To BD or not to BD: functional neuroimaging and the boundaries of bipolarity

Abstract

Bipolar disorders are major mood disorders defined by the presence of discrete episodes of depression and either mania, in bipolar I disorder, or hypomania, in bipolar II disorder. There is little contention that both are serious psychiatric conditions or that they are associated with substantial suffering, disability, risk of suicide and cost to the community. Recently, focus has shifted away from classic manic-depressive illness toward a ‘bipolar spectrum’ model, which allows for much softer presentations to be conceptualized as bipolarity, but the boundaries of this concept remain contentious. In this article, we will consider the contribution of neuroimaging to delineating the bipolar phenotype and differentiating it from similar disorders.

Keywords::

• amygdala
• bipolar disorder
• borderline personality disorder
• fMRI
• limbic system
• major depressive disorder
• neuroimaging
• prefrontal cortex
• striatum

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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/expertimmunology; (4) view/print certificate.

Release date: 20 December 2012; Expiration date: 20 December 2013

Learning objectives

Upon completion of this activity, participants will be able to:

• • Describe classification of BD, based on a review of neuroimaging.

• • Describe patterns of limbic activity and cortical activity in BD, based on a review of neuroimaging.

• • Describe the diagnostic and clinical differentiation of various types of BD from one another and from other psychiatric conditions, based on a review of neuroimaging.

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Publisher, Future Science Group, London, UK

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA

Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Sandy Kuiper, BSc(Med), MBBS

CADE Clinic, Department of Psychiatry, Royal North Shore Hospital Discipline of Psychiatry, Sydney Medical School, The University of Sydney, Sydney,NSW, Australia

Disclosure: Sandy Kuiper has no relevant financial or competing interests disclosure.

Loyola McLean

Westmead Psychotherapy Program, Discipline of Psychiatry, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia

and

Department of Consultation-Liaison Psychiatry, Royal North Shore Hospital, St Leonards, NSW, Australia

Disclosure: Loyola McLean has no relevant financial or competing interests disclosure.

Gin S Malhi, MD

CADE Clinic, Department of Psychiatry, Royal North Shore Hospital Discipline of Psychiatry, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia

Disclosure: GS Malhi has received grant/research support from the National Health and Medical Research Council, Stanley Medical Research Foundation, AstraZeneca, Eli Lilly, Lundbeck, Pfizer, Servier and Wyeth. GS Malhi is also a consultant to AstraZeneca, Eli Lilly, Janssen Cilag, Lundbeck, Pfizer and Servier; and has received payment for lectures from AstraZeneca, Eli Lilly, Janssen Cilag, Lundbeck, Mayo Clinic, Pfizer, Ranbaxy, Servier and Wyeth; as well as compensation for travel/accommodations/meeting expenses from AstraZeneca, Eli Lilly, Lundbeck, Pfizer, Servier and Wyeth; and royalties from Oxford University Press and Hodder Arnold.

Figure 1. Successive and recurrent mechanisms in emotional processing.

Broken arrows indicate enhancing or suppressive effects; solid arrows indicate different emotion regulation strategies at different time points during emotional processing.

CC: Cingulate cortex; dACC: Dorsal anterior cingulate cortex; dlPFC: Dorsolateral prefrontal cortex; mPFC: Medial prefrontal cortex; OFC: Orbitofrontal cortex; vlPFC: Ventrolateral prefrontal cortex; vmPFC: Ventromedial prefrontal cortex.

Reproduced with permission from [15].

Modeling bipolar disorders

The boundaries of bipolarity have been shifting out from manic-depressive illness for some time [1], with decreased focus on syndromal mood episodes and increased interest in interepisodic depressive symptoms and mixed or dysphoric mood instability, which does not reach syndromal intensity or duration [2]. In the case of bipolar II disorder (BD-II), this extension of the phenotype is on reasonably firm ground, with good evidence of both familial relatedness to bipolar I disorder (BD-I), and in addition a pattern of lower cross-sectional intensity but higher episode frequency, rapid cycling, suicidality and comorbidity [3].

