Alfred Psychiatry Research Centre (APRC)

Staff

Students
Kate Hoy
Suzanne Williams
Caroline Winograd
Robyn Laycock
Felicity Butselaar
Simone Field
Jasmina Markovski
Kylie Lloyd
Daniel Upton
Brett Lee
Mark Beltz

This research stream involves the conduct of studies dedicated to understanding the neurobiology of psychiatric disorders such as schizophrenia, depression and bipolar disorder, and the development of novel therapeutic techniques. Some of these studies are outlined on the website.

We also require volunteers without psychiatric illness to act as control subjects for studies. If you are willing to do this, there is usually a small fee to compensate you for the time involved in the research, please contact any of the following research staff:

Jessica Benitez: 9276 6595
Susan McQueen: 9276 6596
Bec Segrave: 9207 1538

Research Tools

• Transcranial magnetic stimulation (single, paired, repetitive)
  • 2 X Magstim 200 and Bistim
  • Medtronic Magpro30
• Electroencephalography and evoked potential recording
  • 64 channel EEG + Neuroscan Stim system
• Functional and structural magnetic resonance imaging
• Near infrared spectroscopy
• Stereotaxic localisation tools
• Cognitive assessment batteries

Research Project Areas

• Depression
  • Clinical Trials with rTMS
    • Priming stimulation
    • Targeting Stimulation (plus magnetic resonance spectroscopy)
    • Neuronetics Inc Trial
    • Healthscope Trial (Victoria Clinic and Palm Beach)
  • Studies of Pathophysiology and Treatment Response
    • An fMRI study of the effects of rTMS in depression
    • An EEG/ERP study of the effects of rTMS
    • Non biological determinants of rTMS response
    • A meta-analysis of the involvement of prefrontal cortex in depression
    • Beliefs and Attitudes towards TMS treatment in depression
  • Relapse, re-treatment and maintenance TMS
  
  
• Schizophrenia
  • Associative and prefrontal plasticity in schizophrenia
  • Motor overflow in Schizophrenia
  • Eye Movements in schizophrenia and depression
  • Auditory Hallucination studies
    • rTMS Treatment
    • Pathophysiology
  • Cognition in Early Psychosis
  • Relapse Prevention
  
  
• Other Areas
  • TMS studies in Autism
    • single, paired pulse and rTMS studies
  • A TMS study of the brain effects of Cannabis use
  • A TMS study of Reading and Dyslexia

Selected Research Summaries

Transcranial Magnetic Stimulation (TMS) Studies in Depression

Transcranial magnetic stimulation (TMS) is a relatively new technology with significant potential to offer therapeutic advances and research insights into a variety of common, disabling and poorly understood psychiatric disorders. TMS is a non-invasive means of stimulating nerve cells in superficial areas of the brain. During a TMS procedure, an electrical current passes through a small hand held coil placed close to the scalp. This current induces a magnetic field that stimulates electrical activity in nerve tissue below the coil. This stimulation may be repeated many times per second and with variation in intensity and orientation. The site of the stimulation, its frequency and the intensity determine its effects and in various forms, TMS stimulation has been shown to effect mood, motor and cognitive functioning.

Over recent years there has been a ground swell of interest in the use of TMS to treat psychiatric disorders. A number of research units locally, in North America and Europe have conducted studies in depression, bipolar disorder, post-traumatic stress disorder, obsessive-compulsive disorder and schizophrenia. Researchers have proposed that TMS may be able to replace electro-convulsive therapy (ECT) for a large number of patients, a treatment that carries considerable treatment expense (including anaesthetic and theatre costs), substantial stigma and significant side effect risks. TMS administration does not require hospital admission or a general anaesthetic, as a seizure is not produced by the procedure. In addition, it may have a therapeutic role in conditions where there are few other treatment choices, for example medication non-responsive symptoms of schizophrenia. The potential application of TMS for depression alone is very large. Depression is a disorder of high prevalence in the community and frequently does not respond to established therapies. Large numbers of patients undergo ECT every year and many more patients remain depressed due to reluctance to utilise this modality by doctors and patients alike. TMS does not have this stigma and is well accepted and tolerated by patients [1].

