Biochemical abnormalities in basal ganglia and executive dysfunction in acute- and euthymic-episode patients with bipolar disorder: A proton magnetic resonance spectroscopy study

Author’s Accepted Manuscript Biochemical abnormalities in basal ganglia and executive dysfunction in acute- and euthymicepisode patients with bipolar disorder: A proton magnetic resonance spectroscopy study Shunkai Lai, Shuming Zhong, Xiaoxiao Liao, Ying Wang, Jingyu Huang, Shanhong Zhang, Yao Sun, Hui Zhao, Yanbin Jia

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S0165-0327(17)30793-0 http://dx.doi.org/10.1016/j.jad.2017.07.036 JAD9102

To appear in: Journal of Affective Disorders Received date: 19 April 2017 Revised date: 11 July 2017 Accepted date: 17 July 2017 Cite this article as: Shunkai Lai, Shuming Zhong, Xiaoxiao Liao, Ying Wang, Jingyu Huang, Shanhong Zhang, Yao Sun, Hui Zhao and Yanbin Jia, Biochemical abnormalities in basal ganglia and executive dysfunction in acuteand euthymic-episode patients with bipolar disorder: A proton magnetic resonance spectroscopy study, Journal of Affective Disorders, http://dx.doi.org/10.1016/j.jad.2017.07.036 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Biochemical abnormalities in basal ganglia and executive dysfunction in acute- and euthymic-episode patients with bipolar disorder: A proton magnetic resonance spectroscopy study

Authors: Shunkai Lai

a, 1

, Shuming Zhong

a, 1

, Xiaoxiao Liao a,Ying Wang b, Jingyu

Huang c, Shanhong Zhang c, Yao Sunb, Hui Zhao a, Yanbin Jia a,*

Affiliation: a

Department of Psychiatry, First Affiliated Hospital of Jinan University, Guangzhou

510630, China b

Medical Imaging Center, First Affiliated Hospital of Jinan University, Guangzhou

510630, China c

School of Management ,Jinan University, Guangzhou 510316, China

1

These authors contributed equally to this work.

* Correspondence to：Tel.: +86 20 38688120; fax: +86 20 38688888 E-mail: [email protected], First Affiliated Hospital of Jinan University, Guangzhou 510630, China.

Abstract Background: Recent studies found abnormal biochemical metabolism and executive

cognitive deficits in acute bipolar disorder (BD). However, the evidence concerning in euthymic BD is limited. Thus, a comparison between acute and euthymic BD is conductive to better understanding the association between cognition and the outcome of neuroimaging. This study sought to investigate the relationship between the executive function and the biochemical metabolism in acute- and euthymic-episode BD patients and delineate the prominent endophenotype of BD.

Methods: Three groups of participants were recruited in this study: 30 BD patients with an acute depressive episode, 22 euthymic BD patients, and 31 healthy controls. All participants were interviewed using the Structured Clinical Interview for DSM-IV, and underwent two-dimensional multivoxel proton magnetic resonance spectroscopy (1H-MRS) to obtain the bilateral metabolite levels in the lenticular nucleus of basal ganglia(BG).

The

ratios

of

N-acetylaspartate

(NAA)/creatine

(Cr)

and

Choline-containing compounds (Cho) /Cr ratios were calculated. Executive function was assessed by using the Wisconsin Card Sorting Test (WCST) and Trail Making Test , Part-B(TMT-B). Results: The comparison of biochemical changes showed that the NAA/Cr ratios in bilateral lenticular nucleus in both acute and euthymic BD patients was significantly lower than that in healthy controls at a confidence level of p<0.05. In the comparison of executive function, both acute and euthymic BD patients showed significantly decreased numbers of categories completed, and increased numbers of total errors, perseverative and noperseverative errors, and TMT-B uptake compared to the healthy controls at a confidence level of p<0.05. There were no significant differences between the acute BD and euthymic BD groups in the biochemical metabolite ratios and executive function. We found that the NAA/Cr ratio in the left in BG in the acute -episode BD patients was positively correlated with the number of categories completed, whereas it was negatively correlated with the total errors and TMT-B uptake. There was no correlation between the NAA/Cr and Cho/Cr ratios in the bilateral BG and the scores of SWCT and TMT-B in euthymic-episode BD patients.

Limitation: The sample size was relatively small and not all the euthymic-episode patients are the ones with an acute episode . Conclusions: Our findings suggest that biochemical abnormalities in the lenticular nucleus and the executive dysfunction may occur early in the course of BD, and persist during remission, and are the most likely markers of endophenotypes of BD. The dysfunction of the neuronal function in the lenticular nucleus may be correlated with the cold dysfunction in patients with acute BD. Keywords: Bipolar disorder; Cold Cognition; putamen; Endophenotype; proton magnetic resonance spectroscopy

1.Introduction Bipolar disorder (BD) is characterized by episodic pathological mood alterations that can be manic, depressive, or mixed (Nenadic et al., 2015). The depressive phase is the most prevalent component of BD. Patients with BD experiencing a depressive episode have a high rate of morbidity and risk of suicide, which are highly heritable and difficult to treat. Moreover, depressed BD patients are often misdiagnosed with unipolar depressive disorder, which leads to mistreatment and poor clinical outcomes for many BD patients. However, the precise underlying pathophysiology of BD remains unclear. Considerable interest has been focused on the determination of the possible pathogenesis of BD by neuroimaging studies. Several studies in patients with BD(Arnone et al., 2009; Hallahan et al., 2011; Selvaraj et al., 2012) using magnetic resonance imaging (MRI) have identified structural abnormalities in regions, including amygdala, the subgenual prefrontal cortex, the thalamus, and the basal ganglia(BG) (Emsell et al., 2013). The results of a previous examination show that basal ganglia regional is affected in patients with bipolar disorder which is known to

be involved in learning and memory, contextual fear conditioning, and neuroendocrine

regulation.

