P50 sensory gating in panic disorder

JOURNAL OF PSYCHIATRIC RESEARCH

Journal of Psychiatric Research 40 (2006) 535–540

www.elsevier.com/locate/jpsychires

P50 sensory gating in panic disorder Eduardo S. Ghisolfi a,b,*, Elizeth Heldt c, Ana Paula Zanardo b, Ivo M. Strimitzer Jr. b, Alexandre S. Prokopiuk b, Jefferson Becker d, Aristides V. Cordioli c, Gisele G. Manfro c, Diogo R. Lara a a

d

Departamento de Cieˆncias Fisiolo´gicas, Faculdade de Biocieˆncias da, Pontifı´cia Universidade Cato´lica do Rio Grande do Sul (PUCRS), Av. Ipiranga, 6681 – Pre´dio 12 A, 90619-900 Porto Alegre, RS, Brazil b Departamento de Bioquı´mica do Instituto de Cieˆncias Ba´sicas da Sau´de, Universidade Federal do Rio Grande do Sul (UFRGS), Brazil c Servic¸o de Psiquiatria, Hospital de Clı´nicas de Porto Alegre, Brazil Servic¸o de Neurologia, Hospital de Clı´nicas de Porto Alegre e Unidade de Neurofisiologia, Universidade Luterana do Brasil (ULBRA), Brazil Received 4 October 2005; received in revised form 2 February 2006; accepted 20 February 2006

Abstract Previous studies with prepulse inhibition in panic disorder (PD) have suggested that the early stages of sensory information processing are abnormal in patients with PD. To further investigate sensory gating function in panic disorder we performed a case-control study in a sample of 28 patients with PD, compared to 28 normal subjects and 28 schizophrenic subjects evaluating auditory mid-latency evoked potential P50 in a double-click paradigm as a measure of sensory gating. PD subjects showed weaker sensory gating as evidenced by higher P50 ratios as compared to normal subjects (62.5% vs. 45.4%, p = 0.03) and higher S2 (test) amplitude (3.5 lV vs. 2.1 lV, p = 0.01). Schizophrenic subjects when compared to healthy controls showed higher P50 ratios as compared to normal subjects (79.2% vs. 45.4%, p < 0.01) and higher S2 amplitude (3.3 lV vs. 2.1 lV, p = 0.01), but were not statistically different from PD subjects (p > 0.1). The present study corroborates recent findings of sensory gating dysfunction in PD. Further studies are still necessary to better understand the pathophysiology of this neurophysiological dysfunction and its nature as a trait or a state marker. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Panic disorder; Sensory gating; EEG; Anxiety

1. Introduction Auditory brain evoked potentials and other neurophysiological examinations have been performed in panic disordered patients in order to understand its underlying pathophysiology. Panic disordered patients were found to exhibit significantly larger N1 amplitudes associated initially to abnormal temporal processing (Knott et al., 1991) and N3 latency abnormalities, correlated to pontine activation, probably through locus ceru*

Corresponding author. Tel.: +55 51 3320 3545; fax: +55 51 3320 3612. E-mail address: ghisolfi@pucrs.br (E.S. Ghisolfi). 0022-3956/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2006.02.006

leus (Levy et al., 1996). These patients also showed enlarged prefrontal P300 in response to stimulus change, related to prefrontal-limbic pathways that could affect the processing of incoming information, supposedly disrupted in panic disorder (PD) (Clark et al., 1996; Turan et al., 2002) or even related to reticulothalamic structures plus septohippocampal limbic system (Gordeev et al., 2003). A standard two-tone discrimination task study (oddball task) showed amplitudes that are also suggestive of alteration of early information processing in PD, specifically N1 and N2 amplitudes for target tones and the N1 amplitude for non-target tones were significantly larger in the PD patients (Iwanami et al., 1997). Another odd-ball study replicated findings of an

