Latest / The Biological Psychiatry Podcast / Brain Aging and Cognitive Recovery in Late-Life Depression
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- Elvisha Dhamala: From the Biological Psychiatry family of journals, this is the Biological Psychiatry podcast, ⁓ where we discuss the latest research on psychiatric disorders and their treatments. ⁓ Thank you for joining us. I'm your host and Social Media Editor, Elvisha Dhamala. ⁓ Depression in older adults doesn't just affect mood, it also often comes with significant cognitive difficulties that may not always get better even when their moods improve. While repetitive transcranial magnetic stimulation, or RTMS, is emerging as a promising treatment for late-life depression that's resistant to medication, we still don't have a way to figure out who's most likely to benefit, particularly when it comes to cognitive improvement. Today, we're discussing a study that looked at whether a brain aging measure can predict whether RTMS will help improve these cognitive difficulties. Joining me is Dr. Katie Dunlop from the University of Toronto and Canada Research Chair Tier 2 in Mood Disorder Heterogeneity at St. Michael's Hospital. She's a senior author of a recent paper in biological psychiatry, Cognitive Neuroscience and Neuroimaging, titled Brain age is associated with cognitive improvement following repetitive transcranial magnetic stimulation in late life depression. Dr. Dunlop, welcome to the Biological Psychiatry Podcast. Katie: Thanks for having me. Elvisha Dhamala: So let's start by talking about late life depression. Can you tell us how it differs from depression in younger adults and why is cognition such an important part of the picture? Katie: Yeah, absolutely. So late-life depression or LLD is basically just depression that occurs in folks over about 60 or 65 years old. but there are some notable differences compared to people who are experiencing depression earlier in life. Namely that the types of symptoms that they experience are different slightly. Such people with late life depression tend to experience more physical or memory symptoms of depression rather than the mood-related symptoms. And this could be reflected by a different underlying mechanism of late life depression. There are some is some evidence suggesting that late life depression arises as a result of cerebrovascular damage, such as reduced blood flow or small vessel damage. As a result of being an older age, treatment is also challenging. folks who are older tend to have more medical comorbidities or and are on more medications, which can make treating people with antidepressant medication quite challenging. for example, we don't want any unnecessary drug-drug interactions, or you know, if they do have cerebrovascular or heart disease, certain medications like SSRIs can exacerbate those kinds of problems. Cognition is important in a couple of different ways. First, cognition, like I mentioned earlier, things like memory issues and cognitive decline, is a primary complaint of folks experiencing late life depression. And we also know that long term, those kinds of cognitive symptoms could translate even into more severe forms of cognitive decline. Late life depression is associated with a two-fold increase in the risk of developing dementia like Alzheimer's. Elvisha Dhamala: So for those who may not be familiar, can you explain what repetitive transcranial magnetic stimulation is and why it's such an important option for people whose depression hasn't responded to medication? Katie: transcranial magnetic stimulation or TMS is a safe and non-invasive form of brain stimulation. It's actually been approved for younger adults now probably about 20 years now in the US. what it does is it uses electromagnetic induction essentially to target areas of the brain using these pulses of electricity passing through the coil, the TMS coil. It targets specific areas of the brain, so it's a very focal level of stimulation. And in the case of depression, we tend to stimulate a specific area of the brain called the dorsolateral prefrontal cortex or DLPFC. The DLPFC is heavily implicated in depression symptoms, particularly difficulties in regulating mood, emotion regulation in that case, as well as executive function. Now, typically, people receive treatment once daily for four to six weeks. And this is typically for people who don't respond to initial what we call first-line treatments like antidepressant medication or psychotherapy. And this represents about one-third of the depression population. Why it's an important option for people? It's kind of an alternative or intermediary step. before something like electroconvulsive therapy, which requires sedation and is associated with greater side effects like memory or cognitive impairments temporarily. Elvisha Dhamala: So the data for this study come from a clinical trial comparing bilateral DLPFC TMS with theta burst Katie: Mm-hmm. Elvisha Dhamala: stimulation. Can you tell us about that original trial and what it found? Katie: Yeah, absolutely. So the original trial, which was led by Dr. Dan Bloomberger at the Center for Addiction and Mental Health, here in Toronto, was the 4D trial, which is a special kind of trial called a non-inferiority trial. that just means that we have what we call standard of care in TMS, which is a treatment that involves 10 hertz stimulation, which is On average, excitatory, it increases excitability in a brain region to the left dorsolateral prefrontal cortex and one hertz stimulation, which we think of as inhibitory, to the right dorsolateral prefrontal cortex. That's the standard of care. Now, unfortunately, it's a very long treatment. It takes about 45 minutes to complete a single session, which is a long time to be sitting in the chair receiving TMS. the alternative is a new pattern of stimulation called Thetaburst, or not so new anymore, but it's called Thetaburst or TBS. and these different patterns of stimulation enable us to modulate these brain areas just as effectively, but in a lot less time. it shortens the treatment down from about 45 minutes to five minutes. and so The goal of a non-inferiority trial is to test this newer, faster treatment against