Brain Ponderings podcast with Mark Mattson

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/

In this episode I talk with Stanford Professor and Nobel laureate Thomas Sudhof about his work that has advanced an understanding of the molecular machinery for neurotransmitter release, a remarkable process that is compex, occurs rapidly (milliseconds) and is highly localized (1 micrometer or less). We then talk about the even more difficult problem of the molecular mechanisms that control the formation, maintenance and plasticity of synapses. The current model of the molecular code for synapse specificity and adaptability involves a uniform array of presynaptic proteins and a highly variable array of postsynaptic proteins. LINKS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866025/pdf/nihms-531222.pdf  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226307/pdf/nihms-1509679.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689449/pdf/nihms914499.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694349/pdf/nihms917636.pdf

Regular exercise improves mood, reduces anxiety, enhances cognition, and protects the brain against depression, Alzheimer’s disease and stroke. In this episode Harvard neuroscientist Christiane Wrann and I talk about recent research that has elucidated how exercise affects the structure, functionality, and resilience of the brain. The mechanisms involve brain intrinsic responses to exercise as well as molecules released from muscle cells that travel to the brain. LINKS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880155/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9554896/pdf/nihms-1829603.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3980968/pdf/nihms-524991.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10317538/pdf/nihms-1724336.pdf https://www.cell.com/action/showPdf?pii=S0896-6273%2823%2900623-2    

Frontotemporal dementia (FTD) is the most common form of dementia for people under the age of 65. As its name implies FTD involves degeneration of neurons in the frontal and parietal lobes and depending upon which neurons degenerate symptoms may mainly involve changes in personality and social behavior, speech and language (aphasia), or difficulty with body movements. UCSF neurologist Bill Seeley has devoted his career to understanding what goes wrong in FTD and using this information to develop ways of early diagnosis and treatments that slow or halt the progression of the disease. Here he talks about the genetics, and cellular and molecular mechanisms responsible for FTD and emerging treatments. LINKS file:///Users/markmattson/Downloads/s41572-023-00447-0%20(2).pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909835/pdf/nihms204382.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647117/pdf/415_2019_Article_9363.pdf