Magnetic Resonance Imaging of Mediodorsal, Pulvinar, and Centromedian Nuclei of the Thalamus in Patients with Schizophrenia

ORIGINAL ARTICLE Magnetic Resonance Imaging of Mediodorsal, Pulvinar, and Centromedian Nuclei of the Thalamus in Patients With Schizophrenia

Eileen M. Kemether, MD; Monte S. Buchsbaum, MD; William Byne, MD, PhD; Erin A. Hazlett, PhD; Mehmet Haznedar, MD; Adam M. Brickman, MPhil; Jimcy Platholi, MA; Rachel Bloom

Background: Postmortem and magnetic resonance im- reduced in all 3 nuclei; differences in relative reduction aging (MRI) data have suggested volume reductions in did not differ among the nuclei. The remainder of the the mediodorsal (MDN) and pulvinar nuclei (PUL) of the thalamic volume (whole thalamus minus the volume of thalamus. The centromedian nucleus (CMN), impor- the 3 delineated nuclei) was not different between schizo- tant in attention and arousal, has not been previously stud- phrenic patients and controls, indicating that the vol- ied with MRI. ume reduction was specific to these nuclei. Volume relative to brain size was reduced in all 3 nuclei and remained Methods: A sample of 41 patients with schizophrenia significant when only patients who had never been ex- (32 men and 9 women) and 60 healthy volunteers (45 posed to neuroleptic medication (n=15) were consid- men and 15 women) underwent assessment with high- ered. For the MDN, women had larger relative volumes resolution 1.2-mm thick anatomical MRI. Images were than men among controls, but men had larger volumes differentiated to enhance the edges and outline of the than women among schizophrenic patients. whole thalamus, and the MDN, PUL, and CMN were out- lined on all slices by a tracer masked to diagnostic Conclusions: Three association regions of the thala- status. mus that have reciprocal connectivity to schizophrenia- associated regions of the cortex have significantly smaller Results: Significantly smaller volumes of the MDN and volumes on MRI in patients with schizophrenia. PUL were found in patients with schizophrenia compared with controls. Volume relative to brain size was Arch Gen Psychiatry. 2003;60:983-991

OSTMORTEM STUDIES of it also has prominent interconnections with schizophrenia have impli- the temporal lobe, a second area of mor- cated abnormalities in the phometric and functional change in schizo- thalamus1,2 and in a number phrenia. Schizophrenia-associated abnor- of structures that have effer- malities of the MDN and PUL have been ent and afferent thalamic connections, in- demonstrated in postmortem studies2,15-20 P 20,21 cluding the amygdala and hippocampal for- and in the anterior nucleus. Changes in mation,3,4 cingulate and prefrontal cortices,5 the ventrolateral posterior nucleus have also temporal lobe, and superior temporal gy- been reported.22 rus.6 Since each thalamic subdivision has Until recently, the study of the anatomy a unique reciprocal circuitry to and from of the thalamus in living subjects has been affected cortical areas,7 separate assess- limited to visualization of the whole thala- ment of these subdivisions is important. mus on magnetic resonance imaging (MRI) Two of the major association nuclei, the me- scans, and findings have been conflict- diodorsal (MDN) and pulvinar nuclei ing.23 Our group1 reported a technique that (PUL), are of particular interest in schizo- allows in vivo neuroimaging visualization phrenia. The connections of the MDN have of the MDN and PUL on MRI scans and been used to define the prefrontal cortex,8 demonstrated MDN volume loss in schizo- a key area of functional and structural al- phrenia and PUL volume loss in schizo- teration in schizophrenia.9 Until the mid- phrenia spectrum disorders. We have also 1970s, it was thought that the prefrontal reported metabolic decreases in the region cortex received its thalamic input solely of the MDN in a separate population24 and from the MDN; however, it is now appar- in a subsample of the current patient group.25 From the Department of ent that the PUL also contributes to its in- The present study is an extension of this Psychiatry, Mount Sinai School nervation.10,11 The PUL is important in vi- work with a greatly enlarged sample, and of Medicine, New York, NY. sual and possibly auditory attention,12-14 and with the addition of delineation of the cen-

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Volume, cm3

Whole Thalamus MDN PUL CMN

Group Right Left Right Left Right Left Right Left Patients with schizophrenia 6.13 (0.73) 5.94 (0.75) 0.66 (0.12) 0.60 (0.12) 1.57 (0.26) 1.51 (0.23) 0.14 (0.05) 0.14 (0.05) (n = 41) Controls 6.37 (0.69) 6.10 (0.68) 0.69 (0.12) 0.66 (0.10) 1.68 (0.29) 1.60 (0.26) 0.15 (0.04) 0.15 (0.05) (n = 60)

Abbreviations: ANCOVA, analysis of covariance; CMN, centromedian nucleus; MDN, mediodorsal nucleus; PUL, pulvinar nucleus.

