Metabolites derived from omega-3 fatty acids could help reduce depression: dream or reality? I am a senior postdoctoral neuroscientist at the Stress, Psychiatry, and Immunology (SPI) Lab, the team that brings you InSPIre the Mind. While I have been working in the field of mental health, for now, more than 10 years, and have previously contributed to this online platform with blogs on neuroinflammation and mental health, it’s only recently that I started to become fascinated by the role of nutrition, and particularly by the so-called omega-3 polyunsaturated fatty acids (or PUFAs), in the context of mental health pathologies. You may have already heard about omega-3 PUFAs. The most commonly known omega-3 PUFAs are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These are often found in the everyday diet, for example in fish oil, such as the one derived from salmon, herring, sardines, or mackerel, as well as in nuts and seeds. While a lot has already been said about these nutritional compounds, and their anti-inflammatory and potentially anti-depressant properties, there is still little knowledge on how they work exactly in the brain to support good mental health. Considering this, I decided to conduct some investigations and assessed the effects of administering high doses of EPA and DHA, first in patients and then in lab-grown neurones, to help clarify how they reduce inflammation and depression. Omega-3 metabolites in patients First, I assessed twenty-two patients with major depression who received either 3 grams of EPA or 1.4 grams of DHA daily for twelve weeks, and then measured metabolites of EPA and DHA in their blood before and after the omega-3 PUFA treatment, along with a score of their depressive symptoms. Do you wonder what we found? Well, results showed that when omega-3 PUFAs are given to patients with depression they are metabolized into smaller molecules called metabolites, or more precisely lipid mediators and that the levels of these in the blood were associated with an improvement in depressive symptoms. Interesting, is it not? This is the first study ever published to report such findings. But, how do these lipid mediators act in the brain? Omega-3 metabolites in lab-grown neurones In order to answer this question, I used human brain cells derived from the hippocampus, a part of the brain known to regulate the production of new neurones — a process called neurogenesis — which is involved in many cognitive functions, such as memory and learning, which are relevant for depression. Subsequently, I exposed these cells to several chemical inflammatory messengers called cytokines — we have been using this experimental model for years as it perfectly mimics inflammation in the brain of depressed patients. Using this experimental model, I was able to show that treating human hippocampal cells with EPA or DHA, before being exposed to inflammatory cytokines prevented the reduction in the number of newly generated neurones, or neurogenesis, which was previously observed in cells exposed to cytokines alone. Further investigation confirmed these effects were mediated by the formation of the same metabolites previously detected in the blood of depressed patients receiving omega-3 PUFAs, namely hydroxyeicosapentaenoic acid (HEPE), hydroxydocosahexaenoic acid (HDHA), epoxyeicosatetraenoic acid (EpETE), and epoxydocosapentaenoic acid (EpDPA). This was the first time we detected these metabolites in human hippocampal neurones! Further investigation showed that treatment with an inhibitor of the enzyme involved in the synthesis of these metabolites can increase their availability, therefore suggesting a possible way by which future treatments could be optimized in order to increase the activity of these metabolites. So, what did we learn? This study, now published in the journal of Molecular Psychiatry, has provided exciting new insight into how omega-3 fatty acids bring about anti-inflammatory effects that improve depression. For some time, we have known that omega-3 PUFAs can induce anti-depressant and anti-inflammatory effects but, without further understanding of how this happens in the human brain, it has been difficult to develop treatments. This study has helped shine a light on the mechanisms involved in this relationship which can inform the development of potential new treatments for depression using omega-3 PUFAs. The metabolites that I have identified are broken down in the body relatively quickly, which means they may only be available for a relatively short time. By testing the effect of inhibitors of the enzymes involved in the metabolism of omega-3 PUFA I was able to show that we can greatly improve how long they can have an effect in the body and ultimately, increase their efficacy. This is very important for the development of new treatments and means that patients could be given higher doses of EPA and DHA together with these enzyme inhibitors to increase the amount of these important compounds in their blood over time. What would be the next step? For sure, the evidence generated here suggests that the metabolites produced by the breakdown of EPA and DHA in the body could be targeted as a mechanism to reduce depression and inflammation. But, remember, there is a need to ensure that their effects are prolonged in order for this approach to be successful! The development of novel drugs able to target the enzyme involved in the synthesis of EPA- and DHA-derived metabolites could be a valid therapeutic option and could be used for inflammation-associated brain disorders, such as depression, where at least a sub-group of patients often have chronic levels of inflammation. There is an ever-growing interest in the links between the immune system, inflammation, and depression but in order to develop new treatments in this area, we need to better understand the mechanisms behind these relationships. By identifying and measuring the exact lipid mediators that are involved, identifying the enzyme that prolongs their effects and finding the same lipid mediators in depressed patients treated with omega-3 PUFA, and demonstrating improvements in symptoms, this study has provided vital information to help shape clinical trials for future therapeutic approaches with omega-3 fatty acids. However, it is important to highlight that this research has not shown that by simply increasing omega-3 fatty acids in our diets or through taking nutritional supplements we can reduce inflammation or depression! The mechanisms behind the associations between depression and omega-3 PUFA are complicated and require further research and clinical trials to fully understand how they work and inform future therapeutic approaches. But for now, I believe this is enough food for thought! Header image source: Whitney E. RD

The Biology of Depression, and Being on the Path to Discovery I am a scientist and I work with a team of researchers who spend their careers trying to understand what depression is, and especially the role of the immune system. That may sound odd, as almost everyone knows what depression is. But what is it on a biological level? Although we have overcome the historic opinions that this is ‘all in the mind’, and we now have a lot of evidence to suggest the immune system may be involved, no one really understands what causes depression in a mechanistic sense and, crucially, where it originates. It is also increasingly apparent that a ‘one size fits all’ approach is not appropriate, and that one person’s experience of depression can be markedly different from the next person’s. This suggests a layer of subtleties we have thus far been unable to pinpoint. Without advancing our knowledge and understanding at a molecular level, we cannot successfully stratify patients appropriately and we will not know what therapies we need to develop to truly help people. Depression affects everyone. It may not be directly, and we may not even know it, but statistically speaking, we will all likely know someone who has or has had depression. This is particularly topical since over the past 18 months, during the pandemic, the prevalence of depression has increased on an almost exponential level, with the Office for National Statistics reporting that around 1 in 5 people experienced depression in early 2021. Strikingly, this is more than double the pre-pandemic rate. Despite its prevalence, very little therapeutic progress has been made over the past thirty years since the introduction of selective serotonin re-uptake inhibitors (SSRI’s, the most common class of antidepressant) and current treatments do not work for everyone. This makes it even more important to understand the nuances of the disease and to aim for a more personalised medicine approach to treatment. Regardless, the impact of depression on society is huge. Not just in terms of the effect it has on an individual’s quality of life, but also their associated medical costs, loss of earnings and the impact of suicide. This is a global problem and is one of the leading causes of disability worldwide. We have been fortunate to be involved in the ‘Neuroimmunology of Mood and Alzheimer’s Disease’ (NIMA) Consortium, a programme of work that has been funded by the Wellcome Trust over a five-year period (now longer thanks to the disruption of COVID-19!). As indicated by the name, this consortium comprises of two research arms (and a long list of incredible scientists), covering both Alzheimer’s disease and mood, and we are involved with the latter. As well as some pre-clinical ‘bench’ studies, this work package included a clinical study that recruited patients with a spectrum of depression; those who were diagnosed with depression but currently untreated, those who had been treated successfully and were therefore no longer depressed, those who were receiving treatment but were still depressed (we refer to this group as treatment-resistant) and healthy controls who did not have a history of depression. The aim of this particular study was to analyse the immune system of these patients and try to identify if and how they differ in terms of their inflammatory signals. If there was a signal, what cells could it be coming from and how does it relate to a patients’ disease outcome? A robust immunophenotyping study (a fancy word that basically means mapping out immune system patterns) often uses a range of techniques to obtain measures of different cell types, different molecules, different biological processes etc., so that researchers get a big picture overview of what is a very complex system. This was done by the NIMA Consortium at great effort and expense, but I will focus on the study our group performed using RNA sequencing (RNAseq) that was recently published in Translational Psychiatry. There are more publication on blood immune measure collected in these patients, such as on c-reactive protein, immune genes, and immune cells. We used RNAseq to measure gene expression in