SCHRES-06696; No of Pages 9 Schizophrenia Research xxx (2015) xxx–xxx

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The association between cognitive deficits and prefrontal hemodynamic responses during performance of working memory task in patients with schizophrenia Shenghong Pu a,⁎, Kazuyuki Nakagome b, Masashi Itakura a, Masaaki Iwata a, Izumi Nagata a, Koichi Kaneko a a b

Division of Neuropsychiatry, Department of Brain and Neuroscience, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago, Tottori, Japan National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, Japan

a r t i c l e

i n f o

Article history: Received 23 October 2015 Received in revised form 23 January 2016 Accepted 25 January 2016 Available online xxxx Keywords: Near-infrared spectroscopy (NIRS) Working memory task Prefrontal cortex Brief Assessment of Cognition in Schizophrenia

a b s t r a c t Schizophrenia-associated cognitive deficits are resistant to treatment and thus pose a lifelong burden. The Brief Assessment of Cognition in Schizophrenia (BACS) provides reliable and valid assessments across cognitive domains. However, because the prefrontal functional abnormalities specifically associated with the level of cognitive deficits in schizophrenia have not been examined, we explored this relationship. Patients with schizophrenia (N = 87) and matched healthy controls (N = 50) participated in the study. Using near-infrared spectroscopy (NIRS), we measured the hemodynamic responses in the prefrontal and superior temporal cortical surface areas during a working memory task. Correlation analyses revealed a relationship between the hemodynamics and the BACS composite and domain scores. Hemodynamic responses of the left dorsolateral prefrontal cortex (DLPFC) and left frontopolar cortex (FPC) in the higher-level-of-cognitive-function schizophrenia group were weaker than the responses of the controls but similar to those of the lower-level-of-cognitive-function schizophrenia group. However, hemodynamic responses in the right DLPFC, bilateral ventrolateral PFC (VLPFC), and right temporal regions decreased with increasing cognitive deficits. In addition, the hemodynamic response correlated positively with the level of cognitive function (BACS composite scores) in the right DLPFC, bilateral VLPFC, right FPC, and bilateral temporal regions in schizophrenia. The correlation was driven by all BACS domains. Our results suggest that the linked functional deficits in the right DLPFC, bilateral VLPFC, right FPC, and bilateral temporal regions may be related to BACS-measured cognitive impairments in schizophrenia and show that linking the neurocognitive deficits and brain abnormalities can increase our understanding of schizophrenia pathophysiology. © 2016 Elsevier B.V. All rights reserved.

1. Introduction Schizophrenia is associated with deficits in multiple cognitive domains, including selective and sustained attention, working memory, episodic memory, processing speed, executive function, and social cognition (Green et al., 2004). Because of the lack of effective treatments for these deficits, schizophrenia often continues to exact a devastating toll, with 80% of patients remaining unemployed and less than 30% living independently (Torrey, 2006). In order to advance the development of therapies aimed at ameliorating the cognitive deficits in schizophrenia, biomarkers must be identified that can be used to determine whether therapeutic candidates elicit the targeted biological effects. In neuropsychiatric research, a biomarker is an indicator of neuronal function — hypothesized to be related ⁎ Corresponding author at: Division of Neuropsychiatry, Department of Brain and Neuroscience, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago, Tottori 683-8504, Japan. E-mail address: [email protected] (S. Pu).

to disease mechanisms — that can serve as an immediate and objective measure of the biological effects of therapeutic candidates (Tregellas et al., 2014). Impairments in working memory and other cognitive functions are cardinal neuropsychological symptoms in schizophrenia, and the prefrontal cortex (PFC) is important for mediating and executing these functions (Badre and D'Esposito, 2009; D'Esposito et al., 1995; Senkowski and Gallinat, 2015; Takizawa et al., 2008). The cognitive impairment associated with schizophrenia stems mainly from abnormalities of the PFC (Green et al., 2004), as supported by the results of functional magnetic resonance imaging (fMRI) studies performed during neurocognitive tasks (Minzenberg et al., 2009; Senkowski and Gallinat, 2015). Previous studies using the n-back neurocognitive assessment task, which is a well-known working memory task, have indicated that patients with schizophrenia have decreased dorsolateral prefrontal cortex (DLPFC) activation (Callicott et al., 2003; Callicott et al., 2000; Jansma et al., 2004; Perlstein et al., 2001; Schneider et al., 2007). On the other hand, other studies have shown that patients with schizophrenia have greater PFC activation compared with healthy

http://dx.doi.org/10.1016/j.schres.2016.01.045 0920-9964/© 2016 Elsevier B.V. All rights reserved.

Please cite this article as: Pu, S., et al., The association between cognitive deficits and prefrontal hemodynamic responses during performance of working memory task in patie..., Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2016.01.045

