Introduction
Bipolar disorder (BD) manifests as cycling between the acute emotional elevations of manic episodes and the acute dysphoria of depressive episodes. The sustained affective states of these episodes are accompanied by disruptions in a broad range of associated behaviours. These include disturbances in neurovegetative functions such as sleep, appetite and sexual drives, excesses or constriction in motivated behaviour, thought abnormalities that are often coloured by the affective state and can reach the level of psychosis, and disruptions in cognitive functions. A brain model for BD would ideally account for these characteristic emotional, neurovegetative, behavioural and cognitive abnormalities in the disorder, as well as its cyclic nature. Additionally, such a model would also account for abnormalities observed during periods between episodes. Although BD has long been thought of as an illness with return to excellent premorbid level of functioning between episodes, it is evident that many individuals with BD do not follow such a course and may experience protracted symptoms and disability even during euthymic periods (Reference Judd, Akiskal and Schettler1–Reference Sajatovic5).
Over the past decade, substantial effort has been put forth in neuroimaging research to understand the neural system abnormalities underlying BD. Significant progress has been made in identifying regional brain differences that likely contribute to the symptoms of acute episodes of BD. In the following text, evidence will be presented to support prominent abnormalities in a ventral prefrontal cortex (VPFC)-amygdala neural system thought to play a key role in the emotional dysregulation of BD and that through its connections with structures such as the ventral striatum, hippocampus, cerebellum and hypothalamus could also contribute to the range of associated symptoms. Moreover, in recent years, subtle differences in this neural system, especially in the VPFC, have been identified during euthymic periods. This suggests trait disturbances that may confer susceptibility to features such as cycling that if characterized, could be targeted in preventive treatment efforts designed to bolster the resiliency of this neural system.
Leads from behavioural neurology
Behavioural neurology provided an initial guide to localise key brain regions involved in BD. Since at least the 1800s, affective and behavioural changes similar to those observed in BD have been reported in individuals with lesions in the VPFC (Reference Bechara, Damasio, Damasio and Lee6–Reference Rolls, Hornak, Wade and Mcgrath11). [Please note that in this article the VPFC will be defined broadly to include orbitofrontal cortex (OFC), inferior and rostral frontal cortices, and the ventral and pregenual components of the anterior cingulate cortex (ACC).] In particular, these changes consist of difficulties in adaptively regulating motivational drives for engaging in pleasurable and risky behaviours despite awareness of the associated negative consequences, as can occur during manic episodes of BD (Reference Bechara, Damasio, Damasio and Lee6,Reference Damasio, Grabowski, Frank, Galaburda and Damasio8,Reference Rolls, Hornak, Wade and Mcgrath11). Furthermore, lesion studies have suggested that the valence of the mood symptomatology depends on the hemispheric lateralisation of the lesion. Individuals with left hemisphere frontal lesions appear more likely to become depressed whereas those with right hemisphere lesions more often experience mania (Reference Sackeim, Greenberg, Weiman, Gur, Hungerbuhler and Geschwind12–Reference Wexler14).
Studies of behaviours associated with seizures have also implicated brain regions involved in BD, particularly regions that probably exhibit excessive activity in the disorder. Flor Henry described BD-type symptoms in patients who had complex partial seizures with mesial temporal seizure foci encompassing the amygdala Reference Flor-Henry(15). Bear and Fedio also observed BD-type symptoms associated with complex partial seizures of temporal lobe origin and additionally, they noted hemispheric lateralisation with respect to the emotional valence of behavioural changes Reference Bear and Fedio(16). Paranoia and diminished humour, characteristic of depressive episodes, were associated with left-sided foci whereas elation, emotionality and hypersexuality, characteristic of manic episodes, were associated with right-sided foci.
Behavioural neurology highlighted the VPFC and amygdala as two key components in affect regulation as well as underscored the importance of hemispheric lateralisation in the valence of emotional behaviour. It suggested a model in which deficits in VPFC functioning and excesses in amygdala activity could produce BD-type symptoms. Given the significant reciprocal inhibitory connections between the VPFC and amygdala and the important role of the top-down VPFC regulation of amygdala responses in emotional behaviour through these connections Reference Rolls(17), it suggested that disruptions in VPFC top-down regulation of the system could lead to the loss of affective homeostasis in BD. However, excesses in amygdala activity themselves could also contribute to the extremes in emotional behaviours seen in BD.
