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[WEB SITE] Largest-ever study to examine anatomical alterations in the brains of epilepsy patients

Largest-ever study to examine anatomical alterations in the brains of epilepsy patients 

An international research consortium used neuroimaging techniques to analyze the brains of more than 3,800 volunteers in different countries. The largest study of its kind ever conducted set out to investigate anatomical similarities and differences in the brains of individuals with different types of epilepsy and to seek markers that could help with prognosis and treatment.

Epilepsy’s seizure frequency and severity, as well as the patient’s response to drug therapy, vary with the part of the brain affected and other poorly understood factors. Data from the scientific literature suggests that roughly one-third of patients do not respond well to anti-epileptic drugs. Research has shown that these individuals are more likely to develop cognitive and behavioral impairments over the years.

The new study was conducted by a specific working group within an international consortium called ENIGMA, short for Enhancing NeuroImaging Genetics through Meta-Analysis, established to investigate several neurological and psychiatric diseases. Twenty-four cross-sectional samples from 14 countries were included in the epilepsy study.

Altogether, the study included data for 2,149 people with epilepsy and 1,727 healthy control subjects (with no neurological or psychiatric disorders). The Brazilian Research Institute for Neuroscience and Neurotechnology (BRAINN), which participated in the multicenter study, was the center with the largest sample, comprising 291 patients and 398 controls. Hosted in Brazil, at the State University of Campinas (UNICAMP), BRAINN is a Research, Innovation and Dissemination Center (RIDC http://cepid.fapesp.br/en/home/) supported by the Sao Paulo Research Foundation – FAPESP.

“Each center was responsible for collecting and analyzing data on its own patients. All the material was then sent to the University of Southern California’s Imaging Genetics Center in the US, which consolidated the results and performed a meta-analysis,” said Fernando Cendes, a professor at UNICAMP and coordinator of BRAINN.

A differential study

All volunteers were subjected to MRI scans. According to Cendes, a specific protocol was used to acquire three-dimensional images. “This permitted image post-processing with the aid of computer software, which segmented the images into thousands of anatomical points for individual assessment and comparison,” he said.

According to the researcher, advances in neuroimaging techniques have enabled the detection of structural alterations in the brains of people with epilepsy that hadn’t been noticed previously.

Cendes also highlighted that this is the first epilepsy study built on a really large number of patients, which allowed researchers to obtain more robust data. “There were many discrepancies in earlier studies, which comprised a few dozen or hundred volunteers.”

The patients included in the study were divided into four subgroups: mesial temporal lobe epilepsy (MTLE) with left hippocampal sclerosis, MTLE with right hippocampal sclerosis, idiopathic (genetic) generalized epilepsy, and a fourth group comprising various less common subtypes of the disease.

The analysis covered both patients who had had epilepsy for years and patients who had been diagnosed recently. According to Cendes, the analysis – whose results were published in the international journal Brain – aimed at the identification of atrophied brain regions in which the cortical thickness was smaller than in the control group.

First analysis

The researchers first analyzed data from the four patient subgroups as a whole and compared them with the controls to determine whether there were anatomical alterations common to all forms of epilepsy. “We found that all four subgroups displayed atrophy in areas of the sensitive-motor cortex and also in some parts of the frontal lobe,” Cendes said.

“Ordinary MRI scans don’t show anatomical alterations in cases of genetic generalized epilepsy,” Cendes said. “One of the goals of this study was to confirm whether areas of atrophy also occur in these patients. We found that they do.”

This finding, he added, shows that in the case of MTLE, there are alterations in regions other than those in which seizures are produced (the hippocampus, parahippocampus, and amygdala). Brain impairment is, therefore, more extensive than previously thought.

Cendes also noted that a larger proportion of the brain was compromised in patients who had had the disease for longer. “This reinforces the hypothesis that more brain regions atrophy and more cognitive impairment occurs as the disease progresses.”

The next step was a separate analysis of each patient subgroup in search of alterations that characterize each form of the disease. The findings confirmed, for example, that MTLE with left hippocampal sclerosis is associated with alterations in different neuronal circuits from those associated with MTLE with right hippocampal sclerosis.

