Longitudinal trajectory of clinical insight and covariation with cortical thickness in first-episode psychosis

https://doi.org/10.1016/j.jpsychires.2016.11.008Get rights and content

Abstract

Among people with a first-episode of psychosis, those with poorer clinical insight show neuroanatomical abnormalities in frontal, temporal and parietal cortices compared to those with better clinical insight. Whether changes in clinical insight are associated with progressive structural brain changes is unknown. We aimed to evaluate 1) associations between clinical insight and cortical thickness at a baseline assessment, 2) covariation between clinical insight and cortical thickness across baseline, one-year and two-year follow-up assessments, and 3) the predictive value of clinical insight for cortical thickness at one-year and two-year follow-ups. Scale for the assessment of Unawareness of Mental Disorder ratings and magnetic resonance imaging scans were acquired at baseline, one-year, and two-year follow-ups in 128, 74, and 44 individuals with a first-episode psychosis, respectively. Cortical thickness metrics were then computed at baseline, one-year and two-year follow-ups and analyzed with linear mixed models. At baseline, clinical insight was not significantly associated with cortical thickness in any region. Longitudinal mixed effects models showed that a worsening in clinical insight between the one-year and two-year assessments was significantly associated with cortical thinning in dorsal pre-central and post-central gyri. Cortical thinning in left fusiform gyrus at two-years was predicted by poorer clinical insight at baseline. Results suggest that poor clinical insight soon after the onset of a first-episode psychosis may lead to progressive cortical changes in temporal lobe, while changes in clinical insight during the second year covary with cortical thinning in circumscribed dorsal frontal and parietal cortices.

Introduction

A considerable proportion of individuals with psychosis lack clinical insight into their illness, including difficulty recognizing their symptoms as pathological and attributable to a mental disorder, and recognizing the need for treatment (Amador et al., 1991, Amador et al., 1994, Babinski, 1914). Poor clinical insight has profound prognostic and therapeutic consequences, and has been associated with low adherence to medication (Olfson et al., 2006), greater frequency of hospitalizations and relapse (Drake et al., 2007, Olfson et al., 2006), poor social and vocational functioning (Francis and Penn, 2001, Lysaker et al., 2002), and neurocognitive difficulties (Aleman et al., 2006). There is now longitudinal evidence suggesting that clinical insight is dynamic during a first episode of psychosis (Buchy et al., 2010). For example, as clinical insight improves, positive, negative, depressive and anxious symptoms also become less severe. Clinical insight is believed to be important for cognitive insight, which is defined as one's capacity to reflect rationally on their anomalous experiences and to recognize that their conclusions are incorrect (Beck et al., 2004). Adherence to treatment is a decisive factor for symptomatic remission and prevention of relapse following a first episode of psychosis (Ascher-Svanum et al., 2006, Malla et al., 2002, Malla et al., 2006), and lack of insight is a risk factor for poor adherence (Fenton et al., 1997, Lacro et al., 2002, Young et al., 1999).

Currently, pharmacology has little impact on clinical insight that is independent from positive symptoms (Buckley et al., 2007). Attempts to better understand the biological determinants of clinical insight have been directed at revealing the underlying neural correlates of clinical insight impairments. For instance, neuroimaging studies have established that volumetric reductions in circumscribed regions of frontal cortex are a cardinal feature of poor insight in enduring schizophrenia (Bassitt et al., 2007, Flashman et al., 2001, Ha et al., 2004, Sapara et al., 2007). In first-episode psychosis, a link has been made between poor awareness of illness and volumetric reductions in right dorsolateral prefrontal cortex using voxel-based morphometry (Shad et al., 2004). Using a fully automated cortical thickness measurement, we have previously observed in a first-episode psychosis sample that poorer awareness of illness is correlated with reduced thickness in left dorsolateral prefrontal and inferior temporal cortices. Furthermore, we uncovered that unawareness of need for and efficacy of treatment was associated with reduced thickness in left middle frontal and inferior temporal cortices as well as bilateral precuneus (Buchy et al., 2011).

