SEMINARS IN NEUROLOGY-VOLUME
10,NO. 2 J U N E 1990
Clinical Utility of Event-Related Potentials in Neurology and Psychiatry
Evoked potentials (EPs) to visual, auditory (AEP), and somatosensory stimulation are now well established in neurologic diagnosis. Eventrelated potentials (ERPs) are evoked by sensory stimulation, but occur at longer latency, involve more complex and heterogeneous processing of sensory stimuli, and are influenced by factors such as state of alertness and medication effect which may not influence early latency EPs. Although ERPs have been recognized for a long time and have been the subject of extensive psychologic study, they have been less systematically applied in neurologic disorders. EPs have generally been related to specific generator sites, although not without controversy concerning possible generators; are stable within the normal population and thus amenable to statistical comparison in pathologic conditions; and vary consistently with the physical characteristics of the stimulus. ERPs may vary to a degree with the type of stimulus but are primarily influenced by the subjective state of the patient, and ERP changes in response to changes of the stimulus are not systematic; in addition, ERP generators are numerous and are not universally agreed on. Nevertheless, ERPs are attracting increasing attention in the neurologic and psychiatric literature, as indices of brain information processing not measured by structural tests such as computed tomography or magnetic resonance imaging and not fully assessed by earlier functional studies such as the electroencephalogram. ERPs are sometimes divided into exogenous and endogenous components. Stimulus-related or exogenous potentials are obligate central nervous system responses to stimulation and are influenced by physical characteristics such as brightness in vi-
sual EPs, loudness in AEPs, and stimulus intensity in somatosensory EPs. Endogenous ERPs depend on psychologic variables of attention and state rather than physical characterstics and can, in fact, be recorded in the absence of physical stimulation when an anticipated stimulus is omitted unexpectedly. Essentially, the same endogenous potentials can be recorded with a variety of stimulus modalities, the best known example being the P300 or P3 response, which can be elicited by novel auditory stimuli, absence or disappearance of a familiar auditory stimulus, or a variety of experimental designs utilizing visual or somatosensory stimuli. Although they can be elicited by a variety of stimuli, and sometimes by no stimulus at all, auditory stimulation is most often utilized to record ERPs. Auditory EPs and ERPs are sometimes divided into three latency categories: early, middle, and long, slow, or late. T h e early latency responses, chiefly the cochlear microphonic and summating potentials and the following brainstem auditory EPS are, of course, the best studied. Middle latency AEPs, of rnixed aural and neural origin, occur between 10 and 50 msec after stimulation; they include transient responses such as the N20 and P30 waveform and steady-state responses epitomized by the 40 Hz potential of midbrain or thalamic origin. Potentials in the third group occur at latencies greater than 50 msec after stimulation and include the N1, P2, and N2 components of the auditory ERP ("late" slow potentials, occurring between 50 and 250 msec after stimulation), as well as the P300 (P3) and contingent negative variation (CNV) and related waveforms ("long" slow potentials, with latencies greater than 250 msec after stimulation). This review will focus on ERPs with some neuro-
Associate Professor of Neurology, T h e Ohio State Universily College of Medicine, Director, Clinical Neurophysiology Laboratory, T h e Ohio State University Hospitals, a n d Director, T h e Ohio State University Comprehensive Epilepsy Program, Columbus, Ohio Reprint requests: Dr. Drake, Department of Neurology, Ohio State University, 463 Means Hall, 1655 Upham Drive, Columbus, O H 43210 Copyright O 1990 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York 10016. All rights reserved.
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Miles E. Drake, Jr., M.D.
CLINICAL UTILITY O F EVEN1-KELATED POTENTIALS-DRAKE
logic and psychiatric interest: the middle latency AEP, the negative components of the auditory ERP, the P300 response, the CNV, and the readiness potential (RP); (Bereitschuftspotential).
the neurologic utility of this potential is limited by its variability and its absence in infants and children." NI (Nd) AND N2
Visual, somatosensory, and especially auditory stimulation with attended and unattended stimuli in random order at a rapid rate will produce negative waveforms, shown in Figure 2, which have Middle latency AEPs follow acoustic stimula- been related to selective attention." The N 1 comtion at latencies between 12 and 50 msec.' Tran- ponent occurs between 60 and 80 msec after stimsient stimuli produce a series of negative and pos- ulation and is augmented when stimuli are disitive waves identified as No, Po, Pa, and Nb. Na tinguished by increasing physical cues, such as (N20) and Pa (P30) are most often studied. These frequency, location, or intensity, and increased in potentials are often obscured by sonomotor re- latency of onset when the discrimination of these sponses of aural rather than neural origin.' Their cues is made more difficult. N1 is maximal in the origin in the auditory cortical regions of the tem- midline frontal regions, while visual stimuli proporal lobe has not been demonstrated. Recordings duce a midline posterior N 1." made with neuromuscular blockade or during N 1 overlaps another negative waveform best sleep have demonstrated these waveforms without demonstrated by subtracting unattended ERPs myogenic contamination, however.They are vari- from attended ERPs. This resultant waveform has able between subjects and are affected by alertness, been termed the negative displacement or negative drugs, and age. They have been suggested to arise difference (Nd), and ranges in latency from 50 to from areas of auditory cortex other than primary 150 msec. Nd has also been termed the processing ones," or from thalamus and its projections to cor- negativity, because it is particularly sensitive to attex or in the midbrain." tentional factors that influence processing of stimWith rapid acoustic stimulation at 35 to 45 per uli. Longer interstimulus intervals produce Nd second, steady-state potentials can be recorded. waveforms of higher amplitude and later occurLow-frequency tone bursts at 500 to 1500 Hz de- rence, while Nd occurs earlier when the differlivered at these high rates produce high amplitude ence between attended and unattended stimuli is sinusoidal potentials at approximately 40 cycles1 greater. It has been suggested that Nd reflects sec."he 40 Hz AEP (Fig. 1) has been widely used comparison of each stimulus to an internal temin fast audiometric screening, and is particularly plate of the attended stimulus: Nd is larger and helpful with low-frequency hearing losses that are longer as the incoming stimulus more closely renot detected by brainstem AEPs (BAEPs).~Brain and brainstem lesions have also been studied, with little effect from temporal lobe lesions but phase shift or latency increase after lesions of the midbrain or t h a l a m u ~ It . ~ has been suggested that 40 Hz AEPs are of thalamic or midbrain origin, but
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MIDDLE LATENCY AUDITORY EVOKED POTENTIALS
msec
msec Figure 1. Middle-latency auditory evoked potentials to 40 Hz click stimulation. The sinusoidal components are variable between individuals, but show phase shifts outward with thalamic or midbrain lesions.
