Posts Tagged ‘depression’

Mit-Dopamine-Tracking_0

By Anne Trafton

Dopamine, a signaling molecule used throughout the brain, plays a major role in regulating our mood, as well as controlling movement. Many disorders, including Parkinson’s disease, depression, and schizophrenia, are linked to dopamine deficiencies.

MIT neuroscientists have now devised a way to measure dopamine in the brain for more than a year, which they believe will help them to learn much more about its role in both healthy and diseased brains.

“Despite all that is known about dopamine as a crucial signaling molecule in the brain, implicated in neurologic and neuropsychiatric conditions as well as our abilty to learn, it has been impossible to monitor changes in the online release of dopamine over time periods long enough to relate these to clinical conditions,” says Ann Graybiel, an MIT Institute Professor, a member of MIT’s McGovern Institute for Brain Research, and one of the senior authors of the study.

Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research, and Rober Langer, the David H. Koch Institute Professor and a member of the Koch Institute, are also senior authors of the study. MIT postdoc Helen Schwerdt is the lead author of the paper, which appears in the Sept. 12 issue of Communications Biology.

Long-term sensing

Dopamine is one of many neurotransmitters that neurons in the brain use to communicate with each other. Traditional systems for measuring dopamine — carbon electrodes with a shaft diameter of about 100 microns — can only be used reliably for about a day because they produce scar tissue that interferes with the electrodes’ ability to interact with dopamine.

In 2015, the MIT team demonstrated that tiny microfabricated sensors could be used to measure dopamine levels in a part of the brain called the striatum, which contains dopamine-producing cells that are critical for habit formation and reward-reinforced learning.

Because these probes are so small (about 10 microns in diameter), the researchers could implant up to 16 of them to measure dopamine levels in different parts of the striatum. In the new study, the researchers wanted to test whether they could use these sensors for long-term dopamine tracking.

“Our fundamental goal from the very beginning was to make the sensors work over a long period of time and produce accurate readings from day to day,” Schwerdt says. “This is necessary if you want to understand how these signals mediate specific diseases or conditions.”

To develop a sensor that can be accurate over long periods of time, the researchers had to make sure that it would not provoke an immune reaction, to avoid the scar tissue that interferes with the accuracy of the readings.

The MIT team found that their tiny sensors were nearly invisible to the immune system, even over extended periods of time. After the sensors were implanted, populations of microglia (immune cells that respond to short-term damage), and astrocytes, which respond over longer periods, were the same as those in brain tissue that did not have the probes inserted.

In this study, the researchers implanted three to five sensors per animal, about 5 millimeters deep, in the striatum. They took readings every few weeks, after stimulating dopamine release from the brainstem, which travels to the striatum. They found that the measurements remained consistent for up to 393 days.

“This is the first time that anyone’s shown that these sensors work for more than a few months. That gives us a lot of confidence that these kinds of sensors might be feasible for human use someday,” Schwerdt says.

Paul Glimcher, a professor of physiology and neuroscience at New York University, says the new sensors should enable more researchers to perform long-term studies of dopamine, which is essential for studying phenomena such as learning, which occurs over long time periods.

“This is a really solid engineering accomplishment that moves the field forward,” says Glimcher, who was not involved in the research. “This dramatically improves the technology in a way that makes it accessible to a lot of labs.”

Monitoring Parkinson’s

If developed for use in humans, these sensors could be useful for monitoring Parkinson’s patients who receive deep brain stimulation, the researchers say. This treatment involves implanting an electrode that delivers electrical impulses to a structure deep within the brain. Using a sensor to monitor dopamine levels could help doctors deliver the stimulation more selectively, only when it is needed.

The researchers are now looking into adapting the sensors to measure other neurotransmitters in the brain, and to measure electrical signals, which can also be disrupted in Parkinson’s and other diseases.

“Understanding those relationships between chemical and electrical activity will be really important to understanding all of the issues that you see in Parkinson’s,” Schwerdt says.

