerative disorders

The brain is a dynamic organ of the biological renaissance due to the existence of neuroplasticity. Adult neurogenesis abides by every aspect of neuroplasticity in the intact brain and contributes to neural regeneration in response to brain diseases and injury. The occurrence of adult neurogenesis has unequivocally been witnessed in human subjects, experimental and wildlife research including rodents, bats and cetaceans. Adult neurogenesis is a complex cellular process, in which generation of neuroblasts namely, neuroblastosis appears to be an integral process that occur in the limbic system and basal ganglia in addition to the canonical neurogenic niches. Neuroblastosis can be regulated by various factors and contributes to different functions of the brain. The characteristics and fate of neuroblasts have been found to be different among mammals regardless of their cognitive functions. Recently, regulation of neuroblastosis has been proposed for the sensorimotor interface and regenerative neuroplasticity of the adult brain. Hence, the understanding of adult neurogenesis at the functional level of neuroblasts requires a great scientific attention. Therefore, this mini-review provides a glimpse into the conceptual development of neuroplasticity, discusses the possible role of different types of neuroblasts and signifies neuroregenerative failure as a potential cause of dementia.     

Neuroplasticity in post-stroke gait recovery and noninvasive brain stimulation

Gait disorders drastically affect the quality of life of stroke survivors,making post-stroke rehabilitation an important research focus.Noninvasive brain stimulation has potential in facilitating neuroplasticity and improving post-stroke gait impairment.However,a large inter-individual variability in the response to noninvasive brain stimulation interventions has been increasingly recognized.We first review the neurophysiology of human gait and post-stroke neuroplasticity for gait recovery,and then discuss how noninvasive brain stimulation techniques could be utilized to enhance gait recovery.While post-stroke neuroplasticity for gait recovery is characterized by use-dependent plasticity,it evolves over time,is idiosyncratic,and may develop maladaptive elements.Furthermore,noninvasive brain stimulation has limited reach capability and is facilitative-only in nature.Therefore,we recommend that noninvasive brain stimulation be used adjunctively with rehabilitation training and other concurrent neuroplasticity facilitation techniques.Additionally,when noninvasive brain stimulation is applied for the rehabilitation of gait impairment in stroke survivors,stimulation montages should be customized according to the specific types of neuroplasticity found in each individual.This could be done using multiple mapping techniques.     

Dopamine Agonist Cotreatment Alters Neuroplasticity and Pharmacology of Levodopa-Induced Dyskinesia

Background

Current models of levodopa (L -dopa)-induced dyskinesia (LID) are obtained by treating dopamine-depleted animals with L -dopa. However, patients with LID receive combination therapies that often include dopamine agonists.

Objective

Using 6-hydroxydopamine-lesioned rats as a model, we aimed to establish whether an adjunct treatment with the D2/3 agonist ropinirole impacts on patterns of LID-related neuroplasticity and drug responses.

Methods

Different regimens of L -dopa monotreatment and L -dopa-ropinirole cotreatment were compared using measures of hypokinesia and dyskinesia. Striatal expression of ∆FosB and angiogenesis markers were studied immunohistochemically. Antidyskinetic effects of different drug categories were investigated in parallel groups of rats receiving either L -dopa monotreatment or L -dopa combined with ropinirole.

Results

We defined chronic regimens of L -dopa monotreatment and L -dopa-ropinirole cotreatment inducing overall similar abnormal involuntary movement scores. Compared with the monotreatment group, animals receiving the L -dopa-ropinirole combination exhibited an overall lower striatal expression of ∆FosB with a distinctive compartmental distribution. The expression of angiogenesis markers and blood–brain barrier hyperpermeability was markedly reduced after L -dopa-ropinirole cotreatment compared with L -dopa monotreatment. Moreover, significant group differences were detected upon examining the response to candidate antidyskinetic drugs. In particular, compounds modulating D1 receptor signaling had a stronger effect in the L -dopa-only group, whereas both amantadine and the selective NMDA antagonist MK801 produced a markedly larger antidyskinetic effect in L -dopa-ropinirole cotreated animals.

Conclusions

Cotreatment with ropinirole altered LID-related neuroplasticity and pharmacological response profiles. The impact of adjuvant dopamine agonist treatment should be taken into consideration when investigating LID mechanisms and candidate interventions in both clinical and experimental settings. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Now is the Critical Time for Engineered Neuroplasticity

Recent advances in neuroscience and devices are ushering in a new generation of medical treatments. Engineered biodevices are demonstrating the potential to create long-term changes in neural circuits, termed neuroplasticity. Thus, the approach of engineering neuroplasticity is rapidly expanding, building on recent demonstrations of improved quality of life for people with movement disorders, epilepsy, and spinal cord injury. In addition, discovering the fundamental mechanisms of engineered neuroplasticity by leveraging anatomically well-documented systems like the spinal cord is likely to provide powerful insights into solutions for other neurotraumas, such as stroke and traumatic brain injury, as well as neurodegenerative disorders, such as Alzheimer’s, Parkinson disease, and multiple sclerosis. Now is the time for advancing both the experimental neuroscience, device development, and pioneering human trials to reap the benefits of engineered neuroplasticity as a therapeutic approach for improving quality of life after spinal cord injury.     

Neuroplasticity in hemispheric syndrome: an interesting case report

Functional hemispherectomy is an accepted treatment in hemispherical intractable epilepsy syndromes. We report a patient who had functional hemispherectomy for intractable seizures secondary to right hemispheric cortical dysplasia. Preoperatively, the patient had mild left hemiparesis and functional magnetic resonance imaging (fMRI) showed bilateral motor function lateralization to normal left hemisphere. The patient remains seizure free at 1-year follow-up, with no deterioration of motor power on left side. This report reviews physiology of neural plasticity for motor function lateralization and also reliability of fMRI in determining the functional shift.     

Neuroplasticity, the aging brain, and Alzheimer's disease.

A variety of neurological disorders are associated with the loss of specific populations of neurons. Alzheimer's, Parkinson's, and Huntington's diseases present unique constellations of behavioral and neurological abnormalities which result from the degeneration of neurons in specific regions of the brain. Approaches to the treatment of these neurodegenerative disorders have met with either limited or no success. New treatment strategies based upon a better understanding of the inherent mechanisms of neuroplasticity might provide more rational approaches to prevent, limit, or treat these and other neurodegenerative disorders. The development and standardization of appropriate animal models of neurodegenerative disorders will be essential to realize this possibility. Using the cholinergic neurotoxin AF64A we have developed a rodent model of cholinergic hypofunction that exhibits behavioral, anatomical, and neurochemical deficits very analogous to those observed in Alzheimer's disease. Furthermore, we have found that administration of neurotrophic factors, such as ganglioside AGF2, and the transplantation of fetal cholinergic neurons into the hippocampus can attenuate both the behavioral and neurobiological alterations induced by AF64A. These efforts should lead to the development of innovative clinical strategies and they should also help to elucidate the neurobiology of brain injury and recovery of function.