Figure 2. Long-latency auditory event-related potentials to rare-tone stimulation. N1 and N2 may be of frontal lobe origin, while some evidence indicates the hippocampus and/or limbic system as the source of P3 (P300). These potentials can be elicited by a variety of stimulus modalities, and also by the omission of expected stimuli.
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198
lated to the paralysis of decision-making processes often encountered in that disorder."
T h e P3 or P300 component (Fig. 2) is the most widely studied ERP. P3 is the largest ERP component and is consistently positive in polarity and 300 to 400 msec in latency after the occurrence of an infrequent stimulus to which the patient or subject is attending." Whereas most ERP components, particularly the aforementioned N1 and N2, require several seconds to return to their full amplitude after relevant signals are detected, P3 amplitude shows a very short recovery or refractory period. P3 has been correlated with the psychologic refractory period, the speed at which sequential decisions can be executed, suggesting that it is generated by neural systems involved in the psychologic decision-making process.'" P3 has a widespread central distribution with a variety of stimulus modalities and can even be recorded approximately 300 msec after an expected click stimulus is omitted, demonstrating the endogenous character of this c ~ m p o n e n t . ~ ~ T h e P3 component becomes larger as the novel stimulus becomes rarer. P3 latency is lengthened with increasing task difficulty or complexity of stimulus eval~ation.'~ Both P3 and reaction time measure the timing of information processing, but while reaction time encompasses all the processes leading to a mental decision and physical response, P3 measures only the duration of stimulus evaluation and is not affected by the time required to select and carry out a response to the s t i m ~ l u s . ' ~ P3 was first recorded in a paradigm in which subjects predicted which of several stimuli would occur next. P3 amplitude was inversely proportional to the probability of a particular stimulus occurring next, being larger for less likely or more uncertain events. It was therefore suggested that the informational role of the stimulus influenced P3 amplitude, the response being greatest to the most relevant information o r that which most completely resolved a condition of uncertainty. Subsequent studies showed that two task-relevant stimuli of equal probability elicited different P3 amplitudes, depending on their incentive value. Highincentive stimuli produced large P3 waveforms, while stimuli of low incentive value elicited much smaller resp~nses.'~ This led to the suggestion that, even more than cognitive processes involved in assessment of stimulus probability and task relevance, P3 was influenced by the affective significance of the stimulus. A relationship between P3 and the motivational properties of stimuli is sup-
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sembles that internal stimulus template. Nd predominates in the frontal areas with all modalities, but is most complex with auditory stimulation.12 Patients with attention deficits have been found to have decreased N1 amplitude to novel stimuli compared with controls. Low voltage N 1 responses to novel and frequent stimuli have been reported in alcoholics, schizophrenics, children with hyperactivity, and adults with conversion disorder.I3-l5 It has been suggested that patients with such disorders may not differentiate normally between relevant and irrelevant stimuli. When a rare novel stimulus is presented in a repetitive homogeneous sequence, another negative waveform is recorded frontally, followed by a positive slow wave over the parietal regions. T h e frontal negativity (N2) occurs at approximately 200 msec. It is dependent on the deviant character of the rare stimuli but independent of their physical properties. This has been called the mismatch negativity (MMN), as it apparently reflects the detection of a mismatch between the usual and deviant stimuli.I6 MMN has been studied primarily with auditory methods and is insensitive to the attentional factors that so prominently influence N 1 and Nd. This has suggested that MMN reflects orienting to sensory input, which is different from a model that has been established by repetitive homogeneous stimuli. This is supported by the direct relationship between degree of stimulus novelty and the amplitude of the MMN: the rarer the deviant stimulus, the larger the MMN.I7 While N1 may reflect selective attention, N 2 has been ascribed to stimulus classification, the next stage of information processing and the basis of sensory discrimination. N2 latency and reaction time are correlated, and N2 latency changes as a function of difficulty of discrimination. N2 is unaffected by motor response, whereas the reaction time measures many aspects of information processing, including stimulus evaluation, response selection and organization, and the eventual execution of a motor response. N 2 can also be obtained when subjects engage in semantic rather than physical discrimination.IR It has been shown to be affected by early stages of Alzheimer's disease, and some studies in epilepsy have suggested N2 diminution in seizure patients both with and without cognitive difficulties and medication effects. N2 latency is prolonged in abstinent alcoholics compared with controls, and alcoholic patients d o not show the usual relationship between N2 latency and the difficulty of making a sensory discriminati~n.~ Some I amplitude changes in N2 have been reported in majbr depression, which may be re-
V O L U M E 10, N U M B E R 2 JUNE 1990
CLINICAL UTILITY OF EVENT-RELATED P O T E N T I A L S D R A K E
pseudodementia of depression (affective cognitive d i ~ o r d e r ) ,but ~ ' P3 measurement must be used in conjunction with clinical information. P3 has also been studied in adults with mental retardation, and latency prolongation has been reported. Systematic prolongation of latency has been described in Parkinson's disease, and P3 may help to differentiate those patients with parkinsonian dementia from others with extrapyramidal disorders. P3 amplitude reduction or asymmetry has been described in frontal lesions and infantile autism. P3 amplitude change with methylphenidate treatment has been reported in children with hyperactivity. Amplitude reduction and latency prolongation have been reported in patients with migraine, which may be related to the mood and affect changes often encountered in migraine, and possibly to the altered perceptions that migraine sufferers P3 latency prolongation has been reported in patients with complex partial seizures, while other studies have shown prolonged P3 latencies in generalized seizure disorders but normal P3 latencies in focal e p i l e p ~ y . ~Additional '-~~ studies have shown essentially normal P3 latency in patients with absence seizures, but undue latency prolongation in more complex tasks requiring sustained maintenance of attention, which is likely to be interrupted by spike-wave bursts. P3 responses of prolonged latency and enhanced amplitude have been reported in complex partial seizure patients, which may be related to some of the interictal changes of behavior and personality reported by such patients, or could reflect dysfunction of cholinergic interneurons thought to be involved in epileptogenesis on the one hand and generation of some ERP components on the other." Differential effects of antiepileptic drug therapy on P3 latency and amplitude have been reported, with amplitude attenuation by phenytoin and phenobarbital and latency prolongation by valproate; this suggests that ERPs might also serve as an objective measure of beneficial or adverse antiepileptic drug effects in seizure patients.55 P3 has also been extensively studied in psychiatric disorders, but remains of limited diagnostic value. Schizophrenia has been associated with P3 latency prolongation, amplitude reduction, and interhemispheric asymmetry, and dramatic differences in P3 lateralization have been reported with computerized topographic brain ma~ping.~""' Some investigators have reported less effect of uncertainty about forthcoming stimulus conditions in schizophrenics than in normal subjects or depressed patients. Longitudinal studies with a comprehensive EP paradigm intermingling left and right median
