Head size and schizophrenia

Schizophrenia Research 55 (2002) 99±104

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Head size and schizophrenia Peter F. Buckley a,*, Lee Friedman b, John A. Jesberger b, S. Charles Schulz c, George Jaskiw b a

Medical College of Georgia, Department of Psychiatry and Behavioral Health, 1515 Pope Avenue, Augusta, GA 30192-3800, USA b From Case Western Reserve University, Cleveland, OH, USA c University of Minnesota, Minneapolis, MN, USA Received 15 February 2000; revised 15 December 2000; accepted 18 December 2000

Abstract There is a small but intriguing body of literature which suggests that head size may be reduced in patients with schizophrenia. This literature sits alongside more substantial and compelling evidence that there is a reduction in cerebral volume in schizophrenia. As an extension of earlier work, measures of extracranial head size derived from standard anthropometric approaches were assessed in 44 patients and 46 control subjects. Head size was found to be normal in schizophrenia. The relationship of brain size to head size is elaborated. q 2002 Elsevier Science B.V. All rights reserved. Keywords: Head size; Neurodevelopment; Schizophrenia

A reduction in intracranial volume or brain size has been noted in neuroimaging and anthropological studies of schizophrenia (Andreasen et al., 1986, 1994; Zipursky et al., 1992; Harvey et al., 1993; Gur et al., 1994; Friedman et al., 1999). Andreasen et al. (1986) ®rst reported that the brain was smaller, especially in the frontal lobes, and that there was a smaller cranial size in persons with schizophrenia. This ®nding was not replicated in a subsequent magnetic resonance imaging (MRI) study from Andreasen's center which matched patients (n ˆ 54) more closely to control (n ˆ 47) subjects (Andreasen et al., 1990). A recent meta-analysis (Wright et al., 2000) of all studies to date concluded that there is a 2% reduction in cerebral volume in schizophrenia. This ®nding is consistent with a previous meta* Corresponding author. Tel.: 11-706-721-3284; fax: 11-706721-1793. E-mail address: [email protected] (P.F. Buckley MD).

analysis from our group (Ward et al., 1996) which revealed a composite effect size in the range of 0.3 (effect size simply expresses mean differences in standard deviation units: 0.3 is of small-to-moderate magnitude) for brain and intracranial size. We did not detect any effect for head size, although this was based on a small number of studies. Lohr and Flynn (1993) examined head size as part of an assessment of minor physical anomalies in patients with schizophrenia (n ˆ 118), mood disorders (n ˆ 33), or normal controls (n ˆ 31). There was no evidence for reduced head size in either patient group. Bracha et al. (1995) found similar results in a study of twins with schizophrenia. Grove et al. (1991) reached a similar conclusion in a study of patients with schizophrenia (n ˆ 16) and their nonpsychotic siblings (n ˆ 34). In contrast, Jones and Lewis (1991) found a signi®cant reduction in head size in elderly patients with schizophrenia. DeMyer et al. (1988) also reported reduced head size in an MRI

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P.F. Buckley et al. / Schizophrenia Research 55 (2002) 99±104

Table 1 Demographics and anthropometric measures broken down by diagnostic group. (Note: All anthropometric measurements are given in centimeters) Control

Race Gender Age (yrs) Education (yrs) Wais Information Subscale a NAART b Abuse/No abuse Stature Elbow width Head circumference Head length Head width Tragus±vertex±tragus arc a b

Schizophrenia

Caucasian

African-American

Caucasian

African-American

20 Male 39.89 ^ 10.51 12.3 ^ 1.7 9.0 ^ 3.8 22.3 ^ 14.7 3/17 171.94 ^ 7.48 7.16 ^ 0.41 57.10 ^ 1.82 19.93 ^ 0.74 13.83 ^ 0.80 34.62 ^ 1.95

26 Male 43.89 ^ 8.23 12.6 ^ 1.9 8.2 ^ 2.0 19.4 ^ 8.6 16/10 174.62 ^ 8.38 7.14 ^ 0.41 57.85 ^ 1.92 20.34 ^ 0.77 13.85 ^ 0.53 34.53 ^ 1.56