Together, this series of reports suggest that clinical insight has a widespread and complex neural signature. However, cross-sectional data cannot determine whether long-term changes in clinical insight are associated with progressive brain changes. Longitudinal studies have demonstrated the dynamic nature of insight over the first few years of a first-episode psychosis (Buchy et al., 2010, Fennig et al., 1996, McEvoy et al., 2006, Saeedi et al., 2007). Progressive cortical changes are also well documented after a first-episode psychosis, most consistently in inferior and middle frontal cortices, anterior cingulate cortex, superior temporal cortex and insula (Chan et al., 2011, Ellison-Wright et al., 2008, Fusar-Poli et al., 2012, Radua et al., 2012, Shepherd et al., 2012, Steen et al., 2006). In one study, the longitudinal covariation between clinical insight and gray matter volume in adolescence with an early-onset first-episode psychosis (i.e. ages 9–17) was evaluated (Parellada et al., 2011). The authors reported that greater frontal and parietal gray matter volume at baseline was significantly correlated with clinical insight two years later. Regression analysis showed that at two-year follow-up, left total frontal and parietal gray matter volumes were two of five significant predictors of insight into the consequences of illness, and two of four significant predictors of insight into having specific psychotic symptoms. Although a regression approach provides important information on the predictive value of gray matter volumes for insight, the analysis forfeits evaluation of potential longitudinal covariation between clinical insight and progressive neural changes. Furthermore, gray matter volumes were extracted for lobar regions of interest, precluding the ability to detect more subtle relations between neural structure and clinical insight. Longitudinal imaging using vertex-wise analyses may overcome this methodological limitation, extend cross-sectional findings described above, and have the potential to reveal progressive brain changes covarying with changes in insight after a first-episode psychosis.

Several studies on the topic of the neural underpinnings of clinical insight in psychosis have used a cortical thickness analysis. The advantage of cortical thickness analysis is its provision of an anatomically meaningful metric of the thickness of the cortical mantle across the whole brain, (Lerch and Evans, 2005), which is believed to capture primarily gray matter morphology such as the size and density of cells. This automated approach has been validated with post-mortem data (Fischl and Dale, 2000). Cortical thickness analysis provides an advantage over voxel-based morphometry as this latter approach is sensitive to registration differences and shape differences that may come about from systematic registration differences during the spatial normalization process, and image noise (Bookstein, 2001, Jones et al., 2005).

Our first aim was to evaluate the cross-sectional association between clinical insight and cortical thickness in a large sample of subjects with a first-episode psychosis. Based on cross-sectional research described above, we hypothesized that better clinical insight is associated with greater cortical thickness in dorsolateral prefrontal cortex, inferior temporal cortex, medial frontal cortex and precuneus. Our second aim was to evaluate the longitudinal covariation between clinical insight and cortical thickness at baseline and one- and two-years later. Our third aim was to evaluate whether clinical insight at baseline predicted cortical thickness at one-year and/or two-year follow-ups. Our second and third aims were exploratory; thus we tested the general hypothesis that if effects were seen, they would emerge in dorsolateral prefrontal cortex, inferior temporal cortex, medial frontal cortex or precuneus.

Section snippets

Participants

Participants were part of a longitudinal naturalistic outcome study of first-episode psychosis treated in a specialized early intervention service, the Prevention and Early Intervention Program for Psychoses (PEPP-Montreal), Douglas Institute in Montreal, Canada. The program involves a comprehensive approach with intensive medical and psychosocial interventions provided within the context of a modified assertive case management program. Inclusion criteria for PEPP were being 14–35 years of age,

Demographic and clinical characteristics

Demographic and clinical characteristics of the sample are shown in Table 1.

Clinical insight significantly correlated with medication adherence percentage at baseline and 1-year follow-up, r = −0.33, p < 0.001, and r = −0.41, p < 0.001, respectively, but not at the 2-year follow-up, r = −0.19, p = 0.57. Thus, medication adherence percentage was entered as a covariate in all imaging analyses.

Mixed models indicated that clinical insight scores did not significantly change over time,

Discussion

The current study evaluated the covariation between clinical insight and cortical thickness at assessments conducted at baseline, one-year and two-year follow-ups, in a large sample of people with a first-episode psychosis. After removing effects of medication adherence, at the baseline assessment no significant correlations were seen between clinical insight scores and cortical thickness in any region. Analyses of longitudinal data indicated that worsening of clinical insight between one-year

Contributors

LB performed behavioral analyses and wrote the first version of the manuscript. CM performed neuroimaging analyses. AM and RJ provided resources for data collection and organization. ML oversaw the project from conception to completion. All authors have contributed to the writing of the manuscript and approved the final version.

