Posts Tagged Depression

[ARTICLE] Adaptive conjunctive cognitive training (ACCT) in virtual reality for chronic stroke patients: a randomized controlled pilot trial – Full Text

Abstract

Background

Current evidence for the effectiveness of post-stroke cognitive rehabilitation is weak, possibly due to two reasons. First, patients typically express cognitive deficits in several domains. Therapies focusing on specific cognitive deficits might not address their interrelated neurological nature. Second, co-occurring psychological problems are often neglected or not diagnosed, although post-stroke depression is common and related to cognitive deficits. This pilot trial aims to test a rehabilitation program in virtual reality that trains various cognitive domains in conjunction, by adapting to the patient’s disability and while investigating the influence of comorbidities.

Methods

Thirty community-dwelling stroke patients at the chronic stage and suffering from cognitive impairment performed 30 min of daily training for 6 weeks. The experimental group followed, so called, adaptive conjunctive cognitive training (ACCT) using RGS, whereas the control group solved standard cognitive tasks at home for an equivalent amount of time. A comprehensive test battery covering executive function, spatial awareness, attention, and memory as well as independence, depression, and motor impairment was applied at baseline, at 6 weeks and 18-weeks follow-up.

Results

At baseline, 75% of our sample had an impairment in more than one cognitive domain. The experimental group showed improvements in attention (χ2FχF2 (2) = 9.57, p < .01), spatial awareness (χ2FχF2 (2) = 11.23, p < .01) and generalized cognitive functioning (χ2FχF2 (2) = 15.5, p < .001). No significant change was seen in the executive function and memory domain. For the control group, no significant change over time was found. Further, they worsened in their depression level after treatment (T = 45, r = .72, p < .01) but returned to baseline at follow-up. The experimental group displayed a lower level of depression than the control group after treatment (Ws = 81.5, z = − 2.76, r = − .60, p < .01) and (Ws = 92, z = − 2.03, r = − .44, p < .05).

Conclusions

ACCT positively influences attention and spatial awareness, as well as depressive mood in chronic stroke patients.

Trial registration

The trial was registered prospectively at ClinicalTrials.gov (NCT02816008) on June 21, 2016.

Background

Cognitive impairments are common after stroke, with incident rates up to 78% [1]. Patients with mild cognitive impairment are at risk for developing dementia [2]. Cognitive deficits correlate with poor functional outcomes and increased risk of dependence [3], have negative effects on the patient’s quality of life [4], and alter the patient’s ability to socialize [5]. However, the current clinical practice seems to lack methods that specifically address cognitive sequelae. According to a meta-analysis that aimed at proposing recommendations for new clinical standards, currently available treatments that are used as control conditions are conventional therapies like physical therapy or occupational therapy, pseudo treatments like mental or social stimulation without therapeutic intent, as well as psychosocial interventions like psychotherapy or emotional support for individuals or groups [6]. Besides, it has been shown that cognitively impaired patients participate less in rehabilitation activities, which potentially contributes to the poorer functional outcome they display [7]. Finding effective cognitive rehabilitation methods that can be incorporated in clinical practice is therefore crucial. Numerous methods to improve cognitive deficits, for instance, specifically attention [8], memory [9], executive function [10], or spatial abilities [11], have been proposed. However, the results show mixed efficacies. A meta-analysis on the impact of attentional treatments showed an effect on divided attention in the short-term, but found no evidence for persisting effects on other attentional domains, global attention, or functional outcomes [12]. Similarly, a meta-review that investigated the effect of memory rehabilitation found that training might benefit subjective reports of memory in the short term, but shows no effect in the long term, on objective memory measures, mood, functional abilities or quality of life [13]. Ultimately, a meta-analysis over 6 Cochrane reviews shows insufficient research evidence or evidence of insufficient quality to support any recommendation for cognitive stroke rehabilitation [14]. Besides methodological issues, one limitation of existing methods could be that they focus on one deficit only, ignoring that patients typically express deficits in multiple cognitive domains [12]. A study on a large sample of heterogeneous stroke patients which aimed at linking lesions to cognitive deficits found that a given lesion location leads to cognitive impairments in several domains [15]. This emphasizes that cognitive functions rely on a network of brain regions. A lesion in one of those regions might cause a disturbance to the network, which leads to a multitude of symptoms. This is further supported by studies that revealed that pathological changes in brain structures are related to the occurrence of various cognitive deficits and symptoms for instance, in Alzheimer’s disease [16] or spatial neglect [17]. Moreover, the presence of multiple cognitive deficits seems to be a marker in patients that are at risk of developing Alzheimer’s disease later in life [18]. To what extent rehabilitation could potentially drive structural or functional changes to alleviate the symptoms of stroke is still under debate [1920]. Nevertheless, rehabilitation methods have to aid the patient in obtaining enough functionality to independently perform instrumental activities of daily living, be it through restoration of function or compensation. With this in mind, focusing on training a single cognitive skill might not be efficient because many daily tasks or jobs require several cognitive abilities for their execution [21]. For instance, most patients would like to be mobile and drive a car again after their stroke. Driving requires the individual to use selective attention to deal with the traffic, traffic signs and distractions, to be cognitively flexible to react to changing situations on the road, to visually scan the mirrors at the front, at the side, and in the back, to have a visual field that includes the sidewalks and to perform all of this while steering the car effectively in real-time [22]. Consequently, rehabilitation methods that address one specific cognitive ability only do not address the requirements of performing the activities of daily living and might not stimulate and train the underlying brain processes adequately. If a stroke leads to impairments in various cognitive domains, then these domains should be treated together to benefit a patient’s performance in everyday life.[…]

 

Continue —-> Adaptive conjunctive cognitive training (ACCT) in virtual reality for chronic stroke patients: a randomized controlled pilot trial | SpringerLink

 