peripheral blood mononuclear cells (PBMCs, an important group of white blood cells found in the circulation) isolated from the study participants. We had four major findings. First, there was no evidence of significantly different expression of individual genes or groups of genes across the different patient populations. Second, when assessing gene expression in an enriched immune cell population (like we did), it is likely that false positive results will preferentially be immune genes by default (this is an important point to be aware of when analysing similar datasets to avoid unintended bias). Third, we did find evidence of biological ageing in the depressed population, albeit subtle. And fourth, this study highlighted that the contribution of weight and body mass index (BMI) to inflammation in depression is complex. As with most scientific research, this study has raised as many questions as it has answered. Our interpretation of the data is such that PBMCs are unlikely to be the source of any inflammatory signal in this patient group. Of course, we have to start somewhere, but there are many other cell types that we are yet to explore, for example, neutrophils (another white blood cell type), endothelial cells (that line blood vessels), and adipocytes (cells in the adipose tissue). Indeed, there are many studies linking inflammation with obesity, and adipocytes are thought to be an important source of pro-inflammatory molecules, however studies like ours often consider the effects of BMI as a confounding factor (something that could distort the variables you are actually interested in). In doing so, however, we may be losing a really crucial part of the biological story since people with depression tend to have a higher BMI than the general population, but we are yet to confirm if this is a causal or consequential relationship. This study also warrants further investigation into the importance of immune ageing as our findings echo other studies that have linked severe depression, and possibly chronic stress, with increased cell ageing. The precise consequence of increased immune age is opaque, but it is thought to be a bad thing since aged cells are less efficient and are more likely to be ‘abnormal’. I think the most important take home message from this study is that it emphasises how complex this field of research really is and highlights the importance of continued efforts to address the many unanswered questions. I feel optimistic that every study takes us that little bit closer to the truth and we are all eternally grateful to the patients who volunteer to be a part of our research. Header Image by Nick Fewings on Unsplash

An interview with Elliott Rae, founder of "Music.Football.Fatherhood." “It was 2015 and mental health wasn’t really a thing at that time”. These are the first words that Elliott says to me, immediately showing why his contribution to the mental health conversation in the last few years has been so crucial. It is not that mental health wasn’t a thing in 2015. It wasn’t a thing that men talked about. Elliott Rae is the founder of Music.Football.Fatherhood (MFF), a successful blog platform where all aspects of fatherhood and masculinity, including mental health, are discussed openly by him and a number of guest writers. Building on this community of writers, earlier this year he published the book, DAD, which he co-wrote and curated along with 20 other fathers: an inspiring collection of stories that represent the diversity of modern fatherhood, exploring everything from childbirth trauma to surrogacy, from bereavement to gender stereotypes, from being a gay father to changing work-life balance, and more. Inspire the Mind Deputy Editor, Melissa Bujtor, read the book and was deeply moved by the raw honesty of the stories. She came to me with the idea of curating a series of blogs on fathers’ mental health, match-making the compelling and inspiring stories of four writers with the scientific and medical perspectives of four academics. (See the Editor’s note at the end of this blog for a snapshot of the programme). And she suggested I started the series with an interview of the man behind this adventure. I started my interview by asking why he, a committed and busy civil servant in the Department of Transport, started MFF. “It all came out of my personal story”, Elliott starts. A tragic medical emergency during the birth of his first (and so far only) daughter, now a healthy and lively 6-year-old girl, but back then, in the hours and days immediately after the birth, suffering from group B streptococcus (GBS) bacteria infection, requiring immediate emergency care. To make things worse, his wife also lost a lot of blood during the delivery. “We went from a normal delivery to an unreal mental zone where doctors and nurses were rushing around trying to save both my wife and my daughter”. He was watching it all as if he were not there, “like through a CCTV camera”. His post-traumatic stress disorder (PTSD) was starting then. After two weeks in the incubator in the hospital, the new family started their new life at home, but things “did not feel normal”. Both he and his wife were very anxious that their daughter could be ill again. “We brought her to A&E eight times in three months, for things that were perfectly normal for a child, but we were terrified it could be the infection coming back”. The first 3–4 months were “just very raw, just getting by”. They would rarely go out. They would try to talk things through between the two of them, to elaborate what had happened, but struggled to really process it. His short paternity leave had been used up at hospital with his daughter. So, he threw himself into work, and did not share with his co-workers what had happened. How could he tell people how bad was he feeling, when they were congratulating him on being a new dad? His wife was diagnosed with postnatal anxiety and received some counselling sessions, but he “did not even know” that he could be seeking help. Unfortunately, at around 6 months after the birth, their daughter suffered from a severe allergic reaction to wheat. In a perhaps even more dramatic reliving of the first medical emergency, in 2–3 minutes she became very red and swollen. The ambulance came and brought her into A&E as a major emergency. This experience triggered the starting of the classic symptoms of PTSD: “flashbacks of the events of both medical emergencies, down to the smell of the antibiotics and the beeping sound of the intensive care unit, reliving the emotions as if they were real and I was there; nightmares, insomnia, crying, feeling overwhelmed and very anxious”. Again, at work, he did not share what was happening. In fact, he would avoid conversing with colleagues, as he felt unable to concentrate, was always very panicky and physically sick. And again, he did not seek help. “I did not know it was possible for me to receive help. I did not know what PTSD was. And I got really good at hiding my emotions. It was easy to blame it all on being a tired new dad”. “In 2017 I started writing the MFF blog, because there was nothing online for fathers. Mums had Mumsnet but we did not have anything”. He started with just a few paragraphs and pictures, as a space that was just for him, where he could write and express his thoughts and emotions. And he immediately started attracting the attention of other fathers who wanted not only to read about fatherhood but also to share their stories and their experience. By the end of the year, he had written a piece on The Independent and been interviewed by the BBC. And then he realised that the blog was not enough to truly bring these stories to life. He needed a book. “And this is how DAD was born. With a dozen of regular contributors to MFF, and a few more fathers that were invited through personal contacts. We wanted to make a book that talked to all fathers, to fathers of all ages, races, and sexualities”. “But the book was such a difficult project”, he emphatically says. They decided to self-produce through crowdfunding, which meant they had to do everything: from editing the chapters to creating the cover, from choosing the paper and font to designing the colour palette, from sorting out contracts and copyright to planning the PR and marketing strategy. “These were not professional writers, they are ordinary dads and that’s the beauty of it”, he continues, “so for every chapter I had to ask them… can you explore more of this… can you describe how you felt then… can you talk about the darkest moments … any lessons that you learnt… but it was a logistical nightmare. I tried to ask them to go further while also being sensitive, while struggling with deadlines for chapter completions.” By the time the crowdfunding was launched, in November 2020, half of the chapters had already been drafted, but all at different stages. And the launch day was scheduled for Father’s Day 2021–20th of June. “But we made it”. And then success arrived. Interviews on radio, TV, and in newspapers. DAD was in June’s top 10 Amazon bestsellers list for parenting. And Elliott started bringing the conversation on masculinity and mental health to the public, to cultural events, to corporate and governmental organisations. Truly impacting the discourse on fatherhood. MFF now host a variety of writers, podcasts, and meetups for dads. It has a reputation for being a safe website, providing evidence-based information. “I wanted it to become fathers’ Mumsnet”, he says. And he might be very close to doing this. Through publishing and speaking revenues, he has been able to leave his job and dedicate all of his energy to his social enterprise. The content of the blogs remains accessible to all, for free. And he is working on a documentary. “And on another child, maybe”, he concludes. Elliott Rae, his wife, and daughter Source: Twitter @iamElliottRae Editor's Note: f you have enjoyed this blog, do not miss the full 10-part series that will explore aspects of modern-day fatherhood, men’s mental health, and the science behind it — starting today. Over the next 5 weeks (20th October through 19th November) every Wednesday we will publish a lived-experience piece from one of the fathers who contributed to Dad or MFF, followed on the Thursday by a scientific piece from one of our contributing scientists exploring the associated mental health aspects. Each writer and scientist couple have been working together to present a cohesive, human, evidence-based portrait of four important areas —  traumatic birth and PTSD, fatherhood during lock-down and post-natal depression, stillbirth, and surrogacy. We will finish the series on International Men’s Day, the 19 November, with a final piece by Will Nicholson, another of DAD’s contributors and an activist for social and system change, bringing together art, health and wellbeing. We hope you enjoy this ITM special series as we shine a spotlight on men’s mental health and fatherhood.

