Ralph Edward Hoffman MD

Professor of Psychiatry and Clinical Professor of Nursing; Medical Director, Intensive Outpatient Program at Yale-New Haven Psychiatric Hospital

Research Interests

Schizophrenia; Psychosis; Hallucinations; Delusions; Paranoia; Language; Pathophysiology; Neural network computer modeling; Transcranial magnetic stimulation; fMRI

Current Projects

  • Randomized clinical trial comparing active versus sham repetitive transcranial magnetic stimulation as an investigational intervention for patients with severe, treatment-resistant auditory hallucinations.
  • An fMRI study of functional connectivity involving regions critical to long-term emotional memory consolidation comparing persons with schizophrenia and healthy controls and to ascertain the relationship between these connectivity abnormalities and psychotic symptoms.
  • Functional neuroimaging studies characterizing regional activation and functional connectivity leading to auditory hallucinations of spoken speech.
  • fMRI study designed to compare rate of cortical consolidation of story memories in persons with schizophrenia and healthy controls.

Research Summary

Dr. Hoffman has employed a variety of methods including brain imaging, transcranial magnetic stimulation, and computer models of brain processes, to better understand psychological and neurobiological factors leading to psychotic experiences reported by persons with schizophrenia. His work has revealed that abnormal brain connectivity and neuroplasticity involving language processing, memory consolidation, and emotionality leading to hallucinations and delusions

Extensive Research Description

Research efforts have been primarily directed to advancing our understanding of schizophrenia and to develop better treatments.

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. 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. These simulations, which are being developed via a collaboration with Professor Risto Miikkulainen (Department of Computer Science, University of Texas, Austin) 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.

Selected Publications

  • Hoffman RE, Grasemann U, Gueorguieva R, Quinlan D, Lane D, Miikkulainen R. Using computational patients to evaluate illness mechanisms in schizophrenia. Biological Psychiatry 2011;69:997-1005
  • Hoffman, R.E, Pittman, B., Constable, R.T., Bhagwagar, Z., Hampson, M. Time-course of regional brain activity accompanying auditory/verbal hallucinations in schizophrenia. British Journal of Psychiatry 2011;198:277-283.
  • Hoffman, R.E., Fernandez, T., Pittman, B., Hampson, M. Elevated functional connectivity along a corticostriatal loop and the mechanism of auditory/verbal hallucinations in patients with schizophrenia. Biological Psychiatry 2011;69:407-14.
  • Hoffman, R.E., Woods, S.W., Hawkins, K., Pittman, B., Tohen, M., Preda, A., Breier, A., Glist, J., Addington, J., Perkins, D.O., McGlashan, T.H. Extracting spurious messages from noise and risk of schizophrenia-spectrum disorders in a prodromal population. British Journal of Psychiatry 2007; 191:355-356
  • Hoffman, R.E. A social deafferentation hypothesis for induction of active schizophrenia. Schizophrenia Bulletin 2007;33:1066–1070.
  • Hoffman, R.E., Hampson, M., Wu, K., Anderson, A. Gore, J., Buchanan, R.J., Constable, T., Hawkins, K., Sahay, N., Krystal, J.H. Probing the pathophysiology of auditory hallucinations by combining functional magnetic resonance imaging and transcranial magnetic stimulation. Cerebral Cortex 2007;17:2733-2743.
  • 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.
  • 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.

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