However, a much more radical extension of the bipolar phenotype has been proposed in the form of the ‘soft bipolar spectrum’ [4], through which bipolarity co-opts a broad range of phenomenology, including brief hypomanic episodes, cyclothymic and hyperthymic personality traits, mixed phenomenology during depressive episodes and even mood swings within a day [5]. Empirical data advanced in support of this model include both the smooth distribution of manic and mixed symptoms across mixed unipolar and bipolar populations [6,7], and the existence of a significant population of patients who endorse subsyndromal manic symptoms [8]. 'Soft bipolar signs' have also been derived from comparison of unipolar and bipolar patients, and explicitly invoked to allow the diagnosis of bipolarity in the absence of elevation [9]. These data, in turn, give rise to a model of ‘bipolar spectrum disorder’, in which an increasing bipolar diathesis presents as an increasing load of manic symptoms, from subsyndromal dysphoria and irritability through to hypomania and mania [10].

This increased focus on softer forms of bipolarity is a laudable undertaking, and the need for accurate distinction of bipolar disorder (BD) from major depressive disorder (MDD) is clear in the context of ongoing underdiagnosis of BD [11]. However, the implication of defining bipolarity on a single axis is that it collapses bipolar diagnostics down to a single ‘depression versus bipolarity’ comparison, and ignores the possibility that other disorders could share similar clinical presentations. This difficulty is most acute in the case of borderline personality disorder (BPD), which shares with bipolarity a clinically significant disturbance of emotional stability and impulsivity, and a predisposition to depressive illness, and which is frequently misdiagnosed as bipolarity [12]. Although it has been suggested that the mood instability of BPD is part of the bipolar spectrum [5], unity of BPD and bipolarity is difficult to support when illness validators such as co-occurrence, heritability, longitudinal course and treatment response are considered [13], and we therefore need to account for the conceptual position of personality disorder when modeling the boundaries of bipolar illness.

Functional neuroimaging & bipolar nosology

Functional neuroimaging provides a novel paradigm for approaching this diagnostically difficult territory. It offers the promise of objective assessment of neural abnormalities associated with specific disorders or core phenomenological domains, and even of eventual development of endophenotypes, which refine our understanding or provide treatment targets. We acknowledge the difficulty of considering functional imaging in isolation, but also note that it offers unique advantages, in that immediate in vivo probing with tasks tied to specific phenomenology allows a much greater conceptual flexibility than structural imaging.

Unfortunately, this promise has, broadly, yet to be fulfilled. At a basic methodological level, study sizes are variable, clinical status and medication are variably reported and controlled for, and imaging parameters and task-related paradigms have yet to be standardized. Further, on assessment we often assume a degree of probe specificity and underlying functional neural dissociability, which may or may not be present. Generalization is limited by all these challenges in addition to significant disparity in the findings of individual studies.

In addition to this, the literature on neuroimaging of mood disorders remains preliminary, and focuses prominently on distinguishing illness from health through pair-wise comparison of either BD (typically BD-I) or MDD from healthy controls. There is very limited examination of the soft bipolar spectrum and no direct comparison of bipolar and borderline patients. Additionally, a substantial proportion of the literature examines acutely unwell patients, which almost ensures that the findings reflect the clinical picture and creates a risk of conflating state-specific findings and/or epi-phenomena with the putative signature of the disorder. Finally, attempts to synthesize disparate and often conflicting findings through meta-analysis is a conceptually muddy exercise – it provides a mathematical summation of the findings and condenses an unruly literature to a digestible format, but it is not necessarily clear what conceptual entity the averaging out of differing populations, mood states and resting and event-related findings actually represents.

Current neural models of bipolarity

Current functional models of emotional processing, grossly simplified here, describe a predominantly limbic-subcortical network that serves to appraise emotional salience, allocate or direct attention and produce an immediate emotional response, subsequent to which a cortical network strives to regulate this through cognitive reappraisal and modulation of the emotional response (Figure 1) [14].

Data for bipolar disorder broadly fit with this pattern, showing a clear trend toward hyperactivation of subcortical, limbic or medial temporal structures and hypoactivation of frontal cortical structures, typically felt to correlate with heightened emotional reactivity and deficient emotional regulation, respectively [14,15]. This pattern is now sufficiently widely replicated that it has been demonstrated in several meta-analyses using heavily overlapping datasets, three of which have examined fMRI studies [16–18], and one which has examined both fMRI and PET studies [19]. Specifically, the amygdala and parahippocampal gyrus appear overactive, and the inferior prefrontal cortex, particularly the ventrolateral prefrontal cortex (VLPFC), appears underactive [16–19].

