Interventions to prevent cognitive decline, dementia

Cognitive training, blood pressure management for people with hypertension, and increased physical activity all show modest but inconclusive evidence that they can help prevent cognitive decline and dementia, but there is insufficient evidence to support a public health campaign encouraging their adoption, says a new report from the National Academies of Sciences, Engineering, and Medicine. Additional research is needed to further understand and gain confidence in their effectiveness, said the committee that conducted the study and wrote the report.

“There is good cause for hope that in the next several years much more will be known about how to prevent cognitive decline and dementia, as more clinical trial results become available and more evidence emerges,” said Alan I. Leshner, chair of the committee and CEO emeritus, American Association for the Advancement of Science. “Even though clinical trials have not conclusively supported the three interventions discussed in our report, the evidence is strong enough to suggest the public should at least have access to these results to help inform their decisions about how they can invest their time and resources to maintain brain health with aging.”

An earlier systematic review published in 2010 by the Agency for Healthcare Research and Quality (AHRQ) and an associated “state of the science” conference at the National Institutes of Health had concluded that there was insufficient evidence to make recommendations about any interventions to prevent cognitive decline and dementia. Since then, understanding of the pathological processes that result in dementia has advanced significantly, and a number of clinical trials of potential preventive interventions have been completed and published. In 2015, the National Institute on Aging (NIA) contracted with AHRQ to conduct another systematic review of the current evidence. NIA also asked the National Academies to convene an expert committee to help inform the design of the AHRQ review and then use the results to make recommendations to inform the development of public health messaging, as well as recommendations for future research. This report examines the most recent evidence on steps that can be taken to prevent, slow, or delay the onset of mild cognitive impairment and clinical Alzheimer’s-type dementia as well as steps that can delay or slow age-related cognitive decline.

Overall, the committee determined that despite an array of advances in understanding cognitive decline and dementia, the available evidence on interventions derived from randomized controlled trials — considered the gold standard of evidence — remains relatively limited and has significant shortcomings. Based on the totality of available evidence, however, the committee concluded that three classes of interventions can be described as supported by encouraging but inconclusive evidence. These interventions are:

cognitive training — which includes programs aimed at enhancing reasoning and problem solving, memory, and speed of processing — to delay or slow age-related cognitive decline. Such structured training exercises may or may not be computer-based. blood pressure management for people with hypertension — to prevent, delay, or slow clinical Alzheimer’s-type dementia. increased physical activity — to delay or slow age-related cognitive decline.

Cognitive training has been the object of considerable interest and debate in both the academic and commercial sectors, particularly within the last 15 years. Good evidence shows that cognitive training can improve performance on a trained task, at least in the short term. However, debate has centered on evidence for long-term benefits and whether training in one domain, such as processing speed, yields benefits in others, such as in memory and reasoning, and if this can translate to maintaining independence in instrumental activities of daily living, such as driving and remembering to take medications. Evidence from one randomized controlled trial suggests that cognitive training delivered over time and in an interactive context can improve long-term cognitive function as well as help maintain independence in instrumental activities of daily living for adults with normal cognition. However, results from other randomized controlled trials that tested cognitive training were mixed.

Managing blood pressure for people with hypertension, particularly during midlife — generally ages 35 to 65 years — is supported by encouraging but inconclusive evidence for preventing, delaying, and slowing clinical Alzheimer’s-type dementia, the committee said. The available evidence, together with the strong evidence for blood pressure management in preventing stroke and cardiovascular disease and the relative benefit/risk ratio of antihypertensive medications and lifestyle interventions, is sufficient to justify communication with the public regarding the use of blood pressure management, particularly during midlife, for preventing, delaying, and slowing clinical Alzheimer’s-type dementia, the report says.

It is well-documented that physical activity has many health benefits, and some of these benefits — such as stroke prevention — are causally related to brain health. The AHRQ systematic review found that the pattern of randomized controlled trials results across different types of physical activity interventions provides an indication of the effectiveness of increased physical activity in delaying or slowing age-related cognitive decline, although these results were not consistently positive. However, several other considerations led the committee to conclude that the evidence is sufficient to justify communicating to the public that increased physical activity for delaying or slowing age-related cognitive decline is supported by encouraging but inconclusive evidence.

None of the interventions evaluated in the AHRQ systematic review met the criteria for being supported by high-strength evidence, based on the quality of randomized controlled trials and the lack of consistently positive results across independent studies. This limitation suggests the need for additional research as well as methodological improvements in the future research. The National Institutes of Health and other interested organizations should support further research to strengthen the evidence base on cognitive training, blood pressure management, and increased physical activity, the committee said. Examples of research priorities for these three classes of interventions include evaluating the comparative effectiveness of different forms of cognitive training interventions; determining whether there are optimal blood pressure targets and approaches across different age ranges; and comparing the effects of different forms of physical activity.

When funding research on preventing cognitive decline and dementia, the National Institutes of Health and other interested organizations should identify individuals who are at higher risk of cognitive decline and dementia; increase participation of underrepresented populations; begin more interventions at younger ages and have longer follow-up periods; use consistent cognitive outcome measures across trials to enable pooling; integrate robust cognitive outcome measures into trials with other primary purposes; include biomarkers as intermediate outcomes; and conduct large trials designed to test the effectiveness of an intervention in broad, routine clinical practices or community settings.