*Data are expressed as mean (SD). Main effect of diagnosis, F1,99 = 5.25 (P = .03); with age as covariate, F1,98 = 7.94 [P = .006]. This lesser volume effect was not significantly stronger for any one of the nuclei (no higher-order interactions with group). Follow-up ANCOVA for each nucleus separately confirmed this

difference for the MDN (F1,98 = 6.18 [P = .02]) and PUL (F = 6.45 [P = .01]) but not for the CMN (F = 1.48 [P = .22]).

tromedian nucleus (CMN), one of the thalamic intralami- handed, 2 were left-handed, and none were mixed in handed- nar nuclei that are believed to play an important role in at- ness. All received a Comprehensive Assessment of Symptoms tention related to arousal and activation of the cortex.26 Like and History interview to exclude those with a history of psy- the MDN and PUL, it has connections with the prefrontal chiatric illness in themselves or in their first-degree relatives. cortex. Lesions of the intralaminar nuclei produce signs of Median educational level was 16 years. Mean±SD parental so- cioeconomic status (SES) in controls (2.89±0.79) was some- executive dysfunction and attentional impairment like those 27 what higher than patients (3.55±1.22; effect size, 0.75). observed with frontal cortical damage. All participants underwent screening by means of medical The present study corroborates findings of re- history, physical examination, and laboratory testing. Individu- duced MDN and PUL volumes on MRI in this larger co- als with a history of substance abuse/dependence, positive find- hort of patients with schizophrenia and provides evi- ings for drugs of abuse in a urine sample tested on the day of the dence that the volume of the CMN may also be reduced. positron emission tomography scan, neurological disorders, or head trauma were excluded. After a complete description of the METHODS study, all participants gave written informed consent and were paid for their participation in this study. Of the 41 participants with schizophrenia, 12 were included from our previous co- PATIENTS hort,1 as improvement in anatomical boundary definition of the Forty-one patients (32 men and 9 women; mean age, 36.9 years; MDN and tracing of an additional thalamic nucleus (CMN) per- SD, 15.2 years; range, 18-73 years) were recruited from the Mount mitted retracing in each of these participants. Sinai, Elmhurst, and Bronx Veterans Affairs hospital centers, New York, NY, where they serve as neighborhood care centers and MRI ACQUISITION AND ASSESSMENT referral centers. We included every referred patient who was not receiving neuroleptic drugs at the point of contact, for whom the The MRI scans were acquired using the same 1.5-T scanner (LX physician and patient would agree to participation in brain- Horizon; GE Medical Systems, Milwaukee, Wis) Signa 5ϫ sys- imaging studies, and who met our competency-to-participate cri- tem with a spoiled-gradient sequence (repetition time, 24 milli- teria. Patients came from emergency department admission, out- seconds; echo time, 5 milliseconds; flip angle, 40°; pixel matrix, patient clinics, and volunteer sources. Most cases entered through 256ϫ256; field of view, 23 cm) yielding 124 contiguous 1.2-mm new emergency department admissions and patients in outpa- thick axial slices. Details of image acquisition, coding, and scal- tient clinics known by physicians not to be taking medications ing are described elsewhere.1 Data were expressed in cubic cen- currently or appearing for clinic visits in an unmedicated state. timeters for each region of interest (ROI) (Table 1 and Table 2) None of the patients were currently undergoing long-term hos- and as relative to brain volume as previously performed. pitalization. Thirty-six patients were right-handed, 1 was left- handed, and 4 were mixed in handedness based on the Edin- OUTLINING THALAMIC NUCLEI burgh Inventory.28 The patients underwent evaluation with the Comprehensive Assessment of Symptoms and History29 and re- Delineation of the whole thalamus, MDN, and PUL began at ceived a diagnosis of schizophrenia (n=37) or schizoaffective dis- the level at which the structure was most clearly demarcated order (n=4) according to DSM-IV criteria. Patients had never pre- as described in detail and illustrated previously.1 A refinement viously received medication (n=15) or had been neuroleptic free to the delineation of the MDN and PUL was possible, as fur- for a minimum of 2 weeks (n=26). Total psychopathology scores ther study of the internal medullary lamina using the Sobel in- on the 18-item Brief Psychiatric Rating Scale30 ranged from 25 tensity-gradient filter indicated that 2 distinct limits (an inner to 89 (mean, 52.4; SD, 12.7; median, 51). Median educational [more medial] and outer [more lateral] boundary) could be dem- level was 13 years. onstrated (Figure 1). At the level of the habenula, between the split lines of the internal medullary lamina, the CMN is found CONTROLS through its extent until the level of the superior colliculus (Fig- ure 1 and Figure 2). Sixty healthy volunteers (45 men and 15 women; mean age, 40.1 years; SD, 15.9 years; range, 20-81 years) were recruited STATISTICAL ANALYSIS by means of advertisement in local newspapers and notices on hospital bulletin boards in support staff areas to minimize dif- With absolute and relative volumes of 3 nuclei and 2 hemi- ferences in educational levels. Fifty-eight volunteers were right- spheres, the strategy of using 12 t tests for basic analysis and

