Bipolar disorder is characterized by periods of both depressive and manic states, and symptoms may range from euphoria and psychosis to anhedonia and suicidal tendencies. Research at the neurobiological level has helped to elucidate these clinical features, and several hypotheses have been postulated to account for the pathophysiology of bipolar disorder. Historically, monoaminergic systems have received much of the focus in accounting for the symptoms observed. Studies examining these neurotransmitters have had applications at the clinical level, such as the administration of monoamine-based antidepressants. However, a delayed therapeutic effect and propensity to induce mania in bipolar patients often occur upon antidepressant intake. This highlights both the importance of molecular processes predating monoamine effects, and the need to further understand the etiology of this disorder at the neuroanatomical and cellular levels.


Structural and Functional Abnormalities
Mitochondrial Dysfunction Hypothesis
Current Limitations and Future Directions

Structural and Functional Abnormalities

Regional abnormalities have been interpreted to account for the cognitive and affective disturbances in bipolar disorder. A recent meta-analysis reveals relatively consistent findings of volumetric reductions in the prefrontal cortex1. Volumetric abnormalities in the limbic regions were not as well replicated, with several reports of increased, decreased, and unchanged volumes in these areas1. Nevertheless, limbic regions remain an important area of study, and functional neuroimaging techniques have also implicated both prefrontal and limbic systems in the pathophysiology of this disorder2.

Prefrontal cortex
The prefrontal cortex has important functions in higher-order cognitive processes, social conduct, and personality3, highlighting its relevance to bipolar disorder. In particular, the orbitofrontal cortex (OFC) has been associated with response inhibition and the assessment of reward value in decision-making processes4. Grey matter reductions in the bilateral OFC have been observed in bipolar subjects relative to controls, which correspondingly accounts for symptoms such as risky decision-making5.
Figure 1. Fractional anisotropy (FA) in the orbitofrontal white matter. Bipolar patients with a history of suicide attempts exhibited lower FA in the left orbitofrontal white matter than patients without a prior suicide attempt.

In addition to between-group comparisons, differences in the OFC among bipolar individuals have also been found. Diffusion tensor imaging studies allow for the integrity of white matter fibre tracts to be measured in vivo6, and this technique has been employed to compare white matter abnormalities among bipolar individuals with and without a history of suicide attempts7. By using fractional anisotropy (FA) as a metric, deep white matter hyperintensities, demyelination, disruptions to microtubules, and overall declining white matter health are reflected by decreased FA6. A recent study reports lower FA among patients who have previously attempted suicide compared to both controls and patients without a history of suicide attempts7. Moreover, FA values within the OFC did not significantly differ between controls and bipolar patients without a prior suicide attempt. Since the OFC has extensive connections to limbic regions such as the amygdala, hippocampus, and cingulate cortex, damage to this region can impact emotional regulation and impulsivity8. Correspondingly, suicidal behaviour can partly be explained by white matter abnormalities in this area, and lower FA values have been found to negatively correlate with motor impulsivity7.

Extant data also show reductions in neuronal and glial density in the dorsolateral prefrontal cortex (DLPFC)9, which have important effects on executive functioning and working memory10. Its functional activity in regards to its connection with the medial prefrontal cortex (MPFC) has shown impairments11. The MPFC is involved in the default mode network and self-referential processes, and thus exhibit higher activity levels during a resting state12. Negative correlations between the DLPFC and MPFC have been demonstrated in healthy subjects, whereas no significant correlations were found in manic bipolar individuals11. Thus, cognitive deficits in executive tasks can be partly explained by an inability to effectively activate the DLPFC and suppress the MPFC during mania.

Further functional impairments in bipolar disorder are demonstrated by hypoactivity in the right DLPFC in a working memory task13. This was observed across depressed, manic, and euthymic bipolar subjects, suggesting that these functional abnormalities are enduring and not state-specific. Notably, heightened activity was also observed in temporal and limbic regions of bipolar subjects during the working memory task, implicating impairments in both cognitive and affective control. This emphasizes the need to examine both the relationships within the prefrontal cortex and its connections to limbic systems.

