Neuroscience of Depression
Depression is the #1 most common mental illness… but why does it feel like there’s still so much we don’t know about it?
With a rise in mental health awareness, it’s becoming a more common practice to see a therapist or take medications for illnesses like depression - yet the likelihood of ever being “cured” is slim to none. In fact, remission and relapse remain at an all-time high.
This goes for more serious cases, but it also explains why the “winter blues” are a recurring thing… (no coincidence this podcast is out in January. 😉)
What if more answers about this all-too-common illness lie beyond just our minds?
In this podcast, we’re looking straight to the source: our brains. Laine walks us through findings from scientists like Davidson, Pizzagalli, De Raedt, and Koster who share what’s going on in the brain that causes depression, why it’s so easy to feel it over and over again, and the warning signs of it worsening in yourself or someone else.
Some of the content in this episode may be hard to listen to, but when it comes to depression, knowing really is everything. We end with some great takeaways for you to support yourself and those you love, and for anyone who would like more resources you can find them under this episode at www.brainblownpodcast.com.
If you have any topics you'd be interested in learning more about, please feel free to send us an email at info@brainblownpodcast.com!!
We'd love to hear from you.
This episode is dedicated to my family; I hope it offers insight into a world we may never fully understand, and that we may now have a better map to continue navigating it together. I love you all so much. - Cherys
TIMESTAMPS
0:55 - Intro
8:07 - “Caveman Jo”
10:08 - Why Neuroscience?
- Break -
13:42 - The Brain + Hand Model Recap
16:12 - Prefrontal Cortex (PFT)
19:05 - Orbital and Ventral Cortex
20:20 - Anterior Cingulate Cortex (ACC)
22:35 - Hippocampus
23:58 - Amygdala
25:07 - Hypothalamus, Pituitary, Adrenal (HPA) + Cortisol
27:38 - Dorsolateral Prefrontal Cortex
29:35 - Serotonin
32:13 - Norepinephrine
33:14 - Dopamine
34:11 - Brain Summary
- Break -
36:47 - The Body
40:54 - The Behavior
- Break -
47:12 - Takeaways
RESOURCES
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
Depression: Perspectives From Affective Neuroscience by Richard J. Davidson, Diego Pizzagalli, Jack B. Nitschke, and Katherine Putnam
Understanding vulnerability for depression from a cognitive neuroscience perspective: A reappraisal of attentional factors and a new conceptual framework by Rudi De Raedt and Ernst H. W. Koster
Jaak Panksepp - "Affective neuroscience of the emotional BrainMind: evolutionary perspectives and implications for understanding depression"
Moshe Bar - "A cognitive neuroscience hypothesis of mood and depression"
Michael T. Treadway and David H. Zald - "Reconsidering Anhedonia in Depression: Lessons from Translational Neuroscience"
General Outline of Episode
Neuroscience of Human Connection -
Origins of how we evolved, and why our brains are shaped the way that they are
This is the first of potentially more seasons of HUMAN HEALTH
Starting with when the connection between the brain and the mind is the origin or the source of the condition being experienced.
In this episode, we’ll be tackling one of the most common and most serious illnesses humans experience: DEPRESSION
DISCLOSURE: speaking largely colloquially instead of clinically
CHERYS: I think it’s just good with a lot of these that we are giving the disclosure of we will be speaking largely colloquially instead of clinically - even though we are clinicians and to do a short snippet on depression (colloquially) vs depression (clinically)
This is the neuroscience of depression.
LAINE
Depression is the most common mental illness (21 million American adults - 8%, 15% of youth)
Depression (colloquially) - feeling sad for a long period of time?
Depression (clinically) - Depressive disorders - different ways to categorize these feelings, with criteria often around other symptoms, frequency of symptoms, and length of time. We think of this as Major depressive disorder, but there is also diagnoses such as persistent depressive disorder, disruptive mood dysregulation disorder, and a few others. For MDD - nearly every day is a big factor, and it needs to be that long for at least two weeks with the right criteria.
This can be important to make sure that the right diagnosis is present - diagnosis is tricky even for professionals - you could feel like you have depression but what a lot of people don’t know is very similar feelings of depression are also a part of a trauma diagnosis (negative alterations in cognitions and mood) OR can be symptoms from low levels of vitamin D. Or you could have depression, but if we were not so thorough in diagnosing - you could also have mania, and certain meds can trigger very unsafe manic episodes.
