Presenters

Neural Reward Systems as a Mechanism and Treatment Target in Adolescent Depression

After a long history of emphasis on disruptions to negative affect and threat systems in depression, clinical and affective neuroscience research on postulated alterations to positive affect and reward systems is finally catching up. A developmental perspective can provide critical insights on the mechanisms of depression, as the emergence of depression typically coincides with changes in reward-related neural systems and behavior during youth. Anhedonia, a symptom reflecting difficulty with motivation for or enjoyment of reward, could be an especially fruitful focus for translational applications of this approach because it is associated with pernicious clinical course. This presentation will describe findings on function in neural reward systems in adolescent depression and anhedonia, with extension to understanding clinical course, disparities in mental health, suicidality, and treatment.

Erika Forbes, PhD, is Professor of Psychiatry, Psychology, Pediatrics, and Clinical and Translational Science at the University of Pittsburgh. She received her AB in History and Literature from Harvard University and her PhD in Clinical and Developmental Psychology from the University of Pittsburgh. She completed a predoctoral clinical psychology internship and a postdoctoral fellowship in the Department of Psychiatry at the University of Pittsburgh and then joined the faculty in 2005. Her research uses longitudinal, developmental psychopathology designs and neuroimaging, ecological momentary assessment, behavioral, and neuromodulation techniques. The central theme of her work is the role of neural reward systems in the development, pathophysiology, and treatment of depression. She has published over 210 peer-reviewed publications, attained an h index of 71, and received honors such as the American College of Neuropsychopharmacology Eva King Killam Award.

Reading List

Eckstrand, Kristen L., et al. “Medial prefrontal cortex activity to reward outcome moderates the association between victimization due to sexual orientation and depression in youth.” Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, vol. 7, no. 12, Dec. 2022, pp. 1289–1297, https://doi.org/10.1016/j.bpsc.2022.08.009.

Forbes, Erika E., and Ronald E. Dahl. “Research review: Altered reward function in adolescent depression: What, when and how?” Journal of Child Psychology and Psychiatry, vol. 53, no. 1, 28 Nov. 2011, pp. 3–15, https://doi.org/10.1111/j.1469-7610.2011.02477.x.

Forbes, Erika E., et al. “Altered striatal activation predicting real-world positive affect in adolescent major depressive disorder.” American Journal of Psychiatry, vol. 166, no. 1, Jan. 2009, pp. 64–73, https://doi.org/10.1176/appi.ajp.2008.07081336.

Gupta, Tina, et al. “Continuous theta burst stimulation to dorsomedial prefrontal cortex in young adults with depression: Changes in resting frontostriatal functional connectivity relevant to positive mood.” Behaviour Research and Therapy, vol. 174, Mar. 2024, p. 104493, https://doi.org/10.1016/j.brat.2024.104493.

Sequeira, Stefanie L., et al. “Association of Neural Reward Circuitry function with response to psychotherapy in youths with Anxiety Disorders.” American Journal of Psychiatry, vol. 178, no. 4, 1 Apr. 2021, pp. 343–351, https://doi.org/10.1176/appi.ajp.2020.20010094.

