A University of Otago-led clinical trial has tested an oral form of ketamine therapy for treatment-resistant depression that has fewer side effects whilst also reducing the risk of abusing the powerful, tightly-regulated anaesthetic.
Working in collaboration with New Zealand’s Douglas Pharmaceuticals, researchers have conducted a trial of ketamine in an extended-release tablet form. The study, published in Nature Medicine, involved 168 adults for whom regular anti-depressant therapy repeatedly failed. They either took a range of oral doses of ketamine or a placebo for 12 weeks.
Professor Paul Glue, Otago’s Hazel Buckland Chair in Psychological Medicine, says the highest dose of ketamine – 180mg – showed significant improvement in depressive symptoms, compared with patients who received placebo.
“Ketamine can be given by injection or nasal spray, but these methods can leave people feeling spaced out, sedated, and increases their blood pressure. This study shows the extended-release ketamine tablets are safe and effective, and overall, tolerability was good, with participants reporting minimal side effects,” he says.
Douglas Pharmaceuticals is now seeking the interest of partners to complete registrational clinical trials and prepare for commercialisation of the tablets.
“We have found there are many people, here in New Zealand and around the world, who have treatment-resistant depression, and who have no or very little chance of accessing ketamine. Because most doses of this tablet formulation can be taken at home, this is potentially a much cheaper and convenient option for these patients compared with weekly clinic visits for ketamine injections or nasal sprays.”
Ketamine has been used legally by doctors in New Zealand since the 1970s for sedation and pain relief, but it has been classified as an illegal drug for recreational use since the 1980s.
Professor Glue says having the drug in a tablet form reduces the risk of abuse as the manufacturing process makes them difficult to manipulate.
While mentally stimulating activities and life experiences can improve cognition in memory clinic patients, stress undermines this beneficial relationship. This is according to a new study published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
Researchers in the late 1980s found that some individuals who showed no apparent symptoms of dementia during their lifetime had brain changes consistent with an advanced stage of Alzheimer’s disease.
It has since been postulated that so-called cognitive reserve might account for this differential protective effect in individuals.
Cognitively stimulating and enriching life experiences and behaviours such as higher educational attainment, complex jobs, continued physical and leisure activities, and healthy social interactions help build cognitive reserve.
Increased risk of dementia
However, high or persistent stress levels are associated with reduced social interactions, impaired ability to engage in leisure and physical activities, and an increased risk of dementia.
Researchers from Karolinska Institutet have now examined the association between cognitive reserve, cognition, and biomarkers for Alzheimer’s disease in 113 participants from the memory clinic at the Karolinska University Hospital, Huddinge, Sweden.
They also examined how this association is modified by physiological stress (cortisol levels in saliva) and psychological (perceived) stress.
Greater cognitive reserve was found to improve cognition, but interestingly, physiological stress appeared to weaken the association.
“These results might have clinical implications as an expanding body of research suggests that mindfulness exercises and meditation may reduce cortisol levels and improve cognition,” says the study’s lead author Manasa Shanta Yerramalla, researcher at the Department of Neurobiology, Care Sciences and Society. “Different stress management strategies could be a good complement to existing lifestyle interventions in Alzheimer’s prevention.”
The relatively small sample of participants reduces the possibility of drawing robust conclusions, but the results are generalisable to similar patient groups.
Link between sleep and cognition
Moreover, since stress disrupts sleep, which in turn disrupts cognition, the researchers controlled for sleeping medications; they did not, however, consider other aspects of sleep that might impair cognition.
“We will continue to study the association between stress and sleeping disorders and how it affects the cognitive reserve in memory clinic patients,” says Dr Yerramalla.
New research from CU Boulder shows that turning to junk food when we’re stressed out may backfire. The study found that in animals, a high-fat diet disrupts resident gut bacteria, alters behaviour and, through a complex pathway connecting the gut to the brain, influences brain chemicals in ways that fuel anxiety.
“Everyone knows that these are not healthy foods, but we tend to think about them strictly in terms of a little weight gain,” said lead author Christopher Lowry, a professor of integrative physiology at CU Boulder. “If you understand that they also impact your brain in a way that can promote anxiety, that makes the stakes even higher.”
For the study, published in the journal Biological Research in May, Lowry worked with first author Sylvana Rendeiro de Noronha, a doctoral student at the Federal University of Ouro Preto in Brazil.
