Needs Assessment Despite the significant morbidity and mortality associated with bipolar disorder, little is known about its neurophysiology. The results of recent studies involving novel neuroimaging techniques have rapidly increased our knowledge of the structural neuroanatomy of this condition and how it appears to arise from dysfunction within discrete brain networks. Learning Objectives At the end of this activity, the participant should be able to: • Identify network models of bipolar disorder neurophysiology. • Identify how neuroimaging is being used to study bipolar disorder. • Describe currently identified brain abnormalities in bipolar disorder.  Target Audience Neurologists and psychiatrists  Accreditation Statement Continuing Medical Education to provide Continuing Medical Education for physicians. Mount Sinai School of Medicine designates this educational activity for a maximum of 3.0 Category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. It is the policy of Mount Sinai School of Medicine to ensure fair balance, independence, objectivity and scientific rigor in all its sponsored activities. All faculty participating in sponsored activities are expected to disclose to the audience any real or apparent discussion of unlabeled or investigational use of any commercial product or device not yet approved in the United States.   This activity has been peer-reviewed and approved by Eric Hollander, MD, professor of psychiatry, Mount Sinai School of Medicine. Review Date: March 6, 2006. To Receive Credit for This Activity Read this article, and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME quiz. To obtain credits, you should score 70% or better. Termination date: April 30, 2008. The estimated time to complete this activity is 3 hours.

 

Abstract

Bipolar disorder is a common psychiatric condition with significant associated morbidity and mortality. Despite its significance, the neurophysiology and neuropathology of this illness is incompletely understood. Recent advances in neuroimaging techniques have helped to begin clarifying these areas. Specifically, bipolar disorder appears to arise from abnormalities within discrete brain networks (eg, the anterior limbic network). The expression of the symptoms of bipolar disorder does not appear to result from single, localized brain lesions, but rather are emergent properties of dysfunction of these brain networks. As neuroimaging techniques continue to improve, the underlying neural basis of bipolar disorder will be clarified.

 

Introduction

Diagnosed in ~1% to 2% of the population,^1,2 bipolar disorder is characterized by both fluctuating affective states that define the illness and a constellation of other symptoms, including impulsivity, specific cognitive deficits, and neurovegetative changes.³ Despite the prevalence of the disorder, the neurophysiology underlying bipolar symptoms remains poorly understood. Nonetheless, recent data suggest that bipolar symptomatology arises from dysfunction in several structures and white matter pathways comprising specific overlapping neural networks.

As early as 1937, Papez⁴ linked emotional expression to a group of structures previously identified by Broca as "le grande lobe limbique."⁵ This limbic network subsequently was extended to include portions of thalamus, amygdala, hippocampal complex, fornix, and anterior cingulate. Recent imaging studies support the hypothesized associations between limbic structures and emotional expression. For example, efforts to induce sadness and anger in healthy subjects during positron emission tomography and functional magnetic resonance imaging result in emotion-related activity in regions of the classic limbic network, in the striatum, and portions of the prefrontal cortex (PFC), including the orbitofrontal, ventral prefrontal, dorsolateral prefrontal (DLPFC), and medial frontal cortices.^6-8  These and other studies led to proposals⁹ that mood and behavior are mediated by neuronal interactions within a cortico-striatal-pallido-thalamic circuit. Other researchers¹⁰ have proposed that a linked cortico-striato-thalamic system is responsible for the regulation of emotive stimuli response.Neuropathology in at least a portion of these networks might underlie affective symptoms.

