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Language, motor and speed of processing deficits in adolescents with subclinical psychotic symptoms
Schizophrenia Research 123 (2010) 71–76
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Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Language, motor and speed of processing deficits in adolescents with subclinical psychotic symptoms Mathieu M. Blanchard a,1, Sarah Jacobson b,1, Mary C. Clarke a, Dearbhla Connor a, Ian Kelleher a, Hugh Garavan b, Michelle Harley c, Mary Cannon a,d,⁎ a b c d
Department of Psychiatry, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland School of Psychology and Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland Department of Child and Adolescent Mental Health, Mater Misericordiae Hospital and St Vincent's Hospital, Fairview, Dublin, Ireland Department of Psychiatry, Beaumont Hospital, Dublin 9, Ireland
a r t i c l e
i n f o
Article history: Received 10 November 2009 Received in revised form 14 March 2010 Accepted 22 May 2010 Available online 1 July 2010 Keywords: Receptive language Motor deficits Speed of processing Executive function Adolescence Psychotic symptoms
a b s t r a c t Objectives: Neuropsychological impairment is a core feature of schizophrenia. Adolescents reporting subclinical psychotic symptoms are considered to be at greater risk of developing a psychotic illness later in life than adolescents who do not report such symptoms and, thus, may represent an at-risk group for further study. We wished to investigate neuropsychological functioning in early adolescence in relation to reports of psychotic symptoms. Methods: Participants were recruited from local primary schools after a two-stage screening and parental consent process. In brief, 277 adolescents were screened and 37 attended for testing. Seventeen adolescents who were deemed to report ‘definite’ psychotic symptoms after clinical interview and 20 control adolescents underwent a clinical interview and a one-hour neuropsychological battery. Results: Adolescents who report psychotic symptoms exhibited significant impairments in receptive language (as measured by the British Picture Vocabulary Scale), motor function (as measured by the Pegboard test) and executive function/speed of processing (as measured by the Trail-Making test). There were no significant differences between the groups on measures of attention, memory or expressive language, abstract reasoning or overall scholastic ability. Conclusions: Taken together with the results from birth cohort, genetic high risk and prodromal studies, these findings are consistent with a neural inefficiency/disconnectivity hypothesis in those at risk for psychosis. These results highlight the need to investigate developmental brain circuits subserving language and motor function and processing speed and how these change over time in at-risk adolescents. © 2010 Elsevier B.V. All rights reserved.
1. Introduction There is evidence that psychosis exists on a continuum in both adult and adolescent samples, but it is not clear whether schizophrenia represents the extreme end of a continuum
⁎ Corresponding author. Department of Psychiatry, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland. Tel.: + 353 1 809 3855; fax: + 353 1 809 3741. E-mail address: [email protected] (M. Cannon). 1 Both authors contributed equally to this work. 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.05.028
within the general population or is a qualitatively distinct identity. The dimensional model of schizophrenia assumes that subclinical psychotic symptoms are relatively common in the general population (van Os et al., 2000). A systematic review and meta-analysis of this topic revealed an overall median prevalence rate of 8% for psychotic experiences in the general population (van Os et al., 2009). The prevalence of subclinical psychotic symptoms among adolescents is about 15% in interview-based cohort studies (Poulton et al., 2000; Horwood et al., 2008) and is even higher when using self-report questionnaires (Laurens et al., 2007;
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Kelleher et al., 2009). The importance of adolescent subclinical psychotic symptoms lies in the possibility that they may index an increased risk of later psychotic illness in adulthood (Poulton et al., 2000; Scott et al., 2009). These individuals have not yet reached the peak age of onset of schizophrenia and are more likely to encompass those individuals who are truly “at risk” than adults who have already passed through the risk period. Children and adolescents with these symptoms could therefore be conceptualised as a ‘symptomatic’ high-risk group for later psychotic disorder, in the same way as offspring of parents with schizophrenia comprise a ‘genetic’ high-risk group, and may yield insights into the earliest pathological processes in vulnerability to adult psychosis. It is well-established that individuals with schizophrenia, as a group, demonstrate significant impairments across a broad range of cognitive domains (Heinrichs and Zakzanis, 1998). These deficits are evident even at the time of the first episode of schizophrenia (Mesholam-Gately et al., 2009) and are likely to have begun even earlier in the course of the disease (Niendam et al., 2003; Cannon et al., 2006). Neuropsychological impairments have also been demonstrated among individuals in the prodrome for psychosis (Niendam et al., 2006; Keefe et al., 2006; Seidman et al., 2006) and among adults with schizotypal traits and subclinical psychotic symptoms (Johns and van Os, 2001; Bergida and Lenzenweger, 2006). Horwood et al. (2008) has shown a relationship between general intellectual functioning and presence of psychotic symptoms in adolescence. However, to our knowledge, this is the first study reporting results from a battery of neuropsychological tests among adolescents with subclinical psychotic symptoms.
about the second stage of the study involving an interview and neuropsychological testing. The study team returned to the school 1 week later to collect the completed forms and administer the questionnaire in the classrooms. For the sake of confidentiality, pupils were asked to complete the questionnaire without allowing anyone else to see their answers but could ask the researcher for clarification of any of the questions that they did not understand.
