Hypofrontality in Men with First-Episode Psychosis

BRITISH JOURNAL OF PSYCHIATRY (2005), 186, 203^208

Hypofrontality in men with first-episode psychosis protocol, patients must have presented with first-episode psychosis with symptoms lasting more than 1 week, not attributable V. MOLINA, J. SANZ, S. REIG, R. MARTIMARTINEZ,¤NEZ, F. SARRAMEA, R. LUQUE, to organic or toxic origin, and unrelated C.BENITO,J.D.GISPERT,J.PASCAUandM.DESCOC. BENITO, J. D.GISPERT, J. PASCAU and M. DESCO to any other Axis I disorder; the presence ofofanyany relevant stressors clearly related to the episode had to be ruled out. We usedusedthesethese criteria in order to avoid recruitingrecruitingpatientspatients with transient psychotic symptoms,symptoms,according to DSM–IV criteria (American Psychiatric Association, 1994).1994). Background Decreased metabolic Decreased metabolic activity in the prefron- After inclusion, all patients were activity in the prefrontal cortex during tal cortex during cognitive activation is a followed for 2 years on an out-patient basis recurrent finding in schizophrenia (Volz with monthly visits, to confirm or rule out a cognitive activation is a recurrent finding et aletal, 1999). If it were not present in other diagnosis of schizophrenia at the end of this and a likely functionalfunctionalmarker marker of psychotic disorders, hypofrontality could period. After this follow-up, two experi- schizophrenia. constitute a distinctive marker for schizo- enced psychiatrists (V.M. and J.S.), masked phrenia. Although other groups have to the results of the PET scans, diagnosed Aims Toinvestigate the occurrence of published data on hypofrontality in schizo- each patient and decided whether the index hypofrontalityin patients with first- phreniform disorders (Andreasen et aletal,, episode was a first break of schizophrenia episode psychosis, with or without 1997), we know of none comparing meta- or, instead, a single psychotic episode that evolution to schizophrenia. bolic patterns in these patients in the light did not evolve into schizophrenia 2 years of whether or not they progress to schizo- after the enrolment. For this final diagnosis MethodMethod Weused fluorodeoxyglucose phrenia. To confirm hypofrontality as a they used all the available follow-up feature typical of schizophrenia, it would information (including total duration of positron emission tomography during the be advisable to study patients in very early significantsignificantsymptoms),symptoms), a semi-structured in- performance of an attentiontask and stages of the disease. This design requires terview, the Structured Clinical Interview magnetic resonance imaging to study the a corroboration of the diagnosis of schizo- for DSM–IVAccess I Disorders – Clinician dorsolateral prefrontal region in13 men phrenia by a prospective follow-up. With Version (SCID–CV; First et aletal, 1997) and with a first episode of psychosis.Data from this goal, we used magnetic resonance the information provided by the families imaging (MRI) and [1818F]fluorodeoxyglu- and clinical personnel. For diagnostic patients who progressed to schizophrenia cose (FDG) positron emission tomography purposes, the duration of symptoms was were compared withthose of patients (PET) to investigate two groups of people calculated covering the period before and who did not meet criteria for this diagnosis with first-episode psychosis: one group in after initiation of treatment. after 2 years. which the diagnosis of schizophrenia was On the basis of their final diagnosis, the confirmed 2 years later, and a group who 13 patients were divided into two groups. ResultsResults Patients who developed did not meet the criteria for this diagnosis The schizophrenia group comprised six schizophrenia demonstrated a significant after the same period. people with a diagnosis of paranoid schizo-schizophrenia according to DSM–IV criteria. TheThe hypofrontalityinthehypofrontality in the dorsolateral non-schizophrenia group comprised six prefrontal cortex in comparison with the METHOD people with a diagnosis of schizophreni- non-schizophrenia and control groups. form psychosis and one person who had Study participants experienced a brief psychotic disorder (with Conclusions Our results suggestthat The existence of gender-related differences a symptom duration of 3 weeks), likewise hypofrontalitycouldhypofrontality could be a marker of in frontal activity cannot be ruled out, con- according to DSM–IV criteria. The latter di- schizophrenia atthe time oftheof the first sidering that structural alterations seem to agnoses meant that these patients’ psychotic psychotic episode, in agreement with be more pronounced in men (Nopoulos episodesepisodeswere shorter than required to qua- et aletal, 1997). For this reason, and to achieve lify as schizophrenia, no other psychotic neurodevelopmental theories of maximum sample homogeneity, our study episode occurred during follow-up and the schizophrenia. was limited to men. Thirteen right-handed patients did not meet schizophrenia criteria men with a first psychotic episode were (including enduring negative symptoms) at Declaration of interest None.None. enrolled in a diachronic study of first-break the end of follow-up. The duration of the Funding detailed in Acknowledgements. schizophrenia; all of them were enrolled disease in the non-schizophrenia group while hospitalised for the first time in the was less than 3 months in all cases. The psychiatric unit of a general hospital. The clinical scores calculated using the Positive PET and MRI scans were performed at and Negative Syndrome Scale (PANSS; the time of inclusion in the study, before KayKay et aletal, 1992) at the time of admission any of the patients had met the criteria and at the end of follow-up are shown in for schizophrenia. To be included in the Table 1.Table1.