In addition to fluctuating affective states, bipolar disorder is associated with cognitive deficits that appear to be limited to specific neurocognitive domains. Bipolar patients frequently perform as well as healthy subjects on tests of verbal or performance IQ; the same is true for specific tests of serial learning and verbal fluency.¹¹ Bipolar patients, however, demonstrate significant deficits in performance on a variety of attention tasks, particularly tasks involving elements of executive function, such as the letter cancellation and trails tasks, and decreased performance on tests of short-term memory, including declarative and working memory.¹¹ Patients with bipolar disorder also demonstrate impaired performance on Stroop tasks, attention tasks that require successful inhibition of prepotent responses.¹¹ Evidence of decreased executive function is manifest in bipolar patients in their performance on some attention and working memory tasks and with performance difficulties on the Wisconsin Card Sort  Task.¹¹

Several of the limbic and prefrontal regions involved in these cognitive domains overlap areas hypothesized to mediate emotional regulation.^12-16 Executive function, for example, has been localized to portions of the PFC, which also mediates performance of attention, working memory, and Stroop tasks. The pattern of attention deficits in patients with bipolar disorder is most consistent with dysfunction in the orbitofrontal cortex, DLPFC, subcortical and medial temporal structures, and portions of the posterior parietal cortex.^13,14 Deficits in working memory similarly suggest abnormalities in the orbitofrontal cortex, DLPFC, the anterior cingulate cortex (ACC), striatum, thalamus, and medial temporal structures.^14,15 Impairment in performance on Stroop tasks may be related to neuropathology of the ACC and DLPFC, which form part of a neural network involved in self-monitoring and inhibition.¹² The pattern of cognitive deficits in bipolar disorder suggests dysfunction within a cerebello-striatal-prefrontal neural circuit.¹⁶ 

Recently, researchers^17,18 have posited that this spectrum of affective and cognitive symptomatology represents dysfunction within a single extended network, the anterior limbic network (ALN [Figure 1]), which includes prefrontal regions, subcortical structures, such as the thalamus, striatum, amygdala, and the midline cerebellum. Prefrontal-striatal-thalamic circuits compose a core aspect of the ALN, and interactions among these structures may be involved in the regulation of socioemotional behaviors.¹⁷ These prefrontal and subcortical structures are also modulated by medial temporal structures involved in both emotional regulation and reward.^17-20 Emotional dysregulation in bipolar disorder has been hypothesized to arise from a lack of inhibitory feedback between medial, dorsal, and inferior frontal cortex, and these subcortical and medial temporal structures of the ALN.¹⁶ Other investigators²¹ have suggested that the abnormal processing of emotional stimuli in patients with bipolar disorder results from impaired feedback between dysfunctional prefrontal regions and the amygdala. Neurovegetative symptoms, including changes in sleep, appetite, and energy, associated with bipolar disorder are hypothesized to result from the effects of dysregulated ALN activity on hypothalamic nuclei.¹⁷ We will now briefly review imaging studies supporting the presence of abnormalities within the anterior limbic network.

 

Prefrontal Cortex

The PFC is a functionally heterogeneous region that integrates stimulus-reward associations, reward-guided behavior, and the modulation of emotion.²² Portions of the PFC also contribute to attention, short-term memory,  the integration of reward, and the inhibition of prepotent responses. The PFC as a whole is richly networked via reciprocal connections with portions of the basal ganglia, thalamus, and medial temporal structures. Specific areas of the PFC map to specific regions of the striatum and thalamus to create iterative loops that produce emotional, cognitive, and social behaviors. Several studies¹⁷ of patients with bipolar disorder have identified morphometric abnormalities and changes in functional activity in portions of the PFC. Reduced prefrontal volume has been found to correlate with performance on a continuous performance test (CPT) of attention.²³ Magnetic resonance spectroscopy (MRS) studies of the PFC have also identified decreased concentrations of N-acetyl-aspartate (NAA), consistent with prefrontal neuronal dysfunction.²⁴ 