Reflections from the President of the Royal College of Psychiatrists: Party Conference season I was pleased to be invited to write this blog for Inspire the Mind. I previously wrote when I first became President in 2020. About 1 and a half years on and we’re in the Autumn of 2021. This time of year tends to bring a start of term feel, and it is also when the political parties in the UK set out their policy priorities. Having seen a much-scaled back conference season in 2020, this year has been a great opportunity for the Labour Party, the Conservatives, and the Lib-Dems to set out their vision for a post-lockdown world. We know that the pandemic has taken a huge toll on the nation’s mental health and so an ambitious response is needed. The Centre for Mental Health estimated last year that 10 million people (8.5 million adults and 1.5 million children and young people) in England will need support for their mental health as a direct result of the pandemic over the next three to five years. Many mental health teams around the country are already seeing high numbers of patients. The College’s analysis shows that nearly 1.5 million people were in contact with mental health services in June 2021, the highest number since records began, and 12.4% more than the same time last year. It is more important than ever that all sides of the political spectrum look at how we will help prevent people from becoming unwell, as well as cope with the unprecedented demand for services. The conference season began with the Liberal Democrats. Although unlike the other parties this was an online event, I was pleased to hear Leader Ed Davey recognise in his speech the impact the pandemic has had on children. They have called for a Children’s Catch-up Fund to help to reverse children’s lost learning and the impact of lockdown on their mental health. Associate Registrar, Tim Ojo, represented the College at this year’s Labour Party Conference taking place in Brighton. He attended a roundtable set up by the Royal College of Physicians and National Voices, along with Alex Norris MP, on how we can tackle the NHS backlog. Tim reminded everyone that you can’t just focus on the visible backlog in surgeries but also need to remember all the patients who need to get help with a mental illness. As has been well documented, I believe that the COVID crisis has had the biggest impact on the nation’s mental health since the Second World War. This is a critical time for mental health, and it is vital that more money is invested to tackle the impact of COVID, meet the new demands placed by the proposed improvements to the Mental Health Act, meet new access standards and targets and deliver the promised reforms in the NHS Long Term Plan. We were pleased to see that Labour Leader Keir Starmer’s conference speech talked about mental health as one of the urgent needs of our time. Moreover, he echoed what the College has been highlighting; that children have been particularly hard hit by the pandemic. For example, we know that 190,271 0–18-year-olds were referred to children and young people’s mental health services between April and June this year, up 134% on the same period last year and 96% on 2019. We welcome his pledge to guarantee NHS mental health treatment within a month for all who need it, along with 8,500 more mental health professionals to support a million more people every year. These promises will require a long-term plan for sustained and fair funding so that every person with a mental illness can get the help they deserve. I have personally just come back from the Conservative Party Conference in Manchester. This was a good opportunity to rub shoulders with those in government and others in the health sector and, importantly, ensure they understand the challenges we are facing in the mental health sector. It was good to have the chance to catch up with MPs like Dean Russell, chair of the All-Party Parliamentary Group for mental health and №10 advisor, Chloe Westley. She has a keen interest in the mental health of children and young people. But it was also an excellent opportunity to catch up with colleagues in the medical profession, including Chair of the British Medical Association (BMA) Council Chaand Nagpaul. I attended two roundtables with politicians and other Royal Colleges, including one posing the question “what does the future of the NHS workforce look like?”. We know that a lack of trained staff is the biggest barrier to expanding mental health services and so that is why it’s so important that we have bold action to increase the workforce in the upcoming Spending Review, such as dramatically expanding the number of places in medical school. The conference was particularly timely as it followed Prime Minister Boris Johnson’s cabinet reshuffle where Gillian Keegan MP was announced as the new Minister of State for Care and Mental Health. It was great to hear her facilitate an interesting discussion in the main auditorium on the impact of social media on children’s mental health. The challenges social media poses to children and young people’s mental health is something the College has long campaigned on. I’m looking forward to working more closely with her on this and other issues as she settles into her brief. As the conference season comes to a close, we know that whether the government is red, blue, green, or orange, they must act to support our nation’s mental health as we emerge from the pandemic. For too long mental health has struggled to be heard at the top table of NHS decision making, leaving many patients with a mental illness unable to access the care they need. That is why it is vital that the upcoming health and care bill is strengthened to guarantee that mental health is not overlooked again. As a College, we continue to work with politicians from across the political spectrum to ensure that the voice of our patients is heard.

Chasing Happiness After the week-long hustle in the office, sitting with a cup of masala tea on a Sunday morning always feels delightful to me. The usual anxious mind is at ease, the relaxed shoulders and legs are in no rush, the brain is trying to decode the language of birds on the balcony and the heart sings a soothing symphony for itself. Is it that I am pursuing happiness on weekdays in this capitalist world and earning it on a weekend? No. Happiness is subjective. I wake up and observe the ‘now’ and the bliss happens. I am not thinking about being happy. I am not asking dreadful existential questions. I am not comparing. I am not running to chase butterflies of joy. I am just being one with the calm. That’s where the bliss lies. Bliss is the ultimate stage of Ananda, where the duality ceases to exist. Happiness? The sensation attached to material gains is usually associated with happiness. Hence, by its nature, happiness is slippery, short-lived, and would be followed by unhappiness. A vicious circle of transcendental emotions. You cannot escape unhappiness. Our life is designed that way. However, you might not find happiness if you keep pursuing it. Research says pursuing happiness comes with significant costs including the constant feeling of time scarcity and paradoxical reduction in happiness itself. The harder we try to make ourselves happy, the more we feel like we are running out of time to achieve that. I have been writing on mental health along with spirituality and wellness for six years and have said across many articles to step down from the hedonic treadmill of chasing happiness or trying to be the most positive person on the planet. Both won’t work and would leave you exhausted. A wagging tail of a dog indicates happiness but does the happiness live in the tail? Happiness lives in the moment. Myths around Happiness People are awful at predicting what would make them happy. Scientists call it affective forecasting. You overestimate the happiness a particular thing might give you. Once it is there, it loses the charm. You can have a favorite food that makes you happy, but you can get fed up with it if you eat it every day. Dean Burnett, author of “Happy Brain: Where Happiness Comes From and Why” says, “If you have $500 that goes into your account every two weeks in your paycheck, that’s nice but that doesn’t really excite you, whereas if you find $20 in the pocket of your jeans, that’s brilliant.” Happiness is often misunderstood. It carries the baggage of our overwhelming expectations and flawed assumptions. More Money = More Happiness Famous economist, Richard Easterlin has been exploring happiness for the past 50 years. The Easterlin paradox is named after him that states at a point in time happiness may vary directly with income both among and within nations, but over time happiness does not trend upward as income continues to grow. So, money helps you until your particular level of needs is met. Beyond that, more money doesn’t make you happier. In 1972, Bhutan decided to prioritize Gross National Happiness over GDP as their nation’s goal. In the race of attaining economic prosperity at any cost in the consumerist world, this perspective shift of understanding that the purpose of life isn’t being rich but to be contented is exemplary and extends to individuals as well. Finland tops the list. Success = Happiness Success, promotions, all might excite you but shouldn’t be the reference point of your joy. Practically speaking, an increase in income would raise the standard of your living but won’t necessarily raise the standard of happiness. Your goal would shift to the next dream car and dream home. The goal can be there with a sense of gratification of the now. The material gains give you instant gratifications but are fleeting. The thrill of anything new and shiny wears down and you feel you are at the baseline again. You start running on this treadmill that never stops. Next mile to cover. Happiness is always on the next rung of this endless ladder. No Negativity = Happiness Escaping negative emotions should never be the goal. Forced positivity always brings frustration and a lost sense of purpose. Don’t get persuaded by catch-phrases like manifestations, affirmations, and positivity. You can use these techniques but without the expectation of them turning your life upside down and with the acceptance of all emotions-irrespective of the good-bad label. Unpleasant emotions often teach us survival skills, coping mechanisms. Sometimes emotions associated