Say you are out on a camping trip with some friends. You're in the woods, the tents are up, the beer is out, the sun is down, the campfire is starting up. As you sit there, you hear the campfire crackling loudly. To most people, the crackling of the campfire is just that: a campfire. Nothing threatening at all. But for someone with a severe anxiety disorder such as post-traumatic stress disorder (PTSD), the crackling of the campfire may be associated with terrible memories, a huge conflagration during house to house fighting or a house fire that destroyed all they loved, causing them horrible distress and terrible anxiety. A campfire during a camping trip and the horrible things they endured are entirely dissimilar things, but in severe anxiety disorders, that makes no difference at all.

No, this post is not about whether or not anxiety disorders are being over diagnosed. Rather, it's about how over-generalization within the brain might influence the development of anxiety disorders. What is the difference between a house fire and a campfire? How does your brain know? It's the idea of pattern separation, an idea that the authors of this review believe could be incredibly important in treating some types of anxiety disorders.

Kheirbek et al. "Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders" Nature Neuroscience, 2012.

Pattern separation is one of the many actions of the hippocampus, the large, curved area in the interior of the brain which is thought to play a role in things like memory and in disorders such as anxiety and depression. Pattern separation was originally observed related to memory, but the authors of this review propose that it may also relate to things like anxiety.

Pattern separation is pretty simple. When you see a new situation, you compare it to others that you have previously seen. For example, this is a kitchen. In previous kitchens I've been in, there was a cookie jar from which I could get cookies. In this kitchen, however, there is no cookie jar. My brain can compare the two scenarios, see the differences, and determine how to act. In this case, it would appear I get no cookies, or perhaps I go hunting around the kitchen til I find them. :)

In some situations you can generalize: two situations are the same. There's a cookie jar in the kitchen, cookies for me! But in others you can discriminate, as in the example above. And discrimination is extremely important, and may be even more important when put into the context of anxiety disorders.

For example, see the figure above. Someone who as been in combat sees a campfire. They smell the smoke, say, and remember combat experience. In someone without PTSD, their brains can safely discriminate these two scenarios, pattern separation occurs, and they aren't worried. But for someone with PTSD, there is a failure of pattern separation. The smell of the campfire and the smell of the smoke in combat are similar, and no other differences between the two situations will make them different.

You might call something like this over-generalization. An over-generalization of fear responses to emotional situations. The cue of the campfire arouses the response, even though the context (the backyard) says that this should be a safe situation. This isn't just for PTSD, people with panic disorder may, say, have a panic attack in a tunnel, and then avoid all tunnels. People with social anxiety may suffer through a bad public speaking experience, and then avoid or severely fear them all. This isn't because they are cowards, but rather because their brains may be over-generalizing for them. They may have a deficit in pattern separation.

There is some clinical evidence for this. For example, there is a task which asks patients to discriminate specific patterns and designs. It requires pattern separation, and people with social anxiety and PTSD perform poorly on it. There is also the example below:

A test that can be performed in both humans and animals, this is a fear conditioning task that requires pattern separation. In the first context, the subject receives a mild shock. They will always receive a mild shock in that context. Then, the context is changed slightly (note the floor for the rodent and the stool for the human). No shock will be delivered. After a few trials, the healthy animal and human are able to tell when the coast is clear. But when re-exposed to the changed context, a rodent or human with anxiety will show a fearful reaction to the context, even though it's a context where they shouldn't get a shock. This is a failure of pattern separation.

But what is the possible mechanism behind the problems with pattern separation? The authors posit that it's an issue of hippicampal neurogenesis. Neurogenesis is the production of new neurons in your brain, something which we currently think only occurs in two places: the olfactory bulb and the hippocampus. In animal models, scientists have shown that reduced neurogenesis can result from things like stress and aging. In those cases, for example, in a state of generalized anxiety disorder, you might get something like this:

With reduced neurogenesis as seen above, there would be impaired pattern separation and impaired processing of ambiguous sensory input, leading to over-generalization and an anxiety response. But if, for example, you gave chronic antidepressants, which cause increased neurogenesis, you might get the following:

With improved synaptic plasticity and increased neurogenesis, you might get improved pattern separation, promoting discrimination and lower anxiety. Unfortunately, this still needs to be proved. But if it is, it's a very interesting idea for how anxiety disorders might form and how they might be treated, by targeting hippocampal neurogenesis specifically.

And the idea of dysregulated pattern separation, the idea that this is too similar to be different, makes me wonder if this could be applied to other disorders such as major depression. One of the hallmarks of major depressive disorder is repetitive thinking of negative thoughts, thoughts that keep coming back and that you cannot be distracted from. What if the triggering of negative thoughts was a failure of pattern separation? You are looking out the window, and something reminds you of the divorce, or the breakup. You check your email, and every time you see the same format in the window, you are reminded of horrible, harassing emails you have received before, and you suddenly feel worthless again. The resulting symptoms are different, but maybe pattern separation could play a role here, too, making the similar situations conflate, and bringing on the negative thought spirals that are so destructive.This is just speculation on my part, but it does make me wonder if more research is devoted to pattern separation, we might find more than memory and anxiety.

Kheirbek, M., Klemenhagen, K., Sahay, A., & Hen, R. (2012). Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders Nature Neuroscience, 15 (12), 1613-1620 DOI: 10.1038/nn.3262