The orbitofrontal cortex is a portion of the PFC that is closely associated with emotional homeostasis.^25,26 Medial orbitofrontal and ventrolateral prefrontal cortex (VLPFC) are reciprocally connected with the amygdala, anterior temporal regions, subgenual ACC, and striatum. Interruptions of these orbitofrontal-striatal connections in particular have been implicated in the development of major depressive symptoms, and increased activity in the orbitofrontal cortex during periods of depression has been negatively correlated with both depression severity and degree of amygdala activity, supporting the behavioral importance of these feedback loops.²¹ Projections from the orbitofrontal cortex to the hypothalamus have also been found to mediate cortisol release, and may be related to increases in neurovegetative symptoms during depression.²¹ Subregions of the PFC project to different portions of the hypothalamus and affect endocrine, autonomic, and behavioral functions through the medial, dorsal, and lateral hypothalamus, respectively.²⁷ Structural neuroimaging and MRS studies^28,29 support this hypothesized orbitofrontal pathology in bipolar disorder. Orbitofrontal gray matter volumes are reduced bilaterally.²⁸ Cecil and colleagues²⁹ reported decreased NAA in the medial orbitofrontal cortex of bipolar adolescents.
 
The VLPFC is also linked with emotional regulation, and dysregulation or dysfunction of this region has been implicated in affective symptomatology. The VLPFC is closely networked with other portions of the PFC, including the orbitofrontal cortex and DLPFC, and it is also reciprocally connected to paralimbic, limbic, and subcortical regions. These include the ACC, medial temporal structures, basal ganglia, thalamus, and brainstem. As a result of these connections, the VLPFC is ideally positioned to modulate emotional processing and bodily sensations and response.^10,25,26 Additionally, subgenual PFC has extensive connections to other regions involved in emotional regulation and reward, including the ventromedial portion of the striatum, made up of the nucleus accumbens, medial caudate nucleus, ventrolateral putamen, and ventral tegmental area (VTA).^21,30-32 Other efferents project to the lateral hypothalamus and brainstem autonomic nuclei leading investigators²¹ to suggest that the ventral PFC may interact with the orbitofrontal cortex in mediating neurovegetative symptoms. Postmortem studies of the PFC in bipolar patients observe neuropathologic changes in subgenual prefrontal tissue,²¹ and MRI studies noted decreased subgenual prefrontal volume.^33,34 Positron emission tomography studies of glucose metabolism suggest concomitant changes in baseline activity in this brain region.²¹

The ACC is also richly connected to other areas of the PFC and seems to be similarly involved in emotional regulation and reward-related feedback.³⁵ Lesions in the ACC have been associated with abnormal emotional responses, and appear to affect decision-making with regard to risk.^25,36 Through reciprocal connections with the orbitofrontal cortex and portions of the ventral PFC, the ACC networks with the basal ganglia, thalamus, and insula as well as paralimbic and limbic structures, including the amygdala and hippocampus.²⁶ The ACC also receives dense dopamine input directly from the VTA, a region that projects to the striatum and seems to be involved in reward.

Structural studies suggest the presence of abnormalities in the cingulate cortex of bipolar patients. Several investigators^37,38 have reported decreased left-sided ACC volume. Using magnetization transfer imaging, Bruno and colleagues³⁹ also reported a loss of neuropil density in the right subgenual cingulate. Moreover, although data are limited, in at least one study⁴⁰ decreased ACC gray matter density in patients with bipolar disorder was associated with poor clinical outcome. Functional neuroimaging studies³³ suggest bipolar disorder is also associated with concomitant decreased ACC metabolism.

 