Some

evidence

further

suggested

that

subtle

neuroanatomical abnormalities are present in the BG in depressed BD patients(Strakowski, Delbello, & Adler, 2005). Meanwhile, putamen is an important part of the BG. In volumetric studies, individuals with BD had a larger striatum and right putamen or bilateral pallidum than healthy controls(Arnone et al., 2009; Bonelli, Kapfhammer, Pillay, & Yurgelun-Todd, 2006; Hallahan et al., 2011). In vivo tissue biochemistry proton magnetic resonance spectroscopy (1H-MRS) is a unique non-invasive and non-radioactive approach capable of measuring the levels of important metabolites in specific brain regions. Its results can provied more detailed information about the neuronal abnormalities at the cellular and metabolic levels than relatively

gross

volumetric

estimates.

Previous

investigations

have

found

morphometrical changes and abnormalities in the BG in patients with acute BD, including decreased N-acetylaspartate levels(Kraguljac et al., 2012), In contrast, increased NAA levels in the bilateral caudate nucleus and the left lentiform nucleus(Port, Unal, Mrazek, & Marcus, 2008), as well as higher choline-containing compounds (Cho)/Creatine (Cr) ratio were established in the BG of euthymic BD patients(Yildiz-Yesiloglu & Ankerst, 2006). A decrease in the activation of the right putamen in remitted BD patients was also reported(Foland-Ross et al., 2012). All above findings suggest that metabolic alterations in the BG may be related to the neuropathology of BD. However, most prominently evidence in the neurometabolites may partly focus on the acute-episode BD and lack of the consistency in patients with BD in euthymic-episode. Additionally, a comparison of the neurometabolites in the putamen between in acute- and euthymic-episode BD patients has not yet been conducted. Cognitive deficits have been recognized as a core feature of the clinical expression and have also been suggested as an important source of psychosocial and functional burden of BD(Lopes & Fernandes, 2012). In both acute and euthymic phases,, the domains affected include verbal learning, executive function, working

memory,

attention,

and

psychomotor

functioning(Kurtz

&

Gerraty,

2009;

Martinez-Aran, Vieta, Reinares, et al., 2004), Recent reports have documented that approximately 60% of the BD patients in remission fail to regain full state(Cardoso, Bauer, Meyer, Kapczinski, & Soares, 2015), which may be partly attributed to cognitive impairment(Robinson et al., 2006). These neuropsychological deficits contribute to an impairment of functional recovery. In fact, the impairment of the executive function plays an important role in cognitive dysfunction in BD and may as an independent predictor of functional recovery(Burdick, Goldberg, & Harrow, 2010; Robinson et al., 2006). Thus, research findings on the executive function in euthymicepisode patients with BD have been consistently reported . However, few studies that compare the executive function between acute-episode and euthymic-episode BD patients. Thus, further comparative studies are needed.. Therefore, in this present study, the executive function in acute-episode and euthymic-episode BD patients was observed by Wisconsin Card Sort Test and the Trail-Making Test, part-B. On the other hand, the pathological mechanism of BDD’s cognitive impairment is still unknow . Previous neuroimaging studies found the presence of an abnormal brain structure and aberrant biochemical metabolism in BD that may significantly associated with cognitive dysfunction(Zhong et al., 2014). As is well known, BG, plays an important role in the emotional and cognitive functions, widely involved in emotion, learning, memory, thought, executive cognitive functions, speech and other advanced nerve function activities. Nevertheless, the relationship between biochemical changes and the executive function in acute- and euthymic-episode BD patients is still unclear, although in a few studies such abnormalities were observed to be accompanied by cognitive deficits in BD. Therefore, more specific neuropsychological tests and functional imaging studies are needed . In this study, a semi-quantitative analysis was performed to quantify the concentrations of NAA, Cho and Cr in the bilateral lenticular nucleus in acute- and euthymic-episode patients with BD. The executive function was assessed by using the WCST and TMT-B task. By comparing the biochemical metabolism ratios and

executive function scores among acute-episode BD patients, euthymic-episode BD patients and healthy controls, we aimed to explore the changes of neurometabolites levels and the outcome of executive function in acute- and euthymic-episode BD patients. Moreover, we computed the correlations between the biochemical metabolism ratios and the executive function scores and hypothesized that the abnormalities in the levels of biochemical parameters, such as the ratios of NAA/Cr and Cho/Cr, and bad performance in WCST and TMT-B task can be found in both acute- and euthymic-episode BD patients. Meanwhile, these deficits of executive function may correlate with the biochemical metabolism of the lenticular nucleus.