In a previous study, the team found that rats fed a high-fat diet consisting primarily of saturated fat showed increases in neuroinflammation and anxiety-like behaviour.
While evidence is mixed, some human studies have also shown that replacing a high-fat, high-sugar, ultra-processed diet with a healthier one can reduce depression and anxiety.
The dark side of serotonin
To better understand what may be driving the fat-anxiety connection, Lowry’s team divided male adolescent rats into two groups: Half got a standard diet of about 11% fat for nine weeks; the others got a high-fat diet of 45% fat, consisting mostly of saturated fat from animal products.
The typical American diet is about 36% fat, according to the Centers for Disease Control and Prevention.
Throughout the study, the researchers collected faecal samples and assessed the animals’ gut microbiome. After nine weeks, the animals underwent behavioural tests.
When compared to the control group, the group eating a high-fat diet, not surprisingly, gained weight. But the animals also showed significantly less diversity of gut bacteria. Generally speaking, more bacterial diversity is associated with better health, Lowry explained. They also hosted far more of a category of bacteria called Firmicutes and less of a category called Bacteroidetes. A higher Firmicutes to Bacteroidetes ratio has been associated with the typical industrialised diet and with obesity.
The high-fat diet group also showed higher expression of three genes (tph2, htr1a, and slc6a4) involved in production and signalling of the neurotransmitter serotonin – particularly in a region of the brainstem known as the dorsal raphe nucleus cDRD, which is associated with stress and anxiety.
While serotonin is often billed as a “feel-good brain chemical,” Lowry notes that certain subsets of serotonin neurons can, when activated, prompt anxiety-like responses in animals. Notably, heightened expression of tph2, or tryptophan hydroxylase, in the cDRD has been associated with mood disorders and suicide risk in humans.
“To think that just a high-fat diet could alter expression of these genes in the brain is extraordinary,” said Lowry. “The high-fat group essentially had the molecular signature of a high anxiety state in their brain.”
A primal gut-brain connection
Just how a disrupted gut can change chemicals in the brain remains unclear. But Lowry suspects that an unhealthy microbiome compromises the gut lining, enabling bacteria to slip into the body’s circulation and communicate with the brain via the vagus nerve, a pathway from the gastrointestinal tract to the brain.
“If you think about human evolution, it makes sense,” Lowry said. “We are hard-wired to really notice things that make us sick so we can avoid those things in the future.”
Lowry stresses that not all fats are bad, and that healthy fats like those found in fish, olive oil, nuts and seeds can be anti-inflammatory and good for the brain.
But his research in animals suggests that exposure to an ultra-high-fat diet consisting of predominantly saturated fats, particularly at a young age, could both boost anxiety in the short-term and prime the brain to be more prone to it in the future.
His advice: Eat as many different kinds of fruits and vegetables as possible, add fermented foods to your diet to support a healthy microbiome and lay off the pizza and fries. Also, if you do have a hamburger, add a slice of avocado. Research shows that good fat can counteract some of the bad.
Rodrigo Cunha de Menezes, professor of physiology at Federal University of Ouro Preto in Brazil, is co- senior author on this paper.
As financial pressures continue to mount globally, it’s imperative to acknowledge the profound impact that financial stress can have on mental health. Whether it’s struggling to pay bills, dealing with debt, or worrying about job security, these are all real-life examples of financial stressors that can significantly impact our mental well-being. Recent studies conducted by reputable organisations such as the South African Depression and Anxiety Group (SADAG) and Sanlam shed light on the alarming correlation between these financial strains and mental wellness. In light of this, we aim to provide insights and guidance to help you manage financial stress and improve your overall well-being.
According to SADAG’s online survey, conducted to assess the impact of the pandemic on South Africans’ mental well-being, a staggering 46% of respondents identified financial stress and pressure as significant contributors to their mental health challenges. Similarly, Sanlam’s report revealed that 57% of respondents cited financial stress as the primary factor affecting their mental well-being, with young individuals aged 18-24 being particularly vulnerable.
In light of these findings, it’s important to recognise the empowering role of proactive financial management in safeguarding mental wellness. Effective financial management can significantly reduce the stress associated with financial uncertainties, contributing to better mental health. By making use of available tools and resources, individuals can gain valuable insights and guidance to manage their finances and budgets more effectively, ultimately supporting their overall well-being.