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controls (HCs), suggesting that the relationship between PFC activation and neuronal function follows an inverted U-curve activity pattern (Callicott et al., 2003; Jansma et al., 2004; Potkin et al., 2009), or a compensatory response using preserved functions (Callicott et al., 2003; Minzenberg et al., 2009; Potkin et al., 2009; Schneider et al., 2007). Therefore, working memory impairment may result from reduced function in specific brain regions related to a given cognitive task (Lett et al., 2014). Elucidating the relationship between working memory-related PFC neural activity and cognitive ability could help clarify the mechanism(s) of cognitive impairment. The Brief Assessment of Cognition in Schizophrenia (BACS) (Keefe et al., 2004) is an instrument used to evaluate the elements of cognition that are most commonly impaired and strongly connected with everyday functioning in patients with schizophrenia (Keefe et al., 2006). The BACS includes five cognitive domains (verbal memory, working memory, motor speed, verbal fluency, attention and speed of information processing, and executive function) and can be administered by a wide range of mental health professionals. Despite the battery's comprehensive nature, high test–retest reliability, predictive value, relationship to functional outcome, and utility in clinical trials (Kaneda et al., 2007; Keefe et al., 2006, 2008; Melau et al., 2015), to our knowledge, no study has reported an association between BACS scores and brain function in schizophrenia. Understanding the brain abnormalities related to BACS performance may allow imaging assessments to help accelerate the development of new therapies. In our previous pilot study (Pu et al., 2014), we investigated the effects of a cognitive remediation therapy on neurocognitive functioning assessed by BACS and on working memory-related PFC neural activity using 52-channel near-infrared spectroscopy (NIRS). The cognitive remediation therapy group, in comparison with the control group, showed significant improvement on the BACS and a significant increase in brain activation in the right frontopolar area, which is associated with working memory, in comparison with the control group. In addition, the amount of enhancement in cognitive subcomponents such as verbal memory and verbal fluency was positively correlated with the magnitude of the increase in the hemodynamic response during the working memory task predominantly in the right hemisphere. These findings suggest that NIRS may be a useful tool for assessing the changes in neural activity that underlie the neurocognitive functioning improvements elicited by neurocognitive rehabilitation. However, the relationship between the working memory-related PFC neural activity and neurocognitive functioning is not yet clear. Our goals in the present study were to test the hypotheses that (1) relative to healthy subjects, patients with schizophrenia have detectable abnormalities in working memory-related PFC neural activity, as measured using multi-channel NIRS imaging, and (2) this neural activity is related to cognitive ability, in particular the working memory or verbal memory and verbal fluency cognitive domains, as the improvement in these subcomponents in BACS was associated with increase in the hemodynamic response caused by cognitive remediation therapy in our previous study (Pu et al., 2014). Findings supporting these hypotheses would suggest that working memory-related PFC neural activity may be a useful biomarker for therapeutic development. 2. Material and methods 2.1. Participants See Table 1 for experimental and control participant information. The participants in the schizophrenia patient group (N = 87; n = 37, male; n = 50, female) were diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV, American Psychiatric Association, 1994), using the Mini-International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998). Members of the schizophrenia group were receiving antipsychotic medication (n = 7, typical; n = 80, atypical). Daily doses of all antipsychotics

were converted to the equivalent dose of chlorpromazine (Inagaki and Inada, 2006). The patients were recruited from both outpatient and inpatient services at the Tottori University Hospital. On the day of the NIRS experiment, psychiatric symptoms and global functioning were evaluated by the same psychiatrists (I.N., and K.K.) using the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) and the Global Assessment of Functioning (GAF) Scale, respectively. Whereas approximately 15% of patients with schizophrenia remain within the normal range on almost all aspects of cognitive function, most patients score 1–1.5 standard deviations (SD) lower on cognitive function assessments than healthy individuals (Bilder et al., 2000; Heinrichs, 2004). To elucidate the effect of cognitive functioning on the cortical activity, participants with schizophrenia were subdivided into two groups according to the BACS composite scores (N− 1 for lower level and ≤−1 for higher level). The BACS composite score ranges were largely overlapping between the higher-level-of-cognitive-function group and HCs (BACS composite score ranges: lower-level-of-cognitive-function group: − 3.592 to − 1.026, higher-level-of-cognitive-function group: − 0.993 to 1.011, HCs: − 0.827 to 1.149). Thus we can make a rough estimate about the differential effect of cognitive functioning and disease per se on the cortical activity through comparison among the three groups. Patients with comorbid neurological illness, previous traumatic brain injury with any known cognitive consequences or loss of consciousness for more than 5 min, a history of electroconvulsive therapy, or alcohol/substance abuse or addiction (except nicotine) were excluded. HCs matched to the patients with respect to age, gender, and premorbid intelligence quotient (IQ) participated in the present study as controls. Premorbid IQ was estimated using the Japanese version of the National Adult Reading Test (Matsuoka et al., 2006). Inclusion criteria for controls were similar to those for the patient sample, although controls were also required to have no previous or current psychiatric illnesses. Individuals (N = 50; n = 20, male; n = 30, female) meeting these criteria were selected to participate in the study. All participants were native Japanese speakers. All participants gave informed written consent. The study was approved by the Ethics Committee of Tottori University Faculty of Medicine (approval No.885), and the investigation was conducted in accordance with the latest version of the Declaration of Helsinki. 2.2. NIRS methodology A 52-channel NIRS (ETG-4000, Hitachi Medical Co.) machine was used to measure changes in the hemoglobin concentration. The NIRS probe comprised 3 × 11 arrays with 17 emitters and 16 detectors. The NIRS probe machines were placed on the frontotemporal region of each participant, with the midcolumn of the probe located over Fpz and the lowest probes located along the T3–Fp1–Fpz–Fp2–T4 line, in accordance with the International 10–20 System used in electroencephalography. The distance between pairs of source-detector probes was set at 3 cm, and each measurement area between pairs of sourcedetector probes was defined as a “channel” (ch). The machine measures points at a depth of 2 to 3 cm below the scalp, which corresponds well with the surface of the cerebral cortex (Okada and Delpy, 2003; Toronov et al., 2001). The correspondence between the NIRS channels and cortical anatomy has been confirmed in a multi-subject study (Okamoto et al., 2004). Spatial information from each channel was estimated using functions from the Functional Brain Science Laboratory at Jichi Medical University in Japan (http://www.jichi.ac.jp/brainlab/ virtual_reg.html) (Tsuzuki et al., 2007). NIRS measures changes in both oxygenated hemoglobin (oxy-Hb) and deoxygenated hemoglobin (deoxy-Hb) at two wavelengths (695 and 830 nm) of infrared light, based on the modified Beer–Lambert law (Yamashita et al., 1996). We could not measure the absolute path length from the scalp to the cerebral cortex; therefore, we recorded

