Brain Ponderings podcast with Mark Mattson

The usual approach for developing treatments for brain disorders is to make a drug that acts on a specific molecular target. But this approach has largely failed. In this episode I talk with Professor Raj Ratan at Weill Cornell Medicine about ways to tap the intrinsic ability of brain cells to respond adaptively to challenges – metabolic, oxidative, and biosynthetic – in ways that protect them against pathological processes such as those occurring in stroke, traumatic brain injury, Alzheimer’s and Parkinson’s diseases.  Raj and his colleagues have developed several different interventions that are highly effective in animal models of stroke and Alzheimer’s disease. Intermittent dosing with such treatments can activate evolutionarily conserved complex and integrated gene expression responses in brain cells that bolster stress resistance and enable recovery and repair. LINKS  Dr. Ratan’s laboratory webpage: https://burke.weill.cornell.edu/ratan-lab/people/rajiv-r-ratan-md-phd  Selenium protects against ferroptosis and stroke: https://www.cell.com/action/showPdf?pii=S0092-8674%2819%2930327-7  HIF prolyl hydroxylase inhibition for stroke ?: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390817/pdf/jcbfm201228a.pdf  2-deoxyglucose for experimental stroke and Alzheimer’s disease: https://pdf.sciencedirectassets.com/272195/1-s2.0-S0896627322X00196/1-s2.0-S0896627323004725/main.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEDMaCXVzLWVhc3QtMSJHMEUCIC02vyvj45WOEJ6cJ%2BO3zLTkbyrmywu3UV2k0tE99ISSAiEAm%2B2Ga7NWSJSMResvqmDJZn87epQuNnoQNFUS%2FM1xh1QquwUIvP%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FARAFGgwwNTkwMDM1NDY4NjUiDKWhJaRjapFKYPcUuSqPBXZt7z6Y%2F%2FFQDTJZNd63uYfGqFnqQ5FraRDyTiOoShRDuHZ%2FFurOQBeXcKh34xKHbYXG3aw4aZ1qknn5rmr5oZKXJEnQKSDQbTIMaZfam7JN223W98JHQjFExQSg1IpIXsJIOpPDRC6SnxewO9HWfK5VsT22Yd1%2FvfyJ6TNHysLd5avZUcCzNwd1Tzg%2F7n5boUZ3bv8ksKJTbXKIa6URMIpJ1Elry%2Bx2cOHHsudyKQHl38MnqJfyBDlsvlSdlvPvqZyiDl41UPQ4wQXG8zxZKtwc4W9Nz3bBDtosARXGGykFw5PGjP8vljwzBmpAIPA2vntVuzKB1GVCjSOPeZIfB%2FT7gbpjO6XFPulqMJfoZSHMIP6U5%2Baluyz25U7gQI0DlHQuqHHQlPp16W1%2FZUDpV6qfCWLDFa86hE3Mk2bUdhVxC7%2F1avNNvRjCVubyOhIY9MrjdQSpJx5FCd9yj2KkOAQSxn0T8ZQ2HZl10eOzNJBv0flA%2BQXys58UySTYb0QHKIOrD1YbjW0M%2B1qrdzwunAYlpugxnqm64BMuZL1aUWPQUzD6Xu59k23wj9IKZ7ysz8OJgHiaxCL%2BmrhMtF1wBO5rkKomJdordmx%2B46wjknrwW9sUy4NFS74JkUYhIGjiZ1lQ6E%2BFcjJe1R%2FeLOfxx2VfcbXyzyjaVgNaS16fRYydqoT0r1xth2rMdDADuFYvT1Mxw909AAZ6ja4ur%2Bcb56eAT7kbwtKDDsTq3l%2FlTVEwX8zAkagg%2Ba2yg2RUF26zTiA9ur%2FR1keAROBxVFyOyhBFg0tX2aHFaPkRmbTLOOeslpmFdWYlYhhLn%2FDgHzXafbqJ6MS29hnDJVpSZNwtkILsv6Fvf7MlT%2FU%2Fdet6sI4w6oKBswY6sQGQdr%2Fyh54qyfoNjp7vTeWRp56lw26rZzdq5JzhPL7AooWioriINJoD5PBTfQ6P9kkjgrbt3KgE0gLwdquV5t8cPemG6Ud6J7FFfiCqdduYGnkdgvqay00lKumUQWivFmbLK1KwV3ZTiHqK6k%2BnwmjmJx6TC2wOb0ri18vlPuaf9tL3twxztVgBXpqCEHtrk2xoln3A%2FxRta1ENiKDj3i%2BeEJsq8LA5%2Ft1DnHnQTTngNeI%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20240605T120054Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYTBFTALVN%2F20240605%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=a28ce7980230f4e238a2b9b01639b4a3771986228a5b71afee77812caae7ec5a&hash=2c8062367af976e82b072e2c70fee70c72e3b4c101e00ffb8e600353969e084d&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0896627323004725&tid=spdf-39789cb0-1edf-4028-964c-0b8b685189bb&sid=957e62f0674d764d5259d1032c07123fda92gxrqa&type=client&tsoh=d3d3LXNjaWVuY2VkaXJlY3QtY29tLnByb3h5MS5saWJyYXJ5LmpodS5lZHU%3D&ua=0f105b59005f5e555053&rr=88f00141e8697283&cc=us