Alzheimer’s disease study links brain health, physical activity

People at risk for Alzheimer’s disease who do more moderate-intensity physical activity, but not light-intensity physical activity, are more likely to have healthy patterns of glucose metabolism in their brain, according to a new UW-Madison study.

Results of the research were published online in Journal of Alzheimer’s Disease. Senior author Dr. Ozioma Okonkwo, assistant professor of medicine, is a researcher at the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Alzheimer’s Institute at the UW School of Medicine and Public Health. First author Ryan Dougherty is a graduate student studying under the direction of Dr. Dane B. Cook, professor of kinesiology and a co-author of the study, and Dr. Okonkwo. The research involved 93 members of the Wisconsin Registry for Alzheimer’s Prevention (WRAP), which with more than 1,500 registrants is the largest parental history Alzheimer’s risk study group in the world.

Researchers used accelerometers to measure the daily physical activity of participants, all of whom are in late middle-age and at high genetic risk for Alzheimer’s disease, but presently show no cognitive impairment. Activity levels were measured for one week, quantified, and analyzed. This approach allowed scientists to determine the amount of time each subject spent engaged in light, moderate, and vigorous levels of physical activity. Light physical activity is equivalent to walking slowly, while moderate is equivalent to a brisk walk and vigorous a strenuous run. Data on the intensities of physical activity were then statistically analyzed to determine how they corresponded with glucose metabolism — a measure of neuronal health and activity — in areas of the brain known to have depressed glucose metabolism in people with Alzheimer’s disease. To measure brain glucose metabolism, researchers used a specialized imaging technique called 18F-fluorodeoxyglucose positron emission tomography (FDG-PET).

Moderate physical activity was associated with healthier (greater levels of) glucose metabolism in all brain regions analyzed. Researchers noted a step-wise benefit: subjects who spent at least 68 minutes per day engaged in moderate physical activity showed better glucose metabolism profiles than those who spent less time.

“This study has implications for guiding exercise ‘prescriptions’ that could help protect the brain from Alzheimer’s disease,” said Dougherty. “While many people become discouraged about Alzheimer’s disease because they feel there’s little they can do to protect against it, these results suggest that engaging in moderate physical activity may slow down the progression of the disease.”

“Seeing a quantifiable connection between moderate physical activity and brain health is an exciting first step,” said Okonkwo. He explained that ongoing research is focusing on better elucidating the neuroprotective effect of exercise against Alzheimer’s disease.

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Identified brain circuitry bridges neural and behavioral roles in PTSD

Specific cerebral circuitry bridges chemical changes deep in the brain and the more outward behavioral expressions associated with post-traumatic stress disorder (PTSD), which could lead to more objective biomarkers for the disorder, according to a comprehensive review of rapidly changing data published June 22 in the New England Journal of Medicine.

In this latest, comprehensive review, the authors — from the Steven and Alexandra Cohen Veterans Center (CVC) in the Department of Psychiatry at NYU Langone Medical Center and the University of Michigan/Veterans Affairs Ann Arbor Health Systems Mental Health Service — have identified four neural-behavioral models associated with PTSD. These models pinpoint specific circuits in the brain that “mediate” between chemical changes — which are being examined as possible PTSD biomarkers — and the expression of certain characteristics often associated with PTSD. These include fear responses, avoidance of trauma reminders, impaired emotional balance and the persistence of defensive responses despite a safe environment.

“These neural-behavioral models account for, and help further explain, many of the peripheral findings in PTSD,” says study co-author Israel Liberzon, MD, professor of Psychiatry, Psychology and Neuroscience from University of Michigan. “These models will be valuable roadmaps in examining whether certain PTSD-related behaviors have particular chemical roots. This, in turn, could advance the identification of objective biomarkers for PTSD.”

The authors point out that one of the major challenges with PTSD is that it is painstakingly difficult to objectively profile and diagnose. PTSD sufferers come from a wide swath of society, with higher rates of illness among socially disadvantaged individuals, younger persons, women, military personnel, police officers, firefighters and first responders to trauma. It also is prevalent in victims of physical and sexual assault, and those requiring assistance from first responders.

The American Psychiatric Association recently updated its diagnostic criteria for PTSD in the fifth edition of its Diagnostic and Statistical Manual of Mental Disorders. But the co-authors point out that even when examining these changes comparatively with the APA’s prior criteria as well as criteria from the World Health Organization, there is only a 30% overlap in those meeting diagnostic criteria across the three measurements.

“There continues to be major concerns with diagnosing PTSD,” says co-author Charles R. Marmar, MD, the Lucius Littauer Professor and chair of psychiatry at NYU Langone and director of the CVC. “While biomarker research continues — and we are making important strides — clinicians need to be alerted to the differences between criteria meant to index PTSD and the broader array of symptoms.”

Study Includes Guidelines to Help Identify PTSD

To address this, the authors included in their review detailed and easy-to-follow tables that provide information to better recognize signs and symptoms of PTSD for healthcare providers like primary care physicians, often the first point of contact for patients.

“We know a lot more about PTSD and related conditions than in the past,” says co-author Arieh Shalev, MD, the Barbara Wilson Professor in the Department of Psychiatry at NYU Langone and a co-director of the CVC. “Our goal is to provide a highly precise and concise summary of all of the evidence-based findings thus far for understanding, diagnosing and treating PTSD.”

