Grant Proposal: Investigating the Effects of Atypical Antipsychotics on Auditory-Steady State Response in Schizophrenia Patients
Student ID: 1539206
Word Count: 1,998
University of Birmingham
An auditory-steady state response (ASSR) is an electrophysiological response known as an auditory evoked potential that indicates individuals hearing ability (Korczak, Smart, Delgado, Strobel, & Bradford, 2012). This response is produced when rapid auditory stimuli is perceived producing synchronised oscillations in the auditory cortex. The auditory stimulus produces ASSR entrained to the stimulus frequency and phase (Galambos, Makeig, & Talmachoff, 1981).
ASSR is diminished in patients with schizophrenia specifically at 40 Hz stimulation at gamma frequency (Kwon et al, 1999). Gamma is produced by synchronised oscillations at approximately 40 Hz. This function is the driving force for integration of sensory information, as research suggests it is responsible for communication between brain regions which allow integration of various modalities and information processing (Singer & Gray, 1995). Indicating that patients with schizophrenia may have abnormal gamma band synchronisation. This could result in deficits in perception and cognition if information is not adequately integrated, (Kwon et al, 1999) characteristic of schizophrenia and other mental illnesses that appear to have the ASSR deficit (Spencer, Salisbury, Shenton, & McCarley, 2008). Thus, it is imperative that this phenomenon is investigated further as it has been indicated that deficits in perception and gamma synchronisation may result in positive symptoms of schizophrenia such as auditory hallucinations (Spencer, Niznikiewicz, Nestor, Shenton, & McCarley, 2009). If this is the case treatments may be orchestrated to attenuate these symptoms by reducing this deficit which is particularly useful with treatment resistant patients.
Additionally, if fundamental knowledge of the deficit is developed this could be utilised as a biomarker in schizophrenia, this has the potential to increase reliability of diagnosis. Thus, individuals genetically at risk of developing schizophrenia could be screened by measuring whether they have a reduction in ASSR at 40Hz. Furthermore, ASSR reduction in first degree relatives of schizophrenia patients has also been found (Hong et al, 2004). As first-degree relatives are 18 times at greater risk of developing schizophrenia. (Kendler, Gruenberg, & Tsang, 1985). Frequent monitoring and support would be beneficial to prevent prodomal stage developing into the active stage of schizophrenia in those most at risk; preventing development of schizophrenia and reducing its cost to society. An increased understanding of the deficit is imperative, as knowledge of gamma deficit and ASSR may increase insight into the aetiology and symptomology of schizophrenia.
To further our knowledge concerning ASSR, limitations of research must be investigated further and rectified. One of which is the lack of control of medication in research. Hong et al (2004) analysed the effect of typical and atypical antipsychotics. The results demonstrated that atypical antipsychotic medications resulted in an increased ASSR in patients compared to patients taking typical antipsychotics and controls. Those taking atypical antipsychotics had a larger ASSR than control participants whereas, patients administering typical antipsychotics didn’t differ from controls. Indicating that antipsychotics may have an effect on ASSR. This is not surprising considering antipsychotics have been found to affect brain structure, function (Torrey, 2002) and EEG responses (Small et al, 1987). Contrastingly, studies which have analysed the effect of antipsychotic medication have found that they had no effect on gamma-band ASSRs. However, the studies sample size is small comparing nine and six participant so it lacks power. Additionally, researchers stated they cannot rule out antipsychotic effects on ASSR as the study was not designed to investigate the consequences of antipsychotics and potential effects of this on ASSR cannot be ruled out even suggesting from their data that if medication does have an effect it would increase the power of ASSR (Tada et al, 2014). Therefore, antipsychotics may have an additive affect on the ASSR response thus, affecting results often attributed to schizophrenia alone (rather than medication). However, research concerning medication effects is not vast and therefore, very little is known about the effect.
Investigating effects of pharmacological interventions is critical to extend previous research such as Hong et al (2004) the finding of increased ASSR when patients are taking atypical antipsychotics may not be as a result of medication however, causal relations have not been determined. The limited research which has been completed especially those that suggest there is not a medication effect have many methodological limitations such as: small participant groups reducing power of findings and comparing chronically medicated participants to un-medicated participants without matching symptoms (Light et al, 2006). When pharmacological effects on ASSR have been determined this will add to knowledge of schizophrenia. Particularly as antipsychotics have been found to affect GABA mechanisms which are implicated in contributing to gamma synchronisation in NMDA receptors (Sivarao, 2015). Evidence that atypical antipsychotics increase ASSR (Hong et al, 2004) and reduction in antipsychotic treatment has found to reduce ASSR in bipolar patients (Rass et al, 2010). Demonstrate that the GABA mechanisms could account for an additive effect of antipsychotics in the ASSR response and potentially contribute to the understanding of what causes this deficit.
The aims for this study are to investigate the effects of atypical antipsychotics on ASSR power. Additionally, to test whether there is a reduced power of the ASSR in schizophrenia patients at 40Hz compared to healthy controls.
The hypotheses include: there will be an effect of atypical antipsychotic medication on power of ASSR at 40Hz in patients. The additional hypothesis is that there will be reduced power of the ASSR at 40Hz in patients compared to healthy controls. Replicating previous results.
