Recurrent prominent mood swings are the most obvious characteristic of bipolar disorder. Thus it is not surprising that models of bipolar disorder emphasize the importance of disturbed emotion processing for the pathogenesis of this disorder. More precisely, models of bipolar disorder focus on abnormal unconscious and conscious evaluation of events (appraisal) relevant to the elicitation and regulation of emotions . The close link between emotion and motivation has received less attention but appears equally important in bipolar disorder as evaluation of stimuli as appetitive (reward) or aversive (punishment) facilitates either approach or avoidance motivation and behavior . Abnormal approach and avoidance behavior is observed in bipolar disorder patients in the manic and depressive states. During mania, patients seek rewarding outcomes more intensively despite potential negative consequences leading to such symptoms as an increase in goal-directed activity (at work, at school, or sexually) and excessive involvement in pleasurable activities. On the contrary, during depression, patients anticipate punishment rather than reward explaining why they show markedly diminished interest in almost all activities.
Despite these theoretical and clinical considerations, brain research in bipolar disorder has mainly focused on automatic emotional responses through the application of paradigms that use emotionally evocative stimuli like faces and words to elicit emotion during passive viewing, action choices, and facilitation or inhibition of responses. Most studies assess the activity of relevant brain regions using functional magnetic resonance imaging (fMRI) [3, 4], a technique that takes advantage of the different magnetic properties of oxygenated and deoxygenated blood. Measurement of this blood-oxygenated-level-dependent (BOLD) contrast reflects hemodynamic metabolic changes associated with neural activation, offering an indirect and complex representation of underlying neural processes [5, 6].
Based on the results of these studies, an imbalance between the activity of ‘core emotional’ brain regions and brain areas associated with both emotion and cognition has been proposed to underlie bipolar symptoms. Ventrally located ‘core emotional’ brain regions like the amygdala, the striatum, the orbitofrontal cortex, the subgenual and ventral anterior cingulate cortex, and the ventromedial prefrontal cortex are thought to be hyper-active in bipolar disorder, whereas regions belonging to the extended emotional and cognitive control network like the hippocampus, the anterior insula, the dorsal prefrontal cortex, and the posterior cingulate cortex are assumed to be hypo-active [7, 8]. Although the simplicity of this model is rather intriguing, one has to consider that each of these regions is itself a complex area that is connected to other regions forming different networks involved in numerous not exclusively emotional processes. In other words, each of these regions that showed abnormal activity in response to emotionally relevant stimuli in bipolar disorder patients is involved in multiple cognitive and emotional processes like emotion elicitation, emotion regulation, and motivation, which are carried out by several of these regions .
In the present chapter, we will review imaging literature examining both emotional and motivational processes as they are tightly linked psychological processes that represent two sides of the same coin. Whereas the focus on emotion implies a certain state of feeling, emphasis of motivation relates to a certain state of goal, pursuit like the achievement of pleasant feelings and the avoidance of unpleasant feelings. Imaging literature examining emotional processes in bipolar disorder will be reviewed, focusing on different stages of emotion processing (early emotional processes, elicitation of an emotional response, emotion regulation). Review of motivational processes will center on anticipation of positive and negative consequences and the delivery of these consequences. We will discuss volumetric alterations in relevant brain areas and we will also describe findings, which examine structural connectivity between these regions. Next we will address the question whether functional and structural abnormalities related to disturbed emotion and motivation processing in bipolar disorder are more likely to evolve during the course of the disease or rather constitute a vulnerability factor for bipolar disorder. We will also discuss current knowledge about the effects of mood states and psychotropic medication on emotional and motivational processes in bipolar disorder.
2. Emotional processes
Various theoretical accounts agree that emotion processing includes different mechanisms that vary with respect to the involvement of attentional and cognitive resources. In more detail, these mechanisms comprise a pre-attentive stage, attention allocation, sensory perception, transient and automatic emotional responses, experience and expression of emotion, higher-level appraisal of emotional stimuli, and finally the regulation of emotions . From an experimental and clinical neuroscience perspective, it is important to make a distinction between these sub-processes in order to be able to validly characterize disturbed or maladaptive processes into psychopathologies. In this chapter, we will roughly divide these mechanisms into (1) early emotional processing, (2) emotional responses including transient, automatic responses and the subjective emotional experience, and (3) expression of emotion and emotion regulation (see Figure 1).
