SCHRES-06372; No of Pages 4 Schizophrenia Research xxx (2015) xxx–xxx
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Cognitive insight in first-episode schizophrenia: Further evidence for a role of the ventrolateral prefrontal cortex Lisa Buchy a, Colin Hawco b, Ridha Joober c, Ashok Malla c, Martin Lepage c,d,e,⁎ a
Department of Psychiatry, University of Calgary, Alberta, Canada Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Ontario, Canada Prevention and Early Intervention Program for Psychoses, Douglas Mental Health University Institute, Verdun, Canada d Department of Psychiatry, McGill University, Montreal, Canada e Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada b c
a r t i c l e
i n f o
Article history: Received 7 April 2015 Received in revised form 1 May 2015 Accepted 4 May 2015 Available online xxxx Keywords: Cognitive insight First-episode psychosis Self-certainty Self-reflectiveness Ventrolateral prefrontal cortex
a b s t r a c t In people with psychoses, Self-Reflectiveness may rely on the right ventrolateral prefrontal cortex (VLPFC). We used functional magnetic resonance imaging (fMRI) and a novel virtual reality paradigm to evaluate the role of the VLPFC for Self-Reflectiveness in 25 first-episode of schizophrenia (FES) participants and 24 controls. Participants first viewed 20 characters each paired with a unique object/location, and later completed source memory judgements during fMRI scanning. Self-Reflectiveness, measured with the Beck Cognitive Insight Scale, was significantly and positively correlated to activation in bilateral VLPFC in FES, but not in controls, providing further evidence that the VLPFC supports Self-Reflectiveness in FES. © 2015 Elsevier B.V. All rights reserved.
1. Introduction The Beck Cognitive Insight scale (BCIS) (Beck et al., 2004) was designed to evaluate how people with psychotic disorders understand their own beliefs, reasoning and judgments. Two core processes are evaluated: Self-Reflectiveness, capturing one's willingness to acknowledge fallibility, corrigibility and recognition of maladaptive reasoning, and Self-Certainty, reflecting overconfidence (Beck et al., 2004). Early works with the scale established that people with psychoses showed lower Self-Reflectiveness and higher Self-Certainty than control subjects, and this has been interpreted as “poorer” cognitive insight (Beck et al., 2004; Riggs et al., 2012). Follow-up studies have identified a link between poorer cognitive insight and greater positive symptom severity (Warman et al., 2007; Engh et al., 2009), lower functional outcome (Favrod et al., 2008), poorer verbal memory (Lepage et al., 2008; Buchy et al., 2010; Engh et al., 2011) and executive dysfunctions (Lysaker et al., 2008; Cooke et al., 2010; Kao et al., 2013). These latter neurocognitive findings have been supported by structural neuroimaging data indicating lower hippocampal volumes and greater fractional anisotropy in the fornix in patients with a first-episode of psychosis (FEP) with low Self-Certainty (Buchy et al., 2010, 2012). ⁎ Corresponding author at: Douglas Mental Health University Institute, 6875 LaSalle Blvd., Verdun, Quebec H4H 1R3, Canada. Tel.: +1 514 761 6131x4393; fax: +1 514 888 4064. E-mail address: [email protected] (M. Lepage).
Very recent research on the neural underpinnings of cognitive insight has identified a role of the right ventrolateral prefrontal cortex (rVLPFC) for Self-Reflectiveness. One study reported that higher SelfReflectiveness correlated to increased rVLPFC gray matter volume in people with schizophrenia (Orfei et al., 2013). Pu et al. (2013) used near infrared spectroscopy to demonstrate in people with schizophrenia that Self-Reflectiveness modulates rVLPFC activation during verbal fluency task performance. Very recently, in a functional magnetic resonance imaging (fMRI) study we demonstrated in a non-clinical sample that Self-Reflectiveness was also modulated by rVLPFC activity while subjects performed an external source memory task (Buchy et al., 2014). In two studies we have used this latter paradigm to evaluate 1) neural activation to source memory relative to object memory in people with a first-episode schizophrenia (FES) vs. controls (Hawco et al., 2015), and 2) neural correlates of cognitive insight in non-clinical subjects. The purpose of the current work was to use this same fMRI and external source memory paradigm to perform a novel and never reported analysis of the role of the rVLPFC for cognitive insight in a FES sample. In line with the literature, we hypothesized that higher Self-Reflectiveness would correlate with greater neural activation in rVLPFC. 2. Experimental material/methods Twenty-five people (age 24.4 ± 3.9, 5 females) with a FES were recruited from the Prevention and Early Intervention Program for
http://dx.doi.org/10.1016/j.schres.2015.05.009 0920-9964/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Buchy, L., et al., Cognitive insight in first-episode schizophrenia: Further evidence for a role of the ventrolateral prefrontal cortex, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.05.009
2
L. Buchy et al. / Schizophrenia Research xxx (2015) xxx–xxx
Fig. 1. Example trials from the Person, Place, and Object conditions.
