S-28-2 Magnetic resonance imaging of the frontal lobe in schizophrenia

S-28 Neuroirnagingand schizophrenia Occurring during the course of neutodevelopment, when the sulco-gyral pattern is determined. More recently we have completed an MR study of the planum temporale, an important biological substrate of language, based on 3D surface renderings from MR scans Here, we observed an mcreaselnsurfacearea in schizophrenics compared to normal controls and we are in the pro cess of validating our measurements using 20 random cases selected from the Levitsky and Geschwind cases reported in Science m 1968. Because the planum area is asymmetric in fetal development, differences between groups may have their origin in neurodevelopment We are now following up on these studies by evaluating schizotypal per sonality disorder (SPD): a d~sorder that is genetically linked to schizophrenia We have been recruited these subjects from the community, consequently these subjects do not suffer the same confounds of medication and/or chronic hospitalization that is often seen in schizephrenia. Preliminary data (n - 11) suggests that many of the cognitive impairments observed in schizophrenia, such as formal thought disorder and verbal memory impair ments, are also observed in SPD Moreover, a neuroradiologist, blind to diagnosis, documented non specific MR abnormalities in 5 of the 6 subjects w h o have received MR scans. More detailed analyses of the MR data is underway. These findings will be discussed in the context of understand ing schizophrenic pathology as a disorder involving regions ~mportant to language, thought, and verbal/associative m e m o r y

References Kikinis. R , Shenton, M E . Gerig. G , Hokama. P4H Ha~mson,J O'Donnell, B F. Wible C G, McCarley, R W r Jolesz, FA (1994) Temporal lobe sulco-gyral pattern anomalies in schizophrenia: An in vivo MR three-dimensional surface rendering study Neuro science Letters 182.7-12 Nestor, PG, Shenton, ME , McCarley, R W halmson. J Smith R S , Q'DonneIF, B F, Kimble. M., Kikinis, R r Joleszr FA (1993) Neuropsychologlcal correlates of MRI temporal lobe abnormalities in schizophrenia American Journal of Psychiatry 150, 1849 1855 Shenton, M E , Kikinis, R , Jolesz, EA , Pollak, S D, LeMay, M , Wible, C.G, Hokamar H H, Martin J. Metcaif. D, Coleman, M r McCarley. R W (1992) Abnormaidies of the left temporal lobe and thought disorder in schizophrenia A quantitative magnetic resonance imaging study. New England Journal of Medicine 327,604~612 Wible. C G, Shenton, M E , Hokama. H H, Kikinis. R , Jolesz, EA, Metcalf, D, McCarley, RW (In Press) Prefrontal cortex, positive symptoms and schizophrenia A quantltat,ve MRI study Archives of General Psychiatry

Ma£1netic resonance imaging of the frontal lobe in schizophrenia

239 Based on the functional abnormalities, it may be hypothesized that structural abnormalities exist in the frontal lobes in patients with schizophrenia. However. studies evaluating the structural aspects of the frontal lobes in schizophrenia have been sparse, and their results are inconclusive. Using Magnetic Resonance Imaging (MRI) or Computer Tomography (CT), morphological abnormalities in the frontal lobes of schizophrenic patients were found in a f e w studies, but in others none were found. More prominent negative symptoms and cognitive deficits in schizophrenic patients were related to smaller frontal lobe volume or frontal sulcal enlargement (suggesting frontal atrophy) as measured by MRI or CT, but not consistently (for review see Gur and Pearlson, 1993). We suggest that the failure to find consistent structural abnormalities in the frontal lobes of schizophrenic patients may be due to methodological measurement issues. The frontal lobes comprise about 30 percent of the total brain volume in humans. When volume measures of the whole frontal lobe are taken it is likely that subtle, localized abnormalities submerge in the individual variation of the whole frontal lobe. If subtle abnormalities exist in some but not all subregions of the frontal lobes, these may remain undetected for the same reason. Animal lesion studies and studies in patients w~th frontal lobe damage have revealed that subregions of the frontal lobes have specialized cognitive functions (for review see Goldman-Rakic. 1987) Therefore. it is possible that in schizophrenic patients a dysfunction of discrete frontal subregions exists and not of the whole frontal lobe. Indeed, this was suggested by a study where a decreased dorsolateral frontal lobe voiume and not total frontal lobe volume measured by two-dimensional MRI was associated with impaired mental flexibility and memory in patients with schizophrenia (Seidman et al. 1994). However, accurate identification of discrete subregions within the frontal lobe is difficult on MRI, unless a three-dimensional (3D) reconstruction of the individual brain can be obtained. Because the boundaries of these regions cannot reliab(y be found in two-dimensional brain MR slices, the estimates made for the dbscrete frontal subregions in the two-dimensional space may hide existing abnormalities. We therefore use a 3D MRI computerreconstruction of the individual brain to identify the brain-surface markers that delineate brain-regions (Hulshoff Pol et al. 1 994). Using this method, the volumes of the dorsolaterat, medial, and orbitofrontal lobes in 15 patients w~th schizophrenia were measured in 0 5 tesla T l - w e i g h t e d 3D gradientecho MR images (1.2 mm slices, TR = 30 ms, TE = 13 ms, 256 mm FOV), and compared to 15 age, sex. and parental education matched, healthy control subjects The results from this study will be discussed in relation to the symptomatology and cognitive functioning. A comparison will be made to the findings from our studies in patients with acquired frontal lobe damage.