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abnormal N2 in PD (Wang et al., 2003). More recently, studies focusing sensory gating based in the pre-pulse inhibition (PPI) were carried out in PD. Panic disorder patients in remission exhibited normal startle reactivity, reduced habituation and significantly reduced pre-pulse inhibition (PPI) and these alterations were more pronounced in patients with high trait and state anxiety (Ludewig et al., 2002). Increased startle response and decreased habituation were found in PD patients that were not under treatment and correlated significantly with higher cognitive dysfunction scores, but this was not the case for PPI (Ludewig et al., 2005). The suppression of the P50 component of the auditory event-related potential has been used as an index of sensory gating in neuropsychiatric research (Freedman et al., 1983; Adler et al., 1998). The P50 wave is a small amplitude, positive wave occurring about 50 ms after an auditory stimulus. In the P50 suppression paradigm, when two stimuli are presented 500 ms apart, the amplitude of the second peak (S2), compared to the first (S1), is usually attenuated in healthy subjects (S2/S1 ratio <0.5), whereas in patients with schizophrenia, acute mania or post-traumatic stress disorder this suppression is impaired (S2/S1 ratio > 0.5) (Adler et al., 1998; Ghisolfi et al., 2004). The hippocampus, as well as structures of brainstem and temporal cortex have been suggested as mediators of P50 suppression and it is generally assumed that impaired suppression due to an inhibitory deficit, which leads to an overflow of information and diminished capacity to filter out irrelevant stimuli (Adler et al., 1998). The neurochemical basis of P50 suppression is not yet completely understood, but cholinergic, GABAergic and monoaminergic systems have been proposed to modulate this phenomenon (Adler et al., 1998; Hershman et al., 1995; Light et al., 1999) and more recently adenosine has been implicated in P50 dysfunction (Ghisolfi et al., 2002). Despite the cumulative evidence for the involvement of auditory sensory processing and for disturbed sensory gating in PD, studies on P50 auditory gating are lacking, as far as we know. This work was designed to compare P50 auditory gating between PD patients and control healthy volunteers as well as schizophrenic patients as an additional control group.

2. Materials and methods 2.1. Subjects This study was approved by the Institutional Review Board of Hospital de Clı´nicas de Porto Alegre. Participants were recruited and signed an informed consent form after complete explanation about the protocol, the purpose and potential risks of this study.

Twenty-eight PD outpatients, previously diagnosed according to DSM-IV criteria assessed by clinical interview and the Mini International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998), were included (10 men and 18 women, mean age of 43.3 ± 10.1 years). At the time of P50 measurements, six PD subjects were not on pharmacological treatment, 11 were on antidepressants alone and 11 were on combined treatment with antidepressants and benzodiazepines. Characteristics of PD subjects are shown on Table 1. Twenty-eight healthy volunteers were recruited for this study among university students and local hospital employees (10 men and 18 women, mean age of 39.7 ± 7.8 years, all non-smokers). As an additional comparison group, 28 schizophrenia outpatients, previously diagnosed according to DSMIV were included (12 men and 16 women, mean age of 37.5 ± 7.4 years). The three groups did not differ regarding age and gender. Healthy volunteers were screened by psychiatrists using a structured clinical interview. Exclusion criteria for healthy volunteers were a DSM-IV axis I diagnosis of any disorder, clinical illness and any current pharmacotherapy, current use of alcohol and drugs of abuse, except for nicotine and oral contraceptives. No control subjects were currently taking psychotropic medication, but some PD patients were on pharmacological treatment. Subjects with family history of schizophrenia or other psychotic disorders, in first or second degree, were also excluded. Participants could not use tobacco in the preceding 2 h, neither caffeine nor any beverages containing methylxanthines over the 4 h preceding the recordings. All schizophrenic patients were on treatment with typical antipsychotics, which do not correct P50 sensory gating deficit (Adler et al., 1998). 2.2. Electrophysiological recordings The method for electrophysiological recordings was based on previously described protocols, with slight modifications (Nagamoto et al., 1996) as used by our group in previous works that replicated the classical findings for schizophrenia (Ghisolfi et al., 2002) and post-traumatic stress disorder (Ghisolfi et al., 2004). In brief, subjects were recorded seated, relaxed, and awake with eyes open and fixed on a distant target to decrease drowsiness during the recording. Electroencephalographic activity was recorded from a disk electrode (positive reference) affixed to the vertex (Cz) and referenced to both ears. Electroencephalogram (EEG) was provided using a Nihon–Kohden MEM-4104K system in 4 channels for recording of evoked responses integrated with auditory stimulator. The mean signal was registered in two channels (A1 and A2), one for each mastoid and amplified 20,000 times with a bandpass filter between 1 Hz and 10 kHz. EEG was collected for 1000 ms for each paired stimulus presented. Additional channels were used to record the electro-oculogram

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Table 1 Clinical features and P50 ratio of panic disorder subjects (n = 28) Age (years)