2. Materials and methods
2.3. Clinical interview
2.1. Screening
Subjects were interviewed by a psychiatrist or psychologist trained in the use of the Schedule for Affective Disorders and Schizophrenia for School-aged Children, Present and Lifetime Versions (K-SADS) (Kaufman et al., 1996) which is a wellvalidated semi-structured research diagnostic interview for the assessment of all Axis-1 psychiatric disorders in children and adolescents. Full K-SADS interviews were carried out with each adolescent and his/her parent interviewed separately. Interviews involved a detailed assessment of 2–4 h. The psychosis section of the K-SADS assessed both current and past psychotictype experiences with positive responses prompting detailed questioning and administration of a Psychosis supplement.
Ethics committee approval for this study was given by Beaumont Hospital Medical Committee. Five large, mixedgender, state primary schools from North and West Dublin, agreed to participate in the present study. The screening took place in a two-stage format. The study team visited the pupils in the 2 most senior classes (aged 11–13 years) and gave a short information session about the study and distributed consent forms. Written consent was necessary from the parent for the child to complete the questionnaire. On the form parents were also asked to indicate whether they would like to be contacted
2.2. Screening instrument A variety of positive psychotic symptoms were assessed in a brief period of time using the 7-item Adolescent PsychoticLike Symptom Screener (APSS) (Kelleher et al., 2009). The APSS questionnaire included 4 of the 5 questions used in the Dunedin birth cohort study (Poulton et al., 2000) which were derived from the Diagnostic interview Schedule for Children (Costello et al., 1985). We also included 3 additional questions on visual hallucinations, delusions of control, and grandiosity in order to broaden the types of symptoms assessed. The questionnaire is shown in Table 1. For each question there were 3 possible responses: “Yes, definitely” (1 point); “Maybe” (0.5 points); “No, never” (0 points). We made an a priori decision to rank those with scores of 2 or more as part of an ‘at-risk’ group for psychotictype experiences. Individuals with a total score of less than 2 (the potential control group) and those who scored 2 or more (the potential at-risk group) on the questionnaire were invited via a letter sent to their parents to take part in the clinical interview. All parents of the children in the at-risk group were contacted along with a random selection of parents of children in the control group.
Table 1 The 7-item Adolescent Psychotic-Like Symptom Screener (APSS), a self-report questionnaire administered in the class-room to screen for the presence of psychotic symptoms. Questionnaire items 1. Some people believe that their thoughts can be read by another person. Have other people ever read your mind? 2. Have you ever had messages sent just to you through TV or radio? 3. Have you ever thought that people are following or spying on you? 4. Have you ever heard voices or sounds that no one else can hear? 5. Have you ever felt you were under the control of some special power? 6. Have you ever seen things that other people could not see? 7. Have you ever felt like you had extra-special powers?
Yes, definitely
Maybe
No, never
□
□
□
□ □ □ □ □ □
□ □ □ □ □ □
□ □ □ □ □ □
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Extensive notes were also taken during the interview. All interview transcripts were reviewed at a consensus diagnostic meeting by 2 psychiatrists (MC, MH) and 1 psychologist (IK) to judge whether a participant had experienced a “definite” psychotic symptom. Participants were rated as having “definite” psychotic-like experiences if there was agreement between all 3 raters. 2.4. Neuropsychological measures A one-hour neuropsychological battery was administered to each subject by a trained psychologist and comprised the following: (1) Motor skills. Motor skills were tested using a modified version of the Purdue Pegboard task (Tiflin and Asher, 1948) which required individuals to place metal pegs into slots on a wooden board as quickly as possible. The number of slots filled in 30 s was recorded and the participants completed three trials per hand which were averaged for the final measure. For analysis, the average score of the dominant and non-dominant hands was used. (2) Memory. Verbal working memory was assessed using the backward span of the Digit Span Task from the Wechsler Intelligence Scale for Children (Wechsler, 1991). Short-Term Memory was assessed using the forward span. Digits were verbally presented to the participants at a rate of one per second. (3) Expressive language. The Controlled Oral Word Association Test is a subtest of the verbal fluency task that requires participants to name as many words possible starting with the letters F, A, and S within one minute per letter (Benton and Hamser, 1983). (4) Receptive language. The British Picture Vocabulary Scale-II (BPVS-II) is a test of receptive language ability for use with children aged 3–15 years (Dunn et al., 1997). The BPVS-II task consists of a series of 4 grid drawings on a page. The participants are asked to name the image which corresponds to the word that was spoken by the experimenter. As the test progresses, word complexity increases. (5) Abstract reasoning. The Similarities subtest of the Wechsler Intelligence Scale for Children was used to assess abstract reasoning (Wechsler, 1991). (6) Attention. The Sustained Attention to Response Reaction Time (SART) task is a ‘Go No-Go’ paradigm that tests attention (Robertson et al., 1997). The digits from ‘1’ to ‘9’ were presented in a cyclic repeating pattern on screen and participants were asked to make a button press response to all digits except ‘3.’ Errors of commission were used for the analysis. (7) Executive function. The Trail-Making tests A and B assess speed of processing and cognitive flexibility (Reitan, 1958) In Trails-A subjects are asked to connect a series of numbers and in Trails-B subjects are asked to connect a series of letters and numbers consecutively. (8) Scholastic Ability. The word reading subtest of the Wide Range Achievement Test 4 (WRAT 4) was used as a measure of general academic competence (Wilkinson and Robertson, 2005).
