Long-term Changes In Brain Function Research Articles

Stress-related neuropeptide systems as targets for treatment of alcohol addiction: A clinical perspective.

Alcohol use is a major cause of disability and death globally. These negative consequences disproportionately affect people who develop alcohol addiction, a chronic relapsing condition characterized by increased motivation to use alcohol, choice of alcohol over healthy, natural rewards, and continued use despite negative consequences. Available pharmacotherapies for alcohol addiction are few, have effect sizes in need of improvement, and remain infrequently prescribed. Research aimed at developing novel therapeutics has in large part focused on attenuating pleasurable or "rewarding" properties of alcohol, but this targets processes that primarily play a role as initiation factors. As clinical alcohol addiction develops, long-term changes in brain function result in a shift of affective homeostasis, and rewarding alcohol effects become progressively reduced. Instead, increased stress sensitivity and negative affective states emerge in the absence of alcohol and create powerful incentives for relapse and continued use through negative reinforcement, or "relief." Based on research in animal models, several neuropeptide systems have been proposed to play an important role in this shift, suggesting that these systems could be targeted by novel medications. Two mechanisms in this category, antagonism at corticotropin-releasing factor type 1, and neurokinin 1/substance P receptors, have been subject to initial evaluation in humans. A third, kappa-opioid receptor antagonism, has been evaluated in nicotine addiction and could soon be tested for alcohol. This paper discusses findings with these mechanisms to date, and their prospects as future targets for novel medications.

Long lasting anxiety following early life stress is dependent on glucocorticoid signaling in zebrafish

Chronic adversity in early childhood is associated with increased anxiety and a propensity for substance abuse later in adulthood, yet the effects of early life stress (ELS) on brain development remain poorly understood. The zebrafish, Danio rerio, is a powerful model for studying neurodevelopment and stress. Here, we describe a zebrafish model of ELS and identify a role for glucocorticoid signaling during a critical window in development that leads to long-term changes in brain function. Larval fish subjected to chronic stress in early development exhibited increased anxiety-like behavior and elevated glucocorticoid levels later in life. Increased stress-like behavior was only observed when fish were subjected to ELS within a precise time window in early development, revealing a temporal critical window of sensitivity. Moreover, enhanced anxiety-like behavior only emerges after two months post-ELS, revealing a developmentally specified delay in the effects of ELS. ELS leads to increased levels of baseline cortisol, and resulted in a dysregulation of cortisol receptors’ mRNA expression, suggesting long-term effects on cortisol signaling. Together, these findings reveal a ‘critical window’ for ELS to affect developmental reprogramming of the glucocorticoid receptor pathway, resulting in chronic elevated stress.

IMG-14. Cognitive deficits and altered functional network organization in pediatric brain tumor patients

INTRODUCTION: Survivors of pediatric brain tumors experience significant cognitive deficits from their diagnosis and treatment. Mechanisms of cognitive injury are poorly understood, and predictors of long-term outcome are lacking. Large-scale, distributed brain systems provide a window into brain organization and function that may yield insight into these mechanisms and outcomes. Recent evidence suggests that systems-level changes are related to cognitive performance across the lifespan. Here, we evaluated brain network architecture, cognitive performance, and brain-behavior relationships in pediatric brain tumor patients. METHODS: Forty-nine patients (ages 7-18y.o.) with any brain tumor diagnosis underwent resting state functional Magnetic Resonance Imaging (rsfMRI) during regularly scheduled clinical visits. All patients were tested with the NIH Toolbox Cognition Battery. One-hundred thirty-nine age- and sex-matched typically developing children were used as controls. All data were processed to minimize artifactual sources of variance. Functional brain networks were created for each patient via rsfMRI data from 300 regions of interest that sample the whole brain. Multilinear models were implemented to examine brain-behavior relationships, while accounting for demographic and clinical factors. RESULTS: Functional network organization was significantly altered in patients compared to controls (p<0.001). Network organization was more affected in patients who received whole-brain radiation therapy than those who did not (t=2.52, p<0.015). Patients demonstrated significant impairments in multiple domains of cognitive performance, e.g. attention (p<0.0001). Weak relationships were found between cognitive performance and network organization, none of which survived multiple comparison correction. CONCLUSIONS: Brain network architecture is significantly altered in pediatric brain tumor patients. Whole-brain radiation was related to the largest changes. Most network and cognitive changes were significant with large effect sizes, yet brain-behavior relationships were weak. Our results suggest that systems-level changes in brain organization may provide insight into long-term changes in brain function in pediatric brain tumor patients.

