Temporal Lobe Abnormalities in a Patient with Schizophrenia Who has Word-Finding Difficulty: Use of High-Resolution Magnetic

Resonance Imaging and Auditory P300 Event-Related Potentials

Martha E. Shenton, PhD, Brian F. O’Donnell, PhD, Paul G. Nestor, PhD,

Cynthia G. Wible, PhD, Ron Kikinis, MD, Steven F. Faux, PhD,* Seth D. Pollak, MA,

Ferenc A. Jolesz, MD, and Robert W. McCarley, MD

Postmortem, magnetic resonance, and event-related potential studies suggest the pres- ence of temporal lobe abnormalities in schizophrenia. Analyses using convergent mea- surements of brain structure and function, however, have rarely been done in the same patients. We recently developed a protocol using high-spatial-resolution magnetic reso- nance scans, auditory P300 event-related potentials, and thought disorder scales to examine temporal lobe structure and function in the same patients. We report a case of schizophrenia that showed left-lateralized volume reduction in the superior tempoml gyrus, hippocampus, and parahippocampal gyrus (also on right), with associated P300 amplitude reduction and thought disorder marked by word-finding difficulties and perseverations. ( W A R D REV PSYCHIATRY 1993~1:110-7.)

We here report the psychopathologic, event-related potential (ERP), and neuropsychological features of a patient with schizophrenia who has unusually severe left temporal lobe volume reduction as shown by a quantitative magnetic resonance imaging (MRI) evaluation. This case is particu- larly instructive, because it shows the clinical utility of combining multiple probes to examine functional, struc-

tural, and clinical pathology in schizophrenia. The struc- tural abnormalities noted in this case report were found to differentiate a schizophrenic group from a control group in a recent study.’ The findings presented in this report are also consistent with recent postmortem, MRI, and P300 ERP studies that suggest that temporal lobe abnormalities, particularly on the left, are implicated in the pathophysiol-

From the Department of Psychiatry, (Drs. Shenton, O’Donnell, Nestor, Wible, and McCarley and Mr. Pollak), Brockton VAMC and Massachusetts Mental Health Center, and the Department of Radi- ology (Dr. Kikinis), MRI Division, Surgical Planning and Labora- tory, Brigham and Women’s Hospital, Brockton, Mass.

Supported by Research Scientist Development Award KOl- MHOO746-04 (M.E.S.) from the National Institute of Mental Health, NIMH grant 40,799 (R.W.M.), the Department of Veterans Affairs (R. W.M.), the Milton Foundation (M.E.S.), the Scottish Rite Foun- dation (M. E.S.), the Commonwealth of Massachusetts Research

110

~

Center (R. W.M.), Research Career Development Award K04- NS01083 (F.A.J.) from the National Institutes of Health, and the Swiss National Foundation (R.K.).

Reprint requests: Robert W. McCarlqv, MD, Department of Psychi- atry-1 16A, Brockton V A Medical Center, 940 Belmont St., Brockton, M A 02401.

*Steven F. Faux, PhD, is now in the Department of Psychology, Drake University, Des Moines, Iowa.

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Harvard Rev Psychiatry Volume 1, Number 2 Shenton et al. 111

ogy of schiz~phrenia.~-~ We suggest that increased functional and structural imaging capabilities will lead to an increased ability to understand the pathophysiology of clinical symp- toms in this disorder.

CASE STUDY

Study criteria B.V.A. met the inclusion and exclusion criteria for our studies, which included the following: male, right-handed,” between the ages of 18 and 55, no known neurologic impair- ment, no history of drug or alcohol dependence and no drug or alcohol abuse in the past 5 years, and a diagnosis of chronic schizophrenia. This diagnosis was based on DSM- 111-R criteria” and was derived from two clinical interviews (the Schedule for Affective Disorders and Schizophrenia [SADS]’2 and an interview with one of the authors [R.W.M.]) and a review of the patient’s chart.

Identifying information B.V.A. is a 54-year-old, non-service-connected, single white man who has been hospitalized almost continuously since 1960. He looks his stated age. He is generally oriented to time, place, and person, although on one previous occasion he was admitted to the hospital insisting that he was a different person and actually believing that his name was different. A notable symptom is that B.V.A. repeats words up to three times. This verbal perseveration is so marked that it is often difficult to understand him. He also hears voices that repeat what they are saying three times.

