Are Sleep Apps Effective Tools For Behavioral Change?

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Smartphones are technological Swiss Army knives – easy to carry and, thanks to apps, able to do almost anything. All you need is a smartphone and an internet connection to unfold a thousand tools.

Apps make communication, traveling, working, and entertainment easier. And they can also allow us to monitor and manage our health, fitness and lifestyle, or even improve them. There are thousands of health and lifestyle apps – for exercise, for nutrition, for weight loss, for meditation, for overall health, for sleep… Their use is on the rise and they have shown great potential in effectively promoting self-improvement.

Technology may actually revolutionize how we take care of ourselves. It can successfully influence behavior and this is empowering in the sense that it offers an opportunity to self-manage our health routines. Apps can be a great aid for lifestyle interventions – they allow us to monitor our behavior and our progress, they can motivate us, give positive reinforcement, and set goals for continued enhancement. A well-designed app, built on scientific background may offer valuable help to behavioral health and lifestyle interventions.

But among the sea of apps, one wonders how many are really effective and how many present evidence-based content and behavioral theory-based interventions. Although it is not clear whether evidence- and theory-based interventions are indispensable for the efficacy of an app, they are known to be effective in changing behavior, being, most likely, a predictor of efficacy.

Traditional theory-based behavioral modification strategies state that behavioral change can be most successfully achieved when multiple strategic approaches and behavioral constructs are combined; these include informational strategies (creating knowledge); cognitive strategies, such as perceived benefits, barriers and risks; behavioral strategies, such as self-monitoring, realistic goal-setting, self-reward, relapse prevention; emotion-focused strategies, such as stress and negative affect management; and therapeutic interventions such as skill-building, for example. Apps that include such features have been proven more effective.

However, app developers are naturally focused on keeping users engaged. Therefore, many app features may tend to favor usability. Also, it is likely that app development may be preferentially aligned with more contemporary behavioral models. These postulate that technology can be designed to change user attitudes and behaviors through persuasion and social influence (Persuasive Technology Theory), and that when technology increases motivation and capacity to change, triggers to change behavior are more likely to work (Fogg Behavioral Model).

But a reliance on either traditional or contemporary behavioral models does not seem to be the case for most health, fitness and lifestyle apps: a 2011 review revealed that most had insufficient evidence-based content; a 2012 analysis showed a general lack of theory-based strategies; a 2013 study of exercise apps found that, overall, the apps contained few features based on behavioral change theory; another 2013 study reached the same conclusion for weight management apps; a 2015 study reported similar findings for alcohol reduction apps.

And what about sleep apps? They are one of the most popular type of lifestyle and health apps, which comes as no surprise – sleep disorders affect millions of people and this creates a huge demand for interventional strategies. But sleep apps are particular in the sense that interventional constructs need to go way beyond motivation.

Therefore, a new study aimed at determining whether sleep apps follow evidenced-based guidelines or are grounded in behavioral change or persuasive technology theories.

The study included the most downloaded and reviewed sleep apps for both iOS and Android. From the 369 apps found using the term “sleep” (in September 2015), 35 apps met the authors’ inclusion criteria. They scored them based on the presence of behavioral and persuasive technology constructs and correlated these scores with the average user rating for each app.

The average behavioral construct score was 34%, whereas the average persuasive technology score was 42%, which is not impressive. Realistic goal setting (86%), time management (77%), and self-monitoring (66%) were the behavioral constructs most commonly included in sleep apps; factors that contributed most to the apps’ persuasiveness were the user interface (94%), provision of positive feedback (54%), and social praise (40%).

Interestingly, the authors found a positive association between the presence of behavioral constructs and the apps’ popularity and ratings, showing that a good scientific design is an indication of probable success.

This also indicates that, since there is still a relatively poor inclusion of theory-based constructs, there is room to grow. Building strong evidence-based apps is likely to result in a real opportunity for effective behavioral intervention and be beneficial to the management of sleep disorders.

(An important side note: one obvious limitation of using smartphone apps for sleep management is the well-known negative impact of LED devices on the circadian rhythm and, consequently, on sleep. Something that should be kept in mind while designing a sleep app is the possibility on minimizing one’s interaction with our phone before bedtime.)

References

Azar KM, et al (2013). Mobile applications for weight management: theory-based content analysis. Am J Prev Med, 45(5):583-9. doi: 10.1016/j.amepre.2013.07.005

Breton E, et al (2011). Weight loss—there is an app for that! But does it adhere to evidence-informed practices? Transl Behav Med, 1(4):523–9. doi: 10.1007/s13142-011-0076-5

Cowan LT, et al (2013). Apps of steel: are exercise apps providing consumers with realistic expectations?: a content analysis of exercise apps for presence of behavior change theory. Health Educ Behav, 40(2):133–9. doi: 10.1177/1090198112452126

Crane D, et al (2015). Behavior change techniques in popular alcohol reduction apps: content analysis. J Med Internet Res, 17(5):e118. doi: 10.2196/jmir.4060

Fogg BJ (2003). Persuasive technology: using computers to change what we think and do (interactive technologies). Morgan Kaufmann, San Francisco. ISBN: 978-1-55860-643-2

Glanz K, et al (2008). Theory, research, and practice in health behavior and health education. In Glanz K, Rimer B & Viswanath K, Health behavior and health education: Theory, research, and practice (4th ed., pp. 23-40). San Francisco, CA: Jossey-Bass. ISBN: 978-0-470-39629-2

Grigsby-Toussainta DS, et al (2017). Sleep apps and behavioral constructs: A content analysis. Prev Med Rep, 6: 126–129. doi: 10.1016/j.pmedr.2017.02.018

Higgins JP (2016). Smartphone Applications for Patients’ Health and Fitness. Am J Med, 129(1):11-9. doi: 10.1016/j.amjmed.2015.05.038

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HIV Reservoirs: Does The Virus Hide in the Brain?

