01991 VOL 22 NO. 2
CLINICAL ELECTROENCEPHALOGRAPHY
Auditory Evoked Potentials In Anxiety Disorder Miles E. Drake, Jr., Ann Pakalnis, Barbara Phillips, Hosi Padamadan and Sharon A. Hietter
neurologic, or psychiatric disorder were studied after ascertaining that their hearing was Anxiety normal and they were taking no medications. Brainstem Auditory Evoked Potentials Evoked potentials were recorded with Nicolet Long-Latency Auditory CA-1000and Pathfinder II evoked potential sysEvent-Related Potentials tems (Nicolet Instrument Corporation, Madison, INTRODUCTION Wisconsin). Grass tin cup electrodes (Grass The virtually ubiquitous and occasionally disInstrument Company, Quincy, Massachusetts) abling state of anxiety has been the focus of were affixed with collodion at International 10increasing clinical, neurophysiologic, and bio20 System positions. BAEPs were recorded chemical study.’ Classic EEG findings include from Cz with reference to the ear ipsilateral and reduced abundance and increased frequency contralateral to stimulation. Rarefaction clicks of alpha activity, a higher proportion of beta were presented monaurally at 70 dB SL and activity, increased photic driving and photic 11.1 per second through shielded head phones, driving at faster frequencies, diminished alpha with 40 dB masking of the contralateral ear. blocking with eye opening or stimulation, and Analysis time was 10 ms, filter band pass was an increased incidence of positive spike dis150-3000 Hz, and 2000 averages were recorded charges.’ Changes in amount and distribution and replicated for each ear. AEPs were reof fast activity have also been demonstrated corded from Cz to linked ear reference, utilizing with computerized topographic EEG a n a l y s i ~ . ~ an analysis time of 1000 ms, interstimulus interSleep changes similar to those in depression val of 1.1 second, and 1-100Hzfilter band pass. have been described in anxiety patients4The Tones of 1000 and 3000 Hz were presented in a Contingent Negative Variation and other slow pseudorandom fashion and 80:20 ratio, with potentials have been frequently studied in a patients and subjects instructed to attend to variety of psychiatric disorders involving anxand count the rare high-pitched tones. Trials in i e t ~ ,while ~ , ~ auditory evoked potentials have which patients and controls appeared drowsy, been less frequently investigated.’ Many of or in which the rare tone count was in error by these studies predate the present classification more than 5, were rejected, in addition to the of anxiety disorders or utilize patients with use of automatic artifact rejection. assorted mental disorders of which anxiety was Absolute and interpeak latencies of Waves I, a symptom. We have studied short-latency Ill, and V of BAEPs and amplitude and latency brainstem auditory evoked potentials (BAEPs) of AEP N1, P2, N2, and P3 components were and long-latency auditory event-related potencompared by Student’s 2-tailed t-test. tials (AEPs) in generalized anxiety disorder, in which anxiety is unassociated with other psychiatric symptoms, and which is a widespread and incompletely understood disorder. Miles E. Drake, Jr., M.D., Ann Pakalnis. M.S.. M.D., Barbara Key Words
Phillips, M.D., H o s Padamadan. M.B B S , and Sharon A . Hietter, R EEG T , are from the Clinical Neurophysiology Laboratory, The Ohio State University Hospitals and the Department of Neurology, TheOhioState University College of Medicine, Columbus, Ohio Presented in part at the 42nd Annual Meeting, Southern EEG Society. St Petersburg, Florida, January 14. 1989 Supported in part by The Clinical Neurophysiology Development Fund, The Ohio State University. Requests for reprints should be addressed to Dr Miles E. Drake, Jr , 466 Means Hall, 1654 Upham Drive, Columbus, Ohio 43210.
