neurosciencestuff:

Team Points to Brain’s ‘Dark Side’ as Key to Cocaine Addiction

Scientists at The Scripps Research Institute (TSRI) have found evidence that an emotion-related brain region called the central amygdala—whose activity promotes feelings of malaise and unhappiness—plays a major role in sustaining cocaine addiction.

In experiments with rats, the TSRI researchers found signs that cocaine-induced changes in this brain system contribute to anxiety-like behavior and other unpleasant symptoms of drug withdrawal—symptoms that typically drive an addict to keep using. When the researchers blocked specific brain receptors called kappa opioid receptors in this key anxiety-mediating brain region, the rats’ signs of addiction abated.

“These receptors appear to be a good target for therapy,” said Marisa Roberto, associate professor in TSRI’s addiction research group, the Committee on the Neurobiology of Addictive Disorders. Roberto was the principal investigator for the study, which appears in the journal Biological Psychiatry.

Carrot or Stick?

In addition to its clinical implications, the finding represents an alternative to the pleasure-seeking, “positive” motivational circuitry that is traditionally emphasized in addiction.

While changes in these pleasure-seeking brain networks may dominate the early period of drug use, scientists have been finding evidence of changes in the “negative” motivational circuitry as well—changes that move a person to take a drug not for its euphoric effects but for its (temporary) alleviation of the anxiety-ridden dysphoria of drug withdrawal. George F. Koob, chair of TSRI’s Committee on the Neurobiology of Addictive Disorders, has argued that these “dark side” brain changes mark the transition to a more persistent drug dependency.

In a series of recent studies, TSRI researchers including Roberto and Koob have highlighted the role of one of these dark-side actors: the receptor for the stress hormone CRF. Found abundantly in the central amygdala, CRF receptors become persistently overactive there as drug use increases, and that overactivity helps account for the negative symptoms of drug withdrawal.

The central amygdala also contains a high concentration of a class of neurotransmitters called dynorphins, which bind to kappa opioid receptors. Much like the CRF system, the dynorphin/kappa opioid system mediates negative, dysphoric feelings—and there have been hints from previous studies that CRF doesn’t work alone in producing such feelings during addiction.

“Our hypothesis was that the dynorphin/kappa opioid receptor system in the central amygdala also becomes overactive with excessive cocaine use,” said Marsida Kallupi, first author of the paper, who was a postdoctoral research associate in Roberto’s laboratory at the time of the study.

Such overactivity would be expected to arise as the brain struggles to maintain “reward homeostasis”—a middle-of-the-road balance between pleasure and displeasure—despite frequent drug-induced swerves toward euphoria. “Dynorphin possibly acts to balance the euphoric effects produced by other opioid systems during recreational drug use,” said Scott Edwards, who is a research associate in the Koob laboratory and a co-author of the study.

Reducing Signs of Addiction

When the TSRI researchers gave rats extended access to cocaine, the rats escalated their daily intake as many human users would. Sensitive electrophysiological measurements revealed signs of a persistent functional overactivity of the GABAergic system in the rats’ central amygdalae—which corresponds to an anxiety-like state in the animals. Probing with compounds that activate or block kappa opioid receptors, the scientists found signs that these receptors, like CRF receptors, do indeed help drive the central amygdala into overactivity during excessive cocaine use.

When the researchers blocked the kappa opioid receptors, central amygdala overactivity was greatly reduced. The same kappa opioid receptor-blocking treatment (antagonist) also reduced two standard signs of addiction in cocaine-using rats—the escalating hyperactive behavior each time the drug is taken and the anxiety-like behavior during withdrawal.

These results give Roberto and her colleagues hope that a similar treatment might help human cocaine addicts feel less compelled to keep using. Kappa opioid receptor blockers are already being developed for the treatment of depression and anxiety.

Blocking negative-motivational factors such as the kappa opioid and CRF systems also has the potential advantage that it spares the positive motivational pathways—the targets of older addiction therapies such as naltrexone. “We need to keep our positive motivational pathways intact so that they can signal the many normal rewarding events in our lives,” said Roberto. By contrast, she suspects, our negative motivational pathways involving CRF and kappa opioid receptors become abnormally active only in disease states such as addiction, and thus may be blocked more safely.

smiliu:

[Article of Interest] National Institute of Mental Health Abandoning the DSM
by Vaughan Bell

