Sara Adaes, PhD – Brain Blogger http://brainblogger.com Health and Science Blog Covering Brain Topics Wed, 30 May 2018 15:00:03 +0000 en-US hourly 1 https://wordpress.org/?v=4.9.6 Do We Sense Each Other’s Sickness? http://brainblogger.com/2017/07/28/do-we-sense-each-others-sickness/ http://brainblogger.com/2017/07/28/do-we-sense-each-others-sickness/#respond Fri, 28 Jul 2017 15:00:08 +0000 http://brainblogger.com/?p=22697 Social behavior is important for our survival as a species. But social interaction also gives pathogens a chance to spread, and it thereby increases our exposure to infection. Our immune system is a complex defense system that has evolved to protect us from infection. Therefore, it makes sense to assume that our immune system must have developed ingenious strategies to protect us from new pathogens that social interaction has exposed us to.

Evidence of a link between the immune system and our social behavior has been accumulating in the recent years. A direct connection between the brain and the immune system, through lymphatic vessels in the meninges, was recently revealed. It was shown that the immune system can directly affect and even control social behavior and the desire for social interaction because an impaired immunity induced deficits in social behavior. This sounds like a clever preventive self-defense mechanism designed to avoid contagion—in times of poor immunity, our brain gets the message to reduce social interaction and, consequently, exposure to pathogens.

This is a self-defense mechanism that is activated when our body signals a poor immunological status; it’s an internal chemical communication system. But is there an external threat signaling system? The ability to detect and avoid infected individuals would clearly be a great evolutionary asset in strengthening our protection mechanisms. Many animals can detect sickness via odors, leading to a restraint in social interaction, most likely intended to reduce exposure to disease. Do humans have a similar sensory sickness detection system, something that allows us to detect infectious threats in others?

To answer this question, a new study aimed at determining whether humans can detect sickness in others from visual and olfactory cues. Sickness was experimentally induced by the injection of lipopolysaccharide (LPS), a molecule found in the membrane of Gram-negative bacteria that provokes robust immune responses. The activation of immune responses leads to an increase in the production of pro-inflammatory molecules that activate sickness responses and behaviors. It is known that visual cues of sickness, such as redness of the skin, allow us to infer the health of others. But although LPS induces a strong sickness response, its observable effects are subtle, and odor cues are difficult to perceive.

Photos of the face and samples of body odors of both sick and healthy individuals were presented to a group of naive participants while their cerebral responses were recorded using fMRI. These participants were not aware that they would be seeing and smelling sick and healthy people. They were asked to focus on the faces while the odors were also presented and rate how much they liked the person. Faces were also rated on attractiveness, health, and desired social interaction, while odors were rated on intensity, pleasantness, and health. This allowed the assessment of the “liking behavior” towards the faces, an indication of the will to approach and interact with others.

The rating of sick and healthy faces showed that photos obtained during acute sickness were generally considered less attractive, less healthy, and less socially desirable than the faces of participants receiving the placebo treatment. When faces were presented concomitantly with an odor, there was a lower liking of sick than of healthy faces, regardless of the odor presented with the face. Participants were not able to perceive sickness in the odors, nor did they rate sick odors as more unpleasant or more intense than healthy odors. Remarkably, however, faces, were less liked when paired with sick body odor regardless of being sick or healthy.

These results show that we can detect early and subtle signs of sickness in others from both facial and olfactory cues, even just a couple of hours after activation of their immune system. Moreover, fMRI data revealed that visual and olfactory sickness cues activated their respective visual face processing and olfactory sensory cortices, as well as multisensory convergence zones. And even though odors were often too weak to be consciously detected, these olfactory sickness cues still led to activation of the olfactory cortex.

The study also revealed that this perception of subtle cues of sickness leads to reduced liking and decreased will for social interaction. This response may represent a human behavioral defense system against disease. The integration of olfactory and visual sickness cues in the brain may be part of a mechanism designed to detect sickness, resulting in behavioral avoidance of sick individuals, and in avoidance of impending threats of infection.

References

Filiano AJ, et al (2016). Unexpected role of interferon-? in regulating neuronal connectivity and social behavior. Nature, 535(7612):425-9. doi: 10.1038/nature18626

Kipnis J (2016). Multifaceted interactions between adaptive immunity and the central nervous system. Science, 353(6301):766-71. doi: 10.1126/science.aag2638

Louveau A, et al (2015). Structural and functional features of central nervous system lymphatic vessels. Nature, 523(7560):337-41. doi: 10.1038/nature14432

Regenbogen C, et al (2017). Behavioral and neural correlates to multisensory detection of sick humans. Proc Natl Acad Sci U S A, pii: 201617357. doi: 10.1073/pnas.1617357114. [Epub ahead of print]

Shattuck EC, Muehlenbein MP (2015). Human sickness behavior: Ultimate and proximate explanations.Am J Phys Anthropol, 157(1):1-18. doi: 10.1002/ajpa.22698.

Image via junko/Pixabay.

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Nurturing the Brain – Part 11, Magnesium http://brainblogger.com/2017/07/26/nurturing-the-brain-part-11-magnesium/ http://brainblogger.com/2017/07/26/nurturing-the-brain-part-11-magnesium/#respond Wed, 26 Jul 2017 15:00:50 +0000 http://brainblogger.com/?p=22677 Magnesium is everywhere—it does not occur free in nature, but in combination with other elements it is the eighth-most abundant chemical element in the Earth’s crust and the third-most abundant element in seawater; it is even the ninth-most abundant in the Milky Way! In the human body, magnesium is the fourth most abundant ion and the eleventh most abundant element by mass, being stored in bones, muscles, and soft tissues.

Magnesium is fundamental for health: it is essential to all cells and to the function of hundreds of enzymes, including enzymes that synthesize DNA and RNA, and enzymes involved in cellular energy metabolism, many of which are vital. Magnesium is involved in virtually every major metabolic and biochemical process in our cells and it plays a critical role in the physiology of basically every single organ.

Low plasma levels of magnesium are common and are mostly due to poor dietary intake, which has lowered significantly in the last decades. Magnesium can be found in high quantities in foods containing dietary fiber, including green leafy vegetables, legumes, nuts, seeds, and whole grains. But although magnesium is widely distributed in vegetable and animal foods, some types of food processing can lower magnesium content up to 90%. Also, the soil used for conventional agriculture is becoming increasingly deprived of essential minerals. In the last 60 years, the magnesium content in fruit and vegetables has decreased by around 20–30%.

Symptomatic magnesium deficiency due to low dietary intake in healthy people is not very frequent, but a consistently poor dietary supply of magnesium has insidious effects. Magnesium deficiency alters biochemical pathways and increases the risk of a wide range of diseases over time, including hypertension and cardiovascular diseases, metabolic diseases, osteoporosis, and migraine headaches.

In the brain, magnesium is an important regulator of neurotransmitter signaling—particularly the main neurotransmitters glutamate and GABA—by modulating the activation of NMDA glutamate and GABAA receptors. It also contributes to the maintenance of adequate calcium levels in the cell by regulating the activity of calcium channels.

These physiological roles make magnesium an essential element in important neuronal processes. Magnesium participates in mechanisms of synaptic transmission, neuronal plasticity, and consequently, learning and memory. Accordingly, increased levels of magnesium in the brain have been shown to promote multiple mechanisms of synaptic plasticity that enhance different forms of learning and memory, as well as delay age-related cognitive decline. Increased levels of magnesium in the brain have also been linked to an increased proliferation of neural stem cells, indicating that it may promote the generation of new neurons (neurogenesis) in adulthood. This is an important feature because neurogenesis is a key mechanism in the brain’s structural and functional adaptability, in cognitive flexibility, and in mood regulation.

Magnesium supplementation has also been shown to modulate the neuroendocrine system and to improve sleep quality by promoting slow wave (deep) sleep, which, among many other functions, is also important for cognition and memory consolidation.

Furthermore, magnesium may enhance the beneficial effects of exercise in the brain, since it has been shown to increase the availability of glucose in the blood, muscle, and brain, and diminish the accumulation of lactate in the blood and muscles during exercise.

But just as increasing magnesium levels can be beneficial, magnesium deficiency can have serious harmful effects.

Magnesium has important roles in the regulation of oxidative stress, inflammatory processes and modulation of brain blood flow. In circumstances of magnesium deficiency, all of these functions can potentially be dysregulated, laying the ground for neurological disorders. Also, in a context of low magnesium availability in the brain, NMDA glutamate receptors, which are excitatory, may become excessively activated, and GABAA receptors, which are inhibitory, may become insufficiently activated; this can lead to neuronal hyperactivity and to a condition known as glutamate excitotoxicity. This causes an excessive accumulation of calcium in neurons, which in turn leads to the production of toxic reactive oxygen species and, ultimately, to neuronal cell death.

Magnesium deficiency has been associated with several neurological and psychiatric diseases, including migraines, epilepsy, depression, schizophrenia, bipolar disorder, stress, and neurodegenerative diseases. Magnesium supplementation has shown beneficial effects on many of these conditions, as well as in post-stroke, post-traumatic brain injury, and post-spinal cord injury therapies. This therapeutic action is likely due to the blocking of NMDA glutamate receptors and decreasing excitotoxicity, reducing oxidative stress and inflammation, and increasing blood flow to the brain, all of which are determinants of the outcome of these conditions.

There are multiple benefits to be obtained from magnesium, both from a health promotion and disease prevention/management perspective. The recommended daily intake of magnesium is 320 mg for females and 420 mg for males. Too much magnesium from food sources has no associated health risks in healthy individuals because the kidneys readily eliminate the excess. However, there is a recommended upper intake level for supplemental magnesium, since it can cause gastrointestinal side effects. So, keep it below 350 mg/day.