PART 1: Terms & Background Info (5-10 minutes)
Has been around forever - 5th Century BC - was in Antiquity by Hippocrates who described it as “if fear and sadness last a long time, such a state is melancholy”.
According to Nancy Schimlpfening who is the administrator for Depression Sanctuary, a non-profit group specializing in depression. Hippocrates argued it was due to an imbalance in the body and treatment was bloodletting, baths, exercise, and diet.
PART 2: What About Neuroscience (5 minutes)
Davidson, Pizzagalli,. Nitschke, and Putnam’s argument is that the diagnostic criteria are much more objective descriptions of symptoms experiencing issues under ‘mood’. Specifically stating one is normal mood and one is not normal. These and other researchers would like to know more about neural bases for these symptoms.
A lot of the research has also wanted to go deeper into more than just mood/negative affect. Also wanting to know how people respond to positivity with depression, what they ruminate on, whether was there trauma, etc. De Raedt and Koster wanted to use neuroscience to understand why remission and relapse were so high. They argue this means treatment is not where we need it to be - they really wanted to look at neuroscience because what they saw was these relapses make it more likely to have a depressive episode again - and wanted to see the correlation and if there were genetic vulnerabilities.
**BREAK**
PART 3: The Science (30-35 minutes)
Prefrontal Cortex
This is vague and large but important to note because to quote Davidson, Pizagalli, Nitschek, and Putnam, “abnormalities in activation of prefrontal regions in depression have been reported more frequently than for any other brain region” and specifically they are seeing these largely in the left side. So what does this look like - one of the things the PFC does is help with goals - making them, achieving them, etc, and its kind of the head manager of these things - helping the rest of the brain to carry this out, especially when we don’t want to, which is real and even more significant to a depressed person, because what we see is people wanting to gravitate to immediate rewards in tasks, and PFC is to help balance that with long term goals, which means the need for delayed gratification. It’s hypothesized that it seems like we are seeing depression cause abnormalities in the brain’s ability to do delayed gratification. Specifically, multiple studies done recently using “event-related functional magnetic resonance imaging (fMRI)” have discovered a “lateralized focus of activation in the right lateral PFC (inferior frontal sulcus)” and this is important in inhibiting our desire to just engage in short term gratification.
Orbital/Ventral frontal cortex
We have both neuroimaging and electrophysiological studies where it is argued that your orbital
and ventral frontal cortex (this is just in front of your eyes) is impacted by depression. This is an area that is likely very important for rewards and punishments - left being reward and right being punishment. In depression, there is a reduction in activation, likely due to a reduction in the volume of gray matter.
ACC
Anterior cingulate cortex - a little farther in (ACC) acts as a bridge between attention and emotion, also helps focus your attention, impacts your affect, and helps you socialize. It’s got a super highway to limbic/paralimbic areas - amygdala, nucleus accumbens, Orbital Frontal Cortex, periaqueductal grey, anterior insula, and autonomic brainstem motor nuclei specifically. It helps you deal with stress, emotions, and social stuff. In anxiety or PTSD - this is highly active, however, with depression, we see significantly decreased activation. What this looks like on a person is likely that flat, blunted effect - this is decreased ACC most likely.
So for example not uncommon that there are things that become expected of us, and we don’t always want to do this. In a nondepressed person your ACC would make a phone call over to your PFC and be like ‘I know we don’t want to do this but we have to suck it up”. With low ACC activation - it’s like your phone service is offline.
Hippocampus -
I have been calling this your brain’s filing cabinet for a while, specifically storing memories of episodic (that one thing that happened that one time), knowledge of where things are, how my memories work in relation, etc. It hangs out near your amygdala. A morphometric study done by Sheline using MRI showed smaller hippocampal volumes when it was analyzing patients with major depression ranging from a reduction of 8 to 19%. They currently don’t know if this causes depression or is caused by depression, though it’s looking more likely depression causes your hippocampus to atrophy.
Amygdala
Sometimes I feel like when anything is going wrong in the brain, it’s probably the amygdala’s fault. With this, it’s hypothesized that your amygdala, or your brain’s alarm, is been going off much more often, causing such a high amount of fear that we see avoidance and that ‘shutting down’. And here of course, we are seeing the opposite which will likely come up a lot this season - we see an increase in amygdala volume, though luckily this can be positively impacted by medication.
HPA Axis - Your hypothalamus and its friends the anterior pituitary gland, and adrenal gland.
