Neuroplasticity and brain change

The hippocampus, neurotrophic factors and depression: possible implications for the pharmacotherapy of depression.: Depression is a prevalent, highly debilitating mental disorder affecting up to 15% of the population at least once in their lifetime, with huge costs for society. Neurobiological mechanisms of depression are still not well known, although there is consensus about interplay between genetic and environmental factors. Antidepressant medications are frequently used in depression, but at least 50% of patients are poor responders, even to more recently discovered medications. Furthermore, clinical res

Orexins/hypocretins control bistability of hippocampal long-term synaptic plasticity through co-activation of multiple kinases.: Aim: Orexins/hypocretins (OX/Hcrt) are hypothalamic neuropeptides linking sleep-wakefulness, appetite and neuroendocrine control. Their role and mechanisms of action on higher brain functions, such as learning and memory, are not clear. Methods: We used field recordings of excitatory post-synaptic potentials (fEPSP) in acute mouse brain slice preparations to study the effects of orexins and pharmacological inhibitors of multiple kinases on long-term synaptic plasticity in the hippocampus. Result

Exergaming and older adult cognition: a cluster randomized clinical trial.: Background: Dementia cases may reach 100 million by 2050. Interventions are sought to curb or prevent cognitive decline. Exercise yields cognitive benefits, but few older adults exercise. Virtual reality-enhanced exercise or "exergames" may elicit greater participation. Purpose: To test the following hypotheses: (1) stationary cycling with virtual reality tours ("cybercycle") will enhance executive function and clinical status more than traditional exercise; (2) exercise effort will explain impr

Serotonin affects transcranial direct current-induced neuroplasticity in humans.: Background: Modulation of the serotonergic system affects long-term potentiation (LTP) and long-term depression (LTD), the likely neurophysiologic derivates of learning and memory formation, in animals and slice preparations. Serotonin-dependent modulation of plasticity has been proposed as an underlying mechanism for depression. However, direct knowledge about the impact of serotonin on neuroplasticity in humans is missing. Here we explore the impact of the serotonin reuptake blocker citalopram

A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression.: Several clinical studies on major depressive disorder (MDD) have shown that blood brain-derived neurotrophic factor (BDNF) - a factor used to index neuroplasticity - is associated with depression response; however, the results are mixed. The purpose of our study was to evaluate whether BDNF levels are correlated with improvement of depression. We performed a systematic review and meta-analysis of the literature, searching Medline, Cochrane Central, SciELO databases and reference lists from retri

Neuroplasticity - exercise-induced response of peripheral brain-derived neurotrophic factor: a systematic review of experimental studies in human subjects.: Exercise is known to induce a cascade of molecular and cellular processes that support brain plasticity. Brain-derived neurotrophic factor (BDNF) is an essential neurotrophin that is also intimately connected with central and peripheral molecular processes of energy metabolism and homeostasis, and could play a crucial role in these induced mechanisms. This review provides an overview of the current knowledge on the effects of acute exercise and/or training on BDNF in healthy subjects and in pers

Neuroplasticity in the mesolimbic dopamine system and cocaine addiction.

The main characteristics of cocaine addiction are compulsive drug use despite adverse consequences and high rates of relapse during periods of abstinence. A current popular hypothesis is that compulsive cocaine use and cocaine relapse is due to drug-induced neuroadaptations in reward-related learning and memory processes, which cause hypersensitivity to cocaine-associated cues, impulsive decision making and abnormal habit-like learned behaviours that are insensitive to adverse consequences. Here, we review results from studies on the effect of cocaine exposure on selected signalling cascades, growth factors and physiological processes previously implicated in neuroplasticity underlying normal learning and memory. These include the extracellular signal-regulated kinase (ERK) signalling pathway, brain-derived neurotrophic factor (BDNF), glutamate transmission, and synaptic plasticity (prim…

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Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction.

Schizophrenia is characterized by reduced hippocampal volume, decreased dendritic spine density, altered neuroplasticity signaling pathways, and cognitive deficits associated with impaired hippocampal function. We sought to determine whether this diverse pathology could be linked to NMDA receptor (NMDAR) hypofunction, and thus used the serine racemase-null mutant mouse (SR(-/-)), which has less than 10% of normal brain D-serine, an NMDAR coagonist. We found that D-serine was necessary for the maintenance of long-term potentiation in the adult hippocampal dentate gyrus and for full NMDAR activity on granule cells. SR(-/-) mice had reduced dendritic spines and hippocampal volume. These morphological changes were paralleled by diminished BDNF/Akt/mammalian target of rapamycin (mTOR) signaling and impaired performance on a trace-conditioning memory task. Chronic D-serine treatment normalized…

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Structural and functional changes in the hippocampus induced by environmental exposures.