2.Methods 2.1 Participants A total of 30 drug-naïve acute depressive episode BD patients, 22 euthymic episode BD patients whose clinical symptoms had disappeared at least six months were recruited at the Department of the psychiatry in the First Affiliated Hospital of Jinan University, Guangzhou, China. The age of all participants was restricted to 18–45 years to diminish the interference of aging and vascular disease. All patients diagnosed by two experienced psychiatrists using the Structured Clinical Interview for DSM-IV (SCID). Clinical state was assessed by the 24-item Hamilton Depression Rating Scale (HDRS) and the Young Mania Rating Scale (YMRS). All scales were finished in 2 days after the MRI. We selected acute depressed patients with BD had a 24-item HDRS total score> 21, and a YMRS total score<7. Exclusion criteria included the presence of (1) other Axis I psychiatric disorders and symptoms, (2) a history of the use of any psychotropic medication, psychotherapy or electroconvulsive therapy, (3) a history of neurological or organic brain disorder, (4) alcohol/substance abuse, (5) any physical illness demonstrated by personal history or clinical or laboratory examinations, pregnancy

and postpartum depression. Euthymic BD patients were also selected whose clinical symptoms had disappeared at least six months, with a 24-item HDRS total score < 8, and a YMRS total score< 7. 24 age- and gender-matched healthy controls (six males) were studied. Healthy controls were carefully screened through a diagnostic interview, the Structured Clinical Interview for DSM-IV Nonpatient Edition (SCID-NP), to rule out the presence of current or past history of substance abuse/dependence or any psychiatric illness in self or in first-degree relatives. All participants were right-handed and were submitted to MRI scanning within 48h of initial contact. The study was approved by the Ethics Committee of First Affiliated Hospital of Jinan University, China. All participants signed informed consent forms after a full written and verbal explanation of the study.

2.2. Image acquisition and preprocessing Both MRI and 1H-MRS were performed on a 3.0 T GE MR system (Discovery MR 750 System, GE Healthcare, Milwaukee, WI) with an 8-channel phased array head coil. Participant was lying in the supine position; nasion served as a landmark. Ear plugs and foam pads were used to reduce noise and minimize head motion. Routine axial T1-weighted fluid attenuation inversion recovery (T1 Flair) [repetition time (TR) = 1750ms, echo-time (TE) = 24ms] and fast spin echo T2-weighted MR images (TR = 8400ms, TE = 145ms) were obtained to confirm the absence of any structural and signal abnormality of the brain. In this study, all the spectra were acquired using 2D multivoxel technique. Axial T2-weighted MR images were used for anatomic localization (TR = 3500ms, TE = 102ms, slice thickness = 5mm without a gap). For 1H-MRS studies, figure 1 showed the location of the lenticular nucleus volume of interest (VOI). The VOI were placed in a uniform manner by the same investigator. The size of the VOI was including 50

nominal voxels (7.5×7.5×10mm3). Figs. 1 shows the VOI location in an MRI scan of the brain. Single section 2D multi-voxel 1H-MRS was acquired using a point resolved spectroscopy sequence (PRESS) with water suppression by a chemical shift selective saturation (CHESS) pulse. The acquisition parameters were the following: TR = 1000ms; TE = 144ms; numbers of excitation = 1; spatial matrix = 18×18cm; field of view= 240×240mm; slice thickness= 10mm; a nominal voxel size of 7.5×7.5×10mm3. Additional saturation bands were placed outside the VOI to minimize lipid contamination from the scalp. Automatic pre-scanning was performed before each spectroscopic scan to achieve an optimal full width half maximum of 10Hz. As a general quality standard spectra with a line width above 10Hz or water suppression above 98% were excluded. Total acquisition time of each participant for 1H-MRS sequence was 5 min and 28 s. Voxels were repositioned in the left and right lenticular nucleus. A trained radiologist who was blind to the diagnosis of each participant carried out voxel placements for spectroscopy. The analysis of the spectral dataset was performed with the functool in GE Advantage Workstation AW4.2_07. Each spectrum was evaluated for the peak area of Cho at 3.22ppm, Cr at 3.03ppm, and NAA at 2.02ppm. The values of the NAA/Cr, Cho/Cr ratios on both left and right side of lenticular nucleus were used for analysis of brain biochemical changes.

2.3 Executive function assessment An extensive battery of neuropsychological tests was used to assess executive function for all three groups. The Wisconisin Card Sorting Test-modified (WCST) (Heaton, 1981) is a measurement of the general ability to identify and to maintain a category (number of categories completed) and the ability to shift the cognitive set when indicated (Total errors, number of perseverative errors and noperseverative errors).

2.4 Statistical analysis All data analysis was performed using SPSS for Windows software, version 15.0 (SPSS Inc., Chicago, III, USA). Two-tailed significance level was set at p<0.05. One-way analysis of variance (ANOVA) was used to determine whether groups displayed differences in terms of two metabolite ratios (NAA/Cr and Cho/Cr on both left and right brain of basal ganglia) and executive function. Post hoc analysis would determine from which group the differences resulted. Spearman's correlation analyses were used to determine whether the brain biochemical metabolite ratios (NAA/Cr, Cho/Cr) correlated to executive function in acute and euthymic BD patients. The significant level was set at p<0.05.