Fig. 1

Fig. 1 Experimental protocol and set-up. a The protocol lasted 18 weeks in total, 6 weeks of training, and 3-months follow-up period. b The set-up of the EG in the hospital consisted of a desktop computer, a Microsoft Kinect and two wristbands with reflective markers that are worn by the patient. A Tobii EyeTracker T120 tracked the eye movement of the patient during the training. The Kinect detects the reflective markers and transposes the movement of the patient’s real arms onto the virtual arms of the avatar in the training scenarios. The patients are seated at a table, and the three training scenarios (c Complex Spheroids, d Star Constellations, and e Quality Controller) are shown on the screen always in the same order. Besides the automated adaptive difficulty mechanism and the embodied training, the system incorporates further principles of neurorehabilitation including the provision of multisensory feedback, feedback of results, variable and structured practice as well as promoting the use of the paretic limb. C Star Constellations, CG control group, D day, EG experimental group, Eval VR evaluation, Q Quality Controller, RGS Rehabilitation Gaming System, S Complex Spheroids

 

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[Infographic] Depression Isn’t Always Suicide Notes And Pill Bottles. It’s Also…

Η εικόνα ίσως περιέχει: ένα ή περισσότερα άτομα, πιθανό κείμενο που λέει "Depression Isn't Always Suicide Notes And Pill Bottles. It's Also... Spending all Faking a smile day in bed Overeating or not eating at all Cracking jokes or being the 00000000 Skipping work "class clown" 1000 to sleep 00000 Being 0000 Not showering emotionally for days at a time distant Social isolation Please check in on your friends, even the goofy ones they can hide it the best @RealDepressionProject"

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[WEB PAGE] AI could play ‘critical’ role in identifying appropriate treatment for depression

Male doctor discussing reports with patient at desk in medical office

Image credits: Wavebreak Media Ltd – Dreamstime

Published Tuesday, February 11, 2020

A large-scale trial led by scientists at the University of Texas Southwestern (UT Southwestern) has produced a machine learning algorithm which accurately predicts the efficacy of an antidepressant, based on a patient’s neural activity.

The UT Southwestern researchers hope that this tool could eventually play a critical role in deciding which course of treatment would be best for patients with depression, as well as being part of a new generation of “biology-based, objective strategies” which make use of technologies such as AI to treat psychiatric disorders.

The US-wide trial was initiated in 2011 with the intention of better understanding mood disorders such as major depression and seasonal affective disorder (Sad). The trial has reaped many studies, the latest of which demonstrates that doctors could use computational tools to guide treatment choices for depression. The study was published in Nature Biotechnology.

“These studies have been a bigger success than anyone on our team could have imagined,” said Dr. Madhukar Trivedi, the UT Southwestern psychiatrist who oversaw the trial. “We provided abundant data to show we can move past the guessing game of choosing depression treatments and alter the mindset of how the disease should be diagnosed and treated.”

This 16-week trial involved more than 300 participants with depression, who either received a placebo or SSRI (selective serotonin reuptake inhibitor), the most common type of antidepressant. Despite the widespread prescription of SSRIs, they have been criticised for their side effects and for inefficacy in many patients.

Trivedi had previously established in another study that up to two-thirds of patients do not adequately respond to their first antidepressant, motivating him to find a way of identifying much earlier which treatment path is most likely to help the patient before they begin and potentially suffer further through ineffectual treatment.

Trivedi and his collaborators used an electroencephalogram (EEG) to measure electrical activity in the participants’ cortex before they began the treatment. This data was used to develop a machine learning algorithm to predict which patients would benefit from the medication within two months.

The researchers found that the AI accurately predicted outcomes, with patients less certain to respond to an antidepressant more likely to improve with other interventions, such as brain stimulation or therapeutic approaches. Their findings were replicated across three additional patient groups.

“It can be devastating for a patient when an antidepressant doesn’t work,” Trivedi said. “Our research is showing that they no longer have to endure the painful process of trial and error.”

Dr Amit Etkin, a Stanford University professor of psychiatry who also worked on the algorithm, added: “This study takes previous research, showing that we can predict who benefits from an antidepressant, and actually brings it to the point of practical utility.”

Next, they hope to develop an interface for the algorithm to be used alongside EEGs – and perhaps also with other means of measuring brain activity like functional magnetic resonance imaging (functional MRI, aka fMRI) or MEG – and have the system approved by the US Food and Drug Administration.

 

via AI could play ‘critical’ role in identifying appropriate treatment for depression | E&T Magazine

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[Slideshow] Myths and Facts About Depression

via Depression Myths: Overwork, Recklessness and More

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[WEB SITE] Coping with Post-TBI Anxiety & Stress – BrainLine

Brain Injury Anxiety and Stress“Social engagements became opportunities for embarrassment and ridicule, causing Melissa terrible personal conflicts. She wanted to be out among the crowds, but simultaneously felt vulnerable and frightened by them. Melissa sank into long sulks and quiet withdrawals. The invitations stopped coming and the phone rarely rang,” writes author and TBI case manager Michael Paul Mason about Melissa Felteau who sustained a brain injury in a car crash.

Anxiety can come in many colors and textures following a brain injury. It can bubble up in crowded, noisy places. It can surface when there is too much quiet — when worries seem to snowball and there is no place to hide.

What exactly are anxiety and stress?

Following a life-changing event like a brain injury, it’s normal to feel intense stress. But sometimes stress can build up and lead to anxiety. The main symptoms of anxiety are fear and worry. In turn, anxiety can cause or go hand-in-hand with other problems including:

People can express anxiety in both emotional and physical ways — from being inordinately irritable to experiencing shortness of breath or feelings of panic. Anxiety becomes a significant concern when these feelings intensify to a point where they interfere with the tasks of life. Anxiety can also be a symptom or effect of post-traumatic stress disorder.

Treatment

Like depression, chronic anxiety can cause low self-esteem and poor quality of life, and without treatment, symptoms can last longer or return. Anxiety is usually treated with medication and/or psychotherapy (counseling) by a trained professional. Treatment is usually quite successful, so there is little reason to delay seeking help. Here are a few strategies that people with anxiety after TBI have suggested:

  • Share things that worry you with others.
  • Set up a routine for your day and try to stick with it.
  • Stay involved in life. Find activities that give you pleasure — ones you used to enjoy, or new ones.
  • Be open to the support of others. Healthy relationships with family and friends are healing.
  • Acknowledge your feelings, and then find ways to accept them. There is no shame in feeling anxious or depressed after a life-changing event like brain injury.