the standard of care, which takes a lot longer, with the ultimate goal of really just wanting to see as if it's as good as what we would see from the standard of care treatment. And so in 4D, what patients were either randomized to the longer conventional treatment or to the faster Theta burst stimulation arm. And what they found was that the Theta burst stimulation was just as efficacious or effective as the traditional treatment, meaning that given the efficacy is just as good, we should probably switch people to the faster treatment so that more people can access care economically. Elvisha Dhamala: You make an important point in the paper that we need to understand the biological markers not just of depression related response to RTMS, but also of cognitive response. Can you elaborate on that distinction on why it matters clinically? Katie: Mm-hmm. Yeah, so other studies have indicated that cognitive and antidepressant improvement doesn't necessarily go hand in hand. So it does make sense that their biomarkers predicting improvements to depression symptoms and cognitive symptoms could be different. One of the goals here is we want to understand the more complete picture of true functional recovery. So not just, you know, the more common symptoms like mood-related symptoms, but also cognition. And this way we can better personalize care, optimize treatment parameters relevant to TMS, and better manage patient expectations. so if we are seeing a patient in the clinic who is experiencing cognitive impairments, we don't want to overpromise or underpromise what kinds of symptoms will improve or not. Elvisha Dhamala: And can you tell us about the cognitive outcomes you were most interested in looking at for this study? Katie: so this is all from a previous paper by Dan Bloomberger's PhD student Katie Goeke. And what they were looking at is they tested a range of different cognitive domains in patients enrolled in this study. and what we would have typically expected given the dorsolateral prefrontal cortex's role in executive function, that that would be the symptom that we would want to focus on. however this wasn't the case. Executive function was not associated with improvements after course of TMS. instead, it was actually verbal learning, which is the ability to take in verbal information and repeat it either immediately or with a small delay. So it's related to sort of verbal processing and memory. Katie used a very important technique here too. one challenge to looking at cognitive symptoms instead of clinical symptoms like depression is it's kind of challenging to test more than once. there are issues with test retest reliability due to things like practice effects. and so what Katie did was use existing knowledge about the test-retest reliability of some of our cognitive domains and identified verbal learning as one of the only ones where there were improvements greater than what we would have expected just by practicing it more than once, which was surprising. But it has been seen in some other studies. Verbal learning was seen to improve in a younger adult population who received TMS in a study by Fidel Villa Rodriguez's group at UBC. and they theorized that this might be related to modulating circuits between the dorsolateral prefrontal cortex and the hippocampus. Elvisha Dhamala: So in this study you use brain charts. A lot of people are familiar with the idea of growth charts for kids, but what exactly are brain charts? Do they work in a similar way as other growth charts and what do they let you measure? Katie: Yeah, so in this study, yes, the type of brain aging tool that we used is very similar statistically to what a family doctor or pediatrician will use to track a child's height or weight. so it leverages the same kinds of statistics to track those changes. in this case, brain charts plots age on one axis and brain measurements like gray matter volume. white matter volume and cerebral spinal fluid volume, on the other axis, and basically develops percentiles across the range of ages. so when putting new data into the tool, we get something called percentile or a sentile score, which reflects that person's scan relative to all of the references that the trajectories were trained on. Elvisha Dhamala: You had three primary aims for the study. Can you tell us about each of them? Katie: Yeah, absolutely. So the first aim of our study was to first look at whether or not those centile scores differed in late life depression as a whole compared to age and sex matched non-depressed older adults. This is just to look at whether or not the diagnosis alone signifies a difference in brain sentile score or not. the next aim was to look at the relationship between sentile scores and cognition. we've previously shown that brain age is related to specific symptom domains in younger adults. and we wanted to explore this in late life depression as well. And then lastly, we wanted to look at whether or not pretreatment centile scores predicted antidepressant or cognitive outcomes following bilateral TMS in the sample. Elvisha Dhamala: And you found that there are three cognitive subtypes that exist in this late life depression sample. Can you describe those subtypes help us understand what distinguishes them from each other? Katie: so again, it was previously published in another paper by Katie Goeke. she used K-means clustering, which is a form of unsupervised clustering, in order to delineate these three groups based on cognitive function across a number of domains. the first was just a cognitively intact group. Which is they didn't differ relative to non-depressed controls on any of the cognitive domains that were tested. The second group was a memory impaired group, which showed some of the greatest deficits relative to controls in specific short recall and long recall memory domains. And then lastly, there was a third group that was more broadly impaired. And they saw cognitive deficits not just in memory, but also in executive function. domains as well. Elvisha Dhamala: So one of those subtypes, the cognitively diminished group, stood out in terms of their brain structure. Can you tell us about that? Katie: Yeah. so while we didn't see that brain