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Treatment advances over the last several decades have dramatically extended the lifespan of patients with human immunodeficiency virus (HIV). However, a continuing problem in HIV treatment is the ability of the virus to remain dormant in a small number of cells throughout the body, including some areas of the brain. Researchers at the University of Montreal in Canada recently discovered a way to locate and destroy hidden HIV viral particles, a finding that could eventually lead to a complete cure for the disease.

HIV currently affects an estimated 36.7 million people worldwide, and infects 2.1 million new individuals each year. HIV infection targets a group of immune cells called CD4+ T cells. These cells are responsible for recognizing and attacking harmful bacteria and viruses that enter the body. When a large proportion of these cells are destroyed by HIV, the body can no longer defend against infections and other diseases. This stage is called acquired immunodeficiency syndrome, or AIDS, and frequently results in premature death due to opportunistic infections and cancer.

The present treatments for HIV include reverse transcriptase inhibitors and protease inhibitors, among several others. These drugs work by targeting the enzymes that convert viral RNA into DNA and produce mature viral particles. These drugs are highly effective and have drastically increased the life expectancy of patients. However, a complete cure for HIV has remained elusive because of the ability of the virus to remain in so-called reservoirs in the body. If a patient in remission forgoes their medication, the virus can become re-activated.

Researchers from several universities, led by Daniel Kauffman of the University of Montreal, recently discovered a way to identify and potentially destroy HIV reservoirs. Their findings are published in the journal Cell Host and Microbe.

First, the researchers sought a new way to identify HIV-infected CD4+ T cells using a method called flow-FISH, which combines two techniques for identifying proteins and nucleotides in cells. Flow cytometry uses a machine to sort and identify cell subpopulations based on surface protein markers, but it is not sensitive or specific enough to identify HIV-infected cells. Fluorescence in situ hybridization, or FISH, uses fluorescent probes directed against specific nucleotide sequences to identify DNA or RNA in a cell with local and temporal specificity. Flow-FISH was used to detect the mRNA of two specific HIV genes in CD4+ T cells, gag and pol.

Using this method, the researchers were able to detect virus-containing cells at concentrations as low as 0.5–1 per million CD4+ T cells. This assay was combined with polychromatic flow cytometry, which analyzes multiple cell surface markers simultaneously. Together, these techniques allowed the researchers to quantify and identify the characteristics of HIV-infected cells in patient blood samples. HIV-infected CD4+ T-cells showed an increase in markers of “immune exhaustion” (PD-1, CTLA-4, and TIGIT), which occurs when T cells have been chronically activated and are no longer responsive. They also were able to estimate the size of the viral reservoir, which was on average 3.56 cells per million CD4+ T cells, but a wide variation was observed among patients on anti-viral therapy.

In the next part of the study, two latency-reversal agents (LRA) were tested on cells from HIV-infected patients. LRAs are used in a “shock and kill” technique that activates dormant viral particles in the body, allowing them to be eradicated by antiretroviral agents. Bryostatin modulates protein kinase C, an enzyme involved in cell signaling pathways, and is currently being tested for use as an anti-cancer, anti-HIV, and memory-enhancing agent. Ingenol is a plant-derived drug with several proposed mechanism of action that include protein kinase C activation, which leads to the activation of immune cells.

The researchers determined that bryostatin and ingenol differed in their ability to activate two subpopulations of CD4+ T cells. Ingenol activated central memory cells, which persist for several years in patients, whereas bryostatin was not as effective against this T-cell subpopulation. This finding suggested that ingenol may be a more effective treatment for latent HIV. While both drugs were capable of killing the HIV virus in vitro, their effectiveness in the body remains unclear. The researchers suggest that their viral detection method will be useful for assessing the effectiveness of LRAs in clinical trials.

This method of reactivating latent HIV provides hope for one day eradicating the virus, but it is not without the potential for side effects. Researchers at Johns Hopkins University recently tested the effect of viral reactivation by LRAs in monkeys with simian immunodeficiency virus (SIV), the correlate of HIV in monkeys. They found that the drug caused a harmful form of brain inflammation. The researchers suspect that this side effects was caused by the existence of HIV reservoirs in the brain.

SIV-infected monkeys were treated with a cocktail of antiretroviral agents (tenofovir, darunavir, ritonavir, and the integrase inhibitor L-870812). Following 400 days on this regimen, viral suppression was confirmed by measuring SIV in plasma. Then two of the monkeys were treated for ten days with the latency-reversing agents ingenol-B and vorinostat. Vorinostat is a histone deacetylase inhibitor that works by changing the expression of genes involved in cell differentiation. The animals continued on the antiretroviral drug cocktail during the treatment with LRAs.

One of the treated monkeys remained healthy under this treatment regimen. However, the second monkey developed symptoms of brain inflammation, including lethargy and lack of appetite. Active SIV and markers of inflammation were detected in the cerebrospinal fluid (CSF), the fluid that surrounds the brain and spinal cord. After the animal was euthanized due to the illness, they removed the brain for examination. They were careful to first remove the monkey’s blood to ensure that the brain tissue wasn’t contaminated by infected blood cells. They found that SIV was present in a part of the brain called the occipital cortex.

The discovery that viral reactivation can cause brain inflammation, possibly by reactivating brain reservoirs of the virus, is a potential drawback for using LRAs to treat latent HIV in humans. Reassuringly, this side effect occurred in only one of the two animals, so these findings are still preliminary. Further, while there are innate differences between SIV and HIV, clinical trials of LRA in humans with HIV must be carried out with caution. Monitoring the CSF for evidence of viral reactivation in the brain should accompany LRA treatment to prevent such side effects.

References

Lugli E., Troiano L, Cossarizza A. (2009) Investigating T cells by polychromatic flow cytometry. Methods Mol Biol. 514:47-63. doi: 10.1007/978-1-60327-527-9_5.

