Brain Ponderings podcast with Dr. Mark Mattson

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

Approximately 20 percent of people in the USA will experience clinical depression during their lifetime and there has been a recent surge in depression and suicide among teenagers and young adults. The early life environment plays a major role in one's vulnerability to depression with childhood maltreatment greatly increasing the risk. Recent research suggests that use of social media is a risk factor. In this episode I talk with psychiatrist/neuroscientist Charles Nemeroff about the neurobiology of stress and depression and interventions to prevent and treat depression. He is a professor of psychiatry and behavioral sciences at the University of Texas at Austin Medical School, Director of the Institute for Early Life Adversity Research, and Director of the Center for Psychedelic Research and Therapy. Professor Nemeroff has served as president of the American Colleges of Psychiatrists and is currently president of the Anxiety and Depression Association of America. LINKS Professor Nemeroff's academic webpage with links to centers: https://dellmed.utexas.edu/directory/charles-nemeroff Review article on depression: https://ajp-psychiatryonline-org.proxy1.library.jhu.edu/doi/epdf/10.1176/appi.ajp.2020.20060845 Childhood maltreatment and depression and anxiety disorders: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567985/pdf/41380_2021_Article_1367.pdf Perspective on psychedelics: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10963929/pdf/main.pdf

Historically, microglia were viewed only as the brain's immune cells that respond to brain injury or infections. While this is true, recent research has shown that microglia play important roles in responding to and regulating neuronal network activity, and adaptations of the brain to physiological challenges such as exercise and intellectual challenges. Microglia are increasingly recognized for their roles in neuroplasticity including learning and memory and regulation of emotions. Professor Long-Jun Wu is working at the forefront of research on microglia and their roles in normal brain function and in disorders such as chronic pain and Alzheimer's disease. In this episode I talk with Dr. Wu about his research and its implications for brain health and new therapeutic approaches for neurological disorders. LINKS: Review articles: https://www-sciencedirect-com.proxy1.library.jhu.edu/science/article/pii/S0166223623002904 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113084/pdf/nihms-1663302.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599472/pdf/nihms-1529800.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10043090/pdf/12264_2022_Article_937.pdf

Transcranial magnetic stimulation (TMS) is a non-invasive technology that enables stimulation (or inhibition) of specified neuronal networks in the brain. In this episode Alvaro Pascual-Leone, a Professor in Neurology at Harvard Medical School, talks about the principle and practice of TMS and its use for the treatment of a range of brain disorders including depression, stroke, and cognitive impairment, chronic pain, and traumatic brain injuries. The technology has advanced to a point where portable in-home devices can be used for treatments under the supervision of medical experts. TMS is also being used to understand how neural networks respond to injury and disease. TMS promises to be a valuable addition to therapies for mental and neurodegenerative disorders. In addition to TMS Dr. Pascual-Leone is working to develop and apply artificial intelligence and digital technologies and intelligent therapy assistant approaches to the broader health care system. In addition to being a Professor at Harvard, Dr. Pascual-Leone is Medical Director, Deanna and Sidney Wolk Center for Memory Health; Senior Scientist, Hinda and Arthur Marcus Institute for Aging ResearchvHebrew SeniorLife; Co Founder and Chief Medical Office Linus Health; Co Founder TI Solutions LINKS: Review articles on TMS: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9700722/pdf/41386_2022_Article_1453.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8996329/pdf/nihms-1787298.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863979/pdf/CPJ2012000737.pdf Article on digital technology intelligent therapy assistants: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639502/pdf/fdgth-03-755008.pdf

In 1997 Makoto Kuro-o and his colleagues reported that they had accidentally discovered a gene that encodes a protein that slows aging and extends the lifespan of mice. They named the protein 'Klotho' after the Greek goddess that 'spins the thread of life'. During the past decade University of California San Francisco professor Dena Dubal has shown that Klotho can enhance learning and memory and protect neurons and synapses aging dysfunction and degeneration in mouse models of Alzheimer's disease. Klotho production is increased by exercise and intermittent fasting. In this episode Dr. Dubal talks about her research on Klotho and the potential of Klotho as a treatment for cognitive impairment, Alzheimer's disease, and other brain disorders.. LINKS: Review article on Klotho: file:///Users/markmattson/Downloads/s41581-018-0078-3%20(1).pdf Klotho enhances cognition in old nonhuman primates: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10432271/pdf/43587_2023_Article_441.pdf Klotho treatment in a mouse model of Alzheimer's disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323521/pdf/zns2358.pdf Klotho treatment in a mouse model of Parkinson's disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816951/pdf/nihms941402.pdf Intermittent fasting and Klotho: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760057/pdf/41380_2021_Article_1102.pdf Neuronal activity and Klotho: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681535/pdf/10.1177_0271678X18762700.pdf