with a catastrophe lead to perspective shifts and a change in the direction of life. Solution? Seek yourself, seek life. The quest itself is a satisfying journey and an end… Sound like philosophical mumbo-jumbo? Neuroscientist Jaak Panksepp says that of seven core instincts in the human brain (anger, fear, panic-grief, maternal care, pleasure/lust, play, and seeking), seeking is the most important. “It is your subcortical SEEKING system that helps energize your neocortex — your intellect — and prompts you to do things like buy this book and also to learn from books, if they are engaging” (Panksepp and Biven, 2012, 102). When this system is underactive, mammals feel depressed and hopeless. Evan Thompson, a philosophy professor at the University of British Columbia, says that the entire field of philosophy can be seen as an expression of this seeking impulse. … Pause. Reflect. Breathe. Cultivate Mindfulness. Introspect. Grow. Cut toxic ties. Give. Share. However, I wonder why everyone’s definition of happiness differs? Cultural and Personal Perspective Ikigai is a Japanese concept that refers to something that gives a person a sense of purpose or a reason for living. It has gained popularity in recent years and the Venn diagram is often seen making rounds on social media. The sense of fulfilment one derives from life is deeply personal and can be different. Ikigai for the older generation in Japan is to fit the standard mold of company and family” whereas the younger generation reported their ikigai to be about “dreams of what they might become in the future”. Similarly, happiness parameters change with every generation or imaginably, with every individual as well. Personally, I feel Ananda* is in compassion; in giving something. It could be back to humanity, nature, and its beings, or in general. Anything that is beyond the world of consumerism and fills you with bliss because of ‘doing’ without a thought of ‘receiving’. The receiving is in the act itself. The joy is in doing. That is my Ikigai. To my surprise, science agrees. According to a study published in Review of General Psychology, “individuals who report a greater interest in helping others, an inclination to act in a prosocial manner, or intentions to perform altruistic or courteous behaviors are more likely to rate themselves as dispositionally happy.” This doesn’t mean that you will be untouched from the other moments where bliss might seem to have evaporated into thin air. Being a human who has bills to pay and bliss to find is nothing short of walking on a tightrope. However, knowing and reminding yourself that the balance can happen if you allow it without the fear of falling or anxieties of reaching the destination, you’d know the art of joyfulness. Chasing happiness? No. Choosing happiness. *Ananda: (in Hinduism, Buddhism, and Jainism) extreme happiness, one of the highest states of being. Header Image by HalasSwiatel from Pixabay

The Immune Factor: A potential contributor to autism spectrum conditions? After almost two years of the COVID-19 pandemic, I bet we’ve all got a rough idea of how critical our immune system is. This highly organized system keeps us safe from bacteria or nasty viruses, including pluri-variant coronaviruses. It does so by orchestrating a timely and targeted immune response. Such a response comes in very handy, especially in those contexts where the odds to encounter pathogens — like bacteria/viruses — are high, for example, in social gatherings or birthday parties. The immune response and beyond… The function of the immune system, however, is not limited to fighting pathogens. There is some evidence that this system also influences the way our brain develops and works. For example, immune factors, from T-cells to cytokines, regulate the formation of brain cells and the signals that are shared among them. As a result, situations in which the immune system does not function properly may trigger a range of brain conditions. Autism spectrum conditions (ASCs) are an example of these. I am a PhD student at the Department of Forensic & Neurodevelopmental Sciences at King’s College London; with my research project entitled ‘The role of immune-related genetic factors in neurodevelopmental disorders: understanding their link to brain variability and behaviours.’, I aim to clarify the role that the immune system could play in ASCs. What are Autism spectrum conditions? ASCs are a group of conditions that usually manifest very early in life, but that last into adulthood. Over the years, there has been growing conversation around the language used to describe variations between peoples’ brains and behaviours. ASCs are just one prime example of what is known as neurodiversity. This refers to the fact that there is no definitive “normal” brain, but rather there is a “typical” one, with variations from the typical simply being “atypical”. Neurodiversity emphasises the fact that neuro-variation does not equate to neuro-deficit; humans naturally vary in cognitive ability, strengths and weaknesses. However, the variation between these strengths and weaknesses can be more pronounced in some people, which can, in turn, bring talent but can also be disabling. Autism is diagnosed in people who have considerable difficulties in social communication and in building interpersonal relationships. Additionally, people with autism may also have repetitive and inflexible behaviors or interests. Though there is much ongoing debate as to whether the increased prevalence in ASC diagnoses are due to increases in screenings thanks to greater attention being drawn to them, or the other way around, both the numbers and the social attention are interesting. We hear about them on social media, and they are even the central theme of some popular TV shows (if you subscribe to Netflix, check out Atypical). The aim of many scientists worldwide is then to understand the factors involved in ASCs with the ultimate goal to improve the quality of life of people who received a formal diagnosis and reduce the challenges they face every day. Sadly, this has turned out way more difficult than expected. What makes it very complicated is the fact that the ASCs seem to be multifactorial, which means that not one but multiple factors can cause them. This multiplicity of factors produces what we call clinical heterogeneity. To put it simply, one person with ASC can be very different from another. If one mainly has social problems, another may mostly struggle with rigid behaviors. To make things more complicated, autism symptoms often occur alongside other mental conditions, like anxiety, or non-psychiatric problems, such as metabolic syndromes. This diversity is so striking that we now wonder: what if there are different subtypes of ASCs? Different routes suggest that the immune system may have something to do with ASCs. We know now that ASCs occur when the brain does not entirely follow its usual developmental trajectory. For example, while brain cells, or neurons, are generally formed by their parent cells in a very precise and regulated manner, in ASCs we witness an overproduction of these neurons. Also, the usual balance between brain signals of excitation (a ‘go’ signal) and inhibition (conversely, a ‘stop’ signal) appears altered in ASCs. What is interesting is that the immune system and its molecules control all these processes in the brain from very early in life. We also see that immune problems, like susceptibility to viral infections or allergies, in some cases come along with symptoms of ASCs. And autoimmune disorders, which consist of misplaced attacks of the immune system towards one’s own cells, are more common in the relatives of a person with autism. Because the ASCs are so heterogenous, is it possible that these immune problems might indicate an immune-based subtype of ASCs? Can genetics tell us more about how the immune system and ASCs are related? Despite what data suggest, we still cannot say confidently that “yes, the immune system has a role in ASCs!”, I believe that genetics can be very useful here. Yeah, I mean that intricate world of genes, DNA chains, and letters that are passed on from one generation to another. Why genetics? Well, let me explain. Genes are the first-line actors in biology: they control the availability of many proteins and molecules that mediate important biological functions. Many of these genes regulate the level of immune molecules that are necessary to make the immune machine work. One thing we have now learned about ASCs is that genes have a considerable impact on these conditions. They are indeed among the most heritable neurodevelopmental conditions. Nevertheless, we still do not fully understand which are all the genes particularly important in ASCs. Hence, my question is what if genes that influence immune functioning also contribute to the brain processes and symptoms that describe ASCs? Immune genes are important to ASCs in general and to some autistic symptoms in particular. When we took a deeper look at the many genes related to ASCs, we could see that indeed some of them support the work of the immune system. For example, some genes associated with ASCs regulate the level of cytokines, small molecules, that our body produces to fight inflammation in general. Other ASC-associated genes allow instead the formation of antibodies, which are molecules created to fight a specific threat when we encounter it. Given that people with ASCs have very diverse profiles, we also studied if immune genes are more associated with one or more particular symptoms. We know that, to some degree, autism symptoms can be also found in people without a diagnosis in the form of traits. These so-called autistic-like traits represent variations in attention, rigid behavior, and sociability and they are influenced by specific genes. We, therefore, measured these autistic-like traits in people across countries and we looked at their genetic codes. By doing so, we learned that immune genes are associated with autistic-like rigidity and attention to detail. What else can we learn about ASCs by looking at immune genes? So, immune genes are associated with ASCs and autistic traits. There are however many questions that remain unsolved: do these immune genes influence the brain processes in ASCs? Can these immune genes be used to prove the case of an immune subtype of ASCs? Our research journey has just started but we hope to learn more about the role of immune genes in ASCs. This information can guide us to better define ASCs, explore any immune subtypes and evaluate the benefits of immune-based therapies. Stay tuned to see what comes next! Header Image Source: Bruno /Germany on Pixabay