Most recent admission B.V.A. was most recently admitted to the hospital in April 1988 with a diagnosis of schizoaffective disorder, manic exacerbation - an exception to his usual diagnosis of schizo- phrenia, either paranoid or undifferentiated type. The admission note described him as having unstable moods, occasional loud or obscene outbursts or both, and sleep difficulties. This diagnosis was later changed to schizo- phrenia. During his hospitalization he developed the habit of keeping written lists of staff, place names, and other words.

Personal history B.V.A. is the youngest of nine children, with three sisters and five brothers, including a fraternal twin brother, J.A. B.V.A.’s parents were both Italian immigrants. His father was a mill worker with 6 years of formal education. His mother had only 2 years of formal education but managed a grocery store and a restaurant. His records include reports from his mother who is deceased that B.V.A.’s birth was “difficult” (the difficulties were unspecified) and that he was a quiet but bright and athletic boy. His sister, A.A., describes

him as a fairly well-adjusted child who had friends and worked in the family store. In his last 2 years of high school, however, B.V.A. remembers spending most of his time alone. Records from his earliest hospitalization, in 1960, indicate that although B.V.A. had girlfriends, he often complained that he could not find women who shared his interests.

After graduating from high school, B.V.A. worked at a paper mill for the summer before entering the army. There he served as a corporal from 1954 to 1958, whereupon he received an honorable discharge. In 1958 he entered college but had difficulty keeping up with the work and left before examinations the following June. He moved in with his parents and then within several months went to New York City, where he lived and worked in a hotel for 4 months, until his first hospitalization. Since then, he has spent most of his time in psychiatric facilities or foster homes. B.V.A. is still in contact with his sister A.A. and his brother J.A.

Onset and course of illness B.V.A. was first hospitalized in 1960 at the age of 24 fol- lowing his precipitous move to New York City from the fam- ily home. He became fearful that the police and people on the street were trying to shoot him. On admission, he felt as though he was “coming apart.” He was diagnosed as suf- fering from a “schizophrenic reaction, undifferentiated type, acute.” After 2 months he was discharged to the care of his family. At home, he began to complain about all the “chis- elers” in town. He thought that people were watching him; he heard fire engines everywhere and saw unusual things coming out of the faucet. These events were followed by a fight with a family member in which B.V.A. pulled a loaded automatic revolver and threatened to shoot. He was rehos- pitalized and given a diagnosis of “schizophrenic reaction, paranoid type.” At the time of this admission he was agitated, delusional, and aggressive.

B.V.A. has been in the hospital almost continuously since 1960, and his behavior during this period has been described as unpredictable. When actively psychotic, he believes that others are “out to get him” and can become verbally and physically abusive. During these periods he also hears voices that comment “on my nationality.” The voices are generally repetitive, repeating the same words three times. In addi- tion, B.V.A. sometimes experiences the feeling of being controlled: “Someone thinks for me, eats for me, and lives for me. It’s cohabitation.” He complains of memory prob- lems and of forgetting people’s names. He also periodically writes long letters to ward staff. At times, when he is more stable, he is able to ignore the voices, and at those times he is generally passive and cooperative.

Medications and medical history B.V.A. is currently receiving thiothixene (Navzne) (15 mg per day), lithium (300 mg four times per day, with levels in

112 Shenton et al. Harvard Rev Psychiatry

July/August 1993

the therapeutic range), benztropine (Cogentin) (1 mg twice per day), and desipramine (50 mg at bedtime). At age 10, B.V.A. had a severe case of scarlet fever with no medical sequelae. He had the usual childhood diseases. He has no major medical problems.

Family history One of B.V.A.’s brothers committed suicide in the spring of 1961. B.V.A.’s mother and a sister had a history of psychi- atric hospitalization (records are unavailable). Another sis- ter has a history of outpatient psychiatric treatment. His twin brother is reported to show abnormal behavior, al- though he has never been hospitalized. The twin’s behavior throughout B.V.A.’s treatment has been intrusive and odd. A letter in the patient’s record from this brother includes a litany of complaints about his brother’s care, which ended with the following postscript: “Demiurge: a name for the Maker of the world, in the Platonic philosophy; in the Gnostic system, conceived of as a being subordinate to the Supreme Being, and sometimes as the author of evil.”

LABORATORY MEASURES AND FtNDINGS

To compare B.V.A. with 15 normal control subjects, we used means and standard deviations derived from the normal controls. Controls were right-handed men (as is B.V.A.) and had a mean age of 38 years (range 23 to 54 years).’ Z scores greater than 2 SD above or below the normal mean were considered abnormal.

