Yingzhi Lu1, Wenbin Zong1, Hanzhen Dong1, Faxin Wang1, Jinyu Pu1, Xingshi Chen2, Yunxiang Tang2

1Department of Psychiatry, Fifth People’s Hospital of Zibo, Zibo  255120, Shandong Province, China
2Department of Neurophysiology, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai  200030, China

Yingzhi Lu☆, Doctor, Chief physician, Department of Psychiatry, Fifth People’s Hospital of Zibo, Zibo  255120, Shandong Province, China

Corresponding author: Xingshi Chen, Professor, Department of Neurophysiology, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai  200030, China; Yunxiang Tang, Doctor, Associate professor,? Department of Neurophysiology, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai  200030, China
chenxingshi2008@163.com;
tangyunxiang1973@tom.com

Supported by: the National Natural Science Foundation of China, No. 30770772*, 30971046*; the Foundation of Shanghai Science and Technology Commission, No. 09411968200*; the Major State Basic Research Development Program of China (973 program), No. S2009051026*

www.crter.cn
www.nrronline.org

doi:10.3969/j.issn.1673-5374.2010.12.010

Abstract
BACKGROUND: Study results of event-related potential in obsessive compulsive disorder (OCD) remain controversial, potentially as a result of different instruments utilized and their differing technical characteristics.
OBJECTIVE: To investigate the differences in several common event-related potentials, i.e. contingent negative variations, P300, and mismatch negativity (MMN), in OCD patients, depression patients, generalized anxiety disorder (GAD) patients, and healthy controls.
DESIGN, TIME AND SETTING: A case-control study was performed in the Department of Electrophysiology, Shanghai Mental Health Center from May 2002 to December 2005.
PARTICIPANTS: A total of 38 OCD patients, 20 depression patients, and 18 GAD patients, who were diagnosed according to the criteria of Chinese Classification of Mental Disorders (Version 3), formulated by the Chinese Psychiatry Association, were selected from the Outpatient Department of Shanghai Mental Health Center. Patients with two or more the above diseases were excluded. In addition, 28 healthy people, gender and age matched, were selected as controls.
METHODS: Contingent negative variations, P300, and MMN were recorded by a Nicolet Spirit Instrument. All electrodes were attached at Cz according to the International 10-20 system, with the mastoid leads as reference and Fpz as ground.
MAIN OUTCOME MEASURES: Amplitude and latency of contingent negative variations, P300, and MMN.
RESULTS: The contingent negative variations, P300, and MMN were different (P < 0.01). OCD patients showed an increased M1 amplitude compared with controls, depression, and GAD patients (P < 0.01). Target P300 amplitudes were significantly lower in OCD, depression, and GAD patients compared with controls (P < 0.01). Moreover, N2 latency and latency of MMN were prolonged in OCD and depression groups compared with controls (P < 0.05).
CONCLUSION: Event-related potentials were different in depression, GAD, and OCD patients and healthy controls. In particular, OCD patients exhibited unique characteristics.
Key Words: obsessive compulsive disorder; depression; generalized anxiety disorder; contingent negative variation; event-related potential-P300; mismatch negativity

INTRODUCTION
   
Objective experimental evidence is lacking in auxiliary diagnosis of obsessive compulsive disorder (OCD)[1]. Studies recording event-related potentials (ERPs) in OCD patients remain controversial[2-5]. For example, OCD patients have significantly greater amplitudes of P3b, a component of P300, compared with healthy controls[4, 6], but others found decreased P300 amplitude in OCD patients[7]. The primary cause of these different results may relate to instrumental and technical differences[8].
Previous studies commonly compared OCD patients with normal controls[6-7], but other mental disorders may show ERP variations. We compared three ERPs, contingent negative variation (CNV), P300, and mismatch negativity (MMN) in OCD, depression, and generalized anxiety disorder (GAD) patients, as well as normal controls.

SUBJECTS AND METHODS

Design
Case-control study.
Time and setting
The study was performed in the Department of Electrophysiology, Shanghai Mental Health Center from May 2002 to December 2005.
 