Please cite this article as: Pu, S., et al., The association between cognitive deficits and prefrontal hemodynamic responses during performance of working memory task in patie..., Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2016.01.045

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Table 1 Demographics and clinical characteristics of participants.

n (women/men)a Age (years) b Estimated premorbid IQ b Edinburgh handedness inventory (%) b PANSS Positive Negative General psychopathology GAF BACS verbal memory b Working memory b Motor speed b Verbal fluency b Attention and speed of information processing b Executive function b Composite score b Age at onset (years) c Duration of illness (years) c Chlorpromazine equivalent dose (mg/day) c Task performance (0-back): Reaction time (ms) d Sensitivity A′ d (2-back): Reaction time (ms) d Sensitivity A′ d

Schizophrenia patients lower level of cognitive function group (mean ± SD)

Schizophrenia patients Higher level of cognitive function group (mean ± SD)

Healthy controls (mean ± SD)

p value

F value

49 (24:25) 33.1 ± 11.0 98.5 ± 8.0 91.3 ± 17.6 16.6 ± 7.3 18.6 ± 5.2 31.6 ± 7.3 53.0 ± 9.8 −1.941 ± 0.833 −1.628 ± 0.798 −2.474 ± 1.191 −1.128 ± 0.639 −1.798 ± 0.718 −1.364 ± 1.759 −1.722 ± 0.598 23.3 ± 7.7 9.8 ± 9.2 587.5 ± 370.9 636.2 ± 176.4 0.988 ± 0.029 802.5 ± 218.8 0.914 ± 0.163

38 (26:12) 34.1 ± 8.7 99.9 ± 7.1 96.3 ± 10.0 14.0 ± 4.2 16.1 ± 4.1 31.9 ± 6.5 60.3 ± 10.2 −0.464 ± 0.854 −0.383 ± 0.851 −0.882 ± 1.336 −0.243 ± 0.758 −0.733 ± 0.623 0.156 ± 0.763 −0.425 ± 0.423 23.3 ± 6.8 10.9 ± 6.4 559.1 ± 322.2 552.4 ± 98.5 0.996 ± 0.019 709.5 ± 211.7 0.975 ± 0.072

50 (30:20) 34.4 ± 10.8 101.5 ± 9.6 93.3 ± 12.1 – – – – 0.062 ± 0.774 0.125 ± 0.965 0.057 ± 0.909 0.394 ± 0.817 0.353 ± 0.798 0.350 ± 0.849 0.224 ± 0.504 – – – 511.5 ± 85.7 1.000 ± 0.000 627.5 ± 170.7 0.985 ± 0.043

0.181 0.824 0.194 0.262 0.057 0.018 e 0.824 0.001 f b0.001g b0.001g b0.001g b0.001g b0.001g b0.001g b0.001g 0.854 0.134 0.773 b0.001h b0.005i b0.001i b0.001i

X2 = 3.41 0.19 1.66 1.35

78.69 51.77 61.89 52.64 109.13 27.56 178.08

X2 = 16.14 X2 = 8.17 X2 = 20.27 X2 = 18.16

Note: PANSS, Positive and Negative Symptom Scale; GAF, Global Assessment of Functioning scale; and BACS, Brief Assessment of Cognition in Schizophrenia. Significant group differences are shown to the right. Otherwise, t-tests were used. p b 0.05 was considered significant. a Chi-square test. b One-way ANOVA and post hoc Gams–Howell tests. c Mann–Whitney U test. d Kruskal–Wallis test were used for testing group differences. e Lower level of cognitive function group N higher level of cognitive function group. f Lower level of cognitive function group b higher level of cognitive function group. g Lower level of cognitive function group b higher level of cognitive function group b healthy controls. h Lower level of cognitive function group, higher level of cognitive function group N healthy controls. i Lower level of cognitive function group b higher level of cognitive function group, healthy controls.

the hemoglobin concentrations from baseline to the activation periods. Relative changes in the hemoglobin concentration are indicated by mM·mm. The sampling frequency was 10 Hz. We determined changes in the task-related signal by calculating a linear fit to two baseline periods that included the last 10-s period (pre-task baseline) of the pre-task period, and the 5-s period (post-task baseline) after the 50-s post-task period (Fig. 1). A moving-average method, using a 5-s window, was applied to remove any short-term motion artifacts. In addition, we rejected noise related to body-movement artifacts (no signal, high frequency, and low frequency) using the algorithm published in Takizawa et al. (2008). 2.3. Working memory task We used a 2-back task with a blocked periodic baseline–activation– baseline design to activate brain regions specialized for the maintenance and manipulation components of verbal working memory, as originally described by Cohen et al. (1994). Subjects were presented with two visually contrasting conditions in 60-s periods on a computer screen that was placed approximately 1 m away from the subjects' eyes. The working memory task consisted of a 60-s pre-task period, a 60-s 2back task period, and a 60-s post-task period (one 180-s block, Fig. 1). During the pre- and post-task period, subjects viewed a series of numbers (0–9) presented one at a time, and were required to press a button with their right index finger whenever the number “9” appeared (0-back). During the 60-s task period, subjects again viewed a series of numbers (0–9), and were required to press a button with their right index finger if the currently presented number was the same as that presented two trials previously (2-back). Each period consisted of 25 stimuli (5 targets, stimulus duration = 1.8 s, stimulus onset asynchrony = 2.3 s). Behavioral performance for the 2-back task was