Your hypothalamus sits in the same area of the amygdala and your hippocampus and it has your anterior pituitary gland and adrenal gland on speed dial. De Raedt and Koster state that we have a lot of studies that show that a hyperactive HPA axis is our most consistent finding when it comes to depression. So it’s messing with hormones, specifically, this is weight gain around your midsection, upper back, and around your face and this happens because cortisol (the stress hormone) has so much of it in your system that it’s causing you to keep weight on. This can also damage this HPA axis permanently. This also causes issues between the PFC and your amygdala.
There is some argument here that this is caused by stressful or traumatic life events, and that is causing the damage to your HPA, which of course puts other parts of your brain out of wack. For example, there was a study done by Heim and Nemeroof of women who had been sexually abused or assaulted as children having significant ACTH secretion and heart rate with large increases in cortisol, even without an active stress item occurring.
So is it depression or is depression a side effect of trauma?
Regardless studies are showing that we need to stabilize your HPA axis with medication if we want long-term remission. And without that Mizoguchi, Shoji, Ikeada, Tanaka, and Tabria are showing that there will be a relapse.
DLPFC
The dorsal Lateral Prefrontal cortex is believed to also help with emotions. It’s also thought that your DLPFC can help calm down your amygdala. Phillips, Drevets, Rauch, and Lane argue that depression could be a result of your DLPFC being unable to tell your amygdala to chill. Especially, according to Mayberg if your DFPFC AND your Vental region can not chill out your brain.
So the DLPFC is also engaged in top-down processing. So often something happens, you get activated and you make sense of it - this is bottom-up - right? Amygdala fires because it saw a snake, you yell loudly, and then your brain tells you that even though it was just a stick, you were justified in yelling at that stick because it scared you. That’s bottom-up processing. Top-down processing is just the opposite. It’s reappraising to regulate response. I saw a stick, and I got scared, before I acted I took one second for my PFC to get online, realized it was a stick, took a deep breath, and continued moving. My emotions and actions are regulated.
Let’s talk about Neurotransmitters
So if were to ask most people what was impacted in the brain with depression, they would say serotonin. Colloquially this is called the happy brain chemical. It’s very common for people with depression to be put on SSRIs or Selective Serotonin Reuptake Inhibitors.
So what is Serotonin? It’s a neurotransmitter (so it’s like brain email) and it actually does a lot of things. It helps with your ability to think, your ability to engage in rewards, your ability to regulate your emotions, your ability to learn and remember, and is even involved in vomiting. Notice nowhere did I say will make you happy.
It is related to the regulation of emotions and an interesting note here - this is likely because it helps you control your attention around negative experiences. So essentially you experience a bad thing, your amygdala fires and responds and it’s like emails coming from your boss when you don’t show up to work.
Now essentially with an SSRI, your brain starts sending out the right amount of emails, letting your HPA axis respond more appropriately, and telling that boss ‘remember how I took the day off like weeks ago”, yeah.
So why SSRIs? What have have seen according to Bar is that we do see that this is a great thing to help decrease the atrophying of the hippocampus. This is new research, a little controversial but exciting. There is some argument that your SSRIs need to actually generate new neurons in this area to successfully treat depression. There are people who don’t respond to SSRIs as much, specifically if we see less activation in the right prefrontal regions and right posterior regions according to Davidson, Heller, and Nitscheke, so with more anxious arousal we see less improvement.
So what does this have to do with serotonin? It’s believed that serotonin can help your DLPC focus its attention- specifically helping the brain not focus so hard on the negative.
A fun fact is that we also have studies that show how you metabolize serotonin (and how you regulate negative experiences) can be impacted by reducing the amount of L-tryptophan you have in your system (this comes from red meat, poultry, eggs, and dairy). This is an amino acid not naturally made by the body and has to be consumed.
Norepinephrine
Norepinephrine is like a text, transmitting nerve signals to the cellphones of the Nerve, Muscle, and Gland. Notice I said muscle - it’s a text that says move your booty! It’s respectable and doesn’t send texts past like 10 pm at night, but around waking time it’s going to start messaging you a lot, and will keep increasing throughout the day. It’s helping with arousal and alertness. Its produced by your adrenal gland. You know, that HPA axis we just talked about? So if it’s the text that tells you to get moving, and your HPA axis cell reception is spotty…see a connection?