Literature from behavioural neurology has also suggested that disruptions in the white matter connections within this VPFC-amygdala neural system could contribute to the BD phenotype as well. Altered emotional and motivational states associated with lesions involving both intra-hemispheric fronto-subcortical connections and inter-hemispheric connections through the corpus callosum (CC) have been observed as early as the beginning of the 20th century by Starr Reference Starr(18). In support of these reports, genetic and postmortem studies have found glial cell, specifically oligodendrocyte, and myelination abnormalities in BD (Reference Bowley, Drevets, Ongur and Price19–Reference Vostrikov, Uranova and Orlovskaya26), leading to a recent surge in studies of white matter integrity and functional connectivity in BD.
In light of a postulated VPFC-amygdala neural system in BD, connections of the VPFC and amygdala point to other brain regions that may sub-serve additional functions disrupted in BD. These regions include the mesial temporal hippocampus, subcortical structures such as the ventral striatum and thalamus, the cerebellum and the hypothalamus (Reference Amaral and Price27–Reference Snider and Maiti33). Associated disruptions in the functioning of these structures could account for the range of symptoms observed in BD. For example, the hippocampus plays an important role in memory and therefore is implicated in the cognitive deficits observed in individuals with BD (Reference Cavanagh, Van Beck, Muir and Blackwood34–Reference Wolfe, Granholm, Butters, Saunders and Janowsky38). Given the role of the ventral striatum in motivation and reward behaviours, ventral striatal abnormalities could contribute to the hedonic excesses of mania and anhedonia of depression Reference Robbins and Everitt(39). The cerebellum plays key roles in motor function and may influence the psychomotor disturbances of depression and mania. Additionally its known involvement in behavioural timing suggests that the cerebellum may influence emotional rhythmicity and timing and potentially mood cycling (Reference Benedetti, Serretti, Colombo, Barbini, Lorenzi, Campori and Smeraldi40–Reference Steeves, King and Zhao42). The hypothalamus is important in the regulation of circadian rhythms including sleep, as well as appetite and sexual behaviours, implicating its influence in the neurovegetative symptoms of BD. Evidence of the involvement of these regions in BD from neuroimaging research are emerging as will be reviewed. Unfortunately, study of the hypothalamus in BD has been limited by the constraints of current imaging methods.
Behavioural neurology has provided important leads in the efforts to understand the neural system contributing to BD. Over the past decade, neuroimaging research has expanded upon these leads. It has identified the VPFC and amygdala as central components in the neural system underlying BD and the other connected brain regions as important contributors to the disruptions of this system. This article will review the findings from structural and functional imaging to support this neural system model of BD. First, the presence of abnormalities within the neural components involved in BD will be discussed, particularly in the VPFC and amygdala, as well as in the hippocampus, striatum, thalamus and cerebellum. Then, diffusion tensor imaging (DTI) findings of abnormalities in the connections between the neural system components in BD will be reviewed. Finally, implications for future studies and for early identification and treatment of BD will be discussed.
Structural neuroimaging studies of BD
VPFC
In 1997, Drevets et al. provided a seminal report showing reduced grey matter volume in left subgenual prefrontal cortex in adults with BD Reference Drevets, Price and Simpson(43). Since that time, numerous groups have reported decreased volumes of frontal sub-regions in adults with BD (Reference Blumberg, Krystal and Bansal44–Reference Nugent, Milham and Bain50). This has been striking as different research groups have utilised various methods for analysing neuroimaging data (Reference Drevets, Price and Simpson43–Reference Wilke, Kowatch, Delbello, Mills and Holland56). This view is supported by consistent findings in postmortem studies of decreased cellular density in the VPFC in BD Reference Ongur, Drevets and Price(21,Reference Rajkowska22). A potential role for the VPFC in vulnerability to mood cycling is suggested by a reported association between greater magnitude of VPFC volume decreases in BD and rapid cycling Reference Blumberg, Krystal and Bansal(44). However, it is also possible that VPFC volume decreases are a result of recurrent affective episodes. Further studies that clarify the role of specific sub-regions within the VPFC in BD, and their associations to cycling, will be important for understanding the role of the VPFC in the disorder. Additionally, future studies in the VPFC will also need to consider individual differences in its anatomy. For example, Fornito et al. point out that anatomy can vary across individuals, such as in the appearance of specific sulcal and gyral morphological patterns, which often has not been accounted for in morphological studies Reference Fornito, Malhi and Lagopoulos(46).
