Neurological soft signs and brain structural abnormalities in patients with first episode psychosis and healthy controls

neurology, psychiatry and brain research 19 (2013) 114–120

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/npbr

Neurological soft signs and brain structural abnormalities in patients with first episode psychosis and healthy controls Fatemeh Rahiminejad a, Homayoun Amini a,b,*, Vandad Sharifi a,b, Maryam Noroozian a,b, Hossein Ghanaati c, Majid Shakiba c, Siamak Molavi d, Neda Abedi a a

Department of Psychiatry, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran Psychiatry and Psychology Research Center, Tehran University of Medical Sciences, Tehran, Iran c Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran d Institute for Cognitive Sciences Studies, Tehran, Iran b

article info

abstract

Article history:

Objectives: To assess and compare neurological soft signs (NSSs) and brain magnetic

Received 3 July 2011

resonance imaging (MRI) findings between the patients with first episode psychosis and a

Received in revised form

group of healthy participants. Methods: Thirty patients with first episode psychosis and

26 December 2012

thirty healthy participants were evaluated for psychiatric disorders using Structured

Accepted 3 May 2013

Clinical Interview for DSM-IV, Axis I disorders (SCID-I). The assessment of NSSs and

Available online 15 June 2013

handedness was done using Neurological Evaluation Scale (NES) and Edinburgh Handedness Inventory (EHI), respectively. Moreover, a brain structural evaluation was done by

Keywords: Brain First-episode psychosis Magnetic resonance imaging Neurological soft signs Schizophrenia

using MRI. Results: In the patients with first episode psychosis, the total score of NES was significantly higher than in the healthy participants. The scores for the subgroups sequencing of motor acts ( p < 0.01), motor coordination ( p < 0.001) and sensory integration ( p < 0.01) were higher for the patients in comparison with the healthy group. Several abnormal findings of MRI were significantly higher in the patients' group as compared with the healthy group consisted of cortical atrophy, decrease in upper temporal cortex, and increase in the width of left Sylvian fissure volume. Conclusion: NSSs were higher in the patients with first episode psychosis than in the healthy participants. NSSs and structural abnormalities in MRI are part of neurological deficit, leading to psychosis, and are not caused by the process of neurological deterioration due to psychosis itself. The current study is cross-sectional, so longitudinal data is required for elucidating if NSSs change during the course of illness. © 2013 Elsevier GmbH. All rights reserved.

* Corresponding author at: Department of Psychiatry, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran. Tel.: +98 21 55412222; fax: +98 21 55419113. E-mail addresses: [email protected] (F. Rahiminejad), [email protected], [email protected] (H. Amini), [email protected] (V. Sharifi), [email protected] (M. Noroozian), [email protected] (H. Ghanaati), m_shakiba50@hotmail. com (M. Shakiba), [email protected] (S. Molavi), [email protected] (N. Abedi). Abbreviations: EHI, Edinburgh Handedness Inventory; MRI, magnetic resonance imaging; NES, Neurological Evaluation Scale; NSSs, neurological soft signs; OR, Odds Ratio; SCID-I, Structured Clinical Interview for DSM-IV, Axis I disorders. 0941-9500/$ – see front matter © 2013 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.npbr.2013.05.002

neurology, psychiatry and brain research 19 (2013) 114–120

1.