Psychosis at the Douglas Mental Health University Institute in Montreal, Canada. Details can be found at http://www.douglas.qc.ca/pages/view? section_id=165. Twenty-four healthy control participants were also recruited. Patient and healthy control details including inclusion and exclusion criteria can be found in our previous publication (Hawco et al., 2015). All participants provided written informed consent and the study was approved by research ethics boards at the Douglas Hospital Research Center and the Montreal Neurological Institute. Self-Reflectiveness and Self-Certainty scores were determined with the BCIS (Beck et al., 2004). Each question is rated on a 5-point scale from 0 (do not agree at all) to 4 (agree completely). The experimental task is described in detail in our previous reports (Buchy et al., 2014; Hawco et al., 2015). Briefly, prior to scanning participants navigated a virtual town and viewed 20 encounters of characters paired with a unique object in a unique location, and were instructed to remember them for a later memory test. A recognition memory test (see Fig. 1) was then performed during fMRI scanning to evaluate the neural activity underlying source memory for the Person and Place from which objects were received in the town. Participants viewed images of a character in a location paired with two objects. They were asked one of four possible recognition questions: Place (which object was seen in this location; person was not associated with either object), Person (which object was paired with this person; place was not associated with either object), Object (which objects was viewed in the town; the second object was new) and bright (which object is brighter). The Place and Person conditions were designed to tap source memory (i.e., memory for where and with whom objects were acquired in the town), the Object condition assessed item (old vs. new) memory, and Bright served as a perceptual control. Two runs of echo-planar images were collected on a Siemens 3T Tim trio MRI (TR = 2000 ms, TE = 30 ms, flip angle = 90, 36 slices of 4 mm thick, 64 × 64 voxel plane with an FOV of 256 mm 4 mm slices and 530 volumes per scan). Data was preprocessed and analyzed in SPM8 (Wellcome Department of Cognitive Neurology, London, UK). Images were realigned to correct for motion, resampled to 2 mm isotropic voxel size and normalized to the ICBM template, and smoothed with an 8 mm kernel. GLM analysis included the canonical HRF plus its first derivative and dispersion, and statistical contrasts were created comparing activation in Place N Object and Person N Object to isolate processes unique to source memory while removing item memory effects. Furthermore, these contrasts of interest allow comparison with our previous publications using the identical fMRI cognitive activation
Table 1 Response accuracy presented as percent correct in the Person, Place and Item memory conditions in controls and participants with a first-episode of schizophrenia.
task. Voxel-wise beta values for the contrasts were then correlated with Self-Reflectiveness and Self-Certainty scores using linear regression. Statistical significance was defined at the cluster level with a t-value = 3.6, p = 0.005 uncorrected at the single voxel level and 20 voxel extent. A bilateral VLPFC mask was created using the AAL atlas (Tzourio-Mazoyer et al., 2002) provided with MRIcron (http:// www.nitrc.org/projects/mricron) using the pars triangularis and pars opercularis, and activity in any significant clusters within the VLPFC mask were reported. 3. Results Mean scores for Self-Reflectiveness were 11.6 (SD = 4.6, Range = 5–23) for FES and 13.1 for control participants (SD = 4.1, range = 5– 24). Mean Self-Certainty scores were 8.0 (SD = 2.7, range = 4–15) for FES and 7.2 for controls (SD = 2.9, range = 2–12). Mean BCIS scores did not differ significantly between FES and controls (Self-Reflectiveness, t = 1.23, p = 0.23; Self-Certainty, t = 1.00, p = 0.32). Mean response accuracy during the recognition memory test for FES and controls is displayed in Table 1. These groups did not differ on accuracy in the Place or Item memory condition; however, controls scored significantly higher on the Person condition. As shown in Table 2, behavioral accuracy in the Place, Person and Object memory conditions did not significantly correlate with cognitive insight scores. As shown in Fig. 2 and Table 3, in the FES group significant positive relationships were observed between SelfReflectiveness and activation in the Place N Object contrast in clusters in bilateral VLPFC. No significant clusters were present in the VLPFC when Self-Reflectiveness was regressed in the Person N Object condition in FES, or Self-Certainty and either contrast. Regressions of SelfReflectiveness and Self-Certainty in controls were presented in Buchy et al. (2014). 4. Discussion The main finding of this study is that in our FES participants SelfReflectiveness was significantly and positively correlated to neural activation in bilateral VLPFC in the Place N Object source memory contrast. Interestingly, this results contrasts with our previous investigation in a non-clinical sample in which we reported that SelfReflectiveness was related to rVLPFC activity in the contrast Person N Object. Although both the Person and Place conditions involve
Table 2 Correlations between cognitive insight variables and behavioral accuracy on the forced choice recognition task in participants with a first-episode of schizophrenia.