monitored and measured in terms of reaction time (RT) to target figures and sensitivity A′ (Grier, 1971). Sensitivity A′ is an index of information processing ability that uses both a “hit rate” (HR) and “false alarm rate” (FAR) and is calculated as follows: A ′ = 0.5 + (HR − FAR) (1+ HR− FAR)/4HR (1− FAR). A high A′ implies high information processing ability. All subjects received a brief period of identical training to ensure that they understood the rules of the task prior to measurement. 2.4. The BACS We assessed cognitive function by using Japanese version of the BACS (Kaneda et al., 2007; Keefe et al., 2004). The BACS evaluation included tests such as the List Learning Test, Digit Sequencing Task, Token Motor Task, Category Instances Test, Controlled Oral World Association Test, Symbol Coding, and Tower of London Test, which measure verbal memory, working memory, motor speed, verbal fluency, attention and speed of information processing, and executive function. All study participants were administered the BACS. Z-scores were calculated for each subcomponent score using means and SDs based on the dataset of 340 Japanese HCs (Kaneda et al., 2007). Composite scores were calculated by averaging all z-scores of the six subcomponents [composite score = (verbal memory z-score + working memory z-score + motor speed z-score + verbal fluency z-score + attention and speed of information processing z-score + executive functions z-score) / 6], and higher scores reflected higher cognitive function. The BACS and NIRS experiment were administered on the same day. 2.5. Statistical analyses Statistical analyses were performed using SPSS Statistics 19.0 (Tokyo, Japan).

Please cite this article as: Pu, S., et al., The association between cognitive deficits and prefrontal hemodynamic responses during performance of working memory task in patie..., Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2016.01.045

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Fig. 1. The working memory task paradigm and the task segments used for statistical analysis in the near-infrared spectroscopy (NIRS) measurements.

Categorical variables were compared using the chi-square test. In all groups, the clinical variables that fit the normal distribution were compared using t-tests and one-way analyses of variance (ANOVAs), while the Mann–Whitney U test and Kruskal–Wallis nonparametric ANOVA were used for clinical variables that were not normally distributed. We tested the difference from the pre-task baseline to the task period in the HCs using t-tests for every channel. Since we performed 52 t-tests for each channel, we adopted the false discovery rate (FDR) method to correct multiple comparisons. We set the value of q, specifying the maximum FDR, to 0.05, so that no more than 5% of channels were falsely positive on average (Benjamini et al., 2001; Singh and Dan, 2006; Tomioka et al., 2015). When there was a significant between-group difference in the performance level (RT and sensitivity A′), we performed additional analyses of co-variance (ANCOVA) using the performance level (RT and sensitivity A′) as a covariate to the oxyHb changes. First, mean oxy-Hb changes during the task period were compared between patients with schizophrenia and HCs using Student's t-test for each channel, adopting the FDR method. In addition, we performed an additional one-way ANOVA comparing among three groups, which are lower-level-of-cognitive-function and higher-levelof-cognitive-function groups of schizophrenia, and HCs to explore the effect of cognitive function among the groups. Post-hoc Gams–Howell tests were performed on these significant channels. Moreover, we used multiple regression analyses and included the BACS scores and group (dummy parameterized, schizophrenia = 1, HCs = 0) as independent variables. Finally, to examine the relationships between the mean oxy-Hb changes and cognitive function (composite scores and subcomponents z-scores) in the schizophrenia group, we calculated Pearson correlation coefficients, adopting the FDR method. In addition, to elucidate the independent contributions of cognitive function to the mean oxy-Hb changes in the channels that showed significant correlations, we performed stepwise multiple regression analyses for the schizophrenia group. In these analyses, the mean oxy-Hb change was the dependent variable, and we controlled for other potential confounding variables such as age, gender (dummy parameterized, male = 1, female = 0), premorbid IQ, task performance on the 2-back (RT and Sensitivity A′), GAF score, PANSS score, and daily dosage of antipsychotic drugs (Chou et al., 2014; Koike et al., 2011; Takizawa et al., 2009) in the analyses of the schizophrenia group, with a probability of F for conservative entry and removal criteria of 0.05 and 0.2, respectively. For significant findings, effect sizes were indicated using the standardized regression coefficient (β).

3. Results 3.1. Demographic and clinical backgrounds Table 1 summarizes the demographic and clinical characteristic of the study groups. There was a significant difference between the lower-level-of-cognitive-function schizophrenia and higherlevel-of-cognitive-function schizophrenia groups for the GAF (p = 0.001; t-test) and negative score (PANSS) (p = 0.018; t-test), while no difference was observed between the groups for the positive and general psychopathology scores (PANSS) (p N 0.05; t-test). 3.2. Task performance A significant difference between groups was observed in the response sensitivity A′ (0-back: Kruskal–Wallis X2 = 8.17, p b 0.005; 2-back: Kruskal–Wallis X2 = 18.16, p b 0.001) and RT (0-back: Kruskal–Wallis X2 = 16.14, p b 0.001; 2-back: Kruskal–Wallis X2 = 20.27, p b 0.001) on the working memory task during NIRS measurement (Table 1). That performance (sensitivity A′ and RT) in the higher-level-of-cognitive-function schizophrenia group was not significantly different from that of HCs (0-back: RT: p ≤ 0.012, sensitivity A′: p ≥ 0.05; 2-back: RT: p ≥ 0.05, sensitivity A′: p ≥ 0.05), whereas the lower-level-of-cognitive-function schizophrenia group significantly differed from both the higher-level-of-cognitive-function schizophrenia group (0-back: RT: p ≥ 0.05, sensitivity A′: p = 0.030; 2-back: RT: p = 0.030; sensitivity A′: p = 0.003) and HCs (0-back: RT: p ≤ 0.001, sensitivity A′: p ≤ 0.001; 2-back: RT: p ≤ 0.001, sensitivity A′: p ≤ 0.001), particularly during the 2-back task. 3.3. Mean oxy-Hb changes during the task period From the pre-task baseline to the task period, the HCs showed significantly increased activation in 49 channels (except ch4 to ch6; FDRcorrected p b 0.047). Patients with schizophrenia group exhibited significantly smaller increases in the mean oxy-Hb during the working memory task than did HCs in 43 channels (ch2, ch6 to ch10, ch12, ch14, ch16 to ch25, and ch28 to ch52; FDR-corrected p ≤ 0.041), which were predominantly in the DLPFC, VLPFC, frontopolar cortex (FPC), and temporal regions. The differences in the mean oxy-Hb changes between the two study groups (schizophrenia vs. HCs) remained significant after correcting for performance levels in 40 channels (ch6,

