Defining Brain Markers of Bipolar Disorder
Bipolar disorder is recognized as the sixth leading cause of disability worldwide and is characterized by recurrent episodes of depression, hypomania or mania, and mixed mood states. While these syndromes manifest differently in individuals and impact their lives to different degrees, the mood disorder affects roughly 3 percent of the global population. Unlike the more understood experience of unipolar depression, which is the most common mental disorder in the United States, bipolar disorder involves polar-opposite symptoms fluctuating between the extremes of depression and mania.
In the Diagnostic and Statistical Manual of Mental Disorders released by the APA, bipolar disorder is defined as two distinct types called bipolar 1 and 2. Individuals with bipolar 1 have at least one episode of mania in their lifetime while those with type 2 experience hypomania and more frequent episodes of depression. Mixed episodes involving both mania and depression are particularly difficult to navigate due to the development of anxiety symptoms and risk of suicide due to higher energy levels.
Over the last few decades neurologists have used a variety of methods to explore the unique brain characteristics of those with bipolar, including neuroimaging scans and genetic sequencing via saliva and blood samples. Their efforts have revealed functional differences in regions of the brain and genetic markers influencing who is at risk of developing the disorder. While new information is always coming to light, some of the more established markers are described here.
Differences in Brain Regions
Earlier this year a meta-analysis of 205 past studies involving 506 neuroimaging experiments with 5,745 participants was conducted in order to discern what brain differences were statistically significant. Five regions of the brain showed notable functional differences including areas of the posterior cingulate cortex, left amygdala, left and right parietal lobules, and orbitofrontal cortex.
More specifically during neuroimaging, the posterior cingulate cortex, which is involved in internally directed thought such as memory recollection, showed different activity. The left amygdala exhibited differences from those in control groups without bipolar during experiments where emotions were induced. This region is a structure of cells in the middle of the brain that support emotion regulation, meaning-making, and decision-making.
During experiments involving mental tasks, the parietal lobes and parts of the orbitofrontal cortex showed excessive activity. The parietal lobes are large regions near the back of the skull that process senses including touch, taste, and temperature. The orbitofrontal cortex regulates reward-related behavior and other cognitive processing, and research has discovered connections between injuries to the orbitofrontal cortex and emotional irregularities and impulsivity. These visible differences in brain activity were consistent across all the mood states of depression, mania, mixed mood, and euthymia.
Decreased Gray Matter
Bipolarity is also linked to decreased inhibitory nerve fibers forming the gray matter between parts of the prefrontal cortex and amygdala. The prefrontal cortex synthesizes sensory information and regulates activity in other brain regions. Mood regulation utilizes inhibitory connections to several subcortical limbic structures including the amygdala, striatum, and thalamus.
Regulation is important as these structures become overactive in response to external stimuli. Impairments in regulatory circuitry can cause issues including disrupted sleep and appetite, hormonal imbalance, sex drive fluctuations, and poor mental coping. Neuroimaging has also found that decreased gray matter and white matter occurs relatively early in bipolar onset.
Gene Mutations
Another brain marker involves the mutations of genes. While several common genetic variants have been known to influence bipolar risk in small ways, the first definitive risk gene was discovered in 2022. International researchers studied 13,933 individuals with bipolar and identified differences in their AKAP11 gene compared to the control group. A-kinase anchor proteins (AKAPs) are a diverse group of scaffold-like proteins which are meant to bind other proteins to certain cells.
Changes in the coding of the AKAP11 gene involve the truncating of these proteins, constraining their activity. Notably, AKAP11 was found to interact with the same protein coding gene (GSK3B) that is targeted by lithium, a traditional medication used for bipolar disorder. While the AKAP11 mutation does not provide a broad scientific understanding of bipolar, it does enhance our understanding of the biological mechanisms underlying this disorder.
There are also smaller chromosomal differences in the genes of those with bipolar disorder that can have a cumulative impact. Meta-analyses have discerned changes in 46 genes, including variability in proteins and enzymes governing serotonin, dopamine, brain-derived neurotrophic factor (BDNF), amino acids, and mitochondrial DNA.