In a potentially seismic move, the National Institute of Mental Health – the world’s biggest mental health research funder, has announced only two weeks before the launch of the DSM-5 diagnostic manual that it will be “re-orienting its research away from DSM categories”.
In the announcement, NIMH Director Thomas Insel says the DSM lacks validity and that “patients with mental disorders deserve better”.
This is something that will make very uncomfortable reading for the American Psychiatric Association as they trumpet what they claim is the ‘future of psychiatric diagnosis’ only two weeks before it hits the shelves.
As a result the NIMH will now be preferentially funding research that does not stick to DSM categories:
Going forward, we will be supporting research projects that look across current categories – or sub-divide current categories – to begin to develop a better system. What does this mean for applicants? Clinical trials might study all patients in a mood clinic rather than those meeting strict major depressive disorder criteria. Studies of biomarkers for “depression” might begin by looking across many disorders with anhedonia or emotional appraisal bias or psychomotor retardation to understand the circuitry underlying these symptoms. What does this mean for patients? We are committed to new and better treatments, but we feel this will only happen by developing a more precise diagnostic system.
As an alternative approach, Insel suggests the Research Domain Criteria (RDoC) project, which aims to uncover what it sees as the ‘component parts’ of psychological dysregulation by understanding difficulties in terms of cognitive, neural and genetic differences.
For example, difficulties with regulating the arousal system might be equally as involved in generating anxiety in PTSD as generating manic states in bipolar disorder.
Of course, this ‘component part’ approach is already a large part of mental health research but the RDoC project aims to combine this into a system that allows these to be mapped out and integrated.
It’s worth saying that this won’t be changing how psychiatrists treat their patients any time soon. DSM-style disorders will still be the order of the day, not least because a great deal of the evidence for the effectiveness of medication is based on giving people standard diagnoses.
It is also true to say that RDoC is currently little more than a plan at the moment – a bit like the Mars mission: you can see how it would be feasible but actually getting there seems a long way off. In fact, until now, the RDoC project has largely been considered to be an experimental project in thinking up alternative approaches.
The project was partly thought to be radical because it has many similarities to the approach taken by scientific critics of mainstream psychiatry who have argued for a symptom-based approach to understanding mental health difficulties that has often been rejected by the ‘diagnoses represent distinct diseases’ camp.
The NIMH has often been one of the most staunch supporters of the latter view, so the fact that it has put the RDoC front and centre is not only a slap in the face for the American Psychiatric Association and the DSM, it also heralds a massive change in how we might think of mental disorders in decades to come.

neurosciencestuff:

Implanted device predicts oncoming seizures in those with epilepsy

A new device may offer hope to people with epilepsy as the technology could predict the onset of seizures in adults who have the condition and can’t be treated with medication, according to Australian scientists.

The small device is implanted in the brain. Researchers at the University of Melbourne said their proof-of-concept study found that it can successfully detect brain activity that would lead to episodes of seizures.

“Knowing when a seizure might happen could dramatically improve the quality of life and independence of people with epilepsy and potentially allow them to avoid dangerous situations, such as driving or swimming, or to take drugs to stop the seizures before they start,” Dr. Mark Cook said.

“The first thing of this was to give people back some independence. If they know when a seizure is going to happen, they can arrange their lives to be better, make themselves safer, go about work and so on in a much more comfortable and relaxed way.”

His complete findings were published Thursday night in the prestigious journal, Lancet Neurology.

Epilepsy is a physical condition marked by sudden, brief changes in the brain’s functioning.

The unusual activity in the brain causes patients to have recurring, unprovoked seizures.

There is a wide spectrum when identifying a seizure, from convulsions on one end to tuning out for just a few seconds before returning to regular activities.

Device monitors abnormal brain activity in patients

In the study, 15 people with focal epilepsy between the ages of 20 and 62 had the device implanted between the skull and brain surface.

The study participants typically experienced between two and 12 seizures per month. Although most cases of epilepsy can be treated with medication, theirs was not responsive to at least two drug therapies.

The device, developed by Seattle-based company NeuroVista, monitors electrical activity in the brain.

Once abnormal electrical activity is flagged, the device sends a message to a second device implanted under the skin of the chest similar to a pacemaker.

The information then makes its way to a wireless, hand-held device that calculates the likelihood of a seizure.

Three coloured lights – red, white or blue – warn users of the probability of encountering a seizure.

The researchers found that the system was right about “high warning” of seizures more than 65 per cent of the time and in about 11 of the 15 subjects.

Eight of the patients kept the device activated for about four months – the accuracy ranged from 56 to 100 per cent.

However, three patients had serious side effects, with two needing the device to be removed.

Cook said the findings are promising. If they’re replicated in larger, longer studies, the technology could even offer insight into how to prevent seizures using fast-acting drugs or brain stimulation to stifle a seizure.

ikenbot:

How Abuse Changes a Child’s Brain

Image: D. Sharon Pruitt/Flickr

The brains of children raised in violent families resemble the brains of soldiers exposed to combat, psychologists say.

They’re primed to perceive threat and anticipate pain, adaptations that may be helpful in abusive environments but produce long-term problems with stress and anxiety.

