I was graduated from Harvard College summa cum laude and from Harvard Medical School. Intending in college to work in psychoanalysis, I became enthralled with neuroscience in medical school. During and after my residency at Massachusetts Mental Health Center, I worked on single-unit recording in the brainstem to determine how REM sleep was generated, and I had the unusual and heady experience of having my first paper published in Science (McCarley RW, Hobson JA, "Cortical unit activity in desynchronized sleep," 167[919]: 901-3, 6 February 1970).

This had implications not only for basic research but for psychiatry, and my twin articles with Allan Hobson in the American Journal of Psychiatry ("The neurobiological origins of psychoanalytic dream theory," 134[11]: 1211-21, November 1977 and "The brain as a dream state generator: an activation-synthesis hypothesis of the dream process," 134[12]: 1335-48, December 1977) on the "Activation-Synthesis" model of REM sleep control, not generated by wish-fulfillment/disguise but by an automatic biological rhythm—and the origins of Freud’s dream theory in early neurobiology—were initially controversial but finally became received wisdom.

“I was convinced brain abnormalities must be at the root of this horribly life-distorting disorder.”

Clinically I treated many individuals with schizophrenia, and when a psychiatry resident, Ron Morstyn, came to me with a proposal to do evoked-potential neurophysiological studies in schizophrenia, I jumped at the chance since I was convinced brain abnormalities must be at the root of this horribly life-distorting disorder. We found a deficit in the P300 evoked potential over the left temporal lobe, prompting a move to CT scans and then to structural MRI’s to find the brain structural correlates. Based on the neurobiology, I naturally hypothesized the language abnormalities must lie in the left temporal lobe of our right-handed subjects, and was delighted to have Marty Shenton (who is also in this Special Topics analysis) as a post-doc trained in thought disorder measurement join in this effort.

As MRI technology matured, Marty and I were able to document this relationship between thought disorder and left superior temporal gyrus (STG) volume reduction in a citation classic, "Abnormalities of the left temporal-lobe and thought-disorder in schizophrenia - a quantitative magnetic-resonance-imaging study" (N. Eng. J. Med. 327[9]: 604-612, 27 August 1992). Further work showed that the P300 abnormalities were indeed also linked to STG volume reduction. This work had been done in chronic patients; collaboration with Dean Salisbury first as a post-doc and then as he moved to McLean Hospital (as well as work from many wonderful post-docs from Japan and Korea) showed that the STG and P300 abnormalities were present at first hospitalization for schizophrenia and were distinct from those seen in manic and affective psychosis at first hospitalization (Yoshio Hirayasu was the first author on many of these papers).

Work in many other brain regions also showed a link with structural volumetric and clinical symptom abnormalities, and this MRI work in collaboration with Marty Shenton continued as she established her own lab at Brigham and Women’s Hospital in 2005. Work on N400 and other language- and semantic-related ERPs in schizophrenia led by Dr. Margaret Niznikiewicz, VA ERP lab chief, further pointed to the biological basis of abnormal language processing in schizophrenia and helped specify the abnormalities (J. Abnormal Psychology 1:85-97, 1997).

My work in neurobiology kept me informed about the increasing evidence of dendritic plasticity, alteration by experience and by excitotoxic phenomena, and in an article published with laboratory members in 1991, I suggested that there was likely to be post-onset progression of brain changes in schizophrenia, in addition to the developmental abnormalities. Obviously this needed testing, and my collaborators and I began a longitudinal study of first-hospitalization subjects with schizophrenic and affective (manic) psychosis using repeated ERPs and MRI scans. Data finally became sufficient to publish documentation in 2003 (Kasai K, et al. "Progressive decrease of left superior temporal gyrus gray matter volume in first-episode schizophrenia," Am. J. Psychiat. 160[1]:156-64, January 2003; and Kasai K, et al., "Progressive decrease of left Heschl’s gyrus and planum temporale gray matter volume in schizophrenia: a longitudinal MRI study of first-episode patients," Arch. Gen. Psychiat. 60[8]: 766-75, August 2003) that left posterior STG and its components of Heschl’s gyrus and planum temporale showed both initially smaller volumes and a post-onset progressive volume reduction of 8-9% over 1.5 years after first hospitalization.

Moreover, in 2007 Dean Salisbury (first author) and I showed that the Mismatch Negativity Evoked Potential to pitch changes shows concomitant progression with Heschl’s gyrus volume reduction ("Progressive and interrelated functional and structural evidence of post-onset brain reduction in schizophrenia," Arch. Gen. Psychiatry 64[5]:521-9, May 2007). More recently Moto Nakamura (first author) and I published data showing that overall neocortical gray matter showed a post-onset volume reduction, most pronounced in temporal and frontal lobes, and specific to schizophrenia vs. manic psychosis ("Neocortical gray matter volume in first-episode schizophrenia and first-episode affective psychosis: a cross-sectional and longitudinal MRI study," Biol. Psychiatry 62[7]:773-83, 1 October 2007).

The idea of post-onset progression was initially controversial, going against the prevailing dogma of purely developmental abnormalities, but our work and that of others has now led to much more widespread acceptance. I and other Harvard researchers now have the support of a major NIMH award (Boston CIDAR) to study vulnerability to progression in schizophrenia, including its genetics, and, with Larry Seidman, extending the scope of study to include individuals prodromal for schizophrenia.

Another offshoot of my work in neurobiology has been in models of abnormal circuitry in schizophrenia. Robby Greene (now at UTSW, and then a collaborator on in vitro work in sleep), Heinz Grunze, and I looked at an in vitro model that indicated that NMDA synapses on inhibitory GABAergic neurons (from pyramidal projection neurons) were much more susceptible to inhibition than those on projection cells (pyramidal cells) by psychotomimetics ("NMDA-dependent modulation of CA1 local circuit inhibition," J. Neurosci. 16[6]:2034-43, 15 March 1996).

This led to the hypothesis of abnormal GABA-pyramidal neuronal interaction in schizophrenia, and to an investigation of Gamma band (~40 Hz) oscillations, which are based on this interaction and form the basis for communication between brain cell columns and regions. We found steady-state (auditory click-elicited) gamma abnormalities in schizophrenia (Kwon JS, et al., "Gamma frequency-range abnormalities to auditory stimulation in schizophrenia," Arch. Gen. Psychiat. 56[11]: 1001-5, November 1999), and then in a PNAS paper, Kevin Spencer and I reported abnormalities elicited by visual gestalt stimuli (Spencer KM, et al., "Neural synchrony indexes disordered perception and cognition in schizophrenia," PNAS 101[49]: 17288-93, 7 December 2004). Work on postulated circuit abnormalities continues by Kevin and, in post-mortem material, by Wilson Woo in the Boston CIDAR.

My interest in schizophrenia came from my empathy with those suffering from this disorder and my frustration at my inability as a clinical psychiatrist to treat patients completely. I believe rational treatment will come only from better understanding of the disorder—but this is a disorder that is multifaceted, multicausal, and with multiple genetic influences. Progress is now being made on many fronts of understanding due to public support of research, but continued support by the public and continued efforts of researchers are needed to better understand and treat this disorder.