Traditionally, neuroscience and psychiatric disorders have been studied through tissue sourced exclusively from postmortem donations. This has perpetuated the assumption that molecular profiles obtained from deceased brain tissue adequately reflect the molecular state of living brains. However, this assumption remained largely untested due to the rarity and technical complexity of collecting living brain samples. Mount Sinai’s Living Brain Project has now systematically addressed this gap by developing a safe, scalable biopsy technique that harvests small quantities of brain tissue during deep brain stimulation (DBS) surgeries.

Leveraging transcriptomics, which scrutinizes the comprehensive expression of RNA transcripts, alongside proteomics, the large-scale analysis of protein content, the researchers studied approximately 300 samples extracted from the prefrontal cortex of living patients undergoing neurosurgical procedures. The project’s methodological sophistication allowed for intricate comparisons between living brain tissue and standard postmortem samples, exposing profound discrepancies that have important implications for brain science and disease research.

The centerpiece publication in Molecular Psychiatry lays this foundation, providing compelling evidence that gene expression profiles acquired from postmortem brains do not always faithfully mirror the gene expression in living brain tissue. This gap in molecular congruence spans across neurological and psychiatric disease signatures as well as normative phenotypes such as aging. As such, this research cautions against overreliance on postmortem data to model living brain function and pathology without validation.

Alexander W. Charney, MD, PhD, co-leader of the Living Brain Project and Director of The Charles Bronfman Institute for Personalized Medicine, underscores the profound significance of these findings. He calls for an integrative approach to brain research that incorporates the molecular insights gleaned exclusively from living tissue to complement traditional postmortem studies. His remarks emphasize that these revelations enhance, rather than diminish, the value of postmortem research by highlighting the vital, previously inaccessible molecular dimension of living brain tissue.

Expanding upon these insights, the subsequent PLOS ONE publication explores the molecular underpinnings in even greater biochemical depth—specifically, RNA splicing, intron usage, and proteomic variation. This study unveils an extraordinary degree of difference, with over 60% of proteins and a staggering 95% of RNA transcripts processed or expressed differently when comparing living brain tissue with postmortem samples. These disparities emphasize the dynamic and context-dependent nature of brain molecular biology that is lost upon death.

Brian Kopell, MD, Director of Mount Sinai’s Center for Neuromodulation and lead author of the PLOS ONE study, articulates the sheer scale of these differentiated molecular phenomena. He notes that nearly all RNA transcripts examined exhibited altered primary or mature RNA levels or splicing rates in the living brain versus postmortem brain. Importantly, even key interactions between RNA and protein co-expression networks were disrupted in postmortem samples, suggesting that molecular dysregulation post-death goes beyond mere static degradation.

Building on these discoveries, this research advocates for a transformative shift in brain biobanking. With millions worldwide undergoing neurosurgical interventions annually, the feasibility of systematically collecting living brain tissue for diverse biomedical research objectives is within reach. This could catalyze revolutionary advances in deciphering real-time molecular changes related to mood regulation, cognitive processing, and therapeutic responsiveness in a wide array of neuropsychiatric disorders and normal brain functions.

The safety profile of the tissue collection technique developed by the team ensures that brain biopsies can be conducted without compromising patient outcomes, offering a scalable method to construct living brain tissue libraries. Such biobanks would support an unprecedented level of molecular neuroscience inquiry with longitudinal and personalized data sets, reshaping biomedical research trajectories over the decades ahead.

Mount Sinai Health System, the institutional powerhouse behind the Living Brain Project, exemplifies cutting-edge clinical and scientific integration. Housing expansive research infrastructure—including hundreds of clinical and research labs and a vast clinician-scientist workforce—it remains at the vanguard of medical innovation. Their multidisciplinary approach harnesses advances in AI, informatics, and personalized medicine to address complex neurological conditions through a molecular lens.

Beyond the hospital and lab, Mount Sinai’s commitment extends to education and community outreach, ensuring that these transformative discoveries translate into tangible therapeutic breakthroughs and enhanced care paradigms accessible to all patients. The system’s standing—repeatedly validated through top rankings in national and global hospital assessments—affirms its capacity to spearhead bold initiatives like the Living Brain Project.