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ported by evidence that the limbic system may be involved in its generation. Although some studies suggest that P3 arises in subcortical areas of the cerebral hemispheres, depth electrode record~ ~ ~ indiings2%nd m a g n e t o e n c e p h a l ~ g r a p hhave cated that the hippocampus is a major generator of this waveform. P3 generally occurs as part of a complex of endogenous potentials, preceded by at least one negative peak (N2) and followed by a prolonged positive slow wave. Since N2 occurs earlier, is modality-specific in scalp distribution, and is more closely correlated to reaction time than P3, it has been suggested that N2 may relate more closely to stimulus evaluation than P3.3' It has also been suggested that the discrimination indexed by N2 is followed by some assessment of the significance of the stimulus, which process is measured by P3.32 P3 to unfamiliar stimuli has been recorded in infants and can be recorded to word stimuli in childhood.33The incompletely understood mental development between childhood and adulthood is associated with the gradual restriction of P3 to the parietal area and a gradual decrease in latency.34 P3 increases in latency, decreases in amplitude, and shifts toward the frontotemporal regions in distribution with senescence."" Most studies have shown P3 latency prolongation in demented individuals. Wide differences have been reported between studies, however, with some investigators claiming P3 abnormality in 80% of demented patients, other studies finding essentially normal P3 values except in advanced dementia, and some series showing latency prolongation, but 50% or smaller incidence of clear prolongation beyond the clinical norms of 2 or 3 standard deviations. This is believed to reflect, in part, differences in severity of dementia between the different study groups. In addition, P3 peak identification is not uniform between studies. P3 may often have redundant components, and generally consists of an early peak (P3A) and a slightly later peak (P3B). P3A predominates in the frontal regions and is related to stimulus novelty, whereas P3B reflects more complex stimulus evaluation, more specifically assessed by tasks involving target detection, and predominates in the parietal areas. Those studies that find P3 prolongation in dementia report it in all diagnostic groups; therefore, the test is of limited specificity in the identification of Alzheimer's disease or some other dementing disorder.""44 P3 may be useful for serial screening of cognitive ability" and has been shown to wax and wane in abnormality in encephalopathies characterized by intermittent c o n f u s i ~ n . " ~It~may ~ " also help to differentiate between dementia and the
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CONTINGENT NEGATIVE VARIATION AND OTHER SLOW POTENTIALS The best-known slow potential is the CNV, described by Walter et al in 1964." In reaction time tests in which an alerting signal (Sl) is followed by an imperative stimulus to which a response must be executed (S2), the CNV is a slowly developing negative potential in the interval between S1 and S2 (Fig. 3). After the imperative stimulus and appropriate response, the potential returns to the baseline or becomes positive. There is sometimes a delay in the development of the positivity, and a negativity persists that is called the postimperative negative variation (PINV) (Fig. 4).70When the testing paradigm includes executing a movement, the Bereitschaftspotential or RP is recorded before the movement (Fig. 5). RP is usually negative and is followed by positive deflection, but in some situations a delayed negativity persists that resembles the PINV.71 200
Figure 3. The contingent negative variation recorded between a warning stimulus (Sl)and an imperative stimulus (S2), at which a motor response must be executed. The usual recording montage is vertex to ear or mastoid reference; the negative baseline shift is normally followed by a positive potential.
The CNV is generally recorded from the vertex with ear or mastoid reference. An analysis time of 2 to 4 seconds is required, with repetition of 10 or more averages. Paired stimuli, generally of different modality, are required, and very slow, longlasting potential changes must be recorded, usually requiring a DC time constant. Under these conditions, pairs of stimuli separated by 1 to 2 seconds, with the first serving as a warning signal and the second as an imperative stimulus at which time a motor action is required, will lead to a negative potential shift between the evoked potential to the warning stimulus and the evoked potential to the imperative stimulus. The warning stimulus must be followed by an imperative stimulus, and a specific motor response to the imperative stimulus of the pair is required. The CNV generally follows the warning stimulus by 4 msec and reaches maximum negativity, usually approximately 50 pV, within 800 msec after the warning stimulus. The CNV is maximal at the vertex, extends into the frontal region, involves the parietal area to a lesser extent, and is minimal in the occipital and posterior temporal area^.^' The CNV requires coopera-
Figure 4. CNV with a prolonged negative potential even after the imperative stimulus (S2). This is postimperative negative variation and has been reported in schizophrenia and some neurologic disorders. Its significance and diagnostic utility are uncertain.
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nerve shocks, auditory clicks, and visual flash stimuli have suggested that P3 becomes attenuated in amplitude and eventually absent during the course of chronic schi~ophrenia.~' Major depression has been associated with relatively normal P3 latency but attenuated P3 amplit ~ d e It. has ~ ~ been suggested that this reflects basically normal stimulus processing but a decrease in task involvement both clinically and in the ERP testing paradigms. Other studies have indicated essentially normal P3 waveform and amplitude in depression. Mania may be associated with minimal P3 attenuation," while P3 has been suggested in one study to be increased in patients with anxiety disorder compared with controls.64P3 amplitude attenuation has been described in both drinking and abstinent alcoholics, who have disorders both of motivation and of memory, and P3 has been suggested to identify the at-risk children of alcoholic p a r e n t ~ . ~ latency 93 prolongation and amplitude attenuation have been reported in patients with psychopathy and personality disorder, possibly providing an electrophysiologic indication of altered stimulus processing in these disorders of interpersonal relation^.^^.^' Psychoactive drugs clearly affect ERP latency and amplitude; their influence has not been systematically studied. In addition, many of the psychiatric disorders wax and wane in severity, making conclusions from single tests difficult." ERP studies are not yet of diagnostic use in psychiatric disorders, but may provide information about underlying brain dysfunction in "functional" illness.