Gender

Disorder duration (years)

HAM-A

CGI

Current treatment

Current comorbidity

Lifetime depression

Smoking

P50 ratio (%)

54 42 22 37 44 44 36 32 55 51 57 41 39 39 53 48 51 40 48 46 47 41 38 39 53 59 33 24

F M M F M F F M F F F M F M F F F F M M F F F F F M F M

24 8 8 9 4 8 0 7 4 13 43 2 11 9 17 9 30 26 5 7 27 3 9 11 20 39 7 11

13 52 30 12 8 41 32 40 41 5 6 19 21 6 13 30 29 43 13 20 4 51 6 10 2 24 25 8

1 6 5 2 1 5 5 5 5 2 1 4 4 2 1 2 5 6 1 4 2 4 1 1 1 5 6 1

None AD + BZD AD + BZD AD + BZD AD AD + BZD AD + BZD AD + BZD AD + BZD AD None AD AD AD None AD + BZD AD AD + BZD None None None AD + BZD AD AD AD AD + BZD AD AD

None Dp/Dyst/GAD/SP SP Dp/Dyst None GAD SP SP GAD/SP None None GAD None None None Dp/Dyst/SP Dist GAD/SP None Dp/Dyst/SP SP Dp/Dyst/GAD/SP None None SP SP SP None

N Y Y N N N Y Y Y Y Y N Y N N Y N N N Y N Y N Y N Y N N

N Y N Y N Y N N N N N N N Y Y Y N N N N N N N N N N N N

21 25 29 31 35 37 38 41 45 46 50 51 54 55 56 59 66 74 75 80 82 83 89 91 96 108 112 120

M = male, F = female, Y = yes, N = no, AD = antidepressants, BZD = benzodiazepines, Dyst = Dysthymic disorder, GAD = Generalized anxiety disorder, SP = Social phobia, HAM-A = Hamilton scale for anxiety, CGI = Clinical global index.

(EOG) between the superior orbita and lateral canthus. Trials were rejected if they contained artifacts indicated by a response of ±50 lV over the area of P50 for evoked potentials or the EOG recordings. Auditory stimuli were presented in a conditioning testing paradigm with an interpair interval of 500 ms and intertrial interval (ITI) of 10 s. A 0.1 ms square wave pulse was amplified in the auditory frequencies (20–12.000 Hz) and delivered through earphones that produce 1 ms sound with an intensity of 60 dB sound pressure level above the auditory threshold. In case of startle reaction, sound intensity was lowered 5 dB until startle reaction was absent. The auditory threshold of each subject was measured 15 min before the recordings. Thirty non-rejected waves were added together to give a grand average signal, which was used for analysis. Two grand average waves were collected in sequence and the mean of both was considered for analysis. The most positive peak between 40 and 90 ms after the conditioning stimulus was selected as the P50 final latency and the wave amplitude (S1) was measured relative to the previous negativity, determining the initial latency and the first P50 wave. The second wave (test) was determined using the corresponding peak between 500 ± 10 ms away from latency

of the first wave form (conditioning) and its amplitude (S2) also measured relative to the previous negative peak. Tracings were analysed by a trained rater blind to the diagnosis, so that the test peaks that were away from the predicted interval (approximately 5%) were not overlooked. Averages with no discernible conditioning P50 waves were excluded from analysis. S1 and S2 amplitudes were obtained for each grand average wave in the two derivations (Cz-A1 and Cz-A2) and test/ conditioning ratios were calculated by dividing the test P50 amplitude (S2) by the conditioning P50 amplitude (S1). This ratio was multiplied by 100, thus representing a percentage. The mean value was obtained to compose both derivations for the first grand average (trials: 1–30), further the same treatment was performed for the second grand average (trials: 31–60). Then other mean values representative of S1, S2 and P50 ratio were obtained, generating two grand average forms, which were used for all the analysis. 2.3. Clinical features Some clinical features were assessed in order to better characterize the PD sample, such as the Hamilton Scale