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Relative Size (SD)†

Whole Thalamus MDN PUL CMN

Right Left Right Left Right Left Right Left Patients with schizophrenia Female 2.01 (0.16) 1.93 (0.13) 0.283 (0.05) 0.256 (0.02) 0.643 (0.07) 0.633 (0.06) 0.146 (0.04) 0.132 (0.03) Male 1.98 (0.14) 1.90 (0.15) 0.298 (0.05) 0.282 (0.05) 0.628 (0.05) 0.615 (0.07) 0.139 (0.03) 0.141 (0.04) Controls Female 2.10 (0.12) 2.01 (0.10) 0.324 (0.05) 0.320 (0.04) 0.683 (0.08) 0.665 (0.06) 0.155 (0.04) 0.154 (0.04) Male 2.01 (0.14) 1.99 (0.34) 0.305 (0.04) 0.301 (0.04) 0.666 (0.07) 0.646 (0.06) 0.150 (0.04) 0.157 (0.04)

Abbreviations: ANCOVA, analysis of covariance; CMN, centromedian nucleus; MDN, mediodorsal nucleus; PUL, pulvinar nucleus; ROI, region of interest.

*Main effect, F1,99 = 16.1, (PϽ.001); with age as covariate, F1,98 = 17.9 (P = Ͻ.001). There were no higher-order interactions with group. Follow-up ANCOVA confirmed this difference for all 3 nuclei separately: the MDN (F1,98 = 7.30 [P = .008]), PUL (F1,98 = 12.25 [PϽ.001]), and CMN (F1,98 = 3.97 [P = .049]). †Expressed as (ROI volume/slice volume)ϫ 100.

another 24 for sex comparisons is vulnerable to type I statistical error. For this reason, as in our previous study, we A B analyzed data with multivariate analysis of covariance (ANCOVA)33 with independent groups (controls and schizophrenic patients), and repeated measures for thalamic nuclei (MDN, PUL, and CMN) and hemisphere (right and left) for absolute and relative volume with age as a covariate. Addi- tional analyses with sex as a second independent group dimen- sion were also performed. We report the univariate F where single nuclei are tested and multivariate F with the Rao R when all 3 nuclei enter the ANCOVA. Where higher-order interactions with groups are not significant, they are not noted. The age ANCOVA does not affect higher-order interactions of group, since the age is identical for all nuclei and hemispheres. Results of the Levene test for inequality of variance between controls and schizophrenic participants for each ROI were not MDN statistically significant. Unless otherwise indicated, data are expressed as PUL mean±SD.