The authors also say that there are more therapeutic options to offer patients, including cognitive behavior therapy, such as prolonged exposure and cognitive processing therapies; eye movement desensitization and reprocessing therapy; stress management; and medication. The review also includes data about the effectiveness of neurofeedback; transcranial magnetic stimulation; and endocannabinoid modulators, such as marijuana-derived medications.

PTSD remains the most prevalent psychological consequence of trauma. An estimated 70 percent of adults worldwide will experience a traumatic event in their lifetime, and approximately 10 percent will develop the disorder. According to the U.S. Department of Veterans Affairs National Center for PTSD, approximately eight million American adults suffer from PTSD in a given year.

 

New technique isolates neuronal activity during memory consolidation

A team, led by researchers from the Cajal Institute (Madrid) belonging to the Spanish National Research Council (CSIC), have discovered some basic processes underlying memory consolidation in collaboration with colleagues at the National Hospital for Paraplegics in Toledo (Spain) and the University of Szeged (Hungary). The work, which is published in Neuron, identifies some of the electrical events responsible for specific neuronal activity in the hippocampus: a region of the brain with fundamental roles in episodic memory.

In the study, highlighted at the front cover of the journal, researchers used machine learning to study brain electrical activity during memory reactivation. “Using artificial neural networks, we have been able to identify electrical fotprints associated to events with similar informational content, presumably encoding the same memory trace. Using sophisticated experimental techniques we have succeeded in isolating the activity of individual neurons during these ‘memories'” explains Liset Menéndez de la Prida, the Cajal Institute researcher who lead the work.

As the researchers observed in their study, activity of hippocampal cells is precisely modulated during memory trace reactivation. “We have seen that most hippocampal cells acutely respond to ‘excitation’ and ‘inhibition’ as a kind of cellular yin-yang, in such a way that the participation of individual neurons of memory traces is extremely selective,” explains Manuel Valero, the first author of the paper.

“Only those hippocampal neurons carrying information about a memory to be reactivated would receive more ‘excitation’ than ‘inhibition’ to be biased for a particular memory trace. This mechanism endows the hippocampus with the ability to reactivate individual memories without merging information.”

In addition, researchers show that an imbalance between ‘excitation’ and ‘inhibition’ -characteristic of some brain diseases such as epilepsy- could be catastrophic for memories. “In epilepsy, we see a link between this mechanism and memory deficits. Our data suggest that alterations of excitation-inhibition balance not only contributes to epileptic activity, but also to the collapse of individual memory traces during consolidation, like an indissoluble mixture,” explains Menéndez de la Prida.

The hippocampus, vital to generating memory

As researchers point out, the function of hippocampus in memory was unveiled by the famous patient HM. “After he underwent bilateral surgical resection of both hippocampi for treating his epilepsy, he was unable to form new episodic memories.”

Menéndez de la Prida explains that with the advancement of neuroscience, it has become increasingly clear that the hippocampus may play a dual role in memory formation. “First, it represents information concerning the time and place where you are at this moment, through sequences of neuronal activity that signal your location in the room and some other temporal contingencies”

Valero adds, “Once this information is collected, it must be transformed it into a long-term memory. This is carried out by the hippocampus through a process called consolidation. During consolidation, neuronal sequences already activated during experience are replayed several times at high speed. It is a process which expends a great deal of energy to leave an electrical footprint.” That footprint seems now to be more easily detected in the apparently noisy brain activity.

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Predicting cognitive deficits in people with Parkinson’s disease

Parkinson’s disease is commonly thought of as a movement disorder, but after years of living with the disease, approximately 25 percent of patients also experience deficits in cognition that impair function. A newly developed research tool may help predict a patient’s risk for developing dementia and could enable clinical trials aimed at finding treatments to prevent the cognitive effects of the disease. The research was published in Lancet Neurology and was partially funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

“This study includes both genetic and clinical assessments from multiple groups of patients, and it represents a significant step forward in our ability to effectively model one of the most troublesome non-motor aspects of Parkinson’s disease,” said Margaret Sutherland, Ph.D., program director at the NINDS.

For the study, a team of researchers led by Clemens Scherzer, M.D., combined data from 3,200 people with Parkinson’s disease, representing more than 25,000 individual clinical assessments and evaluated seven known clinical and genetic risk factors associated with developing dementia. From this information, they built a computer-based risk calculator that may predict the chance that an individual with Parkinson’s will develop cognitive deficits. Dr. Scherzer is head of the Neurogenomics Lab and Parkinson Personalized Medicine Program at Harvard Medical School and a member of the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital, Boston.

Currently available Parkinson’s medications are only effective in improving motor deficits caused by the disease. However, the loss of cognitive abilities severely affects the individual’s quality of life and independence. One barrier to developing treatments for the cognitive effects of Parkinson’s disease is the considerable variability among patients. As a result, researchers must enroll several hundred patients when designing clinical trials to test treatments.

“By allowing clinical researchers to identify and select only patients at high-risk for developing dementia, this tool could help in the design of ‘smarter’ trials that require a manageable number of participating patients,” said Dr. Scherzer.

Dr. Scherzer and team also noted that a patient’s education appeared to have a powerful impact on the risk of memory loss. The more years of formal education patients in the study had, the greater was their protection against cognitive decline.

“This fits with the theory that education might provide your brain with a ‘cognitive reserve,’ which is the capacity to potentially compensate for some disease-related effects,” said Dr. Scherzer. “I hope researchers will take a closer look at this. It would be amazing, if this simple observation could be turned into a useful therapeutic intervention.”

