Tulsa, Okla. – As it is widely hoped that statistical models can improve decision-making related to medical treatments, and because the cost and scarcity of medical outcomes data can make testing data from patients in a different context prohibitive, researchers including Dr. Martin Paulus, Scientific Director and President at Laureate Institute for Brain Research (LIBR) in Tulsa, Okla., examined how well a machine learning model performed across several independent clinical trials of antipsychotic medicine for schizophrenia.
 
Researchers found models predicted patient outcomes with high accuracy within the trial in which the model was developed, but performed no better than chance when applied out-of-sample. Pooling data across trials to predict outcomes in the trial left out did not improve predictions. These results suggest that models predicting treatment outcomes in schizophrenia are highly context-dependent and may have limited generalizability.
 
The research findings, “Illusory Generalizability of Clinical Prediction Models,” were published in the January 11, 2024 edition of Science, the weekly journal of the American Association for the Advancement of Science (AAAS).
 
Researchers used treatment data from five international, multisite randomized controlled trials (RCTs) obtained through the YODA Project (https://yoda.yale.edu/), selected because of their comparability and consistency. All patients had a current DSM-IV diagnosis of schizophrenia at the start of the trial, randomized patients to an antipsychotic medication or placebo, and used the same scale to measure treatment outcomes (the Positive and Negative Syndrome Scale, PANSS). All trials also included a four-week timepoint to measure outcomes and collected similar data about the patients at baseline. The team applied machine learning methods using baseline data to predict whether a patient would achieve clinically significant improvement in symptoms over four weeks of anti-psychotic treatment. Further, the team evaluated the applicability of machine learning models across four distinct scenarios to gain insights into their generalizability: assessing within-trial performance without any external validation; employing within-trial cross-validation; assessing out-of-sample performance in a paired-trial validation; and assessing performance through an extension of the paired-trial validation with a leave-one-trial-out approach.
 
Results suggest that predictive models are fragile and that excellent performance in one clinical context is not a strong indicator of performance on future patients. Researchers from the team say this is “highly concerning” as most predictive studies today rely on internal samples for testing and validation. Further, researchers say the present study offers an “underwhelming but realistic picture of our current ability to develop truly useful predictive models” for schizophrenia treatment outcomes, and that “we should a priori remain skeptical” of any predictive model findings that lack an independent sample for validation.
 
The research team included first author Dr. Adam Chekroud, [email protected], Spring Health, Co-Founder and President, Yale University School of Medicine; Dr. Martin Paulus, [email protected], Laureate Institute for Brain Research; and collaborators from University of Cologne, Max-Planck-Gesellschaft, United Partners Consulting, LLC, Yale University School of Medicine, University Augsburg, and Yale University.
 
No funding source had any role in the study design, data collection, data analysis, data interpretation, writing, or submission of the report. All trials were originally funded by Janssen Research and Development.
 
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CONTACT: For more information about the project, contact Martin Paulus, M.D., at Laureate Institute for Brain Research at [email protected]. For press inquiries, contact: Aimee Tonquest Mehl, Kingmaker Public Relations at [email protected].
 
ABOUT LAUREATE INSTITUTE FOR BRAIN RESEARCH (LIBR)
Launched in 2009, the Laureate Institute for Brain Research (laureateinstitute.org) is home to a multidisciplinary team of scientists and clinical research staff who apply neuroimaging, generic, pharmacological and neuropsychological tools to investigate the biology of neuropsychiatric disorders. LIBR’s creation was supported by The William K. Warren Foundation for the purpose of conducting studies aimed at developing more effective treatments and/or prevention strategies for these disorders. The studies are led by scientists from diverse backgrounds, including physics, cognitive neuroscience, psychology, psychiatry, neurology, developmental neuroscience, computer science, and genetics.

