Summary: A new study reports Alzheimer’s disease does not appear to affect the salience network. Researchers found, when listening to music, the salience network along with other networks, show higher functional connectivity in Alzheimer’s patients.
Source: University of Utah Health.
Ever get chills listening to a particularly moving piece of music? You can thank the salience network of the brain for that emotional joint. Surprisingly, this region also remains an island of remembrance that is spared from the ravages of Alzheimer’s disease. Researchers at the University of Utah Health are looking to this region of the brain to develop music-based treatments to help alleviate anxiety in patients with dementia. Their research will appear in the April online issue of The Journal of Prevention of Alzheimer’s Disease.
“People with dementia are confronted by a world that is unfamiliar to them, which causes disorientation and anxiety” said Jeff Anderson, M.D., Ph.D., associate professor in Radiology at U of U Health and contributing author on the study. “We believe music will tap into the salience network of the brain that is still relatively functioning.”
Previous work demonstrated the effect of a personalized music program on mood for dementia patients. This study set out to examine a mechanism that activates the attentional network in the salience region of the brain. The results offer a new way to approach anxiety, depression and agitation in patients with dementia. Activation of neighboring regions of the brain may also offer opportunities to delay the continued decline caused by the disease.
Using Smartphones and Machine Learning to Quantify Parkinson Disease Severity: The Mobile Parkinson Disease Score
Smart phone technology and app-based approaches for measuring PD symptoms and signs have been around for some time and there are seemingly innumerable companies and groups that all suggest that their approach is the best... The results of this recent study published in JAMA Neurology do however look really impressive. I have always felt that given the heterogeneity of PD (motor and non-motor), a good measuring device will take account of multiple domains. This app measures voice, gait, balance, reaction time and finger tapping (which you might argue are exclusively motor)... but the results suggest that it does measure these really well. The hardest thing is to develop a tool that captures fluctuation well and objectively. Some purpose-built devices do (the PKG for example), but it is impressive to see these kind of results through utilisation of the standard hardware that comes with a smart phone. Furthermore the objective response to dopaminergic therapy is substantial and apparently clinically meaningful.
Will we see this app used in clinical trials in the coming years... I expect we might! - Alastair Noyce
JAMA Neurol. 2018 Mar 26. doi: 10.1001/jamaneurol.2018.0809. [Epub ahead of print] Zhan A, Mohan S, Tarolli C, Schneider RB, Adams JL, Sharma S, Elson MJ, Spear KL, Glidden AM, Little MA, Terzis A, Dorsey ER, Saria S.
IMPORTANCE: Current Parkinson disease (PD) measures are subjective, rater-dependent, and assessed in clinic. Smartphones can measure PD features, yet no smartphone-derived rating score exists to assess motor symptom severity in real-world settings.
OBJECTIVES: To develop an objective measure of PD severity and test construct validity by evaluating the ability of the measure to capture intraday symptom fluctuations, correlate with current standard PD outcome measures, and respond to dopaminergic therapy.
DESIGN, SETTING, AND PARTICIPANTS: This observational study assessed individuals with PD who remotely completed 5 tasks (voice, finger tapping, gait, balance, and reaction time) on the smartphone application. We used a novel machine-learning-based approach to generate a mobile Parkinson disease score (mPDS) that objectively weighs features derived from each smartphone activity (eg, stride length from the gait activity) and is scaled from 0 to 100 (where higher scores indicate greater severity). Individuals with and without PD additionally completed standard in-person assessments of PD with smartphone assessments during a period of 6 months.
MAIN OUTCOMES AND MEASURES: Ability of the mPDS to detect intraday symptom fluctuations, the correlation between the mPDS and standard measures, and the ability of the mPDS to respond to dopaminergic medication.
RESULTS: The mPDS was derived from 6148 smartphone activity assessments from 129 individuals (mean [SD] age, 58.7 [8.6] years; 56 [43.4%] women). Gait features contributed most to the total mPDS (33.4%). In addition, 23 individuals with PD (mean [SD] age, 64.6 [11.5] years; 11 [48%] women) and 17 without PD (mean [SD] age 54.2 [16.5] years; 12 [71%] women) completed in-clinic assessments. The mPDS detected symptom fluctuations with a mean (SD) intraday change of 13.9 (10.3) points on a scale of 0 to 100. The measure correlated well with the Movement Disorder Society Unified Parkinson Disease's Rating Scale total (r = 0.81; P < .001) and part III only (r = 0.88; P < .001), the Timed Up and Go assessment (r = 0.72; P = .002), and the Hoehn and Yahr stage (r = 0.91; P < .001). The mPDS improved by a mean (SD) of 16.3 (5.6) points in response to dopaminergic therapy.