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2.5. Statistical analysis The demographic variables of age and sex were compared between the groups using t-test and chi-square test respectively. Raw scores on the neuropsychological tests were examined for normality and z-scores were computed for the neuropsychological scores results. A multivariate analysis of variance was carried out on the standardised variables to yield a predictive neurocognitive model adjusted for age (in months) and gender. Analyses were conducted using SPSS-15 for Windows. 3. Results 3.1. Subjects Two hundred and seventy seven adolescents aged 11–13 were screened in their schools and, of these 180 parents agreed to be contacted about the next stage of the study. We contacted all parents of adolescents who scored 2 or above on the screener (n = 60) and 28.3% agreed to attend. We contacted a random sample of parents of children who did not score two or more on the screener (n = 80) and 25% agreed to attend. In total, 37 adolescents and their parents agreed to attend for interview and neuropsychological testing in Beaumont Hospital, Dublin. All children were medication free and did not have a history of substance abuse. 3.2. Results of interview No participant received a diagnosis of a psychotic illness following the interview but many participants disclosed psychotic-like experiences during the interview. Nine individuals received a total of 12 diagnoses of other disorders such as social phobia, obsessive compulsive disorder, adjustment disorder with depressed mood, simple phobia and conduct disorder. After the consensus meeting, 17 participitants were deemed to have reported ‘definite’ psychotic symptoms and the remaining 20 participants formed the comparison group. The group with psychotic symptoms were, on average 7 months younger than the comparison group (144 months (sd = 6.9) vs. 151 months (sd = 4.2); t (35) = 3.5, p = 0.001). The gender difference did not reach statistical significance but there was a preponderance of males in the group with psychotic symptoms (41% vs. 25% in the comparison group). Therefore the multivariate analysis was adjusted for both age and gender. There was no significant difference between the at-risk and the comparison groups in hand dominance scores. With regard to the psychotic experiences, auditory hallucinations were the most frequently described symptoms, particularly gedankenlautwerden (hearing one's thoughts aloud). Visual hallucinations were also frequently reported and about half reported that they believed someone may be following or spying on them. Negative symptoms were not reported. 3.3. Results of neurocognitive assessments The differences (in terms of z-scores) between the adolescents with psychotic symptoms and adolescents
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without such symptoms on each test are illustrated in Fig. 1. Table 2 shows the results of the multivariate analyses, adjusted for age and gender. The adolescents with psychotic symptoms performed significantly worse than the comparison group on the receptive language task, on the pegboard task assessing motor skills and on the Trail-Making B task assessing speed of processing/executive function. There were no significant differences between the groups on overall scholastic achievement, memory, attention, verbal fluency (expressive language) or abstract reasoning. 4. Discussion This study provides information about neurocognition in the very early stages of vulnerability to psychosis. These children were all functioning well in school and had no contact with psychiatric services, although many were experiencing a significant level of psychotic symptomatology. It has been reported that, in the majority of cases, subclinical psychotic symptoms are transitory and benign (Hanssen et al., 2005; Cougnard et al., 2007). Nevertheless longitudinal studies show that such symptoms do appear to convey an increased risk of later psychotic illness which is about 3–16 times higher than the risk among adolescents who do not experience such symptoms (Poulton et al., 2000; Scott et al., 2009; Dominguez et al., 2009). Therefore children and adolescents can be viewed as an at-risk group for psychosis. There are several significant findings from our study which will be discussed in turn. Firstly, we found a triad of impairment among adolescents with psychotic symptoms involving receptive language, motor skills and executive functioning/speed of processing. Some of these deficits (notably speed of processing and motor speed) have been frequently reported in studies of patients with established schizophrenia (Heinrichs and Zakzanis, 1998; Dickinson et al., 2007; Mesholam-Gately et al., 2009) and tap into two of the key cognitive domains identified during the NIMH-MATRICS process as important in schizophrenia (Nuechterlein et al., 2004). Both speed of processing and motor performance were found to be impaired among 13-year-old children who went on to develop schizophreniaspectrum disorders in the Dunedin birth cohort (Cannon et al., 2006). In fact, motor dysfunction is one of the most
Table 2 Neuropsychological scores in adolescents with subclinical psychotic symptoms and comparison adolescents. Neuropsychological variable
WRAT 4 (read) BPVS Pegboard Similarities Digit forward Digit backwards Verbal fluency Attention Trails-A ⁎⁎ Trails-B ⁎⁎
Raw scores comparison group (n = 20)
Raw scores symptomatic (n = 17)
Multivariate analysis (adjusted for age and gender)
Mean (sd)
Mean (sd)
f
df
sig
51.3 124.8 13.7 26.15 11.1 8.4 24.2 3.5 36.4 48.9
51.6 (4.5) 114.5 (5.4) 12.9 (1.3) 24.1 (3.6) 10.6 (2.2) 8.9 (2.1) 24.9 (7.4) 4.2 (1.8) 41.7 (14.8) 60.6 (24.5)
.87 5.0 3.1 1.6 .39 1.1 1.1 .12 1.9 3.4
3 3 3 3 3 3 3 3 3 3
.47 .01 .05 .22 .76 .37 .37 .95 .16 .04
(5.4) (12.3) (1.2) (5.34) (1.8) (1.7) (6.2) (1.6) (1.6) (13.6)
Footnote: WRAT = Wide Range Achievement Test 4 — word reading subtest (overall scholastic ability). BPVS = British Picture Vocabulary Scale (receptive language). Trails = Trail-Making test. ⁎⁎ Higher scores reveal greater impairment.