Funding

This study was supported by operating grants from the Canadian Institutes of Health Research (CIHR; #68961) and the Sackler Foundation to Drs. M. Lepage/A.K. Malla. Salary awards include: CIHR Fellowship (L.B.), Canada Graduate Scholarships (CGS-M) (C.M.), Fonds de la Recherche en Santé du Québec (FRSQ) (M.L. & R.J.), and Canada Research Chairs Program (A.M.). The funding sources had no role in study design; the collection, analysis nor interpretation of data; writing of the paper; nor in the

Acknowledgements

The authors would like to thank PEPP-Montreal research staff for help with patient recruitment and carrying out clinical assessments, as well as research staff in the Lepage lab for overseeing MRI sessions and help with data coordination. The authors would also like to thank Alan C. Evans, John Lewis, and Claude Lepage for providing additional resources and guidance for statistical analysis. Finally, the authors are grateful for all participants who took part in the study.

References (75)

  • D.K. Jones et al.

    The effect of filter size on VBM analyses of DT-MRI data

    Neuroimage

    (2005)
  • N. Kabani et al.

    Measurement of cortical thickness using an automated 3-D algorithm: a validation study

    Neuroimage

    (2001)
  • S. Karama et al.

    Cortical thickness correlates of specific cognitive performance accounted for by the general factor of intelligence in healthy children aged 6 to 18

    Neuroimage

    (2011)
  • J.P. Lerch et al.

    Cortical thickness analysis examined through power analysis and a population simulation

    Neuroimage

    (2005)
  • O. Lyttelton et al.

    An unbiased iterative group registration template for cortical surface analysis

    Neuroimage

    (2007)
  • D. MacDonald et al.

    Automated 3-D extraction of inner and outer surfaces of cerebral cortex from MRI

    Neuroimage

    (2000)
  • M.P. McGovern et al.

    The chemical use, abuse, and dependence scale

    J. Subst. Abuse Treat.

    (1992)
  • A. Nair et al.

    Relationship between cognition, clinical and cognitive insight in psychotic disorders: a review and meta-analysis

    Schizophrenia Res.

    (2014)
  • R.C. Oldfield

    The assessment and analysis of handedness: the Edinburgh inventory

    Neuropsychologia

    (1971)
  • M.X. Patel et al.

    How to compare doses of different antipsychotics: a systematic review of methods

    Schizophrenia Res.

    (2013)
  • J. Radua et al.

    Multimodal meta-analysis of structural and functional brain changes in first episode psychosis and the effects of antipsychotic medication

    Neurosci. Biobehav. Rev.

    (2012)
  • P. Rakic

    One small step for the cell, a giant leap for mankind: a hypothesis of neocortical expansion during evolution

    Trends Neurosci.

    (1995)
  • H. Saeedi et al.

    The association of insight with psychotic symptoms, depression, and cognition in early psychosis: a 3-year follow-up

    Schizophrenia Res.

    (2007)
  • A. Sapara et al.

    Prefrontal cortex and insight in schizophrenia: a volumetric MRI study

    Schizophrenia Res.

    (2007)
  • M.U. Shad et al.

    Insight and prefrontal cortex in first-episode Schizophrenia

    Neuroimage

    (2004)
  • A.M. Shepherd et al.

    Systematic meta-review and quality assessment of the structural brain alterations in schizophrenia

    Neurosci. Biobehav. Rev.

    (2012)
  • K.J. Worsley et al.

    Unified univariate and multivariate random field theory

    Neuroimage

    (2004)
  • Y. Ad-Dab'bagh et al.

    The CIVET image-processing environment: a fully automated comprehensive pipeline for anatomical neuroimaging research

  • Y. Ad-Dab'bagh et al.

    Native-space cortical thickness measurement and the absence of correlation to cerebral volume

  • A. Aleman et al.

    Insight in psychosis and neuropsychological function: meta-analysis

    Br. J. Psychiatry

    (2006)
  • X.F. Amador et al.