This pattern is insufficient, however, to establish a diagnostically specific neural signature for bipolar disorder. We need to establish both the state and trait profile of the illness through comparison across mood states and examination of euthymic and at-risk patient groups. We additionally need to establish the specificity of any findings through comparison with similar disorders, such as MDD and BPD. Finally, from the perspective of differential diagnosis, we need to examine ‘soft’ bipolarity and either try to establish a gradient of findings from MDD to BD-I or identify an alternate underlying pattern, and similarly to compare BPD with both soft bipolarity and mania to clarify its nosological positioning. Therefore, in this article we will examine each of the regions in which significant disturbance has been demonstrated in turn.

Core limbic structures: amygdala, insula, parahippocampal gyrus

Hyper-responsiveness of medial temporal structures to emotionally salient stimuli in BD is well described, and is sufficiently robust that meta-analyses demonstrate hyperactivation of parahippocampal gyrus and amygdala [16–19], particularly on the left [17]. This is present in response to both positively and negatively valenced stimuli, and has been demonstrated across mood states [20–23], but appears more prominent in mania [16]. It is most prominent on emotional tasks, but is also present at rest [16]. It is not typically heightened on cognitive tasks [16], but this may occur in manic or mixed states [24,25].

Although common, it is not universally found, with a number of studies either failing to demonstrate increased limbic or amygdala reactivity [26–31] or showing a decrease [32,33]. Similarly, the effect of stimulus valence is unclear. For example, Lennox et al. [32] demonstrated a mood-congruent decrease in amygdala activation to sad expressions in mania, but a later study by the same group [34] demonstrated mood-incongruent valence effects in paralimbic and cortical regions, and suggested that amygdala overactivation and underactivation were a function of implicit and explicit emotional processing, respectively. Meta-analysis has not demonstrated valence effects [18], but this is perhaps unsurprising given that numbers were insufficient to stratify analysis by mood state. The impact of medication is also unclear, with studies showing both attenuation [35,36] and exaggeration [37] of illness-related change, but a recent review concluded that most studies showed either no effect or a trend to normalization [38].

BD-II & soft bipolar spectrum

Increased amygdala reactivity has been demonstrated in mixed BD-I/BD-II populations in both elevation [39] and euthymia [40], and in BD-II depression [41]. However, Marchand et al. [42,43] did not find a change in amygdala activation in BD-II depression, and Ladouceur et al. [44] demonstrated an increase in amygdala activation in BD-I but not bipolar disorder not otherwise specified (BD-NOS) youth.

Trait disturbance in bipolarity

Both state and trait elements are likely to contribute to limbic hyper-reactivity in bipolar disorder. Kaladjian et al. demonstrated a significant decrease in amygdala activation with remission from mania, suggesting a state effect [45]. However, other lines of evidence suggest that limbic hyper-responsiveness persists even in remitted bipolar patients – individual studies variously report its presence [46] or absence [31], but it is sufficiently common to emerge on meta-analysis of euthymic states [16,19]. Studies of at-risk patients also suggest an element of trait limbic disturbance, with increased activity of insula [30] and amygdala [47,48] found in relatives of bipolar patients, and insula hyperactivation found in a recent meta-analysis of all studies examining patients at risk of BD [49].

Other disorders

Increased limbic activity and reactivity to distressing emotional stimuli, particularly in the amygdala, is one of the most widely replicated findings in psychiatric imaging. It is well described in MDD, and has been demonstrated across imaging modalities [50], in patients as young as 3 years old [51], and in both conscious and unconscious processing [52,53]. It is present at rest [54,55], and also on paradigms which tap different elements of depressive phenomenology including rumination [56], approach and withdrawal phenomena [57], and sensitivity to social feedback [58].

