- Chronic Alcohol Consumption Kills Brain Stem Cells
- By Jason von Stietz, MA
- November 19, 2017
Chronic alcohol abuse gone untreated can lead to severe brain damage. Researchers at The University of Texas Medical Branch at Galveston recently investigated the impact of alcohol consumption on stem cells in the brains of mice. Findings indicated that chronic alcohol consumption killed brain stem cells, reduced the production of new nerve cells, and affected females significantly worse than males. The study was discussed in a recent article in MedicalXpress:
Because the brain stems cells create new nerve cells and are important to maintaining normal cognitive function, this study possibly opens a door to combating chronic alcoholism.
The researchers also found that brain stem cells in key brain regions of adult mice respond differently to alcohol exposure, and they show for the first time that these changes are different for females and males. The findings are available in Stem Cell Reports.
Chronic alcohol abuse can cause severe brain damage and neurodegeneration. Scientists once believed that the number of nerve cells in the adult brain was fixed early in life and the best way to treat alcohol-induced brain damage was to protect the remaining nerve cells.
"The discovery that the adult brain produces stem cells that create new nerve cells provides a new way of approaching the problem of alcohol-related changes in the brain," said Dr. Ping Wu, UTMB professor in the department of neuroscience and cell biology. "However, before the new approaches can be developed, we need to understand how alcohol impacts the brain stem cells at different stages in their growth, in different brain regions and in the brains of both males and females."
In the study, Wu and her colleagues used a cutting-edge technique that allows them to tag brain stem cells and observe how they migrate and develop into specialized nerve cells over time to study the impact of long-term alcohol consumption on them.
Wu said that chronic alcohol drinking killed most brain stem cells and reduced the production and development of new nerve cells.
The researchers found that the effects of repeated alcohol consumption differed across brain regions. The brain region most susceptible to the effects of alcohol was one of two brain regions where new brain cells are created in adults.
They also noted that female mice showed more severe deficits than males. The females displayed more severe intoxication behaviors and more greatly reduced the pool of stem cells in the subventricular zone.
Using this model, scientists expect to learn more about how alcohol interacts with brain stem cells, which will ultimately lead to a clearer understanding of how best to treat and cure alcoholism.
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- Should Schizophrenia Be Reconceptualized?
- By Jason von Stietz, MA
- October 26, 2017
People commonly view schizophrenia as a chronic and hopeless brain disease. However, researchers and clinicians are beginning to believe that this is not the case. Rather, some believe that what we now know as schizophrenia is the most severe end of the spectrum or of psychosis. They believe that what we call schizophrenia is actually many different diseases and disorders that we currently lump together. Sciencr discussed this new conceptualization in a recent article:
Today, having a diagnosis of schizophrenia is associated with a life-expectancy reduction of nearly two decades. By some criteria, only one in seven people recover. Despite heralded advances in treatments, staggeringly, the proportion of people who recover hasn’t increased over time. Something is profoundly wrong.
Part of the problem turns out to be the concept of schizophrenia itself.
Arguments that schizophrenia is a distinct disease have been “fatally undermined”. Just as we now have the concept of autism spectrum disorder, psychosis (typically characterised by distressing hallucinations, delusions, and confused thoughts) is also argued to exist along a continuum and in degrees. Schizophrenia is the severe end of a spectrum or continuum of experiences.
Jim van Os, a professor of psychiatry at Maastricht University, has argued that we cannot shift to this new way of thinking without changing our language. As such, he proposes the term schizophrenia “should be abolished”. In its place, he suggests the concept of a psychosis spectrum disorder.
Another problem is that schizophrenia is portrayed as a “hopeless chronic brain disease”. As a result, some people given this diagnosis, and some parents, have been told cancer would have been preferable, as it would be easier to cure. Yet this view of schizophrenia is only possible by excluding people who do have positive outcomes. For example, some who recover are effectively told that “it mustn’t have been schizophrenia after all”.
Schizophrenia, when understood as a discrete, hopeless and deteriorating brain disease, argues van Os, “does not exist”.
BREAKING DOWN BREAKDOWNS
Schizophrenia may instead turn out to be many different things. The eminent psychiatrist Sir Robin Murray describes how:
I expect to see the end of the concept of schizophrenia soon … the syndrome is already beginning to breakdown, for example, into those cases caused by copy number [genetic] variations, drug abuse, social adversity, etc. Presumably this process will accelerate, and the term schizophrenia will be confined to history, like “dropsy”.
Research is now exploring the different ways people may end up with many of the experiences deemed characteristic of schizophrenia: hallucinations, delusions, disorganised thinking and behaviour, apathy and flat emotion.
Indeed, one past error has been to mistake a path for the path or, more commonly, to mistake a back road for a motorway. For example, based on their work on the parasite Toxoplasma gondii, which is transmitted to humans via cats, researchers E. Fuller Torrey and Robert Yolken have argued that “the most important etiological agent [cause of schizophrenia] may turn out to be a contagious cat”. It will not.
Evidence does suggest that exposure to Toxoplasma gondii when young can increase the odds of someone being diagnosed with schizophrenia. However, the size of this effect involves less than a twofold increase in the odds of someone being diagnosed with schizophrenia. This is, at best, comparable to other risk factors, and probably much lower.
For example, suffering childhood adversity, using cannabis, and having childhood viral infections of the central nervous system, all increase the odds of someone being diagnosed with a psychotic disorder (such as schizophrenia) by around two to threefold. More nuanced analyses reveal much higher numbers.