consistently-replicated developmental precursors of schizophrenia and has been reported in population-based birth cohort studies (Welham et al., 2008), in children at genetic risk for schizophrenia (Niemi et al., 2005) and in follow-back studies using archived videotaped footage (Schiffman et al., 2004). Our findings on the motor task and the Trail-Making task also overlap substantially with emerging results on neurocognitive impairment in early prodromal samples (Niendam et al., 2006; Frommann et al., 2010). Taken together these findings suggest continuity in the pattern of neurocognitive compromise seen in adolescents with subclinical symptoms through to those in the prodrome or ultrahigh-risk state and the first episode for psychosis. Secondly, we found that the most significant deficit among adolescents with psychotic symptoms compared with those without such symptoms was on the test of receptive language. Receptive language has been a somewhat neglected area of neurocognition in schizophrenia and does not figure in many of the published meta-analyses (Heinrichs and Zakzanis, 1998; Mesholam-Gately et al., 2009). Language processing figures prominently in studies of childhood developmental deficits
Fig. 1. Illustrates the differences in terms of z-scores between the adolescents with psychotic symptoms and adolescents without symptoms on each test.
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preceding schizophrenia (Welham et al., 2008). Receptive language deficits throughout childhood have been shown to increase risk for adult onset schizophrenia-spectrum disorders in the Dunedin birth cohort study (Cannon et al., 2002). High rates of schizophrenia have also been found in a follow-up study of children with developmental receptive language disorders attending a specialist centre (Clegg et al., 2005). These findings suggest that difficulties in language processing may be the one of the earliest emerging impairments related to vulnerability to psychosis. Electrophysiological and brain imaging studies have shown differences at a neural level in language processing in individuals at varying degrees of risk for psychosis (Van der Stelt et al., 2005; Li et al., 2007; Bhojraj et al., 2009; Sabb et al., 2010). These findings are consistent with a neural inefficiency/disconnectivity hypothesis of risk for psychosis and are supported by studies showing structural and functional disconnectivity among high-risk samples (Mohanty et al., 2005; Modinos et al., 2009; Jacobson et al., 2010; Karlsgodt et al., 2010). Thirdly, deficits in attention and memory were not detected among the adolescents in our sample who displayed psychotic symptoms. However impairments in memory and attention are well-recognised in schizophrenia (MesholamGately et al., 2009) and have also been reported in prodromal samples (Lencz et al., 2005). We have previously hypothesised that memory and attention may be impaired later in the course of progression to psychosis (Cannon et al., 2006). In support of this, Frommann et al. (2010) have recently reported that subjects in the late prodromal phase were impaired in all neurocognitive domains whereas patients in the early prodromal phase had a specific deficit only in the processing speed/executive control domain. In conclusion, our study contributes to the emerging view of vulnerability to schizophrenia or psychosis as a dynamic process involving structural and functional brain changes (Wood et al., 2008; Reichenberg et al., 2010). This study highlights the need for longitudinal studies which incorporate a developmental approach in order to determine which neurocognitive deficits are most predictive of vulnerability for and transition to psychosis. Further investigation of the brain regions or networks that subserve these functions will help elucidate the neural trajectory to psychosis and inform the search for preventive interventions. Role of funding source The funding source had no role in study design, in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Contributors M C designed and directed the study, and contributed to data analysis and writing the manuscript. MMB, SJ, MCC, IK, DC and MH assisted in the collection and analysis of data and contributed to writing and editing the manuscript. HG contributed to editing the manuscript. Conflict of interest The authors have no affiliation with any organisation whose financial interests may be affected by the material in this manuscript. Acknowledgements This work was supported by a Clinician Scientist Award to M. Cannon (CSA/2004/1) from the Health Research Board (Ireland). The work was also supported by a NARSAD Independent Investigator award to M. Cannon. We would like to thank the study participants and their families for giving so
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generously of their time to take part in our study. We would like to thank the Clinical Education Centre, Beaumont Hospital for use of their facilities.
