PhD program alum Liberty Hamilton eavesdrops on how the human brain processes natural sounds

March 6, 2019

“Something we can really add to the field is being able to understand at a much higher level how sounds become meaningful words and concepts.”

Liberty Hamilton, PhD program alum (entering class of 2008)

Because natural sounds such as music and language are so fast and complex, it can be challenging to study how they are represented in the brain. Liberty Hamilton, Assistant Professor at the University of Texas at Austin in the departments of Communication Sciences and Disorders and Neurology, uses a unique approach to overcome this challenge — a technique called electrocorticography (ECoG), where a grid of electrodes is placed directly on the surface of the brain in patients undergoing surgery for epilepsy. Hamilton and her team can then record directly from the surface of the cerebral cortex while the patients are talking or listening to sounds, allowing them to observe neural activity related to speech and language with high spatial and temporal resolution.

As an undergraduate at Scripps College, where she “almost minored” in other fields involving sound — Spanish and piano performance — Hamilton found she was fascinated by the neuroscience underlying sound production and perception. After graduating, she worked as a research assistant doing neuroimaging on patients with schizophrenia. This experience led her to go on to earn a PhD, which she did in the lab of Shaowen Bao at Berkeley, who is now at the University of Arizona. In the Bao lab, she studied sound representation in the auditory cortex in rodents.

After earning her PhD in 2013, Hamilton wanted to return to working with humans, in part because “it’s hard to ask mice what they are thinking and to get them to do what you want them to do.” She began using ECoG as way to study the neurobiology of language as a postdoctoral fellow in the lab of Edward Chang at UCSF. Now in her second year as a faculty member, Hamilton uses ECoG as well as other techniques to study speech and language, and their development, in adults and children.

Read the following Q&A with Hamilton to learn more about her research, what it’s like to work with patients, and why she appreciates her experiences at HWNI even more now that she is a faculty member. This interview has been edited for brevity.

Rachel Henderson: How did you become interested in neuroscience?

Liberty Hamilton: That was a little bit of a winding path. I started out in undergrad as a geophysics major. That was because I had a summer job where I worked with a geophysics company. I saw that they got to travel a lot and go to really cool places with volcanoes and earthquakes and all that sort of stuff, so I thought I wanted to be a geophysicist. I started the classes and then I discovered that I didn’t care as much about geology as I should for someone who is going to do that (laughs).

Instead, I had been taking some other classes. I almost minored in Spanish and piano performance, and I was really interested in sound and how we understand sounds. I ended up taking an intro neuroscience class that I really, really liked. I later took a neurobiology lab course where we recorded action potentials in hippocampal slices, and that got me interested in neuroscience.

After that, I didn’t go to grad school right away because I wasn’t entirely sure that’s what I wanted to do as a career. I worked at UCLA for two years as a research assistant with Katherine Narr. We were doing studies on human fMRI, structural MRI, and DTI. It was a pretty small lab — it was just me and another research assistant to start out with. [Dr. Narr] really gave us a lot of feedback, and I got to work on papers with her and do some independent projects. That was really amazing, and I think that made me decide that’s what I wanted to do — that’s why I applied to grad school.

RH: How did you end up coming to Berkeley for your PhD?

LH: I knew I was interested in auditory neuroscience fairly broadly, but wasn’t entirely sure what level I wanted to study at — if I still wanted to do neuroimaging or if I wanted to do something more low-level.

I had a number of different schools I was trying to decide between. At the interview weekend at Berkeley, I got such a good feeling of camaraderie from the students who were there, and I had really good interactions with the professors at the interviews. It seemed like a place where not only was everyone really smart, but they were also really supportive and fun to be around. I realized that environment seemed really great, so that’s what led me there.

I ended up working with a number of excellent faculty members. In the end, I was really happy with the choice, both for science reasons and also personal reasons. Helen Wills was a really excellent place to be.

RH: Did you do some lab rotations before you joined your thesis lab?

LH: I did. I think that’s a huge benefit to the Helen Wills program. I think having the rotations is really important for both the student and the professor to get to know whether they work well together, and also whether the projects are of interest to them.

I rotated in Jack Gallant’s lab, Frédéric Theunissen’s lab, and Shaowen Bao’s lab. I had an excellent experience in all of them. In my first rotation, with Jack, I was learning MATLAB. It was a more computational rotation, I was dealing with some of their fMRI data in natural vision. That was super fun and an interesting place to be, and great for getting my coding skills up and ready.

