A randomised controlled trial of image guided Transcranial Magnetic Stimulation for depression.

Major depression has a high cost, in terms of personal suffering and to society. It costs the NHS £1.7bn a year and £7.5bn to the economy in England alone. A high proportion of cases respond inadequately to treatment.

Transcranial Magnetic Stimulation (TMS) is approved for treatment of depression in the NHS. Yet only a minority of cases have substantial therapeutic benefit and of these the effect is typically short-lived, lasting only a few months. Identifying cases likely to respond well and for longer is a high priority. 

Recent research confirms that depression is associated with abnormal communication between neurons in distributed brain circuits linking deep brain ‘limbic’ regions involved in emotional expression, with more superficial areas that are accessible to TMS. Our own research has demonstrated a particular limbic region, the insula in the right hemisphere, is a key node within the relevant brain circuits, and is likely to mediate therapeutic effects. Furthermore, in a study of healthy participants, we have shown that a particular type of TMS – ‘theta burst’ – produces changes in the strength of connection between a superficial brain region in frontal cortex and the insula, together with biochemical changes expected to be of therapeutic relevance.

The brain site in the frontal cortex most strongly connected to the insula differs between people, suggesting that the site at which TMS is delivered is likely to influence the therapeutic effect. Using functional Magnetic Resonance Imaging (fMRI) we can identify the putative optimum site in each individual.

In a small pilot study using fMRI to guide TMS therapy in cases of treatment resistant depression, we observed substantially greater therapeutic effects than typically reported in previous studies. In our image-guided pilot study we allocated patients to receive either theta burst TMS or standard repetitive TMS. We found a trend toward greater therapeutic effect with theta burst TMS than repetitive TMS, but due to the small sample size we did not have the power to determine if the magnitude of this therapeutic advantage was significant.

On the basis of our previous studies, including our small pilot study, we have been awarded £1.8m by the National Institute for Health Research and Medical Research Council, for a large multi-site study designed to produce a definitive answer to the question of whether image-guided theta burst TMS is more effective than conventional TMS. If we confirm that this is the case, the findings are likely to guide future clinical practice, with the potential to reduce the burden of depression on lives and on society.

In addition to evaluating therapeutic outcomes, we will use Magnetic Resonance Spectroscopy (MRS) to measure brain chemicals involved in depression, including the inhibitory neurotransmitter, GABA, in the frontal cortex, before and after treatment. We will use the fMRI data and MRS data to determine the brain features that predict which cases are most likely to respond to TMS, and to determine the changes in brain connectivity and brain chemistry that occur during successful treatment. This will provide valuable information about the mechanism of therapeutic change with the potential to facilitate future refinements of therapy of treatment-resistant depression. The study is currently open to recruitment in Nottingham, Northampton, Newcastle and North London and has randomised 76 participants so far. 

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