Neuromodulation for Psychiatric Disorders

Dr Paul Fitzgerald

Psychiatrist, Epworth Centre for Innovation and Mental Health, Melbourne, Australia

Dr Paul Fitzgerald is a psychiatrist from Melbourne, Australia. He currently works at the Epworth centre for innovation and mental health, a research centre within outboard healthcare of the largest private hospital in Australia, with a joint position with Monash University. He has been working in the brain stimulation and related field for over 20 years.

Dr Fitzgerald did his psychiatry training in Melbourne and then went and spent a year doing a fellowship in Toronto. Whilst in Toronto, he predominantly worked with neuroimaging and other technologies, especially TMS machines. When he went back to Australia, he had the opportunity to establish a TMS lab and investigative studies and eventually started doing treatment trials.

How Did We Arrive at Using Transcranial Magnetic Stimulation (TMS) to Treat Psychiatric Disorders?

Transcranial Magnetic Stimulation is a way of using a very strong time varied magnetic field to stimulate the brain. When we apply a really strong magnetic field that is time variable, so switching on or off, to something that conducts electricity will induce an electrical current. So you can apply this TMS magnetic field to the brain, induce currents in the nerve cells in the brain and make them fire. If you stimulate the motor cortex of the brain; it’ll make those nerve cells fire to send a signal down to cause a twitch in the muscles of the hand for example. That was really why the machines were first invented. Neurologists and neurophysiologists had the capacity to electrically stimulate nerves in the arm, for example, to do nerve conduction studies, to study the propagation of electrical activity in peripheral nerves. But to electrically stimulate from the central nervous system, say down to the hand or the lower limb was extremely painful.

The first TMS machines were developed to stimulate the motor cortex and in no way were conceptualized as treatment tools. The initial TMS machines would send in a single magnetic pulse and would then take 4-5 seconds to recharge the capacitors to gather enough electricity to do it again, so you couldn’t use those in any way to modify brain activity. But a few years later, machines were invented that could stimulate repeatedly. An experiment started to demonstrate that when you did repeatedly stimulate nerve cells in the brain, you would change brain activity. Around the late 1980s and early 1990s, the first modern brain imaging studies were starting to happen. People started to do Positron Emission Tomography, PET scans, of people’s brains who had depression. They found that there seemed to be some consistent decrease or under-activity of an area at the left frontal part of the brain.

It was just putting two and two together to say, well, we’ve got this type of brain stimulation that can non-invasively target neurons, it seems to increase neuronal activity if you repeatedly apply it, so let’s target this area at the front of the brain and see what effects we can get. Thus, those initial treatment studies started to happen and yielded some positive results, by the mid-1990s, that doses back then were very low, the trials of a very short period in small numbers of subjects. Still, it was enough to get the field going and demonstrate a proof of concept that TMS seemed to have therapeutic benefits.

How Might TMS Work in the Treatment of Depression?

We knew that the patients who had strokes that particularly affected the dorsolateral prefrontal cortex had a disproportionately high rate of depression. EEG (electroencephalogram) studies had also suggested that there might be an under-activity on the left dorsal prefrontal cortex. However, it still was a relatively blunt tool, and in psychiatry at that time, we had a history of using fairly blunt tools. Electroconvulsive therapy involves stimulation of very broad areas of the brain – this was at least something that was focused towards a very specific target with some form of neurophysiological rationale.

My thinking has certainly gone a long way from that idea, that the main effect of TMS is local. What we know is when we stimulate this dorsal prefrontal cortical area, we’re stimulating millions of neurons that project to other areas of the brain, in particular circuits. So if you make these nerve cells in the prefrontal cortex active, they’re going to send signals down into deeper brain regions to activate nerve cells, and you’re going to get flown effects around a circuit. So I believe that what we’re doing has far more to do with these distributed and circuit-based effects. I think some element of the therapeutic benefit is local, the prefrontal cortex is a cognitive control area, and it’s a regulatory area of the brain. So by increasing activity there, we’re likely to increase the capacity of that prefrontal region of the brain to help regulate some of the emotional areas, the deeper emotional areas of the brain that are more directly implicated in depression. But I think it’s probably a mixture of effects that underpins the benefit of TMS when it does work.

How Effective Is TMS in Depression?

