RESEARCH ARTICLE Abnormal Resting-State ...

RESEARCH ARTICLE Journal of Medical Imaging and Health Informatics

Copyright © 2016 American Scientific Publishers All rights reserved Printed in the United States of America

Vol. 6, 1673–1678, 2016

Abnormal Resting-State Regional Homogeneity Relates to Cognitive Dysfunction in Manic Bipolar Disorder Adolescents: An fMRI Study Dong Cui1 2 † , Weijia Gao3 † , Qing Jiao1 2 ∗ , Weifang Cao1 2 , Rongfeng Qi4 , Yongxin Guo1 2 , Feng Chen5 , Dali Lu6 , Qian Xiao6 , Linyan Su6 ∗ , and Guangming Lu4 1

Department of Radiology, Taishan Medical University, Taian, Shandong, 271016, China 2 Collaborative Innovation Center of Magnetic Resonance Imaging of Brain Disease, Taishan Medical University, Taian, Shandong, 271016, China 3 Department of Child Psychology, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China 4 Department of Medical Imaging, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, Jiangsu, 210002, China 5 Department of Radiology, People’s Hospital of Hainan Province, Haikou, Hainan, 570311, China 6 Mental Health Institute of the Second Xiangya Hospital, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Changsha, Hunan, 410011, China Nineteen manic adolescents (male/female, 7/12) with bipolar disorder and 18 age- and gender-matched normal adolescents (male/female, 6/12) were included in the study. The stroop color-word test (SCWT), visual reproduction test and trail making test (TMT) were used to assess the cognitive function of the patients and the healthy controls (HCs). The regional homogeneity approach was used to study the resting-state brain activity. Correlation between the resting-state brain activity and neuropsychological testing were analyzed. In the neuropsychological tests, the values of the test of SCWT, TMT-A and visual reproduction test of adolescents were significantly decreased compared with those of the HC group (p < 005). Compared with the control group (p < 005), the results of two-sample T-test showed that the brain areas with increased ReHo value included the left middle cingulate cortex (MCC_L) and decreased ReHo value included the left superior parietal gyrus (SPG_L), the inferior occipital gyrus (IOG), the right superior temporal gyrus (STG_R), the right superior occipital gyrus (SOG_R), the left precuneus (PCUN_L), the left supplementary motor area (SMA_L) and the left cerebelum_Crus2. Moreover, the mean ReHo values in the SOG_R were negatively correlated with the TMT-A scores and the mean ReHo values in the STG_R were negatively correlated with the Visual reproduction test scores. Pediatric bipolar disorder (PBD) patients have broad impairment of cognitive functions, including attention, spatial perception, memory and executive functions, which provides a new perspective for clarifying the pathophysiologic basis of cognitive impairment in patients with PBD.

Keywords: Pediatric Bipolar Disorder (PBD), Mania Episode, Functional Magnetic Resonance Imaging (fMRI), Regional Homogeneity (ReHo).

1. INTRODUCTION Bipolar disorder (BD) in children and adolescents is a serious chronic relapsing mental illness, and its main features lie in the rapid cycle of depression and manic symptoms and long-term maintenance of mixed episodes.1 A meta analysis on the epidemiological data of PBD found that 1.8% children and adolescents meet the diagnostic criteria of BD.2 Perlis RH made a retrospective study on adult patients with BD, and found that ∗ †

Authors to whom correspondence should be addressed. These two authors contributed equally to this work.

J. Med. Imaging Health Inf. Vol. 6, No. 7, 2016

up to 67% of the patients with BD begin with the symptoms at an age earlier than 18 years,3 and up to 75% of patients with PBD requires hospitalization, 65% of PBD patients have attempted suicide.4 Compared with adult patients, PBD patients are younger, and more difficult to clearly express their inner feelings, and sometimes they even have self-contradictory emotional expressions. The PBD patients have atypical symptoms, high risk of suicide, chronic disease, the poor efficacy of traditional mood stabilizers, anxiety disorders and attention deficit disorder and other characteristics,5 6 which bring great difficulties and challenges to diagnosis of clinicians. Studies have shown

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doi:10.1166/jmihi.2016.1870 1673

