Neuronal Networks: Depression

It is unlikely that any model of major depressive disorder is likely to find universal signals among those diagnosed because the symptoms are so diverse.  However, it does seem likely that models, such as brain-network models, will be able to identify common dysfunctions among those with similar symptom burdens (for example, those with primarily anhedonic symptoms, dysphoria, or with excessive rumination over their own worthlessness), and then help identify how various modalities may be more or less effective to treat these symptoms specifically. 

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Welcome to Psidactic Residency Edition. I'm Dr. O'Leary and this is the 25th episode of this podcast. It was my goal when I started this venture to release one episode every week. But I'm more on track to average about one every two weeks. Still, I'm gonna pat myself on my back and say, hey, good job, Dr. O. Your glass is definitely half full. But with that in mind, today, I'm gonna be talking about depression. One of those diagnoses that leaves you feeling like your glass is mostly empty. But it has a large number of symptoms and possible symptom combinations. There are eight diagnostic symptoms that you must have, well, that you can have, and at least five that you must have, and those five must include low mood or anhedonia, which means that there are something like a hundred and twenty-six possible combinations of symptoms that will qualify for a diagnosis of major depressive disorder. Please feel free to check my math. I'm probably wrong, but there are a lot. Therefore, it seems like there cannot just be one treatment that will work in all or even most of those cases, and there's also not likely one kind of brain dysfunction expected to be found. And today that's really what I want to talk about. I want to talk about brain networking and how we can use it to understand depression. But I should begin more with a brief review of the criteria for depression and the complex interactions and relationships between these criteria. The primary criteria for depression are that a person must report either a low mood, which is like sadness or melancholy, and that has to be present for a large part of most days over the last two weeks. Or they could report anhedonia, which is like this loss of motivation, pleasure, or interest in all or nearly all daily activities. So really, really unmotivated. And that has to be present over the same two-week period. So I believe that the DSM includes one or both of these because low mood is really different from a loss of pleasure, and the two can be present at the same time, or in a fluctuating kind of demoralizing dance. A depressed person may say that they're not particularly sad, or that they wish they were sad, but instead they're just mla without that internal drive that most of us have to do things. Whether it was something that we used to enjoy, or simply something we just have to do. So when symptoms are mild to moderate, sufferers are often able to get up and go and do their activities of daily living because they know that they have to, but when it's really severe, depression can lead to like a complete lack of interest or motivation, even in caring for oneself, which is like a telltale sign of hypoactive catatonia. The rest of the criteria are not really depression-specific criteria. And by this I mean that, like, in the absence of anhedonia or low mood, they're more likely a part of some other problem. I mean, even in patients with MDD, these other symptoms could be uh that are counted for depression, might actually be signs or sequelia of comorbid disorders or result from uh the actual other criteria of MDD. So, for example, a reduced appetite leading to weight loss can be part of anhedonia because there's like this global lack of not wanting to do things, and that could include preparing food. And then excessive eating with weight gain might just be a way that someone brings a small amount of pleasure into their life because they're just so sad. And then fatigue or low energy, well, that almost always accompanies this reduced sleep. If you're just not sleeping well, you're gonna be tired the next day. Or it could also be reported because of anhedonia, which really prevents a patient from getting excited about much of anything, and so they just feel a lot less energetic. And then feeling worthless and unnecessarily guilt-ridden may also be subsets of sadness and rumination. It may also be a result of anxiety, especially social anxiety, or even a result of feelings like we're letting others down, and that might be a part of like rejection-sensitive dysphoria, which is common among people who have ADHD. Concentration difficulties, or like indecisiveness, that could also be due to like a lack of sleep, or to anhedonia, or to anxiety, or part of rumination. And really, there's only one sign of depression, and it's not present in everyone, and that's like psychomotor retardation or agitation. And these objective signs of depression that are in the criteria are hard to evaluate often because we don't necessarily know what the patient's baseline was and we don't have good collateral. So when someone feels sad or worthless or hopeless, thoughts of death are likely to creep in. And so that's included in the DSM criteria. Maybe not so much because depression is the only place where we have thoughts of death, but because it's so common when you're hopeless, when you're ruminating. So I just spent a couple minutes basically giving examples of how it's really unlikely that any model of major depressive disorder is likely to find universal signals