Study provides further support for genetic factors underlying addictions

Impairment of a particular gene raises increases susceptibility to opioid addiction liability as well as vulnerability to binge eating according to a new study.

Dysfunction of the gene, casein kinase1-epsilon (CSNK1E), increases opioid’s euphoric response and produces a marked increase in sensitivity to binge eating in a female experimental model but not in the male.

Similar to opioid addiction, very little is known regarding the genetic basis of binge eating. These combined findings provide further support indicating that shared genetic factors may underlie behavioral traits associated with the addictions and eating disorders. Furthermore, they also provide an important clue that the genetic basis of binge eating and eating disorders in women versus men is likely to differ. The findings appear online in the journal Genes, Brain and Behavior.

Addiction is a multi-stage process that begins with drug exposure and the initial pleasurable experience and progresses toward tolerance, dependence, physiological and emotional withdrawal upon cessation of use, protracted withdrawal that can last years, and finally, relapse to drug taking. The genes associated with risk for opioid addiction could potentially affect one or more of these stages.

“Because increasing evidence points toward an association between CSNK1E and opioid addiction in humans, our findings indicate that genetic variation in CSNK1E could function as a potential risk factor that influences the initial pleasurable/euphoric response to opioids and thus, could ultimately have implications for personalized medicine with regard to drug choice for therapeutic treatment (e.g., non-opioid pain relief) and therapeutic dosing of opioids,” explained corresponding author Camron Bryant, PhD, assistant professor of pharmacology and experimental therapeutics & psychiatry at BUSM.

The researchers also believe the female-specific binge eating property associated with Csnk1e dysfunction suggests that different genetic loci (position on the chromosome) are likely to be uncovered for binge eating and eating disorders in women versus men and may lead to sex-specific treatments ultimately being developed for treating eating disorders.

According to the researchers CSNK1E may also play a role in a subset of patients with alcohol use disorders. Additionally, CSNK1E is known to be a crucial player in regulating circadian rhythms. “The potential interaction of CSNK1E with circadian biology in affecting addiction is an unexplored area of investigation that could be a crucial piece to the puzzle in fully understanding its role in the addictions,” said Bryant.

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A flip switch for binge-eating?

Researchers have identified a subgroup of neurons in the mouse brain that, upon activation, immediately prompt binge-like eating. Furthermore, repeated stimulation of these neurons over time caused the mice to gain weight. The zona incerta (ZI) is a relatively understudied part of the brain.

Intriguingly, patients receiving deep brain stimulation of the subthalamus, which includes the ZI, for the treatment of movement disorders can exhibit characteristics of binge eating. To explore this phenomenon in greater detail, Xiaobing Zhang and Anthony N. van den Pol optogenetically labelled GABA neurons in the ZIs of mice.

They found that stimulating ZI GABA neurons with axons extending into the paraventricular thalamus (PVT) prompted immediate binge-like eating, just two to three seconds after stimulation. Within ten minutes of continuous ZI GABA stimulation, mice rapidly consumed 35% of their daily high-fat food store, meant to be eaten over a 24-hour period.

The researchers also found that ghrelin, a hormone that signals a reduced energy state in the gut, excited ZI GABA neurons. Upon stimulating the subgroup of ZI neurons for five minutes every three hours over a period of two weeks, the mice significantly increased their food intake, and gained weight.

Yet, once photostimulation was over, the mice showed a significantly reduced food intake compared with that of controls.

Lastly, the authors found that stimulation of excitatory axons from the parasubthalamic nucleus to PVT or direct stimulation of glutamate neurons in the PVT reduced food intake.

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Parents’ use of emotional feeding increases emotional eating in school-age children

Emotional eating — eating when you feel sad or upset or in response to another negative mood — is not uncommon in children and adolescents, but why youth eat emotionally has been unclear. Now a new longitudinal study from Norway has found that school-age children whose parents fed them more to soothe their negative feelings were more likely to eat emotionally later on. The reverse was also found to be the case, with parents of children who were more easily soothed by food being more likely to feed them for emotional reasons.

The findings come from researchers at the Norwegian University of Science and Technology, King’s College London, University College London, and the University of Leeds. They appear in the journal Child Development.