Learning from anxiety

Sometimes facing your darkest emotions, like anxiety and depression, can help you better understand yourself. Melissa Felteau started meditating to help combat her own anxiety and depression; she found a new clarity. “That was my biggest problem,” she says. “I realized that I was always comparing myself to my pre-injury self. I was trapped in a vicious cycle of rumination and depression.”

Six years after her injury, through meditation and mindfulness, Melissa was able to shed her anxiety and use what she had learned to help herself — and others.

via Coping with Post-TBI Anxiety & Stress | BrainLine

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[WEB SITE] How Music Helps Your Mental Health

How Music Helps Your Mental Health

Music is medicine for your mind.

There are very few things that stimulate the brain in the way it does. It’s one of the most demanding cognitive and neural challenging activities. Music requires complex and accurate timing of multiple actions in your brain because of the structural, mathematical, and architectural relationships between the notes. Although it may not feel like it, your brain is doing a lot of computing to make sense of all the incoming stimuli. It’s one of the few activities that activate almost every part of your brain.

The effects of music are cognitive, psychological, social, behavioral, and emotional. Research has shown that listening to musical pieces can reduce anxiety, blood pressure, and pain as well as improve sleep quality, mood, mental alertness, and memory. Active engagement with music has lasting brain benefits, such as improving concentration, memory, self-discipline, and confidence.  The cognitive benefits of music education extend from early childhood to old age. Some studies show that it can make you smarter. It may even help ward off the effects of brain aging.Music is a total brain workout.

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Music Evokes Mental States

Listening to, singing, playing, composing, and improvising music evokes and allows you to express mental states and feelings. New research has determined that the subjective experience of music across cultures can be mapped to at least 13 common feelings, including:

  • amusement,
  • joy,
  • eroticism,
  • beauty,
  • relaxation,
  • sadness,
  • dreaminess,
  • triumph,
  • anxiety,
  • scariness,
  • annoyance,
  • defiance, and
  • feeling pumped up.

Researchers came up with a very cool interactive map, in which musical samples are plotted along the 13 dimensions of the emotional experiences determined. In the map, each letter corresponds to a musical track. You can hover over a letter to play it. Check out the map here.

How Music Helps Your Mental Health
Graphic by Alan Cohen.

Potential applications for these research findings range from informing psychological and psychiatric therapies designed to evoke certain feelings to helping music streaming services like Spotify adjust their algorithms to satisfy customers’ audio preferences or set the mood.

Music’s Mental Health Benefits

Reduces Stress

Research shows that listening to certain melodies can lower the stress hormone, cortisol. In one study reviewed, patients about to undergo surgery who listened to music had less anxiety and lower cortisol levels than people who had taken drugs.

Listening to music triggers the brain’s nucleus accumbens, responsible for releasing the feel-good neurochemical dopamine, which is an integral part of the pleasure-reward and motivational systems and plays a critical role in learning. Higher dopamine levels improve concentration, boost mood, and enhance memory. Dopamine is the chemical responsible for the yummy feelings you get from eating chocolate, having an orgasm, or a runner’s high.

Decreases Depression

Science shows that music can help alleviate depression and help a person feel more hopeful and in control of their life. There is even evidence that listening to music can aid in rewiring trauma in the brain. Creating harmonies with others or enjoying live music, like at a concert, gets the brain hormone oxytocin flowing increasing feelings of connectedness, trust, and social bonding.

A study appearing in the World Journal of Psychiatry found that musical therapy successfully reduced depression and anxiety in patients suffering from neurological conditions such as dementia, stroke, and Parkinson’s disease. Researchers also noted that the therapy had no negative side effects and was a safe, low-risk treatment tool. Other research showed that musical therapy significantly improved depressive symptoms.

How Music Helps Your Mental Health

Boosts Mood

One study found that people who listened to upbeat tunes could improve their mood and boost happiness levels in just two weeks. In the experiment, one group was instructed to try to improve their mood with music. The other participants were told to listen to music but were not guided to try to intentionally elevate their mood. When participants were later asked to describe their happiness levels, those who had purposefully tried to improve their moods reported feeling happier after just two weeks.

Not surprisingly, another study found that different types of music had different effects on mood. Researchers determined that classical and meditation scores offered the greatest mood-boosting benefits. Heavy metal and techno were found to be ineffective and in some cases, detrimental. Surprisingly though, even sad music can bring most listeners pleasure and comfort, according to one study.

While listening to music can bring multiple mental and physical health benefits, creating it can be therapy, too. Singing in a choir has many mood-boosting and mental health benefits. Of course, playing a musical instrument has advantages for both your mental wellbeing and physical brain health.

Increases Motivation and Enhances Performance

There’s a good reason why exercise classes blast the beats or runners have tunes playing in their earbuds. Research shows that listening to fast-paced music motivates people to work out harder.

In one experiment, 12 healthy male students pedaled stationary bikes. The participants rode for 25 minutes in three sessions and listened to six songs. Unbeknownst to the bikers, the researchers were altering the tempos and measuring performances. For example, the songs were played at a normal speed, increased by ten percent, or slowed by ten percent.

The researchers discovered that speeding up the tracks resulted in increased performance in terms of distance covered, the speed of pedaling, and power exerted. Interestingly, listening to faster-paced songs not only caused exercisers to work harder during their workouts; they also reported enjoying the music more. Conversely, slowing down the tempo led to decreases in all of the variables.

Strengthens Social Bonds

In a 2013 review of the research on music, Stefan Koelsch, a music psychologist at the Freie University Berlin, determined the mechanisms through which music allows us to connect with one another. It impacts brain circuits involved in empathy, trust, and cooperation. This might explain how it has survived in every culture of the world. Music is one of the few activities where people around the globe respond in a common way. It connects all kinds of people across a myriad of cultures, traditions, and practices all over the world.

