East Asian Arch Psychiatry 2010;20:62-68

ORIGINAL ARTICLE

A Study of Contingent Negative Variation and Post-imperative Negative Variation: Search for State and Trait Electrophysiological Markers in Schizophrenia
伴随性负变化和指令讯号后负变化的研究:精神分裂症的状态 和性向电生理学指针
J Simlai, SH Nizamie, CRJ Khess

Dr Jayati Simlai, MD, Department of Psychiatry, Ranchi Institute of Neuropsychiatry and Allied Sciences, Ranchi, Jharkhand, India.
Dr S. Haque Nizamie, DPM, MD, Central Institute of Psychiatry, Ranchi, Jharkhand, India.
Dr Christoday R. J. Khess, MD, Department of Psychiatry, Central Institute of Psychiatry, Ranchi, Jharkhand, India.

Address for correspondence: Dr Jayati Simlai, Department of Psychiatry, RINPAS, Ranchi 834006, Jharkhand, India.
Tel: (91) 9431105602; Email: jmou@rediffmail.com

Submitted: 30 November 2009; Accepted: 11 March 2010


pdf Full Paper in PDF

Abstract

Objective: To compare event-related potential measures, contingent negative variation and post- imperative negative variation in drug-naïve or drug-free schizophrenic patients and normal healthy controls, and to study the effect of antipsychotic medication on the above measures.

Methods: A hospital-based prospective study was conducted at Central Institute of Psychiatry, Ranchi, India. The sample constituted 31 drug-naïve or drug-free patients with schizophrenia and 31 normal healthy individuals, matched for age and gender. An S1-S2 paradigm was used, in which the warning stimulus (S1) was auditory and the target stimulus or imperative stimulus (S2) was visual. The early contingent negative variation was marked at 500 milliseconds after S1, and late contingent negative variation was marked as the negative wave just prior to S2. The post-imperative negative variation was measured as the continued negativity after S2.

Results: Drug-naïve and drug-free patients significantly differed from the controls on amplitudes of early and late contingent negative variations, as well as on latency of late contingent negative variation. The rate for correct classification in 80% of cases (Wilks’ lambda = 0.76) was observed in measuring amplitude of late contingent negative variation only. After exposure to antipsychotic drugs, the late contingent negative variation amplitude was found to normalise in the patient group.

Conclusion: The late contingent negative variation could be considered a state marker for schizophrenia.

Key words: Contingent Negative Variation; Evoked potentials; Schizophrenia

摘要

目的: 比较无药物治疗组(即从未接受药物治疗)/停用药物组(即停用药物至少6个月)的精 神分裂症患者和对照组的与事件相关电位:伴随性负变化和指令讯号后负变化,并分析它们对抗精神病疗程的影响。

方法: 这项于印度兰契巿中央精神科医院进行的前瞻性研究包括年龄和性别匹配的31名无药 物治疗组/停用药物组患者和31名对照组成员。 研究使用S1-S2范例,S1为听觉性警告刺激, S2为视觉性目标或命令式刺激,并于S1后500毫秒记下伴随性负变化早成分,而当负波在S2出 现前就量度伴随性负变化晚成分。 指令讯号后负变化则为S2后的持续性负波度。

结果: 不论伴随性负变化早成分跟晚成分的幅度,或者伴随性负变化晚成分的潜伏期,无药物 治疗组/停用药物组在大部分电极位置都跟对照组有显著分别。 只量度伴随性负变化晚成分的时候,能把病例分类的准确度为80%(Wilks’ lambda = 0.76)。 在服用抗精神病药后,患者的伴 随性负变化晚成分的幅度回复正常水平。

结论: 伴随性负变化晚成分可被考虑为精神分裂症的状态指针。

关键词: 伴随性负变化,诱发电位,精神分裂症

Introduction

Among the novel tools for experimental analysis of cognitive function, averaged time-locked event-related potentials (ERPs) have been widely studied. The slow potentials (SPs) are event-related electromagnetic variations, which can be recorded during time intervals in milliseconds that precede expected stimuli.1