Compared with non-cannabis users, the daily use of high-potency, skunk-like cannabis is associated with a fivefold increase in the odds of someone developing psychosis. Compared with someone who has not suffered trauma, those who have suffered five different types of trauma (including sexual and physical abuse) see their odds of developing psychosis increase more than fiftyfold.
Other routes to “schizophrenia” are also being identified. Around 1% of cases appear to stem from the deletion of a small stretch of DNA on chromosome 22, referred to as 22q11.2 deletion syndrome. It is also possible that a low single digit percentage of people with a schizophrenia diagnosis may have their experiences grounded in inflammation of the brain caused by autoimmune disorders, such as anti-NMDA receptor encephalitis, although this remains controversial.
All the factors above could lead to similar experiences, which we in our infancy have put into a bucket called schizophrenia. One person’s experiences may result from a brain disorder with a strong genetic basis, potentially driven by an exaggeration of the normal process of pruning connections between brain cells that happens during adolescence. Another person’s experiences may be due to a complex post-traumatic reaction. Such internal and external factors could also work in combination.
Either way, it turns out that the two extreme camps in the schizophrenia wars – those who view it as a genetically-based neurodevelopmental disorder and those who view it as a response to psychosocial factors, such as adversity – both had parts of the puzzle. The idea that schizophrenia was a single thing, reached by a single route, contributed to this conflict.
IMPLICATIONS FOR TREATMENT
Many medical conditions, such as diabetes and hypertension, can be reached by multiple routes that nevertheless impact the same biological pathways and respond to the same treatment. Schizophrenia could be like this. Indeed, it has been argued that the many different causes of schizophrenia discussed above may all have a common final effect: increased levels of dopamine.
If so, the debate about breaking schizophrenia down by factors that lead to it would be somewhat academic, as it would not guide treatment. However, there is emerging evidence that different routes to experiences currently deemed indicative of schizophrenia may need different treatments.
Preliminary evidence suggests that people with a history of childhood trauma who are diagnosed with schizophrenia are less likely to be helped by antipsychotic drugs. However, more research into this is needed and, of course, anyone taking antipsychotics should not stop taking them without medical advice. It has also been suggested that if some cases of schizophrenia are actually a form of autoimmune encephalitis, then the most effective treatment could be immunotherapy (such as corticosteroids) and plasma exchange (washing of the blood).
Yet the emerging picture here is unclear. Some new interventions, such as the family-therapy based Open Dialogue approach, show promise for a wide range of people with schizophrenia diagnoses. Both general interventions and specific ones, tailored to someone’s personal route to the experiences associated with schizophrenia, may be needed. This makes it critical to test for and ask people about all potentially relevant causes. This includes childhood abuse, which is still not being routinely asked about and identified.
The potential for different treatments to work for different people further explains the schizophrenia wars. The psychiatrist, patient or family who see dramatic beneficial effects of antipsychotic drugs naturally evangelically advocate for this approach. The psychiatrist, patient or family who see drugs not working, but alternative approaches appearing to help, laud these. Each group sees the other as denying an approach that they have experienced to work. Such passionate advocacy is to be applauded, up to the point where people are denied an approach that may work for them.
WHAT COMES NEXT?
None of this is to say the concept of schizophrenia has no use. Many psychiatrists still see it as a useful clinical syndrome that helps define a group of people with clear health needs. Here it is viewed as defining a biology that is not yet understood but which shares a common and substantial genetic basis across many patients.
Some people who receive a diagnosis of schizophrenia will find it helpful. It can help them access treatment. It can enhance support from family and friends. It can give a name to the problems they have. It can indicate they are experiencing an illness and not a personal failing. Of course, many do not find this diagnosis helpful. We need to retain the benefits and discard the negatives of the term schizophrenia, as we move into a post-schizophrenia era.
What this will look like is unclear. Japan recently renamed schizophrenia as “integration disorder”. We have seen the idea of a new “psychosis spectrum disorder”. However, historically, the classification of diseases in psychiatry has been argued to be the outcome of a struggle in which “the most famous and articulate professor won”. The future must be based on evidence and a conversation which includes the perspectives of people who suffer – and cope well with – these experiences.
Whatever emerges from the ashes of schizophrenia, it must provide better ways to help those struggling with very real experiences.
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- Bilateral Communication Increases in Older Adult Brain
- By Jason von Stietz, M.A.
- September 29, 2017
As the human brain ages, how does it manage to continue doing what we need it to do? A recent study found that the brain of an older adult compensates by increasing bilateral communication during a task. The study was discussed in a recent article in MedicalXpress:
The aged brain tends to show more bilateral communication than the young brain. While this finding has been observed many times, it has not been clear whether this phenomena is helpful or harmful and no study has directly manipulated this effect, until now.
"This study provides an explicit test of some controversial ideas about how the brain reorganizes as we age," said lead author Simon Davis, PhD. "These results suggest that the aging brain maintains healthy cognitive function by increasing bilateral communication."
Simon Davis and colleagues used a brain stimulation technique known as transcranial magnetic stimulation (TMS) to modulate brain activity of healthy older adults while they performed a memory task. When researchers applied TMS at a frequency that depressed activity in one memory region in the left hemisphere, communication increased with the same region in the right hemisphere, suggesting the right hemisphere was compensating to help with the task.
In contrast, when the same prefrontal site was excited, communication was increased only in the local network of regions in the left hemisphere. This suggested that communication between the hemispheres is a deliberate process that occurs on an "as needed" basis.
Furthermore, when the authors examined the white matter pathways between these bilateral regions, participants with stronger white matter fibers connecting left and right hemispheres demonstrated greater bilateral communication, strong evidence that structural neuroplasticity keeps the brain working efficiently in later life.