Moving forward, Dr. Scherzer and his colleagues from the International Genetics of Parkinson’s Disease Progression (IGPP) Consortium plan to further improve the cognitive risk score calculator. The team is scanning the genome of patients to hunt for new progression genes. Ultimately, it is their hope that the tool can be used in the clinic in addition to helping with clinical trial design. However, considerable research remains to be done before that will be possible.

One complication for the use of this calculator in the clinic is the lack of available treatments for Parkinson’s-related cognitive deficits. Doctors face ethical issues concerning whether patients should be informed of their risk when there is little available to help them. It is hoped that by improving clinical trial design, the risk calculator can first aid in the discovery of new treatments and determine which patients would benefit most from the new treatments.

“Prediction is the first step,” said Dr. Scherzer. “Prevention is the ultimate goal, preventing a dismal prognosis from ever happening.”

 

Parkinson’s is partly an autoimmune disease, study finds

Researchers have found the first direct evidence that autoimmunity — in which the immune system attacks the body’s own tissues — plays a role in Parkinson’s disease, the neurodegenerative movement disorder. The findings raise the possibility that the death of neurons in Parkinson’s could be prevented by therapies that dampen the immune response.

The study, led by scientists at Columbia University Medical Center (CUMC) and the La Jolla Institute for Allergy and Immunology, was published today in Nature.

“The idea that a malfunctioning immune system contributes to Parkinson’s dates back almost 100 years,” said study co-leader David Sulzer, PhD, professor of neurobiology (in psychiatry, neurology and pharmacology) at CUMC. “But until now, no one has been able to connect the dots. Our findings show that two fragments of alpha-synuclein, a protein that accumulates in the brain cells of people with Parkinson’s, can activate the T cells involved in autoimmune attacks.

“It remains to be seen whether the immune response to alpha-synuclein is an initial cause of Parkinson’s, or if it contributes to neuronal death and worsening symptoms after the onset of the disease,” said study co-leader Alessandro Sette, Dr. Biol. Sci., professor in the Center for Infectious Disease at La Jolla Institute for Allergy and Immunology in La Jolla, Calif. “These findings, however, could provide a much-needed diagnostic test for Parkinson’s disease, and could help us to identify individuals at risk or in the early stages of the disease.”

Scientists once thought that neurons were protected from autoimmune attacks. However, in a 2014 study, Dr. Sulzer’s lab demonstrated that dopamine neurons (those affected by Parkinson’s disease) are vulnerable because they have proteins on the cell surface that help the immune system recognize foreign substances. As a result, they concluded, T cells had the potential to mistake neurons damaged by Parkinson’s disease for foreign invaders.

The new study found that T cells can be tricked into thinking dopamine neurons are foreign by the buildup of damaged alpha-synuclein proteins, a key feature of Parkinson’s disease. “In most cases of Parkinson’s, dopamine neurons become filled with structures called Lewy bodies, which are primarily composed of a misfolded form of alpha-synuclein,” said Dr. Sulzer.

In the study, the researchers exposed blood samples from 67 Parkinson’s disease patients and 36 age-matched healthy controls to fragments of alpha-synuclein and other proteins found in neurons. They analyzed the samples to determine which, if any, of the protein fragments triggered an immune response. Little immune cell activity was seen in blood samples from the controls. In contrast, T cells in patients’ blood samples, which had been apparently primed to recognize alpha-synuclein from past exposure, showed a strong response to the protein fragments. In particular, the immune response was associated with a common form of a gene found in the immune system, which may explain why many people with Parkinson’s disease carry this gene variant.

Dr. Sulzer hypothesizes that autoimmunity in Parkinson’s disease arises when neurons are no longer able to get rid of abnormal alpha-synuclein. “Young, healthy cells break down and recycle old or damaged proteins,” he said. “But that recycling process declines with age and with certain diseases, including Parkinson’s. If abnormal alpha-synuclein begins to accumulate, and the immune system hasn’t seen it before, the protein could be mistaken as a pathogen that needs to be attacked.”

The Sulzer and Sette labs are now analyzing these responses in additional patients, and are working to identify the molecular steps that lead to the autoimmune response in animal and cellular models.

“Our findings raise the possibility that an immunotherapy approach could be used to increase the immune system’s tolerance for alpha-synuclein, which could help to ameliorate or prevent worsening symptoms in Parkinson’s disease patients,” said Dr. Sette.

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Shared decision-making is cornerstone of multiple sclerosis treatment

One of the cornerstones of multiple sclerosis treatment is shared decision-making between patients and their doctors and nurses, according to a report in the journal Practical Neurology.

“Patients with MS are often very interested and involved in their own disease management and therefore should be empowered to play an active role in their care,” wrote author Amy Perrin Ross, APN, MSN, CNRN, MSCN. “Shared decision-making is therefore essential to optimal treatment and quality of life for patients with MS.”

Ms. Perrin Ross, a board-certified neuroscience nurse, is neuroscience program coordinator at Loyola University Medical Center and a member of the board of directors of the Consortium of Multiple Sclerosis Centers.

In shared decision-making, the clinician and patient work together to make decisions and select tests, treatments and care plans. The process encompasses evidence-based treatments as well as lifestyle and environmental factors. The clinician educates the patient about the disease and makes recommendations based on risk factors, genetic factors, potential triggers and other elements.