“Temporal lobe epilepsy occurs in a specific brain region and is therefore termed a focal form of the disease. It’s also the most common treatment-refractory subtype of epilepsy in adults,” Cendes said. “We know it has different and more severe effects when it involves the left hemisphere than the right. They’re different diseases.”

“These two forms of the disease are not mere mirror-images of each other,” he said. “When the left hemisphere is involved, the seizures are more intense and diffuse. It used to be thought that this happened because the left hemisphere is dominant for language, but this doesn’t appear to be the only reason. Somehow, it’s more vulnerable than the right hemisphere.”

In the GGE group, the researchers observed atrophy in the thalamus, a central deep-lying brain region above the hypothalamus, and in the motor cortex. “These are subtle alterations but were observed in patients with epilepsy and not in the controls,” Cendes said.

Genetic generalized epilepsies (GGEs) may involve all brain regions but can usually be controlled by drugs and are less damaging to patients.

Future developments

From the vantage point of the coordinator for the FAPESP-funded center, the findings published in the article will benefit research in the area and will also have future implications for the diagnosis of the disease. In parallel with their anatomical analysis, the group is also evaluating genetic alterations that may explain certain hereditary patterns in brain atrophy. The results of this genetic analysis will be published soon.

“If we know there are more or less specific signatures of the different epileptic subtypes, instead of looking for alterations everywhere in the brain, we can focus on suspect regions, reducing cost, saving time and bolstering the statistical power of the analysis. Next, we’ll be able to correlate these alterations with cognitive and behavioral dysfunction,” Cendes said.

 

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[WEB SITE] Catamenial Epilepsy

Catamenial epilepsy is a form of seizure disorder that occurs in women with the frequency of the seizures related to the time of the menstrual cycle. Its name comes from the Greek word “katomenios”, meaning “monthly”. It seems to be caused by fluctuations in the level of estrogen and progesterone. It makes up about 10% to 70% of epileptic disorders in women of reproductive age.

Progesterone is an endogenous steroid and progestogen sex hormone Credit: Igor Petrushenko/ Shutterstock.com

Pathophysiology

Catamenial epilepsy is thought to be a result of the actions of the female steroid hormones on the central nervous system. These hormones are primarily estrogen and progesterone, produced by the ovaries in women of reproductive age, or their derivatives, and their levels fluctuate in a more or less constant pattern throughout the various phases of the cycle.

Three types of catamenial seizure have been distinguished by Herzog based on whether the highest seizure frequency is during the perimenstrual, periovulatory and inadequate luteal phases of the cycle.  The hormone levels depend upon the occurrence of ovulation during the cycle.

Both estrogen and progesterone affect neuronal development as well as learning by modifying neurotransmitter synthesis and release, while estrogen has been shown to produce seizures subject to a number of variables including age, gender, receptor distribution and type of estrogen used as the stimulus.

On the other hand, a rapid decrease in progesterone levels such as that which occurs during the perimenstrual period is also known to increase seizure frequency. However, experimental evidence that progesterone decreases neuronal excitability and inhibits seizures is still lacking.

Other metabolites of these steroids such as allopregnanolone and pregnanolone are more associated with neuronal activity and are called neurosteroids. They act on GABA receptors and may thus reduce the seizure threshold.

Time of increased seizure frequency

In ovulatory cycles, the estrogen levels are high just before ovulation, while the ratio of estrogen to progesterone goes up during the premenstrual period. These events are linked to a higher seizure frequency at these times. In contrast, the middle of the luteal phase is associated with the lowest seizure frequency probably because the estrogen: progesterone ratio is lowest at this time.


On the other hand, during anovulatory cycles, the luteal phase is characterized by an inadequate rise in progesterone levels leading to a very high estrogen: progesterone ratio during the premenstrual phase, associated with a rise in seizures at this time.

The increased length of anovulatory cycles may lead to non-recognition of this form as catamenial in nature, especially as normal healthy women experience anovulation for about 10% of the time in an irregular fashion.

It is significant that in women with temporal lobe epilepsy, especially of the left brain, this percentage is increased to about 35% or over a third of the time. Thus, the timing of the greatest percentage of seizures does not always correlate with expected hormone levels due to the unpredictable occurrence of anovulation in healthy women.