The interest in slow waves and their neurophysiological basis began with the discovery of contingent negative variation (CNV) by Walter et al.2 The CNV is a surface- negative slow cortical potential elicited between the warning and the imperative stimuli when a response to the imperative stimuli is required. Pressing a button is an example. It is a slow negativity in the electroencephalography that appears during the anticipation period between a warning stimulus and a target response. There are 2 components of a CNV. The first is related to an orienting response to the warning stimulus (‘O’ wave) and the second component (‘E’ wave) is thought to be analogous to readiness potential which immediately precedes voluntary self-paced movement.3 The CNV represents summation of at least 2 components. There is stimulus-related frontally predominant negativity related to the orienting response and a centrally predominant negativity thought to be related to the premotor potential associated with motor response.4-8 The first portion and part of the second portion of CNV are independent of the motor response.4,9-11

The most consistent finding concerning the ERP of schizophrenics is reduced amplitude of CNV.12-14 Further, the CNV often does not return to baseline immediately. This is known as post-imperative negative variation (PINV).12-15 This is usually seen in acute schizophrenia. Among the SPs, CNV and PINV are well established as altered in amplitude and topography, and the former may be treated as a stable marker for schizophrenia.16 Earlier, SPs were suspected to originate from the prefrontal cortex.17

Event-related potentials give us the knowledge about cortical physiological processes during information processing. Depolarisation in the apical dendritic trees of cortical neurons results in surface-negative potentials.18 The difference observed in ERP between psychotic patients and normal subjects has been consistent and is thought to be related to cognitive processes.12,19 The reduction of the ERP amplitude has been interpreted as a sign of impaired information processing, inability to concentrate, increased distractibility or increased trial-to-trial variability of responses.19,20 The CNV is associated with focused attention and may serve as a state-dependent predictor of conscious awareness. Further, CNV has been proposed to reflect central dopaminergic activity.21,22

Unlike attenuation of most ERP components, there is an enhanced surface-negative potential (PINV) following a voluntary motor response.23 The PINV has been attributed to delayed CNV resolution,24,25 increased preparation for further stimulus and response evaluation,18,26 inability to resolve stimulus ambiguity,27 subjective ambivalence and difficulties in fitting the response into a symbolic scheme,28 and uncertainty about the results of actions.19,20

Methods

Subjects

A total of 31 schizophrenic patients fulfilling the Diagnostic Criteria for Research (DCR) accompanying the 10th revision of the International Classification of Diseases (ICD- 10) criteria29 were recruited from the psychiatry inpatient department of the Central Institute of Psychiatry Ranchi, India. The inclusion criteria for the patients were: (1) either drug-naïve (never treated) or drug-free (off-medications for the last 6 months at least); and (2) aged between 20 and 50 years. The patient sample consisted of only males, of which 8 were drug-naïve and 23 were drug-free. A control group matched for age and gender was recruited from normal healthy volunteers. The volunteers were assessed using the General Health Questionnaire-5 (GHQ-5).30 Those scoring 1 or more were excluded from the study. The aims, objectives and procedure of the study were explained, and informed consent was obtained from all subjects. The protocol of this study was approved by the academic and ethics committee of the institute.

After the subjects were enrolled for the study, they were assessed by Mandal et al’s Handedness Preference Schedule,31 a standardised Indian version of Annett’s handedness inventory.32 All subjects were found to be right- handed. Within 24 hours the patients were rated on the Brief Psychiatric Rating Scale (BPRS)33 and Positive and Negative Symptom Scale (PANSS) for schizophrenia34.

At baseline (drug-naïve / drug-free state) and after 1 month of antipsychotic treatment (post-drug state), CNV and PINV recordings were performed once for the control group and twice for the patients. After the baseline investigation, the patients were started on antipsychotics. They received 400 to 600 mg of chlorpromazine equivalent per day. Parkinsonian side-effects were assessed clinically and those who developed them were given trihexyphenidyl (2-4 mg per day). None of the patients were given benzodiazepines.