METHODS Twelve patients ranging in age from 23 to 56 years were studied after meeting diagnostic criteria for generalized anxiety disorder that are summarized in Table 1 (American Psychiatric Association, 1987). Seven were male and five female, and all medications had been discontinued for 1 to 2 weeks at the time of study. Twelve age-matched controls without medical, 97
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Table 1 Clinical features of generalized anxiety disorder (DSM-Ill-R, 1987) A. Six months or longer of anxious mood and worry about misfortune to self or others. 6. No psychotic disorder, affective disorder, substance dependence disorder, or other anxiety disorder. C. Six of 18 symptoms are present when anxious: Motor tension: 1. Trembling, twitching, or feeling shaky 2. Muscle tension, aches, or soreness 3. Restlessness 4. Easy fatigability Autonomic hyperactivity: 5. Shortness of breath or smothering sensation 6. Palpitations or tachycardia 7. Sweating or cold clammy hands 8. Dry mouth 9. Dizziness or light headedness 10. Nausea, diarrhea, or abdominal distress 11. Flushes or chills 12. Frequent urination 13. Trouble swallowing or lumb in throat Vigilance and scanning: 14. Feeling on edge 15. Exaggerated startle response 16. Difficulty concentrating or mind going blank 17. Trouble falling or staying asleep 18. Irritability D. Not sustained by a specific organic factor (e.g., hyperthyroidism, caffeine)
No statistically significant differences were appreciated between anxiety patients and control subjects. AEP components N1, N2, and P2 were slightly longer in latency in the anxious patients, while P3 was slightly less in latency. All waveforms, but particularly N1 and N2, were lower in amplitude in the anxiety patients than in control subjects.
RESULTS BAEP and AEP findings are shown in Table 2. A l l patients and subjects had r e p r o d u c i b l e BAEPs with rarefaction clicks, with the occasional occurrence of Wave Ill redundancy or fusion of Waves I V and V, on account of which the differential effect of contralateral ear reference on Waves II and Ill and on the I V N complex was used to identify these waveforms. AEPs were identified in all patients and subjects, with some morphologic variability in the early negative and positive waveforms, and variability in amplitude but not in latency of the P3 waveform. All anxious patients and control subjects had BAEP absolute and interpeak latencies within 3 standard deviations of clinical normal means. No differences were demonstrable in absolute latencies or in 1-111 and Ill-V interpeak latencies. However, interpeak latencies between Waves I and V were relatively prolonged in anxiety patients (P< 0.05).
DISCUSSION Anxious patients were among the first to be studied w i t h electroencephalography. Early studies reported less abundant alpha, normal alpha frequency d i s t r i b u t i o n w i t h a higher mean than in control subjects, a higher proportion of beta activity, and relative increase of beta power.'Photic driving was more prominent and driving at faster harmonics more often present, while alpha attenuation with eye opening or stimulation was less prominent.' Hughes and Cayaffa' f o u n d a significant correlation between anxiety and the presence of positive
98
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Table 2 BAEP interpeak latencies and AEP latencies and amplitudes in Datients with anxietv and control subiects. ~
BAEPs Control Anxiety AEPs Latency Control Anxiety Amplitude Control Anxiety =
~
~~
I-v
I-Ill
I I I-v
2.20 f 0.13 2.24 k 0.19
1.83 f 0.2 1.85 k 0.16
N1
N2
92.4 i 10.6 94.0 f 8.8
215.3 f 20.2 220.1 f 16.3
10.1 f 4.1 9.6 f 6.3
10.6 7.3 9.1 f 4.5
*
4.02 f 0.16 4.10 f 0.11 ( * )
P2 161.5 f 7.8 164.2 f 0.5 12.8 i 4.6 10.5 f 5.3
P3 328.4 326.5
* 21.4 * 17.3
12.6 3z 2.8 11.1+ 4.8
P < 0.05 by Student’s t-test
spike discharges, especially in older females, and the closest correlation with psychiatric symptoms in apparently normal children with otherwise normal EEGs was f o u n d t o be between anxiety and positive pikes.^ Other neurophysiologic studies have shown a variety of changes in anxious patients. Computerized topographic EEG analysis has shown reciprocal changes in beta and delta activity in patients w i t h generalized anxiety disorder, which are reversed by therapeutic doses of anxiolytic benz~diazepines.~ Reynolds et a14found prolonged sleep latency, increased wakefulness after sleep onset, and reduction of slow wave sleep in anxious patients similar t o that reported in depressives. In early studies of the Contingent Negative Variation,” repetitivestimuli produced slower habituation in anxiety than in the normal state. Reduction of CNV amplitude, an inconsistent pattern of CNV attenuation and persistence of low-amplitude CNV with distraction were later reported i n anxious patients.”,” The presence of a post-imperative negative variation in the CNV was related by Dongier et all3to subjects’ anxiety levels. More recent s t u d i e ~ ~have ~ , ’ ~failed to demonstrate CNV amplitude reduction in anxiety disorders. Early studies of auditory evoked potentials,16 showed reduced latency of AEPs in anxiety, possibly related to a state of increased vigilance, while P300 amplitude was found by Chattopadahyay et al,7 to be increased, perhaps by the same mechanism. Our findings indicated a statistical difference between patients with generalized anxiety disorder and control subjects with respect to