Novelty seeking behavior and engram cells

To study genetic and age-related risk factors in a human age-equivalent, adult-like, and patient-specific neuronal model system, induced neurons (iNs) directly converted from primary human fibroblasts offer unique possibilities to model and study Aging and Alzheimer’s Disease (AD). We and others have previously demonstrated that elderly human donor-derived iNs mirror transcriptomic signatures of brain aging, show impaired nuclear pore sub-cellular transport, and metabolic and mitochondrial aging defects, and other functional signatures of aging, and mirror the epigenetic clock ages of their donors. iNs globally reflect the major risk factor for the development of neurodegenerative disorders, and stand out as a unique and complementary model system to animal and iPSC-based models. Our iN cultures comprise a major fraction of ˜80% excitatory glutamatergic neurons, and a minor fraction of inhibitory neurons and their transcriptomes map to adult human cortical tissue, and endogenously show adult MAPT splicing and tau protein isoform expression including 2N and 4R, which is altered in iNs from tauopathy patients. We have employed direct conversion of AD patient fibroblasts into iNs to generate an age-equivalent neuronal model for late-onset sAD, which exhibited neuronal transcriptome signatures that showed a high level of concordance to post-mortem AD patient bulk and single cell transcriptome data, including the ROSMAP data base. We also generated rejuvenated iPSC-derived neurons from the same mostly sporadic patient cohort, which however showed no significant disease-related signatures. iNs thus provide an attractive disease modeling platform complementary to iPSCs and that offers the unique advantage of displaying age-dependent sporadic AD phenotypes in addition to genetic features. Indeed, AD iNs reflected a hypo-mature neuronal identity, display elevated levels of DNA damage stress, early cell cycle markers without cell division, markers for re-entry into glycolysis, phenotypic neuronal de-differentiation, and senescence-associate secretion of pro-inflammatory factors. Together, these data suggest that AD is a highly multifactorial disease, in which neurons are not merely damaged from the outside but commit to activating a malignant cellular program of fate-loss and vulnerability.

Dr. Gage is the Adler Professor in the Laboratory of Genetics, Adjunct Professor, UCSD and immediate past President of the Salk Institute. He received his Ph.D. from The Johns Hopkins University. Dr. Gage’s work concentrates on the adult central nervous system and unexpected plasticity and adaptability to environmental stimulation that remains throughout the life of all mammals. In addition, he models human neurological and psychiatric disease in vitro using human stem cells. His lab also studies the genomic mosaicism that exists in the brain as a result of mobile elements that are active during neurogenesis.

Dr. Gage is a Fellow of the AAAS, a Member of the National Academy of Sciences and the National Academy of Medicine, and American Philosophical Society, a foreign member of the EMBO and a Member of the American Academy of Arts and Sciences. He served as President of the Society for Neuroscience in 2002, and of the International Society for Stem Cell Research in 2012.

Reading List 

Herdy, Joseph R., Jerome Mertens, et al. “Neuronal senescence may drive brain aging.” Science, vol. 384, no. 6703, 28 June 2024, pp. 1404–1406, https://doi.org/10.1126/science.adi3450.

Herdy, Joseph R., Larissa Traxler, et al. “Increased post-mitotic senescence in aged human neurons is a pathological feature of alzheimer’s disease.” Cell Stem Cell, vol. 29, no. 12, Dec. 2022, https://doi.org/10.1016/j.stem.2022.11.010.

Mertens, Jerome, et al. “Age-dependent instability of mature neuronal fate in induced neurons from alzheimer’s patients.” Cell Stem Cell, vol. 28, no. 9, Sept. 2021, https://doi.org/10.1016/j.stem.2021.04.004.

Parylak, Sarah L., et al. “Neuronal activity‐related transcription is blunted in immature compared to mature dentate granule cells.” Hippocampus, vol. 33, no. 4, 22 Feb. 2023, pp. 412–423, https://doi.org/10.1002/hipo.23515.

Traxler, Larissa, et al. “Warburg-like metabolic transformation underlies neuronal degeneration in sporadic alzheimer’s disease.” Cell Metabolism, vol. 34, no. 9, Sept. 2022, https://doi.org/10.1016/j.cmet.2022.07.014.

Unlocking the Biological Impact of Developmental Cannabis Exposure Relevant to Psychiatric Risk

The dramatic shift of the cannabis sociopolitical landscape has led to the decriminalization, medicalization, and legalization of cannabis use. As the perception of cannabis’ risk has diminished in society, there has been a greater urgency for cannabis research regarding mental health. One significant implication relates to vulnerable populations as pregnant women and teens given concerns as to the potential for cannabis to impact neurodevelopmental processes linked to psychopathology risk. This talk will provide information obtained from preclinical animal models and human studies to address questions regarding biological mechanisms that could underly protracted effects of cannabis/THC into later in life relevant to psychopathology risk and opportunities for intervention.