Wherry, J.E. and Kurachi M. (2015) Molecular and cellular insights into T cell exhaustion. Nature Reviews Immunology 15:486–499. doi: 10.1038/nri3862

Lorenzo-Redondo R., Fryer H.R., Bedford T., Kim E.Y., Archer J., Kosakovsky Pond S.L., et al. (2016) Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature 530:51–56. doi: 10.1038/nature16933

Gama L., Abreu C.M., Shirk E.N., Price S.L., Li M., Laird G.M. et al. (2017) Reactivation of simian immunodeficiency virus reservoirs in the brain of virally suppressed macaques. AIDS. Jan 2;31(1):5-14. DOI: 10.1097/QAD.0000000000001267

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Mental Health, Drug Approval, and Biomedical Research in the 21st Century

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A few weeks before the end of 2016, which was also a few weeks before the end of a congressional session and the end of President Barack Obama’s time in office, the 21st Century Cures Act became law. It had been passed with overwhelming support in the House of Representatives and the Senate and it was signed in to law by President Obama in December. The law makes sweeping, if not controversial, changes to many of the most important issues facing health care today, but we must wait to see how – and if – the law will be funded under a new President and future Congresses.

Originally introduced in 2015, the Act was proposed with the goal of promoting development and speeding approval of new drugs and medical devices, and, in its final form, it offers broad incentives and funding opportunities for many areas of health care research, development, and support.

The law directs increasing the budget for the National Institutes of Health (NIH) and creating an NIH fund to promote innovation in research and support opportunities for young researchers. NIH-funded research plays a crucial role in supporting the approval of many new drugs, so this is a welcome addition for many drug developers and researchers. The bill also commits billions of dollars to research precision medicine, map the human brain, and cure cancer.

A large portion of the Act is devoted to accelerating the drug approval process. The U.S. Food and Drug Administration—the gatekeeper of all drugs and devices in the United States—is now instructed by the Act to consider nontraditional study designs and methods when evaluating approvals of new drugs and indications. While most people, especially those in the health care industry, view the approval of new safe and effective drugs as a laudable goal, the willingness to rely on shorter or smaller clinical trials or observational studies or registries to evaluate safety and effectiveness may prove to be problematic. Such approaches are not as rigorous as randomized, controlled trials, that have been, until now, the gold standard of drug approval data.

The Act also encourages the FDA to rely on biomarkers instead of clinical outcomes to assess effectiveness. However, biomarkers are not always accurate representations or predictors of disease risks and endpoints. The Act does not change FDA approval standards, but it allows the FDA more discretion and leniency in how it approves drugs. Critics argue that the less-than-one-year average approval time does not really need accelerating and the strict research requirements do not need adjusting.

As part of the Act, the FDA can also incentivize hospitals for administering new antimicrobial drugs that have not received confirmatory approval. The Act also incentivizes drugmakers by removing regulatory hurdles that lengthen their approval processes and make them more expensive.

In addition to drug approvals, the Act addresses mental health care in this country: it established provisions for fighting the opioid epidemic, strengthened laws guaranteeing access to mental health care, and provided grants to increase the number of psychologists and psychiatrists. The Act pushes society ahead in our goal of preventing devastating consequences of mental health such as homelessness, incarceration, and suicide.

The Act has, for the most part, good motives, and it includes a little bit for a lot of people. However, it aims to fix problems that may or may not really exist and offers incentives to groups that may or may not benefit from incentives.

Plus, the future of health care in this country is uncertain. The new administration could unwind many of the changes established by the Act and, while the Act provides a framework for authorizing these programs, future Congresses would actually need to vote on and approve the budgets that pay for the provisions in the Act. The benefits and drawbacks of the Act in the real world remain to be seen. Our lawmakers are probably looking in the right direction and trying hard to choose the right path, but just how many obstacles and speed traps we hit along the way will influence just how fast this Act can get us to safe, effective, and accessible health care.

References

21st Century Cures Act. U.S. House of Representatives Committee on Energy and Commerce. http://ift.tt/2o4Rk02. Accessed January 23, 2017.

Avorn J, Kesselheim AS. The 21st Century Cures Act—Will it take us back in time? N Engl J Med. 2015;372:2473-2475. PMID: 26039522

Kesselheim AS, Avorn J. The 21st Century Cures Act. N Engl J Med. 2015;373(17):1679-80. PMID: 26488710

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RNA Storage in Neurons Contributes to Brain Plasticity

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The brain shows a remarkable ability to adapt to environmental stimuli that is critical to the process of learning and memory. This flexibility is attributable in part to rapid modifications of neuronal structure and function. A recent study has illuminated how these rapid changes take place, involving the storage of a readily releasable pool of RNA transcripts in the nucleus of neurons.

The brain is a plastic organ that undergoes frequent structural and functional modifications in response to input from the environment. Neuronal activity produces changes in the expression of proteins at synapses and in the connections between neurons. This plasticity relies on the transcription of different genes, which involves the production of messenger (mRNA) from DNA. The level of specific mRNA transcripts can be measured to determine when a gene is turned on or off.

In response to neuronal activity, two waves of mRNA are produced: immediate early genes, and activity-regulated transcripts. The first set of transcripts are made in approximately 30-60 minutes in response to neuronal activity.  Some of these mRNAs encode transcription factors that activate another transcription cascade to produce proteins involved in growth, cell signaling, and synaptic function. Neuronal activity can also modify transcription through alternative splicing, whereby a single gene can encode multiple proteins. Each gene contains multiple introns and exons. Introns are excised before the final RNA sequence is translated to protein. Different combinations of exons can remain following intron removal, and each combination will produce a different protein.

Previous studies have shown that neuronal cells express a large number of long genes (>100 kilobases) that encode proteins important for synaptic function. Since genes of this length would require several hours to transcribe, this raised the question of how plastic changes occur so rapidly. This is the question Oriane Mauger and colleagues sought to answer in their recent study, “Targeted Intron Retention and Excision for Rapid Gene Regulation in Response to Neuronal Activity,” published in the journal Neuron.