CONCLUSIONS AND RELEVANCE: Using a novel machine-learning approach, we created and demonstrated construct validity of an objective PD severity score derived from smartphone assessments. This score complements standard PD measures by providing frequent, objective, real-world assessments that could enhance clinical care and evaluation of novel therapeutics.
In 2012, a group of male patients underwent heart transplants at Teikyo University’s Department of Surgery, in Tokyo, Japan. As they recovered, closely monitored by attending physicians, an alert onlooker may have noticed a subtle difference in each patient’s recovery room: the ambient noise. Some rooms were silent. In others, Giuseppe Verdi’s “La Traviata” played in the background. From yet other rooms emanated strains of the Berlin Philharmonic’s interpretation of Mozart, or “The Best of Enya.” A final set of rooms was filled with a steady sound frequency between a hundred and twenty thousand hertz.
For six days, researchers observed the patients to see how the different types of background sound would affect their recovery. Would music, they wondered, play a positive role in the healing process? And if so, did it matter what particular kind of music? Their conclusions would be limited: the patients were a group of laboratory mice. Still, the Tokyo researchers had high hopes; how the mice responded could be a step toward improving the recovery process from difficult medical procedures.
The idea that music can have therapeutic value is far from new: in ancient Egypt, chant therapies were seen as integral to the healing process, while in ancient Greece, both Aristotle and Plato embraced its beneficial properties, writing that it could help people become better human beings and overcome emotional difficulties during the process of catharsis. The first major movement in modern psychology, psychoanalysis, held that music could offer an effective means of sublimation—expressing inappropriate desires in socially appropriate ways—and greater access to a patient’s unconscious. More recent approaches have included playing music in hospital wards and waiting areas to help improve patients’ mood and their physical well-being. And we listen to music constantly in everyday life: we flip on Pandora or Spotify to set the mood for drinks with friends, a romantic date, or a workout. Music can psych us up before an important meeting, or calm us down after a stressful conversation. It can even help us vent our anger or express our love, as anyone who has ever created a mix for a significant other—and then a break-up mix when things didn’t quite work out—can tell you.
In a review of over eighty studies on the use of music in therapeutic settings, the pediatrician Kathi Kemper and the psychologist Suzanne Danhauer concluded that music had multiple direct physiological effects: steady rhythms helped regulate breathing and elicited increased activity in the lateral temporal lobe, an area of the brain that helps integrate sensory inputs. In particular, classical music helped improve heart-rate variability, a measure of stress and resilience, while relaxing music led to decreased levels of cortisol, a stress hormone, in a group of students who were engaged in stressful activities. Music had, as well, more indirect effects on both emotion and behavior, making people happier, more relaxed, less anxious, and less overwhelmed. As a result of both the physiology and the psychology, the authors concluded, music was an effective way of improving outcomes for patients who had undergone surgery, or, indeed, any medical procedure.
Since Kemper and Danhauer’s initial review, conducted eight years ago, the data have grown even stronger. Music has now been used therapeutically for a number of diseases, including dementia, schizophrenia, Alzheimer’s, Parkinson’s, and cerebral ischemia. In a study of chronic pain sufferers, researchers at the Cleveland Clinic found that listening to music helped patients experience less physical pain, as well as lower rates of depression; in a study of older people with dementia, scientists from the National Taipei College of Nursing found that playing background music during lunch significantly lowered both verbal and physical aggression. In 2006, researchers discovered that even something as complex as open-heart surgery could be improved with a musical intervention: patients who listened to music during and after heart surgery not only felt less anxious but required, on average, two hundred fewer minutes of intubation than those who had undergone standard procedure.
At Teikyo University, Masanori Niimi and his colleagues began to notice differences between the groups as the mice recovered: the mice placed in the silent or the single-frequency rooms suffered from acute graft rejection, as their immune systems rejected the foreign cells from the transplants. Those who had been listening to either Verdi or Mozart showed significantly improved survival outcomes, living an average of twenty days longer. The Enya listeners were not as fortunate: they did little better than the mice who had listened to nothing at all, living just four days longer, on average, than the mice exposed to noise or silence. The authors speculated that what might have been at play are the particular harmonies and musical features of a piece of music.
