Transcranial Magnetic Stimulation: Research and Beyond
Machine Medicine Interview Series hosted by Dr Jonathan O'Keeffe with Professor Chandramouli Krishnan
Associate Professor, Physical Medicine & Rehabilitation (Kinesiology), Biomedical Engineering, University of Michigan
Prof. Chandramouli Krishnan is currently an associate professor at the University of Michigan at the physical medicine and rehabilitation department. He was a physical therapist with a bachelor degree in physiotherapy in Chennai, India. He practised physical therapy for almost six and a half years, primarily in outpatient sports medicine setup. He later joined the field of spinal rehabilitation and directed the PT department in a multi-super speciality hospital. After that, he moved to the University of Iowa, where he got his master and PhD in sports medicine and biomechanics, primarily focusing on knee injuries and knee rehabilitation. He then did the postdoc when he took a turn away from sports medicine and biomechanics background into neurorehabilitation robotics and non-invasive brain stimulation for rehabilitation at the rehab Institute of Chicago, at Shirley Ryan’s ability lab. In 2012, he joined the University of Michigan as an assistant professor, where he founded the neuromuscular and rehabilitation robotics lab, Neurrolab.
The Importance of Low-Cost Technologies in Healthcare
The primary theme of my lab is low-cost technologies for rehab. In the U.S. there are primarily third-party payers, so insurance cost is very critical for covering rehabilitation services. Thus, it’s tough to penetrate into a rehabilitation clinic if the available tools for rehabilitation are costly. In my postdoc, I was building half a million dollar robotic tools and then I moved away because I quickly realised it is very hard for the most regular clinics to afford those kinds of technologies. A good portion of patients come to the University of Michigan, but you can see the majority of them are treated at smaller outpatient clinics or subacute rehabilitation facilities which cannot afford these large, expensive robotic devices. Plus, these tools cannot penetrate into patients’ homes if you want to extend the dosage of therapy. So that’s kind of the motivation for me, to move along the area of how we can make these technologies low-cost and also make them portable and lightweight so they can be carried home.
What Is Transcranial Magnetic Stimulation (TMS)?
Transcranial Magnetic Stimulation is a magnetic stimulator that sends out a magnetic field into your brain, which gets converted into electrical energy, and sends action potential to stimulate certain regions. All of the connections to the muscles are in the brain, so the lower extremity has some regions in the brain, and you have a motor map of all the muscles in the brain’s primary motor cortex. So when you stimulate these regions, you can measure the responses from the brain to the muscle by putting an electromyographical sensor on the muscles of interest. The other form of looking at it is the evaluation of the torque responses associated with those stimulations.
What Is TMS Used For?
TMS is a broad tool. One use of it is evaluation, which is basically used to see the excitability level of the brain. This is done by using a single pulse or a pad pulse, which is two pulses with some separation between the first and second one. Many protocols are there to evaluate the inhibitory and excitatory circuits in the brain. The other form of TMS is repetitive TMS, where you keep giving the Transcranial Magnetic Stimulation pulses repetitively at a certain frequency. There is a wide variety of protocols about it in the literature. With it, you can either upregulate the brain or downregulate the brain. If you think about stroke -one can argue against it, but- a good amount of literature suggests that the lesioned hemisphere has downregulation of the cortical spinal excitability. Simultaneously, there is some upregulation in the non-lesioned hemisphere in terms of corticospinal excitability. So people have tried various forms where they can either upregulate the lesioned hemisphere or downregulate the non-lesioned hemisphere with various protocols and look at it.
How Spatially Precise Is TMS?
If you think about any non-invasive brain stimulation technologies, they lack spatial resolution in general, you cannot be very specific. If you think about it, the whole motor cortical strip itself is very small and narrow, and it’s not like the entire brain, different regions control different parts. So when it comes to focality, Transcranial Magnetic Stimulation is more focused, at least in spatial resolution, than the conventional transcranial Direct Current Stimulation.
If for example, we are focusing on the lower extremity, we need to go deep into the brain, in the central sulcus, where most of the low extremity representations are. So when we stimulate, we’re going to get stimulations in multiple muscles; it’s not going to be very specific to the muscle we are targeting. One way we circumvent that problem is by giving a background contraction. So if you want to stimulate the tibialis anterior, which is a muscle that controls the foot and lifts it up, you ask the patient to slightly contract their muscles. Then the motor neuron pool, which connects the tibialis anterior from the brain, is already excited. Thus when you stimulate it, most of the impulses go to the muscles of interest. That’s one way of improving the focality.
What Challenges Face the Use of TMS
as a Bidirectional Neural Interface?
One issue with Transcranial Magnetic Stimulation is the hardware limitation, The coil has to charge and discharge, so if you think about some of the neural prostheses where people put a chip into the brain and then try to use the neuronal signals that are coming out to encode that signal and then control a robotic arm, it is very feasible in that kind of neurotechnologies because the temporal resolution is very good, even TMS has a temporal resolution. However in terms of the ability to take information and then also do something to control them, the problem with TMS is that once you trigger a pulse, you need to have some gap. With high-frequency TMS you can stimulate much faster, but then the issue is that it creates an unsafe paradigm where it could start reducing the seizure threshold and create seizures. So there is an established protocol in terms of how fast you can go and beyond which is not safe.
Thus using TMS as a two-way system is a bit hard and how people have circumvented that problem is by using EEG along with TMS. They take information from EEG and then try to stimulate. But still, TMS has not been used, at least to my knowledge, in a continuous modular waveform, where you continuously keep the parameters based on the signals coming up from the neuronal population. The real reason for this, apart from safety, is hardware limitations.
What Are the Therapeutic Challenges and Opportunities of TMS Today?
FDA has already approved TMS for depression. There has been good evidence in terms of people who don’t respond to medications, and they are refractory – people who have depression tend to do well with Transcranial Magnetic Stimulation. So it has been FDA approved and a lot of clinics use it. However in terms of neurorehabilitation, a lot of work needs to be done. And it’s not necessarily just for TMS; this goes more actually into transcranial Direct Current Stimulation technologies (tDCS) – and that’s one reason I am slowly moving away from tDCS. While I’ve used it in the past, the issue of reliability and replicability of the study results is big.
We often work on the promise that these neuromodulatory tools, like tDCS or TMS, alter brain excitability. You can control it to either upregulate or downregulate the excitability and when paired with behavioural interventions, it transforms into better outcomes, better functions and better recovery. But the issue is the ability of neuromodulatory techniques to reliably induce changes in corticospinal excitability. This has been questioned a lot recently because if you see say five studies that show tremendous results, there are equally or more studies that show no or null effect.
Is There a Crisis of Standardisation
in the Neuromodulation Field?
The field of neuromodulation has to do a lot of work, which is a good challenge to the neuromodulation community because they can unify and be device agnostic. It’s time as a field to unite and come up with paradigms that have shown very reliable results. If we want to make the insurance companies to reimburse TMS, they’re going to look at a solid evidence. Right now, we don’t have solid evidence towards one side or the other. So we need to work on that before we can make it a promising tool. Still, I do see TMS modalities to have some good potential in terms of neurorehabilitation. However what we don’t know yet is whether the timing is right, i.e. when we should give this therapy. There are many uncertainties that we need to understand first, like dosage, timing, and how it can be paired with other treatment modalities.
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