As neuroscience embraces these revelations, the research community faces a paradigm recalibration. Understanding the living human brain at the molecular level will no longer be extrapolated solely from postmortem proxies. Instead, it will derive directly from the tissue of living subjects, powering forward novel insights into brain health, disease mechanisms, and precision interventions that can drastically improve lives worldwide.

Subject of Research: People

Article Title: A study of gene expression in the living human brain

News Publication Date: 23-Aug-2025

Web References:

• https://icahn.mssm.edu/research/friedman/living-brain
• https://www.nature.com/articles/s41380-025-03163-1
• https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0332651

References:

• Molecular Psychiatry (DOI: 10.1038/s41380-025-03163-1)
• PLOS ONE (2025 study on RNA splicing and protein expression differences)

Image Credits: Mount Sinai Health System

Keywords:
Molecular neuroscience, Human brain, Proteomics, Omics, Brain, Brain tissue

Dr. Cohen’s laboratory has pioneered the application of induced pluripotent stem cell (iPSC) technology to generate patient-specific brain cells in vitro, allowing detailed exploration of molecular and metabolic anomalies otherwise inaccessible in living individuals. “We now have tools giving us leads we lacked forty years ago,” he explains, highlighting how these experimental models reveal consistent abnormalities in mitochondrial energy metabolism that impair neuronal signaling and resilience. These findings suggest that impaired cellular bioenergetics are not secondary effects but fundamental contributors to neuropsychiatric illness pathophysiology. By identifying precise metabolic targets, Dr. Cohen’s approach paves the way for developing innovative therapeutics aimed at restoring cellular energy balance, potentially altering the disease course rather than merely alleviating symptoms.

The implications of these discoveries are profound, marking a paradigm shift in psychiatric science. Traditionally, research emphasis has rested on the neurotransmitter imbalances presumed to cause mental disorders; however, Dr. Cohen’s metabolic perspective reframes psychiatric conditions as systemic disorders rooted in cellular dysfunction. His lab has demonstrated that neurons derived from patients with schizophrenia, bipolar disorder, and Alzheimer’s disease exhibit intrinsic metabolic deficits detectable before clinical symptom onset, underscoring opportunities for early intervention. This places bioenergetic dysfunction at the forefront of potential preventive therapies, a notion that could revolutionize clinical practices worldwide by enabling interventions before irreversible brain damage and functional decline.

Equally transformative is Dr. Cohen’s critique of conventional diagnostic frameworks in psychiatry, which rely heavily on categorical labels like “schizophrenia” and “bipolar disorder.” He advocates for a dimensional approach that replaces rigid categories with symptom-based spectra reflecting biological and clinical heterogeneity. This approach not only reduces stigma but aligns psychiatric nosology with emerging biological data, enhancing diagnostic precision and personalizing treatment strategies. The dimensional model accounts for variability in symptom expression across individuals and cultures, offering a universal language better suited for global application. Such a system would facilitate the formation of more homogeneous research cohorts, accelerating discovery while improving clinical outcomes through targeted therapies attuned to distinct symptom profiles.

Dr. Cohen’s multidisciplinary methodology exemplifies cutting-edge science by integrating genomics, neuroimaging, and cellular models, producing a richly detailed picture of neuropsychiatric disorder mechanisms. Genomic analyses identify risk variants; brain imaging delineates structural and functional abnormalities; and iPSC-derived neuronal cultures enable experimental manipulation and therapeutic screening. This synergy lends unparalleled power to uncover disease-relevant pathways and potential pharmacological targets, setting a new standard for international psychiatric research. As Dr. Cohen explains, “Understanding the biological complexity requires tools from multiple disciplines, combining molecular data with clinical observations to unravel these enigmatic disorders.”

Beyond the laboratory, Dr. Cohen’s tenure as President and Psychiatrist-in-Chief at McLean Hospital illustrates the real-world impact of his vision. From 1997 to 2005, he led significant institutional reforms that reversed financial decline and fostered a culture of innovation and compassionate care. His leadership emphasized empowering frontline clinicians and minimizing bureaucracy, strategies that resulted in expanded clinical programs, increased research funding, and enhanced educational opportunities. Under his stewardship, McLean pioneered community-focused initiatives including Waverley Place, a peer-run support center designed to integrate mental health care with societal reintegration, demonstrating how psychiatric institutions can balance mission-driven service provision with financial sustainability.