The human auditory cortex—the part of our brain devoted to hearing and listening—can differentiate between extremely specific frequencies of sound. In fact, single neurons can adjust to barely noticeable frequency shifts at a level that exceeds almost all other mammals (bats are the exception). Music with a four-four tempo, which corresponds closely to a normal heart rate, can helpregulate heart rate, circulation, and breathing. Lyrical melodies and rhythms of about sixty to eighty beats a minute, which is common to much classical music and bird song, can stimulate relaxation and alpha brain waves, a type of pattern associated with wakeful relaxation. Yet music that departs from either of those tempos confers none of the benefits.
On September 12th, the Teikyo University team received public recognition for their efforts: the IgNobel Prize in Medicine, awarded annually for research that “makes people laugh and then think.” The implications of their findings may well contribute to more successful organ-transplant surgeries in humans in the future, at little additional medical cost beyond a simple music file. And they may prompt more careful consideration of the exact type of music that’s being played; Enya unfortunately has been a frequent therapeutic choice of prior researchers.
This all comes, of course, with a major disclaimer: what works in mice may not work in humans. In mental health, obesity, and some subsets of oncology, the mouse-to-human translation is fraught with uncertainty. Decades of work on inflammatory diseases, for instance, have led to the sad conclusion that mouse models are severely limited, if not counterproductive, when it comes to humans. As Clif Barry, the chief of the Tuberculosis Research Section at the National Institute of Allergy and Infectious Disease, once told Slate, “The truth is that for some questions, mice give you a very nice and easy model system for understanding what’s happening in humans, but mice are mice, and people are people. If we look to the mouse to model every aspect of the disease for man, and to model cures, we’re just wasting our time.”
In fact, most research on the therapeutic benefits of music in humans has been conducted on either older patients or infants—individuals who are more likely to prefer opera or classical music based on personal taste, on the one end, and, on the other, who’ve yet to develop any personal preferences at all. Babies are, in that latter sense, a bit more like mice, responding to the basic characteristics of the music rather than the music itself. For the generations in the middle, though, for whom opera may be somewhat foreign or a sign of generational rebellion, self-selected alternatives may be the better option. In a recent reviewof the data on music use in modern medicine, the biologist Guenther Bernatzky and his colleagues concluded that, as long as the music follows certain basic parameters, patient self-selection offers the best results in surgical outcomes. If patients don’t find the music inherently enjoyable the positive benefits to their recovery may not be nearly as great. Even the famous (or infamous, as the case may be) Mozart effect went away with a group of over eight thousand British ten- and eleven-year-olds in the face of musical competition: instead of performing better after they’d heard Mozart, the children showed improvement after listening to music that they enjoyed more, recordings from the then popular band Blur. The researchers called it the Blur Effect. (On the other hand, grunge has been shown to negatively affect mood even if people say they like it.)
The Teikyo University mice may well have been responding to the different musical options on a purely physiological level, unlike humans, for whom psychology and preferences matter. But an alternative explanation for the Teikyo results, perhaps, is that no one, not even mice, would ever willingly choose to listen to Enya.
The existence of living organisms on our planet has been dependent on and co-evolved with the foreseeable variations in environmental conditions oscillating over recurring periods. All species have responded to these exogenous rhythms by developing endogenous clocks that allow for an approximate, but reliable estimation of the periodic changes and elicit corresponding adaptive processes.
The importance of these mechanisms for health and disease has been highlighted by the 2017 award of the Nobel Prize in Physiology or Medicine to Jeffrey C. Hall, Michael Rosbash, and Michael W. Young for their discoveries of the genetic control of the daily biological rhythm. They explained in molecular terms how the gene named as period contributed to the emergence (eclosion from the pupal case) rhythm of a population and to the locomotor activity of individual flies (Drosophila melanogaster). The key to the explanation was the discovery of transcription-translation feedback loops of the so-called “clock genes.”
This research topic on Intrinsic Clocks which appeared earlier comprises a well-balanced collection of original research and review articles on endogenous rhythms from seasonal and monthly to daily and hourly oscillations in different experimental model systems with analytical approaches from systemic to cellular and molecular levels.