Tulsa, Okla. – A trailblazing study conducted by researchers at the Laureate Institute for Brain Research (LIBR) in Tulsa, Okla., has made significant strides with a novel technique for treating anorexia nervosa (AN), an eating disorder characterized by low body weight, body image abnormalities, and anxiety. The study, “The impact of floatation therapy on body image and anxiety in anorexia nervosa: a randomized clinical efficacy trial,” appears in the peer-reviewed scientific journal eClinicalMedicine, a part of The Lancet Discovery Science initiative.
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The researchers identified several immediate and sustained effects of Floatation-REST (Reduced Environmental Stimulation Therapy) in inpatients with anorexia nervosa. Also known as “float therapy”, Floatation-REST is a non-pharmacological treatment that involves floating effortlessly in a shallow pool of warm water saturated with Epsom salt, in a lightproof, soundproof, humidity- and temperature-controlled environment, and it is increasingly used by the general public as a stress reduction tool. In the study, the anorexia nervosa inpatients randomized to receive floatation-REST reported immediate and repeated reductions in body image dissatisfaction and improved anxiety relative to a comparison group of anorexia nervosa inpatients randomized to receive care as usual, whose symptoms were unchanged. Moreover, the body image improvements in the floatation-REST group remained after the treatment and lasted for up to six months.

“This breakthrough offers a new therapeutic direction in treating anorexia nervosa, a psychiatric disorder known for its challenging prognosis and high mortality rate,” said psychiatrist Sahib Khalsa, MD, PhD, Director of Clinical Operations at LIBR, and senior author of the study. “Anxiety is a common co-occurrence in anorexia nervosa that does not respond well to standard anxiolytic medications such as benzodiazepines,” he added. “The large anxiety reductions induced by float therapy in these patients suggest that this tool presents a potent opportunity to treat anxiety via non-pharmacological means in anorexia nervosa. Additional research is needed to examine the anxiolytic effects of float therapy in other eating disorders.”

“These findings also make way for new forms of treatment for eating disorders which, in conjunction with traditional treatments, may help to alleviate diagnostic features of AN that are more difficult to treat, such as body image,” commented co-first author Emily Choquette, PhD, a clinical psychologist and postdoctoral scholar at LIBR. “The reliable and sustained effect of floatation-REST on body image dissatisfaction suggests that it may be studied as a tool to augment the effectiveness of traditional psychotherapies.”

Because anorexia nervosa is a severe and persistent psychiatric disorder, the search for effective treatments is ongoing. “This study underscores the importance of continually seeking innovative approaches and broadening the horizons of existing therapeutic options,” added Dr. Scott Moseman, MD, CEDS, Medical Director of the Laureate Eating Disorders Program. “These findings may pave the way for new forms of treatment, such as float-assisted psychotherapy, which aim to further enhance the body image and anxiety improvements obtained via existing evidence-based interventions.”

The research team was led by senior author Sahib Khalsa, MD, PhD, Director of Clinical Operations at the Laureate Institute for Brain Research, Director of the LIBR Float Clinic and Research Center, Associate Professor in the Oxley College of Health Sciences at The University of Tulsa, and conducted in close collaboration with psychiatrist Scott Moseman, MD, CEDS, Medical Director of the Laureate Eating Disorders Program from which the participants were recruited. Co-first authors on the study were Emily Choquette PhD, a post-doctoral research associate at LIBR, and Michael Flux PhD, a former lab volunteer and collaborator at LIBR. Additional collaborators included clinical neuropsychologist Justin Feinstein, PhD, President and Director of the nonprofit Float Research Collective.

The research was supported by the Laureate Institute for Brain Research and was conducted at LIBR between March 2018 and February 2021.

CONTACT: For more information about the study, contact Sahib Khalsa, MD, PhD, at Laureate Institute for Brain Research at [email protected]. 

ABOUT LAUREATE INSTITUTE FOR BRAIN RESEARCH (LIBR)
Launched in 2009, the Laureate Institute for Brain Research is home to a multidisciplinary team of scientists and clinical research staff who apply neuroimaging, genetic, pharmacological, neuropsychological and psychotherapeutic methods to investigate the neurobiology and treatment of psychiatric disorders. LIBR’s creation was supported by The William K. Warren Foundation for the purpose of conducting studies aimed at developing more effective treatments and/or prevention strategies for these disorders. The studies are led by scientists from diverse backgrounds, including psychiatry, psychology, physics, cognitive neuroscience, developmental neuroscience, population neuroscience and genetics, molecular and cellular neurobiology, and computer science.

