Brain Ponderings podcast with Mark Mattson

Every day we communicate with and influence others via language, decision-making, and actions. The complexities of human social interactions and language begs the question of how the brain processes the relevant incoming information and then generates responses so rapidly and effortlessly. Neurosurgeon Ziv Williams and his team at Harvard Medical School have made major advances in answering these questions.  By recording the activities of hundreds of individual neurons in the brains of non-human primates in game-theory paradigms of social cooperation and conflict he has identified neurons in the prefrontal cortex that encode social agent identity. Moreover, by recording from neurons in the brains of human patients undergoing brain surgery his team has identified neurons involved in single elements of speech production or in the semantic encoding during language comprehension.  These findings not only advance an understanding of the neurobiological underpinnings of social interactions and language, but also provide insight into disorders involving alterations in these processes.   LINKS Dr. Williams Harvard webpage https://zivwilliams.mgh.harvard.edu/ Neuronal circuits for social decision-making https://pmc.ncbi.nlm.nih.gov/articles/PMC8517320/pdf/fnins-15-720294.pdf Social agent identity cells in the prefrontal cortex of interacting groups of primates. https://pmc.ncbi.nlm.nih.gov/articles/PMC8571805/pdf/nihms-1752328.pdf Single-neuronal predictions of others' beliefs in humans. https://pmc.ncbi.nlm.nih.gov/articles/PMC7990696/pdf/nihms-1654341.pdf  Single-neuronal elements of speech production in humans. https://pmc.ncbi.nlm.nih.gov/articles/PMC10866697/pdf/41586_2023_Article_6982.pdf Semantic encoding during language comprehension at single-cell resolution. https://pmc.ncbi.nlm.nih.gov/articles/PMC11254762/pdf/41586_2024_Article_7643.pdf

One in seven people experience migraine headaches while others suffer with even more debilitating cluster headaches. The causes of these headaches are not fully understood and current treatments provide only partial relief.  In this episode pharmacologist Antoinette van den Brink and neurologist Rolf Fronczek describe the clinical features of these headaches, the current understanding of their causes, and hormonal and environmental factors that can trigger the headaches. Drugs that inhibit the peptide CGRP and electrical stimulation of the occipital nerve are among treatments shown to be effective in reducing headache intensity or duration. LINKS University webpages: https://www.erasmusmc.nl/en/research/researchers/maassen-van-den-brink-antoinette https://hoofdpijnonderzoek.nl/en/team/dr-rolf-fronczek/ Migraine headache articles https://journals.sagepub.com/doi/epub/10.1177/03331024241238153 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10863119/pdf/10194_2024_Article_1724.pdf Cluster headache articles https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018790/pdf/40263_2019_Article_696.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10755111/pdf/main.pdf

Consciousness is one’s awareness of electrochemically conveyed information coming into the brain from the environment via sensory pathways or generated within the brain’s neuronal networks (i.e., thoughts). In popular culture ‘consciousness’ is often portrayed as a mysterious concept or process. However, research that examines the effects of anesthetics, sleep, brain injuries, and psychedelics on neuronal network activity using fMRI, EEG and other technologies is revealing the circuits and activity patterns that enable consciousness. In this episode University of Cambridge Professor Andrea Luppi talks about his research on the neurochemical and neural network level underpinnings of consciousness. His integration of fMRI and brain connectome data suggest the importance of ‘gateway neuronal networks’ and ‘broadcasters’ (executive control networks) in human consciousness.  We also discuss consciousness from philosophical and evolutionary perspectives. LINKS Professor Luppi’s profile at the University of Cambridge https://neuroscience.cam.ac.uk/member/al857/ Recent review article on consciousness https://www.cell.com/action/showPdf?pii=S0166-2236%2824%2900087-0 Gateway regions and broadcasters https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257694/pdf/elife-88173.pdf

In this episode Richard Lu – a professor of pediatrics at the University of Cincinnati Chldren’s Hospital talks about a type of stem cell in the brain called oligodendrocyte progenitor cells (OPC). OPC normally differentiate into the oligodendrocytes that wrap around the axons of neurons providing insulation that greatly speeds up the propagation of electrical impulses. These cells also provide nutrients to neurons and produce proteins that promote the survival of the neurons.  But OPC can and unfortunately do become transformed into cancer cells.  Dr. Lu talks about the normal roles of OPC in brain development and how they can form brain tumors. LINKS: Dr. Lu’s laboratory web page: https://www.cincinnatichildrens.org/research/divisions/e/ex-hem/labs/lu Oligodendrocytes – review https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018611/pdf/nihms-1686441.pdf Oligodendrocytes – Brain repair and cancers https://www.sciencedirect.com/science/article/pii/S0969996120303156?via%3Dihub  

Arizona State University Professors Visar Berisha and Julie Liss have combined their expertise in engineering and speech communication to develop and apply novel automated speech analysis technology to the field of neurological disorders. Because of the complexity of human speech and the brain circuits involved speech analysis can provide a window into multiple domains of brain function.  In this episode they talk about their research and how speech analysis can be used as a tool for cross sectional and longitudinal studies of people with or a risk for brain dysfunction. Their published findings range from studies of NFL football players to patients with ALS or a mental disorder. Automated speech analysis may prove useful in the early diagnosis of neurodegenerative disorders and for evaluation of the efficacy of treatments.  LINKS Review article on automated speech analysis and its applications https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074691/pdf/nihms-1062578.pdf Study of NFL players https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939664/pdf/nihms-861058.pdf Early diagnosis of ALS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555482/pdf/41746_2020_Article_335.pdf Assessment of mental health https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10031731/pdf/sbac176.pdf Potential for early diagnosis of Alzheimer’s disease https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922000/pdf/nihms-1062581.pdf

