A little while ago, this blog featured an entry by Annick Bosch on the TRACE study, an amazing intervention study using the Elimination Diet to treat ADHD in kids (https://newbrainnutrition.com/adhd-and-elimination-diet/). Very shortly summarized, the Elimination Diet entails that participants can only eat a very restricted set of foodstuffs for several weeks, which can greatly reduce the number of ADHD symptoms in some kids. Subsequently, new foodstuffs are added back into the diet one by one, all the time checking that ADHD symptoms do not return. This ensures that every child for which the Elimination Diet proves successful ends up with a unique diet which suppresses their ADHD symptoms.

Now this is a fascinating study, since it indicates a direct influence of diet on ADHD behavior. What we know from the neurobiology of ADHD, is that it is caused by a myriad of relatively small changes in the structure, connectivity and functioning of several brain networks 1. For the most common treatments of ADHD, like medication with methylphenidate 2, we can quite accurately see the changes these interventions have on brain functioning. However, for the Elimination Diet, this has not been studied before at all. This is why we are now starting with the TRACE-MRI study, where kids that participate in a diet intervention in the TRACE program, are also asked to join for two sessions in an MRI scanner. Once before the start of the diet, and once again after 5 weeks, when the strictest phase of the Elimination Diet concludes. In the MRI scanner, we will look at the structure of the brain, at the connectivity of the brain, and at the functioning of the brain using two short psychological tasks. We made a short vlog detailing the experience of some of our first volunteers for this MRI session.

 

 

With the addition of this MRI session, we hope to be able to see the changes in brain structure and function over the first 5 weeks of the diet intervention. This will help us establish a solid biological foundation of how diet can influence the brain in general, and ADHD symptoms specifically. It can also show us if the effect of the Elimination Diet is found in the same brain networks and systems which respond to medication treatment. And lastly, we can see if there is a difference in the brains for those participants for whom the diet has a strong effect versus those where the diet does little or nothing to improve their ADHD symptoms. This can then help us identify for which people a dietary intervention would be a good alternative to standard treatment.

We will update you on the TRACE-MRI study and on the developments in this field right here on this blog!

 

REFERENCES
Faraone, S. V et al. Attention-deficit/hyperactivity disorder ­­­. Nat. Rev. Dis. Prim. 1, (2015).

Konrad, K., Neufang, S., Fink, G. R. & Herpertz-Dahlmann, B. Long-term effects of methylphenidate on neural networks associated with executive attention in children with ADHD: results from a longitudinal functional MRI study. J. Am. Acad. Child Adolesc. Psychiatry 46, 1633–41 (2007).

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When Alice’s mother first contacted our team to get more information on the dietary intervention at New Brain Nutrition, she mentioned that her daughter seems to be on edge all the time. On a typical day, Alice would be triggered easily over seemingly small things and stay upset for a long time. She told us that these emotional problems caused not only very strained and cheerless moments on the weekends and evenings, they also interfered notably with Alice’s social life. In between her angry or sad moments, Alice seems to be a perfectly happy and energetic 11-year old. Alice’s attention problems didn’t obstruct a healthy didactic development since she started ADHD-medication. However, the emotional problems were still present and seemed to cause severe impairment in social interactions, within the family and with peers. Therefore, her mother asked: Could we please try a dietary intervention to see if Alice’s nutrition may play a role in these problems?

Faraone[1] distinguishes two features in these kind of emotional problems: Emotional Impulsivity and Deficient Emotional Self-Regulation. Some children may experience explosive anger but also recover quickly from it. These children experience high Emotional Impulsivity but low Deficient Emotional Self-Regulation. Alice however, based on her mother’s narrative, seems to experience both high Emotional Impulsivity and high Deficient Emotional Self-Regulation.

The second week into the Elimination Diet treatment, the researcher checks in with the family: She’s still edgy and irritable for most of the time, her mother says, but she seems to break out of it a whole lot sooner. The other day her brother Daniel came home, telling Alice he ate lots of non-elimination diet snacks at his friend’s house. Understandably, Alice became upset but it didn’t last as long as her parents expected. In other words: The Emotional Impulsivity hadn’t decreased yet, but the Deficient Emotional Self-Regulation had.