A Neuropack Sigma 8 software (Nihon Kohden, Japan) was used to record CNV and PINV. The CNV and PINV recordings were undertaken within 1 to 2 hours of food intake (10 am-12 noon, 2-4 pm). All the patients were afebrile at the time of recording. The patient’s scalp and hair were thoroughly washed with soap containing minimum glycerine. The subjects were allowed to dry their hair before the recording procedure. They were made to lie on a cot in the supine position keeping their eyes open and fixed at some specific spot and avoid blinking. They were also asked to remain immobile and stay relaxed. The hair was parted at the site of electrode placement and the skin cleaned by an absorbent cotton pad moistened in acetone. A small amount of skinpure (sand and jelly paste) was rubbed onto the cleaned spot so that the skin impedance was lowered. The electrode was pressed onto the cleaned spot using a small amount of electrode conductance jelly. Electrode resistance was kept to less than 2000 ohms.

The CNV was recorded by making the subject wear a pair of special goggles which emitted a red stroboscopic light produced in an odd-ball paradigm. A continuous masking noise of 75 dB was emitted through the headphones. Initially a warning tone appeared which alerted the subject for the following stroboscopic light stimulus. The moment the red stroboscopic light appeared, the subject was instructed to switch off the light by pressing the button each time as quickly as possible. The type of target stimulus (S2) was visual and the warning stimulus (S1) was auditory. The stimulation rate of S1 was 0.1 Hz and the interval between S1 and S2 was 3 seconds. The tone frequency of S1 was 1.5 KHz with a plateau time of 30 milliseconds; the rise and fall of time being 10 milliseconds. The high-cut filters were at 20 Hz and low-cut at 0.01 Hz for all channels. The preset count was 100. Rejection level was 3 divisions (which was indicated in the machine and its manual) and the paper speed was 25 mm per second. The various parameters measured were: N1, which was the first negative wave; after the S1 stimulus or the ‘O’ wave; N2, which was the early CNV (CNV [i]) marked at a fixed point 500 milliseconds after the stimulus S1, was called the ‘E’ wave; and N3, which was the late CNV (CNV [t]), was marked as a negative wave just prior to the onset of the light stimulus S2. The PINV was measured as the continued negativity after the stimulus S2. The scalp electrode sites used for recording were Fz, Cz, Pz, C3, and C4. The raters were final-year master-degree psychiatry residents who were undergoing postgraduate training. The inter-rater reliability was tested and found to be good (Kappa coefficient, -0.88).

Statistical Analysis

The group comparison of the various measures for drug- naïve / drug-free state versus normal controls and post-drug state versus normal controls was undertaken using one-way analysis of variance. Discriminant analysis was performed to find out whether any of the ERP measures could correctly discriminate between patients and controls. In the patient population, the results obtained in the drug-naïve / drug-free state and the post-drug state were compared to explore the possible effects of antipsychotic medication, using paired t tests.

Results

The mean (SD) age of the patient group was 30 (9) years, and that of the controls was 30 (4) years. The mean (SD) duration of the illness in the patient group was 6 (5) years. The mean (SD) BPRS score in the pre-drug state was 57 (13), and in post-drug state it was 35 (12). The mean (SD) PANSS positive index in the pre-drug state was 2 (8) and 13 (6) in the post-drug state. Corresponding values of the PANSS negative index were 22 (8) and 16 (7), and that of the composite index were 20 (11) and 20 (7), respectively.

The CNV (i) amplitudes between drug-free / drug- naïve schizophrenic patients and normal controls analysed by one-way analysis of variance are shown in Table 1. The results showed a significant difference at Cz electrodes. Table 2 shows the comparison of CNV (t) amplitude, and that there were significant differences at Fz, Cz, and C4 electrodes. A comparison of PINV amplitude between the normal controls and the patients of pre-drug state revealed that there was no significant difference at any of the sites. Table 3 shows the comparison of CNV (t) latency, with significant difference being found at all the 5 electrodes. When comparing PINV latency in the normal controls and pre-drug–state patients, no significant difference was noted at any of the sites. To investigate how correctly the 2 groups were classified as per the various measures described above, a discriminant analysis was performed. The rate for correct classification in 80% of cases (Wilks’ lambda = 0.757) was observed for only the measure of CNV (t) amplitude and hence only this was considered for further analysis. Comparison of CNV (t) amplitude between pre-drug and post-drug state in the patient population was performed using the paired t test, and that Table 4 revealed significant differences at all sites. Finally, comparison of CNV (t) amplitude of the post-drug state in the patient population with normal controls was performed using one-way analysis of variance, but no significant difference was found at any of the sites (Figure).