Behavioral accuracy (%)
Person Place Object
Controls
FES
t-Statistic
p-Value
0.79 0.76 0.92
0.70 0.78 0.91
2.20 0.53 0.34
0.04 0.60 0.74
Note, FES: first-episode schizophrenia.
Person Place Object
Self-Reflectiveness
Self-Certainty
−0.04 (0.87) 0.29 (0.19) −0.09 (0.71)
−0.20 (0.20) −0.02 (0.92) 0.19 (0.41)
Note. Results expressed as Spearman's correlations with corresponding p-value in brackets.
Please cite this article as: Buchy, L., et al., Cognitive insight in first-episode schizophrenia: Further evidence for a role of the ventrolateral prefrontal cortex, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.05.009
L. Buchy et al. / Schizophrenia Research xxx (2015) xxx–xxx
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Fig. 2. Top: bilateral VLPFC mask created using the AAL atlas (Tzourio-Mazoyer et al., 2002) from MRIcron (http://www.nitrc.org/projects/mricron) using the pars triangularis and pars opercularis, shown overlain onto a 3D projection of the cortex and in a selected coronal slice. Lower: bilateral ventrolateral prefrontal cortex clusters showing a positive relationship between source memory (Place N Object) and Self-Reflectiveness scores.
source memory processes, they differ in complexity. For instance, each place in the virtual town was qualitatively distinct (e.g., church, bus stop, daycare, bike rack, bank), whereas each of the 20 people shared certain characteristics, for example 10 were male, 10 were female, and 9 of 10 in each gender were young adults (although clothed differently). This leads to the suggestion that in controls, the Place condition may lack difficulty to engage the VLPFC, whereas FES may use greater prefrontal resources even though groups show equivalent behavioral accuracy in this condition (Hawco et al., 2015). This finding is consistent with literature documenting abnormal neural activation during cognitive task performance in people with psychosis as compared to controls when matched for behavioral performance (Cannon et al., 2005). This result also supports the “inefficiency” hypothesis of schizophrenia (Callicott et al., 2003) which states that patients may engage a more disperse and lower magnitude network activity to achieve the same behavioral output (Rypma et al., 2002). The results also overlap with studies in schizophrenia reporting that higher SelfReflectiveness is correlated with greater rVLPFC activation during verbal fluency task performance (Pu et al., 2013) and increased rVLPFC gray matter volume (Orfei et al., 2013). The current result complements data linking the VPFC to the ability to generate flexible behavior within social contexts (Nelson and Guyer, 2011), and to studies proposing that the VLPFC may integrate cognitive and motivational information to guide flexible goal-directed behavior (Sakagami and Pan, 2007). Other research reports have established a role for the VLPFC in controlled access to stored conceptual representations (Badre and Wagner, 2007; Levy and Wagner, 2011). In the context of Self-Reflectiveness, one's willingness to admit fallibility, corrigibility and recognition of dysfunctional reasoning may in part depend on controlled retrieval of information in memory, mediated by the VLPFC.