"Good roads make for efficient travel, and the brain is no different. By taking advantage of available pathways, aging brains may find an alternate route to complete the neural computations necessary for functioning," said Davis.
These results suggest that greater bilaterality in the prefrontal cortex might be the result of the aging brain adapting to the damage endured over the lifespan, in an effort to maintain normal function. Future brain-stimulation techniques could target this bilateral effect in effort to promote communication between the hemispheres and, hopefully, engender healthy cognition throughout the lifespan.
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- Expressive Writing "Cools" The Worried Brain
- By Jason von Stietz, M.A.
- September 22, 2017
It is often recommended that people write about their feelings. However, does writing calm a worried brain? Researchers at Michigan State University found that expressive writing frees cognitive resources and improves performance on a cognitive task. The study was discussed in a recent article in MedicalXpress:
The research, funded by the National Science Foundation and National Institutes of Health, provides the first neural evidence for the benefits of expressive writing, said lead author Hans Schroder, an MSU doctoral student in psychology and a clinical intern at Harvard Medical School's McLean Hospital.
"Worrying takes up cognitive resources; it's kind of like people who struggle with worry are constantly multitasking – they are doing one task and trying to monitor and suppress their worries at the same time," Schroder said. "Our findings show that if you get these worries out of your head through expressive writing, those cognitive resources are freed up to work toward the task you're completing and you become more efficient."
Schroder conducted the study at Michigan State with Jason Moser, associate professor of psychology and director of MSU's Clinical Psychophysiology Lab, and Tim Moran, a Spartan graduate who's now a research scientist at Emory University. The findings are published online in the journal Psychophysiology.
For the study, college students identified as chronically anxious through a validated screening measure completed a computer-based "flanker task" that measured their response accuracy and reaction times. Before the task, about half of the participants wrote about their deepest thoughts and feelings about the upcoming task for eight minutes; the other half, in the control condition, wrote about what they did the day before.
While the two groups performed at about the same level for speed and accuracy, the expressive-writing group performed the flanker task more efficiently, meaning they used fewer brain resources, measured with electroencephalography, or EEG, in the process.
Moser uses a car analogy to describe the effect. "Here, worried college students who wrote about their worries were able to offload these worries and run more like a brand new Prius," he said, "whereas the worried students who didn't offload their worries ran more like a '74 Impala – guzzling more brain gas to achieve the same outcomes on the task."
While much previous research has shown that expressive writing can help individuals process past traumas or stressful events, the current study suggests the same technique can help people – especially worriers – prepare for stressful tasks in the future.
"Expressive writing makes the mind work less hard on upcoming stressful tasks, which is what worriers often get "burned out" over, their worried minds working harder and hotter," Moser said. "This technique takes the edge off their brains so they can perform the task with a 'cooler head.'"
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- Dancing Improves Brain Health in Older Adults
- By Jason von Stietz, M.A.
- September 14, 2017
Most people have heard that exercise is good for the brain? However, what are the benefits of dancing? A recent study found that a dance program involving teaching older adults a new dance move each session led to not only increases in hippocampal volume but also improvements in maintaining postural control/balance. The study was discussed in a recent article in Medical Express:
"Exercise has the beneficial effect of slowing down or even counteracting age-related decline in mental and physical capacity," says Dr Kathrin Rehfeld, lead author of the study, based at the German center for Neurodegenerative Diseases, Magdeburg, Germany. "In this study, we show that two different types of physical exercise (dancing and endurance training) both increase the area of the brain that declines with age. In comparison, it was only dancing that lead to noticeable behavioral changes in terms of improved balance."
Elderly volunteers, with an average age of 68, were recruited to the study and assigned either an eighteen-month weekly course of learning dance routines, or endurance and flexibility training. Both groups showed an increase in the hippocampus region of the brain. This is important because this area can be prone to age-related decline and is affected by diseases like Alzheimer's. It also plays a key role in memory and learning, as well as keeping one's balance.
While previous research has shown that physical exercise can combat age-related brain decline, it is not known if one type of exercise can be better than another. To assess this, the exercise routines given to the volunteers differed. The traditional fitness training program conducted mainly repetitive exercises, such as cycling or Nordic walking, but the dance group were challenged with something new each week.
Dr Rehfeld explains, "We tried to provide our seniors in the dance group with constantly changing dance routines of different genres (Jazz, Square, Latin-American and Line Dance). Steps, arm-patterns, formations, speed and rhythms were changed every second week to keep them in a constant learning process. The most challenging aspect for them was to recall the routines under the pressure of time and without any cues from the instructor."
These extra challenges are thought to account for the noticeable difference in balance displayed by those participants in dancing group. Dr Rehfeld and her colleagues are building on this research to trial new fitness programs that have the potential of maximizing anti-aging effects on the brain.
"Right now, we are evaluating a new system called "Jymmin" (jamming and gymnastic). This is a sensor-based system which generates sounds (melodies, rhythm) based on physical activity. We know that dementia patients react strongly when listening to music. We want to combine the promising aspects of physical activity and active music making in a feasibility study with dementia patients."
Dr Rehfeld concludes with advice that could get us up out of our seats and dancing to our favorite beat.
"I believe that everybody would like to live an independent and healthy life, for as long as possible. Physical activity is one of the lifestyle factors that can contribute to this, counteracting several risk factors and slowing down age-related decline. I think dancing is a powerful tool to set new challenges for body and mind, especially in older age."
This study falls into a broader collection of research investigating the cognitive and neural effects of physical and cognitive activity across the lifespan.