Anxiety, attention-deficit disorder, depression and loneliness have increased dramatically recently as a result, at least in part, of information overload and a relative lack of time for ‘slow thinking’ and self-reflection. In this episode I talk with University of Wisconsin Professor Richard (Richie) Davidson about his research on mindfulness meditation and the neuroscience of happiness. His research has shown that mental well being is a skill that can be learned. He describes the effects of meditation on neuronal networks and well being and talks about ‘the four pillars of a healthy mind: attentiveness, communication, insight, and purpose. He and his colleagues have developed a free App called ‘The Healthy Minds Program’ which has been demonstrated to be effective in bolstering these four pillars.  LINKS Center for Healthy Minds:  https://centerhealthyminds.org Free Healthy Minds Program App: https://hminnovations.org/meditation-app?gad_source=1 Review articles on mindfulness-based intervention research: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609495/pdf/nihms-1521077.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597263/pdf/nihms-1025535.pdf Review article on challenges in research on mindfulness and meditation: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627495/pdf/nihms704718.pdf  

Many of the drugs that are used recreationally or prescribed by physicians were originally isolated from plants. Increasing evidence suggest that in many instances the function of such phytochemicals is to communicate with insects and other organisms in ways that enhance the fitness of the plants.  Pamela Maher at the Salk Institute has been working to identify phytochemicals that can protect neurons from being damaged in experimental models of neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s disease.. Here she talks about several phytochemicals that are particularly promising including fisetin, sterubin, cannabinol, and a synthetic derivative of fisetin called CMS121.   LINKS: Fisetin: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990461/pdf/bpl-6-bpl200104.pdf Sterubin: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309122/pdf/main.pdf CMS121: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394765/pdf/main.pdf Cannabinol: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11002867/pdf/main.pdf Perspective article on neuroprotective phytochemicals: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841445/pdf/nihms946635.pdf

In this episode I talk with Professor Sandrine Thuret at Kings College London about her research on how different molecules in the diet affect neuroplasticity in general and hippocampal neurogenesis in particular. She has shown in preclinical studies that certain dietary factor including omega-3 fatty acids can counteract the adverse effects of chronic psychological stress on neurogenesis. She has also shown that intermittent fasting enhances hippocampal neurogenesis and improves cognition. Thuret has also found that factors circulating in the blood can either enhance or inhibit neurogenesis, and may either promote brain health or contribute to brain dysfunction in disorders such as depression and Alzheimer’s disease.  LINKS: Effects of intermittent fasting on neurogenesis and memory: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760057/pdf/41380_2021_Article_1102.pdf Omega-3 fatty acids and neurogenesis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341841/pdf/41398_2020_Article_908.pdf Phytochemicals and brain resilience: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081729/pdf/pr.113.007757.pdf Serum factors: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10151193/pdf/awac472.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8612606/pdf/ad-12-8-2151.pdf

Professor John Cryan discusses gut microbiome-brain communication in health and disease, emphasizing the impacts of diet, lifestyle, and gut bacteria on brain health. The podcast explores the mechanisms of microbial influence on the brain involving the vagus nerve and bacterial chemicals. Topics include optimizing gut bacterial composition for lifelong brain health, treatment of neurological disorders, and the importance of fermented foods and fiber.