When Anxiety Gets Physical I’m Alice. I’m a freelance writer and editor with anxiety and depression, fibromyalgia and functional neurological symptoms in the form of tics and muscle spasms, likely related to my fibro nonsense. I’d like to talk about my experience with anxiety and the role it’s played in shaping my physical health. All in your head? I was about 12 or 13 when I had my first panic attack on a school bus. But I didn’t recognise it as one. In fact, I wouldn’t notice the deep-set anxiety worming its way into my brain until I was at university. I have memories of being very young and feeling perpetually nauseous or being unable to sleep because my heart was pounding. These things worried me, but I felt unable to speak up about them, convinced I wouldn’t be believed. I thought it was normal to secretly hate everything about yourself, to believe everyone else hated you too, to second guess every single decision you made. All the signs were there, but I either didn’t have the language, the self-awareness, or the knowledge to recognise them. Anyone who lives with it will tell you that anxiety can have a lot of physical tells, some of which can be quite distressing and disruptive to your everyday life. Dizziness, fatigue, dry mouth, pins and needles in your hands and feet, digestive problems, chest pain, heart palpitations, forgetfulness, mental fogginess – all these can be a direct result of anxiety. It’s not just being a little too worried, and it’s never ‘all in your head’. A strong reaction to stress is the leftover of a survival instinct from our caveman days. Adrenaline makes our hearts beat faster to get the blood flowing to where it’s needed, to get us out of danger quicker. This fight-or-flight response from our autonomic nervous system (this internal system of reflexes in our brain that unconsciously regulate many bodily functions including heart rate, respiratory rate, and digestion) was developed to keep us safe, but it was only designed to be a short-term solution. When the rush of hormones from stress keeps flooding our body, over and over, the response can become damaging. We have trouble eating, sleeping, concentrating, and even breathing. We’re taking in too much information through our heightened senses and it’s overwhelming. You’re ‘Just’ Anxious When it comes to openness about mental illnesses like depression and anxiety, we’ve come a long way. We’re talking about it more on social media and with our friends and family members. Going to therapy is seen less as a thing to be ashamed of and more as an act of self-care that anyone should have access to. But we’re not all the way there. The stigma still exists — we see it in comments from others that surely we’re just not trying hard enough, or that we did something to cause it, or it’s all in our heads, or that we’d feel better if we went outside and did some exercise. This kind of thinking — which has been discussed throughout various InSPIre the Mind pieces over the years — dismisses mental health and illness, only making it harder for those struggling to share how they really feel, leaving them to believe that perhaps nobody is really hearing them. It isolates us inside our heads and makes the healing process longer. Just as frustratingly, if the physical symptoms we experience are judged as belonging to a mental illness, they are often dismissed too. While it’s true with treatment such as talk therapy, medication, and CBT, our symptoms can improve over time, the hurt they cause is all too real and all too distressing. I’ve had physical symptoms attributed to anxiety dismissed as inconsequential by some doctors and later validated by different doctors. I felt vastly different leaving these appointments. Being told what I was experiencing was real did help how I thought about and dealt with the distressing symptoms I was experiencing. How we talk about and think about all aspects of mental health matters – it never stays just in our heads. Anxiety or Chronic Illness? Often, the trouble with the physical symptoms of anxiety is that they don’t just point to anxiety. They can be unhelpfully vague and apply to a whole range of conditions and chronic illnesses. A couple of years ago, I began experiencing hip pain that suddenly spread to the whole of my body, along with fatigue and cognitive difficulties, best described as ‘brain fog’. It stopped me from doing anything except lying on the sofa or hobbling to an endless parade of hospital appointments. What was eventually thought to be a spectacularly bad case of vitamin D deficiency eventually morphed into a diagnosis of fibromyalgia – or fibro for short, as I’ll be referring to it. The main three symptoms of fibro are widespread chronic pain, fatigue, and issues with mental processes like concentration and memory, known to some as fibro fog. Another common component for many fibro patients is anxiety. Anxiety and fibro have a messy, messy involvement with each other. Fibro as a condition is not well understood. The NHS website lists it as a long-term condition, and I’ve also seen it described as a musculoskeletal condition, not a muscle condition, neurological, a mental illness, not a mental illness, an autoimmune condition, not an autoimmune condition, a chronic pain condition, and by some doctors, not even real. Anxiety is listed as a symptom of fibro, with some also suggesting anxiety itself could be a potential cause, leaving me in a particularly impossible quandary. Are my symptoms of anxiety all actually because of fibro, and it’s just that the anxiety happened to be discovered first? Did my anxiety come first and develop itself into this chronic illness? Or do these two conditions co-exist inside me, both doing their worst to torture my body and mind? I will probably never get the answer to this. When Medicine Has No Answers There can be a couple of troubling dualities when considering the links between mental and physical health – these symptoms can all be rooted in a mental illness, with no physical cause to be found and no physical treatment that would help solve them. However, this can be a painful revelation and a difficult conclusion to be left with. The mental health aspect might not be considered until all physical tests have been exhausted – or at least not given as much weight – leaving it feeling like a last resort and a way to brush off a patient there seems to be no other way of helping. In contrast, considering the tremendous stigma around mental health and its relationship with physical health, some patients may instead feel dismissed because they’re told their anxiety is causing physical symptoms that they’ve been experiencing – it’s ‘just’ because of anxiety. Do we chase a physical diagnosis because of the lingering stigma of our symptoms all being due to a mental illness? Simply put, no. The experience of the symptoms is not any less real just because the root is in our mind rather than our bodies. Other possible diagnoses for people with medically unexplained symptoms are conditions such as somatic disorders or descriptions such as functional symptoms. While this may explain their pain, fatigue, or other health concerns, there is again a level of stigma associated with these conditions which we – both patient and doctor – need to be aware of. Anyone experiencing troubling symptoms deserves reassurance, empathy and care, no matter the origin of their symptoms. Over the past couple of years, I have developed muscle spasms and tics. A referral to a neurologist led to a tentative diagnosis of functional neurological symptoms, described as a “software glitch rather than a hardware issue”. My nerves are physically normal, but the signals being sent to them, perhaps due to being in constant pain, are buggy. Other functional symptoms can include limb weakness, paralysis, seizures, tremors, blurred vision, and more. A third of new neurology patients have medically unexplained symptoms, and a study into their experience concluded their distress and disability were very real and should be taken seriously. It’s Not Our Fault For many like me, physical aspects of mental illness can leave you with a strong sense of self-blame – we must have done something ‘wrong’ to cause ourselves this pain. I believe this reveals the work we still have to do in how we think about mental illness and how we balance its importance alongside physical wellbeing. The ways it can manifest so strongly physically indicate a need for us to understand it better and take it as seriously as any other health condition. It’s common for people with chronic illnesses to have worsening mental health conditions. When you spend every day in pain and drag yourself to appointment after appointment, and see others go out and do things you’re no longer able to do, it’s natural that your mental state would suffer. And to add to the fun, higher levels of anxiety and depression are likely to also impact and worsen your physical symptoms, such as pain and fatigue. Yay. So why isn’t counselling or CBT or some kind of mental wellbeing check-in standard with chronic illness diagnosis? Why is the mental wellbeing of chronically ill patients so often overlooked? Why does it have to get to a crisis point before it enters the discussion? Given the high chance that you’re going to end up needing mental health support, surely it would make more sense for us to be given the tools at the very start of our journeys? I live in the UK, and while the NHS is incredible in so many respects, our mental health services are chronically underfunded, which is really damaging people’s wellbeing by preventing the fast access to services that they need. This isn’t the NHS’s fault, but it’s yet another indication of how little mental wellbeing is prioritised compared to physical health in our society. There is an undeniable and strong link connecting our mind and body, with evidence that stress can lower our immune systems, impact how well we fight illnesses or even respond to vaccines, and even increase our risk for cardiac conditions. When one is sick, the other is likely to follow. It’s more than past time they were both given the same level of importance.