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- Robotic Exoskeleton Improves Walking Ability in Children With Cerebral Palsy
- By Jason von Stietz, M.A.
- August 27, 2017
Children with cerebral palsy, a neurological and movement disorder, often limits mobility and independent life functioning in children. Researchers at Northern Arizona University and the National Institutes of Health examined the use of a robotic exoskeleton to improve waling ability in children with cerebral palsy. The study was discussed in a recent article in Medical Xpress:
According to the Centers for Disease Control and Prevention, cerebral palsy (CP)—caused by neurological damage before, during or after birth—is the most common movement disorder in children, limiting mobility and independence throughout their lives. An estimated 500,000 children in the U.S. have CP.
Although nearly 60 percent of children with the disorder can walk independently, many have crouch gait, a pathological walking pattern characterized by excessive knee bending, which can cause an abnormally high level of stress on the knee. Crouch gait can lead to knee pain and progressive loss of function and is often treated through invasive orthopedic surgery.
Assistant professor of mechanical engineering Zach Lerner, who joined Northern Arizona University's Center for Bioengineering Innovation in 2017, recently published a study in the journal Science Translational Medicine investigating whether wearing a robotic exoskeleton—a leg brace powered by small motors—could alleviate crouch gait in children with cerebral palsy.
"We evaluated a novel exoskeleton for the treatment of crouch gait, one of the most debilitating pathologies in CP," Lerner said. "In our exploratory, multi-week trial, we fitted seven participants between the ages of five and 19 with robotic exoskeletons designed to increase their ability to extend their knees at specific phases in the walking cycle."
After being fitted with the assistive devices, the children participated in several practice sessions. At the end of the trial, six of the seven participants exhibited improvements in walking posture equivalent to outcomes reported from invasive orthopedic surgery. The researchers also demonstrated that improvements in crouch increased over the course of the exploratory trial, which was conducted at the National Institutes of Health Clinical Center in Bethesda, Maryland.
"Together, these results provide evidence supporting the use of wearable exoskeletons as a treatment strategy to improve walking in children with CP," Lerner said.
The exoskeleton was safe and well-tolerated, and all the children were able to walk independently with the device. Rather than guiding the lower limbs, the exoskeleton dynamically changed their posture by introducing bursts of knee extension assistance during discrete portions of the walking cycle, which resulted in maintained or increased knee extensor muscle activity during exoskeleton use.
"Our results suggest powered knee exoskeletons should be investigated as an alternative to or in conjunction with existing treatments for crouch gait, including orthopedic surgery, muscle injections and physical therapy," Lerner said.
Lerner leads NAU's Biomechatronics Lab, where his goal is to improve mobility and function in individuals with neuromuscular and musculoskeletal disabilities through innovations in mechanical and biomedical engineering. Building on the encouraging results of this study, his team is working toward conducting longer-term exoskeleton interventions to take place at home and in the community.
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- Fear-Memories Can Be Erased, Study Finds
- By Jason von Stietz, M.A.
- August 25, 2017
At times, fear is healthy and necessary. For example, an individual hiking in the woods should feel fear and avoid approaching a bear or other wild animals. However, often times individuals develop unhealthy or unhelpful fears such as a phobia of dogs, even if they are domesticated and friendly. Researchers at University of California, Riverside investigatesd the use of a method of selectively erasing fear-memories by weakening the connections of the neurons involved in the formation of those memories. The study was discussed in a recent article in Medical Xpress:
To survive in a dynamic environment, animals develop fear responses to dangerous situations. But not all fear memories, such as those in PTSD, are beneficial to our survival. For example, while an extremely fearful response to the sight of a helicopter is not a useful one for a war veteran, a quick reaction to the sound of a gunshot is still desirable. For survivors of car accidents, it would not be beneficial for them to relive the trauma each time they sit in a car.
In their lab experiments, Jun-Hyeong Cho, M.D., Ph.D., an assistant professor of molecular, cell, and systems biology, and Woong Bin Kim, his postdoctoral researcher, found that fear memory can be manipulated in such a way that some beneficial memories are retained while others, detrimental to our daily life, are suppressed.
The research, done using a mouse model and published today in Neuron, offers insights into how PTSD and specific phobias may be better treated.
"In the brain, neurons communicate with each other through synaptic connections, in which signals from one neuron are transmitted to another neuron by means of neurotransmitters," said Cho, who led the research. "We demonstrated that the formation of fear memory associated with a specific auditory cue involves selective strengthening in synaptic connections which convey the auditory signals to the amygdala, a brain area essential for fear learning and memory. We also demonstrated that selective weakening of the connections erased fear memory for the auditory cue."
In the lab, Cho and Kim exposed mice to two sounds: a high-pitch tone and a low-pitch tone. Neither tone produced a fear response in the mice. Next, they paired only the high-pitched tone with a mild footshock administered to the mice. Following this, Cho and Kim again exposed the mice to the two tones. To the high-pitch tone (with no accompanying footshock), the mice responded by ceasing all movement, called freezing behavior. The mice showed no such response to the low-pitch sound (with no accompanying footshock). The researchers found that such behavioral training strengthened synaptic connections that relay the high-pitch tone signals to the amygdala.
The researchers then used a method called optogenetics to weaken the synaptic connection with light, which erased the fear memory for the high-pitch tone.
"In the brain, neurons receiving the high- and low-pitch tone signals are intermingled," said Cho, a member of the Center for Glial-Neuronal Interactions in the UC Riverside School of Medicine. "We were able, however, to experimentally stimulate just those neurons that responded to the high-pitch sound. Using low-frequency stimulations with light, we were able to erase the fear memory by artificially weakening the connections conveying the signals of the sensory cue—a high-pitch tone in our experiments - that are associated with the aversive event, namely, the footshock."