The hippocampus, noted as (HC), plays a crucial role in the processes of learning, memory formation, and spatial navigation. Recent research reveals that this brain region can undergo structural and functional changes due to environmental exposures, including stress, noise pollution, sleep deprivation, and microgravity. This review synthesizes findings from animal and human studies, emphasizing the HC's plasticity in response to these factors. It examines changes in volume, architecture, neurogenesis, synaptic plasticity, and gene expression and highlights critical periods of vulnerability to environmental influences impacting cognition and behavior. It also investigates underlying mechanisms such as glucocorticoid signaling, epigenetic alterations, and neural circuit adaptations. Understanding how the HC reacts to various environmental exposures is vital for developing strategies to enh…

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Neural basis of major depressive disorder: Beyond monoamine hypothesis.

The monoamine hypothesis has been accepted as the most common hypothesis of major depressive disorder (MDD) for a long period because of its simplicity and understandability. Actually, most currently used antidepressants have been considered to act based on the monoamine hypothesis. However, an important problem of the monoamine hypothesis has been pointed out as follows: it fails to explain the latency of response to antidepressants. In addition, many patients with MDD have remained refractory to currently used antidepressants. Therefore, monoamine-alternate hypotheses are required to explain the latency of response to antidepressants. Such hypotheses have been expected to contribute to identifying hopeful new therapeutic targets for MDD. Past studies have revealed that the volume of the hippocampus is decreased in patients with MDD, which is likely caused by the failure of the hypothal…

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Role of BDNF epigenetics in activity-dependent neuronal plasticity.

Brain-derived neurotrophic factor (BDNF) is a key mediator of the activity-dependent processes in the brain that have a major impact on neuronal development and plasticity. Impaired control of neuronal activity-induced BDNF expression mediates the pathogenesis of various neurological and psychiatric disorders. Different environmental stimuli, such as the use of pharmacological compounds, physical and learning exercises or stress exposure, lead to activation of specific neuronal networks. These processes entail tight temporal and spatial transcriptional control of numerous BDNF splice variants through epigenetic mechanisms. The present review highlights recent findings on the dynamic and long-term epigenetic programming of BDNF gene expression by the DNA methylation, histone-modifying and microRNA machineries. The review also summarizes the current knowledge on the activity-dependent BDNF…

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Brain-actuated functional electrical stimulation elicits lasting arm motor recovery after stroke.

Brain-computer interfaces (BCI) are used in stroke rehabilitation to translate brain signals into intended movements of the paralyzed limb. However, the efficacy and mechanisms of BCI-based therapies remain unclear. Here we show that BCI coupled to functional electrical stimulation (FES) elicits significant, clinically relevant, and lasting motor recovery in chronic stroke survivors more effectively than sham FES. Such recovery is associated to quantitative signatures of functional neuroplasticity. BCI patients exhibit a significant functional recovery after the intervention, which remains 6-12 months after the end of therapy. Electroencephalography analysis pinpoints significant differences in favor of the BCI group, mainly consisting in an increase in functional connectivity between motor areas in the affected hemisphere. This increase is significantly correlated with functional improv…

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Single blind randomised controlled trial of GAME (Goals - Activity - Motor Enrichment) in infants at high risk of cerebral palsy.

Background: Cerebral palsy (CP) is caused by a lesion in the developing infant brain. Recent neuroplasticity literature suggests that intensive, task-specific intervention ought to commence early, during the critical period of neural development. Aims: To determine whether "GAME" (Goals - Activity - Motor Enrichment), a motor learning, environmental enrichment intervention, is effective for improving motor skills in infants at high risk of CP. Methods and procedures: Single blind randomised controlled trial of GAME versus standard care. Primary outcome was motor skills on the Peabody Developmental Motor Scales-2 (PDMS-2). Secondary outcomes included Canadian Occupational Performance Measure (COPM), Bayley Scales of Infant and Toddler Development (BSID-III) and Gross Motor Function Measure-66 (GMFM-66). Outcome assessors were masked to group allocation and data analyzed with multiple regr…

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Treadmill exercise elevates striatal dopamine D2 receptor binding potential in patients with early Parkinson's disease.