Subjects
All patients were selected from the Outpatient Department of Shanghai Mental Health Center. They were diagnosed by two experienced psychiatric doctors according to the Chinese Classification of Mental Disorders (Version 3) for OCD, depression, and GAD, formulated by the Chinese Psychiatry Association[9]. Patients who had two or more the above diseases were excluded. All included patients were right-handed and free of neuroleptic drugs or other physical and mental disorders, with normal hearing.
OCD group (n = 38): They were assessed by neuropsychological tests, such as Yale-Brown Obsessive Compulsive Scale for OCD (> 16 scores), Hamilton rating scale for depression (HAMD, < 17 scores) and Hamilton rating scale for anxiety (HAMA, < 14 scores)[10].
Depression group (n = 20): a score of > 21 on HAMD  and < 14 on HAMA[11].
GAD group (n = 18): the patients scored > 14 on HAMA and < 17 on HAMD[12].
Normal control group (n = 28): patients were in good physical and mental state as confirmed by clinical examination. None of these patients had a history of alcoholism or drug abuse or family history of psychiatric illness.
Written informed consents were obtained from all participants, and the experiments were performed in accordance with the Administrative Regulations on Medical Institution, formulated by the State Council of the People's Republic of China[13].
Methods  
ERPs of patients were assessed using an American Nicolet Spirit Instrument. All electrodes were attached at Cz according to the international 10-20 system, with the mastoid leads as reference and Fpz as ground[14].
CNV detection: CNV was composed of two stimuli. S1 was a short sound stimulus as a hint signal, and S2 was a goggle flash stimulation as a command signal. The subjects were asked to expect the appearance of S2 after receiving S1 and press a key to discontinue S2 when they received S2.
P300 detection: P300 was elicited from the scalp by presenting the subject an auditory oddball paradigm. It was comprised of standard stimuli (tone of 500 Hz, 80 dB and emerging probability of 0.8) and deviant stimuli (tone of 2 000 Hz, 85 dB and a probability of 0.2). P300 recordings were made when each subject was asked to count the number of emerging deviant stimuli. Inter-stimulus interval was maintained at 1 second. A total of 200 stimuli were presented in one round. Sounds were delivered binaurally through earphones. Each subject had to undertake two rounds of auditory stimuli.
MMN detection: Comprised of standard stimuli (tone of 500 Hz, 80 dB and emerging probability of 0.8) and deviant stimuli (tone of 2 000 Hz, 85 dB and a probability of 0.2). Inter-stimulus interval was maintained at 1 second. MMN recording was obtained while each subject was asked not to count the number of deviant stimuli during the first round.
Main outcome measures
Amplitudes and latencies of CNV, P300, and MMN were identified and measured.
Statistical analysis
Statistical analysis was performed using SPSS 10.0 (SPSS Inc., Chicago, IL, USA) for Windows statistical packages. Intergroup differences of ERP measures were tested using an analysis of variance and Duncan test. Chi-square test was used for the incidence (%) of post-imperative negative variation (PINV) and contingent positive variation (CPV). A value of P < 0.05 was considered statistically significant.

RESULTS

Quantitative analysis of participants
All 104 participants were included in the final analysis.
Baseline data
The baseline data of 104 participants were harvested (Table 1).

CNV comparison among groups
The amplitude and latency of CNV primary wave patterns, M1, M2, and incidence of post-imperative negative variation (PINV) and contingent positive variation (CPV) showed significant differences in M1 amplitude among all groups (P < 0.01). Compared with normal controls, M1 amplitude significantly decreased in depression and GAD groups (P < 0.01), while M1 amplitude was greater in OCD patients than normal controls. In addition, the incidence of PINV was significantly greater in OCD, depression, and GAD patients than controls (P < 0.01). In particular, depression patients exhibited the greatest incidence of PINV, followed by OCD and GAD patients. There were no differences in M1, M2 latency, M2 amplitude or CPV incidence among the groups (P > 0.05;  Table 2).
 