Introduction

Neurological soft signs (NSSs) are objective, non-localizable and minor signs, which are thought to reflect damage(s) in the connection between the cortical and subcortical regions or between different areas in the cortex.1,2 NSSs are neurological signs that cannot be attributed to the functional disorders in particular parts of the brain or any particular syndrome. In contrast, ``Hard Neurological Signs'' can be related to particular areas of neurological damage.3 Some researchers believe that NSSs are caused by a developmental lag rather than by a fixed abnormality.4 Most researches have confirmed the presence of many NSSs on the patients with schizophrenia in different stages of the disorder.2,5–14 Moreover, some studies have suggested that NSSs can be considered among the candidate neurological and cognitive endophenotypes for schizophrenia.15 However, an evaluation in the early stages of psychosis can be of particular significance: firstly, it can clarify whether NSSs are part of a neurodysfunction that underlies psychosis and schizophrenia rather than the consequence of degenerative processes. In addition, in the patients with first episode psychosis who have not yet received significant doses of neuroleptics, the effect of this interfering factor on the development of NSSs can be evaluated.16,17 The important point is that first episode psychosis includes a heterogeneous group of disorders such as schizophrenia and affective psychoses; however, this limitation is unavoidable since any delay in evaluation until a definite diagnosis of the type of psychosis can cast doubt on the disorder assessments.16. The prevalence of NSSs in drugnaive schizophrenia10 and first episode psychosis18,19 has so far been estimated to vary between 20 and 97%. Since the prevalence of NSSs in healthy participants has also been estimated to be in the range of 5–50%, the comparison of these signs in first episode psychosis patients and healthy participants seems to be of significant importance. Furthermore, other useful means of assessing the possible presence of neurological abnormalities at the onset of schizophrenia are such structural studies as magnetic resonance imaging (MRI), which could add further insight into the pathophysiology and etiopathology of NSSs through anatomical investigations. However, to date, few studies have investigated the anatomical correlates of NSSs.16 Previous studies have shown that the existence of NSSs correlates with the increasing volume of ventricles and decrease of gray matter in the cortical and subcortical areas.18,20 Hirayasu et al. showed significant decrease of gray matter in the left posterior–superior temporal gyrus in the patients with first episode of schizophrenia as compared with the patients with first episode of affective psychoses, and a significant decrease in the brain cortex and subcortical gray matter as compared with the healthy controls.21 Also Fannon et al. showed significant deficits in cortical and subcortical gray matter and increase in the volume of lateral and third ventricles in untreated patients.22 The study of neurological and anatomical correlations in schizophrenia can be valuable for localization of such deficits. A limitation of most of the previous studies is the lack of comparison with a group of healthy controls. Comparison

115

of patients and healthy controls might reveal whether the participants with more NSSs have more brain structural abnormalities than the other participants, and also where the abnormalities could be located. The aim of the present study was to compare the frequency of NSSs and the structural findings of brain MRI in a group of patients with first episode psychosis and a group of healthy participants.

2.

Methods

2.1.

Subjects

The participants belonged to one of the two groups: patients with first episode psychosis and healthy controls. Inclusion criteria for patients included: the presence of an affective or non-affective psychotic disorder according to the Persian version of ``Structured Clinical Interview for DSM-IV Axis I disorders'' (SCID-I)23,24 and the index episode should be the first episode of the illness. Exclusion criteria were: the presence of any major psychiatric disorder other than psychotic or mood disorder, substance induced psychotic disorder, psychotic disorder due to medical conditions, a history of any neurological disorder and mental retardation. Sampling was done using consecutive sampling. Thirty patients who had been consecutively presented to Roozbeh Hospital, a referral academic hospital in Tehran, entered the study. Following an announcement, we chose thirty healthy participants matched by sex and age (5 years) as controls. A written consent was obtained from all participants prior to entering the study.

2.2.

Measurements

In addition to administration of the Persian version of Structured Diagnostic Interview for DSM-IV, all of the patients were assessed using Neurological Evaluation Scale (NES)25 and Edinburgh Handedness Inventory (EHI)26 to evaluate NSS and handedness, respectively. NES is a structured instrument that includes 26 soft signs in four subgroups: (1) sensory integration, (2) motor coordination, (3) sequencing of complex motor acts, and (4) others. A higher score in NES indicates a worse neurological problem; and a higher score in each subgroup is indicative of the severity of neurological dysfunction. The neurological examination was carried out by a senior resident of psychiatry (FR) well trained by a neurologist (MN). The resident carried out the pilot study on five patients and on five healthy participants and received the necessary feedback. Additionally, all the participants underwent brain anatomical evaluation by using MRI. Conventional brain studies were performed with 1.5 T Echospeed MR Machine (GE Healthcare, Milwaukee, USA). The results of MRI were reported independently by three experienced radiologists, who were blind to the diagnosis. They used a checklist to examine the selected brain structures consisted of any change in volume of cortices, gyri, fissures, and sulci (the region-of-interest approach). They assessed qualitatively the size of the selected brain structures without using any morphological criteria except for the evaluation of the atrophic changes that was based on four