The research was funded by the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Neurological Disorders and Stroke, the Army Research Office, the Saks Kavanaugh Foundation, the Nancy Lurie Marks Family Foundation, and Dr. Tenley Albright.

https://news.mit.edu/2018/brain-dopamine-tracking-sensors-0912

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A 3-D rendering of the serotonin system in the left hemisphere of the mouse brain reveals two groups of serotonin neurons in the dorsal raphe that project to either cortical regions (blue) or subcortical regions (green) while rarely crossing into the other’s domain.

As Liqun Luo was writing his introductory textbook on neuroscience in 2012, he found himself in a quandary. He needed to include a section about a vital system in the brain controlled by the chemical messenger serotonin, which has been implicated in everything from mood to movement regulation. But the research was still far from clear on what effect serotonin has on the mammalian brain.

“Scientists were reporting divergent findings,” said Luo, who is the Ann and Bill Swindells Professor in the School of Humanities and Sciences at Stanford University. “Some found that serotonin promotes pleasure. Another group said that it increases anxiety while suppressing locomotion, while others argued the opposite.”

Fast forward six years, and Luo’s team thinks it has reconciled those earlier confounding results. Using neuroanatomical methods that they invented, his group showed that the serotonin system is actually composed of at least two, and likely more, parallel subsystems that work in concert to affect the brain in different, and sometimes opposing, ways. For instance, one subsystem promotes anxiety, whereas the other promotes active coping in the face of challenges.

“The field’s understanding of the serotonin system was like the story of the blind men touching the elephant,” Luo said. “Scientists were discovering distinct functions of serotonin in the brain and attributing them to a monolithic serotonin system, which at least partly accounts for the controversy about what serotonin actually does. This study allows us to see different parts of the elephant at the same time.”

The findings, published online on August 23 in the journal Cell, could have implications for the treatment of depression and anxiety, which involves prescribing drugs such as Prozac that target the serotonin system – so-called SSRIs (selective serotonin reuptake inhibitors). However, these drugs often trigger a host of side effects, some of which are so intolerable that patients stop taking them.

“If we can target the relevant pathways of the serotonin system individually, then we may be able to eliminate the unwanted side effects and treat only the disorder,” said study first author Jing Ren, a postdoctoral fellow in Luo’s lab.

Organized projections of neurons

The Stanford scientists focused on a region of the brainstem known as the dorsal raphe, which contains the largest single concentration in the mammalian brain of neurons that all transmit signals by releasing serotonin (about 9,000).

The nerve fibers, or axons, of these dorsal raphe neurons send out a sprawling network of connections to many critical forebrain areas that carry out a host of functions, including thinking, memory, and the regulation of moods and bodily functions. By injecting viruses that infect serotonin axons in these regions, Ren and her colleagues were able to trace the connections back to their origin neurons in the dorsal raphe.

This allowed them to create a visual map of projections between the dense concentration of serotonin-releasing neurons in the brainstem to the various regions of the forebrain that they influence. The map revealed two distinct groups of serotonin-releasing neurons in the dorsal raphe, which connected to cortical and subcortical regions in the brain.

“Serotonin neurons in the dorsal raphe project to a bunch of places throughout the brain, but those bunches of places are organized,” Luo said. “That wasn’t known before.”

Two parts of the elephant

In a series of behavioral tests, the scientists also showed that serotonin neurons from the two groups can respond differently to stimuli. For example, neurons in both groups fired in response to mice receiving rewards like sips of sugar water but they showed opposite responses to punishments like mild foot shocks.

“We now understand why some scientists thought serotonin neurons are activated by punishment, while others thought it was inhibited by punishment. Both are correct – it just depends on which subtype you’re looking at,” Luo said.

What’s more, the group found that the serotonin neurons themselves were more complex than originally thought. Rather than just transmitting messages with serotonin, the cortical-projecting neurons also released a chemical messenger called glutamate – making them one of the few known examples of neurons in the brain that release two different chemicals.

“It raises the question of whether we should even be calling these serotonin neurons because neurons are named after the neurotransmitters they release,” Ren said.

Taken together, these findings indicate that the brain’s serotonin system is not made up of a homogenous population of neurons but rather many subpopulations acting in concert. Luo’s team has identified two groups, but there could be many others.

