DMPFC & targeting by patient biotype

Dr.Rustin Berlow discusses the salience network, specific patient bio types and the most effective methods.

Stimulating the salience network as a way to access depression relating structures is a newer and advanced way of conceptualizing the treatment of depression. Instead of treating the lateral frontal cortex, the DLPFC, one can stimulate the DMPFC, the medial, and that includes Brodmann’s area 32 and 24, which involve the anterior cingulate cortex, which is known to be involved in motivation, emotion, cognitive control and a mood regulation. By stimulating DMPFC, certain patients that don’t get better with the other stimulation may get better.

There are certain bio types, as described by Drysdale and his colleagues. Those biotypes are certain configurations and patterns in terms of the resting state connectivity and certain tendencies within the clinical picture of a patient, not exactly, but similar to anxiety insomnia as opposed to psychomotor retardation and anhedonia. These different types may have a differential response to stimulation of the salience network and I’ve in particular seen with the mPFC stimulation, patients who have anhedonia as their remaining symptom of depression have a complete remission. Many times with either medications or with DLPFC stimulation, one gets an improvement in mood, improved concentration, improved cognitive abilities but there still is a lack of the ability to enjoy things and get interested in things. DMPFC stimulation allows us to directly target that symptom.

In your opinion, what’s the most exciting area of TMS research currently?

Treating TMS clinicians are going to have more and more options in the future and both the Drysdale article that describes different biotypes based on resting connectivity as well as William’s review article of the different networks relating to depression and the different possible treatments that may be appropriate for problems with each network. These give clinicians guidance in terms of what kind of clinical picture is associate with what kind of response to a certain stimulation. Mind you, the Drysdale article says that the rate of prediction of success with TMS by clinical prediction alone is in the high 60’s, where if you have an MRI connectivity study, it gets into the 80’s and 90’s but not every clinician has an MRI machine, but we do have the ability to ask about symptoms and instead of having one treatment fits all, the cookie cutter approach of everybody getting the same stimulation in the same place with the same frequency, we can tailor the TMS to the individual, especially if the first week or two of stimulation has not yielded greater than ten percent or greater than twenty percent improvement in symptoms. The idea that one should continue with six weeks of stimulation with the treatment that has produced no benefit in the first two weeks is a questionable notion at best. There are people who have no response in the first two weeks, who begin getting better in weeks three, four, five and six but the vast majority do not. If a person has not responded to DLPFC in the first week or two, the option to use other kinds of stimulation is a very powerful tool in the armamentarium of the TMS physician.

The first location to stimulate would likely be the right sided DLPFC with a low frequency stimulation. This is often the treatment of choice with bipolar depressions, where you want to be absolutely sure that the person doesn’t develop a treatment emergent mania but if the left sided stimulation doesn’t work, a right sided inhibition with 1 Hertz can be very helpful. From there, one can consider things like DMPFC, the orbital frontal cortex and other places.

What methods do you find to be most effective?

So when we think about the future and the most exciting areas of research with TMS, there are practical aspects like what part of the brain, or what frequency or how many seconds on vs how many seconds off but each one of these is part of a greater picture and that picture is called the ‘parameter space exploration problem’ because there are many settings that the machine can be at and nobody has really determined what the relationship is between stimulation and response, between location and response. Nobody’s really set up a dose response curve for TMS the way we have for psychopharmacology and so the real frontier is parameter space exploration.

What’s the most effective way to measure the response of your patients to TMS treatment?

At this point, the measurement of response to TMS is essentially a clinical one. We do standardized questionnaires that patients fill out weekly and we track the numbers as they do or they do not improve. We also look at the particular symptoms that are or are not getting better to see if there are any ways that we can enhance the treatment with therapy, with medications, with alternative treatments but in the future we’re looking forward to a time when biomarkers will help us predict what will happen down the road. For example, there’s some indication that if you do an EEG brain scan or an electroencephalogram, you can see a certain peak in the alpha region, and each individual person has an individual peak. Some people believe that if you stimulate at that peak frequency, you get a better response. That has not been our experience but we have seen, as was described by Dr. Arns in the Netherlands, that patients who come in and have an individual alpha around 8 Hertz, have a much lower tendency of response to TMS than patients who have an individual alpha above that. We’ve had zero response from patients who’ve had 8 Hertz, 50/50 with patients who’ve had 9 Hertz and then when you get up to 10 Hertz, that’s the normal range and then there’s about a 50% remission rate and about a 30% response rate.