116

neurology, psychiatry and brain research 19 (2013) 114–120

Fig. 1 – Magnetic resonance image (MRI) scans. Left, T2-weighted axial imaging shows normal frontal lobes. Right, T2-weighted axial imaging shows bifrontal cortical atrophy.

criteria as follow: (i) bifrontal horn to intracranial diameter ratio > 0.33 (Evans criterion), (ii) temporal horn width > 3 mm, (iii) five mm widening of the bifrontal anterior and interhemispheric subarachnoid spaces, and (iv) widening of bifrontal lobes to anterior vault more that 10 mm.27,28 We illustrated two figures, Fig. 1 that shows bifrontal cortical atrophy compared with normal frontal lobes and Fig. 2 that shows increased Sylvian fissure compared with normal Sylvian fissure. Each item was reported abnormal if at least two out of the three reports were abnormal. The interrater reliability between the radiologists' reports was assessed and kappa was obtained as 0.5–0.7.

2.3.

Statistical analysis

The obtained data were analyzed using appropriate statistical tests including Student's t-test, x2 statistical test, Fischer's exact test, Kruskal–Wallis test, Mann–Whitney's test, and Spearman's correlation coefficient. A logistic regression, Enter model was later used to explore the possible associations of the presence of psychosis (as dependent factor) with various dimensions of NSSs (as independent factors) after adjustment in terms of age and sex. In addition, we used Eta coefficient to show correlation of the brain MRI findings and total NES score in both patient and healthy control groups. Eta squared is the percent of variance in dependent variable explained by

Fig. 2 – Magnetic resonance image (MRI) scans. Left, T2-weighted axial imaging shows normal Sylvian fissures. Right, T2-weighted axial imaging shows increased left Sylvian fissure.

117

neurology, psychiatry and brain research 19 (2013) 114–120

Table 1 – Distribution of participants with regard to sex, education, occupation and study group. Variablea

Patients (N = 30) N (%)

Healthy participants (N = 30) N (%)

<9 9–12 12< Missing

15 (50.0) 27.1  10.5 14 (46.9) 10 (33.3) 5 (16.5) 1 (3.3)

15 (50.0) 33.4  11.7 10 (33.3) 12 (40) 8 (26.7) 0 (0)

Occupation

Unemployed Employed

12 (40.0) 18 (60.0)

1(3.3) 29 (96.7)

Marital status

Single Married Divorced Widow

22 6 1 1

11 17 2 0

Sex Age (year) (mean  SD) Education (year)

a

Female

3.

Results

3.1.

Demographic and clinical characteristics

3.2.

Neurological soft signs

All participants were examined for NSSs. In most instances, more abnormal NSSs were found in the patients in comparison with the healthy participants. In addition, the two groups were compared with regard to the subgroups of NES. As shown in Table 2, there are significant differences between the two groups in all soft sign subgroups except for the ``others'' subgroup; and the mean scores of neurological soft sign subgroups were higher in the patients in all instances as compared with the healthy group. A logistic regression model was later used to explore the possible association between the presence of psychosis and sex, age and various dimensions of NSSs (Table 3). As shown, a significant association between ``motor coordination'' subscore and presence of psychosis was found.

Table 2 – NES total and dimension scores in patients with first episode psychosis and healthy controls. Score

Complex motor acts Motor coordination Sensory integration Others Total

Patients Healthy (N = 30) participants (N = 30) Mean  SD Mean  SD 2.93  2.27 1.57  1.38 1.27  1.26 3.57  1.99 9.33  4.95

Significant. Mann–Whitney's U test.

1.50  1.70 0.20  0.48 0.50  0.68 3.00  1.70 5.20  2.68

3.3.

Handedness

The mean scores for handedness (from 100 for complete left handedness to +100 for complete right handedness) were not significantly different between the two groups. In addition, Spearman's correlation coefficient between the total score as well as the soft sign subscores and the final handedness score was not significant (Table 4).

The distribution of the two groups with regard to sex, age, education, employment and marital status is shown in Table 1.

a

(36.7) (56.7) (6.7) (0)

Age, employment and marital status differed significantly between the patients and healthy participants (p < 0.05).

independent variable. The significance level was considered using 95% confidence interval.

*

(73.3) (20.0) (3.3) (3.3)

Za

p Value

2.59 4.79 2.75 0.85 3.83

0.010* 0.001* 0.006* 0.397 0.001*

3.4.