The TRACK-PD study: protocol of a longitudinal ultra-high field imaging study in Parkinson\u2019s disease

BackgroundThe diagnosis of Parkinson’s Disease (PD) remains a challenge and is currently based on the assessment of clinical symptoms. PD is also a heterogeneous disease with great variability in symptoms, disease course, and response to therapy. There is a general need for a better understanding of this heterogeneity and the interlinked long-term changes in brain function and structure in PD. Over the past years there is increasing interest in the value of new paradigms in Magnetic Resonance Imaging (MRI) and the potential of ultra-high field strength imaging in the diagnostic work-up of PD. With this multimodal 7 T MRI study, our objectives are: 1) To identify distinctive MRI characteristics in PD patients and to create a diagnostic tool based on these differences. 2) To correlate MRI characteristics to clinical phenotype, genetics and progression of symptoms. 3) To detect future imaging biomarkers for disease progression that could be valuable for the evaluation of new therapies.MethodsThe TRACK-PD study is a longitudinal observational study in a cohort of 130 recently diagnosed (≤ 3 years after diagnosis) PD patients and 60 age-matched healthy controls (HC). A 7 T MRI of the brain will be performed at baseline and repeated after 2 and 4 years. Complete assessment of motor, cognitive, neuropsychiatric and autonomic symptoms will be performed at baseline and follow-up visits with wearable sensors, validated questionnaires and rating scales. At baseline a blood DNA sample will also be collected.DiscussionThis is the first longitudinal, observational, 7 T MRI study in PD patients. With this study, an important contribution can be made to the improvement of the current diagnostic process in PD. Moreover, this study will be able to provide valuable information related to the different clinical phenotypes of PD and their correlating MRI characteristics. The long-term aim of this study is to better understand PD and develop new biomarkers for disease progression which may help new therapy development. Eventually, this may lead to predictive models for individual PD patients and towards personalized medicine in the future.Trial registrationDutch Trial Register, NL7558. Registered March 11, 2019.

Divergent Synaptic Scaling of Miniature EPSCs following Activity Blockade in Dissociated Neuronal Cultures.

Neurons can respond to decreased network activity with a homeostatic increase in the amplitudes of miniature EPSCs (mEPSCs). The prevailing view is that mEPSC amplitudes are uniformly multiplied by a single factor, termed "synaptic scaling." Deviations from purely multiplicative scaling have been attributed to biological differences, or to a distortion imposed by a detection threshold limit. Here, we demonstrate in neurons dissociated from cortices of male and female mice that the shift in mEPSC amplitudes observed in the experimental data cannot be reproduced by simulation of uniform multiplicative scaling, with or without the distortion caused by applying a detection threshold. Furthermore, we demonstrate explicitly that the scaling factor is not uniform but is close to 1 for small mEPSCs, and increases with increasing mEPSC amplitude across a substantial portion of the data. This pattern was also observed for previously published data from dissociated mouse hippocampal neurons and dissociated rat cortical neurons. The finding of "divergent scaling" shifts the current view of homeostatic plasticity as a process that alters all synapses on a neuron equally to one that must accommodate the differential effect observed for small versus large mEPSCs. Divergent scaling still accomplishes the essential homeostatic task of modifying synaptic strengths in the opposite direction of the activity change, but the consequences are greatest for those synapses which individually are more likely to bring a neuron to threshold.SIGNIFICANCE STATEMENT In homeostatic plasticity, the responses to chronic increases or decreases in network activity act in the opposite direction to restore normal activity levels. Homeostatic plasticity is likely to play a role in diseases associated with long-term changes in brain function, such as epilepsy and neuropsychiatric illnesses. One homeostatic response is the increase in synaptic strength following a chronic block of activity. Research is focused on finding a globally expressed signaling pathway, because it has been proposed that the plasticity is uniformly expressed across all synapses. Here, we show that the plasticity is not uniform. Our work suggests that homeostatic signaling molecules are likely to be differentially expressed across synapses.

The long and short term effects of motherhood on the brain.