V O L U M E 10, NUMBER 2 JUNE 1990
C L I N I C A L U T I L I T Y OF EVENT-RELATED POTENTIALS-DRAKE
0.5 Sec
Figure 5. The Bereitschaftspotential(readiness potential) is recorded when the imperative stimulus requires a motor response. The RP is a negative potential preceding the motor action at the imperative stimulus (M). Abnormalities have been reported in extrapyramidal and cerebellar disorders.
demented patients, and this may provide a means of further assessing early cognitive complaints in possible Alzheimer's disease.'WNV attenuation after head trauma has been related to clinical outcome in some series, whereas in others CNV amplitude increase after injury may parallel behavioral disinhibition." A CNV increase may help characterize vascular headaches as opposed to other types and has been related to alteration of central aminergic pathway^.'^ CNV decrement in dyslexia, aphasia, and speech disorders has been ascribed to a faulty attentional mechanism.'"eduction in CNV amplitude during EEG discharges has been described in temporal lobe epilepsy but not in generalized seizure disorders." Abnormalities of RP have been reported in Parkinson's disease, Tourette's syndrome, and cerebellar disord e r ~ Such . ~ ~ slow potentials are still of limited utility in neurologic or psychiatric diagnosis, but deserve further investigation as the mechanisms and diagnostic role of evoked potentials are clarified, and as methods for computerized analysis and topographic mapping of neurophysiologic data become more widely available.
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tion and expectancy, and so cannot be elicited in infants or uncooperative subjects; it increases in latency and changes with the subject's ability to shift attention in advancing age.'" The clinical utility of CNV remains limited, although it has been extensively studied in psychiatric disorders and in relation to psychiatric drugs. CNV amplitude is reduced and particularly subject to distraction in schizophrenics. Schizophrenics have also been reported to have a PINV more often than normal or nonpsychotic subjects, the PINV predominating in early schizophrenia and being of greater amplitude and longer duration in those with hallucinations or without depression and anxiety. An RP is reported more often and for longer duration than in normal controls or patients with other psychiatric disorder^.'^ T h e CNV is reportedly reduced in amplitude in depression, and amplitude increases with remission. An increased incidence of PINV and more frequent PINV when under stress are described in depression, and a prolonged RP is described with motor tasks. CNV attenuation, frequent PINV, and higher amplitude PINV than in depressed states have been reported in manic patients. Some series have suggested CNV is reduced in anxiety, whereas others indicate a greater susceptibility to distraction and a relationship between anxiety level and PINV. High-amplitude CNV and persistent PINV with stimulation by phobic objects have been reported in patients with phobia, and CNV reportedly normalizes and PINV subsides with successful treatment of the phobia. An enhanced CNV and PINV intermediate between normality and psychosis have been described in obsessive-compulsive disorder. Low-amplitude CNV but a more rapid ascent of the negative potential has been described in hysteria, whereas marked attenuation of the CNV is reportedly characteristic of some personality disorders. Alcohol may decrease CNV amplitude, marijuana is said to increase CNV amplitude and augment PINV, phenobarbital and benzodiazepines decrease or leave unchanged CNV amplitude in normal volunteers, and CNV is reportedly increased by methadone in drug addicts. Caffeine, amphetamine, and nicotine reportedly increase or decrease CNV amplitude, depending on change in alertness. CNV amplitude is reportedly reduced in normal subjects given antipsychotics, whereas CNV increases in schizophrenics given neuroleptics. Antidepressants and lithium carbonate reportedly increase CNV amplitude in patients requiring those drug^.'^ T h e diagnostic utility of CNV in neurologic disease is uncertain. Failure of CNV to recover after attenuation by distraction has been shown in
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SEMINARS IN NEUKOLOGY
Rodin E, Khabbazeh Z, Twitty G, Schmaltz S: T h e cognitive evoked potential in epilepsy patients. Clin Electroencephalogr l989;20: 176-82 Mirsky AF, Duncan CC, Myslobodsky MS. Petit ma1 epilepsy: a review and integration of recent information. J Clin Neurophysiol 1986;3:179-208 ~ a k a l n i A, s Drake ME, Hietter SA. Effect of seizure type o n long-latency auditory event-related potentials. Epilepsia l988;27:2 16 Pakalnis A, Hietter S, Huber SJ, Drake ME. Effects of carbamazepine and valproate o n long-latency auditory event-related potentials. J Epilepsy 1989;2:27-9 Shagass C, Straumanis JJ, Roemer RA, Amadeo M: Evoked potentials of schizophrenics in several sensory modalities. Biol Psychiatry 1977; 12:22 1-35 Roth WT, Pfefferbaum A, Horvath T B , et al. P3 reduction in auditory evoked potentials of schizophrenics. Electroencephalogr Clin Neurophysiol 1980;49:497505 Roth WT, Horvath TB, Pfefferbaum A, Kopell BS. Event-related potentials in schizophrenics. Electroencephalogr Clin Neurophysiol 1980;48: 127-39 Roth WT, Pfefferbaum A, Kelly AF, et al. Auditory event-related potentials in schizophrenia and depression. Psychiatry Res 1981;4:199-212 Morstyn R, Duffy FH, McCartey RW. Altered P300 topography in schizophrenia. Arch Gen Psychiatry 1983; 40:729-34 Shagass C. Evoked potentials in adult psychiatry. In: Hughes JR, Wilson WP, eds. EEG and evoked potentials in psychiatry and behavioral neurology. Boston: Butterworths, 1983: 169-2 10 Shagass C, Roemer RA, Straumanis JJ, Amadeo M. Topography of sensory evoked potentials in depressive disorders. Biol Psychiatry 1980; 15: 183-207 Shagass C, Roemer RA, Straumanis JJ, Amadeo M. Evoked potential correlates of psychosis. Biol Psychiatry 1978; 13: 163-84 Chattopadhyay P, Cooke E, Toone B, Lader M. Habituation of physiological responses in anxiety. Biol Psychiatry 1980; l7:7 1 1-21 Porjesz B, Begleiter H. Brain dysfunction and alcohol. In: Kissin B, Begleiter H , eds. T h e pathogenesis of alcoholism. New York: Plenum Press, 1983;415-83 Blackwood DHR, St. Clair DM, Kutcher SP. P300 eventrelated potential abnormalities in borderline personality disorder. Biol Psychiatry 1986;2 1:560-4 Kutcher SP, Blackwood DHR, St. Clair D, et al. Auditory P300 in borderline personality disorder and schizophrenia. .4rch Gen Psychiatry 1987;44:645-650