There are insufficient data to comment definitively on differences in limbic reactivity between BD and MDD. Studies directly comparing the two groups have found both an increase in BD [22] and no difference [59], and although meta-analysis suggests that limbic activation might be greater in BD [18], this finding did not control for mood state or clinical severity. There may, however, be a greater likelihood for limbic hyperactivity to normalize with treatment in MDD [60] than in BD, although other data support the possibility that altered amygdala function may be a trait marker in MDD [61–63].

Increased limbic reactivity is also a core feature of BPD, with both hyperintense and prolonged amygdala activation [64–67], as well as increased activation on paradigms examining trauma [68], trust [69] and emotional over-involvement [70]. Limbic hyperarousal has also been demonstrated in disrupted attachment [71] and trauma exposure [72] in the absence of BPD diagnosis.

The range of conditions across which limbic reactivity is altered is quite extensive. Not surprisingly, limbic hyperactivity is also a core feature of anxiety disorders [73]. It has additionally been reported to be elevated in the presence of neurotic or anxious personality traits [74] and the short allele of the 5-HTTLPR genotype [75]. On a syndromal level, limbic reactivity is notably decreased in schizophrenia [76], and venturing further afield, decreased amygdala activity has been reported following acupuncture [77], mindfulness [78] and chanting ‘om’ [79].

Striatum & cortico-basal ganglia circuit

The striatum and cortico-basal ganglia circuitry (including globus pallidus and thalamic nuclei) are felt to be broadly overactive in BD [80]. Meta-analysis across mood states suggests a pattern of prominent increased activation of striatum and globus pallidus in response to emotional tasks, and a less prominent decrease in activation in response to cognitive tasks [16]. Further, this may be region and valence-specific; for example, Delvecchio et al. found an increase in reactivity of putamen and pulvinar thalamus to negative emotional stimuli, and of caudate to positive stimuli [18].

However, dissecting these findings is difficult, with significant variability across individual studies. Available data consistently support an increase in activity in mania, variably localized to the striatum [81,82], globus pallidus [81] and thalamus [82], which is thought to broadly correlate with increased intensity of affective experience. This increased activity in mania has been further linked to faulty reward processing, with a demonstrated decrease in the differential striatal activation normally observed in response to receipt versus omission of reward [83], plausibly hypothesized to relate to impaired judgment and increased engagement in pleasure-seeking activities.

Findings in depression observe the same trend toward overactivity, with a number of studies of BD-I depression demonstrating striatal overactivity both at rest [84] and in response to emotional [34] and motor [85] tasks. The thalamus and globus pallidus [86] also appear to be overactive in bipolar depression.

BD-II & soft bipolar spectrum

Available data suggest an increase in striatal activity, in both mixed BD-I/BD-II samples [36,84,39], and in BD-II depression [41,43], where it has been shown to correlate with depression severity [43]. Left thalamic hyperactivation has also been reported in BD-II depression [43].

Trait disturbance in bipolarity

Individual studies variably report increases [81,87,88] and decreases [26,89–91] in striatal activity in euthymic BD, which on preliminary meta-analysis resolves into an increase in caudate and putamen reactivity [16]. However, the latter finding is far from robust, with studies simultaneously examining multiple mood groups producing conflicting results [39,92]. Additionally, on longitudinal examination [93], increased caudate reactivity resolves as manic patients return to euthymic mood. Examination of high-risk groups has also been uninformative. For example, although Pompei et al. [94] found striatal hypoactivation in BD patients and their relatives with affective illness, Whalley et al. [48] found that ventral striatal activity correlated with depressive symptoms rather than diagnosis, and altered striatal activity was not a finding on meta-analysis of all high-risk patients [49].

Other disorders

The general trend in MDD appears to be toward striatal underactivity [80], although overactivity is also demonstrated [22,59]. Meta-analysis of emotional-task fMRI data in depressed MDD patients suggests decreased activation in the striatum relative to healthy controls, specifically in the left caudate and right putamen [18]. This appears to be mood congruent, with reduced striatal activation shown to correlate with decreased subjective experience of pleasure [95] and to occur in response to positive but not negative stimuli [96]. Consistent with this, reduced striatal reactivity to reward has been demonstrated in remitted MDD [97], where it is felt to potentially represent trait-related reward insensitivity, although activation appears normal on emotional [98] or memory [99] tasks. Mood-congruent decreases in activation of pulvinar thalamus on processing happy faces has also been demonstrated on meta-analysis [18].