Cho explained that for adaptive fear responses to be developed, the brain must discriminate between different sensory cues and associate only relevant stimuli with aversive events.
"This study expands our understanding of how adaptive fear memory for a relevant stimulus is encoded in the brain," he said. "It is also applicable to developing a novel intervention to selectively suppress pathological fear while preserving adaptive fear in PTSD."
The researchers note that their method can be adapted for other research, such as "reward learning" where stimulus is paired with reward. They plan next to study the mechanisms involved in reward learning which has implications in treating addictive behaviors.
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- Ritalin's Impact on the Developing Brain
- By Jason von Stietz, M.A.
- July 31, 2017
Does medication taken to treat ADHD in children have a long-term impact on the brain? Researchers in the Netherlands examined the impact of methylphenidate, or ritalin, on the developing brain. The researchers used magnetic resonance spectroscopy scans to determine that methylphenidate use before the age of 23 related to altered levels of GABA, an inhibitory neurotransmitter, in the medial frontal cortex. The study was discussed in a recent article in Medical Xpress:
“The prevalence of ADHD has increased rapidly over the last few years,” said Michelle M. Solleveld of the University of Amsterdam, the study’s corresponding author. “With this, prescription rates of methylphenidate, also known as Ritalin, are increasing as well. The safety and efficacy of methylphenidate treatment in adults has been studied thoroughly. However, methylphenidate treatment for ADHD is actually more common in children, and no studies so far have investigated the possible long-term effects of methylphenidate on the developing brain.”
“Animal studies show that when animals were treated with methylphenidate during their childhood, persisting effects in the brain remained present well into adulthood,” Solleveld told PsyPost. “This alarmed me, as this hasn’t been studied in humans, but psychiatrists are increasingly prescribing methylphenidate to children to acutely decrease their symptoms of ADHD. I, together with the rest of the research group, therefore wanted to investigate this in humans in order to gain more knowledge about these possible persisting effects.”
The researchers used Magnetic Resonance Spectroscopy scans to examine GABA levels in the medial prefrontal cortex of 44 male ADHD patients. They found evidence that methylphenidate use by children produced long-lasting alterations in GABA neurotransmission in this region of the brain.
“This study focuses on one specific neurotransmitter system: the GABA system,” Solleveld explained. “We report that there are lasting changes in this neurotransmitter system when ADHD patients are treated before the age of 23 years old, i.e. during brain development.”
“This was not the case when treatment was started after the age of 23, when the brain was matured. These results indicate that treatment with methylphenidate in childhood does alter this specific neurotransmitter system in the brain in a long-lasting manner.”
Patients who were treated for the first time with stimulants as children showed significantly lower GABA levels in the medial prefrontal cortex, compared to those who started treatment as adults. A dose of methylphenidate also produced a significant increase in GABA levels in patients treated in childhood, but not in patients treated in adulthood.
But more research is needed to strengthen the preliminary findings and understand its implications.
“We now know that there are lasting alterations in the GABA system in the brain after treatment during brain development,” Solleveld told PsyPost. “We do however not know yet whether and how this is expressed in for example a person’s behavior, performance on psychological tests or other personal characteristics.
“Additionally, we only focused on a specific neurotransmitter system, in only 1 voxel (‘cube’ of 2.5×3.5×2.5cm) in the brain, namely in the medial prefrontal cortex. Future studies should address other systems in the brain or focus on behavioral aspects of possible lasting effects of methylphenidate treatment during brain development.”
“This study is part of a larger project, called the ‘effects of Psychotropic drugs on Developing brain (ePOD),'” Solleveld added. “This study consists of a randomized clinical trial part, in which 50 children and 49 adults were treated for 4 months with either methylphenidate or placebo, and a cross-sectional study. We are currently analyzing all the data of both the cross sectional study and the clinical trial, and expect to report more on this topic in the near future. Please find another publication of our group here: http://jamanetwork.com/journals/jamapsychiatry/fullarticle/2538518.”
The study, “Age-dependent, lasting effects of methylphenidate on the GABAergic system of ADHD patients“, was also co-authored by Anouk Schrantee, Nicolaas A.J. Puts, Liesbeth Reneman, and Paul J. Lucassen.
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- Poverty and Malnutrition's Affect on the Brain
- By Jason von Stietz, M.A.
- July 25, 2017
Researchers in Dhaka Bangladesh are studying the link between stunted growth related to impoverished conditions and brain development. About 40% of children in Dhaka suffer from stunted growth by the age of two and findings from magnetic resonance imaging scans show these children to have significantly lower smaller volumes of grey matter than their healthy counterparts. The study was discussed in a recent article in Nature:
In the late 1960s, a team of researchers began doling out a nutritional supplement to families with young children in rural Guatemala. They were testing the assumption that providing enough protein in the first few years of life would reduce the incidence of stunted growth.
It did. Children who got supplements grew 1 to 2 centimetres taller than those in a control group. But the benefits didn't stop there. The children who received added nutrition went on to score higher on reading and knowledge tests as adolescents, and when researchers returned in the early 2000s, women who had received the supplements in the first three years of life completed more years of schooling and men had higher incomes.
“Had there not been these follow-ups, this study probably would have been largely forgotten,” says Reynaldo Martorell, a specialist in maternal and child nutrition at Emory University in Atlanta, Georgia, who led the follow-up studies. Instead, he says, the findings made financial institutions such as the World Bank think of early nutritional interventions as long-term investments in human health.
