2021 Leading Research Achievements
We are pleased to present you with the 2021 Leading Research Achievements by BBRF Grantees, Prizewinners & Scientific Council Members. They are presented in the order of their publication in scientific journals.
Low Maternal Vitamin D in Early Pregnancy Is Linked With ADHD Risk in the Child
Diagnostic Tools/Early Intervention: ADHD
- Andre Sourander, M.D., Ph.D., University of Turku, Finland; 2008 BBRF Independent Investigator
Researchers discovered that a low level of maternal vitamin D during the early part of pregnancy raises the odds that a child born of that pregnancy will develop clinically diagnosed ADHD by adolescence. The team studied 1,067 mother-child pairs in which the child was diagnosed with ADHD within 12 years of birth, and an equal number of mother-child pairs, matched demographically, in which the child was not diagnosed with ADHD. Maternal vitamin D levels were based on blood samples taken in the first or early second trimester of pregnancy. Vitamin D receptors, expressed in the brain, help regulate calcium signaling between brain cells; the nutrient also impacts factors which help neurons mature and grow. It is theorized that vitamin D depletion can lead to alterations in dopamine signaling, possibly giving rise to "hyperlocomotion" and increased activity. Read more.
Journal of the American Academy of Child & Adolescent Psychiatry, January 1, 2021
New Technology Enables Manipulation of Neurons in Peripheral Organs & Reveals Mechanism of Appetite Suppression
New Technologies: Eating Disorders
- Sung Il Park, Ph.D., Texas A&M University; 2018 BBRF Young Investigator
Dr. Park and colleagues invented a new technology called optoelectronics that enabled them to activate and deactivate neurons in peripheral organs via tiny wireless devices. Testing it, they discovered an unexpected mechanism for suppressing appetite. In contrast to optogenetic technology, which can manipulate neuronal activity within the brain only, optoelectronic devices can be implanted successfully in peripheral organs. The focus of team's test were endings of the vagus nerve within the stomach, known to be important in the regulation of appetite. By activating specific vagus nerve endings in a specific area of the stomach in mice, appetite was suppressed—to the point of almost complete suppression when the stimulation ¬was increased in intensity. This could have future implications in the treatment of eating disorders as well as obesity. Read more.
Nature Communications, January 8, 2021
Repeated Ketamine Infusions Over 2 Weeks Significantly Reduced Chronic PTSD Symptoms
Next-Generation Treatments: PTSD
- Adriana Feder, M.D., Ichan School of Medicine at Mount Sinai; 2015 BBRF Independent Investigator, 2002 BBRF Young Investigator
A small clinical trial showed that repeated infusions of the drug ketamine over a 2-week period can significantly reduce PTSD symptom severity, while also helping to reduce depression symptoms that often accompany PTSD. The first randomized study to test the efficacy of a course of repeated infusions in individuals with PTSD, the study recruited 30 chronic PTSD patients with moderate to severe symptoms, half of whom received 6 infusions of ketamine over 2 weeks while half received placebo infusions. Those responding to ketamine (reduction in symptoms of 30% of more) were followed until their symptoms returned. The positive results suggest the team can now test whether FDA-approved esketamine has similar benefits in chronic PTSD; and whether psychotherapy, added to a course of ketamine or esketamine, might reduce the likelihood of relapse once the infusions end. Read more.
American Journal of Psychiatry, February 1, 2021
Study Links Schizophrenia Medicines’ Anticholinergic Impact to Risk of Cognitive Impairment
Diagnostic Tools/Early Intervention; Basic Research: Schizophrenia, Psychosis
- Yash B. Joshi, M.D., Ph.D., University of California, San Diego; 2018 BBRF Young Investigator
- Gregory A. Light, Ph.D., University of California, San Diego; 2009 BBRF Independent Investigator, 2001 BBRF Young Investigator
A study of antipsychotic and other medications commonly prescribed to people with chronic schizophrenia and has concluded that medicines with anticholinergic effects can "substantially" contribute to the risk of long-term cognitive impairment. The study assessed the total burden of anticholinergic medications (blocking action of the neurotransmitter acetylcholine) taken by 1,120 chronic schizophrenia outpatients, many of whom take medicines for comorbid health conditions that also have anti-cholinergic effects. Overall, 63% of participants had a significant burden, which the team associated with generalized impairments in cognitive functioning. Results, if validated, could help guide prescribing physicians make medication decisions that reduce patients' cognitive impairment risk. Read more.