We have previously demonstrated changes in dopaminergic neurotransmission after intensive exercise in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of Parkinson's disease (PD), including an increase in the dopamine D2 receptor (DA-D2R), using noninvasive PET imaging with the radioligand [18F]fallypride. The purpose of this feasibility and translational study was to examine whether intensive exercise leads to similar alterations in DA-D2R expression using PET imaging with [18F]fallypride in individuals with early-stage PD. In this pilot study, four patients with early-stage PD were randomized to receive intensive exercise (treadmill training sessions three times/week for 8 weeks) or no exercise. Two healthy age-matched individuals participated in treadmill training. Alterations in the DA-D2R binding potential (BP) as a marker for receptor expression were determined…

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Random noise stimulation improves neuroplasticity in perceptual learning.

Perceptual learning is considered a manifestation of neural plasticity in the human brain. We investigated brain plasticity mechanisms in a learning task using noninvasive transcranial electrical stimulation (tES). We hypothesized that different types of tES would have varying actions on the nervous system, which would result in different efficacies of neural plasticity modulation. Thus, the principal goal of the present study was to verify the possibility of inducing differential plasticity effects using two tES approaches [i.e., direct current stimulation (tDCS) and random noise stimulation (tRNS)] during the execution of a visual perceptual learning task.

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Neuroplasticity-based cognitive training in schizophrenia: an interim report on the effects 6 months later.

Background: New cognitive treatments for schizophrenia are needed that drive persistent gains in cognition and functioning. Using an innovative neuroplasticity-based cognitive training approach, we report our interim findings on the effects on cognition and functional outcome at 6 months after treatment. Methods: Thirty-two clinically stable schizophrenia subjects were randomly assigned to either targeted cognitive training (TCT, N = 22) or a computer games (CGs) control condition (N = 10). Twelve TCT subjects completed 50 hours of auditory based training; 10 TCT subjects completed an additional 50 hours of training targeting visual and cognitive control processes. Subjects were assessed on neurocognition and functional outcome after training and at 6-month follow-up. Results: Both TCT subject groups showed significant durable gains at 6 months on measures of verbal learning/memory and c…

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Using neuroplasticity-based auditory training to improve verbal memory in schizophrenia.

Objective: Impaired verbal memory in schizophrenia is a key rate-limiting factor for functional outcome, does not respond to currently available medications, and shows only modest improvement after conventional behavioral remediation. The authors investigated an innovative approach to the remediation of verbal memory in schizophrenia, based on principles derived from the basic neuroscience of learning-induced neuroplasticity. The authors report interim findings in this ongoing study. Method: Fifty-five clinically stable schizophrenia subjects were randomly assigned to either 50 hours of computerized auditory training or a control condition using computer games. Those receiving auditory training engaged in daily computerized exercises that placed implicit, increasing demands on auditory perception through progressively more difficult auditory-verbal working memory and verbal learning task…

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Structural brain alterations following 5 days of intervention: dynamic aspects of neuroplasticity.

Activation-dependent brain plasticity in humans on a structural level has been demonstrated in adults after 3 months of training a visio-motor skill. The exact timescale of usage-dependent structural changes, whether days, months, or years, is, however, still debated. A better understanding of the temporal parameters may help elucidate to what extent this type of cortical plasticity contributes to fast adapting cortical processes that may be relevant to learning and effects of treatments. Using voxel-based morphometry, we are able to show that repetitive transcranial magnetic stimulation delivered to the superior temporal cortex causes macroscopic cortical changes in gray matter (GM) in the auditory cortex as early as within 5 days of continuous intervention. These structural alterations are mirrored by changes in cortical evoked potentials attributed to the GM changes and demonstrate th…

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Dopaminergic modulation of cortical plasticity in Alzheimer's disease patients.

In animal models of Alzheimer's disease (AD), mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD) are impaired. In AD patients, LTP-like cortical plasticity is abolished, whereas LTD seems to be preserved. Dopaminergic transmission has been hypothesized as a new player in ruling mechanisms of cortical plasticity in AD. We aimed at investigating whether administration of the dopamine agonist rotigotine (RTG) could modulate cortical plasticity in AD patients, as measured by theta burst stimulation (TBS) protocols of repetitive transcranial stimulation applied over the primary motor cortex. Thirty mild AD patients were tested in three different groups before and after 4 weeks of treatment with RTG, rivastigmine (RVT), or placebo (PLC). Each patient was evaluated for plasticity induction of LTP/LTD-like effects using respectively intermittent…

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Repeatedly pairing vagus nerve stimulation with a movement reorganizes primary motor cortex.