Among studies of the VPFC in adolescents with BD, there are some disparate findings, including reports of no differences in the VPFC (Reference Frazier, Breeze and Makris52–Reference Sanches, Sassi and Axelson58). The variability in findings could be related to developmental influences on the VPFC. In both an earlier cross-sectional study and a more recent longitudinal within-subject study, Blumberg et al. and Kalmar et al. have noted age-related decline in VPFC volumes that appear accelerated in adolescents and young adults with BD, implicating differences in VPFC neurodevelopment in BD (Reference Blumberg, Krystal and Bansal44,Reference Kalmar, Wang and Spencer53,Reference Blumberg, Kaufman, Martin, Charney, Krystal and Peterson59). This suggests an interaction between the maturation of the VPFC during adolescence and the disorder, and possible abnormalities in the mechanisms that underlie structural maturation of the VPFC during this epoch in BD Reference Blumberg, Kaufman, Martin, Charney, Krystal and Peterson(59). The potential progression of the VPFC differences over adolescence could affect the detection of VPFC differences in BD samples depending on the maturational stage of the study participants Reference Wilke, Kowatch, Delbello, Mills and Holland(56).
Effects of medication on VPFC volumes have been reported as well. Pre-clinical studies provide compelling evidence for neurotrophic and neuroprotective effects of mood-stabilising medications that are used to treat BD, including lithium and valproate, on cortico-limbic structures Reference Manji, Moore and Chen(60). In 2000, Moore et al. reported cortical grey matter increases in individuals with BD following 4 weeks of lithium treatment Reference Moore, Bebchuk, Wilds, Chen and Manji(61). Since that report, several cross-sectional studies found larger frontal volumes in individuals with BD treated with mood-stabilising medications as compared with individuals with the disorder who were unmedicated at the time of study (Reference Blumberg, Krystal and Bansal44,Reference Drevets62,Reference Sassi, Nicoletti and Brambilla63). A recent longitudinal within-subject study of healthy individuals found increases in prefrontal volume after 4 weeks of lithium treatment Reference Monkul, Matsuo and Nicoletti(64). In addition, increases in cortical grey matter have been reported in BD individuals treated with lithium Reference Bearden, Thompson and Dalwani(65).
Amygdala
While some studies have reported amygdala volume decreases in adults with BD, others have reported increases or no differences in volume among BD adults (Reference Altshuler, Bartzokis, Grieder, Curran and Mintz66–Reference Strakowski, Delbello, Sax, Zimmerman, Shear, Hawkins and Larson69). The discrepant findings could relate to salient differences between clinical subtypes within BD, such as early-onset BD and BD with psychotic features, as well as differences in demographic characteristics, such as age and sex, developmental factors, duration of illness and medication exposure Reference Blumberg, Kaufman and Martin(67). Evidence also indicates potential effects of genetic polymorphisms on amygdala volume, such as the 5-hydroxytryptamine transporter-linked polymorphic region (5-HTTLPR) genotype Reference Scherk, Gruber and Menzel(70).
In contrast to the studies of BD adults, studies of BD adolescents have reported highly consistent findings of amygdala volume decreases (Reference Dickstein, Milham, Nugent, Drevets, Charney, Pine and Leibenluft57,Reference Blumberg, Kaufman and Martin67,Reference Chang, Karchemskiy, Barnea-Goraly, Garrett, Simeonova and Reiss71–Reference Delbello, Zimmerman, Mills, Getz and Strakowski73). The differences in findings between adults and adolescents with BD may relate to fewer recurrences of affective episodes or shorter duration of illness in adolescents than in adults. They may also reflect less exposure to medications in adolescents compared with adults. Amygdala volumes have been reported to be larger in both adolescents and adults who were taking mood-stabilising medication at the time of study as compared with those who were not, suggesting possible neurotrophic effects of these medications in the amygdala Reference Chang, Karchemskiy, Barnea-Goraly, Garrett, Simeonova and Reiss(71,Reference Foland, Altshuler and Sugar74). Alternatively, the differences may also indicate that early-onset BD represents a separable phenotype within BDs.