centile was significantly different in the whole group of late life depressed individuals compared to non-depressed controls, we did see that that cognitively diminished group, which is the one with broad cognitive impairments, had the lowest centile scores. and this was largely driven by reductions in white matter volume. so their their sentile scores were lower indicating potentially abnormal white matter volume and potentially something like accelerated brain age. Elvisha Dhamala: more broadly across all of the different individuals, how are sentile scores related to their cognitive performance at baseline? and where there are specific aspects of cognition that track most closely with brain age. Katie: Yeah, so we we explored these like with linear regression analyses to look at which domains in particular were affected and covaried with brain age. And what we found was a few things. two measurements related to more broad cognitive function, the MOCA and the TOPF, which is a measurement of premorbid function, were correlated with brain centile scores. and also two specific domains from a color switching task. In this task, participants are asked to name the color of a word or read the word itself, and they have to switch between the two. and so the two specific domains from that task were the ability to inhibit one of those two options, or s the ability to switch between naming the color of the word. or the actual word itself, which are measurements of executive function. So in sum, it was more broad level of cognition that was correlated with brain sentel scores, but also some more specific measurements related to executive function. Elvisha Dhamala: And the Sentile scores did not predict whether someone's depression got better with RTMS, but they did predict improvement specifically in verbal learning. What does that tell us about what they're capturing? Katie: so we don't fully understand what brain age represents. and it's probably a much more complicated story and and a multidimensional one. keep in mind that a lot of these models, be it brain centile scores or machine learning regression based ones, which is another form of predicting age using neuroimaging data, all of these are trained on cross-sectional data and typically just one modality, so only structural MRI or only telomere information. And so we don't fully understand where the pathophysiology of something like accelerated brain aging is coming from. But what is really exciting about dissociating between the antidepressant outcomes and the clinical outcomes Is that these could represent separate neurobiological constructs that could be relevant for predicting outcomes to an intervention like TMS more holistically? We often just typically rely on sort of these clinically defined cutoffs for response, like 50% or more on a given clinical scale in terms of improvement. and these are kind of arbitrary cutoffs and they don't reflect, you know, other aspects of global functioning that could be really relevant to personalizing care. And so the dissociation here means that, you know, we're capturing something separable that could be relevant to really getting kind of the complete picture in terms of predicting outcomes. Elvisha Dhamala: And you note that the cognitive improvement effect that you saw wasn't driven by any specific tissue type and it was independent of depression severity, comorbidities, and medication use. How should we interpret that? Katie: Yeah, no, it it was something that was surprising to us as well. And I think this goes back to the point of like we don't fully understand how brain age arises. and it's probably some summary statistic that's potentially like a proxy of help. interestingly, you know, like we're using these centile scores that are trained on very global measures. so the brain sentiles are derived on like total cortical gray matter volume, total subcortical gray matter volume, all white matter volume, and all CSF volume. And so it's not telling us where the deviations lie or the underlying pathophysiology. So is it a glia issue, is it a you know immune issue? we we don't know. and so Others and and our group are continuing to kind of leverage these models, but try to build some explainability into it, leveraging measurements like the SHAPS, which is a way of trying to understand how models make their predictions, in order to sort of better get at why you know it might be predicting these measurements like brain age might be predicting outcomes, but maybe one factor related to them like white matter volume might not be individually predictive. Elvisha Dhamala: And lastly, if there's one key message you'd want clinicians treating older adults with depression to take away from this work, what would it be? Katie: so I think just like younger adults, late life depression is as heterogeneous or even more heterogeneous in terms of clinical presentation. cognitive impairment isn't just simply one additional symptom of depression. it might be biologically separable, it could reflect underlying brain vulnerabilities as measured by brain age, and it's definitely relevant. not just to consider when thinking about treatments, but it's also an important factor when we think about recovery in late life depression. Elvisha Dhamala: That's all for today's episode. Thank you to Dr. Dunlop for joining us to share her work on brain-aging markers in late life depression. listeners, can find the full paper in Biological Psychiatry, Cognitive Neuroscience, and Neuroimaging, and we'll include the link in our episode description. To learn more about our journals, please visit biologicalpsychiatryjournal.com. You can find The Biological Psychiatry Podcast wherever you get your podcasts. Subscribe now so you don't miss our next episode and follow us on our social media channels for highlights and updates. Thanks for listening. ⁓ This podcast is for informational purposes only and does not constitute medical or professional advice. ⁓ The views expressed are those of the participants and do not necessarily reflect those of the Society of Biological Psychiatry, ⁓ its family of journals, or its editors ⁓ All rights reserved, including those for text and data mining or use in AI systems. ⁓