Neuropsychology measures and clinical scates B.V.A. was evaluated with the same neuropsychology scales as other patients in our studies.’ Clinical assessment mea- sures included the Thought Disorder Index13.14 (TDI); the Scale for the Assessment of Positive Symptoms l6 (SAPS); the Scale for the Assessment of Negative Symptoms“ (SANS); and neuropsychological tests to measure verbal intelligence (assessed by the verbal subtests of the Wechsler Adult Intelligence Scale-Revised” WAIS-R]), memory (as- sessed by various subtests of the Wechsler Memory Scale- Revised” [WMS-Rl, including immediate and delayed recall of stories [Logical Memory I and I13 and word pairs [verbal Paired Associates I and 111); and concept formation (as- sessed by the Wisconsin Card Sorting Test’’ [WCST]). All ratings were done independent of one other.

Neuropsychology and clinical findings Based on the SANS and SAPS, B.V.A. was classified as having “mixed” symptoms. His affect was flat and blunted. His TDI score was 44, which is abnormally high (normal scores are 55.0) and indicative of severe thought disorder. The most noteworthy feature of his thought disorder was

the extraordinary amount of word-finding difficulty, similar to that of paraphasic anomia; his verbal output was fluent but he substituted abnormal words or phrases. For example, when he could not produce a word, B.V.A. either stated that he could not think of the name or substituted a verbal production that was wrong, such as when he said, “I ah, I tried to avoid, no, you know, the word, the word, um, I can’t think of the word. . . . I discasted it. I discasted it.” Here, B.V.A. substituted the word “discasted” for another word that he could not find. Almost all thought disorder scored for B.V.A. (the TDI includes language and thought disorder and does not distinguish between the two) was in the category of word-finding difficulty followed by perseveration and peculiar word usage.

B.V.A. scored in the overall average range in verbal intelligence (VIQ = 92); his highest scores were on tests of general fund of information and mental arithmetic, both of which are often well preserved in patients with schizophre- nia. In contrast, he exhibited significant deficits on tests of abstraction and concept formation, both of which have long been associated with schizophrenic-related neuropsycholog- ical deficits. In fact, on the WCST, B.V.A. achieved none of the six sorting categories. Of note, however, is that his scores on tests of memory for new information were gener- ally consistent with his overall intellectual abilities, falling approximately in the average range. This is of particular interest given the loss of tissue in his medial temporal lobe structures (see MRI Scan Findings; see also Discussion).

MRI measures Magnetic resonance images of whole brain were acquired in the axial and coronal plane on a 1.5-Tesla MR General Electric SIGNA System (GE Medical Systems, Milwaukee, Wis.) with a standard 30 cm head coil. The axial slices used for the automated segmentation1.20az of whole brain con- sisted of 3 mm contiguous (no gaps) slices. (For the axial slices, the parameters were echo time [TE] = 30 msec and 80 msec, repetition time [TR] = 3000 msec, slice thick- ness = 3 mm, field of view = 24 cm, matrix = 256 x 256 [192 phase encoding steps with zero filling], and 0.5 excita- tions.) The voxel (volume of pixel) dimensions were 0.975 x 0.975 x 3. (For more details, see work published elsewhere, e.g., reference 1.)

For the manual and semiautomated region of interest definitions, the coronal images were used to assess the tem- poral lobe and temporal lobe structures. (For the three- dimensional Fourier-transform spoiled gradient recalled ac- quisition [3DFT SPGR] images, the parameters were TE =

5 msec, TR = 35 msec, one repetition, 45 = degree nutation angle, 24 cm field of view, and matrix = 256 x 256 [again, 192 phase encoding steps] x 124.) The data were stored and analyzed as 124 coronal slices of 1.5 mm thickness.

Harvard Rev Psychiatty Volume 1, Number 2 Shenton et al. 113

TABLE 1. A Comparison of MRI and P300 Measures Between B.V.A. and a Group of Normal Controls

Data from 15 Normal Control Subjects B.V.A.

