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

Neurodevelopmental Outcomes of Preterm Infants Fed Human Milk: A Systematic Review.

The neurodevelopmental benefits of breast milk feedings for preterm infants have been controversial. However, the effect on preterm infant neurodevelopment is sustained into childhood. The effects of breast milk feeding during the neonatal period and the duration of breastfeeding display effects on cognition into adolescence. The volume of breast milk received is a key factor in these effects. Additionally, emerging studies support the effects of human milk on structural brain development, such as increased white matter development and increased cortical thickness. The components of breast milk thought to mediate improved cognitive outcomes include long-chain polyunsaturated fatty acids and human milk oligosaccharides.

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Fear conditioning and the basolateral amygdala.

Fear is a response to impending threat that prepares a subject to make appropriate defensive responses, whether to freeze, fight, or flee to safety. The neural circuits that underpin how subjects learn about cues that signal threat, and make defensive responses, have been studied using Pavlovian fear conditioning in laboratory rodents as well as humans. These studies have established the amygdala as a key player in the circuits that process fear and led to a model where fear learning results from long-term potentiation of inputs that convey information about the conditioned stimulus to the amygdala. In this review, we describe the circuits in the basolateral amygdala that mediate fear learning and its expression as the conditioned response. We argue that while the evidence linking synaptic plasticity in the basolateral amygdala to fear learning is strong, there is still no mechanism that…

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Synaptic plasticity in depression: molecular, cellular and functional correlates.

Synaptic plasticity confers environmental adaptability through modification of the connectivity between neurons and neuronal circuits. This is achieved through changes to synapse-associated signaling systems and supported by complementary changes to cellular morphology and metabolism within the tripartite synapse. Mounting evidence suggests region-specific changes to synaptic form and function occur as a result of chronic stress and in depression. Within subregions of the prefrontal cortex (PFC) and hippocampus structural and synapse-related findings seem consistent with a deficit in long-term potentiation (LTP) and facilitation of long-term depression (LTD), particularly at excitatory pyramidal synapses. Other brain regions are less well-studied; however the amygdala may feature a somewhat opposite synaptic pathology including reduced inhibitory tone. Changes to synaptic plasticity in s…

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The impact of sleep deprivation on neuronal and glial signaling pathways important for memory and synaptic plasticity.

Sleep deprivation is a common feature in modern society, and one of the consequences of sleep loss is the impairment of cognitive function. Although it has been widely accepted that sleep deprivation affects learning and memory, only recently has research begun to address which molecular signaling pathways are altered by sleep loss and, more importantly, which pathways can be targeted to reverse the memory impairments resulting from sleep deprivation. In this review, we discuss the different methods used to sleep deprive animals and the effects of different durations of sleep deprivation on learning and memory with an emphasis on hippocampus-dependent memory. We then review the molecular signaling pathways that are sensitive to sleep loss, with a focus on those thought to play a critical role in the memory and synaptic plasticity deficits observed after sleep deprivation. Finally, we hig…

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Lipid signaling: sleep, synaptic plasticity, and neuroprotection.

Increasing evidence indicates that bioactive lipids participate in the regulation of synaptic function and dysfunction. We have demonstrated that signaling mediated by platelet-activating factor (PAF) and cyclooxygenase (COX)-2-synthesized PGE2 is involved in synaptic plasticity, memory, and neuronal protection [Clark GD, Happel LT, Zorumski CF, Bazan NG. Enhancement of hippocampal excitatory synaptic transmission by platelet-activating factor. Neuron 1992; 9:1211; Kato K, Clark GD, Bazan NG, Zorumski CF. Platelet-activating factor as a potential retrograde messenger in CA1 hippocampal long-term potentiation. Nature 1994; 367:175; Izquierdo I, Fin C, Schmitz PK, et al. Memory enhancement by intrahippocampal, intraamygdala or intraentorhinal infusion of platelet-activating factor measured in an inhibitory avoidance. Proc Natl Acad Sci USA 1995; 92:5047; Chen C, Magee CJ, Bazan NG. Cycloox…

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The hippocampus in aging and disease: From plasticity to vulnerability.