among those diagnosed. However, it does seem likely that models, like brain network models, will be able to identify some common dysfunctions among those with similar symptoms. For example, those who have primarily anhedonic symptoms or who have excessive rumination over their worthlessness. And then that could help us identify various modalities or treatments that might help with these particular symptoms. So that's what I want to talk about today: how understanding different brain functions and dysfunction in the symptom clusters of depression can help us to choose a treatment or to understand how a treatment's working. It might sound like I'm plugging like a trans-diagnostic approach to treatment, and well, I guess it it could be that I am, but that's not my intention in this podcast today. My intention is to explain how the brain works or how it is dysfunctional in ways that give people the symptoms of major depression and how we can treat that. So let me reorient you to some of the networks that I'll be talking about today. I recently talked about a lot of these in prior episodes. So I'll be referencing that central executive network, also called the lateral frontoparietal network, as well as the salience network and the default mode network. So these are part of what's been called the triple network model. I'll also mention some other networks that may communicate with these three and also with other networks unmentioned in the brain. There are a lot of them. But in the literature, there are many named networks, and some of these have overlapping nodes or hubs or neuronal pathways, and this is really confusing to me. I'm not a neuroscientist. And the fact that their nomenclature is so varied makes it difficult to understand. I mean, I imagine even for other neuroscientists who are trying to figure out this stuff. And this is called a problem of taxonomy, when how you name things or how you group things into nameable groups is important for how you talk about them. So the same is true in evolutionary biology, but I don't want to go too deep into that. I just want you to have a realistic, grounded suspicion about the information that I'm going to give you. So I'm gonna give it my best try. Though it is difficult for me to always color within the lines because my intellect, as a metaphor, is more akin to a box of jumbo-sized crowns than to like a case of precisely sharpened colored pencils. So let's pull out those crowns. In a broad view, that the connections between different brain regions can be viewed as structural or functional. Structural simply means that there exists some kind of tracks between the two regions. You can potentially interrupt communication between regions by cutting those tracks. Functional connections means that there is actually traffic between the two regions. While structural connections are necessary for functional connectivity, they're not sufficient for it. I've also read about effective connections, which means that there exist structural and functional connections already, but there is also some sort of organized or directed control of the communication along these tracks. If you have undirected functional connections, that can result in, well, dysfunction or ineffective functioning. I'm going to start by reporting an article by Lee et al. That's Lee L. et al. in CNS Neuroscience and Therapeutics, and it was published in 2018. It was called A Brain Network Model for Depression, from symptom understanding to disease intervention. So what they propose is that there's this functional connection in brain regions that can explain things like dysphoria, rumination, anhedonia, and then problems with cognitive control, what they call disrupted cognitive control. So for a patient sitting in your office, this could be someone who's excessively and persistently sad, constantly thinking about what a failure they are, or how the world would be better off without them. And they also have trouble concentrating and completing tasks. But it could also be someone who is doing very little, barely eating or talking, basically withdrawing from the rest of the world. Lee et al. propose multiple networks in conjunction with each other. So they talk about a region called the affective network, and it includes the ventral anterior cingulate gyrus, the orbital frontal cortex, the amygdala, and the hippocampus. And it is supposed to be responsible for dysphoria. They also talk about a region called the reward network. So that includes the prefrontal cortex and the caudate nucleus and the nucleus accumbens. And this is supposed to be responsible for anhedonia or a lack of attention to rewarding stimuli. There's another region they call the cognitive control network, and it includes the dorsal anterior cingulate cortex, which I've talked about in the past as a hub of the salience network. And the dorsolateral prefrontal cortex, which I've talked about as a hub of the central executive network. So the cognitive control network has parts of the salience network and the central executive network in it. And this is supposed to be responsible for cognitive deficits that are seen in MDD. And finally, these authors propose that the default mode network is responsible for rumination. So let me start by discussing the affective network. So it's responsible for, well, our affect, our mood, and in depressed patients, it has a preference for sadness and misery. It's more active during resting states in depressed patients than in healthy controls. And it spins more time, for example, giving attention to sad faces, while healthy controls give more time attending to happy faces. So in depressed patients, there