Speaking on the importance of financial tools and resources, Lerato Thwane, Head of e-Commerce, shares her insights. “Amidst the challenges posed by financial stress, it’s essential for individuals to have access to tools and resources that can provide clarity and support. Through XDS, we empower consumers, giving them the control they need to navigate their financial journey confidently, ultimately promoting financial stability and mental well-being. XDS offers a comprehensive range of products and services to support individuals at every stage of their financial lifecycle. These include credit reports and financial guidance.”
Thwane continues: “Research has shown that financial stability is closely linked to mental well-being. When individuals have control over their finances and feel secure about their future, they experience lower levels of stress and anxiety. This, in turn, can lead to improved overall mental health, better relationships, and increased productivity in other areas of life. Financial literacy is an important part of achieving financial security. A clear understanding of how to manage money and the basics of budgeting can help individuals gain control over their finances and feel more empowered.”
To improve your financial management skills and overall well-being, consider seeking professional help such as financial counselling. Additionally, accessing your XDS credit profile and score on Splendi can help you better understand your financial status. These resources offer valuable guidance to boost financial literacy, develop healthier money habits, and secure your financial future.
About Mettus
Mettus is a collective of intelligence companies offering end-to-end data solutions. Established in August 2022 through a private equity-backed management buyout, Mettus is home to three established brands across the fast-growing and in-demand data and technology markets. Our specialities include credit bureau services, background screening and vetting, data platforms and analytics.
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With this in mind, we are committed to providing smarter and more technologically advanced information solutions to credit grantors and other data users so that they can make better decisions regarding the granting of credit to new customers. We maintain the highest standards of integrity relating to data privacy, confidentiality, and information quality, and we comply fully with all relevant legislation, such as the National Credit Act. We seek to build long-term partnerships with our customers as we help them to grow their businesses.
Evidence suggests serotonin-boosting actions relieve depression by restoring normal communication and connections in the brain
Photo by Sydney Sims on Unsplash
Researchers at the University of Colorado Anschutz Medical Campus have established a new framework for understanding how classic antidepressants work in treating major depressive disorder (MDD), reemphasising their importance and aiming to reframe clinical conversation around their role in treatment.
The nature of the dysfunction at the root of MDD has been under investigation for decades. Classic antidepressants, such as SSRIs (selective serotonin reuptake inhibitors, such as fluoxetine) cause an elevation in serotonin levels, a key neurotransmitter. This observation led to the idea that antidepressants work because they restore a chemical imbalance, such as a lack of serotonin.
But subsequent years of research showed no significant decrease in serotonin in people with depression. While experts have moved away from this hypothesis due to lack of concrete evidence, this has led to a shift in public opinion on the effectiveness of these medications.
Antidepressants, such as SSRIs and serotonin and norepinephrine reuptake inhibitors (SNRIs), are still effective in alleviating depressive episodes in many patients, however. In a paper published in Molecular Psychiatry, researchers outline a new framework for understanding how antidepressants are efficacious in treating MDD. This framework helps clarify how antidepressants like SSRIs can still be helpful, even if MDD isn’t caused by a lack of serotonin.
Evidence points to a communication problem
“The best evidence of changes in the brain in people suffering from MDD is that some brain regions are not communicating with each other normally,” said Scott Thompson, PhD, professor in the Department of Psychiatry and senior author. “When the parts of the brain responsible for reward, happiness, mood, self-esteem, even problem-solving in some cases, are not communicating with each other properly, then they can’t do their jobs properly,” Thompson said.
“There is good evidence that antidepressants that increase serotonin, like SSRIs, all work by restoring the strength of the connections between these regions of the brain. So do novel therapeutics such as esketamine and psychedelics. This form of neuroplasticity helps release brain circuits from being ‘stuck’ in a pathological state, ultimately leading to a restoration of healthy brain function,” Thompson said.
Thompson and colleagues liken this theory to a car running off the road and getting stuck in a ditch, requiring the help of a tow truck to pull the car out of its stuck state, allowing it to move freely down the road again. Researchers are hoping healthcare providers will use their examples to bolster conversations with apprehensive patients about these treatments, helping them better understand their condition and how to treat it.