brainstem function, indicated by relatively increased I-V interpeak latency. In clinical testing this would not exceed clinical norms, however. The anatomic location of such dysfunction is uncertain, as no differences were found in 1-111 or Ill-V interpeak latencies, but evidence of brainstem dysfunction would accord with sleep suggesting sleep disturbances in depressed and anxious patients that might be ascribed to abnormality of brainstem adrenerg i c pathways. Considerable evidence links brainstem pathways generally and the locus ceruleus particularly to the physiological symptoms and psychological alterations in anxiety disorders.” It would be useful in subsequent studies to correlate BAEP latencies with clinical measures of anxiety, psychophysiological indices of arousal and vigilance, or cerebrospinal fluid measures of adrenergic metabolites. Our patients with generalized anxiety disorder had slightly reduced AEP amplitudes and mildly prolonged AEP latencies. This differs from earlier reports of shorter AEP latency16 and increased a m p l i t ~ d eThis . ~ difference may reflect the more homogenous nature of our patients with generalized anxiety disorder as compared to earlier studies in which other conditions could have coexisted with anxiety. In addition, some residual medication effects may still have been present; although patients had been instructed to discontinue medications, they may have continued to take some medication, and use of over-the-counter preparations or alcohol were not assessed. Earlier authors have ascribed AEP differences i n anxious patients to increased arousal and vigilance, but 99
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thalamus and periaqueductal gray matter. All of these areas could also be involved in the pathophysiology of anxiety, and therefore relevant to ERPchanges in anxious patients. As with BAEP alterations, subsequent correlation of AEP amplitudes and latencies with psychophysiological measures of vigilance and clinical indices of anxious symptoms may clarify the relevance of these evoked potentials to anxiety disorders.
chronically and generally anxious patients could also have difficulty attending to stimuli and concentrating on a testing paradigm, which could reduce response amplitude and increase response latency. The amplitude reduction and latency increase of the early negative and positive waveforms may reflect difficulty with attention maintenance or direction. as these waveforms have been suggestea to eflect exogenous attentional proc e s s e ~ .Changes '~ in the later components, particularly P3, may reflect alteration in motivation of task involvement as the ease of elicitation of P3 and its amplitude are related to the motivational value of the Stereoelectroencephalography2' and magnetoencephatography" have suggested that the hippocampal formation and limbic system may bethe generators of the P3 waveform. This area may also be linked to normal and pathological anxiety, as it is a prominent siteof action for benzodiazepines and is involved in the inhibitory neurotransmission of gamma aminobuteric acid (GABA), and the benzodiazepine-GABA receptor complex is increasingly linked to the pathogenesis of a n ~ i e t y . 'There ~ is also some evidence for involvement of other sites in P300 generation. Johnsonz4 found no difference in P300 with temporal lobectomy that removed hippocampal and limbic structures, while phase reversals suggesting posterior temporal generators were recorded by Wood et al.25Evidence for a frontal lobe P300 generator was found in intracranial recordings by McCarthy and Wood,*' and Yingling and HosobuchiZ7reported f i n d i n g endogenous ERPs in depth electrodes in the
SUMMARY The pathophysiology of anxiety has recieved much recent attention. EEG findings in anxiety are nonspecific, and some changes in psychophysiological measures have been reported. We recorded short-latency brainstem auditory evoked potentials (BAEPs) and long-latency auditory event-related potentials (AEPs) in 12 patients with generalized anxiety disorder. All 12 patients had BAEP latencies within clinical norms, but I-V lnterpeak latencies were significantly longer in patients with anxiety than controls. N1, N2, P2, and P3 AEP components were within normal limits; N 1 and P2 were reduced in amplitude in anxiety patients, but differences from controls were not significant. The BAEP findings may suggest altered brainstem f u n c t i o n i n anxiety, w h i c h has been implied by biochemical studies of anxiety and depression. AEP differences may be related to difficulties in concentration and attention direction reported by anxious patients. ACKNOWLEDGMENTS The authors appreciate the preparation of the manuscript by Mrs. Victoria L. Grimes.