The article, Four Ways Music Strengthens Social Bonds, explains that music helps people feel connected in four ways:

  1. It increases contact, coordination, and cooperation with others.
  2. Music causes your brain to release oxytocin.
  3. It strengthens our “theory of mind” and empathy.
  4. Music increases cultural cohesion.

Source: https://www.thebestbrainpossible.com/wp-content/uploads/2017/02/logo.png?ezimgfmt=rs:1039×177/rscb1/ng:webp/ngcb1

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[ARTICLE] Epilepsy Benchmarks Area I: Understanding the Causes of the Epilepsies and Epilepsy-Related Neurologic, Psychiatric, and Somatic Conditions – Full Text

Abstract

The 2014 NINDS Benchmarks for Epilepsy Research included area I: Understand the causes of the epilepsies and epilepsy-related neurologic, psychiatric, and somatic conditions. In preparation for the 2020 Curing Epilepsies Conference, where the Benchmarks will be revised, this review will cover scientific progress toward that Benchmark, with emphasize on studies since 2016.

Introductory Vignette by Lizbeth Carmichael. Epilepsy, Depression, and SUDEP—A Parent’s Perspective

My son John developed epilepsy in his late teens, and despite medications, his seizures remained severe and uncontrolled. John was a talented and creative musician and a caring and thoughtful brother and son. He had many friends, and he desperately wanted an independent life. As John’s epilepsy progressed, he also experienced declining mental health. John, who was normally a very peaceful individual, had periods of severe irritability and rage. He also became very anxious at times, and this was a sign of an impending seizure. John heard voices and developed paranoia, hallucinations, and depression. Our family was told to see specialists, but we found that the communication and coordination of care between epileptologists and mental health professionals was impossible, even when he was hospitalized and referrals were made. Ultimately, his mental health issues were not understood or addressed and contributed significantly to his decline. John died of sudden unexpected death in epilepsy (SUDEP) in 2012. Our family’s wish is that those around John had been more attuned to the mental health comorbidities that he was experiencing, and that his medical issues were jointly managed as the outcome for him might have been different.

Significant comorbidities often accompany epilepsy and can be more debilitating than the seizures themselves. A better understanding of the underlying mechanisms of epilepsy-associated comorbidities and appropriate clinical care is critical for increased quality of life for those impacted by epilepsy and their families.

Lizbeth Carmichael. Forever John’s Mom. Citizens United for Research in Epilepsy (CURE).

Introduction

In this review, we provide an update on preclinical and clinical advances into our understanding of the many etiologies of the epilepsies, as well as progress in assigning etiology to epilepsy-related neuropsychiatric and somatic comorbidities. Since the most recent summary in this area,1 expansion in our knowledge of epilepsy genetics and autoimmune epilepsies has continued to result in fewer individuals being labeled with epilepsy of unknown etiology. With the advent of next-generation sequencing technologies, the number of “epilepsy genes” continues to expand. Assigning a causative role to such genes requires verification in not only larger cohorts with statistical rigor but also a number of criteria that take into account normal variation, determination of how a genetic change leads to altered molecular function, and the demonstration of an epilepsy or epilepsy-related phenotype in genetically manipulated model organisms.2 Similar considerations apply for autoimmune epilepsies, for which the relative epileptogenic effects of T-cell infiltration and circulating antibodies continue to be clarified.

Preclinical models of genetic, autoimmune, and brain injury-related epilepsies have been essential to advance our knowledge into upstream and downstream cellular and neurophysiological perturbations that may promote hypersynchrony and the transition to the ictal state. It is only with this type of knowledge that we will be able to better inform treatment of epilepsy related to these types of epilepsy. Incomplete penetrance and variable phenotypes in both humans and animal models strongly implicate genetic modifiers of susceptibility, which need to be identified and validated so as to appreciate mechanisms by which epilepsy may be therapeutically modulated.

In parallel with efforts to address the causes of epilepsy and epileptogenesis, there has been an expansion in efforts designed to unravel the genesis of epilepsy’s various psychiatric comorbidities. Generally, these are etiologically related to broad network dysfunction that may be secondary to the underlying epileptogenic lesion (genetic, structural, or unknown) and actively modulated by the burden of ongoing seizures (if present) and antiseizure medications. Animal models of monogenic epilepsies provide the most tractable route to assigning etiology to epilepsy-associated comorbidities, albeit with some limitations in the ability to assess psychiatric comorbidities in various models. Incorporating optogenetic and chemogenetic strategies in these models affords the ability to definitively test whether specific network abnormalities affect seizure risk or impact limbic function or cognitive function or both.

We conclude our review with a set of general recommendations for future research into the causes of epilepsy spectrum disorders that will guide our understanding into epilepsy prevention (area II), treatment options (area III), and the adverse consequences of seizures themselves (area IV).

Key Advances in Area I

Epilepsy Genetics

Advances in our understanding of the genetics of the epilepsies have continued to accrue since the last Benchmarks update and have been reviewed in several excellent publications.36 Many new variants associated with epilepsy are identified as “de novo dominant,” meaning that they are present in the heterozygous state in sporadically affected individuals. At a cellular level, these genes encode proteins that display a broad range of functions that extend well beyond ion channels, including cell adhesion (eg, PCDH19), DNA binding and chromatin remodeling (eg, CHD2), and neurotransmitter release (eg, STXBP1).7 The importance of genetic etiologies in focal epilepsy in particular has become even more clear, with the involvement of DEPDC5 and associated GATOR1-complex mTOR repressors in epileptogenic cortical malformations being notable examples.8

De novo postzygotic (somatic) mutation has been increasingly recognized to play a role in focal epilepsy, largely involving the mTOR pathway in the pathogenesis of lesional epilepsies such as focal cortical dysplasia and hemimegalencephaly, with a majority of cases explained by this mechanism.911 Extending the discovery of somatic mutation to a new pathway and, interestingly, to both focal cortical dysplasia (type I) and nonlesional focal epilepsy was a report on mosaic variants in the gene SLC35A2, which encodes an UDP-galactose transporter previously associated in nonmosaic form with developmental and epileptic encephalopathy.12 The discovery of these 2 distinct pathways may point to very different targeted therapies after further study, which is promising but also demands attention to precision in classifying individuals with focal epilepsy and establishing a molecular diagnosis before pursuing experimental therapy.