 
P300 and MMN comparison among groups
All participants exhibited significant differences in N2 latency and P3 target amplitude as well as P2 non-target amplitude (F = 6.87, P < 0.01; F = 16.91, P < 0.01; F = 3.89, P < 0.05). Compared with normal controls, OCD and depression patients had decreased P3 amplitude and delayed N2 latency (P < 0.01). GAD and depression patients had decreased P3 target amplitude compared with normal controls (P < 0.01), and GAD patients exhibited decreased P2 non-target amplitude of compared with OCD patients (P < 0.01; Table 3).
MMN latency and amplitude were different in OCD, depression, and normal controls (F = 3.35, P < 0.05; F = 59.9, P < 0.01). Compared with normal controls, OCD and depression patients showed delayed MMN latency (P < 0.05), but OCD patients showed increased MMN amplitude (P < 0.01) more than depressed pa-tients (P < 0.01; Table 3).
 

DISCUSSION

We compared event related potential data in OCD, depression, and GAD patients with normal controls. Patients were assessed by the Yale-Brown Obsessive Compulsive Scale, HAMD, and HAMA to select those with a single disease.
Simplified analysis of CNV, the main components of CNV, M1 and M2, and the typical incidence of PINV were analyzed, with flash stimulation as a command signal. Results showed decreased M1 amplitude of CNV in depression and GAD groups compared with normal controls and OCD group. Moreover, the incidence of PINV in depression, GAD, and OCD groups was greater compared with normal controls, consistent with previous results[8, 15-17]. CNV can reflect orientation to warning stimulus and anticipation of the imperative stimulus[18-19], suggesting the over activation of attention-related fronto-parietal networks in OCD patients. CPV is seldom observed in normal people, occasionally in children, but commonly observed in patients with schizophrenia and Alzheimer’s disease, which was the inversion of location in CNV[16]. CPV did not occur in normal controls or GAD, but was detected in OCD and depression patients.
OCD and depression groups showed delayed N2 latency compared with normal controls, suggesting a delay of cognitive processing, which may relate with dysfunction of cortico-subcortical circuits[20]. OCD, depression, and GAD groups exhibited decreased P3 amplitude compared with normal controls. As P3 amplitude reflects temporoparietal cortex activation[9], the findings here suggest the hypoactivation of temporoparietal regions in OCD patients. In addition, the GAD group showed significantly decreased P2 non-target amplitude compared with OCD and normal control groups. Previous studies demonstrated an absence of the principal constituent of P300 in OCD patients[17], consistent with the present study. However, OCD patients have delayed latency on P2[4], in particular in the left hemisphere. Moreover, OCD patients show decreased N2 and P2 target latency compared with other groups[3]. This is different from our results, probably due to differences in stimulation patterns and ERP instruments[2-5, 21-22].
MMN changes like P300[20] but reflects the automatic identification of a change in standard and deviant stimuli while the subjects do not attempt to discriminate the stimulus deviance[23-24], which helps the subjects to complete the task. We found a delayed latency in OCD and depression groups compared with normal controls, increased amplitude in the OCD group compared with normal controls, and decreased amplitude in depression patients compared with normal controls and OCD group. The MMN waveform of the GAD group was not analyzed due to computer fault.
We found larger CNV and MMN amplitude in OCD patients compared with depression and GAD patients. Generally, increased amplitude is rarely observed in psychiatric disorders[15-17]. High CNV amplitudes reflect the predominant role of dopaminergic and cholinergic systems in OCD patients, whereas reduced CNV amplitude indicates dopaminergic hypoactivity, clinical low emotional state, and thought retardation[15]. Further study suggested that reduced CNV amplitude in GAD patients was caused by high attention disturbance[16], while increased CNV amplitude and reduced reaction time represent high motivational state of OCD and phobia patients[9].
In conclusion, OCD patients showed significantly greater amplitudes of CNV and MMN compared with depression and GAD patients, and the MMN amplitudes were even greater than the normal controls, which might contribute to brain hyperactivity in OCD patients. The ERP instrument has good spatial resolving power. Therefore, further studies are required to investigate the pathogenesis of OCD patients and disease controls in combination with other means of brain electrophysiology and brain imaging.

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 (Edited by Pan JY, Sui RB/Su LL/Song LP)