The study, led by Peter Scheiffele from the Institut Pasteur in Paris, investigated whether alternative splicing is involved in rapid neuronal plasticity. Alternative splicing takes only seconds to a few minutes, and occurs during transcription. One type of alternative splicing is intron retention, where introns are retained in fully transcribed, mature transcripts. These transcripts are identified by the presence of a stretch of adenine bases, called the polyA+ tail, at the end of the mRNA sequence.

To investigate the role of intron retention in plasticity, the researchers first isolated and sequenced mature polyadenylated RNA sequences from brain cortex samples. The samples were isolated from mice on postnatal day 10 (juvenile) and day 50 (adult), and from 16.5-day-old mouse embryos that had been cultured for 2 weeks. They calculated the number of transcripts that were spliced and the number that retained introns. The intron-retaining (IR) transcripts made up 5-6% of all of the isolated transcripts.

They then treated cells with transcription inhibitors and found that the majority (84%) of intron retention events persisted. They theorized that these retained introns might be excised in response to neuronal activity in order to rapidly modify gene expression. They tested this hypothesis by treating cells with bicuculline, a drug that increases neuronal network activity. Some introns showed increased retention, while others were excised in response to neuronal stimulation. These results were validated for several specific transcripts, showing that the excision of Clk1, Fnbp11, and Tia1 occurred rapidly in response to bicuculline. Using drug treatments, the researchers were also able to show that activity-dependent intron excision is triggered by calcium signaling downstream of synaptic glutamate receptors, called NMDA receptors.

A gene ontology analysis was performed to see what categories of genes were modified by activity-dependent intron excision. In instances where an intron was excised in response to neuronal activity, these genes were shown to be involved in cell signaling and cellular architecture, including microtubule proteins, actin cytoskeleton proteins, phosphoisositide 3-kinase, protein kinase C, and Rho.

Cell fractionation experiments were performed to determine where in the cell the intron-containing transcripts were located. These experiments showed the presence of these transcripts in the cell nucleus. Neuronal stimulation caused an increase in the number of spliced transcripts in the cytosol, suggesting that they were exported. These cytosolic transcripts were found to be associated with ribosomes, indicating that they were being translated, or turned into protein.

Altogether, these experiments showed that a pool of mature DNA transcripts retain their introns. These introns are rapidly excised in response to neuronal activity, and the spliced RNA is transported to the cytoplasm for translation to protein. This mechanism allows new proteins to be rapidly generated in response to neuronal activity, modifying cellular architecture and supporting plasticity.

References

Ebert, D.H., and Greenberg, M.E. (2013). Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493, 327–337. doi:10.1038/nature11860

Beyer, A.L., and Osheim, Y.N. (1988). Splice site selection, rate of splicing, and alternative splicing on nascent transcripts. Genes Dev. 2, 754–765. doi:10.1101/gad.2.6.754

Mauger, O., Lemoine, F., and Scheiffele, P. (2016) Targeted Intron Retention and Excision for Rapid Gene Regulation in Response to Neuronal Activity. Neuron 92(6), 1266–1278. doi:10.1016/j.neuron.2016.11.032

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Best and Worst in Health and Healthcare – May 2017

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In May, next generation therapies took the spotlight: brain-computer interfaces, brain training, tDCS, DNA vaccines, probiotics… Yet, they weren’t all successful.

Here’s the best and worst news of May.

The best

Brain–computer interface therapy for post-stroke motor rehabilitation

Functional recovery from motor disabilities can be a major challenge following stroke. A new study tested a new therapy for motor-related disabilities affecting the arm in hemiparetic stroke survivors. It consisted of an exoskeleton driven by a brain–computer interface (BCI) that used neural activity from the unaffected brain hemisphere to control the movement of the affected hand. By using BCI control to associate imagined hand movements with the opening and closing of the affected hand, participants would train the uninjured parts of their brain to take over movements that were previously controlled by the injured areas of the brain. This BCI-based therapy was shown to be effective in improving motor performance. Another important aspect of this study was the fact that this method was designed and configured for home-based neurorehabilitation. Its efficacy therefore showed that BCI-driven neurorehabilitation can be effectively delivered in the home environment.

A probiotic for IBS-associated depression

Irritable bowel syndrome (IBS) affects 11% of the world’s population and is commonly accompanied by psychiatric symptoms, namely depression and anxiety. The gut microbiota is increasingly acknowledged as a key player in IBS and, via the gut-brain axis, as a likely contributor to the development of the associated psychiatric disorders. Therefore, a new study aimed at evaluating the effects of a probiotic bacteria on anxiety and depression in patients with IBS. The probiotic Bifidobacterium longum NCC3001 (BL) was administered to 44 adults with IBS and anxiety and/or depression for 6 weeks. It was shown that patients who received the probiotic were more likely to have a reduction in depression scores (but not anxiety) and increased quality of life than patients in the placebo group. BL had no effect on IBS, indicating that the reduction in depression scores was not merely a consequence of a reduction in IBS symptoms. Through fMRI analysis, these effects were shown to be linked to changes in brain activation patterns reflecting an effect of the probiotic on the limbic system.

Brain training for chronic TBI

Brain training has shown beneficial effects in acute traumatic brain injury (TBI) therapy, but studies on its effects in chronic TBI are still lacking. Therefore, a new study aimed at determining how the injured brain responds to cognitive training months-to-years after injury. Subjects with chronic TBI received cognitive training for 8 weeks. Cortical thickness and brain connectivity were assessed as indicators of brain plasticity before training, immediately after training, and 3 months after training.

Results showed that cortical thickness and brain connectivity were improved after strategy-based reasoning training, which focused on selective attention, abstract reasoning, and other cognitive strategies. Importantly, these improvements were evident even 3 months after training was completed, indicating a sustained effect.