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for Anxiety (HAM-A) (Hamilton, 1959) and Clinical Global Index (CGI) in the occasion of P50 measurements, duration of panic disorder, age of onset of panic disorder or concomitant common illness (as social phobia, dysthymia, depression, and generalized anxiety disorder). Life-time history of depression was also considered. The PD subjects were also categorically labeled regarding smoking status and use of benzodiazepines and/or antidepressants. 2.4. Statistical analysis P50 ratio (i.e. S2/S1), amplitudes (S1 and S2) and latencies, considered apart as dependent variables, were compared between groups (PD, schizophrenia or controls). Data for the three evaluated groups were analyzed with one-way ANOVA preceded by Levene’s test for homogeneity of variances and followed by LSD posthoc test when significant ANOVA was obtained. When Levene’s test was significant, Dunnett’s T3 was used as post-hoc test. Data considering P50 variables and clinical PD characteristics (gender, age, age of onset, smoking, history of past or present illness, use of benzodiazepines or antidepressants, HAM-A and CGI scores) were analyzed by a linear regression model. The level of significance was defined as p < 0.05 (twotailed). All analyses were implemented with the SPSS 10.0 for Windows (Chicago, IL). Data are shown as mean ± SD for all results.

higher P50 ratios compared to healthy controls: PD vs. healthy (p = 0.035), schizophrenic vs. healthy (p < 0.001). There was no significant difference between panic and schizophrenic patients (p = 0.172) (Fig. 1). Analysis of variance did not show significant differences for S1 amplitude (F(2,81) = 1.538, p = 0.221) (Fig. 2). A significant ANOVA was obtained for S2 amplitudes (F(2,81) = 6.299, p = 0.003) followed by Dunnett’s T3 as post-hoc test. Both patient groups showed higher S2 (test) amplitudes compared to healthy conP50 Ratio (S2/S1) * p<0.001

180 160 *p=0.035

140 120

%

538

100 80 60 40 20 0

Healthy

Panic

Schizo

Fig. 1. Dot-plot of P50 ratio (%) in patients with panic disorder (n = 28) with (r) and without (e) treatment, healthy comparison subjects (n = 28) and schizophrenia comparison subjects (n = 28). ANOVA (F(2,81) = 9.279, p < 0.001) followed by Dunnett’s T3 as post-hoc test. PD vs. healthy (p = 0.035). Schizophrenic vs. healthy (p < 0.001). PD vs. schizophrenic (p = 0.172).

Conditioning Amplitudes (S1) 14

3. Results Table 1 presents relevant clinical features and P50 ratios of PD subjects. Both grand average signals (blocks) yielded similar results, so the average of both is expressed. P50 ratio, S1 and S2 amplitudes and latencies are presented on Table 2 (mean ± SD) for each group. Analysis of variance did not show significant differences for latency (F(2,81) = 0.931, p = 0.398). P50 ratios were compared between groups with ANOVA (F(2,81) = 9.279, p < 0.001) followed by Dunnett’s T3 as post-hoc test. Both patient groups showed

micro volts

12 10 8 6 4 2 0

Healthy Panic

Schizo

Fig. 2. Dot-plot of P50 conditioning amplitudes (S1) in patients with panic disorder (n = 28) with (r) and without (e) treatment, healthy comparison subjects (n = 28) and schizophrenia comparison subjects (n = 28). Non-significant ANOVA (F(2,81) = 1.538, p = 0.221).

Table 2 P50 ratio, amplitudes and latencies in patients with panic disorder (n = 28), healthy controls (n = 28) and schizophrenia subjects (n = 28) Group

P50 ratio (%) (S2/S1)

Conditioning (lV) (S1)

Test (lV) (S2)

Latency (ms) (conditioning)

Healthy controls Panic disorder Schizophrenia

45.4 ± 20.9 62.5 ± 27.7* 79.2 ± 37.3**

5.6 ± 2.9 6.5 ± 3.3 5.2 ± 3.1

2.1 ± 1.1 3.5 ± 1.7* 3.3 ± 1.8**

56.3 ± 5.5 55.6 ± 7.6 57.8 ± 5.5

Data presented as mean ± SD. *p < 0.05, **p < 0.01 significant difference compared to healthy controls. No significant difference was found between panic and schizophrenic groups.

