Impaired P50 Sensory Gating in Machado-Joseph Disease

Clinical Neurophysiology 115 (2004) 2231–2235 www.elsevier.com/locate/clinph

Impaired P50 sensory gating in Machado-Joseph disease

Eduardo S. Ghisolﬁa,c,d,*, Gustavo H.B. Maegawae, Jefferson Beckerf,g, Ana Paula Zanardoa, Ivo M. Strimitzer Jr.a, Alexandre S. Prokopiuka, Maria Luiza Pereiraa,e, Thiago Carvalhoa, Laura B. Jardimb,e, Diogo R. Larad

aDepartamento de Bioquı´mica da Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil bDepartamento de Medicina Interna da Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil cDepartamento de Cieˆncia da Sau´de da Universidade Regional Integrada do Alto Uruguai e das Misso˜es, campus de Frederico Westphalen, Frederico Westphalen, Brazil dDepartamento de Cieˆncias Fisiolo´gicas, Faculdade de Biocieˆncias, Pontifıćia Universidade Cato´lica do Rio Grande do Sul (PUCRS), Av. Ipiranga, 6681, Pre´dio 12A, Caixa Postal 1429, 90619-900 Porto Alegre, RS, Brazil eServiço de Gene´tica Me´dica do Hospital de Clıńicas de Porto Alegre, Porto Alegre, Brazil fServiço de Neurologia do Hospital de Clıńicas de Porto Alegre, Porto Alegre, Brazil gUnidade de Neurofisiologia da Universidade Luterana do Brasil, Canoas, Brazil

Accepted 25 April 2004 Available online 25 June 2004

Abstract Objective: Machado-Joseph disease (MJD), an autosomal dominant spinocerebellar degeneration caused by an expanded CAG repeat on chromosome 14q32.1, is a disorder with wide range of neurological ﬁndings and brain regions involved. Studies evaluating neurophysiological parameters related to sensory gating in MJD are lacking. Methods: This study intends to investigate P50 suppression, an auditory mid-latency evoked potential in a test-conditioning paradigm, considered as an index of sensory gating function. Twelve patients with MJD, 24 normal subjects and 12 schizophrenic patients were evaluated. Results: MJD subjects had higher P50 ratios as compared to normal subjects (76.2 vs. 42.1%, P ¼ 0:001), but similar to the group of schizophrenic patients. The difference from controls was due to greater test amplitudes (3.4 vs. 2.0 mV, P ¼ 0:002), rather than to conditioning amplitudes. Latencies were higher for the MJD subjects than for controls (60.4 vs. 56.1 ms, P ¼ 0:016). Conclusions: MJD may present sensory gating dysfunction. However, the pattern of this dysfunction seems to slightly differ from that classically found in schizophrenia, were both test and conditioning amplitudes seem to be implicated. Signiﬁcance: These results point out the P50 paradigm as a potential tool for further neurophysiological surveying in MJD. q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Keywords: Machado-Joseph Disease; Sensory gating; Event related potentials; P50; Spinocerebellar ataxias; Polyglutamine diseases

1. Introduction manifestations include cerebellar ataxia, pyramidal syndrome, a supranuclear, progressive external Machado-Joseph disease (MJD) is an autosomal ophthalmoplegia, extrapyramidal signs (dystonia, rigidity dominant multisystem degeneration manifested as a form and/or bradykynesia), a lower motor neuron disease, of spinocerebellar ataxia (Nakano et al., 1972; Rosemberg sensation loss, abnormal tendon reflexes, eyelid retraction, et al., 1976; Woods and Schaumburg, 1972), caused by an contraction fasciculations, weight loss and a sleep disorder expanded CAG repeat on chromosome 14q32.1 (Kawagushi (Durr et al., 1996; Fukutake et al., 2002; Jardim et al., 2001). et al., 1994; Takyiama et al., 1993). Less frequently, deficient emotional control with laughter This disorder has a wide range of neurological findings, and crying, similar to those found in pseudobulbar palsy, which evolve in a chronic and progressive pattern. Clinical can be seen later in the course of the disease. Cognitive functions are spared (Radvany et al., 1993). * Corresponding author. Tel.: þ55-51-3320-3545x4158; fax: þ55-51- Some electrophysiological studies have been performed 3320-3612. E-mail address: ghisolfi@pucrs.br (E.S. Ghisolfi). in MJD showing considerable degree of dysfunction.

