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Schizophrenia Research Forum: Researcher Profile - Ralph Hoffman
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Researcher Profile - Ralph Hoffman

RESEARCHER INFORMATION
First Name:Ralph
Last Name:Hoffman
Title:Professor
Advanced Degrees:M.D.
Affiliation:Yale University
Department:Psychiatry
Street Address 1:Yale - New Haven Psychiatric Hospital
Street Address 2:184 Liberty Street
City:New Haven
State/Province:CT
Zip/Postal Code:06519
Country/Territory:U.S.A.
Phone:203-688-9734
Fax:203-688-9709
Email Address:ralph.hoffman@yale.edu
Disclosure:
(view policy) 
Member reports no financial or other potential conflicts of interest. [Last Modified: 29 April 2006]
View all comments by Ralph Hoffman
Clinical Interests:
auditory hallucinations, Schizophrenia
Research Focus:
Brain imaging, Neurodevelopment, Phenomenology/diagnosis, transcranial magnetic stimulation, Neuroanatomy/Systems Neuroscience, Clinical trials
Work Sector(s):
University
Reasearcher Bio
Dr. Hoffman’s research efforts in the area of schizophrenia have focused on three primary areas.

One set of studies focuses on the pathophysiology and treatment of auditory hallucinations. These studies rely on fMRI data, which have permitted maps of the time course of activation preceding onset of hallucinations and are also used to map abnormal functional connectivity. Dr. Hoffman’s research group is also collecting high resolution structural MRI data to identify brain areas with grey matter loss that are specific to schizophrenic patients with auditory hallucinations. These functional and structural MRI data are also used to position “suppressive, 1-Hz rTMS for a clinical trial. Results of the trial highlight the importance of Wernicke’s area and the adjacent supramarginal cortex in the genesis of auditory hallucinations, with level of activation in Broca’s emerging as a potent moderator of rTMS effects. A long-term objective of these studies is to develop potent somatic interventions for refractory psychotic disorders that combine rTMS, medication and psychosocial treatments.

A second set of studies utilizes computer simulations of complex neural networks capable of complex language comprehension and production of story-based narratives biased by simulated emotionality. These simulations are subjected to lesions and neuromodulatory disturbances within and between modules. The overall objective is to determine which disturbances cause these neural systems to most clearly reproduce language disturbances characteristic of persons with schizophrenia, i.e., positive thought disorder, negative thought disorder, and fixed delusions. The latter are simulated as the narrative production of locked-in, repetitively reproduced untrue emotion-charged stories. Simulation studies are conducted in parallel with a human subject study involving narrative memory and reproduction that compares patients with schizophrenia and normal controls. Types of memory distortion exhibited by actual patients will be used to set parameters for the computer simulations to enhance their fidelity in reproducing actual psychopathology.

Dr. Hoffman’s third research focus has been to characterize complex interactions of neurocognitive and psychosocial factors that predict induction of schizophrenia. This work in part is based on a data collected from a randomized clinical trial of persons with prodromal symptoms of schizophrenia comparing olanzapine and placebo. In parallel with this study, Dr. Hoffman is undertaking computer simulations designed to estimate the complexity of gene-gene and gene-environment interactions that produce schizophrenia. Other empirical data used to anchor these simulations are obtained through a collaboration with Dr. Carsten Pedersesn utilizing the national health registry of Denmark. These research findings suggest that schizophrenia arises from complex, multiplicative interactions involving 3 co-occurring genetic loci that are each very common in the human population and confer adaptive advantages rather than illness vulnerability when occurring in isolation.

Top Papers
Hoffman, R.E. Verbal hallucinations and language production processes in schizophrenia. Behavioral and Brain Sciences 9:503 517, 1986.

Hoffman, R.E., McGlashan T.H. Synaptic elimination, neurodevelopment and the mechanism of hallucinated 'voices' in schizophrenia. American Journal of Psychiatry 154:1683-1689, 1997.

Hoffman, R.E., Rapaport J, Mazure C.M., Quinlan, D.M. Schizophrenic patients reporting hallucinated “voices” demonstrate selective speech perception alterations. American Journal of Psychiatry 156:393-399, 1999

Hoffman, R.E., Boutros, N.N., Hu, S., Berman, R,M., Krystal, J.H., Charney, D.S. Transcranial magnetic stimulation and auditory hallucinations in schizophrenia. Lancet 355: 1073-5, 2000

McGlashan, T.H., Hoffman, R.E. Schizophrenia as a disorder of developmentally-reduced synaptic connectivity. Archives of General Psychiatry 57:637-648, 2000

Hoffman, R.E., Shi, W.-X., Bunney, B.S. Anatomic basis of sequence-dependent predictability exhibited by nigral dopamine firing patterns. Synapse 39:133-138, 2001.

Hoffman, R.E., Quinlan, D.M., Mazure, C.M., McGlashan, T.M. Cortical instability and the mechanism of mania: A neural network simulation and perceptual test. Biological Psychiatry 49: 500-509, 2001

Hoffman, R.E., Cavus, I. Slow transcranial magnetic stimulation, long-term depotentiation, and brain hyperexcitability disorders. American Journal of Psychiatry 2002;159:1093-1102.

Hoffman, R.E., Hawkins, K.A., Gueorguieva, R. Boutros, N.N., Rachid, F., Carroll, K., Krystal, J.H. transcranial magnetic stimulation of left temporoparietal cortex and medication-resistant auditory hallucinations. Archives of General Psychiatry 2003;60:49-56

Hoffman, R.E., Gueorguieva, R., Hawkins, K.A., Varanko, M., Boutros, N.N., Wu, Y.-T., Carroll, K., Krystal, J.H.. Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and predictors in a fifty patient sample. Biological Psychiatry 2005; 58:97-104.
What are the top three papers (not yours) you have read recently?
Kapur's discussion of salience in relationship to dopaminergic mechanisms and schizophrenia published in the AJP.

Kendler's recent guest editorial discussing the fallacy of simple causal models of genetic abnormalities in relationship to psychiatric disorders also published in the Americal Journal of Psychiatry.

The CATIE report on comparative efficacy of antipsychotic drugs in the New England Journal of Medicine
If resources were not limited, what research projects would you pursue?
1. I would develop transcranial magnetic stimulation methods for studying brain connectivity that could be applied to a variety of disorders.
2. I would develop animal models of specific forms of neuroplasticity that would be used to investigate the pathophysiological basis of psychosis.
3. I would conduct a study of at-risk patients with prodromal symptoms of schizophrenia utilizing perceptual studies to characterize specific markers highly predictive of conversion to schizophrenia (I have pilot data suggesting this can be done).
What is your leading hypothesis?
Schizophrenia arises from overzealous pruning of local connections in association cortex during late adolescence. I am working on a related hypothesis based on new empirical data but I need to get these ideas into manuscript form and submitted before I go public. I would very much like to share theses idea with others -- potentially using this forum -- when I get all of this written up.
What piece of missing evidence would help prove it?
Direct evidence in the living brain of excessive pruning of cortical connections in patients with schizophrenia. THis can in theory be done using TMS combined with neuroimaging.
What is your fallback position?
I will have to think about that.



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