Limbic system
Figure 2. Ventral prefrontal cortex (VPFC)-amygdala functional coupling. a) Healthy controls exhibited an inverse relationship between VPFC and amygdala. b) This negative relationship is weakened in bipolar subjects.
The amygdala is crucial to emotional learning, such as fear conditioning, and emotional appraisal14,15. Functional MRI analyses reveal a negative correlation between the amygdala and VLPFC among healthy subjects, and this functional relationship is weakened in bipolar individuals16,17. In particular, manic patients have shown to exhibit marked impairments to this fronto-limbic network during an emotional-labeling task, and thus increased activity in the amygdala17. The emotional-labeling task requires subjects to assign labels to facial expressions, and this may require suppression of the amygdala depending on the level of difficulty. The functional abnormalities seen in fronto-limbic connections impact affective processing and integration, which correlate with the mood vulnerabilities observed in manic episodes. Similarly, in a continuous performance task that utilized emotional distracters, a negative functional coupling was observed between the right amygdala and left inferior frontal gyrus in controls, whereas a positive functional coupling was exhibited in manic patients18. In bipolar depressed groups, this relationship appears to revert to negative functional coupling, however a change to a positive correlation between the right amygdala and right insula is observed18. The insula has been implicated in disgust and social emotion such as empathy19,20, which may partly account for the heightened responses to negative stimuli observed during a depressive episode. Furthermore, a recent study reports normal activation of the amygdala during euthymia21. Taken together, these studies lend support to the hypothesis that state-independent abnormalities in the prefrontal regions provide a mechanism for state-dependent impairments in limbic structures, resulting in mood dysregulation11,21.

With the exception of the anterior cingulate cortex, where several studies have observed decreased volumes1,22, extant data at the structural level are notably rudimentary and inconsistent in regards to limbic regions. For instance, there are reports of increases, decreases, and no change in amygdalar and hippocampal volumes1,23,24,25,26. However, research initiatives that have attempted to examine detailed patient and illness characteristics have helped to elucidate the variable data. Treatment exposure to lithum has been correlated with increased volumes in cortical and subcortical areas26,27. A recent meta-analysis also suggests a relationship between lithium intake and volume increases, specifically in the amygdala25. Pediatric bipolar patients were observed to have significantly smaller amygdala volumes relative to controls, whereas the adult bipolar population did not significantly differ from controls due to inconsistent findings. Illness duration was additionally postulated to account for these results, and shorter illness durations and fewer numbers of episodes have also been associated with larger hippocampus volumes23.

Present studies suggest that structural deficits and functional impairments in prefrontal and limbic systems are common, although the literature remains equivocal. Efforts to account for these research findings must consider factors such as treatment exposure, episodic states, genetic variability, and illness duration and subtype. In recognizing the appreciable heterogeneity in the patient population and course of illness, an effective framework that guides the interpretation of these results can be established.

Mitochondrial Dysfunction Hypothesis

While research at the neuroanatomical level has made significant advancements in elucidating the symptoms of bipolar disorder, studies at the cellular and molecular level are important in accounting for these broader structural abnormalities. Examining the processes that predate the patterns of volumetric deficits are important to understanding the etiology of this disorder, and necessary to improving and developing effective treatments. The mitochondrial dysfunction hypothesis of bipolar disorder has been postulated to underlie these processes.

Altered energy metabolism
The predominant source of energy in the brain comes from ATP generated by the mitochondria via the ATP synthase28. Brain bioenergetics and functions are coupled to substantial energy demands. Despite only comprising a small amount of total body weight, the brain utilizes a fifth of total body oxygen and a quarter of total body glucose29. Thus, disruptions to the energy generating processes have important implications to neuronal health.

Mitochondria are dynamic organelles that continuously undergo fusion and fission30. Deviations to these processes are reflected in mitochondrial morphology, which have implications in mitochondrial function and cell death30. Smaller mitochondria in the prefrontal cortex of bipolar patients relative to controls have recently been found, and this did not appear to correlate with lithium treatment31. Increased fragmentation may possibly account for these observations, which is consistent with the hypothesis of altered energy metabolism31.

Figure 3. Altered mitochondrial morphology. Decreased mitochondrial area is observed in bipolar subjects relative to controls. The dotted line and dark circles represent the mitochondria population in bipolar disorder, and the light circles and dashed lines serve as the control. Fewer mitochondria in the neurons of bipolar subjects are found with increasing area size, whereas the opposite is true for controls.

Further support for this hypothesis comes from magnetic resonance spectroscopy research32. Studies utilizing this technique include findings of reduced levels of N-acety-aspartate (NAA) and phosphocreatine plus creatine (PCr + Cr), in addition to increased levels of lactate32,33. Consistent with research at the structural level, a recent study found decreased NAA in the MPFC and left DLPFC, and decreased PCr + Cr in the right MPFC and left DLPFC white matter of pediatric bipolar patients33. The precise function of NAA is currently unknown, however it has close associations with the energetics of mitochondria and neuronal loss34. PCr is synthesized from Cr and ATP, buffers cytosolic ATP in response to ATP consumption, and thus decreases in these levels indicate impaired energy metabolism35. In another study, levels of NAA were found unchanged in an unmedicated bipolar sample35. These conflicting results may suggest that some abnormalities may be present only in a subset of the bipolar population or reflect more severe cases of the illness35, thereby emphasizing the need to appreciate the heterogeneity within clinical populations in the interpretation of results.