Becoming a mother is associated with dramatic changes in physiology, endocrinology, immune function, and behaviour that begins during pregnancy and persists into the postpartum. Evidence also suggests that motherhood is accompanied by long-term changes in brain function. In this review, we summarize the short (pregnancy and postpartum) and long-term (beyond the postpartum and into middle age) effects of pregnancy and motherhood on cognition, neuroplasticity, and neuroimmune signalling. We also discuss the effects of previous history of pregnancy and motherhood (parity) on brain health and disease (neurodegenerative diseases and stroke outcomes) and on efficacy of hormone and antidepressant treatments. Finally, we argue that pregnancy and motherhood are unique female experiences that need to be taken into account to better understand female brain function and aging.

Caregiver maltreatment causes altered neuronal DNA methylation in female rodents.

Negative experiences with a caregiver during infancy can result in long-term changes in brain function and behavior, but underlying mechanisms are not well understood. It is our central hypothesis that brain and behavior changes are conferred by early childhood adversity through epigenetic changes involving DNA methylation. Using a rodent model of early-life caregiver maltreatment (involving exposure to an adverse caregiving environment for postnatal days 1-7), we have previously demonstrated abnormal methylation of DNA associated with the brain-derived neurotrophic factor (Bdnf) gene in the medial prefrontal cortex (mPFC) of adult rats. The aim of the current study was to characterize Bdnf DNA methylation in specific cell populations within the mPFC. In the prefrontal cortex, there is approximately twice as many neurons as glia, and studies have recently shown differential and distinctive DNA methylation patterns in neurons versus nonneurons. Here, we extracted nuclei from the mPFC of adult animals that had experienced maltreatment and used fluorescence-activated cell sorting to isolate cell types before performing bisulfite sequencing to estimate methylation of cytosine-guanine sites. Our data indicate that early-life stress induced methylation of DNA associated with Bdnf IV in a cell-type and sex-specific manner. Specifically, females that experienced early-life maltreatment exhibited greater neuronal cytosine-guanine methylation compared to controls, while no changes were detected in Bdnf methylation in males regardless of cell type. These changes localize the specificity of our previous findings to mPFC neurons and highlight the capacity of maltreatment to cause methylation changes that are likely to have functional consequences for neuronal function.

Saccadic Impairment Associated With Remote History of Mild Traumatic Brain Injury.

Evidence suggests that mild traumatic brain injury (TBI) is associated with long-term changes in brain function, but conventional neurocognitive tools are often insensitive to deficits after 90 days. Eye movements have been proposed as a means to identify more chronic forms of impairment. In this study, saccadic, manual, and conventional neuropsychological measures were compared between participants with remote mild TBI and well-matched control participants. Saccadic impairment was more frequent within the mild TBI group, and a history of multiple injuries or high symptom burden appeared to compound this risk. However, other neurocognitive measures did not differ by group, number of injuries, or symptom severity. These results suggest that saccadic impairment may reflect chronic effects of mild TBI that conventional measures are unable to detect.

Choline and the Brain: An Epigenetic Perspective.

Choline is an essential nutrient that is required for normal development of the brain. Via its metabolite betaine, it participates in the synthesis of S-adenosylmethionine, a major methyl donor for histone and DNA methylation, two epigenetic mechanisms that regulate gene expression and may alter brain function. Besides its role in methyl group metabolism, choline also has pivotal functions, including the maintenance of structural integrity of membranes and modulation of cholinergic neurotransmission, functions that are often dysregulated in some neurodegenerative disorders. Emerging evidence suggests that environmental factors, including lifestyle or diet, sometimes cause epigenetic changes in the expression of neuronal genes resulting in long-term changes in brain function. Recently, choline has been implicated as an epigenetic modifier of the genome that may alter gene methylation, expression, and cellular function. Abnormal level of choline during fetal or early postnatal life has been shown to alter memory functions during adulthood. It may also contribute to the etiology of stress-related disorders and age-related decline in memory later in life. Conversely, rodent studies suggested that perinatal choline supplementation enhances performance in memory-related tasks during adulthood. In this chapter, we will focus on the impact of choline-gene interaction on brain function in early life and during adulthood. In particular, we will emphasize the potential role of choline as a neuroprotectant that may mitigate some of the adverse effects of neurodegenerative disorders and protect mental health across the lifespan.

Mechanisms of neuroimmune gene induction in alcoholism.