Methods
Participants
The target sample size is 60 participants who will be in two different conditions: schizophrenia antipsychotic naïve patients and a healthy control group with 30 participants in either group. This number of participants will have enough power to conclude substantial findings and will be sufficient if there is participant drop out however, small enough to fit the controlled criteria. The participants diagnosed with schizophrenia will be recruited from Early Intervention in Psychosis (EIP) scheme conducted by the NHS via a volunteer sample. In order to be referred to this service individuals must be distressed, have a substantial decline in social functioning and either transient or attenuated psychotic symptoms, apparent experience of psychosis or a first-degree relative diagnosed with psychosis or schizophrenia (Smith, 2008). Participants must be diagnosed with schizophrenia as well as confirmation of this conducted by an assessment by our psychiatrist using the Structured Clinical Interview for DSM-IV (SCID) (First, Spitzer, Gibbon, & Williams, 1997) due to the unreliability of diagnosis. Participants that will be recruited will have psychiatrists who have decided on a treatment plan of prescribed atypical antipsychotics. This is to control for the effect of typical antipsychotics as research has shown that they have differing effects on ASSR (Hong et al 2004).
The control condition will be recruited via volunteering through advertisements placed in the local paper. Eligibility criteria for all participants include: no history of substance abuse, brain trauma, neurological illness, experience of electroconvulsive treatment, currently not on medication, no history of mental illness and no history of illness in first degree relatives. As this is a variable which has been found to affect ASSR (Hong et al, 2004) the other criteria have been included as these factors often have effects on EEG response (Hirsch & Brennerm, 2010). A structured interview assessing this will be completed by participants and their mental health status will be measured by the Structured Clinical Interview for DSM-III-R Non-Patient Edition (First, Spitzer, Gibbon, & Williams, 2007). Participants will be matched on IQ measured by WAIS-IV (Weschler, 2008), sex and age. Informed consent will be gained from all participants.
Procedure
Initially participants will be evaluated utilising the criteria above. Patients electrophysiological activity produced by neuronal responses to the auditory stimulus will be measured using electroencephalography (EEG) recorded continuously using 64 channel electrode cap according to the 10-20 system of electrode placement.
Participants will be asked to relax, keep their eyes open and keep movement to a minimum, whilst listening to a succession of clicks through earphones. These clicks were clicks of one millisecond in duration. Successions of 150 clicks with 700 millisecond intermissions will be presented in series at 40Hz for 475 milliseconds based on Kwon et als (1999) research. For the group of participants diagnosed with schizophrenia this will be a baseline test conducted before participants start their course of antipsychotic medication so effects of medication can be measured.
Upon completing the initial procedure all participants will be required to return to complete an identical procedure again after 2 weeks as this is when antipsychotics have taken most effect (Agid, Seeman, & Kapur, 2006). To measure if there is a change in the patients due to medication and a measure from healthy controls so results can be compared. Additionally, SCID interviews will be conducted to check symptom severity and monitor diagnosis in both measurements. If participants are prescribed different medication or if their dosage is altered they will be informed that they should notify researchers as medication alterations are made independent to this study.
Patients will be monitored in both testing sessions for their wellbeing and symptom severity using SCID measurement. If a participants mental health seems to deteriorate, they will be reported to the EIP service and also to their mental health team.
Analysis
Data will be averaged across signal to remove noise and artefacts from data to obtain the ASSR. Epohcs that represent response to the tone will be extracted and then analysed by fast fourier transformation to form a power spectra representing the power of the 40Hz response. The EEG recordings will be analysed and acquired in the same manner as Kwon et al (1999).
A between ANOVA will be used to compare power differences of ASSR between controls and schizophrenia in the baseline tests to confirm there is a 40Hz deficit in schizophrenia patients compared to healthy controls. This will be conducted because if it is not significant the secondary measures will not be required as we can conclude that in our sample there is no ASSR deficit at 40Hz in schizophrenia patients.
Another between ANOVA will be used to compare differences in power of ASSR between controls and schizophrenia patients when they are tested again. Control patients as displayed in previous research should remain the same. Therefore, if there is no significant difference this indicates that atypical antipsychotics have increased the power of the 40Hz ASSR. If there is a significant difference the atypical antipsychotics have either had no affect or reduced the power of the ASSR further in schizophrenia patients.
A mixed ANOVA will be conducted to show whether the difference between power in schizophrenia and controls is significantly different between time one and time two measurement. It will display whether there is an interaction and whether the schizophrenia groups response power increases, decreases or remains the same.
Expected Results
Initially, a replication of the substantial finding that patients with schizophrenia will have a significant reduction in their ASSR power at 40Hz. Additionally, an increased response in the 40Hz frequency measured in the ASSR of the healthy controls is expected compared to the patients as these are robust findings (Spencer et al., 2008).
As previous research suggests there should be a significant difference between the patients group ASSR in the two measurements. If the atypical antipsychotics do have an additive effect to ASSR suggested by Hong et al (2004) then the results should indicate an increase in ASSR power when antipsychotics are administered. This will be a consequential finding adding to the limited knowledge of gamma band deficits in patients and allowing future research to investigate whether increased ASSR reduces symptoms.
However, results with medicated and un-medicated schizophrenia patients have demonstrated inconsistent results. Therefore, there may be no significant difference between when patients were medication naïve to when they started taking antipsychotics. However, this remains a substantial finding as researchers could begin to rule this effect of antipsychotic treatment on ASSR out.
Subsequently, future research regarding how various medications specifically effect ASSR would be beneficial. Then specific circuits that antipsychotics affect can be investigated further. Adding to knowledge concerning the aetiology of schizophrenia, functional deficits and how medication influences brain function.
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