RESEARCH ARTICLE cognitive impairment in the attention, memory, executive function and other aspects in adolescent patients of bipolar disorder, and the damage will continue to exist in a stable period.7 8 Among them, the impairment in verbal memory and executive function of patients with PBD is the most obvious,9 seriously affecting the growth and studies of children and adolescents and bringing serious economic and emotional burden to the patient’s family. The relationship between such damaged cognitive function and brain activity, however, remains unclear in PBD patients. The fMRI study can explore the brain activity and structural changes. Therefore, RS-fMRI studies on PBD may help to illustrate the pathophysiological mechanisms of cognitive impairment in patients with PBD. The task-dependent fMRI based on the emotion processing, cognitive processing and other neuropsychological models has been widely used in studies of patients with PBD. In a variety of emotion tasks, the PBD patients showed the enhanced or diminished activity in the ventral prefrontal cortex (VLPFC),10–13 the dorsal prefrontal cortex (DLPFC)10 12 14 and the anterior cingulate cortex (ACC)15 16 compared with the control group. In cognitive tasks, the DLPFC,14 17 superior frontal gyrus (SFG),18 putamen (PUT) and thalamus (THA)19 activity of the PBD patients increased. Resting-state functional connectivity (RSFC) study showed a negative RSFC in the left VLPFC and the right STG.20 In Lu’s application of the ALFF, the results showed that the values of ALFF were significantly enhanced in the brain regions of left SFG, the right ACC and the IOG of PBD patients by comparing with PBD group and the control group.21 Compared with HCs, the values of ReHo in the anterior central gyrus (ACG), the parietal lobe, superior frontal gyrus (SFG), PCUN of PBD patients were significantly weakened, and the values of ReHo were significantly enhanced in the ACC, THA, parahippocampal gyrus (PHG), caudate nucleus (CAU) of PBD patients.22 Most of these studies revolved about brain functional changes in PBD patients, giving fewer clues on the relationship between brain activity and cognitive behavior of PBD. Given the above, the objective of this study is to explore the brain regions or brain network associated with cognitive impairment in PBDmania patients. To achieve these goals, the ReHo23 of the blood oxygenation level-dependent (BOLD) fMRI signals is calculated to observe the brain abnormalities and used to analyze the relationship between brain abnormalities and neuropsychological test scores.

2. MATERIALS AND METHODS 2.1. Subjects Twenty PBD-mania adolescents were recruited at the Mental Health Institute of the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, People’s Republic of China. Twenty age and gender matched HCs were also recruited from the public middle schools of Changsha. None of HCs had a history of neurological or psychiatric disorder. All participants were right-handed and Han nationality. Exclusion criteria of all subjects were: Full-Scale intelligence quotient (IQ) 203) and a minimum cluster size of 44 voxels). Threshold correction was performed by using Monte Carlo simulation (AlphaSim: individual voxel p value = 001, 10000 simulations, FWHM = 8 mm, with mask) in the REST software. Demographic data were analyzed with the independent-sample t-test and chi-square 2 tests respectively. Relationship between the neuropsychological tests scores and activity of brain areas was assessed using Pearson’s correlations analysis of SPSS software (v19.0, IBM Corporation, NY, USA).

Table I. Sample characteristics. Characteristics

PBD-mania

Gender (male/female) Age (years) Education (years) IQ YMRS scores Onset age (years) Illness duration (months) Onset frequency The first episode bipolar disorder (mania/depression) Psychotic symptoms (yes/no) BP-I/BP-II Familial BD history (yes/no)

7/12 6/12 15.05 ± 1.78 14.06 ± 1.55 8.11 ± 1.66 7.22 ± 1.99 97.53 ± 13.77 105.61 ± 7.61 33.05 ± 6.09 3.72 ± 2.08 13.84 ± 1.64 13.95 ± 11.75 3.11 ± 1.73 7/12

HC

p value 0823a 007b 0151b 0035b 0000b

10/9 15/4 5/14

Notes: The data were shown in mean ± standard deviation; a Pearson chi-square test; b Independent sample T test. Abbreviations: BP-I, bipolar disorder type I; BP-II bipolar disorder type II.

3. RESULT 3.1. Subjects No subject fell asleep in the scanning process. One patient and 2 healthy controls were excluded because head motion exceeded 1.0 mm or any angular motion exceeded 1.0 during scanning. There was no significant difference between PBD-mania and HC groups in age, gender, full-scale IQ. But the mean YMRS score was significantly higher in patients than that in the controls. For PBD-mania patients, onset age was (1384 ± 164), illness duration was (1395 ± 1175), and onset frequency was (311 ± 173). Seven patients of the first episode bipolar disorder were mania (36.8%), 10 patients had psychotic symptoms (52.6%), 15 patients were type I BD (78.9%), and 5 patients had a familial BD history (26.3%). The demographic data are presented in Table I. All of the healthy subjects completed the whole neuropsychological test, but only 17 patients completed the SCWT-1, SCWT-2, SCWT-3 and TMT-A tests, and 15 patients completed the TMT-B and Visual reproduction tests. There were significant group differences in the SCWT-1, SCWT-2, SCWT-3, TMT-A and Visual reproduction tests scores between the PBD patients and the HCs (P < 005). The neuropsychological tests scores are presented in Table II. 3.2. Between-Group ReHo Differences As shown in Table III and Figure 1, compared to HCs, the PBDmania group showed significant increased ReHo value in the MCC_L. Regions showed that decreased ReHo value included