DNA vaccines for Alzheimer’s disease

DNA vaccines may be the next generation of vaccines. They are designed to induce the production of antigens through the action of genetically engineered DNA, thereby triggering a protective immunological response. Although they are not yet approved for human use, they have been showing interesting beneficial effects in pre-clinical research. A new study has tested a DNA A?42 trimer vaccine (targeting amyloid plaques) for its effect on experimental Alzheimer’s disease.

It was shown that DNA A?42 immunization produced a high antibody response and that the antibodies generated after vaccination were able to detect amyloid plaques in the brain, suggesting a promising preventive effect for Alzheimer’s disease.

Cannabinoids for age-related cognitive decline

The activity of the endocannabinoid system declines during aging, with the expression of the CB1 cannabinoid receptor and the levels of the major endocannabinoid (2-AG) being reduced in the brain of older animals. In a letter published in Nature Medicine, new data shows that a prolonged exposure to low doses of the cannabinoid delta-9-tetrahydrocannabinol (THC, the main psychoactive substance in cannabis) can reverse the age-related cognitive decline in mice, improving spatial memory, long-term memory and learning flexibility.

The effect was accompanied by an increase in synaptic density in the hippocampus and a restoration of hippocampal gene transcription to patterns similar to those of young animals. This indicates a potential beneficial effect of cannabinoids in treating age-related cognitive impairments.

The worst

Sleep disturbances may increase the risk of dementia

Sleep disturbances are known to contribute to an overall deterioration of health. An association between sleep disorders and the development of dementia has also been proposed. A new study aimed at determining if this association is indeed observable in population-based studies. A first phase of the study took place between 1984 and 1989, when data about the sleeping patterns of the participants was collected. The incidence of dementia in those participants was now assessed using data from health registries. It was found that the risk ratio for dementia was significantly higher in individuals with frequent sleep disturbances.

Maternal stress and fetal development

Corticotropin-releasing hormone (CRH) and urocortin (UCN) are two proteins with important roles in both human stress regulation and pregnancy. Therefore, a new study investigated the association between an acute stress response, social overload (as an indicator of chronic stress) and the levels of CRH and UCN in the amniotic fluid of healthy, second-trimester pregnant women. The analyzes revealed that an acute maternal stress response was not associated with increased levels of the two peptides, but that maternal chronic social overload and amniotic CRH were positively correlated. Amniotic CRH was found to be able to influence fetal growth albeit in a non-linear way. This indicates that, although acute maternal stress may not be as influential, chronic maternal stress may affect the production of molecules, such as CRH, that can potentially influence fetal development.

tDCS does not improve the effect of cognitive training

Transcranial direct-current stimulation (tDCS) has been suggested be able to enhance cognitive abilities when associated with cognitive training. This claim has been tested in a new study of 123 older adults, in whom the effects of 20 sessions of anodal tDCS over the left prefrontal cortex and simultaneous working memory training on cognitive performance was assessed. Results showed that tDCS failed to improve the efficacy of cognitive training. A meta-analysis including younger and older individuals was also performed. It also indicated that tDCS is not effective at improving the effect of cognitive training in working memory and global cognition. It is possible that the inefficacy of tDCS may be due to an inadequacy of current tDCS protocols for enhancing the effects of cognitive training, indicating that those protocols may need to be optimized.

The onset of cocaine addiction

Cues associated with the consumption of cocaine can lead to dopamine release in the striatum brain region. This response is believed to be associated with the the motivation to consume. The acquisition of drug-seeking behaviors is believed to be associated with conditioned dopamine responses in the ventral striatum. But as drug use continues and becomes a habit, the conditioned responses shift to the dorsal striatum, which may be associated with compulsive drug use and susceptibility to addiction. A new study used PET imaging and  personalized cocaine cues to assess the pattern of the dopamine response in in recreational cocaine users without a substance use disorder. The results showed that the exposure to cues associated with the opportunity to use the drug increased the dopamine response in the dorsal striatum in recreational cocaine users. This indicates that a susceptibility to addiction may be developing even though there are no psychiatric signs of a substance abuse disorder.

Inflammation and oxidation in Huntington’s disease

Chronic neuroinflammation and oxidative stress are believed to play an important role in driving Huntington’s disease progression. NRF2 is a transcription factor with a chief role in regulating cellular anti-inflammatory and antioxidant defense genes. A new study has reveled that NRF2 activation was suppressed in neural stem cells of Huntington’s disease patients, suggesting that these cells may be abnormally susceptible to oxidative stress. On the bright side, it was shown that the pharmacological activation of NRF2 was able to decrease inflammatory responses in glial cells, the main cellular mediators of neuroinflammation, and in blood monocytes from Huntington’s disease patients. These findings also suggest that NRF2 may be an important therapeutic target in Huntington’s disease.

References

Bilkei-Gorzo A, et al (2017). A chronic low dose of ?9-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nat Med. doi: 10.1038/nm.4311. [Epub ahead of print]

Bundy DT, et al (2017). Contralesional Brain-Computer Interface Control of a Powered Exoskeleton for Motor Recovery in Chronic Stroke Survivors. Stroke. pii: STROKEAHA.116.016304. doi: 10.1161/STROKEAHA.116.016304. [Epub ahead of print]

Cox SML, et al (2017). Cocaine Cue-Induced Dopamine Release in Recreational Cocaine Users. Sci Rep, 7: 46665. doi:  10.1038/srep46665

Han K, et al (2017). Strategy-based reasoning training modulates cortical thickness and resting-state functional connectivity in adults with chronic traumatic brain injury. Brain Behav, 7(5):e00687. doi: 10.1002/brb3.687s.