18 Male 37.50 ^ 6.62 11.1 ^ 3.8 6.53 ^ 3.5 22.0 ^ 14.9 6/12 173.59 ^ 6.05 7.06 ^ 0.41 57.33 ^ 1.17 19.97 ^ 0.68 14.04 ^ 0.60 34.66 ^ 0.99

26 Male 42.67 ^ 10.57 11.1 ^ 2.2 6.0 ^ 2.5 12.3 ^ 12.0 15/11 176.35 ^ 6.61 7.42 ^ 0.49 58.41 ^ 2.07 20.27 ^ 0.86 14.10 ^ 0.62 35.38 ^ 1.80

Data not available for one schizophrenia group participant (Caucasian). Data not available for two participants in the control group (one African-American, one Caucasian).

study of 24 patients with schizophrenia and 24 normal subjects. There are also two studies (McNeil et al., 1993; Kunugi et al., 1996) of preschizophrenic neonates which reported reduced head circumference at birth. A Swedish study (Hultman et al., 1997) reported that reduced head circumference at birth was a risk factor for the subsequent development of schizophrenia. Thus, there exists a contentious, but intriguing literature on head size and schizophrenia. Reduced head size in schizophrenia may be related to maldevelopment in utero. This proposition is supported by the obstetrical complications and early neonate studies (McNeil et al., 1993; Kunugi et al., 1996; Hultman et al., 1997) which report reduced head circumference in those destined later to develop schizophrenia. The hypothesis for the current study of adult patients with schizophrenia was in accordance with this neurodevelopmental perspective and, speci®cally, we hypothesized that patients with schizophrenia would show decreased size in at least one anatomic measure of head size. To test this hypothesis, we undertook here a comprehensive study of head size using measures derived from standard anthropometric approaches (Lohman et al., 1998). We were not interested in whether our patients with schizophrenia were simply smaller overall (and had small heads), but whether, after controlling for

stature and frame, there was any difference in extracranial size between the schizophrenia and control groups.

1. Methods 1.1. Subjects The patients in the schizophrenia group (n ˆ 44) were drawn from a state psychiatric hospital (Northcoast Behavioral Healthcare System, Northeast Ohio), and from a university-based psychiatry inpatient ward (University Hospitals of Cleveland, Ohio). The control subjects (n ˆ 46) were recruited from the waiting room of an internal medicine clinic at a county hospital (MetroHealth Medical Center, Cleveland, Ohio) and from a substance-abuse clinic at a local Veterans Affairs Hospital (Brecksville, Ohio). All subjects were male. The groups were matched for age and race (Table 1). Potential subjects were excluded from either group if they were younger than 18 years or older than 65 years of age. Potential subjects were also excluded if they had a history of skeletal fractures likely to affect any of the anthropometric measures in the present study (e.g. skull or elbow fractures). Potential

P.F. Buckley et al. / Schizophrenia Research 55 (2002) 99±104

subjects were also excluded if they had any condition likely to have an effect on normal growth and development of the skeletal frame in general and the skull in particular (including, but not necessarily limited to, dwar®sm, gigantism, acromegaly, and hydrocephaly, etc.). Only patients with currentepisode diagnoses of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatric Press, 1994) were included in the study. The diagnosis was derived from a comprehensive review of extensive medical records from this population of long-stay inpatients. Patients were excluded if they had a comorbid axis II diagnosis of moderate-tosevere mental retardation. Control subjects were excluded if they had a ®rst-degree relative with a major psychiatric illness (schizophrenia, major depression, bipolar disorder, suicide) or if they have ever been medicated or hospitalized for a mental disorder other than simple substance abuse. Fortyone percent of the controls and 48% of the patients had a history of substance abuse. The history of substance abuse was determined by brief questions at interview and by record review (for the patient and VA control group). Subjects were also questioned regarding their years of formal education. All subjects were assessed on the information subtest of the Wechsler scale (Wechsler, 1981) and on the North American version of the National Adult Reading Test (Blair and Spreen, 1989). Written informed consent was obtained from all subjects. The study was approved by the Institutional Review Boards of participating hospitals. 1.2. Measures There are numerous accepted standard anthropometric measures that can be made of the head (Farkas, 1994). For the purpose of assessing gross head size, we selected a subset of these measures as follows. We started with a subset of standard anthropometric measures for head width, length and height, as well as sagittal, transverse, and coronal arc lengths. Head length: projective distance from glabella to opsithocranion. Head width: projective distance between the tragions.