“After reviewing and educating patients about the available options, clinicians should take time to listen to the patient and learn about their values and preferences, as these should be taken into account during consideration of optimal treatment,” Ms. Perrin Ross wrote. “The more patients are involved in shared decision-making, the more likely they will be adherent to the therapy and lifestyle recommendations we might be making for them.”

The five steps of shared decision-making are:

  • Engage patient participation
  • Explore and compare treatment options
  • Assess patient values and preferences
  • Reach a decision on treatment with the patient
  • Evaluate the patient decision

A comprehensive team approach, like the one used at Loyola Medicine, often is needed to ensure patients are well informed about effective treatments and a healthy lifestyle. The team can include a neurologist, nurse, physician assistant, primary care provider, physical therapist, occupational therapist, speech therapist, podiatrist, psychiatrist, urologist, nutritionist and pharmacist. A nurse coordinator or nurse case manager can help coordinate care and guide patients through the process.

Shared decision-making can be time consuming, especially in the beginning. But the more patients feel they are supported, “the more comfortable they are to manage their own disease and feel empowered to make decisions about their care and their lives,” Ms. Perrin Ross wrote.

The article is titled “Shared Decision-Making in Multiple Sclerosis Management.” It can be found online at: http://practicalneurology.com/2017/04/shared-decision-making-in-multiple-sclerosis-management/

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First randomized controlled trial of deep brain stimulation for chronic pain shows promise

Deep brain stimulation (DBS) of the ventral striatum/anterior limb of the internal capsule is safe and feasible in addressing the affective component of pain in patients with post-stroke pain syndrome.

Cleveland Clinic investigators reported findings from the first prospective, randomized, controlled trial of DBS for neuropathic pain in a presentation at the 2017 annual scientific meeting of the American Association of Neurological Surgeons. The study was also published in the May 2017 issue of Annals of Neurology.

“We showed that active versus sham DBS of the ventral striatum/anterior limb of the internal capsule produced significant improvements in multiple outcome measures associated with the affective sphere of chronic pain,” says lead investigator Andre Machado, MD, PhD, Chairman of Cleveland Clinic’s Neurological Institute. “This trial represents a paradigm shift in chronic pain management in that it targeted neurostimulation to brain structures related to the affective, rather than sensory, sphere of chronic pain.”

Dr. Machado sees that as the investigation’s key point of distinction, since previous studies of DBS and other forms of neurostimulation for pain have focused nearly exclusively on modulation of pain transmission and pain amplitude.

“In this study, we departed from an analgesia-based approach and focused on neural networks related to control of emotion and behavior,” he explains, “based on our hypothesis that modulating the affective sphere of pain would improve quality of life or relieve pain-related disability, with or without attenuation of pain intensity.”

To test that hypothesis, Dr. Machado and his team designed their investigator-initiated study as a six-month, randomized, double-blind, placebo-controlled, crossover trial.

They enrolled 10 Cleveland Clinic patients with longstanding post-stroke pain syndrome who had hemibody pain and anesthesia dolorosa secondary to a contralateral lesion. “We chose post-stroke pain syndrome because it is associated with severe, refractory pain and patients with this syndrome are in need of therapies to alleviate suffering and disability,” said Dr. Machado. “Because these patients have complete or near-complete damage to the sensory-discriminative pathways, they also provided a unique model for studying the effects of neuromodulation specifically on brain networks related to emotion and behavior control.”

All patients underwent bilateral implantation of electrode array leads through the anterior limb of the internal capsule (ALIC) into the ventral striatum (VS). Surgical targeting was based on the investigators’ experience with DBS for obsessive-compulsive disorder (OCD) and treatment-resistant depression. “We targeted the VS/ALIC because of its well-established role in controlling emotion and behavior and the documented safety of DBS in this brain region for treating OCD and treatment-resistant depression,” said Dr. Machado.

One month after implantation, patients were randomized to active DBS or sham for three months and then crossed over to the other arm for another three months. After this blinded phase, patients underwent an 18-month open stimulation phase.

The study was negative for its primary and secondary end point, with no significant difference seen in pain-related disability on the PDI between active and sham treatment during the blinded stimulation phase. However, significant differences in favor of active DBS were seen in multiple outcomes associated with the affective dimension of chronic pain.

“Although the primary end point was not achieved, the efficacy of DBS was manifested by significant improvements in indices of the affective component of pain, such as depression, anxiety and quality of life,” Dr. Machado observes. “These improvements — achieved without significant reductions in the amplitude of pain — corroborate our hypothesis and suggest that DBS of the VS/ALIC specifically modulated the affective sphere of pain in patients with post-stroke pain syndrome.”

The findings suggest that analgesia may not be the appropriate treatment goal in central pain syndromes, said Dr. Machado. “We contend that neuromodulation therapies should focus on reducing pain-related suffering or disability rather than pain intensity,” he says. “We propose a shift in surgical targeting away from neural networks underlying the sensory-discriminative domain toward the networks that mediate the affective-motivational sphere of chronic pain.”

He adds that his team’s future work will involve analyzing functional neuroimaging and neurophysiological data obtained during this study to develop objective biomarkers that could help improve patient selection. These data will also be used to examine the neural substrates underlying how DBS impacts the affective aspect of pain.

The team also plans to initiate a multicenter study to confirm these findings elsewhere and potentially expand the study population to include patients with other types of chronic pain. “We believe the present findings justify further investigation of this treatment approach,” said Dr. Machado.