References

Chen HY, et al (2014). Magnesium enhances exercise performance via increasing glucose availability in the blood, muscle, and brain during exercise. PLoS One, 9(1):e85486. doi: 10.1371/journal.pone.0085486

de Baaij JH, et al (2015). Magnesium in man: implications for health and disease. Physiol Rev, 95(1):1-46. doi: 10.1152/physrev.00012.2014

Held K, et al (2002). Oral Mg(2+) supplementation reverses age-related neuroendocrine and sleep EEG changes in humans. Pharmacopsychiatry, 35(4):135-43. doi: 10.1016/j.pbb.2004.01.006

Jia S, et al (2016). Elevation of Brain Magnesium Potentiates Neural Stem Cell Proliferation in the Hippocampus of Young and Aged Mice. J Cell Physiol, 231(9):1903-12. doi: 10.1002/jcp.25306

National Institutes of Health, Office of Dietary Supplements. Magnesium Fact Sheet for Health Professionals

Slutsky I, et al (2010). Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010 Jan 28;65(2):165-77. doi: 10.1016/j.neuron.2009.12.026

Image via Brett_Hondow/Pixabay.

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Prevention Is the Best Medicine for Dementia http://brainblogger.com/2017/07/14/prevention-is-the-best-medicine-for-dementia/ http://brainblogger.com/2017/07/14/prevention-is-the-best-medicine-for-dementia/#respond Fri, 14 Jul 2017 15:00:29 +0000 http://brainblogger.com/?p=22670 Population aging is bringing about a substantial increase in the prevalence of neurocognitive disorders. Current projections estimate that, by 2050, more that 130 million people will be affected by dementia worldwide. As experts assemble to devise strategies to face this incoming challenge, one conclusion stands out: prevention is crucial.

The goal of prevention is obvious: to promote good health and take action before disease onset, thereby reducing the incidence of disease. And this is obviously better than having to manage a disease and its complications, and losing quality of life – “prevention is better than cure.”

But in order for preventive behaviors to be acquired, knowledge is essential – knowledge of modifiable risk factors and preemptive actions that can be adopted, and knowledge of how effective they really are. Studies addressing the benefit of lifestyle interventions for the prevention of dementia have identified numerous modifiable risk and protective factors and have shown that change can indeed be beneficial.

Modifiable risk factors for cognitive impairment include lifestyle factors such as smoking, high alcohol intake, diet (saturated fats, sugar, processed foods), and poor physical activity; these then manifest in other risk factors that are already a consequence of inadequate lifestyle options, namely vascular and metabolic diseases (cerebrovascular and cardiovascular diseases, diabetes, hypertension, overweight and obesity, high cholesterol). In the end, it all builds up to speed up cognitive decline.

Protective factors include opposite lifestyle choices, such as quitting smoking, moderate alcohol intake, healthier diet (Mediterranean diet, polyunsaturated fatty acids and fish-related fats, vitamins B6 and B12, folate, antioxidant vitamins (A, C and E), vitamin D, physical activity, and mentally stimulating activity.

Still, cognitive disorders are complex, multifactorial conditions – even if you lead the healthiest life, dementia may still strike you. But this should not be an excuse to let go because research shows is that preventive behaviors shift the odds in your favor.

An important aspect of behavioral change is that it should be integrative. Single-domain interventions provide some benefit: physical activity and cognitive training have been positively associated with cognitive performance in multiple studies; also, a recent meta-analysis showed that an increased consumption of fruit and vegetables reduces the risk of cognitive impairment and dementia. But multi-domain interventions, in which multiple risk factors are targeted simultaneously are more likely to deliver better results.

For example, a 2015 Finnish study assessed the effect of a 2-year multimodal intervention in adults aged 60-77 years at risk of cognitive decline but without pronounced cognitive impairment. Four intervention targets were included: diet, exercise, cognitive training, and vascular risk. The program’s design included a diet with high consumption of fruit and vegetables, consumption of wholegrain cereal products and low-fat milk and meat products, low sucrose intake, use of vegetable margarine and rapeseed oil instead of butter, and fish consumption at least two portions per week.

The physical exercise training program included progressive muscle strength training, aerobic exercise, and exercises to improve postural balance. Cognitive training consisted of computer-based training targeting executive processes, working memory, episodic memory, and mental speed. Metabolic and vascular risk factors were monitored throughout the study. Social activities were also stimulated through the numerous group meetings of all intervention components.

The study showed that simultaneous changes in multiple risk factors, even of small magnitude, had beneficial effects on the risk of cognitive decline, on overall cognition, complex memory tasks, executive functioning and processing speed, and on also BMI, dietary habits, and physical activity.

But a timely prevention seems fundamental – these lifestyle interventions may not be as effective once cognitive impairment is manifest. A recent study evaluated the impact of a 3-year omega-3 fatty acid supplementation with or without multi-domain lifestyle interventions on cognitive function in adults aged 70 years or older. These adults already had symptoms of cognitive impairment: either memory complaints, limitations in one instrumental daily living activity, or slow gait speed. The multi-domain intervention included cognitive training, physical activity, nutrition, and management of cardiovascular risk factors.

In this case, neither the omega-3 supplementation alone, nor the combination with the lifestyle interventions were able to reduce cognitive decline. Also, the adherence to lifestyle interventions over time was lower in this study when compared to other studies with younger seniors, with no clinical manifestations of dementia onset. But still, those with increased risk of dementia were the ones who benefited the most.

Early prevention is probably the best strategy. Instead of trying to prevent dementia later in life, focusing on preventing earlier, milder, and more common forms of cognitive impairment may be a better strategy that may end up also preventing cardiovascular and metabolic diseases and, ultimately, dementia. Because they’re all fruits from the same tree.

References

Andrieu S, et al (2017). Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol, 16(5):377-389. doi: 10.1016/S1474-4422(17)30040-6

Jiang X, et al (2017). Increased Consumption of Fruit and Vegetables Is Related to a Reduced Risk of Cognitive Impairment and Dementia: Meta-Analysis. Front Aging Neurosci, 9:18. doi: 10.3389/fnagi.2017.00018

Kivipelto M, et al (2017). Can lifestyle changes prevent cognitive impairment? Lancet Neurol, 16(5):338-339. doi: 10.1016/S1474-4422(17)30080-7

Ngandu T, et al (2015). A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet, 385(9984):2255-63. doi: 10.1016/S0140-6736(15)60461-5

Shah H, et al (2016). Research priorities to reduce the global burden of dementia by 2025. Lancet Neurol, 15(12):1285-1294. doi: 10.1016/S1474-4422(16)30235-6

Solomon A, et al (2016). Advances in the prevention of Alzheimer’s disease and dementia. J Intern Med, 275(3):229-50. doi: 10.1111/joim.12178

Image via Couleur/Pixabay.

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Are Sleep Apps Effective Tools For Behavioral Change? http://brainblogger.com/2017/07/12/are-sleep-apps-effective-tools-for-behavioral-change/ http://brainblogger.com/2017/07/12/are-sleep-apps-effective-tools-for-behavioral-change/#respond Wed, 12 Jul 2017 15:00:04 +0000 http://brainblogger.com/?p=22659 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

Image via 1haboeri/Pixabay.

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Best and Worst in Health and Healthcare – May 2017 http://brainblogger.com/2017/06/28/best-and-worst-in-health-and-healthcare-may-2017/ http://brainblogger.com/2017/06/28/best-and-worst-in-health-and-healthcare-may-2017/#respond Wed, 28 Jun 2017 15:30:59 +0000 http://brainblogger.com/?p=22701 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]

“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]

Image via DarkoStojanovic/Pixabay.

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Can Our Immune System Drive Social Behavior? http://brainblogger.com/2016/10/24/can-our-immune-system-drive-our-social-behavior/ http://brainblogger.com/2016/10/24/can-our-immune-system-drive-our-social-behavior/#respond Mon, 24 Oct 2016 15:00:31 +0000 http://brainblogger.com/?p=22171 The immune system is our main defense mechanism against disease. Dysfunctions in the immune system are therefore associated with a myriad of complications, including several neurological and mental disorders.

Yet, for a long time the brain and the immune system were considered to be isolated from each other – it was believed that the brain was not supplied by the lymphatic system (which carries white blood cells and other immune cells through a network of vessels and tissues) because no evidence of lymphatic supply to the brain had ever been found.

But recently, a research team from the University of Virginia School of Medicine was able to find lymphatic vessels in the meninges that cover the brain. This was a huge discovery that shattered the long-standing belief that the brain was “immune privileged,” lacking a direct connection to the immune system.

After discovering the direct link between the brain and the lymphatic system, the same group has demonstrated that immune cells can influence learning behavior, exerting their effects apparently from the meninges, the membranes that cover the central nervous system. Now, the same group has shown that the immune system has another surprising effect on the brain – it can directly affect, and even control social behavior, such as the desire to interact with others.

Using mice with impaired immunity, the authors showed that partial elimination of immune cells from the meninges was sufficient to induce deficits in social behavior. These social deficits were reversed when the mice were repopulated with immune cells. These immune impaired mice also exhibited hyper-connectivity in specific brain regions associated with social behavior. Again, repopulating mice with immune cells reversed the abnormal hyper-connectivity observed. Other functionally connected regions not directly implicated in social function were not affected by a deficiency in adaptive immunity.

Despite their proximity to the brain, immune cells in the meninges don’t enter the brain. Their effects therefore have to be exerted by releasing molecules that can cross into the brain. The authors were able to identify which molecule acts as a messenger between the immune system and the brain in regulating social behavior.

The molecule is called interferon gamma (IFN-gamma) and it can be produced by a substantial number of meningeal immune cells. Blocking the production of this molecule caused similar social deficits and abnormal hyper-connectivity in the same brain regions as in immune impaired mice. Restoring the levels of the molecule restored the brain activity and behavioral patterns, through the action of IFN-gamma in GABAergic inhibitory neurons. Importantly, the authors also demonstrated that rodents living in a social context (group-housing) had natural increases in the production of IFN-gamma, whereas rodents in social isolation had a marked loss of IFN-gamma. Zebrafish and flies showed a similar pattern.

These striking results thereby show how that a molecule produced by the immune system can have a determining influence on social behavior. But such as the immune system can drive sociability, it is possible that immune dysfunctions may contribute to an inability to have normal social interactions and play a role in neurological and mental disorders characterized by social impairments, such as autism spectrum disorder, frontotemporal dementia, and schizophrenia, for example.