There are approximately 7000 rare diseases each affecting fewer than 200,000 Americans.  Most rare disorders are caused by gene mutations, manifest in childhood, include neurological problems, and progress rapidly resulting in death in the first several decades of life. Examples include fragile X and Rett syndromes, some childhood epilepsies, Batten diseases, and several types of ataxias,  In most instances there are no treatments that slow or reverse the disease process. In this episode I talk with Professor Erika Augustine who is the Associate Chief Science Officer and Director of the Clinical Trials Unit at the Kennedy – Krieger Institute which is devoted to research on and treatment of neurological conditions caused by genetic disorders, birth complications, or traumatic injuries with a focus on children and adolescents.  Dr. Augustine talks about the scope of the problems faced by patients with a rare disorder, their families, neurologists, government agencies, and the pharmaceutical industry. To exemplify both the challenges and progress towards effective treatments Dr. Augustine focuses on Batten diseases caused by mutations that impair lysosome functions and cause severe progressive neurological deficits that begin early in life. An effective treatment for one of the Batten diseases was recently approved by the FDA providing one of the first successes in moving from basic research to the clinic. LINKS: Dr. Augustine’s biography in Wikipedia: https://en.wikipedia.org/wiki/Erika_F._Augustine Kennedy – Krieger Institute: https://www.kennedykrieger.org/?gad_source=1&gclid=CjwKCAjwl6-3BhBWEiwApN6_ksQGX9fZCTAZpUSzJNw4sHdr2EyRmm_d3tYPHzQpAEOpBuC0uDGZVRoCSGQQAvD_BwE Batten Diseases Clinical Trials: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736171/pdf/nihms-1641434.pdf Enzyme replacement therapy for CLN2 Batten disease: https://www.pedneur.com/action/showPdf?pii=S0887-8994%2820%2930149-1 Gene therapy for rare neurological disorders: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527017/pdf/fnmol-14-695937.pdf

In this episode I provide an overview of what happens in brain cells during aging and how those changes result in impaired brain function and predispose to Alzheimer’s and Parkinson’s diseases. I then describe three lifestyle anti-aging interventions that are known to slow brain aging and counteract disease process: physical exercise; intermittent fasting; and intellectual challenges.  LINKS Hallmarks of brain aging: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039826/pdf/nihms979409.pdf Exercise and brain health: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880155/pdf/cshperspectmed-BEX-a029736.pdf Intermittent fasting and brain health: https://www.amazon.com/Intermittent-Fasting-Revolution-Optimizing-Performance/dp/0262046407 Environmental enrichment: https://pubmed.ncbi.nlm.nih.gov/30723309/ Hormesis and brain health: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096685/pdf/10.1177_1559325818784501.pdf

Chronic pain is a highly prevalent problem in need to improved treatments. In this episode I talk with Dr. Shiqian Shen of Harvard Medical School about his research on interactions between the immune and nervous systems in chronic pain. He has found an interesting connection between the gut microbiota, immune cells, and neurons in chronic pain. These findings suggest new approaches for treating chronic pain.   LINKS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575957/pdf/nihms887104.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9974100/pdf/jci-133-166408.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11320346/pdf/ACEL-23-e14177.pdf

Anxiety disorders are all too common in children and adolescents and their incidence has increased considerably during the past decade. Social interactions (positive or negative) in the home, schools, and the digital world have a major influence on a child’s risk for anxiety and major depression. In this episode I talk with Dr. Danny Pine at the National Institute of Mental Health who has devoted his career to the problem of mental health problems in children. His research has advanced an understanding of the complex factors that determine whether or not a child develops an anxiety disorder, the brain circuits involved, and the behavioral and pharmacological interventions that can provide effective treatments.  LINKS  Dr. Pine’s NIH webpage: https://www.nimh.nih.gov/research/research-conducted-at-nimh/research-areas/clinics-and-labs/edb/sdan Articles https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9248771/pdf/nihms-1797515.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490291/pdf/nihms-1734583.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9931491/pdf/nihms-1858084.pdf    

Cells in all organ systems experience the same ‘hallmarks of aging’ which include the accumulation of oxidatively damaged proteins, DNA, membranes and mitochondria, impaired DNA repair and autophagy, senescence, and inflammation. In this episode Professor Ron DePinho of the MD Anderson Cancer Center in Houston talks about his remarkable career during which he and his trainees established fundamental mechanisms that control cell proliferation and differentiation in normal development and how alterations in these mechanisms result in aging and cancers. He then describes how the telomerase protein influences hallmarks of aging by controlling gene expression, and how age-related reductions in telomerase levels contribute to normal aging and the pathogenesis of Alzheimer’s disease. Ron and his colleagues have recently identified a chemical called TAC that can increase telomerase levels in cells. Treatment of old mice with TAC rejuvenates multiple organ systems, and can restore neuroplasticity and cognition in mouse models of Alzheimer’s disease.  LINKS: DePinho laboratory web page: https://www.mdanderson.org/research/departments-labs-institutes/labs/depinho-laboratory.html Related Articles: https://www.cell.com/action/showPdf?pii=S0092-8674%2820%2931750-5 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733214/pdf/nihms487161.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759755/pdf/nihms-1761822.pdf https://pubmed.ncbi.nlm.nih.gov/38908367/