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Ta b l e 1 Demographic and clinical characteristics of participants regional metabolic activity in the PET image (Molina et aletal, 2003).,2003). Schizophrenia Non-schizophrenia Control group (nn¼6) group ((group nn¼7) group ((group nn¼8)8) MRI protocol Mean (s.d.) Mean (s.d.) Mean (s.d.) Magnetic resonance images were acquired on a Philips Gyroscan 1.5 T scanner (Philips Age, years 24.2 (4.4) 29.1 (8.8)(8.8)29.1 28.7 (6.0)(6.0)28.7 Medical Systems, Reigate, UK) using a TT11-- Education, years 11.5 (4.6)10.9 (6.0)11.8 (4.9) weighted three-dimensional gradient echo Duration of disease, months before inclusion1.1(0.8) 1.1 (0.8) 0.9 0.9(0.6) (0.6) sequence with the following parameters: Parental socio-economic level 2.1 (1.8)2.2 (1.8)2.0 (1.6) matrix size 25666256, pixel size 0.9 mm66 PANSS score 0.9 mm (field of view approximately Positive symptoms 25625666256 mm), flip angle 3088, echo time Enrolment 19.9 (5.1)20.3 (6.1) 4.6 ms, slice thickness 1.1–1.5 mm. In addi-

Follow-up 10.0 (3.4)7.2 (2.3) tion,tion, TT22-weighted sequences were acquired Negative symptoms for tissue segmentation and for other clini- Enrolment 15.6 (6.3)12.9 (7.5) cal purposes (turbo spin echo, turbo factor 15, echo time 120 ms, matrix size Follow-up 20.6 (8.3)7.4 (4.1) 25625666256, slice thickness 5.5 mm). General symptoms Enrolment 33.4 (7.1) 30.5 (8.8)(8.8)30.5 Follow-up 30.1 (9.5)(9.5)30.1 17.4 (7.7) PET protocolprotocolPET The PET study used a Siemens Exact 47 PANSS, Positive and Negative Syndrome Scale. tomograph (Siemens, Erlangen, Germany). Scans were obtained 20 min after injecting All patients were antipsychotic-naıantipsychotic-naıve¨ve after completing the treatment). The period 370 MBq of [1818F]FDG, while the partici- prior to the presenting episode; they were of complete remission of these symptoms pant performed a contingent continuous treated solely during the 2 days prior to was greater than 1 year in all cases. performance test (Rosvold et aletal, 1956).,1956). the PET scan. This was a practical means Eight healthy men were also recruited Participants were instructed to push a button of enrolling a sample representative of the as a control reference group. To match if a letter T immediately followed the letter usual presentation of schizophrenia, avoid- them with the patient group, none had an L, presented on a computer screen. The ing a selection bias related to the impaired education to college level. No difference interstimulus interval was 1 s. During the ability of patients with acute psychosis to in age or parental socio-economic level PET scan a neuropsychologist supervised cooperate during neuroimaging procedures. (Hollingshead & Frederick, 1953) was the appropriate response and full compli- All patients received the same treatment observed between the groups (Table 1). ance with the performance test of all parti- (haloperidol 10 mg per day liquid formula- Exclusion criteria for patients and con- cipants. After an intravenous line had been tion) and the medication was discontinued trols were learning disability, neurological inserted for FDG administration, the