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How can cognitive remediation therapy modulate brain activations in schizophrenia?
Psychiatry Research: Neuroimaging 192 (2011) 160–166
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Psychiatry Research: Neuroimaging 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 / p s yc h r e s n s
How can cognitive remediation therapy modulate brain activations in schizophrenia? An fMRI study Julie Bor a,b,c,d, Jérôme Brunelin a,b,c,d,⁎, Thierry d'Amato a,b,c,d, Nicolas Costes d, Marie-Françoise Suaud-Chagny a,b,c,d, Mohamed Saoud a,b,c,d, Emmanuel Poulet a,b,c,d a
Université de Lyon, Lyon, F-69003, France Université Lyon 1, Lyon, EA4166, France CH Le Vinatier, Bron, F-69677, France d CERMEP-Imagerie du vivant, Lyon, France b c
a r t i c l e
i n f o
Article history: Received 18 May 2010 Received in revised form 30 November 2010 Accepted 9 December 2010 Keywords: Schizophrenia Cognitive remediation Functional magnetic resonance imaging fMRI
a b s t r a c t Cognitive remediation therapy (CRT) is a non biological treatment that aims to correct cognitive deficits through repeated exercises. Its efficacy in patients with schizophrenia is well recognized, but little is known about its effect on cerebral activity. Our aim was to explore the impact of CRT on cerebral activation using functional magnetic resonance imaging (fMRI) in patients with schizophrenia. Seventeen patients and 15 healthy volunteers were recruited. Patients were divided into two groups: one group received CRT with Rehacom® software (n = 8), while a control group of patients (non-CRT group) received no additional treatment (n = 9). The three groups underwent two fMRI sessions with an interval of 3 months: they had to perform a verbal and a spatial n-back task at the same performance level. Patients were additionally clinically and cognitively assessed before and after the study. After CRT, the CRT group exhibited brain over-activations in the left inferior/middle frontal gyrus, cingulate gyrus and inferior parietal lobule for the spatial task. Similar but nonsignificant over-activations were observed in the same brain regions for the verbal task. Moreover, CRT patients significantly improved their behavioural performance in attention and reasoning capacities. We conclude that CRT leads to measurable physiological adaptation associated with improved cognitive ability. Trial name: Cognitive Remediation Theraphy and Schizophrenia. http://clinicaltrials.gov/ct2/show/NCT01078129. Registration number: NCT01078129. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Cognitive deficits are a core feature in schizophrenia and are associated with poor long-term functioning and frontal lobe abnormalities (McGurk and Mueser, 2004; Green, 2006; Stober et al., 2009). Such deficits can be ameliorated by cognitive remediation therapy (CRT), a set of cognitive drills or compensatory interventions designed to enhance cognitive functioning (Kern et al., 2009). Despite the reported neuropsychological efficiency of CRT in a growing number of studies, the underlying neurobiological mechanisms are not yet well understood, but some evidence points to involvement of the frontal cortex. Recent functional magnetic resonance imaging (fMRI) studies in healthy volunteers suggest that changes in brain activity can be induced by cognitive training (Olesen et al., 2004; Westerberg and Klingberg, 2007). However, only a few studies have used neuroimaging methods to
⁎ Corresponding author. Service Pr. d'Amato, Batiment 520, 95 Boulevard Pinel, 69677 Bron cedex, France. Tel.: +33 4 37 91 55 65; fax: +33 4 37 91 55 49. E-mail address: [email protected] (J. Brunelin). 0925-4927/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pscychresns.2010.12.004
evaluate the effect of CRT in patients with schizophrenia: using single photon emission computed tomography (SPECT), Penades et al. (2002) showed that cognitive improvements after CRT may be related to the reduction of the functional hypoactivity in the frontal regions. Studies conducted with fMRI have demonstrated increases in activation in frontal regions after CRT (Wykes et al., 2002). These studies have all investigated the impact of CRT on brain activation during a verbal working memory (WM) task, because performance on WM tasks has been shown to be related to social functioning in schizophrenia (Silver et al., 2003). However, the WM system is related to different domain modalities, and spatial WM might also be related to specific forms of brain activation (Olesen et al., 2004). There is evidence for domain dominance in the frontal cortex with the left inferior frontal cortex being more specific for nonspatial and the right prefrontal cortex being more specific for spatial WM functions (Walter et al., 2003). In order to take both these modalities (spatial and verbal WM) into account (Bor et al., 2011), we decided to investigate the impact of CRT on both spatial and verbal WM systems. The present fMRI study investigated brain activation during verbal and spatial working memory tasks, at two time points, in patients
J. Bor et al. / Psychiatry Research: Neuroimaging 192 (2011) 160–166
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Fig. 1. Cerebral activations for the contrast [(CRT Patients 2 − CRT Patients 1) − (non-CRT Patients 2 − non-CRT Patients 1)] for spatial working memory represented on axial brain slices. First row, cross-hair at the level of the left middle frontal gyrus. Second row cross-hair at the level of the left inferior parietal lobule. Pcorrected b 0.05.
with schizophrenia receiving CRT (CRT patients) compared with patients not receiving CRT (non-CRT patients) and healthy controls not receiving CRT. We expected an enhanced activation or even a normalization of activation in brain areas usually involved in WM, after CRT. 2. Material and methods 2.1. Design In a randomized single-blind parallel-arms design (rater investigator: MS and EP), patients were allocated to receive CRT or no intervention (non-CRT group), and physicians were not aware of the treatment assignment during neuropsychological assessments. Clinical and cognitive assessments were done twice for patients: at the beginning of the study and after an interval of 10 weeks. The fMRI sessions were done twice for patients and controls: at the beginning of the study and after an interval of 10 weeks. Healthy volunteers were cognitively assessed only at the inclusion. The CRT intervention took place for 7 weeks during the interval. This study is part of a larger randomized controlled trial on 80 patients with schizophrenia, investigating clinical and neuropsychological effects of CRT. Participants in the fMRI study were selected randomly from all participants (d'Amato et al., 2011). 2.2. Participants Twenty clinically stable outpatients with DSM IV TR with schizophrenia and 15 healthy volunteers, who were matched for age, gender and education level, were recruited. All patients met DSM-IV-TR criteria for schizophrenia, and all participants had to be free of axis II disorders. Patients received antipsychotic medication at stable doses for at least 3 months before inclusion without any change
through the course of the study (aripiprazole: n = 4, amisulpride: n = 3, olanzapine: n = 3, risperidone: n = 7). Healthy participants had also to be free of any lifetime history of axis I disorder and free of any family history of psychotic disorder. Exclusion criteria for both groups included a lifetime history of seizures or significant head trauma, substance abuse or dependency during the previous 6 months, and any contraindication for MRI scanning. Clinical and demographic characteristics are provided in Table 1. After complete description of the study to the participants, written informed consent was obtained. The study was approved by the local ethics committee (CPP Sud Est III, Lyon, France, 24 January 2006). Two patients were excluded because they did not attend both sessions; one patient was excluded because a brain cyst was discovered during the first session. Our final group consisted of 17 schizophrenic patients and 15 healthy control participants. 2.3. Neuropsychological evaluations Seven cognitive domains disrupted in schizophrenia were assessed using the Cogtest ® battery (http://www.cogtest.com/home.html). – Attention/vigilance: The Continuous Performance Test-Identical Pairs version (CPT-IP). It requires a participant to respond whenever two identical stimuli appear in a row within a sequence of 150 rapidly flashed trials. We used the two-digit version. We retained (1) the index of perceptual sensitivity to signal to noise differences [d′ index] and (2) the response criterion, i.e. the amount of perceptual evidence that the participant required to decide if a stimulus was a target [natural log of beta]. A valid CPT-IP test was defined as a “d′index” greater than 0. We also could consider the CPT Numbers condition as an index of verbal attention as the stimuli can be verbally encoded to aid performance.