American Journal of Psychiatry, May 14, 2021
Brain Lesions and Treatment Targets in Depression Are Found to Affect the Same Circuitry, Suggesting New Treatment Possibilities
Basic Research; Next-Generation Therapies: Depression
- Shan H. Siddiqi, M.D., Harvard Medical School, Brigham & Women's Hospital; BBRF Scientific Council, 2019 BBRF Young Investigator
Researchers discovered that the brain circuitry underlying depression is the same or similar in a wide variety of patients and circumstances. Specifically, their work revealed that physical brain damage, or "lesions," that result in depression affect the same or similar brain circuitry as the circuitry targeted by both invasive and non-invasive brain stimulation therapies that alleviate depression symptoms. These and other results of the study could lead to identification of new treatment targets in depression and possibly other neuropsychiatric disorders. Read more.
Nature Human Behaviour, July 8, 2021
Excessive Sensory Response at Birth May Signal Risk for Later Anxiety, Research Suggests
Basic Research; Diagnostic Tools/Early Intervention: Anxiety
- Chad M. Sylvester, M.D., Ph.D., Washington University, St. Louis; 2017 BBRF Young Investigator
The response of various brain systems to unexpected stimuli provides insights into processes in the brain that enable individuals to respond to salient information and to suppress responses to stimuli that are not relevant or helpful in a given context. New evidence in infants connects sensory overresponse to unexpected auditory stimuli and risk of anxiety disorder. Brain network activity levels in the newborns were shown to be correlated with their mothers' scores on a standard measure of anxiety, suggesting their potential utility as biomarkers. In older children and adults with anxiety disorder, researchers have noted weakened inhibitory responses. Results of this study suggest neural stimulus-response properties near birth signal risk for processes in the brain that generate later-life anxiety and elevated risk in adulthood of depression, substance-use disorders, eating disorders, and bipolar disorder. Read more.
American Journal of Psychiatry, August 1, 2021
Positive Preliminary Results in Highly Personalized Deep-Brain Stimulation Therapy for Treatment-Resistant Depression
Next-Generation Therapies: Depression
- Katherine W. Scangos, M.D., Ph.D., University of California, San Francisco; 2018 BBRF Young Investigator
- Andrew D. Krystal, M.D., University of California, San Francisco; 1997, 1993 BBRF Young Investigator
Researchers reported initial success in using a novel, highly personalized, and technologically advanced deep-brain stimulation (DBS) approach to rapidly relieve symptoms, eliminate suicidal thoughts, and by 4 months, achieve remission in a patient with lifelong and severe treatment-resistant depression. The team used a form of brain stimulation called closed-loop neuromodulation, in which prior extensive mapping of the patient's neural circuitry preceded the implantation, via surgery, of a battery-powered deep-brain stimulation (DBS) device. The device was "tuned" to activate briefly (in 6-second bursts) throughout each day in response to signals within the brain sensed by the device and which had been linked with the onset of the patient's depressed moods. Read more.
Nature Medicine, October 4, 2021
Non-Invasive Brain-Stimulation Protocol for Treatment-Resistant Depression Enabled 79% to Experience Remission Following 5-Day Treatment Course
Next-Generation Treatments: Depression
- Nolan R. Williams, M.D., Stanford University; 2019 BBRF Klerman Prize; 2018, 2016 BBRF Young Investigator
In its first randomized, placebo-controlled test, an enhanced form of non-invasive brain stimulation called SNT (Stanford Neuromodulation Therapy, formerly called SAINT) generated "a large antidepressant effect" that enabled 79% of treatment-resistant patients to experience remissions within 4 weeks of the conclusion of the 5-day course of treatment. Over a 4-week period following the treatment course, over 85% of participants who received SNT responded (symptom reduction of 50% or greater). In addition to other possible applications, the brevity of the SNT treatment course compared with standard rTMS therapy and its high rate of effectiveness suggests its potential utility in treating patients in emergency or inpatient settings. Read more.
American Journal of Psychiatry, October 29, 2021
Two Signaling Pathways Involved in Regulating Synaptic Plasticity Suggest Novel Targets for Rapid-Acting Antidepressants
Basic Research, Next-Generation Treatments: Depression
- Kanzo Suzuki, Ph.D., Vanderbilt University; 2018 BBRF Young Investigator
- Ege Kavalali, Ph.D., Vanderbilt University; 2012 BBRF Distinguished Investigator
- Lisa Monteggia, Ph.D., Vanderbilt University; BBRF Scientific Council, 2014 BBRF Distinguished Investigator, 2010 BBRF Independent Investigator, 2005 BBRF Freedman Prize, 2003, 2001 BBRF Young Investigator
Researchers reported the involvement of two chemical signaling pathways in generating homeostatic plasticity, which they suggest plays a key role in rapid anti-depressant action such as that seen following the administration of the drug ketamine. The research could advance the search for novel drugs that will have ketamine's rapid action, but fewer side effects. It suggests how changes in pathways "downstream" of the NMDA receptor—thought to be the target of ketamine and precipitated by ketamine's blockade of the receptor—may produce homeostatic plasticity, which appears to modulate circuit function globally in the brain, and does not directly affect synaptic plasticity mechanisms that process and store information. Drugs targeting homeostatic mechanisms thus might preserve memory and cognitive function. Read more.