parti- for 12 h prior to the PET scan. No other disease, MRI findings deemed clinically cipant began the task, which was divided treatment was administered before scan- relevant (from a neurological perspective) into four blocks of 5 min each, with a ning. One patient from the schizophrenia by a radiologist masked to the diagnosis, 1 min rest between blocks; FDG was group and two from the non-schizophrenia history of head trauma with loss of con- administered 1 min after initiating the task. group had received benzodiazepines for sciousness, and history of substance misuse Participants were instructed to fast for at insomnia before inclusion, but they had during the past 6 months (other than occa- least 6 h before the scan, with particular iscontinuediscontinuedthisthis medication for more than sional hypnotics). A urinalysis was done in emphasis on avoiding coffee and other 2 weeks. No acute dystonic reaction all cases to rule out a toxic cause of the psychoactive beverages. occurred, thus there was no need to psychotic episode. Tracer activity values were proportion- administer anticholinergic medication After they had been given full infor- ally normalised to the global activity of before scanning. Nursing personnel verified mation, an informed consent form was each scan (Frackowiak et aletal, 1997) thus treatment compliance. signed by the participants and their relatives. representing relative activity. Total meta- Patients in the schizophrenia group The independent ethics committee approved bolic activity for each region of interest were maintained on antipsychotic treat- the study.thestudy. was divided by the region’s volume, thus ment for the entire follow-up period. In providing a measurement independent of the non-schizophrenia group, the anti- the amount of tissue sampled. psychotic treatment was continued for a period of 6–12 months following the PET Image analysis scan, on the basis of clinical criteria. None To determine the metabolic activity in the Segmentation of the patients in the non-schizophrenia dorsolateral prefrontal cortex and the To obtain metabolic measurements of the group presented clinically relevant negative occipital lobe, we used a procedure based prefrontal cortex and occipital lobe, we symptoms, disorganisation or persistent on MRI/PET image fusion. This method used a method for semi-automated segmen- behavioural alterations at the end of the uses the anatomical information of the tation of the brain based on the Talairach follow-up period (i.e. more than a year MRI to allow detailed measurement of reference system, similar to that described

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Fig. 11Fig. Sagittal (a) and axial (b) views illustrating aTalairach grid built upon an edited magnetic resonance scan and fused with the grey matter segmentationofthe positron emission tomographic scan.TheTalairach grid cells describing the left dorsolateral prefrontal region are highlighted in blue.This regiregionon of interest is defined as the cortexcortexencompassed encompassed in Brodmann areas 8,9,10 and 46, according to theTalairach atlas (Talairach & Tournoux,1988).