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Brain stimulation protocol reduces spasticity in spinal cord injury patients

Spasticity, uncontrolled muscle contractions, is a common disorder experienced by patients with spinal cord injuries (SCI). Previous studies have shown that excitatory repetitive transcranial magnetic stimulation (rTMS) can reduce spasticity. In a new study published in Restorative Neurology and Neuroscience, researchers found that a protocol of rTMS, excitatory intermittent theta burst stimulation (iTBS), was successful in reducing spasticity in patients with SCI and therefore may be a promising therapeutic tool.

“The aim of this study was to assess whether a different rTMS protocol may have significant beneficial clinical effects in the treatment of lower limb spasticity in SCI patients, namely iTBS, a safe, non-invasive and well-tolerated protocol of rTMS. Patients receiving real iTBS, compared to those receiving sham treatment, showed significant improvement,” explained lead investigator Raffaele Nardone, MD, PhD, Paracelsus Medical University, Salzburg, Austria, and the Franz Tappeiner Hospital, Merano, Italy.

Ten patients with chronic SCI, classified as grades C or D according to the American Spinal Cord Injury Association Impairment Scale, participated in the study. Five received real treatment and the remaining five received sham treatment. After two months, the sham group was switched to real iTBS and the study continued. All eligible patients took antispastic medications and received physical therapy, both before and after the study.

Patients receiving real iTBS showed significant positive effects in several measurements of nerve function, suggesting increased cortical excitability and decreased spinal excitability. Other improvements measured by the Modified Ashworth Scale and the Spinal Cord Injury Assessment Tool persisted up to one week after the end of the iTBS treatment.

Motor-evoked potentials (MEP) were measured in the soleus, or calf muscle, during magnetic stimulation over the most responsive area of the scalp. M-wave and H reflexes, which are measures of muscle contractions due to stimulation of the tibial nerve, were assessed for each subject and a Hmax/Mmax ratio was determined. These measurements were used to assess any changes in spasticity over the two-week stimulation period and the four weeks afterwards.

“Although this study has a small sample size and validation with data from a larger group of patients is needed to confirm the results, our findings clearly suggest that iTBS can be considered as a promising tool for the treatment of spasticity in patients with traumatic SCI and perhaps for other pathological conditions. In comparison with standard rTMS protocols, iTBS represents a more feasible approach because of lower stimulation intensity and shorter duration of application in each single session,” commented Dr. Nardone.

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What is mindfulness-based meditation and why should i try it?

It seems like we are hearing more and more about mindfulness-based meditation and the role it plays in stress reduction. But what exactly is mindfulness-based meditation and why is the practice getting so much attention?

The practice of mindfulness dates back thousands of years and has roots in both yoga and meditation. “The overarching goals of mindfulness are for the individual to learn to be present in the moment and to be able to quiet his or her mind. This can make a significant impact on an individual’s stress level and overall wellbeing,” explains Jodie Katz, M.D., Director, Center for Integrative Medicine, The Valley Hospital.

It also enables us to let go of judging ourselves and our experiences. The process of knowing the experience as it is and ourselves as we are, without relentless judgment, is a large component of the attitudinal foundation of mindfulness. We are encouraged to have a warm, open curiosity about life. In addition, according to an article in the Harvard Business Review, “Neuroscientists have also shown that practicing mindfulness affects brain areas related to perception, body awareness, pain tolerance, emotion regulation, introspection, complex thinking, and sense of self.”

Another wonderful aspect of mindfulness is that it is flexible and can be personalized to fit into an individual’s lifestyle. You can actually benefit from short meditations and, believe it or not, you can meditate just about anywhere!

Greater Good in Action, which was formed through a collaboration between UC Berkeley’s Greater Good Science Center and HopeLab, has the following tips for beginning your mindfulness practice:

  • Pay close attention to your breathing, especially when you’re feeling intense emotions.
  • Notice — really notice — what you’re sensing in a given moment, the sights, sounds, and smells that ordinarily slip by without reaching your conscious awareness.
  • Recognize that your thoughts and emotions are fleeting and do not define you, an insight that can free you from negative thought patterns.
  • Tune into your body’s physical sensations, from the water hitting your skin in the shower to the way your body rests in your office chair.

Mindfulness-based meditation can make a genuine impact on an individual’s ability to manage his or her stress. Adds Dr. Katz, “And, in today’s fast paced and competitive environment, being able to mitigate the impact of life’s stressors on our physical and emotional health is more important than ever!”

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Psychiatric medication protects developing mouse brain from birth defects

A clinically available anxiety drug safely and effectively protects against brain defects caused by the mouse version of a common human virus, finds new research published in The Journal of Neuroscience.

More than half of U.S. adults are infected with cytomegalovirus (CMV), but most people do not experience any symptoms because a healthy immune system keeps the virus in check. However, CMV infection in babies can cause unusually small brain size (microcephaly) like the less common Zika virus, deafness, blindness, mental dysfunction, and other neurological problems that can last a lifetime. There is no effective CMV vaccine, and current treatments are not recommended during pregnancy or in newborns because of their potential to cause other birth defects and cancer.

Anthony van den Pol and colleagues found that a daily low dose of the mood stabilizer valnoctamide reduced the amount of CMV in the body of infected newborn mice and suppressed further replication of the virus that had already reached the brain, without negative side effects. The treatment also normalized neurological and behavioral development in the infected mice, including impaired social interactions thought to link CMV infection and autism spectrum disorder. Finally, the authors show that the drug suppresses replication of CMV in human fetal brain cells.

