The Brain Circuit That Links Depression, OCD, ADHD, and PTSD

We're going to start off covering the fronto-striato-limbic circuit.

1. Key Areas of the Fronto-Striato-Limbic Circuit

2. The Importance of the Frontostriato-Limbic Circuit in Depression

And the reason why we're going to do this is because this is a crucial circuit that mediates a number of functions, which are disturbed in a range of psychiatric disorders, for example, anhedonia, cognitive disturbances. So when we look at this particular circuit, this is affected in depression, particularly the more severe forms of depression.

It's also affected in OCD, ADHD, bipolarity, post-traumatic stress disorder, etc.

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I'm Sanil Rege, consultant psychiatrist.

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So let's look at what this circuit looks like.

What we can see here is this is the amygdala. We know that the amygdala is the threat area of the brain, and it also encodes traumatic memories.

And the way it does that, of course, it's the trauma-related learning. This is through the connection with the hippocampus. We know that the hippocampus is a store of memory.

And the aim is to enhance fear extinction in the amygdala in certain disorders such as post-traumatic stress disorder or complex trauma disorder.

Then we have the striatum.

Now the striatum is a key element of the basal ganglia, including this, where it mediates movements. So you can imagine in depression, this part could mediate both agitation, but also psychomotor retardation.

Then we have another key area here, which is known as interchangeably the ventral striatum or nucleus accumbens.

Now the nucleus accumbens plays a key part in the mesolimbic pathway.

And we'll cover the mesolimbic pathway just in a bit when we think about the ventral tegmental area and the connections to this nucleus accumbens area.

You see, the nucleus accumbens area is the reward center of the brain in a way.

The nucleus accumbens mediates reward learning. It mediates the sensation of reward as well.

And of course, dopamine is a key neurotransmitter here.

Then we have the anterior cingulate cortex. Now the anterior cingulate cortex has connections both to the sort of primitive limbic system, but also to the prefrontal cortex and the areas.

The anterior cingulate cortex is best thought of as an emotional regulation area.

And it also puts value onto the emotional stimuli.

So it appraises the emotional situations as say positive, negative, fearful, etc.

So in disorders such as post-traumatic stress disorder or depression, when the anterior cingulate cortex is affected, one can appraise threat situations differently.

Similarly in depression, when the anterior cingulate cortex is affected, it's a key part of what we call the salience network.

So when we have internal and external stimuli, when the anterior cingulate cortex is affected, it can result in self-referential thinking, which is what we call ruminations.

And when these are, of course, negative and significant, that's when we have symptoms such as nihilistic ideation or overvalued obsessional guilt, etc.

Then we have key areas of the prefrontal cortex.

So this one around here is the orbitofrontal cortex. The orbitofrontal cortex has connections to kind of make this reward network.

It has connections to the nucleus accumbens and the thalamus. The thalamus, as we know, is a key sort of processing center.

Besides the orbitofrontal cortex, we also have what's called the ventromedial prefrontal cortex.

Now, the ventromedial prefrontal cortex, along with this orbitofrontal cortex, sometimes is called the medial prefrontal cortex.

Now this particular part of the brain, the ventromedial prefrontal cortex, is sort of the mood area.

And it has connections to the anterior cingulate cortex and nucleus accumbens to form a sort of a further mood-mediating network.

And then we have the dorsolateral prefrontal cortex. This is the seat of executive function.

This is the part that helps us make decisions, evaluate risks and benefits, the planning, sequencing, detecting errors, for example, initiation of tasks and completion of tasks.

And the dorsolateral prefrontal cortex has connections to the striatum because the decision-making occurs in the dorsolateral prefrontal cortex, which will then send messages to the striatum to implement those actions, which, of course, require movements.

So now when we take a step back and think about depression or major depressive disorder, it is basically a disturbance of three key functions.

We've got activity, cognition, and emotion.

Now, I often tend to think about emotion along with reward.

So, now let's look at where these symptoms are mediated from when we connect this, localize this, to these particular areas.

So, when activity is affected, we know that we're looking at the striatal involvement.

When cognition is affected, we start looking at the dorsolateral prefrontal cortex involvement.

And when we think about emotion, we've got a number of circuits here because we know that the anterior cingulate cortex is the appraisal area.

We've also got the reward system, which is the ventral striatum or the nucleus accumbens.

But we've also got to think about the other emotions that occur as a result of the amygdala when it experiences threat.

Therefore, when we think about depression, what we have is activity changes. We can have psychomotor agitation or psychomotor retardation.

Then we have cognitive changes and emotional changes.

But these emotional changes could also mean low mood, sadness, and then moving into the thought patterns of guilt, hopelessness, and worthlessness.

Now, when we think about treatment and antidepressants, we know that antidepressants work through certain mechanisms that involve neurotransmitters.

So let's look at the key neurotransmitters involved. There are, of course, a number of newer hypotheses.

But let's look at the key neurotransmitters so that we can apply this to antidepressant mechanisms of action.

So the first neurotransmitter, dopamine.

We know that dopamine neurons are situated in two key areas. We have the ventral tegmental area and we have the substantia nigra.

The substantia nigra, we know, is affected in Parkinson's disease.

The ventral tegmental area has connections to the ventral striatum.

And we know that this mediates the mesolimbic system activity.

So this is the reward pathway. We also know that this pathway in schizophrenia is affected.

Furthermore, we have connections from the ventral tegmental area all throughout the prefrontal cortex, the frontal lobe.

And this mediates cognition, emotion as well, and the connection from the reward pathway to the nucleus or the reward center from nucleus accumbens to the orbitofrontal cortex.

So dopamine is a key neurotransmitter that mediates a number of the prefrontal cortex functions.

Then we have the connections from the substantia nigra to the movement areas.

And this is responsible for activity. So if there is decreased dopamine in these areas, it will result in significant slowing, for example, or psychomotor retardation.

Then we have in the locus coeruleus, in the midbrain, we have the noradrenergic neurons.

The noradrenergic neurons go through very, very similar pathways in the frontal lobe.

So there are overlapping functions of both dopamine and noradrenaline.

So dopamine and noradrenaline mediate functions such as cognition. And we know that this is relevant in both depression but also ADHD.

They're important in memory consolidation. The difference between the two is that dopamine is responsible for reward-based learning.

Whilst noradrenaline is responsible for novelty-based learning. It also involves the stress-based learning or aversive stimuli-based learning.

Now one of the important things that we've got to recognize is noradrenaline has pretty strong connections to the amygdala.

We know that the noradrenergic neurons that significantly innervate this particular part of the brain, the amygdala, are involved in the agitation states.

But are also involved significantly in post-traumatic stress disorder.

And then finally, we have in the dorsal raphe nucleus, serotonin.

Now 90% of the serotonin actually comes from the gut. We've got some serotonin being produced in the brain.

And this mediates a number of functions, but serotonin has cross-talk connections with other neurotransmitters.

So modulating certain serotonin receptors through agonistic activity or antagonistic activity can affect other neurotransmitters.

And finally, serotonin also has a close relationship with dopamine.

The final point is that when we think about dopamine, we've got a range of receptors there as well.

In the front part of the brain, the D1 receptors predominate.

And from a noradrenergic point of view, we have the alpha-2A receptors that we're really trying to stimulate for cognition in the front part of the brain.

So this is the fronto-striato-limbic circuit that is involved in a number of psychiatric disorders.

And understanding of these functions allows us to target psychopharmacology appropriately.