by Andreasen et aletal (1996) and Kates et aletal corresponding to the first three tissue 1994). Data from the occipital cortex (1999). We used a two-step procedure types on to each individual’s Talairach allowed us to discard a potential difference (Desco(Desco et aletal, 2001): the first step involved reference grid (Fig. 1), where the regions in overall metabolic activity between patient editing the MRI to remove skull and of interest were defined as sets of groups. The absence of bias due to a global extracranial tissue, registration of the cells. On the MRI/PET fused images, vol- effect was confirmed by the similar values PET and MRI scans, and an initial ume and activity were measured by sum- of metabolic activity in the occipital region segmentation of cerebral tissues into grey ming the data from the grid cells found in all the groups studied. matter, white matter and cerebrospinal associated with each region of interest Since there were slight age differences fluid; in the second stage we applied the (Desco(Desco et aletal, 2001).,2001). between groups, we used Spearman’s corre- Talairach reference system (Talairach & Validity of the Talairach-based pro- lation coefficients to discard a significant Tournoux, 1988) to define regions of inter- cedure as an automated segmentation tool effect of age on activity data. None of the est and to obtain final metabolic activity suitable for schizophrenia research has been correlation coefficients between age and data (Fig. 1). proved (Andreasen et aletal, 1996; Kates et aletal,, metabolic activity variables was statistically The edited MRI (without extracranial 1999). A single operator performed all significant.significant. tissue) was co-registered with the PET image manual procedures, thus avoiding any using the Automated Image Registration potential interrater variability. Reliability Statistical analysis (AIR) algorithm (Woods et aletal, 1993). Fusion of the entire segmentation procedure had results were visually checked in all cases been previously assessed by repeating the The study hypothesis was approached by and the observed co-registration was measurements three times for 15 cases comparing the relative activity in both the always optimal. An initial segmentation of selected at random. Repeatability of meta- right and left dorsolateral prefrontal cortex cerebral tissue was performed using an bolic activity values ranged from 93% to in the three groups: the schizophrenia automated method, currently included as 99% (Molina et aletal, 2003).,2003). patient group, the non-schizophrenia patient a standard processing tool in the Statistical Region of interest variables included in group and the control group. Because of the Parametric Mapping (SPM) program the analysis were the dorsolateral prefron- small sample sizes we used non-parametric (Ashburner & Friston, 1997). This method tal cortex and the occipital lobe, which statistics: the Kruskal–Wallis test to assess classifies all MRI pixels into four tissue was used only as a reference structure (see overall differences among the three groups, types: grey matter, white matter, cerebro- below). The dorsolateral prefrontal cortex and the Wilcoxon rank sum test for inde- spinal fluid and ‘other tissues’. The algorithm was defined as the cortex encompassing pendent samples to check the differences also removes the effect of radiofrequency Brodmann areas 8, 9, 10 and 46. The occi- between the schizophrenia group and each field inhomogeneities (Ashburner & Friston, pital lobe was defined according to bound- of the other two comparison groups. All ana- 1997). This segmentation was checked for aries previously established by other lyses were carried out using the Statistical inconsistencies and manually corrected authors also using the Talairach method Analysis System (SAS) version 6.12. whenever necessary by an experienced (Andreasen(Andreasen et aletal, 1996; Kates et aletal, 1999).,1999). radiologist masked to diagnosis. We studied this brain regionas a control RESULTSRESULTS In the second stage, the regions of for potential global effect bias in our mea- interest were obtained by superimposing surements of metabolic activity due to the The mean activity for each region is shown the three-dimensional tissue masks short-course treatment (Bartlett et aletal,, in Table 2. In the comparison among the

