Researchers probe how and why this change occurs

[00:00:00] Host Amber Smith: Upstate Medical University in Syracuse New York invites you to be "The Informed Patient" with the podcast that features experts from Central New York's only academic medical center. I'm your host, Amber Smith. Some people with dementia lose their personal warmth and social interests, and they stop responding to the feelings of others. They lose their empathy. But why? I'm talking with one researcher who tackled that question. Hannah Phillips is a postdoctoral associate leading graduate students in Dr. Wei-Dong Yao's lab at Upstate. Welcome to "The Informed Patient," Dr. Phillips.

[00:00:37] Hannah Phillips, PhD: Hi. Thank you for having me.

[00:00:39] Host Amber Smith: You and your team are studying why patients who develop dementia suffer a loss of empathy. Let me first ask you to tell us what that looks like in patients.

[00:00:50] Hannah Phillips, PhD: Empathy is the ability to share the feelings of others and to adopt, really to adopt another's sensory and emotional state. And it plays fundamental roles in one's wellbeing, in kinship, in our emotional and social lives. It's an important contributor to successful social interactions, enabling us not only to communicate and interact with each other in effective ways, but also to predict the actions and intentions and feelings of others.

[00:01:21] Host Amber Smith: Is there a way that it's measured so that you can say this person has this much empathy and this person has that much?

[00:01:29] Hannah Phillips, PhD: I should disclose, I'm not a clinician, I'm not a medical doctor, but based on my understanding of the literature and how it's measured in patients, basically clinicians rely on, I think in children, they rely a lot on reports of others, like caretakers, but often in adults, they administer various questionnaires that are associated with specific empathy scales, which is called "behavioral scoring," and that's how they look at empathy in patients.

[00:02:01] Host Amber Smith: Does everyone who develops dementia lose empathy?

[00:02:06] Hannah Phillips, PhD: Not necessarily. Dementia is more of an umbrella term. There's many subtypes of dementia that are defined based on the clinical features that appear first and most prominently. It depends mostly on the location of the degeneration, the region of the brain responsible for empathy. If there's specific atrophy to that region, then the patient will ultimately lose or have a progressive loss of empathy.

[00:02:35] Host Amber Smith: Now one of those types of dementia, the frontotemporal lobe dementia, can you kind of describe that for us in comparison with Alzheimer's?

[00:02:44] Hannah Phillips, PhD: The most unique feature that sets the two apart is the early onset of FTD. It is considered the No. 1 cause of pre-senile dementia, so this means that it affects individuals primarily between the ages of 45 and 65, whereas Alzheimer's disease is the No. 1 cause of dementia for individuals over the age of 65. Also, as I mentioned, the areas of the brain that are affected, first and most prominently are different between different types of dementia, which gives rise to these different behavioral patterns that we see. So with Alzheimer's disease, very early on, there's a loss of memory and cognitive function. With frontal temporal dementia, we see these hallmark patterns that include the loss of empathy and social behaviors and eating habits early on. And it's more so in later disease stages that there's a loss of memory.

[00:03:44] Host Amber Smith: So the loss of empathy may be an early symptom of FTD?

[00:03:49] Hannah Phillips, PhD: Yeah, that's correct. It is considered one of the more early to mid-stage behavioral symptoms of FTD.

[00:03:56] Host Amber Smith: Well, please tell us about your work that was published in the journal, Neuron.

[00:04:01] Hannah Phillips, PhD: OK. So we're very excited about this study that just came out. We basically, for this story we first set out to develop a mouse paradigm of empathy so that we could study it. We developed one that captures two forms of empathy -- both emotional contagion, which is a basic form of affective empathy, and distress-induced other directed consolation or comforting, which is an empathy driven pro-social behavior.

It was actually initially observed in the highly social monogamous rodent species, prairie vole. And so after we had established this paradigm of empathy, we then established a mouse model deficient in empathy and observed that these aged somatic transgenic mice that are expressing a G4C2 repeat expansion in the C9orf72 gene, which is the most common gene risk of FTD. And we found that these mice, at about 12 months old, exhibited blunted emotional contagion, and they failed to console distressed conspecifics by affiliative contact.

And then further, we found that this distressed-induced comforting behavior specifically activated a region of the brain called the dorsal medial prefrontal cortex. And further, we found that mutant neurons in the dorsal medial prefrontal cortex fire significantly less action potentials compared to healthy control neurons from healthy control mice at the same age, indicating that there is, indeed, profound parameter neuron hypoexcitability in these aged mutant mice at a late disease stage.

And most importantly is that we showed that chemogenetically enhancing this region of the brain, the dorsal medial prefrontal cortex, by enhancing the excitability in this brain region, we could rescue empathy deficits in the mutant mice, even at advanced stages where we saw substantial cortical atrophy or neurodegeneration had occurred.