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A diagnostic test for ALS

Researchers at VIB, KU Leuven, and UZ Leuven, in collaboration with researchers at the University of Jena, have demonstrated that measuring neurofilaments provides reliable confirmation of an ALS diagnosis. This diagnostic test represents a significant step forward because valuable time is still lost at present in diagnosing ALS. Diagnosis takes an average of one year from the first symptoms. The researchers hope that these tests will allow treatment to be started sooner.

ALS, a diagnosis feared by patients and doctors alike

Wednesday, June 21 is World ALS Day. It is a day to stop and consider amyotrophic lateral sclerosis, or ALS for short. This neurodegenerative disease causes the death of motor neurons, the nerve cells controlling the muscles. The result is a loss of strength which spreads throughout the body. Besides the muscles in the limbs, it also affects the muscles used for swallowing, breathing, and speaking. The average survival rate after the onset of the first symptoms is just 2 to 5 years. ALS is relatively rare; about 400 people a year are diagnosed with the condition in Belgium.

As Prof. Philip Van Damme (VIB-KU Leuven, UZ Leuven) tells us: “Despite the severity of the disease, an ALS diagnosis relies heavily on the physician’s clinical acuity. The typical disease progression of ALS, with the loss of strength extending from one body region to another, allows a definite diagnosis. In the early stages of the disease, diagnosis is difficult. Consequently the average time between the first symptoms and diagnosis is approximately one year. Better tests are needed for a faster ALS diagnosis, which we hope to achieve with this test.”

Neurofilaments can help to diagnose ALS

Neurofilaments are structural proteins in the cytoskeleton, which are present in high concentrations in motor neurons. It has been known for a long time that the lumbar fluid in ALS patients contains a higher concentration of neurofilaments, perhaps because they are released from sick motor neurons. Researchers led by Prof. Koen Poesen (Laboratory of Medicine, UZ Leuven, and the Laboratory for Molecular Neurobiomarker Research, KU Leuven) and Prof. Philip Van Damme (Neurology UZ Leuven, and VIB-KU Leuven Center for Brain Research) have carried out detailed research into this phenomenon.

Prof. Koen Poesen (UZ Leuven, KU Leuven): “We have demonstrated that a certain type of neurofilament (pNfH, phosphorylated neurofilament heavy) in particular increases sharply in the lumbar fluid of ALS patients. This is even true when compared to patients presenting loss of strength symptoms due to other conditions (known as ALS mimics). The test meets all the requirements for use as a reliable diagnostic test. However, it requires an epidural because we can still only reliably measure the neurofilaments in the lumbar fluid.”

The researchers have also demonstrated that there is a good correlation between the degree of neurofilament increase and the extent of the motor neuron loss. This indicates that the test reflects the underlying disease process. Whether the implementation of the test will also lead to a shorter time before diagnosis is currently still being researched.

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Materials provided by VIB – Flanders Interuniversity Institute for Biotechnology. Note: Content may be edited for style and length.

Viral vectors for gene transfer travel longer distances in the brain than thought

Gene transfer is seen as a hopeful therapy for Alzheimer’s and Parkinson’s patients. The approach involves using harmless laboratory-produced viruses to introduce important genes into the brain cells. In a study on mice, a team of researchers from Vetmeduni Vienna for the first time investigated how far these viruses spread in the brain and which cells they infect. Some of the artificial viruses travelled from the injection site in the brain as far as the olfactory bulb or the cerebellum and infected not only neurons but also other cells. The results, which were published in the journal Histochemistry and Cell Biology, could help to improve the selection of suitable viral “gene transporters” for custom therapies using gene transfer. Purposefully infecting brain cells with viruses may seem somewhat odd. But for patients suffering from neurodegenerative diseases such as Alzheimer’s or Parkinson’s, this type of therapy could be a glimmer of hope. The viruses used in this approach do not trigger any disease themselves. They serve as harmless transporters for genes specifically intended to treat these disorders. The therapy, called gene transfer, uses the ability of viruses to insert their genes into the genome of a host cell. This method could therefore be used to purposefully introduce helpful genetic information into neurons.

Viral vectors don’t stay put

Viruses suitable for gene transfer are injected into the brain. Previously, however, there had been no studies of how far the viral transporters can spread from the injection site. Earlier studies had usually only investigated the immediate area around the injection canal. A new study with mice has now shown for the first time that some of the tested viruses can travel long distances into different areas of the brain. “In our study, we injected the viral vectors into key areas of the cerebrum responsible, among other things, for the coordinationof body movement ,” explains Kirsti Witter from the Institute for Anatomy, Histology and Embryology at Vetmeduni Vienna. From there, some of the viruses spread into distant areas such as the cerebellum or the olfactory bulb. “This information is important because, depending on the type of neurodegenerative disease, it may be desirable to have as broad a distribution of the virus as possible or to infect a specific, strictly delimited area,” says first author Juraj Hlavaty. “This study also shows that all tested viruses can infect the neurons and the surrounding glial cells as expected. Depending on the type of virus, however, there were differences in the number and ratio of the infected cell types.”

Inflammation could influence which brain cells are infected

Depending on the virus strain used, the injection triggered a mild or more pronounced reaction of the nerve tissue in the treated mice. The stronger the immune response, the more glial cells were infected. “The fact that individual viruses infected these cells better than the neurons must, however, still be confirmed in future experiments,” says Hlavaty. The results of the work, achieved in collaboration with the University of West Bohemia, Pilsen, Czech Republic, and the Paul-Ehrlich-Institute, Langen, Germany, should contribute to improve the selection of viral transporters. “The goal is to create a toolbox of possible viruses in order to choose exactly the right transporter for the custom treatment of a neurodegenerative disease,” says Witter.