Study aims to reshape the conversation
“We are hoping this framework provides clinicians new ways to communicate the way these treatments work in combating MDD,” said C. Neill Epperson, MD, co-author of the paper and professor of the Department of Psychiatry at the CU School of Medicine.
“Much of the public conversation around the effectiveness of antidepressants, and the role serotonin plays in diagnosis and treatment, has been negative and largely dangerous,” Epperson said. “While MDD is a heterogenous disorder with no one-fits-all solution, it is important to emphasise that if treatments or medications are working for you, then they are lifesaving. Understanding how these medications promote neuroplasticity can help strengthen that message.”
Using population-wide registry data, researchers investigated whether mental disorders can be transmitted within social networks formed by school classes.
The study is the largest and most comprehensive so far on the spread of mental disorders in social networks, with more than 700 000 ninth-grade pupils from 860 Finnish schools participating. The adolescents were followed from the end of ninth grade for a median of 11 years.
The researchers, from the University of Helsinki, the Finnish Institute for Health and Welfare, the University of Jyväskylä and the University of Manchester, demonstrated that the number of classmates diagnosed with a mental disorder was associated with a higher risk of receiving a mental disorder diagnosis later in life.
“The observed link was the strongest during the first year of follow-up in the study. This was not explained by a number of factors related to parents, school and residential area. The link was most pronounced in the case of mood, anxiety and eating disorders,” says Associate Professor Christian Hakulinen of the University of Helsinki.
Schools well-suited to social network research
According to Hakulinen, prior studies have yielded similar results: for example, American researchers have observed indications of depressive symptoms potentially being transmitted from one individual to another in social networks.
In prior research, however, social networks have typically been chosen independently by the research subjects, which may result in bias in the data. Hakulinen points out that school classes are social networks well suited to research, as people are usually not able to choose their classmates.
“Defining the social networks and following adolescents were made possible by extensive Finnish registers. The findings significantly deepen our understanding of how mental health problems develop and affect other people in our social networks,” he says.
Hakulinen nevertheless notes that the connection observed in the study is not necessarily causal. Furthermore, the study did not investigate how mental disorders can potentially be transmitted between individuals.
“It may be possible, for instance, that the threshold for seeking help for mental health issues is lowered when there are one or more people in your social network who have already sought help for their problems. In fact, this kind of normalisation of diagnosis and treatment can be considered beneficial contagion of mental disorders,” Hakulinen says.
The study involved a total of 713 809 Finnish citizens born between 1985 and 1997. The adolescents were investigated from the end of comprehensive school until they received their first mental disorder diagnosis, relocated from the country or died. At the latest, the follow-up was discontinued at the end of 2019, resulting in a median follow-up period of 11.4 years.
More preventive measures?
Mental disorders are a significant global challenge, adversely affecting individuals, society and the economy. According to Hakulinen, anxiety and mood symptoms in particular have in recent years increased among young people.
Previous studies have shown that, in roughly half of all cases, the onset of mental disorders in adulthood occurs when people are under 18. In fact, Hakulinen emphasises the importance of preventive measures and early intervention.
“When taking preventive measures, it’s worthwhile considering that mental disorders can spread from one adolescent to another,” Hakulinen says.
New research led by King’s College London has found that thousands of DNA sequences originating from ancient viral infections are expressed in the brain, with some contributing to susceptibility for psychiatric disorders such as schizophrenia, bipolar disorder, and depression.
Around 8% of the human genome is made up of sequences called Human Endogenous Retroviruses (HERVs), which are products of ancient viral infections that occurred hundreds of thousands of years ago. Until recently, it was assumed that these ‘fossil viruses’ were simply junk DNA, with no important function in the body. However, due to advances in genomics research, scientists have now discovered where in our DNA these fossil viruses are located, enabling us to better understand when they are expressed and what functions they may have.
This new study, published in Nature Communications, builds upon these advances and is the first to show that a set of specific HERVs expressed in the human brain contribute to psychiatric disorder susceptibility, marking a step forward in understanding the complex genetic components that contribute to these conditions.
Dr Timothy Powell, co-senior author on the study and Senior Lecturer at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, said: “This study uses a novel and robust approach to assess how genetic susceptibility for psychiatric disorders imparts its effects on the expression of ancient viral sequences present in the modern human genome. Our results suggest that these viral sequences probably play a more important role in the human brain than originally thought, with specific HERV expression profiles being associated with an increased susceptibility for some psychiatric disorders.”