Although sensory and motor systems support different functions, both systems exhibit experience-dependent cortical plasticity under similar conditions. If mechanisms regulating cortical plasticity are common to sensory and motor cortices, then methods generating plasticity in sensory cortex should be effective in motor cortex. Repeatedly pairing a tone with a brief period of vagus nerve stimulation (VNS) increases the proportion of primary auditory cortex responding to the paired tone (Engineer ND, Riley JR, Seale JD, Vrana WA, Shetake J, Sudanagunta SP, Borland MS, Kilgard MP. 2011. Reversing pathological neural activity using targeted plasticity. Nature. 470:101-104). In this study, we predicted that repeatedly pairing VNS with a specific movement would result in an increased representation of that movement in primary motor cortex. To test this hypothesis, we paired VNS with movements …

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Physical exercise modulates peripheral levels of brain-derived neurotrophic factor (BDNF): a systematic review of experimental studies in the elderly.

Unlabelled: The objective of this study was to conduct a systematic review of studies that analyzed the effect of physical exercise on the peripheral levels of BDNF in elderly individuals. Method: We conducted a search in PsycINFO, Biological Abstracts, Pubmed, Web of Science, and Science Direct from 1990 to 2011, using the following keywords: "physical exercise", "physical activity", "physical therapy", "training", "BDNF", "neuroplasticity", "neurotrophins", "neuroplasticity proteins", "aged", "older", "elderly". The articles were considered for inclusion in the review if they were studies with elderly, assessed peripheral (serum and/or plasma) BDNF and evaluated an acute exercise or chronic exercise (training). Results: Five randomized controlled trial and one randomized non-controlled trial studies were analyzed. Five out of six studies reported a significantly higher BDNF response to…

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High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: interplay between clinical and animal studies.

High-dose corticosteroids have been reported to reduce symptoms of acute stress and post-traumatic stress in polytrauma patients and in animal studies. The underlying mechanism of action remains largely unclear. These issues were addressed in parallel in the clinical and preclinical studies below. In this preliminary study, 25 patients with acute stress symptoms were administered a single intravenous bolus of high-dose hydrocortisone (100-140 mg) or placebo within 6 h of a traumatic event in a prospective, randomized, double-blind, placebo-controlled pilot study. Early single high-dose hydrocortisone intervention attenuated the core symptoms of both the acute stress and of subsequent PTSD in patients. High-dose hydrocortisone treatment given in the first few hours after a traumatic experience was associated with significant favorable changes in the trajectory of exposure to trauma, as ex…

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Neural plasticity and behavior - sixty years of conceptual advances.

This brief review summarizes 60 years of conceptual advances that have demonstrated a role for active changes in neuronal connectivity as a controller of behavior and behavioral change. Seminal studies in the first phase of the six-decade span of this review firmly established the cellular basis of behavior - a concept that we take for granted now, but which was an open question at the time. Hebbian plasticity, including long-term potentiation and long-term depression, was then discovered as being important for local circuit refinement in the context of memory formation and behavioral change and stabilization in the mammalian central nervous system. Direct demonstration of plasticity of neuronal circuit function in vivo, for example, hippocampal neurons forming place cell firing patterns, extended this concept. However, additional neurophysiologic and computational studies demonstrated t…

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Hippocampal neuroplasticity induced by early-life stress: functional and molecular aspects.

Whereas genetic factors contribute crucially to brain function, early-life events, including stress, exert long-lasting influence on neuronal function. Here, we focus on the hippocampus as the target of these early-life events because of its crucial role in learning and memory. Using a novel immature-rodent model, we describe the deleterious consequences of chronic early-life 'psychological' stress on hippocampus-dependent cognitive tasks. We review the cellular mechanisms involved and discuss the roles of stress-mediating molecules, including corticotropin releasing hormone, in the process by which stress impacts the structure and function of hippocampal neurons.

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BDNF-TrkB receptor regulation of distributed adult neural plasticity, memory formation, and psychiatric disorders.

Brain-derived neurotrophic factor (BDNF) and its single transmembrane receptor, tropomysin-related kinase B (TrkB), are essential for adult synaptic plasticity and the formation of memories. However, there are regional and task-dependent differences underlying differential mechanisms of BDNF-TrkB function in the formation of these memories. Additionally, the BDNF pathway has been implicated in several psychiatric disorders including posttraumatic stress disorder, phobia, and panic disorder. Gaining a better understanding of this pathway and the neurobiology of memory through fundamental research may be helpful to identify effective prevention and treatment approaches both for diseases of memory deficit as well as in cases of enhanced aversive memory, such as in anxiety disorders.

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Multidisciplinary rehabilitation reduces hypothalamic grey matter volume loss in individuals with preclinical Huntington's disease: A nine-month pilot study.

