Neurobiology of Bipolar Disorder: Genetic & Brain Imaging Links

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Bipolar disorder, formerly known as manic depression, is a chronic mental illness characterized by dramatic shifts in mood and energy levels.

It affects about 2-4% of the population worldwide.

While we still don’t fully understand what causes bipolar disorder, research over the past couple decades has uncovered important clues into the biological mechanisms behind this complex brain disorder.

Key Facts About the Neurobiology of Bipolar Disorder:

  • It is highly heritable, with genetics explaining about 70-80% of risk. While no genes have been identified as the main cause, variations in many different genes each make small contributions to increasing risk.
  • Disruptions in cellular signaling pathways related to calcium, energy metabolism, and inflammation appear to be involved.
  • Brain imaging reveals differences in structure and function compared to healthy brains, especially in regions linked to emotion regulation.
  • People with bipolar disorder show changes in neurochemicals like BDNF, cytokines, and cortisol.
  • There are abnormalities in circadian rhythms and sleep patterns.

Genetics of Bipolar Disorder

Family, twin, and adoption studies have firmly established that genetics plays a major role in bipolar disorder.

Compared to the general population, a person’s risk is increased 10-fold if they have a parent with bipolar disorder.

However, no single gene has been found to cause the majority of cases.

Rather, it is influenced by many common genetic variants, each contributing a small amount to overall susceptibility.

Through genome-wide association studies (GWAS), researchers have identified about 30 genomic regions harboring these common variants associated with increased bipolar risk.

The genes implicated are involved in pathways regulating neuronal excitability, signaling between brain cells, and the formation of synapses.

Examples include CACNA1C, ANK3, and ODZ4.

While important, altogether these known variants account for only about 30% of the heritability.

This missing heritability may be explained by rarer variants, gene-environment interactions, and epigenetic changes.

Disruptions in Cellular Signaling

At the molecular level, converging lines of evidence point to disruptions in cellular signaling pathways involved in critical nervous system functions as contributing to bipolar disorder.

Calcium signaling is one of the key pathways implicated, as calcium ions play an important role in neuron excitability, neurotransmitter release, and other cellular processes.

Genetic findings as well as studies on patient brain cells suggest that voltage-gated calcium channels may be overactive in bipolar disorder.

Lithium, one of the main medications used to treat bipolar, is thought to help regulate calcium signaling.

There are also indications that bipolar disorder involves problems with the way brain cells produce energy.

Imaging studies show differences in metabolism and studies on patient brain cells point to impaired mitochondria and oxidative stress.

In addition, elevated inflammation seems to be present, at least during mood episodes.

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Levels of inflammatory markers like cytokines and changes in kynurenine metabolism point to immune system activation.

This may relate to the mitochondrial and metabolic issues as inflammation can disrupt these cellular processes.

Psychological stress and the body’s stress response system via the HPA axis are also involved.

Many with bipolar disorder have elevated cortisol levels and reduced sensitivity to cortisol feedback, indicative of chronic HPA axis overactivity.

Bipolar Disorder & Brain Imaging Findings

Thanks to advances in neuroimaging techniques like MRI and fMRI, scientists can non-invasively study the structure and function of living brains.

A consistent finding is that people with bipolar disorder show thinning of the cortex (outer layer of the brain) in regions important for mood regulation, especially prefrontal and limbic areas involved in emotional processing and control.

Enlarged ventricles (fluid-filled cavities within the brain) are also commonly found.

Diffusion tensor imaging (DTI) shows reduced integrity of white matter tracts connecting cortical regions, including those linking emotional and cognitive control networks.

Disruptions in functional connectivity between areas like the amygdala, striatum, and prefrontal cortex also occur when viewing emotional stimuli or during cognitive tasks.

While imaging has not yielded definitive diagnostic biomarkers yet, it reveals how bipolar disorder impacts emotion/reward circuitry and networks underlying executive function.

Characteristic connectivity and signaling patterns are associated with manic, depressed, and euthymic states.

Neuroimaging also aids understanding of how lithium and other medications exert their mood-stabilizing effects through modulating activity and connectivity in mood-related regions.

Neurochemistry & Hormone Changes in Bipolar Disorder

Bipolar disorder also involves dysregulation of key signaling molecules in the brain.

Multiple studies show reduced levels of BDNF, a growth factor vital for neuron health and plasticity, in bipolar patients.

Disrupted BDNF signaling likely impairs the brain’s ability to adapt to stressors.

There are also abnormalities in hormones that regulate sleep, mood, and stress response.

Many people with bipolar disorder have altered circadian rhythms and melatonin secretion.

High cortisol levels and loss of sensitivity to cortisol feedback inhibition are commonly found, indicating overactivity of the HPA axis stress system.

By integrating these genetic, cellular, neurochemical, and neuroimaging findings, researchers are steadily piecing together the biological puzzle behind bipolar disorder.

While not yet translatable to the clinic, these insights provide leads to better understand this illness and develop more targeted, personalized therapies.

Continued interdisciplinary collaboration and emerging technologies will further unravel the neurobiology underlying bipolar disorder in coming years.

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