La Marca-Ghaemmaghami P, et al (2017). Second-trimester amniotic fluid corticotropin-releasing hormone and urocortin in relation to maternal stress and fetal growth in human pregnancy. Stress, 21:1-10. doi: 10.1080/10253890.2017.1312336pregnanc. [Epub ahead of print]

<p class=“p1″>Lambracht-Washington D, et al (2017). Evaluation of a DNA A?42 vaccine in adult rhesus monkeys (Macaca mulatta): antibody kinetics and immune profile after intradermal immunization with full-length DNA A?42 trimer.Alzheimers Res Ther, 9(1):30. doi: 10.1186/s13195-017-0257-7.

Luojus MK, et al (2017).Self-reported sleep disturbance and incidence of dementia in ageing men. J Epidemiol Community Health, 71(4):329-335. doi: 10.1136/jech-2016-207764.

Nilsson J, et al (2017). Direct-Current Stimulation Does Little to Improve the Outcome of Working Memory Training in Older Adults. Psychol Sci. doi: 10.1177/0956797617698139. [Epub ahead of print]

Pinto-Sanchez MI, et al (2017).Probiotic Bifidobacterium longum NCC3001 Reduces Depression Scores and Alters Brain Activity: a Pilot Study in Patients With Irritable Bowel Syndrome.Gastroenterology. pii: S0016-5085(17)35557-9. doi: 10.1053/j.gastro.2017.05.003. [Epub ahead of print]

Quinti L, et al (2017). KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington’s disease patients.Proc Natl Acad Sci U S A, pii: 201614943. doi: 10.1073/pnas.1614943114. [Epub ahead of print]

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Best and Worst of Neuroscience and Neurology – May 2017

The latest from http://brainblogger.com!

What is genetic basis of our intelligence? How to stimulate deep areas of the brain? How to prevent Alzheimer’s disease?  How to slash the cost of treatment of multiple sclerosis? These are some of the questions highlighted in this monthly review of research literature. As usual, while we answer some questions, research studies also dispel some myths and assumption. Whether positive or negative,  the findings always help us to advance further our knowledge of brain and its abilities.

This month, we marked the birthday of Stanley Prusiner, the discoverer of prions – self-replicating proteins behind many neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease. Recognising the importance of prions finally put the research aimed at finding the cure for these conditions on the right track.

 THE BEST

New genes for intelligence identified

Intelligence is highly heritable: it is estimated that 80% of our intelligence in adulthood is explained by genetic factors. However, our knowledge of specific genes involved in intelligence is very limited. New study published this month and based on the analysis of genetic data from 78,000 individuals reported 52 genes associated with intelligence, 40 of which are completely novel. Interestingly, many of these genes are also involved in determining other traits such as obesity, BMI, depressive syndromes, Alzheimer’s disease and others.

Brain region responsible for the fear of uncertain future is identified

Many people find it difficult to cope with an uncertain future. Surprisingly, it turned out that this particular behavioural feature closely relates to the size of one specific part of the brain – the striatum. New research suggests that a larger striatum is typically seen in people who have troubles dealing with uncertainties.  The study was done on psychologically healthy individuals, but an enlarged striatum has also been reported to be associated with general anxiety disorder and obsessive compulsive disorder.  Researchers speculate that an enlarged striatum may be linked to a higher risk of developing these disorders later in life.

Non-invasive method of stimulating deep parts of brain

Electric stimulation of deep parts of the brain has proven to be beneficial in treating a number of brain disorders, such as Parkinson’s disease, obsessive compulsive disorder, epilepsy, and depression. However, the approach requires implanting of an electrode directly inside the brain, which involves a risky and costly surgery. A new technique reported this month avoids this problem by using a pair of electrodes located on the surface of the scalp. The method relies on the use of a phenomenon known as temporal interference. This techniques allows the targeted delivery of electrical stimulation to deep areas of brain, such as hippocampus, without stimulating the surface brain area.

New cheap treatment for multiple sclerosis

Antibiotic minocycline, traditionally used as an acne medicine, may provide a safe new method of treating multiple sclerosis (MS), at a fraction of current cost of treating this disease. This drug was developed over 50 years ago. It attracted the attention of researchers studying MS due to its spectrum of anti-inflammatory activities. Phase III trials demonstrated that minocycline slows the progress of disease in patients diagnosed during the early stages of MS.

DNA-based vaccine for Alzheimer’s

Despite our growing understanding of the molecular mechanisms behind the development of Alzheimer’s disease, we still have no single treatment that could cure this condition or stop its progression. An earlier attempt to develop a vaccine preventing the development of Alzheimer’s disease has also failed due to severe side effects. However, new article published this month reports a new promising DNA-based vaccine that inhibits the accumulation of amyloid proteins in animals and shows no side effects observed in previous trials. It remains to be seen if these effects can be reproduced in humans.

Blood-brain barrier and omega-3 fatty acids

Omega-3 fatty acids are well known for their positive effects on general health. Recent findings demonstrate that these compounds are critical players in maintaining the integrity of the blood-brain barrier, the key structure for protecting the brain from various pathogens and toxins. Moreover, researchers demonstrated that permeability of the blood-brain barrier can be regulated by suppressing a protein that transports omega-3 acids to blood vessel cells. Making the barrier more penetrable is advantageous for efficient delivery of drugs when treating patients with various brain disorders.
THE WORST

No stress relief from high doses of tetrahydrocannabinol

Users of cannabis often claim that they use the drug for relaxation and stress relief. More detailed investigation of this effect shows a mixed picture. While experimenting with different doses of tetrahydrocannabinol (THC), the major active substance in marijuana, researchers found that small doses of the compound do indeed reduce stress. However, a slightly higher doses (sufficient to produce a mild “high”) produce an opposite effect and increase anxiety.

Visual cortex develops and matures much slower than assumed

It is traditionally believed that our visual system, including the parts of brain involved in the analysis of visual information, matures within the first few years of life. A new article published this month demonstrates that this assumption is incorrect. Visual cortex continues developing till the late 30s – early 40s. The authors of the article speculate that other parts of the brain may also reach maturity much later in life than currently assumed.