By the end of the first 5 weeks of the dietary intervention, Alice’s parents reported a convincing decrease in emotion regulation problems. The teacher also reported that the attention problems had stabilized, as much as they did with the ADHD-medication that Alice had before. The family decided to continue the Elimination Diet and start with the re-introduction phase. Every two weeks a new product was re-introduced to see if this may elicit symptoms. This was probably the most interesting period for the family, as emotion regulation problems and attention problems arose and subsided over different phases.

After one year, Alice and her family had figured out a set of foods that, when eliminated from her diet, helped diminishing both the attention problems and emotional problems. Alice is less responsive to emotional triggers and more balanced during social interactions. Alice’s personalized diet or personalized nutrition is based on her experiences and symptoms during the dietary intervention. Her mother is very glad that they discovered this lifestyle intervention as an alternative to their previous treatment with ADHD-medication.

Writers note: This is the story of one individual participating in the New Brain Nutrition study. Evaluating the role of nutrition in treatment of mental health with scientific evidence is part of our future.

More information can be found in [1] Faraone S.V., Rostain A.L., Blader J., Busch B., Childress A.C., Connor D.F., & Newcorn J.H. (2018). Practitioner Review: Emotional dysregulation in attention‐deficit/hyperactivity disorder – implications for clinical recognition and intervention. Journal of Child Psychology and Psychiatry. https://doi.org/10.1111/jcpp.12899

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In my previous blogs, I explained the research questions of my study. This study will be performed in two cohorts which I will elaborate on in this current blog about early life nutrition and studying gut microbiota. The cohorts are called BIBO and BINGO.  

BIBO stands for ‘Basale Invloeden op de Baby’s Ontwikkeling’ (in English: basal influences on  infant’s development). Recruitment of this cohort started in 2006, and a total of 193 mothers and their infants were included. At age 10, 168 mothers and their children still joined the BIBO study; the attrition rate is thus low. The majority of the mothers are highly educated (76%). The number of boys (52%) and girls (48%) in this cohort are roughly equally divided. A unique aspect of the BIBO study is the number of stool samples collected in early life. Also, detailed information about early life nutrition has been recorded during the first six months of life (e.g. information on daily frequency of breastfeeding, formula feeding, and mixed feeding). Together, these stool samples and nutrition diaries provide important insights in the relations between early life nutrition and gut microbiota development. Data about children within the BIBO cohort will be collected at age 12,5 years and 14 years. At 12,5 years, the participants will be invited to the university for an fMRI scan (more information about the fMRI scan will be given in a future blog). At age 14, children’s impulsive behavior will be assessed by means of behavioral tests and (self- and mother-report) questionnaires.

BINGO stands for ‘Biologische INvloeden op baby’s Gezondheid en Ontwikkeling’ (in English: biological influences on infant’s health and development). When investigating biological influences on infant’s health and development, it is important to start before birth. Therefore, 86 healthy women were recruited during pregnancy. Recruitment took place in 2014 and 2015. One unique property of the BINGO cohort is the fact that not only mothers were recruited, but also their partners. The role of fathers is often neglected in research, and thus an important strength of this BINGO cohort. Another unique property is that samples of mothers’ milk were collected three times during the first three months of life, to investigate breast milk composition. As for many infants their diet early in life primarily consists of breast milk, it is interesting to relate breast milk composition to later gut microbiota composition and development. Currently, 79 mothers and children, and 54 fathers are still joining the BINGO study. The average age of the participants at the time of recruitment was 32 years for mothers and 33 years for the father. Majority of the parents within this cohort are highly educated (77%) and from Dutch origin (89%). The number of boys (52%) and girls (48%) in this cohort are roughly equally divided. At age 3, children’s impulsive behavior will be assessed by means of behavioral tests and mother-report questionnaires.

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Why 12 genetic markers for ADHD are exciting news for New Brain Nutrition

We are finally here: for the first time, genome-wide significant markers are identified that increase the risk for Attention Deficit / Hyperactivity Disorder (ADHD). This research was conducted by an international consortium of more than 200 experts on genetics and ADHD, and includes several researchers that are also involved in our Eat2beNICE project (the scientific basis of this New Brain Nutrition website). The findings were recently published in the prestigious journal “Nature Genetics” and will greatly advance the field of ADHD genetics research.