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– Working memory — non-verbal: Spatial Working Memory test (SWM). The goal of the task is to determine how accurately participants recall the spatial locations of briefly presented visual targets. A key measure was the long median which reflects the distance to the target. – Working memory — verbal: Auditory Number Sequencing (ANS). The participants are presented with clusters of numbers (e.g. 936) of increasing length (from 2 digits to a maximum of 8 digits). They are asked to tell the tester the numbers in order, from lowest to highest. A key measure was the maximal span. – Verbal learning and memory: Word List Memory test (WLM). Participants have to recall as many as possible of 16 words that have been auditorily presented by the computer. Key measures were the total recall on the first trial and the delayed recall correct. – Visual learning and memory: Face Memory Test (FMT). The study phase involves viewing 20 faces for 3 s each, followed by a recognition phase of 20 trials in which each original face is paired with a distracter face, i.e., one randomly selected from a set that was not seen before. The participant presses a mouse button on the same side as the face appeared that he/she saw before. Key measures were the percentage of correct immediate recall and delayed recognition. – Speed of processing: Finger Tapping Test (FTT). It permits to capture the total number of taps with the index finger of each hand. Key measures were the total taps of the left hand and right hand. – Reasoning and problem solving: Strategic Target Detection test (STDT). This test is similar to the paper-and-pencil ‘cancellation’ tests or the ‘cross-out’ subtest of the WAIS-III, where participants are required to cross-out target stimuli embedded among distracters. The participant must learn which the correct target is by choosing one of the stimuli and observing feedback that indicates whether the choice was right or wrong. This feature is similar to that used in the Wisconsin Card Sorting Test (WCST). Key measures were the four shape strategic efficiency (the shorter, the better strategy) and the total errors. 2.4. Cognitive remediation therapy This therapy comprised 14 individual sessions, each 2 h in length, over a 7-week period. CRT was conduced with a psychologist on a computer with Rehacom® software. This program enables patient progression and feedback. Four cognitive functions were trained using various trough diverse exercises: attention/concentration, working memory, logical thinking, and executive functions. None of these exercises included an n-back task.
In a previous open study, we showed the efficacy of Rehacom-CRT in patients with schizophrenia (Cochet et al., 2006). 2.5. MRI activation task The load chosen for this study was “2-back”. With the “TEST” instructions, participants were asked to respond by pressing a button with the right index when the stimulus on the screen was the same as that occurring two stimuli previously. To control perception and motor responses, we used a “0-back” task. In this task, participants had to respond when the pre-defined stimulus “X” appeared. Stimuli were presented using Presentation® (Neurobehavioral Systems, 2003, version 0.60, http://nbs.neuro-bs.com/) on a screen that the participants could see through a mirror. Stimuli were presented for 700 ms with an inter-stimulus interval of 1300 ms. Two modes of the “0 and 2-back” tasks were used in this study: a “verbal” mode and a “spatial” mode. For the verbal task, four letters (A, O, V, and X) were presented in white in the centre of a black screen, and for the spatial task, white circles were presented in four positions on a black screen (Right, Left, Up, and Down) with a grey cross as an inter-stimulus screen to re-focalize the sight for a duration of 15 s. Performances under the scan were measured as the ratio: (total number of good answers) / (number of targets). Reaction times were analysed for correct hits only. All included patients were trained before the fMRI session until performances were at least 80% of good responses. This last point is of prior importance because patients and healthy controls often differ in performance and taking the performance into account permits to compare groups at the same difficulty level (Karlsgodt et al., 2009). 2.6. MRI protocol Two MRI sessions were conducted, the first at baseline and the second 3 months later, whatever the group. Patients were trained 1 h before entering the scanner for the first time. For each MRI examination, subjects underwent four acquisition runs of 10 min each. Each run, either spatial or verbal, contained four blocks of four tasks (two “2-back” and two “0-back” in a random order). Runs of verbal or spatial tasks were randomly presented among participants. Each task was preceded by a 3-s instruction, either “TEST” or “TARGET X”. For each task (2-back or 0-back, without instruction), 11 MRI volumes were acquired consecutively, so 88 volumes at total were acquired for the 2-back tasks and 88 volumes for the 0-back tasks, for each of the four runs.
Table 1 Socio-demographic characteristics of patients and healthy controls who completed the study. None of the group significantly differed on the socio-demographic variables of gender, age and education level. Patient groups did not differ for illness duration, PANSS (Positive and Negative Syndrome Scale) scores or antipsychotic medication. Characteristics
CRT patients (n = 8)
Gender Male Female Other characteristics Age (years) Education (years) Duration of illness (years) PANSS total score PANSS positive scale PANSS negative scale Antipsychotic medication (mg/day chlorpromazine equivalent) Schizophrenia subtypes Paranoid Disorganised Undifferentiated
N 6 2 Mean 30.5 10.9 5.4 75.5 17.8 21 408 n 7 0 1
Non-CRT patients (n = 9) % 75.0 25.0 S.D. 8.3 2.4 3.4 18.1 5.3 5.5 228
N 6 3 Mean 28.5 13.3 5.9 72.4 16.7 21 306 n 6 1 2
Healthy controls (n = 15) % 66.7 33.3 S.D. 7.2 2.5 5.2 10.2 5.5 3.5 112
N 10 5 Mean 30.1 12.6
% 66.7 33.3 S.D. 7.5 1.7
J. Bor et al. / Psychiatry Research: Neuroimaging 192 (2011) 160–166
2.7. MRI data acquisition Scanning took place in a conventional 1.5-T Sonata Maestro Class system equipped with a standard headcoil, at the “CERMEP-Imagerie du vivant” research imaging centre of Lyon, France. Functional images were acquired over four runs, using a T2*-weighted gradient echo-planar imaging sequence, TR = 3 s, and TE= 52 ms. Twenty-five axial slices oriented along the AC-PC axis were acquired in ascending interleaved order with the following parameters: flip angle of 90°, field of view (FOV) = 230×230 mm, voxel size = 3.6×3.6×4 mm3. A total of 220 volumes were acquired for each of the four sessions. The first five volumes of each run were discarded. These volumes corresponded to the fixation time at the beginning of the run. Additionally, structural images were obtained with a standard T1weighted pulse sequence as follows: TR=1.97 ms, TE=3.93 ms, flip angle of 15°, FOV=256×256 mm, voxel size=1.0×1.0×1.0 mm.
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Resulting SPM t-maps were reported at puncorrected ≤ 0.005 at peak voxel level and a pcorrected ≤ 0.05 at a cluster level. Anatomical regions are denominated according to the atlas of Talairach and Tournoux (1988). Reported coordinates are given for the maxima of the cluster according to the average 305 MNI template of the ICBM consortium. 3. Results 3.1. Participants characteristics at baseline Table 1 summarizes clinical and demographic characteristics of included participants at baseline. No significant differences were observed between the three groups on the socio-demographic baseline variables. There was also no clinical baseline difference between the two groups of patients.
2.8. Statistical analysis of neuropsychological evaluations
3.2. CRT effects on clinical level
Statistics were performed using Statistica 5.5 software (http://www. statsoft.fr/). Performances on n-back tasks expressed in percentages were entered in separate Chi-square analyses testing for main effects of group (CRT patients, non-CRT patients and healthy controls) and time (1st or 2nd session). Concerning other variables, we used non-parametric statistics. Skewness and kurtosis normality tests revealed that normal distribution of cognitive performances could not be evidenced for all variables. For that reason we used non-parametric tests for intersession comparisons. Three-group comparisons were performed using the H-Kruskal-Wallis analysis of variance (ANOVA), and in case of significance, ANOVAs were followed by the Mann-Whitney U test for between-group analyses and by the Wilcoxon t test for intra-group analysis (pre and post).
We observed no specific effect of CRT on clinical characteristics of patients measured by the Positive and Negative Syndrome Scale (PANSS). Regardless of group, PANSS scores improved between the two sessions, −23% (from 17.8±5.3 to 15.0±1.7) in the CRT group and −15% (from 16.7±5.5 to 12.8±3.8) in the non-CRT group.