Transcranial direct-current stimulation  does not enhance cognitive training

Transcranial direct-current stimulation () is increasingly used as a method of improving learning abilities. The technique relies on passing weak electric impulses to the brain via electrodes attached to the scalp. Despite the growing popularity of this technique, the evidence in support of its advantages are very limited. A paper published this month casts further doubt on any benefits provided by tDCS. The author reported no improvements of working memory in a large group of subjects using this method, as compared to controls. Furthermore, the analysis of the existing literature on the subject also does not provide any meaningful support to the method. Clearly, further research on tDCS should be done to confirm or rule out the existence of its effects.

Poor sense of smell in humans is a misconception

The superiority of animals sense of smell compared to humans appears to be obvious to most people. After all, we do rely on a dog’s sense of smell for hunting, and it is well known how quickly sharks can detect the slightest smell of blood. However, a new article published this month in Science attempts to dispel the view that the human ability to detect smells is as bad as we are used to thinking. The number of brain cells involved in smell detection in humans is almost the same as in animals, and it is estimated that we can distinguish up to one trillion of different odors. We may lack the degree of specialization demonstrated by many animals in interpreting the information obtained through olfactory system, but the human ability to recognize smells is definitely much stronger than we are accustomed to think.

Women are not better than men at face recognition

It is commonly assumed that women are better  at recognizing and reading faces and correctly interpreting facial expressions. However, a study published this month casts serious doubts on this assumption. Using a series of tests, scientists demonstrated that no detectable difference in facial recognition exists between two genders. Importantly, the neuroimaging of the areas of brain known to be involved in face recognition has shown identical neural activity in both men and women when they were watching a video clip featuring multiple familiar and non-familiar faces.

References:

Suzanne Sniekers, Sven Stringer, Kyoko Watanabe, Philip R Jansen, Jonathan R I Coleman, Eva Krapohl, Erdogan Taskesen, Anke R Hammerschlag, Aysu Okbay, Delilah Zabaneh, Najaf Amin, Gerome Breen, David Cesarini, Christopher F Chabris, William G Iacono, M Arfan Ikram, Magnus Johannesson, Philipp Koellinger, James J Lee, Patrik K E Magnusson, Matt McGue, Mike B Miller, William E R Ollier, Antony Payton, Neil Pendleton, Robert Plomin, Cornelius A Rietveld, Henning Tiemeier, Cornelia M van Duijn, Danielle Posthuma. Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence. Nature Genetics, 2017; DOI: 10.1038/ng.3869

Justin Kim, PhD, Jin Shin, James Taylor, PhD, Alison Mattek, Samantha Chavez, and Paul Whalen, PhD. Intolerance of Uncertainty Predicts Increased Striatal Volume. Emotion, May 2017 DOI: 10.1037/emo0000331

Nir Grossman, David Bono, Nina Dedic, Suhasa B. Kodandaramaiah, Andrii Rudenko, Ho-Jun Suk, Antonino M. Cassara, Esra Neufeld, Niels Kuster, Li-Huei Tsai, Alvaro Pascual-Leone, Edward S. Boyden. Noninvasive Deep Brain Stimulation via Temporally Interfering Electric Fields. Cell, 2017; 169 (6): 1029 DOI: 10.1016/j.cell.2017.05.024

Luanne M. Metz, David K.B. Li, Anthony L. Traboulsee, Pierre Duquette, Misha Eliasziw, Graziela Cerchiaro, Jamie Greenfield, Andrew Riddehough, Michael Yeung, Marcelo Kremenchutzky, Galina Vorobeychik, Mark S. Freedman, Virender Bhan, Gregg Blevins, James J. Marriott, Francois Grand’Maison, Liesly Lee, Manon Thibault, Michael D. Hill, V. Wee Yong. Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis. New England Journal of Medicine, 2017; 376 (22): 2122 DOI: 10.1056/NEJMoa1608889

Doris Lambracht-Washington, Min Fu, Pat Frost, Roger N. Rosenberg. Evaluation of a DNA A?42 vaccine in adult rhesus monkeys (Macaca mulatta): antibody kinetics and immune profile after intradermal immunization with full-length DNA A?42 trimer. Alzheimer’s Research & Therapy, 2017; 9 (1) DOI: 10.1186/s13195-017-0257-7

Benjamin J. Andreone, Brian Wai Chow, Aleksandra Tata, Baptiste Lacoste, Ayal Ben-Zvi, Kevin Bullock, Amy A. Deik, David D. Ginty, Clary B. Clish, Chenghua Gu. Blood-Brain Barrier Permeability Is Regulated by Lipid Transport-Dependent Suppression of Caveolae-Mediated Transcytosis. Neuron, 2017; 94 (3): 581 DOI: 10.1016/j.neuron.2017.03.043

Emma Childs, Joseph A. Lutz, Harriet de Wit. Dose-related effects of delta-9-THC on emotional responses to acute psychosocial stress. Drug and Alcohol Dependence, 2017; DOI: 10.1016/j.drugalcdep.2017.03.030

Caitlin R. Siu, Simon P. Beshara, David G. Jones and Kathryn M. Murphy. Development of glutamatergic proteins in human visual cortex across the lifespan. Journal of Neuroscience, May 2017 DOI: 10.1523/JNEUROSCI.2304-16.2017

Jonna Nilsson, Alexander V. Lebedev, Anders Rydström, Martin Lövdén. Direct-Current Stimulation Does Little to Improve the Outcome of Working Memory Training in Older Adults. Psychological Science, 2017; 095679761769813 DOI: 10.1177/0956797617698139

John P. McGann. Poor human olfaction is a 19th-century myth. Science, 2017; 356 (6338): eaam7263 DOI: 10.1126/science.aam7263

Suzanne Scherf, Daniel B. Elbich, Natalie V. Motta-Mena. Investigating the Influence of Biological Sex on the Behavioral and Neural Basis of Face Recognition. eneuro, 2017; ENEURO.0104-17.2017 DOI: 10.1523/ENEURO.0104-17.2017

Image via kennethr/Pixabay.