“Understanding where emotional eating comes from is important because such behavior can increase the risk for being overweight and developing eating disorders,” according to the study’s lead author, Silje Steinsbekk, associate professor of psychology at the Norwegian University of Science and Technology. “If we can find out what influences the development of emotional eating in young children, parents can be given helpful advice about how to prevent it.”

When children eat to soothe their negative feelings, their food tends to be high in calories (e.g., sweets) so they consume more calories. If they emotionally overeat often, they are also more likely to be overweight. Emotional eating is also tied to the development of later eating disorders (e.g., bulimia and binge eating). This study sought to determine why children eat emotionally and is the first research to consider the issue in school-age children.

Researchers examined emotional feeding and eating in a representative group of 801 Norwegian 4-year-olds, looking at these issues again at ages 6, 8, and 10. They sought to determine whether parents involved in the study (mostly mothers) shaped their children’s later behavior by offering food to make them feel better when they were upset (emotional feeding), and whether parents whose children were easily soothed by food (those who calmed when given food) were more likely to offer them more food for comfort at a subsequent time. Parents were asked to complete questionnaires describing their children’s emotional eating and temperament (how easily they became upset, how well they could control their emotions), as well as their own emotional feeding. Approximately 65% of the children displayed some emotional eating.

The study found that young children whose parents offered them food for comfort at ages 4 and 6 had more emotional eating at ages 8 and 10. But the reverse was also true: Parents whose children were more easily comforted with food were more likely to offer them food to soothe them (i.e., to engage in emotional feeding). Thus, emotional feeding increased emotional eating, and emotional eating increased emotional feeding. The findings held even after accounting for children’s body-mass index and initial levels of feeding and eating.

Moreover, higher levels of negative affectivity (i.e., becoming angry or upset more easily) at age 4 increased children’s risk for emotional eating and feeding at age 6. And this contributed to the bidirectional relation between emotional feeding and emotional eating.

“We know that children who are more easily upset and have more difficulty controlling their emotions are more likely to eat emotionally than calmer children, perhaps because they experience more negative emotions and eating helps them calm down,” notes Lars Wichstrøm, professor of psychology at the Norwegian University of Science and Technology, who coauthored the study. “Our research adds to this knowledge by showing that children who are more easily upset are at highest risk for becoming emotional eaters.”

The authors suggest that instead of offering children food to soothe them when they are sad or upset, parents and other caregivers try to calm youngsters by talking, offering a hug, or soothing in ways that don’t involve food. “Food may work to calm a child, but the downside is teaching children to rely on food to deal with negative emotions, which can have negative consequences in the long run,” adds Steinsbekk.

The authors caution that because the study was conducted in Norway, which has a relatively homogenous and well-educated population, the findings should not be generalized to more diverse populations or to cultures with other feeding and eating practices without further study.

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Could genetics influence what we like to eat?

Have you ever wondered why you keep eating certain foods, even if you know they are not good for you? Gene variants that affect the way our brain works may be the reason, according to a new study. The new research could lead to new strategies to empower people to enjoy and stick to their optimal diets.

Silvia Berciano, a predoctoral fellow at the Universidad Autonoma de Madrid, will present the new findings at the American Society for Nutrition Scientific Sessions and annual meeting during the Experimental Biology 2017 meeting, to be held April 22-26 in Chicago.

“Most people have a hard time modifying their dietary habits, even if they know it is in their best interest,” said Berciano. “This is because our food preferences and ability to work toward goals or follow plans affect what we eat and our ability to stick with diet changes. Ours is the first study describing how brain genes affect food intake and dietary preferences in a group of healthy people.”

Although previous research has identified genes involved with behaviors seen in eating disorders such as anorexia or bulimia, little is known about how natural variation in these genes could affect eating behaviors in healthy people. Gene variation is a result of subtle DNA differences among individuals that make each person unique.

For the new study, the researchers analyzed the genetics of 818 men and women of European ancestry and gathered information about their diet using a questionnaire. The researchers found that the genes they studied did play a significant role in a person’s food choices and dietary habits. For example, higher chocolate intake and a larger waist size was associated with certain forms of the oxytocin receptor gene, and an obesity-associated gene played a role in vegetable and fiber intake. They also observed that certain genes were involved in salt and fat intake.