68. Straumanis JJ, Shagass C, Roemer RA. Influence of antipsychotic and antidepressant drugs o n evoked potential correlates of psychosis. Biol Psychiatry 1982;17:1101-122 69. Walter WG, Cooper R, Aldridge VJ, et al. Contigent negative variation: an electric sign of sensorimotor association and expectancy in the human brain. Nature 1964;203:380-4 70. Shagass C. Contingent negative variation and other slow potentials in adult psychiatry. In: Hughes JR, Wilson WP, eds. EEG and evoked potentials in psychiatry and behavioral neurology. Boston: Butterworths, 1983: 149-67 71. Kornhueber H H , Deecke L. Cerebral potential changes in voluntary and passive movements in man: readiness potential and reafferent potential. Pfluegers Arch 1965;284: 1-17 72. Tecce JJ, Cattanach L. Contingent negative variation. I n : Niedermeyer E, Lopes da Silva F, eds. Electroencephalography. Baltimore: Urban & Schwarzenberg, 1987;657-79 73. Dongier M. Clinical application of the CNV: a review. In: McCallum WC, Knott JR, eds. Event-related slow potentials of the brain: their relation to behavior. Amsterdam: Elsevier, 1973:309-15 74. Bachneff SA, Engelsman F. Contingent negative variation, postimperative negative variations, and psychopathology. Biol Psychiatry 1980;15:323-8 75. Timsit-Berthier M, Timsit M. Toward a neurochemical interpretation of the contingent negative variation in psychiatry. Adv Biol Psychiatry 198 1;6: 165-72 76. Tecce JJ, Cattanach L, Boehner-Davis MB, et al. Absence of CNV rebound in Alzheimer's patients. In: McCallum WC, Zapopoli R, Denoth F, eds. Cerebral psychophysiology: studies in event-related potentials. Amsterdam: Elsevier, 1987:453-4 77. Rizzo PA, Amabile G , Caporali M, et al. A CNV study in a group of patients with traumatic head injuries. Electroencephalogr Clin Neurophysiol 1978;45:281-5 78. Maertens d e Nordhout A, Timsit-Berthier M, Timsit M, Schoenen J : Contingent negative variation in headache. Ann Neurol 1986; 19:78-80 79. Cohen J . Cerebral evoked responses in dyslexic children. Prog Brain Res 1980;54:502-6 80. Zappoli R, Papini M, Cabras PL. Spontaneous generalized and focal temporal epileptic EEG discharges and contingent negative variation. Riv Patol Nerv Ment 1970;91:157-68
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CLINICAL UTILITY OF EVENT-RELATED POTENTIALS-DRAKE
10,NO. 2 J U N E 1990
Clinical Utility of Event-Related Potentials in Neurology and Psychiatry
Evoked potentials (EPs) to visual, auditory (AEP), and somatosensory stimulation are now well established in neurologic diagnosis. Eventrelated potentials (ERPs) are evoked by sensory stimulation, but occur at longer latency, involve more complex and heterogeneous processing of sensory stimuli, and are influenced by factors such as state of alertness and medication effect which may not influence early latency EPs. Although ERPs have been recognized for a long time and have been the subject of extensive psychologic study, they have been less systematically applied in neurologic disorders. EPs have generally been related to specific generator sites, although not without controversy concerning possible generators; are stable within the normal population and thus amenable to statistical comparison in pathologic conditions; and vary consistently with the physical characteristics of the stimulus. ERPs may vary to a degree with the type of stimulus but are primarily influenced by the subjective state of the patient, and ERP changes in response to changes of the stimulus are not systematic; in addition, ERP generators are numerous and are not universally agreed on. Nevertheless, ERPs are attracting increasing attention in the neurologic and psychiatric literature, as indices of brain information processing not measured by structural tests such as computed tomography or magnetic resonance imaging and not fully assessed by earlier functional studies such as the electroencephalogram. ERPs are sometimes divided into exogenous and endogenous components. Stimulus-related or exogenous potentials are obligate central nervous system responses to stimulation and are influenced by physical characteristics such as brightness in vi-
sual EPs, loudness in AEPs, and stimulus intensity in somatosensory EPs. Endogenous ERPs depend on psychologic variables of attention and state rather than physical characterstics and can, in fact, be recorded in the absence of physical stimulation when an anticipated stimulus is omitted unexpectedly. Essentially, the same endogenous potentials can be recorded with a variety of stimulus modalities, the best known example being the P300 or P3 response, which can be elicited by novel auditory stimuli, absence or disappearance of a familiar auditory stimulus, or a variety of experimental designs utilizing visual or somatosensory stimuli. Although they can be elicited by a variety of stimuli, and sometimes by no stimulus at all, auditory stimulation is most often utilized to record ERPs. Auditory EPs and ERPs are sometimes divided into three latency categories: early, middle, and long, slow, or late. T h e early latency responses, chiefly the cochlear microphonic and summating potentials and the following brainstem auditory EPS are, of course, the best studied. Middle latency AEPs, of rnixed aural and neural origin, occur between 10 and 50 msec after stimulation; they include transient responses such as the N20 and P30 waveform and steady-state responses epitomized by the 40 Hz potential of midbrain or thalamic origin. Potentials in the third group occur at latencies greater than 50 msec after stimulation and include the N1, P2, and N2 components of the auditory ERP ("late" slow potentials, occurring between 50 and 250 msec after stimulation), as well as the P300 (P3) and contingent negative variation (CNV) and related waveforms ("long" slow potentials, with latencies greater than 250 msec after stimulation). This review will focus on ERPs with some neuro-
Associate Professor of Neurology, T h e Ohio State Universily College of Medicine, Director, Clinical Neurophysiology Laboratory, T h e Ohio State University Hospitals, a n d Director, T h e Ohio State University Comprehensive Epilepsy Program, Columbus, Ohio Reprint requests: Dr. Drake, Department of Neurology, Ohio State University, 463 Means Hall, 1655 Upham Drive, Columbus, O H 43210 Copyright O 1990 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York 10016. All rights reserved.
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Miles E. Drake, Jr., M.D.
