Cracking the multisensory code: a conversation with Janelle Pakan.

Janelle Pakan, PhD, is a group leader in neuroscience at the Otto-von-Guericke University in Magdeburg, Germany. She runs the Neural Circuits and Network Dynamics group which focuses on multisensory and motor integration in the brain. Pakan recently spoke with science writer Fred Schwaller to discuss her research. Below is an edited transcript from the interview.

FS – Can you tell me a little bit about the research that goes on in your lab?

JP – We’re interested in the transfer of sensory information to a behavioral output. Animals live in constantly changing sensory environments, so to produce meaningful behaviors, we have to combine sensory systems with motor outputs in the brain. We do basic research in mice to look at the cross-talk between sensory and motor processing in whole brain connections. We also look at disease states where sensory inputs and behavioral outputs don’t match.

FS – What sort of disease states do you look at?

JP – One thing we’re interested in is an effect you see in Parkinson’s disease. These patients have multiple motor perturbations: one is called freezing of gate where patients aren’t able to initiate a movement. Patients can’t initiate walking and say they feel like their feet are stuck to the floor, but if you give them a periodic sensory input, it breaks this inability to start the movement. For example, if you put tape on the floor as a visual cue, or have a metronome as an auditory cue, or a rhythmic vibration stimulus as a somatosensory cue, then they can walk down the hallway just fine. It’s a really interesting phenomenon. The idea is that a sensory input from the environment is fed into the motor system which breaks the inability to begin movement. It’s this interaction between sensory and motor systems that got me interested in this. We’re looking into modelling this in mice.

FS – What are the bigger questions your lab is aiming to tackle?

JP – My background is in visual neuroscience. It’s a particularly interesting system to study because we know a lot about the fundamental principles of how it works. That means we can ask really detailed questions about how the system works in different situations. As a field, and in the lab, we’re moving more towards the idea of combining sensory systems. Traditionally there was a dogmatic view that the brain was separated into separate entities. The view was that vision is processed separately from auditory stimuli, which is processed separately from touch stimuli. Of course, this is true to some extent, but realistically when you get to a certain level of processing in the brain, and it’s earlier in the processing stream than we thought, these sensory systems work together and affect each other. We now know that even in the primary sensory cortices, you get a lot of input from multiple sensory systems as well as motor systems.

FS – Reading from your paper in Current Biology, I was struck by reward having has such a fundamental role in processing visual information very early in this processing stream in the primary visual cortex (V1)

JP – Exactly, and I think this is really a fundamental principle seen across multiple brain regions. The first time I saw these robust reward signals in V1, I was really surprised. And I think its contributing to the paradigm shift that we’re looking at the brain more as a whole processing unit.

FS – How do you think this information is getting from the reward pathways to the primary visual cortex?

JP – We just don’t know yet. We’re looking into this by combining anatomical techniques with functional techniques. Mice offer such unique genetic opportunities to manipulate and trace circuits, which has opened up the possibility to look at these circuits.

It’s likely that there’s some neuromodulatory inputs from brainstem reward pathways, but also top-down inputs from other cortical regions like the retrosplenial cortex and premotor cortex. These pathways can coordinate higher level processing to combine things like reward with visual information. We’re aiming to narrow down these circuits to see what’s going on.

FS – Which technologies are helping the field to answer important questions about the neuroscience behind behaviors?

JP – One of the things that has pushed this forward is working in awake-behaving animals. Seminal work in the past was all done in anaesthetised preparations, which have their limitations. New technology allows us to have experimental paradigms in more naturalistic environments, both using VR and in open environments. It’s been really important to be able to observe animals in real time; it’s how we’ve seen the full importance of things like reward affecting sensory processing across the brain.

FS – What is particularly exciting for you in your field?

JP – One exciting thing about modern neuroscience is how were realizing that the brain is a predictive construct. It’s not so much a computer doing computations, but it’s really trying to form predictions about what’s happening in our environment based on our past experiences. Then it compares these predictions with reality, or its current construct of reality, and if they don’t match then we have really salient stimuli, but if they do match then we can kind of ignore what’s happening and nothing catches our immediate attention.

FS – Or stimuli could be more salient when predictions do match with reality, but it’s rewarding?

JP – Exactly. Important sensory elements going on around you create this kind of change in your behavioral state. This is an overarching effect trickling down to all sensory systems, and creating plasticity changes based on our experiences of the world. It turns out that even our basic primary sensory systems don’t necessarily represent the world in ‘true reality’, but are always impacted by previous experiences.

In another paper we published in Cell Reports, we also saw spatial processing directly in the primary visual cortex. We think there’s this feedback from spatial processing regions, so not only is reward processed there, but also visual stimuli linked to particular locations. This builds larger cognitive maps and realistically all of our sensory input and motor output are likely linked to these maps in some sort of way – after all, we exist and function quite well in the world, which is a very complex 3D environment.

FS – What’s beneficial about using VR systems for these experiments?

JP – Indeed, the benefit is being able to use more complex environments and behavioral paradigms, but still in a controlled experimental setting: we can directly measure behavioral changes of the animal and simultaneously record from neurons at the same time.

It really helps us to step forward in neuroscience by looking beyond brain areas operating in isolation. It’s about linking single-cell and population activity during complex behaviors which is great because you get the full picture of the complexity of brain systems. We have to move forward in the field by looking at more naturalistic behaviors so we can ask how the brain is functioning in more real-world environments, and VR systems help with that.

But these experiments are complex, mostly because the data is difficult to analyze. We see a lot of noise in brain activity in these environments, and we have to accept that. Maybe this is a unique feature of how the brain functions. Maybe we have to redefine what we call ‘noise’, because the brain really functions with this noise all the time – perhaps it is necessary. Still, for our experiments, inside this noise are signals, which we have to somehow extract in order to make sense of what we’re seeing.

FS – I have an image of my mother listening to techno saying “this is all just noise!” but then later embracing the noise and understanding it as music.

What are the new exciting technologies or approaches in your field are really opening new questions in the next decade?

JP – I come from the imaging field. For us it’s important to directly visualize cells and see cell-specific activity. Not only do we have complicated circuits between brain regions, but we also have different cell types within each region. All these cell types play different roles and we still don’t fully understand how they communicate with each other before they pass on information to other brain areas. The advantage of imaging is you get cell-type specific information. Knowledge from these studies can also be combined, for instance, with electrophysiology techniques. Technologies like Neuropixel recording allows you to collect massive amounts of data about cell activity across different brain regions. This is really a push forward. But you need the cell-type specificity from imagining to complement it. So, if you combine the optical precision of imagining and the bulk data from electrophysiology, then you get powerful data. So, pushing both technologies forward is really important for neuroscience research.

FS – Great, thanks for the interview and joining me here today.

JP – Thanks! It’s been a pleasure talking to you.