Social behavior is crucial for the survival of a species through foraging, protection, breeding, and even, in higher-order species, mental health. On the other hand, social interaction also brought about an increased exposure to different pathogens; as a consequence, our immune system had to develop new ways to protect us from the diseases to which social interaction exposed us. And social behavior is obviously beneficial to pathogens, since it allows them to spread.The authors of the study therefore hypothesized that the relationship between humans and pathogens may have driven the development of our social behavior. There may have been a co-evolutionary pressure to increase an anti-pathogen response as sociability increased, and it is possible that IFN-gamma may have acted as an evolutionary mechanism to simultaneously enhance social behavior while also enhancing our anti-pathogen responses.

The implications and the questions that arise from these findings are tremendous. Is it possible that our immune system modulates our everyday behaviors or even our personality? Can new pathogens influence human behavior? Can we target the immune system while treating neurological or psychiatric disorders? New research avenues are wide open.

References

Derecki NC, et al (2010). Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med, 207(5):1067-80. doi: 10.1084/jem.20091419

Filiano AJ, et al (2016). Unexpected role of interferon-? in regulating neuronal connectivity and social behaviour. Nature, 535(7612):425-9. doi: 10.1038/nature18626

Kennedy DP, Adolphs R (2012). The social brain in psychiatric and neurological disorders. Trends Cogn. Sci. 16, 559–572. doi: 10.1016/j.tics.2012.09.006

Kipnis J (2016). Multifaceted interactions between adaptive immunity and the central nervous system. Science, 353(6301):766-71. doi: 10.1126/science.aag2638

Louveau A, et al (2015). Structural and functional features of central nervous system lymphatic vessels. Nature, 523(7560):337-41. doi: 10.1038/nature14432

Image via allinonemovie / Pixabay.

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Artificial Light and Circadian Rhythm – Are We Messing It Up? http://brainblogger.com/2016/10/22/artificial-light-and-circadian-rhythm-are-we-messing-it-up/ http://brainblogger.com/2016/10/22/artificial-light-and-circadian-rhythm-are-we-messing-it-up/#respond Sat, 22 Oct 2016 10:22:50 +0000 http://brainblogger.com/?p=22177 The day-night cycle is one of the most defining patterns of life as we know it. We live in a cyclic environment and circadian rhythms are an essential element in the biology of living organisms.

Many physiological processes are synchronized with the day-night cycle, being modulated by environmental timing cues such as sunlight. Our biological clock must detect the cyclic variations in light in order to manage our physiological functions accordingly. To do so, light changes are sensed by specialized cells in the retina called retinal ganglion cells; these retinal photoreceptors receive light and send information to the brain, more specifically to a structure located in the hypothalamus called suprachiasmatic nucleus (SCN). SCN neurons then convey temporal information to other tissues, producing synchronized circadian rhythms in many of our bodily processes.

Evolution made us adapt to our cyclic environment and these external cycles have become essential to the maintenance of a healthy state. But modern societies have tainted these cycles. The widespread use of artificial lighting, for example, has heavily disrupted the natural daily light-dark cycle in a way that is far from innocuous. Continuous exposure to light is regarded as a risk factor for frailty, with a number of studies supporting the idea that this disruption in our circadian rhythms can have a significant impact on health.

This is a major issue since it is estimated that about 75% of the world’s population may be exposed to light during the night. Also, shift work is considerably common (around 20% of workers in Europe and 29% in the US), and epidemiological studies have shown that shift workers have an increased occurrence of breast cancer, metabolic syndrome, obesity, bone dysfunctions, cardiovascular disease, stroke and sleep impairments.

But although these studies indicate a correlation between artificial light exposure and health issues, a causal relationship is hard to determine in human studies. Animal research has helped us understand the real impact of circadian rhythm disruption and has revealed a number of mechanisms through which it can influence health. However, most studies used relatively brief periods of light exposure disruption which largely fail to reproduce the patterns of light exposure in some human contexts, such as shift work, or intensive care settings and nursing homes, for example.

A recent study has set about filling this gap by investigating the relationship between a long-term disruption of circadian rhythms and disease. In this work, mice were exposed to continuous light for 24 weeks and several health parameters were measured: rhythmicity in the central clock (the SCN), skeletal muscle function, bone microstructure, and immune system function were assessed at various time points during and following the 24 weeks of continuous light.

The findings showed that a disrupted circadian rhythm induces detrimental effects on several biological processes. Neuronal recordings revealed that the long-term exposure to continuous light caused a marked reduction in rhythmicity in the circadian pacemaker in the brain, the SCN. Continuous light also reduced muscle function, caused bone changes, and induced a transient pro-inflammatory state.

In fact, many of these changes were consistent with a state of accelerated aging, namely the decline in muscle strength, physical endurance and motor coordination which are often observed in elderly adults.

Relevant changes in bone structure were also observed. Bones are formed by two types of bone tissue: trabecular (or spongy) bone and cortical (or compact) bone. As one ages, spongy bone becomes less dense, whereas compact bone tends to thicken. The continuous exposure to light in mice induced a progressive loss of trabecular bone similar to that observed in early age-related osteoporosis, and an increased thickness of cortical bone consistent with an accelerated effect of aging. Up to 21% of elderly adults have osteoporosis and some of these changes have actually been reported in shift workers: studies have shown that female shift workers have an increased risk of bone fractures and decreased bone mineral density.

Continuous exposure to light also induces a heightened pro-inflammatory state. Upon an immune stimulus, mice exposed to continuous light showed an increased production of pro-inflammatory molecules and a decreased secretion of anti-inflammatory compounds, even though this effect was transient. This intensified pro-inflammatory state is also observed during aging. Furthermore, human studies have also shown that shift workers have an increased risk of cancer and metabolic syndrome associated with immune system dysfunction, which is also known to aggravate age-related pathologies.

The reduction in rhythmicity in the SCN of mice continuously exposed to light also matches rhythm changes that occur in aged individuals. In fact, recent research suggests that impairments in the circadian clock within the SCN may be a defining factor in aging, being likely that an aged circadian system may actually contribute to the age-related decline in health.

This study solidified the notion that long-term exposure to continuous light can have a significant impact on health. Interestingly, most of the health parameters measured quickly returned to normal after restoring a regular light-dark cycle. Nevertheless, it becomes clear that exposure to artificial light is not at all harmless. By messing with our circadian rhythms through constant exposure to light, we may be accelerating our aging process and be actively weakening our health and resistance to disease.

References

Lucassen EA, et al (2016). Environmental 24-hr Cycles Are Essential for Health. Curr Biol, 26(14):1843-53. doi: 10.1016/j.cub.2016.05.038

Michaud M, et al (2013). Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc, 14(12):877-82. doi: 10.1016/j.jamda.2013.05.009

Nakamura TJ, et al (2016). The suprachiasmatic nucleus: age-related decline in biological rhythms. J Physiol Sci, 66(5):367-74. doi: 10.1007/s12576-016-0439-2

Quevedo I, Zuniga AM (2010). Low bone mineral density in rotating-shift workers. J Clin Densitom, 13(4):467-9. doi: 10.1016/j.jocd.2010.07.004

Stevens RG, et al (2014). Breast cancer and circadian disruption from electric lighting in the modern world. CA Cancer J Clin, 64(3):207-18. doi: 10.3322/caac.21218

Wang XS, et al (2011). Shift work and chronic disease: the epidemiological evidence. Occup Med (Lond), 61(2):78-89. doi: 10.1093/occmed/kqr001

Image via qimono / Pixabay.

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Can Stroke be Prevented By Lifestyle Changes? http://brainblogger.com/2016/10/20/can-stroke-be-prevented-by-lifestyle-changes/ http://brainblogger.com/2016/10/20/can-stroke-be-prevented-by-lifestyle-changes/#respond Thu, 20 Oct 2016 10:22:39 +0000 http://brainblogger.com/?p=22174 Stroke is a leading cause of death and disability. But can stroke be prevented? Probably not totally, but it sure is possible to drastically reduce the odds of having a stroke. A huge international study on the risk factors for stroke recently published in The Lancet has shown that the majority are potentially modifiable behaviors.

The study was carried out between 2007 and 2015, with over 13000 patients with acute first stroke (and a similar number of healthy controls) being recruited in 32 countries across Asia, America, Europe, Australia, the Middle East, and Africa. This study also assessed how risk factors vary between stroke subtype, throughout the world, and according to age or sex.

Overall, it was established that over 90% of the worldwide risk of stroke can be attributed to only ten risk factors: hypertension, low physical activity, high apolipoprotein (Apo)B/ApoA1 ratio (predictor of coronary heart disease risk), diet, abdominal obesity, psychosocial factors, current smoking, cardiac causes, alcohol consumption, and diabetes. Of these, hypertension was identified as the most important risk factor for stroke.

Some risk factors were shown to be predominantly associated with a subtype of stroke. Hypertension, although highly risky for both subtypes, was more associated with cerebral hemorrhage; smoking, diabetes, apolipoproteins, and cardiac causes, on the other hand, were more associated with ischemic stroke.

These risk factors were consistent across world regions, sex, and age groups. Still, some sex differences were observed: abdominal obesity and cardiac causes were associated with larger odds in women than in men, while the risk associated with smoking and alcohol intake was greater among men than in women, but in this case it was most likely due to the higher prevalence of smoking and drinking in men. Age differences were also found: hypertension, abdominal obesity, and cardiac factors increased the odds of stroke in younger individuals, whereas diet had a stronger association with stroke in older adults.

Overall, the combined contribution of these ten risk factors to stroke risk was consistent in all populations, but there were some interesting regional variations in the importance of individual risk factors, providing an indication of how lifestyle and cultural behaviors define the impact of each risk factor. In fact, the most remarkable conclusion to be taken from this data is that all of the major risk factors for stroke can be potentially modified by lifestyle changes.

Dietary changes are the most obvious target in stroke prevention. A healthy diet can help reduce hypertension, the most important risk factor for stroke, the ApoB/ApoA1 ratio, which indicates the relative levels of bad and good cholesterol, abdominal obesity, and diabetes.

