Bipolar Disorder: Where Does It 'Live' in the Brain?

Stephen M. Strakowski, MD


January 27, 2016

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Hello. I am Dr Stephen M. Strakowski. I am a professor at the University of Cincinnati in the departments of psychiatry, psychology, and biomedical engineering, where I also serve within the affiliated UC Health system as senior vice president and chief strategy officer.

Today I want to talk about the functional neuroanatomy of bipolar disorder—where in the brain bipolar disorder "lives." There have been a lot of advances, particularly through neuroimaging techniques, to better understand where bipolar disorder lives in the brain and what brain regions are involved. We will review those today and then think about where the field is going next.

Bipolar disorder is defined by the occurrence of mania, particularly type I bipolar disorder. Mania is a unique syndrome in that it is very heritable. It is also very predictive of a bipolar course of illness, perhaps the most predictive syndrome in all of psychiatry. Mania is characterized by a loss of emotional control and extreme mood states, from euphoria, to lability, to irritability. Some parts of mania even include depression. Mania also is characterized by loss of control of activation levels, behavior (particularly impulsivity), novelty seeking, and other really primitive behaviors that are not modulated during the manic syndrome. Taken together from what we know about brain function, these clinical presentations suggest that there has been a loss of prefrontal modulation of deeper brain structures. That seems to be a key part of thinking about mania.

Figure 1. Prefrontal cortex loops – nuancing behavior.

Figure 1 demonstrates the primary brain areas that we are going to talk about. In particular, on the left side of the brain is the orbitofrontal or ventral prefrontal cortex. This part of the brain is important in that it modulates deeper structures through iterative networks of loops, including the nucleus accumbens and striatum. These loop through the thalamus and globus pallidus and then are managed and innervated back and forth with the amygdala. The prefrontal cortex is a uniquely human structure that is underdeveloped in other animals. The ventral portion seems to be predominately involved in managing emotional behaviors. It is not a big stretch to imagine that mania involves abnormalities in these networks.

Figure 2. Emotional network abnormalities in bipolar disorder: summary.

Figure 2 is a schematic of those same networks. You can see two important loops or circuits within the emotional control of human beings. On the left-hand side is a circuit that begins in the ventrolateral prefrontal cortex. It's typical of prefrontal networks. It then goes through the striatum, pallidus, and thalamus, and back to form an iterative network that manages external emotional control and responds to external emotional cues. On the right-hand side of the diagram is a similar loop that initiates in the ventromedial prefrontal cortex and manages internal emotional cues, like how you are feeling, autonomic responses to environment, etc.

The amygdala is a central component to emotional control—particularly with threat response and assessment—and is associated with the emotions of fear and anxiety. These emotional systems provide feedback and input into other components of the network, including cognition and dorsal prefrontal cortex, which are cognitive brain responses. In fact, in human beings, often when the ventral or emotional brain is online, the cognitive brain is reciprocally decreased in activation. All of us know that when we are upset we don't pay attention and focus as well.

These two networks are where bipolar disorder appears to live, according to recent neuroimaging data. In Figure 2 you will see a number of codes that define what we know about abnormalities. Things in green boxes are areas where the functional response of these brain regions to different cognitive paradigms in bipolar patients is different versus in healthy persons. Throughout these prefrontal networks there are abnormal responses in persons with bipolar disorder. Similarly, connections to the amygdala and to other brain regions through the arrows vary across these structures. Dotted arrows are areas found to have some functional loss of conductivity in bipolar disorder. In particular, the prefrontal connection with the amygdala and some striatal regions seems to get lost during manic phases of the illness but then recovers during euthymia. It suggests that the actual physical connection is still in place but the functional relationship changes during the course of bipolar disorder.

Finally, you have the color in the boxes. Blue boxes are structural abnormalities that have been shown to occur maybe even prior to the onset of the illness. Abnormalities within these systems may predate the first manic episode. Rust-colored, or red-colored, boxes are areas that change over time. We have done studies that have shown that early in the course of bipolar disorder the trajectory of amygdala development—physical and structural development—is different in bipolar patients than in healthy subjects, teenagers with attention-deficit/hyperactivity disorder (ADHD), or people with other psychiatric conditions. Taken together, the goal of this image is to help us think about where bipolar disorder lives in the brain and to observe that it is not located in a single structure. Rather, it appears to be a failure of how these prefrontal networks are formed during development and how they interact with other parts of the brain—including the amygdala and other cognitive regions—ultimately to lead to the symptomatic expression of bipolar disorder. Again, changes in connectivity that occur across mood states suggest that even physically these connections may be in place. They don't function as they do in healthy people. That leads to these at-risk situations where people develop mood syndromes.

The next step is to understand how treatment impacts these networks. A number of groups, including ours, currently are examining what happens with successful treatment to restore or change these abnormal connections and abnormal functional responses in these brain areas. The second line of ongoing research is to understand how these abnormalities develop over time. As we begin to understand responses to treatment and development over time, we hope to better identify specific treatments that will affect this brain system and lead to better outcomes.

Given the work that has been done, the good news is that there is a steady consensus that these areas of the brain are where bipolar disorder primarily arises. The next step is to think about what has gone awry and how we can fix it more effectively than with our current medications and treatments. It's likely that interventions will include not only drugs, but also different cognitive and psychotherapy strategies to help us manage this plastic brain, particularly in adolescents during critical periods of development (which is also the period of time when bipolar disorder starts). You can help patients understand the brain basis of their disorder and explain that an increasingly sophisticated understanding of this disorder is developing. There is hope that as time passes, as science progresses, and as we understand the brain better, we will have better treatments for them.

I hope this is useful, and I thank you for your attention.


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