Reward system dysfunction is likely also present in BPD. Reduced striatal activation has been shown in response to positive reinforcement [100], and likewise reduced caudate and putamen metabolism have been shown during a reward processing and learning task [101]. Conversely, however, Enzi et al. [102] demonstrated a failure of reward system deactivation in the presence of emotional distractors, and Salavert et al. [103] did not demonstrate altered metabolism in thalamus or basal ganglia at rest in BPD patients.

Anterior cingulate cortex

Savitz and Drevets [14] have suggested that subgenual anterior cingulate cortex (ACC) function in bipolar depression is broadly organized into a pattern of left-sided underactivity [104,105] and right-sided overactivity [106], and that this pattern is reversed in mania [107]. A number of recent studies also suggest a trend toward bilateral dorsal ACC hypofunction [39,108,109], which may normalize with treatment [110]. However, other authors have shown an increase in ACC function on a variety of tasks [106,111]. Meta-analysis provides tentative support for both dorsal ACC underactivity and lateralization of function, with decreased left dorsal ACC activation to fearful faces and decreased right dorsal ACC activation to happy faces [18], although it is unclear how this specifically relates to mood states.

BD-II & soft bipolar spectrum

The majority of studies in soft bipolar populations do not report changes in ACC metabolism [42,43,84], but right-sided dorsal ACC overactivity has been reported in BD-II depression [41].

Evidence for trait disturbance in bipolarity

Overactivity of dorsal ACC has been demonstrated in euthymic bipolar patients on a working memory task [40], but is a sufficiently uncommon finding that it does not feature prominently on meta-analysis [16,19]. Changes in ACC function have not been demonstrated in at-risk groups [49].

Findings in other disorders

A similar pattern of decreased left subgenual anterior cingulate cortex (sgACC) metabolism and increased right sgACC metabolism is likely also present in MDD [14]. Increase in right sgACC activity is particularly prominent during acute depressive episodes and improves with treatment [112], and is robust enough to appear on meta-analysis, where it may extend to both right ventral and dorsal ACC [113]. Meta-analytic comparison of MDD and BD suggests that the magnitude of right sgACC activation is greater in BD, whereas left-sided pregenual anterior cingulate cortex activation is greater in MDD [18], although these findings do not control for mood states or illness severity. However, increased dorsal ACC activation in MDD has also been demonstrated on direct comparison of unipolar and bipolar depressed women [59].

Anterior cingulate cortex activation in BPD may be valence-specific, with a decrease in activation to negative and neutral [114] or fearful [115] stimuli, and an increase in response to anger-related stimuli [115]. However, several studies suggest a decreased ability to activate ACC in the service of emotional regulation [68,116].

Prefrontal & other cortical regions

The most reliable cortical finding in BD at present is that of decreased activation of inferior frontal gyrus (BA47), including VLPFC and part of the orbitofrontal cortex (OFC) [16–19]. This is more prominent on the right [17], and is present across both emotional and cognitive tasks [16]. It has been reported in bipolar depression [27], mania [20,117,118] and euthymia [119], but is found most robustly in mania [16], where it may form part of a broader pattern of frontal underactivity and temporal overactivity [19]. Similarly, underactivation of lingual gyrus [90] is sufficiently common to persist on meta-analysis [16,18].

Findings in other cortical areas are substantially more disparate. Several studies suggest an increase in VMPFC activation in mania [20,120], and DMPFC may be overactive in euthymia [40,87,121], possibly reflecting enhanced self-referential processing in cortical midline structures [122], but this receives limited support from meta-analyses [16]. Dorsolateral prefrontal cortex (DLPFC) findings are markedly conflicting, with different data suggesting it is underactive across mood states [123], both overactive and underactive in mania compared with other mood states [39,92], and both overactive and underactive on presentation of emotional stimuli [44,124] and cognitive tasks [25,125], sometimes within the same study [126]. Meta-analyses likewise tap different datasets to suggest that the predominant trend is toward DLPFC underactivity [17,19] or overactivity [16,127], confirming the preliminary nature of these findings.

