Brainstem Evoked Potentials in Panic Disorder - Europe PMC

Brainstem Evoked Potentials in Panic Disorder* Verner J. Knott, D. Phil., David Bakish, M.D., John Barkley, B.A. Institute of Mental Health Research, Royal Ottawa Hospital, Ottawa, Ontario Submitted: October 14, 1992 Accepted: March 29, 1994

Patient reports and laboratory tests support the notion that panic attacks are generated by stimulation of brainstem nuclei. Scalp-recorded brainstem auditory evoked potentials may serve as a unique measurement'strategy for the noninvasive assessment of the role of brainstem functioning in panic disorder. Ipsilateral and contralateral BSAEP recordings were examined in response to separate left and right ear click stimulation in 28 patients with a diagnosis of panic disorder and in 18 normal controls. Latency measures did not differentiate between the patient and control groups but amplitudes of wave III and V were found to be larger in patients. These findings are discussed in relation to pathophysiological and neurochemical theories of panic and specific emphasis is placed on serotonergic function. Key Words: panic disorder, brainstem auditory evoked potentials (BSAEPs), serotonin

INTRODUCTION

The accumulated evidence gleaned from preclinical infrahuman experiments, pharmacological provocation tests and clinical observations strongly implicate panic disorder as a brainstem phenomenon. Accordingly, individuals who are predisposed or who are vulnerable to panic are believed to experience anxiety attacks as a result of stimulation from either an endogenous toxin or aberrant neural transmission of hyperexcitable foci in one or more brainstem regions which include the pontine locus ceruleus, the medullary chemoreceptors and the midbrain dorsal raphe (Gorman et al 1989). Investigations of brainstem integrity frequently involve assessment via scalp recording of five to seven short latency, sub-microvolt, positive potentials which are elicited within *Portions of this paper were presented at the XV Annual Meeting of the Canadian College of Neuropsychopharmacology, Saskatoon, Saskatchewan, May 31st, 1992. Address reprint requests to: Vemer J. Knott, M.D., Neurophysiology Section, Basic Sciences Branch, Institute of Mental Health Research, Department of Psychology and Psychiatry, University of Ottawa and Royal Ottawa Hospital, 1145 Carling Avenue, Ottawa, Ontario, Canada K1Z 7K4.

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one to ten milliseconds following acoustic stimulation (Chiappa 1983). Referred to as brainstem auditory evoked potentials (BSAEPs), this series of electrical waves is presumed to represent volume-conducted events which reflect the sequential activation of brainstem relays along the auditory pathway (Jewett 1970; Jewett et al 1970; Jewett and Widdiston 1971). Although the precise generator of each of these potentials is still uncertain, there is a general consensus, as shown in Figure 1, that they implicate origins in both peripheral and central portions of the auditory system and that wave I originates from the distal VIlIth nerve, wave III from the lower pons (possibly the superior olivary complex) and wave V from the (upper pons) midbrain (Wada and Starr 1983a, 1983b, 1983c). Although it is generally accepted that BSAEPs are resistant to alteration by anything other than structural pathology in the brainstem auditory tracts, not being significantly affected even by barbiturates or general anaesthesia, there is evidence which suggests that these potentials may indeed be sensitive to specific state-trait variables as they have been shown to vary with arousal (McEvoy et al 1979), attention (Lukas 1980, 1981), psychotic conditions (Josiassen et al 1980) and behavioral symptom clusters (Hayashida et al

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ence at least one panic attack during the washout period. Eighteen nonpatient volunteers (8 M) with no past or current psychiatric or head trauma history and requiring no current central nervous system medications served as normal controls. The average age of the patients and controls was 36.1 years (range 21 to 52) and 34.1 years (range 23 to 52), respectively. All subjects were given an explanation of the nature and procedures of the study and they all gave their informed consent. BSA EP recordings Acoustic stimulation tests for patients and controls consisted of standard pure tone audiometric threshold assessments and threshold assessments for clicks to be used in BSAEP recordings. The pure tone audiogram (assessed with a descending method of limits procedure) was considered abnormal if thresholds for any of the low to medium (500 Hz, 1000 Hz, 2000 Hz) test frequencies exceeded 25 dB or if inter-ear threshold differences exceeded 40 dB on these same frequencies. None of the patients or controls exhibited abnormal pure tone thresholds and statistical analysis of click thresholds (established by a descending method of limits procedure) did not reveal any significant differences between groups for either left or right ear stimulation. During the BSAEP recording session the subjects sat in a comfortable reclining chair situated in a sound-attenuated, electrically shielded chamber adjacent to the control room housing stimulators, amplifiers and computers. A Nicolet (Pathfinder -II) system was used to present acoustic stimuli and to record electrical potentials. The stimuli consisted of 2000 rarefaction clicks, intensity 70 dB(SL) and duration

