An Interview with Amit Etkin, M.D., Ph.D.
|Associate Professor, Psychiatry & Behavioral Science|
Investigator, VA Sierra-Pacific Mental Illness Research Education and Clinical Center
Dana Foundation Grantee: 2011-2016
laboratory has been investigating the use of repetitive transcranial magnetic
stimulation (rTMS) in combination with whole-brain EEG and functional MRI
(fMRI) to treat depression and to help unravel its underlying brain circuitry. First,
why has depression been so difficult to treat?
There are many reasons, but I think you have to start with the
fact that we don’t really know what the disorder is about. Different people
report different symptoms, which may reflect biologically distinct conditions. It
stands to reason that the nature of the intervention can’t possibly be the same
for all those different forms of what we call depression. So partly, we need to
better understand the biology of depression.
Related to that is the fact that we’ve never developed a clear
idea of what we’re targeting. All of our current interventions have been
discovered by serendipity. To this day we don’t really know how antidepressants
work. We know a lot of things change in the brain when you take an antidepressant,
but we don’t really know what is causing those changes because we don’t really
know what’s wrong in the first place.
science move beyond this quagmire?
In an ideal world, we could design an intervention that we understood,
that we could control, and that could tell us if we’re on the right track in
changing what we want to change. That’s why we decided to do this study.
With medication, there is no way to alter how the medication works
to better fit some particular brain target. But with targeted brain
stimulation, you have an infinite amount of flexibility. For example, where do
I stimulate in the brain? Does it matter if I stimulate the left side or the
right side? Frontally or in the parietal cortex? Which part of the frontal
cortex? Does it matter how I do the
stimulation? Which frequencies or pulse patterns produce the downstream effects
I’m looking for?
With this combined TMS-fMRI approach, we can produce a
physiological readout that tells me if I’m hitting my target and am on the
right track or not. If I need to, I can immediately devise a different protocol
that engages that target better and assess whether the readout changed. Therapeutically,
it puts us in a much better place than where we are now.
How is this
work helping to elucidate the systems neurobiology of depression?
We need to have a handle. In this case, the critical handle is
causality. One reason depression and other psychiatric conditions have been
hard to understand based on brain imaging is that you inevitably find
differences in patients’ brains. You might find an overwhelming number of
differences all happening at the same time, and it’s impossible to know what’s related
to the clinical state vs. what might be compensatory changes.
Having the tool of TMS allows me to ask what happens when I
stimulate this part of the brain, or when I turn this part up or this part down.
It‘s a brain-systems level intervention that carries with it the really
important component of causality.
Your lab at
Stanford is one of only a handful worldwide who are using TMS and fMRI
concurrently. What are the benefits of combining these two?
The big advantage is causality. It gets us out of the
chicken-or-egg problem where we see a lot of things change in the brain but we
don’t really know why. It also allows us to go very quickly from assessing
brain circuits to treating brain circuits, because the tool that we’re using to
understand what’s working and what’s not can then be applied therapeutically to
induce long-lasting change in a circuit. You can’t do that with imaging alone.
Some brain structures can simply not be assessed without fMRI. The
amygdala, which we think is very important for a range of emotional and
behavioral disorders, is one example: you can’t assess amygdala activity with
EEG, and you can’t really know if you have affected it by looking only at
behavior. The ability to image the amygdala and other deep brain structures in
response to discrete TMS stimuli gives you a huge advantage in terms of finding
new targets and new methods to modulate these regions.
TMS in an MRI. Photo courtesy of Amit Etkin Lab|
this work advance the treatment of depression?
By stimulating brain activity and assessing circuit-level changes
as they happen, we can garner important insight into what is wrong in
depression and how to fix it in an optimized, personalized matter.
I’ll give you one concrete example: It matters whether stimulation
is done to an area in the patient’s brain that is abnormal or normal. For any
treatment in any psychiatric disorder, we don’t actually know whether the goal
of treatment is to normalize abnormal brain activity or to engage compensatory
circuitry. It’s a fundamental question that we cannot answer without a direct
tool for manipulating brain systems and assessing the effects.
applied EEG to your studies, and have found a signature pattern of brain
activity that tells you whether the person is likely to respond to a particular
regimen of TMS. How does that inform treatment?
That EEG signature not only tells us who is likely to respond, it tells
us a change happened and the magnitude of that change. Those three things combined
give us a platform for optimizing rTMS for depression. If we can replicate our
initial result—and we’re
trying to do that now—we should be able to tailor stimulation to any given
person based on their EEG readout. We’ll be able to know how well we’re doing
and what kind of protocol to use.
It gives us a target, a signal to chase. Then you can try
different protocols and optimize your treatment fairly quickly until you find the
signal you’re chasing.
this research advance the nascent field of clinical TMS?
The bigger picture and long-term significance is that we can start
thinking about rTMS a lot more powerfully, as a personalized tool that we can
optimize. Unlike any other tool in psychiatry, we can treat to a target rather
than, for example, blindly elevating the dose of an antidepressant medication without
knowing what brain system we’re trying to affect. We can even think of
something called closed-loop TMS, where we can read out the effects as the
procedure is done and adjust parameters as necessary based on real-time assessment
of how neural circuits are responding.
All of these things would radically shift how we use rTMS in the
clinic for depression and open up a completely new window for using TMS to
target other systems. We talk a lot about personalized medicine within
psychiatry and medicine at large. This is personalized medicine in essence
because we can optimize the therapy as we go vs. just finding a match between
an existing intervention and a profile of symptoms. I’m hoping this becomes the
beginning of a shift in how we approach depression and how we optimize and
personalize treatment for depression.
Has TMS really
caught on as a treatment in psychiatric disorders?
Sort of. It’s used in the clinic, and is paid for by insurance
companies fairly routinely in most parts of the country. Yet, psychiatrists
aren’t really used to doing procedures, and TMS is a procedure. They’re not
used to touching their patients, and they’re not used to working with brain
circuitry, so it takes a bit of a shift in mindset within psychiatry. Also, the
experience of how to do TMS is fairly limited in the field, and it has been
limited somewhat by the business model of one of the leading device makers,
which has decreased the flexibility of clinicians to innovate. Consequently, relatively
few patients have access to TMS.
Do you see
potential outside of depression in other psychiatric disorders for this method that
you are developing?
Yes, absolutely. The bulk of the published research so far has
been in depression, but there is absolutely no reason why you couldn’t use TMS
in a proper and flexible manner in other conditions. We’re using TMS/fMRI in
patients with post-traumatic stress disorder and in stroke recovery. Others are investigating it in
autism and bipolar disorder.
We’re now considering other brain targets, other EEG or fMRI
signals, and other plasticity protocols aimed at inducing long-term change in
the brain. You can move beyond disorders per se and think about how to use
these principles to characterize an individual’s brain, to say for example, “this
circuit is intact and this one is not,” and then target the stimulation
protocol accordingly. It may be that in some people you want to decrease a
particular target signal but in others you want to increase it.
I think one should see this as the germinal phase of applying TMS
to psychiatric disorders. We’ve found a signal that we can use to understand
how the brain works and how our interventions can be optimized. We see this is as
just the tip of the iceberg.