Advantages of TMS over established options such as ECT include:

1. Improved safety and tolerability profile: TMS is not associated with any fatal treatment complications, has few side effects and is very well tolerated. There are no established cognitive side effects with TMS as are seen with ECT.
2. TMS does not require anaesthetic facilities: TMS is applied with the patients awake and alert. It does not involve the risks or the costs associated with providing a general anaesthetic.
3. TMS can be freely applied as an outpatient treatment. Patients are able to drive and travel to and from the hospital. This limits costs associated with admission for ECT and the observation of the subject in recovery and the hours following an ECT procedure.
4. TMS does not have the substantial stigma associated with ECT. This stigma prevents some patients accessing treatment and substantially impacts on the experience of others who undergo the procedure.
5. TMS is suitable for the treatment of medically unwell patients who may not be able to be treated with other modalities, such as ECT or medication due to the effects of their medical illness.

We have conducted a number of studies of this technique and research is currently ongoing. We aim to improve the way in which TMS is provided and research potential methods for the selection of subjects who are likely to respond to treatment. This research has involved the conduct of clinical trials as well as the use of brain imaging and electrophysiology to study the mechanisms of action of TMS in depression.

Study 1. (Currently Underway) - A Randomised, Parallel Group, Sham-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of the Neuronetics Model 2100 CRS Repetitive Transcranial Magnetic Stimulation (rTMS) System in Patients with Major Depression

(P Fitzgerald, B Goodfellow, J Benitez, R Segrave, S McQueen)

Though encouraging, prior studies of rTMS have typically used suboptimal dose parameters, short durations of treatment, and have been conducted in small samples. The current study has been designed to address these methodological drawbacks and to assess the efficacy and safety of the latest model of TMS equipment. This study is an international multi-centre trial using a novel rTMS device. Patients who complete the trial but fail to respond to rTMS (e.g., sham patients) will be offered open-label treatment with active rTMS. Additionally, all responders to rTMS (assuming they continue to meet inclusion criteria) will be offered enrolment in a 6 month follow-on trial evaluating durability of the anti-depressant effects and possibly additional rTMS treatments in the event of relapse during the period of this protocol.

A total of 286 patients with Major Depression will take part in this study world wide, approximately 20 participants will attend the Alfred Psychiatry Research Centre site.

Study 2. (Currently Underway and Recruiting) - A Randomised Double Blind Trial of Targeted Repetitive TMS in Major Depressive Disorder

(P Fitzgerald, B Goodfellow, J Benitez, R Segrave, S McQueen)

All published rTMS studies in patients with depression to date have applied stimulation using a simple localisation technique based on the location of the dorsolateral PFC (DLPFC) relative to the hand motor cortex that is located with TMS stimulation. This method has recently been shown to incorrectly position the stimulation coil over DLPFC in greater than 50% of subjects. If we presume, as many

Investigators

In this trial, we are assessing whether accurate localization of the site of stimulation results in improved therapeutic response. We use a DLPFC localization method based upon individual structural or functional MRI data (brain scans), and a frameless stereotaxic system (a system that allows us to find a spot on the scalp that corresponds to the area of the brain we want to target for the treatment). The relative effectiveness of stimulation-based localization with this system will be compared to standard methods. This system, which has a spatial resolution of 1.8mm, will also allow the testing of differences in response to stimulation of alternative PFC regions, for example Brodmann area 9 or 46, the two most frequently implicated PFC regions in depression. We are also conducting brain scans to measure brain activity and the concentration of certain neurotransmitters pre and post treatment.

A total of 76 people will participate in this project, 60 patients and 16 control participants without depression.

Study 3. (Currently Underway and Recruiting) - A randomised double-blind trial of low and high frequency stimulation TMS in Major Depression: Priming Stimulation

(P Fitzgerald, B Goodfellow, J Benitez, R Segrave, S McQueen)

The purpose of this project is to help understand the most effective parameters for Transcranial Magnetic Stimulation (TMS) treatment in Major Depression. Previous research suggests that repetitive Transcranial Magnetic Stimulation (rTMS) in the frontal regions of the brain clearly has antidepressant effects (i.e. it helps people with depression) and that the response to rTMS is clinically significant in some patients. Most rTMS research conducted as a treatment for depression has used high frequency stimulation of the left side of the brain. However, low frequency stimulation on the right has also been shown to be effective and appears to be better tolerated. Research has not clearly established, however, the most effective way to apply rTMS. A promising approach to improve responses to rTMS may be to combine high and low frequency in a way in which they are both provided to the right side of the brain. In this approach, high frequency stimulation is provided first which may ‘prime’ or pre-prepare the brain for the low frequency stimulation in a way that enhances its response to the low frequency stimulation. The primary aim of this study is to test the efficacy of this treatment regime. We will compare the effect of standard low frequency treatment to ‘priming stimulation’ where low frequency stimulation is preceded by some high frequency stimulation. We will also test if left sided stimulation works in patients who don’t respond to right sided treatment.