Mean (ml) SD Value Z Score -C 2

A. Automated procedures Total ICC absolute volume Relative volumes

Gray White Lateral ventricles Third ventricle Fourth ventricle Subarachnoidal CSF Left temporal horn Right temporal horn

B. Semiautomated procedures Relative volumes

Left amygdala Right amygdala Left hippocampus Right hippocampus Left superior temporal gyms* Right superior temporal gyms* Left parahippocampal gyms* Right parahippocampal g y m s * Left temporal lobe Right temporal lobe

C. P300 at T3 and T4 (kV) T3 electrode site T4 electrode site

1562.10

48.65 43.57

0.85 0.13 0.10 6.70 0.003 0.013

0.151 0.177 0.250 0.234 0.470 0.523 0.142 0.143 4.41 4.60

5.00 5.20

104.95

6.11 6.12 0.28 0.06 0.03 1.91 0.003 0.009

0.031 0.028 0.049 0.049 0.066 0.088 0.017 0.015 0.352 0.272

2.400 1.900

1854.70

39.74 50.41 2.73 0.12 0.05 6.65 0.04 0.01

0.09 0.14 0.13 0.18 0.34 0.42 0.06 0.10 3.61 4.60

2.90 4.30

+ 2

+ 2

+3

-2

-2

-3 -2

Difference 2.1 .9

Note: Differences in MRI values from normal control subjects for measures of temporal lobe were also seen in total sample of patients with schizophrenia (with or without B.V.A.), with exception that those with schizophrenia, as a group, showed reduction in left anterior amygdala-hippocampal formation rather than left posterior hippocampus, as noted in B.V.A.

*Gray matter of the gyri were assessed, not white matter.

The voxel dimensions were 0.975 x 0.975 x 1.5. (For more details, see work published elsewhere, e.g., reference 1.)

We defined regions of interest to include the whole amygdala-hippocampal structure (i.e., from the most ante- rior appearance of the white matter track linking temporal lobe to frontal lobe to the most posterior slice showing the fornix crossing over the hippocampus) as well as the gray matter of the superior temporal gyrus, gray matter of the parahippocampal gyrus, and gray and white matter of the temporal lobe (see definitions).'

To reduce flow-related artifacts (cerebrospinal fluid [CSFI and blood), we performed gradient moment nulling and presaturation of a slab inferior to the head in both the axial and 3DFT SPGR MRI acquisitions.

The magnetic resonance images for B.V.A., as with all cases in our studies, were evaluated independently by a clinical neuroradiologist, who reported no gross abnormali-

ties. Moreover, both the automated and semiautomated mea- surements were done without knowledge of whether the subject was a normal control subject or a psychiatric patient. I t was only later that the identification of subjects was known and a closer examination of specific cases was afforded.

MRI scan findings Table 1 gives the values in milliliters for the whole brain for B.V.A. and the 15 normal control subjects. Because B.V.A. had a larger intracranial cavity than the normal controls (Z score = + 2), we adjusted the volume measurements for head size to show the relative volumes for the automated measures of whole brain (gray matter, white matter, and CSF) and for the semiautomated measures of the temporal lobe. Table 1 shows that B.V.A.'s lateral ventricle size was greater than 2 SD above the mean for the normal control subjects. This difference was most marked in the left tem-

114 Shenton et al.

Harvard Rev Psychiatry JulyIAugust 1993

FIGURE 1. Four 1.5 mm coronal slices of brain, through two anatomic regions in temporal lobe, for normal control subject (A and C) and B.V.A. (B and D). Images in A and B are magnified equally, but slightly less than images in C and D. L, Subject left; R, subject right. A and B depict coronal slice passing through temporal lobe at approximately the level of internal acoustic meatus, and C and D depict more posterior coronal slice near splenium of corpus callosum. Note excellent gray and white matter contrast for images of normal control (A and C); CSF appears black (low signal intensity). Coronal slice of B.V.A. in B is at approximately same level as normal control (A). Note increase in temporal horn volume (CSF in black-see arrow) and tissue loss in surrounding amygdala-hippocampal formation. Also visible is loss of gray matter in left superior temporal gyrus, and left and right (though less dramatic) parahippocampal gyrus. Brain image of B.V.A. in D is at approximately same anterior-posterior level as normal control in C. Note enlargement of B.V.A.’s lateral ventricles and reduced size of hippocampus.

Harvard Rev Psychiatty Volume 1, Number 2 Shenton et al. 115

5.0 4 . 3 3.6 2.9 2.1 I. 4 0.7 +B. euu

6.5 6.0 5.5 5.0 4.5 4 . 8 3.5 3.8 2.5 2.0 1.5 1.0 0.5 +e . euu

FIGURE 2. Topographic distribution of P300 voltage for 15 normal control subjects (left) and for B.V.A. (right) is shown. Normal topography is distinguished by maximal voltage over parietal region and lateral symmetry. In contrast, B.V.A.’s topography shows asymmetric distribution, with larger voltages over right hemisphere, particularly over temporal scalp region.

poral horn region of the lateral ventricles. No other differ- ences were noted for the whole-brain measures.