Although most newly discovered pathogenic variants each seem to be causative in only a small number of individuals, taken together their combined impact is substantial. From the perspective of practicing epileptologists, we now benefit from a relatively high rate of identifiable genetic causes in neonatal and early childhood epilepsies, particularly in those individuals with comorbid intellectual disability, so that more routine usage of next-generation sequencing methods in this population may be warranted.13,14 Much more research is needed, however, to separate out the effects of seizures, genetic changes, and treatments on the intellectual impairments that are found in the epileptic encephalopathies.15

Animal models have permitted important insights into the specific mechanisms by which genetic aberrations may promote hyperexcitability. In additional to conventional “knockout” mice, mutants with conditional gene deletions (permitted via Cre-LoxP technology) have helped dissect the individual contributions of specific neuronal populations to seizure generation. For example, mice with a conditional deletion of Lgi1 in parvalbumin-positive interneurons alone are devoid of spontaneous seizures, while conditional deletions of Lgi1 in forebrain glutamatergic neurons result in frequent early-life seizures and premature death,16 just as in Lgi1 knockout mice.17 These results not only provide guidance to future gene replacement strategies but also show that while Lgi1 is an extracellularly secreted protein that is expressed in both GABAergic and glutamatergic neurons, restoring Lgi1 expression in glutamatergic neurons may be more likely to ameliorate seizures. The lack of spontaneous seizures in mice with heterozygous deletions of Lgi1 (recapitulating the haploinsufficiency of LGI1 mutation-related lateral temporal lobe epilepsy [TLE]) illustrates an important point with regard to gene dosage in animal models. Similar findings exist with other epilepsy genes, including KCNQ2,18 CDKL5,19 and DEPDC5. 20 Heterozygous DEPDC5 variants are found in cases of familial focal epilepsy as well as focal cortical dysplasia–associated epilepsy.20,21 Mice or rats with homozygous germ line deletions of Depdc5 had embryonic lethality,2224 which is itself etiologically nonspecific and may even reflect placental pathology.25 In contrast, rats with heterozygous deletions of Depdc5 do not display spontaneous seizures.24 Mice with a conditional brain-specific homozygous deletion of Depdc5 display extremely rare seizures, together with macrocephaly, impaired survival, and biochemical evidence of mTOR1 complex activation.22 Thus, it appears that for certain genetic variants strongly associated with epilepsy in humans, mice with corresponding gene deletions or transgenic “knock-ins” of variants seen in individuals with the specific epilepsy syndrome may not display spontaneous seizures or even reflex audiogenic seizures, a common expression of epilepsy in mice. This phenomenon may reflect the influences of variations in genetic background or fundamental differences in mechanisms of genetic epileptogenesis between mice and humans.

Confirming the epilepsy-inducing or epilepsy-modifying effects of specific variants may be greatly aided through the use of other vertebrate models, such as zebrafish (Danio rerio). Classically employed as a model to study embryology and development, zebrafish has now been adopted to study a variety of neurological disorders, including epilepsy. This species is amenable to exon deletion via homologous recombination, and specific single-nucleotide variants can be introduced via CRISPR-Cas9 technology.2628 As with mice, stereotyped spontaneous or induced seizures can be identified by video tracking and/or electroencephalography. The small size and rapid development of zebrafish also permit high-throughput drug screening29 that may be individualized to identify a treatment for a specific variant.30

Despite the impressive array of genetic advances, the translation of these findings into gene-related or pathway-based clinical treatments has had mixed results.31 There are genetic diagnoses for which specific antiepileptic therapies are either indicated or relatively contraindicated (eg, GLUT1 deficiency, pyridoxine dependency, SCN1A-related epilepsy), and mTOR inhibitors are now known to be at least partially effective for tuberous sclerosis complex–associated epilepsy.32 By contrast, the use of quinidine for KCNT1-related epilepsy, initially thought to be promising following the report of a single case,33 has not been shown to reduce seizure frequency in subsequent studies.34 Overall, these and other findings suggest that simply modulating a causative pathway featuring a rational drug target can lead to variable responses. More work is clearly necessary to bring genetic discoveries from the bench successfully to therapeutic application at the bedside.

Interneuronopathy-Related Epilepsies

Interneuronopathies can be broadly defined as those conditions in which epilepsy or neuropsychiatric comorbidities arise as a consequence of either developmental or functional changes in interneurons. Alterations in interneuron migration or numbers have been identified in multiple epilepsy mouse models, including mice with deletions of Cntnap2,35 Wwox,36 and Syngap1,37 as well as in certain models of acquired epilepsy,38,39 and after traumatic brain injury.40,41 Epilepsy that occurs in Dravet syndrome associated with pathogenic variants in SCN1A may also be classified in this category based on evidence that interneurons in Scn1a heterozygous mice display a selective decrease in excitability, and selective deletions of Scn1a in interneurons are sufficient to recapitulate the spectrum of Dravet-related phenotypes.4244 The term “interneuronopathy” was first used in the setting of a very severe genetic epilepsy syndrome (X-linked lissencephaly with ambiguous genitalia, XLAG) caused by pathogenic variants in ARX, with significant reductions in interneuron density in hippocampal and cortical regions observed in this condition.4547

A more detailed understanding of interneuron development and migration patterns will be critical for developing novel treatments for these specific genetic epilepsy syndromes and will guide our explorations into the therapeutic potential of either transplantation48,49 and/or optogenetic/chemogenetic manipulations of interneurons.