Studies Using rTMS Methods to Study Brain Activity

(K Hoy, P Fitzgerald, N Georgiou-Karistianis,, M Farrow, J Bradshaw, & C Armatas)

Motor overflow is a blanket term used to describe involuntary movement which sometimes accompanies the production of voluntary movement (Armatas et al. 1994). There are two main theories behind overflow production, the first – Transcallosal Facilitation – states that that activation of a cortical region resulting from voluntary movement will facilitate activation of the same area in the opposite hemisphere, via interhemispheric connections. This facilitation will thus result in motor overflow unless it is inhibited, again via interhemispheric connections. When overflow does occur, according to this theory, the normal inhibitory processes mediated by the CC (TCI) are absent. Alternatively, according to the Transcallosal Inhibition theory, overflow occurs due to activation of an ipsilateral pathway. The corticospinal tract is the major motor pathway which controls limb movement. Normally movement on one side of the body is controlled by the contralateral brain hemisphere. There is, however, a portion of this tract which projects ipsilaterally and is normally inhibited. This theory of motor overflow proposes that movements produced by the contralateral hemisphere result in a degree of ipsilateral movement.

There have been a number of TMS studies looking at both overflow theories and the results have been somewhat surprising; simply put it seems that both theories are correct – depending upon the population. Naturally occurring motor overflow, that which is seen in children and normal adults under effort inducing conditions, is believed to be due to Transcallosal Facilitation. However, congenital mirror movements, those which are present from birth, appear to be the result of activation of the ipsilateral corticospinal tract. One study examined this theory directly by looking at the differences between ‘congenital mirror movements’ (CMM) and ‘associated movements’ in normal children (Reitz & Muller, 1998). They found that in children with CMM unilateral TMS stimulation resulted in bilateral motor evoked potentials (MEPs) of identical latencies, such a finding does not allow for a transcallosal pathway considering a transcallosal conduction time of 10 –13 ms. Therefore it was concluded that these CMM mirror movements were the result of ipsilateral corticospinal projection activation. In direct contrast, in response to unilateral TMS the normal children showed considerably longer latencies for the ipsilateral MEPs, possibly indicating that the associated movements are in fact due to Transcallosal facilitation of the hemisphere opposite to the TMS.

Other studies have revealed the same findings in adults, i.e. that CMM’s in adult populations appear to be the result of ipsilateral corticospinal projection activation, while normal adults exhibiting overflow under effort induced conditions have been shown to be the result of transcallosal facilitation of the opposite hemisphere.

The presence of motor overflow in children under ten, normal adults in effort inducing conditions, and those suffering from congenital brain dysfunction has been extensively investigated. Yet, there is also substantial evidence of the presence of motor overflow in a number of neurological and psychiatric disorders, namely schizophrenia. Therefore, the current study aims to establish the cortical origin of motor overflow in schizophrenia, thus gaining increased knowledge regarding the neurological abnormalities of this mental illness.

A total of 60 participants will take part in this study, 30 patients with schizophrenia and 30 controls.

(P Fitzgerald, J Benitez, T Oxley, J Kulkarni)

Funding: NHMRC
NARSAD Lieber Young Investigator Award (PF)

Background:

Project Aims:
We are using Transcranial Magnetic Stimulation (TMS) to investigate inhibitory function and plasticity of cortical circuits in patients with schizophrenia and depression. These studies allow us to confirm or refute some important recent theories of the causality of these and related conditions.

Current research involves the stimulation of the motor cortex and the measurement of electromyography (EMG) output. This is electrical muscle activity, for example, in the hand, which is produced by the stimulation of the brain. We measure the response of the brain to stimulation (a motor evoked potential), a subsequent period of the suppression of activity (silent period) and various markers of brain 'excitability'.

Figure: This is an example recording of EMG activity taken from a hand muscle during TMS stimulation of the relevant motor area in the brain: The trace shows a Motor Evoked Potential (MEP) which is the EMG recording of activity felt by the subject as a muscle twitch. This reflects how 'excitable' the brain is. The trace also shows a Cortical Silent Period (CSP): this is a period of suppression of ongoing muscle activity produced by the effect of TMS in stimulating inhibitory GABAergic neurons in the brain.