Discussion

The institute where this study was conducted is a 673- bedded tertiary centre catering to a large, predominantly rural population. Outpatient consultations are free but the patients have to buy their own medicines. This could be a reason why some poor patients were off-medication (drug- free) when seen for consultations. Hence we were able to recruit such individuals along with never-treated (drug- naïve) patients.

Age, gender, and psychoactive substances are known to influence CNV genesis,35 so the age and gender were matched for the control group, whilst the effects of antipsychotics on ERP measures were studied in the patient group. The earlier studies of ERP in schizophrenia were plagued by methodological constraints, including diagnostic uncertainties due to lack of operationalised diagnostic guidelines and signal averaging techniques. Furthermore, they did not address the influence of medications. Although ERP studies have been conducted on diverse sample population in various clinical laboratories, most of this data come from western countries. This study was conducted on Indian patients (who are ethnically and genetically quite different), in the knowledge that ethnicity may have an effect on CNV.36,37 We used the ICD-10 DCR criteria29 for diagnostic purposes to ensure a reliable and homogenous sample of schizophrenic patients. For the normal controls, who were matched for age and gender, GHQ-530 was used to ensure the absence of any psychopathology. For signal averaging, we used the Neuropack Sigma 8 software. The effect of antipsychotic drugs on CNV was examined by studying patients when they were drug-naïve / drug-free and after they had been treated with antipsychotics for 1 month.

In this study, we compared the amplitude and latency of CNV (i), CNV (t), and PINV. Although there were significant differences between the patient group and the controls, we only focused on the amplitude of CNV (t) based on discriminant analysis yielding an overall hit rate of 80%, the reason being that this measure could accurately classify the patients and the normal controls. The CNV (t) amplitude of the patient population was significantly smaller than that in the controls at the Fz, Cz, and C4 sites (in the fronto-central regions). After exposure to antipsychotic drugs, the CNV (t) amplitude was found to normalise in the patient group. Hence, it may be possible that CNV (t) amplitude helps discriminate schizophrenic patients from normal controls. Further, antipsychotic treatment causes normalisation or enhancement of the CNV (t) amplitude.

A study of schizophrenics suggest a negative CNV- dopamine association.38 Patients, who are presumed to have an overactivity of dopaminergic systems, show consistently low CNV amplitudes. When dopamine antagonists are administered they exhibit enhanced CNV amplitudes, which indicates an inverse relationship between CNV and dopamine.38 The CNV can be a reliable state marker for schizophrenia, which is characterised by a hyper- dopaminergic state in the acute phase of the illness, which is reversed by antipsychotic medication. In recent times, growing evidence39,40 indicates that the SPs originate not only from the prefrontal cortex but from other cortical areas including association areas and posterior cortices. Moreover, some SPs may not be related to task performance itself but to preparatory processes such as selective attention or the mere attempt to perform the task.39,40 Since ERP objectively records the neural activity associated with perceptual and cognitive processes, these procedures possess enormous face validity in the study of diseases such as schizophrenia. However, to realise their full potential in the study of psychiatric disorders, additional fundamental studies are required. The latter include efforts to relate ERP components to their neuro-anatomical and neurophysiological substrates on one hand, and to psychological processes on the other. When these data become available, it will be possible to use ERP to probe psychological and physiological derangements in schizophrenia. Until then the intriguing ERP differences that have been described cannot be fully integrated with psychological and biological theories of schizophrenia.41

The inference that CNV amplitudes normalised after treatment and that this was due to the antipsychotic effects of the medications is unequivocal, but whether this was due to the resolution of symptoms or treatment response cannot be concluded in this study. Although the overall BPRS and PANSS scores showed improvement after treatment (as detailed in the results), it would have been more useful if the patients who responded and those who had not were compared. This remains a major shortcoming of this study, as it is known that the CNV amplitude may normalise either with antipsychotic treatment or in association with remission of the acute stage of the disease.42-44

Declaration

The authors declared that there was no financial support for this study and that they had no conflicts of interest.