Indeed, a healthier diet was associated with a lower risk of stroke in most regions. However, there was an interesting finding that highlights how there can be misconceptions on what a healthy diet is. A “healthier diet” did not reduce the risk of stroke in of south Asia and Africa; in fact, in south Asia, a seemingly healthier diet seemed to even be associated with an increased risk of stroke. This seems counterintuitive, but it is actually most likely due to not-so-healthy options in south Asian diet. For example, the combined intake of fruit and vegetables in south Asia is lower than in other regions. Even though a large proportion of the population in south Asia is vegetarian (about 40%) and the consumption of vegetables is very high, recent studies have shown that south Asia has one of the lowest intakes of fruit in the world, that there has been a decrease in the consumption of whole plant foods, and that there is a high use of hydrogenated vegetable oil-based ghee in cooking, which is not that healthy.

Regardless of regional differences, keeping in mind that the ten risk factors mentioned above account for around 90% of the risk of having a stroke, what stands out in this study is that stroke can be largely prevented by modifying behaviors.

And it’s not only diet that can be changed. Given the tremendous impact of hypertension, a great reduction in the occurrence of stroke may be achieved through control of blood pressure. Regular exercise can obviously counterbalance the effects of physical inactivity as well as contribute to metabolic improvements. Moderate alcohol intake and quitting smoking are also obvious actions towards stroke prevention.

 

References

O’Donnell MJ, et al (2010). Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet, 376(9735):112-23. doi: 10.1016/S0140-6736(10)60834-3

O’Donnell MJ, et al (2016). Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study. Lancet, 388(10046):761-75. doi: 10.1016/S0140-6736(16)30506-2

Image via geralt / Pixabay.

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Best and Worst in Health and Healthcare – July & August 2016 http://brainblogger.com/2016/09/23/best-and-worst-in-health-and-healthcare-july-august-2016/ http://brainblogger.com/2016/09/23/best-and-worst-in-health-and-healthcare-july-august-2016/#respond Fri, 23 Sep 2016 16:42:02 +0000 http://brainblogger.com/?p=22179 The northern hemisphere’s summer is ending and that is definitely bad news. The good news is that this was not a silly season in health and healthcare research.

Here’s the best and worst news of the summer.

The best

Drug repurposing screening reveals possible candidates for anti-Zika therapy

Developing a new drug is a long process, but the Zika virus outbreak has created a global health emergency and a pressing need for therapies that is incompatible with the timings of drug development. This led to a major study published in Nature Medicine in which over 6,000 compounds were screened for possible drug repurposing, including approved drugs, clinical trial drug candidates and pharmacologically active compounds. This screening allowed the identification of compounds that were able to inhibit Zika infection, suppress the effects of infection in neurons, or inhibit viral replication. Furthermore, combination treatments using neuroprotective and antiviral compounds showed a potentiation of a protective effect from Zika-induced cell death in human neuronal cell progenitors and glial cells. Besides allowing a fast identification of potential anti-Zika therapies, these results also highlight the efficacy of this screening strategy. Maybe drug repurposing screenings should be a more common procedure.

Docosahexaenoic acid (DHA) in post stroke management

Omega-3 fatty acids are known to have many beneficial effects. It has been suggested that their neuroprotective effects may be useful in post stroke therapy. To test this hypothesis, a study published in PLoS One used emulsions of docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) to treat mice with stroke-like brain injury. It was found that treatment with DHA was able to reduce oxidative damage and improve short- and long-term neurological outcomes. This effect was associated with an accumulation of DHA in brain mitochondria and DHA-derived bioactive metabolites in brain tissue that led to prolonged neuroprotection. Maybe diet can hold the answer to post stroke management.

A new opioid drug with less side-effects

Opioids such as morphine or oxycodone are highly effective pain killers but they have an extensive list of side-effects, including addiction and fatal respiratory depression. Finding a molecule that could have a similar efficacy without the side-effects could be a great discovery. A new study published in Nature therefore aimed at identifying molecules that could selectively act on opioid receptors with similar analgesic effects to current opioid drugs but without inducing respiratory depression. A computational analysis of over 3 million molecules was performed in order to determine which molecules could potentially bind to the mu-opioid-receptor. From all the compounds analyzed, one stood out: it is called PZM21 and it was shown to be an effective analgesic while being devoid of many of the side effects of current opioids.

Brain-machine interface therapies effective in paraplegic patients

There may be a new promising therapy for paraplegic patients. A study published in Scientific Reports tested the use of brain-machine interface training for rehabilitation of chronic spinal cord injured paraplegics. The training paradigm combined immersive virtual reality training, enriched visual-tactile feedback, and walking with two EEG-controlled robotic actuators, including a custom-designed lower limb exoskeleton capable of delivering tactile feedback to subjects. After 12 months of training, all the participants showed neurological improvements in sensation and regained voluntary motor control in muscles below the spinal cord injury level, which was associated with a marked improvement in walking. Half of the patients were even upgraded to an incomplete paraplegia classification. This was an impressive recovery that shows the tremendous potential of brain-machine interface therapies.

Exercise improves cognition in schizophrenia patients

Cognitive deficits are common among people with schizophrenia. Given the known cognitive benefits of exercise, it is possible that it may be helpful in counterbalancing the cognitive effects of schizophrenia. To evaluate this hypothesis, a meta-analysis of all controlled trials investigating the cognitive outcomes of exercise interventions in schizophrenia was conducted. The results were published in the Schizophrenia Bulletin and showed that exercise significantly improved cognition, including working memory, social cognition, and attention/vigilance. Interventions which were supervised by physical activity professionals were shown to be more effective. This study thereby indicates that regular exercise can be beneficial and have therapeutic potential for individuals with schizophrenia.

The worst

Traumatic brain injury increases the risk of neurodegenerative changes later in life  

According to a new study published in JAMA Neurology, traumatic brain injury can increase the likelihood of developing neurodegenerative disorders later in life. This work compiled data from other studies to include a total of 7130 participants. A history of traumatic brain injury with loss of consciousness was compared with the incidence of dementia, Alzheimer’s disease, Pakinson’s disease, mild cognitive impairment, and neuropathologic outcomes such as neurofibrillary tangles, neuritic plaques, microinfarcts, cystic infarcts, Lewy bodies, and hippocampal sclerosis. Data indicated that traumatic brain injury with loss of consciousness is associated with an increased risk for Lewy body accumulation, progression of parkinsonism, and Parkinson’s disease. No association was found with dementia, Alzheimer’s disease, neuritic plaques, or neurofibrillary tangles.

Poor sleep increases inflammation

Good sleep is essential for good health. Since sleep disturbances have been associated with an increased risk of inflammatory diseases, a systematic review and meta-analysis published in Biological Psychiatry aimed at assessing the evidence linking sleep disturbance, sleep duration, and inflammation in adult humans. It was found that sleep disturbance and long sleep duration, but not short sleep duration, are associated with increases in markers of systemic inflammation. Increased systemic inflammation has been associated with a number of disorders, including neurological and metabolic disorders; it also plays an important role in aging. This study therefore reinforces the notion that poor sleep can contribute to the development of various pathologies.

What happens when we stop exercising?

There is extensive evidence showing how exercise is great for health, including brain health. But what happens to the brain when we stop exercising? One answer to this question was recently published in Frontiers in Aging Neuroscience. The effects of 10 days of detraining on physically fit older adults was assessed and it was shown that the interruption of regular exercise induced a decrease in resting cerebral blood flow in eight gray matter brain regions, including the hippocampus. A decreased cerebral blood flow can have a significant negative impact on cognitive functions. This study indicates that the beneficial effects of exercise may rely on the maintenance of regular physical activity throughout life.

The effect of lead on brain development

Lead is a toxic heavy metal that can affect brain development in children. However, little was known about the mechanisms of lead neurotoxicity in children. A study published in Environmental Health Perspectives assessed the effect of lead on neural stem cells aiming at linking changes in those cells to neurodevelopmental outcomes in children who were exposed to lead. It was shown that lead exposure significantly alters the expression of 19 genes, including genes associated with oxidative stress response and neuroprotection. By interfering with the expression of these genes, lead can have a significant impact on cognitive development, explaining the neurodevelopmental deficits observed in children exposed to lead.

Calcium supplementation may increase the risk of dementia

Recently, the use of calcium supplements has been questioned due to possible detrimental effects on health. A study published in Neurology therefore aimed to determine if calcium supplementation may be associated with the development of dementia in women. The study followed dementia-free women aged 70–92 years for five years. Data showed that calcium supplementation was associated with the development of dementia in women with a history of stroke or presence of white matter lesions, but not in groups without these conditions. Although further studies may be needed to validate these findings, this indicates that calcium supplementation may increase the risk of developing dementia in elderly women with cerebrovascular disease.

References

Alfini AJ, et al (2016). Hippocampal and Cerebral Blood Flow after Exercise Cessation in Master Athletes. Front Aging Neurosci, 8:184. doi: 10.3389/fnagi.2016.00184

Crane PK, et al (2016). Association of Traumatic Brain Injury With Late-Life Neurodegenerative Conditions and Neuropathologic Findings. JAMA Neurol [Epub ahead of print]. doi: 10.1001/jamaneurol.2016.1948

Donati AR, et al (2016). Long-Term Training with a Brain-Machine Interface-Based Gait Protocol Induces Partial Neurological Recovery in Paraplegic Patients. Sci Rep, 6:30383. doi: 10.1038/srep30383

Firth J, et al (2016). Aerobic Exercise Improves Cognitive Functioning in People With Schizophrenia: A Systematic Review and Meta-Analysis. Schizophr Bull [Epub ahead of print]. doi: 10.1093/schbul/sbw115

Irwin MR, et al (2016). Sleep Disturbance, Sleep Duration, and Inflammation: A Systematic Review and Meta-Analysis of Cohort Studies and Experimental Sleep Deprivation. Biol Psychiatry, 80(1):40-52. doi: 10.1016/j.biopsych.2015.05.014

Kern J, et al (2016). Calcium supplementation and risk of dementia in women with cerebrovascular disease. Neurology [Epub ahead of print]. doi: 10.1212/WNL.0000000000003111

Manglik A, et al (2016). Structure-based discovery of opioid analgesics with reduced side effects. Nature, 17:1-6. doi: 10.1038/nature19112

Mayurasakorn K, et al (2016). DHA but Not EPA Emulsions Preserve Neurological and Mitochondrial Function after Brain Hypoxia-Ischemia in Neonatal Mice. PLoS One, 11(8):e0160870. doi: 10.1371/journal.pone.0160870

Wagner PJ, et al (2016). In Vitro Effects of Lead on Gene Expression in Neural Stem Cells and Associations between Upregulated Genes and Cognitive Scores in Children. Environ Health Perspect, [Epub ahead of print]. doi: 10.1289/EHP265

Xu M, et al (2016). Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med [Epub ahead of print] doi: 10.1038/nm.4184

Image via WikiImages / Pixabay.