Please cite this article as: Pu, S., et al., The association between cognitive deficits and prefrontal hemodynamic responses during performance of working memory task in patie..., Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2016.01.045

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ch7, ch9, ch10, ch12, ch14, ch16 to 23, ch25, ch28 to ch52; FDRcorrected p ≤ 0.038) with an ANCOVA using RT and sensitivity A′ as a covariate to the mean oxy-Hb changes. In 42 channels, an ANOVA revealed significant differences among the three study groups in terms of the changes in the mean oxy-Hb during the working memory task (ch2, ch5, ch9, ch10, ch12 to ch25, ch28 to ch36, and ch38 to ch52; FDR-corrected p b 0.040). The channels were in the DLPFC, VLPFC, part of the FPC, and temporal regions. The differences in the mean oxy-Hb changes among the three study groups remained significant after correcting for performance levels in 30 channels (ch12, ch14, ch15, ch17, ch18, ch20, ch22, ch23, ch25, ch28 to ch30, ch32 to ch36, ch38 to ch47, and ch49 to 51; FDR-corrected p b 0.029) with an ANCOVA using RT and sensitivity A′ as a covariate to the mean oxy-Hb changes. The post-hoc analysis (Fig. 2) indicated that in 29 channels (ch12, ch14, ch17, ch18, ch20, ch22, ch23, ch25, ch28 to ch30, ch32 to ch36, ch38 to ch47, and ch49 to 51) in the PFC (all subregions mentioned above) and temporal regions, the increase in mean oxy-Hb changes induced by the working memory task was significantly smaller in the lower-level-of-cognitive-function group than in HCs (Fig. 2A). The post-hoc analysis also showed that in four channels (ch29, ch39, ch49, and 50) in the left DLPFC and left FPC regions, the increase in the mean oxy-Hb changes induced by the working memory task was significantly smaller in the higher-level-of-cognitive-function group than it was in HCs (Fig. 2B). Moreover, in 10 channels (ch12, ch20, ch32 to ch35, ch40, and ch43 to ch45) in the right DLPFC, bilateral VLPFC, and right temporal regions, the increase in the mean oxy-Hb changes was significantly smaller in the lower-level-of-cognitive-function group than it was in the higher-level-of-cognitive-function group (Fig. 2C).

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Among all 52 channels, multiple regression analyses revealed significant contributions of group (schizophrenia and HCs) in 19 channels (ch2, ch6 to ch8, ch10, ch17 to ch19, ch28, ch29, ch37 to ch40, and ch46 to ch50) in the FPC, left DLPFC, and left VLPFC when the BACS composite score was used as a confounding factor. Significant contributions were found for the BACS composite score in 29 channels (ch4, ch9, ch12 to 16, ch20 to ch25, ch30 to ch36, ch40 to ch45, and ch50 to ch52) in the right DLPFC, bilateral VLPFC, right FPC, and bilateral temporal regions when the group (schizophrenia and HCs) was used as a confounding factor, as shown in Table 2. 3.4. Correlational analyses of oxy-Hb changes and cognitive function In patients with schizophrenia, the mean oxy-Hb change showed a significant positive correlation with the BACS composite scores in 23 channels (ch12, ch13, ch15, ch20, ch22 to ch24, ch30 to ch36, ch40 to ch45, and ch50 to ch52; R = 0.288 to 0.478; FDR-corrected p b 0.022, Fig. 3) in the right DLPFC, bilateral VLPFC, right FPC, and bilateral temporal regions. Among those 23 channels, where there were significant correlations with the BACS composite scores in the schizophrenia group; multiple regression analyses revealed significant contributions of the BACS composite scores in all channels (β = 0.300 to 0.501; p b 0.05), among other confounding factors (Table 3). Age and GAF score did not significantly contribute to brain cortical activity. Significant contributions were found for general psychopathology (PANSS) in 13 channels (ch20, ch23, ch30 to ch34, ch41, ch43, ch44, ch45, ch51, and ch52), sensitivity A′ (performance on the 2-back task) in one channel (ch45), premorbid

Fig. 2. Three-dimensional topographic maps of the mean oxy-Hb changes in the prefrontal cortex sub-regions. Study groups were patients with schizophrenia with high and low levels of cognitive function and healthy controls (HCs). The brain area in yellow corresponds to the NIRS channels with significantly smaller mean oxy-Hb changes in the higher-level-of-cognitivefunction patients with schizophrenia than in the HCs (A), those in the lower-level-of-cognitive-function patients with schizophrenia vs. HCs (B), and those in the higher level vs. lower level of cognitive function patients with schizophrenia (C).

