Martha G. Welch, MD
Associate Professor of Psychiatry (in Pediatrics and Pathology & Cell Biology) at CUMC
Dr. Welch is exploring the biological mechanisms of nurture and the ways they can be exploited to provide new treatments for developmental and behavioral disorders. The effort involves two closely coordinated initiatives. In basic research the BrainGut Initiative is exploring the biological processes and mechanisms that account for the profound therapeutic actions of mother-infant nurture. In clinical research the Biologically-based Therapy Initiative will translate basic findings into testable nurture-based treatments. Work with the Office of Clinical Trials has begun. Together with Dr. David Ruggiero, Dr. Welch demonstrated for the first time that the gut peptide secretin is synthesized in the forebrain by the hypothalamus. They also demonstrated that chronic GI inflammation leads to brain activation patterns in areas known to be abnormal in autism. In collaboration with Drs. Michael D.Gershon and Hadassah Tamir, they demonstrated the presence of oxytocin receptors in the gut. Recently, Drs. Gershon and Welch established the Columbia University Brain Gut Initiative to further investigate mechanisms of nurture as they condition the brain-gut axis. This research program derives from investigation of a novel therapeutic approach to the treatment of dysregulation of brain and gut demonstrating efficacy of combined secretin and oxytocin in the treatment of gastrointestinal inflammation and concomitant brain effects in acquired and congenital/genetic rodent models of colitis.
Role of the vagus nerve in mediating communication between the CNS and GI tract: Dr. Welch's laboratory has recently completed an initial study of the effect of vagotomy (severing the vagus nerve) on the communication between the gut and the brain of animals. This finding will have important implications for research on Secretin/Oxytocin Therapy (S/OT) and other therapeutic approaches to somatic and regulatory disorders. The figure to the left shows C-fos reactive cell counts in the central amgydala (CEA), the piriform cortex (PIR) and the para-ventricular nucleus of the hypothalamus (PVH). The initial study has suggested that bilateral vagotomy disrupts communication between the brain and the gut as demonstrated by changes in brain activation (reduction of c-fos expression in the central amygdala and the hypothalamus) following chemically induced inflammation in an animal model of Inflammatory Bowel Disease (IBD). Prior experiments with this animal model were among the first to report the possibility of significant relationships between events in the GI tract and gene expression in areas of the brain that have been linked to a variety of disorders; the new findings provide additional evidence in support of this relationship and illuminate potential regulatory pathways. These pathways will act as important potential targets for translational research while providing a biological basis for observed clinical finding.
Intra-ventricular(ICV) administration of S/OT: Prinicipal Investigator: Martha G. Welch. (Hypothesis: Secretin/Oxytocin administration will affect the brain directly, crossing the CSF-blood barrier and acting on the central amygdala and the hypothalamus.) Another collaborative effort between the laboratories of the BGI, this set of experiments is designed to explore both the pharmacokinetics of secretin/oxytocin and explore the effect on previously identified regions of the brain known to be sensitive to intravenous administration of S/OT. The figure to the left shows the results of treating gut inflammation with combined S/OT peptides via ICV administration. Fos-ir is shown as a percentage of saline control (100%). The PVH and the CEA appear to be particularly responsive when S/OT is injected directly in the cerebrospinal fluid, as demonstrated by reduced c-fos activation. This finding is significant in that it demonstrates the ability of S/OT to act directly on the brain; in combination with prior results it offers the possibility that multiple pathways may be affected-and that simultaneous or near-simultaneous activation of oxytocin receptors and other peptide receptors may be necessary for observed effects. New research questions have been raised by this finding, and analysis of GI pathology is currently being analyzed in samples taken from animal subjects in these experiments.
Oxytocin receptors in the gut: Prinicipal Investigator: Martha G. Welch. (Hypothesis: Oxytocin signaling is an essential component of regulation of the GI tract and associated inter-systemic regulation.) This major collaborative effort between the laboratories of Dr. Welch, Dr. Haddasah Tamir, and Dr. Michael Gershon is proceeding rapidly. This effort has identified, for the first time, the presence of oxytocin receptors within the gastrointestinal system. The figure to the left shows Western Blot staining. This monogenetic method is being used by Dr. Tamer's lab to detect protein in a given sample of tissue homogenate as a means to identify the oxytocin receptor. The significance of this finding is that it has been presupposed that there is no role for oxytocin in the gut. Localization of oxytocin receptors to the GI tract for the first time may constitute a landmark finding, one that will likely result in important publications and inform future basic and clinical research.