Associated structures
The hippocampus has had variable findings of volume abnormalities with reports of significant or trend-level decreases or no differences in BD adolescents (Reference Blumberg, Kaufman and Martin67,Reference Chang, Karchemskiy, Barnea-Goraly, Garrett, Simeonova and Reiss71,Reference Bearden, Soares and Klunder75,Reference Frazier, Chiu and Breeze76) and adults (Reference Altshuler, Bartzokis, Grieder, Curran and Mintz66–Reference Strakowski, Delbello, Sax, Zimmerman, Shear, Hawkins and Larson69,Reference Altshuler, Bartzokis and Grieder77–Reference Velakoulis, Pantelis and Mcgorry82). Multiple factors could contribute to the variable findings including differences related to sex Reference Frazier, Chiu and Breeze(76) and increases in volume in association with mood stabilisers Reference Bearden, Soares and Klunder(75) as well as contribution from genetic variation Reference Chepenik, Fredericks and Papademetris(83,Reference Mcintosh, Moorhead and Mckirdy84). The hippocampus is one of the first structures in which volume differences were associated with a specific genetic variation in BD. Chepenik et al. reported smaller hippocampus volumes with decreases most prominent in the left hippocampus in BD individuals carrying the brain-derived neurotrophic growth factor (BDNF) Val66Met allele, compared with healthy individuals and BD individuals not carrying the met allele Reference Chepenik, Fredericks and Papademetris(83). A longitudinal study of adults with BD also showed an association between the BDNF Val66Met polymorphism and temporal grey matter loss that included the left hippocampus Reference Mcintosh, Moorhead and Mckirdy(84). These findings suggest genetic subtypes within BD that have particular vulnerability for volume deficits in the hippocampus.
Alterations in the other previously discussed brain regions implicated in BD have also been observed. Decreases in volume localised to the nucleus accumbens have been found Reference Dickstein, Milham, Nugent, Drevets, Charney, Pine and Leibenluft(57). Studies have reported differences in basal ganglia volume or shape especially in individuals with BD who were unmedicated (Reference Delbello, Zimmerman, Mills, Getz and Strakowski73,Reference Hwang, Lyoo and Dager85,Reference Strakowski, Adler and Delbello86). Abnormalities in the cerebellar vermis associated with the number of prior affective episodes (Reference Delbello, Strakowski, Zimmerman, Hawkins and Sax87–Reference Monkul, Hatch and Sassi89) and family history of BD Reference Brambilla, Harenski and Nicoletti(90) have been reported as well.
Functional neuroimaging studies of BD
VPFC
As functional neuroimaging studies capture regional brain activity that reflects the mental state at the time of scanning, such studies that have been performed during manic, depressed and euthymic states of BD have revealed both mood state- and trait-dependent features of the disorder. As predicted by the lesion studies described previously, mania has primarily been associated with deficits in VPFC activation that tends to be more lateralised to the right hemisphere across a variety of emotion and cognitive processing tasks (Reference Altshuler, Bookheimer and Townsend91–Reference Rubinsztein, Fletcher and Rogers95). Depressive states in BD have been more associated with relative increases in VPFC activation that tends to be left-lateralized (Reference Blumberg, Leung and Skudlarski92,Reference Chen, Lennox and Jacob96,Reference Lawrence, Williams and Surguladze97). Increasingly studies across mood states in BD, and specifically of euthymic individuals, show VPFC abnormalities that suggest differences in VPFC functioning may be associated with the BD trait in adults (Reference Blumberg, Leung and Skudlarski92,Reference Blumberg, Donegan and Sanislow98–Reference Malhi, Lagopoulos, Sachdev, Ivanovski and Shnier102).