3. Results 3.1 Demographic result Table 1 shows the demographic and clinical data of all study participants. We included 29 acute depressive episode BD patients (16 males and 13 females) with a mean age of 24.79± 8.09 (range 18–45) years, 22 euthymic episode BD patients (12 males and 10 females) with a mean age of 26.82± 8.86 (range 18–45) years and 24 healthy controls (13 males and 11 females) with a mean age of 29.5± 11.42 (range 18–45) years. The mean number of education years was 13.93±3.16 years for acute BD patients, 13.73±2.80 years for euthymic BD patients and 15±1.58 years for healthy controls. There were no significant differences in sex, age, and years of education among three groups. For the acute BD patients, the mean duration of illness was 57±67.52 months, the mean HDRS score was 25.81±2.95, and the mean Y-MRS score was 0.81±0.56. For the euthymic BD patients, the mean duration of illness was 59.5±51.58 months, the mean HDRS score was 2.59±1.84, and the mean Y-MRS

score was 0.55±1.29. There were no significant differences in the mean duration of illness and the number of episodes between the two patients group. The acute BD group showed significantly higher HDRS score and YMRS score when compared to the euthymic BD group and healthy controls.

3.2 Comparison of biochemical metabolite ratios (NAA/Cr and Cho/Cr) in terms of bilateral lenticular nucleus. Table 2 shows the result of comparison of the NAA/Cr, Cho/Cr ratios in bilateral lenticular nucleus in acute and euthymic episode patients with BD and healthy controls. Both acute and euthymic episode patients with BD showed significantly lower NAA/Cr ratio in bilateral lenticular nucleus when compared to the healthy controls at the confidence level of p<0.05 (F=5.614, p=0.005 and F=7.811, p=0.001 ). There was no significant difference among three groups in Cho/Cr ratios in bilateral basal ganglia.

3.3. Comparison of Executive function among three groups Table 3 shows the result of comparisons of executive function with the number of categories completed, total errors, number of perseverative errors and noperseverative errors. Both acute and euthymic episode patients with BD showed significantly decreased in number of categories completed when compared to the healthy controls at the confidence level of p<0.05 (F=25.09, p=0.000). Significantly increased in Total errors, number of perseverative errors and noperseverative errors. But there was no significant difference between the acute BD patient group and euthymic BD patient group.

3.4. Correlation between executive function and biochemical metabolite ratios in the

acute and euthymic BD patient Table 4 shows that the NAA/Cr ratio in left basal ganglia in the acute episode BD patients was positively correlated with the number of categories completed (r=0.369, p=0.049), and was negatively correlated with the total errors (r=-0.383, p=0.040). There was no correlation between the NAA/Cr in the right basal ganglia and the scores of SWCT in acute episode BD patients, and there was no correlation between the Cho/Cr in the bilateral basal ganglia and the scores of SWCT in acute episode BD patients. Table 5 shows that there was no correlation between the NAA/Cr, Cho/Cr ratios in the bilateral basal ganglia and the scores of SWCT in euthymic episode BD patients.

4. Discussion To the best of our knowledge, the present study, is one of the very early examinations using a 3.0 T multi-voxel 1H-MRS to investigate the biochemical abnormalities in BG in acute- and euthymic-episode BD patients, as well as the relationship between the biochemical abnormalities in BG and the executive function in the two patient groups. In our study, both acute and euthymic BD patients showed significantly lower NAA/Cr ratios in the bilateral lenticular nucleus compared that in healthy controls. Likewise, executive dysfunction was found in both acute and euthymic BD patients. We also established that the NAA/Cr ratio in the left BG in acute-episode BD patients was positively correlated with the number of categories completed, but was negatively correlated with the number of total errors and TMT-B uptake.

Comparison between the Biochemical Metabolite Ratios in bipolar depression episode and euthymic

In our study, the acute-episode BD patients had significantly lower NAA/Cr ratios in the bilateral lenticular nucleus of the BG than he healthy controls,which suggest that the biochemical abnormalities in the lenticular nucleus may occur early in the course of depressive BD. Our findings are consistent with those of most previous studies on the topic(Kraguljac et al., 2012). Other evidence indicates that in BD, the NAA/Cr ratios in the right lenticular nuclei were significantly lower than those in the left lenticular nuclei in BD(Ohara et al., 1998). Mark(Frye et al., 2007) suggested that even in mania, BG is involved in the pathology of BD and NAA reduction may mark the early stages in the course of manic episode burden. However, the findings of several studies were different. No significant difference was also found in the N-acetyl-aspartate (NAA)/Cr and NAA/Cho ratios in the right lenticular nuclei between bipolar patients and healthy controls(Ohara et al., 1998). Other inconsistent results have also been reported that NAA and NAA/Cr ratio in the BG were significantly lower in manic subjects than in controls, or NAA in the former was even abnormally absent(Hamakawa, Kato, Murashita, & Kato, 1998; Kato et al., 1996). Although, they evaluated patients by using 1H-MRS and obtained results that were different from ours, the current study focused on depressed BD patients, which contributed to the avoidance of the influence of the other episodes(encompassed depressive, manic or mixed episodes). However, some of these examinations did not compare the depressed and remitted BD patients and 1H-MRS used only a 1.5-T magnet. As is known, NAA is mostly localized in the neurons and the oligodendrocyte precursors mature oligodendrocytes(Currie et al., 2013). NAA is used in clinical and experimental MRS studies as a marker of neuronal/axonal tissue that includes functional aspects of formation and/or maintenance of myelin and dendritic and synaptic proliferation (Bhakoo & Pearce, 2000; Urenjak, Williams, Gadian, & Noble, 1993). There is clear evidence of neuronal and glial cell reduction in bipolar disorder(Ongur, Drevets, & Price, 1998; Rajkowska, Halaris, & Selemon, 2001). In vivo expression of NAA by oligodendrocytes was observed by Bhakoo(Bhakoo & Pearce, 2000). These changes are associated with an underlying pathology of the myelination process. Recent animal and human studies have suggested that the