The hippocampus has a pivotal role in learning and in the formation and consolidation of memory and is critically involved in the regulation of emotion, fear, anxiety, and stress. Studies of the hippocampus have been central to the study of memory in humans and in recent years, the regional specialization and organization of hippocampal functions have been elucidated in experimental models and in human neurological and psychiatric diseases. The hippocampus has long been considered a classic model for the study of neuroplasticity as many examples of synaptic plasticity such as long-term potentiation and -depression have been identified and demonstrated in hippocampal circuits. Neuroplasticity is the ability to adapt and reorganize the structure or function to internal or external stimuli and occurs at the cellular, population, network or behavioral level and is reflected in the cytologica…

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Effects of high- and low-frequency repetitive transcranial magnetic stimulation on motor recovery in early stroke patients: Evidence from a randomized controlled trial with clinical, neurophysiological and functional imaging assessments.

Background: Repetitive transcranial magnetic stimulation (rTMS) can modulate cortical excitability, and may be beneficial for motor recovery after stroke. However, the neuroplasticity effects of rTMS have not been thoroughly investigated in the early stage after stroke. Objective: To comprehensively assess the effects of high- and low-frequency repetitive transcranial magnetic stimulations on motor recovery in early stroke patients, using a randomized controlled trial based on clinical, neurophysiological and functional imaging assessments. Methods: Sixty hospitalized, first-ever ischemic stroke patients (within 2 weeks after stroke) with motor deficits were randomly allocated to receive, in addition to standard physical therapy, five consecutive sessions of either: (1) High-frequency (HF) rTMS at 10 Hz over the ipsilesional primary motor cortex (M1); (2) Low-frequency (LF) rTMS at 1 Hz …

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RNA-sequencing of the brain transcriptome implicates dysregulation of neuroplasticity, circadian rhythms and GTPase binding in bipolar disorder.

RNA-sequencing (RNA-seq) is a powerful technique to investigate the complexity of gene expression in the human brain. We used RNA-seq to survey the brain transcriptome in high-quality postmortem dorsolateral prefrontal cortex from 11 individuals diagnosed with bipolar disorder (BD) and from 11 age- and gender-matched controls. Deep sequencing was performed, with over 350 million reads per specimen. At a false discovery rate of <5%, we detected five differentially expressed (DE) genes and 12 DE transcripts, most of which have not been previously implicated in BD. Among these, Prominin 1/CD133 and ATP-binding cassette-sub-family G-member2 (ABCG2) have important roles in neuroplasticity. We also show for the first time differential expression of long noncoding RNAs (lncRNAs) in BD. DE transcripts include those of serine/arginine-rich splicing factor 5 (SRSF5) and regulatory factor X4 (RFX4)…

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Novelty exploration elicits a reversal of acute stress-induced modulation of hippocampal synaptic plasticity in the rat.

Acute behavioural stress has been recognized as a strong influence on the inducibility of hippocampal long-term synaptic plasticity. We have reported previously that in adult male rats, acute behavioural stress impairs long-term potentiation (LTP) but enhances long-term depression (LTD) in the hippocampal CA1 region. In this study we report that the effects of stress on LTP and LTD were reversed when animals were introduced into a novel 'stimulus-rich' environment immediately after the stress. Novelty exploration-induced reversal of stress effects was prevented when the animals were given the NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid, the cholinergic antagonist atropine and the protein phosphatase (PP) 2B inhibitors cyclosporin A and cypermethrin, but not the alpha1-adrenergic antagonist prazosin, the beta-adrenergic antagonist propranolol or the PP1/2A inhibitor o…

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Effects of combined dietary intervention and physical-cognitive exercise on cognitive function and cardiometabolic health of postmenopausal women with obesity: a randomized controlled trial.

Background: Postmenopausal women with obesity are markedly at risk of cognitive impairment and several health issues. Emerging evidence demonstrated that both diet and exercise, particularly physical-cognitive exercise are involved in cognitive and health benefits. However, the comparative effect of diet, exercise, and combined interventions in postmenopausal women with obesity on cognition and cardiometabolic health is still lacking. Identifying the effective health promotion program and understanding changes in cardiometabolic health linking these interventions to cognition would have important medical implications. This RCT aimed to examine the effect of single and combined interventions of diet and exercise on cognitive function and cardiometabolic health in postmenopausal women with obesity. Methods: Ninety-two postmenopausal women with obesity were randomly assigned to diet group (…

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Longitudinal DNA methylation in parent-infant pairs impacted by intergenerational social adversity: An RCT of the Michigan Model of Infant Mental Health Home Visiting.