Description of the Projects:

Study 1: Cortical Plasticity In Schizophrenia

A number of TMS techniques can be used in the study of cortical plasticity in animal and human experiments. Plasticity refers to the way in which the brain responds to repeated stimuli and results in synaptic or cellular changes.

In these experiments, repetitive TMS was applied for a period of time to induce a plastic change in synaptic activity that were assessed by measuring the effects of single and paired TMS pulses on cortical excitability (for example as assessed by MEP size) before and after the rTMS trains. In normal control subjects, rTMS applied at 1 Hz reduces the excitability of local nerve cell, for a duration of up to one hour.

In patients with schizophrenia, we found that this effect was reduced or absent, indicating an abnormality of cortical plasticity. We were also able to assess the activity of inhibitory GABA nerve cells in the same patients: we found that this activity was reduced and there was a direct relationship between reduced plasticity and reduced inhibition.

Figure: This shows the change in resting motor threshold levels (RMT: this is a measure of how excitable the brain is) in the controls and patients with rTMS. There is an increase in RMT level in the controls (reflecting reduced excitability) but the opposite change in patients on and off medication.

Figure: This shows the change in resting motor threshold levels (RMT: this is a measure of how excitable the brain is) in the controls and patients with rTMS. There is an increase in RMT level in the controls (reflecting reduced excitability) but the opposite change in patients on and off medication.

Study 2: A Study of Premotor Cortical Plasticity in Schizophrenia

In a similar study, we provided rTMS stimulation to the premotor cortex, an area of the brain involved in the control of movements. We measured how this stimulation affected excitability in the motor cortex of patients with schizophrenia as compared to control subjects. In this study, the patients with schizophrenia also demonstrated abnormal plastic responses.

The figure shows the change in RMT levels with rTMS in a group of patients and a control group. As with the first study there was an opposite effect in the patients from the controls.

Study 3: A Study of the Effects of Drugs with GABA and Glutamate Receptor Activity on repetitive TMS Induced Plasticity in the Human Motor Cortex.

Repetitive TMS effects depend upon certain neurotransmitters or chemicals in the brain. Lorazepam (LR) is a frequently prescribed benzodiazepine, and is known to have effects on the GABAergic neurotransmitter system. Previous research has suggested that GABA inhibition may play a role in cortical plasticity. Similarly, a drug known as dextromethorphan (DM, commonly found in cold and flu preparations) has action at the NMDA neurotransmitter sites; it is hypothesised that these are involved in cortical plasticity.

The purpose of this project is to investigate the way in which two different types of medication may influence the manner in which the brain responds to repeated stimulation (cortical plasticity). We administer a dose of 1 of 3 drugs (either a placebo or the 2 medications above) and then use TMS to provide repeated stimulation (over 15 minutes) and to measure how responsive the brain is before and after this time.

A total of 45 people will participate in this project which is currently underway.

4. New Studies

We are currently in the process of commencing several new studies extending our findings to date. In the first of these, we will test how patients and controls respond to a combination of TMS and gentle peripheral nerve stimulation: this allows the testing of a different type of cortical plasticity that seems to be involved in normal brain function. In the second study, we will combine TMS and EEG to study cortical plasticity in areas of the brain such as the prefrontal and temporal cortex. These seem to be critical regions for the development of schizophrenia.

Publications:
Fitzgerald PB, Brown T, Daskalakis ZJ, Chen R, Kulkarni, J. Intensity – dependent effects of 1 Hz rTMS on human corticospinal excitability. Clinical Neurophysiology, 113; 1136-1141, 2002

Fitzgerald PB, Brown T, Daskalakis ZJ, Kulkarni, J. A Transcranial Magnetic Stimulation study of inhibitory deficits in the motor cortex in-patients with schizophrenia. Psychiatry Research NeuroImaging, 114; 11-22, 2002

Fitzgerald PB, Daskalakis ZJ, Brown T, Kulkarni, J. A study of transcallosal inhibition in schizophrenia using Transcranial Magnetic Stimulation. Schizophrenia Research, 56; 199-209, 2002

Fitzgerald PB, Brown T, Daskalakis ZJ, de Castella A, Kulkarni, J. A Trancranial Magnetic Stimulation study of the effects on motor cortical excitability of olanzapine and risperidone in-patients with schizophrenia. Psychopharmacology, 162; 74-81, 2002

Fitzgerald PB, Brown T, Marston NAU, Oxley TJ, Daskalakis ZJ, Kulkarni J. A Transcranial Magnetic Stimulation study of abnormal cortical inhibition in schizophrenia. Psychiatry Research, 118: 197-207, 2003

Fitzgerald PB, Brown T, Marston NAU, Oxley TJ, Daskalakis ZJ, Kulkarni J. Reduced Plastic Brain Responses in Schizophrenia: A Transcranial Magnetic Stimulation Study. Schizophrenia Research (accepted for publication Jan 2004).