Dr. Yasmin Hurd is the Ward-Coleman Chair in Translational Neuroscience as well as Professor of Psychiatry, Neuroscience and Pharmacological Sciences at the Icahn School of Medicine in New York. She is also the Director of the Addiction Institute at the Mount Sinai Behavioral Health System. She is an internationally renowned neuroscientist whose preclinical and clinical translational research examines the neurobiology of substance use disorders and related psychiatric disorders with primary focus on opioid abuse and the developmental effects of cannabis. Based on her high scientific accomplishments she was inducted into both the National Academy of Sciences and the National Academy of Medicine.

Reading List

Ellis, Randall J., et al. “Prenatal Δ9-tetrahydrocannabinol exposure in males leads to motivational disturbances related to striatal epigenetic dysregulation.” Biological Psychiatry, vol. 92, no. 2, 15 July 2022, pp. 127–138, https://doi.org/10.1016/j.biopsych.2021.09.017.

Ferland, Jacqueline-Marie N., Randall J. Ellis, Graeme Betts, et al. “Long-term outcomes of adolescent THC exposure on translational cognitive measures in adulthood in an animal model and computational assessment of human data.” JAMA Psychiatry, vol. 80, no. 1, 1 Jan. 2023, p. 66, https://doi.org/10.1001/jamapsychiatry.2022.3915.

Ferland, Jacqueline-Marie N., Randall J. Ellis, Gregory Rompala, et al. “Dose mediates the protracted effects of adolescent THC exposure on reward and stress reactivity in males relevant to perturbation of the basolateral amygdala transcriptome.” Molecular Psychiatry, vol. 28, no. 6, 2 Mar. 2022, pp. 2583–2593, https://doi.org/10.1038/s41380-022-01467-0.

Hinckley, Jesse D., et al. “The developmental trajectory to cannabis use disorder.” American Journal of Psychiatry, vol. 181, no. 5, 1 May 2024, pp. 353–358, https://doi.org/10.1176/appi.ajp.20231006.

Rompala, Gregory, et al. “Maternal cannabis use is associated with suppression of immune gene networks in placenta and increased anxiety phenotypes in offspring.” Proceedings of the National Academy of Sciences, vol. 118, no. 47, 15 Nov. 2021, https://doi.org/10.1073/pnas.2106115118.

Probing the Energetic Basis of Mind-Body Processes through Mitochondria

Energy is the missing dimension of biomedicine. Guided by a machine-based mechanical paradigm, the health sciences have mainly focused on deciphering with increasing precision the molecular features of disease. But living systems are dynamic processes whose parts obey not only mechanical rules, but also dynamic energy-based principles specific to living organisms. An energy-based, first-principles scientific approach to human health and healing emphasizes questions that, once resolved and their solutions practically harnessed, will provide a basis for a Science of Healing that overcomes our focus on disease. Aiming to discover such principles, we have studied the interaction of bioenergetic processes within mitochondria and the human mind – which broadly includes human experiences and brain-body patterns of energy in motion (emotions). An energetic understanding of mood and how it relates to inter-individual variations in mitochondrial biology may contribute to this developing picture. As the resulting field of Mitochondrial Psychobiology develops and connects with other concepts across disciplines, new opportunities emerge for young interdisciplinary scientists to contribute to creating an increasingly holistic and accurate model of the healing process that underlies human health.