In fact, Robert Malenka, a professor and associate chair of psychiatry and behavioral sciences at Stanford’s School of Medicine, and his team recently discovered a group of serotonin neurons in the dorsal raphe that project to the nucleus accumbens, the part of the brain that promotes social behaviors.

“The two groups that we found don’t send axons to the nucleus accumbens, so this is clearly a third group,” Luo said. “We identified two parts of the elephant, but there are more parts to discover.”

https://medicalxpress.com/news/2018-08-brain-serotonin.html

BY ARISTOS GEORGIOU

Young people suffering from treatment-resistant depression (TRD) showed a significant reduction of their symptoms after being administered ketamine injections, according to a study published in the Journal of Child and Adolescent Psychopharmacology.

Researchers from the University of Minnesota (UM) and the nonprofit Mayo Clinic found that ketamine caused an average decrease of 42 percent on the Children’s Depression Rating Scale (CDRS)—the most widely used rating scale in research trials for assessing the severity of depression and change in depressive symptoms among adolescents.

Ketamine is perhaps best known for being a popular recreational drug and a useful medical anesthetic, but a growing body of research is indicating that the compound could be an effective treatment for depression. Several recent studies have shown that even a single dose in adults can lead to rapid reductions in depressive symptoms. However, relatively little research has been conducted into ketamine’s antidepressant effects in adolescents.

“Adolescence is a very important time for studying depression, first because depression often starts during these years, and second because it is an important time for brain development,” Kathryn Cullen, from the Department of Psychiatry at UM, told Newsweek.

“When adolescent depression persists without successful treatment, it can interfere with achieving important developmental milestones. Finding the right treatment is critical to allow the restoration of healthy brain development and prevent negative outcomes like chronic depression, disability and suicide.”

Unfortunately, about 40 percent of adolescents do not respond to their first intervention and only half of nonresponders respond to the second treatment, according to the researchers.

“Standard antidepressant treatments do not work for everyone and take weeks to months to take effect, a time period when patients are at risk for continued suffering and suicide attempts,” Cullen said. “The field is in need of new treatment options. Ketamine has a very different mechanism of action than standard treatments.”

The latest study involved 13 young people ages 12 to 18 who had failed two previous trials of antidepressants. During a two-week period, the researchers gave them six ketamine infusions.

They found that the treatment was well tolerated, with the participants showing an average decrease in CDRS scores of 42.5 percent. Five of the participants met the criteria for clinical response and remission. Of these, three were still in remission after six weeks, while the remaining two relapsed within two weeks.

According to the scientists, the results demonstrate the potential role for ketamine in treating adolescents with TRD. However, they note that the study was limited by its small sample size, so future research will be needed to confirm these results.

“The purpose of our study was to investigate the effects of ketamine for TRD in younger patients for whom this indication for ketamine administration is not well studied,” Mark Roback, a professor of pediatrics at the University of Minnesota, told Newsweek.

“I think our results show promise for this population, however this study is just a beginning. The study serves to point out the need for further, rigorous, study designed to answer the many questions that remain about ketamine for TRD, such as optimal dosing and route of administration, dosing interval and treatment length, and long-term effects—just to name a few.”

James Stone, a clinical senior lecturer from the Institute of Psychiatry, Psychology and Neuroscience at King’s College London, who was not involved in the study, told Newsweek that there is “a lot of potential for the use of ketamine as a second or third line antidepressant where other treatments have failed.”

“Although ketamine is potentially a huge breakthrough in the treatment of depression, we still don’t know about the long-term safety, or about how to keep people well from depression without requiring regular ketamine dosing,” Stone added. “Further studies are needed to address these questions.”

https://www.newsweek.com/ketamine-shows-promise-treatment-adolescents-depression-1054021

By Michelle Star

People who live with depression have low blood levels of a specific molecule, new medical research has revealed. It’s called acetyl-L-carnitine, and those with particularly severe, treatment-resistant or childhood onset depression were found to have the lowest levels.

Naturally produced by the body, acetyl-L-carnitine plays a crucial role in metabolising fat and the production of energy. It’s also widely available as a dietary supplement – not some strange and esoteric thing.

Now researchers from multiple institutions have found a link to depression, noticing a clear correlation between the condition and noticeably low levels of acetyl-L-carnitine.