The study analysed data from large genetic studies involving tens of thousands of people, both with and without mental health conditions, as well as information from autopsy brain samples from 800 individuals, to explore how DNA variations linked to psychiatric disorders affect the expression of HERVs.
Although most genetic risk variants linked to psychiatric diagnoses impacted genes with well-known biological functions, the researchers found that some genetic risk variants preferentially affected the expression of HERVs. The researchers reported five robust HERV expression signatures associated with psychiatric disorders, including two HERVs that are associated with risk for schizophrenia, one associated with risk for both bipolar disorder and schizophrenia, and one associated with risk for depression.
Dr Rodrigo Duarte, first author and Research Fellow at the IoPPN, King’s College London, said: “We know that psychiatric disorders have a substantial genetic component, with many parts of the genome incrementally contributing to susceptibility. In our study, we were able to investigate parts of the genome corresponding to HERVs, which led to the identification of five sequences that are relevant to psychiatric disorders. Whilst it is not clear yet how these HERVs affect brain cells to confer this increase in risk, our findings suggest that their expression regulation is important for brain function.”
Dr Douglas Nixon, co-senior author on the study and and researcher at the Feinstein Institutes for Medical Research at Northwell Health, in the US, said: “Further research is needed to understand the exact function of most HERVs, including those identified in our study. We think that a better understanding of these ancient viruses, and the known genes implicated in psychiatric disorders, have the potential to revolutionise mental health research and lead to novel ways to treat or diagnose these conditions.”
A head-mounted device that generates an ultra-low frequency ultralow magnetic field has been found to improve the symptoms of four male patients diagnosed with major depressive disorder. Future trials using the device may offer a safe and noninvasive way of treating depression. The results were published in theAsian Journal of Psychiatry.
The presence of a magnetic field with frequencies typically ranging from 0 to 300 Hz is known as an Extremely Low Frequency Magnetic Environment (ELF-ELME). Although the interaction between magnetic fields and biological systems is complex and not well understood, this frequency is believed to stimulate mitochondria and induce their renewal. Since mitochondria generate energy, they offer a potential way to treat many of the symptoms associated with depression such as lethargy.
For this study, the research team led by Professor Toshiya Inada at Nagoya University Graduate School of Medicine and Masako Tachibana of Nagoya University Hospital in Japan enrolled four male Japanese participants diagnosed with depression and receiving treatment between the ages of 18 and 75 years in a clinical trial known as an exploratory first-in human study.
In exploratory studies such as this, both participants and researchers are aware of the treatment being administered. Although the sample size is small and there is no control group, researchers can focus on gathering preliminary data to explore the safety, dosage, and potential efficacy of a new intervention.
Throughout the trial, participants wore a head-mounted magnetic field device that exposed them to ELF-ELME for two hours per day for eight weeks. As predicted, the researchers found that all patients reported a drop in their level of depression.
Although the experiment was an exploratory trial with a limited number of participants and no control group, the findings suggest that larger scale clinical trials are feasible. If such trials prove to be effective, their research could lead to a groundbreaking change in the current clinical practice of depression treatment.
Inada believes that the device has great potential to treat depression more effectively in a patient-centred way. “The magnetic field generated by the device is non-invasive, being 1/4.5 of the Japanese geomagnetic field and less than 1/60 of the International Commission on Non-Ionizing Radiation Protection’s general public exposure standard,” he said, “We anticipate that patients will be able to receive daily home treatment without even being aware of being in a low magnetic field environment.”
He continued: “Compared to current depression treatments, such as long-term antidepressant medications, electroconvulsive therapy, and repetitive transcranial magnetic stimulation, this therapy is superior in terms of convenience and lack of anticipated side effects. We could see our device being used for patients who prefer not to take medication or safely in combination with other treatments.”
New research has found a significant association between participating in low to moderate intensity exercise and reduced rates of depression. Researchers carried out an umbrella review of studies carried out across the world to examine the potential of physical activity as a mental health intervention.