Martin Picard, PhD is an Associate Professor at Columbia University Irving Medical Center where he leads the Mitochondrial Psychobiology Group (www.picardlab.org) and co-directs the Columbia Science of Health program. His research investigates the intersection of the science of energy and the human experience of energy. After identifying novel membrane structures for mitochondrial communication in primary mitochondrial diseases, his laboratory showed that cell-free mitochondrial DNA (cf-mtDNA) and the energetic resistance biomarker GDF15 are psychological stress-inducible molecules detectable in blood and saliva, developed a mitochondrial health index (MHI) to study the mind-mitochondria connection in immune and brain tissues, and developed a longitudinal cellular lifespan model to show how chronic stressors increase the cost of living and accelerate epigenetic aging in human cells. Dr. Picard’s team has also contributed to defining the diversity of mitochondria across the brain and body, showed that hair greying is reversible, and established how genetic mitochondrial defects influence stress physiology, energy expenditure, and the rate of aging. Together with an international team of collaborators, he leads the NIH-funded Mitochondrial Stress, Brain Imaging and Epigenetics (MiSBIE) study that integrates deep molecular, bioenergetic, clinical and psychosocial phenotyping among individuals with primary mitochondrial disorders. Investigators and trainees in the translational Mitochondrial Psychobiology research group combine clinical, cellular, and computational approaches to create a holistic vision of the energetic underpinning of human health and healing.

Reading List 

Bobba-Alves, Natalia, et al. “The energetic cost of allostasis and allostatic load.” Psychoneuroendocrinology, vol. 146, 6 Oct. 2022, p. 105951, https://doi.org/10.1016/j.psyneuen.2022.105951.

Kelly, Catherine, et al. A Platform to Map the Mind-Mitochondria Connection and the Hallmarks of Psychobiology: The Misbie Study, 22 July 2024, https://doi.org/10.31219/osf.io/6evn7.

Picard, Martin. “Energy transduction and the mind–mitochondria connection.” The Biochemist, vol. 44, no. 4, 1 Aug. 2022, pp. 14–18, https://doi.org/10.1042/bio_2022_118.

Picard, Martin. “Why do we care more about disease than health?” Phenomics, vol. 2, no. 3, 28 Jan. 2022, pp. 145–155, https://doi.org/10.1007/s43657-021-00037-8.

Trumpff, Caroline, et al. “Psychosocial experiences are associated with human brain mitochondrial biology.” Proceedings of the National Academy of Sciences, vol. 121, no. 27, 18 June 2024, https://doi.org/10.1073/pnas.2317673121.

The Significance of Opioid Properties of Ketamine

In recent years, there has been considerable attention paid to the opioid effects of ketamine.   This presentation reviews the literature on the preclinical and clinical effects of ketamine on mu opioid mediated activity. Our interest began with clinical studies of others that pointed to rapid and somewhat sustained effects of intravenous ketamine in depressed patients. These data have been viewed as due to the drug’s NMDA receptor antagonism. However, other NMDA antagonists have not been associated with antidepressant effects in man, let alone rapid relief of depressive symptoms. Further, ketamine has long been known to have mild affinity for mu opioid receptors (MOR’s) suggesting an alternative mechanism of action. We hypothesized that the MOR effects were responsible for the rapid antidepressant response and that the MoA could be tested by randomizing patients who are receiving ketamine to being pretreated with naltrexone or placebo.  We then tested the hypothesis and demonstrated that naltrexone does block the antidepressant effects of ketamine.  Results of that study have been replicated in a number of preclinical studies and a direct clinical replication. The clinical implications of these studies for patients’ receiving ketamine are discussed as are the importance for future antidepressant development.

Alan F. Schatzberg, MD received his MD from NYU in 1968. He completed his psychiatric residency at the Massachusetts Mental Health Center and a clinical fellowship in psychiatry at Harvard Medical School. After serving in the United States Air Force, he joined the staff at McLean Hospital and served in several leadership positions there. He became clinical director of the Massachusetts Mental Health Center and professor of psychiatry at Harvard Medical School, while continuing his research program at McLean Hospital on the biology and treatment of depression. In 1991, Dr. Schatzberg became the Kenneth T. Norris, Jr., Professor and Chairman of the Department of Psychiatry and Behavioral Sciences at Stanford University, where he served as chair until 2010. He now directs the Stanford Mood Disorders Center. Dr. Schatzberg has been an active investigator in the biology and psychopharmacology of depressive disorders. He has authored over 700 publications and abstracts and co-edited the Textbook of Psychopharmacology (now in its Sixth Edition) and the Manual of Clinical Psychopharmacology (now in its 10^th Edition. He has been president of the American Psychiatric Association (APA), the American College of Neuropsychopharmacology (ACNP), and the Society of Biological Psychiatry (SOBP). He has received numerous awards for excellence and leadership from the APA, ACNP, SOBP, Max Planck Psychiatric Institute, Brain and Behavior Foundation, Anna Monika Foundation, University of Pennsylvania, Weill Cornell Medical College, etc. He has three honorary doctorates and has been elected to the National Academy of Medicine.