H.E. Hulshoff Pol. W.F.C. Baar~, C C Gispen-de Wied, W RTh.M. Mali, R.S Kahn. Departments of psych~atry and Radiology, Unrversity Hospital

References

Utrecht, and Rudolf Magnus Institute for Neurosciences, Heidelberg/aan 100, 3584 CX Utrecht, the Netherlands

Andreasen, N C , Rezai, K, Alliger, R, Swayze, ~ZW, Flaum, M, Kirchner, R, Cohen, G and O'Leary, D S (1992) Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia. Assessment with xenon 133 single-photon emission computed tomography and the Tower of London. Arch Gen. Psychiatry, 49, 943-958 Goldman-Rakic, PS (1987) Circuitry of primate prefrontal cortex and regulation of behavior by representational memory. In J M Brookhart (Ed), Handbook of physiology: The Nervous System, k4 Higher Functions of the Nervous System. Bethesda, V.B. Mountcastle, pp 373417 Gur, RE and Pearlson, GD. (1993) Neuroimaging in schizophrenia research, Schizophr Bull, 19, 163 179 Hulshoff Pol, H.E Tufleken, CA F, Hiiman. R, Viergever. M A , Kahn, RS and Van Ree, J M {1994) Three-dimensional reconstruction of the frontal lobes, Schizophrenia Research, 11, 134 Seidmanr LJ, Yurgelun-Todd, D. Kremen, W.S, Woods, BT, Goldstein, J.M., Faraone, S.V and Tsuang, BT (1994) Relationship of prefrontal and temporal lobe MRI measures to neuropsychological performance in chronic schizophrenia, Biol Psychiatry, 35. 235-246

Schizophrenia ~s a complex, chronic and invalidating disease that affects many aspects of cognition and behavior Its etboiogy in unknown. Although treatments exist for relief of some of the accompanying symptoms (such as pharmacological treatment of psychotic episodes) these offer no cure for the disease However, is has become abundantly clear that schizophrenia,s a brain disorder, implying that understanding the nature of the brain abner realities in schizophrenia may eventually ~mprove diagnosis and treatment Kraepelin, who in 1896 first described the illness as we know it, stated that the disorder is linked to dysfunctions in the frontal and temporal lobes The deficits m planning and judgement (i.e. the negative symptoms) seen m patients with schizophrenia reflected frontal lobe damage, while the part~c uladties in speech and auditory hallucinations (i e the positive symptoms) he attributed to temporal lobe damage. That frontal lobe abnormalities indeed exnst in schizophrenic patients ~s indicated by several lines of evidence The negative symptoms but also the cognitive deficits observed in schizoohremc patients display similarities with the cognitwe deficits found m patients following frontal lobe damage In functional brain imaging studies using positron emission tomography or single photon emission computer tomograohy a decreased frontal glucose metabolism or bloodflow was measured m schizophremc patients during cognitive processes that actwate the frontal lobes in healthy subjects, such as p(anning and word generation Interestingly, the frontal hypoactlvity has been related to the degree of negative s y m p t o m a t o l o g y i n patients However. patients with predominant positive symptoms may also have frontal lobe abnormalities as suggested by a study in which increased bloodflow was reported in the frontal lobe of schizophrenic patients during auditory hallucinations. Thus, there is evidence for frontal lobe dysfunction in pa tientswith schizophrenia(for r e w e w s e e A q d r e a s e n e t a l 1992)

Receptor binding studies in schizophrenia G Sedvall. Karo/inska Institute, Department of C/in/ca/Neuroscience, Psychiatry Section, Stockholm, Sweden Perturbed dopamine regulated signalling in the brain has been implicated in the pathophys~o/ogy of schizoph renia for more than thirty years. Five distinct dopamme receptor subtypes with pre- and/or postsynaptic Ioca(izations to a vast number of brain regions might represent components of altered dopamine signalling in schizophrenia. Whereas D2 dopamine receptors have previously been in the focus of interest, current studies focus also on D3, D4 as well as D1 receptors. For the D2 dopamine receptor family (D2. O3, D4} the analysis is complicated due to the lack of highly selective I~gands for any of these receptors Thus, practically all suitable ligands with