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Can Technology Change How Our Brain Works? http://brainblogger.com/2016/08/06/can-technology-change-how-our-brain-works/ http://brainblogger.com/2016/08/06/can-technology-change-how-our-brain-works/#respond Sat, 06 Aug 2016 15:00:52 +0000 http://brainblogger.com/?p=22014 Smartphones and other electronic devices have changed the way we communicate and the way we interact with the world. But to what extent can technology change us? Most importantly, can it change our brain?

When neurons communicate with each other they generate brain waves. These are the result of the synchronized rhythmic activity of thousands or even millions of neurons. There are different types of brain waves and they can be detected through electroencephalographic (EEG) recordings, each having a specific EEG pattern. Each type of brain wave is associated with different states of brain functioning.

During deep, dreamless sleep, our brain is in its slowest state of activity; this type of sleep is known as slow-wave sleep and the typical low frequency brain waves that characterize it are called gamma waves. When we’re dreaming, during REM sleep, brain activity increases and originates another type of brain waves; these are called theta waves, and they’re also characteristic of light sleep and meditative or drowsy states.

When we wake up, our brain activity increases. In a wakeful resting state, alpha brain waves predominate; they are also associated with a state of relaxed, flowing thoughts, for example.

During normal wakeful consciousness and reasoning, alertness, active thinking, active concentration, logic, and critical reasoning, the frequency of our brain waves further increases; the brain waves associated with this state era called beta waves.

During high cognitive demand tasks, when we’re processing and integrating information arising from different brain areas, gamma brain waves predominate; these are the highest frequency brain waves, and they are important in learning and memory; they are believed to underlie perception and consciousness.

This is a broad description of brain waves and there are other types of rare or unusual brain waves, referred to as “normal EEG variants”. There are also brain waves that are associated with dysfunction or disease.

But going back to theta brain waves, even though they’re commonly associated with dreaming and drowsy states, they are also present during certain behaviors, particularly when they require mental effort, attention, concentration, calculation, or problem solving, as well as during emotional reactions. They have been described, for example, during aiming and shooting a rifle, during driving simulations, or while listening to music.

Recently, it has been reported that theta brain waves may also be present during text messaging. But it’s not just random theta brain waves – it’s a specific pattern of brain waves that falls within the frequency interval of theta brain waves. And apparently, it only occurs during text messaging, since it hasn’t been found during any other type of activities associated with speech, motor performance, concentration-attention, memory, and cognitive performance. This brain activity pattern has been named “the texting rhythm” and it seems to be a new technology-specific theta wave rhythm that occurs during texting.

Text messaging is a state of alertness that requires a concentrated form of enhanced mental activation associated with speech, visual perception, and specific fine motor skills. Furthermore, the smaller screen size of a smartphone may require a particularly high level of attention while sending a text message. It’s a very specific type of activity, which may account for its distinct brain wave pattern.

Text messaging is one of the most widely used forms of communication, particularly by younger people. Even though this brain wave pattern is not pathological, if it really is restricted to text messaging, it is certainly new and created by technological advances – it’s the brain adapting to new behavioral needs.

But it’s not just brainwaves that change. EEG studies on the brain’s response to touch on thumb, index, and middle fingertips found that sensory processing is also altered by the use of touchscreen electronic devices, leading to an enhanced representation of the thumb in the sensory cortex after intense use of smartphones.

This is still a poorly studied topic, but apparently, the use of technology can indeed change our brain. And this is a great example of neuroplasticity.

References

Colgin, L. (2013). Mechanisms and Functions of Theta Rhythms Annual Review of Neuroscience, 36 (1), 295-312 DOI: 10.1146/annurev-neuro-062012-170330

Gindrat, A., Chytiris, M., Balerna, M., Rouiller, E., & Ghosh, A. (2015). Use-Dependent Cortical Processing from Fingertips in Touchscreen Phone Users Current Biology, 25 (1), 109-116 DOI: 10.1016/j.cub.2014.11.026

Tatum, W., DiCiaccio, B., Kipta, J., Yelvington, K., & Stein, M. (2015). The Texting Rhythm Journal of Clinical Neurophysiology DOI: 10.1097/WNP.0000000000000250

Tatum, W., DiCiaccio, B., & Yelvington, K. (2016). Cortical processing during smartphone text messaging Epilepsy & Behavior, 59, 117-121 DOI: 10.1016/j.yebeh.2016.03.018

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Diabetes-Associated Cognitive Impairment – Not Just For the Elderly http://brainblogger.com/2016/08/01/diabetes-associated-cognitive-impairment-not-just-for-the-elderly/ http://brainblogger.com/2016/08/01/diabetes-associated-cognitive-impairment-not-just-for-the-elderly/#respond Mon, 01 Aug 2016 15:00:11 +0000 http://brainblogger.com/?p=21966 The prevalence of type 2 diabetes is on the rise; it can actually be regarded as an epidemic propagating as a consequence of poor lifestyle choices – bad feeding habits and sedentarism. The International Diabetes Federation (IDF) estimates that there are over 380 million cases of diabetes throughout the world and predict that it may rise to around 600 million in the next 20 years.

One of the consequences of diabetes is cognitive decline. There are several studies showing that diabetes causes an acceleration of age-related cognitive decline. But it’s not just age-related cognitive decline – patients with diabetes also have a higher risk of developing cognitive decline associated with different brain pathologies. Diabetes increases the likelihood of developing vascular diseases, Alzheimer’s disease, mild cognitive impairment and dementia. Although these diseases have different onset mechanisms, they can all be potentiated by diabetes.

Hyperglycemia is known to increase neuronal cell death through oxidation processes and generation of free radicals, thereby having neurodegenerative effects. Hyperglycemia can also cause damage to blood vessels through inflammatory mechanisms, leading to reduced blood flow to the brain and, consequently, reduced oxygen delivery, which results in the development of brain injuries.

If we add hypertension to the equation, which is commonly observed in patients with diabetes, vascular deficits become even worse, increasing the risk of stroke, for example, which is indeed more common in diabetic patients.

Younger diabetics are also at risk

This effect of diabetes is not only observed in the elderly. Although type 2 diabetes accelerates age-related cognitive decline, younger patients also show signs of cognitive impairment. In a study that followed dementia-free diabetic patients with a mean age of 40 years at the start of the study it was shown that, seven years later, diabetes had led to a degradation of memory, visual perception, and attention performance, as well as to a loss of brain integrity. Diabetes and higher fasting blood glucose levels were correlated with gray matter loss in the brain. This shows that cognitive decline is clearly anticipated in diabetes patients.

Another study, which followed patients with an average initial age of 54 throughout 10 years, showed that, compared with healthy participants, those with diabetes had a 45% faster decline in memory (10 year difference in decline), a 29% faster decline in reasoning, and a 24% faster decline in the global cognitive score. Furthermore, diabetes patients who had a poorer glycemic control had a faster decline in memory and reasoning, while participants with pre-diabetes or newly diagnosed diabetes had similar rates of decline to those with normal glycaemia.

It seems that the earlier the onset of diabetes, the higher the risk of accelerated cognitive decline. And even teenagers can be affected by the neurological consequences of type 2 diabetes. A pilot study following adolescents with type 2 diabetes showed that there are significant volume losses in a number of areas of the brain, as well as reduced white matter integrity. Given the fast increase in the incidence of type 2 diabetes (and other metabolic diseases) that is being observed in teenagers, this is clearly a reason for concern.

Therapeutic strategies designed to control glycaemia will most likely help reduce the effects of diabetes on the brain. Many of the mechanisms of diabetes-associated dementia and cognitive impairment can be counterbalanced by a good diet and by exercise. Early intervention is fundamental.

Just to show how important diet and exercise are to diabetes care: there is scientific evidence showing that lifestyle changes are actually more effective than antidiabetic drugs. But instead of using diet and exercise as a way to control all the detrimental effects of diabetes, it would actually be better to use them to prevent it.

References

Cheng, G., Huang, C., Deng, H., & Wang, H. (2012). Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies Internal Medicine Journal, 42 (5), 484-491 DOI: 10.1111/j.1445-5994.2012.02758.x

Chiu, W., Ho, W., Liao, D., Lin, M., Chiu, C., Su, Y., Chen, P., & , . (2015). Progress of Diabetic Severity and Risk of Dementia The Journal of Clinical Endocrinology & Metabolism, 100 (8), 2899-2908 DOI: 10.1210/jc.2015-1677

Rofey, D., Arslanian, S., El Nokali, N., Verstynen, T., Watt, J., Black, J., Sax, R., Krall, J., Proulx, C., Dillon, M., & Erickson, K. (2015). Brain volume and white matter in youth with type 2 diabetes compared to obese and normal weight, non-diabetic peers: A pilot study International Journal of Developmental Neuroscience, 46, 88-91 DOI: 10.1016/j.ijdevneu.2015.07.003

Sheen, Y., & Sheu, W. (2016). Association between hypoglycemia and dementia in patients with type 2 diabetes Diabetes Research and Clinical Practice, 116, 279-287 DOI: 10.1016/j.diabres.2016.04.004

Tuligenga, R., Dugravot, A., Tabák, A., Elbaz, A., Brunner, E., Kivimäki, M., & Singh-Manoux, A. (2014). Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: a post-hoc analysis of the Whitehall II cohort study The Lancet Diabetes & Endocrinology, 2 (3), 228-235 DOI: 10.1016/S2213-8587(13)70192-X

van Praag, H., Fleshner, M., Schwartz, M., & Mattson, M. (2014). Exercise, Energy Intake, Glucose Homeostasis, and the Brain Journal of Neuroscience, 34 (46), 15139-15149 DOI: 10.1523/JNEUROSCI.2814-14.2014

Weinstein, G., Maillard, P., Himali, J., Beiser, A., Au, R., Wolf, P., Seshadri, S., & DeCarli, C. (2015). Glucose indices are associated with cognitive and structural brain measures in young adults Neurology, 84 (23), 2329-2337 DOI: 10.1212/WNL.0000000000001655

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Cannabinoids Hold Promise for Alzheimer’s Disease Treatment http://brainblogger.com/2016/07/26/cannabinoids-hold-promise-for-alzheimers-disease-treatment/ http://brainblogger.com/2016/07/26/cannabinoids-hold-promise-for-alzheimers-disease-treatment/#respond Tue, 26 Jul 2016 15:00:09 +0000 http://brainblogger.com/?p=21984 Alzheimer’s disease (AD) is a neurodegenerative condition and the most common form of dementia worldwide, accounting for around 70% of dementia cases. Deposition of the amyloid-beta (A-beta) peptide in the form of amyloid plaques is one of the hallmarks of the disease, occurring early in the development of this condition. As disease progresses, degenerative changes accumulate, leading to neuronal death, oxidative damage, and neuroinflammation.