1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2004.04.025 2232 E.S. Ghisolﬁ et al. / Clinical Neurophysiology 115 (2004) 2231–2235

However, proper works evaluating sensory gating in MJD women, mean age of 43.1 ^ 7.8 years). The MJD patients are lacking. Previous studies have mostly focused their were all Brazilian with Azorean-Portuguese ascendance, attention on routine neurophysiological tests. Kondo et al. with a mean disease duration of 9.5 ^ 2.6 years. (1990) have found alterations of the auditory brain-stem The expanded CAG lengths varied between 71 and 77 response and somatosensory central pathways in repeats. Regarding clinical presentation, 7 patients were clinically diagnosed patients with MJD in Japanese families. classified as type II and two patients as type III. The disease Yamamoto et al. (1997) have found abnormalities of in the other 3 patients had such a long duration that it was somatosensory pathways in MJD, specifically accessing impossible to classify them. Twenty-four healthy volunteers pain and electric SEP that were not related to the clinical were recruited for this study among university students and severity of sensory impairment, but suggest that MJD local hospital employees (4 men and 20 women, mean age presents a subclinical abnormality for the ascending of 38.5 ^ 5.8 years). Twelve DSM-IV schizophrenic somatosensory pathways not only for vibratory sense but outpatients were included as an additional comparison also for pain sense. Other evoked potential studies have group (two men and 10 women, mean age of 38.1 ^ 8.4 confirmed multimodal abnormalities in MJD (Arpa et al., years). All groups were balanced regarding age and gender. 2000; Colding-Jorgensen et al., 1996; Takegoshi and Healthy volunteers were interviewed by medical doctors Murofushi, 2000). with psychiatric training and submitted to a structured The suppression of the P50 component of the auditory interview. Exclusion criteria were a DSM-IV in axis I event-related potential has been used as an index of sensory diagnosis of any disorder, clinical illness and any current gating in neuropsychiatric research. (Adler et al., 1998; pharmacotherapy, current use of alcohol and drugs of abuse, Freedman et al., 1983). The P50 wave is a small amplitude, except for nicotine and oral contraceptives. None of MJD positive wave occurring about 50 ms after an auditory and control subjects were currently taking psychotropic stimulus. In the P50 suppression paradigm, when two medication, but all schizophrenic patients were on stable stimuli are presented 500 ms apart, the amplitude of the treatment with typical antipsychotics. Subjects with familiar second peak (S2), compared to the first (S1), is usually history of schizophrenia or other psychotic disorders in first attenuated in healthy subjects, whereas in patients with or second degree were also excluded. Subjects could not use schizophrenia or acute mania this suppression is impaired tobacco in the preceding 2 h neither used caffeine or (Adler et al., 1998). The hippocampus as well as structures any beverages containing methyl-xanthines over the 4 h of brain-stem and temporal cortex have been suggested to preceding the recordings. mediate P50 suppression and it is generally assumed that impaired suppression in schizophrenia is due to an 2.2. Electrophysiological recordings inhibitory deficit, which leads to an overflow of information and diminished capacity to filter out irrelevant stimuli (Adler The method for electrophysiological recordings has et al., 1998). The neurochemical basis of the P50 been previously described (Ghisolfi et al., 2002). In brief, suppression is not yet completely understood, but subjects were recorded seated, relaxed, and awake with cholinergic, GABAergic and monoaminergic systems have eyes open and fixed on a distant target to decrease been proposed to modulate this phenomenon (Adler et al., drowsiness during the recording. Electroencephalographic 1998; Hershman et al., 1995; Light et al., 1999) and more activity was recorded from a disk electrode affixed to the recently adenosine has been implicated in P50 dysfunction vertex (Cz) and