Dr. Cohen’s personal journey deeply informs his scientific philosophy. His early fascination with physics and mathematics instilled a rigorous analytic mindset that propelled his psychiatric research. The turning point came during medical training when witnessing a young patient’s remarkable recovery on psychotropic medication solidified his commitment to psychiatry’s transformative potential. Despite personal challenges, including social anxieties, he underscores perseverance and intellectual curiosity as drivers of scientific success. His enduring family support, notably from his prominent internist father and long-standing marriage, provides a grounding that sustains his demanding career. This human dimension enriches the narrative, illustrating how personal and professional experiences intertwine to propel scientific advancement.

Looking ahead, Dr. Cohen expresses guarded optimism about the trajectory of psychiatric research. He highlights the emergence of targetable mechanisms shaping illness risk and underscores the feasibility of preventive interventions, especially as psychotic disorders and dementias typically emerge after adolescence and late adulthood respectively. Advances in cellular reprogramming and high-throughput genomic technologies democratize access to cutting-edge tools, enabling a global scientific community to accelerate discovery. Dr. Cohen calls for broader support of unconventional ideas and early-career investigators, cautioning against funding biases favoring incremental “next step” research within established paradigms. His inclusive vision aligns with open-access models championed by organizations like Genomic Press, ensuring that breakthroughs transcend institutional and geographical barriers.

This richly detailed interview embodies the essence of innovation in psychiatric research — merging molecular biology, clinical insight, and compassionate leadership to unravel one of medicine’s most challenging frontiers. Dr. Bruce M. Cohen’s multidisciplinary approach not only elucidates complex determinants of psychiatric disorders but offers a blueprint for global scientific collaboration and clinical transformation. His insights invite a reimagination of psychiatry’s future — one that embraces biological complexity, fosters diagnostic precision, and prioritizes prevention, ultimately aiming to alleviate the profound human burden of mental illness worldwide.

Subject of Research: People

Article Title: Bruce M. Cohen: An eclectic life and a multidisciplinary approach to the complex determinants and diverse presentations of psychiatric disorders

News Publication Date: 14 October 2025

Web References: http://dx.doi.org/10.61373/gp025k.0104

Image Credits: Bruce M. Cohen

Keywords: neuropsychiatric disorders, mitochondrial dysfunction, induced pluripotent stem cells, energy metabolism, psychiatric diagnostics, dimensional model, genomics, brain imaging, schizophrenia, bipolar disorder, Alzheimer’s disease, psychiatric research innovation

Kasper’s early academic formation was deeply influenced by his exposure to brain anatomy, which sparked his curiosity about neural substrates of psychiatric disorders. This foundation was significantly strengthened during his studies at the Central Institute of Mental Health in Mannheim, Germany. It was here that Kasper linked Michel Jouvet’s seminal animal research on lesions to the raphe nuclei—a critical serotonergic brainstem cluster—with the prominent sleep disturbances evident in depressed patients. This connection challenged the then-prevailing norepinephrine theory of depression and pivoted research focus towards serotonin’s central role, sparking a paradigm shift in understanding mood regulation at a neurochemical level.

The significance of Kasper’s insight cannot be overstated. By identifying the serotonergic system as a crucial modulator in depression, Kasper laid groundwork that would lead to the development and clinical adoption of selective serotonin reuptake inhibitors (SSRIs). These compounds became a cornerstone of antidepressant therapy due to their ability to enhance synaptic serotonin availability, thus alleviating depressive symptoms. Kasper’s clinical acumen and laboratory investigations bridged the translational gap, moving from theoretical neuroscience to tangible patient outcomes, a hallmark of his scientific philosophy.

Extending beyond pharmacology, Kasper’s research pursued circadian biology and its relationship to mood disorders. During his tenure at the National Institute of Mental Health in the United States, he spearheaded the first epidemiological studies correlating latitude and seasonal affective disorder (SAD), revealing intriguing geographic variations in mood symptomatology. These findings illuminated how environmental factors interplay with neurobiological mechanisms, a complex interface that requires multi-disciplinary research approaches to fully elucidate.