Table 3 Significant activations within the regression analysis of Self-Reflectiveness and Place N Object in participants with a first-episode of schizophrenia. Peak t
Voxel extent
X
Y
Z
Location
4.07 3.45
23 102
−54 52
34 38
0 0
Left VLPFC Right VLPFC
Limitations include a relatively small sample size. Moreover, verbal memory and executive cognitive functions, previously associated with cognitive insight in psychosis, were not evaluated and may be of interest in future works. Nevertheless, the results suggest that the VLPFC is one brain region that appears to support Self-Reflectiveness in FES. Cognitive insight has been linked to several other variables including psychopathology, clinical insight and functional outcome, among others (Riggs et al., 2012). Future work may apply multivariate statistical models to explore latent factors and mediating relations between these variables and cognitive insight in schizophrenia. Role of the funding source This study was supported by operating grants from CIHR (#68961) and the Sackler Foundation to Drs. M. Lepage and A. Malla. M. Lepage is supported by a salary award from FRSQ. A. Malla is supported by the Canada Research Chairs Program. L. Buchy is supported by a CIHR Fellowship. C. Hawco is supported by a CIHR Banting Postdoctoral Fellowship. Contributors The first author assisted in conceptualizing the study, managed the literature review, interpreted results and wrote the manuscript. The second author assisted in conceptualizing the study, performed the functional neuroimaging analyses, and collaborated in the writing of the final version of the manuscript. The third and fourth authors provided laboratory space and resources for data collection, and collaborated in the writing of the final version of the manuscript. The fifth author assisted in conceptualizing the study, provided laboratory space and resources for data collection, and collaborated in the writing of the final version of the manuscript. All authors contributed to and have approved the final manuscript. Conflict of interest All authors declare no conflict of interest. Acknowledgments The authors thank PEPP research staff for their help with recruitment and conducting the clinical assessments. We are grateful to all people who participated in the study.
References Badre, D., Wagner, A.D., 2007. Left ventrolateral prefrontal cortex and the cognitive control of memory. Neuropsychologia 45 (13), 2883–2901. Beck, A.T., Baruch, E., Balter, J.M., Steer, R.A., Warman, D.M., 2004. A new instrument for measuring insight: the Beck Cognitive Insight Scale. Schizophr. Res. 68 (2–3), 319–329.
Please cite this article as: Buchy, L., et al., Cognitive insight in first-episode schizophrenia: Further evidence for a role of the ventrolateral prefrontal cortex, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.05.009
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Buchy, L., Czechowska, Y., Chochol, C., Malla, A., Joober, R., Pruessner, J., Lepage, M., 2010. Toward a model of cognitive insight in first-episode psychosis: verbal memory and hippocampal structure. Schizophr. Bull. 36 (5), 1040–1049. Buchy, L., Luck, D., Czechowska, Y., Malla, A., Joober, R., Lepage, M., 2012. Diffusion tensor imaging tractography of the fornix and belief confidence in first-episode psychosis. Schizophr. Res. 137 (1–3), 80–84. Buchy, L., Hawco, C., Bodnar, M., Izadi, S., Dell'elce, J., Messina, K., Lepage, M., 2014. A functional magnetic resonance imaging study of external source memory and its relation to cognitive insight in non-clinical subjects. Psychiatry Clin. Neurosci. 68 (9), 683–691. Callicott, J.H., Mattay, V.S., Verchinski, B.A., Marenco, S., Egan, M.F., Weinberger, D.R., 2003. Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. Am. J. Psychiatry 160 (12), 2209–2215. Cannon, T.D., Glahn, D.C., Kim, J., Van Erp, T.G., Karlsgodt, K., Cohen, M.S., Nuechterlein, K.H., Bava, S., Shirinyan, D., 2005. Dorsolateral prefrontal cortex activity during maintenance and manipulation of information in working memory in patients with schizophrenia. Arch. Gen. Psychiatry 62 (10), 1071–1080. Cooke, M.A., Peters, E.R., Fannon, D., Aasen, I., Kuipers, E., Kumari, V., 2010. Cognitive insight in psychosis: the relationship between self-certainty and self-reflection dimensions and neuropsychological measures. Psychiatry Res. 178 (2), 284–289. Engh, J.A., Friis, S., Birkenaes, A.B., Jonsdottir, H., Klungsoyr, O., Ringen, P.A., Simonsen, C., Vaskinn, A., Opjordsmoen, S., Andreassen, O.A., 2009. Delusions are associated with poor cognitive insight in schizophrenia. Schizophr. Bull. 36 (4), 830–835. Engh, J.A., Sundet, K., Simonsen, C., Vaskinn, A., Lagerberg, T.V., Opjordsmoen, S., Friis, S., Andreassen, O.A., 2011. Verbal learning contributes to cognitive insight in schizophrenia independently of affective and psychotic symptoms. Prog. Neuropsychopharmacol. Biol. Psychiatry 35 (4), 1059–1063. Favrod, J., Zimmermann, G., Raffard, S., Pomini, V., Khazaal, Y., 2008. The Beck Cognitive Insight Scale in outpatients with psychotic disorders: further evidence from a French-speaking sample. Can. J. Psychiatry Rev. Can. Psychiatr. 53 (11), 783–787. Hawco, C., Buchy, L., Bodnar, M., Izadi, S., Dell'Elce, J., Messina, K., Joober, R., Malla, A., Lepage, M., 2015. Source retrieval is not properly differentiated from object retrieval in early schizophrenia: an fMRI study using virtual reality. Neuroimage Clin. 7, 336–346.