Recognising empathy as a cornerstone for making a meaningful impact in a post-COVID world: The Shepley Parkin Empathy Award Emerging from a life of lockdowns has posed unique challenges, demonstrating the need for empathy and its extension into every aspect of life. I am a third-year medical student at King’s College London (KCL) and the inaugural winner of the Shepley Parkin Empathy Award. Worth £1000, the Shepley Parkin Empathy Award was developed by Stuart Parkin to honour his parents Janet Shepley and Derek Parkin who both trained at King’s in the 1950s, as well as reflect Stuart’s own recognition of the need for empathy. It is such an honour to have been selected as the first winner of this award in recognition of my work in the mental health sector and my university community. As I observe clinicians effortlessly integrate empathy into their clinical practice to optimise the delivery of patient-centred care, I am constantly reminded of its importance. Working in both a hospital and GP setting this past year I’ve seen a world where many of us are feeling more disconnected than ever. After speaking to patients, I noted this can partly be attributed to the repercussions of the pandemic, along with the increasing dominance of social media, and its role in distorting our perceptions of social connection. For these reasons the importance of empathy became increasingly clear to me. It is important to articulate the difference between empathy and sympathy to truly understand why empathy is so essential to our wellbeing. Brené Brown, research professor at the University of Houston who has studied empathy, beautifully illustrates this difference in her video for the Royal Society for Arts, Manufactures and Commerce. Brown describes “Empathy fuels connection. Sympathy drives disconnection.” Contrast the following responses to someone telling you they had a miscarriage: “at least you know you can get pregnant” with “I don’t even know what to say right now, I’m just so glad you told me.” To empathise, you choose vulnerability and connecting with your own experiences to form an emotional connection with someone else. To sympathise, however, we attempt to create a silver lining to reduce the personal emotional burden of a difficult conversation whilst isolating the individual experiencing their challenges. Prior to starting medical school, I volunteered as a Youth Programme Facilitator for the mental health charity Mind for three years, working as a Youth Mental Health First Aider. This gave me an opportunity to help deliver psychoeducation programmes, providing healthy coping strategies for young people with mental health conditions, along with the chance to meet others with similar experiences and build support networks. During my second year of university I furthered these skills through my General Practice placement, and thanks to the support of my GP tutor, have open conversations about mental health with patients. I have seen how an empathetic approach facilitates the development of rapport between healthcare professionals and patients, increasing patient confidence in clinicians. In turn this can make difficult conversations easier, and ultimately improve the patient journey and experience. Engaging with wider university life has always been something I have been passionate about and found immensely rewarding. As the 20/21 Sponsorship Officer for the Medical Students’ Association (MSA) at KCL, I secured over £2000 to support our work representing all medical students at the university, and built new partnerships with local businesses to support the local community. Listening to peers and reflecting on my own experiences of virtual learning last academic year, I created collaborations between the MSA and medical education organisations to deliver free webinars during the pandemic. The goal was to support students at King’s and beyond in developing their clinical knowledge amidst the pandemic. As someone who has received immense support from medical students further along the course, I have always strived to help others in the same way and be an approachable person that friends and colleagues can turn to. For these reasons, I was delighted to hear that some of my peers nominated me for the award! Collectively, society has made tremendous progress in challenging outdated and inappropriate views on mental health, however, there is continuous room for improvement. As the current MSA Vice President for Welfare, I am committed to making a lasting impact on my university community, supporting my team in breaking the stigma surrounding mental health in medical school. My goal is to ensure every student knows they are supported through welfare initiatives integrated throughout the academic year. Having empathy is invaluable within every field of medicine and I look forward to seeing this and furthering it myself during my future placements this coming academic year and beyond. Header Image Source: Tim Mossholder on unsplash

Addiction: The depths and the recovery with professional boxer Charlie Duffield In my twenties, I suffered from a gambling addiction that plagued my life until my early thirties. Dealing with this addiction daily, I have become intrigued by how others deal with their addiction to gambling and how it has affected their lives. Facing my addiction through talking to others has helped me significantly. I recently had an intimate chat with Charlie Duffield, a professional boxer and ex gambling addict. Here is his story. The 33-year-old Canning Town-born professional boxer, Charlie Duffield, battles addiction daily and refuses to give in. I decided to approach Charlie Duffield about an interview after seeing a post on his Twitter account from July 16, 2019, about his struggles. What is addiction and the problems of gambling: According to the NHS website, addiction is defined as “not having control over doing, taking or using something to the point where it could be harmful to you”. Gambling is becoming an enormous problem in society. According to a BBC report, as many as 1% of the population has a problem with gambling. The same BBC report stated that, in the year to March 2019, UK gamblers lost £14.4 billion. This is an alarming statistic that shows many lives are being affected. Gambling is seen by many as a form of escapism — an avoidance mechanism to distract someone from an uncomfortable situation. I found from personal experience that addiction grabs hold of you, and as you will read in this interview, it can damage your life and those around you. About Charlie’s addiction “I have battled this addiction for a long time. On occasions, I did not know who or where to turn to for help. It was so stressful”. Charlie continued: “I would lie to cover up the mess I was making. It took a toll on my mental health. I was lying to all the people that loved me”. The way he talked about lying to cover his gambling is a familiar story to most addicts. When I asked Charlie the reason behind his lies, he replied without hesitation: “I felt ashamed. I did not know how to begin to explain the hole I was in.” How talking about his addiction helped Charlie Many addicts struggle to open up about their addiction, and I wanted to ask Charlie how opening up had helped him. “Yes, I felt like as soon as I spoke out for the first time, I could finally breathe”. Charlie added: “I began to feel relief. I was always scared about speaking up, but when I did, it was so therapeutic.” The power of opening-up “One day I had enough, I broke down to my wife Carly and my little brother Frankie. I had to tell them. I couldn’t lie to my wife anymore.” Charlie continued: “Carly was becoming suspicious. We would be saving money, and I would be spending it. We were trying to save for our wedding, and I was losing so much on roulette machines.” He added emotionally: “When I told Carly and Frankie, I just broke down. It was horrible having to tell them how bad my addiction was. But looking back, it was the first step for me. Without my family and friends, I genuinely do not know where I would be. They have given me the support I needed and an incentive to change and be a better man.” Charlie continued: “I am so lucky to have a devoted wife, a loving family, and some very loyal friends. Before I opened up, I had a constant feeling that I was alone.” According to the NHS website, cognitive behavioural therapy (CBT) is proven to have a positive impact on all addictions, not only gambling. Talking to your GP about options could be the first step for many people. There are other places to turn to: Gamcare is the leading non-profit provider of support for any affected by problematic gambling — and run face-to-face therapy sessions across the country. More on this at the end of this blog, where I share sources that can help you or anyone struggling with addiction. Gambling addiction frequently spawns from a life-changing event: a relationship break-up, the death of a loved one or traumatic childhood events. There may be other reasons, such as ambition for more money or unaddressed psychological issues. Finding the reason behind the start of the addiction is key to recovery. Dealing with loss A major life event impacted Charlie’s mental health severely and sent him further down the path of gambling. Charlie went through the heartbreak of losing his brother Dean to suicide. “I watched him go from the life and soul of the party to the very pits of despair.” He added: “I wanted to save him, but I couldn’t. I didn’t know how bad things were.” While dealing with the devastating loss of his brother, Charlie’s gambling addiction was fast becoming a bigger problem than ever. Charlie was grieving for his brother and used gambling as a form of escapism. Before beginning to deal with his gambling addiction, Charlie confessed to considering committing suicide. Hearing Charlie talk about taking his own life stopped me in my tracks. The importance of having a healthy outlet Many people suffering from mental health issues and dealing with addictions often talk about a void in their life. Charlie seemed to realise boxing could be his outlet and the importance of Mark Tibbs, his trainer, in his continued recovery is evident in his words. “Boxing has been and continues to be the therapy I need. I wish I had the strong team in my early twenties that I have around me now. I needed Mark Tibbs back then. He would have kept me in check.” Charlie added: “I am so lucky to have boxing and Mark in my life, keeping me focused on my career and personal life. I still have my bad days. But when I am in the Peacock Gym — I am a lot more positive.” Helping others Charlie is now an official ambassador for CALM (Campaign Against Living Miserably), a mental health organisation leading a movement against suicide. I asked him what being an ambassador for CALM means to him? He drifted away for a moment of clarity and said poignantly: “It’s an honour.” Charlie spreads positivity through his Twitter account, @CharlDuffield1. After struggling in silence for so long, he now encourages people to open up and talk. Charlie loves boxing — and uses the sport as a healthy outlet. He is living proof that finding your outlet can help you deal with your addiction, one day at a time. If you are struggling and in need of support, below are a few incredibly helpful organisations that provide both resources and direct help: Shout Crisis Text Line — you can text Shout to 85258 if you are experiencing a personal crisis, are unable to cope and need support. Talk to Samaritans — they offer 24-hour emotional support in full confidence. You can call them for free on 116 123 CALM (Campaign Against Living Miserably) offers a chat and hotlines service from 5 pm till midnight Papyrus (Suicide Prevention Charity) offers similar service for adolescents and young adults under the age of 35 Talk to your GP If you are in need of support for problematic gambling, below are some helpful organisations that can provide support and resources: Gamcare is the leading provider of information and support for anyone harmed by gambling. They can be contacted 24 hours a day, every day of the year by calling them free on 0808 8020 133. Gamblers Anonymous is a group of men and women who have joined together to do something about their own gambling problem and to help other gamblers. You can find out more by emailing them at info@gamblersanonymous.org.uk. You can also call their National information line on 0330 094 0322

