Professor Yoshikazu Ugawa – The origins of the Quadripulse technique

Professor Ugawa is director and professor of the Department of Neurology and Vice President of Fukushima Medical University, where he has been since 2007. He graduated from Tokyo University in 1978 and studied physiology of movement disorders under Professor Marsden and Professor Rothwell in Queen Square, London in 1987-1990, after which he returned to Tokyo University.

Professor Ugawa is interested in clinical neurophysiology and one of the pioneers of transcranial magnetic stimulation (TMS). He started to study pathophysiological mechanisms underlying various involuntary movements, especially myoclonus, using EEGs, evoked potentials and MEGs. After the invention of TMS and neuroimaging techniques, he also used those newly developed methods for this purpose. He extended the target disorders to Parkinson’s disease and related disorders. After the invention of repetitive TMS (rTMS), he studied neuroplasticity in humans and developed a new plasticity induction method [quadripulse stimulation (QPS)]. In addition to studies of normal plasticity, he applied the plasticity induction method to the treatment of neurological disorders, and he is now developing new treatments using rTMS for movement disorders, especially Parkinson’s disease.

This month Professor Ugawa kindly spoke with us on his thoughts on the future of brain stimulation.

Good morning Professor Ugawa, tell us, what gave you the initial idea for the QPS technique?
Regular rTMS (repetitive application of a single pulses at a single frequency, e.g. 1 Hz or 20 Hz)) was already known to show some long-term effects. In addition, theta burst stimulation, around the time at which we were developing QPS, was already important but its effect was not that robust and sometimes variable. There had been one report which said that repetitive paired-pulse stimulation could evoke some long-term effects. My idea was to increase the number of bursts. I tried with four pulses, just a simple idea. It could have been six pulses or eight pulses but we were limited by what we had available at the time.

Was the technique created around the same time as theta burst?
Yes, it was. I had tried to use theta burst on Japanese subjects, but the effect was not that stable. I wanted to find a technique that had a more robust, replicable results, even in Japanese people.

So, was the QPS technique used to prolong the effect of TMS?
Not to make longer. With QPS, the effect is larger but the duration is similar. The most important part is the low variability. This means that we can induce the expected effect very reproducibly. There is less variability with the QPS technique than there is with the theta burst technique.

What have been some recent, exciting advances in technology for brain research and brain stimulation?
A really exciting area is research involving IPS cells (Induced pluripotent stem cells); using these cells and some additional molecules, it seems that almost all the cerebellum can be manufactured from a single cell. I think about half of the processes of cerebellum generation can be mimicked in the experimental field.

Another interesting area are robotic protheses that use a BMI (brain-machine interface) to record brain activity and use it as a control signal to drive robotic devices to support or move objects. The combination of this method with our QPS method may be a good candidate for treatment.

I am also interested in current research in neurodegeneration, which is when the cell or the neuron itself dies without any cause. Investigations in this area will be similar to that of cancer research. Cancer is unregulated cell division, without any regulation whereas neurodegeneration is the opposite; the cells die by themselves, without any cause. These mechanisms may be due to DNA or the cell itself – perhaps a mechanism or substance in the cell itself. Cancer research development may provide useful information for the treatment of neurodegenerative disorders.

Another exciting area is the accumulation of toxic large molecules in neurodegeneration. For example, amyloid causes Alzheimer’s disease and is a toxic substance for cells, so the accumulation of amyloid causes cell death. Usually we try to decrease the creation of amyloid. However, the amyloid is also degraded and leaves the brain through the lymphatic systems or glymphatic system. So now, the lymphatic system of the brain is another target for the treatment of degeneration.  We have usually considered treating neurons but the waste released from the brain may be another target. Thus in the future, treatment for neurological disorders may not only focus on neurons; other pathways or systems may be helpful.  Another target could be the glial cells that support the neuron.

It sounds like there are lots of exciting things to look at in the future then?
Yes. I usually use non-invasive brain stimulation to influence neurons, but maybe stimulation can affect the lymphatic release or excretion of toxic substances or some other prion – the cell-to-cell propagation of some toxic substances may aggravate nervous system disorders. So, stimulation may stop prional propogation. Again this is an example of how treatments may move in the future from targeting neurons to other systems in the brain.