The exact pathological mechanisms that drive Alzheimer’s disease remain to be clarified and are the subject of extensive research (and debate). With the goal of further elucidating some of the processes that drive Alzheimer’s progression, new research published in the Nature Partner Journal Aging and Mechanisms of Disease studied the association between A-beta accumulation and the development of neuroinflammation, as well as possible therapeutic interventions. Their results were promising.

Does A-beta accumulation cause inflammation?

Neuroinflammation is a characteristic of the aging process and is one of the main causes of cognitive impairment. In the context of neurodegenerative diseases, inflammatory responses are further increased and contribute to the accelerated rate of cognitive decline that is observed. The increased inflammatory response found in the brain of Alzheimer’s patients has been mostly regarded as a consequence of the activation of glial cells in the brain.

This study, carried out in vitro, indicates that this may not be so: it establishes a direct link between A-beta and inflammation, demonstrating that A-beta production in cultured human central nervous system neurons leads to the synthesis of a number of proinflammatory molecules and to the activation of inflammatory pathways. Most of the proinflammatory molecules known to be excessively produced in the brain of Alzheimer’s patients were shown to also be overproduced in neurons after the induction of A-beta production.

Furthermore, these results suggest that A-beta production in neurons may induce inflammation even before it starts accumulating and forming amyloid plaques in the brain.

Are NSAIDs a bad choice for Alzheimer’s patients?

Non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to delay clinical features of Alzheimer’s disease, but clinical trials have never supported that idea. NSAIDs act by inhibiting a family of enzymes called cyclooxygenases (COX), which are responsible for the production of prostaglandins. Since prostaglandins can induce inflammatory responses, the inhibition of COX by NSAIDs results in decreased inflammation. Since COX-2 is known to be increased in the brain of Alzheimer’s patients, in theory, blocking the action of COX-2 using NSAIDs should be beneficial.

But the regulation of inflammation is not the only function of prostaglandins, which actually depends on the receptors they activate. As it turns out, according to this study, the prostaglandins PGE2 and PGD2 are actually neuroprotective, similarly to what has been found in ischemic stroke and in other neurodegeneration models. The increase in COX-2 production may therefore be a defense mechanism that neurons set in motion. By inhibiting this defense system, NSAIDs may actually promote further cellular damage.

This work showed that the detrimental action of A-beta can be mediated by the action of molecules produced by another enzyme called 5-lipoxygenase (5-LOX). These molecules, called leukotrienes, seem to be the ones that potentiate A-beta’s toxicity. It was shown that the inhibition of 5-LOX was able to prevent cell death, therefore holding better therapeutic potential than NSAIDs.

Cannabinoids effectively block A-beta toxicity

Interestingly, both prostaglandins and leukotrienes derive from the same molecule: arachidonic acid. And arachidonic acid is also a component of a family of endogenous cannabinoids produced in the brain.

Cannabinoids had already been studied in the context of Alzheimer’s disease, having been shown that they can reduce A-beta accumulation and improve memory. Not only endogenous cannabinoids, but also tetrahydrocannabinol (THC), the main psychoactive component of cannabis, are also known to be able to reduce inflammation.

Therefore, this study also investigated whether cannabinoids could have therapeutic potential for Alzheimer’s disease. It was shown that an endocannabinoid called arachidonoyl ethanol amide (AEA), as well as synthetic analogs to this molecule, could promote neuronal survival and block A-beta accumulation. The inhibition of the enzyme that degrades AEA was also shown to be protective.

THC was also tested in this study and the results were very promising: THC had a marked protective effect, being able to remove intraneuronal A-beta, to dramatically reduce the elevated production of damaging leukotrienes, and to block neuronal cell death.

The results of this study show that cannabinoids may indeed hold promise for the treatment of Alzheimer’s disease. It remains to be determined if similar effects will also be obtained in vivo.

References

Bayer, . (2010). Intracellular accumulation of amyloid-beta – a predictor for synaptic dysfunction and neuron loss in Alzheimer’s disease Frontiers in Aging Neuroscience DOI: 10.3389/fnagi.2010.00008

Burstein, S., & Zurier, R. (2009). Cannabinoids, Endocannabinoids, and Related Analogs in Inflammation The AAPS Journal, 11 (1), 109-119 DOI: 10.1208/s12248-009-9084-5

Campbell, V., & Gowran, A. (2009). Alzheimer’s disease; taking the edge off with cannabinoids? British Journal of Pharmacology, 152 (5), 655-662 DOI: 10.1038/sj.bjp.0707446

Currais, A., Quehenberger, O., M Armando, A., Daugherty, D., Maher, P., & Schubert, D. (2016). Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids npj Aging and Mechanisms of Disease, 2 DOI: 10.1038/npjamd.2016.12

Kim, E., Kwon, K., Park, J., Lee, S., Moon, C., & Baik, E. (2002). Neuroprotective effects of prostaglandin E2 or cAMP against microglial and neuronal free radical mediated toxicity associated with inflammation Journal of Neuroscience Research, 70 (1), 97-107 DOI: 10.1002/jnr.10373

Martín-Moreno, A., Brera, B., Spuch, C., Carro, E., García-García, L., Delgado, M., Pozo, M., Innamorato, N., Cuadrado, A., & de Ceballos, M. (2012). Prolonged oral cannabinoid administration prevents neuroinflammation, lowers ?-amyloid levels and improves cognitive performance in Tg APP 2576 mice Journal of Neuroinflammation, 9 (1) DOI: 10.1186/1742-2094-9-8

Valera, E., Dargusch, R., Maher, P., & Schubert, D. (2013). Modulation of 5-Lipoxygenase in Proteotoxicity and Alzheimer’s Disease Journal of Neuroscience, 33 (25), 10512-10525 DOI: 10.1523/JNEUROSCI.5183-12.2013

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Nurturing The Brain – Part 10, Ketogenic Diets http://brainblogger.com/2016/07/24/nurturing-the-brain-part-10-ketogenic-diets/ http://brainblogger.com/2016/07/24/nurturing-the-brain-part-10-ketogenic-diets/#respond Sun, 24 Jul 2016 15:00:50 +0000 http://brainblogger.com/?p=21938 Fasting has been used as a form of therapy for epilepsy throughout the history of medicine. But in 1921, Dr Woodyatt at Rush Medical College in Chicago observed that that there were a couple of ketone molecules that appeared in the blood of subjects undergoing starvation or low-carbohydrate/high-fat content diets, while Dr Wilder at the Mayo Clinic proposed that similar effects to those of fasting on epilepsy could be obtained by inducing the production of those same molecules through diet.

This was the origin of ketogenic diets, which became one of the most widely used treatments for epilepsy in children. It is still used to this day as an alternative to pharmacological treatments, although it is not known how it works.

The ketogenic diet is characterized by a continued intake of low amounts of carbohydrates, high doses of fat, and regular amounts of protein. This changes our body’s metabolism by turning fat into our main fuel: Instead of obtaining energy primarily from carbohydrates, our body obtains energy from stored fat and becomes more efficient at using fat as the main energy source. Although the intake of fat is higher, the net result is loss of stored fat.

Ketogenic low-carbohydrate/high-fat diets have been shown to be highly effective in promoting weight loss. They are called ketogenic because they lead to the production of molecules known as ketone bodies.

Ketone bodies, our brain’s other fuel

Glucose is our body’s primary source of energy. When regular amounts of carbohydrates are ingested, our carbohydrate stores keep being replenished and glucose keeps being used as fuel. But when blood glucose levels drop and carbohydrate stores are exhausted, fats stored in adipose tissue are broken down and free fatty acids are released into the blood.

Fatty acids are then taken up by cells to be used to produce energy. This happens, for example, during periods of carbohydrate restriction, fasting or starvation, or prolonged intense exercise.

However, fatty acids cannot cross the blood-brain barrier and therefore cannot be used by neurons and glia in the central nervous system. However, the liver can use acetyl-CoA obtained from fatty acid metabolism to produce ketone bodies – acetone, beta-hydroxybutyrate and acetoacetate. Ketone bodies are able to cross the blood-brain barrier and can be used as a replacement for glucose in the brain.

One of the reasons why ketogenic diets are often more effective than low-fat diets in promoting weight loss is the fact that ketone bodies may actually suppress appetite by acting on the hypothalamus, where signals from appetite-regulating hormones such as leptin or ghrelin are combined, by interacting with these hormonal signals.

Ketone bodies and brain health

The effects of ketogenic diets are not limited to seizure prevention. Ketogenic diets have shown beneficial effects and are being studied as therapeutic options for an impressively high range of neurological disorders: cognitive impairment, migraine, pain, traumatic brain injury, stroke, Alzheimer’s disease, Parkinson’s disease, sleep disorders, autism, amyotrophic lateral sclerosis and multiple sclerosis, for example.