RESULTS V

ABSOLUTE NUCLEAR VOLUMES C Internal Medullary Lamina Mediodorsal Patients with schizophrenia had a significantly smaller Anterior volume of the 3 delineated nuclei considered together than controls (Table 1). The effect sizes for the differences between controls and patients with schizophrenia Intralaminar for the mean of the right and left hemispheres for Reticular the MDN, PUL, and CMN were 0.40, 0.38, and 0.21, Ventral Anterior respectively. The percentage reductions were 6.7%, 6.1%, and 6.7%, respectively, for the mean of the right Ventral Lateral Pulvinar and left hemispheres for the 3 nuclei. Patients with Lateral Dorsal Medial Geniculate schizophrenia had smaller mean brain volumes than Lateral Posterior Ventral Posterior Lateral normal volunteers (1246±116 vs 1297±121 cm3; Centromedian Ventral Posterior Medial Lateral Geniculate t=2.11 [P=.04]), suggesting the need to examine the regional specificity of the effect using thalamic volumes corrected for brain volume. Correlations between whole Figure 1. Centromedian nucleus (CMN). A, Axial magnetic resonance (MR) image though the middle of the thalamus in the dorsal-ventral axis shows brain volume and thalamic volumes were positive and how the internal medullary lamina (white arrows) and corticotectal tract significant for the left and right hemispheres for whole (black arrowheads) together with the ventricular space (V) define the thalamus (0.34 and 0.39, respectively), MDN (0.24 and boundaries of the mediodorsal (MDN) and pulvinar nuclei (PUL). B, Filtered MR image of the thalamus at the same level as in part A shows the internal 0.34, respectively), and PUL (0.22 and 0.32, respec- medullary lamina (arrowheads) splits to surround the CMN, which is not tively), but not the CMN (0.07 and 0.12, respectively). visible in the unfiltered image. C, Diagram of the thalamus viewed from the We also corrected for thalamic volume with and with- lateral side showing the location of the CMN and the thick surround of the internal medullary lamina. This figure was adapted from Kandel and out the constituent nuclei as a second examination of Schwartz31 (copyright 1985, Elsevier Science Publishing Co) and Netter specificity. (copyright 1984, CIBA Pharmaceutical Co).32

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D E F

G H I

J K L

Figure 2. Outline of the centromedian nucleus (CMN) in 4 participants. A, Anatomical magnetic resonance image of the thalamus. B, Differentiated view with enhancement of edges. C, Outline of the CMN created with fitting of spline curve. Points are deposited on the differentiated image on white lines with a mouse, and the spline curve is fitted through these points. Three additional participants are shown in D-F, G-I, and J-L.

