BRITISH JOURNAL OF PSYCHIATRY 2001), 178, 337^343 Schizophrenia and the frontal lobes from three centres Oxford, Belfast and Wickford in Essex)) in the UK and then Post-mortem stereological study of tissue volume assigned a randomised code by a third party so that measurements could be made blind to gender, diagnosis and age. Brains were J.J.ROBINHIGHLEY,MARYA.WALKER,MARGARETM.ESIRI, ROBIN HIGHLEY, MARY A. WALKER, MARGARET M. ESIRI, stored in formalin for an average of 3.25 BRENDAN McMcDONALD,DONALD, PAUL J. HARRISONand TIMOTHY J. CROW years prior to use in the study. It has been observed that any volume alterations related to fixation stabilise after a maxi- mum of 3 weeks Quester & SchroSchroder,È der, 1997), and therefore, as all brains were fixed in excess of this duration, it can be as- Background It has been suggested Evidence from both functional and sumed that they had reached their stable thatthatthere there is frontallobe involvement neuropathological studies suggests that the state.state. frontal lobes are affected in schizophrenia The brains were screened to ensure that in schizophrenia, and thatitthat it may be Goldman-Rakic & Selemon, 1997), raising they were free of neuropathological disease. lateralised and gender-specific. the issue of the potential for differences in Brains from patients who had undergone the volume of frontal lobe tissue between leucotomy were excluded. Patients' clinical Aims ToclarifyTo clarify the structure ofofthe the individuals with and without schizo- notes were assessed by a psychiatrist T.J.C. frontallobesinfrontallobes in schizophrenia in a post- phrenia. There is some evidence in the or Steven J. Cooper see Acknowledgements)) mortem series. existing literature for either a reduction in to ensure that diagnoses conformed to frontal lobe grey matter volume or a global DSM±IV American Psychiatric Association, MethodMethod The volume of white matter cortical reduction that is more marked in 1994) criteria for schizophrenia or schizo- and cortical components oftheof the frontal the frontal lobes Breier et aletal, 1992). There affective disorder. The control subjects' lobes was measured in brains of controls is additional evidence for lateralised altera- clinical notes were screened to ensure that they were free of psychopathology. and patients with schizophrenia using tions in the frontal lobe volume in schizo- phrenia Bilder et aletal, 1994). Early studies The mean age, cerebrum weight and planimetry and the Cavalieriprinciple. defined the posterior limit of the frontal post-mortem delay, as well as hospital of The components measured were: lobes with some arbitrary landmark e.g. origin, cause of death and number of cases superior frontal gyrus, middle frontal the genu of the corpus callosum), as in the different groups, are given in Table 1. gyrus, a composite of inferior frontal opposed to the central sulcus, which is ana- As can be seen from Table 1, the females tomically a more valid boundary. A pre- were significantly older than the males. gyrus and orbito-frontal cortex, as well as vious study of the present brain collection For this reason, age was entered into all total frontallobefrontal lobe cortex and white matter. HighleyHighley et aletal, 1998,1998aa) suggests that taking ANOVAs as a covariate. In addition, the anterior cingulate gyrus proper account of the central sulcus may was measured. be important. In that study, the length from the frontal pole to the central sulcus was MethodsMethods ResultsResults No diagnosis, gender, measured dorsally over the external surface The frontal lobes were defined as all cortex diagnosisdiagnosis66side, diagnosis66gender ororgender of both frontal lobes on post-mortem and white matter anterior to the central brains and a striking gender66diagnosisdiagnosis diagnosisdiagnosis66gendergender66side interactions sulcus. The basal ganglia, insula, ventricles interaction was found see Discussion). and internal capsule were not included. were observedinobservedinthe the volume of anyof The present study was performed to eluci- All brains were stripped of the leptome- the components, the grey matter as a date the nature of volumetric differences ninges and bisected in the median sagittal whole or the white matter.No evidence if present) in the brain in schizophrenia, plane. The temporal and occipital lobes for volumetric inter-group differences when the frontal lobes are defined in a were dissected away by sectioning the white non-arbitrary manner. The following struc- matter running between the temporal and was found for the anterior cingulate tures were measured: the pre-central gyrus, frontal lobes and insula, and a cut through gyrus.gyrus. the superior frontal gyrus, the middle fron- the parietal lobes. tal gyrus, a composite of the inferior frontal Either