appears to be hyperactivity of negative experience and memories in this affective network. And this dysfunction also includes a greater than normal functional connectivity with the orbitofrontal cortex, connecting with the hippocampus and the amygdala. The amygdala specifically also affects the cognitive control network, especially in its connections with that dorsal lateral prefrontal cortex and the dorsal anterior cinglet. There are a lot of studies looking at this, and the precise nature of the dysfunction is not really well understood. However, there's this general pattern of reduced functional and affective connectivity between the regions of the prefrontal cortex and the anterior cingulate, with that orbital frontal cortex and those limbic structures, which means that the regions of the brain that are necessary for our higher functioning are really unable to effectively regulate our affective network. Dysphoria appears to be a state that our brain's in if we can't tell it not to be there. It might be, in part, not actually the opposite of a positive affect, but maybe the lack of a positive affect. Depression's relationship to anhedonia, or that complete lack of motivation, may be similar to its relationship with a negative affect. The nucleus accumbens and caudite nucleus are key players in our reward network, and they communicate with the prefrontal cortex and the uh putamin or the striatum to make like plans of action. So in depressed patients, this frontostriatal regulation is reduced. The more severe the depression, the lower is the functional connectivity between the frontal lobes and that reward network. So since these players help regulate a sense of pleasure that motivates us to plan and do things, we can't really get that motivated. Also, salient stimuli are not processed in the same way. Normally, new or unexpected sensory stimuli are especially rewarding to the brain, cause a lot of dopamine release, and we're drawn to investigate them. But in depression, there's like this lack of a motivating response, or it just kind of peters out really quickly. Like many of my depressed patients note that they can still experience some positive affect and motivation in certain social situations, but they just can't maintain these feelings once that constant external stimuli is gone. Their reward network seems to lack enough functional connectivity to their cognitive networks at baseline to promote any normal reward responses. Instead, what seems to happen in depression is that patients are drawn away from what would be normally rewarding experiences for other people, into a flood of activity in the default mode network, into a swamp of rumination. This rumination is often associated with that flood of negative affect, or with maybe a lack of motivation to do anything else. The default mode network drives rumination and directs our salience network toward internal stimuli when patients are depressed instead of external stimuli. The default mode network may even predispose patients to depression by being persistently or stably overactive, even when a patient's not meeting criteria for MDD. This means that for people who have been depressed, the default mode network is still likely to be overactive even when they're back into a euthymic state. In patients prone to depression, who are in remission and recovered, default mode activity at baseline is still higher than in controls. And functional connectivity between the default mode network and executive regions is reduced. And it continues to be reduced, even when they recover frequently, which means that the default mode network, it's really not being reliably suppressed by our central executive network. So in depression-prone patients, the default mode network is in a persistently ruminative state, and it's just kind of waiting for some bad or negative experience to drive itself back into self-defeating rumination. The default mode network may also be telling our salience networks to drive our salience toward internal or like negative stimuli and away from that big, beautiful world around us. This might be a risk factor for developing depression, say in response to like highly stressful events or grief or chronic stress. The default mode network is supposed to tone itself down in the presence of like task-specific things, like when the executive network tells us to pay attention or do something or plan something out. But in patients with depression, the default mode network might only be able to transiently respond to suppression by the central executive network, but not remain stably suppressed. Being forced by your default mode network, basically, into a ruminative state, it might not actually be inherently pathological or bad at all times. I mean, some social isolation and soul searching might be necessary to do things like imagine a new way forward for yourself or to question your own actions or your own previously held beliefs. But if your affective network and your reward networks are also not responding reliably to executive control, then they might be giving the default mode network just a sad and unrewarding place to sit and think. Now let me move on more to like treatments, because like knowing that an aberrant functioning of the brains is associated with depression, I mean, it it doesn't help us unless we can start to see why certain treatments might be helpful. So, pharmacological agents can promote or suppress functioning in certain regions of the brain. I'll just talk about a couple here. So, for example, a study of ketamine infusions by Evans and colleagues in biological psychiatry in 2018, which they titled Default Mode Connectivity in