Inversion of the hemispheric laterality of the anterior cingulate gyrus in schizophrenics

Inversion of the Hemispheric Laterality of the Anterior Cingulate Gyrus in Schizophrenics Alfonso M. Albanese, Alicia B. Merlo, Tom4s A. Mascitti, Elba B. Tornese, Elena E. G6mez, Victor Konopka, and Eduardo F. Albanese

The anterior cingulate gyrus (acg) is involved in mechanisms of attention and emotion, where the right hemisphere is considered to be dominant. One of the models for neuropsychological dysfunction in schizophrenia suggests an impairment in the balance of lateralized functions. Fourteen adult human female brains, having no macroscopic lesions, were used in this stud}'. Seven brains came from .female patients with clinical diagnoses of residual schizophrenia (DSM-111-R; APA 1987). Seven female brains were used as controls. Thirteen male brains were also studied, with the sole purpose of establishing the ~,picali~ of the female controls. All schizophrenic" brains were age matched with control brains. Right laterali~ for weight (71.4%) and su~. ace (85. 7%) was observed in the acg of.female control brains. The inversion of this lateraliO, in a significant number of the schizophrenic" cases was the most relevant finding in this study. Key Words: Cingulate, schizophrenia, asymmetry, dominance, attention, emotion

Introduction Since Kraepelin's (1896) statement "a neuropathological basis of schizophrenia would eventually be found," numerous areas of the central nervous system have been identified showing structural abnormalities. In postmortem studies attention has been focused repeatedly on the lateral ventricles (Brown et al 1986; Bruton et al 1990), the basal ganglia (Bogerts et al 1985; Heckers et al 1991) and the limbic system (Jakob and Beckmann 1986; From the [nstituto Latinoamericano de lnvestigaciones Medicas de la Universidad del Salvador (ILAIMUS) (AMA, ABM, EEG, EFA]: Cfitedra de Anatomfa, Facuhad de Medicina, Universidad del Salvador (AMA. EFAt: Departamento de Anato mia. Unidad de Neurociencias, Facultad de Medicina, Universidad de Buenos Aires (AMA, TAM, EBT, EFA~; C~tedra de Anatomla Humana, Facuhad de Farmacia y Bioqu/mica, Universidad de Buenos Aires (AMA, EFA): and Hospital Neuropsiqui~itrico Braulio Moyano (EBT, VK). Buenos Aires, Argentina. Address reprint requests to Dr. Allbnso M. Albanese, Cfitedra de Anatomfa, Facuhad de Medicina. Universidad del Salvador, Tucum4n 1859 (10501, Buenos Aires, Argentina. Received November 3, 1993: revised August 5. 1994.

© 1995 Society of Biological Psychiatry

Falkai et al 19881. In the limbic system, a volumetric decrease of the hippocampus and the amygdala (Bogerts et al 1985), the entorhinal region (Falkai et al 1988), the medialdorsal thalamic nucleus (Pakkenberg 1992) and thinning of the cortex of the parahippocampal gyrus (Bogerts et al 1985, 1990; Brown et al 1986; Altshuler et al 1990) have been reported. Cytoarchitectonic abnormalities have been described in the rostral entorhinal cortex and ventral insula (Jakob and Beckmann 1986), hippocampus (Scheibel and Kovelman 1981; Kovelman and Scheibel 1984; Falkai and Bogerts 1986; Altshuler et al 1987; Benes et al 1991b), septal basal forebrain and periventricular areas (Stevens 1982), anterior cingulate cortex (Benes et al 1986, 1987; Benes and Bird 1987; Albanese et al 1992), nucleus accumbens septi (Dora et al 1982), pulvinar (Dora 1975) and medialdorsal thalamic nucleus (Pakkenberg 1992). The anterior cingulate gyrus (acg) has extensive anatomical connections which convey limbic information to the 0006-3223/95/$09.50 SSDI 0006-3223(94)00257-4