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The Neuroanatomy of Gossips

The latest from http://brainblogger.com!

We talk a lot. We are the only species on the planet that exchange information predominantly through talking. Other species, such as dolphins or primates, have their own languages, but they do not rely on verbal communication to the same degree, almost to the exclusion of other communication channels, as we do. Verbal communication is a cornerstone of our society. So what are we talking about so much? According to scientific research, we talk mostly about other people. In fact, a whopping two-thirds of our conversations consist of gossips. Of course, we discuss other things such as work, politics, sports, and weather, but overwhelmingly we talk about other people’s affairs, often not in a very positive light.

The scientific statistics on gossiping came as a surprise to me: what the intelligent, sensible and, as a rule, genuinely compassionate people around me would gain from spending so much time on gossips? I always believed that I almost never gossip. But when I tried to recall the topics of recent conversations with my friends, I have to admit that discussing other people does indeed take the lion’s share of what we talk about. Gossiping might be just a reflection of curiosity that all humans possess.

However, according to psychologists and evolutionary scientists, gossiping plays a key role in societal cohesion by spreading reputational information. The studies show that:

Individuals readily communicate reputational information about others, and recipients used this information to selectively interact with cooperative individuals and ostracize those who had behaved selfishly, which enabled group members to contribute to the public good with reduced threat of exploitation.

Thus, gossips mitigate egoistic behavior and counteract possible incentives to exploit the cooperative tendencies of others. They also serve to protect vulnerable members of society. Not bad!

The term “gossip” tends to have a negative connotation. Cambridge Dictionary defines gossip as conversation or reports about other people’s private lives that might be unkind, disapproving, or not true. Typically, the information shared via gossips is not substantiated by hard evidence. Although gossips are indeed often negative (and we will see below why we find negative gossiping more engaging), we do often talk about positive aspects of other people’s behavior too. We simply don’t view this kind of information sharing as gossiping. Negative gossiping might require a degree of secrecy (i.e., the subjects of the gossips are not informed about the fact that they were discussed – we talk about them behind their back). Unsurprisingly, people do not like when they find that they are being gossiped about, and hence there is a moral stigma attached to the people who are gossiping too much. However, more often than not, the gossips are not entirely negative – they tend to be a mixture of both positive and negative things. We provide other people with our assessment of another person’s reputation as we see it, typically involving both the person’s strengths and weaknesses, and with only limited evidence to substantiate either. These assessments might still be viewed unfavorably by the subjects of gossips, even when the assessment is predominantly positive. Nonetheless, we accept positive assessments with pleasure, but tend to be annoyed by criticism.

Being social creatures, we pay lots of attention to the opinion of others about us. Positive assessments by others are associated with higher social status, a larger number of friends and followers, and better chances of succeeding in any new venture and finding and attracting the best mating partners.

The part of the brain responsible for our social behavior is the prefrontal cortex. The prefrontal cortex is involved in social cognition and executive control. Social cognition refers to our ability to regulate our behavior and actions based on the real or assumed presence of other people. This is a trait that makes some want to conform to the norms and rules of society in which we live. Executive control channels our actual behavior and thoughts in the desirable direction. Studies with the use of functional MRI brain scans revealed the patterns of activation in the prefrontal cortex in response to positive and negative gossip about themselves, their best friends, and celebrities. A very interesting and revealing picture has emerged from these studies.

Two separate areas of the prefrontal cortex get activated in response to positive and negative gossip: positive gossip activates the orbital prefrontal cortex region, while negative gossip activates the superior medial prefrontal cortex. The intensity of responses was, however, very different depending on whether the gossip was about the subject of study or other people. Substantial activation of the superior medial prefrontal cortex was observed in both cases, regardless of the subject of the negative gossip. The orbital prefrontal cortex region was highly activated by positive gossip about the subjects themselves. However, this response was rather muted when the subjects listened to positive gossip about their friends or celebrities.

This study revealed volumes about the internal processes in our brain. It is quite clear that our ego makes us very attentive to any kind of information about ourselves passed around by other people. However, when it comes to information about others, we are biased to notice and register negative information preferentially. No wonder that the stories of scandals involving celebrities attract more attention than anything good these people do! Our own neuroanatomy makes celebrity magazines filled with the stories of scandals, cheating, and divorces, much more popular that magazines about happy family life.

References

Baumeister, R., Zhang, L., & Vohs, K. (2004). Gossip as cultural learning.(2), 111-121 DOI: 10.1037/1089-2680.8.2.111

Bosson, J. et al. (2006). Interpersonal chemistry through negativity: Bonding by sharing negative attitudes about others Personal Relationships, 13 (2), 135-150 DOI:10.1111/j.1475-6811.2006.00109.x

Dunbar, R. (2004). Gossip in evolutionary perspective. Review of General Psychology, 8 (2), 100-110 DOI:10.1037/1089-2680.8.2.100

Feinberg, M., Willer, R., & Schultz, M. (2014). Gossip and Ostracism Promote Cooperation in Groups Psychological Science, 25 (3), 656-664 DOI: 10.1177/0956797613510184

Feinberg, M., Willer, R., Stellar, J., & Keltner, D. (2012). The virtues of gossip: Reputational information sharing as prosocial behavior. Journal of Personality and Social Psychology, 102 (5), 1015-1030 DOI: 10.1037/a0026650

Martinescu, E., Janssen, O., & Nijstad, B. (2014). Tell Me the Gossip: The Self-Evaluative Function of Receiving Gossip About Others Personality and Social Psychology Bulletin, 40 (12), 1668-1680 DOI: 10.1177/0146167214554916

Peng X, Li Y, Wang P, Mo L, & Chen Q (2015). The ugly truth: negative gossip about celebrities and positive gossip about self entertain people in different ways. Social neuroscience, 10 (3), 320-36 PMID: 25580932

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