referenced to both ears. Electroenceph- (Ghisolfi et al., 2002). alogram (EEG) was provided using a Nihon-Kohden The main purpose of this study is to perform a sensory MEM-4104K system in 4 channels for recording of gating evaluation through a double-click paradigm of P50 evoked responses integrated with auditory stimulator. evoked potential in patients with MJD comparing to healthy The mean signal was registered in two channels, one for and schizophrenic subjects. each side of the cranium, and amplified 20,000 times with a bandpass filter between 10 Hz and 10 kHz. EEG was collected for 1000 ms for each paired stimulus 2. Methods presented. Additional channels were used to record the electro-oculogram (EOG) between the superior orbita and 2.1. Subjects lateral canthus. Trials were rejected if they contained artefacts indicated by an EEG tension of ^ 100 mV over This study was approved by our local ethical committee the area of P50 for evoked potentials or the EOG and all the participants have signed an informed consent recordings. Auditory stimuli were presented in a form after complete explanation about the protocol, conditioning testing paradigm with an interpair interval the purpose of this study and potential risks involved in of 500 ms and intertrial interval of 10 s. A 0.1 ms square lay terms. wave pulse was amplified in the auditory frequencies Twelve MJD outpatients with a previously detected CAG (20–12,000 Hz) and delivered through earphones that expansion in the MJD1 gene were included (two men and 10 produce 1 ms sound with an intensity of 60 dB sound E.S. Ghisolfi et al. / Clinical Neurophysiology 115 (2004) 2231–2235 2233 pressure level over the auditory acuity threshold. 3. Results The auditory acuity threshold of each subject was measured 15 min before the recordings. Thirty Patients with MJD showed lower suppression, evidenced non-rejected waves were added together to give a by greater P50 ratios when compared to normal subjects grand average signal, which was used for analysis. (Table 1, Fig. 1). Conditioning amplitudes ðS1Þ did not Two grand average waves were collected in sequence differ, whereas test ðS2Þ amplitudes were significantly and the mean of both was considered for analysis. greater for MJD and schizophrenic patients than for controls The most positive peak between 40 and 90 ms after the (Table 1, Figs. 2 and 3). Latencies of the conditioning ðS1Þ conditioning stimulus was selected as the P50 final P50 component of auditory evoked potentials were longer latency and the wave amplitude ðS1Þ was measured for MJD subjects than for controls and schizophrenic relative to the previous negativity, determining the initial patients (Table 1, Fig. 4). The results of both grand average latency and the first P50 wave. The second wave (test) signals (blocks) collected in sequence were very similar. was determined using the corresponding peak almost Considering clinical subtypes, no difference between always between 500 ^ 10 ms away from latency of the subgroups was found, except for latencies in subtype III, first wave form (conditioning) and its amplitude ðS2Þ also which was significantly longer than any other subgroups of measured relative to the previous negative peak. Tracings MJD and controls (healthy and schizophrenic subjects). were analysed by a blind rater, so that the test peaks that However, in face of the small number of subjects in this were away from the predicted interval (approximately stratified analysis, this finding should be considered 5%) were not overlooked. Averages with no discernible preliminary. conditioning P50 waves were excluded from analysis. No correlation was found between disease duration and Test/conditioning ratios were calculated by dividing the P50 variables. The CAG lengths at the MJD1 gene were also not associated with P50 ratios, conditioning and test test P50 amplitude ðS2Þ by the conditioning P50 : amplitudes, or with latencies. amplitude ðS1Þ This ratio was multiplied by 100, thus representing a percentage. The data were collected by an unblinded researcher and analysed by an independent trained ratter blinded to the diagnosis. 4. Discussion