David Nutt has made major contributions to understanding mechanisms by which psychoactive drugs affect the brain and has conducted numerous clinical trials of a wide range of drugs in patients with various mental disorders.  He has also been an outspoken critic of the disconnect between drug science and government drug policies. For example, alcohol is legal, widely available, and causes tremendous harm to individuals and society.  On the other hand psychedelics are illegal and yet very safe and can be very beneficial for mental health. In this episode I talk with Professor Nutt about the relative harms and benefits of different drugs to individuals and society.  His efforts and those of many other scientists and psychiatrists are pushing governments to accept the facts and help facilitate rather than obstruct science-based progress in drug research and use of that knowledge for medicine and society.  David Nutt is a distinguished professor in the Division of Brain Sciences at Imperial College in London.  He is the founder and chairman of Drug Science and host of the Drug Science Podcast.  LINKS: Drug Science website: https://www.drugscience.org.uk/drug-information/?gad_source=1&gclid=CjwKCAjwuJ2xBhA3EiwAMVjkVG_peCbmMCI9tKIYTUldYjmfjHNxCLeLX2WYvkLPezA7zaJpciU8HhoCGHcQAvD_BwE Drug Science podcast: https://open.spotify.com/show/2hLSRIS777SKphWxv4HyDK  Recent relevant articles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10291338/pdf/fpsyt-14-1183740.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9669276/pdf/fpsyt-13-1027159.pdf https://www.sciencedirect.com/science/article/pii/S0028390822003161?via%3Dihub https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625009/pdf/nutrients-13-03938.pdf

Some elderly individuals remain cognitively ‘sharp as a tack’ despite the accumulation of large amounts of amyloid in their brains, whereas others exhibit profound cognitive impairment with less amyloid pathology.  In this episode Columbia University Professor Yaakov Stern talks about the concepts of ‘cognitive reserve’ and ‘brain maintenance’ and how he and others have elucidated factors that explain individual differences in cognitive trajectories during aging. The data show that regular exercise and intellectually challenging endeavors promote successful brain aging in the absence or presence of Alzheimer’s disease pathology. We also discuss neural mechanisms that may explain cognitive reserve and brain maintenance during aging.  LINKS: Professor Stern’s webpage at Columbia University: https://www.neurology.columbia.edu/profile/yaakov-stern-phd Review articles on cognitive reserve and brain maintenance: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507991/pdf/nihms416640.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517622/pdf/acab049.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859943/pdf/nihms-1530897.pdf

What are the foundational principles by which acquired information is organized and processed in the human brain?  In this episode University of Rome Professor Anna Borghi talks about several prominent working theories of cognition including embodied cognition (interactions with objects and other people), inner speech, and abstract concepts. She talks about how language is a prominent feature of these theories and the methods used to test these theories. We also touch on evolutionary and developmental perspectives that help explain these cognitive abilities.  LINKS The embodied mind extended: using words as social tools: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640182/pdf/fpsyg-04-00214.pdf Inner speech: https://www.cell.com/action/showPdf?pii=S1364-6613%2823%2900210-3 Abstract concepts: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9674746/pdf/426_2022_Article_1698.pdf

Traumatic brain injuries (TBI) are a major cause of long-term disability and burden on families and health care systems.  University of Cambridge Professor David Menon is a leader in global efforts to better understand and treat TBI.  In this episode Dr. Menon talks about what happens to neurons, glial cells, and blood vessels in the brain after a TBI.  He explains risk factors for TBI, how patients with TBI are currently evaluated and treated, and emerging therapeutic interventions to enhance their recovery. LINKS Review articles on TBI https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10427240/pdf/nihms-1921257.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253145/pdf/12028_2020_Article_994.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10809021/?report=printable  

Mitochondria are best known as the powerplants within cells. But recent research is revealing that mitochondria play fundamental roles in regulating the structure and function of neuronal networks and the behaviors that those networks control. Martin Picard directs the Mitochondrial Psychobiology Group at Columbia University. In this episode I talk with Dr. Picard about: the biogenesis and movement of mitochondria within cells, the disposal of damaged mitochondria, the diversity of mitochondria within and amongst neurons in the brain, how this diversity contributes to neuroplasticity, and how aberrancies in mitochondria are involved in mental and neurodegenerative disorders. We also talk about how ‘bad’ and ‘good’ stress affect mitochondria.  LINKS: Reviews on Mitochondrial Diversity and Psychobiology: file:///Users/markmattson/Downloads/s42255-023-00783-1%20(1).pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9692202/pdf/nihms-1844878.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339630/pdf/nihms-1529320.pdf   Mitochondrial Diversity and Anxiety: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10415311/pdf/41467_2023_Article_39941.pdf   Human Brain Map of Mitochondrial Diversity: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10942385/pdf/nihpp-2024.03.05.583623v1.pdf