Table II. Neuropsychological tests scores in PBD-mania versus HC subjects. Characteristics SCWT-1 SCWT-2 SCWT-3 TMT-A TMT-B Visual reproduction test

PBD-mania

HC

p valuea

53.35 ± 17.26 70.47 ± 20.11 30.18 ± 7.16 38.94 ± 12.81 87.53 ± 31.53 8.93 ± 3.63

65.44 ± 12.36 87.11 ± 8.83 40.22 ± 9.42 30.5 ± 9.29 82.17 ± 29.51 13.17 ± 1.51

0023 0003 0001 0032 0618 0000

Notes: The data were shown in mean ± standard deviation; visual reproduction test is come from the wechsler memory scale; a Independent sample T test.

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Table III. Regions showing significant differences in ReHo between PBD-mania and HCs. Brain regions PBD versus HC PBD > HC MCC_L PBD < HC SPG_L IOG_L IOG_R STG_R SOG_R PCUN_L SMA_L Cerebelum_Crus2_L

Peak MNI coordinate Cluster size

x

y

z

t value

60

−9

−30

39

381

131 85 80 88 65 62 52 45

−24 −36 45 51 24 −18 −6 −9

−60 −72 −54 −60 −81 −60 12 −84

60 −9 −21 24 33 21 48 −27

−478 −379 −441 −366 −285 −441 −370 −405

Abbreviations: MNI, Montreal Neurological Institute.

the SPG_L, the IOG, the STG_R, the SOG_R, the PCUN_L, the SMA_L and the left cerebelum_Crus2. 3.3. Correlations Correlations between ReHo values in regions had significant group differences and TMT-A and Visual reproduction tests scores were evaluated in PBD-mania patients. It was observed in patients that there was negative relationship of TMT-A scores with mean ReHo values in the SOG_R (r = −0509, p = 0037) and negative relationship of Visual reproduction test scores with mean ReHo values in the STG_R (r = −0580, p = 0030). (See Fig. 2).

4. DISCUSSIONS ReHo was used to show neural synchronization of local brain regions in PBD-mania patients during resting-state. The current results revealed a significantly increased ReHo value in the MCC_L in PBD adolescents compared with that of the HCs. Meanwhile, diffuse brain regions showed decreased ReHo Fig. 2. Correlation analysis between trail making test, visual reproduction test scores and mean ReHo values in the PBD-mania patients (p < 005, corrected).

Fig. 1. T-statistical different maps between PBD-mania patients and healthy controls (two-sample t test; p < 005, corrected). Notes: The ReHo showed decrease (cold colors) in the cerebelum_Crus2_L (A), IOG (B1 and B2), STG_R (C), PCUN_L (D), SOG_R (E), SMA_L (G) and SPG_L (H). An increase (hot colors) in MCC_L (F). Abbreviations: L, left; R, Right.

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values in PBD-mania patients. These regions were distributed over the SPG_L, the IOG, the STG_R, the SOG_R, the PCUN_L, the SMA_L and the left cerebelum_Crus2. Moreover, the mean ReHo values in the SOG_R were negatively correlated with the TMT-A scores and the mean ReHo values in the STG_R was negatively correlated with the visual reproduction test scores. Compared with that of the HCs, a significantly reduced ReHo value in STG in PBD manic adolescents was found in the present study, suggesting an abnormal deactivation in the regional homogeneity in this brain region. The STG was located between the lateral fissure and superior temporal sulcus, and contained two important brain regions, namely, the primary auditory cortex and Wernicke area. Primary auditory cortex was responsible for sound perception, while the Wernicke area of dominant hemisphere was sensory language center, and was widely related to the contact cortex relevant with the somatic sensation, hearing and vision.31–33 PET study had shown that an appearance of activation in the memory coding and reproduction of the STG, indicating that the STG was related to the memory processes.34 35