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Contents lists available at ScienceDirect
Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Language, motor and speed of processing deficits in adolescents with subclinical psychotic symptoms Mathieu M. Blanchard a,1, Sarah Jacobson b,1, Mary C. Clarke a, Dearbhla Connor a, Ian Kelleher a, Hugh Garavan b, Michelle Harley c, Mary Cannon a,d,⁎ a b c d
Department of Psychiatry, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland School of Psychology and Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland Department of Child and Adolescent Mental Health, Mater Misericordiae Hospital and St Vincent's Hospital, Fairview, Dublin, Ireland Department of Psychiatry, Beaumont Hospital, Dublin 9, Ireland
a r t i c l e
i n f o
Article history: Received 10 November 2009 Received in revised form 14 March 2010 Accepted 22 May 2010 Available online 1 July 2010 Keywords: Receptive language Motor deficits Speed of processing Executive function Adolescence Psychotic symptoms
a b s t r a c t Objectives: Neuropsychological impairment is a core feature of schizophrenia. Adolescents reporting subclinical psychotic symptoms are considered to be at greater risk of developing a psychotic illness later in life than adolescents who do not report such symptoms and, thus, may represent an at-risk group for further study. We wished to investigate neuropsychological functioning in early adolescence in relation to reports of psychotic symptoms. Methods: Participants were recruited from local primary schools after a two-stage screening and parental consent process. In brief, 277 adolescents were screened and 37 attended for testing. Seventeen adolescents who were deemed to report ‘definite’ psychotic symptoms after clinical interview and 20 control adolescents underwent a clinical interview and a one-hour neuropsychological battery. Results: Adolescents who report psychotic symptoms exhibited significant impairments in receptive language (as measured by the British Picture Vocabulary Scale), motor function (as measured by the Pegboard test) and executive function/speed of processing (as measured by the Trail-Making test). There were no significant differences between the groups on measures of attention, memory or expressive language, abstract reasoning or overall scholastic ability. Conclusions: Taken together with the results from birth cohort, genetic high risk and prodromal studies, these findings are consistent with a neural inefficiency/disconnectivity hypothesis in those at risk for psychosis. These results highlight the need to investigate developmental brain circuits subserving language and motor function and processing speed and how these change over time in at-risk adolescents. © 2010 Elsevier B.V. All rights reserved.
1. Introduction There is evidence that psychosis exists on a continuum in both adult and adolescent samples, but it is not clear whether schizophrenia represents the extreme end of a continuum
⁎ Corresponding author. Department of Psychiatry, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland. Tel.: + 353 1 809 3855; fax: + 353 1 809 3741. E-mail address: [email protected] (M. Cannon). 1 Both authors contributed equally to this work. 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.05.028
within the general population or is a qualitatively distinct identity. The dimensional model of schizophrenia assumes that subclinical psychotic symptoms are relatively common in the general population (van Os et al., 2000). A systematic review and meta-analysis of this topic revealed an overall median prevalence rate of 8% for psychotic experiences in the general population (van Os et al., 2009). The prevalence of subclinical psychotic symptoms among adolescents is about 15% in interview-based cohort studies (Poulton et al., 2000; Horwood et al., 2008) and is even higher when using self-report questionnaires (Laurens et al., 2007;
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Kelleher et al., 2009). The importance of adolescent subclinical psychotic symptoms lies in the possibility that they may index an increased risk of later psychotic illness in adulthood (Poulton et al., 2000; Scott et al., 2009). These individuals have not yet reached the peak age of onset of schizophrenia and are more likely to encompass those individuals who are truly “at risk” than adults who have already passed through the risk period. Children and adolescents with these symptoms could therefore be conceptualised as a ‘symptomatic’ high-risk group for later psychotic disorder, in the same way as offspring of parents with schizophrenia comprise a ‘genetic’ high-risk group, and may yield insights into the earliest pathological processes in vulnerability to adult psychosis. It is well-established that individuals with schizophrenia, as a group, demonstrate significant impairments across a broad range of cognitive domains (Heinrichs and Zakzanis, 1998). These deficits are evident even at the time of the first episode of schizophrenia (Mesholam-Gately et al., 2009) and are likely to have begun even earlier in the course of the disease (Niendam et al., 2003; Cannon et al., 2006). Neuropsychological impairments have also been demonstrated among individuals in the prodrome for psychosis (Niendam et al., 2006; Keefe et al., 2006; Seidman et al., 2006) and among adults with schizotypal traits and subclinical psychotic symptoms (Johns and van Os, 2001; Bergida and Lenzenweger, 2006). Horwood et al. (2008) has shown a relationship between general intellectual functioning and presence of psychotic symptoms in adolescence. However, to our knowledge, this is the first study reporting results from a battery of neuropsychological tests among adolescents with subclinical psychotic symptoms.
about the second stage of the study involving an interview and neuropsychological testing. The study team returned to the school 1 week later to collect the completed forms and administer the questionnaire in the classrooms. For the sake of confidentiality, pupils were asked to complete the questionnaire without allowing anyone else to see their answers but could ask the researcher for clarification of any of the questions that they did not understand.