The analysis, published in the journal Neuroscience and Biobehavioural Reviews, found that physical activity reduced the risk of depression by 23% and anxiety by 26%. A particularly strong association was found between low and moderate physical activity, which included activities such as gardening, golf and walking, and reduced risk of depression. But this was not strongly observed for high intensity exercise.
Physical activity was also significantly associated with reduced risk of severe mental health conditions, including a reduction in psychosis/schizophrenia by 27%. The results were consistent in both men and women, and across different age groups and across the world.
Lead author Lee Smith, Professor of Public Health at Anglia Ruskin University (ARU), said: “Preventing mental health complications effectively has emerged as a major challenge, and an area of paramount importance in the realm of public health. These conditions can be complex and necessitate a multi-pronged approach to treatment, which may encompass pharmacological interventions, psychotherapy, and lifestyle changes.
“These effects of physical activity intensity on depression highlight the need for precise exercise guidelines. Moderate exercise can improve mental health through biochemical reactions, whereas high-intensity exercise may worsen stress-related responses in some individuals.
“Acknowledging differences in people’s response to exercise is vital for effective mental health strategies, suggesting any activity recommendations should be tailored for the individual.
“The fact that even low to moderate levels of physical activity can be beneficial for mental health is particularly important, given that these levels of activity may be more achievable for people who can make smaller lifestyle changes without feeling they need to commit to a high-intensity exercise programme.”
A new study led by investigators at Beth Israel Deaconess Medical Center (BIDMC) suggests that female mice that are prone to anxiety may prefer and actively seek out a starvation-like state in response to repeated exposure to stress. The findings, published in the journal Neuron, may provide a useful experimental model for investigating the neural mechanisms underlying anorexia nervosa – particularly its onset.
“While anorexia nervosa has been documented for over 300 years, its underlying causes remain unknown,” said first author Hakan Kucukdereli, PhD, of the division of Endocrinology, Diabetes and Metabolism in the Department of Medicine at BIDMC.
“Current animal models fail to capture a key hallmark of the disorder – wilful starvation. Thus, there has been the pressing need for a pre-clinical mouse model that captures the intentional seeking of a starvation state.”
In healthy individuals, the state of hunger (or caloric deficit) is a mildly uncomfortable state that drives food-seeking behavior. In the lab, Kucukdereli, senior author Mark L. Andermann, and colleagues knew that precise stimulation of a few thousand neurons known as AgRP neurons will cause even a well-fed mouse to seek out another meal.
They also knew that actual food restriction – which activates these AgRP neurons – and the artificial starvation state caused by stimulating these neurons can tamp down anxiety, thereby promoting food-seeking. (Imagine a hungry mouse in your kitchen that needs to be bold enough to hunt for food, even when your cat is around.)
Based on prior associations between stress, anxiety, and anorexia nervosa, Andermann and colleagues hypothesised that exposure to high levels of stress may actually trigger individuals to wilfully seek starvation as a means of reducing anxiety. The scientists trained 15 male and 17 female mice to run through a virtual reality corridor where they could choose to stop in one room associated with stimulation of their AgRP neurons or a second room associated with no stimulation.
In the absences of stress, male mice avoided AgRP stimulation; however, only a minority of female mice exhibited a strong aversion to it. Subsequent to repeated stress, however, many of these same mice behaved very differently. When the researchers exposed the mice to a five-minute period of unpredictable tail shocks, the males became, on average, less averse to AgRP stimulation. Meanwhile, female mice tended to preferAgRP stimulation following stress.
“Strikingly, a subset of females, but not males, began to vigorously seek this starvation-like state following stress,” said Andermann, who is also a professor of Medicine and Neurobiology at Harvard Medical School. “Surprisingly, individuals’ baseline levels of anxiety-like behavior measured weeks before the experiment could predict which females will develop a preference for this starvation-like state.”
Using machine learning to analyse the animals’ facial expressions, the researchers found that, after exposure to stress, female mice with strong preference for AgRP stimulation also showed facial expressions that directly correlated with their behaviour, potentially reflecting relief associated with a reduction in anxiety.
“Future research can link these moment-to-moment changes in facial expressions with ongoing activity of many neurons in brain regions that track physiological states or that process negative emotions,” Kucukdereli said. “Our approach lays the groundwork for future work that will identify the neural circuits that underlie the voluntary maintenance of long-term starvation in individuals with anorexia nervosa.”