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prefrontal and parietal neocortex and receives projections from midbrain ventral tegmental areas (Vogt et al 1979; Pandya et al 1981; Mesulam 1985). The acg has been involved in emotional and attentional mechanisms (Cohen et al 1992; Morecraft et al 1993) which are altered in schizophrenia (Posner et al 1988; for review see Csernansky et al 1991). On the other hand, one of the models for neuropsychological dysfunction in schizophrenia suggests an impairment in the balance of lateralized function (Gur 1977; Gruzelier and Flor-Henry 1979; Harvey et al 1993). Crow et al (1989) reported that "'anomalous asymmetry is specific in schizophrenia" and added that "the disease process in some way disturbs the mechanism of lateralization." The findings of morphological asymmetry in schizophrenic brains, such as a decrease of the normal asymmetry and the appearance of other asymmetries not present in control brains, seem to indicate that a change accompanies the disease or that the process that leads to schizophrenia somehow alters laterality (Gruzelier et al 1988). By the same token, some models try to explain the symptoms of schizophrenia through the overactivation of the left hemisphere (Gur 1978; Gruzelier and Flor-Henry 1979; Taylor et al 1979; Walker and Mc Guire 1982) or dysfunction of the right hemisphere (Murphy and Cutting 1990). The primary point of focus that has emerged from these latter studies is the analysis of the possible asymmetry of cortical areas, such as the acg, which are related to attention and other functions compromised in schizophrenia. Laterality studies in postmortem schizophrenic brains have been carried out (Brown et a11986; Jakob and Beckman 1986: Crow et al 1989; Jeste and Lohr 1989; Altshuler et al 1990; Bogerts et al 1990; Conrad et al 1991 ; Falkai et al 1992; Rossi et al 1992). Most limbic system studies on laterality consist of computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) analyses (Jernigan et al 1991; Breier et al 1992: Shenton et al 1992; Weinberger et al 1992). Few limbic system studies on laterality have been performed on postmortem brains. Thus far, no acg asymmetry studies have been performed in postmortem schizophrenic brains. The objective of this work is to compare left versus right measurements of weight and cortical surface for the acg in schizophrenic brains versus control brains.

Materials and Methods Fourteen human adult brains without visible macroscopic lesions were used. All brains were from patients who had died from cardiac or pulmonary diseases. Seven brains ranging from 42-80 years of age (mean _+ ES: 60.7 + 4.7 years) came from female schizophrenic patients (Braulio Moyano Neuropsychiatric Hospital, Buenos Aires, Argen-

tina). Controls were seven female normal brains ranging from 44-80 years of age (mean -+ ES: 56.9 + 4.5 years) at time of death. Thirteen male brains ranging from 21-71 years of age (mean 2 ES: 45.8 --- 4.9 years) were also studied, with the sole purpose of establishing the typicality of the female controls in order to obtain normal parameters of comparison. The group of schizophrenic brains was obtained from chronically hospitalized patients. The mean age at the time of their initial psychopathology was between 16 and 25 years (mean 2 ES: 20.3 2 1.1 years). The evolution period of the disease was between 26 and 61 years (mean _+ ES: 40.4 - 4.7 years). At time of death, each received the final diagnoses of residual schizophrenia. All had histories which included thought disorders, inappropriate mood and affect, delusions, and hallucinations. The patients fulfilled DSMIII-R (APA 1987) criteria for residual schizophrenia. Symptoms were categorized according to the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS). All schizophrenic patients had received neuroleptic treatment. All schizophrenics were right-handed (see Table 2) according to the Edinburgh test (Oldfield 1971). Schizophrenic patients were evaluated by means of neurologic and general physical examinations and had no history of neurologic illness or major alcohol or drug abuse. None had evidence of mental retardation (IQ > 70). Control subjects, all right-handed (see Tables I and 2) according to the Edinburgh Test, had been evaluated for evidence of psychiatric and/or neurologic disease by a psychiatrist and a neurologist. All schizophrenic brains were consecutively matched with female control brains. Male/female control brains were also age matched. The brains were fixed in formaldehyde (5%) during the first 72 hours postmortem, and stored in formaldehyde (5%) for at least 150 days before being processed in order to ensure a stable volume in accordance with Haug et al (1984). All postmortem brains were treated in the same manner. The method employed requires only fixation in formaldehyde, without dehydration, gelatin embedding, or similar procedures. According to Heckers et al (1991), shrinkage is less than 3% by means of this process. As both hemispheres of each brain were processed simultaneously, the shrinkage would be equal in both hemispheres and, consequently, adequate for calculation of asymmetry. The limits of the acg were determined according to Von Economo (1929), and Bailey and Von Bonin (1951). These are: sulcus cinguli, sulcus paraolfatorius, lamina terminalis, sulcus corpus callosi, and a vertical line drawn from the dorsal end of the sulcus centralis that Von Economo (1929) considers the limit between the anterior and posterior cingulate gyrus representing the transition between the agranular