2. Materials and methods
2.3. Clinical interview
2.1. Screening
Subjects were interviewed by a psychiatrist or psychologist trained in the use of the Schedule for Affective Disorders and Schizophrenia for School-aged Children, Present and Lifetime Versions (K-SADS) (Kaufman et al., 1996) which is a wellvalidated semi-structured research diagnostic interview for the assessment of all Axis-1 psychiatric disorders in children and adolescents. Full K-SADS interviews were carried out with each adolescent and his/her parent interviewed separately. Interviews involved a detailed assessment of 2–4 h. The psychosis section of the K-SADS assessed both current and past psychotictype experiences with positive responses prompting detailed questioning and administration of a Psychosis supplement.
Ethics committee approval for this study was given by Beaumont Hospital Medical Committee. Five large, mixedgender, state primary schools from North and West Dublin, agreed to participate in the present study. The screening took place in a two-stage format. The study team visited the pupils in the 2 most senior classes (aged 11–13 years) and gave a short information session about the study and distributed consent forms. Written consent was necessary from the parent for the child to complete the questionnaire. On the form parents were also asked to indicate whether they would like to be contacted
2.2. Screening instrument A variety of positive psychotic symptoms were assessed in a brief period of time using the 7-item Adolescent PsychoticLike Symptom Screener (APSS) (Kelleher et al., 2009). The APSS questionnaire included 4 of the 5 questions used in the Dunedin birth cohort study (Poulton et al., 2000) which were derived from the Diagnostic interview Schedule for Children (Costello et al., 1985). We also included 3 additional questions on visual hallucinations, delusions of control, and grandiosity in order to broaden the types of symptoms assessed. The questionnaire is shown in Table 1. For each question there were 3 possible responses: “Yes, definitely” (1 point); “Maybe” (0.5 points); “No, never” (0 points). We made an a priori decision to rank those with scores of 2 or more as part of an ‘at-risk’ group for psychotictype experiences. Individuals with a total score of less than 2 (the potential control group) and those who scored 2 or more (the potential at-risk group) on the questionnaire were invited via a letter sent to their parents to take part in the clinical interview. All parents of the children in the at-risk group were contacted along with a random selection of parents of children in the control group.
Table 1 The 7-item Adolescent Psychotic-Like Symptom Screener (APSS), a self-report questionnaire administered in the class-room to screen for the presence of psychotic symptoms. Questionnaire items 1. Some people believe that their thoughts can be read by another person. Have other people ever read your mind? 2. Have you ever had messages sent just to you through TV or radio? 3. Have you ever thought that people are following or spying on you? 4. Have you ever heard voices or sounds that no one else can hear? 5. Have you ever felt you were under the control of some special power? 6. Have you ever seen things that other people could not see? 7. Have you ever felt like you had extra-special powers?
Yes, definitely
Maybe
No, never
□
□
□
□ □ □ □ □ □
□ □ □ □ □ □
□ □ □ □ □ □
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Extensive notes were also taken during the interview. All interview transcripts were reviewed at a consensus diagnostic meeting by 2 psychiatrists (MC, MH) and 1 psychologist (IK) to judge whether a participant had experienced a “definite” psychotic symptom. Participants were rated as having “definite” psychotic-like experiences if there was agreement between all 3 raters. 2.4. Neuropsychological measures A one-hour neuropsychological battery was administered to each subject by a trained psychologist and comprised the following: (1) Motor skills. Motor skills were tested using a modified version of the Purdue Pegboard task (Tiflin and Asher, 1948) which required individuals to place metal pegs into slots on a wooden board as quickly as possible. The number of slots filled in 30 s was recorded and the participants completed three trials per hand which were averaged for the final measure. For analysis, the average score of the dominant and non-dominant hands was used. (2) Memory. Verbal working memory was assessed using the backward span of the Digit Span Task from the Wechsler Intelligence Scale for Children (Wechsler, 1991). Short-Term Memory was assessed using the forward span. Digits were verbally presented to the participants at a rate of one per second. (3) Expressive language. The Controlled Oral Word Association Test is a subtest of the verbal fluency task that requires participants to name as many words possible starting with the letters F, A, and S within one minute per letter (Benton and Hamser, 1983). (4) Receptive language. The British Picture Vocabulary Scale-II (BPVS-II) is a test of receptive language ability for use with children aged 3–15 years (Dunn et al., 1997). The BPVS-II task consists of a series of 4 grid drawings on a page. The participants are asked to name the image which corresponds to the word that was spoken by the experimenter. As the test progresses, word complexity increases. (5) Abstract reasoning. The Similarities subtest of the Wechsler Intelligence Scale for Children was used to assess abstract reasoning (Wechsler, 1991). (6) Attention. The Sustained Attention to Response Reaction Time (SART) task is a ‘Go No-Go’ paradigm that tests attention (Robertson et al., 1997). The digits from ‘1’ to ‘9’ were presented in a cyclic repeating pattern on screen and participants were asked to make a button press response to all digits except ‘3.’ Errors of commission were used for the analysis. (7) Executive function. The Trail-Making tests A and B assess speed of processing and cognitive flexibility (Reitan, 1958) In Trails-A subjects are asked to connect a series of numbers and in Trails-B subjects are asked to connect a series of letters and numbers consecutively. (8) Scholastic Ability. The word reading subtest of the Wide Range Achievement Test 4 (WRAT 4) was used as a measure of general academic competence (Wilkinson and Robertson, 2005).