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As with absolute data, patients with schizophrenia had No differences between patients who previously and never significantly smaller relative volumes of the 3 associa- received medication were found when all 3 nuclei were tion nuclei than controls (Table 2). The effect sizes for entered into multivariate ANOVA, and the follow-up uni- the MDN, PUL, and CMN were 0.78, 0.55, and 0.36, re- variate ANCOVA for the MDN and PUL also revealed no spectively. We also computed the volume relative to the significant differences in size. However, the absolute size thalamic volume (nucleus in each hemisphere divided of the CMN was larger in the patients with schizophre- by the whole thalamic volume in that hemisphere) and nia who previously received medication (0.151 cm3) com- corrected thalamic volume (nucleus in each hemi- pared with those who never did (0.119 cm3) (ANCOVA sphere divided by the difference of the whole thalamic with age as covariate, F1,38=5.41 [P=.03]), but this effect volume in that hemisphere and the nuclear volume). was not significant for the relative volume data (F1,38=1.09 These ANCOVA findings were similar, confirming smaller [P=.30]), which showed the differences between con- nuclei for MDN, PUL, and CMN in patients with schizo- trols and patients above. When we compared volume in phrenia (significant main effects of diagnostic group, controls with that in the 15 patients who never received F1,98=4.23 and F1,98=4.26, respectively [P=.04]). medication, the findings remained significant for the absolute (F1,72=4.81 [P=.03]) and the relative MDN size WHOLE THALAMUS VOLUME (F1,72=6.99[P=.01]). The findings also remained significant for the PUL (absolute F1,72=8.32 [P=.005]; relative Whole thalamus absolute volumes of right and left hemi- F1,72=8.80 [P=.004]) and CMN (absolute F1,72=8.69 spheres did not differ significantly between the schizo- [P=.004]; relative F1,72=8.79 [P=.004]). phrenic (6.13±0.73 cm3 and 5.94±0.75 cm3, respectively) and control groups (6.37±0.69 cm3 and 6.10±0.68 EFFECT OF AGE 3 cm , respectively; F1,98=3.63 [P=.059]), and follow-up group differences were also not statistically significant There was no statistically significant difference in the mean when tested (1 tailed) (right thalamus, t99=1.65 [P=.10]; age of controls (40.1±15.9 years) vs schizophrenic pa- left thalamus, t99=1.07 [P=.29]). tients (36.9±15.2 years). With the Statistica Test of Par- When the relative volume was tested, patients allelism,33 the slopes of the age regression lines did not with schizophrenia had smaller volumes than controls differ between controls and schizophrenic patients for (main effect of group, F1,98=6.69 [P=.01]). When we the absolute left (F1,97=0.676 [P=.41]) or right (F1,97=1.86 examined the whole thalamus volume minus the 3 [P=.18]) or relative left hemispheric thalamus (F1,97=0.257 association nuclei, then the absolute volume [P=.61]) or right (F1,97=0.262 [P=.61]); therefore, age (ANCOVA, F1,98=0.63 [P=.42]) and the relative vol- was used as a covariate in all ANCOVAs on each ROI. ume (ANCOVA F=0.008 [P =.92]) did not differ Regression analysis for total thalamic volume in con- between groups, indicating that any whole thalamic trols revealed a significant negative correlation between 2 size decrease, whether absolute or relative size, was total thalamic size and age for the right (R 1,58=0.20 Ͻ 2 Ͻ attributable to the MDN, PUL, and CMN and not the [P .001]) and left hemispheres (R 1,58=0.16 [P .001]). remaining thalamic structures. However, in schizophrenic patients, this correlation was not statistically significant for either hemisphere (right, 2 2 EFFECT OF SEX R 1,39=0.225 [P=.35]; left, R 1,39=0.0401 [P=.21]). Simi- lar analyses on absolute and relative measures demon- Men had larger absolute thalamic nuclei than women strated a tendency for all parts of the thalamus to be some- Ͻ (F1,97=11.56 [P .001]), but when relative size was what reduced in older participants. However, ANOVA examined, there were no significant sex effects or comparison of participants older and younger than the higher-order interactions with diagnosis in the 4-way mean age of 39 years failed to produce any significant analysis of variance (ANOVA) with diagnosis and sex as diagnostic groupϫage interactions for any of the 3 independent group dimensions. No significant differ- nuclei. ences between men and women were observed in relative thalamic size when all 3 nuclei were examined. COMPARISON WITH PREVIOUS SAMPLE However, follow-up ANCOVA revealed a significant ϫ diagnosis sex interaction for the MDN (F1,97=4.94 When the 12 patients with schizophrenia and 12 con- [P=.03]) that was larger in women (.0032) than men trols (previously reported1) were removed from this co- (.0030) among controls but larger in men (.0029) than hort and the 3-way ANCOVAs were repeated (n=77), the women (.0026) among schizophrenic patients. No sig- results were quite similar (despite reduction in power) nificant interactions with sex were observed for the for the MDN (main effect of diagnosis, F1,72=11.02 PUL or the CMN for absolute or relative data. There [P=.001]; diagnosisϫsex interaction in the smaller co- were no significant differences between men and hort, F1,72=3.33 [P=.07]) and PUL (main effect of diag- women with schizophrenia for performance on a serial nosis, F1,72=10.75 [P=.002]). For the CMN, there were verbal learning test (mean number of words correct, no significant main effects or group interactions. In an 7.94±3.80 vs 8.07±4.51; t35=−0.07 [P=.94]) or for examination of the left mediodorsal volume alone, which mean Brief Psychiatric Rating Scale total scores was not significantly smaller in the original sample (con- 3 (49.6±17.5 vs 52.0±14.0; t=−0.43 [P=.66]). trols, n=12; patients, n=12; 313 vs 290 mm ; t22=1.70