Serchov and Heumann in their review focus on the role of Ras, an enzyme which hydrolyzes guanosine triphosphate and dependent intracellular signaling cascades in the regulation of the circadian rhythm in mice. They elegantly summarize how Ras activity forms a molecular bridge between entrainment of the suprachiasmatic nucleus that is the master clock in the brain and synaptic plasticity in dependent brain regions, such as the hippocampus, and corresponding functions. The extensive study by Chiang et al. specifically investigated rhythmic alterations in the murine hippocampus. They characterized the protein phosphorylation using a mass spectrometry approach with which they provided large-scale quantitative analysis of the daily oscillation of hippocampal phosphorylation events over a range of biological pathways. The hippocampus is a key focus also in the review by Urs Albrecht. It features the role of circadian proteins in the control of adult hippocampal neurogenesis, reciprocally implicated in depression and antidepressant responses. He discusses neurobiological mechanisms implicated in the pathogenesis of mood disorders, such as monoaminergic neurotransmission and stress response by the hypothalamic–pituitary–adrenal axis. The hypothalamus and the pituitary are further involved in seasonal cycles as highlighted in the review by Lewis and Ebling who elaborate in detail on the role of tanycytes, pituitary radial glial cells, in the regulation of circannual clocks in hamsters. They provide evidence supporting their hypothesis that tanycytes serve as central organizers of seasonal rhythms in the adult hypothalamus. Raible et al. present in their review on marine animals the current insight in the cellular mechanisms in molecular detail the monthly or semi-monthly rhythms. They express their worry about light pollution and further review the relevance of circalunar rhythms to mammalian physiology and reproduction in specific. They speculate that these rhythms may be the remnant of evolutionary ancient clocks, which were uncoupled from a natural entrainment mechanism.
Bourguignon and Storch summarize recent findings of the cellular substrate and mechanism, which generate locomotor activity with periods of 2–6 h. Such rhythms are normally integrated with circadian rhythms, but often lack the period stability and expression robustness. They further review the concept of the dopaminergic ultradian oscillator and show that ultradian locomotor rhythms rely on cells in the brain using dopamine for transmission. Intriguingly, Monje et al. report in their study on interleukin-6 knockout mice that the ultradian locomotor rhythm was impaired under both light-entrained and free-running conditions, whereas the circadian period and the level of locomotor activity as well as the phase shift response to light exposure at night remained normal. During the day, Cry1 and Bhlhe41 expression levels were increased whereas those of Nr1d2 were decreased in the hippocampus. Liu and Zhang first created mutants of cryptochrome circadian clock 1 (Cry1) protein at potential phosphorylation sites and conducted thereafter a screen in Cry1/Cry2 double deficient cells. They targeted at identifying mutations that disrupted circadian rhythms. They found that these single amino acid substitutions changed not only the circadian period, but also repression activity, protein stability, or cellular localization of the protein. Concerning the circadian period, Narasimamurthy and Virshup elucidate in their review the molecular mechanisms that regulate an enigma of the clock. Unlike other chemical reactions, the output of the clock as measured with the period remains nearly constant with fluctuations in ambient temperature. This is called as temperature compensation. The key lies especially in the mechanism that controls the stability of period circadian clock 2 protein. Clock-enhancing small molecules have become of particular interest as candidate chronotherapeutics, since there is a close association of circadian amplitude dampening with progression of chronic diseases, especially that of mood disorders. Gloston et al. present in their review an update of the regulatory mechanisms of circadian amplitude and the current status of these small molecules of therapeutic interest. Millius and Ueda introduce the readers to study of biology which takes advantage of engineering and mathematical tools to model and test the behaviors of the intrinsic clocks. It has evolved through the development of both wet lab and in silico work. The goal here is to understand the clocks that are made up of a range of complex properties of cells, tissues, and organisms.
The cross-section of studies comprised in this research topic on Intrinsic Clocks highlights the vibrant scientific activity in the field of the investigation of endogenous biological rhythms and their relevance for physiology and pathology.
TP and DP planned and wrote the manuscript together.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Scientists observe tremors associated with Parkinson’s disease in fruit flies
Posted on 5 December 2017
Scientists say they have a better understanding of the tremors commonly associated with Parkinson’s disease after observing the movements in fruit flies.
Researchers were able to observe for the first time the detail of movement deficits in fruit flies. Pic Credit: Diana Ivanoiu, Amy Cording and Chris Elliott.
A mutation in the LRRK2 gene is the single most common inherited cause of Parkinson’s disease. However, the precise mechanism that leads to Parkinson’s is still unclear.
The researchers were able to observe for the first time the detail of movement deficits in fruit flies carrying the faulty LRRK2 gene.