1986; Lindstrom et al 1987). BSAEP abnormalities have been observed in patients with generalized anxiety disorder (Drake et al 1991) and several reports, albeit with relatively small sample sizes and vague methodologies, have evidenced altered BSAEPs in panic disorder patients (Yeudall et al 1983; Jacob et al 1985, 1989). BSAEP alterations have also been observed during the acute provocation of panic attacks (Knott and Lapierre 1986). Given that BSAEPs allow one to cautiously infer functional activity in brainstem and midbrain regions, the purpose of this study was, within a purely descriptive exploratory framework (Abt 1983), to compare the BSAEP potentials of patients suffering from panic disorder with those of non-psychiatric, healthy controls and, by so doing, provide data for the generation of testable hypotheses concerning the role of brainstem pathophysiology in panic disorder. METHODS Experimental subjects Twenty-eight consecutive patients (11 M) were selected from an outpatient programme according to DSM-III-R criteria for panic disorder without agoraphobia (n = 4) or panic disorder with agoraphobia (n = 24). Prior to testing, patients were drug-free for a three to seven day period during which time they were placed on a placebo pill washout. Patients who had taken an MAO inhibitor within two weeks of entry into the placebo washout period or who had experienced symptoms of withdrawal during the washout were excluded from the study. As an inclusion criteria all patients had to experi-

Right Ear - (Cz - Ai)

Left Ear - (Cz - Ai) Pre-stimulus Baseline

's

I

11

Ill

11 1 Il V v

IV V

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I/ .15 tV

1.1 msec

-

Right Ear- (Cz - Ac)

Left Ear - (Cz - Ac)

\\7' Stimulus Onset

Fig. 1.

I

lay-

Averaged ipsilateral (Cz-Ai) and contralateral (Cz-Ac) BSAEP recordings to right and left ear click stimulation in a single control subject. Stimulus artifact is omitted from waveform averages.

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Patients - Right Ear (Cz Ai)

Patients - Left Ear (Cz - Ai)

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J.151

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1.1 msec Controls - Left Ear (Cz - Ai)

Controls - Right Ear

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(Cz - Al)

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Stimulus Onset

Fig. 2.

Grand (group) averages of ipsilateral (Cz-Ai) BSAEPs to left and right ear stimulation in patients and controls. Stimulus artifact has been omitted from waveform averages.

0.1 milliseconds, which were presented unilaterally to left and right ears via TDH-49 headphones at a rate of 10.1/seconds No contralateral masking was used. BSAEPs were recorded with a tin electrode placed at the vertex (Cz) and referred separately to ipsilateral (Ai) and contralateral (Ac) earlobes. An additional electrode was placed on a midforehead site to serve as a ground and all electrode impedances were kept below 2 Kohms. Ipsilateral (Cz-Ai) and contralateral (Cz-Ac) electrical activity were amplified with bandpass settings of 100 Hz-3 KHz and potentials were averaged on-line over a 11 milliseconds epoch with digitized sample

intervals of 20 micro-seconds beginning 1 msec prior to stimulus onset. An automatic artifact rejection feature was employed which eliminated single trials with electrical activity exceeding 95% of the amplification gain of 20 V peak-topeak. Patients were also visually monitored by video camera and if consistent movement artifacts were apparent the recording was halted and re-started. Earphones were checked before and after recordings to guard against displacement by movement artifacts.

Table 1

Wave mean

I

V

1.68 2.73 3.74 4.92 5.70

I - III I - IV III - V

2.07 4.02 1.96

II III IV

BSAEP latencies for panic disorder patients and normal controls Absolute latencies (msec) Patients Controls Left ear Left ear Right ear sd mean sd sd mean mean 0.19 1.67 0.24 1.68 0.19 1.65 0.20 2.79 0.17 0.20 2.73 2.74 0.19 3.78 0.21 3.83 0.25 3.75 0.27 5.01 0.24 0.34 4.83 5.03 0.26 5.71 0.29 5.74 0.34 5.61 Peak-to-trough amplitudes (pV) 0.17 2.11 0.18 0.22 2.07 2.15 0.22 4.03 0.27 4.06 0.38 3.95 0.21 1.92 0.30 0.26 1.90 1.84