Medial Temporal Structures

The amygdala and hippocampus together make up part of the mesolimbic cortex. The amygdala is involved in emotional regulation, expression, and memory, and networks, including the amygdala, have been implicated in a wide range of both cognitive and affective domains.²² Portions of the medial cortex and VLPFC are reciprocally connected to the amygdala and hippocampus and additional projections into the amygdala arise from orbital and medial PFC, lateral PFC, perirhinal cortex, lateral entororhinal cortex, piriform cortex, and the hippocampus.^22,25,26 Additional amygdala inputs arise from posterior orbital cortex, anterior insula, and both subgenual and pregenual portions of the ACC, increased activation of which may be associated with increased amygdala activation.²¹ While the resolution of functional imaging studies limit identification of specific nuclei,²¹ primate studies suggest that amygdala efferents to the PFC arise largely from the basal nucleus, with the ventromedial basal nucleus projecting to the orbital prefrontal network, and ventrolateral basal nucleus projecting to the medial prefrontal network.⁴¹ Hippocampal efferents to the PFC arise primarily from the rostral part of the subiculum and surrounding cells.^41,42 Other amygdala efferents arise from the central nucleus of the amygdala and stimulate corticoptropin-releasing factor release from the paraventricular nucleus of the hypothalamus.^21,43 Amygdala projections to neurons in the hypothalamus and periaqueductal gray area have been associated with neurovegetative symptoms in patients with bipolar disorder.²¹

Structural studies suggest^17,28,44,45 that medial temporal neuropathology is integral to deficits in the ALN. While volumetric studies of the amygdala in bipolar adults have been equivocal, studies including bipolar adolescents have consistently observed decreased amygdala volume. Postmortem studies are also indicative of amygdala neuropathology; decreased Nissl-staining neurons have been observed in the dorsal raphe nucleus in major depressive and bipolar disorders.³¹ Reduced hippocampal volume was also observed in a population of older bipolar patients and in bipolar children and adolescents.^17,44 Reductions of non-pyramidal neurons in the hippocampus, and reduced arborisation of subicular apical dendrites, suggest that these findings are associated with reduced synaptic formation.³⁹

 

Subcortical Structures

The basal ganglia, and in particular the striatum, play a significant role in both cortical and emotional regulation. Multiple striatal pathways project to orbitofrontal, medial, and lateral prefrontal regions implicated in the modulation of emotional behavior.^26,46 These prefrontal areas project to the ventromedial striatum and thalamus to create feedback loops through which the PFC influences psychomotor response to emotion.^25,26 The nucleus accumbens, which forms part of the ventral striatum, is a central structure in these interconnected limbic and striatal networks. The nucleus accumbens projects to the ventral pallidus, hypothalamus, and brainstem, and receives abundant afferents from the prelimbic cortex, hippocampal formation, thalamus, and amygdala.^22,25,26 The nucleus accumbans is particularly closely associated with the amygdala; the extended amygdala and portions of the nucleus accumbens may be part of a common functional anatomic continuum.²²

Structural and MRS findings in the basal ganglia suggest the presence of primary functional deficits in these subcortical structures. Putamen volume is increased in bipolar patients as well as in both affected and non-affected bipolar twins, suggesting deficits in pruning that may be related to increased activity in these structures.17 Increased basal ganglia choline levels in bipolar patients are also consistent with altered neuronal energetics in this brain region.⁴⁷

 

Cerebellum

The cerebellum is a heterogeneous structure that receives input from areas known to be involved in cognition and affect in what has been termed a cerebro-cerebellar circuit.⁴⁸ The cerebellum receives input from the hypothalamus, parahippocampus, cingulate, superior temporal cortex, posterior parietal cortex, and PFC.⁴⁸ MRI studies suggest the presence of functional connections between the left dentate nucleus of the cerebellum and portions of the thalamus, caudate, right putamen, right hippocampal complex, portions of the posterior PFC, DLPFC (Brodmann areas 9 and 46), medial frontal gyrus (Brodmann area 8), VLPFC (Brodmann area 10), and ACC.⁴⁸ Decreased cerebellar vermal volume was reported in bipolar patients,^49,50 and decreased NAA concentrations are present in bipolar adolescents,²⁹ suggesting primary deficits in this region.