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 [P=.10]), we had previously observed a similar effect size Thus, the demographic characteristics seem weakly (0.575) to the effect size in the additional controls and associated with brain size and are less pronounced in patients (0.777) (controls, n=48; patients, n=29; ANOVA where brain size has been removed. This inter- 0.305±0.035±0.042±0.040 vs 290; t76=3.12 [P=.02]; pretation is supported by the appearance of significant ϫ dataϫ100 to match relative table convention in the interactions of age structure (F2,112=7.21 [P=.001]), ϫ present report). sex structure (F2,112=5.79 [P=.004]), and hemisphere ϫ structure (F2,112=3.22 [P=.04]) when the whole thala- CLINICAL CORRELATIONS mus size is entered as a covariate in an analysis of the absolute volumes. Within the patient group, there were no significant correlations between relative nuclear size and total Brief Psy- chiatric Rating Scale scores, positive or negative symp- COMMENT tom scale scores, or age of illness onset. We also examined the differences between patients with good and poor out- In this large sample, we were able to replicate the MDN comes as defined elsewhere34 and found no significant and PUL MRI findings in an independent sample, to dem- differences. We examined the correlations between onstrate that the decrement in volume does not affect all nuclear volume and performance on a serial verbal learn- thalamic regions, and to observe that the effect was great- ing task on an exploratory basis35 and found positive cor- est in patients who had never received medication, in- relations between the serial order score on the volume dicating that it was not a product of pharmacological treat- of the right CMN for absolute (r1,40=0.52; [P=.001]) and ment. With the connections of all 3 of the delineated nuclei relative volumes (r=0.44 [P=.002]); these correlations and the frontal lobe, these findings tend to implicate the were not found in the controls. In controls, the number importance of prefrontal-thalamic circuits in schizophre- correct was significantly correlated with the volume of nia. Recent data suggesting fewer projections from the the right MDN (r=0.28 [P=.03]). MDN to the prefrontal cortex are consistent with this view.36 Similarly, temporal-thalamic circuits are impli- CONTROLS cated by volume reductions in the PUL and the temporal lobe. In the postmortem study from our group,2 the We examined the demographic and structural charac- MDN and PUL were reduced in volume in patients with teristics of the thalamus in the control group alone in a schizophrenia. Patients also showed reduced neuronal 4-way ANOVA on absolute size with independent groups number in the MDN, parvocellular subdivision, and PUL for age (above and below the average age of 39 years), and reduced neuronal size in the MDN, caudodorsal sub- sex (men and women), structure (MDN, PUL, and CMN), division, and PUL. and hemisphere (right and left). Men had larger nuclei In the present MRI study, we were able to demon- than women (F1,56=6.30 [P=.02]), and this effect was sig- strate the specificity of volume loss to the delineated nu- nificantly more pronounced (sexϫstructure interac- clei, with the volumes of the remainder of the thalamus tion, F2,112=5.79 [P=.004]; Rao R2,55=3.13 [P=.051]; clearly not different in controls vs patients with schizo- Greenhouse-Geisser P=.02) for the PUL (1.674 vs 1.490 phrenia. We also demonstrated that the nuclear volume 3 cm ;F1,56=6.98 [P=.01]) than for the MDN (0.685 vs effect size was larger when the data were expressed rela- 0.647 cm3) or the CMN (0.152 vs 0.139 cm3). The right tive to whole brain size than when absolute data were hemisphere nuclei were larger than the left (F1,56=4.59 analyzed, indicating that the phenomenon in patients was [P=.04]), and this right/left hemispheric asymmetry was not merely smaller total brain with proportionately smaller significantly more pronounced for the PUL (1.616 vs 1.548 thalamic nuclei, but a loss of thalamic nuclear volume 3 cm ;F1,56=4.89 [P=.03]) than for the MDN (0.677 vs beyond variation in whole brain size. Although the CMN 0.655 cm3) or the CMN (0.148 vs 0.143 cm3) by ANOVA was not significantly smaller in the much smaller post- ϫ (hemisphere structure interaction, F2,112=3.22 [P=.04]; mortem sample, relative size data were significant in the but Rao R2,55=2.12 [P=.13]). Younger participants had large MRI sample. A review of other MRI studies of tha- larger nuclei than older participants (F1,56=7.49 [P=.08]), lamic volume shows several reports indicating reduced and this difference was significantly more pronounced relative volume37-42 but some failures to detect size dif- 3 43,44 for the PUL (1.684 vs 1.480 cm ;F1,56=8.53 [P=.005]) ferences. Automated deformation-based morphom- than for the MDN (0.686 vs 0.646 cm3) or the CMN (0.151 etry also detected reduced thalamic size.45 In our study, vs 0.139 cm3), as statistically confirmed by ANOVA the effect sizes for the relative size were 0.78 for the MDN, ϫ (age structure interaction, F2,112=7.21 [P=.001]; Rao 0.44 for the relative whole thalamus, and 0.10 for the re- R2,55=3.90 [P=.03]). mainder of the thalamus after subtraction of the MDN, For relative data, the same pattern was largely PUL, and CMN. Our effect size of 0.44 for the whole thala- present, with younger individuals having relatively larger mus is slightly larger than the estimate of 0.35 from the 42 nuclei (main effect of age, F1,56=3.41 [P=.07]) and the meta-analysis, which was based on 11 studies with 313 ϫ effect being larger (age structure interaction, F2,112=3.05 patients with schizophrenia and whole thalamus vol- [P=.0515]; but Rao R2,55=3.97 [P=.03]) in the PUL ume adjusted for brain size. Thus, the effect is not large (0.00681 vs 0.00641; F1,56=5.34 [P=.02]) than in the MDN but seems to affect all of the delineated nuclei. The effect or the CMN. The ageϫstructureϫhemisphere interac- size in our postmortem sample (full cohort), which in- tion with means similar to those found for absolute cluded only the chronically and severely ill, was 1.02. This volume was at a trend level (Rao R2,55=2.97 [P=.059]). may reflect greater tracing precision in histological ma-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 terial or greater effects associated with old age, greater differences are attenuated or reversed in schizophrenic severity, or