Why is this finding so important?

The genetics of ADHD are very complex. While ADHD is highly heritable, there are likely to be thousands of genes that contribute to the disorder. Each variant individually increases the risk by only a tiny fraction. To discover these variants, you therefore need incredibly large samples. Only then can you determine which variants are linked to ADHD. The now published study by Ditte Demontis and her team combined data from many different databases and studies, together including more than 55,000 individuals of whom over 22,000 had an ADHD diagnosis.

We can now be certain that the twelve genetic markers contribute to the risk of developing ADHD. Their influence is however very small, so these markers by themselves can’t tell if someone will have ADHD. What’s interesting for the researchers is that none of these markers were identified before in much smaller genetic studies of ADHD. So this provides many new research questions to further investigate the biological mechanisms of ADHD. For instance, several of the markers point to genes that are involved in brain development and neuronal communication.

Why are our researchers excited about this?

A second important finding from the study is that the genetic variants were not specific to ADHD, but overlapped with risk of lower education, higher risk of obesity, increased BMI, and type-2 diabetes. If genetic variants increase both your risk for mental health problems such as ADHD, and for nutrition-related problems such as obesity and type-2 diabetes, then there could be a shared biological mechanism that ties this all together.

We think that this mechanism is located in the communication between the gut and the brain. A complex combination of genetic and environmental factors influence this brain-gut communication, which leads to differences in behaviour, metabolism and (mental) health.genetic markers for adhd

The microorganisms in your gut play an important role in the interaction between your genes and outside environmental influences (such as stress, illness or your diet). Now that we know which genes are important in ADHD, we can investigate how their functioning is influenced by environmental factors. For instance, gut microorganisms can produce certain metabolites that interact with these genes.

The publication by Ditte Demontis and her co-workers is therefore not only relevant for the field of ADHD genetics, but brings us one step closer to understanding the biological factors that influence our mental health and wellbeing.

Further Reading

Demontis et al. (2018) Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature Genetics. https://www.nature.com/articles/s41588-018-0269-7

The first author of the paper, Ditte Demontis, also wrote a blog about the publication. You can read it here: https://mind-the-gap.live/2018/12/10/the-first-risk-genes-for-adhd-has-been-identified/

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Breaking news: It has long been assumed that the gut and the brain communicate not only via a slow, hormonal pathway, but that there must be an additional, faster association between gut and brain. Melanie Maya Kelberer and her colleagues from Duke University, NC, now managed to detect this connection. Their paper has just been published in the renowned journal ‘Science’.

By researching a mouse model, they were able to show that the gut and the brain are connected via one single synapse. This is how it works: A cell in the gut (the so-called enteroendocrine cell) transfers its information to a nerve ending just outside the gut. At the connecting nerve ending (the synapse), the neurotransmitter glutamate – the most important excitatory transmitter in the nervous system – passes on the information about our nutrition to small nerve endings of the vagal nerve, which spreads from the brain to the intestines.

Vagal nerveBy travelling along this vagal nerve, the information from the gut reaches the brainstem within milliseconds. The authors now state that a new name is needed for the enteroendocrine cells, now that they have been shown to be way more than that. The name ‘neuropod cells’ has been suggested. The authors interpret their findings as such, that this rapid connection between the gut and the brain helps the brain to make sense of what has been eaten. Through back-signalling, the brain might also influence the gut. In sum, this finding is an important step towards a better understanding of how the gut and the brain communicate. Findings such as this one help us to find ways to positively influence our brain states and our mental health by our food choices.

Read the original paper here: http://science.sciencemag.org/content/361/6408/eaat5236.long

Kaelberer, M.M., Buchanan, K. L., Klein, M. E., Barth, B. B., Montoya, M. M., Shen, X., and Bohórquez, D. V. (2018), A gut-brain neural circuit for nutrient sensory transduction, ​Science,
​ Vol. 361, Issue 6408

 

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Maladaptive or uncontrolled impulsivity and compulsivity lead to emotional and social maladjustment, e.g. addiction and crime, and underlie psychiatric disorders. Recently, alterations in microbiota composition have shown to have implications for brain and social behaviors as we have been explaining in our lasts blogs. The microbiota-gut-brain axis may be involved in this process but the mechanisms are not fully identified (1). The supplementation of probiotics can modulate the microbial community and now has been suspected to contribute to ameliorating symptoms of a psychiatric disease with possible influence on social behaviors (2). To date, no randomized controlled trial has been performed to establish feasibility and efficacy of this intervention targeting the reduction of impulsivity and compulsivity. This gave us the idea to perform a study to investigate the effects of supplementation with probiotics, working with adults with Attention Deficit Hyperactivity Disorder (ADHD) and Borderline Personality Disorder (BPD) which in most cases present high levels of impulsivity, compulsivity and aggression.

