Approximately five years ago, I was chatting with the folks at one of the TMS device companies and asked them what the standard advice was for patient activity during the TMS stimulation sessions. Their response was that, as the manufacturer, they didn’t specify, and the FDA label didn’t specify either. The only thing the company explained in their training materials was that the patient should remain awake throughout the session.
In my time at various TMS treatment centers I’ve noticed that some have televisions that patients can watch during treatment (with some offices specifying what types of shows should be allowed and others allowing the patient to decide), others have technicians who are also licensed therapists engaging the patient in behavioral therapy before, during or after TMS treatment, and others have a single technician operating several TMS machines simultaneously – the technician moves in and out of treatment rooms to ensure that the device is working appropriately and the patients are well.
As an Experimental Psychologist, and someone who has used TMS for over a decade, I feel strongly about this and have seen that the effects of participant activity just before or during the TMS session can impact treatment. From a basic physiological level we know that state (behavioral, emotional, and neurological) has an effect on subsequent response to stimulation, so why are we not controlling it? As with everything, the answer is not a simple one. What state is optimal? Is there a negative effect of certain states? Are these manipulations feasible? Ethical? What are the added costs associated?. I will try to dive a bit into some of these questions below.
I have observed first-hand the effect of patient state on TMS response and my colleagues, and I have published on these findings. In some of my previous studies where we have measured the size of a motor twitch of the hand to understand how much the brain (in this case the motor cortex) was affected by our stimulation protocol, factors like attention to the hand, motivation, novelty, and how much the motor cortex was active just prior to stimulation not only made the difference between getting an effect or not but also shifted the direction of the effect. One might think that if a region was active just before treatment, that would “prime” the stimulation to be more effective. But in fact, the brain can only shift so much, and if there is too much activity in a region just prior to stimulation, the region may respond with a paradoxical suppression of response rather than facilitation. There have been several studies showing this in the motor cortex. Similarly, if a brain region is actively suppressed just prior to treatment, this may result in greater facilitation than if it was simply at rest. This is what we refer to as “metaplasticity” or how likely a region is to change based upon its previous state of change.
You may say, “Yes, but this is the motor cortex… what does that have to do with depression?.” Well, TMS to the dorsolateral prefrontal cortex (DLPFC) for depression still works via the same basic physiological principles as TMS to the motor cortex. There is no reason to believe that different brain regions follow different rules. If one translates this to depression treatment, then you would certainly want to consider what that brain region (DLPFC) is doing just prior to or during the stimulation. But exactly what it should be doing is still unclear. If you did TMS to DLPFC right after cognitive behavioral therapy (CBT), which engages similar brain regions and networks, would you get a paradoxical or primed effect? What about doing CBT during TMS, ….would you get a synergistic effect?
The honest answer is, we don’t know. There are studies that have attempted to look at this but have run into difficulty with feasibility, tolerability, and appropriate control conditions. In terms of feasibility, it is difficult to establish rapport and maintain attention for a CBT session while every 30 seconds receiving a train of TMS. Certainly, noise, distraction, discomfort, earplugs, etc. reduce feasibility for such approaches. In terms of acceptability, if you use the standard protocol plus a CBT session and you do it sequentially (rather than simultaneously), you are asking people to come in for 2-hour sessions, which may not be possible for them. Finally, what would you compare this combined approach to? Just TMS? TMS plus a “control behavioral therapy”? What would be considered a “control behavioral therapy” and won’t people know whether they have been randomized to that versus “real CBT”? Needless to say, there is not a straight forward answer to the best way to test this, but there are folks out there trying to design feasible, tolerable, and scientifically sound ways to ask and answer these questions.
Another open question is what mental or cognitive state exactly is best for a synergistic effect? You might imagine for depression that you want the person to be in a happy or content emotional state rather than a negative, fearful or angry state. And my gut tells me that you would be right, however, there is data to suggest that if people’s symptoms are provoked, the effect of TMS is stronger. This is the case with protocols aiming to treat OCD, PTSD, and Addiction for example. Studies show that when you use stimuli that provoke the patient’s symptoms just prior to or during stimulation, the effects of the TMS are greater than they are for individuals whose symptoms are not provoked. Is this something special related to treatment for these specific conditions? Or should we also have participants think about their worries or negative ruminative thoughts? Again, my gut says no. In fact, I know groups who do mindfulness meditation while participants receive TMS and believe that this is the most beneficial state that the patient can be in. In my mind, the jury is still out. There simply have not been studies that have effectively looked into the question.
So until these studies are completed, what should Clinicians do? I would say engage with the patient. If the TMS operator is a therapist or can be trained in Behavioral Activation Tools, prior to the stimulation, the operator may ask the patient about his/her day or week and activities that they may or may not have participated in. What has he/she been doing over the past day or week that has put them in a more positive or hopeful mood? This only takes a few minutes and can be done while the patient is getting settled into the session or while the operator is getting the equipment set up. Then during the session, to the extent that it is feasible, keep the patient engaged. Even if it is a simple conversation.
Remember, the DLPFC that is the prime target for TMS depression treatment is a higher cognitive processing region. If the person is engaged and processing information, even if it is simple conversation or remembering what he/she has done in the recent past, this may serve to prime this region for modulation more effectively than a silent room or an unengaging television show where the patient may be left to his/her own ruminations.
When the patient leaves the TMS session to encourage them to stop on the way home, to do something that may help build upon the brain activation that you just facilitated with the TMS. If the patient does see a therapist, and it can be scheduled this way, arranging the therapy session immediately before or after TMS may also be beneficial.
As new research is published in this area, I promise to share and continue the discussion on new protocols and procedures — and combinations thereof — that may make TMS and other noninvasive brain stimulation techniques more effective for more people in the future.