Findings of brain MRI

Anatomical results based on MRI showed that 20 (66.7%) out of the 30 participants in the patients' group had at least one abnormality; while this rate in the healthy control was significantly lower (10 people, 33.3%) (Chi square = 6.67, df = 1, p = 0.01; Odds Ratio (OR) = 2.00, 95% CI: 1.14–3.52). As shown in Table 5, the most abnormal reports in the patients' group belong to cortical atrophy (19 people, 63.3%). The difference between the psychotic and control groups in MRI was significant in cortical atrophy ( p < 0.001, OR = 8.64, 95% CI: 2.57–29.07), decrease in upper temporal cortex volume ( p = 0.006, OR = 12.43, 95% CI: 1.46–105.74), and increase in the width of left Sylvian fissure ( p < 0.0001, OR = 12.25, 95% CI: 2.46–60.91). The correlation of the brain MRI findings and total NES score in both patient and healthy control groups have been demonstrated in Table 5. Eta squared is the percent of variance in dependent variable explained by independent variable. In addition, we considered the total number of positive MRI findings as an ordinal variable to evaluate its correlation with the total score of NES. There was no correlation between NES subscores and the MRI results neither in the psychosis nor the control groups (Spearman's rho = 0.032, p = 0.867; Spearman's rho = 0.019, p = 0.922, respectively).

4.

Discussion

Our findings in this research are in accordance with the results of other studies, showing that NSSs and structural abnormalities in MRI are more frequent in individuals with first episode psychosis than in the healthy participants.1,9,10,16,29–33 These

118

neurology, psychiatry and brain research 19 (2013) 114–120

Table 3 – Associations of Neurological Evaluation Scale (NES) dimensions with the presence of psychosis (patients with first-episode psychosis (N = 30) and healthy participants (N = 30)). Statistica NES dimensions

Complex motor acts Motor coordination Sensory integration Others * a b c d

Bb

S.E.c

Waldd

df

p Value

Adjusted OR

0.275 1.797 0.565 0.102

0.216 0.557 0.476 0.228

1.614 10.419 1.408 0.202

1 1 1 1

0.204 0.001* 0.235 0.653

1.316 6.033 1.760 1.108

95.0% C.I. for adjusted OR Lower

Upper

0.862 2.026 0.692 0.709

2.010 17.967 4.475 1.732

Significant. Logistic regression. The coefficient of the predictor variables. Standard error. The Wald's statistic.

results indicate that NSSs may be part of neurological dysfunctions that form the grounds on which psychosis develops, and are not neurological consequences of the disorder itself. In addition, our findings showed that NSSs are not caused by long term exposure to antipsychotic drugs. The difference of NSSs in the subgroups of motor coordination, sensory integration and sequencing of motor acts between the patients' group and the healthy individuals was significant. However, no significant difference was found in the ``others'' subgroup in this regard. Also in the structural study, the abnormal findings of MRI in the patients with first episode psychosis were meaningfully more than in the healthy group. The most frequent abnormal findings of MRI in the patients' group were bilateral cortical atrophy (with more severity on the right hemisphere), decrease of upper temporal cortex volume and increase of the left Sylvian fissure width, all of which are detectable at the beginning of the disorder before any treatment. In support of the present study former studies9,20,22 have shown obvious defects in the gray matter of temporal cortex and decreased brain volume in the patients with first episode psychosis. However, the results of some studies have not been consistent. Some have shown an association of NSSs with dilation of the cerebral ventricles,34–36 while others in line with our study have described no correlation between NSSs and ventricular size.37 Accordingly, it can be concluded that anatomical abnormalities in the brain structure are neither due to the deteriorative process of the disease nor the medication side effects, but they may be

related to the development of the disease. In contrast to the findings of some previous studies, we found no correlation between NSSs and structural defects in MRI.20,38–40 Dazzan et al. reported that higher scores of NSSs were associated with a reduction of the gray matter volume of subcortical structures.20 This conflicting result may be due to the use of different methods to evaluate NSSs or due to the differences between the samples, especially in ethnic composition. Dazzan et al. used voxel-based morphometry, a more valid method, to investigate brain structures.20 Also, no significant difference was found regarding the handedness in these groups. In addition, the correlation of the laterality with the total score of NSSs and their subgroups was not significant. Brown et al. showed that there are more NSSs in schizophrenic patients with mixed handedness.19 Some other limitations of the present study include the lack of blindness of the examiner regarding the diagnosis of the participants in the study, the small number of samples and non-homogeneity of the patients especially regarding the diagnosis. Also, lack of voxel-based brain volumetric assessment and lack of operationalized criteria for MRI finding were major limitations of our study. Performing other studies by overcoming the mentioned limitations and using more valid methods of structural neuroimaging will be useful in investigating the correlation of NSSs with structural abnormalities of the brain in the patients with first episode of psychosis.