We analysed a sample of over a thousand patients who had participated in clinical trials done from the early 2000s through to about 2014. This included a whole lot of clinical trials back in the early 2000s where the dose we used was quite low on a historical basis, and we had a response rate in that sample of about 47% – 48%. These were very treatment-resistant patients, who on average failed about six antidepressant medication trials. There’s been a recent series of publications from a large registry in the US, a group of about 5,000 patients reporting response rates depending on how you cut the data in that sort of 40% – 50% or even greater per cent range. So TMS has really clinically meaningful benefits; it doesn’t work for everybody, and I think it’s important anybody going down the pathway of TMS treatment would realise that it’s not a miracle cure that works for everybody. Still, it does have life-changing benefits for a substantial proportion of patients. That leaves a group of patients that we still want to make TMS better for. We think that with enhanced technology and particularly increasing the degree of personalisation of treatment and better understanding how we apply treatment in individual patients, we can probably improve on those response rates. Still, they’re kind of good as they stand, but we do want to get them better.

Might TMS and Electro-Convulsive Therapy (ECT)

Share the Same Therapeutic Mechanism of Action?

I think it’s an interesting concept, while I don’t think we’ve got much evidence one way or the other. ECT mechanistically is very crude, but it’s an extraordinarily effective treatment in many patients, and we don’t know how ECT works. I think there are several potential theoretical things that could bind the mechanism of action of ECT and TMS, but they’re still very theoretical. For example, we know that there’s reasonable evidence that patients with depression have a reduction in activity of one of the neurochemicals in the brain, a thing called GABA that is what we call inhibitory, so it suppresses other neuronal activity.

At ECT, the natural response to the brain having these repeated seizures is to increase the production of neurotransmitters that’s going to dampen down further activity, to increase GABA levels. There’s some limited evidence that that might be the case and you could imagine that when you’re driving the electrical activity with TMS, you may get a similar effect. The brain works with patterns of oscillations, patterns of synchronized electrical activity between different brain areas and some of the major oscillatory patterns and circuits that underpin cognitive function involve these frontal areas of the brain and then a series of deeper areas of the brain in what we call recurrent circuits.

We know that there’s recurrent electrical activity around these circuits in individuals at specific frequencies, and it’s certainly possible that when we’re artificially stimulating at a fixed frequency, these circuits that we could be resetting or in some way modifying the recurrent dominant electrical frequencies in a way that does have therapeutic benefit, it’s certainly possible that this is kind of a more focal “defibrillation”. But at this stage, we don’t have significant evidence to support that idea. I think we underestimate the importance of frequency in particular in thinking about the importance of brain function and brain dysfunction, and it’s something we’re certainly interested in learning more about over time. Hopefully, we’ll be able to fill in some of those gaps.

Can We Predict an Individual’s Response Probability Before TMS?

The answer to that, at this stage, is no we can’t, but that may well be because we haven’t looked in the right ways. So the sort of traditional things that people have looked at which have been general characteristics of illness duration, severity and those sort of things certainly can have an association with the likelihood of response, but in no way are those relationships strong enough to say to somebody – this is not worth doing, or this is much more likely to work for you, there are subtle relationships at best.

I think we may eventually find what you’re describing, but we certainly haven’t got any data that’s meaningfully spoken to that yet. Still, it’s certainly something that people are increasingly interested in. I think that we just haven’t drilled down into fine enough detail to really be able to understand what the significance might be. There are some preliminary data coming out that show that maybe there are certain different patterns of clinical symptoms that may relate even to potentially different targets in the brain. You might want to target different areas if you’ve got different symptom clusters, however, that line of research is still very early on and requires a lot more before we become confident enough to translate it into day-to-day clinical use.

What Approaches Exist for

Personalising TMS Therapy for Better Outcomes?

There are two quite divergent ways of personalisation. We’re very interested in the issue of personalisation in the spatial domain – where do we target and how do we hit the right circuit. The other thing we’re very actively working on now is personalisation in the frequency domain – can we do something in terms of the particular frequency of stimulation that might be useful? So we started exploring the spatial issue many years ago and did a number of neuroimaging studies and a meta-analysis of them of patients who got depression and tried to understand better where we should target. We came up with a punitive target that we thought was likely to be better than the approach that was being done, and we used what’s called neuronavigation, which is a way of taking somebody’s brain scan and using that to work out where to place the TMS coil.

We did the first study showing that you could improve clinical outcomes with neuralnavigationally-based targeting. The methods that we used for that study weren’t really clinically translatable. We’re only really now getting to the point where neuronavigation systems are easy enough to use, that you could potentially start seeing them being used in clinical practice. In the intervening years, there’s been a very interesting approach developed, initially by some researchers in Boston, that looks at the connectivity in one particular circuit and uses a particular type of functional magnetic resonance imaging scan to try to work out a personalised location in the prefrontal cortex. We’ve done some work using that approach and shown that if you do these scans on an individual basis, there seems to be a relationship between an increasing personalisation of target and better clinical outcomes. That needs to be validated in prospective trials, but it certainly looks very promising.

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