In recent years, more and more evidence has been building to suggest this link. Since at least 1991, medical researchers have been aware of acetyl-L-carnitine’s potential to treat depression, particularly in geriatric and comorbid patients, with the substance showing greater efficacy than a placebo.

More recently, Carla Nasca of the Rockefeller University led a study on rodents, which found that acetyl-L-carnitine had a fast-acting antidepressant effect on rats, kicking into effect in just a few days, rather than the weeks it takes for drugs like SSRIs.

Now Nasca and colleagues have conducted a study on human patients to see if there’s a basis for a similar trial in people.

“As a clinical psychiatrist, I have treated many people with this disorder in my practice,” said Stanford University School of Medicine psychiatrist Natalie Rasgon.

“It’s the number one reason for absenteeism at work, and one of the leading causes of suicide. Worse, current pharmacological treatments are effective for only about 50 percent of the people for whom they’re prescribed. And they have numerous side effects, often decreasing long term compliance.”

The research team recruited 71 patients with a diagnosis of depression. These were men and women, aged between 20 and 70. They also recruited 45 demographically matched healthy controls.

The patients had to fill out a detailed questionnaire, undergo a clinical assessment and medical history, and give a blood sample. Of the patients with depression, 28 had moderate depression and 43 had severe depression at the time of the study.

When compared to the age- and sex-matched healthy controls, the patients with depression had substantially lower levels of acetyl-L-carnitine.

Those with the most severe depression had the lowest levels. This included patients whose depression had resisted antidepressant drugs, those with early onset, and those who had experienced childhood abuse, neglect, poverty or violence.

These patients constitute around 25-30 percent of all people suffering depression, and are the most in need of help, the researchers said.

But there are a few steps to be done before acetyl-L-carnitine supplements can be approved as a treatment. In particular, clinical trials on human patients with depression, since, as we know, results from rodent models can’t always be replicated in humans.

The researchers also don’t know the reason for the correlation, or the effect it has. The rat research suggests that acetyl-L-carnitine plays a role in the brain, preventing the excessive firing of excitatory neurons, but this will need to be explored further as well.

“We’ve identified an important new biomarker of major depression disorder,” Rasgon said.

“We didn’t test whether supplementing with that substance could actually improve patients’ symptoms. What’s the appropriate dose, frequency, duration? We need to answer many questions before proceeding with recommendations, yet. This is the first step toward developing that knowledge, which will require large-scale, carefully controlled clinical trials.”

https://www.sciencealert.com/depression-linked-to-low-blood-levels-of-acetyl-l-carnitine-human-study

By Rachael Rettner

Many people tend to look back on the past with rose-colored glasses, remembering the good times and the good feelings…while forgetting the bad.

But a new study suggests that heavy marijuana users may have some trouble letting go of negative emotions tied to memories — a phenomenon that’s also seen in people with depression. Earlier research has also linked marijuana use with depression.

Although the new results are very preliminary, the findings, presented here on Friday (May 25) at the annual meeting of the Association for Psychological Science, may offer clues about the link between marijuana use and depression.

Rose-colored memories

The study explored a psychological phenomenon called “fading affect bias,” in which people tend to hold on to positive feelings tied to their memories more than they hold on to negative feelings. In other words, negative feelings related to our memories fade faster than positive ones.

Psychologists have hypothesized that this phenomenon, which is generally seen in people without mental health conditions, may serve as a sort of “psychological immune system,” said study lead author Daniel Pillersdorf, a graduate student in psychology at the University of Windsor in Ontario. This may be “so that we think more pleasantly in general, and don’t have that cognitive burden of holding on to negative emotions associated with memories,” Pillersdorf said.

Some previous studies have suggested that this fading affect bias may be different for people who use drugs, but no studies have looked at whether marijuana use could affect this phenomenon.

In the new study, the researchers analyzed information from 46 heavy marijuana users — most of whom used the drug at least four times a week — and 51 people who didn’t use marijuana. Participants were asked to recall, and provide written descriptions of, three pleasant memories and three unpleasant memories from the past year. The participants were then asked to rate the intensity of emotion tied to those memories, on a scale of negative 10, meaning extremely unpleasant, to positive 10, or extremely pleasant. They rated their emotions both at the time the memory was made, and at the current time. (Marijuana users were not under the influence at the time the researchers asked them the questions.)

