A post-mortem study of von Economo neurons in the frontal cortex of brains of persons with PWS

Although PWS is best known for hypothalamic obesity and hyperphagia, the cognitive and behavioral issues are the most challenging for families. Brain difference is the underpinning of the characteristics that define the Prader-Willi personality: food related behaviors, excessive/repetitive behaviors, stress sensitivity/mood disorder, cognitive rigidity, disruptive behavior and skin picking. A few brain imaging studies of individuals with PWS have shown how the brain actually looks different, and functional magnetic resonance imaging (fMRI) brain scans have shown how the brain functions differently during tasks, specifically with respect to food reward and satiety. Recent fMRI and electrophysiological studies have demonstrated that people with PWS have difficulty reading emotional expression in pictures of faces, and when they do, they read happy faces better than sad or angry ones. They respond better to reward than punishment, and they have diminished disgust, embarrassment and shame. A few studies have demonstrated differences in the connectivity (patterns of neuronal transmission and/or communication) between various regions of the brain in persons with PWS compared to normally developing individuals. Previous neuroanatomical studies in PWS have examined cells in the hypothalamus. To date, no data are available on the structure of the brain in PWS at the level of the neuron in the frontal lobe where executive function for decision making, sensory perception and social behavior reside. This proposal seeks to study the number and structure of a modified type of pyramidal cell, the von Economo neuron (VENs). These neurons are found typically in greater numbers in the right hemisphere of the brain in the anterior cingulate cortex (ACC) and frontoinsular (FI) cortex. They are believed to be responsible for sensory awareness, social perception, problem-solving behavior, and maintaining the balance in the autonomic nervous system which determines psychological as well as physiological state. They are abnormal in number and/or distribution in disorders such as autism, schizophrenia, and frontotemporal dementia. These neurons are found in higher primates, elephants and cetaceans whose survival requires social communication; they cannot be studied in mice models of PWS.

Through the generosity of the families who lost a loved with PWS, there are brains available for study at the NIH NeuroBioBank. An oversight committee reviews each proposal to guarantee research qualifications, ethical standards and legal obligations. The proposal for this study was approved and 19 brains have been released for study at Dr. Hof’s laboratory at the Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai in New York City, New York. This proposal aims to examine the FI and the ACC, that are responsible for integrating sensory information from the body with the social, perceptual and thinking part of the brain. Samples from the right and left hemispheres will undergo special tissue preparation and staining to allow microscopic analysis of neuronal structure and architecture. Stereological examination will determine the size and shape of the neurons.

Outcomes and Significance of Key Research Finding (From Dr. Hof - 02/28/2017)

This project is the first to stereologically assess areas outside the hypothalamus in PWS. We examined VENs and pyramidal cells in the frontoinsular (FI) and anterior cingulate cortex (ACC), neuroanatomical structures essential to interoception, social salience, and balance in the autonomic nervous system. We used stereological methods to determine the density and volume of VENs and pyramidal cells in ACC. Three findings pertinent to PWS have been discovered thus far in this study. First, the discovery of VENs in the posterior insula of PWS is of great interest because stereological studies of brain from normal, psychopathogical states, and other species suggest they are not typically found in this area. Second, the spatial orientation of VENs in the insula was oblique in some of the PWS cases studied. This finding was not unexpected, as it has been observed in autism spectrum disorder (ASD). Third, our stereological data show increased density of VENs in ACC compared to control and ASD. This is an unexpected finding. Stereological studies in ASD with increased number of VENs suggest a clinical correlation with increased interoception and heightened sensory sensitivity (Uppal et al. 2014). Increased number of VENs was also found in suicide victims with schizophrenia, who had greater insight into their condition, compared to non-suicidal controls (Brune et al. 2011). The authors’ interpretation of this finding is that the increased VENs conferred a greater capacity for negative self-appraisal that was ultimately a risk factor for suicide. Clinical information from this PWS case identifies the donor as a 17-year old donor had male with PWS (deletion condition) and autonomic dysfunction leading to hypothermia and death. He was not identified as having a psychiatric diagnosis nor was he receiving any psychotropic medications at the time of death. Clinical interpretation of increased VENs density in one PWS case is difficult to ascertain, especially at the age of 17. Additional stereological data from PWS donors who were older at time of death and had more clinical information about psychiatric status will be necessary for a robust correlation, and this work is currently underway.

Autism spectrum disorder: neuropathology and animal models. Varghese M, Keshav N, Jacot-Descombes S, Warda T, Wicinski B, Dickstein DL, Harony-Nicolas H, De Rubeis S, Drapeau E, Buxbaum JD, Hof PR.   Acta Neuropathologica. 2017 Jun 5. 

Awarded to:

Patrick Hof, MD


$75,600 (In partnership with Prader-Willi France)


Icahn School of Medicine at Mount Sinai


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