Brain Ponderings podcast with Mark Mattson

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

Age-related macular degeneration, glaucoma, diabetic retinopathy, and genetic disorders such as retinitis pigmentosa are major causes of blindness. In this episode Professor Russ van Gelder at the University of Washington talks about exciting advances in vision restoration using retinal cell replacement, gene therapy, visual prosthetic devices, and small molecule ‘photoswitches’. Several of these technologies have shown promising results in clinical trials.  LINKS: Review articles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10718186/pdf/nihms-1949762.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444397/pdf/nihms-663143.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486303/pdf/nihms-1729966.pdf

The molecular and cellular mechanisms by which the human brain develops cannot be directly studied. Stanford professor Sergiu Pasca is at the forefront of using induced human pluripotent stem cells to establish 3D cultures of individual brain regions (organoids) and multiple interacting brain regions (assembloids). His work has shown that functional neuronal connections can be established and the underlying molecular and cellular regulation of human brain development established.  Human neuroassembloids are also being used to identify the root causes of developmental brain disorders such as autism. LINKS: Human brain organoid and assembloid review: https://www.cell.com/action/showPdf?pii=S0092-8674%2821%2901177-6 Human cortical – spinal cord – muscle neuroassembloid: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8711252/pdf/nihms-1649341.pd  CRISPR screen – developmental brain disorder genes: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10567561/pdf/41586_2023_Article_6564.pdf Timothy Syndrome: https://www.cell.com/action/showPdf?pii=S1934-5909%2821%2900483-5

Stroke is the leading neurological cause of disability and death throughout the world and is increasing on the African continent where rates of hypertension are high and Westernized dietary habits are on the rise. At the forefront of the global battle against stroke and other age-related neurological disorders is Mayowa Owolabi, Dean of the Faculty of Clinical Sciences and Director of the Center for Genomic and Precision Medicine at the University of Ibadan, Nigeria.  In this episode Dr. Owolabi talks about the four pillars of reducing the global burden of stroke – epidemiological surveillance; health promotion and disease prevention; acute care; and rehabilitation. While the negative health impacts of profit-driven forces such as the processed food and fossil fuel industries are proving difficult to overcome, considerable progress has been made. Dr. Owolabi talks about the strategies for reducing the global burden of stroke and dementia by implementing bottom-up and top-down approaches.    Stroke in Africa: profile, progress, prospects and priorities. Akinyemi RO et al. .. Owolabi MO. Nature Reviews Neurology. 2021 Oct;17(10):634-656: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441961/pdf/41582_2021_Article_542.pdf Global synergistic actions to improve brain health for human development. Owolabi MO, et al Nature Reviews Neurology 2023 Jun;19(6):371-383: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10197060/pdf/41582_2023_Article_808.pdf  

Because neurons are very active cells they consume high amounts of oxygen and produce high amounts of oxygen free radicals (oxyradicals). Because most neurons in the brain exist throughout life and cannot be replaced it is critical that they be able to efficiently remove oxyradicals and repair damage caused to DNA, proteins and membranes caused by oxyradicals. During normal aging and moreso in Alzheimer’s disease neurons accumulate oxidative damaged molecules and mitochondria. In this episode professor George Perry talks about oxidative stress and its roles in synaptic dysfunction and neuronal degeneration in Alzheimer’s disease. He also talks about approaches to preventing and treating Alzheimer’s disease based on holistic rather than targeted interventions.  LINKS: Review articles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091392/pdf/nihms288394.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10451948/pdf/antioxidants-12-01628.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452017/pdf/EMBJ-36-1474.pdf

There is currently no effective treatment for Alzheimer’s disease. EEG recordings have shown that gamma frequency electrical oscillations are diminished and aberrant excitatory glutamatergic neurotransmission is increased in the brain’s of people with Alzheimer’s disease.  In this episode MIT Professor Li-Huei Tsai talks about her discovery that gamma frequency (40 Hz) light and sound stimulation can enhance GABAergic inhibitory tone, ameloriate the disease process, and preserve cognition in animal models of Alzheimer’s disease. This research led to initial phase I and II clinical trials of gamma light and sound stimulation in Alzheimer’s disease with encouraging results.  A large phase III trial is in progress. LINKS: Preclinical studies: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774262/pdf/nihms-1538841.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697125/pdf/nihms-1528873.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656389/pdf/nihms886326.pdf   Phase I and II trials in AD patients: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714926/pdf/pone.0278412.pdf   Ongoing phase III trial in AD patients: https://classic.clinicaltrials.gov/ct2/show/NCT05637801?term=cognito&cond=alzheimer%27s&draw=2&rank=1

DNA damage, most often caused by oxygen free radicals, can result in mutations in proliferative cells that transform them into cancer cells. Impaired DNA repair is implicated in aging and neurodegenerative disorders.  In this episode Professor Will Bohr talks about his research on the molecular mechanisms by which cells repair their nuclear and mitochondrial DNA, the involvement of impaired DNA repair in neurons in premature aging syndromes and Alzheimer’s disease, and the potential of NAD+ supplementation to sustain DNA repair and prevent neuronal degeneration. LINKS: Professor Bohr’s lab page: https://icmm.ku.dk/english/research-groups/bohr-group/ Review articles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588127/pdf/cshperspectmed-AGE-a025130.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341618/pdf/nihms848291.pdf  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494058/pdf/nihms-900941.pdf