Abstract
Background: Schizophrenia is a severe mental disorder characterized by positive, negative, and cognitive symptoms, and can lead to functional impairment in life. Around a third of patients with schizophrenia do not respond to antipsychotic treatment and would be recognised as treatment resistant if they show no clinical improvement after at least two treatment episodes with different antipsychotics. Therefore, a major challenge is to shorten the time needed to evaluate treatment effect and identify pharmaco-resistance as early as possible so that refractory patients can be prescribed the appropriate medication (such as clozapine) sooner. To date there are no reliable biomarkers for treatment resistance in patients with schizophrenia. Recent work demonstrated that the combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) may be a sensitive tool for measuring changes in cortical excitation and inhibition, and thus may have the potential to provide biomarkers or treatment response in schizophrenia.Method: There are three parts to the thesis. In the first part (chapter 2), we conducted a systematic review of the literature that examined TMS-EEG response in patients with schizophrenia. In the second part (chapter 3), we recruited 19 male right-handed patients with a diagnosis of schizophrenia or a psychotic disorder who were receiving a single antipsychotic medication (olanzapine, aripiprazole, paliperidone or risperidone). Seventeen healthy participants served as a control group. TMS-EEG responses were measured from each participant in the resting state in a single experimental session. Single-pulse TMS at 90% of the resting motor threshold was delivered over the dominant (left) primary motor cortex using a figure-of-eight coil. The outcome measures included TMS-evoked EEG potentials (TEPs) and TMS-related spectral perturbation which reflect the TMS-EEG responses in the time and time-frequency domains, respectively. In the third part (chapter 4), the 19 patients from chapter 3 plus 7 patients newly recruited under the same inclusion criteria (26 in total) made up the patient sample in this chapter. The patients were divided into 14 treatment responders and 12 with treatment resistant schizophrenia to explore the effect of treatment response on TMS-EEG activity. TMS-EEG activity was assessed using the same study design and outcome measures as in chapter 3.
Results: Most of the TMS-EEG studies included in our systematic review investigated TMS-EEG response in the frequency domain. Findings from the systematic review suggest that higher-frequency (beta/gamma) oscillations may be impaired in frontal regions (including motor, premotor and dorsolateral prefrontal cortices) of schizophrenia patients. Both production and modulation of gamma oscillations were found to be impaired in the dorsolateral prefrontal cortex of patients, as assessed by single-pulse TMS and the long-interval intracortical inhibition paradigm, respectively. The findings of the systematic review support TMS-EEG as a useful tool for measuring differences in brain excitability between patients and healthy controls, and thus have highlighted the potential of TMS-EEG to provide biomarkers for illness and treatment response in schizophrenia. They also informed the design and analysis of the empirical studies in chapters 3 and 4, such as introducing procedures to properly reduce the peripheral input caused by TMS to minimize its contribution to cortical EEG responses, as well as analysing the data in both the time and time-frequency domains.
In the time domain, we found significant differences in TEP amplitudes between schizophrenia patients and healthy controls between 15-66 msec (TOI1 and TOI2) and 180-360 msec (TOI4). When the patients were stratified according to treatment response, both the treatment responders and patients with treatment resistant schizophrenia (TRS) showed changes in TEP amplitudes in TOIs (i.e. time windows of interest) 1 and 4 and their amplitudes were altered in the same direction relative to the healthy controls. In TOI2, however, there was no significant difference in TEP amplitude between TRS patients and healthy controls, whereas treatment responders showed reduced signal amplitude compared to the other 2 groups. In the time-frequency domain, the patients as one group showed reduced delta, theta and gamma power within the first 200 msec following TMS, as well as reduced suppression of alpha, beta and gamma power between around 200-600 msec, compared to the healthy controls. However, there was no significant difference in TMS-related spectral perturbation between treatment responders and TRS patients.
Conclusion: Our findings extended the previous literature which suggested the involvement of impaired GABAergic and glutamatergic neurotransmission in the pathophysiology of schizophrenia by demonstrating deficits in specific processes of cortical inhibition and excitation in patients as assessed by TMS-EEG. Further, the study showed that TMS-EEG was able to detect a significant difference in TEP amplitude between treatment responders and TRS patients which could indicate a difference in the neurobiology of treatment resistant and responsive schizophrenia with respect to neural excitation and inhibition. Thus, TMS-EEG may have the potential to provide biomarkers for treatment resistant schizophrenia and it is worth exploring in future research whether TMS-EEG could help with early prediction of the condition.
| Date of Award | 1 May 2023 |
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| Original language | English |
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| Supervisor | Sukhi Shergill (Supervisor) & Isabella Premoli (Supervisor) |