And Dopamine
Another neurotransmitter - dopamine is very good at sliding into your nerve cells’ DMs. Dopamine isn’t always just sending pics though, it’s also planning dates, and thinking about ways to make you smile. It helps you focus and believe that the other person is interesting. It also impacts the heart rate, impacts your blood vessels, helps you sleep, controls nausea and vomiting, processes pain, helps with lactation, learning, motivation, helps control eating, etc. We think about it often in regards to pleasure, as it has been shown to be released at orgasm, or eating choloate. But pleasure, like many things, is something we have simplified. According to Ribot pleasure includes “including reinforcement, desire, predicted utility, subjective pleasure, experienced utility, remembered utility, and so forth”. According to Treadway and Zald, “DA neurons give rise to three ascending pathways: the nigrostriatal, mesolimbic and mesocortical pathways”. Nigoststriatal is habit learning, mesolimbic impacts the amygdala and hippocampus and impacts associations and reinforcement (no surprise there), and mesocortical impacts your ACC with additional impact in your orbital cortex and insula. See how this email thing is impacting your brain? Dopamine is generated in a few areas one of them being your hypothalamus. This HPA’s bad cell phone service just never ends.
So let’s put this all together, from how I understand it. You have a negative experience that fires in your amygdala, it then makes a phone call to your HPA axis. But you’ve had a lot of negative experiences, so it’s like politics in a swing state in October. It’s a lot of calls, ads, dm messages, emails, and texts. Your HPA axis becomes impaired from all the cortisol - and it is impaired doesn't mean it shuts down - it means it’s the 2020 elections. It’s on. All of this has caused your DLPFC to just stop responding. It’s exhausted and done and doesn’t care anymore. Meaning all the negative things - it’s not going to move past them. It stops calming down your amygdala, causing a cycle effect. Your ACC has that highway limbic/paralimbic areas - the amygdala, nucleus accumbens, Orbital frontal cortex, periaqueductal grey, anterior insula, and autonomic brainstem motor nuclei specifically, right, so there’s no shot it’s not impacted, and suddenly it’s not helping you focus your attention on more positive things, or helping you positively impact your mood. It’s not far away from your Orbital and Ventral cortex, which means you stop being motivated by rewards because all of this has just taken a beating. Meaning your whole PFC says screw it, and you stop moving toward goals and stop having the ability to make changes. All the while your amygdala is still running unchecked, meaning your hippocampus is taking serious damage and is no longer in the right weight class to handle this. And the more decreased your hippocampus gets, the less the ability you have to fight off depression long term.
Body
Feel it on a scale of 1-Diagnosis (1-5)
If we go back to Season 1, Episode 4 in the Neuroscience of Safety - looking at our vagus nerve - Porages argues that depression is a reaction of the dorsal vagal nerve. So he is stating that if your dorsal vagal nerve is active, that means your heart rate is lower, you are tired, your blood pressure might be low, and there is an overall heaviness and desire to hide in the body - because we are in such a freeze state where we feel we can not fight what is occurring anymore, so the body starts to shut down. Dorsal means there is not enough energy to run the system and “utilities are on but no one is home”
Behavior
Share examples
Warning sign
De Raedt and Koster argue that a warning sign is to look at how individuals respond to depressive symptoms, specifically arguing that “People who respond to a sad mood and to depressive symptoms by engaging in uncontrollable ruminative thinking about the causes and
consequences of their depression are more likely to remain longer in a depressed episode. They are citing work from Nolen-Hoeksema, Morrow, & Fredrickson. We are seeing multiple studies from the past 30 years that show that rumination is significantly impacting both the onset of depression, as well as long-term experience of depression. Specifically cognitive reactivity and uncontrollable rumination.
Bar expands on why this might be, explaining that the way our brains make sense of our world is through patterns. Remembering in Season 1, Episode 9 The Neuroscience of Music, we group things together to learn and remember them. However, this can also cause serious issues such as ‘all black people are bad. Bar is also arguing that it can cause depression, stating that associations cause predictions. This is how we can predict music we’ve never heard before, and find the act of doing so successfully enjoyable. But it also means that if things feel bad, our brain can expand on that association to all things are bad.
Bar argues that even on a new encounter, we are still looking at past experiences to make sense of it, and we apply that knowledge to get through it. “Central to the proposal put forward here is the distinction between narrow and broad associative activations. Narrow associative thinking, or rumination, refers to associations that surround a narrow focus (e.g., the context of my bad comment over dinner last night: what I said, what I should have said, the resulting facial expressions and verbal responses to it, possible future implications and so forth).”
If we can adjust this rumination to even just be for example ‘what I said at dinner was wrong last night, but someone still gave me a hug when I left or the food was still good or I knew the right beverage to pair with the food, etc. This can take us into places of I should call the person who hugged me, I should cook more, I should host more.