The researchers found that both marijuana users and non-users showed fading affect bias, but for marijuana users, the fading was a lot less.

“They were hanging on to that unpleasant affect over time, much more” than non-users, Pillersdorf told Live Science. “They were less able … to shed that unpleasantness associated with their memories.”

The study also found that marijuana users tended to recall life events in more general terms than specific ones. For example, when asked about a happy event in the past year, marijuana users were more likely to respond with general or broad answers such as “I went on vacation,” rather than recalling a specific event or day, such as “I attended my college graduation.” This phenomenon is known as over-general autobiographical memory, and it’s also linked with depression, Pillersdorf said.

It’s important to note that the new study found only an association and cannot determine why marijuana users show less fading affect bias, and more overgeneral memory, than non-users.

Link with depression?

Even so, the new findings agree with previous research that has found a link between heavy marijuana use and depression. However, researchers don’t know why marijuana and depression are linked — it could be that marijuana use plays a role in developing depression, or that people who are already depressed are more likely to use the drug. [7 Ways Marijuana May Affect the Brain]

Based on the new findings, one hypothesis is that the decreased “fading” of negative memories in marijuana users could be contributing to the development or continuing of depression, Pillersdorf said. “It may be that, chronic or frequent cannabis use is putting [a person] more at risk for the development or continuing of depression,” he said. However, Pillersdorf stressed that this is just a hypothesis that would need to be investigated with future research.

To further investigate the link, researchers will need to study marijuana users and non-users over long periods of time. For example, researchers could start with people in their late teens or early 20s, who don’t have depression, and see if those who use marijuana frequently are more likely to eventually develop depression than non-users.

Additional studies could also investigate whether other substances have an effect on fading affect bias, Pillersdorf said.

The study has not yet been published in a peer-reviewed journal.

https://www.livescience.com/62679-marijuana-negative-memories.html?utm_source=notification

Psychologists at the University of Sussex have found a link between depression and an acceleration of the rate at which the brain ages. Although scientists have previously reported that people with depression or anxiety have an increased risk of dementia in later life, this is the first study that provides comprehensive evidence for the effect of depression on decline in overall cognitive function (also referred to as cognitive state), in a general population.

For the study, published today, Thursday 24 May 2018, in the journal Psychological Medicine, researchers conducted a robust systematic review of 34 longitudinal studies, with the focus on the link between depression or anxiety and decline in cognitive function over time. Evidence from more than 71,000 participants was combined and reviewed. Including people who presented with symptoms of depression as well as those that were diagnosed as clinically depressed, the study looked at the rate of decline of overall cognitive state – encompassing memory loss, executive function (such as decision making) and information processing speed – in older adults.

Importantly, any studies of participants who were diagnosed with dementia at the start of study were excluded from the analysis. This was done in order to assess more broadly the impact of depression on cognitive ageing in the general population. The study found that people with depression experienced a greater decline in cognitive state in older adulthood than those without depression. As there is a long pre-clinical period of several decades before dementia may be diagnosed, the findings are important for early interventions as currently there is no cure for the disease.

Lead authors of the paper, Dr Darya Gaysina and Amber John from the EDGE (Environment, Development, Genetics and Epigenetics in Psychology and Psychiatry) Lab at the University of Sussex, are calling for greater awareness of the importance of supporting mental health to protect brain health in later life.

Dr Gaysina, a Lecturer in Psychology and EDGE Lab Lead, comments: “This study is of great importance – our populations are ageing at a rapid rate and the number of people living with decreasing cognitive abilities and dementia is expected to grow substantially over the next thirty years.

“Our findings should give the government even more reason to take mental health issues seriously and to ensure that health provisions are properly resourced. We need to protect the mental wellbeing of our older adults and to provide robust support services to those experiencing depression and anxiety in order to safeguard brain function in later life.”