E.S. Ghisolfi et al. / Journal of Psychiatric Research 40 (2006) 535–540 Test Amplitudes (S2) * p=0.003

9

micro volts

8 7

* p=0.013

6 5 4 3 2 1 0

Healthy

Panic

Schizo

Fig. 3. Dot-plot of P50 test amplitudes (S2) in patients with panic disorder (n = 28) with (r) and without (e) treatment, healthy comparison subjects (n = 28) and schizophrenia comparison subjects (n = 28). ANOVA (F(2,81) = 6.999, p = 0.003) followed by Dunnett’s T3 as post-hoc test. PD vs. healthy (p = 0.013). Schizophrenic vs. healthy (p = 0.003). PD vs. schizophrenic (p = 0.976).

trols: PD vs. healthy (p = 0.013), schizophrenic vs. healthy (p = 0.003). There was no significant difference between panic and schizophrenic patients (p = 0.976) (Fig. 3). A linear regression model with the demographic, pharmacologic (including smoking status) and comorbidity variables at entrance and a backward exclusion cut off significance criterion of 10% (R = 0.800, R2 = 0.640, adjusted R2 = 0.529) was obtained for P50 ratio. The generated model showed as major predictor variables social phobia (B = 30.3, p = 0.085) and generalized anxiety disorder (B = 23.8, p = 0.074) increasing P50 ratio and use of benzodiazepines (B = 43.1, p = 0.004) diminishing P50 ratio. The remaining variables were excluded according to the criteria.

4. Discussion In the present study PD patients showed diminished sensory gating, expressed by a deficit in P50 suppression, compared to healthy subjects. This deficit was mainly due to a failure to suppress S2 response. The magnitude of this alteration was mostly indistinguishable from the findings in our schizophrenic patients, which replicated previous results from the literature (Adler et al., 1998). Deficit of P50 suppression was positively associated with anxiety disorders and negatively associated with benzodiazepine use. The deficit to suppress the response to test stimulus is interpreted as reflecting an impaired central inhibitory activity. The present results may also indicate a dysfunction in brain regions responsible for P50 suppression, among which the hippocampus has been considered (Adler et al., 1998). This inhibitory deficit can affect sensory gating from external stimuli, but could also be interpreted in the case of PD patients as an impaired ability to filter out the perception of internal stimuli.

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Among the putative candidate neurochemical systems that mediate this inhibitory deficit are the cholinergic system through a-7 receptors and GABAergic system through GABA-B receptors (Adler et al., 1998), as well as adenosine, an inhibitory neuromodulator released upon neuronal stimulation (Ghisolfi et al., 2002). The present data also suggest that GABA-A receptors or anxiety status can also influence sensory gating given the association of benzodiazepine use with lower P50 ratio. Also the noradrenergic system may be involved, as the a-2 antagonist yohimbine can both induce panic attacks (Charney et al., 1987) and disrupt P50 sensory gating in healthy subjects (Adler et al., 1994). However, the present protocol is not suitable to identify which of these factors are involved in P50 alterations in PD patients. GABA-B receptors may also be involved since the GABA-B agonist baclofen has been shown to reduce panic symptoms (Breslow et al., 1989) and GABA-B antagonists decreased sensory gating suppression in an animal model mostly due to effects on test response (Hershman et al., 1995). Although the benzodiazepine diazepam failed to alter P50 parameters in healthy volunteers (Van Luijtellar, 2003), this does not exclude that such GABA-A co-agonists could affect sensory gating in subjects with anxiety disorders, as suggested by the present results. The neuromodulator adenosine may also underlie such alterations on P50 sensory gating in PD. Caffeine is a non-selective antagonist of adenosine A1 and A2 receptors that has been shown to induce panic attacks and anxiety. PD patients showed hypersensitivity to anxiogenic and non-anxiogenic effects of caffeine and may consume less caffeine (DeMet et al., 1989; Lee et al., 1988). Genetic studies have also reported an association between A2A receptor polymorphism and risk for panic disorder (Deckert et al., 1998; Yamada et al., 2001; Hamilton et al., 2004) and risk for caffeineinduced anxiety (Alsene et al., 2003). Regarding the P50 evoked potential, theophylline, which is a metabolite of caffeine and also an antagonist of adenosine receptors, impaired P50 sensory gating in normal volunteers (Ghisolfi et al., 2002). Also caffeine impaired P50 sensory gating, and increase S2 wave amplitude was found in subject with low habitual intake of caffeine (Ghisolfi et al., 2006). Limitations to our study include current use of medication in patient groups and the presence of comorbidities. In fact, the positive association with other anxiety disorders suggest that the findings in PD patients are not specific for this disorder and may reflect a common diathesis for anxiety disorders, e.g., harm avoidance. In conclusion, this study extends previous neurophysiological findings suggesting a sensory gating deficit in PD. Also, growing data support the notion that alterations in P50 sensory gating are not restricted to patients

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