2.9. fMRI data analysis Data analysis was performed using SPM2 (Wellcome Department of Imaging Neuroscience, London, www.fil.ion.ucl.ac.uk/spm/) implemented in Matlab® V6.0 (MathWorks, Natick, MA). Image pre-processing included slice timing interpolation, inter-scan realignment to correct for head motion, spatial normalization into stereotaxic space as defined by the ICBM template provided by the Montreal Neurological Institute and image smoothing using a Gaussian filter (6 mm full width at half maximum) to minimize noise and residual differents in gyral anatomy among participants. Statistical parametric maps were calculated based on a voxel-by-voxel method, using a general linear model and a canonical hemodynamic response function, with a three groups by two time points analysis design. 2.9.1. First level analysis At this level, fMRI scan sessions were analysed independently for each session. The statistical design matrix included four runs (2 verbal and 2 spatial runs), each run with two regressors (0-back and 2-back, respectively). After parameters estimation, contrast images were constructed for each subject for verbal 2-back minus 0-back and spatial 2-back minus 0-back to identify regions associated with verbal or spatial working memory and to exclude those linked to the motor effects of the task. 2.9.2. Second level analysis Each participant's contrast images entered the second level analysis for group (CRT, non-CRT, and healthy controls), conditions (verbal and spatial) and session (pre and post treatments) analysis using an ANOVA. Pre and post sessions were contrasted within and between groups to elucidate group- and condition-specific activations.
3.3. Neuropsychological performances CRT patients and non-CRT patients did not significantly differ for neuropsychological performances at baseline measured by the Cogtest ® battery (see Table 2). Normality of neuropsychological performances was assessed with a skewness and kurtosis normality test. Since normal distribution was not evidenced for all the variables, non-parametric tests were used for intersession comparison of neuropsychological performances. A Mann–Whitney test applied to the inter-session improvements between groups revealed a significant difference in the CPT-IP test (U=3.5, Z=−3.127, p=0.002): CRT patients improved their performance from 36% and non-CRT patients lowered their performance from 19%. Moreover, CRT patients made fewer errors on the STDT test during the second session and this improvement (−41% errors) was significantly different from the non-CRT control group (−2% errors) (U = 14, Z=2.117, p=0.034). 3.4. n-back performance Performance data are summarized in Table 3. As expected, following training sessions, performance accuracy on the 2-back task did not significantly differ between groups at session 1 for the verbal (χ2 = 4.87, dl= 2, p N 0.05) or for the spatial task (χ2 = 1.1, dl = 2, p N 0.05) task; it also did not differ at session 2 for the verbal (χ2 = 3.14, dl= 2, p N 0.05) or for the spatial (χ2 = 1.57, dl= 2, p N 0.05) task. There was also no significant difference concerning reaction times at session 1 for the verbal (χ2 = 2.30, dl = 2, p N 0.05) or for the spatial (χ2 = 0.18, dl = 2, p N 0.05) task and at session 2 for the verbal (χ2 = 2.77, dl= 2, p N 0.05) or for the spatial (χ2 = 3.19, dl= 2, p N 0.05) task. Patients and healthy controls also did not significantly improve or worsen their performance between scans: neither CRT patients (χ2 = 2.63, dl = 1, p N 0.05), nor non-CRT patients (χ2 = 1.12, dl = 1, p N 0.05) nor healthy participants (χ2 = 0.16, dl = 1, p N 0.05). 3.5. BOLD fMRI responses 3.5.1. Group analyses The contrast 2-back − 0-back revealed a widespread network encompassing bilateral posterior parietal cortex including precuneus and inferior parietal lobules (BA 7/40), bilateral premotor cortex (BA
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Table 2 Performances on the neuropsychological tests for patients and healthy volunteers. CPT-IP=Continuous Performance Test-Identical Pairs, SWM=Spatial Working Memory test, ANS=Auditory Number Sequencing, WLM=Word List Memory test, FMT=Face Memory Test, FTT=Finger Tapping Test, STDT=Strategic Target Detection test, S.D.=standard deviation. Domains and tests
CRT patients (n = 8)
Non-CRT patients (n = 9)
Session 1 Mean Attention/vigilancea CPT-IPa D prime Non-verbal working memory SWM Long median Verbal working memory ANS Span Verbal learning and memory WLM First recall WLM Delayed recall Visual learning and memory FMT Immediate recall FMT Delayed recognition Speed of processing FTT Total left FTT Total right Reasoning/problem solvinga STDTa Strategic efficiency STDTa Total errors a
Session 2 S.D.
Session 1
Mean
S.D.
Mean
Session 2 S.D.
Mean
S.D.
4.3
1.8
5.9
1.8
3.7
1.3
3.0
0.7
58.1
20.9
42.4
6.4
62.9
27.5
61.5
24.8
6.9
1.0
7.1
0.8
7.0
1.1
7.4
0.5
8.0 12.5
2.0 3.9
9.1 12.9
2.0 2.9
6.9 11.2
1.8 2.9
6.6 10.3
2.6 3.1
0.8 0.8
0.1 0.1
0.8 0.7
0.1 0.1
0.7 0.6
0.1 0.2
0.8 0.7
0.1 0.1
212 247
39 49
232 262
50 52
239 255
36 53
240 264
44.8 38.4
15,928 21.9
3956 11.9
13,651 12.9
2601 8.1
14,907 19.7
3376 7.8
14,362 19.3
3015 7.3
Improved after CRT.
6/8), bilateral prefrontal cortex (BA 9/10/46), thalamus and cerebellum. At baseline, as previously reported in a larger sample (Bor et al., 2011), the comparison between patients (n = 17) and control (n = 15) revealed hyper-activations for patients compared to controls for the verbal and spatial WM in regions of the thalamus and basal ganglia. Moreover hyperactivations were found for the spatial WM only in the cerebellum and in prefrontal regions. There was no difference between CRT (n = 8) and non-CRT (n = 9) groups.
3.5.2.2. Spatial task (Table 4, Fig. 1). Comparisons between CRT patients with healthy controls, and non-CRT patients with healthy controls did not reveal any significant difference. Between-group contrast [i.e. (CRT Patients session 2 − CRT Patients session 1) − (non-CRT Patients session 2 − non-CRT Patients session 1)] revealed that, compared to non-CRT patients, CRT patients had greater frontal and parietal activation in the left inferior/middle frontal gyrus (Brodmann's area 44/45; Broca's area), cingulate gyrus (Brodmann's area 24) and inferior parietal lobule/precuneus (Brodmann's area 40/2) after CRT during the spatial WM task.
3.5.2. Between-group analysis 3.5.2.1. Verbal task. None of the contrasts between groups of patients (CRT and non-CRT) and healthy controls revealed any statistically significant activation for the verbal task at pcorrected b 0.05.
3.5.3. Within-group analysis There was no difference between the first and second sessions whatever the group (CRT patients, non-CRT patients and healthy controls) at pcorrected b 0.05 for the verbal n-back orr for the spatial n-back.
Table 3 Performance during n-back tasks for schizophrenia patients with cognitive remediation therapy (CRT), non-CRT patients and healthy controls. Performance was comparable across groups whatever the session. Results
fMRI session 1 CRT patients (n = 8) Mean
Performance 0-back Verbal Spatial 2-back Verbal Spatial Reaction time 0-back Verbal Spatial 2-back Verbal Spatial
93.8 94.7 77.5 82.8
518 497 766 676
S.D. 12.6 7.2 12.6 13.7
81 107 210 213
fMRI session 2 Non-CRT patients (n = 9)
Healthy volunteers (n=15)
CRT patients (n = 8)
Mean
Mean
Mean
97.8 94.7 71.7 87.8
520 495 801 626
S.D. 4.9 5.3 14.6 9.6
70 81 191 154
96.7 96.5 83.7 90.2
500 502 704 665
S.D. 6.7 3.5 13.5 10.6
64 75 226 182
95.3 95.0 76.9 85.3
548 518 740 682
S.D. 5.9 5.5 17.1 17.0
105 109 213 174
Non-CRT patients (n = 9)
Healthy volunteers (n=15)
Mean
Mean
99.7 96.9 83.8 89.1
501 488 723 608
S.D. 1.3 3.6 13.4 12.5
56 79 180 163
97.3 95.5 86.8 89.3
503 513 652 628
S.D. 4.9 6.3 15.3 12.2
62 74 131 163
J. Bor et al. / Psychiatry Research: Neuroimaging 192 (2011) 160–166 Table 4 Brain regions that showed significant activations for the contrast (CRT Patients session 2 − CRT Patients session 1)− (non-CRT Patients session 2 − non-CRT Patients session 1) for spatial working memory. Pcorrected b 0.05. L = left. Region of signal change
Brodmann's Nb of Coordinates a area voxels x y z
L inferior/middle 44/45 frontal gyrus L cingulate gyrus 24 L inferior parietal 40/2 lobule/precuneus a b
1006 413 346
− 60
Cluster Z corrected p score
14 24 b0.001
− 34 − 8 24 − 22 − 48 44
0.011 0.027
b
4.66 4.5 3.58
MNI coordinates. Z-score of the local maximal F value in each cluster.