RationaleAlcoholism is a primary, chronic relapsing disease of brain reward, motivation, memory, and related circuitry. It is characterized by an individual’s continued drinking despite negative consequences related to alcohol use, which is exemplified by alcohol use leading to clinically significant impairment or distress. Chronic alcohol consumption increases the expression of innate immune signaling molecules (ISMs) in the brain that alter cognitive processes and promote alcohol drinking.ObjectivesUnraveling the mechanisms of alcohol-induced neuroimmune gene induction is complicated by positive loops of multiple cytokines and other signaling molecules that converge on nuclear factor kappa-light-chain-enhancer of activated B cells and activator protein-1 leading to induction of additional neuroimmune signaling molecules that amplify and expand the expression of ISMs.ResultsStudies from our laboratory employing reverse transcription polymerase chain reaction (RT-PCR) to assess mRNA, immunohistochemistry and Western blot analysis to assess protein expression, and others suggest that ethanol increases brain neuroimmune gene and protein expression through two distinct mechanisms involving (1) systemic induction of innate immune molecules that are transported from blood to the brain and (2) the direct release of high-mobility group box 1 (HMGB1) from neurons in the brain. Released HMGB1 signals through multiple receptors, particularly Toll-like receptor (TLR) 4, that potentiate cytokine receptor responses leading to a hyperexcitable state that disrupts neuronal networks and increases excitotoxic neuronal death. Innate immune gene activation in brain is persistent, consistent with the chronic relapsing disease that is alcoholism. Expression of HMGB1, TLRs, and other ISMs is increased several-fold in the human orbital frontal cortex, and expression of these molecules is highly correlated with each other as well as lifetime alcohol consumption and age of drinking onset.ConclusionsThe persistent and cumulative nature of alcohol on HMGB1 and TLR gene induction support their involvement in alcohol-induced long-term changes in brain function and neurodegeneration.

General Anesthesia

Appropriate balance between excitatory and inhibitory neural activity patterns is of utmost importance in the maintenance of neuronal homeostasis. General anesthetic-induced pharmacological interference with this equilibrium results not only in a temporary loss of consciousness but can also initiate long-term changes in brain function. Although these alterations were initially considered deleterious, recent observations suggest that at least under some specific conditions, they may eventually improve neural function. The goal of this review is to provide insights into the mechanisms underlying these dual effects. Basic science issues on the important role of critical periods during neural circuitry assembly will be discussed to better understand how even brief exposures to general anesthetics could initiate context-dependent lasting changes in neuronal structure and function. Recent series of observations suggesting a developmental stage-dependent impact of these drugs on synaptogenesis will then be summarized together with currently known molecular mechanisms underlying these effects. Particular emphasis will be placed on how anesthetic drugs modulate neural plasticity in the adult brain and how this may improve neural function under some pathological states. The ensemble of these new observations strongly suggests that general anesthetics should not merely be considered toxic drugs but rather acknowledged as robust, context-dependent modulators of neural plasticity.

Dexamethasone induces apoptosis in the developing rat amygdala in an age-, region-, and sex-specific manner

Exposure to glucocorticoids (GCs) in early development can lead to long-term changes in brain function and behavior, although little is known about the underlying neural mechanisms. Perinatal exposure to GCs alters adult anxiety and neuroendocrine responses to stress. Therefore, we investigated the effects of either late gestational or neonatal exposure to the GC receptor agonist dexamethasone (DEX), on apoptosis within the amygdala, a region critical for emotional regulation. DEX was administered to timed-pregnant rat dams from gestational day 18 until parturition, or postnatal day 4-6. Offspring were sacrificed the day following the last DEX treatment, and tissue was processed for immunohistochemical detection of cleaved caspase-3, a marker for apoptotic cells. Prenatal DEX treatment significantly increased the number of cleaved caspase-3-positive cells in the amygdala of both sexes, largely due to increases within the medial and basomedial subregions. Postnatal DEX treatment also increased cleaved caspase-3 immunoreactivity within the amygdala, although effects reached significance only in the central nucleus of females. Overall, DEX induction of cleaved caspase-3 in the amygdala was greater following prenatal compared with postnatal treatment, yet in both instances, elevations in cleaved caspase-3 correlated with an increase in pro-apoptotic Bax mRNA expression. Dual-label immunohistochemistry of cleaved caspase-3 and the neuronal marker NeuN confirmed that virtually all cleaved caspase-3-positive cells in the amygdala were neurons, and a subset of these cells (primarily following postnatal treatment) expressed a GABAergic calcium-binding protein phenotype (calbindin or calretinin). Together these results indicate that early developmental GC exposure induces neuronal apoptosis within the amygdala in an age-, sex-, and region-dependent manner.