In the present study, visual reproduction test scores of PBD adolescents were lower than those of the control group, indicating a decreased short-term memory capacity and delayed recall ability in the patients. Furthermore, the ReHo value of STG was negatively correlated with visual regeneration test scores, thus it is believed that dysfunction of the STG may be the pathophysiological basis of memory impairment of PBD adolescents. Occipital lobe is situated behind the link line between the occipital parietal fissure and preoccipital incisures, and is responsible for processing visual information. Occipital striated region is extensively related to other regions of the two hemispheres, and plays a vital role in the process of integrating information collected from the visual information, the auditory and other sensory systems, as well as linking the visual information with the language and other brain processing systems with executive function.36 It was found in the present study that a decreased ReHo of SOG_R and bilateral IOG in PBD adolescents, indicating a weakened resting-state spontaneous neural activity consistency of occipital lobe visual cortex area. Compared with the control group, the manic PBD patients have a significantly increased ALFF value of bilateral IOG according to the study,21 which shows that neural activity of the brain region in this part is abnormal in the manic phase. In the present study, the TMT scores of patients with PBD were lower than those of the HCs, and the mean ReHo values of SOG_R were negatively correlated with the scores of TMT-A, indicating that the occipital lobe dysfunction may be responsible for the weakened implementation of attention, spatial perception and hand-eye coordination in PBD adolescents. A noteworthy finding is the decreased ReHo values in the left cerebellar peduncle Zone 2 of PBD adolescents. At present, some scholars believe that the cerebellum may be involved in the construction of the limbic system, which is an important structure in the regulation of mood and emotion.37 Related neuroanatomical studies have shown that in addition to receiving the connection of motor cortex, the cerebellum also receives information from other brain regions closely related to cognitive and emotional adjustment, such as the inferior thalamus, the PHG, the upper part of the temporal lobe, the prefrontal and the cingulate gyrus.38 The concept of cerebellar cognitive affective syndrome is proposed in some literatures, which usually is usually referred to as the emotion blunting, depression to affective disorder, and the appearance of executive, visual, spatial and language barriers.39 Therefore, the cerebellum plays a role in emotion regulation and cognitive function. The study finds that the PBD adolescents have abnormality in the left cerebellar peduncle, which may prompt the involvement of cerebellum in cognitive function and emotional regulation. The function of parietal lobe is involved in the processing of touch sensation and proprioceptive information, the understanding of languages as well as the writing and spatial orientation, and the parietal lobe is closely related to the attention function.40 41 The defect in attention is one of the more common symptoms of patients with bipolar disorder; so many studies speculate that the abnormalities in the structure and function of parietal lobe are related to the pathogenesis of bipolar disorder.42 We have found that the TMT scores and the SCWT-2 scores are reduced in PBD adolescents, suggesting an attention functional disorder in patients. Therefore, the reduced ReHo value of SPG in PBD manic adolescents, which was found in the present study,

RESEARCH ARTICLE may provide a further evidence for the key role of this brain region attention. In this study, adolescents with bipolar disorder were selected as subjects. Compared with adult patients, the impacts of long-term exposure to the drug, substance abuse, recurrent mood symptoms and psychosocial factors on adolescents are relatively small, so adolescents can provide important information on the relationship between brain development and bipolar disorder.43

5. LIMITATION There are two limitations in our study including psychotropic medications, comorbidity and sample size. Firstly, in the present study, 84% of the PBD patients used more than one kind drug (lithium, valproate, antipsychotic and antidepressant drugs) for psychological treatment. Till now the effect of psychopharmacological treatment on cognitive function remains unclear. Psychopharmacological treatment can generally affect attention, psychomotor speed and memory. It was believed, however, that illness itself, rather than antipsychotic treatment, was responsible for some aspect of cognitive function, such as information processing impairment.44 For example, although lithium may have side effects on memory and concentration,45 it was shown that most aspects of cognitive function were not affected by lithium.46 Tricyclic antidepressants may improve the performance of depressed patients on memory and learning tests despite their adverse effects on mnemonic.47 Considering the small sample of the present study, we may not research the issue deeply. Much data needed for explicating the neurocognitive effect of medication in our future work. Secondly, some adolescents also suffered from other psychiatric disorders. Some studies suggest that comorbidity may affect the functional imaging change of PBD. However, the samples included in this study are relatively small, thus failing to carry out further inspection after the test, and these comorbidities may influence the above results to a certain extent.

6. CONCLUSION In summary, the regional homogeneity alterations are evaluated by the analysis of the resting-state BOLD signal, and several brain regions are found to have showed significant changes in the PBD-mania group, including the STG_R, the SOG_R, the left cerebellar peduncle Zone 2 and the SPG_L. These regions are important for memory, spatial perception, hand-eye coordination and attention. Combined with more large samples and clinical indicators in the future, this method may be helpful in diagnosis for the cognitive dysfunction of PBD.

Acknowledgments: This work was supported by the Funds for the National Natural Science Foundation of China (30470510, 30670600 to GL, 30770767 to LS, 81371531 to QJ, 81301209 to RQ and 81260218 to FC). The authors gratefully acknowledge the assistance of all people whose participation and help are essential in the successful completion of the study.

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Received: 11 April 2015. Revised/Accepted: 5 June 2016.

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