Also shown on Table 1 is a detailed, quantitative, volu- metric, semiautomated evaluation of the temporal lobe re- gions of interest that showed that B.V.A. had volumes more than 2 SD less than normal control subjects for the left hippocampus, left superior temporal gyrus, and left and right parahippocampal gyrus. Figure 1 clearly depicts these changes.

ERP measures We used the same protocol as in our previous ~ t u d i e s . ~ Briefly, an auditory “oddball” protocol was used to elicit the P300 ERP component. The P300 component (a positive deflection in the electroencephalogram) occurs about 300 to 500 msec after a subject processes a novel, low-probability stimulus, for example, by counting it. Reduction of the P300 component, particularly over the left temporal region, is one of the most robust physiologic findings in schizo- phrenia.’

The ERPs were recorded to frequent (P = 0.851, 1000 Hz tone pips and infrequent, target 1500 Hz tone pips. Both were presented against a white noise background. The interstimulus interval was 1.2 seconds. Four blocks of 200 trials were used, with an average of 680 trials to frequent tones and 120 trials to infrequent tones. Subjects were asked to count the target tones. Each ERP consisted of a 700 msec epoch including a 100 msec prestimulus period to establish baseline voltages. After data processing, ERPs to target stimuli were averaged. P300 amplitude was defined as the average amplitude value of the ERP to target stimuli between 300 and 400 msec after stimulus presentation, as in previous studies from this lab~ra tory .~

ERP findings P300 amplitude in B.V.A. showed a lateral asymmetry consis- tent with left temporal lobe damage (Figure 2). P300 ampli- tude at T3 was 2.9 JLV, while amplitude at T4 was 4.3 pV (Table 1). Because of the large standard deviation on this measure among control subjects, B.V.A.’s Z scores did not exceed 2 at this electrode site. The amplitude difference, how- ever, for P300 between normal control subjects and B.V.A. was larger at T3 (2.9 pV vs 5.0 for control subjects) than at T4 (4.3 pV vs 5.2 pV for control subjects), which is similar to our findings for group differences between schizophrenic subjects and normal ~ o n t r o l s . ~ . ~ ~ This asymmetry is consis- tent with the hypothesis that in B.V.A., left temporal lobe pathology was reflected by reduced P300 amplitude over the left temporal region relative to the right temporal region.

DISCUSSION

Our laboratory has developed a protocol using both func- tional and structural probes to characterize the pathophys- iology of schizophrenia. Here we report a case study of a patient with schizophrenia who has left-lateralized abnor- malities in the temporal lobe that appear functionally as a reduction in P300 amplitude. Structurally, these abnormal- ities consist of increased CSF in the left temporal horn and decreased tissue volumes in left hippocampus, superior tem- poral gyrus, and parahippocampal gyrus (the latter also on the right). Clinically this patient showed both positive and negative symptom^.^^.^^ On the TDI he showed profound word-finding difficulty, followed by perseveration, and pecu- liar word usage.

These findings suggest that left-lateralized volume reduc- tion in superior temporal gyrus, which includes primary

116 Shenton et al. Harvard Rev Psychiatry

July/Augus! 1993

auditory cortex and associative cortex- the latter region long implicated as a biologic substrate of lang~age'~-'~ - may be related t o both auditory hallucinations' and thought disorder in schizophrenia.

These regions are highly anatomically interconnected; the parahippocampal gyrus connects the hippocampus to many areas of the cortex, including the superior temporal g y r ~ s . ' ~ We theorize that these areas form a functional ~ y s t e m ~ @ ~ ~ that is abnormal in schizophrenics with auditory hallucinations and thought disorder. Evidence from lesion, recording, and stimulation studies supports the argument that these three areas form the neural substrate for a verbal memory ~ y s t e r n . ' ~ . ~ ~ - ~ ~ A dysfunction of the processes in- volved in retrieval and storage of verbal memory may thus account for both auditory hallucinations and thought disor-

Tissue reduction in these regions may result in abnormal retrieval or activation of auditory and verbal memory, and these observed left temporal gray matter deficits may, in turn, be related t o auditory perseverations in thought, verbal word-finding difficulties, and perceptual perseverations as measured by the T D F 4 and illustrated so clearly in B.V.A.

der.32,36-40

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