Please cite this article as: Pu, S., et al., The association between cognitive deficits and prefrontal hemodynamic responses during performance of working memory task in patie..., Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2016.01.045

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Table 2 Summary of the multiple regression analysis for brain activation with both BACS composite scores and group (schizophrenia and HCs). No. of channelsa,b

R2

Adjusted R2

Independent variables Group

Ch1 Ch2 Ch3 Ch4 Ch5 Ch6 Ch7 Ch8 Ch9 Ch10 Ch11 Ch12 Ch13 Ch14 Ch15 Ch16 Ch17 Ch18 Ch19 Ch20 Ch21 Ch22 Ch23 Ch24 Ch25 Ch26 Ch27 Ch28 Ch29 Ch30 Ch31 Ch32 Ch33 Ch34 Ch35 Ch36 Ch37 Ch38 Ch39 Ch40 Ch41 Ch42 Ch43 Ch44 Ch45 Ch46 Ch47 Ch48 Ch49 Ch50 Ch51 Ch52

0.040

0.032

0.032

0.024

0.038 0.041 0.038 0.073 0.094

0.030 0.033 0.030 0.066 0.086

0.208 0.095 0.075 0.078 0.059 0.079 0.093 0.069 0.198 0.060 0.217 0.220 0.140 0.078

0.202 0.088 0.068 0.071 0.052 0.072 0.086 0.062 0.192 0.052 0.210 0.213 0.133 0.071

0.140 0.192 0.178 0.128 0.216 0.255 0.219 0.177 0.126 0.036 0.136 0.190 0.228 0.198 0.146 0.245 0.243 0.228 0.125 0.088 0.092 0.183 0.236 0.227 0.146

0.133 0.186 0.172 0.121 0.210 0.249 0.213 0.171 0.119 0.029 0.130 0.184 0.216 0.192 0.140 0.239 0.237 0.223 0.119 0.081 0.085 0.177 0.225 0.221 0.139

BACS composite scores

β

p

−0.199

0.025

−0.196 −0.203 −0.195

0.028 0.024 0.026

−0.307

0.001

−0.281 −0.305 −0.263

−0.374 −0.438

β

p

0.179

0.046

4. Discussion 0.270

0.002

0.457 0.308 0.274 0.279 0.242

0.000 0.000 0.001 0.001 0.005

0.445 0.244 0.465 0.469 0.374 0.279

0.000 0.007 0.000 0.000 0.000 0.001

0.422 0.358 0.465 0.505 0.468 0.421 0.354

0.000 0.000 0.000 0.000 0.000 0.000 0.000

0.310 0.445 0.382 0.495 0.493 0.478

0.003 0.000 0.000 0.000 0.000 0.000

0.251 0.476 0.382

0.016 0.000 0.000

0.001 0.000 0.002

0.000 0.000

−0.190 −0.369 −0.436 −0.211

0.028 0.000 0.000 0.045

−0.354 −0.296 −0.303 −0.428 −0.279

0.000 0.001 0.000 0.000 0.007

to ch35, ch40, ch41, ch43 to ch46, and ch50; R = 0.275 to 0.474; FDR-corrected p b 0.014; VLPFC, right DLPFC, and right temporal regions), motor speed (16 channels: ch20, ch23, ch30 to ch34, ch40 to ch45, and ch50 to ch52; R = 0.308 to 0.489; FDR-corrected p b 0.015; VLPFC, and temporal regions), verbal fluency (30 channels: ch4, ch12 to ch15, ch17, ch19, ch20, ch22 to ch25, ch28 to ch36, ch39 to ch41, ch43 to ch45, and ch50 to ch52; R = 0.238 to 0.499; FDR-corrected p b 0.029; VLPFC, DLPFC, part of the FPC, and temporal regions), attention and speed of information processing (2 channels: ch20 and ch31; R = 0.351 to 0.364; FDR-corrected p b 0.002; left temporal region), and executive function (1 channel: ch15; R = 0.360; FDR-corrected p b 0.001; DLPFC).

Note: BACS, Brief Assessment of Cognition in Schizophrenia; HCs, healthy controls; No., number; and Ch, channels. a Group and BACS composite scores were included in the multiple linear regression analysis. b Group and BACS composite scores did not show significant contributions to the brain activation in ch1, ch3, ch5, ch11, ch26, or ch27.

IQ in one channel (ch15), daily dosage of antipsychotic drugs in one channel (ch35), and gender in one channel (ch31), as shown in Table 3. Moreover, in patients with schizophrenia, the mean oxy-Hb change was positively correlated with all of the BACS domains: verbal memory (3 channels: ch12, ch30, and ch51; R = 0.318 to 0.341; FDR-corrected p b 0.003; VLPFC), working memory (15 channels: ch20, ch22, ch30