Major Depressive Disorder Measured Up to 10 Days After Ketamine Administration, showed like an immediate increase in functional connectivity between the default mode network and a lot of other brain regions, which wasn't there previously. And it might account for ketamine's ability to rapidly alleviate a lot of the symptoms of depression. However, after 10 days, this increased connectivity was no longer significant. There have also been multiple studies that were reported in a paper from Gerloch et al. in Neuroimage Clinical in 2022 that showed that in response to SSRIs, there's an increased activity in the dorsolateral prefrontal cortex. And in fact, this increase after treatment was present regardless of whether a response was shown on symptom rating scales. So the increase in the activity of the dorsolateral prefrontal cortex might help suppress the default mode network, but it also doesn't reliably lead to remission. Another paper by Deany et al. in Frontiers in Human Neuroscience. It's called Dynamic Functional Connectivity Predicts Treatment Response to Electroconvulsive Therapy in Major Depressive Disorder, showed increased functional connectivity between the cognitive control network, which includes our executive and salience networks, and the default mode network following ECT. And this was in 191 patients with depressive disorders that received ECT compared to 61 healthy controls that also got ECT. So in past episodes, I've discussed the recent breakthroughs, especially like the SAINT protocol, which is Stanford's protocol for accelerated doses of transcraniomagnetic stimulation using intermittent theta burst stimulation of the brain, and it targets the left dorsolateral prefrontal cortex and its connections with the subgenual anterior cingulate cortex. This protocol excites this brain region and may restore from some of the functional connectivity between our central executive network and other networks of the brain, though I haven't really seen studies that specifically look at that. But what has been demonstrated is that by increasing activity in these regions, patients have a rapid resolution of depressive symptoms, and these response rates, at least right now, are rivaling those of ECT. Psychotherapies may also have their therapeutic effects by modulating functional connections between brain areas or brain networks. So a study by Tenga et al. and it's published in 2022 in the Journal of Affective Disorders, reported a study of 23 patients with MDD who had not received any psychoactive medications compared with 27 health controls, all of which received CBT. So let me quote like an extremely long run-on sentence from that paper here. So it says, the results of the current study indicate that the salience network it has an it had an inhibitory effect on the central executive network and the default mode network. And only the default mode network had an excitatory effect on the salience network in MDD patients at the time zero stage, which was different from the healthy control group, and might reflect that MDD patients altered function of attention switching, leading to the increased salience of negative emotional stimuli and rumination, and negative self-reference processing at the cost of attention to the external environment, coupled with impaired emotional regulation and cognitive control. This interpretation is in line with negative mood-congruent processing biases and negative self-schema of Beck's cognitive model. Whew. I'm sure they there's a million ways they could have written that better than the way that they did. But I think it's very interesting. So because I'd like to point out that the negative self-schema in Beck's cognitive model, then they're not actually necessarily the things causing dysfunction, but instead they might represent temporal aberrant brain functioning. So the schema might be created by dysfunction instead of causally creating the dysfunction. And CBT then might be effective not by changing the schema directly, but by engaging that central executive network in all this cognitive work? CBT might be changing the way that our networks actually function, and therefore reducing the amount of time our brains spend in this pointless self-referential thought. I point this out because the mechanism of cause and of change are really what's important here. Is intentional engagement of our executive functioning with CBT changing schemas, or is it changing our brain's ability to escape from temporal networking dysfunction? The way we talk about mechanisms will change how we imagine future therapies. So to summarize, there are multiple potential brain networking dysfunctions that could result in the signs and symptoms of MDD. Many of these dysfunctions seem to be related to an increase of the functioning of the default mode network and the affective network, especially with response to negative feelings, and a reduced capacity of our executive or cognitive control systems to dampen down these other networks. It may also be that the default mode network is training our salience network toward more internal stimuli, and when these stimuli are negative to ruminate on them. The treatments we have, in many cases, have been shown to make patients' brains network more like healthy controls, where the central executive network is able to tone down the default mode network, and the salience network is able to attend to more external stimuli. Thank you for joining me today. I hope in future episodes I'll be able to bring you more about how brain networks work in different psychiatric disorders. But until next time, I'm Dr. O. This has been an episode of Psydactic Residency Edition.