REFERENCES Roth M, Noyes R. Burroughs GD. Handbook of Anxiety, Vol. I: Biological, Clinical, and Cultural Perspective. Amsterdam, Elsevier, 1988. Small JG. Psychiatric disorders and EEG. In: Niedermeyer E, Lopes da Silva F (eds). Electroencephalography. Baltimore, Urban a n d Schwarzenberg; 1987:523-540. Buchsbaum MS, Hazlett E, Sicotte N et al. Topographic EEG changes with benzodiazepine administration in generalized anxiety disorder. Biol Psychiat 1985;20:832-842. Reynolds CF, Shaw DH. Newton TF, et al. EEG sleep in outpatients with generalized anxiety: a preliminary comparison with depressed outpatients. Psychiatric Research 1983;8:81-89.
5. Shaaass C. Evoked Dotentials in adult Dsvchiatrv In: H-ughes, JR, Wilson WP (eds). EEGand Evoked Potentials in Psychiatry and Behavioral Neurology. Boston, Butterworths; 1983:169-210. 6. McCallum WC. Some psychological, psychiatric, and neurological aspects of the CNV. In. Fessard A, Lelord D (eds). Human Neurophysiology, Psychology, Psychiatry: Average evoked responses and their conditioning in normal subjects and psychiatric patients. Paris, Inserrn; 1973:295-324. 7. Chattopadahyay P, Cocce E, Toone B, Lader M. Habituation of physiological responses in anxiety. Biol Psychiatry 1980;15:711-721. 8. Hughes JR, Cayaffa JJ. Positive spikes revisited - i n the adult. C l i n Electroencephalogr 1978; 9~52-59.
100
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9. Bosaeus E, Sellen U. Psychiatric assessment of healthy children with various EEG patterns. Acta Psychiatr Scand 1979;59:180-210.
ment of a brain norepinephrine system in anxiety. In: Fann WE, Karacan I, Pokorney A, Williams R L (eds). Phenomenology and Treatment of Anxiety. New York. Scientific Press;1979:153-204.
10. Walter WG, Cooper R, Aldridge VJ et al. Contingent negativevariation: an electric sign of sensory motor association and expectancy in the human brain. Nature 1964;203:380-384. 11 Bostem R, Rousseau JC, Degosset Y,Dongier M. Psychopathological correlations of the nonspecific portion of visual and auditory evoked potentials and the associated contingent negative variation. In: Cobb W, Morocutti C (eds). The Evoked Potentials. Amsterdam, Elsevier; 1967:131-138.
19. Picton TW, Stuss DT. Thecomponent structure of human event-related potentials. In: Kornhueber HH, Deecke L (eds). Motivation, Motor and Sensory Processes of the Brain: Electrical potentials, behavior, and clinical use. Amsterdam, Elsevier; 1980:17-49. 20. Beigleiter H, Porjesz B, Chou CL, Aunon JI. P3 and stimulus incentive value. Psychophysiology 1983; 20195-101.
12. McCallum WC, Walter WG. The effects of attention and distraction on the contingent negative variation in normal and neurotic subjects. Electroencephalogr Clin Neurophysiol 1968;25:319-329.