Our results show that the working memory-related hemodynamic responses over the PFC surface decreased according to the level of cognitive deficits in schizophrenia. The hemodynamic responses in the higher-level-of-cognitive-function schizophrenia group were weaker than the responses of the HCs but were not significantly different when compared with the hemodynamic responses in the left DLPFC and left FPC in the lower-level-of-cognitive-function schizophrenia group. In contrast, the hemodynamic responses in the right DLPFC, bilateral VLPFC, and right temporal regions decreased as the cognitive deficits in the patients with schizophrenia increased. In addition, the hemodynamic responses correlated positively with the level of cognitive function (BACS composite scores) in the right DLPFC, bilateral VLPFC, right FPC, and bilateral temporal regions in patients with schizophrenia. To the best of our knowledge, this is the first study to directly compare differences in hemodynamic responses with respect to the level of cognitive deficits in schizophrenia and HCs. We demonstrated different patterns of impairment according to the level of cognitive deficits by using multichannel NIRS. In addition, this is the first study to report a significant association between cognitive task-related PFC hemodynamic responses and a broad-spectrum measure of cognition in schizophrenia. The relationship between hemodynamic responses and cognitive performance was obtained in a broad area of cognitive functioning than we expected. One possibility is that the n-back task not only taps the domain of working memory per se but also requires motor speed, attention, executive control in set-shifting, which may have led to the broad relationship. Alternatively, the unitary cognitive construct of BACS, which was indicated by a single-factor solution obtained in factor analysis (Hochberger et al., 2016), may have led to the non-specific finding in the present study. These findings suggest that abnormal working memory-related PFC neural activity is a characteristic feature of schizophrenia that is associated with composite cognitive dysfunction, and our results support working memory-related PFC neural activity as a candidate biomarker. Impairments in working memory and other cognitive functions are cardinal neuropsychological symptoms in schizophrenia, and the PFC is important for mediating and executing these functions (Badre and D'Esposito, 2009; D'Esposito et al., 1995; Takizawa et al., 2008). Cognitive deficits have been repeatedly associated with reductions of grey matter density and volumes of frontal lobe structures commonly found in schizophrenia patients (for a review, see Antonova et al. (2004)). Numerous fMRI studies (Driesen et al., 2008; Kim et al., 2010; Mahurin and Velligan, 1998; Perlstein et al., 2001; Silver et al., 2005) reported that the cognitive deficits in patients with schizophrenia were associated with dysfunction of the frontal and parietal lobes, and cingulate gyrus, and, particularly, the PFC was shown to play an important role in sustained working memory, attention, and higher cognitive function (Kim et al., 2015). The cognitive impairment associated with schizophrenia stems mainly from abnormalities of the PFC (Green et al., 2004), as supported by the results of fMRI studies performed during neurocognitive tasks (Andreasen et al., 1992; Fu et al., 2005; Minzenberg et al., 2009; Perlstein et al., 2001; Veltman et al., 2003).

Please cite this article as: Pu, S., et al., The association between cognitive deficits and prefrontal hemodynamic responses during performance of working memory task in patie..., Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2016.01.045

S. Pu et al. / Schizophrenia Research xxx (2015) xxx–xxx

7

Fig. 3. Cortical distribution of the areas of significant correlation between the mean oxy-Hb changes and cognitive function. Above: The brain area in yellow corresponds to the NIRS channels in which the mean oxy-Hb changes show significant correlation with cognitive function (Brief Assessment of Cognition in schizophrenia [BACS] composite scores; Pearson correlation coefficient; FDR-corrected p b 0.05). Below: Scatter diagrams showing the relationships among the BACS composite scores and mean oxy-Hb changes in channels 45 (right VLPFC), 35 (right DLPFC), 41 (left DLPFC), and 40 (left VLPFC). The locations of the NIRS channels were estimated probabilistically and labeled anatomically in the standard brain space in accordance with Tsuzuki et al. (2007).

The results of the present study support our previous finding that a therapeutic intervention such as a cognitive remediation training that increases working memory-related PFC neural activity may lead to

Hence, dysfunctional information processing in the PFC could be, at least to some extent, accountable for WM and other cognitive deficits in schizophrenia (Lett et al., 2014; Senkowski and Gallinat, 2015).

Table 3 Summary of stepwise multiple regression analysis in channels showing significant correlation with BACS composite scores in schizophrenia patients. No. of channelsa

R2

Adjusted R2

Independent variables

Other factors

Composite scores β

p

Ch12 Ch13 Ch15 Ch20 Ch22 Ch23 Ch24 Ch30 Ch31

0.155 0.092 0.162 0.288 0.133 0.224 0.104 0.274 0.349

0.144 0.08 0.141 0.27 0.122 0.203 0.093 0.256 0.322

0.394 0.303 0.300 0.501 0.364 0.423 0.323 0.429 0.493

b0.001 0.007 0.005 b0.001 0.001 b0.001 0.003 b0.001 b0.001

Ch32 Ch33 Ch34 Ch35 Ch36 Ch40 Ch41 Ch42 Ch43 Ch44 Ch45

0.183 0.241 0.25 0.147 0.099 0.151 0.27 0.176 0.195 0.256 0.275

0.162 0.221 0.231 0.127 0.088 0.141 0.252 0.155 0.185 0.237 0.248

0.393 0.453 0.422 0.325 0.315 0.388 0.450 0.347 0.442 0.437 0.470

b0.001 b0.001 b0.001 0.002 0.003 b0.001 b0.001 0.001 b0.001 b0.001 b0.001

Ch50 Ch51 Ch52

0.108 0.238 0.26

0.097 0.219 0.242

0.329 0.424 0.319

0.002 b0.001 0.001

IQ: β = 0.232, p = 0.027 PANSS (general psychopathology): β = −0.245, p = 0.012 PANSS (general psychopathology): β = −0.249, p = 0.017 PANSS (general psychopathology): β = −0.327, p = 0.001 Gender: β = 0.286, P = 0.004; PANSS (general psychopathology): β = −0.280, p = 0.005 PANSS (general psychopathology): β = −0.207, p = 0.046 PANSS (general psychopathology): β = −0.226, p = 0.027 PANSS (general psychopathology): β = −0.290, p = 0.004 CPZ: β = −0.208, P = 0.045