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groups, we found a significant effect of the DISCUSSION et aletal, 1992; Schroeder et aletal, 1994).,1994). diagnosis on the left side (ww22¼9.54, d.f.9.54,d.f.¼2;2; Although the participants in our schizo- PP¼0.008, Kruskal–Wallis test). We found Hypofrontality in early stages phrenia group were slightly younger than the same tendency on the right side of schizophrenia those in the comparison groups, their hypo- ((ww22¼5.60, d.f.5.60,d.f.¼2;2; PP¼0.06, Kruskal–Wallis Our results, obtained in a male sample frontality cannot be attributed to age differ- test). The schizophrenia group showed hy- population, agree with the hypothesis that ences, since there was no association pofrontality in comparison with the control people with a first episode of schizophrenia between age and activity in our sample. group in the Wilcoxon test (ZZ¼772.51,2.51, demonstrate hypofrontality during the Besides, cortical metabolic activity in the PP¼0.01, on the left side). The schizo- performance of an attention task; people normal population declines with age phrenia group also demonstrated hypofron- with acute psychosis who do not progress (Marchal(Marchal et aletal, 1992).,1992). tality compared with the non-schizophrenia to schizophrenia do not demonstrate this group in the Wilcoxon test (ZZ¼772.21,2.21, anomaly. This finding fits with the neuro- PP¼0.03, on the left side; ZZ¼772.50,2.50, development theories of schizophrenia, Pharmacological effects PP¼0.01, on the right side) (Fig. 2). There which postulate the existence of a set of on hypofrontality was no difference in the metabolic activity alterations that appear to be present even The hypofrontality found in this study does values of the occipital cortex among the in the earliest phases of the disease. This not seem to be attributable to pharmaco- three groups (ww22¼0.52, d.f.0.52,d.f.¼2,2, PP¼0.78;0.78; hypofrontality in the initial stages of first- logical effects, since both patient groups ww22¼3.47, d.f.3.47,d.f.¼2;2; PP¼0.18, respectively for episode schizophrenia is similar to that had received the same treatment before the left and right sides, Kruskal–Wallis found in treatment-naıtreatment-naıve¨ve patients and those the PET scan. The higher activity in the test).test). with chronic schizophrenia (Buchsbaum dorsolateral prefrontal region in the psychosis patients without schizophrenia could be tentatively attributed to poorer treat- Ta b l e 2 Metabolic activity values (per ml) for each group in the dorsolateral prefrontal and occipital ment compliance by these patients than by regions (significant differences in comparison of the values of the schizophrenia group vv. the control and non- those with schizophrenia. However, the schizophrenia groups by a Wilcoxon rank sum test for two independent samples are marked with asterisks) nursing personnel carefully verified this as- pect and the haloperidol was administered Cortical regionSchizophrenia Non-schizophrenia ControlControl as a liquid formulation, so lack of compli- group (nn¼6) group ((group nn¼7)7) gorup (nn¼8)8) ance may reasonably be ruled out. On the Mean (s.d.) Mean (s.d.) Mean (s.d.) other hand, there is no reason a prioriapriori toto expect better treatment compliance from Left DLPF 93.5 (4.4) 102.1 (4.5)** 102.8 (7.7)** the schizophrenia group than from the Right DLPF 99.2 (3.2)(3.2)99.2 105.8 (5.2)*(5.2)*105.8 105.0 (6.3) non-schizophrenia group of patients. Also, Left occipital 104.0 (5.7)(5.7)104.0 102.4 (2.7)(2.7)102.4 104.9 (5.3)(5.3)104.9 in the event of better treatment compliance Right occipital 104.3 (6.0) 100.0 (3.0) 103.4 (3.4) by the schizophrenia group, we should have observed a corresponding change in the DLPF, dorsolateral prefrontal. metabolic activity of the occipital lobe **PP550.05; **PP550.01.0.01. (Bartlett(Bartlett et aletal, 1994), which was not the case (Table 2). A different treatment response in each of the patient groups might explain the lower dorsolateral prefrontal cortical activity in the people who went on to develop schizophrenia than in the non-schizophrenia patient group. This possibility was sugsuggestedgested by a previous study (Bartlett et aletal, 1998),,1998), which showed that patients who did not respond to treatment demonstrated more marked changes in activity in this brain area than responders. This does not seem to be the case in our sample, since patients in our schizophrenia group did, in fact, respond to treatment, except for negative symptoms (Table 1). In addition, other studies have shown the same hypofrontal pattern in completely drug-free patients (Buchsbaum et aletal, 1992; Andreasen et aletal,, Fig. 22Fig. Raw values of metabolic activity for the left and right dorsolateral prefrontal cortex in patients and 1997). On the other hand, if the hypo- controls. Mean values for each group are shown linked.Values for the schizophrenia group (nn¼6) were signifi- frontality were caused by differences in cant in the left and right dorsolateral prefrontal cortex compared with the non-schizophrenia group (nn¼7) andand7) response or in compliance with also in the left dorsolateral prefrontal cortex when compared with the control group (nn¼8).8). haloperidol treatment, this would not