Seizures in catamenial epilepsy are also increased during the perimenopausal period but typically reduce after menopause, again justifying the association with high estrogen levels. However, one study showed that over 40% of catamenial epileptics had aggravated or new-onset seizures after menopause, contrary to other research findings.

Diagnosis and management

Keeping a seizure and menstrual diary can help in making the diagnosis especially by helping to see the relation between different cycles of varying length and the timing of the seizure. Anovulation is more likely to be a trigger in catamenial epilepsy and thus both types of cycles must be observed, if present in the same woman, to distinguish the correlation.

The treatment of catamenial epilepsy is unspecified as of now. Both hormonal and nonhormonal therapy has been used. Most conventional drugs fail to control the seizures or mitigate their frequency in these women, leading to its being termed pharmacoresistant.

Hormonal therapy including progesterone or its metabolites, or estrogen antagonists, are mostly used in combination with conventional anti-seizure drugs. These are associated with a significant decrease in seizure frequency by up to 72%.

Gonadotropin-releasing hormone analogs are used in perimenstrual catamenial epilepsy which does not respond to other treatments, to reduce estrogen production via lowering of luteinizing hormone levels.

Antiepileptic drugs have been used, but consideration should be given to the effects of these drugs on bone density in postmenopausal women. This is because many of them (valproate, phenytoin, carbamazepine) are cytochrome P450 inducers, which may lead to faster metabolism of vitamin D and bone loss in these women.

Nonhormonal drugs including acetazolamide are also prescribed in intermittent fashion at the time of greatest seizure risk. Cyclical benzodiazepine therapy has been tried on an intermittent dosage basis for long-term control.

Clomiphene and ganaxolone are among other therapies that are sometimes attempted in these cases. More research is needed to identify the most effective protocol for management of catamenial epilepsy.

Reviewed by Afsaneh Khetrapal Bsc (Hons)

Further Reading

 

Last Updated: Feb 23, 2018

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[WEB SITE] UC study explores how low risk stress reduction treatments may benefit epilepsy patients

Patients with epilepsy face many challenges, but perhaps the most difficult of all is the unpredictability of seizure occurrence. One of the most commonly reported triggers for seizures is stress.

A recent review article in the European journal Seizure, by researchers at University of Cincinnati Epilepsy Center at the UC Gardner Neuroscience Institute, looks at the stress-seizure relationship and how adopting stress reduction techniques may provide benefit as a low risk form of treatment.

The relationship between stress and seizures has been well documented over the last 50 years. It has been noted that stress can not only increase seizure susceptibility and in rare cases a form of reflex epilepsy, but also increase the risk of the development of epilepsy, especially when stressors are severe, prolonged, or experienced early in life.

“Studies to date have looked at the relationship from many angles,” says Michael Privitera, MD, director of the UC Epilepsy Center and professor in the Department of Neurology and Rehabilitation Medicine at the UC College of Medicine. “The earliest studies from the 1980s were primarily diaries of patients who described experiencing more seizures on ‘high-stress days’ than on ‘low-stress days.'”

Privitera and Heather McKee, MD, an assistant professor in the Department of Neurology and Rehabilitation Medicine, looked at 21 studies from the 1980s to present–from patients who kept diaries of stress levels and correlation of seizure frequency, to tracking seizures after major life events, to fMRI studies that looked at responses to stressful verbal/auditory stimuli.

“Most all [of these studies] show increases in seizure frequency after high-stress events. Studies have also followed populations who have collectively experienced stressful events, such as the effects of war, trauma or natural disaster, or the death of a loved one,” says Privitera. All of which found increased seizure risk during such a time of stress.

For example, a 2002 study evaluated the occurrence of epileptic seizures during the war in Croatia in the early 1990s. Children from war-affected areas had epileptic seizures more often than children not affected by the war. Additionally, the 10-year follow up showed that patients who had their first epileptic seizure during a time of stress were more likely to have controlled epilepsy or even be off medication years later.