Kasper’s methodological innovation is epitomized by his advocacy for “back-translation”—the iterative process by which clinical observations inform basic science hypotheses, which in turn guide improved clinical interventions. Rather than unidirectional bench-to-bedside science, this bidirectional dialogue optimizes research relevance and accelerates discovery. His work exemplifies this approach, particularly visible in his early recognition of the mood-enhancing effects of transcranial magnetic stimulation (TMS), initially discovered serendipitously through epileptology collaborators. After personally verifying TMS’s safety and efficacy, Kasper championed its adoption for treatment-resistant depression, pioneering non-invasive neuromodulation therapies now deployed worldwide.

Kasper’s contributions extend into psychopharmacology beyond depression. He extensively researched atypical antipsychotics, scrutinizing their unique receptor profiles which confer efficacy not only against schizophrenia’s positive symptoms but also depressive and negative symptoms traditionally resistant to treatment. These agents exhibit improved side effect profiles compared to earlier generations, facilitating better patient adherence and quality of life. Kasper’s work in this domain has helped reconfigure schizophrenia treatment paradigms, influencing prescribing practices globally.

At the organizational level, Kasper has been a formidable force in shaping psychiatric research agendas and clinical standards through leadership of key international bodies. As the founding president of the Austrian Society of Neuropsychopharmacology and Biological Psychiatry and former leader of the World Federation of Societies of Biological Psychiatry and International College of Neuropsychopharmacology, Kasper helped unify disparate research efforts. His stewardship fostered global collaboration, standardized research methodologies, and accelerated the translation of neuroscience discoveries into clinical guidelines.

A testament to his impact is evident in his leadership of the European Group for the Study of Resistant Depression, which synthesized data from over 3000 patients across Europe. Their consensus criteria for treatment-resistant depression have gained regulatory endorsement, including adoption by the European Medicines Agency, and informed the development of intranasal esketamine — a novel, rapid-acting antidepressant therapy addressing an unmet clinical need. This collaborative effort has recalibrated clinical thinking about treatment resistance and expanded therapeutic options for patients worldwide.

Kasper’s career honors encompass Austria’s most prestigious decorations, reflecting national and international recognition of his scientific excellence. Awards such as the Grand Decoration of Honor in Silver, the Austrian Cross of Honor for Science and Art First Class, and the 2025 CINP Pioneer Award underscore his transformative role in psychiatric science. These accolades celebrate not only research achievements but also his dedication to mentoring emerging scientists, thereby ensuring sustained advancement in the field through successive generations.

Beyond empirical rigor, the interview reveals Kasper’s humanistic philosophy toward research and patient care. He emphasizes attentive listening to patients combined with a vigilant engagement with scientific literature, embodying Louis Pasteur’s dictum that “chance favors only the prepared mind.” This approach reflects a scientific temperament that is both curious and disciplined, recognizing that breakthrough discoveries often arise at the intersection of careful observation and robust experimentation.

Kasper also shares personal facets that illuminate the broader context of his scientific creativity. His affinity for nature, time spent at his informal research retreat in Puglia, Italy, and companionship with his Lakeland terrier provide a grounded, holistic perspective on the scientific endeavor. These elements highlight how diverse life experiences and environmental inspiration can fuel innovative thinking in medical research, humanizing the portrait of a celebrated scientist.

This comprehensive Genomic Press interview is part of the Innovators & Ideas series, which spotlights leading figures advancing fundamental biomedical knowledge and its clinical translation. Kasper’s narrative offers a compelling blend of personal reflection and technical insight, illustrating the profound impact that a single visionary scientist can have on an entire discipline. By weaving rigorous research with human storytelling, the interview resonates widely, offering both scientific inspiration and a meaningful connection to the individuals driving progress.

For readers and researchers keen to explore the full interview, it is freely accessible via Open Access in the September 2, 2025 issue of Brain Medicine. This journal serves as a critical platform for cross-disciplinary research spanning basic neuroscience to clinical neurology and psychiatry, committed to understanding and treating brain disorders with innovation and scientific excellence.

Subject of Research: People

Article Title: Siegfried Kasper: The importance of back-translation of clinical findings to basic science

News Publication Date: 2-Sep-2025

Web References: http://dx.doi.org/10.61373/bm025k.0104

Image Credits: Credit: Siegfried Kasper, MD

Keywords: Siegfried Kasper, biological psychiatry, treatment-resistant depression, selective serotonin reuptake inhibitors, atypical antipsychotics, transcranial magnetic stimulation, circadian rhythms, seasonal affective disorder, back-translation, psychiatric research, neuroscience, intranasal esketamine