Introduction: Early childhood development is a strong predictor of long-term health outcomes, potentially mediated via epigenetics (DNA methylation). The aim of the current study was to examine how childhood experiences, punitive parenting, and an intergenerational psychotherapeutic intervention may impact DNA methylation in young children and their mothers. Methods: Mothers and their infants/toddlers between 0 and 24 months were recruited at baseline (n = 146, 73 pairs) to participate in a randomized control trial evaluating the effectiveness of The Michigan Model of Infant Mental Health Home Visiting (IMH-HV) parent-infant psychotherapy compared to treatment as usual. Baseline and 12-month post-enrollment data were collected in the family's home and included self-report questionnaires, biological saliva samples, home environment observation, video-taped parent-child interaction, and au…

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Effects of attachment-based compassion therapy (ABCT) on brain-derived neurotrophic factor and low-grade inflammation among fibromyalgia patients: A randomized controlled trial.

Fibromyalgia (FM) is a disabling syndrome characterized by chronic pain associated with fatigue. Its pathogenesis is unknown, but alterations in central sensitization, involving an imbalance of brain-derived neurotrophic factor (BDNF) and inflammatory biomarkers, appear to be implicated. The aim of this study was to evaluate the impact of attachment-based compassion therapy (ABCT) on levels of BDNF, the inflammatory markers TNF-α, IL-6, IL-10, and the C-reactive protein (CRP), analysing whether biomarkers play a mediating/moderating role in improvements in FM functional status. Thirty-four female patients with FM participated in a RCT and were assigned to ABCT or relaxation therapy. Blood extractions were conducted at baseline and post-intervention, with self-report assessments of functional status (FIQ) at baseline, post-intervention and 3-month follow-up. A pro-inflammatory composite w…

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A nonrandomized controlled clinical pilot trial on 8 wk of intermittent fasting (24 h/wk).

Objective: The aim of the study was to evaluate whether intermittent fasting (IF) is an effective preventive measure, and whether it is feasible for healthy volunteers under every day conditions. Methods: A nonrandomized controlled clinical trial on IF was performed with healthy volunteers over a period of 8 wk, and a subsequent 4-mo follow-up. Outcomes were assessed at baseline, after 8 wk, and after 6 mo. Volunteers who were not interested in fasting served as a control group. Participants in the fasting group were asked to continue their regular nutritional habits on the nonfasting days, whereas the control group maintained their habitual nutrition throughout the whole period. Outcomes included changes of metabolic parameters (insulin, glucose, insulin resistance, insulin-like growth factor-1, brain-derived neurotropic factor, lipids, liver enzymes, hemoglobin A1c) and coagulation mar…

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Mindfulness Meditation Reduces Intraocular Pressure, Lowers Stress Biomarkers and Modulates Gene Expression in Glaucoma: A Randomized Controlled Trial.

Background: Reducing intraocular pressure (IOP) in primary open-angle glaucoma (POAG) is currently the only approach to prevent further optic nerve head damage. However, other mechanisms such as ischemia, oxidative stress, glutamate excitotoxicity, neurotrophin loss, inflammation/glial activation, and vascular dysregulation are not addressed. Because stress is a key risk factor affecting these mechanisms, we evaluated whether mindfulness-based stress reduction can lower IOP and normalize typical stress biomarkers. Materials and methods: In a prospective, randomized trial 90 POAG patients (180 eyes; age above 45 y) were assigned to a waitlist control or mindfulness meditation group which practiced daily for 21 days. We measured IOP (primary endpoint), quality of life (QOL), stress-related serum biomarkers [cortisol, β-endorphins, IL6, TNF-α, brain-derived neurotrophic factor (BDNF), react…

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Bounce Back Now! Protocol of a population-based randomized controlled trial to examine the efficacy of a Web-based intervention with disaster-affected families.

Disasters have far-reaching and potentially long-lasting effects on youth and families. Research has consistently shown a clear increase in the prevalence of several mental health disorders after disasters, including depression and posttraumatic stress disorder. Widely accessible evidence-based interventions are needed to address this unmet need for youth and families, who are underrepresented in disaster research. Rapid growth in Internet and Smartphone access, as well as several Web based evaluation studies with various adult populations has shown that Web-based interventions are likely to be feasible in this context and can improve clinical outcomes. Such interventions also are generally cost-effective, can be targeted or personalized, and can easily be integrated in a stepped care approach to screening and intervention delivery. This is a protocol paper that describes an innovative s…

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The effect of transcutaneous vagus nerve stimulation on cortical excitability.