C i n g u l a t e A s y m m e t r y in S c h i z o p h r e n i c s

BIOL PSYCHIATRY 1995:38:13-21

15

T a b l e 1. A n t e r i o r C i n g u l a t e G y m s : I n d i v i d u a l V a l u e s o f M a l e a n d F e m a l e C o n t r o l B r a i n s Hemisphere Right

%of a s y m m e t r y for values of

Left

Casc

Age (yr)

LQ

Weight (g)

Surface (cm:)

Ra (g/cm 2)

Weight (g)

Surface (cm :)

Ra (g/cm 2)

M44 M53 M40 M t0 M36 M34 F08 M33 M43 F22 F48 F37 M50 M0t FI8 F47 M05 M30 M38 F20

21 26 30 31 32 40 44 46 48 49 50 53 55 56 59 63 70 70 71 80

100 100 82 I O0 54 82 I O0 67 69 67 64 54 80 83 85 100 69 69 50 80

16.26 16.83 19.33 13.77 10.18 11.52 14.49 6.02 16.50 I I. 74 I 1.74 10.35 11.45 13.26 13.65 9.07 10.22 10.10 8.82 I0.15

43.38 41.12 47.21 37.90 30.76 33.33 3 Z 64 20.31 45.66 33.57 34.89 31.70 37.56 37,04 40.69 31.08 33.01 30.88 30.20 28.12

.37 .41 .41 .36 . 33 ,35 .38 .30 .36 .35 .34 .33 .30 .36 .34 .29 .31 .33 .29 .36

11.00 10.30 14.05 14.19 10.59 9.67 9. 08 4. I I 12.40 9.54 6.44 7.97 12.73 I 1.64 12.32 9.60 9.03 8.52 6.68 9.29

34.48 21.90 34.39 37.56 30.49 28.59 24.62 12.54 32.85 23.47 18.67 25.04 38.90 29.94 34.23 32.06 25.96 22.17 23.35 24.35

.32 .47 .41 .38 .35 .34 .37 .33 .38 .41 .34 .32 .33 .39 .36 .30 .35 .38 .29 .38

Weight

Surface

19.30 R 24.07 R 15.82 R --8.73 R 22.95 R 18.85 R 14.19 R 10.34 R 29.15 R 13.00 R 5.29 L 6.51 R 5.12 R

11.43 R 30.50 R 15.71 R -7.66 R 20. 91 R 23.65 R 16.32 R 1Z 71 R 30.28 R 11.74R -10.60 R 8.62 R

6.18 R 8.49 R 13.81 R --

11.96 R 16.42 R 12.79 R 7.19 R

I

M, F = respecti;'ely, male and female: Ra = v,eight/surface: R, L = respecti~,ely, right dominance, left dominance; I = level of asymmetry lower than 5%; LQ = laterality quotient [Edinburgh Handedness Inventory).

