Brain Ponderings podcast with Mark Mattson

Remarkable advances are being made in the development and clinical applications of stimulation devices that enable recovery of motor function in patients who have suffered a spinal cord injury, a stroke, and even those with rare disabling genetic disorders.  At the forefront of this research is Marco Capogrosso at the University of Pittsburgh. He has shown that certain patterns of stimulation of sensory pathways in the spinal cord can activate motor neurons that were otherwise silenced by the injury or stroke. Initial clinical trials have shown that this approach results in recovery of function which are in some cases very dramatic in patients that have had a stroke, a spinal cord injury, and in people with the genetic disorder spinal muscular atrophy.  In this episode Dr. Capogrosso talks about the development of this stimulation-based therapeutic approach, the clinical trials, and the potential applications of this technology to other neurodegenerative disorders. LINKS Dr. Capogrosso’s profile at the University of Pittsburgh: https://www.neurosurgery.pitt.edu/people/marco-capogrosso Key studies discussed in this podcast:  Stroke https://pmc.ncbi.nlm.nih.gov/articles/PMC10291889/pdf/nihms-1904547.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC12393459/pdf/nihpp-rs7271578v1.pdf Spinal cord injury https://pmc.ncbi.nlm.nih.gov/articles/PMC5108412/pdf/emss-70056.pdf https://www.cell.com/neuron/fulltext/S0896-6273(25)00658-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627325006580%3Fshowall%3Dtrue#  Spinal muscular atrophy https://www.nature.com/articles/s41591-024-03484-8

Dietary iron is essential for health as it plays important roles in the ability of hemoglobin to carry oxygen throughout the body and brain. In addition, iron is involved in various functions in cells including the generation of ATP in mitochondria and DNA synthesis. The vast majority of iron is bound to proteins such as ferritin and heme. However, in its ionic form (Fe2+) iron can react with the hydrogen peroxide produced from mitochondrial superoxide radical to generate the highly toxic hydroxyl radical.  Hydroxyl radical damages DNA and can also act on the carbon=carbon double bonds in unsaturated member lipids and trigger an autocatalytic process called lipid peroxidation. Lipid peroxidation in neurons occurs in Alzheimer’s and Parkinson’s disease and may play a major role in the death of neurons in these disorders a process called ‘ferroptosis’. In this episode I talk with Scott Ayton a Professor at the Florey Institute at the University of Melbourne about both the normal functions of iron in neurons, its involvement in Alzheimer’s and Parkinson’s disease, and the potential of interventions that prevent ferroptosis in the treatment of these disorders.  LINKS Professor Aytons profile at the Florey Institute: https://florey.edu.au/researcher/scott-ayton/ Relevant articles file:///Users/markmattson/Downloads/s41583-025-00930-5%20(1).pdf https://nyaspubs.onlinelibrary.wiley.com/doi/epdf/10.1196/annals.1306.004?saml_referrer https://www.nejm.org/doi/pdf/10.1056/NEJMoa2209254 https://jamanetwork.com/journals/jamaneurology/article-abstract/2825846

Health depends upon proper regulation of circadian rhythms of cell and organ functions. Disruption of circadian rhythms has detrimental consequences for brain function and resilience and abnormal circadian rhythms are a common feature of Alzheimer’s disease. In this episode neurology professor Erik Musiek talks about the roles of specific circadian clock proteins in neurons and glial cells in brain health and Alzheimer’s disease. His research is revealing the ways in which these circadian regulatory proteins affect brain cell functions and how disruption of circadian rhythms may contribute to the neuropathological features of Alzheimer’s disease (amyloid plaques and neurofibrillary tangles. We also talk about ways in which we can bolster our circadian rhythms by sleep, exercise, diet, light exposure, etc. LINKS Professor Musiek’s webpage: https://physicians.wustl.edu/people/erik-musiek-md-phd/ Articles discussed in this podcast: https://pmc.ncbi.nlm.nih.gov/articles/PMC12352436/pdf/nihms-2097957.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC11996435/pdf/nihpp-2025.03.31.645805v1.pdf https://www.nature.com/articles/s43587-025-00950-x https://pmc.ncbi.nlm.nih.gov/articles/PMC9008766/pdf/nihms-1794994.pdf

Chronic uncontrolled stress is a risk factor for many different diseases including mental and neurodegenerative disorders. The effects of such stress on the brain differ considerably between females and males. However, the vast majority of preclinical studies in animal models have included only males which in some cases has resulted in therapeutic interventions that are less effective in females compared to males. In this episode Georgia Hodes talks about sex differences in the effects of stress on the brain and neuroendocrine systems and how these differences can influence disease processes and treatments.  LINKS Prof. Hodes webpage at VT:  https://neuroscience.vt.edu/our-people/research-faculty/hodes-georgia.html  Review articles: https://pmc.ncbi.nlm.nih.gov/articles/PMC10845083/pdf/CN-22-475.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC10189838/pdf/nihms-1896436.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC8630768/pdf/nihms-1528739.pdf  