Table 4 – Correlation between Neurological Evaluation Scale (NES) subscores and Edinburgh Handedness Inventory (EHI) score among the patients with first episode psychosis, and the healthy controls. Edinburgh Handedness Inventory (EHI) NES Dimension

Patients (n = 30) Spearman correlation coefficient

Healthy controls (n = 30) p Value

Spearman correlation coefficient

p Value

Complex motor acts Motor coordination Sensory integration Others

0.06 0.10 0.20 0.08

0.76 0.59 0.29 0.69

0.07 0.15 0.13 0.22

0.70 0.43 0.49 0.25

Total

0.13

0.50

0.11

0.57

b

0.500 0.685 0.856 0.659

b

0.194 0.211 0.182 0.215

0.415 0.587 0.418 0.621 0.695 0.014 0.034 0.194 0.185 0.225

0.679 0.634 0.653 0.412 0.711 0.415 0.676 0.644 0.561 0.553

Conclusion

The findings of this study are generally compatible with the idea that NSSs and structural abnormalities in MRI are part of neurological deficit, leading to psychosis, and are not caused by the process of neurological deterioration due to psychosis itself; however, it does not confirm the trait-like nature and familial origin of all NSSs. The current study is cross-sectional, so longitudinal data is required for elucidating if NSSs change during the course of illness.

Conflicts of interest

b

Significant. Eta squared is the percent of variance in dependent variable explained by independent variable. The statistic is not computable. a

b

5.40 7.10 60.91 9.66 0.19 0.82 2.46 0.97

b b

This research was a part of Dr. Fatemeh Rahiminejad's post graduate dissertation. The study was supported by a grant from Tehran University of Medical Sciences, Tehran, Iran. We would like to thank the participants in this study, as well as the staff of Roozbeh Hospital who kindly collaborated with us in the execution of this study. In addition, we would like to thank Dr. Nahid Seddighi and Dr. Elham Rahimian for reporting of the MR images.

1.0 2.41 12.25 3.06

(13.3) (63.3) (10) (6.7) (30) (3.3) (10) (46.7) (46.7) (43.3) 4 19 3 2 9 1 3 14 14 13 Ventricular dilation Cortical atrophy Subcortical atrophy Decrease of precentral gyrus Decrease of upper temporal cortex Decrease of middle cortex Increase of sulcus fluid Increase of temporal horn Increase of left Sylvian fissure Increase of right Sylvian fissure

1 5 3 3 1 0 3 8 2 6

(3.3) (16.7) (10.0) (10.0) (3.3) (0.0) (10) (26.7) (6.7) (20)

1.96 13.61 0.00 0.22 7.68 1.02 0.000 2.58 12.27 3.77

1 1 1 1 1 1 1 1 1 1

0.353 0.000* 1.0 1.0 0.006* 1.0 1.0 0.108 0.000* 0.052

4.46 8.64 1.0 0.64 12.43

0.47 2.57 0.19 0.10 1.46

42.51 29.07 5.40 4.15 105.74

0.195 0.166 0.205 0.046 0.045 0.051 0.068 0.128 0.050 0.032

Acknowledgements

*

Etaa for brain MRI finding as dependent Etaa for total NES score as dependent Etaa for brain MRI finding as dependent Etaa for total NES score as dependent Upper Lower

95% CI OR p Value df Chi square/ Fisher's Exact

119

The authors have not transmitted any conflicts of interest.

Patients (N = 30) N (%)

Healthy participants (N = 30) N (%)

5.

Group Brain MRI finding

Table 5 – Brain MRI findings in the patients with first episode psychosis and the healthy participants.