 

Functional Imaging Studies

Although resolution is limited, and neurofunctional specificity bounded by the nature of the cognitive probes employed, measures of network dysfunction can be inferred from patterns of response to cognitive and emotional stimuli in functional imaging studies. During performance of an identical pairs continuous performance attention task, bipolar patients showed increased activation of the VLPFC, as well as limbic and paralimbic structures, suggesting that reciprocal connections between these regions play a role in bipolar neuropathology.¹³ Working memory tasks are similarly associated with increased activation in the VLPFC, left thalamus and left caudate,¹⁵ and decreased activity in the ACC.⁵¹ Furthermore, increases in the VLPFC (Brodmann area 10) in patients with bipolar disorder have been associated with increasing working memory load.²⁸ Together, these findings suggest that performance of continuous performance and working memory tasks is associated with over-activation of striato- and thalamo-frontal portions of the ALN, with consequent inhibition of the ACC. Further, deficits in working memory performance may be related to inhibition of other portions of the PFC, including the DLPFC (Figure 2).

Stroop studies in euthymic bipolar adults together demonstrate a similar pattern of abnormal activation in the VLPFC, and decreased activation in the ACC, as well as in the temporal cortex, putamen and cerebellar vermis.^12,52 Other functional imaging studies in adult euthymic bipolar patients show a similar pattern of findings. Bipolar patients performing a gambling task demonstrate increased activity in VLPFC (Brodmann area 10), and suppression of DLPFC (Brodmann areas 9 and 46) activity observed in healthy subjects.²⁸

Bipolar patients also show decreased DLPFC activity, which was associated with increased amygdala activation, in response to fearful facial affect.⁵³ Malhi and colleagues⁵² observed that while viewing pictures intended to evoke emotions was associated with activation of the PFC and ACC in both bipolar and healthy subjects, bipolar patients also activated portions of the amygdala, thalamus, hypothalamus, and striatum. These functional imaging studies support a picture of increased reactivity in those portions of the ALN most identified with emotional regulation and consequent inhibition of other ALN structures, including the DLPFC and ACC. Increased activity in the ventral PFC may be closely tied to increased subcortical activity through prefrontal-striatal and thalamic feedback loops that are disrupted in patients with bipolar disorder.

 

White Matter Tracts

Recent imaging studies suggest that anterior limbic network dysfunction observed in bipolar disorder may be related to neuropathology of the white matter tracts linking the structures of the ALN. White matter hyperintensities (WMH), areas of increased signal intensity on T2 MRI images that may be indicative of neuropathological changes in white matter tracts, are more common in bipolar patients, particularly patients with bipolar I disorder compared with healthy controls.⁵⁴ WMH may be suggestive of early signs of demyelination³⁵ but remain poorly understood. Nonetheless, WMH are associated with both poor outcome and cognitive deterioration.⁵⁵ WMH can appear throughout the brain but have been observed to be more common in the frontal cortical portions of the ALN.⁴⁷

In addition to increased numbers of WMH, patients with bipolar disorder show overall deficits in white matter volume⁵⁶ that may extend to unaffected twins of bipolar patients.⁵⁷ Imaging studies of white matter volume and density³⁹ localize deficits to frontostriatal networks, in particular. Morphometric findings,³⁹ however, are non-specific and may reflect myelin changes and/or reduced axon density. The former interpretation is supported by findings of reduced expression of oligodendrocyte, myelin-related genes, and the transcription factors involved in myelin gene expression in bipolar patients.³⁵ 

Diffusion tensor imaging (DTI) is a magnetic resonance technique that utilizes measurement of water diffusion to study white matter tracts in vivo (Figure 3). Although relatively few DTI studies have been performed in patients with bipolar disorder, the limited data available suggest abnormalities in white matter tracts connecting portions of the PFC to subcortical structures in the ALN. Haznedar and colleagues16 observed decreased fractional anisotropy, suggesting white matter pathology, in the anterior fronto-occipital fasciciulus, which includes tracts connecting the orbitofrontal cortex to the temporal and occipital lobes, and in the posterior internal capsule, particularly in the anterior genu (cortiocthalamic fibers) in bipolar spectrum patients. Adler and colleagues⁵⁸ and Adler and colleagues⁵⁹ similarly observed decreased fractional anisotropy in prefrontal white matter tracts. Fractional anisotropy values inversely correlated with the number of depressive episodes, suggesting that impairment in these prefrontal-subcortical white matter tracts may be related to the appearance of mood states⁶⁰