Bar calls this associate activation - it's allowing our thought process to move from one thought to a very different thought.
Depression is often not looking at the bigger picture or not taking things into perspective. Bar, De Raedt, and Koster are all stating this happens because of ruminating.
De Raedt and Koster make a case that we have studies on depression impacting your ability to control your attention. That being said studies on attention focusing in general when related to depression - not so much. Specifically what we see is a decreased ability to switch tasks or handle two tasks. To quote “This phenomenon is typically referred to as attentional bias, whereby depressed individuals, compared with nondepressed controls, show greater attention toward negative material than toward neutral material.”. Williams specifically argues that “depression
is not associated with mood-congruent attentional bias but is instead related to strategic elaboration of negative material, which causes improved explicit memory for this type of information”. Your brain is making you sad. To make it worse there’s research showing that this attention bias can also impact your rumination (fixating on the bad thing) and memory (not remembering the good). Both can impact inability (I should stop focusing on the bad thing or doing the things that hurt me) and working memory - which negatively impacts your ability to regulate your emotions.
De Raedt and Koster argue that there is a serious critical link between “cognitive and biological vulnerability is attentional control”. They state because it’s so hard to focus your attention and control what you focus on you won’t stop ruminating on the bad and focusing on how negative this will impact your life. Again because your amygdala gets scared, your DLPFC stops keeping it in check, your ACC stops mediation between the two and you all of a sudden don’t have the parts of your brain needed to stop focusing on how everything sucks and it’s terrible. What’s worse is that ‘what fires together wires together’, right? So the more this happens, the stronger this connection between mood and these negative thinking patterns gets!
What does this mean - well it helps make sense of why depression and anxiety are so commonly found together - since we know anxiety is a byproduct of the amygdala - more on that next month.
Essentially in anxiety amagdaly fires, you freak out and you stay freaked out. Depression is that Episode 4 of Season 1 or Episode 2-3 of Season 1 - you just start to give up. You are the yolked dog who just keeps taking the shock. And it starts to feel like you have no way to stop it and no way to get out of it, because you’ve stopped having any control over how to avoid the shock. You just ruminate on how much the shock sucks, because that’s the only tool your brain has left - just survive somehow. Until its too much and you can’t take shocks anymore and death starts to look like the only way you can make it stop.
We want to learn WHY we do what we do as humans, and we’ve looked to the brain for explanations…
**BREAK**
PART 4: TAKEAWAYS (10-15 minutes)
Takeaways - talking about suicide does not make someone more likely to commit it. Talking about it is super important.
De Raedt and Koster argue that actions to learn more about might be mindfulness-based cognitive therapy, due to its potential to control thoughts, have an impact on our DLPFC, and help to stop rumination. There is some research on repetitive transcranial magnetic stimulation. Not a surprise to anyone except insurance companies but there is an argument for both medication and therapy - largely due to reducing remission, but arguing that there needs to be more work on attention control.
Panksepp argues a lot for an increase in play, specifically in adults with depression because it utilizes a positive affect system in the brain. We, in our current culture, often don’t hold up that absolute power of ply and even in mental health it's not looked at past a certain point (play therapy is valued in children because it's their first language, and providing care without that language to someone so young is very hard) but Panksepp is arguing for the expansion of this work to help recontextualize these ‘scars’ from depression.
Bar argues to remember that likely what leads to depression is evolutionary based (remember brains want to you be safe, not happy) so this is part of learning how to do what I used to call getting you off autopilot. Bar is discussing this within changing your associations and is also arguing around noticing when you are ruminating and learning how to not ruminate. Sometimes just by distraction, but warns that we need to change the association or the distraction doesn’t work long term. Bar also hints at the trauma and depression potentially being linked
On a quick thought - studies are suggesting that honestly just reading very quickly. Doesn’t matter the content, the act can make you feel more positive “Reading causes the activation of concepts, and, presumably, faster reading activates more concepts” this could assist in broad association activation - hard to ruminate when there is so much in your head, and it’s mentally demanding meaning it makes for a good distraction.
Since I went after insurance, I’m also going to go after therapy. Bar cites that CBT has been noted for a long time as a treatment for depression. Specifically, the work is helping patients identify thoughts that are connected to negative feelings and learn how to distance those thoughts, and learn when their brain works against them. Bar argues although this has some success, more so when coupled with medication, it's important to remember the high level of functioning and ability to do introspection and whether this is going to work on a large number of patients.