Tumor-Related Epilepsies

The incidence of epilepsy in individuals with brain tumors ranges from 70% to 80% in glioneuronal tumors (including gangliogliomas and dysembryoplastic neuroepithelial tumors) to 20% to 35% in individuals with brain metastases.50 Epileptogenesis associated with gliomas, the most common malignant primary brain tumor, has been a focus of intense research, with 2 nonmutually exclusive mechanisms explored extensively.

For some neurodevelopmental tumors such as ganglioglioma, a genetic profile has become apparent in the form of a BRAF V600E variant, suggesting the possibility of treatment with BRAF inhibitors.51 Furthermore, in some tumors, malignant glial cells release excessive amounts of glutamate through the cystine/glutamate transporter (SLC7A11), a gene whose expression is upregulated in at least half of all glial tumors.52 SLC7A11-mediated glutamate release results in hyperexcitability that spreads to adjacent tissues,53 and in preclinical studies, a currently available SLC7A11 inhibitor (sulfasalazine, utilized in the treatment of Crohn disease) resulted in improved seizure frequency and prolonged survival.54 Mutations in isocitrate dehydrogenase (IDH1) are a strong predictor of epilepsy in patients with low-grade glial tumors.55 Mutant IDH1 converts isocitrate to 2-hydroxyglutarate (instead of α-ketoglutarate), which is structurally similar to glutamate and sufficient to lengthen burst duration in cultured rat cortical neurons in an NMDA-receptor-dependent fashion.55

A second potential mechanism involves the dysregulation of chloride homeostasis in peritumoral cortical neurons through the aberrant downregulation of KCC2 (potassium chloride cotransporter) and upregulation of NKCC1 (sodium potassium chloride cotransporter) within these cells.56 Under these conditions, γ-aminobutyric acid (GABA) binding to ionotropic receptors results in depolarization, and inhibitors of NKCC1 (which reverse altered chloride gradients) in preclinical glioma models improve seizure susceptibility.57 It remains to be seen whether similar mechanisms of epileptogenesis may be involved in epilepsies related to meningiomas or metastatic lesions, for which preclinical models are less well developed. Clearly, cortically based or invading tumors seem to possess the greatest risk of epilepsy.50

Autoimmune Epilepsies

As of 2019, antibodies to at least 11 different antigens have been associated with epilepsy occurring in the context of encephalitis. Antibodies against extracellular antigens raise neuronal excitability and impose synaptic dysfunction either by disrupting specific protein interactions (eg, LGI1, NMDAR), enhancing receptor internalization (AMPAR), or by functioning as an antagonist (GABA-BR).58 In contrast, antibodies against intracellular antigens are thought to produce epilepsy as a consequence of direct cytotoxic T-cell infiltration (eg, amphiphysin, GAD-65). The clinical presentation of autoimmune encephalitides is highly variable (signs and symptoms of limbic or motor dysfunction may or may not be present), and seizures may be the presenting symptom, a late symptom, or absent entirely.59

Establishing a direct causative link between individual antibodies and their specific mechanisms of epileptogenesis has been possible through experiments in which patient-derived antibodies are infused into mouse or rat models. For example, hippocampal specimens from mice that received intracerebroventricularly infused LGI1 antibodies over 14 days displayed reduced synaptic expression of the voltage-gated potassium channel KV1.1 (KCNA1) together with increases in presynaptic-release probability and postsynaptic current amplitudes, as well as diminished long-term potentiation and impairments in learning and memory.60 These mice did not develop spontaneous seizures, suggesting that at least in mice, either longer durations of anti-LGI1 antibody exposure or higher antibody titers may be necessary for seizure generation. In contrast, similar infusions of anti-NMDAR antibodies in mice produced spontaneous seizures without impairments in memory or motor function.61

Recent genome-wide association studies have revealed that particular human leukocyte antigen (HLA) haplotypes may increase the risk of specific antibody-mediated encephalitides,59,62,63 just as with other autoimmune conditions such as type I diabetes mellitus or ankylosing spondylitis; these HLA associations provide pathophysiological insights into the genesis of these antibodies. Fortunately, only a minority of patients who display acute symptomatic seizures during active encephalitis go on to develop epilepsy.58 Early immunomodulatory therapy appears to be critical to avoid future drug resistance, while other factors, such as medical complications or hypoxia, may also contribute to long-term seizure risk.58,59

Epilepsy-Related Conditions

Adults have a median of 2 chronic medical conditions, but this number rises to 6 in individuals older than 65 years.64 Thus, “comorbidities” are a central aspect of all chronic medical conditions, and epilepsy is no exception. In epilepsy, comorbidities can be broadly divided into those which affect mental health (including sleep), general physical health (including trauma), and reproductive health.65,66 Together, these comorbidities contribute tremendously to overall disability, impairments in quality of life, and premature mortality.67,68 Outside of chance or artifactual comorbidities that may reflect various forms of bias,64 4 main mechanisms of comorbidity have been proposed69: (1) independent comorbidity (etiologically unrelated to epilepsy), (2) consequent comorbidity (a direct consequence of epilepsy), (3) iatrogenic comorbidity (treatment related), and (4) shared risk factor (in which epilepsy and its comorbidity independently arise from a single etiology). Importantly, shared risk factors may epidemiologically resemble a bidirectional association (in which each condition causes the other).

Psychiatric comorbidities in epilepsy have received the greatest emphasis. Epilepsy is associated with significantly higher rates of mood and anxiety disorders,70,71 psychosis,72 fatigue,73 and autism spectrum disorder.74 These entities are each independently associated with varying degrees of intellectual disability. Cross-sectional and/or prospective human data provide a framework for mechanistic hypotheses into their etiology; ultimately, these hypotheses require verification in animal models. Unfortunately, this schema is inherently limited since many psychiatric endophenotypes are either absent entirely (eg, suicidality) or difficult to measure (eg, depressed mood, psychosis) in animal models.