References

  1. Basile LF, Yacubian J, de Castro CC, Gattaz Widespread electrical cortical dysfunction in schizophrenia. Schizophr Res 2004;69:255-66.
  2. Walter WG, Cooper R, Aldridge VJ, McCallum WC, Winter Contingent negative variation: an electric sign of sensorimotor association and expectancy in the human brain. Nature 1964;203:380- 4.
  3. Rohrbaugh JW, Gaillard Sensory and motor aspects of the contingent negative variation. In: Gaillard AW, Ritter W, editors. Tutorials in event-related potential research: endogenous components. Advances in psychobiology. Vol 10. Amsterdam, North Holland Publication; 1983: 269-310.
  4. Loveless NE, Sanford AJ. Slow potential correlates of preparatory set. Biol Psychol 1974;1:303-14.
  5. Rohrbaugh JW, Syndulko K, Lindsley DB. Brain wave components of the contingent negative variation in humans. Science 1976;191:1055- 7.
  6. Rohrbaugh JW, Syndulko K, Sanquist TF, Lindsley DB. Synthesis of the contingent negative variation brain potential from noncontingent stimulus and motor elements. Science 1980;208:1165-8.
  7. Sanquist TF, Beatty JT, Lindsley DB. Slow potential shifts of human brain during forewarned reaction. Electroencephalogr Clin Neurophysiol 1981;51:639-49.
  8. Morgan JM, Wenzl M, Lang W, Lindinger G, Deecke L. Frontocentral DC-potential shifts predicting behavior with or without a motor Electroencephalogr Clin Neurophysiol 1992;83:378-88.
  9. Simons RF, Hoffman JE, MacMillan FW The component structure of event-related slow potentials: task, ISI, and warning stimulus effects on the ‘E’ wave. Biol Psychol 1983;17:193-219.
  10. Ruchkin DS, Sutton S, Mahaffey D, Glaser Terminal CNV in the absence of motor response. Electroencephalogr Clin Neurophysiol 1986;63:445-63.
  11. Brunia CH, Damen EJ. Distribution of slow brain potentials related to motor preparation and stimulus anticipation in a time estimation Electroencephalogr Clin Neurophysiol 1988;69;234-43.
  12. Pritchard WS. Cognitive event-related potential correlates of schizophrenia. Psychol Bull 1986;100:43-66.
  13. McCallum WC. Potentials related to expectancy, preparation and motor activity. In: Picton TW, Human event-related potentials. EEG Handbook. Vol 3 (revised series). Amsterdam, Elsevier; 1988: 427-534.
  14. Wagner M, Rendtorff N, Kathmann N, Engel CNV, PINV and probe-evoked potentials in schizophrenics. Electroencephalogr Clin Neurophysiol 1996;98:130-43.
  15. Löw A, Rockstroh B, Harsch S, Berg P, Cohen R. Event-related potentials in a working-memory task in schizophrenics and controls. Schizophr Res 2000;46:175-86.
  16. Verleger R, Wascher E, Arolt V, Daase C, Strohm A, Kömpf D. Slow EEG potentials (contingent negative variation and post-imperative negative variation) in schizophrenia: their association to the present state and to Parkinsonian medication effects. Clin Neurophysiol 1999;110:1175-92.
  17. Fuster JM. The prefrontal cortex: anatomy, physiology and neuropsychology of the frontal lobe. 2nd ed. New York, Raven Press;
  18. Rockstroh B, Elbert T, Canavan AG, Lutzenberger W, Birbaumer Slow cortical potentials and behaviour. 2nd ed. Munich: Urban and Schwarzenberg; 1989.
  19. Cohen R. Event-related potentials and cognitive dysfunction in In: Hafner H, Gattaz WF, editors. Search for the causes of schizophrenia. Vol 2. Berlin: Springer; 1991: 341-60.
  20. Callaway E 3rd. Schizophrenia and interference. An analogy with a malfunctioning computer. Arch Gen Psychiatry 1970;22:193-208.
  21. Marczynsky TJ. Multidisciplinary perspectives in event related brain potential research. Proceedings of the 4th International Congress on Event Related Slow Potentials of the Brain (EPIC IV); Hendersonville, April 1976. United States Government Printing Office, Washington DC; 1978: 25-35.