The new findings could be used to inform precision-medicine approaches that help minimize a person’s risk for common diseases — such as diabetes, cardiovascular disease and cancer — by tailoring diet-based prevention and therapy to the specific needs of an individual.

“The knowledge gained through our study will pave the way to better understanding of eating behavior and facilitate the design of personalized dietary advice that will be more amenable to the individual, resulting in better compliance and more successful outcomes,” said Berciano.

The researchers plan to perform similar investigations in other groups of people with different characteristics and ethnicities to better understand the applicability and potential impact of these findings. They also want to investigate whether the identified genetic variants associated with food intake are linked to increased risks for disease or health problems.

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Religiosity does not increase the risk of anorexia nervosa

Religiosity has been associated with various forms of fasting and self-starvation for thousands of years. Many believe that extreme religiosity can be a risk factor of anorexia nervosa. However, a recent population study conducted in Finland showed that religiosity does not increase the risk of anorexia nervosa.

“Many medieval saints fasted themselves to death. The most famous of them was St Catherine of Siena,” says Associate Professor Anna Keski-Rahkonen from the University of Helsinki, Finland, who led the recent study. “But nobody has looked into this issue in any systematic way. We wanted to examine whether religiosity is associated with a higher risk of anorexia nervosa in modern women.”

This is the first study to examine the potential connection between religiosity and anorexia nervosa in a nationwide setting. Researchers at the University of Helsinki followed almost 3000 women from the Finnish Twin Cohorts from the age 16 until their mid-twenties.

“We found that religiosity does not appear to be a central factor in the development of anorexia nervosa in Finland, a highly secularized Christian country,” said Dr Pyry Sipilä who analyzed the data and authored the article. “Being raised in a highly religious family is also not associated with an increased risk of anorexia nervosa.”

“However, it is important to note that extreme religiosity is quite rare in Finland and many Protestants don’t observe Lent. Ideally, this study should be repeated in a country where fasting during religious festivals is very common.”

Nevertheless, Dr Sipilä has some further good news: “There is a possibility that religiosity might have a small positive effect on body image.”

The paper was published in International Journal of Eating Disorders.

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Model of anorexia nervosa created using stem cells

An international research team, led by scientists at University of California San Diego School of Medicine, has created the first cellular model of anorexia nervosa (AN), reprogramming induced pluripotent stem cells (iPSCs) derived from adolescent females with the eating disorder.

Writing in the March 14th issue of Translational Psychiatry, the scientists said the resulting AN neurons — the disease in a dish — revealed a novel gene that appears to contribute to AN pathophysiology, buttressing the idea that AN has a strong genetic factor. The proof-of-concept approach, they said, provides a new tool to investigate the elusive and largely unknown molecular and cellular mechanisms underlying the disease.

“Anorexia is a very complicated, multifactorial neurodevelopmental disorder,” said Alysson Muotri, PhD, professor in the UC San Diego School of Medicine departments of Pediatrics and Cellular and Molecular Medicine, director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine. “It has proved to be a very difficult disease to study, let alone treat. We don’t actually have good experimental models for eating disorders. In fact, there are no treatments to reverse AN symptoms.”

Primarily affecting young female adolescents between ages 15 and 19, AN is characterized by distorted body image and self-imposed food restriction to the point of emaciation or death. It has the highest mortality rate among psychiatric conditions. For females between 15 and 24 years old who suffer from AN, the mortality rate associated with the illness is 12 times higher than the death rate of all other causes of death.

Though often viewed as a non-biological disorder, new research suggests 50 to 75 percent of risk for AN may be heritable; with predisposition driven primarily by genetics and not, as sometimes presumed, by vanity, poor parenting or factors related to specific groups of individuals.

But little is actually known about the molecular, cellular or genetic elements or genesis of AN. In their study, Muotri and colleagues at UC San Diego and in Brazil, Australia and Thailand, took skin cells from four females with AN and four healthy controls, generated iPSCs (stem cells with the ability to become many types of cells) from these cells and induce these iPSCs to become neurons.