Since the Guatemalan research, studies around the world — in Brazil, Peru, Jamaica, the Philippines, Kenya and Zimbabwe — have all associated poor or stunted growth in young children with lower cognitive test scores and worse school achievement2.
A picture slowly emerged that being too short early in life is a sign of adverse conditions — such as poor diet and regular bouts of diarrhoeal disease — and a predictor for intellectual deficits and mortality. But not all stunted growth, which affects an estimated 160 million children worldwide, is connected with these bad outcomes. Now, researchers are trying to untangle the links between growth and neurological development. Is bad nutrition alone the culprit? What about emotional neglect, infectious disease or other challenges?
Shahria Hafiz Kakon is at the front line trying to answer these questions in the slums of Dhaka, Bangladesh, where about 40% of children have stunted growth by the age of two. As a medical officer at the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) in Dhaka, she is leading the first-ever brain-imaging study of children with stunted growth. “It is a very new idea in Bangladesh to do brain-imaging studies,” says Kakon.
The research is innovative in other respects, too. Funded by the Bill & Melinda Gates Foundation in Seattle, Washington, it is one of the first studies to look at how the brains of babies and toddlers in the developing world respond to adversity. And it promises to provide important baseline information about early childhood development and cognitive performance.
Kakon and her colleagues have run magnetic resonance imaging (MRI) tests on two- and three-month-old children, and identified brain regions that are smaller in children with stunted growth than in others. They are also using other tests, such as electroencephalography (EEG).
“Brain imaging could potentially be really helpful” as a way to see what is going on in the brains of these young children, says Benjamin Crookston, a health scientist at Brigham Young University in Provo, Utah, who led studies in Peru and other low-income countries that reported a link between poor growth and cognitive setbacks.
The long shadow of stunting
In 2006, the World Health Organization (WHO) reported an extensive study to measure the heights and weights of children between birth and the age of five in Brazil, Ghana, India, Norway, Oman and the United States3. The results showed that healthy, well-fed children the world over follow a very similar growth trajectory, and it established benchmarks for atypical growth. Stunted growth, the WHO decided, is defined as two standard deviations below the median height for a particular age. Such a difference can seem subtle. At 6 months old, a girl would be considered to have stunted growth if she was 61 centimetres long, even though that is less than 5 centimetres short of the median.
The benchmarks helped to raise awareness about stunting. In many countries, more than 30% of children under five meet the definition; in Bangladesh, India, Guatemala and Nigeria, over 40% do. In 2012, growing consensus about the effects of stunting motivated the WHO to pledge to reduce the number of children under five with stunted growth by 40% by 2025.
Even as officials started to take action, researchers realized there were serious gaps in protocols to identify the problems related to stunting. Many studies of brain development relied on tests of memory, speech and other cognitive functions that are ill-suited to very young children. “Babies do not have much of a behavioural repertoire,” says Michael Georgieff, a paediatrician and child psychologist at the University of Minnesota in Minneapolis. And if parents and doctors have to wait until children are in school to notice any differences, it will probably be too late to intervene.
That's where Kakon's work fits in. At 1.63 metres, she is not tall by Western standards, but at the small apartment-building-turned-clinic in Dhaka where she works, she towers over most of her female colleagues. On a recent morning she was with a mother who had phoned her in the middle of the night: the woman's son had a fever. Before examining the boy, Kakon asked his mother how the family was and how he was doing at school, as she usually does. Many parents call Kakon apa — a Bengali word for big sister.
About five years ago, the Gates Foundation became interested in tracking brain development in young children living with adversity, especially stunted growth and poor nutrition. The foundation had been studying children's responses to vaccines at Kakon's clinic. The high rate of stunting, along with the team's strong bonds with participants, clinched the deal.
To get the study off the ground, the foundation connected the Dhaka team with Charles Nelson, a paediatric neuroscientist at Boston Children's Hospital and Harvard Medical School in Massachusetts. He had expertise in brain imaging — and in childhood adversity. In 2000, he began a study tracking the brain development of children who had grown up in harsh Romanian orphanages. Although fed and sheltered, the children had almost no stimulation, social contact or emotional support. Many have experienced long-term cognitive problems.
Nelson's work revealed that the orphans' brains bear marks of neglect. MRIs showed that by the age of eight, they had smaller regions of grey and white matter associated with attention and language than did children raised by their biological families4. Some children who had moved from the orphanages into foster homes as toddlers were spared some of the deficits.
The children in the Dhaka study have a completely different upbringing. They are surrounded by sights, sounds and extended families who often all live together in tight quarters. It is the “opposite of kids lying in a crib, staring at a white ceiling all day”, says Nelson.
But the Bangladeshi children do deal with inadequate nutrition and sanitation. And researchers hadn't explored the impacts of such conditions on cerebral development. There are brain-imaging studies of children growing up in poverty — which, like stunting, could be a proxy for inadequate nutrition6. But these have mostly focused on high-income areas, such as the United States, Europe and Australia. No matter how poor the children there are, most have some nutritious foods, clean water and plumbing, says Nelson. Those in the Dhaka slums live and play around open canals of sewage. “There are many more kids like the kids in Dhaka around the world,” he says. “And we knew nothing about them from a brain level.”
The marks of adversity
By early 2015, Nelson's team and the Bangladeshi researchers had transformed the humble Dhaka clinic into a state-of-the-art lab. For their EEG equipment, they had to find a room with no wires in the walls and without air-conditioning units, both of which could interfere with the device's ability to detect activity in the brain.