Kao, Y.C., Liu, Y.P., Lien, Y.J., Lin, S.J., Lu, C.W., Wang, T.S., Loh, C.H., 2013. The influence of sex on cognitive insight and neurocognitive functioning in schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 44, 193–200. Lepage, M., Buchy, L., Bodnar, M., Bertrand, M.C., Joober, R., Malla, A., 2008. Cognitive insight and verbal memory in first episode of psychosis. Eur. Psychiatry 23 (5), 368–374. Levy, B.J., Wagner, A.D., 2011. Cognitive control and right ventrolateral prefrontal cortex: reflexive reorienting, motor inhibition, and action updating. Ann. N. Y. Acad. Sci. 1224, 40–62. Lysaker, P.H., Warman, D.M., Dimaggio, G., Procacci, M., Larocco, V.A., Clark, L.K., Dike, C.A., Nicolo, G., 2008. Metacognition in schizophrenia: associations with multiple assessments of executive function. J. Nerv. Ment. Dis. 196 (5), 384–389. Nelson, E.E., Guyer, A.E., 2011. The development of the ventral prefrontal cortex and social flexibility. Dev. Cogn. Neurosci. 1 (3), 233–245. Orfei, M.D., Piras, F., Macci, E., Caltagirone, C., Spalletta, G., 2013. The neuroanatomical correlates of cognitive insight in schizophrenia. Soc. Cogn. Affect. Neurosci. 8 (4), 418–423. Pu, S., Nakagome, K., Yamada, T., Itakura, M., Satake, T., Ishida, H., Nagata, I., Kaneko, K., 2013. Association between cognitive insight and prefrontal function during a cognitive task in schizophrenia: a multichannel near-infrared spectroscopy study. Schizophr. Res. 150 (1), 81–87. Riggs, S.E., Grant, P.M., Perivoliotis, D., Beck, A.T., 2012. Assessment of cognitive insight: a qualitative review. Schizophr. Bull. 38 (2), 338–350. Rypma, B., Berger, J.S., D'Esposito, M., 2002. The influence of working-memory demand and subject performance on prefrontal cortical activity. J. Cogn. Neurosci. 14 (5), 721–731. Sakagami, M., Pan, X., 2007. Functional role of the ventrolateral prefrontal cortex in decision making. Curr. Opin. Neurobiol. 17 (2), 228–233. Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., Crivello, F., Etard, O., Delcroix, N., Mazoyer, B., Joliot, M., 2002. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. NeuroImage 15 (1), 273–289. Warman, D.M., Lysaker, P.H., Martin, J.M., 2007. Cognitive insight and psychotic disorder: the impact of active delusions. Schizophr. Res. 90 (1–3), 325–333.
Please cite this article as: Buchy, L., et al., Cognitive insight in first-episode schizophrenia: Further evidence for a role of the ventrolateral prefrontal cortex, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.05.009
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Cognitive insight in first-episode schizophrenia: Further evidence for a role of the ventrolateral prefrontal cortex Lisa Buchy a, Colin Hawco b, Ridha Joober c, Ashok Malla c, Martin Lepage c,d,e,⁎ a
Department of Psychiatry, University of Calgary, Alberta, Canada Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Ontario, Canada Prevention and Early Intervention Program for Psychoses, Douglas Mental Health University Institute, Verdun, Canada d Department of Psychiatry, McGill University, Montreal, Canada e Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada b c
a r t i c l e
i n f o
Article history: Received 7 April 2015 Received in revised form 1 May 2015 Accepted 4 May 2015 Available online xxxx Keywords: Cognitive insight First-episode psychosis Self-certainty Self-reflectiveness Ventrolateral prefrontal cortex
a b s t r a c t In people with psychoses, Self-Reflectiveness may rely on the right ventrolateral prefrontal cortex (VLPFC). We used functional magnetic resonance imaging (fMRI) and a novel virtual reality paradigm to evaluate the role of the VLPFC for Self-Reflectiveness in 25 first-episode of schizophrenia (FES) participants and 24 controls. Participants first viewed 20 characters each paired with a unique object/location, and later completed source memory judgements during fMRI scanning. Self-Reflectiveness, measured with the Beck Cognitive Insight Scale, was significantly and positively correlated to activation in bilateral VLPFC in FES, but not in controls, providing further evidence that the VLPFC supports Self-Reflectiveness in FES. © 2015 Elsevier B.V. All rights reserved.
