Bipolar I disorder (BPI) affects at least 1% of the population, is associated with increased mortality, and is among the top 10 most disabling illnesses worldwide. The disorder also presents a significant societal cost, with poor clinical and functional outcome, and is associated with a significant suicidality increase [1
BPI is a disorder in which patients experience episodes of depression and clear manic episodes. When one takes into account those with bipolar II and subthreshold bipolar disorder capturing those with briefer or only treatment-emergent hypomania, lifetime prevalence rates approach 5% [2
One major issue in diagnosing and treating bipolar disorder is the high rate of misdiagnosis or late diagnosis. In one community sample of diagnosed bipolar disorder patients, approximately 70% had a missed diagnosis. A total of 60% of those were diagnosed with major depressive disorder, with one third going 10 years or more without a correct diagnosis. In addition, these patients had on average 3.5 other diagnoses and saw on average four physicians before receiving the correct diagnosis [3
Also, the depression associated with bipolar disorder frequently continues to be treated as unipolar depression (UPD). Bipolar depression has been shown to respond poorly to antidepressants [4
] and is associated with increased rates of switching to a manic state. As such, once bipolar disorder or UPD is correctly diagnosed, providing effective treatment is a primary concern.
Taken together, these findings highlight two major dilemmas for psychiatrists trying to provide effective treatment for depression: 1) correctly diagnosing depression as belonging to UPD or bipolar disorder and 2) initiating and individualizing treatment as early as possible.
The recently released research agenda for the DSMV
stresses an etiologic- and pathophysiologically based diagnostic system, as opposed to the symptomatologic and syndromic approach of the third and fourth editions. For each affected individual, these pathophysiologic processes involve dynamic interplay among genetic, epigenetic, and environmental factors interacting to create a cumulative liability to illness expressed as a phenotype. The greater the number of factors involved in generating an illness, the more complex the phenotype and the more complex any attempt at genetic analysis will be. An endophenotype is an objective marker—often used synonymously with “biomarker” or “vulnerability marker”—that is more closely related to the disorder's underlying pathophysiology than the condition's “fuzzy” symptomatology and therefore can be used to classify and diagnose complex psychiatric diseases. Endophenotypes should be consistently associated with the illness and represent persistent “trait” rather than episodic or “state” features. They also should be found in high-risk individuals such as nonaffected first-degree family members at a higher rate than in the population [5
Identifying endophenotypic markers for bipolar disorder at this time would seek to serve two main goals: 1) to clarify diagnosis and discriminate the depression in bipolar disorder from that of UPD to treat accordingly and 2) to identify at-risk individuals for early diagnosis with the goal of intervening before illness onset.
Neuroimaging techniques are now some of the most powerful tools we have for identifying endophenotypes. Brain imaging techniques such as MRI, positron emission tomography (PET), and diffusion tensor imaging (DTI) are being used increasingly to directly quantify neural system abnormalities associated with bipolar disorder and UPD. These neural system abnormalities are in turn providing direct evidence of disorder-specific abnormalities in neural systems. These neural systems are linked to core domains of pathology in bipolar disorder and UPD and, therefore, endophenotypes to target the previously described treatment goals.
In this critical review, we scrutinize recent findings from neuroimaging studies examining these core domains of pathology in bipolar disorder and UPD, as well as emerging studies seeking to define biomarkers differentiating the depression in bipolar disorder from that of UPD.
Core domains of pathology in bipolar disorder: impaired emotion processing and executive control
Bipolar disorder exists as a multisystem disorder involving disruptions across several symptom domains [6
]. One core domain of pathology is mood instability, which presents as variable states of depression and/or mania or hypomania, as well as other aspects of affective lability, including anxiety and irritability. A second core domain implicated in bipolar disorder is disrupted cognitive function, specifically impaired executive control. This refers to a broad collection of cognitive processes, including attention, working memory, and inhibitory control, that together allow the flexible organization of complex behavior [7
]. Executive function disruptions can result in altered concentration, decision making, and memory. These in turn likely will impact upon daily living activities, occupational productivity, and general social function. Executive deficits are likely to further impair the ability to regulate mood [8
]: individuals with bipolar disorder may be unable to use appropriate cognitive-control processes such as reappraisal, suppression, or inhibitory processes to regulate and maintain appropriate emotional states [9
Neural systems underlying emotion processing and executive control
Existing data in healthy individuals point toward distinguishable neural systems for emotion processing and executive control. Functional neuroanatomic investigations in healthy individuals to date implicate a network of subcortical anterior limbic structures for appropriate emotion processing. These include such regions as the amygdala, ventral striatum, subgenual (ventral) cingulate, ventromedial prefrontal cortex, anterior hippocampus, and anterior insula [10
However, neural systems responsible for coordinating appropriate executive function include lateral prefrontal cortical areas containing dorsolateral (DLPFC) and ventrolateral prefrontal cortex (VLPFC) [11
], which are closely interconnected with striatal regions involved in response selection and the hippocampus, a key node in memory encoding and retrieval [12
Abnormalities in neural systems underlying emotion processing and executive control in bipolar disorder
Relevant findings in bipolar disorder to date have centered around functional and structural neuroimaging studies. We first describe findings from functional neuroimaging studies that have helped to elucidate the nature of emotion processing and executive control neural system abnormalities in bipolar disorder. We then review the most pertinent structural neuroimaging findings in bipolar disorder studies. We end by reviewing the emerging trends and technologies that may increase understanding of neural system abnormalities in bipolar disorder.