CLINICAL UTILITY O F EVEN1-KELATED POTENTIALS-DRAKE
logic and psychiatric interest: the middle latency AEP, the negative components of the auditory ERP, the P300 response, the CNV, and the readiness potential (RP); (Bereitschuftspotential).
the neurologic utility of this potential is limited by its variability and its absence in infants and children." NI (Nd) AND N2
Visual, somatosensory, and especially auditory stimulation with attended and unattended stimuli in random order at a rapid rate will produce negative waveforms, shown in Figure 2, which have Middle latency AEPs follow acoustic stimula- been related to selective attention." The N 1 comtion at latencies between 12 and 50 msec.' Tran- ponent occurs between 60 and 80 msec after stimsient stimuli produce a series of negative and pos- ulation and is augmented when stimuli are disitive waves identified as No, Po, Pa, and Nb. Na tinguished by increasing physical cues, such as (N20) and Pa (P30) are most often studied. These frequency, location, or intensity, and increased in potentials are often obscured by sonomotor re- latency of onset when the discrimination of these sponses of aural rather than neural origin.' Their cues is made more difficult. N1 is maximal in the origin in the auditory cortical regions of the tem- midline frontal regions, while visual stimuli proporal lobe has not been demonstrated. Recordings duce a midline posterior N 1." made with neuromuscular blockade or during N 1 overlaps another negative waveform best sleep have demonstrated these waveforms without demonstrated by subtracting unattended ERPs myogenic contamination, however.They are vari- from attended ERPs. This resultant waveform has able between subjects and are affected by alertness, been termed the negative displacement or negative drugs, and age. They have been suggested to arise difference (Nd), and ranges in latency from 50 to from areas of auditory cortex other than primary 150 msec. Nd has also been termed the processing ones," or from thalamus and its projections to cor- negativity, because it is particularly sensitive to attex or in the midbrain." tentional factors that influence processing of stimWith rapid acoustic stimulation at 35 to 45 per uli. Longer interstimulus intervals produce Nd second, steady-state potentials can be recorded. waveforms of higher amplitude and later occurLow-frequency tone bursts at 500 to 1500 Hz de- rence, while Nd occurs earlier when the differlivered at these high rates produce high amplitude ence between attended and unattended stimuli is sinusoidal potentials at approximately 40 cycles1 greater. It has been suggested that Nd reflects sec."he 40 Hz AEP (Fig. 1) has been widely used comparison of each stimulus to an internal temin fast audiometric screening, and is particularly plate of the attended stimulus: Nd is larger and helpful with low-frequency hearing losses that are longer as the incoming stimulus more closely renot detected by brainstem AEPs (BAEPs).~Brain and brainstem lesions have also been studied, with little effect from temporal lobe lesions but phase shift or latency increase after lesions of the midbrain or t h a l a m u ~ It . ~ has been suggested that 40 Hz AEPs are of thalamic or midbrain origin, but
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MIDDLE LATENCY AUDITORY EVOKED POTENTIALS
msec
msec Figure 1. Middle-latency auditory evoked potentials to 40 Hz click stimulation. The sinusoidal components are variable between individuals, but show phase shifts outward with thalamic or midbrain lesions.
Figure 2. Long-latency auditory event-related potentials to rare-tone stimulation. N1 and N2 may be of frontal lobe origin, while some evidence indicates the hippocampus and/or limbic system as the source of P3 (P300). These potentials can be elicited by a variety of stimulus modalities, and also by the omission of expected stimuli.
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198
lated to the paralysis of decision-making processes often encountered in that disorder."
T h e P3 or P300 component (Fig. 2) is the most widely studied ERP. P3 is the largest ERP component and is consistently positive in polarity and 300 to 400 msec in latency after the occurrence of an infrequent stimulus to which the patient or subject is attending." Whereas most ERP components, particularly the aforementioned N1 and N2, require several seconds to return to their full amplitude after relevant signals are detected, P3 amplitude shows a very short recovery or refractory period. P3 has been correlated with the psychologic refractory period, the speed at which sequential decisions can be executed, suggesting that it is generated by neural systems involved in the psychologic decision-making process.'" P3 has a widespread central distribution with a variety of stimulus modalities and can even be recorded approximately 300 msec after an expected click stimulus is omitted, demonstrating the endogenous character of this c ~ m p o n e n t . ~ ~ T h e P3 component becomes larger as the novel stimulus becomes rarer. P3 latency is lengthened with increasing task difficulty or complexity of stimulus eval~ation.'~ Both P3 and reaction time measure the timing of information processing, but while reaction time encompasses all the processes leading to a mental decision and physical response, P3 measures only the duration of stimulus evaluation and is not affected by the time required to select and carry out a response to the s t i m ~ l u s . ' ~ P3 was first recorded in a paradigm in which subjects predicted which of several stimuli would occur next. P3 amplitude was inversely proportional to the probability of a particular stimulus occurring next, being larger for less likely or more uncertain events. It was therefore suggested that the informational role of the stimulus influenced P3 amplitude, the response being greatest to the most relevant information o r that which most completely resolved a condition of uncertainty. Subsequent studies showed that two task-relevant stimuli of equal probability elicited different P3 amplitudes, depending on their incentive value. Highincentive stimuli produced large P3 waveforms, while stimuli of low incentive value elicited much smaller resp~nses.'~ This led to the suggestion that, even more than cognitive processes involved in assessment of stimulus probability and task relevance, P3 was influenced by the affective significance of the stimulus. A relationship between P3 and the motivational properties of stimuli is sup-
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sembles that internal stimulus template. Nd predominates in the frontal areas with all modalities, but is most complex with auditory stimulation.12 Patients with attention deficits have been found to have decreased N1 amplitude to novel stimuli compared with controls. Low voltage N 1 responses to novel and frequent stimuli have been reported in alcoholics, schizophrenics, children with hyperactivity, and adults with conversion disorder.I3-l5 It has been suggested that patients with such disorders may not differentiate normally between relevant and irrelevant stimuli. When a rare novel stimulus is presented in a repetitive homogeneous sequence, another negative waveform is recorded frontally, followed by a positive slow wave over the parietal regions. T h e frontal negativity (N2) occurs at approximately 200 msec. It is dependent on the deviant character of the rare stimuli but independent of their physical properties. This has been called the mismatch negativity (MMN), as it apparently reflects the detection of a mismatch between the usual and deviant stimuli.I6 MMN has been studied primarily with auditory methods and is insensitive to the attentional factors that so prominently influence N 1 and Nd. This has suggested that MMN reflects orienting to sensory input, which is different from a model that has been established by repetitive homogeneous stimuli. This is supported by the direct relationship between degree of stimulus novelty and the amplitude of the MMN: the rarer the deviant stimulus, the larger the MMN.I7 While N1 may reflect selective attention, N 2 has been ascribed to stimulus classification, the next stage of information processing and the basis of sensory discrimination. N2 latency and reaction time are correlated, and N2 latency changes as a function of difficulty of discrimination. N2 is unaffected by motor response, whereas the reaction time measures many aspects of information processing, including stimulus evaluation, response selection and organization, and the eventual execution of a motor response. N 2 can also be obtained when subjects engage in semantic rather than physical discrimination.IR It has been shown to be affected by early stages of Alzheimer's disease, and some studies in epilepsy have suggested N2 diminution in seizure patients both with and without cognitive difficulties and medication effects. N2 latency is prolonged in abstinent alcoholics compared with controls, and alcoholic patients d o not show the usual relationship between N2 latency and the difficulty of making a sensory discriminati~n.