(Previously, Muotri and colleagues had created stem cell-derived neuronal models of autism and Williams syndrome, a rare genetic neurological condition.)

Then they performed unbiased comprehensive whole transcriptome and pathway analyses to determine not just which genes were being expressed or activated in AN neurons, but which genes or transcripts (bits of RNA used in cellular messaging) might be associated with causing or advancing the disease process.

No predicted differences in neurotransmitter levels were observed, the researchers said, but they did note disruption in the Tachykinin receptor 1 (TACR1) gene. Tachykinins are neuropeptides or proteins expressed throughout the nervous and immune systems, where they participate in many cellular and physiological processes and have been linked to multiple diseases, including chronic inflammation, cancer, infection and affective and addictive disorders.

The scientists posit that disruption of the tachykinin system may contribute to AN before other phenotypes or observed characteristics become obvious, but said further studies employing larger patient cohorts are necessary.

“But more to the point, this work helps make that possible,” said Muotri. “It’s a novel technological advance in the field of eating disorders, which impacts millions of people. These findings transform our ability to study how genetic variations alter brain molecular pathways and cellular networks to change risk of AN — and perhaps our ability to create new therapies.”

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Materials provided by University of California – San Diego. Original written by Scott LaFee. Note: Content may be edited for style and length.

 

Deep brain stimulation for patients with chronic anorexia is safe and might improve symptoms

Small study in 16 people suggests technique is safe and might help improve mood, anxiety and wellbeing, while increasing weight.

Deep brain stimulation might alter the brain circuits that drive anorexia nervosa symptoms and help improve patients’ mental and physical health, according to a small study published in The Lancet Psychiatry.

Despite having the highest mortality rate of any psychiatric disorder, there are few effective ways to manage treatment-resistant anorexia. While the study only included 16 patients, it suggests that the intervention is safe and could help improve some symptoms of anorexia, but more research is needed.

Worldwide, 0.5% of people have anorexia, and teenage girls account for the majority of cases. The eating disorder is characterised by persistent concerns about bodyweight, shape and size, leading patients to maintain a low weight. Many patients experience mood and anxiety disorders, deny their illness and avoid seeking medical help for it.

Chronic anorexia causes severe health problems as a result of malnutrition, including weak bones and muscles, sexual problems, infertility, heart problems and seizures. The condition can be fatal and those who become acutely ill are admitted to specialised hospital units to receive nutritional support, medical stabilisation and behavioural therapy.

The small study followed 16 women aged between 21 and 57 years old who had had anorexia for an average of 18 years and were severely underweight (with an average body mass index (BMI) of 13.8). They were selected for the study as all other available treatments did not work for them and they were at risk of early death because of anorexia.

All patients underwent deep brain stimulation, which involves implanting electrodes and stimulating areas of the brain that control dysfunctional behaviours. The technique is currently used to target the brain circuits involved in Parkinson’s disease, dystonia, and tremors, where it has been shown to be highly effective in controlling symptoms.

The study looked at how safe deep brain stimulation was for patients with anorexia, and how it affected their BMI, mood, anxiety and wellbeing. Using PET scans, the researchers also looked at how brain activity changed after one year of stimulation.

Electrodes were placed into their subcallosal cingulate, an area located in the centre of the brain that has been shown to have altered serotonin binding in patients with anorexia. Once implanted, the electrodes stimulated the area for one year at a level of 5 — 6.5 volts every 90 micro-seconds.

The treatment had few serious adverse events; however, five patients had pain that persisted for longer than usual following the surgery (more than 3-4 days) and one had an infection at the site of the surgery which resulted in the electrodes needing to be removed and re-implanted. Most adverse events were a result of the patients’ chronic anorexia and included having very low sodium and potassium levels. One patient had an unexplained seizure several months after their electrodes were implanted.

During the study, two patients asked to have the electrodes removed, potentially a result of them being uncomfortable with their weight gain. This meant that there were only 14 patients included at follow-up.

For these patients, mental health symptoms improved over the study with mood and anxiety symptoms reducing in five patients and depression reducing in 10 out of 14 patients. They also reported better quality of life.