Cell Reports, November 2, 2021
Researchers Propose a New Understanding of Dopamine's Role in Learning and Memory
Basic Research: Addiction
- Erin S. Calipari, Ph.D., Vanderbilt University; 2016 BBRF Young Investigator
- Munir Gunes Kutlu, Ph.D., Vanderbilt University; 2019 BBRF Young Investigator
Researchers proposed a markedly new way of understanding the role of dopamine in the brain. Ubiquitous throughout the brain and body, and serving a variety of functions, dopamine has long been regarded as key to the brain’s reward system, and thus has often been thought of as playing a key role in the biology of addiction. Dysregulation of the dopamine system has also been hypothesized in depression, anxiety, and schizophrenia. For the last 20 years, dopamine has been thought to be central in a mechanism that enables individuals to adapt once expected rewards do not materialize. The new research suggests "reward-prediction error" is only part of what dopamine does. While rewards increase dopamine levels in the brain, so do stressful stimuli: dopamine helps encode information about all types of important and relevant events and drives adaptive behavior—regardless of whether it is positive or negative. The revised view has potentially broad implications for our understanding of behavioral control and a number of psychiatric disorders. Read more.
Current Biology, November 8, 2021
2021 Leading COVID-Related Discoveries
- Donald C. Goff, M.D., NYU Langone Medical Center; 2009, 2003 BBRF Independent Investigator
A study conducted in a major New York City hospital system found that people with schizophrenia have 2.7 times the overall risk of dying within 45 days if they are infected with the COVID-19 virus. Higher mortality was not seen in people with depression or anxiety who contracted the virus. Read more.
JAMA Psychiatry, January 27, 2021
- Maura Boldrini, M.D., Columbia University; 2014 BBRF Independent Investigator, 2006, 2003 BBRF Young Investigator
Neuropsychiatric symptoms in COVID-19 patients suggest independent brain damage attributable to viral infection, researchers said. Symptoms include cognitive and attention deficits ("brain fog"), anxiety, depression, psychosis, seizures, and suicidal behavior. Inflammation in the central nervous system is a likely contributor, they said. The researchers noted that COVID-19 proteins have been found in the lining of blood vessels in the brain. They suggested various means by which viral particles might leak through the blood-brain barrier, a membrane designed to protect the brain from viruses, toxins, and other harmful factors. Read more.
JAMA Psychiatry, March 26, 2021
- Lu Wang, Ph.D., University of California, San Diego; 2019 BBRF Young Investigator
Researchers published new evidence suggesting how the COVID virus gains access to the brain. They found that cells called pericytes which surround the brain's blood vessels may act as "Trojan horses," providing a path for the virus to enter, replicate, and then infect surrounding brain cells and tissue. The team discovered that pericytes contain ACE2 receptors, a known passageway for COVID entry into cells elsewhere in the body. ACE2 receptors are found in abundance in the lungs, arteries, heart, kidney and intestines, but were not previously known to be produced in human pericytes. Read more.
Nature Medicine, July 9, 2021
- Paul J. Harrison, M.D. FRCPsych, Oxford University, UK; 2004 BBRF Independent Investigator
In a study involving over 273,000 patients, researchers provided a detailed picture of "long COVID:" how common its 9 core symptoms are and who is most likely to experience them. Most commonly reported was depression/anxiety, experienced by 22% within 6 months of diagnosis and 15% 3 to 6 months after diagnosis. Among other observations: long-COVID features were recorded in children and young adults, and also in more than half of non-hospitalized patients, confirming that they occur even in young people and those with relatively mild illness. This is significant in public health terms given that most people with COVID-19 are in the latter group, the researchers noted. Read more.
PLOS Medicine, September 28, 2021
- Gregory P. Strauss, Ph.D., University of Georgia; 2018 BBRF Young Investigator
Researchers found that social distancing and isolation stemming from the pandemic caused a significant worsening of negative symptoms (flattened emotions, reduced motivation, difficulty speaking, a disinclination to socialize or seek pleasure) in schizophrenia patients, and to a lesser degree in those at clinically high risk of developing psychosis. Read more.
European Archives of Psychiatry & Clinical Neuroscience, October 30, 2021