β1‐Adrenergic receptors activate two distinct signaling pathways in striatal neurons

Monoamine action in the dorsal striatum and nucleus accumbens plays essential roles in striatal physiology. Although research often focuses on dopamine and its receptors, norepinephrine (NE) and adrenergic receptors are also crucial in regulating striatal function. While noradrenergic neurotransmission has been identified in the striatum, little is known regarding the signaling pathways activated by β-adrenergic receptors in this brain region. Using cultured striatal neurons, we characterized a novel signaling pathway by which activation of β1-adrenergic receptors leads to the rapid phosphorylation of cAMP response element binding protein (CREB), a transcription-factor implicated as a molecular switch underlying long-term changes in brain function. NE-mediated CREB phosphorylation requires β1-adrenergic receptor stimulation of a receptor tyrosine kinase, ultimately leading to the activation of a Ras/Raf/MEK/MAPK/MSK signaling pathway. Activation of β1-adrenergic receptors also induces CRE-dependent transcription and increased c-fos expression. In addition, stimulation of β1-adrenergic receptors produces cAMP production, but surprisingly, β1-adrenergic receptor activation of adenylyl cyclase was not functionally linked to rapid CREB phosphorylation. These findings demonstrate that activation of β1-adrenergic receptors on striatal neurons can stimulate two distinct signaling pathways. These adrenergic actions can produce long-term changes in gene expression, as well as rapidly modulate cellular physiology. By elucidating the mechanisms by which NE and β1-adrenergic receptor activation affects striatal physiology, we provide the means to more fully understand the role of monoamines in modulating striatal function, specifically how NE and β1-adrenergic receptors may affect striatal physiology.

Mapping Brain Function Using a 30-Day Interval between Baseline and Activation: A Novel Arterial Spin Labeling fMRI Approach

By comparing hemodynamic signals acquired immediately before and during activation, functional magnetic resonance imaging (fMRI) is well suited for mapping acute changes in brain function. However, it remains unclear whether fMRI can map functional changes over longer periods. Here, we address this issue by empirically testing the feasibility of arterial spin labeling (ASL) fMRI to detect changes in cerebral blood flow (CBF) with baseline and task separated by 1 month. To increase the sensitivity of the method, we applied an algorithm that yielded flow density (CBFd) images that were independent of tissue content. To increase the accuracy, we developed a technique that generated arterial transit time at each voxel, independently. Results showed that activation changes in CBFd during the same session were statistically the same as across 30 days. The activation CBFd on day-30 was 34% (motor) and 25% (visual) higher than the respective baselines of 83 and 107 mL/100 g/min obtained on day-1. Furthermore, the signal-to-noise ratio of the CBFd measurement was 2.1 and 2.9 times higher than that of the conventional CBF for within-subject and across-subjects comparisons, respectively (n=9 healthy young subjects). Taken together, these results indicate that CBFd measure could be better suited than net CBF to map long-term changes in brain function.

Postnatal handling reverses social anxiety in serotonin receptor 1A knockout mice

Mice lacking the serotonin receptor 1A (Htr1a knockout, Htr1a(KO)) show increased innate and conditioned anxiety. This phenotype depends on functional receptor activity during the third through fifth weeks of life and thus appears to be the result of long-term changes in brain function as a consequence of an early deficit in serotonin signaling. To evaluate whether this phenotype can be influenced by early environmental factors, we subjected Htr1a knockout mice to postnatal handling, a procedure known to reduce anxiety-like behavior and stress responses in adulthood. Offspring of heterozygous Htr1a knockout mice were separated from their mother and exposed 15 min each day from postnatal day 1 (PD1) to PD14 to clean bedding. Control animals were left undisturbed. Maternal behavior was observed during the first 13 days of life. Adult male offspring were tested in the open field, social approach and resident-intruder tests and assessed for corticosterone response to restraint stress. Knockout mice showed increased anxiety in the open field and in the social approach test as well as an enhanced corticosterone response to stress. However, while no effect of postnatal handling was seen in wild-type mice, handling reduced anxiety-like behavior in the social interaction test and the corticosterone response to stress in knockout mice. These findings extend the anxiety phenotype of Htr1a(KO) mice to include social anxiety and demonstrate that this phenotype can be moderated by early environmental factors.

Transcriptional correlates of human substance use.