How long in the future do you think?
I don’t know. Maybe ten years? Maybe thirty years! There is still a lot of work to be done before treatment.

Do you think that quadripulse would be a good technique to use for these investigations?
I think so.

And would more pulses be better or is quadripulse the optimum?
That’s a good question. I think quadripulse may be optimal. We tried octopulse stimulation, which is more powerful and the effect is a bit longer and larger but the increase in duration is not so drastic, say 1.2 times or 1.3 times longer, so I think 4 is enough. It’s not a linear increase in effectiveness.

Do you think now is the time that quadripulse might start to overtake theta burst in research?
It depends on the price. Theta burst stimulation duration is very short, it’s five minutes or so, so it’s very easy to do whereas quadripulse takes 30 minutes. However, if we would like to know what really happens and see less inter-individual variability then maybe researchers should try QPS.

Do we think maybe that QPS could inform a better way to use theta burst in a clinical setting?
Actually in the clinical setting, the effect, even if it is a placebo is okay. So, theta burst is a shorter intervention and perhaps used more often especially by psychiatrists or psychologists. It’s very easy to use theta burst because of the duration, and the effect, even if variable, is thought to do something useful. So theta burst is used more frequently than QPS in the clinical environment. However, if we want to target a real nervous system effect rather than placebo, we should use QPS instead of TBS.  In the field of research, QPS will be used more often.

Do you think more variability in the configuration of future QPS devices could be beneficial?
In the research field, we can change the parameters but if we sell a machine to use for treatment and it’s fixed, it may be easier for users. However, researchers would like to change the parameters by themselves, so it depends on the purpose of the product.

With QPS, each stimulator is set to a consistent power output. Is there any benefit in having the ability to change the power outputs for each stimulator?

We don’t know. If it is changeable it is excellent for us. However as I said before, although researchers would like to change the intensity of each of the pulses, for practical commercial use maybe a fixed configuration is better.

So really, what we need for future developments of QPS for research is maximum flexibility?

What are your opinions on non-invasive brain stimulation techniques moving forward?
Ultrasound is another good candidate for new techniques. The key merit of ultrasound is that deeper structures are stimulated. It is already used as a treatment for DBS but in that case high intensity pulses are applied to create small lesions. If ultrasound can be applied to stimulate the brain without producing damage, then it may be a candidate for future use.

Another possibility is integrating non-invasive brain stimulation (including tDCS) with other methods such as with IP cells or some biochemical substance, perhaps together with robotics. So combined treatments are one way forwards.

You mentioned also the use of TMS and tDCS. Are there any examples where TMS and tDCS are used in combination or always in isolation?
Maybe in combination. At the present time there is great interest in combining treatments or in multi-site simultaneous- or timed-stimulation. For example we can consider stimulating bilateral M1 with TMS together with some tDCS but whether it is effective or not, I don’t know.

We know the whole brain is changeable and that one area may react and change its response after stimulation of another area. Non-invasive brain stimulation methods may be a good way to probe interactions within complex brain networks.

How about brain stimulation in combination with brain imaging techniques, for example TMS-EEG or fMRI, fNIRS? How can we improve that?
I have no experience of TMS-EEG but we have used TMS in combination with imaging methods such as fMRI. We also have a PET-MRI for simultaneous imaging which we can also explore with TMS. And, of course, we can record EEG as well, so in the end we would have three recording methods available to probe the effect of one stimulation.

We look forward to learning more about this fascinating work!

A comment from Professor John Rothwell, University College London:

The odd thing about QPS, is that, despite the number of papers that Professor Ugawa’s group have published on the method, very few other labs have used the technique. One of the main reasons for this is cost: QPS requires 4 separate monophasic TMS machines, all connected to the same coil by a combining unit. At the present time the total cost of this is more than a standard rTMS device. In addition, as Prof Ugawa points out, another factor is time: it takes about 30min to apply QPS whereas a theta burst protocol may only take a few minutes. My own lab in London is one of the few that have tried QPS, and our results were broadly in line with those from Japan. So I would encourage more labs to explore QPS and to compare it with other rTMS protocols. If it is confirmed that QPS give more reproducible results than other rTMS methods, then it represents a very important practical advance. If it is better, then we need to understand why it is better and use that insight to develop ever more effective forms of brain stimulation.