Tulsa, Okla. – (August 7, 2023) – The Laureate Institute for Brain Research (LIBR) in Tulsa, OK has received funding through the prestigious National Institutes of Health (NIH) Director’s Pioneer Award (DP1 Mechanism) for an innovative collaborative research project “Kipiyecipakiciipe - Coming Home” between the LIBR and the Shawnee Tribe. The research will be led by Dr. Evan J. White, Principal Investigator and Director of Native American Research at LIBR. This partnership, which is supported by a $5.9 million, five-year NIH DP1 grant (DP1DA058986), aims to establish clinical cultural neuroscience as an indispensable tool in community-driven research to reduce substance misuse and disorder.
 
The goal of the project is to address substance use problems that impact Native American people at higher rates than the general population. “Being involved in traditional ways of life has many benefits, and research shows that reducing and preventing substance use is one benefit,” said White. “Our goal is to use modern clinical neuroscience to help understand the way this impacts the brain to promote substance use recovery and prevention.” The project will combine two important approaches: involving the community to consider cultural perspectives and knowledge; and using neuroscience to understand brain processes relevant for substance use disorders. “By combining these approaches, the project aims to make progress in reducing the disparities in substance use problems and understanding how the brain is involved in addiction and recovery,” added White.
 
To do this, the project will work closely with the Tribe, using brain imaging techniques to study how cultural engagement affects the brain and its relationship to substance use. “The Shawnee Tribe will help to define what cultural engagement means for the community,” continued White. “This is important because culture is a complex concept that includes many aspects of people's lives. There is deep cultural knowledge in communities about well-being and living a healthy life. In my view, our job as researchers is to use our scientific toolkit to translate this knowledge into data and information that can be used by medical policymakers and providers to promote wellbeing in Native communities.”
 
As the Shawnee Tribe builds its Behavioral & Mental Health Department, tribal leadership hopes to ensure Shawnee cultural knowledge and practices play a central role. A key component of this collaborative research project is a Community Advisory Board comprising Shawnee citizens and ceremonial leaders; the board will inform and oversee Dr. White & LIBR’s research process.
 
“Shawnee folks deserve Shawnee ways of healthcare,” said Chief Ben Barnes. “I think it’s imperative that our cultural knowledge be the bedrock of any health and human services we provide to our people. We’re extremely fortunate to have experts like Dr. White as one of our own, and I can’t wait to see what his research unravels for not only our nation but Indian Country and healthcare in general.”
 
Dr. Evan White is an enrolled Absentee Shawnee citizen with Eastern Shawnee and Shawnee Tribe ancestry on his paternal grandmother’s side. He is also a devoted husband and father to two young children, a Shawnee Language Immersion Program student, and actively involved at the White Oak ceremonial grounds and in the Native American Church of Oklahoma.
 
The funding program to which Dr. White’s team at LIBR applied—the NIH Director’s Pioneer Award mechanism—seeks to identify scientists with high-impact ideas that may be risky or at a stage too early to fare well in the traditional peer review process. The mechanism is designed to support a small number of investigators of exceptional creativity who propose bold and highly innovative research approaches with the potential for high impact on significant problems in any area relevant to NIH. Depending on funding, approximately 7 applications are expected to be funded each year. During the years 2018-2022, the success rate for applicants was 4.5%.
 
“The project’s results will provide valuable information on how cultural factors can protect against substance use problems. It will also serve as a model for studying cultural factors in other minority groups, and social determinants of health broadly with the goal of improving health for everyone,” commented White.

The research team will be led by principal investigator Evan J. White, Ph.D., Principal Investigator, Director of Native American Research, Director of Electroencephalography Core at LIBR and Research Associate Professor in the Oxley College of Health Sciences at The University of Tulsa. Kyle Miller, Director of Behavior and Mental Health, will be the lead investigator from the Shawnee Tribe and primary liaison between the LIBR team and the Community Advisory Board.
 
Dr. White’s research for this project will continue through mid-2028. News and outcomes from the study will be published online through the National Institutes of Health’s RePORTER tool.
 
Scan here to see “Kipiyecipakiciipe – Coming Home” on RePORTER: [QR code to https://reporter.nih.gov/search/NWnyJ1uLq0qH2IJPRzZBdg/project-details/10740237]
 
“Kipiyecipakiciipe - Coming Home” is supported by the National Institute on Drug Abuse of the National Institutes of Health under Project Number DP1DA058986. The content reported in this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 
 
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CONTACT: For more information about the project, contact Evan J. White, Ph.D. at Laureate Institute for Brain Research at [email protected].
 