BD-II & soft bipolar spectrum

Decreases in frontal metabolism, particularly in ventral regions, have also been demonstrated in mixed BD-I/BD-II depression [84] and BD-II depression [42]. However, increased OFC metabolism has also been reported in BD-II depression [41].

Trait disturbance in bipolarity

It is unclear to what extent decreased ventral prefrontal cortex (PFC) activity is a trait marker of bipolarity. In one comparison of multiple mood states [39] and one meta-analysis [16], decreased ventral PFC activation is specific to mania, but is has also been observed across mood states in another study [92] and reported as a finding in euthymia on meta-analysis [19]. Decreased activation of lingual gyrus also appears to be a trait finding [16].

A number of studies in high-risk groups have suggested increased activity in ventromedial prefrontal cortex [30,47,128] or left frontal pole [30,129], although other studies have shown an opposite effect [130]. Meta-analysis of all at-risk patients suggests increased responsiveness in left superior frontal gyrus and medial frontal gyrus [49].

Other disorders

VLPFC underactivity is not demonstrated in MDD – conversely, it may be overactive, possibly functioning as a ‘pleasure-dampening’ inhibitory system related to anhedonia [131].

However, MDD shares with BD a pattern of relative overactivation of medial PFC, in both VMPFC and DMPFC [132], felt likely to relate to a failure of inhibition of the default mode network [132,133], in turn causing rumination and depressive self-focus [133,134] in a manner potentially central to depressive illness [135]. Conversely, DLPFC is typically felt to be underactive [14], to the extent that it is conceptualized as an etiologically significant correlate of failing top-down inhibitory modulation of emotion [14]. Consistent with this, antidepressants tend to increase cortical activation, particularly dorsally [60]. However, despite the prominence of these findings, there are enough conflicting data that changes in prefrontal activation do not survive meta-analysis [18,113]. In other cortical regions, on emotional challenges MDD may be associated with hypoactivity of the somatosensory cortex, rather than hypoactivity of the lingual gyrus seen with BD [18], perhaps reflecting subtle differences in allocation of socially or emotionally salient sensory attention between the two disorders.

In borderline personality disorder, decreased activation has been demonstrated on attempted inhibition of emotion in VMPFC [66,136], and OFC [137], but increased activation has also been demonstrated in OFC in response to unresolved life events [138] and anger [139], and in VLPFC on presentation of emotional stimuli [140] and emotional regulation [116]. Dorsal PFC is generally underactive [66,68,141,142], and consistent with this, dialectic behavioral therapy has been shown to increase dorsal PFC activation [143]. However, DLPFC has also been shown to be overactive in response to abandonment stimuli [144]. These data coarsely trend toward increased activation in response to emotionally salient stimuli, and decreased activation on regulatory paradigms. Other data suggest a trend toward decreased frontal and increased temporal cortical activation [116,145], which bears some similarities to the activation pattern seen in mania [19]. It is unclear, however, to what extent these findings are specific to BPD and to what extent they are a function of trauma exposure, as findings are similar in both clinical BPD groups and nonclinical trauma-exposed groups [68].

Expert commentary

Although the narrative review format we have employed here runs the risk of prematurely synthesizing conflicting data, a number of patterns are nonetheless broadly apparent, as summarized in Table 1. On a basic level, the proposition of increased limbic activity and variable or decreased cortical activity holds true, and it is certainly possible to interpret these data in line with existing models of bipolarity that revolve around ‘bottom up’ limbic hyperactivation and ‘top down’ failure of cortical regulation [14]. However, once multiple diagnoses are considered, it becomes clear that this pattern is common to multiple disorders and is not a particularly useful heuristic for understanding differential diagnosis.

Consistent with this, a number of findings in BD are nonspecific. Increased limbic activation is evidently not specific to BD or even mood disorder, and occurs in such a wide range of conditions that it is likely part of the phenotype of any condition defined by heightened emotional distress. Although it is probable that it is a trait disturbance in BD, and that its pattern differs quantitatively [18] and qualitatively [69,144] between disorders, these data remain preliminary and a BD-specific signature of limbic dysfunction has yet to emerge. Likewise, there are also similarities across disorders in the functional disturbance of the sgACC and medial prefrontal cortex which, variously interpreted through the lens of cortical midline structures [122] and default mode network [132], are perhaps part of the abnormal emotional processing and self-focus associated with mood disorders in general.