cuprizone (CPZ, a copper chelator) may damage oligodendrocytes by causing demyelinating insult and leading to the appearance of abnormal mental functions, such as schizophrenia symptoms (Xu, Yang, Rose, & Li, 2011). Hepatolenticular degeneration is one of the biochemical abnormalities induced by copper that may cause mood symptoms and behavior abnormalities.. Therefore, our results together with these findings suggest the decreased neuronal density or neuronal dysfunction in the BG of depressed BD patients, but further work is still encouraged to better understand these findings. In this study, we also found the decreased NAA levels in euthymic bipolar patients, which is consistent with the findings of a previous study, in which the NAA levels did not rise after the treatment of BD patients after the acute depressive state changed to remission(Kraguljac et al., 2012). However, other studies have reported an association between NAA and duration of treatment (Cecil, DelBello, Sellars, & Strakowski, 2003), especially such resulting from treatment with lithium, which has been shown to increase NAA levels to normal or higher in brain regions such as the BG(Moore & Galloway, 2002; Silverstone et al., 2003). However, the elevation of NAA/Cr was not observed in euthymic bipolar patients treated with divalproex sodium(Silverstone et al., 2003).The present finding of reduced basal ganglia NAA did not find an association to the treatment with divalproex sodium. Although the majority of the subjects were being treated with divalproex sodium in our study,the reduction of NAA content would be more reliable if we clarified the treatment of euthymic bipolar patients. However, no significant effect of psychotropic medication on the levels of metabolites measured in the BG was observed by Hamakawa(Hamakawa et al., 1998). Therefore, further investigation is needed to examine the effect of medications. On the comparison of correlation of clinical data and biochemical metabolite ratios, we did not find a significant correlation between the biochemical metabolite ratios (NAA/Cr or Cho/Cr) and clinical data (HDRS scores, the duration of illness, age, or age of onset) in both acute- and euthymic-episode BD patients. Taken together, there is evidence that NAA is a trait biomarker and the decreased NAA/Cr ratios in BG are

trait-independent and appear to hold the promise as a potential endophenotype marker in BD patients.. No significant differences were found in the Cho/Cr ratio in the bilateral lenticular nucleus of BG among the three groups. However, negative findings(Kaymak, Demir, Oguz, Senturk, & Ulug, 2009), and increased Cho

levels in depressive patients have

also been reported(Kumar et al., 2002). Cho is a marker of cell membrane integrity(Strakowski et al., 2005), that is abundant in oligodendrocytes (Urenjak et al., 1993). Previous studies established significant elevation of Cho concentration or Cho/Cr peak ratio in the BG in the patients with bipolar disorder (Hamakawa et al., 1998), but the patients were in both the depressive and euthymic state. Thus,, it is still uncertain that whether the increase in Cho concentrations in bipolar disorder patients is state- or trait-dependent.. Higher AC and BG Cho levels in BD patients have also been reported(Sharma, Venkatasubramanian, Barany, & Davis, 1992). However, research conducted in the euthymic episode found no significant changes in the Cho concentrations in in the thalamus, DLPFC and FC(Castillo, Kwock, Courvoisie, & Hooper, 2000; Cecil et al., 2003; Deicken, Eliaz, Feiwell, & Schuff, 2001; Hamakawa, Kato, Shioiri, Inubushi, & Kato, 1999; Winsberg et al., 2000). In mania, studies have revealed no difference in Cho levels in (Blasi et al., 2004; Michael et al., 2003). Conversely, BD patients in the manic sate had a decrease in AC Cho concentrations(Davanzo et al., 2003). Lower Cho levels may indicate decreased membrane turnover or impaired intracellular signal transduction systems. Despite the inconsistencies present, the literature suggests that Cho levels in BD undergo alterations. Therefore, as is doing with our study further work still encouraged.

Comparison between the executive function in bipolar depression episode and euthymic In the current study, we recruited non-late-life, treatment-naive acute-episode BD patients and employed the WCST and TMT-B tests to assess their executive functions.