21. Halgren E, Squires NK, Wilson CL et al. Endogenous potentials generated in the human hippocampal formation and amygdala by infrequent events. Science 1980;210:803-805.
13. Dongier M.Separation of thevarious independent phenomenon among the slow potential changes (CNVs) Electroencephalogr Clin Neurophysiol 1969; 27:108-109.
22. OkadaYC, Kaufman L, Williamson SJ.The hippocampal formation as a source of the slow endogenous potentials. Electroencephalogr Clin Neurophysiol 1983;55:417-426.
14. Timsit-Berthier M . CNV, slow potentials, and motor potential studies in normal subjects and psychiatric patients. In: Fessard A, LaLord D (eds). Human Neurophysiology, Psychology, Psychiatry: Average evoked responses and their conditioning in normal subjects and psychiatric patients. Paris, lnserm 1973;327-366.
23. Brier A, Paal SM. Anxiety in the benzodiazepineGABA receptor complex. In: Roth M, Noyes R, Burroughes GD (eds). Handbook of Anxiety, Vol. I: Biological, Clinical, and Cultural Perspectives. Amsterdam, Elsevier; 1988:193-222.
15. Timsit M, Koninckx N, Dargent J, et al. Variations contingentes negatives en psychiatrie. Electroencephalogr Clin Neurophysiol 1970;28:41-47. 16. Bond AJ, James CC, Lader MH. Physiological and psychological measures in anxious patients. Psychol Med 1974;4:364-373 17. Akiskal HS, Lemmi H, Dixon H, et al. Chronic depression, Part II. Sleep EEG differentiation of primary dysthymic disorders from anxious depressives. J Affect Dis 1984;6:294-295. 18. Redmond DE. New and old evidence for the involve-
24. Johnson R, Jr. Scalp-recorded P300 activity in patients following unilateral temporal lobectomy. Brain 1988;111: 1517-1529. 25. Wood CC, McCarthy G, Squires NK et al. Anatomical and physiological substrates of event-related potentials: two case studies. Ann NY k c a d Sci 1984;425:681-721. 26. McCarthy G, Wood CC: lntracranial recordings and endogenous ERPs in humans. Electroencephalogr Clin Neurophysiol 1987;(supp1)39:331-337. 27. Yingling CD. Hosobuchi Y:Asubcortical correlate of P300 in man. Electroencephalogr Clin Neurophysiol 1984;59:72-76.
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Auditory Evoked Potentials In Anxiety Disorder Miles E. Drake, Jr., Ann Pakalnis, Barbara Phillips, Hosi Padamadan and Sharon A. Hietter
neurologic, or psychiatric disorder were studied after ascertaining that their hearing was Anxiety normal and they were taking no medications. Brainstem Auditory Evoked Potentials Evoked potentials were recorded with Nicolet Long-Latency Auditory CA-1000and Pathfinder II evoked potential sysEvent-Related Potentials tems (Nicolet Instrument Corporation, Madison, INTRODUCTION Wisconsin). Grass tin cup electrodes (Grass The virtually ubiquitous and occasionally disInstrument Company, Quincy, Massachusetts) abling state of anxiety has been the focus of were affixed with collodion at International 10increasing clinical, neurophysiologic, and bio20 System positions. BAEPs were recorded chemical study.’ Classic EEG findings include from Cz with reference to the ear ipsilateral and reduced abundance and increased frequency contralateral to stimulation. Rarefaction clicks of alpha activity, a higher proportion of beta were presented monaurally at 70 dB SL and activity, increased photic driving and photic 11.1 per second through shielded head phones, driving at faster frequencies, diminished alpha with 40 dB masking of the contralateral ear. blocking with eye opening or stimulation, and Analysis time was 10 ms, filter band pass was an increased incidence of positive spike dis150-3000 Hz, and 2000 averages were recorded charges.’ Changes in amount and distribution and replicated for each ear. AEPs were reof fast activity have also been demonstrated corded from Cz to linked ear reference, utilizing with computerized topographic EEG a n a l y s i ~ . ~ an analysis time of 1000 ms, interstimulus interSleep changes similar to those in depression val of 1.1 second, and 1-100Hzfilter band pass. have been described in anxiety patients4The Tones of 1000 and 3000 Hz were presented in a Contingent Negative Variation and other slow pseudorandom fashion and 80:20 ratio, with potentials have been frequently studied in a patients and subjects instructed to attend to variety of psychiatric disorders involving anxand count the rare high-pitched tones. Trials in i e t ~ ,while ~ , ~ auditory evoked potentials have which patients and controls appeared drowsy, been less frequently investigated.’ Many of or in which the rare tone count was in error by these studies predate the present classification more than 5, were rejected, in addition to the of anxiety disorders or utilize patients with use of automatic artifact rejection. assorted mental disorders of which anxiety was Absolute and interpeak latencies of Waves I, a symptom. We have studied short-latency Ill, and V of BAEPs and amplitude and latency brainstem auditory evoked potentials (BAEPs) of AEP N1, P2, N2, and P3 components were and long-latency auditory event-related potencompared by Student’s 2-tailed t-test. tials (AEPs) in generalized anxiety disorder, in which anxiety is unassociated with other psychiatric symptoms, and which is a widespread and incompletely understood disorder. Miles E. Drake, Jr., M.D., Ann Pakalnis. M.S.. M.D., Barbara Key Words
Phillips, M.D., H o s Padamadan. M.B B S , and Sharon A . Hietter, R EEG T , are from the Clinical Neurophysiology Laboratory, The Ohio State University Hospitals and the Department of Neurology, TheOhioState University College of Medicine, Columbus, Ohio Presented in part at the 42nd Annual Meeting, Southern EEG Society. St Petersburg, Florida, January 14. 1989 Supported in part by The Clinical Neurophysiology Development Fund, The Ohio State University. Requests for reprints should be addressed to Dr Miles E. Drake, Jr , 466 Means Hall, 1654 Upham Drive, Columbus, Ohio 43210.
METHODS Twelve patients ranging in age from 23 to 56 years were studied after meeting diagnostic criteria for generalized anxiety disorder that are summarized in Table 1 (American Psychiatric Association, 1987). Seven were male and five female, and all medications had been discontinued for 1 to 2 weeks at the time of study. Twelve age-matched controls without medical, 97
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Table 1 Clinical features of generalized anxiety disorder (DSM-Ill-R, 1987) A. Six months or longer of anxious mood and worry about misfortune to self or others. 6. No psychotic disorder, affective disorder, substance dependence disorder, or other anxiety disorder. C. Six of 18 symptoms are present when anxious: Motor tension: 1. Trembling, twitching, or feeling shaky 2. Muscle tension, aches, or soreness 3. Restlessness 4. Easy fatigability Autonomic hyperactivity: 5. Shortness of breath or smothering sensation 6. Palpitations or tachycardia 7. Sweating or cold clammy hands 8. Dry mouth 9. Dizziness or light headedness 10. Nausea, diarrhea, or abdominal distress 11. Flushes or chills 12. Frequent urination 13. Trouble swallowing or lumb in throat Vigilance and scanning: 14. Feeling on edge 15. Exaggerated startle response 16. Difficulty concentrating or mind going blank 17. Trouble falling or staying asleep 18. Irritability D. Not sustained by a specific organic factor (e.g., hyperthyroidism, caffeine)
No statistically significant differences were appreciated between anxiety patients and control subjects. AEP components N1, N2, and P2 were slightly longer in latency in the anxious patients, while P3 was slightly less in latency. All waveforms, but particularly N1 and N2, were lower in amplitude in the anxiety patients than in control subjects.
RESULTS BAEP and AEP findings are shown in Table 2. A l l patients and subjects had r e p r o d u c i b l e BAEPs with rarefaction clicks, with the occasional occurrence of Wave Ill redundancy or fusion of Waves I V and V, on account of which the differential effect of contralateral ear reference on Waves II and Ill and on the I V N complex was used to identify these waveforms. AEPs were identified in all patients and subjects, with some morphologic variability in the early negative and positive waveforms, and variability in amplitude but not in latency of the P3 waveform. All anxious patients and control subjects had BAEP absolute and interpeak latencies within 3 standard deviations of clinical normal means. No differences were demonstrable in absolute latencies or in 1-111 and Ill-V interpeak latencies. However, interpeak latencies between Waves I and V were relatively prolonged in anxiety patients (P< 0.05).