4. Discussion At the first level (2-back minus 0-back), contrasts revealed the widespread network already described by a meta-analysis that who analysed coordinates of 24 studies of n-back tasks (Owen et al., 2005). As expected, after CRT we observed different brain activations between CRT and non-CRT patients during a spatial and a verbal WM task. During the spatial WM, we reported that after therapy CRT patients showed over-activation within the left ventrolateral prefrontal cortex (Broca's area), the left anterior cingulate cortex and left parietal areas. This over-activation was associated with an improvement in attention/vigilance and reasoning/problem solving cognitive tasks. A positive correlation was found between activations in BA 44/ 45 and performances on the CPT-IP (R2 = 0.56) in CRT patients only. However, we reported neither correlation in the non-CRT group nor correlations with the STDT task. The same contrast for the verbal task did not reveal any significant activation. However, activations were found in the same areas as for the spatial task in terms of the number of activated voxels and the extent of the clusters, but did not reach significance (p = 0.08), probably due to a lack of power. Few authors have investigated the impact of CRT on brain activations in patients with schizophrenia. Our results corroborate their reports of activation in frontal cortex during a WM task after CRT (Penades et al., 2002; Wykes et al., 2002). Moreover, we also reported an activation of Broca's area (Brodmann's area 44/45). The increase in activation of Broca's area during the second scan in the CRT group could be explained by the use of language function by patients. Indeed, language function could be used to name the positions of the white circles during the spatial 2-back instead of a passive remembering of the positions (from a real spatial task to a verbal task using “Right, Left, Up, Down” words as stimuli). CRT consists in encouraging participants to adopt an organised approach to diverse tasks and particularly to increase the use of specific information processing strategies. This could imply that CRT permits to CRT patients to change their strategy from a spatial task to an easier verbal task when this strategic change is not possible in the verbal memory task. Indeed, Smith and Jonides (1998) have suggested that the left parietal cortex subserves the storage component of working memory and that left hemisphere speech areas subserve rehearsal. The use of a spatial memory task in which the verbal encoding of stimuli is not possible could help to confirm this hypothesis. Strong improvements in reasoning and attention could be attributed to CRT as the patients were hardly trained in those functions with other tasks in the CRT. However, we did not observe any effect of CRT on memory as in a recent meta-analysis (McGurk et al., 2007). This is in accordance with the hypothesis that fMRI modifications are more due to a strategic change than a memory improvement. This strategy change in association with CRT was also found in the study of Wykes (1998): in this study, changes in strategy during the performance of a verbal fluency task were associated with changes in brain activations identified by SPECT and these strategy changes produced gains on other neuropsychological tests.
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To confirm our results, further studies are needed. For example, it would be interesting to study the outcomes of healthy volunteers with/without CRT and compare psychological assessments and fMRI data between schizophrenic patients and healthy volunteers with/ without CRT. A second important study would be to compare fMRI data in patients with and without improvement of cognitive ability in the CRT group and/or to compare the effect of CRT in patients with/ without cognitive impairments. Before we conclude that CRT was responsible for the observed variations in brain activation during the spatial WM task, we have to exclude some limitations. Indeed, age, gender, education, medication, illness duration and clinical characteristics of participants could influence performances in WM tasks. However, there was no difference between groups for those variables in our sample. Moreover, differences in activation could also be explained by task difficulty level but, due to the training of participants until 80% accuracy, performances on the 2back task were not different between groups and sessions. This training before CRT in all participants may also facilitate cognitive task performance in patients with schizophrenia by changing the dynamics of activity within critical control-related brain regions (Edwards et al., 2010). However, this late effect could not explain observed difference post-CRT. In the present study we demonstrated that cerebral functioning can be modified by psychological treatment. It remains to be seen whether such improvements in brain functions are sustained after many months or if a maintenance therapy is required. The research community has now amassed enough evidence that psychological therapy changes cognition in schizophrenia, and with evidence of accompanying brain changes, we now have further hope of alleviating some of the misery associated with this disorder. One can hypothesize that neuroplasticity could be implied in observed fMRI brain modifications. Conflict of interest All authors report no competing interests. Acknowledgments This work was done in “Le Vinatier” hospital, 95 Boulevard Pinel, 69677 Bron cedex, France and in the “CERMEP-Imagerie du vivant” imaging centre, 59 Boulevard Pinel, 69677 Bron cedex, France. References Bor, J., Brunelin, J., Sappey-Marinier, D., Ibarrola, D., Suaud-Chagny, M.F., D'Amato, T., Saoud, M., 2011. Thalamus abnormalities during working memory in schizophrenia. An fMRI study. Schizophrenia Research 125 (1), 49–53. Cochet, A., Saoud, M., Gabriele, S., Broallier, V., El Asmar, C., Dalery, J., D'Amato, T., 2006. Impact of a new cognitive remediation strategy on interpersonal problem solving skills and social autonomy in schizophrenia. L'Encéphale 32 (2 Pt 1), 189–195. d'Amato, T., Bation, R., Cochet, A., Jalenques, I., Galland, F., Giraud-Baro, E., PacaudTroncin, M., Augier-Astolfi, F., Llorca, P.M., Saoud, M., Brunelin, J., 2010. A randomized, controlled trial of computer-assisted cognitive remediation for schizophrenia. Schizophrenia Research 125 (2–3), 284–290. Edwards, B.G., Barch, D.M., Braver, T.S., 2010. Improving prefrontal cortex function in schizophrenia through focused training of cognitive control. Frontiers in Human Neuroscience 4, 32. Green, M.F., 2006. Cognitive impairment and functional outcome in schizophrenia and bipolar disorder. The Journal of Clinical Psychiatry 67 (Suppl 9), 3–8 discussion 36–42. Karlsgodt, K.H., Sanz, J., van Erp, T.G., Bearden, C.E., Nuechterlein, K.H., Cannon, T.D., 2009. Re-evaluating dorsolateral prefrontal cortex activation during working memory in schizophrenia. Schizophrenia Research 108 (1–3), 143–150. Kern, R.S., Glynn, S.M., Horan, W.P., Marder, S.R., 2009. Psychosocial treatments to promote functional recovery in schizophrenia. Schizophrenia Bulletin 35 (2), 347–361. McGurk, S.R., Mueser, K.T., 2004. Cognitive functioning, symptoms, and work in supported employment: a review and heuristic model. Schizophrenia Research 70 (2–3), 147–173. McGurk, S.R., Twamley, E.W., Sitzer, D.I., McHugo, G.J., Mueser, K.T., 2007. A meta-analysis of cognitive remediation in schizophrenia. The American Journal of Psychiatry 164 (12), 1791–1802.