Our findings suggest that the acute-episode patients with BD had a significantly lower number of categories completed and significantly high numbers of total errors, perseverative and noperseverative errors as well as TMT-B uptake than healthy controls , which revealed the presence of executive function deficits in BD. Our finding is in line with those of several previous studies on acute-episode BD patients (Maalouf et al., 2010; Ryan et al., 2012), that reported impairment in abstraction (Altshuler et al., 2004), set-shifting(El-Badri, Ashton, Moore, Marsh, & Ferrier, 2001; Martinez-Aran, Vieta, Colom, et al., 2004), or both (Kolur, Reddy, John, Kandavel, & Jain, 2006) and suggested that the speed of the processes such as resource mobilization, flexible organization, response inhibition, cognitive regulation and forward planning in depressed state of the brain is slower. Meanwhile, persistent or trait-like cognitive deficits are experienced by patients with executive function deficits in the euthymic state(Clark, Kempton, Scarna, Grasby, & Goodwin, 2005; Dixon, Kravariti, Frith, Murray, & McGuire, 2004). In the present study, euthymic BD patients showed also significantly decreased in the number of categories completed, and increased numbers of total errors, perseverative and noperseverative errors and TMT-B uptake than healthy controls. Therefore, executive function deficits in bipolar disorder cases may persist across different mood states both in acute- and euthymic-episode. Some previous studies also reported the availability of executive dysfunction in remitted bipolar patients (Bora, Yucel, & Pantelis, 2009; Ferrier, Stanton, Kelly, & Scott, 1999; Mur, Portella, Martinez-Aran, Pifarre, & Vieta, 2007; Volkert et al., 2016). However, other cross-sectional investigations found no differences between the executive function deficits in manic or hypomanic states(Basso, Lowery, Neel, Purdie, & Bornstein, 2002; Kurtz & Gerraty, 2009; Martinez-Aran, Vieta, Reinares, et al., 2004; van Gorp, Altshuler, Theberge, Wilkins, & Dixon, 1998). Therefore, these results suggest that the executive dysfunction may be a depression-specific(Maalouf et al., 2010). Another possible reason for these inconsistencies may be that the previous reports did not control the compounding effects of pharmacological treatments and aging on cognition(Cotrena, Branco, Shansis, & Fonseca, 2016). In our current study, we recruited non-late-life,

treatment-naive acute-episode BD patients to exclude the effect of aging and medication, which contributed to the high reliability of our results. Additionally, another study also found that medication load was not related to the EF factor scores(Ryan et al., 2012). Therefore, we found no significant correlation between executive function and HDRS scores, the duration of illness, age, or age of onset, which indicates that cognitive function impaired can be distinguished from affective symptoms(Martinez-Aran, Vieta, Reinares, et al., 2004; Robinson & Ferrier, 2006). As is well known , “Cold” cognitive impairments are reliably by the California Verbal Learning Test, the Trail-Making Test, and the Wisconsin Card Sort Test(Roiser & Sahakian, 2013), patients suffering from such impairments have a poor response to antidepressant medication(Potter, Kittinger, Wagner, Steffens, & Krishnan, 2004). Therefore, these findings suggest that executive function could be a “Cold” cognitive process which is emotion-independent but independent of symptom severity. Furthermore, it could be considered as a maker of cognitive alterations(Kim, An, Kwon, & Shin, 2014). Recent studies have converged to show that executive functioning (EF) deficits in the euthymic state demonstrate persistent or trait-like cognitive deficits(Clark et al., 2005; Dixon et al., 2004). Cognitive measures are considered heritable (Glahn, Bearden, Niendam, & Escamilla, 2004), three earlier reports provided further evidence that cognitive impairment in patients with bipolar disorder is also present in high-risk relatives. (Bora et al., 2009; Drysdale, Knight, McIntosh, & Blackwood, 2013; Juselius, Kieseppa, Kaprio, Lonnqvist, & Tuulio-Henriksson, 2009). Endophenotypes are a measurable construct in the genes-to-behaviors pathways, which in general refer to a disease-related trait marker, that is more closely linked to the phenotype expression and genetic variability but is distinct from psychiatric symptoms(Gould & Gottesman, 2006). They bridge a gap between disease and distal genotype(Gottesman & Gould, 2003). The current study provides evidence for cognitive impairments that may represent potential endophenotype markers in BD, such as verbal memory, executive function and sustained attention deficits (Bora et al., 2009; Hasler, Drevets, Gould, Gottesman, & Manji, 2006). Therefore, our findings together with those of previous studies suggest

that executive function such as set shifting seem to be more related to the genetic risk of BD and may represent a valid cognitive endophenotype for bipolar disorder.

Correlation between Executive function and Biochemical Metabolite Ratios

Cognitive impairments have been linked to structural and functional alterations in several brain regions. However, the precise underlying pathological mechanism of BDD’s cognitive impairment is still uncertain. Now, it is well established that the executive function is supported by BG regions(Monchi, Petrides, Strafella, Worsley, & Doyon, 2006) , and brain imaging studies provided evidence that abnormal activity in BG is related to cognitive processes and motor control (Gunaydin & Kreitzer, 2016). In the present study, we found that the decreases in NAA/Cr ratios in bilateral BG were negatively correlated with the the numbers of total errors, perseverative, and noperseverative errors and TMT-B uptake. In addition, the reductions in the NAA/Cr ratios in the bilateral BG were positively correlated with the numbers of correctly completed categories, suggesting that the executive dysfunction may be related to the neuronal and/or axonal dysfunction of putamen in basal ganglia. A recent study on subcortical brain abnormalities have also revealed that the right putamen volume sizes may reflect severity of the impairment of the executive functioning in patients with BD(Hartberg et al., 2011). Moreover, the alterations in the putamen have also been reported in patients with ADHD and that they have a relationship with the cognitive impairments in executive abilities (Cao et al., 2009). Our findings therefore indicate that the dysfunction and abnormal activity in these regions may underline the emotional dysregulation and the cognitive regulation tasks in bipolar depressive episodes. Unfortunately, there was no correlation between the NAA/Cr and Cho/Cr ratios in the bilateral BG and the scores of SWCT and TMT-B in the euthymic-episode BD patients. The research group of Liberg, concluded that the euthymic bipolar disorder was characterized by changes in the the shape of the right putamen regions and contributed to the executive functions dysfunction.(Liberg, Ekman, Sellgren,