isocortex, LA area of Von Economo or 24 of Brodmann (corresponding to the acg), and the granular isocortex, LC area o f V o n Economo or 23 of Brodmann (corresponding to the posterior cingulate gyrus) (Brodmann 1909; Von Econo m o 1929). In those cases in which the sulcus cinguli was bifurcated, the branch of the bifurcation closer to the corpus

callosum was taken as the limit following the criteria of Pandya et al ( 1981 ) and Room et al (1985). According to the cytoarchitecture and connections, these authors consider that the area between the two branches of the bifurcation-area 32 of Brodmann--pertains to the prefrontal cortex and not to the acg.

T a b l e 2. A n t e r i o r C i n g u l a t e G y r u s : I n d i v i d u a l V a l u e s o f F e m a l e C o n t r o l a n d S c h i z o p h r e n i c B r a i n s Hemisphere Right

% of a s y m m e t r y for values of

Left

Case

Age (yr)

LQ

Wcight (g!

Surface (cm:)

Ra (g/cm 2)

Weight (g)

Surface (cm 2)

Ra (g/cm 2)

SO,? F08 F22 F48 S02 F37 S07 F I8 $04 F47 S06 S05 F20 SOl

42 44 49 50 52 53 56 59 60 63 64 71 80 80

87 100 67 64 64 54 100 85 7l 100 82 I00 80 73

9.81 14.49 I 1.74 I 1.74 8.15 10.35 8.60 13.65 6.12 9.07 10. 59 10.88 10.15 9. 39

35.67 37.64 33.57 34.89 2Z 1 l 31.70 21.35 40.69 23.58 31.08 29. 84 31.87 28.12 30. 77

.28 .38 .35 .34 ,30 .33 .40 .34 .26 .29 .35 .34 .36 .31

11.28 9.08 9.54 6.44 9.01 7.97 10.49 12.32 7.69 9.60 I O. 74 I0.14 9.29 7, 38

36.23 24.62 23.47 18.67 32.26 25.04 29.88 34.23 25.03 32.06 28.56 34.26 24.35 27. 52

.31 .37 .41 .34 .28 .32 .35 .36 .31 .30 .38 .30 .38 .27

Weight

Surface

6.97L 22.95 R 10.34 R 29.15 R 5.01 L 13.00 R 9.90L 5.12 R 11.37L --

-20.91 R 17.71 R 30.28 R 8.67L 11.74 R 16.65L 8.62 R ---

-

-

I 11.99 R

-

-

7.19 R 5.58 R

F 5"= respectively, control, schizophrenic: Ra = weighffsufface; R, L = respecti~ el>, right dominance, left dominance' - - = level of asymmetry lower than 5%" LQ = laterality quotient IEdinburgh Handedness Inventor,vl.

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In order to obtain the acg specimens for the present study, we considered the acg as that formed by all the tissue in the gyms; that is to say, the superficial and deep gray cortex, and the corresponding white matter. Consequently, the gyral weight was considered to be the weight of the cortical gray matter plus the weight of the white matter both of the gyrus proper, including fibers that leave and reach this cortex.