1. Introduction The Beck Cognitive Insight scale (BCIS) (Beck et al., 2004) was designed to evaluate how people with psychotic disorders understand their own beliefs, reasoning and judgments. Two core processes are evaluated: Self-Reflectiveness, capturing one's willingness to acknowledge fallibility, corrigibility and recognition of maladaptive reasoning, and Self-Certainty, reflecting overconfidence (Beck et al., 2004). Early works with the scale established that people with psychoses showed lower Self-Reflectiveness and higher Self-Certainty than control subjects, and this has been interpreted as “poorer” cognitive insight (Beck et al., 2004; Riggs et al., 2012). Follow-up studies have identified a link between poorer cognitive insight and greater positive symptom severity (Warman et al., 2007; Engh et al., 2009), lower functional outcome (Favrod et al., 2008), poorer verbal memory (Lepage et al., 2008; Buchy et al., 2010; Engh et al., 2011) and executive dysfunctions (Lysaker et al., 2008; Cooke et al., 2010; Kao et al., 2013). These latter neurocognitive findings have been supported by structural neuroimaging data indicating lower hippocampal volumes and greater fractional anisotropy in the fornix in patients with a first-episode of psychosis (FEP) with low Self-Certainty (Buchy et al., 2010, 2012). ⁎ Corresponding author at: Douglas Mental Health University Institute, 6875 LaSalle Blvd., Verdun, Quebec H4H 1R3, Canada. Tel.: +1 514 761 6131x4393; fax: +1 514 888 4064. E-mail address: [email protected] (M. Lepage).
Very recent research on the neural underpinnings of cognitive insight has identified a role of the right ventrolateral prefrontal cortex (rVLPFC) for Self-Reflectiveness. One study reported that higher SelfReflectiveness correlated to increased rVLPFC gray matter volume in people with schizophrenia (Orfei et al., 2013). Pu et al. (2013) used near infrared spectroscopy to demonstrate in people with schizophrenia that Self-Reflectiveness modulates rVLPFC activation during verbal fluency task performance. Very recently, in a functional magnetic resonance imaging (fMRI) study we demonstrated in a non-clinical sample that Self-Reflectiveness was also modulated by rVLPFC activity while subjects performed an external source memory task (Buchy et al., 2014). In two studies we have used this latter paradigm to evaluate 1) neural activation to source memory relative to object memory in people with a first-episode schizophrenia (FES) vs. controls (Hawco et al., 2015), and 2) neural correlates of cognitive insight in non-clinical subjects. The purpose of the current work was to use this same fMRI and external source memory paradigm to perform a novel and never reported analysis of the role of the rVLPFC for cognitive insight in a FES sample. In line with the literature, we hypothesized that higher Self-Reflectiveness would correlate with greater neural activation in rVLPFC. 2. Experimental material/methods Twenty-five people (age 24.4 ± 3.9, 5 females) with a FES were recruited from the Prevention and Early Intervention Program for
http://dx.doi.org/10.1016/j.schres.2015.05.009 0920-9964/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Buchy, L., et al., Cognitive insight in first-episode schizophrenia: Further evidence for a role of the ventrolateral prefrontal cortex, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.05.009
2
L. Buchy et al. / Schizophrenia Research xxx (2015) xxx–xxx
Fig. 1. Example trials from the Person, Place, and Object conditions.