There is great interest about the therapeutic potentialities of transcutaneous vagus nerve stimulation (tVNS) applied to neuropsychiatric disorders. However, the mechanisms of action of tVNS and its impact on cortical excitability are unclear. To this regard, transcranial magnetic stimulation (TMS) can be useful because it is able of evaluating non-invasively excitatory and inhibitory circuitry of the human cortex. Aim of the present study is to investigate the effects of tVNS on cerebral cortex excitability in healthy volunteers by means of TMS. Ten healthy subjects participated in this randomized placebo-controlled double-blind study. Real tVNS was administered at left external acoustic meatus, while sham stimulation was performed at left ear lobe, both of them for 60 min. We evaluated motor thresholds, motor evoked potential amplitude, recruitment curves, and short-interval intracorti…

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Influence of chronic moderate sleep restriction and exercise training on anxiety, spatial memory, and associated neurobiological measures in mice.

Sleep deprivation can have deleterious effects on cognitive function and mental health. Moderate exercise training has myriad beneficial effects on cognition and mental health. However, physiological and behavioral effects of chronic moderate sleep restriction and its interaction with common activities, such as moderate exercise training, have received little investigation. The aims of this study were to examine the effects of chronic moderate sleep restriction and moderate exercise training on anxiety-related behavior, spatial memory, and neurobiological correlates in mice. Male mice were randomized to one of four 11-week treatments in a 2 [sleep restriction (∼4h loss/day) vs. ad libitum sleep] × 2 [exercise (1h/day/6 d/wk) vs. sedentary activity] experimental design. Anxiety-related behavior was assessed with the elevated-plus maze, and spatial learning and memory were assessed with th…

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Modulation of training by single-session transcranial direct current stimulation to the intact motor cortex enhances motor skill acquisition of the paretic hand.

Background and purpose: Mechanisms of skill learning are paramount components for stroke recovery. Recent noninvasive brain stimulation studies demonstrated that decreasing activity in the contralesional motor cortex might be beneficial, providing transient functional improvements after stroke. The more crucial question, however, is whether this intervention can also enhance the acquisition of complex motor tasks, yielding longer-lasting functional improvements. In the present study, we tested the capacity of cathodal transcranial direct current stimulation (tDCS) applied over the contralesional motor cortex during training to enhance the acquisition and retention of complex sequential finger movements of the paretic hand. Method: Twelve well-recovered chronic patients with subcortical stroke attended 2 training sessions during which either cathodal tDCS or a sham intervention were appli…

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The effect of the Mediterranean diet on plasma brain-derived neurotrophic factor (BDNF) levels: the PREDIMED-NAVARRA randomized trial.

Objectives: There are no human studies assessing the effect of nutritional interventions on plasma brain-derived neurotrophic factor (BDNF) concentrations. The aim of this study was to assess the role of a nutritional intervention based on a Mediterranean diet (MeDiet) on plasma BDNF levels. Methods: PREvención con Dieta MEDiterránea (PREDIMED) is a randomized clinical trial designed to assess the effect of a Mediterranean diet (MeDiet) on the primary prevention of cardiovascular disease. For this analysis, 243 participants from the Navarra centre were randomly selected. Participants were assigned to one of three dietary interventions: control (low-fat) diet, MeDiet supplemented with virgin olive oil (MeDiet+VOO), or MeDiet supplemented with nuts (MeDiet+Nuts). Plasma BDNF levels were measured after 3 years of intervention. Multivariate-adjusted means of BDNF for each intervention were c…

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Restoration of sensorimotor functions after spinal cord injury.

The purpose of this review is to discuss the achievements and perspectives regarding rehabilitation of sensorimotor functions after spinal cord injury. In the first part we discuss clinical approaches based on neuroplasticity, a term referring to all adaptive and maladaptive changes within the sensorimotor systems triggered by a spinal cord injury. Neuroplasticity can be facilitated through the training of movements with assistance as needed, and/or by electrical stimulation techniques. The success of such training in individuals with incomplete spinal cord injury critically depends on the presence of physiological proprioceptive input to the spinal cord leading to meaningful muscle activations during movement performances. The addition of rehabilitation technology, such as robotic devices allows for longer training times and provision of feedback information regarding changes in movemen…

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Mindfulness practice leads to increases in regional brain gray matter density.