In stressful situations the brain communicates with the adrenal glands stimulating them to release adrenaline and cortisol. This stress responsive neuroendocrine system plays important adaptive roles by regulating energy metabolism, attention, and learning and memory. However, without a recovery period chronic uncontrolled stress such as psychosocial stress can damage neural circuits in the brain and contribute to a range of mental disorders as well as Alzheimer’s disease.  In this episode I have the pleasure of talking with two pioneers in the field of stress research – Professors Marian Joëls and Ron de Kloet. Their work which spans five decades has shown how two different cortisol receptors determine how the brain responds to physiological and pathological stress. They have revealed how a “cortisol switch” determines brain vulnerability or resilience.  Links Marian Joëls’ webpage: https://www.rug.nl/staff/m.joels/cv Ron de Kloet publications on Google Scholar: https://scholar.google.com/citations?user=Eao7yZIAAAAJ&hl=en&oi=ao The “Cortisol Switch” file:///Users/markmattson/Downloads/s41380-022-01934-8.pdf https://www.sciencedirect.com/science/article/pii/S0091302218300116?via%3Dihub  

Clearly demonstrated as being effective for cardiovascular disease, lifestyle medicine is becoming an important discipline for the prevention and treatment of age-related brain disorders including Alzheimer’s and Parkinson’s diseases.  In this episode I talk with Dr. Josh Helman about his experience working with patients at lifestyle medicine centers. He provides his views on what people can do now to reduce their risk for these brain disorders, and what the future holds in terms of therapeutic interventions. LINKS Dr. Helman’s webpage: https://drjosh.com/ Lifestyle medicine approach:  https://pmc.ncbi.nlm.nih.gov/articles/PMC10907160/pdf/main.pdf  

The calcium ion controls neuronal network activity, synapse function and synaptic plasticity, and is a fundamental mediator of learning and memory. With aging and much more so in Alzheimer’s disease the ability of neurons to properly regulate their intracellular calcium levels becomes compromised. Evidence from human and laboratory animal studies have provided compelling evidence that excessive elevation of calcium levels in neurons results in their dysfunction and degeneration in Alzheimer’s disease, as well as in Parkinson’s disease, and stroke.  In this episode, I talk with Professor Beth Stutzmann about her research which has advanced an understanding about how calcium regulation becomes disrupted in neurons in Alzheimer’s disease. Her findings point to excessive release of calcium from intracellular pools (in the endoplasmic reticulum) as being particularly important in Alzheimer’s. This research points to new therapeutic interventions for this devastating disease. LINKS Stutzmann laboratory: https://www.rosalindfranklin.edu/academics/faculty/grace-e-stutzmann/ Relevant articles: https://pmc.ncbi.nlm.nih.gov/articles/PMC7763805/pdf/cells-09-02655.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC9894236/pdf/pnas.202211999.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC12305934/pdf/40478_2025_Article_2023.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC3091392/pdf/nihms288394.pdf

Long believed to function only as the cell’s powerhouse research is revealing that mitochondria actively control a cell’s response to various types of stress. Even more amazingly mitochondria send stress-related signals between cells. In this episode UC Berkeley Professor Andy Dillin has made major advances in understanding basic mechanisms of aging, how cells and animals respond to stress, and how the aging process can be influenced by mitochondrial responses to stress. In this episode I talk with Andy about his work and its implications for optimizing health and longevity.  LINKS Dillin Laboratory: https://mcb.berkeley.edu/labs/dillin/ Publications https://pmc.ncbi.nlm.nih.gov/articles/PMC10399134/pdf/load001.pdf https://pubmed.ncbi.nlm.nih.gov/32449292/ https://www.cell.com/action/showPdf?pii=S1097-2765%2817%2930395-7 https://pmc.ncbi.nlm.nih.gov/articles/PMC10575585/pdf/sciadv.adi1411.pdf  

While neurons and the circuits the form have been the major focus of brain research the human brain contains at least as many cells that are not neurons of which astrocytes are by far the most abundant. During the past decade there have been numerous studies that reveal novel and very active roles for astrocytes in regulating the growth of neurons, the formation and modification of synapses, the activities of neural networks, and behaviors in laboratory animals. In this episode Marc Freeman talks about the fascinating world of astrocytes including their diversity, complex morphologies, and roles in neuroplasticity and disease processes.  LINKS: Marc Freeman’s webpage at the Vollum Institute: https://www.ohsu.edu/vollum-institute/marc-freeman-phd  Articles discussed in this podcast: https://pmc.ncbi.nlm.nih.gov/articles/PMC11513168/pdf/nihms-2030570.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC7897322/pdf/nihms-1657553.pdf https://pmc.ncbi.nlm.nih.gov/articles/PMC5161596/pdf/nihms-822004.pdf https://pubmed.ncbi.nlm.nih.gov/39386551/

Because neurons in the brain are electrically excitable and active 24/7 the brain consumes relatively large amounts of energy and must adapt to varying demands on its neural networks. The cellular and molecular complexity of the brain presents a major challenge for understanding not only its second-by-second function but also how neural networks are affected by aging and disease. In this episode Dr. Polina Schichkova talks about how large datasets on cellular energy metabolism gene expression are being used to elucidate how aging affects the brain as a whole. Her findings from analyses of data from brains of young adults and elder humans show that aging results in reduced flexibility of the brain’s bioenergetics and electrical activity. Computer modeling reveals how the brain is altered during aging as well as potential interventions to counteract age-related processes.  LINKS Breakdown and repair of metabolism in the aging brain: file:///Users/markmattson/Downloads/fsci-3-1441297%20(2).pdf Multiscale electro-metabolic model of the brain: https://pmc.ncbi.nlm.nih.gov/articles/PMC12112163/pdf/pcbi.1013070.pdf Online modeling: https://www.openbraininstitute.org/jupyterhub_metabolism/user/mpaulmattson@gmail.com/lab/tree/obi_platform_analysis_notebooks/Metabolism/analysis_notebook.ipynb