Psychosis at the Douglas Mental Health University Institute in Montreal, Canada. Details can be found at http://www.douglas.qc.ca/pages/view? section_id=165. Twenty-four healthy control participants were also recruited. Patient and healthy control details including inclusion and exclusion criteria can be found in our previous publication (Hawco et al., 2015). All participants provided written informed consent and the study was approved by research ethics boards at the Douglas Hospital Research Center and the Montreal Neurological Institute. Self-Reflectiveness and Self-Certainty scores were determined with the BCIS (Beck et al., 2004). Each question is rated on a 5-point scale from 0 (do not agree at all) to 4 (agree completely). The experimental task is described in detail in our previous reports (Buchy et al., 2014; Hawco et al., 2015). Briefly, prior to scanning participants navigated a virtual town and viewed 20 encounters of characters paired with a unique object in a unique location, and were instructed to remember them for a later memory test. A recognition memory test (see Fig. 1) was then performed during fMRI scanning to evaluate the neural activity underlying source memory for the Person and Place from which objects were received in the town. Participants viewed images of a character in a location paired with two objects. They were asked one of four possible recognition questions: Place (which object was seen in this location; person was not associated with either object), Person (which object was paired with this person; place was not associated with either object), Object (which objects was viewed in the town; the second object was new) and bright (which object is brighter). The Place and Person conditions were designed to tap source memory (i.e., memory for where and with whom objects were acquired in the town), the Object condition assessed item (old vs. new) memory, and Bright served as a perceptual control. Two runs of echo-planar images were collected on a Siemens 3T Tim trio MRI (TR = 2000 ms, TE = 30 ms, flip angle = 90, 36 slices of 4 mm thick, 64 × 64 voxel plane with an FOV of 256 mm 4 mm slices and 530 volumes per scan). Data was preprocessed and analyzed in SPM8 (Wellcome Department of Cognitive Neurology, London, UK). Images were realigned to correct for motion, resampled to 2 mm isotropic voxel size and normalized to the ICBM template, and smoothed with an 8 mm kernel. GLM analysis included the canonical HRF plus its first derivative and dispersion, and statistical contrasts were created comparing activation in Place N Object and Person N Object to isolate processes unique to source memory while removing item memory effects. Furthermore, these contrasts of interest allow comparison with our previous publications using the identical fMRI cognitive activation
Table 1 Response accuracy presented as percent correct in the Person, Place and Item memory conditions in controls and participants with a first-episode of schizophrenia.
task. Voxel-wise beta values for the contrasts were then correlated with Self-Reflectiveness and Self-Certainty scores using linear regression. Statistical significance was defined at the cluster level with a t-value = 3.6, p = 0.005 uncorrected at the single voxel level and 20 voxel extent. A bilateral VLPFC mask was created using the AAL atlas (Tzourio-Mazoyer et al., 2002) provided with MRIcron (http:// www.nitrc.org/projects/mricron) using the pars triangularis and pars opercularis, and activity in any significant clusters within the VLPFC mask were reported. 3. Results Mean scores for Self-Reflectiveness were 11.6 (SD = 4.6, Range = 5–23) for FES and 13.1 for control participants (SD = 4.1, range = 5– 24). Mean Self-Certainty scores were 8.0 (SD = 2.7, range = 4–15) for FES and 7.2 for controls (SD = 2.9, range = 2–12). Mean BCIS scores did not differ significantly between FES and controls (Self-Reflectiveness, t = 1.23, p = 0.23; Self-Certainty, t = 1.00, p = 0.32). Mean response accuracy during the recognition memory test for FES and controls is displayed in Table 1. These groups did not differ on accuracy in the Place or Item memory condition; however, controls scored significantly higher on the Person condition. As shown in Table 2, behavioral accuracy in the Place, Person and Object memory conditions did not significantly correlate with cognitive insight scores. As shown in Fig. 2 and Table 3, in the FES group significant positive relationships were observed between SelfReflectiveness and activation in the Place N Object contrast in clusters in bilateral VLPFC. No significant clusters were present in the VLPFC when Self-Reflectiveness was regressed in the Person N Object condition in FES, or Self-Certainty and either contrast. Regressions of SelfReflectiveness and Self-Certainty in controls were presented in Buchy et al. (2014). 4. Discussion The main finding of this study is that in our FES participants SelfReflectiveness was significantly and positively correlated to neural activation in bilateral VLPFC in the Place N Object source memory contrast. Interestingly, this results contrasts with our previous investigation in a non-clinical sample in which we reported that SelfReflectiveness was related to rVLPFC activity in the contrast Person N Object. Although both the Person and Place conditions involve
Table 2 Correlations between cognitive insight variables and behavioral accuracy on the forced choice recognition task in participants with a first-episode of schizophrenia.
Behavioral accuracy (%)
Person Place Object
Controls
FES
t-Statistic
p-Value
0.79 0.76 0.92
0.70 0.78 0.91
2.20 0.53 0.34
0.04 0.60 0.74
Note, FES: first-episode schizophrenia.
Person Place Object
Self-Reflectiveness
Self-Certainty
−0.04 (0.87) 0.29 (0.19) −0.09 (0.71)
−0.20 (0.20) −0.02 (0.92) 0.19 (0.41)
Note. Results expressed as Spearman's correlations with corresponding p-value in brackets.