    Awareness of illness in schizophrenia and schizoaffective and mood disorders

    Archives General Psychiatry

    (1994)
  • X.F. Amador et al.

    Awareness of illness in schizophrenia

    Schizophr. Bull.

    (1991)
  • H. Ascher-Svanum et al.

    Medication adherence and long-term functional outcomes in the treatment of schizophrenia in usual care

    J. Clin. Psychiatry

    (2006)
  • M.J. Babinski

    Contribution a l'etude des troubles mentaux dans l'hemiplgie organique cerebrale

    Rev. Neurol.

    (1914)
  • D.P. Bassitt et al.

    Insight and regional brain volumes in schizophrenia

    Eur. Arch. Psychiatry Clin. Neurosci.

    (2007)
  • L. Buchy et al.

    A 12-month outcome study of insight and symptom change in first-episode psychosis

    Early Interv. Psychiatry

    (2010)
  • P.F. Buckley et al.

    Lack of insight in schizophrenia: impact on treatment adherence

    CNS Drugs

    (2007)
  • Cited by (14)

    • Neuroimaging correlates of insight in non-affective psychosis: A systematic review and meta-analysis

      2022, Revista de Psiquiatria y Salud Mental
      Citation Excerpt :

      Within this realm, neuroimaging studies indicated diverse brain alterations in patients with versus without impaired insight, suggesting specific neurobiological patterns underpinning lack of insight.17 Nevertheless, findings from magnetic resonance imaging (MRI) studies bear inconsistencies.18–20 The current neurobiological basis of understanding insight is based on the anosognosia model, suggesting the implication of several distributed cortical correlates of insight; related alterations have been reported in dorsolateral prefrontal, orbitofrontal, anterior cingulate, and parietal cortex.21

    • Long term cortical thickness changes after a first episode of non- affective psychosis: The 10 year follow-up of the PAFIP cohort

      2021, Progress in Neuro-Psychopharmacology and Biological Psychiatry
      Citation Excerpt :

      The clinical and functional implications of these changes need to be clarified as well. Reductions in cortical thickness over time in first-episode psychosis (FEP) patients have been correlated with a worsening in their clinical state and with the severity of the disorder(Buchy et al., 2017; van Haren et al., 2011), while there are also short-term studies that have reported that cortical thinning takes place in the absence of clinical or cognitive deterioration(Gutierrez-Galve et al., 2015). Previous longitudinal results from our group in the short term in FEP patients support the nonprogression of alterations in cortical thickness; in addition, neither associations of cortical changes with clinical nor cognitive outcomes were found(Roiz-Santianez et al., 2015).

    • Brain areas associated with clinical and cognitive insight in psychotic disorders: A systematic review and meta-analysis

      2020, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      This meta-analysis did not show significant results. Four studies could not be included in the meta-analysis for several reasons (see Tables 11 and 12): sample overlap with a more recent sample (Buchy et al., 2017, 2011), not reporting associations with total clinical insight but only with sub-dimensions (Buchy et al., 2012; Cooke et al., 2008) and reporting on metacognitive insight (Spalletta et al., 2014). Of these studies, Buchy et al. (2011) reported no significant correlations for VBM-data, but significant positive correlations between awareness of illness and cortical thickness in left middle frontal and inferior temporal gyri, and between need for treatment and cortical thickness of the left medial frontal gyrus, precuneus and temporal gyri (Buchy et al., 2011).

    • Cognitive capacity similarly predicts insight into symptoms in first- and multiple-episode psychosis

      2019, Schizophrenia Research
      Citation Excerpt :

      Given our results, cognitive remediation could be an interesting therapeutic avenue for FEP patients, too. Perhaps more comprehensive forms of cognitive interventions—such as cognitive enhancement therapy, which integrates remediation of social and nonsocial cognitive skills—could enhance clinical insight by influencing some of its cortical underpinnings (Buchy et al., 2017; Eack et al., 2010; Shad and Keshavan, 2015). Strengths of the present study include applying SEM analyses within well-defined samples of both FEP and MEP patients while controlling for measurement error.

    View all citing articles on Scopus
    1

    These authors contributed equally to this manuscript.

    View full text