Artificial copies of viruses as hopeful therapy

Copies of lentiviruses are especially well-suited for gene transfer therapy. “The genome of laboratory-produced lentiviruses consists only of areas that are necessary for the infection and incorporation into the genome. This represents a fundamental difference between these viruses and naturally occurring pathogenic viruses,” explains Hlavaty. Through the ability of the artificial viruses to enter a host, the inserted human genes are introduced into the infected cells to assume the tasks that the patients’ cells no longer perform themselves.

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Egocentric hearing: How we can tell where a sound is coming from

A new UCL and University of Nottingham study has found that most neurons in the brain’s auditory cortex detect where a sound is coming from relative to the head, but some are tuned to a sound source’s actual position in the world.

The study, published in PLOS Biology, looked at whether head movements change the responses of neurons that track sound location.

“Our brains can represent sound location in either an egocentric manner — for example, when I can tell that a phone is ringing to my left — or in an allocentric manner — hearing that the phone is on the table. If I move my head, neurons with an egocentric focus will respond differently, as the phone’s position relative to my ears has changed, while the allocentric neurons will maintain their response,” said the study’s first author, Dr Stephen Town (UCL Ear Institute).

The researchers monitored ferrets while they moved around a small arena surrounded by speakers that emitted clicking sounds. Electrodes monitored the firing rates of neurons in the ferrets’ auditory cortex, while LEDs were used to track the animals’ movement.

Among the neurons under investigation that picked up sound location, the study showed that most displayed egocentric orientations by tracking where a sound source was relative to the animal’s head, but approximately 20% of the spatially tuned neurons instead tracked a sound source’s actual location in the world, independent of the ferret’s head movements.

The researchers also found that neurons were more sensitive to sound location when the ferret’s head was moving quickly.

“Most previous research into how we determine where a sound is coming from used participants with fixed head positions, which failed to differentiate between egocentric and allocentric tuning. Here we found that both types coexist in the auditory cortex,” said the study’s senior author, Dr Jennifer Bizley (UCL Ear Institute).

The researchers say their findings could be helpful in the design of technologies involving augmented or virtual reality.

“We often hear sounds presented though earphones as being inside our heads, but our findings suggest sound sources could be created to appear externally, in the world, if designers incorporate information about body and head movements,” Dr Town said.

The study was funded by the Medical Research Council, Human Frontiers Science Foundation, Wellcome and the Biotechnology and Biological Sciences Research Council.

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How to educate future therapists more effectively

This is a question addressed by Concordia alumnus Jason Butler (PhD 14) in an article recently published by The Arts in Psychotherapy.

In the course of a North American and UK study, he found that the conflicting demands of education and therapy within the classroom can cause emotional stress and confusion among students in drama therapy and other professions using dramatic enactment.

His conclusion? The use of personal material must be better defined to protect both students and faculty.

“When educating therapists, particularly using experiential methods, things can become blurry,” Butler notes.

“Instructors often take for granted that doing role-plays or other enactments within the classroom are relatively benign acts. However, this research shows that material can resonate with students in complex ways that often inhibit their learning and development.”

Butler’s study offers eight recommendations for improving the practice of drama therapy education.

These include increased transparency between teachers and students; clearer policies on the use of affective material in the classroom; guidelines for evaluating and assessing emotional performance; and discussions within the professions about ethical and pedagogical practices.

“These findings point us in in the direction of creating better systems and pedagogical approaches to enhance the student experience and educate more effective therapists.”

The impact of self-regulation

In the study, students reported that they were asked to incorporate personal material into their assignments with the caveat that they avoid anything overwhelming.

The expectation of self-regulation without clear guidelines for evaluating what was appropriate created stress and uncertainty.

Some students also found the transition from mock therapy to teaching jarring, as it left emotional impacts insufficiently addressed or resolved. Others experienced uncertainty over how or if their emotional engagement would be graded.

For example, in a teaching demonstration an instructor might ask a student to assume the role of a trauma survivor without knowing they have direct experience as such. The student may feel obliged to engage with potentially harmful material in an inappropriate setting due to classroom pressure and the potential for evaluation.

Butler is quick to point out that affect is not the problem, however.

“Affective engagement can be a powerful tool for facilitating learning,” he notes.

“Research has shown that therapists who are more aware of their own emotional experience are better equipped to work with the emotional experiences of their clients. The challenge here is to channel that affect in a responsible and transparent manner.”

Better systems and pedagogical approaches

Butler conducted interviews and focus groups with students and faculty members at three drama therapy training programs in North America and the United Kingdom.

The data was sorted into themes and coded inductively to form a larger picture or research model of the student experience of affective engagement in the classroom.

That model showed that students wrestle with expectations regarding the appropriate level of engagement. This often leads to strong emotional responses in the classroom, which in turn lead to negative consequences. Some students leave or fail out of the program; it is recommended that all seek therapy.

For Butler, the findings suggest that more transparent communication is required between teachers and students.

“Without an understanding of the processes at play, we are not able to capitalize on the strengths that come from these approaches to learning.”

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Materials provided by Concordia University. Note: Content may be edited for style and length.