After that I rotated in Frédéric Theunissen’s lab, and did a behavioral project on perception of musical timbre. I was working with a postdoc named Taffeta Elliot and we ran participants where we had them listen to different instrumental sounds and rate how different they were on various perceptual dimensions, and then looked at which acoustics correlated with that.  

Then I rotated with Shaowen Bao, whose lab I ended up joining. His lab studies auditory cortex development and plasticity using rodent models. During the rotation, I was learning how to train rats on discriminating different types of sounds. I also learned how to do electrophysiological extracellular recordings, which was super fun.

We had a really great team in the lab. There were three Helen Wills graduate students ahead of me — Heesoo Kim, Hania Köver, and Michèle Insanally — who took me under their collective wing and taught me how to do all this different stuff. So that ended up making me choose to go there, but I really could’ve gone to any of the three labs. It was really good to have done them all. I got a slightly different experience in each one, and got to see how different faculty run their labs, what the lab culture is like, what the problems are they are trying to solve, and learn different techniques at different levels — from more systems and molecular neuroscience to more cognitive neuroscience.

RH: Beyond the research, what was your experience like in Helen Wills?

LH: Helen Wills was a super supportive place, and I’ve come to realize that from seeing other graduate programs. Everywhere is different, but we were really privileged to have things like Neurofriends, for example, where you go to lunch with your fellow cohort of first-years and the department pays for it. I became really good friends with all the people in my cohort, I still talk to all of them. We’re now talking about faculty job searches or job searches in general. We’ve all stayed really close, and I think Neurofriends certainly helped with that.

Also, we had a lot of events, like the Brain Lunch Journal Club, which were always great too. We had a lot of great opportunities to both talk about science but also not talk about science. I have very fond memories of the retreat — just getting to spend time with other grad students and have people going through the same experience. Even though it’s sometimes really difficult, and you feel challenged, and maybe you feel like you don’t know as much as you would like to know, or maybe you are feeling kind of stupid, having other people who are also going through that was super helpful. I felt like all of them had my back.

And same with the administrators — Kati Markowitz was our administrator for most of my grad school career. Now I realize how much she did for us on the backend (laughs). I really appreciate that now. Now I’m a faculty member, so I’m trying to figure out how we support students in these different ways. I had no idea how she did some of the stuff! And she was hilarious, which also really helped.

I was really good friends with a lot of the people at Helen Wills and I still feel like those are some of my closest friendships. That is one thing I do miss.

RH: What was your thesis about?

LH: My thesis was looking at sound representation in the auditory cortex of mice and rats. I was looking at the role of inhibitory interneurons in the encoding of simple and complex sounds. In one of my papers, we looked at recordings of extracellular potentials in the auditory cortex of mice while we stimulated parvalbumin-positive inhibitory interneurons. Then we looked at how that changed interactions between simultaneously recorded sites, and also how it changed the receptive field properties of cells.

That was a really exciting project. It was pretty early on when optogenetics was just taking off. We started that in 2008. I remember having a conversation with Shaowen about starting this project that no one in the lab was doing. He’d never tried optogenetics before, but we both agreed it was this really exciting new method, and I wanted to learn how to use it. So with the help from a lot of people from Yang Dan’s lab and Dan Feldman’s lab, we got that stuff up and running. Seung-Hee Lee, who was a postdoc in Yang’s lab at the time, helped me immensely in learning how to do virus injections for optogenetics. Also, the Deisseroth lab provided some reagents and things like that. It was fun — it was this new frontier.

We ended up finding that when you stimulate these inhibitory interneurons, this increases signal to noise in the auditory cortical areas, and makes the tuning curve less noisy, so you have less background firing to random other sounds and more obvious, strong responses to pure tones that are within the receptive field.  

We also used a 16-channel probe to record from 16 sites in primary auditory cortex at the same time. It seemed that the amount of information sent from layer 4 to the more superficial layers increased with the inhibitory stimulation as well, but there was no change in within-layer dynamics. So we saw a strong feed-forward increase, and nothing within layer. This suggested that these inhibitory interneurons were mediating more of that feedforward, stimulus-driven response.