Please cite this article as: Buchy, L., et al., Cognitive insight in first-episode schizophrenia: Further evidence for a role of the ventrolateral prefrontal cortex, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.05.009
L. Buchy et al. / Schizophrenia Research xxx (2015) xxx–xxx
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Fig. 2. Top: bilateral VLPFC mask created using the AAL atlas (Tzourio-Mazoyer et al., 2002) from MRIcron (http://www.nitrc.org/projects/mricron) using the pars triangularis and pars opercularis, shown overlain onto a 3D projection of the cortex and in a selected coronal slice. Lower: bilateral ventrolateral prefrontal cortex clusters showing a positive relationship between source memory (Place N Object) and Self-Reflectiveness scores.
source memory processes, they differ in complexity. For instance, each place in the virtual town was qualitatively distinct (e.g., church, bus stop, daycare, bike rack, bank), whereas each of the 20 people shared certain characteristics, for example 10 were male, 10 were female, and 9 of 10 in each gender were young adults (although clothed differently). This leads to the suggestion that in controls, the Place condition may lack difficulty to engage the VLPFC, whereas FES may use greater prefrontal resources even though groups show equivalent behavioral accuracy in this condition (Hawco et al., 2015). This finding is consistent with literature documenting abnormal neural activation during cognitive task performance in people with psychosis as compared to controls when matched for behavioral performance (Cannon et al., 2005). This result also supports the “inefficiency” hypothesis of schizophrenia (Callicott et al., 2003) which states that patients may engage a more disperse and lower magnitude network activity to achieve the same behavioral output (Rypma et al., 2002). The results also overlap with studies in schizophrenia reporting that higher SelfReflectiveness is correlated with greater rVLPFC activation during verbal fluency task performance (Pu et al., 2013) and increased rVLPFC gray matter volume (Orfei et al., 2013). The current result complements data linking the VPFC to the ability to generate flexible behavior within social contexts (Nelson and Guyer, 2011), and to studies proposing that the VLPFC may integrate cognitive and motivational information to guide flexible goal-directed behavior (Sakagami and Pan, 2007). Other research reports have established a role for the VLPFC in controlled access to stored conceptual representations (Badre and Wagner, 2007; Levy and Wagner, 2011). In the context of Self-Reflectiveness, one's willingness to admit fallibility, corrigibility and recognition of dysfunctional reasoning may in part depend on controlled retrieval of information in memory, mediated by the VLPFC.
Table 3 Significant activations within the regression analysis of Self-Reflectiveness and Place N Object in participants with a first-episode of schizophrenia. Peak t
Voxel extent
X
Y
Z
Location
4.07 3.45
23 102
−54 52
34 38
0 0
Left VLPFC Right VLPFC
Limitations include a relatively small sample size. Moreover, verbal memory and executive cognitive functions, previously associated with cognitive insight in psychosis, were not evaluated and may be of interest in future works. Nevertheless, the results suggest that the VLPFC is one brain region that appears to support Self-Reflectiveness in FES. Cognitive insight has been linked to several other variables including psychopathology, clinical insight and functional outcome, among others (Riggs et al., 2012). Future work may apply multivariate statistical models to explore latent factors and mediating relations between these variables and cognitive insight in schizophrenia. Role of the funding source This study was supported by operating grants from CIHR (#68961) and the Sackler Foundation to Drs. M. Lepage and A. Malla. M. Lepage is supported by a salary award from FRSQ. A. Malla is supported by the Canada Research Chairs Program. L. Buchy is supported by a CIHR Fellowship. C. Hawco is supported by a CIHR Banting Postdoctoral Fellowship. Contributors The first author assisted in conceptualizing the study, managed the literature review, interpreted results and wrote the manuscript. The second author assisted in conceptualizing the study, performed the functional neuroimaging analyses, and collaborated in the writing of the final version of the manuscript. The third and fourth authors provided laboratory space and resources for data collection, and collaborated in the writing of the final version of the manuscript. The fifth author assisted in conceptualizing the study, provided laboratory space and resources for data collection, and collaborated in the writing of the final version of the manuscript. All authors contributed to and have approved the final manuscript. Conflict of interest All authors declare no conflict of interest. Acknowledgments The authors thank PEPP research staff for their help with recruitment and conducting the clinical assessments. We are grateful to all people who participated in the study.
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Please cite this article as: Buchy, L., et al., Cognitive insight in first-episode schizophrenia: Further evidence for a role of the ventrolateral prefrontal cortex, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.05.009