~ Some I amplitude changes in N2 have been reported in majbr depression, which may be re-
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CLINICAL UTILITY OF EVENT-RELATED P O T E N T I A L S D R A K E
pseudodementia of depression (affective cognitive d i ~ o r d e r ) ,but ~ ' P3 measurement must be used in conjunction with clinical information. P3 has also been studied in adults with mental retardation, and latency prolongation has been reported. Systematic prolongation of latency has been described in Parkinson's disease, and P3 may help to differentiate those patients with parkinsonian dementia from others with extrapyramidal disorders. P3 amplitude reduction or asymmetry has been described in frontal lesions and infantile autism. P3 amplitude change with methylphenidate treatment has been reported in children with hyperactivity. Amplitude reduction and latency prolongation have been reported in patients with migraine, which may be related to the mood and affect changes often encountered in migraine, and possibly to the altered perceptions that migraine sufferers P3 latency prolongation has been reported in patients with complex partial seizures, while other studies have shown prolonged P3 latencies in generalized seizure disorders but normal P3 latencies in focal e p i l e p ~ y . ~Additional '-~~ studies have shown essentially normal P3 latency in patients with absence seizures, but undue latency prolongation in more complex tasks requiring sustained maintenance of attention, which is likely to be interrupted by spike-wave bursts. P3 responses of prolonged latency and enhanced amplitude have been reported in complex partial seizure patients, which may be related to some of the interictal changes of behavior and personality reported by such patients, or could reflect dysfunction of cholinergic interneurons thought to be involved in epileptogenesis on the one hand and generation of some ERP components on the other." Differential effects of antiepileptic drug therapy on P3 latency and amplitude have been reported, with amplitude attenuation by phenytoin and phenobarbital and latency prolongation by valproate; this suggests that ERPs might also serve as an objective measure of beneficial or adverse antiepileptic drug effects in seizure patients.55 P3 has also been extensively studied in psychiatric disorders, but remains of limited diagnostic value. Schizophrenia has been associated with P3 latency prolongation, amplitude reduction, and interhemispheric asymmetry, and dramatic differences in P3 lateralization have been reported with computerized topographic brain ma~ping.~""' Some investigators have reported less effect of uncertainty about forthcoming stimulus conditions in schizophrenics than in normal subjects or depressed patients. Longitudinal studies with a comprehensive EP paradigm intermingling left and right median
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ported by evidence that the limbic system may be involved in its generation. Although some studies suggest that P3 arises in subcortical areas of the cerebral hemispheres, depth electrode record~ ~ ~ indiings2%nd m a g n e t o e n c e p h a l ~ g r a p hhave cated that the hippocampus is a major generator of this waveform. P3 generally occurs as part of a complex of endogenous potentials, preceded by at least one negative peak (N2) and followed by a prolonged positive slow wave. Since N2 occurs earlier, is modality-specific in scalp distribution, and is more closely correlated to reaction time than P3, it has been suggested that N2 may relate more closely to stimulus evaluation than P3.3' It has also been suggested that the discrimination indexed by N2 is followed by some assessment of the significance of the stimulus, which process is measured by P3.32 P3 to unfamiliar stimuli has been recorded in infants and can be recorded to word stimuli in childhood.33The incompletely understood mental development between childhood and adulthood is associated with the gradual restriction of P3 to the parietal area and a gradual decrease in latency.34 P3 increases in latency, decreases in amplitude, and shifts toward the frontotemporal regions in distribution with senescence."" Most studies have shown P3 latency prolongation in demented individuals. Wide differences have been reported between studies, however, with some investigators claiming P3 abnormality in 80% of demented patients, other studies finding essentially normal P3 values except in advanced dementia, and some series showing latency prolongation, but 50% or smaller incidence of clear prolongation beyond the clinical norms of 2 or 3 standard deviations. This is believed to reflect, in part, differences in severity of dementia between the different study groups. In addition, P3 peak identification is not uniform between studies. P3 may often have redundant components, and generally consists of an early peak (P3A) and a slightly later peak (P3B). P3A predominates in the frontal regions and is related to stimulus novelty, whereas P3B reflects more complex stimulus evaluation, more specifically assessed by tasks involving target detection, and predominates in the parietal areas. Those studies that find P3 prolongation in dementia report it in all diagnostic groups; therefore, the test is of limited specificity in the identification of Alzheimer's disease or some other dementing disorder.""44 P3 may be useful for serial screening of cognitive ability" and has been shown to wax and wane in abnormality in encephalopathies characterized by intermittent c o n f u s i ~ n . " ~It~may ~ " also help to differentiate between dementia and the
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CONTINGENT NEGATIVE VARIATION AND OTHER SLOW POTENTIALS The best-known slow potential is the CNV, described by Walter et al in 1964." In reaction time tests in which an alerting signal (Sl) is followed by an imperative stimulus to which a response must be executed (S2), the CNV is a slowly developing negative potential in the interval between S1 and S2 (Fig. 3). After the imperative stimulus and appropriate response, the potential returns to the baseline or becomes positive. There is sometimes a delay in the development of the positivity, and a negativity persists that is called the postimperative negative variation (PINV) (Fig. 4).70When the testing paradigm includes executing a movement, the Bereitschaftspotential or RP is recorded before the movement (Fig. 5). RP is usually negative and is followed by positive deflection, but in some situations a delayed negativity persists that resembles the PINV.71 200
Figure 3. The contingent negative variation recorded between a warning stimulus (Sl)and an imperative stimulus (S2), at which a motor response must be executed. The usual recording montage is vertex to ear or mastoid reference; the negative baseline shift is normally followed by a positive potential.