  22. Maertens de Noordhout A, Timsit-Berthier M, Timsit M, Schoenen Contingent negative variation in headache. Ann Neurol 1986;19:78- 80.
  23. Klein C, Rockstroh B, Cohen R, Berg Contingent negative variation (CNV) and determinants of post-imperative negative variation (PINV) in schizophrenic patients and healthy controls. Schizophr Res 1996;21: 97-110.
  24. Timsit M, Koninckx N, Dargent J, Fontaine O, Dongier Contingent negative variation in psychiatry [in French]. Electroencephalogr Clin Neurophysiol 1970;28:41-7.
  25. Timsit-Berthier M, Delaunoy J, Koninckx N, Rousseau JC. Slow potential changes in psychiatry. I. Contingent negative Electroencephalogr Clin Neurophysiol 1973;35:355-61.
  26. Birbaumer N, Elbert T, Rockstroh B, Lutzenberger On the dynamics of the postimperative negative variation (PINV). In: McCallum WC, Zappoli R, Denoth F, editors. Cerebral psychophysiology. Amsterdam: Elsevier; 1986: 212-9.
  27. Delaunoy J, Gerono A, Rousseau Experimental production of post- imperative negative variation in normal subjects. In: Otto DA, editor. Multidisciplinary perspectives in event-related potential research. Washington: US Environmental Protection Agency; 1978: 355-7.
  28. Dongier M. Separation of the various independent phenomena among the slow potential changes (contingent negative variations). Electroencephalogr Clin Neurophysiol 1969;27:108-9.
  29. ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. Geneva: World Health Organization; 1993.
  30. Shamsunder C, Sriram TG, Muraliraj SG, Shanmugham Validity of a short 5-item version of General Health Questionnaire. Indian J Psychiatry 1986;28:217-9.
  31. Mandal KM, Pandey G, Singh KS, Asthana SH. Hand preference in India. Int J Psychol 1992;27:433-42.
  32. Annett M. A classification of hand preference by association analysis. Br J Psychol 1970;61:303-21.
  33. Overall JE, Gorham D. The Brief Psychiatric Rating Scale (BPRS): recent developments in ascertainment and scaling. Psychopharm Bull 1988;24:97-9.
  34. Kay SR, Opler LA, Lindenmayer Reliability and validity of the positive and negative syndrome scale for schizophrenics. Psychiatry Res 1988;23:99-110.
  35. Fukui Y, Nakamura M, Kadobayashi I, Katoh The property of contingent negative variation (CNV) in psychiatric patients: schizophrenia and neurosis. Folia Psychiatr Neurol Jpn 1978;32:539- 52.
  36. Correll J, Urland GR, Ito Event-related potentials and the decision to shoot: the role of threat perception and cognitive control. J Exp Soc Psycho 2006;42:120-8.
  37. Caldara R, Rossion B, Bovet P, Hauert CA. Event-related potentials and time course of the “other-race” face classification advantage. Neuroreport 2004;15:905-10.
  38. Tecce JJ. Dopamine and CNV: studies of drugs, disease and nutrition. In: Brunia CH, Mulder G, Verbaten MN, editors. Event-related brain research (EEG Suppl 42). New York: Elsevier Science Publishers B.V.; 1991: 153-64.
  39. Basile LF, Ballester G, Castro CC, Gattaz Prefrontal cortex activity assessed by high-resolution EEG and current density reconstruction. Int J Psychophysiol 2002;45:227-40.
  40. Basile LF, Baldo MV, Castro CC, Gattaz The generators of slow potentials obtained during verbal, pictorial and spatial tasks. Int J Psychophysiol 2003;48:55-65.
  41. Holzman PS. Recent studies of psychophysiology in Schizophr Bull 1987;13:49-75.
  42. Tecce JJ, Cole The distraction – arousal hypothesis, CNV and schizophrenia. In: Mostofsky DJ, editor. Behavioural control and modification of physiological activity. London: Prentice Hall; 1976: 162-220.
  43. McCallun WC, Abraham P. The contingent negative variation in psychosis. Electroencephalogr Clin Neurophysiol Suppl 1973;33: S329-35.
  44. Knott JR, Peters JR, Robinson MD, Smith A, Andreasen NH. Contingent negative variation (CNV) in schizophrenic and depressed patients. Electroencephalogr Clin Neurophysiol 1976;40:329-30.
View My Stats