As noted with VPFC structural abnormalities, VPFC functional abnormalities may also progress over adolescence and young adulthood. In a preliminary cross-sectional study, Blumberg et al. noted that VPFC activation increased with age in healthy adolescents who were performing a colour-naming Stroop task, consistent with the view that the VPFC increasingly comes online with age in the service of providing adaptive inhibition of prepotent response tendencies Reference Blumberg, Martin and Kaufman(103). This age-related pattern was not seen in adolescents with BD suggesting an alteration in this functional maturation of the VPFC in BD. In other studies of adolescents, VPFC deficits have been noted during commission errors on a stop-signal task Reference Leibenluft, Rich and Vinton(104) as well as both increases and decreases in VPFC activation relative to controls during the performance of emotional processing tasks Reference Pavuluri, O’connor, Harral and Sweeney(105,Reference Rich, Vinton and Roberson-Nay106). These studies suggest that some aspects of BD-related VPFC functional abnormalities may emerge during adolescence and may progress during this epoch in BD.
Mood-stabilizing pharmacotherapy has been associated with reduction of differences in VPFC activation. Deficits in activation were diminished in individuals taking mood-stabilizing medications as compared with those who were not taking medication at the time of scanning Reference Blumberg, Donegan and Sanislow(98,Reference Jogia, Haldane, Cobb, Kumari and Frangou107). The mechanisms underlying the reversal of functional deficits are not known; their elucidation could prove important for developing new treatment strategies for BD. One possibility is raised by a recent study of the 5-HTTLPR polymorphism in BD showing effects on regional brain function in the disorder that were most prominent in the ventral ACC, which has a high concentration of serotonin receptors Reference Shah, Wang and Kalmar(108). This suggests that mechanisms related to serotonergic transmission may have influences especially in the ventral ACC region in BD and individuals may respond to serotonergic interventions differently depending on their genetic composition.
Amygdala
Functional neuroimaging studies of individuals with BD at rest or performing emotional processing tasks during scanning have been relatively consistent in observing abnormal elevations in amygdala activation (Reference Lawrence, Williams and Surguladze97,Reference Blumberg, Donegan and Sanislow98,Reference Pavuluri, O’connor, Harral and Sweeney105–Reference Jogia, Haldane, Cobb, Kumari and Frangou107,Reference Altshuler, Bookheimer and Proenza109–Reference Yurgelun-Todd, Gruber, Kanayama, Killgore, Baird and Young115). These findings have been reported in both adolescents and adults with BD, irrespective of mood state. This suggests that dysregulated amygdala activity may be an early trait feature of BD.
As observed in the VPFC, mood-stabilizing pharmacotherapy has also been associated with reduction of differences in activation in the amygdala. Excess activation in the amygdala appears to be blunted by mood-stabilizing medication (Reference Blumberg, Donegan and Sanislow98,Reference Jogia, Haldane, Cobb, Kumari and Frangou107,Reference Drevets, Price, Bardgett, Reich, Todd and Raichle111). As in the VPFC, the mechanisms contributing to the reversal of functional differences in the amygdala are unclear. The reversal may reflect theorised mood-stabilising effects achieved through restoration of homeostatic balance of excitatory glutamate as compared to inhibitory gamma amino butyric acid (GABA) activity Reference Krystal, Sanacora and Blumberg(116). This potential mechanism is supported by studies of anti-convulsant effects on synaptic neurotransmission in the amygdala. For example, lamotrigine has shown effects on GABA transmission in the amygdala Reference Braga, Aroniadou-Anderjaska, Post and Li(117), and valproic acid has been suggested to influence excitatory synaptic responses mediated by NMDA receptors in the amygdala Reference Tian and Alkadhi(118).
Associated structures
Activation differences in other subcortical structures have also been reported in BD. The thalamus and striatum have shown functional abnormalities during both acute episodes and euthymic periods in BD adolescents Reference Blumberg, Martin and Kaufman(103,Reference Chang, Wagner, Garrett, Howe and Reiss110) and adults (Reference Lawrence, Williams and Surguladze97,Reference Ketter, Kimbrell and George112,Reference Blumberg, Stern and Martinez119–Reference Malhi, Lagopoulos, Sachdev, Mitchell, Ivanovski and Parker121). These abnormalities may also be reversed by medication Reference Caligiuri, Brown and Meloy(120,Reference Goodwin, Cavanagh, Glabus, Kehoe, O'carroll and Ebmeier122).