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Olesen, P.J., Westerberg, H., Klingberg, T., 2004. Increased prefrontal and parietal activity after training of working memory. Nature Neuroscience 7 (1), 75–79. Owen, A.M., McMillan, K.M., Laird, A.R., Bullmore, E., 2005. N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies. Human Brain Mapping 25 (1), 46–59. Penades, R., Boget, T., Lomena, F., Mateos, J.J., Catalan, R., Gasto, C., Salamero, M., 2002. Could the hypofrontality pattern in schizophrenia be modified through neuropsychological rehabilitation? Acta Psychiatrica Scandinavica 105 (3), 202–208. Silver, H., Feldman, P., Bilker, W., Gur, R.C., 2003. Working memory deficit as a core neuropsychological dysfunction in schizophrenia. The American Journal of Psychiatry 160 (10), 1809–1816. Smith, E.E., Jonides, J., 1998. Neuroimaging analyses of human working memory. Proceedings of the National Academy of Sciences of the United States of America 95 (20), 12061–12068. Stober, G., Ben-Shachar, D., Cardon, M., Falkai, P., Fonteh, A.N., Gawlik, M., Glenthoj, B.Y., Grunblatt, E., Jablensky, A., Kim, Y.K., Kornhuber, J., McNeil, T.F., Muller, N., Oranje, B., Saito, T., Saoud, M., Schmitt, A., Schwartz, M., Thome, J., Uzbekov, M., Durany, N.,
Riederer, P., 2009. Schizophrenia: from the brain to peripheral markers. A consensus paper of the WFSBP task force on biological markers. The World Journal of Biological Psychiatry 10 (2), 127–155. Talairach, J., Tournoux, P., 1988. Co-Planar Stereotactic Atlas of the Human Brain. Thieme Medical Publishers, New York, NY. Walter, H., Bretschneider, V., Gron, G., Zurowski, B., Wunderlich, A.P., Tomczak, R., Spitzer, M., 2003. Evidence for quantitative domain dominance for verbal and spatial working memory in frontal and parietal cortex. Cortex 39 (4–5), 897–911. Westerberg, H., Klingberg, T., 2007. Changes in cortical activity after training of working memory—a single-subject analysis. Physiology & Behavior 92 (1–2), 186–192. Wykes, T., 1998. What are we changing with neurocognitive rehabilitation? Illustrations from two single cases of changes in neuropsychological performance and brain systems as measured by SPECT. Schizophrenia Research 34 (1–2), 77–86. Wykes, T., Brammer, M., Mellers, J., Bray, P., Reeder, C., Williams, C., Corner, J., 2002. Effects on the brain of a psychological treatment: cognitive remediation therapy: functional magnetic resonance imaging in schizophrenia. The British Journal of Psychiatry 181, 144–152.
Contents lists available at ScienceDirect
Psychiatry Research: Neuroimaging 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 / p s yc h r e s n s
How can cognitive remediation therapy modulate brain activations in schizophrenia? An fMRI study Julie Bor a,b,c,d, Jérôme Brunelin a,b,c,d,⁎, Thierry d'Amato a,b,c,d, Nicolas Costes d, Marie-Françoise Suaud-Chagny a,b,c,d, Mohamed Saoud a,b,c,d, Emmanuel Poulet a,b,c,d a
Université de Lyon, Lyon, F-69003, France Université Lyon 1, Lyon, EA4166, France CH Le Vinatier, Bron, F-69677, France d CERMEP-Imagerie du vivant, Lyon, France b c
a r t i c l e
i n f o
Article history: Received 18 May 2010 Received in revised form 30 November 2010 Accepted 9 December 2010 Keywords: Schizophrenia Cognitive remediation Functional magnetic resonance imaging fMRI
a b s t r a c t Cognitive remediation therapy (CRT) is a non biological treatment that aims to correct cognitive deficits through repeated exercises. Its efficacy in patients with schizophrenia is well recognized, but little is known about its effect on cerebral activity. Our aim was to explore the impact of CRT on cerebral activation using functional magnetic resonance imaging (fMRI) in patients with schizophrenia. Seventeen patients and 15 healthy volunteers were recruited. Patients were divided into two groups: one group received CRT with Rehacom® software (n = 8), while a control group of patients (non-CRT group) received no additional treatment (n = 9). The three groups underwent two fMRI sessions with an interval of 3 months: they had to perform a verbal and a spatial n-back task at the same performance level. Patients were additionally clinically and cognitively assessed before and after the study. After CRT, the CRT group exhibited brain over-activations in the left inferior/middle frontal gyrus, cingulate gyrus and inferior parietal lobule for the spatial task. Similar but nonsignificant over-activations were observed in the same brain regions for the verbal task. Moreover, CRT patients significantly improved their behavioural performance in attention and reasoning capacities. We conclude that CRT leads to measurable physiological adaptation associated with improved cognitive ability. Trial name: Cognitive Remediation Theraphy and Schizophrenia. http://clinicaltrials.gov/ct2/show/NCT01078129. Registration number: NCT01078129. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Cognitive deficits are a core feature in schizophrenia and are associated with poor long-term functioning and frontal lobe abnormalities (McGurk and Mueser, 2004; Green, 2006; Stober et al., 2009). Such deficits can be ameliorated by cognitive remediation therapy (CRT), a set of cognitive drills or compensatory interventions designed to enhance cognitive functioning (Kern et al., 2009). Despite the reported neuropsychological efficiency of CRT in a growing number of studies, the underlying neurobiological mechanisms are not yet well understood, but some evidence points to involvement of the frontal cortex. Recent functional magnetic resonance imaging (fMRI) studies in healthy volunteers suggest that changes in brain activity can be induced by cognitive training (Olesen et al., 2004; Westerberg and Klingberg, 2007). However, only a few studies have used neuroimaging methods to
⁎ Corresponding author. Service Pr. d'Amato, Batiment 520, 95 Boulevard Pinel, 69677 Bron cedex, France. Tel.: +33 4 37 91 55 65; fax: +33 4 37 91 55 49. E-mail address: [email protected] (J. Brunelin). 0925-4927/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pscychresns.2010.12.004
evaluate the effect of CRT in patients with schizophrenia: using single photon emission computed tomography (SPECT), Penades et al. (2002) showed that cognitive improvements after CRT may be related to the reduction of the functional hypoactivity in the frontal regions. Studies conducted with fMRI have demonstrated increases in activation in frontal regions after CRT (Wykes et al., 2002). These studies have all investigated the impact of CRT on brain activation during a verbal working memory (WM) task, because performance on WM tasks has been shown to be related to social functioning in schizophrenia (Silver et al., 2003). However, the WM system is related to different domain modalities, and spatial WM might also be related to specific forms of brain activation (Olesen et al., 2004). There is evidence for domain dominance in the frontal cortex with the left inferior frontal cortex being more specific for nonspatial and the right prefrontal cortex being more specific for spatial WM functions (Walter et al., 2003). In order to take both these modalities (spatial and verbal WM) into account (Bor et al., 2011), we decided to investigate the impact of CRT on both spatial and verbal WM systems. The present fMRI study investigated brain activation during verbal and spatial working memory tasks, at two time points, in patients
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Fig. 1. Cerebral activations for the contrast [(CRT Patients 2 − CRT Patients 1) − (non-CRT Patients 2 − non-CRT Patients 1)] for spatial working memory represented on axial brain slices. First row, cross-hair at the level of the left middle frontal gyrus. Second row cross-hair at the level of the left inferior parietal lobule. Pcorrected b 0.05.
with schizophrenia receiving CRT (CRT patients) compared with patients not receiving CRT (non-CRT patients) and healthy controls not receiving CRT. We expected an enhanced activation or even a normalization of activation in brain areas usually involved in WM, after CRT. 2. Material and methods 2.1. Design In a randomized single-blind parallel-arms design (rater investigator: MS and EP), patients were allocated to receive CRT or no intervention (non-CRT group), and physicians were not aware of the treatment assignment during neuropsychological assessments. Clinical and cognitive assessments were done twice for patients: at the beginning of the study and after an interval of 10 weeks. The fMRI sessions were done twice for patients and controls: at the beginning of the study and after an interval of 10 weeks. Healthy volunteers were cognitively assessed only at the inclusion. The CRT intervention took place for 7 weeks during the interval. This study is part of a larger randomized controlled trial on 80 patients with schizophrenia, investigating clinical and neuropsychological effects of CRT. Participants in the fMRI study were selected randomly from all participants (d'Amato et al., 2011). 2.2. Participants Twenty clinically stable outpatients with DSM IV TR with schizophrenia and 15 healthy volunteers, who were matched for age, gender and education level, were recruited. All patients met DSM-IV-TR criteria for schizophrenia, and all participants had to be free of axis II disorders. Patients received antipsychotic medication at stable doses for at least 3 months before inclusion without any change
through the course of the study (aripiprazole: n = 4, amisulpride: n = 3, olanzapine: n = 3, risperidone: n = 7). Healthy participants had also to be free of any lifetime history of axis I disorder and free of any family history of psychotic disorder. Exclusion criteria for both groups included a lifetime history of seizures or significant head trauma, substance abuse or dependency during the previous 6 months, and any contraindication for MRI scanning. Clinical and demographic characteristics are provided in Table 1. After complete description of the study to the participants, written informed consent was obtained. The study was approved by the local ethics committee (CPP Sud Est III, Lyon, France, 24 January 2006). Two patients were excluded because they did not attend both sessions; one patient was excluded because a brain cyst was discovered during the first session. Our final group consisted of 17 schizophrenic patients and 15 healthy control participants. 2.3. Neuropsychological evaluations Seven cognitive domains disrupted in schizophrenia were assessed using the Cogtest ® battery (http://www.cogtest.com/home.html). – Attention/vigilance: The Continuous Performance Test-Identical Pairs version (CPT-IP). It requires a participant to respond whenever two identical stimuli appear in a row within a sequence of 150 rapidly flashed trials. We used the two-digit version. We retained (1) the index of perceptual sensitivity to signal to noise differences [d′ index] and (2) the response criterion, i.e. the amount of perceptual evidence that the participant required to decide if a stimulus was a target [natural log of beta]. A valid CPT-IP test was defined as a “d′index” greater than 0. We also could consider the CPT Numbers condition as an index of verbal attention as the stimuli can be verbally encoded to aid performance.