Background:

Aim of Project:
To explore the effect of cannabis on inhibitory circuitry in the human motor cortex.

Methodology:
Transcranial Magnetic Stimulation is a non-invasive means of stimulating nerve cells in superficial areas of the brain and provides a powerful method for the study of motor cortical function. A number of experimental methods suggest that the measures obtained from TMS provide information about the activation of local inhibitory GABAergic circuits. Hence, this study will apply TMS techniques to a group of regular, irregular cannabis users and normal controls (i.e. non users) to measure the impact of THC on GABA. In addition to this, the following study also hopes to further explore these findings in relation to cannabis user’s neuropsychological performance, as there is a significant body of evidence that associates the use of cannabis with a variety of cognitive impairments, which implicate cortical regions of the brain.

THE EFFECT OF PREFRONTAL 1HZ RTMS (REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION) ON COGNITIVE PROCESSING

Investigators

Professor Jayashri Kulkarni
Associate Professor Paul Fitzgerald
Mr Anthony de Castella

Background

Previous research suggests that dysfunction of the dorsolateral region of the prefrontal cortex (DLPFC) may result in schizophrenia related symptoms. A proposed mechanism for this dysfunction is that DLPFC cells are unable to adequately adapt to changing environmental inputs.

In this study, we will use low frequency (1Hz) repetitive TMS (rTMS) to explore this mechanism in healthy individuals, then investigate whether the response to DLPFC 1Hz rTMS is altered in schizophrenia. This region is thought to be heavily involved in brain functions that require cognitive control. For this reason, we will assess behavioural and electrophysiological (EEG) measures associated with various cognitive tasks before and after the delivery of rTMS to this region. This study will contribute to our understanding of brain areas linked to schizophrenia and provide insight regarding the nature of mechanisms that may result in aspects of this disorder.

Current Status

At present, we are analysing data collected from 15 control participants and hope to begin recruitment and testing of individuals with schizophrenia shortly.

DIFFERENTIATION BETWEEN MELANCHOLIC AND NON-MELANCHOLIC DEPRESSION USING ELECTROENCEPHALOGRAM (EEG)

Investigators

Associate Professor Paul Fitzgerald
Ms Tessa Mellow

Aims & Hypotheses

This study aims to assess cognitive/brain function in melancholic and non-melancholic depressed patients using modern assessment techniques. The particular tasks will involve the use of computer based cognitive assessment protocols and responses during electroencephalography (EEG) recordings. Patients with melancholic and non-melancholic depression and normal control subjects will be included.

Current Status

At present, 29 patients and 11 control subjects have been assessed. Analyses will be performed on the data which has been generated.

CAN TRANSCRANIAL MAGNETIC STIMULATION ALTER MOTOR FUNCTION IN AUTISM AND ASPERGER'S DISORDER?

Investigators

Associate Professor Paul Fitzgerald
Ms Nicole Rinehart
Mr Bruce Tonge
Mr John Bradshaw
Dr Peter Enticott
Mr Robin Laycock

Funding: Cure Autism Now Foundation

Background

Despite the lack of recognition of the significance of motor abnormalities within DSM-IV criteria, movement abnormalities remain a striking feature throughout the developmental trajectory of autism and Asperger's disorder. In some cases, motor features predate social-communicative symptoms of these disorders.

In this study we are investigating whether low-frequency (1Hz) repetitive transcranial magnetic stimulation (rTMS) to the motor cortex (i.e., supplementary motor area and primary motor cortex) can improve motor function in 14-16 year-old adolescents with autism and Asperger's disorder. Our primary outcome measure is movement-related potentials recorded over the supplementary motor area; these are averaged EEG traces that reflect cortical activity associated with the preparation of movement.

Aims and Hypotheses

We expect that 1Hz rTMS to the supplementary motor area will result in a significant improvement in pre-movement supplementary motor area activity, and that this will be associated with improved motor preparation. A second phase of this study involves a rTMS treatment trial to assess the effects of a prolonged treatment course on motor functioning as determined by gait analysis and a broad range of autism-related symptoms.