Dr Chris Elliott, from the University of York’s Department of Biology said it was a “small but significant step” in the search for an effective treatment for Parkinson’s.
He said: “Our research has shown that the movement disorder can be narrowed down and determined accurately and that opens up the possibility of testing novel drugs.”
The research, which is published in the journal Nature Parkinson’s Disease, was funded by Parkinson’s UK and the Wellcome Trust.
“What is particularly new about this is the idea that the flies can show tremor, nobody has modelled it in that level of detail before, “ said Dr Elliott.
The team were able to observe how the fruit fly used its proboscis to reach out and drink a sugary substance – mimicking the movement humans make when reaching out a hand for a drink, and one of the standard tests for Parkinson’s .
Dr Elliott added: “What we observed was the proboscis reaches out slowly and it shakes. We have been able to show that this movement is controlled just by this one gene, expressed in just one nerve cell.
“It is this idea of a very precise measurement of movement that opens up the way to start looking at drugs that could reverse the symptoms.”
Dr Elliott said the next stage is to test compounds that work in the test-tube in the living organism, an essential part of the drug development programme.
Commenting on the paper, David Dexter, Deputy Research Director at Parkinson’s UK, said: "Modelling the symptoms of Parkinson’s can help researchers better understand the condition, but can be difficult to do in animal models such as flies.
“New and improved technologies and methods not only allow a greater understanding of the causes of Parkinson’s, but they also importantly serve as a tool for the more rapid development of new drugs that can protect nerve cells against damage or directly improve movement.
“We hope this new technique will allow researchers to delve deeper into the biology of Parkinson’s, opening new doors and expediting the delivery of new and better treatments.”
Parkinson's is a progressive neurological condition and there are an estimated 127,000 people in the UK with the condition.
New research finds listening to music helps tackle anxiety, depression and agitation among people living with dementia, and calls for a dedicated music and dementia task force.
NCVO London CC BY 2.0
The potential of music to empower and soothe people living with dementia has been outlined in a new report, which calls for increased collaboration between politicians, technology companies, arts organisations and the healthcare sector to make access to the artform easier.
The evidence roundup, produced by independent think tank the International Longevity Centre (ILC-UK), concludes music can help minimise agitation, depression and other symptoms of dementia, whilst helping to increase social interaction.
It also finds evidence of a “memory bump”, in that people with dementia retain the clearest memories for music they enjoyed and heard between the ages of 10 and 30.
The report authors use the conclusions to urge music streaming services such as Spotify to offer limitless streaming to people with dementia at reduced prices or for free. They also urge the Government to create an independent, non-political Ambassador for Dementia and Music, who would lead a dedicated task force to deliver “universal access to music” for people with dementia.
“People with dementia often live in a silent world, yet music can bring a person back to life,” said Neil Utley of the Utley Foundation, one of the funders of the research.
“The ability to connect to music is an innate aspect of being human; having a diagnosis of dementia need not undermine this.”
Produced by ILC-UK’s Commission on Dementia and Music, the report examines the existing offer and the future potential for using therapeutic music with dementia.
The number of people living with dementia is expected to reach one million by 2025, and many of these will suffer neuropsychiatric symptoms, such as agitation, depression, apathy and anxiety. The annual cost of dementia to the UK is £26.3bn and this is expected to exceed £50bn over the next three decades.
The researchers conclude music and dementia is currently the terrain of devoted advocates operating in a “complex and poorly coordinated ecosystem”. They found specialist music therapy provision is “sporadic” and estimate that good-quality arts and music provision is currently available in just 5% of care homes.
“We want to see provision reaching all people with dementia, including the most vulnerable individuals who may not have family or friends to speak on their behalf,” the authors add.
The report concludes the sector would benefit from increased funding, which should be supported by more research into the cost effectiveness of such programmes – recognising the tight budgets of local authorities and clinical commissioning groups – and more investment from philanthropic trusts.
It also calls for a large-scale campaign to raise awareness of the value of music interventions, and a national database to summarise local provision for people living with dementia.
Sally Bowell, Research Fellow at ILC-UK, added: “Music should not just be considered a nice-to-have, or an ‘add-on’. Music has tangible, evidence-based benefits for people with dementia, such as helping to minimise the behavioural and psychological symptoms of dementia, tackling depression and anxiety, and, importantly, helping to improve quality of life.
“We want to raise awareness of these important benefits and rally organisations and individuals alike to help champion access to music for people with dementia.”