The researchers also set up a room for functional near-infrared spectroscopy (fNIRS), in which children wear a headband of sensors that measure blood flow in the brain. The technique gives information about brain activity similar to that from functional MRI, but does not require a large machine and the children do not have to remain motionless. fNIRS has been used in infants since the late 1990s, and is now gaining traction in low-income settings
The researchers are also performing MRIs, at a hospital near the clinic. So far, they have scanned 12 babies aged 2 to 3 months with stunted growth. Similar to the Romanian orphans and the children growing up in poverty in developed countries, these children have had smaller volumes of grey matter than a group of 20 non-stunted babies. It is “remarkably bad”, Nelson says, to see these differences at such a young age. It's hard to tell which regions are affected in such young children, but having less grey matter was associated with worse scores on language and visual-memory tests at six months old.
Some 130 children in the Dhaka study had fNIRS tests at 36 months old, and the researchers saw distinct patterns of brain activity in those with stunting and other adversity. The shorter the children were, the more brain activity they had in response to images and sounds of non-social stimuli, such as trucks. Taller children responded more to social stimuli, such as women's faces. This could suggest delays in the process by which brain regions become specialized for certain tasks, Nelson says.
EEG detected stronger electrical activity among children with stunted growth, along with a range of brainwaves that reflect problem solving and communication between brain regions. That was a surprise to the researchers, because studies in orphans and poor children have generally found dampened activity7. The discrepancy could be related to the different types of adversity that children in Dhaka face, including food insecurity, infections and mothers with high rates of depression.
Nelson's team is trying to parse out which forms of adversity seem to be most responsible for the differences in brain activity among the Dhaka children. The enhanced electrical signals in EEG tests are strongly linked to increases in inflammatory markers in the blood, which probably reflect greater exposure to gut pathogens.
If this holds up as more children are tested, it could point to the importance of improving sanitation and reducing gastrointestinal infections. Or maternal depression could turn out to be strongly linked to brain development, in which case helping mothers could be just as crucial as making sure their babies have good nutrition. “We don't know the answers yet,” says Nelson.
The participants tested at 36 months are now around 5 years old, and the team is getting ready to take some follow-up measurements. These will give an idea of whether or not the children have continued on the same brain-development trajectory, Nelson says. The researchers will also give the five year olds IQ and school-readiness tests to gauge whether the earlier measurements were predictive of school performance.
A better baseline
One of the challenges of such studies is that researchers are still trying to work out what normal brain development looks like. A few years before the Dhaka study began, a team of British and Gambian researchers geared up to do EEG and fNIRS testing on children in rural Gambia during the first two years of life. They were also funded by the Gates Foundation.
Similar to the Dhaka study, the researchers are looking at how brain development is related to a range of measures, including nutrition and parent–child interaction. But along the way, they are trying to define a standard trajectory of brain function for children.
There is a big push at the Gates Foundation and the US National Institutes of Health to nail down that picture of normal brain development, says Daniel Marks, a paediatric neuroscientist at Oregon Health & Science University in Portland, and a consultant for the foundation. “It is just a reflection of the urgency of the problem,” he says.
One of the hopes for the Dhaka study, and the motivation for funding it, is that it will reveal distinct patterns in babies' brains that are predictive of poor outcomes later in life and could be used to see whether interventions are working, says Jeff Murray, a deputy director of discovery and translational sciences at the Gates Foundation.
Any such intervention will probably have to include nutrition, says Martorell. He and his colleagues are doing yet another follow-up study of the Guatemalan villagers to see whether those who got protein supplements before the age of 7 have lower rates of heart disease and diabetes 40 years later. But nutrition alone is unlikely to be enough — either to prevent stunting or to promote normal cognitive development, Martorell says. So far, the most successful nutritional interventions have helped to overcome about one-third of the typical height deficit. And such programmes can be very expensive; in the Guatemalan study, for example, the researchers ran special centres to provide supplements.
Nevertheless, researchers are striving to improve interventions. A group involved in the vaccine study in Bangladesh is planning to test supplements in pregnant women in the hope of boosting babies' birth weight and keeping their growth on track in the crucial first two years of life. Tahmeed Ahmed, senior director of nutrition and clinical services at the diarrhoeal-disease research centre, is planning a trial of foods such as bananas and chickpeas, to try to promote the growth of good gut bacteria in Bangladeshi children aged 12 to 18 months. A healthy bacterial community could make the gut less vulnerable to infections that interfere with nutrient absorption and that ramp up inflammation in the body.
Ultimately, it's not about whether children have stunted growth or even what their brains look like. It's about what their lives are like as they grow older. Studies such as the one in Dhaka strive to help determine whether interventions are working sooner rather than later. “If you have to wait until kids are 25 years old to see whether they are employed,” Murray says, “it could take you 25 years to do every study.”
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- fMRI Predicts And Monitors Change in PTSD Symptoms Following Psychotherapy
- By Jason von Stietz, M.A.
- July 19, 2017
Researchers from Stanford University School of Medicine investigated the use of brain imaging to predict the effectiveness of psychotherapy and measure changes in the brain following treatment. The researchers utilized functional magnetic resonance imaging (fMRI) with 66 participants diagnosed with post-traumatic stress disorder (PTSD), who were undergoing exposure therapy. The findings were discussed in a recent article in MedicalXpress:
PTSD is a serious mental disorder that can develop after a dangerous or traumatic event. Patients experience recurring memories of the event; avoid situations, people or thoughts that remind them of the event; and experience altered mood and thinking patterns. Nearly 7 percent of people in the United States will suffer from PTSD at some point in their lifetime, according to the National Institute of Mental Health.