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2.5. Statistical analysis The demographic variables of age and sex were compared between the groups using t-test and chi-square test respectively. Raw scores on the neuropsychological tests were examined for normality and z-scores were computed for the neuropsychological scores results. A multivariate analysis of variance was carried out on the standardised variables to yield a predictive neurocognitive model adjusted for age (in months) and gender. Analyses were conducted using SPSS-15 for Windows. 3. Results 3.1. Subjects Two hundred and seventy seven adolescents aged 11–13 were screened in their schools and, of these 180 parents agreed to be contacted about the next stage of the study. We contacted all parents of adolescents who scored 2 or above on the screener (n = 60) and 28.3% agreed to attend. We contacted a random sample of parents of children who did not score two or more on the screener (n = 80) and 25% agreed to attend. In total, 37 adolescents and their parents agreed to attend for interview and neuropsychological testing in Beaumont Hospital, Dublin. All children were medication free and did not have a history of substance abuse. 3.2. Results of interview No participant received a diagnosis of a psychotic illness following the interview but many participants disclosed psychotic-like experiences during the interview. Nine individuals received a total of 12 diagnoses of other disorders such as social phobia, obsessive compulsive disorder, adjustment disorder with depressed mood, simple phobia and conduct disorder. After the consensus meeting, 17 participitants were deemed to have reported ‘definite’ psychotic symptoms and the remaining 20 participants formed the comparison group. The group with psychotic symptoms were, on average 7 months younger than the comparison group (144 months (sd = 6.9) vs. 151 months (sd = 4.2); t (35) = 3.5, p = 0.001). The gender difference did not reach statistical significance but there was a preponderance of males in the group with psychotic symptoms (41% vs. 25% in the comparison group). Therefore the multivariate analysis was adjusted for both age and gender. There was no significant difference between the at-risk and the comparison groups in hand dominance scores. With regard to the psychotic experiences, auditory hallucinations were the most frequently described symptoms, particularly gedankenlautwerden (hearing one's thoughts aloud). Visual hallucinations were also frequently reported and about half reported that they believed someone may be following or spying on them. Negative symptoms were not reported. 3.3. Results of neurocognitive assessments The differences (in terms of z-scores) between the adolescents with psychotic symptoms and adolescents
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without such symptoms on each test are illustrated in Fig. 1. Table 2 shows the results of the multivariate analyses, adjusted for age and gender. The adolescents with psychotic symptoms performed significantly worse than the comparison group on the receptive language task, on the pegboard task assessing motor skills and on the Trail-Making B task assessing speed of processing/executive function. There were no significant differences between the groups on overall scholastic achievement, memory, attention, verbal fluency (expressive language) or abstract reasoning. 4. Discussion This study provides information about neurocognition in the very early stages of vulnerability to psychosis. These children were all functioning well in school and had no contact with psychiatric services, although many were experiencing a significant level of psychotic symptomatology. It has been reported that, in the majority of cases, subclinical psychotic symptoms are transitory and benign (Hanssen et al., 2005; Cougnard et al., 2007). Nevertheless longitudinal studies show that such symptoms do appear to convey an increased risk of later psychotic illness which is about 3–16 times higher than the risk among adolescents who do not experience such symptoms (Poulton et al., 2000; Scott et al., 2009; Dominguez et al., 2009). Therefore children and adolescents can be viewed as an at-risk group for psychosis. There are several significant findings from our study which will be discussed in turn. Firstly, we found a triad of impairment among adolescents with psychotic symptoms involving receptive language, motor skills and executive functioning/speed of processing. Some of these deficits (notably speed of processing and motor speed) have been frequently reported in studies of patients with established schizophrenia (Heinrichs and Zakzanis, 1998; Dickinson et al., 2007; Mesholam-Gately et al., 2009) and tap into two of the key cognitive domains identified during the NIMH-MATRICS process as important in schizophrenia (Nuechterlein et al., 2004). Both speed of processing and motor performance were found to be impaired among 13-year-old children who went on to develop schizophreniaspectrum disorders in the Dunedin birth cohort (Cannon et al., 2006). In fact, motor dysfunction is one of the most
Table 2 Neuropsychological scores in adolescents with subclinical psychotic symptoms and comparison adolescents. Neuropsychological variable
WRAT 4 (read) BPVS Pegboard Similarities Digit forward Digit backwards Verbal fluency Attention Trails-A ⁎⁎ Trails-B ⁎⁎
Raw scores comparison group (n = 20)
Raw scores symptomatic (n = 17)
Multivariate analysis (adjusted for age and gender)
Mean (sd)
Mean (sd)
f
df
sig
51.3 124.8 13.7 26.15 11.1 8.4 24.2 3.5 36.4 48.9
51.6 (4.5) 114.5 (5.4) 12.9 (1.3) 24.1 (3.6) 10.6 (2.2) 8.9 (2.1) 24.9 (7.4) 4.2 (1.8) 41.7 (14.8) 60.6 (24.5)
.87 5.0 3.1 1.6 .39 1.1 1.1 .12 1.9 3.4
3 3 3 3 3 3 3 3 3 3
.47 .01 .05 .22 .76 .37 .37 .95 .16 .04
(5.4) (12.3) (1.2) (5.34) (1.8) (1.7) (6.2) (1.6) (1.6) (13.6)
Footnote: WRAT = Wide Range Achievement Test 4 — word reading subtest (overall scholastic ability). BPVS = British Picture Vocabulary Scale (receptive language). Trails = Trail-Making test. ⁎⁎ Higher scores reveal greater impairment.