RH: Tell me about your experience as a postdoc.

LH: After my PhD I wasn’t sure exactly what I wanted to do. I thought about potentially going into industry, I thought about going into a postdoc — I was kind of on the fence for both. I ended up interviewing at a few ECoG labs, because I had interacted with a few people in Bob Knight’s lab [who use ECoG]. I knew I was still interested in auditory neuroscience — if I were to stay in neuroscience — but I wanted the chance to work with people again.

Although the cell type manipulations I did in my dissertation were super cool, one problem with working with mice is that it’s hard to ask mice what they are thinking and to get them to do what you want them to do (laughs). I was thinking, if we could look at sound and language and speech in people, then you can more easily ask them to do a task.

I ended up having a really good conversation with Eddie Chang at UCSF. He had been doing kind of similar work to what the Bao lab was doing in terms of looking at the encoding of sounds in the auditory cortex, but in humans instead of rodents. He and I talked about how I could use similar methods to what I’d used in my dissertation, but work with data that was from intracranial recordings in patients with epilepsy. I ended up working in his lab for three years.

We got to do some really amazing stuff with high density ECoG — so recording directly from surface of brain in patients with epilepsy. Generally, still looking at the encoding of natural sounds like speech in the temporal lobe, and in related motor areas if we were looking at speech production.

Working with these patient populations is super interesting. It’s really real. You have to talk to people who are going through something really difficult — epilepsy surgery — and as a researcher, you want to be really sensitive to that. So we felt that if [participating in the research] was something they wanted to do that could help pass the time, that could be a sort of fun way of relieving boredom in the hospital room. A lot of them are waiting to have seizures so they can be localized [in the brain], and they might be in the hospital up to a couple of weeks.

We actually made a lot of meaningful relationships with some of the people we worked with. I got to meet people I wouldn’t otherwise have been able to meet. I think collecting that data makes you realize how rare and special that is, to get to work with those types of people. So I try to be sensitive to that now in my own lab.

RH: What’s your role when working with patients?

LH: I don’t have any role in the placement of electrodes, because I’m not trained as surgeon. That’s all clinically determined. [The neurosurgeon] decides based on clinical considerations where they should put these grids or depth electrodes. If they have coverage over certain temporal areas, we’d tend to run more speech perception-type tasks, or if they have good motor coverage, maybe we’d do more speech production tasks instead.

I’ve been developing an ECoG program here at UT Austin, and I’m developing collaborations with the neurosurgeons and epileptologists at both a children’s hospital — Dell Children’s Medical Center — that has an epilepsy monitoring unit, and Dell Seton Medical Center for adult epilepsy patients.

I have been working together with the neurosurgeons and epileptologists — we’ll go to case conferences where they discuss which patients are coming in and whether or not they’ll have placement of intracranial electrodes if their epilepsy is severe enough. If there are patients that have [electrode] coverage over an area we might be able to look at for speech and language tasks, we’ll reach out to those patients and see if they are interested in participating in research during their stay.

It’s a big collaborative process between the clinicians who are making the decisions about where everything goes, and my lab where we are running specific tasks looking at perception and production of natural speech.

RH: Since ECoG is invasive, what are its advantages over other techniques to look at brain activity, such as EEG or fMRI?

LH: The huge advantage of ECoG is that you have extremely high signal to noise, and you have very high spatial and temporal resolution. With something like fMRI, it’s difficult to look at very fast processes — so things like phonetic selectivity that’s happening on the order of milliseconds is more difficult to measure using the BOLD [fMRI] signal, because that’s evolving over seconds. It’s not that you can’t do it, but with ECoG it’s much easier to see the fast fluctuations that are occurring in speech processing. Also, because the electrodes are directly on the surface of the brain, we can record signals that are more similar to extracellular invasive potentials that you could record with penetrating electrodes.

With EEG, the skull blocks out the high frequency signals that are associated with neural multiunit firing. So you can get an overall view of what’s going on but at a much wider spatial scale. [With ECoG] it’s a small signal, but with those electrodes directly on the surface of the brain, we are able to measure it and it’s a spatially localized signal.

RH: What projects are currently going on in your lab?