Right ear sd 0.16 0.16 0.17 0.19 0.30 0.13 0.25 0.18

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Table 2 BSAEP latencies for panic disorder patients and normal controls Baseline-to-peak amplitudes (jV) Wave

Controls

Patients

I II III IV V I/V

mean 0.12 0.10 0.17 0.18 0.20 0.50

I II III IV (pre-IV) IV (post-V) V I/V

0.23 0.20 0.22 0.22 0.29 0.33 0.84

Left ear sd 0.13 0.11 0.09 0.11 0.10 0.65

0.11 0.10 0.07 0.11 0.15 0.13 0.67

Left ear Right ear mean sd mean sd 0.08 0.07 0.13 0.11 0.06 0.08 0.12 0.11 0.12 0.08 0.19 0.11 0.11 0.05 0.18 0.11 0.13 0.08 0.16 0.08 0.46 0.79 0.71 1.09 Peak-to-trough amplitudes (.V) 0.16 0.13 0.24 0.11 0.12 0.10 0.18 0.09 0.21 0.16 0.10 0.09 0.15 0.10 0.21 0.10 0.27 0.08 0.33 0.15 0.32 0.11 0.30 0.11 0.88 0.71 0.85 0.58

Data analysis BSAEP averages were stored on disc and analyzed offline with the aid of computer cursers and software which updated digital values of latencies and amplitudes of specified peaks. Figure 2 shows typical ipsilateral and contralateral BSAEP recordings to left and right ear stimulation in a

mean 0.10 0.07 0.15 0.15 0.18 0.75 0.19 0.13 0.15 0.18 0.26 0.32 0.65

Right ear sd 0.09 0.10 0.10 0.08 0.11 1.11 0.10 0.07 0.13 0.14 0.08 0.16 0.43

RESULTS

BSA EP group comparisons Examination of individual latency values relative to normative published standards (Chiappa et al 1979) indicated that the majority of subjects displayed normal BSAEP latencies within 3.0 standard deviations of expected means. For single subject. absolute latencies, one patient and one control exhibited Left and right ear stimulated ipsilateral BSAEP averaged abnormally slow wave V latencies and for inter-peak latenrecordings were scored for absolute latencies of peaks I, III, cies two patients showed abnormally long HI-V intervals IV and V. Inter-peak latencies (IPL) of the major compo- while three controls showed abnormally slow I-V or I-III nents, between I-III, III-V and I-V of the ipsilateral (Cz-Ai) intervals. Grand (group) averaged ipsilateral BSAEP waverecordings were also analyzed. Contralateral recordings of forms for left and right ear stimulation in patients and controls shown in Figure 2. each average were employed only to aid in the identification areMean latency values for patient and control groups are of ipsilateral peaks IV and V. Amplitude measures, via shown in Table 1. Both the patient and control latency baseline-to-peak and peak-to-trough (i.e., trough following averages were well within the normal ranges derived from the peak) procedures, were also carried out for peaks I, III, our laboratory and other published data. IV and V. For peak IV, peak-to-trough amplitudes were No significant group differences were observed on absomeasured from the peak to the trough of the following wave lute, inter-ear or inter-peak latency values. BSAEP amplitude (post-V) and to the trough preceding peak IV (pre-IV). The values for patients and controls are shown in Table 2. Although, in general, baseline-to-peak amplitudes apamplitude ratio of wave I to V (I/V) was also scored. to be larger for patients than controls, significant peared Statistical analysis employed in group comparisons of group differences were observed only for peak III (F = 3.93, each latency and amplitude measure included separate df = 1/40, p = 0.054) with patients exhibiting greater positive 2(Group) x 2(Ear) split-plot analysis of variance (ANOVA) amplitudes and for peak V since follow-up of a significant procedures which, if significant, were followed up with Group x Ear interaction (F = 5.72, df = 1/41, p = 0.022) t-tests. Group inter-ear comparisons were also carried out by indicated that patients had larger amplitudes than controls deriving right-minus-left difference scores for each measure with left ear stimulation (t = 2.50, df = 43, p = 0.016). Peak-to-trough amplitude measurements showed similar and subjecting these to one-way ANOVAs.