I am a child and adolescent psychiatrist and neuroscientist working with the Stress, Psychiatry, and Immunology Laboratory (the team that bring you Inspire the Mind ), as well as the Mind-Body Interface Laboratory (MBI-Lab) at China Medical University Hospital in Taiwan. My research interests include nutritional psychiatric research in children and adolescents with a special focus on attention deficit hyperactivity disorder (ADHD) and omega-3 fatty acids. I have previously written about ADHD for InSPIre the mind, “More Fish, Better Attention? It Really Depends”, and “The missing pieces of the ADHD Puzzle: inflammation, neurotrophin, and cortisol?”. In this latest piece, I will discuss our recently published meta-analysis that looked at cortisol levels and inflammatory biomarkers in children with ADHD. You can read the full paper in Translational Psychiatry. Attention deficit hyperactivity disorder (ADHD) is a common childhood disorder with a global prevalence rate of 5–10%. Children with ADHD often present with symptoms such as inattention, hyperactivity, and impulsivity. They often have difficulty sitting still in class, are easily distracted by noises or actions of other classmates, and are often unable to complete tests or homework assignments on time. This inattention and hyperactivity can sometimes result in a slip in academic grades, in frequent fights with peers, or in constant quarrels with their parents. All of which may lead the individual to have increased feelings of stress, anxiety, ill-health and helplessness, and decreased communication with their parents. ADHD has been linked with an imbalance of several biological systems, including the hypothalamus-pituitary-adrenal (HPA) axis and inflammation, however, what the science tells us so far has been inconsistent. Dysregulation of the HPA axis (reflected in the levels of cortisol) has been suggested to play a role in ADHD. The HPA axis is important for our survival in that it helps to decide whether we should fight or flight in the context of danger. For example, when we see a bear ready to attack us during a hike, our brain and body will process the information for us swiftly and we make a decision in the moment whether to fight the bear head-on with the tree branch next to our feet or to run for our lives! Cortisol, also known as the stress hormone, will be released into our bloodstream when we are under great stress such as this, when we engage in situations that will elicit the fight or flight response. Interestingly, an inadequate amount of cortisol has been associated with poor cognitive development in children, and too little cortisol has also been associated with novelty-seeking behaviors (activities that may involve risk-taking in search for new experiences), commonly seen in children with ADHD. Inflammation, on the other hand, is a result of the protective reaction of our body when we are trying to fight off foreign invaders, such as bacteria and viruses, and to heal injuries. However, prolonged inflammation or chronic inflammation may be harmful, leaving our bodies in a constant state of alertness. This has a negative impact on our tissues and organs, including the developing brain and cognitive function. The state of inflammation in our body can be indicated by inflammatory biomarkers. Biomarkers are the biological molecules found in blood, other body fluids, or tissues that are signs s of a normal or abnormal process, or of a condition or disease, and can be used to see how well the body responds to a treatment for a disease or condition. For example, an increase or decrease in the levels of inflammation biomarkers (such as C-reactive protein (CRP) or interleukin-6 (Il-6)) may be used to tell us if our body has an imbalance in the inflammation process. Children with ADHD have also been suggested to have more comorbidities with chronic inflammatory diseases, such as allergic rhinitis and atopic dermatitis. The results of the existing research on the levels of cortisol and inflammatory biomarkers have been mixed where some children with ADHD have lower levels while others have no difference in levels than typically developing children. Our recently published meta-analysis examined the levels of cortisol (upon awakening, noon, 6 pm, and before bedtime) and inflammatory biomarkers (Interleukin-1β (IL-1β), IL-6, IL-10 and tumor necrosis factor-alpha (TNF-α)) across 19 studies in 916 children with ADHD and 947 typically developing children. In addition, we also looked at the cortisol levels collected at different time-points throughout the day to see if changes during the day have an effect on the cortisol levels in these children. In fact, cortisol levels tend to follow a pattern across the day, reaching its peak within an hour after waking and declining thereafter, until reaching the lowest point at approximately midnight. Interestingly, we found that children with ADHD, when compared to typically developing children, have lower baseline cortisol levels (from both salivary and blood samples). This may further suggest the children with ADHD have an off-balanced HPA-axis to fight against stress. Children with ADHD also have lower morning cortisol levels, especially awakening cortisol levels, but not lower afternoon cortisol levels, than typically developing children. This is exciting news, since, in the near future, a simple morning spit of saliva may perhaps be able to tell the difference between a child with ADHD and a typically developing child. The finding of lower morning cortisol levels in children with ADHD suggests that there may be an altered diurnal rhythm of cortisol levels in children with ADHD, where children with ADHD require a longer time for their cortisol to peak in the morning. This may help explain why children with ADHD may feel more tired in the morning and have a harder time waking for activities like school. We also found that children with ADHD have lower levels of inflammatory biomarkers, in this case, measured by TNF-α, than children without ADHD. This tells us that children with ADHD may have an imbalanced inflammation system. Another interesting finding is that differences in the DNA sequences of the TNF-α gene have also been associated with attention measures in children with ADHD. A gene is the basic physical and functional unit of our heredity (the sum of all biological processes by which particular characteristics are transmitted from parents to their offspring) and is made up of DNA. Investigating TNF-α, as well as their genomic sequences should be an important consideration in future ADHD studies to clarify its role in ADHD. Well, it seems that children with ADHD have an altered diurnal cortisol rhythm presented with a lower morning cortisol level measured in the salivary sample and an atypical manifestation of inflammation biomarker levels from our current research. However, more research is needed to investigate how to recover the altered diurnal rhythm of cortisol levels and restore the balance to the inflammation system in children with ADHD, in order to improve their clinical symptoms and help them keep the balance in their lives. I look forward to sharing more with you on the research findings on the association between the changes in cortisol levels and inflammatory biomarkers and ADHD treatments in the near future!

So many of our greatest successes start from a dark place Watching a TV program about 1995, I realized that year held some of the darkest moments of my life. I was not long out of the army, suffering from post-traumatic stress disorder (PTSD) and full of the doubt that accompanies a soldier heading into civilian life. Look After The Basics. In my early years, I was a happy and gentle child. It was a time largely punctuated by the family holidays which we spent at a caravan site on the southwest coast of Scotland. Among the rocks of the rugged coastline, I found a love of nature and the outdoors and nurtured an ever-increasing sense of adventure. I left school in 1983 and, after a brief spell of casual work as a laborer, I soon found myself unemployed. Life quickly descended into chaos: I would spend a few days drinking heavily when the unemployment cheque came in, and after the money from that was spent, I would then have to survive with no money and little food until the next cheque came in. I became depressed, stopped looking after myself, and lost all sense of self-esteem. Looking in the mirror, I was barely able to recognize the carefree adventurer of my childhood. The turning point came for me when I refused to accept the person that I saw in my reflection: bleary-eyed, hungover, and scruffy. I was better than that and I knew it. In the early 80s, Margaret Thatcher’s government was looking after the police and the army. I joined the army in 1984 at the age of 17. Respect for and looking after ourselves and each other was drummed into us during basic military training. We learned the value of sleep, proper and regular eating, hygiene, and cleanliness. Where before I held little value in myself or regard for the people around me, just the fact that we were constantly part of a team in Basic Training made me see a value in myself in so much as I was contributing to the team. The constant physical demands of the training helped us all to realize the value of getting sleep when we could and making sure we were well fed. I hadn’t really cared much about looking after myself before I joined the army but within just a few short months I emerged into an army career as a confident, physically fit, and well-presented young man. Look For The Light In The Darkness. I returned to civilian life after 10 years of military service and an 18-month tour of duty in Northern Ireland, at the time in deep political turmoil. By going there, I had hoped I might be able to have some influence, however small, on helping people find a more tolerant and peaceful way of life. Though physically unharmed I had been destroyed spiritually and mentally by the evil and the violence I had experienced around me and the ways in which I had reacted to it. Of course, the suffering and death, physical injuries, and the adverse mental effects of the conflict such as PTSD were not confined just to the soldiers. Catholic or Protestant, military or civilian, we all suffered the consequences of that conflict. For 4 years afterward, I was hyper-alert, full of anxiety, and depressed. I drunk heavily often to try and forget. Such a far cry from the carefree child who loved the world around me and completely trusted the people in it. The turning point at that time was when I decided I was not to let my problems detract from me being the best dad I could be to my three young daughters. The light of that love shone out of the darkness and enabled me to temporarily bury my problems. When they needed it in their young lives, I was able to be the fun guy with all the answers. Remember Those Who Love You. As our children grew up, my wife and I started to grow apart. Our marriage had worked because we both wanted to raise a family and we focused on the children. Without them to focus on, we were different people with different dreams. I soon found myself alone in a new flat coming to terms with the guilt of breaking up our marriage. I felt like my whole life plan had been a failure. Again, I turned to drink and sunk deep into depression. My self-value plummeted. My daughters understood and accepted why their parents had separated and kept themselves close to both of us. No matter how much I hated myself, the realization that they loved me saved me and helped me to turn my life around once more. It’s Never Too Late To Get Help. Twenty-five years after I left the army, I was asked to attend a business meeting in Belfast. This brought on a huge anxiety attack as my memories from the conflict in Northern Ireland came flooding back. By the time I eventually took time off work and went to see my GP, I was physically and mentally exhausted and deeply depressed. I remember feeling at the time that I wasn’t sure whether I was more afraid of going to sleep at night or waking up in the morning. When I went to bed, I lay awake most of the time worrying about problems I needed to solve at work. I was constantly on edge and often felt physically sick. I was diagnosed with anxiety and depression and put on a prescription of sertraline. Due to the nature of the medication, it increased my sense of anxiety for a few weeks until it settled into my system. Once settled, it certainly took the edge off my anxiety and my sleep improved. Initially, I was referred to a Psychologist on the NHS for Cognitive Behaviour Therapy (CBT) to control my anxiety. After my initial session, however, my psychologist recommended counseling to try and address the root of the problems which were causing my anxiety. Counseling wasn’t easy. Doors in my mind were opened that I’d kept locked for decades. I had to deal with the emotions and guilt that I’d spent my life repressing. In the end, however, the process helped me to understand and accept emotions and forgive myself for things I had thought and done. I emerged from the process more at peace with myself than I had been for decades. Lessons Learned These are the lessons that I have learned in my journey: Get counseling as soon as you think you need it. Serving in the military even in peacetime involves a life where danger is commonplace. During armed combat, even if not directly coming under fire, we experience things that affect us deeply yet which no one outside of combat could ever understand. The combination of these factors often leads to complex mental health issues which we simply can’t unravel by ourselves. You are amazing, somebody cares, and somebody loves you. If you can’t find your own strength to get back up, that’s OK. The strength is there in the hearts of the people who love you and it’s more than enough to get you back on your feet. Be gentle with yourself and don’t get too caught up in how you came to be down in the first place. The rigors of life knock everyone down at some point. What’s important is picking yourself back up again. So many of our greatest successes start from a dark place.