“Stress is a subjective and highly individualized state of mental or emotional strain. Although it’s quite clear that stress is an important and common seizure precipitant, it remains difficult to obtain objective conclusions about a direct causal factor for individual epilepsy patients,” says McKee.

Another aspect of the stress-seizure relationship is the finding by UC researchers that there were higher anxiety levels in patients with epilepsy who report stress as a seizure precipitant. The researchers suggest patients who believe stress is a seizure trigger may want to talk with their health care provider about screening for anxiety.

“Any patient reporting stress as a seizure trigger should be screened for a treatable mood disorder, especially considering that mood disorders are so common within this population,” adds McKee.

The researchers report that while some small prospective trials using general stress reduction methods have shown promise in improving outcomes in people with epilepsy, large-scale, randomized, controlled trials are needed to convince both patients and providers that stress reduction methods should be standard adjunctive treatments for people with epilepsy.

“What I think some of these studies point to is that efforts toward stress reduction techniques, though somewhat inconsistent, have shown promise in reducing seizure frequency. We need future research to establish evidence-based treatments and clarify biological mechanisms of the stress-seizure relationship,” says Privitera.

Overall, he says, recommending stress reduction methods to patients with epilepsy “could improve overall quality of life and reduce seizure frequency at little to no risk.”

Some low risk stress reduction techniques may include controlled deep breathing, relaxation or mindfulness therapy, as well as exercise, or establishing routines.

Source: UC study explores how low risk stress reduction treatments may benefit epilepsy patients

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[WEB SITE] Study investigates plasticity of motor representations in patients with brain tumors

Winner of the Brainlab Community Neurosurgery Award, Sandro Krieg, MD, presented his research, Plasticity of Motor Representations in Patients with Brain Lesions: a Navigated TMS Study, during the 2017 American Association of Neurological Surgeons (AANS) Annual Scientific Meeting.

This study investigated the spatial distributions of motor representations in terms of tumor-induced brain plasticity by analyzing navigated transcranial magnetic stimulation (nTMS) motor maps derived from 100 patients with motor eloquently located brain tumors in or adjacent to the precentral gyrus (PrG).

The research evoked 8,774 motor potentials (MEPs) that were elicited in six muscles of the upper and lower extremity by stimulating four gyri in patients with five possible tumor locations. Regarding the MEP frequency of each muscle-gyrus subdivision per patient, the expected frequency was 3.53 (8,774 divided by 100 patients, further divided by six muscles and four gyri). Accordingly, the patient ratio for each subdivision was calculated by defining the per-patient minimum data points as three.

The tumor-location specific patient ratios were higher for frontal tumors in both gyri than for other tumor locations. This suggests that the finger representation reorganization in these frontal gyri, which corresponds to location of dorsal premotor areas, might be due to within-premotor reorganization rather than relocation of motor function from PrG into premotor areas one might expect from the Rolandic tumors. The research indicates that reorganization of the finger motor representations might be limited along the middle-to-dorsal dimension of the dorsal premotor areas (posterior MFG and SFG) and might not cross rostrally from the primary motor cortex (PrG) to the dorsal premotor cortex.

Source: Study investigates plasticity of motor representations in patients with brain tumors

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[ARTICLE] Force control in chronic stroke

Highlights

  • Post stroke motor impairments involving force control capabilities are devastating.
  • Bimanual motor synergies provide robust data on coordinating forces between hands.
  • Low-force frequency patterns reveal fine motor control strategies in paretic hands.
  • Analyzing both novel approaches advance understanding of post stroke force control.

Abstract

Force control deficits are common dysfunctions after a stroke. This review concentrates on various force control variables associated with motor impairments and suggests new approaches to quantifying force control production and modulation. Moreover, related neurophysiological mechanisms were addressed to determine variables that affect force control capabilities. Typically, post stroke force control impairments include:

(a) decreased force magnitude and asymmetrical forces between hands,

(b) higher task error,

(c) greater force variability,

(d) increased force regularity, and

(e) greater time-lag between muscular forces.