While psychological symptoms improved soon after the stimulation began, changes in weight started after three months, suggesting that improving mental health symptoms may precede or even enable changes in weight. Over the course of the study, average BMI of the group increased to 17.3 — an increase of 3.5 points — and six patients achieved a normal BMI (of 18.5 or more).

When comparing the scan results for brain activity before treatment and after a year of stimulation, the researchers found that there were changes in the regions linked to anorexia, suggesting that deep brain stimulation was able to directly affect the related brain circuits. This included less activity in the putamen, thalamus, cerebellum amongst other areas, and more activity in the peripheral cortical areas which are also linked to social perception and behaviour.

“Anorexia remains the psychiatric disorder with the highest mortality rate, and there is an urgent need to develop safe, effective, evidence-driven treatments that are informed by a growing understanding of brain circuitry,” said study author, Professor Andres Lozano, University of Toronto, Canada. “While our results show some early promise, more research will be needed before this becomes available for patients with anorexia. Our findings emphasise the need for continued research into novel neuromodulation strategies for anorexia nervosa, and for psychiatric disorders more broadly.”

“Our study suggests that a focal brain intervention, deep brain stimulation, may have an impact on the circuitry of symptoms that serve to maintain anorexia and make it so difficult to treat.” said lead author, Dr Nir Lipsman, Sunnybrook Health Sciences Centre, Canada.

The researchers note some limitations within their work, including that the group was small and there was no control group. In addition, all patients were aware they were being given treatment so the results seen could be affected by placebo effect. However, the authors note this is unlikely as the results lasted for a year and were confirmed with the brain activity scans.

Writing in a linked Comment Dr Carrie McAdams, University of Texas, USA, said: “Conventional treatment of anorexia nervosa includes behavioural modifications to improve feeding, combined with psychological therapy to address cognitive distortions related to self-esteem, eating, and body dissatisfaction. Nevertheless, after intensive treatment, nearly half of adult women with anorexia nervosa relapse within a year… This work shows how modern neuroscience can lead to a new treatment and simultaneously improve understanding of perpetuating factors in a complex, multifactorial disease… Both mood and social function warrant further examination as potential neural factors that might perpetuate anorexia nervosa in adults. Difficulty in changing these factors, which are not part of the diagnostic symptoms of anorexia nervosa, could contribute to the poor outcomes seen with conventional treatments.”

Lasting autistic traits in women with anorexia

Women with anorexia display clear autistic traits, even once the eating disorder is under control and they have achieved a normal weight, according to research from Sahlgrenska Academy. The similarities between anorexia and autism in women are also seen in a part of the brain which process social skills.

“A traditional eating disorder is usually linked to fixation with food and weight, but there are also a large number of other thoughts and behavior in individuals with anorexia nervosa that have previously been considered typical for autism,” says Louise Karjalainen, PhD and psychologist at the Gillberg Neuropsychiatry Centre in Gothenburg.

It has long been known that individuals with autism have disturbed eating behavior. However, it has been unclear whether typical autistic behavior surrounding food also exists in those with anorexia nervosa.

One of the groups studied by Louise Karjalainen included around 30 women with anorexia nervosa between the ages of 15-25. After a year when their health had generally begun to improve, they still had the negative thought patterns and behavior around food that characterizes individuals with autism.

“Their general eating patterns improved during the follow-up year, but it was specifically noteworthy that they were still at the same level in their autistic behavior in terms of meal times,” says Louise Karjalainen.

New insight

A food smell that is unbearable, a dining companion making loud mouth noises or an aversion to the whole idea of eating together with others. These were the types of things that could make women regress long after the acute stage of anorexia. The autistic traits remained even after the body had been nourished and repaired.

“Cognitively, a person functions better once they have regained normal weight from an eating disorder, but the social aspects of meal times were still uncomfortable. They actually also had problems with multi-tasking. Cutting food and chewing at the same time was a challenge, and this is something that is also prevalent in individuals with autism,” says Louise Karjalainen.

“The fact that this is hard for patients with anorexia is something that has not previously been noticed or understood. It may be suspected that this partly is to do with the food and weight anxiety, but it was so clear that it is also linked to social factors,” she continues.