Reading List

Bonaventura, Jordi, et al. “Pharmacological and behavioral divergence of ketamine enantiomers: Implications for abuse liability.” Molecular Psychiatry, vol. 26, no. 11, 15 Apr. 2021, pp. 6704–6722, https://doi.org/10.1038/s41380-021-01093-2.

Sanacora, Gerard, and Alan F Schatzberg. “Erratum: Ketamine: Promising path or false prophecy in the development of Novel Therapeutics for Mood Disorders?” Neuropsychopharmacology, vol. 40, no. 5, 13 Mar. 2015, pp. 1307–1307, https://doi.org/10.1038/npp.2014.338.

Sanacora, Gerard, and Alan F Schatzberg. “Ketamine: Promising path or false prophecy in the development of Novel Therapeutics for Mood Disorders?” Neuropsychopharmacology, vol. 40, no. 2, 26 Sept. 2014, pp. 259–267, https://doi.org/10.1038/npp.2014.261.

Schatzberg, Alan F. “A word to the wise about intranasal esketamine.” American Journal of Psychiatry, vol. 176, no. 6, 1 June 2019, pp. 422–424, https://doi.org/10.1176/appi.ajp.2019.19040423.

Schatzberg, Alan F. “A word to the wise about ketamine.” American Journal of Psychiatry, vol. 171, no. 3, Mar. 2014, pp. 262–264, https://doi.org/10.1176/appi.ajp.2014.13101434.

Williams, Nolan R., Boris D. Heifets, Brandon S. Bentzley, et al. “Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism.” Molecular Psychiatry, vol. 24, no. 12, 29 Aug. 2019, pp. 1779–1786, https://doi.org/10.1038/s41380-019-0503-4.

Williams, Nolan R., Boris D. Heifets, Christine Blasey, et al. “Attenuation of antidepressant effects of ketamine by opioid receptor antagonism.” American Journal of Psychiatry, vol. 175, no. 12, 1 Dec. 2018, pp. 1205–1215, https://doi.org/10.1176/appi.ajp.2018.18020138.

Richard J. Davidson received his Ph.D. from Harvard University in Psychology and has been at Wisconsin since 1984.  He has published more than 400 articles, numerous chapters and reviews and edited 14 books. He is the author (with Sharon Begley) of “The Emotional Life of Your Brain” published by Penguin in 2012. He is co-author with Daniel Goleman of “Altered Traits: Science Reveals How Meditation Changes Your Mind, Brain, and Body”, published by Penguin Books in 2017.

He is the recipient of numerous awards for his research including a National Institute of Mental Health Research Scientist Award, a MERIT Award from NIMH, an Established Investigator Award from the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), a Distinguished Investigator Award from NARSAD, the William James Fellow Award from the American Psychological Society, and the Hilldale Award from the University of Wisconsin-Madison. He was the year 2000 recipient of the most distinguished award for science given by the American Psychological Association –the Distinguished Scientific Contribution Award. He was the Founding Co-Editor of the new American Psychological Association journal EMOTION and is Past-President of the Society for Research in Psychopathology and of the Society for Psychophysiological Research.