Drugs of abuse produce both acute and chronic changes in brain function, each of which is reflected in altered gene expression patterns. A number of large-scale gene expression studies have employed microarray analysis of human postmortem brain to identify transcriptional correlates of antemortem substance use. These studies have identified changes in transcripts encoding proteins functionally involved in neuronal function and synaptic plasticity, oligodendrocyte function and myelination, lipid and energy metabolism, mitochondrial function, oxidative phosphorylation, and cytoskeleton-related signal transduction. Overall, different types of substance use appear to share some of these effects, but there are more differences than similarities in gene expression for different types of substance use. Moreover, data suggest that transcriptional subtypes within a diagnostic classification of substance use may occur. These transcriptional subtypes, or "endophenotypes," may reflect complex patterns of substance use and co-morbid neuropsychiatric disorders or other diseases, which may interact with substance use to differentially affect gene expression. A broader understanding of the manner in which substance abuse causes long-term changes in brain function may be obtained from studies replicating and expanding the present gene expression data. In particular, cross-referencing comprehensive transcriptional data on regional and/or substance use-specific changes with genetic and proteomic data may further aid in identifying candidate biomarkers of altered brain function in substance-use disorders.

Pharmacotherapy targets for regulating cocaine-induced plasticity

Several decades of drug addiction research have failed to yield an effective pharmacotherapy for the treatment of cocaine addiction. However, significant progress has been made in elucidating cocaineinduced long-term changes in brain function that may underlie the vulnerability to relapse. The present review discusses potential neural targets and associated pharmacotherapies for the reversal of cocaine-induced neuroadaptations. While alterations in many neurotransmitter systems are associated with cocaine addiction, the current manuscript focuses on changes in the glutamatergic and GABAergic systems, while also discussing the neurotrophic factors BDNF and GDNF. A variety of pharmaceuticals have been identified which effectively decrease drug-seeking behavior in both animal models of addiction and human clinical trials. However, the effects seen in clinical trials are modest and we propose that focus should be placed on the development of drugs which affect more than one addiction-associated neurotransmitter system.

Repeated neonatal handling with maternal separation permanently alters hippocampal GABAA receptors and behavioral stress responses.

Increasing evidence suggests that postnatal events, such as handling or maternal separation, can produce long-term changes in brain function. These are often expressed as changes in the profile of endocrine or behavioral responses to stress. Changes in gamma-aminobutyric acid type A receptors (GABARs), which mediate the majority of fast synaptic inhibition in adult brain, have been proposed as one potential mediator of these behavioral effects. In the current article, we use a combination of single-cell electrophysiology and antisense mRNA amplification to demonstrate permanent molecular and functional differences in GABARs within hippocampal dentate granule neurons after as few as two episodes of neonatal handling with brief maternal separation. Adult animals that as pups experienced handling with maternal separation maintained a more immature GABAR phenotype and exhibited increased activity in response to swim stress. These findings demonstrate the exquisite sensitivity of the developing GABAergic system to even subtle environmental manipulations and provide an unique molecular mechanism by which postnatal handling with maternal separation may alter stress-related behavior.

Suppression and control of epileptiform activity by electrical stimulation: a review

Epilepsy is a devastating disease affecting /spl sim/1% of the world's population. Although drug therapy is effective in many patients, 25% are not responsive to anticonvulsants. In addition, up to 50% of those receiving regular mediation suffer major side effects. Surgical resection is another treatment also associated with serious complications. An alternative method to control seizure activity is electrical stimulation. Several electrical stimulation protocols have been developed in animal models of epilepsy that can reduce or completely suppress seizures. Moreover, in over 5000 patients worldwide, electrical stimulation has been used to control seizures. The mechanisms underlying some of the techniques of seizure control are not understood. Some stimulation protocols, such as DC stimulation, rely on the effects of fields and currents on the membrane polarization. Other methods using single pulses, such as phase-resetting, desynchronization, and chaos control rely on the modulation of the dynamic properties of the neuronal networks. Both low- and high-frequency periodic stimulation can suppress seizures not only during stimulation, but also by inducing long-term changes in brain function. The purpose of this review is to present these approaches and to discuss their underlying mechanisms and potential for clinical implementation.

Side effects of repetitive transcranial magnetic stimulation.

The side effects of repetitive transcranial magnetic stimulation are largely unexplored and the limits of safe exposure have not been determined except as regards the acute production of seizures. Although tissue damage is unlikely, however, cognitive and other adverse effects have been observed and the possibility of unintended long-term changes in brain function are theoretically possible.