consistently-replicated developmental precursors of schizophrenia and has been reported in population-based birth cohort studies (Welham et al., 2008), in children at genetic risk for schizophrenia (Niemi et al., 2005) and in follow-back studies using archived videotaped footage (Schiffman et al., 2004). Our findings on the motor task and the Trail-Making task also overlap substantially with emerging results on neurocognitive impairment in early prodromal samples (Niendam et al., 2006; Frommann et al., 2010). Taken together these findings suggest continuity in the pattern of neurocognitive compromise seen in adolescents with subclinical symptoms through to those in the prodrome or ultrahigh-risk state and the first episode for psychosis. Secondly, we found that the most significant deficit among adolescents with psychotic symptoms compared with those without such symptoms was on the test of receptive language. Receptive language has been a somewhat neglected area of neurocognition in schizophrenia and does not figure in many of the published meta-analyses (Heinrichs and Zakzanis, 1998; Mesholam-Gately et al., 2009). Language processing figures prominently in studies of childhood developmental deficits
Fig. 1. Illustrates the differences in terms of z-scores between the adolescents with psychotic symptoms and adolescents without symptoms on each test.
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preceding schizophrenia (Welham et al., 2008). Receptive language deficits throughout childhood have been shown to increase risk for adult onset schizophrenia-spectrum disorders in the Dunedin birth cohort study (Cannon et al., 2002). High rates of schizophrenia have also been found in a follow-up study of children with developmental receptive language disorders attending a specialist centre (Clegg et al., 2005). These findings suggest that difficulties in language processing may be the one of the earliest emerging impairments related to vulnerability to psychosis. Electrophysiological and brain imaging studies have shown differences at a neural level in language processing in individuals at varying degrees of risk for psychosis (Van der Stelt et al., 2005; Li et al., 2007; Bhojraj et al., 2009; Sabb et al., 2010). These findings are consistent with a neural inefficiency/disconnectivity hypothesis of risk for psychosis and are supported by studies showing structural and functional disconnectivity among high-risk samples (Mohanty et al., 2005; Modinos et al., 2009; Jacobson et al., 2010; Karlsgodt et al., 2010). Thirdly, deficits in attention and memory were not detected among the adolescents in our sample who displayed psychotic symptoms. However impairments in memory and attention are well-recognised in schizophrenia (MesholamGately et al., 2009) and have also been reported in prodromal samples (Lencz et al., 2005). We have previously hypothesised that memory and attention may be impaired later in the course of progression to psychosis (Cannon et al., 2006). In support of this, Frommann et al. (2010) have recently reported that subjects in the late prodromal phase were impaired in all neurocognitive domains whereas patients in the early prodromal phase had a specific deficit only in the processing speed/executive control domain. In conclusion, our study contributes to the emerging view of vulnerability to schizophrenia or psychosis as a dynamic process involving structural and functional brain changes (Wood et al., 2008; Reichenberg et al., 2010). This study highlights the need for longitudinal studies which incorporate a developmental approach in order to determine which neurocognitive deficits are most predictive of vulnerability for and transition to psychosis. Further investigation of the brain regions or networks that subserve these functions will help elucidate the neural trajectory to psychosis and inform the search for preventive interventions. Role of funding source The funding source had no role in study design, in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Contributors M C designed and directed the study, and contributed to data analysis and writing the manuscript. MMB, SJ, MCC, IK, DC and MH assisted in the collection and analysis of data and contributed to writing and editing the manuscript. HG contributed to editing the manuscript. Conflict of interest The authors have no affiliation with any organisation whose financial interests may be affected by the material in this manuscript. Acknowledgements This work was supported by a Clinician Scientist Award to M. Cannon (CSA/2004/1) from the Health Research Board (Ireland). The work was also supported by a NARSAD Independent Investigator award to M. Cannon. We would like to thank the study participants and their families for giving so
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generously of their time to take part in our study. We would like to thank the Clinical Education Centre, Beaumont Hospital for use of their facilities.
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