Recent advances in force control analyses post stroke indicated less bimanual motor synergies and impaired low-force frequency structure.Brain imaging studies demonstrate possible neurophysiological mechanisms underlying force control impairments:

(a) decreased activation in motor areas of the ipsilesional hemisphere,

(b) increased activation in secondary motor areas between hemispheres,

(c) cerebellum involvement absence, and

(d) relatively greater interhemispheric inhibition from the contralesional hemisphere.

Consistent with identifying neurophysiological mechanisms, analyzing bimanual motor synergies as well as low-force frequency structure will advance our understanding of post stroke force control.

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[WEB SITE] Brain stimulation offers hope for depression, but don’t try it at home.

OPINION: Around 350 million people worldwide have depression. Antidepressant medications are often prescribed to treat the condition, alongside talking therapies and lifestyle changes such as regular exercise.

But a substantial proportion of people either don’t respond to antidepressants, or experience such significant side effects that they’d prefer not to take them.

In search of alternative solutions, researchers around the world, including our team, are investigating transcranial direct current stimulation (TDCS) as an alternative treatment for depression. But this isn’t something you can safely try at home.

Unlike electroconvulsive therapy, TDCS uses very mild electric current to stimulate the brain and has few side effects. The mechanics of TDCS are quite simple, involving a battery, two leads and the electrodes through which the current is passed.

The stimulation works by changing the activity of nerve cells in the brain. In depression, the left frontal areas of the brain are often less active than usual. TDCS stimulates this area to restore brain activity.

We’re still evaluating the effectiveness of TDCS, but so far studies have found that TDCS works better than a placebo (or simulated treatment) at reducing symptoms of depression.

When combined with the antidepressant medication sertraline (marketed as Zoloft in Australia), the combination TDCS-drug therapy works better than medication or TDCS alone.

Research has found that among people with depression, a course of TDCS can improve the brain’s “neuroplasticity”, which is the brain’s ability to learn and adapt to changes in the environment.

The therapy has a good safety profile – if administered by clinicians and researchers trained in stimulation technique and safety. Our research team has administered thousands of TDCS sessions without incident.

But this is not the case when TDCS is used in the “DIY” context, with DIY users trying to stimulate their own brains.

This phenomenon is often guided by online forums and websites dedicated to DIY TDCS. Users comment on their own experience and share tips on how TDCS can be used to treat their own depression. People with no medical training and limited understanding of TDCS self-treat their depression and advise others on treatment.

So, what can go wrong?

The most obvious concern is that poor technique and improper electrode placement could cause skin burns.

What’s more concerning is the ability for TDCS to produce lasting changes in brain functioning. Depending on how TDCS is given, these changes could be good or bad.

A DIY user could, for example, cause lasting impairment to their thinking and memory. For people with severe depression, incorrect application could worsen their condition or induce a hypomanic (manic) episode.

When it comes to medications, it’s important to get the right dose and dosing schedule. That’s why this role falls to qualified clinicians and researchers. The same goes for TDCS: current intensity, electrode size and position, and the duration and frequency of the stimulation determine the effects in the brain.

The relationship between dosing, intensity and position is highly complex. This isn’t a simple case of “the stronger the better”. Even researchers are yet to fully understand the effects of varying stimulation approaches and much more research is needed.

As with other forms of treatment, TDCS is not suitable for everyone. In clinical research trials, participants are screened for suitability to receive stimulation and their likelihood of responding to treatment. The stimulation is carefully controlled and the participants’ mood is carefully monitored during and after the course of treatment.

TDCS represents a promising future, where simple and cost-effective treatment for depression is possible, without drugs. Researchers worldwide are continuing to study this experimental treatment, which may one day become a conventional treatment for depression.

The acceptance and popularity of TDCS among the general community is encouraging. But TDCS is still experimental and isn’t safe to administer at home. DIY users are not trained in proper technique nor are they trained to identify, prevent or deal with unexpected outcomes.

If you’re interested in participating in our TDCS trials for depression, contact the research team at the Black Dog Institute for more information.

Kerrie-Anne Ho is a PhD candidate in non-invasive brain stimulation at UNSW.

Colleen Loo is a Professor of Psychiatry at UNSW.

This opinion piece was first published in The Conversation.

via Health News – Brain stimulation offers hope for depression, but don’t try it at home.

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