Patients

Healthy participants

neurology, psychiatry and brain research 19 (2013) 114–120

references

1. Gupta S, Andreasen NC, Arndt S, Flaum M, Schultz SK, Hubbard WC, et al. Neurological soft signs in neurolepticnaive and neuroleptic-treated schizophrenic patients and in normal comparison subjects. American Journal of Psychiatry 1995;152:191–6. 2. Rossi A, De Cataldo S, Di Michele V, Manna V, Ceccoli S, Stratta P, et al. Neurological soft signs in schizophrenia. British Journal of Psychiatry 1990;157:735–9. 3. Woods BT, Kinney DK, Yurgelun-Todd DA. Neurological ``hard'' signs and family history of psychosis in schizophrenia. Biological Psychiatry 1991;30:806–16. 4. Blondis TA, Snow JH, Accardo PJ. Integration of soft signs in academically normal and academically at-risk children. Pediatrics 1990;85:421–5. 5. Tucker GJ, Campion EW, Kelleher PA, Silberfarb PM. The relationship of subtle neurologic impairments to disturbances of thinking. Psychotherapy and Psychosomatics 1974;24:165–9. 6. Quitkin F, Rifkin A, Klein DF. Neurologic soft signs in schizophrenia and character disorders. Organicity in schizophrenia with premorbid asociality and emotionally unstable character disorders. Archives of General Psychiatry 1976;33:845–53. 7. Flyckt L, Sydow O, Bjerkenstedt L, Edman G, Rydin E, Wiesel FA. Neurological signs and psychomotor performance in patients with schizophrenia, their relatives and healthy controls. Psychiatry Research 1999;86:113–29. 8. Nasrallah HA, Tippin J, McCalley-Whitters M. Neurological soft signs in manic patients. A comparison with Schizophrenic and control groups. Journal of Affective Disorders 1983;5:45–50.

120

neurology, psychiatry and brain research 19 (2013) 114–120

9. Rubin P, Vorstrup S, Hemmingsen R, Andersen HS, Bendsen BB, Stromso N, et al. Neurological abnormalities in patients with schizophrenia or schizophreniform disorder at first admission to hospital: correlations with computerized tomography and regional cerebral blood flow findings. Acta Psychiatrica Scandinavica 1994;90:385–90. 10. Venkatasubramanian G, Latha V, Gangadhar BN, Janakiramaiah N, Subbakrishna DK, Jayakumar PN, et al. Neurological soft signs in never-treated schizophrenia. Acta Psychiatrica Scandinavica 2003;108:144–6. 11. Heinrichs DW, Buchanan RW. Significance and meaning of neurological signs in schizophrenia. American Journal of Psychiatry 1988;145:11–8. 12. Bachmann S, Bottmer C, Schroder J. Neurological soft signs in first-episode schizophrenia: a follow-up study. American Journal of Psychiatry 2005;162:2337–43. 13. Prikryl R, Ceskova E, Kasparek T, Kucerova H. Neurological soft signs and their relationship to 1-year outcome in firstepisode schizophrenia. European Psychiatry 2007;22:499–504. 14. Boks MP, Liddle PF, Burgerhof JG, Knegtering R, van den Bosch RJ. Neurological soft signs discriminating mood disorders from first episode schizophrenia. Acta Psychiatrica Scandinavica 2004;110:29–35. 15. Chan RC, Gottesman II. Neurological soft signs as candidate endophenotypes for schizophrenia: a shooting star or a Northern star? Neuroscience and Biobehavioral Reviews 2008;32:957–71. 16. Dazzan P, Murray RM. Neurological soft signs in firstepisode psychosis: a systematic review. British Journal of Psychiatry Supplement 2002;43:s50–7. 17. Whitty PF, Owoeye O, Waddington JL. Neurological signs and involuntary movements in schizophrenia: intrinsic to and informative on systems pathobiology. Schizophrenia Bulletin 2009;35:415–24. 18. Group TSSR. The Scottish First Episode Schizophrenia Study. I. Patient identification and categorisation. British Journal of Psychiatry 1987;150:331–3. 19. Browne S, Clarke M, Gervin M, Lane A, Waddington JL, Larkin C, et al. Determinants of neurological dysfunction in first episode schizophrenia. Psychological Medicine 2000;30:1433–41. 20. Dazzan P, Morgan KD, Orr KG, Hutchinson G, Chitnis X, Suckling J, et al. The structural brain correlates of neurological soft signs in AESOP first-episode psychoses study. Brain 2004;127:143–53. 21. Hirayasu Y, Shenton ME, Salisbury DF, Dickey CC, Fischer IA, Mazzoni P, et al. Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. American Journal of Psychiatry 1998;155:1384–91. 22. Fannon D, Tennakoon L, Sumich A, O'Ceallaigh S, Doku V, Chitnis X, et al. Third ventricle enlargement and developmental delay in first-episode psychosis: preliminary findings. British Journal of Psychiatry 2000;177:354–9. 23. Sharifi V, Assadi SM, Mohammadi MR, Amini H, Kaviani H, Semnani Y, et al. A Persian translation of the Structured Clinical Interview for Diagnostic and Statistical Manual of