Background: Hypothalamic pathology is a well-documented feature of Huntington's disease (HD) and is believed to contribute to circadian rhythm and habitual sleep disturbances. Currently, no therapies exist to combat hypothalamic changes, nor circadian rhythm and habitual sleep disturbances in HD. Objective: To evaluate the effects of multidisciplinary rehabilitation on hypothalamic volume, brain-derived neurotrophic factor (BDNF), circadian rhythm and habitual sleep in individuals with preclinical HD. Methods: Eighteen individuals with HD (ten premanifest and eight prodromal) undertook a nine-month multidisciplinary rehabilitation intervention (intervention group), which included exercise, cognitive and dual task training and social events, and were compared to a community sample of eleven individuals with premanifest HD receiving no intervention (control group). Hypothalamic volume, ser…

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The role of sleep in regulating structural plasticity and synaptic strength: Implications for memory and cognitive function.

Dendritic spines are the major sites of synaptic transmission in the central nervous system. Alterations in the strength of synaptic connections directly affect the neuronal communication, which is crucial for brain function as well as the processing and storage of information. Sleep and sleep loss bidirectionally alter structural plasticity, by affecting spine numbers and morphology, which ultimately can affect the functional output of the brain in terms of alertness, cognition, and mood. Experimental data from studies in rodents suggest that sleep deprivation may impact structural plasticity in different ways. One of the current views, referred to as the synaptic homeostasis hypothesis, suggests that wake promotes synaptic potentiation whereas sleep facilitates synaptic downscaling. On the other hand, several studies have now shown that sleep deprivation can reduce spine density and at…

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Exercise Augmentation of Exposure Therapy for PTSD: Rationale and Pilot Efficacy Data.

Brain-derived neurotrophic factor (BDNF) is associated with synaptic plasticity, which is crucial for long-term learning and memory. Some studies suggest that people suffering from anxiety disorders show reduced BDNF relative to healthy controls. Lower BDNF is associated with impaired learning, cognitive deficits, and poor exposure-based treatment outcomes. A series of studies with rats showed that exercise elevates BDNF and enhances fear extinction. However, this strategy has not been tested in humans. In this pilot study, we randomized participants (N = 9, 8 females, M(Age) = 34) with posttraumatic stress disorder (PTSD) to (a) prolonged exposure alone (PE) or (b) prolonged exposure+exercise (PE+E). Participants randomized to the PE+E condition completed a 30-minute bout of moderate-intensity treadmill exercise (70% of age-predicted HR(max)) prior to each PE session. Consistent with pr…

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Is serum brain-derived neurotrophic factor a biomarker for cognitive enhancement in schizophrenia?

Background: Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and plasticity; decreased BDNF functioning may contribute to the pathogenesis of schizophrenia. However, BDNF levels are not static; in animal experiments, brain BDNF increases during spatial learning, and in clinical depression, successful antidepressant treatment raises serum BDNF. We asked: would neuroplasticity-based cognitive training in schizophrenia result in increased serum BDNF? Methods: Fifty-six schizophrenia outpatients and 16 matched healthy comparison subjects were assessed on baseline cognitive performance and serum BDNF. Schizophrenia subjects were randomly assigned to either 50 hours (10 weeks) of computerized auditory training or a computer game control condition, followed by reassessment of cognition and serum BDNF. Results: At baseline, schizophrenia participants had signifi…

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BDNF - a key transducer of antidepressant effects.

How do antidepressants elicit an antidepressant response? Here, we review accumulating evidence that the neurotrophin brain-derived neurotrophic factor (BDNF) serves as a transducer, acting as the link between the antidepressant drug and the neuroplastic changes that result in the improvement of the depressive symptoms. Over the last decade several studies have consistently highlighted BDNF as a key player in antidepressant action. An increase in hippocampal and cortical expression of BDNF mRNA parallels the antidepressant-like response of conventional antidepressants such as SSRIs. Subsequent studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect. Importantly, the antidepressant-like response to conventional antidepressants is attenuated in mice where…

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Cognitive and neural plasticity in old age: A systematic review of evidence from executive functions cognitive training.

Cognitive training is a popular intervention aimed at attenuating age-related cognitive decline, however, the effects of this intervention on brain structure and function have not been thoroughly explored. Core executive functions (working memory, inhibition, cognitive flexibility) are dependent upon prefrontal brain regions-one of the most vulnerable areas of age-related decline. They are also implicated in numerous cognitive processes and higher-order functions. Training executive functions should therefore promote cognitive and neural enhancements in old age. This systematic review examined the effects of executive functions training on brain and cognition amongst healthy older adults across 20 studies. Behavioral performance consistently improved on trained cognitive tasks, though mixed findings were reported for untrained tasks. Training-related structural changes were reported, evi…

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