The brains of males and females are different and it is important to understand how these differences give rise to different behavioral traits of men an women. These sex differences arise during brain development, manifest throughout life and are controlled in part by estrogen and testosterone. The brains of females and males, and their differential vulnerability to mental and other neurological disorders may be influenced by prenatal and early life environmental factors including stress or exposure to pollutants such as 'forever chemicals'. Professor Mariha Kundakovic at Fordham University is making major contributions to understanding brain sex differences and particularly the roles of 'epigenetic' molecular and structural modifications to the genome. Here she talks about her research and its implications for the causes of and treatments for anxiety disorders and depression. LINKS: Review article: epigenetic mechanisms and sex differences in the brain and behavior: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10841872/pdf/nihms-1935382.pdf Review on influence of hormones on the brain during the estrous cycle: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10050126/pdf/nihms-1850437.pdf Sex hormones and risk for anxiety disorders and depression: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9715398/pdf/nihms-1848030.pdf

Bipolar disorder is a mental illness that causes often dramatic shifts in a person's energy and activity levels, and concentration. It affects approximately 1 in every 50 people worldwide and 6 million Americans. Many people with bipolar disorder exhibit remarkable creativity and productivity. This relationship between creativity and mania was noted by the Greek philosopher Aristotle who wrote: "no great genius has ever existed without a strain of madness". In this epidose Spanish psychiatrist Eduard Vieta at the University of Barcelona talks about the intriguing features of bipolar disorder, advances in identifying the genetic and environmental underpinnings of this disorder, and the many treatments that enable patients to live enjoyable and productive lives. LINKS: Professor Vieta's webpage at the Barcelona Clinic: https://www.clinicbarcelona.org/en/professionals/eduard-vieta Review article on bipolar disorder: file:///Users/markmattson/Downloads/nrdp20188.pdf Bipolar disorders and creativity: https://www-annualreviews-org.proxy1.library.jhu.edu/doi/pdf/10.1146/annurev-clinpsy-050718-095449 Bipolar disorder risk calculator: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465101/pdf/brainsci-10-00525.pdf

Ataxia Telangiectasia (AT) is a rare inherited disorder in which young children develop severe ataxia (inability to control body movements) as a result of degenration of 'Purkinje neurons' in the cerebellum. AT children are highly prone to cancers and usually die before the age of 20. In this episode Professor Tanya Paull talks about research that has revealed a remarkably broad array of functions of 'ATM' the gene mutated in AT. The disorder is inherited in a recessive manner such that both parents pass on a defective Atm gene to their child. A major function of ATM is to facilitate repair of damaged DNA. This deficiency increases the likelihood that gene mutations will accumulate that cause cancers. The degeneration of Purkinje neurons may involve DNA damage, oxidative stress and the accumulation of dysfunctional mitochondria. A better understanding of ATM functions is leading to novel approaches for preventing and treating neurodegenerative disorders and cancers. LINKS: Dr. Paull's lab page: https://sites.cns.utexas.edu/paulllab/home Review article on AT: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123280/pdf/13023_2016_Article_543.pdf Review article on ATM: file:///Users/markmattson/Downloads/s41580-021-00394-2%20(1).pdf

In this episode I talk with Dr. Bondy Lee, a psychiatrist who has devoted her life to advancing an understanding the causes of violence and developing ways to reduce violence. As a psychiatrist she is particularly interested in the behavioral features of people who are a danger to society, particularly those with psychopathic traits and behaviors such as lack of empathy and remorse, egocentricity, conning and manipulative behaviors, taking pleasure in other people's hardships and pain, and criminal versatility. Beginning prior to the 2016 elections Dr. Lee has been outspoken in raising concerns about Donald Trump's mental states and his dangerous words and actions. She organized a meeting of eminent psychiatrists and psychologists for a conference at Yale to discuss "The Dangerous Case of Donald Trump" which resulted in an edited book of the same title. Since then the conclusion that Trump is a psychopath and a danger to society has been firmly established based on an enormous amount of data in the public record. Dr. Lee's predictions as to the potential consequences of his aberrant behaviors for the country proved correct as evidenced by the January 6, 2021 attack on the US Capitol, the multitude of crimes for which Trump and many of his minions have either been convicted or indicted, and even more importantly the division amongst many Americans who had previously got along with each other. We also discuss deficiencies of mechanisms for preventing the ascension individuals with dangerous mental states to positions in which they can wreak havoc on society. LINKS: The Dangerous Case of Donald Trump: https://www.amazon.com/Dangerous-Case-Donald-Trump-Psychiatrists/dp/1250179459 Book: Violence: https://www.amazon.com/Violence-Interdisciplinary-Approach-Causes-Consequences/dp/1119240670 World Mental Health Coalition: https://worldmhc.org/ Political affiliation and prejudice: file:///Users/markmattson/Downloads/s41562-021-01287-2%20(1).pdf How Psychopathic Behavior can Undermine Democracy: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595043/