Probiotics for healthWe call our project PROBIA, which is an acronym of “PROBiotics for Impulsivity in Adults”. This study will be performed in three centers of Europe including, Goethe University in Frankfurt, Semmelweis University in Budapest and Vall d’Hebron Research Institute (VHIR) in Barcelona, the coordinator of the clinical trial. We are planning to start recruiting patients in January of 2019 and obtain the results in 2021. In our study, we will explore the effects of probiotics by measuring the change in ADHD or BPD symptoms, general psychopathology, health-related quality of life, neurocognitive function, nutritional intake, and physical fitness. The effect of the intervention on the microbiome, epigenetics, blood biomarkers, and health will be also explored by collecting blood, stool, and saliva samples.

We are looking forward to having the results of this amazing study in order to understand the mechanisms involved in the crosstalk between the intestinal microbiome and the brain. If improvement effects can be established in these patients, new cost-effective treatment will be available to this population.

 This was co-authored by Josep Antoni Ramos-Quiroga, MD PhD, psychiatrist and Head of Department of Psychiatry at Hospital Universitari Vall d’Hebron in Barcelona, Spain. He is also professor at Universitat Autònoma de Barcelona.

Sources

  1. Desbonnet L, Clarke G, Shanahan F, Dinan TG, Cryan JF. Microbiota is essential for social development in the mouse. Mol Psychiatry [Internet]. The Author(s); 2013 May 21;19:146. Available from: http://dx.doi.org/10.1038/mp.2013.65
  2. Felice VD, O SM. The microbiome and disorders of the central nervous system. 2017 [cited 2017 Oct 16]; Available from: https://ac.els-cdn.com/S0091305717300242/1-s2.0-S0091305717300242-main.pdf?_tid=b52750d8-b2ae-11e7-819b-00000aab0f02&acdnat=1508185089_58e99184d2c0f677d79ff1dd88d02667

 

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Have you experienced drowsiness after eating a large meal? Has an important presentation made your stomach turn? Seeing a special someone made you feel butterflies in your stomach? If you have (and you most likely have), then you know how strong the connection between the brain and the gut is.

Scientists have found that many chronic metabolic diseases, type 2 diabetes, mood disorders and even neurological diseases, such as Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis, are often associated with functional gastrointestinal disorders (1). The importance of the association between the gut and the brain is gaining momentum with each new study. However, the way HOW the signaling between these two integral parts of the body exactly works hasn’t been clear until recently.

It was thought for a long time that the only “communication channel” between the gut and the brain was the passive release of hormones stimulated by the consumed nutrients. Hormones entered the bloodstream and slowly notified the brain that the stomach is full of nutrients and calories. This rather slow and indirect way of passing messages takes from minutes to hours.

But now, a recent study (2) has elegantly proven that the gut can message the brain in seconds! Using a rabies virus enhanced with green fluorescence, the scientists traced a signal as it traveled from the intestines to the brainstem of mice, crossing from cell to cell in under 100 milliseconds – faster than the blink of an eye.

The researchers had also noticed that the sensory cells lining the gut were quite similar to the receptors in the nose and on the tongue (3). The effects, however, differ. In the mouth, the taste of fatty acids triggers signals to increase hunger, whereas in the small intestine, fatty acids trigger signals of satiety. This means that the discovered “gut feeling” might be considered as a sixth sense, a way of how the brain is being signaled when the stomach is full.

This new knowledge will help to understand the mechanism of appetite, develop new and more effective appetite suppressants and help those struggling with weight and problematic eating patterns.