longer-term illness. patients.53,54 Based primarily on extrapolations from ani- Our thalamic and nuclear volumes for the post- mal research,55 it is widely believed that sexual differen- mortem and MRI tracings follow the same relative pro- tiation of the human brain is largely a midtrimester event.56 portions; the MDN, PUL, and CMN are 14%, 22%, and A midtrimester event has also been implicated in the 3%, respectively, of the total thalamus in postmortem pathogenesis of schizophrenia.57-59 A midtrimester per- controls and 11%, 24%, and 2%, respectively, in the turbation of normal brain development might, there- MRI scans. The postmortem volumes tend to be smaller fore, alter the normal course of brain sexual differentia- by about 25%, consistent with estimates of shrinkage tion in addition to setting the stage for the subsequent artifact in formalin-fixed frozen postmortem sections. If development of schizophrenia. tissue is embedded in a hydrophobic polymer for slic- Our group has previously reported significant cor- ing, the volume loss may be up to 75%. This variation relations between Brief Psychiatric Rating Scale scores in shrinkage depending on histological method and glucose metabolism in the thalamus, indicating that accounts for some of the apparent discrepancies in the functional measures may be more sensitive to the clini- postmortem literature and indicates advantages for in cal state in schizophrenia than measures only of volume vivo imaging. reduction.25 Although efforts were made to recruit vol- The CMN showed significantly smaller relative unteers matched by educational level and parental SES, size in the present study, and the direction of the differ- a small bias toward individuals with more years of col- ence in CMN volume between controls (0.163±0.027 lege (4 vs 1) and higher parental SES (2.89 vs 3.55) was cm3) and schizophrenic patients (0.141±.042 cm3)isin observed. Since parental SES and education might be the same direction in the postmortem data (P=.16 for anticipated to be correlated with liability for schizo- the analysis as performed in the postmortem study with phrenia, removing these differences with ANCOVA age, postmortem interval, fixation time, and brain could be misleading. weight as covariates; F1,19=4.35 [P=.051] for CMN vol- Decreased gray matter density in the thalamus was ume divided by brain weight with only age as a covari- reported60 when MR images were compared using sig- ate as in the MRI data). It might be argued that because nificance probability mapping. The reduced volume the CMN is widely regarded as having primarily motor seen in our MRI studies combined with the reduced functions, regulating the output of the caudate nucleus volume and neuronal number,2,16,19,20 neuronal size,2 and putamen in concert with the dopaminergic input and reduced metabolic rate24 is consistent with the con- from the substantia nigra,46 it might be less directly cept that the MDN in patients with schizophrenia is involved in schizophrenia than the MDN with its exten- compromised and that smaller numbers of smaller (and sive frontal cortical connections. However, the CMN presumably less active) neurons carry out a reduced also projects to cortical regions involved in schizophre- amount of information processing. The reduction in nia and is believed to participate in functions that are size is seen with absolute data and those expressed rela- impaired in schizophrenia. The present data suggest tive to whole brain volume. This may reflect the that the size of the CMN may vary as a function of neu- removal of irrelevant body-size associated variance, roleptic exposure, consistent with the observation in because effect sizes were larger when data corrected for rats that this nucleus is activated by exposure to typical total brain size were examined; if the thalamus merely and atypical neuroleptics,47 and consistent with its con- shrank along with all other brain structures, we might nections with other structures that also exhibit volume have anticipated a smaller effect size for relative than expansion with neuroleptic exposure. Volume increase absolute data. The percentage reduction in absolute in the caudate nucleus in schizophrenia has been MDN volume we observed is small (6.7%) compared hypothesized to reflect increased dopaminergic innerva- with the larger volume reductions seen in the postmor- tion, probably secondary to neuroleptic treatment or an tem studies by the research groups of Pakkenberg,16 interaction between neuroleptic treatment and the Byne et al,2 Popken et al,19 and Young et al20 cited above pathophysiology underlying schizophrenia, since 2 lon- (27%, 15%, 17%, and 24%, respectively). This may gitudinal MRI follow-up studies found progressive reflect a combination of factors, including statistically enlargement in striatal volume after neuroleptic treat- more variable measurement of volume in MRI than ment.48,49 In a recent study from our group,50 reduced postmortem material, differential contributions to MRI caudate volume was found in schizophrenic patients density of different types of neurons, and characteristics who never received medication compared with con- of the parvocellular subregion that might shift the lat- trols, and increased (relative to control values) dorsal eral edge of the entire MDN on MRI. Nevertheless, our putamen volume was found in those who previously findings match those of the 4 postmortem studies and received medication. Similar findings were reported in provide data on a much larger and younger cohort other subsequent studies,51 including greater increases without the confounding factor of old age, variation in in the putamen than caudate nucleus in patients who postmortem interval, and fixation shrinkage. Since previously received medication.51,52 However, abnor- putatively atrophic changes have been described in 1 malities in glutamatergic synapses in the thalamus in of the cortical targets of the MDN, these data are schizophrenia must also be considered.36 also consistent with our overarching hypothesis that The significant diagnosisϫsex interaction that schizophrenia-related pathology in a particular subdivision we observed for the volume of the MDN is consistent of the thalamus is etiologically related to pathology in its with several previous observations in which normal sex projectionfields.Thelocalizationofschizophrenia-associated