So these results were very exciting because they established cortical hypoexcitability as a new, or novel pathophysiological basis of empathy loss in FTD, and also suggests that enhancing the activity of the frontotemporal cortex, may serve as a viable therapeutic strategy for BvFTD (behavioral variant fronto temporal dementia) for which there are currently no approved and few effective treatments.

[00:06:45] Host Amber Smith: I want to ask you a lot more about that, but let me get back to, I'm still kind of struck with these mice. So you were able to create mice that lacked empathy essentially, compared to mice that have empathy? I guess I never even thought of mice having empathy. Did they behave differently, side by side, in cages?

[00:07:08] Hannah Phillips, PhD: Yes. Yeah, they did. And it's, empathy is a behavior that classically we think of only in humans, or historically it's considered a process experienced solely by humans.

But more recently it's becoming appreciated that many species, including rodents, display what evolutionarily conserved behavioral antecedents of empathy, or these more primitive forms of empathy, such as emotional contagion, which, in our case, we looked at the social transfer of fear or observational fear. Also consolation and social buffering of stress and even helping and sharing has been shown in rodents, and now in mice. And that's what we saw with this disease model, is that in these mice that harbor these repeat expansions, which as I mentioned is the most common gene or familial cause of FTD, side by side they show significantly less emotional contagion or this fear-related response when during the observational fear task and also empathy or comforting related behaviors. In our case, we looked at body touching and allogrooming or grooming the other mouse to comfort it.

We found significantly less of these behaviors in the mutant mouse compared to the control mouse at the same age. So it was very striking.

[00:08:39] Host Amber Smith: And did you say that the brain cells were less active in the early stages of disease?

[00:08:46] Hannah Phillips, PhD: So this is actually more of a late disease stage model, mid- to late because these mice are 12 months old, which is equivalent to about 45 to 50 human years.

And so we consider this more mid- to late disease stage, the mouse model that we're using. And we found that the mutant neurons in the dorsal medial prefrontal cortex of these mice fire significantly less action potentials, almost half the amount of action potentials compared to controls, so they're less excitable.

[00:09:22] Host Amber Smith: This is Upstate's "The Informed Patient" podcast. I'm your host, Amber Smith, talking with Dr. Hannah Phillips. She leads a team of graduate students in the laboratory of Dr. We--Dong Yao at Upstate, and their research about loss of empathy in frontotemporal dementia was published recently in the journal, Neuron.

So let's talk about how brain cells can be made to be more active, because that's sort of, we're on the cusp of wanting to be able to do that, right?

[00:09:52] Hannah Phillips, PhD: Yeah, yeah, definitely. So in patients, I mean, again, I'm not a clinician or a medical doctor, but based on my understanding, so there's a couple different types of approaches that can be used to manipulate brain activity that include transcranial magnetic stimulation, and then deep brain stimulation is very commonly used.

Transcranial magnetic stimulation is more of a noninvasive form of brain stimulation, whereas deep brain stimulation is an invasive procedure where they implant these electrodes into certain areas of the brain that produce electrical impulses to regulate abnormal brain activity.

This is a very exciting potential approach to be used for diseases where there's changes in activity in the brain. But, we need to work with clinicians because any of these techniques, although very powerful, can affect many brain cells. And the goal is really more to target those disease neurons specifically. And even though that's the hope and the potential at these stages, there's still a lot of work to be done to figure out how to apply this to modulate brain activity and reduce like potential side effects. But in theory, if we can increase brain activity, then we could ultimately alleviate these empathy deficits.

However, when you actually do it in patients, it's obviously much more complicated. So there's a lot of work still to be done, but it's a very exciting forefront.

[00:11:27] Host Amber Smith: Well, I understand you're starting a fellowship at Harvard University soon. Do you expect that you'll continue focusing your research on frontotemporal lobe dementia?

[00:11:36] Hannah Phillips, PhD: I won't be working on FTD here, but, I will still be studying the neural mechanisms of social behaviors and social impairments, so I'm very excited about that. And, my goal and hope one day is to have my own lab, and I would be very excited to continue researching the neural mechanisms of FTD and hopefully make significant contributions to the field and toward new and effective therapies.

[00:12:01] Host Amber Smith: Well, thank you so much for making time for this interview, Dr. Phillips.

[00:12:05] Hannah Phillips, PhD: Yeah, of course. Thank you for having me.

[00:12:07] Host Amber Smith: My guest has been Dr. Hannah Phillips, a postdoctoral associate in Dr. Wei-Dong Yao's laboratory at Upstate. "The Informed Patient" is a podcast covering health, science and medicine, brought to you by Upstate Medical University in Syracuse, New York, and produced by Jim Howe. Find our archive of previous episodes at Upstate.edu/Informed. This is your host, Amber Smith, thanking you for listening.