Prolonged exposure therapy for PTSD consists of a series of sessions and homework assignments that lead patients to gradually approach trauma-related memories and situations. Patients begin by imagining scenarios that trigger their PTSD symptoms—such as a crowded park. Then, they work up to deliberately putting themselves in those scenarios. Revisiting traumatic experiences in this manner can, over time, allow the brain to slowly reduce its response to emotional triggers. However, not all PTSD patients derive benefit from the treatment, and about a third drop out of the arduous process, according to Etkin, who is also an investigator at the Veterans Affairs Palo Alto Health Care System. About two-thirds of patients receiving prolonged exposure therapy see a 50 percent reduction in symptoms, and 40 percent of them achieve remission, he said.
To learn how prolonged exposure therapy works in the brain, the studies used functional magnetic resonance imaging to measure the brain activity of 66 patients diagnosed with PTSD as they completed five tasks tapping a variety of emotional and cognitive functions. During these tasks, patients would view, for example, images of faces or scenes—like happy, neutral or scared faces or a scene depicting an event meant to induce negative emotions, such as an argument or physical violence—and either respond to questions about the images or try to control their response to the image's content.
After the initial brain imaging, about half the participants underwent nine to 12 sessions of prolonged exposure therapy; the remainder did not. At the end of the trial, all participants went through the same emotional response and regulation tests while researchers measured brain activity.
A step closer to personalized treatment
One of the studies focused on whether brain activity levels before treatment could help scientists predict which participants would respond well to prolonged exposure therapy. The researchers measured how active certain brain regions were during the five tasks and looked for associations with reduced symptoms post-treatment.
Prior to receiving prolonged exposure therapy, patients with both lower activity in the amygdala and higher activity in various regions of the frontal lobe while viewing faces with fearful expressions showed a larger reduction in PTSD symptoms following therapy. Fonzo refers to the amygdala, seated deep within a primitive region of the brain, as the brain's alarm system, as it plays an important role in fear and other emotional responses. The frontal lobe is the outer layer of the human brain in the area behind the forehead; it plays a role in complex functions such as behavior, personality and decision-making.
The researchers also found that patients with greater activation in a deep region of the frontal lobe when ignoring the distracting effects of conflicting emotional information—such as a picture of a scared face with the word "happy" written across it—responded better to exposure therapy.
"The better able the brain is at deploying attention- and emotion-controlling processes, the better you respond to treatment," said Fonzo.
Using this information about how the brain responds in emotional regulation and processing tasks, the team was able to predict how effective prolonged exposure therapy treatment would be for patients with up to 95.5 percent accuracy. This kind of screening approach, perhaps using the less expensive and more widely available electroencephalogram rather than fMRI, could help doctors determine the best course of PTSD therapy in the future, the researchers said.
"Not only could it provide a ray of hope for patients who would benefit from prolonged exposure to make it through the tough course," said Goodkind, "it means patients who wouldn't derive a benefit wouldn't have to start the treatment."
Therapy changes the brain
In the second study, the researchers found that prolonged exposure therapy led to lasting changes in participants' brains that were associated with improvement in PTSD symptoms. About four weeks after therapy ended, fMRI showed elevated activity in the front-most region of the frontal lobe, an area called the frontopolar cortex. This region is the most recently evolved part of the human brain. It balances internal and external attention and helps coordinate multiple processes in the brain simultaneously, said Fonzo, as would occur when multitasking and remembering future to-do list items.
The role the frontopolar cortex plays in prolonged exposure therapy was surprising, Fonzo said, because much of the scientific attention on emotional processes in PTSD has centered on the amygdala.
Specifically, the changes the researchers observed in frontopolar cortex activity occurred when participants were instructed to regulate their emotional response to an image of a negative or stressful scenario, such as one depicting an argument. The researchers also noted changes in frontopolar cortex activity in these participants during a resting, nonfocused state. The changes in frontopolar cortex activity indicate a shift in frontopolar function following therapy, according to the authors.
The post-therapy brain changes also included increased connectivity between the frontopolar cortex and deeper brain regions closer to emotional processing areas. The authors wrote that psychotherapy may train the frontopolar cortex "to better evoke or amplify attention toward an internal regulatory process that mediates successful emotion regulation."
The degree to which activity in the frontopolar cortex increased following therapy was associated with the degree of improvement in PTSD symptoms and emotional well-being.
Exploring use of transcranial magnetic stimulation
To confirm whether the frontopolar cortex controls important brain regions for emotional processing, the team used a noninvasive method of stimulating brain activity called transcranial magnetic stimulation, or TMS, to activate the frontopolar cortex in healthy people. They simultaneously recorded brain activity with fMRI and confirmed that the frontopolar cortex modulated downstream activity in lower cortical regions closer to emotion-processing parts of the brain.
They also explored whether TMS might help PTSD patients respond to prolonged exposure treatment. Building off their findings that greater frontal lobe and less amygdala activation predicts better treatment outcome, the researchers activated a region of the frontal cortex with TMS probes while imaging the brain. They found that doing so inhibited activity in the amygdala, and the degree to which that happened also predicted the degree to which a patient's symptoms improved. In the future, stimulating this region may help increase patients' responsiveness to psychotherapy, they said. Indeed, some small-scale studies in which therapeutic TMS was used daily on the same region of the frontal cortex, without the addition of psychotherapy, have already shown promising results.
"These findings put a place marker in our understanding of psychotherapy writ large. We can really put psychiatric disorders on the map in terms of hard science and help fight the stigma that surrounds these illnesses and their treatment," said Etkin. "Within the field of PTSD, it gives a concrete sense of hope for people undergoing treatment and starts laying the groundwork for new treatments based on understanding brain circuitry."
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