LH: We have a number of different projects. We’ve been building up our ECoG group at the Dell Children’s Medical Center, and something that I’m particularly interested in is the development of auditory responses in children. In my postdoc work I had looked at this particular type of response to speech, where in the temporal lobe, you see that there is this area in posterior superior temporal gyrus that specifically responds to the onsets of sentences and phrases. This is different from most of the other speech-selective areas that will respond the same, no matter where a particular speech sound is in sentence.

So if you just heard an “ah” sound you could have an “ah”-selective electrode that is always responding the same amount to “ah.” But if it’s one of these onset electrodes, you can see that it will respond to “ah” more if it occurs at the beginning of a sentence. And there are even ones that are non-selective, but just mark that something interesting has started to happen.

Photograph: Hamilton (left) piloting an EEG study in her lab at UT Austin with graduate student Maansi Desai.

One thing I’m interested in looking at in kids is — how do those onset responses change as a function of development? We’re really just at the beginning of this study, we’ve recorded from just a few patients, so it’s way too early to say what’s happening. But I think this is an important type of response that might be related to some of the improvements in timing judgments that develop over later childhood, between the ages of maybe 6 to 11, so we’re interested in seeing how this changes. There isn’t much data, especially in pediatric ECoG, on this type of specific response.

I’m branching out into EEG as well. We have a 64-channel EEG system that we’re using in addition to our ECoG system. We’re trying to do some multimodal studies where we’re looking at both the signals in the invasive recordings that we get [from] epilepsy patients, but then also more non-invasive recordings that we can do in non-patient populations.  

I have two brand-new PhD students and a Master’s student and some undergrads, so it’s a good group right now. We’re excited for the next year, I think things are going to start to take off as we get more and more data.

RH: How would you describe your big picture goal — the contribution you want to make to science?

LH: One of the major contributions would be to understand how we process natural sounds. This is something that is becoming more and more popular. I think because of computational restrictions, we used to perform these highly controlled experiments where we’d just use single words or single syllables, have people listen to them, and then try and extrapolate from that to talk about speech and language.

This is actually based on work I did through all three rotations at Helen Wills — all three labs were interested in naturalistic sound processing. I think something that we can really add to the field is being able to understand at a much higher level how sounds become meaningful words and concepts.

Also, from the patient end, one thing I would really like to do is to be able to relate what we record in ECoG to patient outcomes. For these epilepsy surgeries, the [surgeons] will ablate certain areas that are involved in seizure onset or are the focus of the seizures. Sometimes patients will have transient [post-operative] problems with naming or verbal working memory, or other language and memory issues. I’d really like to see if our knowledge about the underlying neural architecture and neurophysiology of those areas can help us predict the kind of deficits we might see, and help people develop targeted therapies for addressing those deficits.

RH: What has your first year of being a faculty member been like?

LH: It’s been interesting! With every career stage there’s another jump in how much I learn. From last year to now, I have learned so much, not even in things I necessarily thought I’d learn about. I’m affiliated with our Institute for Neuroscience here, but the groups I work with are much more interdisciplinary. I teach classes for audiologists, for example. I also teach an undergrad class on language and the brain. That’s new, I hadn’t taught much before my faculty position.

I feel like I’ve learned how to work in shorter chunks of time (laughs). Now there are a lot more demands on my time. So whether that’s meeting with students — which is really fun because you get to work on a bunch of different projects at once and see people’s thought processes evolve — and then there’s my teaching, office hours, faculty meetings, committee meetings, talks to go to, talks to give, there’s all sorts of stuff. Now I definitely pay attention to my calendar much more than I used to out of necessity (laughs).

I’ve learned a ton about how universities work, which I didn’t appreciate [before]. That’s why I appreciate what was going on behind the scenes at Helen Wills, especially the fact they had training grant support for us and things like that. I’m trying to figure out how to get that system going here.

RH: What do you do in your free time — do you have any hobbies?

Photo: Hamilton and her spouse Alex Huth, also a HWNI PhD program alum and Assistant Professor at UT Austin.

LH: We got a dog, so hanging out with the dog. We started bouldering, so that’s a new thing. Weirdly, I never really climbed while I was at Berkeley, I feel like that was a big thing for other people but not me — but now I’m doing that, so that’s fun. Austin has a lot of fun music events and things like that, so I like to go those when I can. And really good restaurants, I like going out to eat when time permits.

by Rachel Henderson

Original Publication: March 6, 2019

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