Depression, or major depressive disorder, has and will continue to be a major focus of comorbidity research. Individuals with epilepsy are twice as likely to develop depression over their lifetime,70 and either entity can occur first.75 The severity of depression is associated with the risk of epilepsy.76 Depression and suicidality tend to be more prominent in individuals with TLE compared with those who have genetic generalized epilepsies,77,78 and within TLE, depression severity correlates with pharmacoresistance but does not correlate with the side57 or the extent of hippocampal atrophy,79 if present. Improvements in depression that follow temporal lobectomy are strongly associated with improvements in seizure control.80 To date, there has been no high-quality evidence to suggest that antidepressants (in conjunction with standard anticonvulsant therapy) are sufficient to either impact epilepsy risk or reduce seizure frequency.81 On the other hand, behavioral interventions such as cognitive behavioral therapy or mindfulness training have been shown to improve both seizure control and quality of life.82 Overall, this body of evidence argues strongly for the presence of shared noniatrogenic neurobiological risk factors that simultaneously raise the risk of depression and epilepsy.

What are these risk factors? Genetic or epigenetic factors may play only a modulatory role since major depression and epilepsy display little to no evidence of genetic overlap (unlike autism and epilepsy).78 The roots of epilepsy–depression comorbidity may be related to changes in network functional connectivity. In major depression, such functional rearrangements are broad, bilateral, and vary by depression subtype.83,84 At least within TLE circuits,85 hyperexcitability within the anterior hippocampus (corresponding to the ventral hippocampus in rodents) may be one such anatomical substrate for comorbidity. In mice, ventral hippocampal injections of kainic acid produce epileptic seizures together with memory impairments and anhedonic behavior; these behavioral comorbidities were not observed in mice that received dorsal kainic acid injections.86 Hypersynchrony in the anterior/ventral hippocampus region may contribute to depressive symptoms by compromising functional connectivity to ipsilateral frontal regions.87

Testing these hypotheses in preclinical models is now possible with optogenetics, in which an anatomically or molecularly defined neuronal population is genetically or virally transduced to express an excitatory or inhibitory ion channel that is activated by light of a specific wavelength. Bilateral optogenetic activations of ventral hippocampal afferent pathways in nonepileptic mice are sufficient to produce depression and anxiety-like symptoms.88,89 Similarly, the optogenetic inhibition of mossy cells within the dentate gyrus (simulating mossy fiber loss) is sufficient to produce impairments in object memory in mice.90 Aside from these focal network derangements, aberrations in a variety of other neuromolecular axes have been proposed as substrates that may raise seizure risk and compromise mood, including disturbances in neurotransmitter signaling (glutamate, GABA, serotonin), dysfunctional hypothalamo–pituitary–adrenal axis signaling, and a host of cellular and secreted mediators of neuroinflammation.57,91

Looking Forward: Opportunities and Challenges

Given the progress over the past several years and the remaining gaps in knowledge in the field, we have identified some ambitious but feasible future priorities in epilepsy research that we believe should guide our scientific efforts in this area over the next decade. First, it is notable that a large portion of this update has been devoted to genetic advances, given the substantial work in this area. We also recognize that many patients worldwide have epilepsy primarily caused by infection, head injury, birth trauma, hypoxic–ischemic insult, or any of a number of other perturbations of nervous system function. We support an increased focus on investigating the underlying causes and mechanisms of all forms of epilepsy, including these acquired forms of epilepsy, in order to improve our ability to prevent and treat these conditions successfully.

We also support further work on the cognitive and behavioral deficits that accompany epilepsy through experimental animal models, including further use of chemogenetic and optogenetic strategies to study specific cellular populations in the pathogenesis of epilepsy and related conditions. An important question with direct clinical relevance centers on the transition to the ictal state: Since seizures occur only in discrete episodes in most instances, we need a better understanding of what allows them to arise at any particular time and what limits transition to an ictal state at other times.92

We support continued attention on interneuron pathology, central neuronal signaling pathways, and autoimmune factors as underlying mechanistic factors in both genetic and acquired epilepsy syndromes. Further, invoking another less well-studied cell type in the nervous system, we support evaluation of the role of glia in epileptogenesis and seizure propagation. The pathogenesis of infection-related epilepsy, including virus-induced epilepsy and parasite-induced epilepsy, the latter of which is a leading cause of epilepsy worldwide but lacks a relevant animal model, needs further exploration. In general, the links between the brain and immune system and the relationship between inflammation and neural excitability should be critical targets of investigation. Despite the large volume of new advances in epilepsy genetics, we believe there needs to be further characterization of genes associated with the most prevalent early-life syndromes and further research on the use of “rational” therapy design to modulate known pathogenic pathways.

Although some work has been devoted to understanding the causality behind some of the most common epilepsy-related comorbidities, much more is required. We would support further research aimed at disentangling the effects of seizures, genetic changes, and antiseizure medication in contributing to the intellectual impairments that are present in patients with epileptic encephalopathies. In addition, we believe that further timely study of epilepsy etiologies in elderly individuals, who represent a second peak of epilepsy incidence after early childhood, could be highly impactful. Recent findings related to hippocampal hyperexcitability in individuals with Alzheimer disease93 and the discovery of associations between lifestyle risk factors and late-onset epilepsy94 provide tantalizing suggestions of important etiological connections in older adults who had multiple medical conditions.

“Doctor, what is causing my seizures?” At the current time, in a significant majority of individuals, including those without a definite brain lesion, an encephalitic prodrome, evidence for a familial epilepsy syndrome, or a comorbid neurodevelopmental syndrome, the answer to this question remains unknown. Fortunately, 65% of individuals will experience seizure freedom with 1 or more currently available antiseizure medications.95 To improve the lives of all individuals affected by epilepsy, however, we must address the fundamental causes of epilepsy and its associated conditions. As demonstrated in the introductory vignette, we also have a responsibility to translate our scientific advances toward the treatment of epilepsy and fcognitive and psychiatric comorbidities in a coordinated fashion.

Source: https://doi.org/10.1177/1535759719895280

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[Abstract] Effects of Seizure Frequency, Depression and Generalized Anxiety on Suicidal Tendency in People with Epilepsy

Highlights

  • Seizure frequency was positively associated with suicidal tendency.
  • Depression mediated the relationship between seizure frequency and suicidal tendency.
  • Generalized anxiety moderated the effect of seizure frequency on suicidal tendency.