Researcher Amber John, who carried out this research for her PhD at the University of Sussex adds: “Depression is a common mental health problem – each year, at least 1 in 5 people in the UK experience symptoms. But people living with depression shouldn’t despair – it’s not inevitable that you will see a greater decline in cognitive abilities and taking preventative measures such as exercising, practicing mindfulness and undertaking recommended therapeutic treatments, such as Cognitive Behaviour Therapy, have all been shown to be helpful in supporting wellbeing, which in turn may help to protect cognitive health in older age.”

The research paper, ‘Affective problems and decline in cognitive state in older adults’ will be available at: https:// doi.org/10.1017/S0033291718001137 from Thursday 24 May 2018.

http://www.sussex.ac.uk/broadcast/read/44977


The study simulated long-term consumption of three cups of coffee a day.

It is well known that memory problems are the hallmarks of Alzheimer’s disease. However, this dementia is also characterized by neuro-psychiatric symptoms, which may be strongly present already in the first stages of the disorder. Known as Behavioural and Psychological Symptoms of Dementia (BPSD), this array of symptoms — including anxiety, apathy, depression, hallucinations, paranoia and sundowning (or late-day confusion) — are manifested in different manners depending on the individual patient, and are considered the strongest source of distress for patients and caregivers.


Coffee and caffeine: good or bad for dementia?

Caffeine has recently been suggested as a strategy to prevent dementia, both in patients with Alzheimer’s disease and in normal ageing processes. This is due to its action in blocking molecules — adenosine receptors — which may cause dysfunctions and diseases in old age. However, there is some evidence that once cognitive and neuro-psychiatric symptoms develop, caffeine may exert opposite effects.

To investigate this further, researchers from Spain and Sweden conducted a study with normal ageing mice and familial Alzheimer’s models. The research, published in Frontiers in Pharmacology, was conducted from the onset of the disease up to more advanced stages, as well as in healthy age-matched mice.

“The mice develop Alzheimer’s disease in a very close manner to human patients with early-onset form of the disease,” explains first author Raquel Baeta-Corral, from Universitat Autònoma de Barcelona, Spain. “They not only exhibit the typical cognitive problems but also a number of BPSD-like symptoms. This makes them a valuable model to address whether the benefits of caffeine will be able to compensate its putative negative effects.”

“We had previously demonstrated the importance of the adenosine A1 receptor as the cause of some of caffeine’s adverse effects,” explains Dr. Björn Johansson, a researcher and physician at the Karolinska University Hospital, Sweden.

“In this study, we simulated a long oral treatment with a very low dose of caffeine (0.3 mg/mL) — equivalent to three cups of coffee a day for a human — to answer a question which is relevant for patients with Alzheimer’s, but also for the ageing population in general, and that in people would take years to be solved since we would need to wait until the patients were aged.”

Worsened Alzheimer’s symptoms outweigh cognition benefits

The results indicate that caffeine alters the behavior of healthy mice and worsens the neuropsychiatric symptoms of mice with Alzheimer’s disease. The researchers discovered significant effects in the majority of the study variables — and especially in relation to neophobia (a fear of everything new), anxiety-related behaviors, and emotional and cognitive flexibility.

In mice with Alzheimer’s disease, the increase in neophobia and anxiety-related behaviours exacerbates their BPSD-like profile. Learning and memory, strongly influenced by anxiety, got little benefit from caffeine.

“Our observations of adverse caffeine effects in an Alzheimer’s disease model, together with previous clinical observations, suggest that an exacerbation of BPSD-like symptoms may partly interfere with the beneficial cognitive effects of caffeine. These results are relevant when coffee-derived new potential treatments for dementia are to be devised and tested,” says Dr. Lydia Giménez-Llort, researcher from the INc-UAB Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, and lead researcher of the project.

The results of the study form part of the PhD thesis of Raquel Baeta-Corral, first author of the article, and are the product of a research led by Lydia Giménez-Llort, Director of the Medical Psychology Unit, Department of Psychiatry and Legal Medicine and researcher at the UAB Institute of Neuroscience, together with Dr Björn Johansson, Researcher at the Department of Molecular Medicine and Surgery, Karolinska Institutet and the Department of Geriatrics, Karolinska University Hospital, Sweden, under the framework of the Health Research Fund project of the Institute of Health Carlos III.

Long-term caffeine worsens symptoms associated with Alzheimer’s disease