The CNV is generally recorded from the vertex with ear or mastoid reference. An analysis time of 2 to 4 seconds is required, with repetition of 10 or more averages. Paired stimuli, generally of different modality, are required, and very slow, longlasting potential changes must be recorded, usually requiring a DC time constant. Under these conditions, pairs of stimuli separated by 1 to 2 seconds, with the first serving as a warning signal and the second as an imperative stimulus at which time a motor action is required, will lead to a negative potential shift between the evoked potential to the warning stimulus and the evoked potential to the imperative stimulus. The warning stimulus must be followed by an imperative stimulus, and a specific motor response to the imperative stimulus of the pair is required. The CNV generally follows the warning stimulus by 4 msec and reaches maximum negativity, usually approximately 50 pV, within 800 msec after the warning stimulus. The CNV is maximal at the vertex, extends into the frontal region, involves the parietal area to a lesser extent, and is minimal in the occipital and posterior temporal area^.^' The CNV requires coopera-
Figure 4. CNV with a prolonged negative potential even after the imperative stimulus (S2). This is postimperative negative variation and has been reported in schizophrenia and some neurologic disorders. Its significance and diagnostic utility are uncertain.
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nerve shocks, auditory clicks, and visual flash stimuli have suggested that P3 becomes attenuated in amplitude and eventually absent during the course of chronic schi~ophrenia.~' Major depression has been associated with relatively normal P3 latency but attenuated P3 amplit ~ d e It. has ~ ~ been suggested that this reflects basically normal stimulus processing but a decrease in task involvement both clinically and in the ERP testing paradigms. Other studies have indicated essentially normal P3 waveform and amplitude in depression. Mania may be associated with minimal P3 attenuation," while P3 has been suggested in one study to be increased in patients with anxiety disorder compared with controls.64P3 amplitude attenuation has been described in both drinking and abstinent alcoholics, who have disorders both of motivation and of memory, and P3 has been suggested to identify the at-risk children of alcoholic p a r e n t ~ . ~ latency 93 prolongation and amplitude attenuation have been reported in patients with psychopathy and personality disorder, possibly providing an electrophysiologic indication of altered stimulus processing in these disorders of interpersonal relation^.^^.^' Psychoactive drugs clearly affect ERP latency and amplitude; their influence has not been systematically studied. In addition, many of the psychiatric disorders wax and wane in severity, making conclusions from single tests difficult." ERP studies are not yet of diagnostic use in psychiatric disorders, but may provide information about underlying brain dysfunction in "functional" illness.
V O L U M E 10, NUMBER 2 JUNE 1990
C L I N I C A L U T I L I T Y OF EVENT-RELATED POTENTIALS-DRAKE
0.5 Sec
Figure 5. The Bereitschaftspotential(readiness potential) is recorded when the imperative stimulus requires a motor response. The RP is a negative potential preceding the motor action at the imperative stimulus (M). Abnormalities have been reported in extrapyramidal and cerebellar disorders.
demented patients, and this may provide a means of further assessing early cognitive complaints in possible Alzheimer's disease.'WNV attenuation after head trauma has been related to clinical outcome in some series, whereas in others CNV amplitude increase after injury may parallel behavioral disinhibition." A CNV increase may help characterize vascular headaches as opposed to other types and has been related to alteration of central aminergic pathway^.'^ CNV decrement in dyslexia, aphasia, and speech disorders has been ascribed to a faulty attentional mechanism.'"eduction in CNV amplitude during EEG discharges has been described in temporal lobe epilepsy but not in generalized seizure disorders." Abnormalities of RP have been reported in Parkinson's disease, Tourette's syndrome, and cerebellar disord e r ~ Such . ~ ~ slow potentials are still of limited utility in neurologic or psychiatric diagnosis, but deserve further investigation as the mechanisms and diagnostic role of evoked potentials are clarified, and as methods for computerized analysis and topographic mapping of neurophysiologic data become more widely available.
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tion and expectancy, and so cannot be elicited in infants or uncooperative subjects; it increases in latency and changes with the subject's ability to shift attention in advancing age.'" The clinical utility of CNV remains limited, although it has been extensively studied in psychiatric disorders and in relation to psychiatric drugs. CNV amplitude is reduced and particularly subject to distraction in schizophrenics. Schizophrenics have also been reported to have a PINV more often than normal or nonpsychotic subjects, the PINV predominating in early schizophrenia and being of greater amplitude and longer duration in those with hallucinations or without depression and anxiety. An RP is reported more often and for longer duration than in normal controls or patients with other psychiatric disorder^.'^ T h e CNV is reportedly reduced in amplitude in depression, and amplitude increases with remission. An increased incidence of PINV and more frequent PINV when under stress are described in depression, and a prolonged RP is described with motor tasks. CNV attenuation, frequent PINV, and higher amplitude PINV than in depressed states have been reported in manic patients. Some series have suggested CNV is reduced in anxiety, whereas others indicate a greater susceptibility to distraction and a relationship between anxiety level and PINV. High-amplitude CNV and persistent PINV with stimulation by phobic objects have been reported in patients with phobia, and CNV reportedly normalizes and PINV subsides with successful treatment of the phobia. An enhanced CNV and PINV intermediate between normality and psychosis have been described in obsessive-compulsive disorder. Low-amplitude CNV but a more rapid ascent of the negative potential has been described in hysteria, whereas marked attenuation of the CNV is reportedly characteristic of some personality disorders. Alcohol may decrease CNV amplitude, marijuana is said to increase CNV amplitude and augment PINV, phenobarbital and benzodiazepines decrease or leave unchanged CNV amplitude in normal volunteers, and CNV is reportedly increased by methadone in drug addicts. Caffeine, amphetamine, and nicotine reportedly increase or decrease CNV amplitude, depending on change in alertness. CNV amplitude is reportedly reduced in normal subjects given antipsychotics, whereas CNV increases in schizophrenics given neuroleptics. Antidepressants and lithium carbonate reportedly increase CNV amplitude in patients requiring those drug^.'^ T h e diagnostic utility of CNV in neurologic disease is uncertain. Failure of CNV to recover after attenuation by distraction has been shown in
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CLINICAL UTILITY OF EVENT-RELATED POTENTIALS-DRAKE