However, a number of salient differences are present. Nosologically, it is important that the functional neural abnormalities, which appear most likely to differentiate bipolarity, namely decreased inferior frontal (VLPFC, OFC) and increased striatal activity, are both most prominent in mania and have a plausible functional relationship to mania. The VLPFC is known to modulate emotional responses according to context [146], and along with the OFC has been associated with impulsivity and distractibility [16]. Therefore, deactivation in these areas is a possible neural substrate for the impulsive, stimulus-driven, disinhibited behavior associated with mania. Similarly, the central role of the striatum in processing pleasure and reward [80] offers an appealing face validity to the apparent pattern of overactivity in BD and underactivity in MDD, although this is clearly an oversimplification of function. The prominence of mania-related findings in the neural signature of bipolarity is highly likely to be related to dominance of BD-I in study populations, but it is nonetheless fair to say that current neuroimaging data support an illness model in which bipolarity is differentiated by syndromal mania rather than subthreshold symptoms.

Data for BD-II remain very limited, particularly given the degree of heterogeneity in the imaging literature, but suggest overlap with BD-I. However, there is scant imaging evidence for softer forms of bipolarity or for a bipolar spectrum, and the one study that has compared BD-I with BD-NOS found substantial differences in activation pattern [44].

Comparison of BPD and BD is also based on limited data. Both clearly share increased limbic arousal, consistent with the shared experience of emotional dysregulation, but this is of unclear nosological import due to the lack of specificity already discussed. Similarly, both BPD and bipolar mania share a pattern of decreased frontal and increased temporal cortical activation which may relate to more primitive and reflexive emotional processing [19,145], but this is state-specific in mania and trait-finding in BPD, consistent with formulation of the former as an episodic illness and the latter as an ongoing process. Other abnormalities of emotional and reward processing are also demonstrable in BPD, but these do not at this stage appear to cohere into the pattern associated with bipolar mania.

Finally, the role of psychological function in the imaging of this area is likely underestimated. It has long been recognized that disrupted attachment and relational function are central to the borderline personality construct [147], and this has accordingly been demonstrated in the neuroimaging of BPD, with neural reactivity linked to core psychopathological domains like abandonment [144] and trust [69]. Additionally, we know that core psychological schemata (a very similar construct to attachment) differentiate BPD from BD [148]. Although this has yet to be specifically replicated in a neuroimaging paradigm, we know that experience modulates the development of emotional circuitry in early life [149], and that attachment disruption and trauma produce altered patterns of neural activation that persist into adulthood [150], which may resolve into a neural signature of disorganized attachment [151]. This highlights two possibilities – first, that attempting to separate out ‘biological’ emotional reactivity from its psychological context may be an intrinsically flawed exercise when modeling diagnosis, and second, that BPD may be a prototype of an attachment-driven model of neural dysfunction.

Five-year view

Although functional neuroimaging continues to expand our knowledge of bipolar disorders at a rapid rate, there are still significant gaps in our understanding and current models remain very much preliminary. The current trend toward studies of greater scope, including multiple time points and/or mood states, is likely to substantially assist in clarifying the state and trait signature of bipolarity, as will the evolution of new imaging paradigms such as functional connectivity analysis. This greater clarity will itself substantially assist in diagnostic modeling, but neuroimaging is also likely to be a major testing ground for the integrity of the bipolar spectrum model as more direct comparisons are performed between BD-I, the putative ‘soft bipolar’ illnesses, and other diagnostically relevant conditions such as BPD. Eventually, as the respective signatures of personality-based emotional dysregulation and bipolar mood dysregulation become increasingly crisp, we may be able to use functional neural profile to assist in clarifying diagnosis or treatment options in clinically muddy presentations, although a great deal of work will need to be done before imaging will be sufficiently robust to be used in this manner.

Table 1. Summary of neuroimaging findings in bipolar disorder, borderline personality disorder and major depressive disorder.