Johansson, & Landen, 2014). A diffusion tensor imaging (DTI) study found mean diffusivity alterion in the fornix, anterior thalamic radiation, spleniumand the truncus of the corpus callosum in BD patients and indicate a direct link between abnormal WM microstructural integrity of fronto-limbic tracts and executive cognitive function in euthymic bipolar patients(Oertel-Knochel et al., 2014). Possible reason for these inconsistencies may be that the sample size was relatively small and not all the euthymic-episode patients are the ones wtih an acute episode .. Since our review might not have adequate power to rule out such differences, the conclusions drawn are preliminary, and additional studies are needed to confirm our findings. Anadditional limitation was that the methods we used did not allow us toresolve the smaller 1H-MRS peaks and detect a significant difference in them, such as mlns , glutamate (Glu) and glutamine (Gln), further studies to verify our conclusion in the current study could use a more scientifically recognized method for data analysis, as Jmrui or Tarquin or lcmodel. Although the data for the euthymic-episode BD patients in our study might seem consistent with those of previous examinations, it is still suggested that executive cognitive deficit seems to be the most prominent endophenotype of BD that also appears to involve the putamen in BG-related cognitive impairments.

Conclusion The reduced NAA/Cr ration in the bilateral lenticular nucleus indicated dysfunction of neuronal viability in the BG of acute- and euthymic-episode BD patients. Executive dysfunction has been found in both acute- and euthymic-episode BD patients. These findings suggest that biochemical abnormalities in the lenticular nucleus and executive dysfunction may occur early in the course of BD and may persist during remission.These abnormalities are most likely markers of potential endophenotypes of BD. Additionally, dysfunction of the neuronal function in the lenticular nucleus may correlate with the executive dysfunction in acute patients with BD and that also appears to involve the putamen in BG-related cognitive impairments. However, our investigation was preliminary, and thus further studies with a larger sample size will be needed to confirm our results.

Role of funding source Funding for this work was provided by the National Natural Science Foundation of China (No: 81671351), Planned Science and Technology Project of Guangzhou, China (No: 201607010204; 201604020184), Fundamental Research Funds for the Central Universities (No: 21615466), Planned Science and Technology Project of Guangdong Province, China (No: 2014A020212401), and High-Level University Special Fund Program (No: 88016013022). The founders have not played any roles in study design, data collection, analysis, manuscript writing and decision to publish.

Conflict ofinterest The authors declare that they have no conflict of interest.

Acknowledgments This work was supported by grants from the National Natural Science Foundation of China (No: 81671351), Planned Science and Technology Project of Guangzhou, China (No: 201607010204; 201604020184), Fundamental Research Funds for the Central Universities (No: 21615466), Planned Science and Technology Project of Guangdong Province, China (No: 2014A020212401), and High-Level University Special Fund Program (No: 88016013022).

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Table 1

Demographic and clinical data of participants [mean(SD)]

Group I

Group II

HC

Number of subjects

n=30

n=22

n=31

Sex male/female

16/14

10/12

15/16

23.90(6.95)

26.82(8.86)

26.52(10.37)

Age (year)

doi:

Education (year)

13.5(2.76)

13.73(2.80)

14.74(1.43)

Age of onset (year)

19.03(7.81)

21.32(6.61)

-

Duration of illness (month)

53.33(65.38)

59.50(51.58)

-

2.53(1.11)

3.73(1.08)

-

12

6

0

24-item HDRS score

26.77(4.98)*

2.59(1.84)

2.65(1.53)

Y-MRS score

1.03(1.27)*

0.55(1.29)

0.77(0.84)

Number of episodes

Family history

Group I:

Acute depressive episode bipolar disorder patients.

Group II: Euthymic bipolar disorder patients

HC: Healthy controls 24-item HDRS: 24-item Hamiltion Depression Rating Scale.

Y-MRS: Young manic rating scale. *p< 0.05 significant.

Table 2

Comparison of NAA/Cr, Cho/Cr ratios at three cerebral sites among three experimental

groups [mean(SD)].

F

pa

pb

1.71±0.30

4.096

0.020*

Group I,II
1.65±0.29

7.811

0.001*

Group I,II
Group I

Group II

HC

n=30

n=22

n=31

Left

1.58±0.28

1.5±0.17

Right

1.52±0.21

1.5±0.18

Number of subjects NAA/Cr ratios

Cho/Cr ratios

Left

0.97±0.71

0.71±0.08

0.93±0.63

1.408

0.251

Right

0.89±0.55

0.91±0.84

0.93±0.72

0.019

0.981

Group I: Acute depressive episode bipolar disorder patients.

Group II: Euthymic bipolar disorder patients HC: Healthy controls NAA/Cr: N-acetylaspartate/creatine.

Cho/Cr, Choline/creatine.

a

One-Way ANOVA analyses, p< 0.05 significant.

b

Bonferronis correction test, p< 0.05 significant.

Table 3

Comparison of cold function among three groups[mean(SD)].