Changes in care

MRI scans also showed that women in the group had the same changes as women with autism in the parts of the brain linked to social cognition. This is due to thinning of the gray matter just behind the temple area, which was not present in the healthy comparison groups or in men with autism.

“We need to know more in order to understand how this is all linked, but nevertheless it is a highly interesting discovery,” says Louise Karjalainen, who believes that, in future, care for anorexics should be changed.

“It’s obvious that anorexia care must be food-focused; this is primarily about saving lives, but there are also other key factors in reducing the risk of relapse and to get people healthy at all levels,” she says.

Link to thesis: https://gupea.ub.gu.se/handle/2077/44865

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Materials provided by University of Gothenburg. Original written by Margareta Gustafsson Kubista. Note: Content may be edited for style and length.

 

Stimulating the brain with electricity may reduce bulimia symptoms

Key symptoms of bulimia nervosa, including the urge to binge eat and restrict food intake, are reduced by delivering electricity to parts of the brain using non-invasive brain stimulation, according to new research by King’s College London.

Bulimia is an eating disorder characterised by a vicious cycle of repeated bouts of distressing binge eating and inappropriate attempts to compensate for overeating through vomiting, extreme dieting, or the misuse of different medicines. These symptoms are typically driven by an intense preoccupation with body weight, shape or appearance. Over time these features become compulsive and resemble those of an addiction.

Bulimia typically emerges in adolescence and is much more likely to develop in women. It is thought that 1-2 per cent of women have bulimia at some stage in their life. The disorder is associated with multiple medical complications and up to 4 per cent of people with bulimia die prematurely from the disorder.

Whilst existing treatments such as cognitive behavioural therapy (CBT) are effective for many people with bulimia, a substantial proportion do not get better with talking therapies. There is a pressing need for new techniques and researchers are increasingly looking towards neuroscience-based technologies that could target the underlying neural basis of eating disorders, such as problems with reward processing or self-control.

Previous studies published by the Eating Disorders Research Group at King’s found that repetitive transcranial magnetic stimulation (rTMS), already an approved treatment for depression in the US, was effective in reducing food craving in people with bulimia.

This new study, published today in PLOS ONE, examined the use of transcranial direct current stimulation (tDCS), a less expensive and more portable form of brain stimulation. tDCS uses electrodes placed on the head to stimulate specific parts of the brain, which could improve cognitive function in areas related to reward processing and self-control. The treatment is painless and the most common side effect is a slight itching or tingling on the scalp.

In the study, 39 people received real tDCS and placebo tDCS, with a period of at least 48 hours between both sessions. The researchers used questionnaires before and after each session to measure their urge to binge eat and a range of other bulimia symptoms, including concerns about weight and shape, restriction of food intake, levels of self-control and self-esteem.

They found that these bulimia symptoms were significantly reduced by the tDCS treatment but not the placebo session. For example, baseline scores on the urge to binge eat scale decreased by 31 per cent following tDCS.

The researchers also used a decision-making task where participants had to choose between a smaller amount of money available immediately and a larger amount available in three months.

They found that people showed a greater tendency to delay gratification following the tDCS session compared to the placebo session. This means they showed more prudent decision-making by waiting for larger, later rewards, rather than choosing the smaller, sooner option.

Maria Kekic, first author of the study, from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, said: ‘Our study suggests that a non-invasive brain stimulation technique suppresses the urge to binge eat and reduces the severity of other common symptoms in people with bulimia nervosa, at least temporarily. We think it does this by improving cognitive control over compulsive features of the disorder.

‘Although these are modest, early findings, there is a clear improvement in symptoms and decision-making abilities following just one session of tDCS. With a larger sample and multiple sessions of treatment over a longer period of time, it is likely that the effects would be even stronger. This is something we’re now looking to explore in future studies.’

Professor Ulrike Schmidt, senior author of the study, from the IoPPN at King’s College London, said: ‘The advantage of tDCS is that it’s much less expensive and more portable than other brain stimulation techniques, which raises the prospect of one day offering treatment that could be self-delivered at home by patients with bulimia. This could either be as an addition to talking therapies such as CBT to improve outcomes, or as a stand-alone alternative approach.’