Functional neuroimaging studies have also noted abnormalities in the cerebellum among euthymic adults with BD (Reference Ketter, Kimbrell and George112,Reference Malhi, Lagopoulos, Owen, Ivanovski, Shnier and Sachdev123,Reference Strakowski, Adler, Holland, Mills, Delbello and Eliassen124). Decreased activation in the cerebellum has been observed in response to positive affect induction and during a counting Stroop interference task Reference Malhi, Lagopoulos, Owen, Ivanovski, Shnier and Sachdev(123,Reference Strakowski, Adler, Holland, Mills, Delbello and Eliassen124). Additionally, abnormalities in cerebellar blood flow in BD have also been shown Reference Ketter, Kimbrell and George(112). These abnormalities may be influenced by antipsychotic treatment Reference Loeber, Gruber, Cohen, Renshaw, Sherwood and Yurgelun-Todd(125).
White matter integrity and connectivity
Decreases in glial cells, particularly oligodendrocytes, in both frontal regions and the amygdala, as well as down-regulation of oligodendrocyte- and myelin-related genes in frontal regions in BD, suggest the presence of white matter abnormalities in the disorder (Reference Bowley, Drevets, Ongur and Price19–Reference Uranova, Vostrikov, Orlovskaya and Rachmanova25). Moreover, findings of alteration in grey matter brain regions that are highly interconnected further support the presence of abnormalities within the white matter that connect these structures. Structural magnetic resonance imaging (MRI) studies have shown decreases in frontal white matter volume in adults with BD (Reference Blumberg, Krystal and Bansal44,Reference Nugent, Milham and Bain50,Reference Atmaca, Ozdemir and Yildirim126–Reference Haznedar, Roversi and Pallanti128). In addition, abnormalities within the CC such as decreased mid-sagittal CC areas have been reported in adults with BD (Reference Atmaca, Ozdemir and Yildirim126,Reference Coffman, Bornstein, Olson, Schwarzkopf and Nasrallah127,Reference Brambilla, Nicoletti and Sassi129–Reference Caetano, Silveira and Kaur131). This is of particular interest as the anterior component of the CC provides inter-hemispheric connections between the left and right prefrontal cortices thought to integrate hemispheric functioning and to play a key role in the integration of emotional and cognitive information Reference Schmahmann and Pandya(132).
To further characterise the findings of white matter abnormalities observed by structural imaging, DTI methods have recently been implemented in the study of BD. These methods may be more sensitive to detecting microstructural differences within white matter connections of regions involved in BD than structural MRI morphometry methods. Fractional anisotropy (FA) is one of the principal DTI measures that has been utilised and that provides an index of the coordinated directionality of fibres within white matter fibre bundles Reference Beaulieu(133). DTI studies of BD have shown differences in FA primarily in ventral frontal regions, in regions carrying fibers between the VPFC and the amygdala, hippocampus, striatum and thalamus as well as in the CC (Reference Adler, Holland, Schmithorst, Wilke, Weiss, Pan and Strakowski134–Reference Wang, Jackowski and Kalmar142). As research efforts utilising DTI progress, methods to isolate and intensively study specific white matter bundles of interest are emerging, especially those key in the neural circuitry of BD. For example, Wang et al. used methods to define the anterior region of the cingulum bundle Reference Wang, Jackowski and Kalmar(142). This cingulum sub-region is especially implicated in BD as it provides substantial connections between the regions discussed above. Wang et al. showed decreases in FA in the anterior cingulum in adults with BD, as compared with a healthy group of adults Reference Wang, Jackowski and Kalmar(142). Another bundle of particular interest in BD is the uncinate fasciculus, a ventral white matter structure that inter-connects the VPFC and amygdala. Utilising tract-based spatial statistics, Versace et al. found abnormalities in FA in the uncinate fasciculus in adults with BD Reference Versace, Almeida and Hassel(140). The above findings support abnormalities in the ventral white matter that provides significant connectivity within the VPFC-amygdala neural system in BD.