Simply put, certain genes create proteins that in turn make neurotransmitters like serotonin and dopamine for regulating mood. BDNF is a protein that influences learning and memory, and decreased levels have been observed during both mania and depression. Taking amino acid supplements such as tyrosine, tryptophan, and taurine has been linked to potential reduction in symptoms. Finally, research has tied mitochondrial DNA dysfunction with bipolar syndromes.
Inflammation of The Brain and Body
Glial cells are the major moderators of inflammation within the central nervous system, and are key to promoting brain immunity. Studies have shown that chronic stress associated with bipolar disorder can lead to imbalance and inflammation in glial neuronal synaptic units and overproduction of glutamate, causing difficulties with decision-making and making behavioral choices in real time. These include decisions about communication, eating, working, and sleep. During manic episodes, shortened processing and overactivity among glial receptors in the hippocampus can cause rapid changes in behavior. During episodic depression, neuroinflammation occurs in the anterior cingulate cortex, prefrontal cortex, and insula, which are involved with executive function.
Studies have found that inflammation in the body also increases during depressive and manic episodes. Inflammatory agents in the blood caused by stress break down the barrier between the brain and body, resulting in neuro-inflammation. This can lead to decreased levels of dopamine, the neurotransmitter involved in reward and pleasure, generating depressive symptoms of anhedonia and slowing down of thoughts and movement. Because inflammation is known to decrease during euthymic episodes, use of stabilizing medications meant to decrease or reverse inflammation are important.
The Influence of Aging
Bipolar onset tends to occur in adolescence or young adulthood with the greatest percentage occurring between ages 15-25. This is primarily due to decreases in prefrontal cortex and amygdala size during this time period. Decreases in volume and thickness are normal in humans around this age due to gray matter changes and cortical thinning, as both are part of the synaptic pruning process resulting in denser gray matter. However, this occurrence is heightened for those with bipolar.
Normal aging can also worsen symptoms, as levels of inflammation naturally increase with age and impact memory, processing speed, and overall cognition. For those with bipolar, neuroinflammation can lead to neuro-progression, a progressive stage-related process of increased brain changes that can cause cognitive impairment. Soberingly, those at highest risk of suicide attempts are older adults with bipolar aged 40 years or older. For this reason neuroimaging studies are shifting focus from studying adolescents and young adults to looking more closely at older adult’s brains.
Future Treatments
There are numerous treatments being explored to address these neurobiological markers of bipolar. Multidisciplinary research groups are exploring interventions that would help support neural functioning and growth, and the prevention of cell death. These include new medications that show promise for reducing structural differences in specific brain regions.
Additionally, researchers at Yale University are developing a new psycho-behavioral treatment called Brain Emotion Circuitry-Targeted Self-Monitoring and Regulation Therapy (BE-SMART). This therapy targets neural circuitry by instilling healthy habits for regulating emotions. BE-SMART may augment the benefits of Interpersonal and Social Rhythm Therapy (IPSRT), an established approach that focuses on stabilizing sleep patterns and daily routines in order to promote stable mood.
A third progression in treatment is research on meditation. Studies have shown that mindfulness-based meditation practices strengthen areas of the brain including the prefrontal cortex and amygdala, and can contribute to neural integration. Further, changes in amygdala regulation have proven to hold steady even when subjects are not meditating, demonstrating a lasting boost to overall well-being. Research centers are currently studying the potential for meditation and mindfulness to grow brain regions impacted by bipolarity.
Finally, the study of psychedelic-assisted therapy continues to evolve. Experts caution the use of psilocybin or magic mushrooms for bipolar disorder because of the risk of increasing mania. However, some argue that the risks may be low relative to the serious treatment needs of this population. Another psychedelic drug undergoing careful exploration is ketamine, a dissociative anesthetic traditionally used by anesthesiologists. Based on results from studies with unipolar depression showing decreases in inflammation, positive effects on glutamate and BDNF levels, and increases in neuroplasticity, some researchers are advocating for further study on the benefits for bipolar disorder. All these potential resources can provide hope to those suffering from this illness and may lead to the development of new interventions.
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