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– Working memory — non-verbal: Spatial Working Memory test (SWM). The goal of the task is to determine how accurately participants recall the spatial locations of briefly presented visual targets. A key measure was the long median which reflects the distance to the target. – Working memory — verbal: Auditory Number Sequencing (ANS). The participants are presented with clusters of numbers (e.g. 936) of increasing length (from 2 digits to a maximum of 8 digits). They are asked to tell the tester the numbers in order, from lowest to highest. A key measure was the maximal span. – Verbal learning and memory: Word List Memory test (WLM). Participants have to recall as many as possible of 16 words that have been auditorily presented by the computer. Key measures were the total recall on the first trial and the delayed recall correct. – Visual learning and memory: Face Memory Test (FMT). The study phase involves viewing 20 faces for 3 s each, followed by a recognition phase of 20 trials in which each original face is paired with a distracter face, i.e., one randomly selected from a set that was not seen before. The participant presses a mouse button on the same side as the face appeared that he/she saw before. Key measures were the percentage of correct immediate recall and delayed recognition. – Speed of processing: Finger Tapping Test (FTT). It permits to capture the total number of taps with the index finger of each hand. Key measures were the total taps of the left hand and right hand. – Reasoning and problem solving: Strategic Target Detection test (STDT). This test is similar to the paper-and-pencil ‘cancellation’ tests or the ‘cross-out’ subtest of the WAIS-III, where participants are required to cross-out target stimuli embedded among distracters. The participant must learn which the correct target is by choosing one of the stimuli and observing feedback that indicates whether the choice was right or wrong. This feature is similar to that used in the Wisconsin Card Sorting Test (WCST). Key measures were the four shape strategic efficiency (the shorter, the better strategy) and the total errors. 2.4. Cognitive remediation therapy This therapy comprised 14 individual sessions, each 2 h in length, over a 7-week period. CRT was conduced with a psychologist on a computer with Rehacom® software. This program enables patient progression and feedback. Four cognitive functions were trained using various trough diverse exercises: attention/concentration, working memory, logical thinking, and executive functions. None of these exercises included an n-back task.
In a previous open study, we showed the efficacy of Rehacom-CRT in patients with schizophrenia (Cochet et al., 2006). 2.5. MRI activation task The load chosen for this study was “2-back”. With the “TEST” instructions, participants were asked to respond by pressing a button with the right index when the stimulus on the screen was the same as that occurring two stimuli previously. To control perception and motor responses, we used a “0-back” task. In this task, participants had to respond when the pre-defined stimulus “X” appeared. Stimuli were presented using Presentation® (Neurobehavioral Systems, 2003, version 0.60, http://nbs.neuro-bs.com/) on a screen that the participants could see through a mirror. Stimuli were presented for 700 ms with an inter-stimulus interval of 1300 ms. Two modes of the “0 and 2-back” tasks were used in this study: a “verbal” mode and a “spatial” mode. For the verbal task, four letters (A, O, V, and X) were presented in white in the centre of a black screen, and for the spatial task, white circles were presented in four positions on a black screen (Right, Left, Up, and Down) with a grey cross as an inter-stimulus screen to re-focalize the sight for a duration of 15 s. Performances under the scan were measured as the ratio: (total number of good answers) / (number of targets). Reaction times were analysed for correct hits only. All included patients were trained before the fMRI session until performances were at least 80% of good responses. This last point is of prior importance because patients and healthy controls often differ in performance and taking the performance into account permits to compare groups at the same difficulty level (Karlsgodt et al., 2009). 2.6. MRI protocol Two MRI sessions were conducted, the first at baseline and the second 3 months later, whatever the group. Patients were trained 1 h before entering the scanner for the first time. For each MRI examination, subjects underwent four acquisition runs of 10 min each. Each run, either spatial or verbal, contained four blocks of four tasks (two “2-back” and two “0-back” in a random order). Runs of verbal or spatial tasks were randomly presented among participants. Each task was preceded by a 3-s instruction, either “TEST” or “TARGET X”. For each task (2-back or 0-back, without instruction), 11 MRI volumes were acquired consecutively, so 88 volumes at total were acquired for the 2-back tasks and 88 volumes for the 0-back tasks, for each of the four runs.
Table 1 Socio-demographic characteristics of patients and healthy controls who completed the study. None of the group significantly differed on the socio-demographic variables of gender, age and education level. Patient groups did not differ for illness duration, PANSS (Positive and Negative Syndrome Scale) scores or antipsychotic medication. Characteristics
CRT patients (n = 8)
Gender Male Female Other characteristics Age (years) Education (years) Duration of illness (years) PANSS total score PANSS positive scale PANSS negative scale Antipsychotic medication (mg/day chlorpromazine equivalent) Schizophrenia subtypes Paranoid Disorganised Undifferentiated
N 6 2 Mean 30.5 10.9 5.4 75.5 17.8 21 408 n 7 0 1
Non-CRT patients (n = 9) % 75.0 25.0 S.D. 8.3 2.4 3.4 18.1 5.3 5.5 228
N 6 3 Mean 28.5 13.3 5.9 72.4 16.7 21 306 n 6 1 2
Healthy controls (n = 15) % 66.7 33.3 S.D. 7.2 2.5 5.2 10.2 5.5 3.5 112
N 10 5 Mean 30.1 12.6
% 66.7 33.3 S.D. 7.5 1.7
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2.7. MRI data acquisition Scanning took place in a conventional 1.5-T Sonata Maestro Class system equipped with a standard headcoil, at the “CERMEP-Imagerie du vivant” research imaging centre of Lyon, France. Functional images were acquired over four runs, using a T2*-weighted gradient echo-planar imaging sequence, TR = 3 s, and TE= 52 ms. Twenty-five axial slices oriented along the AC-PC axis were acquired in ascending interleaved order with the following parameters: flip angle of 90°, field of view (FOV) = 230×230 mm, voxel size = 3.6×3.6×4 mm3. A total of 220 volumes were acquired for each of the four sessions. The first five volumes of each run were discarded. These volumes corresponded to the fixation time at the beginning of the run. Additionally, structural images were obtained with a standard T1weighted pulse sequence as follows: TR=1.97 ms, TE=3.93 ms, flip angle of 15°, FOV=256×256 mm, voxel size=1.0×1.0×1.0 mm.
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Resulting SPM t-maps were reported at puncorrected ≤ 0.005 at peak voxel level and a pcorrected ≤ 0.05 at a cluster level. Anatomical regions are denominated according to the atlas of Talairach and Tournoux (1988). Reported coordinates are given for the maxima of the cluster according to the average 305 MNI template of the ICBM consortium. 3. Results 3.1. Participants characteristics at baseline Table 1 summarizes clinical and demographic characteristics of included participants at baseline. No significant differences were observed between the three groups on the socio-demographic baseline variables. There was also no clinical baseline difference between the two groups of patients.
2.8. Statistical analysis of neuropsychological evaluations
3.2. CRT effects on clinical level
Statistics were performed using Statistica 5.5 software (http://www. statsoft.fr/). Performances on n-back tasks expressed in percentages were entered in separate Chi-square analyses testing for main effects of group (CRT patients, non-CRT patients and healthy controls) and time (1st or 2nd session). Concerning other variables, we used non-parametric statistics. Skewness and kurtosis normality tests revealed that normal distribution of cognitive performances could not be evidenced for all variables. For that reason we used non-parametric tests for intersession comparisons. Three-group comparisons were performed using the H-Kruskal-Wallis analysis of variance (ANOVA), and in case of significance, ANOVAs were followed by the Mann-Whitney U test for between-group analyses and by the Wilcoxon t test for intra-group analysis (pre and post).