REFERENCES
(1) Pellegrini C et al (2018) Interplay among gut microbiota, intestinal mucosal barrier and enteric neuro-immune system: a common path to neurodegenerative diseases? Acta Neuropathol 136:345. doi:10.1007/s00401-018-1856-5

(2) Kaelberer et al (2018) A gut-brain neural circuit for nutrient sensory transduction. Science 361(6408):eaat5236. doi:10.1126/science.aat5236

(3) Bohórquez and Liddle (2015) The gut connectome: making sense of what you eat. J Clin Invest 125(3):888–890. doi:10.1172/JCI81121

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A hot topic these days, that one can hear more and more information about is the microbiota-gut-brain axis, the bidirectional interaction between the intestinal microbiota and the central nervous system nowadays, this has become a hot topic. We are becoming increasingly aware that gut microbiota play a significant role in modulating brain functions, behavior and brain development. Pre- and probiotics can influence the microbiota composition, so the question arises, can we have an impact on our mental health by controlling nutrition and using probiotics?

Burokas and colleagues aimed to investigate this possibility in their study (2017), where the goal was to test whether chronic prebiotic treatment in mice modifies behavior across domains relevant to anxiety, depression, cognition, stress response, and social behavior.

In the first part of the study, the researchers fed mice with prebiotics for 10 weeks. They were administered the prebiotics fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), a combination of both, or water. FOS and GOS are soluble fibers that are associated with the stimulation of beneficial bacteria such as bifidobacterium and lactobacillus.

Behavioral testing started from the third week including

  • the open field test (anxiety – amount of exploratory behavior in a new place),
  • novel object test (memory and learning – exploration time of a novel object in a familiar context), and
  • forced swimming test (depression-like behavior – amount of activity in the cylinder filled water).

Meanwhile, plasma corticosterone, gut microbiota composition, and cecal short-chain fatty acids were measured. Taken together, the authors found that the prebiotic FOS+GOS treatment exhibited both antidepressant and anxiolytic (anti-anxiety) effects. However, there were no major effects observed on cognition, nociception (response to pain stimulus), and sociability; with the exception of blunted aggressive behavior and more prosocial approaches.

In the second part, FOS+GOS or water-treated mice were exposed to chronic psychosocial stress. Behavior, immune, and microbiota parameters were assessed. Under stress, the microbiota composition of water-treated mice changed (decreased concentration of bifidobacterium and lactobacillus), which effect was reversed by treatment with prebiotics.

Furthermore, it was found that three weeks of chronic social stress significantly reduced social interaction, and increased stress indicators (basal corticosterone levels and stress-induced hyperthermia), whereas prebiotic administration protected from these effects.

After stimulation with a T-cell activator lectin (concanavalin A), the stressed, water-treated mice group presented increased levels of inflammatory cytokines (interleukin 6, tumor necrosis factor alpha), whereas in animals with prebiotics had these at normal levels.

Overall, these results suggest a beneficial role of prebiotic treatment in mice for stress-related behaviors and supporting the theory that modifying the intestinal microbiota via prebiotics represents a promising potential for supplement therapy in psychiatric disorders.

Watch YouTube Video:
https://youtu.be/E479yto8pyk

REFERENCES
Burokas, A., Arboleya, S., Moloney, R. D., Peterson, V. L., Murphy, K., Clarke, G., Stanton, C., Dinan, T. G., & Cryan, J. F. (2017). Targeting the Microbiota-Gut-Brain Axis: Prebiotics Have Anxiolytic and Antidepressant-like Effects and Reverse the Impact of Chronic Stress in Mice. Biological Psychiatry, 82(7), 472–487. https://doi.org/10.1016/j.biopsych.2016.12.031

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New research has been published in September 2018 which reveals preliminary evidence that symptoms of depression can be reduced by adherence to the Mediterranean diet and anti-inflammatory foods.  New Brain Nutrition is advancing this research with never-before-done clinical trials testing the protective effects of nutrition and specifically the Mediterranean diet.

You can download our FREE REPORT, learn what we know now, and then be updated on our progress as the clinical trials produce results.

Download your free report today!!

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Recently, the idea that gastrointestinal microbiota are able to affect host behaviour is gaining momentum and it is based on studies conducted with animal models but also in humans with neurological disorders. However, the mechanisms that underlay this complex interplay between gut, brain and microbiota are not completely understood. Here we discuss recent findings on how microbial products could potentially affect the gut-brain axis.