Conclusions and future directions for the field of BD neuroimaging research
Studies examining changes in behaviour associated with lesions and seizures laid important groundwork for identifying the brain regions involved in BD. Since those studies, the field of BD research has advanced in understanding the structural and functional disruptions within the neural system contributing to BD and has progressed in the neuroimaging techniques used to study these disruptions. Recent developments in the field include studies that integrate multiple neuroimaging modalities to examine the relationships between grey and white matter and between structure and function. For example, a recent study in the amygdala combined structural and functional magnetic resonance imaging (fMRI) methods to show a significant inverse association between volume decreases and activation increases in adolescents with BD suggesting a mechanistic relationship between the structural and functional abnormalities observed Reference Kalmar, Wang and Chepenik(143). Another study integrated fMRI functional connectivity and DTI methods to show associations between abnormalities in VPFC-amygdala coordinated activity and the structural integrity of the white matter that connects them suggesting that white matter abnormalities may contribute to functional disruptions in the brain circuitry of BD Reference Wang, Kalmar and He(144).
As neuroimaging research advances, a comprehensive neural system model for BD is evolving. Evidence suggests that the VPFC, the amygdala, and their interactions are critical and central to the neuropathophysiology of the disorder. Data support influences by other brain structures interconnected with the VPFC and amygdala, such as the hippocampus, ventral striatum, thalamus and cerebellum, on the neural system contributing to BD. The specific mechanisms of such influences are unclear. However, these structures may mutually affect one another's development and function. Additionally, findings indicate effects of genetic, developmental and treatment factors on this VPFC-amygdala neural system as well. In this VPFC-amygdala neural system model of BD, a complex interplay of different influences leads to disruptions within the neural circuitry that manifest in the range of BD symptoms, including affective episodes, mood cycling, cognitive disturbances, neurovegetative symptoms and psychomotor disturbances. Although the proposed model highlights the central role of the VPFC and amygdala in BD, the potential contribution by other brain regions to the disorder is also important. Thus, efforts to understand such contributions should continue in conjunction with those to elucidate the roles of the VPFC and amygdala in BD. Such investigations may lead to mapping of specific BD symptoms, such as mood cycling or cognitive disturbances, onto certain components of the neural system underlying the disorder.
As a neural system model of BD emerges, there is a great hope for the application of research findings to the timely and accurate diagnosis and effective treatment of BD. Work to translate findings from neuroimaging research to prevention and treatment strategies for BD has commenced. Findings of structural and functional brain abnormalities in adolescents with BD suggest that alterations in the development and function of some brain regions may emerge in adolescence and may progress during this epoch when the symptoms of BD often first present Reference Blumberg, Kaufman, Martin, Charney, Krystal and Peterson(59). In conjunction with reports that suggest the beneficial effects of medication on structural and functional abnormalities in BD, these findings emphasise the importance of early identification and treatment strategies. The differentiation of BD from other psychiatric disorders such as attention-deficit hyperactivity disorder and major depressive disorder among adolescents and young adults remains challenging. With the progress in the BD imaging field, future investigations can focus on direct comparisons between these disorders in adolescents and young adults. Such comparison studies could contribute significantly to improving diagnosis of BD in adolescents and young adults. Furthermore, studies of youths with BD, as well as emerging studies of unaffected family members at-risk for BD, could prove pivotal for the development of tools to identify and intervene early in those vulnerable to BD. Additionally, the emergence of studies that show influence of specific genetic variations on the brain circuitry of BD hold particular promise as they can point to specific molecular mechanisms that could be targeted for the development of new preventive and treatment strategies.
Acknowledgements
The authors are supported by grants from the National Institute of Mental Health R01MH69747 (HPB), R01MH070902 (HPB), R25MH071240 (FYW), T32MH14276 (JHK), K01MH086621 (FW), the Department of Veterans Affairs Research Enhancement Award Program (REAP) (HPB) programs, the National Alliance for Research in Schizophrenia and Depression (Great Neck, NY) (HPB, JHK, FW), The Attias Family Foundation (HPB), The Ethel F. Donaghue Women's Investigator Program at Yale (New Haven, CT) (HPB), the Klingenstein Foundation (JHK, FW), and Marcia Simon Kaplan (JHK). HPB has received honoraria from Eli Lilly and Abbott Laboratories and consultant fees from Pfizer, Inc. FYW, JHK and FW have no conflicts of interest to disclose.