ABOUT LAUREATE INSTITUTE FOR BRAIN RESEARCH (LIBR)
Launched in 2009, the Laureate Institute for Brain Research (laureateinstitute.org) is home to a multidisciplinary team of scientists and clinical research staff who apply neuroimaging, genetic, pharmacological, neuropsychological and psychotherapeutic methods to investigate the neurobiology and treatment of psychiatric disorders. LIBR’s creation was supported by The William K. Warren Foundation for the purpose of conducting studies aimed at developing more effective treatments and/or prevention strategies for these disorders. The studies are led by scientists from diverse backgrounds, including psychiatry, psychology, physics, cognitive neuroscience, developmental neuroscience, population neuroscience and genetics, molecular and cellular neurobiology, and computer science.
 
ABOUT THE SHAWNEE TRIBE
The Shawnee Tribe is a sovereign nation of more than 4,000 citizens living across North America and abroad. Tribal headquarters are located in Miami, Oklahoma. For more information, visit shawnee-nsn.gov. 

Tulsa, Okla. – A pioneering study conducted by researchers at the Laureate Institute for Brain Research (LIBR) in Tulsa, Okla., has made significant strides in understanding the elusive gut-brain connection, a complex relationship that has long puzzled scientists due to the difficulty of accessing the body's interior. The study, “Parieto-occipital ERP indicators of gut mechanosensation in humans,” appears in the peer-reviewed scientific journal Nature Communications.
 
The research team successfully had participants swallow a minimally invasive vibrating capsule to measure neural responses during gastrointestinal stimulation, providing a novel approach to study this intricate connection. The capsule was developed by Vibrant Ltd. Participants in the study included healthy adult male and female volunteers ages 18-40. The researchers found that the volunteers were able to sense the stimulation of the vibrating capsule under two conditions: normal and enhanced. The enhanced stimulation condition led to improved perceptual accuracy, faster detection of the stimulation, and reduced variability in reaction time, indicating potential for studying this method in different clinical populations. This is a significant breakthrough as it demonstrates the feasibility of this novel approach to studying gut feelings.
 
The researchers also discovered the “gastric evoked potential,” a late neural response in certain areas of the brain specifically induced by capsule stimulation. These neural responses increased in amplitude depending on the intensity of the stimulation and were significantly correlated with perceptual accuracy. This discovery provides a new way to measure and understand the neural processes governing the gut-brain connection.
 
“We were able to localize most of the capsule stimulations to the gastroduodenal segments of the digestive tract using abdominal X-ray imaging,” said Dr. Sahib Khalsa, a psychiatrist and neuroscientist at LIBR, and senior author of the study. “This finding is crucial as it provides a more precise understanding of where these gut-brain interactions are originating.”
 
“The potential clinical implications for the results of this study are substantial,” said Dr. Khalsa. “The vibrating capsule method could transform the clinical approach to disorders of gut-brain interaction, including eating disorders and certain gastrointestinal disorders such as irritable bowel syndrome (IBS) or functional dyspepsia.”
 
Dr. Khalsa continued. “This would provide a much-needed tool for assessing gut sensation in these conditions and could lead to more personalized and effective treatment strategies. It also opens up the possibility of identifying perceptual or biological mediators of successful treatment, which could serve as predictive markers for future therapeutic interventions.”
 
The research team was led by senior author Sahib Khalsa, MD, PhD, Director of Clinical Operations at the Laureate Institute for Brain Research and Associate Professor in the Oxley College of Health Sciences at The University of Tulsa. Co-first authors on the study were Ahmad Mayeli, PhD and Obada Al Zoubi, PhD who were a PhD student and postdoctoral scholar, respectively, from LIBR at the start of the project.
 
The research was supported by the National Institute of Mental Health and the Laureate Institute for Brain Research and was conducted at LIBR between September 2019 and February 2022.
 
CONTACT: For more information about the project, contact Sahib Khalsa, MD, PhD, at Laureate Institute for Brain Research at [email protected]. 