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explain the absence of differences in the prognosis and first episodes evolving to diagnosed as having schizophrenia and occipital cortex, since the aforesaid decrease schizophrenia. those who were not. In conclusion, our data in activity – observed solely in the non- suggest that the existence of hypofrontality responders – was generalised in the cortex could contribute to predicting which (Bartlett(Bartlett et aletal, 1998). Finally, the Scottish Methodological issues patients with a first episode of psychosis Schizophrenia Research Group (Anonymous, Our study has various limitations. One of are likely to progress to schizophrenia. 1998) reported the existence of hypo- them is the small sample size. However, frontality prior to initiation of treatment the short duration of the disease and ACKNOWLEDGEMENTS and its persistence after 6 months of treat- the prospective diagnosis in patients with ment. Analysed together, these data sup- first-episode psychosis worked in our The authors thank Dr M. A. Pozo and Dr A. port the fact that no treatment-related favour. Only a prospective follow-up can Maldonado from the Centro PET Complutense for factor would explain the differences between separate recent-onset schizophrenia from their advice and collaboration in performing the our patient groups. other psychotic episodes. This approach PET scans. The study was supported in part by grants from Fondo de Investigaciones Saniterias offers the advantage of studying the (02/1178,02/3095, Red TemaTematica¤tica IM3), Ministerio de patients very early, as cerebral changes Ciencia y Tecnolog|Tecnolog|a¤a TIC (2001-3697-C03-03)(2001-3697-C03-03) and Hypofrontality in other types due to the disease may take place even in FundacioFundacion¤nLaCaixa(99/042-00). La Caixa (99/042-00). of psychosis the first months (Gur et aletal, 1998; Rapoport There is little information on cerebral activ- et aletal, 1999; Pantelis et aletal, 2003). Besides, REFERENCES ity in schizophreniform psychoses with our patients were not exposed to other good prognosis. Nevertheless, clinical data potentially brain-damaging situations, such American Psychiatric Association (1994) DiagnosticDiagnostic support the theory that cerebral substrates as drug misuse or severe behaviour disorga- and Statistical Manual of Mental Disorders (4th edn) may differ between schizophreniform and nisation. In consequence, although our (DSM^IV).Washington, DC: APA. schizophrenic psychoses; for example, in a sample is small, it should offer greater Andreasen, N. C., Rajarethinam, R., Cizadio,T., et aletal (19 9 6) Automatic atlas-based volume estimation of recent study persistent primary symptoms homogeneity than other studies using a human brain regions from MR images. Journal ofofJournal were not found in 61 people with schizo- cross-sectional design on a sample of people Computer Assisted Tomography,, 20,98^106., 98^106.

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Gur, R. E., Cowell, P., Turetsky, B. I., et aletal (19 9 8) AA follow-up magnetic resonance imaging study of && Hypofrontality seems to be a marker of schizophrenia even at the time of the schizophrenia. Relationship of neuroanatomical changes patient’s first psychotic episode. to clinical and neurobehavioral measures. Archives ofofArchives General Psychiatry,, 5555,145^152.,145^152. && If the predictive value of hypofrontality is confirmed, decisions about the most Hollingshead, A. & Frederick, R. (1953) SocialSocial suitable treatment will be facilitated. stratification and psychiatric disorders. American Sociological Review,, 1818,163^189. && The presence of hypofrontality in first-episode psychosis fits with the Kates,W. R.,Worsofsky, I. S., Patwardhan, A., et aletal neurodevelopmental theories of schizophrenia. (19(1999) 9 9) Automated Talairach atlas-based parcellation and measurement of cerebral lobes in children. PsychiatryPsychiatry LIMITATIONS Research: Neuroimaging,, 91,11^30. Kay, S. R., Opler, L. A. & Fiszbein, A. (1992) PositivePositive && Our results are limited to a male population.Conclusions should be confirmed in a and Negative Syndrome Scale (PANSS): Manual.NewYork: Multi-Health Systems. larger sample size including both men and women. Marchal, G., Rioux, P., Petit-Taboue, M. C., et aletal && The brief treatment administered might have affected our results. However, the (19 92) Regional cerebral oxygen consumption, blood possible confounding effect should be minimal because both groups of patients flow, and blood volume in healthy human aging. ArchivesArchives of Neurology,, 4949,1013^1020. received the same treatment.

McGuire, P.K., Quested, D. J., Spence, S. A., et aletal && Other forms of psychosis, such as bipolar disorder or psychotic depression, may (19 9 8) Pathophysiology of ‘positive’‘positive’thought thought disorder in schizophrenia. British Journal of Psychiatry,, 173173, 231^235. also show hypofrontality at early stages.

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