The standardized method used for the isolation of the acg and their subsequent processing was developed by our laboratory and previously published (Aibanese et al 1989). This method allows us to obtain the anatomical pieces in an adequate state for the determination of weight in a standardized fashion and for the exposure of the deep cortex. The cortex was sectioned following the depth of the sulci and in the zones where the sulci were interrupted along the line uniting the ends of the sulci. The white matter was sectioned by the plane delimited by the lines uniting the deepest points of the cortex of the sulci surrounding the gyms. The isolated gyrus was superficially dried with filter paper (until the paper no longer appeared wet) and immediately weighed on an analytical scale (sensitivity 0.01 mg). In order to determine the superficial and deep cortical surfaces, the gyrus was divided following the secondary sulci to expose the deep cortical surface. An acrylic mold of the total cortical surface of each of these portions was obtained by carefully covering the cortical surface with a thin layer of white acrylic. Forty to sixty minutes later, the acrylic mold was manually extracted in a single block; the anatomical piece was recovered unaltered. Since the mold obtained cannot be distended, it is perfectly appropriate for subsequent processing. The acrylic mold was flattened by means of the necessary cuts allowing it to be unfolded on a flat surface. It was then put on a piece of black paper. Then, both the mold and the black paper were adhered onto a sheet of millimetered paper by means of a transparent sheet of contact paper. A magnified photocopy (1:1.41) of the sheet was made. We considered the area of the photocopy corresponding to 1 cm 2 of the original as the surface unit. At least seven samples, corresponding to 25 units, each of surface area were carefully cut from the center and edges of the photocopy in which the millimetered design could be observed. Each sample of paper was weighed on an analytical scale, and the weight was divided by 25 in order to obtain the weight corresponding to one unit of surface area. Then, the flu -+ SD and the coefficient of variation (C%) of these values were calculated. The photocopies of the acrylic molds were cut and weighed and their surfaces calculated taking Xu into account. The reproducibility of the method was previously controlled by obtaining nine acrylic molds of a portion of cerebral cortex. The Yfu was 8.33 cm 2 and the coefficient of variation was only 1.92%.

The corresponding values of weight, surface area, and weight/surface area ratio were calculated separately for both hemispheres of all the brains studied. Weight and surface area asymmetry were determined for the acg in all brains studied. The sum of the values corresponding to both hemispheres was considered as 100% and the difference between the percentage which was provided by each portion of the pair was considered as the percentage of asymmetry (A%): A%=(R-L)

x IO0/R + L

where R and L are the right and left values of the pair, respectively. We determined the level of asymmetry as the absolute value ofA % (that is, the value without considering the sign) indicative of the quantitative value of asymmetry independent of the predominant side. The resultant sign of A%, positive or negative, indicates the predominant side, the right or the left of the pair, respectively. Using 100 as the factor permits the asymmetry to be expressed as a percentage. This formula differs from that used by Galaburda et al (1987) in the estimation of asymmetry--which these authors labeled coefficient of asymmetry---only in the constant factor. They used a factor of 2 instead of a factor of 100. They considered "asymmetry" as a structure with a coefficient of asymmetry higher than 0.1 or lower than -0.1. These values correspond to our A% = 5 and A% = -5, respectively. Coinciding with their formula, we considered an absolute value of A% = 5% as the minimum level of asymmetry. The percentage of cases reaching levels of asymmetry of at least 5% was determined for female control and schizophrenic groups, as well as for the male control group. All values from the schizophrenic brains were age matched with the female control brains. The values of the female and male controls were age matched as well. The proportion of cases with right/left weight and cortical surface laterality, as well as that of nonasymmetric cases of the schizophrenic group, was compared to that corresponding to the female control group by means of the chi square test. The results of the female control group were compared in turn to the results of the male control group. The correlation coefficient (r) and its statistical significance between weight and cortical surface was determined separately for the 7 female controls, the 7 female schizophrenic brains, and the 13 male controls using the pairs of values corresponding to both hemispheres.

Results The individual values obtained from each female and male control brain are shown in Table 1, arranged according to age. As shown in Table 1 and Figure 1. the controls exhib-

Cingulate Asymmetry in Schizophrenics

100

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17

% OF GASES

80 60 Figure 1. Anteriorcingulate gyrus: Laterality of male and female controls using weight and surface values. NOT AS-not asymmetric.

40 20 0

LEFT

RIGHT

NOT AS.

LEFT

WEIGHT

RIGHT

NOT AS.