In the present study MJD patients showed diminished 2.3. Statistical analysis sensory gating expressed by a deficit in P50 suppression compared to healthy subjects. MJD subjects presented P50 variables of both groups were compared comprising higher P50 ratios between conditioning and test amplitudes, = P50 ratio (i.e. S2 S1), P50 amplitudes (S1 and S2) and which was mostly due to a failure to suppress S2 response. latencies, which were considered apart as dependent The pattern of this dysfunction was mostly indistinguishable variables, and the characteristic of the group (MJD or from the findings in our schizophrenic patients, which controls) as the independent variable. Comparisons between replicated previous results from the literature in this disorder groups were performed using Student’s t test for means, (Adler et al., 1998). Although schizophrenic patients might preceded by Levene’s Test for Equality of Variances. also have diminished S1 response, especially when off The effect of the length of CAG repeats and of the disease treatment with antipsychotics, normal S1 response was duration on P50 variables were assessed by the Spearman found in MJD. Nevertheless, in our sample there was a trend correlation coefficient. Statistical significance was towards smaller S1 amplitude in schizophrenic patients, so considered to be P , 0:05: All analyses were implemented their treatment with typical antipsychotics could be with the SPSS 10.0 for Windows. regarded as a conservative bias.

Table 1 Amplitudes (test, conditioning, their ratio) and latencies of the P50 evoked potential

= ; ; ; Group Ratio ðS2 S1Þ % Conditioning ðS1Þ mV Test ðS2Þ mV Latency (conditioning), ms

Control ðn ¼ 24Þ 42.1 ^ 4.4 5.5 ^ 0.6 2.0 ^ 0.2 56.1 ^ 1.1 MJD ðn ¼ 12Þ 76.2 ^ 7.3 5.6 ^ 0.7 3.4 ^ 0.3 60.4 ^ 1.3 Schizophrenia ðn ¼ 12Þ 87.2 ^ 12.8 4.2 ^ 0.5 3.2 ^ 0.3 56.8 ^ 1.7

Signiﬁcance (P) MJD £ cont 0.001* 0.964 0.002* 0.016* MJD £ SCH 0.463 0.154 0.714 0.103 SCH £ cont ,0.001* 0.122 0.006* 0.709

*Signiﬁcant between-group difference. Data presented as mean ^ SEM. 2234 E.S. Ghisolﬁ et al. / Clinical Neurophysiology 115 (2004) 2231–2235

Fig. 1. Dot-plot of P50 ratio (%) in patients with Machado-Joseph disease ; ðn ¼ 12Þ healthy comparison subjects ðn ¼ 24Þ and Schizophrenia Fig. 3. Dot-plot of test amplitudes of P50 ðS2Þ in patients with Machado- comparison subjects ðn ¼ 12Þ: Joseph disease ðn ¼ 12Þ; healthy comparison subjects ðn ¼ 24Þ and Schizophrenia comparison subjects ðn ¼ 12Þ: The result that most clearly distinguished MJD patients from both healthy and schizophrenic controls could also influence other domains such as timing or pain was increased latency for the S1 response. This result response. The present results may also indicate a using the P50 wave seems to be in accordance with dysfunction in brain regions responsible for P50 previous findings showing delayed transmission of suppression, among which the CA3 region of the hippo- sensory stimuli (Colding-Jorgensen et al., 1996) using campus has been considered (Adler et al., 1998). classical neurophysiological parameters in patients with Interestingly, hippocampus seemed to be spared in the MJD. Diversely from several other neurological findings, majority of neuropathological studies of MJD (Sequeiros the increased latency and ratio of P50 potentials were not and Coutinho, 1993). However, structural and functional associated with CAG length or with disease duration. MRI studies have shown abnormal perfusion and atrophy of The finding of the longer latencies in the two type III the frontal and temporal lobes (Etchebehere et al., 2001; patients should be interpreted with caution, due to the Murata et al., 1998), which are brain regions implicated in small number of the sample. P50 sensory gating (Adler et al., 1998). The deficit in suppressing the response to test stimulus is A putative candidate molecule to mediate this inhibitory classically regarded to reflect an impaired central inhibitory deficit is adenosine, an inhibitory neuromodulator released activity. This inhibitory deficit can affect sensory gating, but upon neuronal activity. Besides this rationale, we recently showed that the adenosine receptor antagonist

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