101

This was chosen over the inter-eurion distance because the tragions were readily identi®able in all subjects, while the eurions could be dif®cult to locate in subjects with very thick and dense hair. Head height: perpendicular distance from the Frankfurt horizontal to the vertex. Axial arc length: head circumference. Coronal arc length: arc length between the tragions and through the vertex. Sagittal arc length: arc length between glabella and opisthocranion and through the vertex. We were careful to select only the measures above that could be obtained reliably. Therefore, we conducted a series of reliability studies of these measures on nonstudy subjects prior to the initiation of the formal study. Head height and sagittal arc length could not be measured reliably after repeated efforts and were therefore dropped. The ®nal selected measurements of extracranial head size were: head circumference, head length, head width, and the tragus±vertex±tragus arc length. All measures and landmarks were obtained from standard anthropometric procedures (Lohman et al., 1998), and are illustrated in Fig. 1. Head circumference and tragus±vertex±tragus arc length were measured with a high quality plastic tape measure placed as indicated in Fig. 1. The head length (glabella to opisthocranion) and head width (tragus to tragus) were determined using the anthropometer (Harpenden Anthropometer). Two measures of overall body size were obtained. Stature was measured with an anthropometer. Elbow width is de®ned as the distance between the epicondyles of the humerus. This distance was measured on the right arm using bicondylar vernier calipers. Elbow width is an accepted index of the relative size of the body frame (skeleton) (Lohman et al., 1998; Frisancho and Flegel, 1983). In a study of body frame in 16,494 US adults, elbow breadth was found to be a reliable indicator of body frame for both males and females (Frisancho and Flegel, 1983). Prior to the initiation of the study, interrater reliability was established in a series of methodological studies on separate non-overlapping groups. Intraclass correlation coef®cients (ICC, Bartko and Carpenter, 1976) for all measures were above 0.9.

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P.F. Buckley et al. / Schizophrenia Research 55 (2002) 99±104

Fig. 1. Key measurements. Landmarks for head size measures. Glabella (g): the most prominent midline point between the eyebrows. Opisthocranion (op): the point in the occipital region most distant from the glabella. Vertex (v): the highest point on the head. Tragions (tr): the notches on the upper margin of the tragus of each ear. Head size measures. Head circumference: the distance around the head in the axial plane along a contour across the top of the eyebrows, and passing through the opisthocranion. Head length: the linear distance from the glabella to the opisthocranion. Head width: the linear distance between the tragions. Tragus±vertex±opisthocranion arc length: the shortest distance along the head surface between the glabella and opisthocranion, passing through the vertex.

1.3. Statistical analysis The groups were compared on age, stature and elbow width with an ANOVA with two independent factors: diagnosis and race. The groups were compared on head size measures with a two factor (diagnosis and race) ANOVA, with age, stature and elbow width as covariates. This allowed a comparison between the groups controlling for potential differences in age, stature or frame size.

2. Results Group differences on age, stature and elbow width The African-Americans were slightly older, regardless of diagnosis (Table 1). There were no diagnosis or race effects for stature. There was a statistically signi®cant interaction of diagnosis with race for the elbow width measure (Table 2). The interaction stems from the fact that there was no race effect in the control

group, but within the patient group, the AfricanAmericans had larger elbow widths than the controls, whereas Caucasians had smaller elbow widths than controls. Group differences on head size measures controlling for age, stature and elbow width (Table 3). Elbow width was a statistically signi®cant covariate for head circumference and head width. Stature was a statistically sign®ciant covariate for tragus±vertex± tragus arc. Age was not a statistically signi®cant covariate for any measure. There were no statistically signi®cant main effects of diagnosis or race on any head size measures, nor was there a statistically signi®cant diagnosis by race interaction for any head size measure. 3. Discussion On balance, patients with schizophrenia have smaller brains, estimated at an overall 2% reduction

P.F. Buckley et al. / Schizophrenia Research 55 (2002) 99±104 Table 2 ANOVA for age, stature and elbow width

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Table 3 ANOVA for head size measures

Source

Variable

df

F

Sig.