PANSS (general psychopathology): β = −0.299, p = 0.002 PANSS (general psychopathology): β = −0.291, p = 0.006 PANSS (general psychopathology): β = −0.307, p = 0.003 PANSS (general psychopathology): β = −0.230, p = 0.017; Sensitivity A’: β = 0.193, p = 0.046 PANSS (general psychopathology): β = −0.274, p = 0.006 PANSS (general psychopathology): β = −0.422, p b 0.001

Note: BACS, Brief Assessment of Cognition in Schizophrenia; No., number; Ch, channels; IQ, intelligence quotient; PANSS, Positive and Negative Syndrome Scale; and CPZ, chlorpromazine equivalent dosage. a BACS composite scores, age, gender, premorbid IQ, task performance on the 2-back (Reaction time[RT] and Sensitivity A′), Global Assessment of Functioning (GAF), PANSS scores, and daily dosage of antipsychotic drugs were included in the multiple linear regression analysis.

Please cite this article as: Pu, S., et al., The association between cognitive deficits and prefrontal hemodynamic responses during performance of working memory task in patie..., Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2016.01.045

8

S. Pu et al. / Schizophrenia Research xxx (2015) xxx–xxx

improvement in cognition in schizophrenia (Pu et al., 2014). The results of our previous study indicated that 6 months of cognitive remediation training has the potential to produce functional plasticity in cortical areas associated with this training task. Thus, it is possible that improvement in brain function, as indicated by oxy-Hb increases predominantly in the right hemisphere, may lead to improved cognitive function. It is interesting that in both our previous and present study a significant relationship between working memory-related PFC neural activity and neurocognitive functioning was found predominantly in the right hemisphere. Moreover, the present study showed that in the left DLPFC and left FPC regions, the increase in mean oxy-Hb changes induced by the working memory task was significantly smaller even in the higherlevel-of-cognitive-function group than it was in the HCs (Fig. 2B) and similar between the higher- and lower-level-of-cognitive-function groups (Fig. 2C). We had already found that reduced activation during working memory in the left DLPFC remained unchanged even after cognitive function improvement was attained by cognitive remediation training. These findings may indicate that, within this working memory neural network, brain activity in the left DLPFC and left FPC remains decreased irrelevant to cognitive functioning levels or changes. That performance (sensitivity A′ and RT) in the higher-level-ofcognitive-function schizophrenia group was not significantly different from that of HCs (2-back: RT: p N 0.05, sensitivity A′: p N 0.05), particularly during the 2-back task. With the aim of simplifying the task so as to reduce the influence of set-shifting processing only one block of the 2-back task was used, which in turn may have reduced the sensitivity of the sensitivity A′ and RT variables owing to the small number of targets. Our findings need to be interpreted within the context of the study limitations. First, multichannel NIRS has limited spatial resolution compared to fMRI due to pervasive light scattering in tissue. Unlike fMRI, NIRS is non-invasive and is relatively restraint-free. Accordingly, NIRS is better suited for assessing brain function in many psychiatric patients in medical practice. Second, although we did not find any relationships between oxy-Hb signals and the duration of illness or medication dosages in the patients with schizophrenia, most patients in this study were chronically ill and medicated. Thus, to fully rule out medication effects, future studies are warranted using first-episode and/or drug-naïve patients. Third, patients' PANSS scores might be a confounding variable because the severity of symptoms might influence the cortical activity. In our previous studies, we did not find significant correlations between the PANSS scores and cortical activity (Pu et al., 2013a, b). However, in this study, we found that the PANSS general psychopathology scale scores had significant effects on the cortical activity in schizophrenia. The PANSS general psychopathology scale covers a wide range of psychopathology including cognitive components, such as “unusual thought content”, “disorientation”, “poor attention” and “lack of judgement and insight”, which may have led to its significant relationship to the cortical activity. Finally, it is unclear whether abnormal working memory-related PFC neural activity and its association with cognitive function is specific to schizophrenia or a rather universal finding. Studies examining cognitive function and working memoryrelated PFC neural activity in healthy subjects and other patient populations (e.g., patients with bipolar disorder) are needed to examine this possibility.

5. Conclusions This study is the first to observe significant correlations between abnormal working memory-related hemodynamic responses in the PFC and a broad-based measure of cognition in schizophrenia. Our results suggest that working memory-related PFC neural activity may be a useful biomarker for therapeutic development for cognitive dysfunction in schizophrenia.

Role of funding source This research was supported by an Intramural Research Grant for Neurological and Psychiatric Disorders from the NCNP (National Center of Neurology and Psychiatry) (No. 23-10 and 26-3 to K.K. and S.P.) and by support from the Takeda Science Foundation (No. 2014 to S.P.). Funding agencies had no role in study delineation, data collection and analysis, decision to submit the paper to the present journal, or preparation of the manuscript.

Contributors Shenghong Pu, Kazuyuki Nakagome, and Koichi Kaneko designed the study and wrote the protocol. Shenghong Pu and Kazuyuki Nakagome undertook the statistical analysis. Shenghong Pu, Masashi Itakura, Masaaki Iwata, Izumi Nagata, and Koichi Kaneko conducted data acquisition. Shenghong Pu and Kazuyuki Nakagome analyzed the data. Shenghong Pu and Kazuyuki Nakagome wrote the first draft of the manuscript, and the other authors revised it critically for important intellectual content. All authors have approved the final version of the manuscript.

Conflict of interest All the authors declare that they have no conflicts of interest with respect to this study or its publication.

Acknowledgement The authors thank all the participants in this study. The authors also thank the Hitachi Medical Corporation for providing technical advice.

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