Abstract

Purpose

The highest risk of suicide was identified among patients diagnosed with both epilepsy and comorbid psychiatric disease. The most common comorbid psychiatric conditions of epilepsy are anxiety and depression. This study examines whether and how seizure frequency, depression and generalized anxiety interact to influence suicidal tendency.

Methods

A consecutive cohort of PWE was recruited from the First Affiliated Hospital of Chongqing Medical University. Each patient completed the Neurological Disorders Depression Inventory for Epilepsy scale[NDDI-E], the Generalized Anxiety Disorder-7 (GAD-7), and the suicidality module of Mini-International Neuropsychiatric Interview(MINI) v.5.0.0. Spearman’s correlation and moderated mediation analysis were used to examine the associations among seizure frequency, depression, generalized anxiety and suicidal tendency.

Results

Seizure frequency was positively associated with suicidal tendency. Depression severity partially mediated the relationship between seizure frequency and suicidal tendency. The indirect effect of seizure frequency on suicidal tendency was positive, and accounted for 50.2% of the total effect of seizure frequency on suicidal tendency. The indirect effect of seizure frequency on suicidal tendency through depression severity was positively moderated by generalized anxiety severity.

Conclusions

Reducing seizure frequency may be the basis of suicide prevention in PWE. At the same time, the effect of seizure frequency on suicidal tendency can be partially explained by the mediation of depression severity, and the magnitude of the indirect effect of seizure frequency on suicidal tendency was contingent upon generalized anxiety severity. In addition to depression severity, generalized anxiety severity also exerts an important effect on suicidal tendency in PWE.

via Effects of Seizure Frequency, Depression and Generalized Anxiety on Suicidal Tendency in People with Epilepsy – ScienceDirect

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[BLOG POST] The Difference Between Depression and Sadness

As our society grows and we are slowly beginning to destigmatize mental health, one of the most common and discussed mental illnesses is depression. And while it’s great that we are slowly starting to have open conversations, I fear there is a misunderstanding when it comes to what depression really is.

When people think of depression, they tend to associate it with sadness. For the record, let’s make something incredibly, ridiculously, absolutely crystal clear. Sadness is an emotion. Depression is a clinical mental illness.

Everybody is bound to experience sadness at some point. Whether it’s a disappointing test score, a friend’s betrayal or a heart-wrenching breakup, you will feel sad. But then you’ll feel better. And you’ll move on with your life and be bigger and better. You’ll feel sad, but you won’t necessarily be depressed.

Depression is a clinical illness. It’s been scientifically proven and documented that depression has a literal, physical effect on your brain. No ifs, ands or buts.

Depression is not just feeling sad.

In fact, it’s not feeling… anything. At all.

It’s the feeling of numbness, a sense of nothingness.

It’s the feeling of “why”… about everything.

Existential crisis after existential crisis.

Being sad and being depressed are not the same thing. Next time you’re feeling down, please still try to be wary of your words. If you’re sad, you’re sad. If you’re depressed, you’re depressed. Both are equally valid and equally important but don’t throw around “depression” like a colloquial phrase. It’s not meant to help you emphasize a point. It’s a mental illness. We have a hard enough time as is, please do not make it any harder by making it invalid – in your eyes and in the eyes of others.

Depression is not something we just “get over”.

Depression is nothing something that a pint of ice cream and a funny movie can fix.

Depression is a mental illness.

Depression is not sadness.

Lead Image From Thinkstock

 

via The Difference Between Depression and Sadness | The Mighty

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[WEB SITE] If You Have an Acquired Disability, Resist the Urge to Isolate Yourself, Kessler Expert Advises

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Helen M. Genova, PhD, assistant director of the Kessler Foundation’s Center for Neuropsychology and Neuroscience Research and director of the Social Cognition and Neuroscience Laboratory, shares her thoughts on how dealing with an acquired disability can affect someone mentally and physically.

What are the emotional effects an acquired disability can have on an individual?

People who have an acquired disability may have a number of emotional issues — physical and mental changes that may raise the risk for depression and anxiety. For example, people who have typically led an active lifestyle may find new physical limitations challenging in designing a new exercise program. Some individuals (like those with multiple sclerosis or a traumatic brain injury) may experience cognitive symptoms, such as memory problems, learning problems or severe fatigue, which make it difficult to spend time with friends or attend family holiday festivities. All of these symptoms may lead to depression, or make preexisting depression worse.

Are people with acquired disabilities more prone to loneliness than non-disabled individuals?

Unfortunately, people with acquired disabilities may be more prone to loneliness for a number of reasons. For one, they may experience new physical and mental limitations that may not allow them to lead the life they want to lead. For example, someone who had a career and an active social life before their diagnosis may find it difficult to “keep up” with their old way of living, because they are too fatigued to participate in life the way they used to, or they physically cannot perform the same activities they use to perform. This may lead to social isolation and loneliness. Further, some people with disabilities isolate themselves from others because they do not want to be a “burden” to their families and friends. They may feel that their disability is an inconvenience to others, or tire of having to explain why they are not feeling well, need to cancel plans, or leave early, etc. These feelings may lead them to avoid social interaction altogether, which only leads to more loneliness, and a cycle that can be difficult to break.

What advice would you give to people who are living with an acquired disability and experiencing feelings of loneliness (especially during the holidays)?

I recommend that they resist the urge to isolate themselves. In other words, find good friends who understand their disability and can provide unconditional support. Another option is to find support groups or classes geared towards people with similar disabilities. Spending time with people who truly understand what they are going through can be very comforting. Realizing that others are experiencing similar life struggles may reduce feelings of loneliness, and help you to feel more connected to others.

 [Source(s): Kessler Foundation, PRWeb]

 

via If You Have an Acquired Disability, Resist the Urge to Isolate Yourself, Kessler Expert Advises – Rehab Managment

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