Tulsa, Oklahoma – Researchers at the Laureate Institute for Brain Research (LIBR) in Tulsa, OK, have identified an abnormal link between the autonomic and central nervous systems, specifically via communication between the heart and part of the brain’s frontal cortex, in women with generalized anxiety disorder (GAD). The team’s objective was to test whether individuals suffering from GAD show dysfunction in the neural circuitry underlying cardiovascular arousal and whether that may be associated with certain disorder-related symptoms such as anxiety and body sensation. To conduct the study, they completed a randomized clinical trial of 58 adult female participants (29 with GAD and 29 matching healthy comparisons). During the study they stimulated the cardiovascular system using a medicine called isoproterenol, which mimics the effects of adrenaline but, unlike adrenaline, cannot cross the blood-brain-barrier to directly impact brain activity. Intravenous infusions of isoproterenol or saline were administered during functional magnetic resonance imaging, allowing them to assess whether the brains of patients with GAD differ in the processing of information received from the body, a function known as ‘interoception’. The main findings were that patients with GAD differed significantly from healthy participants on several variables, but only during the lower of two dosages of isoproterenol. Specifically, they perceived their heartbeats to be more intense and had relatively higher heart rates and lower neural activity in the ventromedial prefrontal cortex, a brain area known to regulate the autonomic nervous system and to facilitate feelings of fear or safety. Self-reported anxiety was significantly higher only for those with GAD compared to healthy participants in response to either dose.
 
The research findings, “Association of Generalized Anxiety Disorder with Autonomic Hypersensitivity and Blunted Ventromedial Prefrontal Cortex Activity During Peripheral Adrenergic Stimulation,” were published in the February 2, 2022 edition of JAMA Psychiatry.
 
For lead author Adam Teed, a postdoctoral associate at LIBR, the fact that the abnormal results observed for those with GAD occurred during lower, but not higher, doses of medicine was the primary finding from the study: “administering isoproterenol allowed us to provide causal evidence that an abnormally sensitive cardiovascular system and an abnormally insensitive frontal cortex in GAD patients lowers their ability to regulate bodily arousal. This could help to explain why they experience anxiety so frequently and in a wide variety of contexts.” The authors hope that their study prompts further research into the ventromedial prefrontal cortex as a therapeutic target for novel treatments helping individuals with GAD to regulate physiological and emotional responses to stress.
 
Beyond the novel link revealed by this study, it is noteworthy that cardiovascular hypersensitivity was observed for GAD patients at all. This is because the Diagnostic and Statistical Manual of Mental Disorders (DSM–5), the standard classification system used by mental health professionals in the United States, describes autonomic symptoms such as sweating, rapid heart rate, or shortness of breath, as being less prominent in GAD than other anxiety disorders, such as panic disorder. As senior author Sahib Khalsa, MD, PhD, a psychiatrist and principal investigator at LIBR puts it, “this study shows us that anxiety is not only something that happens within our brains but within our bodies as well.” Thus, these findings show that abnormal functioning of the autonomic nervous system is not only a factor in GAD, but it occurs in combination with abnormal functioning of certain areas of the brain. Such associations are what Dr. Khalsa believes to be the most important product of this research: “it is the interaction between our brain and body that may be essential for determining whether an innocuous situation creates a state of fear in individuals with GAD. We need to better understand how this abnormal physiological response relates to the functional impairments that commonly interfere with the daily lives of such individuals.”
 
The research team was led by senior author Sahib Khalsa, MD, PhD, also an associate professor in the Oxley College of Health Sciences at The University of Tulsa, and lead author Adam Teed, PhD, and included others from LIBR as well as The University of Oklahoma (OU), the University of California at Los Angeles (UCLA), and the University of California at San Diego (UCSD).
 
The research was supported by the National Institute of Mental Health, The William K. Warren Foundation, and the National Institute of General Medicine Sciences and was conducted at LIBR between January 2017 and November 2019.
 
CONTACT: For more information about the project, contact Sahib Khalsa, MD, PhD, at Laureate Institute for Brain Research at [email protected]. ​

​Drs. Sahib Khalsa and Robin Aupperle appeared on Good Day Tulsa this morning to discuss a mobile health application developed during the 4-year Tulsa 1000 study at LIBR. The Tulsa Life Chart (TLC), uses information provided during a survey to create a web-based graphic representation of an individual's life history to make it easier for clinicians to effectively diagnose and provide treatment for medical and mental health conditions.

Full publication: Web-Based Graphic Representation of the Life Course of Mental Health: Cross-Sectional Study Across the Spectrum of Mood, Anxiety, Eating, and Substance Use Disorders