 

Effects of Mood State on Network Dysfunction

Relatively limited data are available to compare network function in manic versus depressed patients. During a manual reaction time task, manic patients demonstrated increased activation of the left globus pallidus and decreased activation in the right globus pallidus, compared with depressed bipolar patients.⁶¹ Similar differences in laterality were observed by Blumberg and colleagues⁶² in bipolar patients performing a Stroop task. Manic patients showed decreased right VLPFC activity compared with euthymic subjects, while depressed patients showed increased activity in the left VLPFC. The ALN of bipolar patients may react differently to environmental cues across mood state as well. Chen and colleagues¹⁰ noted different activation patterns in the fronto-striatal-thalamic network during mania and depression while performing a facial affect task.

 

Conclusion

Until relatively recently many neuroimaging studies have treated neurophysiological findings as a form of phrenology, suggesting that specific portions of the brain are associated with specific cognitive and emotional traits. More recent neuroimaging studies suggest that emotion regulation is an emergent phenomenon that arises out of specific neural networks and that bipolar disorder represents the consequences of dysregulation in these networks. The work of several independent investigators drawing on a new wealth of neurophysiological findings in healthy subjects suggests that bipolar disorder represents dysfunctional changes in an anterior limbic network that includes traditional limbic structures and portions of the frontal cortex and cerebellum that have been found to be active in both emotional regulation and specific cognitive processes.

Convergent evidence from morphological studies of structures that make up the ALN, functional studies of both affective and cognitive stimuli, and more recent evidence of white matter pathology suggest that ALN dysfunction derives from several potentially overlapping areas of pathology in both specific neural structures and white matter tracts. Moreover, evidence suggests that some of these pathological changes are developmental in origin while others may represent the consequences of lesions elsewhere in the ALN. Healthy network formation requires both increased myelination of white matter tracts and synaptic pruning of gray matter.⁶³ Subcortical structures, such as the amygdala, basal ganglia, and thalamus, are mature by puberty,⁶⁴ and increased striatal volume in patients with bipolar disorder suggests a failure of pruning in at least a portion of the subcortical portion of the ALN. These findings are buttressed by evidence of abnormal striatal development in bipolar children and adolescents.⁶⁵ Similar abnormal developmental processes may be related to findings of white matter pathology as well.

Associations between measures of abnormal white matter diffusion and number of depressive episodes in bipolar disorder further support the clinical relevance of these developmental deficits. Pathological changes in portions of the PFC, particularly the VLPFC, seem to manifest later in the course of bipolar disorder and may be secondary to pathology elsewhere in the ALN. Morphologic changes in the VLPFC, for example, are not apparent in first-episode patients⁶⁶ but gradually appear in studies of multi-episode patients.⁶⁷ Progressive losses of volume in the VLPFC may be related to the excitotoxic effects of increased glutamate release in the PFC that may in turn be a consequence of over-activity in subcortical structures, and exacerbated by mitochondrial dysfunction in bipolar patients.⁶⁸

Future studies utilizing imaging and other techniques designed to better investigate network dysfunction are necessary to parse primary and secondary effects of network dysregulation in patients with bipolar disorder. Studying abnormalities of neuronal connections in these patients will further clarify the role of network dysfunction in the development and presentation of bipolar disorder with important consequences for facilitating our understanding of the underlying neurophysiology of this condition. Understanding these processes is essential for early identification of patients at risk for developing bipolar disorder and may lead to the development of new treatments aimed at preserving normal network activity, while protecting portions of the ALN that may be especially vulnerable to the effects of network dysregulation. By focusing on network dysfunction, rather than specific structures, we will continue to move away from the phrenology of bipolar disorder to a more complete understanding of the complex neuronal processes that underlie the spectrum of bipolar symptomatology.  CNS

 

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