I am a researcher at the Stress, Psychiatry and Immunology (SPI) Lab at Kings College London, a Nutritionist and part of the team that brings you InSPIre the Mind. I am also in the final stages of my Ph.D. research, which looks at the associations between modifiable health behaviors, such as diet, and their associations with mental health in children and adolescents. I’m particularly interested in advances in the field of nutritional psychiatry. Longer-term, I want to understand the mechanisms, at the level of the body and the brain, underlying the effect of nutrition on mental health. Especially in the crucial early years! WHAT DO WE KNOW SO FAR? Let’s start with inflammation, you have probably all heard of and experienced inflammation in some form. Like when a wound swells up, turns red, and hurts — that’s inflammation! It is a physiological response to cellular and tissue damage, designed to protect the host from bacteria, viruses, and infections by eliminating the bad guys (pathogens), promoting cellular repair, and restoring balance internally — our internal hero! However, a prolonged inflammatory state termed by scientists as chronic low-grade inflammation that persists day in and day out has the opposite effect — including irreparable damage to tissues and organs, and increased risk of disease status — our internal villain… Interestingly, science has started to show that there is a precise biological mechanism that links the physical response to inflammation, to a behavioral response — in other words, it also affects our mental health. This is explained very nicely here in a previous piece by my colleague Dr. Nettis. So, in its villainous role, inflammation can go from the body to the brain and has been established as a risk factor for several neuropsychiatric disorders such as ADHD, depression, and schizophrenia, including in children and adolescents. Interestingly, this presents an opportunity! Inflammation is therefore an important therapeutic target to study. But what causes our hero to turn into a villain? What triggers a state of chronic low-grade inflammation in children and adolescents? Well, the potential factors are diverse. Stressors such as trauma through adverse childhood experiences, psychosocial stress, as well as modifiable lifestyle sources such as limited physical exercise or smoking are all capable of evoking a deleterious inflammatory response. So then, can diet? Overall, it is well established that a healthy diet in childhood and adolescence is crucial for physical health including optimal growth and development and for disease prevention. In terms of mental health, scientists are also starting to show associations between a higher quality dietary intake and a reduced risk of adverse mental health outcomes in both children and adolescents. However, many questions remain unanswered. Including, why and how dietary pattern intake and/or specific nutrients can exert a positive or negative effect on mental health outcomes, and why these effects are stronger in some people than in others. To answer these questions we need an understanding of the key biological mechanisms underpinning these pathways. Bringing it all together, since we know that inflammation can influence mental health, and dietary intake is associated with mental health — is the missing link in the biological pathway inflammation? Does dietary intake influence inflammation in children and adolescents? And if so, how? WHERE TO NEXT? So, we decided to conduct what is known as a systematic review — essentially seeking out all available, existing research on a topic that we want to learn more about and distilling it down to some key findings. The literature is selected and studied collectively with pre-specified criteria in mind. This helps us to identify patterns, similarities, and differences in the findings and then draw conclusions and derive new hypotheses for future study directions. After an intense process of sifting through 10,611 (to be precise!) potential scientific papers we whittled down the relevant body of literature that fit our criteria to 53 papers and set about teasing out the key messages. WHAT DID WE LEARN? You can read the full breadth of my findings in the systematic review, which is in fact the first systematic review to be published that examines dietary intake and biological markers of inflammation in both children and adolescents. Before we continue, you might be asking what are biological markers of inflammation? Briefly, these markers, including C-reactive protein (CRP) and cytokines analyzed from blood samples circulate in the body when inflammation is triggered. These small proteins are messengers released to inform the body an infection needs fighting, they are important signaling molecules in the immune response — our hero! For scientists, they are an important indication of levels of inflammation. An over-production of cytokines is indicative of a pro-inflammatory state through chronic low-grade inflammation, which can have deleterious results including irreparable damage to tissues and organs, and increased risk of diseased states. Our villain! So what did I find in the research with regards to dietary intake and inflammation in children and adolescents — does it foster the hero or the villain? Certainly, healthy dietary patterns of high quality, such as adherence to a Mediterranean Diet, rich in vegetables, fruit, whole grains, legumes, nuts, fish, and low-fat dairy, coupled with low intakes of red meat and adequate intakes of healthy fats such as omega-3 polyunsaturated fatty acids (omega-3 PUFA’s which you might know as “fish oil”), has been shown to reduce systemic inflammation. As well, studies that had examined the individual constituents of such healthful patterns separately including vegetables and fruit, healthy fats like omega-3 polyunsaturated fatty acids (PUFAs) or vitamins C and E also showed positive results, whereby high intakes of these individual constituents were associated with decreased levels of circulating inflammatory biomarkers. In fact, research from our own lab has demonstrated omega-3 PUFAs, regulate the immune response by inhibiting the activation of pro-inflammatory pathways and reducing cytokine expression. Other colleagues have also demonstrated intake of a high-dose eicosapentaenoic acid (an omega-3 fatty acid) improves cognitive symptoms (symptoms associated with impaired memory and learning) in Attention Deficit Hyperactivity Disorder (ADHD) youth that have lower than optimal levels of EPA evident in their blood. Lastly, our research in animal models has demonstrated inflammation-induced reductions in neurogenesis (production of neurons) can be prevented through omega-3 PUFAs intake. SEEMS DIET FOSTERS THE HERO? Not so fast, it can also foster the villain… In contrast to a healthful dietary pattern, the Western dietary pattern which is comprised of high intakes of ultra-processed foods like potato chips, cakes, and sweetened breakfast cereals, sodium (salt), and foods that contain trans- and saturated fatty acids like fried fast foods elicits a pro-inflammatory response and increases levels of circulating inflammatory biomarkers. Similarly, across the studies included in my review that examined the Dietary Inflammatory Index (DII), a tool that assesses the inflammatory potential of a diet, I found that diets with high inflammatory potential (a higher score in the DII), inducing a higher inflammatory response, increased pro-inflammatory biomarkers. WHAT DOES ALL THIS MEAN? Well, in children and adolescents a good quality diet, high in vegetable and fruit intake, whole grains, fiber, and healthy fats is essential for optimal growth, development, and the amelioration of low-grade inflammation — aka, fosters our inner hero! Further, modifying dietary intake as early as during childhood and adolescence to encompass high quality, nutrient-dense foods represents an important and promising therapeutic strategy in order to maintain a regular immune response and to reduce the risk of adverse mental health disorders and associated co- and multi-morbid conditions later in life. Indeed, as Professor Pariante discussed in his piece last year focussed on the retraction of free school meals during lock-down, even mild undernutrition through poor quality diets has far-reaching mental, physical and social problems in children and adolescents, with overall effects that can last two to three generations. However, further interventional research (experimental studies) is needed to establish the strength of associations between dietary intake and inflammatory biomarkers and subsequently mental health outcomes, and ultimately to develop a better understanding of the exact biological mechanisms underlying and attenuating such associations. This will enable the development of the optimal therapeutic solution. Put plainly, we need more information on exactly why and how dietary pattern intake and/or specific nutrients exert a positive effect on physical and mental health outcomes in children and adolescents, and why they work better in some patients than in others. I look forward to finding out!