24.

25.

26. 27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

Mental Disorders, Fourth Edition: psychometric properties. Comprehensive Psychiatry 2009;50:86–91. Spitzer RL, Williams JB, Gibbon M, First MB. The Structured Clinical Interview for DSM-III-R (SCID). I: history, rationale, and description. Archives of General Psychiatry 1992;49:624–9. Buchanan RW, Heinrichs DW. The Neurological Evaluation Scale (NES): a structured instrument for the assessment of neurological signs in schizophrenia. Psychiatry Research 1989;27:335–50. Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971;9:97–113. Evans WA. An encephalographic ratio for estimating ventricular enlargement and cerebral atrophy. Archives of Neurology and Psychiatry 1942;47:931–7. Huckman MS, Fox J, Topel J. The validity of criteria for the evaluation of cerebral atrophy by computed tomography. Radiology 1975;116:85–92. Chan RCK, Xu T, Heinrichs RW, Yu Y, Wang Y. Neurological soft signs in schizophrenia: a meta-analysis. Schizophrenia Bulletin 2009. http://dx.doi.org/10.1093/schbul/sbp1011. Chen YL, Chen YH, Mak FL. Soft neurological signs in schizophrenic patients and their nonpsychotic siblings. Journal of Nervous and Mental Disease 2000;188:84–9. Ismail B, Cantor-Graae E, McNeil TF. Neurological abnormalities in schizophrenic patients and their siblings. American Journal of Psychiatry 1998;155:84–9. Sanders RD, Keshavan MS, Schooler NR. Neurological examination abnormalities in neuroleptic-naive patients with first-break schizophrenia: preliminary results. American Journal of Psychiatry 1994;151:1231–3. Yazici AH, Demir B, Yazici KM, Gogus A. Neurological soft signs in schizophrenic patients and their nonpsychotic siblings. Schizophrenia Research 2002;58:241–6. Mohr F, Hubmann W, Cohen R, Bender W, Haslacher C, Honicke S, et al. Neurological soft signs in schizophrenia: assessment and correlates. European Archives of Psychiatry and Clinical Neuroscience 1996;246:240–8. Schroder J, Niethammer R, Geider FJ, Reitz C, Binkert M, Jauss M, et al. Neurological soft signs in schizophrenia. Schizophrenia Research 1991;6:25–30. Weinberger DR, DeLisi LE, Perman GP, Targum S, Wyatt RJ. Computed tomography in schizophreniform disorder and other acute psychiatric disorders. Archives of General Psychiatry 1982;39:778–83. King DJ, Wilson A, Cooper SJ, Waddington JL. The clinical correlates of neurological soft signs in chronic schizophrenia. British Journal of Psychiatry 1991;158:770–5. Janssen J, Diaz-Caneja A, Reig S, Bombin I, Mayoral M, Parellada M, et al. Brain morphology and neurological soft signs in adolescents with first-episode psychosis 2009:227–33. Dazzan P, Morgan KD, Chitnis X, Suckling J, Morgan C, Fearon P, et al. The structural brain correlates of neurological soft signs in healthy individuals. Cerebral Cortex 2006;16:1225–31. Keshavan MS, Sanders RD, Sweeney JA, Diwadkar VA, Goldstein G, Pettegrew JW, et al. Diagnostic specificity and neuroanatomical validity of neurological abnormalities in first-episode psychoses. American Journal of Psychiatry 2003;160:1298–304.