side of the central sulcus, the pre- Conclusions Such structural gyrus and orbito-frontal cortex, the total and post-central gyri were painted with abnormalities as are presentinthepresent in the frontal frontal lobe cortex and white matter. In permanent ink of different colours. The lobes are more subtle than addition, the anterior cingulate volume frontal lobes were then sectioned into straightforward alterationsintissue was assessed. serial, parallel coronal slices using 5-mm guides. After slicing, the slices were reas- volume; theymayinclude changesin shape sembled into a stack excluding the first and the pattern of gyral folding. METHOD and last slices), the length of which was measured and divided by the number of Declaration of interest This work Tissue slices, to generate the mean slice thickness. was supported byThe Medical Research Brains were fixed by suspension from the For all further measures, allall slices including Council and The WellcomeTrust. basilar artery in 10% formalin, collected first and last) were included. 337 Downloaded from https://www.cambridge.org/core. 03 Oct 2021 at 03:14:36, subject to the Cambridge Core terms of use. HIGHLEY ET AL TaTable b l e 1 The mean s.d.) age, cerebrum weight and post-mortem delay, as well as hospital of origin and and cause of the hemisphere, it lies superior to the of death of cases cingulate. Anteriorly it wraps around the front of the cingulate to meet up with the orbito-frontal cortex. The superior ControlSchizophrenia frontal gyrus lies superior to the middle FemaleMale FemaleMale frontal gyrus, separated from it by the superior frontal sulcus. Number of cases 13 15 919 155 TheThe middle frontal gyrus lies between Age11,,years years74.6 13.3) 74.6 13.3)67.2 14.5)73.3 17.6)60.9 15.3) the superior and inferior frontal gyri and Cerebrum weight22 0.96 0.14)0.14)0.96 1.12 0.09)0.09)1.12 0.86 0.15)0.15)0.86 1.15 0.13) is bounded by the superior and inferior brain less brain-stem, kg) frontal sulci. Posteriorly it abuts the pre- DeathDeathtopost-mortemdelay to post-mortem delay33,, 43.3 26.9)26.9)43.3 42.6 28.5)28.5)42.6 43.44 38.1)48.2 33.1) central gyrus, and is separated from it by hourshours the pre-central sulcus. Duration in fixative44,,years years2.54 1.33)2.54 1.33) 2.13 1.30)1.30)2.13 5.22 1.86)1.86)5.22 3.79 2.12)2.12)3.79 TheThe infero-orbital cortex is a composite of the inferior frontal gyrus and the orbito- HospitaloforiginHospital of origin55,, 0/10/30/13/2 6/1/26/1/2 5/5/55/5/5 frontal cortex. These two were com- Belfast/Oxford/Runwell pounded because it proved to be impossible Cause of death66,, 8/1/38/1/3 12/3/012/3/0 2/3/22/3/2 5/4/55/4/5 to reliably separate one from the other. The cardiac/respiratory/other inferior frontal gyrus is inferior to the 1. Femalessignificantly older than males:by ANOVA, FF1,48)5.43,5.43, PP0.024. middle frontal gyrus, separated from it by 2. Femalessignificantly lighter than males:by ANCOVAwith age ascovariate, FF1,46)1,46)30.24,30.24, PP550.0005.0.0005. the inferior frontal sulcus. Medially, the 3. No inter-group differences: all FF1,46)1,46)440.10,0.10, PP440.7.0.7. 4.4.Controls Controlssignificantly significantly shorter shorter than than patients patients FF1,47)1,47)20.70,20.70, PP550.0005); trend to femaleslonger than males orbito-frontal cortex is bounded by that FF1,47)1,47)3.73,3.73, PP0.059).0.059). portion of the anterior cingulate that lies 5. No control brainswerebrains were collected collected at at Belfast,sothere Belfast, so there were were significant significant group group differencesin differences hospitalin hospital of origin: of origin: underneath the rostrum of the corpus ww2225.27,d.f.6,6, PP550.0005. Runwell Hospital located at Wickford in Essex. 6. No inter-group differences: ww2211.23, d.f.d.f.11.23, 6,6, PP0.081.0.081. callosum and anterior to the genu. All grey matter on the inferior surface of the frontal lobes was included in this measure. The posterior aspect of each slice was Between the most anterior extent of the TheThe frontal pole was defined as all the patted dry of excess moisture and photo- central sulcus and the level at which the grey matter on the most anterior one or graphed using colour slide film, with a ruler frontal and temporal lobes are no longer two slices in the situation where the differ- in the field of view, ensuring that the planes connected, the inferior boundary of the ent gyri were indistinguishable. The sole of the camera lens and the brain slice were white matter was defined by a straight line use of this measure was to be summated parallel. These photographs were then from the superior insular circular sulcus to with the other grey matter measures to give projected, in a random position, at an the most supero-lateral point of the lateral the total frontal lobe cortical volume.