This effect may be due to a neuroprotective action of ketone bodies. Although the mechanisms are poorly understood, studies in animal and cellular models have shown that ketone bodies can protect neuronal and glial cells against different types of cellular injury and even death. It is believed that this effect may be due to increased energy production and energy storage, since ketone bodies are actually more effective energy sources for neurons. This may arm neurons with an improved ability to resist metabolic insults.

Importantly, ketone bodies can have antioxidant and anti-inflammatory effects. Oxidation and inflammation are the main motors of aging and of a number of pathologies, particularly neurodegenerative diseases. By reducing oxidative stress and chronic inflammation, ketogenic diets can delay aging and delay or even decrease the development of many of the diseases mentioned above.

Furthermore, ketogenic diets are effective routes to weight loss, as already mentioned; since obesity has been associated with – for example, accelerated cognitive decline and increased risk of dementia, Alzheimer’s disease and stroke – weight loss by itself can bring great benefits to brain health.

Another important therapeutic action of ketogenic diets may be an anti-cancer effect. Cancer cells have high metabolic rates that allow their fast proliferation. It is possible that depriving these cells from glucose, the fuel they grew on, may hamper their growth. Research has shown that animals with brain tumors that are placed on a ketogenic diet show a marked decrease in the rate of tumor growth, most likely due to the lack of glucose. There are even case reports of humans with brain tumors who have greatly improved due to the adoption of a ketogenic diet.

But besides the neurological effects of ketogenic diets, there are many other health benefits described for a ketone-based metabolism. Ketogenic diets can decrease both plasma glucose and insulin concentrations, decreasing the likelihood of developing type 2 diabetes and other metabolic diseases; the levels of blood triglycerides can also be diminished, LDL cholesterol can be reduced and HDL cholesterol can be increased, thereby also decreasing the risk of cardiovascular diseases.

It is arguable that evolution hasn’t prepared us for the amount of carbs we ingest. Maybe we would be better off running on ketone bodies.

References

Barañano, K. W., & Hartman, A. L. (2008). The ketogenic diet: Uses in epilepsy and other neurologic illnesses. Current Treatment Options in Neurology, 10(6), 410–419. doi:10.1007/s11940-008-0043-8

Gano, L. B., Patel, M., & Rho, J. M. (2014). Ketogenic diets, mitochondria, and neurological diseases. The Journal of Lipid Research, 55(11), 2211–2228. doi:10.1194/jlr.r048975
Gasior, M., Rogawski, M. A., & Hartman, A. L. (2006). Neuroprotective and disease-modifying effects of the ketogenic diet. Behavioural Pharmacology, 17(5-6), 431–439. doi:10.1097/00008877-200609000-00009

Gibson, A. A., Seimon, R. V., Lee, C. M. Y., Ayre, J., Franklin, J., Markovic, T. P., … Sainsbury, A. (2014). Do ketogenic diets really suppress appetite? A systematic review and meta-analysis. Obesity Reviews, 16(1), 64–76. doi:10.1111/obr.12230

Kinzig, K. P., Honors, M. A., & Hargrave, S. L. (2010). Insulin sensitivity and glucose tolerance are altered by maintenance on a Ketogenic diet. Endocrinology, 151(7), 3105–3114. doi:10.1210/en.2010-0175

Klein, P., Tyrlikova, I., & Mathews, G. C. (2014). Dietary treatment in adults with refractory epilepsy: A review. Neurology, 83(21), 1978–1985. doi:10.1212/wnl.0000000000001004

Seyfried, T. N., Marsh, J., Shelton, L. M., Huysentruyt, L. C., & Mukherjee, P. (2012). Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer? Epilepsy Research, 100(3), 310–326. doi:10.1016/j.eplepsyres.2011.06.017

Stafstrom, C. E., & Rho, J. M. (2012). The Ketogenic diet as a treatment paradigm for diverse neurological disorders. Frontiers in Pharmacology, 3. doi:10.3389/fphar.2012.00059

Wheless, J. W. (2008). History of the ketogenic diet. Epilepsia, 49, 3–5. doi:10.1111/j.1528-1167.2008.01821.x

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Best and Worst in Health and Healthcare – June 2016 http://brainblogger.com/2016/07/19/best-and-worst-in-health-and-healthcare-june-2016/ http://brainblogger.com/2016/07/19/best-and-worst-in-health-and-healthcare-june-2016/#respond Tue, 19 Jul 2016 15:00:50 +0000 http://brainblogger.com/?p=21986 In June, the beneficial effects of exercise were on the spotlight again, along with a few potentially effective new therapies. On the down side, there were a number of studies highlighting the negative side-effects of commonly used drugs. Here is the best and worst news of June.

THE BEST

Consensus on the effect of physical activity on children and youth

In April 2016, a multi-disciplinary group of 24 researchers from 8 countries gathered in Denmark to discuss the scientific evidence on the effect of physical activity in children and youth. This conference led to the publication of a consensus statement that was made available in June in the British Journal of Sports Medicine. The statement was made up of 21 items divided into 4 themes addressing the effect of physical activity on fitness and health; cognitive functioning; engagement, motivation and psychological well-being; and social inclusion.

Overall, it reinforces that physical activity is great, which is always worth underlining. The statement can be read here.

Dietary supplement mix can delay aging

There are many neurological and neurodegenerative diseases that are driven by inflammation and oxidation. These processes are also responsible for aging and the associated cognitive decline. Dietary supplements containing natural ingredients with strong anti-inflammatory and anti-oxidant proprieties may therefore be a great alternative to drugs in the treatment of neurological conditions and in delaying cognitive aging.

A study published in Environmental and Molecular Mutagenesis therefore assessed the effect of a multi-ingredient dietary supplement on a mouse model of accelerated aging that is characterized by chronic oxidative stress, increased inflammation, severe cognitive decline, physical deterioration, and reduced longevity. It was shown that the supplement, containing around 30 ingredients, could reverse brain cell loss and cognitive decline, and increase sensory and motor function in aged mice, highlighting the therapeutic potential of dietary approaches.

A new approach to counteract the negative effects of general anesthesia

General anesthesia can have undesired cognitive and behavioral side-effects, particularly in children, whose brain is still developing. Effective preventive therapies are still lacking. A new study published in Science Translational Medicine has shown that ketamine anesthesia is responsible for a significant reduction in neuronal activity during the post-anesthesia recovery period. Since ketamine acts mainly by inhibiting glutamate receptors, the study tested the effect, in neonatal mice, of a drug designed to potentiate the activity of AMPA receptors (a type of glutamate receptor).

Administration of the drug during emergence from anesthesia led to an increase in neuronal activity, thereby counterbalancing the effects of ketamine. This therapeutic intervention was able to prevent the development of synaptic and motor learning deficits induced by repeated neonatal anesthesia, indicating that this may be an effective approach to reduce the detrimental effects of anesthesia on brain development.

A new drug delivery method for brain injuries

One of the main difficulties in the treatment of traumatic brain injury is the delivery of drugs to the affected area in a way that is both non-invasive (not requiring surgery) and directed to the injured area, minimizing potential undesired side-effects.

In June, Nature Communications published an article reporting a new drug delivery method that can specifically target injured areas of the brain. The authors identified a specific peptide that selectively binds to molecules that are overproduced following injury in the brains of both mice and humans. Using nanoparticles coated with this peptide allowed a targeted delivery of drugs by a simple intravenous administration. These findings may allow for significant improvements in the treatment of brain injuries.

Neural stem cells successfully applied to aged brains

New potential applications of neural stem cells keep appearing. A new study published in Stem Cells Translational Medicine adds to the list by showing that grafting neural stem cells into the hippocampus of both young and aged rats is effective and enduring, leading to the differentiation of those cells and to the formation of new neurons.

These results are important because they show that an aged brain retains the ability to allow the grafting of those cells and their proliferation. This opens a new line of potential treatments for neurodegenerative diseases and age-related cognitive decline, since the hippocampus plays a key role in some of the cognitive functions that are most affected by these conditions, namely memory.

THE WORST

Serotonin reuptake inhibitors negatively affect fetal brain development

There are many drugs that can affect fetal development and that are therefore counter-indicated during pregnancy. Animal studies had already provided evidence of a potential negative effect of antidepressant serotonin reuptake inhibitors (SRI) on brain development. Now, the journal Cerebral Cortex published a new study that used electroencephalography (EEG) to study if similar effects are also observed in newborn humans.

EEG recordings showed that there are indeed a number of developmental brain structural deficits in newborns exposed to SRIs during fetal development.

Acetaminophen during pregnancy may affect neurodevelopmental behavioral outcomes

Another drug whose effect during pregnancy has been the subject of research published in June is acetaminophen, also known as paracetamol. Acetaminophen is extensively used, including during pregnancy, but its effect on fetal brain development is poorly studied.

As reported in the International Journal of Epidemiology, the offspring of women who took acetaminophen during pregnancy showed a greater number of symptoms associated with autism spectrum disorder, in a way that was dependent on the frequency of exposure. However, this effect was only observed in males. Adverse effects on attention-related outcomes were observed for both genders.

Prolonged opioid treatment increases mortality

Opioids are widely used for the treatment of pain, but they present a myriad of undesired side-effects, including cardiorespiratory deficits that may lead to death. New research published in The Journal of the American Medical Association compared the mortality of patients with chronic non-cancer pain who were prescribed either opioids or non-opioid analgesic treatment, aiming to determine if continued opioid treatment could lead to a higher risk of death.

This study determined that, when compared with anticonvulsants or cyclic antidepressants, long-acting opioids were indeed associated with significantly higher mortality.

The link between stress and epileptic seizures

Stress can increase the frequency of epileptic seizures. Research published in Science Signaling showed that stress and anxiety induce the production of a neuropeptide called corticotropin-releasing factor (CRF), which coordinates many responses to stress in the central nervous system.

But while in normal conditions CRF acts to decrease excitability in areas prone to the occurrence of seizures, in the context of epilepsy this neuropeptide acquires other functions due to changes in cellular signaling pathways, becoming a promotor of seizures. So, what would otherwise be a protective response to stress, becomes a damaging response to stress in subjects with epilepsy, explaining why stress and anxiety can increase the occurrence of seizures.