SURFACE

MALE (n-13)

~

FEMALE (n-7)

ited a high incidence of right laterality regardless of sex. The individual results of female controls and schizophrenic brains are shown in Table 2. Left laterality was frequently observed in the acg among the schizophrenic brains. Such laterality (for an A% > or = 5%) for weight values was observed in four out of the seven brains, and for surface values was observed in two out of the seven brains. Figure 2 shows the laterality of female control and schizophrenic groups. The proportion of cases with left laterality is the most conspicuous significant morphological difference we found between control and schizophrenic brains. Also, as observed in Figure 2, the proportion of cases with right laterality is significantly lower in schizophrenics.

The coefficient of correlation r and its statistical significance, comparing values of weight and surface determined by using right and left hemispheric pairs (26, 14, and 14, respectively, for male controls and female controls and schizophrenics) were: male controls 0.93 (p < .001), female controls 0.90 (p < .01), and schizophrenic brains 0.69 (p < .02).

Discussion Based on these data, we report a morphological pattern in the acg of control brains characterized by right laterality of the cortical surface and gyral weight. Left laterality was not observed among female controls and was an exception for

% OF GASES 1001

80

Figure 2. Anterior cingulate gyrus: Laterality of female controls and schizophrenic patients using weight and surface values. NOT AS-not asymmetric. *p < .05 @p < .01 (Ch?) in relation to controls.

i

LEFT

RIGHT

NOT All.

WEIGHT i

CONTROl.8 (n-7)

•

LEFT

RIGHT

NOT All.

SURFACE SCHIZOPHRENIC8 (It,,T)

18

BIOL PSYCHIATRY 1995:38:13-21

male control brains. Contrary to this, a high incidence of left laterality was found among the schizophrenic brains: the number of cases with this particularity was significant when compared with the control group. The right laterality of the acg in control brains and the inversion of this laterality in a significant number of the schizophrenic brains were the most relevant findings in this study. The results concerning the reversed laterality of the acg in this paper are of interest, since this structure is involved in mechanisms of attention and emotion where the right hemisphere is considered to be dominant, being altered in schizophrenia. Schizophrenic brain reversed asymmetry was described in the planum temporale (Rossi et al 1992) and in the sylvian fissure (Falkai et al 1992). No studies of acg laterality in postmortem control and schizophrenic brains were found in the literature (Falkai et a11992). Nevertheless, some acg morphological aspects not related to laterality have been studied in postmortem schizophrenic brains. Rosenthal and Bigelow (1972) determined in serial sections that the distance between the sulcus corpus callosi and the sulcus cinguli did not show significant differences in schizophrenic and control brains. Brown et al (1986), who estimated the perimeter corresponding to the cortex of the gyrus cinguli in a single standard coronal slide taken at the level just anterior to the mammillary bodies, did not find significant differences between control and schizophrenic brains. It must be emphasized that these studies, regardless of the methods employed, do not deal specifically with asymmetry and laterality. Studies of laterality have been performed in other regions in postmortem schizophrenic brains, especially in structures of the temporal lobe and in the basal ganglia. In the let) hemisphere, reduced volumes of the hippocampus (Bogerts et al 1985; Jeste and Lohr 1989), hippocampal formation, and amygdala (Bogerts et al 1985), parahippocampal cortex (Brown et al 1986), entorhinal cortex (Falkai et a11988) and an increased striatal volume (Heckers et al 1991) have been found. In the right hemisphere, reduced volume of the caudate nucleus (Brown et a11986) and increased volume of the palidum (Heckers et al 1991) have been found. Jakob and Beckmann (1986) described bilateral temporal lobe alterations of the sulcogyral pattern being more marked in the left hemisphere. Using MRI, Shenton et al (1992) found a reduction of the gray matter of the hippocampus, amygdala, parahippocampus, and superior temporal gyrus in the left hemisphere. Recent anatomical findings suggest that the limbic system is strongly involved in the neuropsychological dysfunction of schizophrenia (Ciprian-Olliver 1988; Roberts 1991 : Benes et al 1991a; Falkai et al 1992). Studies of circuit organization in the limbic system emphasize the connections of the acg with structures including basal ganglia.