Gene expression in strains of high-vocalizing and low-vocalizing juvenile mice. Aaron Bran comb, a research scientist in the laboratory of Dr. Susan Brunel (Division of Developmental Neuroscience) had proposed to conduct novel research on gene expression in strains of high-vocalizing and low-vocalizing juvenile mice as a model of stress response and child-maternal interaction. Several meetings were held to discuss the project, which will ultimately focus on the effects S/OT on the well-characterized behavioral endpoints that define these strains. This is an important step forward, allowing behavioral data to be collected on the effects of S/OT. Dr. Bran comb's initial findings indicate that low vocalizing mice have fewer GI lesions than are seen in high vocalizing strains. Statistically significant differences have been established between high and low vocalizes; data collection is underway and quantitative analysis is being completed.
Replication and expansion studies. An intensive 3-month effort to replicate initial findings, expand the sample size, and verify results of S/OT experiments in animal models. By taking an objective approach and running multiple, independent samples, the goal of this effort is to produce more definitive data that will be readily accepted by reviewers and colleagues.
Ablation of Spinal Nerves. A new study to investigate the signaling component of the brain-gut axis transmitted via the spinal nerves is underway. The goal of these planned experiments is to collect data on c-fos activation in brain regions associated with gut inflammation in the absence of transmission by spinal nerves.
Separate Peptide Treatment. In an effort to better characterize the separate effects of secreting and oxytocin, we will also test whether single peptides (secreting and oxytocin separately) cause differential effects when administered directly to the brain (ICV administration). As there was no observed effect on measured endpoints during prior experiments using system (intravenous) administration, this is an important follow-up experiment and may reveal additional information about mechanism.
Meeting with Clinical Trials Office (CTO): October 19th meeting with the Clinical Trials Office at Columbia University Medical Center to review a BGI proposal for a clinical trial of combined Secretin/Oxytocin Therapy (S/OT) for treatment of Inflammatory Bowel Disease (see attached). Present: Dr. Welch, R. Ludwig, and M. Opler, Dr. John Ennever (Medical Director), Richard Hlenski (Director of Finance & Strategic Planning), Eileen Leach (Director) and associates. Several action steps were agreed upon including review of available FDA data on secretin and oxytocin; attempts would be made to solicit data on safety (pre-clinical data) from prior investigational new drug applications; CTO Director Eileen Leach was particularly enthusiastic about the trial will determine what clinical resources and specifically which members of the faculty at CUMC will assist and collaborate in this study; future discussions with R. Hlenski would be held regarding study budget and funding sources, to be coordinated by R. Hlenski's office; mid-November follow-up meeting was planned for to review progress.
A brief proposal was submitted to a collaborator in Mexico, Cecile Katchadourian, a clinical therapist who specializes in attachment and behavioral disorders using Welch Method therapies (see attached). As director of a clinical treatment center, C. Katchadourian's interest in a study of high nurture therapy has resulted in a unique opportunity-to conduct clinical research using state-of-the art methods, i.e. a controlled trial comparing high nurture therapy to "standard care." Additionally, plans were discussed for the use of videoconference technology to perform assessments and collect data using blinded methods that will facilitate the conduct of an unbiased analysis of the therapy. A specialist consultant, Dr. Kenneth Kobak of the University of Wisconsin has expressed interest in collaborating to facilitate the technical aspects of this proposed study and will be coming to New York for further discussions in mid-March.
A new opportunity for collaborations with young psychiatrists and researchers in Romania has been made possible through the efforts of Dr. Mark Opler. On the invitation of the Academy of Psychiatric Medical Residents (Romania), a series of seminars offered the opportunity to discuss new approaches to research and treatment, including pharmacologic and behavioral methods. The participants expressed considerable interest and a new proposal for development in this area may be merited. Of particular note, the need for interventions within the Romanian orphanage system and the chance to study the impact of nation-wide events on developmental disorders was discussed.
Thomas Franke: Over the last few weeks Dr. Franke of NYU Medical Center Department of Psychiatry has been engaged in extensive conversations with Dr. Martha Welch about the possibility of joining the BGI. He is specifically interested in working with BGI to develop a new paradigm for the study and treatment of developmental and related life-long disease. He is especially motivated by the idea of studying common mechanisms that act on both the gut and the brain. He has very pertinent experience and skills in developmental neurobiology and cell signaling that will be extremely valuable to this effort.