Structure	BD (overall)	BD (trait)	BD-II	BPD	MDD
Core limbic structures (amygdala, parahippocampal gyrus, insula)	↑	⇑	⇑	↑	↑
Striatum	↑	⇑	⇑	⇑⇓	↓
sgACC	⇓left; ⇑right			⇓	⇓left; ⇑right
pgACC	⇓				⇑right
VLPFC	↓	⇓		⇑⇓	⇑
VMPFC + DMPFC	⇑	⇑	⇑⇓		⇑
DLPFC	⇑⇓			⇓	⇓

↑Probable increase.

↓Probable decrease

⇑Possible increase.

⇓Possible decrease.

⇑⇓Conflicting findings.

BD: Bipolar disorder; BPD: Borderline personality disorder; DLPFC: Dorsolateral prefrontal cortex; DMPFC: Dorsomedial prefrontal cortex; MDD: Major depressive disorder; pgACC: Pregenual anterior cingulate cortex; sgACC: Subgenual anterior cingulate cortex; VLPFC: Ventrolateral prefrontal cortex; VM: Ventromedial; VMPFC: Ventromedial prefrontal cortex.

Key issues

• • Current models of bipolarity describe a spectrum of illness in which increasing predisposition to bipolarity manifests as increasing manic symptom load, from ‘pure’ unipolar depression to subthreshold bipolarity, bipolar II disorder and, ultimately, bipolar I disorder.

• • This is essentially untested in the neuroimaging literature, which examines predominantly bipolar I disorder populations, and thus supports an illness model in which bipolarity is distinguished from other disorders through findings in syndromal mania.

• • Core limbic structures such as the amygdala and parahippocampal gyrus appear to be overactive in bipolar disorder (BD), likely as both a state and trait finding. However, limbic reactivity is also increased in a wide range of other conditions including major depressive disorder (MDD) and borderline personality disorder (BPD).

• • Increased striatal reactivity, particularly to emotional stimuli and reward, appears to be characteristic of BD, and may differentiate BD from MDD.

• • BD is also characterized by decreased activity of the inferior prefrontal gyrus, including the ventrolateral prefrontal cortex and part of the orbitofrontal cortex, which is most prominent in mania but may also be a trait finding. This does not clearly occur in MDD or BPD.

• • Other findings in BD include a decrease in activity of lingual gyrus, a possible decrease in activity of the dorsal anterior cingulate cortex and a possible increase in activity of the medial prefrontal cortex.

• • Further research is needed to directly test bipolar spectrum models and clarify their relationship to other conditions associated with significant emotional instability, such as BPD.

References

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To BD or not to BD: functional neuroimaging and the boundaries of bipolarity

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

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1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. Based on the review by Dr Kuiper and colleagues, which of the following statements about classification of bipolar disorder (BD) is most likely correct?

• □ A The presence of discrete episodes of hypomania or mania is not necessary for the diagnosis of BD

• □ B Current models of bipolarity focus exclusively on manic-depressive illness

• □ C Unlike bipolar II disorder (BD-II), bipolar I disorder (BD-I) is a serious psychiatric condition associated with significant suffering, disability, risk of suicide, and societal cost

• □ D In the ‘bipolar spectrum’ model, increasing manic symptom load ranges from ‘pure’ unipolar depression to subthreshold bipolarity, BD-2, and BD-1

2. Your patient is a 32-year-old woman thought to have BD. Based on the review by Dr. Kuiper and colleagues, which of the following statements about patterns of limbic activity and cortical activity in BD is most likely correct?

• □ A The amygdala and parahippocampal gyrus appear to be underactive in BD

• □ B Striatal reactivity is increased, particularly to emotional stimuli and reward

• □ C Activity of inferior prefrontal cortex is increased

• □ D Activity is increased in the lingual gyrus and dorsal anterior cingulate cortex

3. Based on the review by Dr. Kuiper and colleagues, which of the following statements about differentiation of various types of BD from one another and from other psychiatric conditions would most likely be correct?

• □ A Increased limbic reactivity is highly specific for BD

• □ B Increased striatal reactivity, particularly to emotional stimuli and reward, may differentiate BD from major depressive disorder (MDD)

• □ C Decreased activity of the inferior prefrontal cortex, including VLPFC and part of OFC, is more prominent in MDD and BPD than in mania

• □ D Temporal cortical activation is increased in BPD but not in bipolar mania