DISCUSSION Anxious patients were among the first to be studied w i t h electroencephalography. Early studies reported less abundant alpha, normal alpha frequency d i s t r i b u t i o n w i t h a higher mean than in control subjects, a higher proportion of beta activity, and relative increase of beta power.'Photic driving was more prominent and driving at faster harmonics more often present, while alpha attenuation with eye opening or stimulation was less prominent.' Hughes and Cayaffa' f o u n d a significant correlation between anxiety and the presence of positive
98
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Table 2 BAEP interpeak latencies and AEP latencies and amplitudes in Datients with anxietv and control subiects. ~
BAEPs Control Anxiety AEPs Latency Control Anxiety Amplitude Control Anxiety =
~
~~
I-v
I-Ill
I I I-v
2.20 f 0.13 2.24 k 0.19
1.83 f 0.2 1.85 k 0.16
N1
N2
92.4 i 10.6 94.0 f 8.8
215.3 f 20.2 220.1 f 16.3
10.1 f 4.1 9.6 f 6.3
10.6 7.3 9.1 f 4.5
*
4.02 f 0.16 4.10 f 0.11 ( * )
P2 161.5 f 7.8 164.2 f 0.5 12.8 i 4.6 10.5 f 5.3
P3 328.4 326.5
* 21.4 * 17.3
12.6 3z 2.8 11.1+ 4.8
P < 0.05 by Student’s t-test
spike discharges, especially in older females, and the closest correlation with psychiatric symptoms in apparently normal children with otherwise normal EEGs was f o u n d t o be between anxiety and positive pikes.^ Other neurophysiologic studies have shown a variety of changes in anxious patients. Computerized topographic EEG analysis has shown reciprocal changes in beta and delta activity in patients w i t h generalized anxiety disorder, which are reversed by therapeutic doses of anxiolytic benz~diazepines.~ Reynolds et a14found prolonged sleep latency, increased wakefulness after sleep onset, and reduction of slow wave sleep in anxious patients similar t o that reported in depressives. In early studies of the Contingent Negative Variation,” repetitivestimuli produced slower habituation in anxiety than in the normal state. Reduction of CNV amplitude, an inconsistent pattern of CNV attenuation and persistence of low-amplitude CNV with distraction were later reported i n anxious patients.”,” The presence of a post-imperative negative variation in the CNV was related by Dongier et all3to subjects’ anxiety levels. More recent s t u d i e ~ ~have ~ , ’ ~failed to demonstrate CNV amplitude reduction in anxiety disorders. Early studies of auditory evoked potentials,16 showed reduced latency of AEPs in anxiety, possibly related to a state of increased vigilance, while P300 amplitude was found by Chattopadahyay et al,7 to be increased, perhaps by the same mechanism. Our findings indicated a statistical difference between patients with generalized anxiety disorder and control subjects with respect to
brainstem function, indicated by relatively increased I-V interpeak latency. In clinical testing this would not exceed clinical norms, however. The anatomic location of such dysfunction is uncertain, as no differences were found in 1-111 or Ill-V interpeak latencies, but evidence of brainstem dysfunction would accord with sleep suggesting sleep disturbances in depressed and anxious patients that might be ascribed to abnormality of brainstem adrenerg i c pathways. Considerable evidence links brainstem pathways generally and the locus ceruleus particularly to the physiological symptoms and psychological alterations in anxiety disorders.” It would be useful in subsequent studies to correlate BAEP latencies with clinical measures of anxiety, psychophysiological indices of arousal and vigilance, or cerebrospinal fluid measures of adrenergic metabolites. Our patients with generalized anxiety disorder had slightly reduced AEP amplitudes and mildly prolonged AEP latencies. This differs from earlier reports of shorter AEP latency16 and increased a m p l i t ~ d eThis . ~ difference may reflect the more homogenous nature of our patients with generalized anxiety disorder as compared to earlier studies in which other conditions could have coexisted with anxiety. In addition, some residual medication effects may still have been present; although patients had been instructed to discontinue medications, they may have continued to take some medication, and use of over-the-counter preparations or alcohol were not assessed. Earlier authors have ascribed AEP differences i n anxious patients to increased arousal and vigilance, but 99
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@1991VOL. 22 NO 2
CLINICAL ELECTROENCEPHALOGRAPHY
thalamus and periaqueductal gray matter. All of these areas could also be involved in the pathophysiology of anxiety, and therefore relevant to ERPchanges in anxious patients. As with BAEP alterations, subsequent correlation of AEP amplitudes and latencies with psychophysiological measures of vigilance and clinical indices of anxious symptoms may clarify the relevance of these evoked potentials to anxiety disorders.