Findings of increased lactate concentrations in the cerebrospinal fluid of bipolar patients have been used to suggest the presence of a glycolytic shift36. When ATP generation is impaired in the mitochondria, increased levels of anaerobic glycolysis are observed37. Pyruvate is converted into lactate, which accumulates when energy generation from the mitochondria becomes insufficient for meeting the energy demands of the cell38.

Altogether, research implicates altered energy metabolism in the pathophysiology of bipolar disorder. In addition to energy metabolism, mitochondria also play a role in the buffering of cytosolic calcium (Ca2+)39. Levels of ATP impact the storage of calcium, and excessive Ca2+ uptake may lead to the opening of a pore in the inner and outer mitochondrial membrane, named the mitochondrial permeability transition pore (MPTP)39,40. Consequently, cytochrome c from the electron transport chain (ECT) is released, enabling the actions of caspase-3 following the activation of caspase-939. These caspases lead to DNA cleavage, cytoskeleton damage and apoptosis39. Similarly, MPTP can also be opened by oxidative stress, which has also been implicated in the pathology of this disorder.

Oxidative stress
Following glycolysis and the Krebs cycle, NADH and FADH2 transfer high-energy electrons to the electron transport chain (ECT) along the inner mitochondrial membrane. The electrons flow down a protein complex, and the drop in energy is ultimately used to drive ATP synthesis through oxidative phosphorylation. While the processes outlined are crucial for meeting the high-energy demands in the central nervous system, the mitochondria are also a primary source of intracellular reactive oxygen species (ROS)40. During the transport of electrons, single electrons may escape and convert molecular oxygen into its reduced form, the superoxide anion (O2-)41, a precursor for the majority of ROS40. Oxidative stress occurs in the absence of sufficient antioxidant defenses, in which ROS can cause alterations and damage to the mitochondrion itself, DNA, proteins and lipids40. This compromises the integrity of the cell and may ultimately lead to cellular death29.

Most of the O2- produced is from complex I of the ECT40. In a recent study, impaired activity in complex I owing to decreased levels of the NDUFS7 subunit was found in bipolar patients, but not in patients with depression or schizophrenia42. O2- can be converted to peroxynitrite (ONOO-) following a reaction with nitric oxide (NO)42. 3-Nitrotyrosine is produced when ONOO- nitrates tyrosine residues in protein, thereby reflecting an aspect of oxidative damage42. ROS can also cause alterations to lipids, and 4-Hydroxynonenal (4-HNE) is an important product of lipid peroxidation43. Increased levels of 3-Nitrotyrosine in the prefrontal cortex42 and 4-HNE in the anterior cingulate cortex43 were found in bipolar individuals, thereby reflecting both oxidative stress and a convergence of data from the structural and molecular levels.

Low quantities of superoxide radicals are created during normal physiological respiration40. Thus, in addition to an abnormal excess of ROS levels, oxidative stress may also result from a lack of antioxidant defenses to normal physiological processes in the brain. Consistent with this idea, decreased levels of the major brain antioxidant, glutathione, was found in the prefrontal cortex of bipolar individuals44. Although this does not imply a direct role for ROS production in oxidative stress, the oxidative stress generated by deficient antioxidant systems may nonetheless result from, or induce, mitochondrial dysfunction. Thus, the mitochondrial dysfunction hypothesis provides a plausible mechanism that may underlie the widespread structural and functional abnormalities observed, and accordingly, the symptoms of bipolar disorder.

Current Limitations and Future Directions

Despite the advancements from studies on the pathophysiology of bipolar disorder, the field remains poorly understood. Studies examining the structural and functional abnormalities in the brains of bipolar patients are not conclusive, although extant research nonetheless indicates that impairments to the prefrontal and limbic regions are prevalent. However, the cross-sectional nature of several of these studies makes it difficult to establish whether these abnormalities precede or follow illness onset. A focus on longitudinal studies may be helpful in this regard, and efforts to account for the heterogeneity in the course of illness should be made to help explain for inconsistencies in data. Evidence in support of the mitochondrial dysfunction hypothesis is growing, however a long way remains before a complete picture is established. It is likely that several physiological processes are at play, which perhaps account for the diverse clinical manifestations within the bipolar population. Data from several lines of evidence is needed for a comprehensive understanding of this illness, and studies examining the symptoms, genetics, and treatment effects will all help to elucidate its pathophysiology. Furthermore, alternations between depressed and manic states are a hallmark of bipolar disorder, but despite this, there is a dearth of studies examining the endogenous correlates for this feature45. Future research into the neurobiological aspects of this process is encouraged. Fundamental to developing novel treatment that alleviates the illness burden is a comprehensive understanding of bipolar disorder at the endophenotypic level.

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