Brain Ponderings podcast with Mark Mattson

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

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