Therapeutic interventions that incorporate training in mindfulness meditation have become increasingly popular, but to date little is known about neural mechanisms associated with these interventions. Mindfulness-Based Stress Reduction (MBSR), one of the most widely used mindfulness training programs, has been reported to produce positive effects on psychological well-being and to ameliorate symptoms of a number of disorders. Here, we report a controlled longitudinal study to investigate pre-post changes in brain gray matter concentration attributable to participation in an MBSR program. Anatomical magnetic resonance (MR) images from 16 healthy, meditation-naïve participants were obtained before and after they underwent the 8-week program. Changes in gray matter concentration were investigated using voxel-based morphometry, and compared with a waiting list control group of 17 individuals…

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Voluntary exercise induces anxiety-like behavior in adult C57BL/6J mice correlating with hippocampal neurogenesis.

Several studies investigated the effect of physical exercise on emotional behaviors in rodents; resulting findings however remain controversial. Despite the accepted notion that voluntary exercise alters behavior in the same manners as antidepressant drugs, several studies reported opposite or no effects at all. In an attempt to evaluate the effect of physical exercise on emotional behaviors and brain plasticity, we individually housed C57BL/6J male mice in cages equipped with a running wheel. Three weeks after continuous voluntary running we assessed their anxiety- and depression-like behaviors. Tests included openfield, dark-light-box, elevated O-maze, learned helplessness, and forced swim test. We measured corticosterone metabolite levels in feces collected over a 24-h period and brain-derived neurotrophic factor (BDNF) in several brain regions. Furthermore, cell proliferation and adu…

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Neural substrates of treatment response to cognitive-behavioral therapy in panic disorder with agoraphobia.

Objective: Although exposure-based cognitive-behavioral therapy (CBT) is an effective treatment option for panic disorder with agoraphobia, the neural substrates of treatment response remain unknown. Evidence suggests that panic disorder with agoraphobia is characterized by dysfunctional safety signal processing. Using fear conditioning as a neurofunctional probe, the authors investigated neural baseline characteristics and neuroplastic changes after CBT that were associated with treatment outcome in patients with panic disorder with agoraphobia. Method: Neural correlates of fear conditioning and extinction were measured using functional MRI before and after a manualized CBT program focusing on behavioral exposure in 49 medication-free patients with a primary diagnosis of panic disorder with agoraphobia. Treatment response was defined as a reduction exceeding 50% in Hamilton Anxiety Rati…

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Short-term learning induces white matter plasticity in the fornix.

Magnetic resonance imaging (MRI) has greatly extended the exploration of neuroplasticity in behaving animals and humans. Imaging studies recently uncovered structural changes that occur in gray and white matter, mainly after long-term training. A recent diffusion tensor imaging (DTI) study showed that training in a car racing game for 2 h induces changes in the hippocampus and parahippocampal gyri. However, the effect of short-term training on the white matter microstructure is unknown. Here we investigated the influence of short learning tasks on structural plasticity in the white matter, and specifically in the fornix, in humans and rats. Human subjects performed a 2 h spatial learning task, and rats underwent training for 1 d in a Morris water maze. Between tasks, subjects were scanned with DTI, a diffusion MRI framework sensitive to tissue microstructure. Using tract-based spatial st…

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Hippocampal N-acetylaspartate concentration and response to riluzole in generalized anxiety disorder.

Background: Previous research has suggested the therapeutic potential of glutamate-modulating agents for severe mood and anxiety disorders, potentially resulting from enhancement of neuroplasticity. We used proton magnetic resonance spectroscopic imaging ((1)H MRSI) to examine the acute and chronic effects of the glutamate-release inhibitor riluzole on hippocampal N-acetylaspartate (NAA), a neuronal marker, in patients with generalized anxiety disorder (GAD) and examined the relationship between changes in NAA and clinical outcome. Methods: Fourteen medication-free GAD patients were administered open-label riluzole and then evaluated by (1)H MRSI before drug administration, and 24 hours and 8 weeks following treatment. Patients were identified as responders (n = 9) or nonresponders (n = 5). Seven untreated, medically healthy volunteers, comparable in age, sex, IQ, and body mass index to …

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