Cerebral vascular conditions as risk factors for dementia

Cerebral atherosclerosis limits the flow of blood and oxygen to the brain, therefore having the potential to negatively affect brain function. A study published in The Lancet Neurology assessed clinical data recorded between 1994 and 2015 to determine whether cerebral blood vessel diseases could increase the likelihood of developing dementia and cognitive impairment associated with Alzheimer’s disease.  

The results of this work, which included 1143 subjects, showed that cerebral atherosclerosis and arteriolosclerosis are associated with Alzheimer’s disease dementia and decreased cognitive scores. This data indicates that cerebral vascular pathologies may be a risk factor for dementia associated with Alzheimer’s disease.

References

Arvanitakis, Z., Capuano, A., Leurgans, S., Bennett, D., & Schneider, J. (2016). Relation of cerebral vessel disease to Alzheimer’s disease dementia and cognitive function in elderly people: a cross-sectional study The Lancet Neurology, 15 (9), 934-943 DOI: 10.1016/S1474-4422(16)30029-1

Avella-Garcia, C., Julvez, J., Fortuny, J., Rebordosa, C., García-Esteban, R., Galán, I., Tardón, A., Rodríguez-Bernal, C., Iñiguez, C., Andiarena, A., Santa-Marina, L., & Sunyer, J. (2016). Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms International Journal of Epidemiology DOI: 10.1093/ije/dyw115

Bangsbo J, Krustrup P, Duda J, Hillman C, Andersen LB, Weiss M, Williams CA, Lintunen T, Green K, Hansen PR, et al (2016). The Copenhagen Consensus Conference 2016: children, youth, and physical activity in schools and during leisure time. Br J Sports Med [Epub ahead of print] doi: 10.1136/bjsports-2016-096325

Huang, L., Cichon, J., Ninan, I., & Yang, G. (2016). Post-anesthesia AMPA receptor potentiation prevents anesthesia-induced learning and synaptic deficits Science Translational Medicine, 8 (344), 344-344 DOI: 10.1126/scitranslmed.aaf7151

Lemon, J., Aksenov, V., Samigullina, R., Aksenov, S., Rodgers, W., Rollo, C., & Boreham, D. (2016). A multi-ingredient dietary supplement abolishes large-scale brain cell loss, improves sensory function, and prevents neuronal atrophy in aging mice Environmental and Molecular Mutagenesis, 57 (5), 382-404 DOI: 10.1002/em.22019

Mann, A., Scodeller, P., Hussain, S., Joo, J., Kwon, E., Braun, G., Mölder, T., She, Z., Kotamraju, V., Ranscht, B., Krajewski, S., Teesalu, T., Bhatia, S., Sailor, M., & Ruoslahti, E. (2016). A peptide for targeted, systemic delivery of imaging and therapeutic compounds into acute brain injuries Nature Communications, 7 DOI: 10.1038/ncomms11980

Narla, C., Scidmore, T., Jeong, J., Everest, M., Chidiac, P., & Poulter, M. (2016). A switch in G protein coupling for type 1 corticotropin-releasing factor receptors promotes excitability in epileptic brains Science Signaling, 9 (432) DOI: 10.1126/scisignal.aad8676

Ray, W., Chung, C., Murray, K., Hall, K., & Stein, C. (2016). Prescription of Long-Acting Opioids and Mortality in Patients With Chronic Noncancer Pain JAMA, 315 (22) DOI: 10.1001/jama.2016.7789
Shetty AK, Hattiangady B (2016). Grafted Subventricular Zone Neural Stem Cells Display Robust Engraftment and Similar Differentiation Properties and Form New Neurogenic Niches in the Young and Aged Hippocampus. Stem Cells Transl Med [Epub ahead of print]. doi: 10.5966/sctm.2015-0270

Videman, M., Tokariev, A., Saikkonen, H., Stjerna, S., Heiskala, H., Mantere, O., & Vanhatalo, S. (2016). Newborn Brain Function Is Affected by Fetal Exposure to Maternal Serotonin Reuptake Inhibitors Cerebral Cortex DOI: 10.1093/cercor/bhw153

Image via Unsplash / Pixabay.

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New Link Between Autism and the Gut Microbiota http://brainblogger.com/2016/07/16/new-link-between-autism-and-the-gut-microbiota/ http://brainblogger.com/2016/07/16/new-link-between-autism-and-the-gut-microbiota/#respond Sat, 16 Jul 2016 15:00:48 +0000 http://brainblogger.com/?p=21928 The fact that diet has a huge influence on our health should be common knowledge by now. But what research has been showing us in recent years is just how fundamental the influence of diet on our health can be. Surprising links between diet and a number of previously unsuspected diseases are being continuously established. But food does not affect us only after we are born, it actually starts to shape our health during pre-natal development.

Poor nutrition during pregnancy is known to be associated with developmental disorders. Maternal obesity due to high-fat diets during pregnancy, for example, has been linked to a number of conditions, including the development of autism spectrum disorder (ASD) in the offspring. Since obesity is on the rise across all contexts, obesity during pregnancy is more and more a matter of concern.

Many of these associations between diet and disease, including neurological diseases, are now known to be modulated by the gut microbiota. Research on the gut-brain axis is a blooming field where new and important findings keep streaming. And just as our gut can have such a huge impact on our health when we are fully developed, it seems likely that it can also shape it when we are still developing, including in the womb.

Looking into the impact of maternal diet on the gut microbiota and determining its consequences therefore seems like a highly relevant research topic. Indeed, maternal obesity has been associated with alterations in the gut microbiota of the offspring in humans. It is possible that neurodevelopmental disorders that have been associated with maternal obesity may also occur through the action of the gut-brain axis.

Individuals with ASD often also have gastrointestinal problems and dysbiosis of the gut microbiota, being unclear whether an altered gut flora is a cause of a co-morbidity of ASD. It has been suggested that changes in the gut microbiota may indeed play a role in the development of the behavioral symptoms associated with ASD, but the possible mechanisms of this link remain unknown.

The journal Cell recently published a noteworthy study regarding the impact of maternal diet on ASD, establishing a new role for the gut microbiota. Research carried out in mice showed that a maternal high-fat diet leads to changes in the gut microbiota of the offspring, inducing a reduction in specific bacterial species. These changes were associated with behavioral alterations, namely social deficits that mimic those of autism spectrum disorder.

The correction of their gut microbial profile was able to reverse the social deficits induced by the maternal high-fat diet. It was also shown that germ-free mice presented social impairments that could be reversed by transplanting fecal microbiota from the offspring of mice with a regular diet, while transplants from the offspring of mice on a high-fat diet was unable to induce the same effect. One particular bacterial species, named Lactobacillus reuteri, was shown to be dramatically reduced in the maternal high-fat diet offspring. The administration of L. reuteri to those mice was also able to restore their social behavior.

Data from this study also indicates a possible route through which L. reuteri improves social behavior – it increased the levels of oxytocin in the paraventricular nuclei of the hypothalamus, where it is primarily synthesized. Direct treatment of the high-fat diet offspring with oxytocin also normalized their social behavior.

Therefore, this indicates that the high-fat diet of the mother may lead to a decrease in the levels of L. reuteri in the gut of the offspring, which in turn leads to a decrease in the production of oxytocin and of its action on the fetus. The precise mechanism by which L. reuteri modulates the production of oxytocin in the brain remains to be determined. The authors of this study hypothesize that this may happen though the vagus nerve, one of the main communication routes between the brain and the gut, as supported by other studies.

There have already been a number of studies linking the gut microbiota to the development of ASD. For example, the restoration of gut permeability using probiotics in a mouse model of ASD was able to improve some behavioral dysfunctions, but not social behaviors. In this study, on the other hand, social behavior was improved, but other behavioral patterns associated with ASD were not. This points towards the possibility that a selective combination of probiotics may be a useful therapy for ASD.

Importantly, this adds to the growing notion of just how important our gut and our diet are.

References

Bresnahan, M., Hornig, M., Schultz, A. F., Gunnes, N., Hirtz, D., Lie, K. K., … Lipkin, W. I. (2015). Association of maternal report of infant and toddler gastrointestinal symptoms with autism. JAMA Psychiatry, 72(5), 466. doi:10.1001/jamapsychiatry.2014.3034

Buffington, S. A., Di Prisco, G. V., Auchtung, T. A., Ajami, N. J., Petrosino, J. F., & Costa-Mattioli, M. (2016). Microbial Reconstitution reverses maternal diet-induced social and Synaptic deficits in offspring. Cell, 165(7), 1762–1775. doi:10.1016/j.cell.2016.06.001

Connolly, N., Anixt, J., Manning, P., Ping-I Lin, D., Marsolo, K. A., & Bowers, K. (2016). Maternal metabolic risk factors for autism spectrum disorder-an analysis of electronic medical records and linked birth data. Autism Research. doi:10.1002/aur.1586

Galley, J. D., Bailey, M., Kamp Dush, C., Schoppe-Sullivan, S., & Christian, L. M. (2014). Maternal obesity is associated with alterations in the gut Microbiome in toddlers. PLoS ONE, 9(11), e113026. doi:10.1371/journal.pone.0113026

Hsiao, E. Y., McBride, S. W., Hsien, S., Sharon, G., Hyde, E. R., McCue, T., … Mazmanian, S. K. (2013). Microbiota modulate behavioral and physiological abnormalities associated with Neurodevelopmental disorders. Cell, 155(7), 1451–1463. doi:10.1016/j.cell.2013.11.024

Krakowiak, P., Walker, C. K., Bremer, A. A., Baker, A. S., Ozonoff, S., Hansen, R. L., & Hertz-Picciotto, I. (2012). Maternal metabolic conditions and risk for autism and other Neurodevelopmental disorders. PEDIATRICS, 129(5), e1121–e1128. doi:10.1542/peds.2011-2583

Mayer, E. A., Padua, D., & Tillisch, K. (2014). Altered brain-gut axis in autism: Comorbidity or causative mechanisms? BioEssays, 36(10), 933–939. doi:10.1002/bies.201400075

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