Intestinal microbiota grow through the fermentation of undigested carbohydrates that end up in the large intestine. It was shown that absence of microbes or disruption of the microbiota, led to increased populations of impaired microglia cells in mice. Microglia cells are the primary effector cells for immune signalling to the central nervous system. The presence of a complex microbiota community, was shown to be essential for proper microglia maturation and function [1].

The main products of microbial fermentation in the gut are; acetate, propionate and butyrate, collectively known as short chain fatty acids(SCFA’s). Their beneficial role in human physiology have been well described, and recently evidence suggests that these molecules are able to cross blood brain barrier [2]. Moreover, gut microbiota have been associated with the brain barrier integrity. Mice raised in absence of bacteria are reported to have reduced brain barrier integrity. Once colonized with either a butyrate or an acetate/propionate producing bacteria, significant improvements were reported in the barrier [3]. Notably the integrity of the blood-brain barrier from the germ free mice was able to be restored through the oral administration of butyrate.

Gut_Microbes and Mental HealthSCFA’s are among the molecules having the privilege to cross the blood brain barrier and access the brain directly, their role should be studied in detail.

Recent studies also demonstrate that gut microbes regulate levels of intestinal neurotransmitters. The enteric nervous system interacts with a plethora of neurotransmitters (more than 30 have been identified so far.) Actually, the bulk of serotonin production ~90%, a neurotransmitter associated with mood and appetite is located in the gut. Specialized cells known as enterochromaffin cells are the main serotonin producers in the gut. In the absence of intestinal microbiota gastrointestinal serotonin levels are depleted. However, they can be restored by the addition of a specific spore forming consortium of intestinal bacteria. Specific bacterial metabolites have been reported to mediate this effect [4].

Other intestinal microbiota have been reported also to regulate the levels of the GABA neurotransmitter. Reduced levels of GABA have been associated with anxiety, panic disorder and depression. Bacterial GABA producers have been known to exist for years but it was not until 2016 that a gut bacteria was identified as GABA consumer [5]. For example, decreased levels of bacterial GABA producers were identified in a human cohort of depressed individuals. Studies in mice reinforce these findings. Intervention with the lactic acid bacteria Lactobacillus rhamnosus (JB-1) in healthy mice reduced anxiety related symptoms (accompanied by a reduction in the mRNA expression of GABA receptors in the Central Nervous System.) Lactic acid producing bacteria have also been reported to produce GABA in several food products such as kimchi, fermented fish and cheese [6].

Collectively, our gut microbiota encodes for ~100 times more genes than the human genome. The potential for some of these microbial genes to produce compounds able to interact with the nervous system and regulate critical pathways implicated in the gut brain axis is realistic and worth being explored.

Authors Prokopis Konstanti, MSc and Clara Belzer, PhD are working in the Department of Molecular Ecology, Laboratory of Microbiology, Wageningen University, Netherlands.

Footnotes

  1. Erny, D., et al., Host microbiota constantly control maturation and function of microglia in the CNS. Nature neuroscience, 2015. 18(7): p. 965-977.
  2. Joseph, J., et al., Modified Mediterranean Diet for Enrichment of Short Chain Fatty Acids: Potential Adjunctive Therapeutic to Target Immune and Metabolic Dysfunction in Schizophrenia? Frontiers in Neuroscience, 2017. 11(155).
  3. Braniste, V., et al., The gut microbiota influences blood-brain barrier permeability in mice. Science translational medicine, 2014. 6(263): p. 263ra158-263ra158.
  4. Yano, J.M., et al., Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell, 2015. 161(2): p. 264-276.
  5. P. Strandwitz, K.K., D. Dietrich, D. McDonald, T. Ramadhar, E. J. Stewart, R. Knight, J. Clardy, K. Lewis; , Gaba Modulating Bacteria of the Human Gut Microbiome. 2016.
  6. Dhakal, R., V.K. Bajpai, and K.-H. Baek, Production of gaba (γ – Aminobutyric acid) by microorganisms: a review. Brazilian Journal of Microbiology, 2012. 43(4): p. 1230-1241.

 

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