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trends with peaks I (F = 4.97, df = 1/41, p = 0.03 1), II (F = 5.72, df = 1/39, p = 0.022) and III (F = 4.88, df = 1/40, p = 0.033) being significantly larger in patients than in controls. group

DISCUSSION This exploratory study examined certain aspects of brainstem function in panic disorder patients via measurement of BSAEP components which are known to reflect some (not all) rapid neural activity generated by known structures in the

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BSAEPs may be one useful method of linking this present data with current neurochemical theories of panic disorder. It is well established by way of histochemical, pharmacological and electrophysiological studies that neurotransmitter mechanisms govern activity of neurons in the pre-thalamic auditory pathway. With respect to BSAEPs, infrahuman studies have provided specific evidence for the presence of cholinergic and serotonergic mechanisms in the inhibitory modulation of amplitudes, but not latencies, of these peaks. Whereas in rats nicotine and 5-hydroxytryptophan produce significant decrements in waves Ill and V (Bhargava et al 1978), administration of serotonin-depleting drugs (reserpine or p-chlorophenylalanine) have been shown to cause amplitude increments (Bhargava and McKean 1977; Bhargava et al 1981). Administration of catecholamine-depleting drugs and L-dopa fail to modify BSAEP amplitudes. Larger peak Ill amplitudes in our panic disorder patients may well reflect excessive noradrenergic activity in the pontine nuclei of the locus ceruleus, but it may alternatively be related to activity of serotonergic nuclei of the dorsal raphe region of the midbrain. Several lines of evidence have indicated that serotonergic transmission may play an important role in panic attacks (Gorman et al 1989). Studies stimulating serotonergic function with tryptophan or serotonergic agonists have yielded discrepant data regarding the appearance of panic symptoms but it is of interest to note that the locus ceruleus receives serotonergic fibres from the raphe nuclei and that stimulation of the raphe in animals causes anxiety-like responses (Bobillier et al 1976; Stein et al 1973). Clinically more important is the observation that medications with main activity on serotonergic transmission such as fluoxetine are found to be relatively successful in blocking panic (Gorman et al 1987). Combined examination of clinical symptoms and BSAEPs in panic patients, pre- and postacute/chronic treatment with these same medications would be an obvious route for investigating the role of brainstem/midbrain pathophysiology and serotonergic dysfunction in this disorder. Investigating the effects of acute tryptophan depletion and/or supplementation on BSAEPs and concomitant self-reported anxiety symptoms may also be a useful approach in unravelling the relationship between serotonergic activity and brainstem functions in panic symptomatology. These same studies might include longerlatency cortical evoked auditory potentials which also appear to be augmented in panic disorder (Knott et al 1991), perhaps as a result of effects of abnormal functioning of neural activity in the subcortical auditory pathway.

brainstem auditory pathway. Clinical and pathological studies have shown that a variety of neurological diseases involving brainstem structures result in BSAEP alterations, the most clinically reliable and useful being latency changes as marked intersubject variability has rendered amplitude measures of BSAEP peaks to be clinically less useful and precise (Chiappa 1983). In the present study, latency values of BSAEP peaks of panic patients were not found to differ from those of normal controls. Although one may thus conclude that panic disorder is not dependent upon disordered auditory brainstem pathways generating the BSAEP peaks, one can not rule out the possibility that other brainstem systems, not indexed by these far-field electrical peaks, are involved in the pathophysiology of panic. The extralemnsical pathway is one such system which subserves audition and alerting/arousing processes (Hobson and Brazier 1980; Courchesne et al 1985). While latency characteristics did not distinguish study groups, it is interesting to note that the less traditional amplitude measurements of BSAEPs were found to differentiate patient and control groups. Peak III amplitudes appeared to be significantly larger in patients than in nonpatients regardless of which ear was stimulated or which measurement techniques were employed. Similar group effects were also shown with peak-to-trough measures of peaks I, II and baseline-to-peak measurements of peak V following left ear stimulation also indicated larger amplitude values for patients suffering from panic disorder. Although wave I reflects, more or less, a noncentral nervous system effect specific to cochlear functioning, waves Ill and V are more specific to the central nervous system in that the former indicates an effect in the medullary-pontine region while the latter indicates a pontine-midbrain effect (Buchwald and Huang 1975; Starr and Hamilton 1976). Thus, these findings add some weight to the hypothesis that acute attacks may be generated by aberrant neural discharge in the brainstem (Gorman et al 1989). However, it must be cautioned that these observations are exploratory and are not considered confirmatory in the sense of rejecting a preselected null hypotheses. As suggested by Abt (1983) these findings must be reexamined with future replication attempts being preferably couched within a framework of a priori hypotheses and ACKNOWLEDGEMENTS statistical analyses which account for the experiment error rate.

Given this cautionary restriction, awareness of the avail- Research was supported by McNeil Pharmaceuticals able studies focusing on neurotransmitter manipulations of (Canada) Ltd.

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