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 changes to thalamic subregions is a step in the under- 13. Robinson DL. Functional contributions of the primate pulvinar. Prog Brain Res. standing of neuronal circuit impairments that may be in- 1993;95:371-380. 14. Wester K, Irvine DR, Hugdahl K. Auditory laterality and attentional deficits after volved in the symptomatology of the schizophrenias. thalamic haemorrhage. J Neurol. 2001;248:676-683. The finding of reduced PUL volume in the large sample 15. Dom R, de Saedeler J, Bogerts B, Hopf A. Quantitative Cytometric Analysis of used in the present study adds weight to our previous ob- Basal Ganglia in Catatonic Schizophrenics. Amsterdam, the Netherlands: Elsevier servations based on much smaller in vivo1 and postmor- Science Inc; 1981. tem samples.2 The PUL is a large, heterogeneous struc- 16. Pakkenberg B. Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenics. Arch Gen Psychiatry. ture that occupies nearly a quarter of the total thalamic 1990;47:1023-1028. volume and consists of several subdivisions with unique 17. Pakkenberg B. The volume of the mediodorsal thalamic nucleus in treated and patterns of connectivity.11 If our overarching hypothesis untreated schizophrenics. Schizophr Res. 1992;7:95-100. is correct, subsequent postmortem studies may find 18. Pakkenberg B. Leucotomized schizophrenics lost neurons in the mediodorsal tha- that the volume changes in the PUL disproportionately lamic nucleus. Neuropathol Appl Neurobiol. 1993;19:373-380. 19. Popken GJ, Bunney WE Jr, Potkin SG, Jones EG. Subnucleus-specific loss of affect its medial portion, which may be further subdi- neurons in medial thalamus of schizophrenics. Proc Natl Acad Sci U S A. 2000; vided into a centrolateral subdivision with a preponder- 97:9276-9280. ance of prefrontal connections similar to those of the 20. Young KA, Manaye KF, Liang C, Hicks PB, German DC. Reduced number of me- MDN, and a medial subdivision (ie, the medial subdivi- diodorsal and anterior thalamic neurons in schizophrenia. Biol Psychiatry. 2000; sion of the medial PUL) with a preponderance of tempo- 47:944-953. 21. Danos P, Bauman B, Bernstein H, Franz M, Stauch R, Northoff G, Krell D, Falkai ral connections. P, Bogerts B. Schizophrenia and anteroventral thalamic nucleus: selective decrease of parvalbumin-immunoreactive thalamocortical projection neurons. Psy- Submitted for publication June 10, 2002; final revision chiatry Res. 1998;82:1-10. received March 11, 2003; accepted March 14, 2003. 22. Danos P, Baumann B, Bernstein HG, Stauch R, Krell D, Falkai P, Bogerts B. 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