“For them to detect early cues that might signal danger is adaptive. It allows them to react, to try and avoid the danger,” said psychologist Eamon McCrory of University College London. However, “a very similar neural signature characterizes quite a few anxiety disorders.”

In a study published Dec. 5 in Current Biology, McCrory’s team used functional magnetic resonance imaging, or fMRI, to measure blood flows in the brains of 43 children exposed to violence at home as they looked at pictures of sad or angry faces.

Previous studies have shown that abuse affects kids’ brains; as they grow up, abused children become adults with high levels of aggression, anxiety, depression and other behavioral problems. But according to McCrory, the new study is the first to use fMRI to study the form of those changes.

“Understanding the neural mechanisms might give us clues as to how someone’s future might be shaped by their experience,” McCrory said.

His team compared fMRIs from abused children to those of 23 non-abused but demographically similar children from a control group. In the abused children, angry faces provoked distinct activation patterns in their anterior insula and right amygdala, parts of the brain involved in processing threat and pain. Similar patterns have been measured in soldiers who’ve seen combat.

Another recent study found that depression in people who were abused as children is especially difficult to treat. McCrory hopes future work will give a more complete picture of abuse’s neurological effects — and, perhaps, the effects of interventions that help children heal.

“Can children change in response to an act of intervention? To a better home environment? We’re quite optimistic that’s the case, that this is reversible. But that’s something we need to test,” McCrory said.

stayspectacular:

mildlyamused:

An artist with Alzheimer’s drawing self-portraits.

Terrible, frightening disease.

this is one of the saddest things ever.

neurosciencestuff:

Single gene might explain dramatic differences among people with schizophrenia

Some of the dramatic differences seen among patients with schizophrenia may be explained by a single gene that regulates a group of other schizophrenia risk genes. These findings appear in a new imaging-genetics study from the Centre for Addiction and Mental Health (CAMH).

The study revealed that people with schizophrenia who had a particular version of the microRNA-137 gene (or MIR137), tended to develop the illness at a younger age and had distinct brain features – both associated with poorer outcomes – compared to patients who did not have this version. This work, led by Drs. Aristotle Voineskos and James Kennedy, appears in the latest issue of Molecular Psychiatry.

Treating schizophrenia is particularly challenging as the illness can vary from patient to patient. Some individuals stay hospitalized for years, while others respond well to treatment.

“What’s exciting about this study is that we could have a legitimate answer as to why some of these differences occur,” explained Dr. Voineskos, a clinician-scientist in CAMH’s Campbell Family Mental Health Research Institute. “In the future, we might have the capability of using this gene to tell us about prognosis and how a person might respond to treatment.”

“Drs. Voineskos and Kennedy’s findings are very important as they provide new insights into the genetic bases of this condition that affects thousands of Canadians and their families,” said Dr. Anthony Phillips, Scientific Director at the Canadian Institutes of Health Research Institute of Neurosciences, Mental Health and Addiction.

Also, until now, sex has been the strongest predictor of the age at which schizophrenia develops in individuals. Typically, women tend to develop the illness a few years later than men, and experience a milder form of the disease.

“We showed that this gene has a bigger effect on age-at-onset than one’s gender has,” said Dr. Voineskos, who heads the Kimel Family Translational Imaging-Genetics Research Laboratory at CAMH. “This may be a paradigm shift for the field.”

The researchers studied MIR137 — a gene involved in turning on and off other schizophrenia-related genes — in 510 individuals living with schizophrenia. The scientists found that patients with a specific version of the gene tended to develop the illness at a younger age, around 20.8 years of age, compared to 23.4 years of age among those without this version.

“Although three years of difference in age-at-onset may not seem large, those years are important in the final development of brain circuits in the young adult,” said Dr. Kennedy, Director of CAMH’s Neuroscience Research Department. “This can have major impact on disease outcome.”

In a separate part of the study involving 213 people, the researchers used MRI and diffusion tensor-magnetic resonance brain imaging (DT-MRI). They found that individuals who had the particular gene version tended to have unique brain features. These features included a smaller hippocampus, which is a brain structure involved in memory, and larger lateral ventricles, which are fluid-filled structures associated with disease outcome. As well, these patients tended to have more impairment in white matter tracts, which are structures connecting brain regions, and serving as the information highways of the brain.

Developing tests that screen for versions of this gene could be helpful in treating patients earlier and more effectively.

“We’re hoping that in the near future we can use this combination of genetics and brain imaging to predict how severe a version of illness someone might have,” said Dr. Voineskos. “This would allow us to plan earlier for specific treatments and clinical service delivery and pursue more personalized treatment options right from the start.”

(Image: Akelei van Dam)