Group I

Group II

HC

F

pa

pb

Number of Correctly WSCT

4.97±1.45

4.68±1.73

6.87±1.477

17.05

0.000

Controls>Group I,II

Total errors WSCT

11.43±7.37

13.14±10.039

3.97±6.74

10.59

0.000

Controls
perseverative errors WSCT

6.77±5.606

8.32±8.60

1.81±4.915

8.063

0.001

Controls
Noperseverative errors WSCT

3.97±1.608

4.77±2.36

1.9±4.585

5.854

0.004

Controls
TMT-B Time

59.95±25.00

54.57±17.93

49.48±14.69

2.135

0.125

TMT-B errors

0.53±0.86

0.18±0.66

0.23±0.56

2.050

0.135

TMT-B uptake

0.97±1.37

1.36±1.59

0.23±0.56

6.143

0.003

Group I:

Acute depressive episode bipolar disorder patients.

Group II: Euthymic bipolar disorder patients HC: Healthy controls SWCT: Wisconsin Card Sorting test

TMT-B:Trail Making Test B

a

One-Way ANOVA analyses, p< 0.05 significant.

b

Bonferronis correction test, p< 0.05 significant.

Controls
Table 4

Correlation between cold function and biochemical metabolite ratios in acute episode

patients with BD

NAA/Cr

Cho/Cr

Left

Right

Left

Right

Number of Correctly WSCT

0.411*

-0.188

0.203

-0.075

Total errors WSCT

-0.403*

0.074

-0.137

0.079

perseverative errors WSCT

-0.331

-0.078

-0.102

0.131

Noperseverative errors WSCT

-0.269

0.124

-0.052

0.129

TMT-B Time

-0.343

0.043

-0.205

0.039

TMT-B errors

-0.256

-0.006

0.006

0.171

TMT-B uptake

-0.358*

-0.025

-0.122

0.306

NAA/Cr: N-acetylaspartate/creatine.

Cho/Cr, Choline/creatine.

SWCT: Wisconsin Card Sorting test

TMT-B:Trail Making Test B

*p< 0.05 significant.

Table 5

Correlation between cold cognition and biochemical metabolite ratios in euthymic

episode patients with BD

NAA/Cr

Number of Correctly WSCT

Cho/Cr

Left

Right

Left

Right

0.367

0.084

-0.274

-0.140

Total errors WSCT

-0.222

-0.159

-0.139

0.007

perseverative errors WSCT

-0.184

-0.090

-0.126

-0.005

Noperseverative errors WSCT

-0.288

-0.364

-0.159

0.048

TMT-B Time

0.053

-0.056

0.045

-0.083

TMT-B errors

-0.123

-0.07

-0.246

-0.056

TMT-B uptake

0.026

-0.128

-0.055

-0.174

NAA/Cr: N-acetylaspartate/creatine.

Cho/Cr, Choline/creatine.

SWCT: Wisconsin Card Sorting test

TMT-B:Trail Making Test B

*p< 0.05 significant.

Table 6

Correlation between biochemical metabolite ratios and clinical data of BD patients

NAA/Cr

Cho/Cr

Left

Right

Left

Right

Age (year)

-0.029

-0.155

-0.120

-0.202

Age of onset (year)

-0.222

-0.159

-0.139

0.007

Duration of illness

-0.258

-0.235

-0.098

-0.064

Duration of euthymic illness

-0.202

0.095

-0.09

-0.098

Number of episodes

-0.288

-0.364

-0.159

0.048

24-item HDRS score

-0.120

-0.029

-0.202

0.155

Y-MRS

0.232

0.073

-0.008

0.058

NAA/Cr: N-acetylaspartate/creatine.

Cho/Cr, Choline/creatine.

*p< 0.05 significant.

Table 7

Correlation cold function and clinical data of BD patients Age of onset

Duration of illness

Number of episodes

24-item HDRS score

Y-MRS

Number of Correctly WSCT

-0.142

0.334

0.068

0.087

-0.023

Total errors WSCT

0.175

-0.03

-0.074

-0.098

0.068

perseverative errors WSCT

0.203

-0.118

-0.012

-0.153

0.041

Noperseverative errors WSCT

0.110

-0.261

-0.197

-0.232

-0.238

TMT-B Time

0.062

-0.103

0.159

0.158

0.133

TMT-B errors

0.117

-0.309

0.175

0.224

0.066

TMT-B uptake

0.082

-0.35

-0.049

-0.097

0.023

NAA/Cr: N-acetylaspartate/creatine.

Cho/Cr, Choline/creatine.

24-item HDRS: 24-item Hamiltion Depression Rating Scale.

Y-MRS: Young manic rating scale. SWCT: Wisconsin Card Sorting test.

TMT-B:Trail Making Test B.

*p< 0.05 significant.

Fig.1-2. Magnetic resonance image (MRI) scan of healthy control subject showing location of magnetic resonance spectroscopy (MRS) of volume of interest (VOI) placed in the putamen, and proton magnetic resonance spectra in the left and right putamen. The large white box represents the VOIx for MRS acquisition, and small

white boxes depict the individual VOIs for spectral analysis. Note: NAA, N-acetylaspartate; Cho, choline; mI, myo-Inositol; Cr, creatine HIGHLIGHTS 1. Both acute and euthymic episode patients with bipolar disorder had biochemical abnormalities in the lenticular nucleus and cold cognition dysfunction. 2. Cold cognition dysfunction and biochemical abnormalities are the most likely candidates as endophenotypes for bipolar disorders. 3. Dysfunction of neuronal function in the lenticular nucleus may correlate with the cold cognition dysfunction in acute patients with BD