A . M . A l b a n e s e et al

prefrontal areas, hippocampus, amygdala, medialdorsal thalamic nucleus, and basal forebrain (Irle and Markowitsch 1982; Alexander et al 1986; Alheid and Heimer 1988). Recently, Pakkenberg (1992) reported a reduction of the medialdorsal nucleus in schizophrenics. This finding is of interest if we consider the development that this nucleus undergoes in humans compared to other primates (Armstrong 1990) and, on the other hand, its tight relationship to the limbic striatum and the cingulate (Goldman-Rakic and Porrino 1985). It has often been argued from anatomical (GoldmanRakic 1988), functional (Cohen et al 1988; Petersen et al 1988; Posner and Petersen 1990) and clinical (Mesulam 1981 ; Mirsky 1987; Grossman et al 1992) data that the acg plays an important role in aspects of emotion and attention including neglect. The right hemisphere is considered specialized in emotion and attention (Mesulam 1981; Hellman et al 1986; Cohen et al 1992). These functions are altered in schizophrenia (Cullum et al 1993; Harvey et al 1993). It has been said that "the derangements of attention constitute a cardinal component of schizophrenia" (Bleuler 1911 ), and recently, that "this parallelism in the integrity of attention and emotion is also noted in a number of other psychiatric and neurological conditions, and schizophrenia is certainly no exception to this clinical correlation" (Mesulain and Geschwind 1978). Physiologically, the attentional mechanisms are dependent on noradrenergic pathways which arise from the locus coeruleus (Aston-Jones et al 1984) and which are strongly lateralized to the right hemisphere (Robinson 1985; Kruglikov and Orlova 1991). The acg receives one of the most important noradrenergic projections (Lewis 1992). The acg is one of the cerebral regions with important dopaminergic innervation (Reynolds and Czudek 1988; Goldman-Rakic et al 1992; Lewis et al 1992). Changes in the dopaminergic projections to the limbic system have been reported to be associated with the pathogenesis of schizophrenia over the last 20 years (Stevens 1973: Reynolds and Czudek 1988; Joyce 1993). Among the dopaminergic circuits that have been considered to be altered are the connections of the acg with the striatum (for a review, see Csernansky et al 1991). Heckers et al (1991) and Jernigan et al ( 1991 ) reported left l aterality of the striatum in schizophrenics, whereas in this study the reversal of laterality to the left in the acg is demonstrated in a significant number of cases. In this work we observed that the correlation between the weight of the acg and the cortical surface is excellent in the control brains and less so, although significant, in schizophrenics. Considering the small sample size of our study, it would be premature to draw final conclusions from the results we

Cingulate Asymmetry in Schizophrenics

obtained. Nevertheless, the left laterality of acg found in schizophrenics in contrast with the constant occurrence of right laterality in controls demonstrates the morphological differences related to the laterality observed in other structures. On the other hand, the inversion of the laterality of the acg in schizophrenics does not contradict the present theories on the pathogenesis of schizophrenia. Further studies are necessary to confirm our findings and subsequently to determine the pathological nature of these structural changes.

BIOLPSYCHIATRY 1995:38:13-21

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Studies of male schizophrenics are necessary to determine if the reversal laterality found in our study is gender specific.

This study was supported, in part, by a grant from Roemmers Foundation, Argentina. We would like to thank Dr. Anton E. Coleman from the Beth Israel Hospital, Department of Neurology, Harvard Medical School, for his helpful comments on the manuscript, and to Dr. Jorge Negrete and Mr. Washington Sesma for providing technical assistance.

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Albanese E, Albanese A, Mascitti T, Tornese E, Konopka V. Merlo A ( 1992): Gyrus cinguli anterior: densidad neuronal en cerebros controles y esquizofr6nicos. Medicina 52:450. Alexander GE, De Long MR, Strick PL ( 1986): Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Ann Rev Neurosci 9:357-381.

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