chronically and generally anxious patients could also have difficulty attending to stimuli and concentrating on a testing paradigm, which could reduce response amplitude and increase response latency. The amplitude reduction and latency increase of the early negative and positive waveforms may reflect difficulty with attention maintenance or direction. as these waveforms have been suggestea to eflect exogenous attentional proc e s s e ~ .Changes '~ in the later components, particularly P3, may reflect alteration in motivation of task involvement as the ease of elicitation of P3 and its amplitude are related to the motivational value of the Stereoelectroencephalography2' and magnetoencephatography" have suggested that the hippocampal formation and limbic system may bethe generators of the P3 waveform. This area may also be linked to normal and pathological anxiety, as it is a prominent siteof action for benzodiazepines and is involved in the inhibitory neurotransmission of gamma aminobuteric acid (GABA), and the benzodiazepine-GABA receptor complex is increasingly linked to the pathogenesis of a n ~ i e t y . 'There ~ is also some evidence for involvement of other sites in P300 generation. Johnsonz4 found no difference in P300 with temporal lobectomy that removed hippocampal and limbic structures, while phase reversals suggesting posterior temporal generators were recorded by Wood et al.25Evidence for a frontal lobe P300 generator was found in intracranial recordings by McCarthy and Wood,*' and Yingling and HosobuchiZ7reported f i n d i n g endogenous ERPs in depth electrodes in the
SUMMARY The pathophysiology of anxiety has recieved much recent attention. EEG findings in anxiety are nonspecific, and some changes in psychophysiological measures have been reported. We recorded short-latency brainstem auditory evoked potentials (BAEPs) and long-latency auditory event-related potentials (AEPs) in 12 patients with generalized anxiety disorder. All 12 patients had BAEP latencies within clinical norms, but I-V lnterpeak latencies were significantly longer in patients with anxiety than controls. N1, N2, P2, and P3 AEP components were within normal limits; N 1 and P2 were reduced in amplitude in anxiety patients, but differences from controls were not significant. The BAEP findings may suggest altered brainstem f u n c t i o n i n anxiety, w h i c h has been implied by biochemical studies of anxiety and depression. AEP differences may be related to difficulties in concentration and attention direction reported by anxious patients. ACKNOWLEDGMENTS The authors appreciate the preparation of the manuscript by Mrs. Victoria L. Grimes.
REFERENCES Roth M, Noyes R. Burroughs GD. Handbook of Anxiety, Vol. I: Biological, Clinical, and Cultural Perspective. Amsterdam, Elsevier, 1988. Small JG. Psychiatric disorders and EEG. In: Niedermeyer E, Lopes da Silva F (eds). Electroencephalography. Baltimore, Urban a n d Schwarzenberg; 1987:523-540. Buchsbaum MS, Hazlett E, Sicotte N et al. Topographic EEG changes with benzodiazepine administration in generalized anxiety disorder. Biol Psychiat 1985;20:832-842. Reynolds CF, Shaw DH. Newton TF, et al. EEG sleep in outpatients with generalized anxiety: a preliminary comparison with depressed outpatients. Psychiatric Research 1983;8:81-89.
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