In 2003 he was elected to the American Academy of Arts and Sciences and in 2004 elected to the Wisconsin Academy of Sciences, Arts and Letters. Named one of the 100 most influential people in the world by Time Magazine in 2006.  In 2006 awarded the first Mani Bhaumik Award by UCLA for advancing the understanding of the brain and conscious mind in healing. Madison Magazine named him Person of the Year in 2007. In 2008, he founded the Center for Healthy Minds, a research center dedicated to the study of positive qualities, such as kindness and compassion. In 2011 given the Paul D. MacLean Award for Outstanding Neuroscience Research in Psychosomatic Medicine. Serves on the Scientific Advisory Board at the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig from 2011-2020 and was Chair of the Psychology section of the American Association for the Advancement of Science from 2011-2013. In 2013 received the NYU College of Arts and Science Alumni Achievement Award. He is a current member of the World Economic Forum’s Global Agenda Council on Mental Health. From 1992-2017, he was a member of the Mind and Life Institute’s Board of Directors.  In 2017 elected to the National Academy of Medicine, the premier authority dedicated to the health and medical sciences. In 2018, appointed to the Governing Board of UNESCO’s Mahatma Gandhi Institute of Education for Peace and Sustainable Development (MGIEP).

His research is broadly focused on the neural bases of emotion and emotional style and methods to promote human flourishing including meditation and related contemplative practices.  His studies have included persons of all ages from birth though old age and have also included individuals with disorders of emotion such as mood and anxiety disorders and autism, as well as expert meditation practitioners with tens of thousands of hours of experience.  His research uses a wide range of methods including different varieties of MRI, positron emission tomography, electroencephalography and modern genetic and epigenetic methods.

Ned H. Kalin, MD, is Hedberg Professor and Chairman of the Department of Psychiatry at the University of Wisconsin School of Medicine and Public Health. He is the Editor in Chief of the American Journal of Psychiatry, the premier scientific journal of the American Psychiatric Association. Dr. Kalin is the Director of the HealthEmotions Research Institute and the Lane Neuroimaging Laboratory, a Professor in the Department of Psychology at the University of Wisconsin, and an affiliate scientist at the Wisconsin Regional Primate Center and the Harlow Primate Laboratory. He serves as the principal investigator for several ongoing NIH funded research projects and has published over 200 peer-reviewed journal articles related to the adaptive and maladaptive expression of emotion and anxiety. His research focuses on uncovering basic mechanisms that relate stress to the development of psychopathology and to understanding the mechanisms that cause some children to be vulnerable for the development of anxiety and depression. In addition to his research activities, he treats patients who suffer from anxiety and depression who are refractory to standard treatment.

Dr. Kalin earned his medical degree from Jefferson Medical School in Philadelphia, Pennsylvania, did his residency in the Department of Psychiatry at the University of Wisconsin, and a fellowship in Neuropsychopharmacology at the National Institute of Mental Health. Dr. Kalin is board certified by the American Board of Psychiatry and Neurology. He is a Fellow Emeritus of the American College of Neuropsychopharmacology and a Fellow of the American College of Psychiatry. He has been recognized for numerous awards including the 1985 A.E. Bennett Award for basic science research in biological psychiatry, 2005 Edward A. Strecker Award, 2007 American College of Psychiatrists Award for research in mood disorders, 2007 Gerald Klerman Senior Investigator Award, 2015 Anna-Monika Prize of the European College of Neuropsychopharmacology, Institute of Living/Hartford Hospital 2020 C. Charles Burlingame Award for compelling contributions to the field of psychiatry throughout his career , and most recently the International Society of Psychoneuroendocrinology Bruce McEwen Lifetime Achievement Award.. In 2013 he was inducted as a Fellow in the American Association for the Advancement of Science, and in 2015 he was elected as a member of the National Academy of Medicine. In 2017, Dr. Kalin was inducted as a Distinguished Life Fellow of the American Psychiatric Association. He has served as President of the International Society of Psychoneuroendocrinology and President of the Society of Biological Psychiatry, as a member of the National Advisory Mental Health Council and as Co-Editor for the international journal, Psychoneuroendocrinology. In 2019, Dr. Kalin was appointed as the Editor-in-Chief of the American Journal of Psychiatry and continues to serve as the editor today.