We observed no specific effect of CRT on clinical characteristics of patients measured by the Positive and Negative Syndrome Scale (PANSS). Regardless of group, PANSS scores improved between the two sessions, −23% (from 17.8±5.3 to 15.0±1.7) in the CRT group and −15% (from 16.7±5.5 to 12.8±3.8) in the non-CRT group.
2.9. fMRI data analysis Data analysis was performed using SPM2 (Wellcome Department of Imaging Neuroscience, London, www.fil.ion.ucl.ac.uk/spm/) implemented in Matlab® V6.0 (MathWorks, Natick, MA). Image pre-processing included slice timing interpolation, inter-scan realignment to correct for head motion, spatial normalization into stereotaxic space as defined by the ICBM template provided by the Montreal Neurological Institute and image smoothing using a Gaussian filter (6 mm full width at half maximum) to minimize noise and residual differents in gyral anatomy among participants. Statistical parametric maps were calculated based on a voxel-by-voxel method, using a general linear model and a canonical hemodynamic response function, with a three groups by two time points analysis design. 2.9.1. First level analysis At this level, fMRI scan sessions were analysed independently for each session. The statistical design matrix included four runs (2 verbal and 2 spatial runs), each run with two regressors (0-back and 2-back, respectively). After parameters estimation, contrast images were constructed for each subject for verbal 2-back minus 0-back and spatial 2-back minus 0-back to identify regions associated with verbal or spatial working memory and to exclude those linked to the motor effects of the task. 2.9.2. Second level analysis Each participant's contrast images entered the second level analysis for group (CRT, non-CRT, and healthy controls), conditions (verbal and spatial) and session (pre and post treatments) analysis using an ANOVA. Pre and post sessions were contrasted within and between groups to elucidate group- and condition-specific activations.
3.3. Neuropsychological performances CRT patients and non-CRT patients did not significantly differ for neuropsychological performances at baseline measured by the Cogtest ® battery (see Table 2). Normality of neuropsychological performances was assessed with a skewness and kurtosis normality test. Since normal distribution was not evidenced for all the variables, non-parametric tests were used for intersession comparison of neuropsychological performances. A Mann–Whitney test applied to the inter-session improvements between groups revealed a significant difference in the CPT-IP test (U=3.5, Z=−3.127, p=0.002): CRT patients improved their performance from 36% and non-CRT patients lowered their performance from 19%. Moreover, CRT patients made fewer errors on the STDT test during the second session and this improvement (−41% errors) was significantly different from the non-CRT control group (−2% errors) (U = 14, Z=2.117, p=0.034). 3.4. n-back performance Performance data are summarized in Table 3. As expected, following training sessions, performance accuracy on the 2-back task did not significantly differ between groups at session 1 for the verbal (χ2 = 4.87, dl= 2, p N 0.05) or for the spatial task (χ2 = 1.1, dl = 2, p N 0.05) task; it also did not differ at session 2 for the verbal (χ2 = 3.14, dl= 2, p N 0.05) or for the spatial (χ2 = 1.57, dl= 2, p N 0.05) task. There was also no significant difference concerning reaction times at session 1 for the verbal (χ2 = 2.30, dl = 2, p N 0.05) or for the spatial (χ2 = 0.18, dl = 2, p N 0.05) task and at session 2 for the verbal (χ2 = 2.77, dl= 2, p N 0.05) or for the spatial (χ2 = 3.19, dl= 2, p N 0.05) task. Patients and healthy controls also did not significantly improve or worsen their performance between scans: neither CRT patients (χ2 = 2.63, dl = 1, p N 0.05), nor non-CRT patients (χ2 = 1.12, dl = 1, p N 0.05) nor healthy participants (χ2 = 0.16, dl = 1, p N 0.05). 3.5. BOLD fMRI responses 3.5.1. Group analyses The contrast 2-back − 0-back revealed a widespread network encompassing bilateral posterior parietal cortex including precuneus and inferior parietal lobules (BA 7/40), bilateral premotor cortex (BA
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Table 2 Performances on the neuropsychological tests for patients and healthy volunteers. CPT-IP=Continuous Performance Test-Identical Pairs, SWM=Spatial Working Memory test, ANS=Auditory Number Sequencing, WLM=Word List Memory test, FMT=Face Memory Test, FTT=Finger Tapping Test, STDT=Strategic Target Detection test, S.D.=standard deviation. Domains and tests
CRT patients (n = 8)
Non-CRT patients (n = 9)
Session 1 Mean Attention/vigilancea CPT-IPa D prime Non-verbal working memory SWM Long median Verbal working memory ANS Span Verbal learning and memory WLM First recall WLM Delayed recall Visual learning and memory FMT Immediate recall FMT Delayed recognition Speed of processing FTT Total left FTT Total right Reasoning/problem solvinga STDTa Strategic efficiency STDTa Total errors a
Session 2 S.D.
Session 1
Mean
S.D.
Mean
Session 2 S.D.
Mean
S.D.
4.3
1.8
5.9
1.8
3.7
1.3
3.0
0.7
58.1
20.9
42.4
6.4
62.9
27.5
61.5
24.8
6.9
1.0
7.1
0.8
7.0
1.1
7.4
0.5
8.0 12.5
2.0 3.9
9.1 12.9
2.0 2.9
6.9 11.2
1.8 2.9
6.6 10.3
2.6 3.1
0.8 0.8
0.1 0.1
0.8 0.7
0.1 0.1
0.7 0.6
0.1 0.2
0.8 0.7
0.1 0.1
212 247
39 49
232 262
50 52
239 255
36 53
240 264
44.8 38.4
15,928 21.9
3956 11.9
13,651 12.9
2601 8.1
14,907 19.7
3376 7.8
14,362 19.3
3015 7.3
Improved after CRT.
6/8), bilateral prefrontal cortex (BA 9/10/46), thalamus and cerebellum. At baseline, as previously reported in a larger sample (Bor et al., 2011), the comparison between patients (n = 17) and control (n = 15) revealed hyper-activations for patients compared to controls for the verbal and spatial WM in regions of the thalamus and basal ganglia. Moreover hyperactivations were found for the spatial WM only in the cerebellum and in prefrontal regions. There was no difference between CRT (n = 8) and non-CRT (n = 9) groups.
3.5.2.2. Spatial task (Table 4, Fig. 1). Comparisons between CRT patients with healthy controls, and non-CRT patients with healthy controls did not reveal any significant difference. Between-group contrast [i.e. (CRT Patients session 2 − CRT Patients session 1) − (non-CRT Patients session 2 − non-CRT Patients session 1)] revealed that, compared to non-CRT patients, CRT patients had greater frontal and parietal activation in the left inferior/middle frontal gyrus (Brodmann's area 44/45; Broca's area), cingulate gyrus (Brodmann's area 24) and inferior parietal lobule/precuneus (Brodmann's area 40/2) after CRT during the spatial WM task.
3.5.2. Between-group analysis 3.5.2.1. Verbal task. None of the contrasts between groups of patients (CRT and non-CRT) and healthy controls revealed any statistically significant activation for the verbal task at pcorrected b 0.05.
3.5.3. Within-group analysis There was no difference between the first and second sessions whatever the group (CRT patients, non-CRT patients and healthy controls) at pcorrected b 0.05 for the verbal n-back orr for the spatial n-back.