Factor

Dependent variable

df

F

Sig.

Diagnosis

Age Stature Elbow width Age Stature Elbow width Age Stature Elbow width

1,86 1,86 1,86 1,86 1,86 1,86 1,86 1,86 1,86

0.934 1.184 0.863 5.174 3.079 3.319 0.059 0.001 4.219

0.337 0.280 0.356 0.025 0.083 0.072 0.808 0.980 0.043

Elbow

Circumference Head length Head width Tragus±tragus arc Circumference Head length Head width Tragus±tragus arc Circumference Head length Head width Tragus±tragus arc Circumference Head length Head width Tragus±tragus arc Circumference Head length Head width Tragus±tragus arc Circumference Head length Head width Tragus±tragus arc

1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83 1,83

6.116 0.580 13.635 0.596 1.1135 3.029 0.247 6.259 0.725 1.086 0.612 2.530 0.263 0.282 1.796 0.563 3.197 3.217 0.092 0.316 0.046 0.261 0.732 1.101

0.015 0.449 0.000 0.442 0.290 0.086 0.620 0.014 0.397 0.300 0.436 0.115 0.610 0.597 0.184 0.455 0.077 0.077 0.763 0.575 0.830 0.611 0.395 0.297

Race Diagnosis by race

in cerebral volume (Wright et al., 2000). However, on the basis of the extant literature (including our previous meta-analysis, Ward et al., 1996) and the ®ndings of the present study, it is reasonable to conclude that head size is not reduced in schizophrenia. It seems intuitive, as consistent with Dr Andreasen's original ®ndings (Andreasen et al., 1986), that if patients with schizophrenia had smaller brains then they would also have smaller heads. Indeed, in commenting on an MRI study which carefully measured cerebral and intracranial volume (Breier et al., 1992), Stevens (1994) concluded the measure of total cerebral volume could be considered equivalent to the measurement of head circumference. We addressed this issue in a previous anthropometric study which used a unique osteologic collection (Friedman et al., 2000). In that study of 123 male cadavers, we examined the relationship between external head measurements and cranial capacity (total intracranial volume). We observed that carefully evaluated measure of head size accounted for only 60% of the variance in cranial capacity. Thus, the contribution of skull thickness, sinus, scalp, muscles, and subcutaneous fat collectively make a modest but important difference between intracranial size and extracranial (head) size. It is also important to note that the observed reduction in cerebral volume is modest indeed (2%), and only detectable using sophisticated MRI technology. The methodology for anthropometrics is likely to be less sensitive and even though points of measurement have been articulated with great detail (Farkas, 1994; Lohman et al., 1998), it is plausible that this technique is not sensitive or reliable enough to detect meaningful differences which might exist in head size. The present study

Stature

Age

Diagnosis

Race

Diagnosis by race

selected only those measures which could be obtained with a high degree of reliability. This study suggests there is no head size difference between these groups or the effect is very small. In the latter case, only studies with very high statistical power (perhaps 100 or more subjects per group) may reliably detect such a small effect. Another methodological consideration critical for structural imaging studies is the selection of controls (Weinberger et al., 1987; DeMyer et al., 1988; Stevens, 1994; Buckley and Waddington, 1992). It is noteworthy that a subsequent clinical study of head size in schizophrenia which reported a reduction in size used dementia patients as a control group (Jones and Lewis, 1991). Furthermore, the group that initially reported reduced cranial size in schizophrenia (Andreasen et al., 1990) did not replicate their ®nding using a well-matched control group. We carefully matched patients and control subjects here for age, gender, and race. We did include subjects with substance abuse, although the proportions were comparable in each group and there was no evidence

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