Table 3 Performance during n-back tasks for schizophrenia patients with cognitive remediation therapy (CRT), non-CRT patients and healthy controls. Performance was comparable across groups whatever the session. Results
fMRI session 1 CRT patients (n = 8) Mean
Performance 0-back Verbal Spatial 2-back Verbal Spatial Reaction time 0-back Verbal Spatial 2-back Verbal Spatial
93.8 94.7 77.5 82.8
518 497 766 676
S.D. 12.6 7.2 12.6 13.7
81 107 210 213
fMRI session 2 Non-CRT patients (n = 9)
Healthy volunteers (n=15)
CRT patients (n = 8)
Mean
Mean
Mean
97.8 94.7 71.7 87.8
520 495 801 626
S.D. 4.9 5.3 14.6 9.6
70 81 191 154
96.7 96.5 83.7 90.2
500 502 704 665
S.D. 6.7 3.5 13.5 10.6
64 75 226 182
95.3 95.0 76.9 85.3
548 518 740 682
S.D. 5.9 5.5 17.1 17.0
105 109 213 174
Non-CRT patients (n = 9)
Healthy volunteers (n=15)
Mean
Mean
99.7 96.9 83.8 89.1
501 488 723 608
S.D. 1.3 3.6 13.4 12.5
56 79 180 163
97.3 95.5 86.8 89.3
503 513 652 628
S.D. 4.9 6.3 15.3 12.2
62 74 131 163
J. Bor et al. / Psychiatry Research: Neuroimaging 192 (2011) 160–166 Table 4 Brain regions that showed significant activations for the contrast (CRT Patients session 2 − CRT Patients session 1)− (non-CRT Patients session 2 − non-CRT Patients session 1) for spatial working memory. Pcorrected b 0.05. L = left. Region of signal change
Brodmann's Nb of Coordinates a area voxels x y z
L inferior/middle 44/45 frontal gyrus L cingulate gyrus 24 L inferior parietal 40/2 lobule/precuneus a b
1006 413 346
− 60
Cluster Z corrected p score
14 24 b0.001
− 34 − 8 24 − 22 − 48 44
0.011 0.027
b
4.66 4.5 3.58
MNI coordinates. Z-score of the local maximal F value in each cluster.
4. Discussion At the first level (2-back minus 0-back), contrasts revealed the widespread network already described by a meta-analysis that who analysed coordinates of 24 studies of n-back tasks (Owen et al., 2005). As expected, after CRT we observed different brain activations between CRT and non-CRT patients during a spatial and a verbal WM task. During the spatial WM, we reported that after therapy CRT patients showed over-activation within the left ventrolateral prefrontal cortex (Broca's area), the left anterior cingulate cortex and left parietal areas. This over-activation was associated with an improvement in attention/vigilance and reasoning/problem solving cognitive tasks. A positive correlation was found between activations in BA 44/ 45 and performances on the CPT-IP (R2 = 0.56) in CRT patients only. However, we reported neither correlation in the non-CRT group nor correlations with the STDT task. The same contrast for the verbal task did not reveal any significant activation. However, activations were found in the same areas as for the spatial task in terms of the number of activated voxels and the extent of the clusters, but did not reach significance (p = 0.08), probably due to a lack of power. Few authors have investigated the impact of CRT on brain activations in patients with schizophrenia. Our results corroborate their reports of activation in frontal cortex during a WM task after CRT (Penades et al., 2002; Wykes et al., 2002). Moreover, we also reported an activation of Broca's area (Brodmann's area 44/45). The increase in activation of Broca's area during the second scan in the CRT group could be explained by the use of language function by patients. Indeed, language function could be used to name the positions of the white circles during the spatial 2-back instead of a passive remembering of the positions (from a real spatial task to a verbal task using “Right, Left, Up, Down” words as stimuli). CRT consists in encouraging participants to adopt an organised approach to diverse tasks and particularly to increase the use of specific information processing strategies. This could imply that CRT permits to CRT patients to change their strategy from a spatial task to an easier verbal task when this strategic change is not possible in the verbal memory task. Indeed, Smith and Jonides (1998) have suggested that the left parietal cortex subserves the storage component of working memory and that left hemisphere speech areas subserve rehearsal. The use of a spatial memory task in which the verbal encoding of stimuli is not possible could help to confirm this hypothesis. Strong improvements in reasoning and attention could be attributed to CRT as the patients were hardly trained in those functions with other tasks in the CRT. However, we did not observe any effect of CRT on memory as in a recent meta-analysis (McGurk et al., 2007). This is in accordance with the hypothesis that fMRI modifications are more due to a strategic change than a memory improvement. This strategy change in association with CRT was also found in the study of Wykes (1998): in this study, changes in strategy during the performance of a verbal fluency task were associated with changes in brain activations identified by SPECT and these strategy changes produced gains on other neuropsychological tests.
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To confirm our results, further studies are needed. For example, it would be interesting to study the outcomes of healthy volunteers with/without CRT and compare psychological assessments and fMRI data between schizophrenic patients and healthy volunteers with/ without CRT. A second important study would be to compare fMRI data in patients with and without improvement of cognitive ability in the CRT group and/or to compare the effect of CRT in patients with/ without cognitive impairments. Before we conclude that CRT was responsible for the observed variations in brain activation during the spatial WM task, we have to exclude some limitations. Indeed, age, gender, education, medication, illness duration and clinical characteristics of participants could influence performances in WM tasks. However, there was no difference between groups for those variables in our sample. Moreover, differences in activation could also be explained by task difficulty level but, due to the training of participants until 80% accuracy, performances on the 2back task were not different between groups and sessions. This training before CRT in all participants may also facilitate cognitive task performance in patients with schizophrenia by changing the dynamics of activity within critical control-related brain regions (Edwards et al., 2010). However, this late effect could not explain observed difference post-CRT. In the present study we demonstrated that cerebral functioning can be modified by psychological treatment. It remains to be seen whether such improvements in brain functions are sustained after many months or if a maintenance therapy is required. The research community has now amassed enough evidence that psychological therapy changes cognition in schizophrenia, and with evidence of accompanying brain changes, we now have further hope of alleviating some of the misery associated with this disorder. One can hypothesize that neuroplasticity could be implied in observed fMRI brain modifications. Conflict of interest All authors report no competing interests. Acknowledgments This work was done in “Le Vinatier” hospital, 95 Boulevard Pinel, 69677 Bron cedex, France and in the “CERMEP-Imagerie du vivant” imaging centre, 59 Boulevard Pinel, 69677 Bron cedex, France. References Bor, J., Brunelin, J., Sappey-Marinier, D., Ibarrola, D., Suaud-Chagny, M.F., D'Amato, T., Saoud, M., 2011. Thalamus abnormalities during working memory in schizophrenia. An fMRI study. Schizophrenia Research 125 (1), 49–53. Cochet, A., Saoud, M., Gabriele, S., Broallier, V., El Asmar, C., Dalery, J., D'Amato, T., 2006. Impact of a new cognitive remediation strategy on interpersonal problem solving skills and social autonomy in schizophrenia. L'Encéphale 32 (2 Pt 1), 189–195. d'Amato, T., Bation, R., Cochet, A., Jalenques, I., Galland, F., Giraud-Baro, E., PacaudTroncin, M., Augier-Astolfi, F., Llorca, P.M., Saoud, M., Brunelin, J., 2010. A randomized, controlled trial of computer-assisted cognitive remediation for schizophrenia. Schizophrenia Research 125 (2–3), 284–290. Edwards, B.G., Barch, D.M., Braver, T.S., 2010. Improving prefrontal cortex function in schizophrenia through focused training of cognitive control. Frontiers in Human Neuroscience 4, 32. Green, M.F., 2006. Cognitive impairment and functional outcome in schizophrenia and bipolar disorder. The Journal of Clinical Psychiatry 67 (Suppl 9), 3–8 discussion 36–42. Karlsgodt, K.H., Sanz, J., van Erp, T.G., Bearden, C.E., Nuechterlein, K.H., Cannon, T.D., 2009. Re-evaluating dorsolateral prefrontal cortex activation during working memory in schizophrenia. Schizophrenia Research 108 (1–3), 143–150. Kern, R.S., Glynn, S.M., Horan, W.P., Marder, S.R., 2009. Psychosocial treatments to promote functional recovery in schizophrenia. Schizophrenia Bulletin 35 (2), 347–361. McGurk, S.R., Mueser, K.T., 2004. Cognitive functioning, symptoms, and work in supported employment: a review and heuristic model. Schizophrenia Research 70 (2–3), 147–173. McGurk, S.R., Twamley, E.W., Sitzer, D.I., McHugo, G.J., Mueser, K.T., 2007. A meta-analysis of cognitive remediation in schizophrenia. The American Journal of Psychiatry 164 (12), 1791–1802.
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