2.1. Early emotional processes
Early emotional processes refer to the attribution of salience to motivationally relevant stimuli and the allocation of attentional resources to these stimuli. These processes are known to rely on the amygdala, thalamus, prefrontal cortex, parietal cortex, and visual processing areas [9, 11, 12]. In bipolar disorder, the identification of disturbances in neural networks during these early stages of emotional processing is complicated by general attention deficits. Applying the Stroop color-word selective attention task, blunted activation in the ventral prefrontal cortex [13-16], anterior cingulate cortex , and parietal cortex  has been reported for bipolar disorder patients compared to healthy controls. Reduced activation in the anterior cingulate cortex and the parietal cortex has also been reported during high attentional control during a n-back task . Furthermore, manic bipolar disorder patients displayed stable amygdala hyper-activation and striatal and thalamic deactivation during sustained attention compared to healthy persons .
In contrast to ‘pure’ attentional tasks where bipolar disorder patients showed hypo-activation of the ventral prefrontal cortex, the anterior cingulate cortex, and the parietal cortex in response to non-emotional targets, studies examining attention to non-emotional targets while emotional distractors are presented have produced rather conflicting results in bipolar disorder patients. In response to emotional distractors, the medial orbitofrontal and medial prefrontal cortex were hyper- [20-22] and hypoactive [21, 23] in euthymic and manic bipolar disorder patients. Similar hyper- [18, 20, 24] and hypo-activity  of the anterior cingulate cortex as well as hyper-  and hypo-activity [21, 26, 27] of the dorsolateral prefrontal cortex have been observed during the presentation of emotional distractors. Furthermore, the hyper-activity of the insula [20, 21] and posterior regions such as the precuneus , parietal cortex , and posterior cingulate cortex  have occasionally been reported.
More consistently, striatal hyper-activity in response to emotional distractor, has been observed in euthymic bipolar disorder patients using various tasks such as an emotional go/no go task , an emotional Stroop task , an emotional n-back paradigm , and a task asking participants to direct attention to non-emotional aspects (age, gender) of emotional faces [22, 26, 27]. Furthermore, hyper-activation of the amygdala in euthymic bipolar disorder patients has also been frequently reported using different paradigms, testing the influence of emotion on attentional processes [18, 21, 24, 28, 29]. However, there have also been reports of no alterations in amygdala activity [27, 30] and hypo-activity of amygdala . Interestingly, several authors reported reduced connectivity between the amygdala and various regions such as the dorsal anterior cingulate cortex , the perigenual anterior cingulate cortex , the posterior cingulate cortex, and the parahippocampal cortex  – all implicated in ‘pure’ attentional deficits of bipolar disorder patients.
Thus, in contrast to ‘pure’ attentional tasks associated with hypo-activity of frontal and parietal brain regions in bipolar disorder patients, attention allocation on non-emotional targets in the presence of emotional distractors is not clearly associated with hypo- or hyper-activity of the frontal and parietal areas. Inconsistencies concerning the activity of the frontal and parietal brain regions during attention allocation on non-emotional targets might be related to reduced connectivity between these regions and the amygdala, which was reported to be rather hyperactive during attention allocation on non-emotional targets. As most results stem from studies investigating euthymic bipolar disorder patients, reports of hyper-activity of frontal and parietal brain regions might point towards a compensatory mechanism meant to down-regulate subcortical structures. Further, striatal hyper-activation during attention allocation on non-emotional targets was the most robust finding. Although this has not been investigated so far, altered connectivity between the striatum and frontal brain regions might also be of importance during attention allocation on non-emotional targets.
With regard to emotional targets of attention, studies have produced very discrepant results. When pediatric bipolar patients were asked to direct their attention towards emotional aspects of emotional faces, either hyper-activation of the amygdala  or no alterations in amygdala activity [33, 34] were observed. Furthermore, hypo-activation in the prefrontal cortex and the anterior cingulate cortex and hyper-activation in the right precuneus and the fusiform gyrus were reported . Using an emotional go/no go task, enhanced response of the ventral prefrontal cortex to emotional targets was reported for manic bipolar disorder patients .
Some of the discrepancies described above are likely due to methodological variety as studies used paradigms addressing different psychological processes such as selective attention [21, 22, 26, 27, 30, 33, 34] and executive functions involving attention such as response inhibition [20, 35], set-shifting , and working memory  corresponding to different neural circuits. Furthermore, studies varied with respect to emotional valence of distractors – some used only negative and neutral distractors , whereas others applied positive, negative and neutral distractors [18, 20, 28, 30, 35]. In addition, bipolar disorder patients in different mood states were examined. Further, conflicting results might also be due to effects of psychotropic medication. However, this influence was not tested in three of the studies reviewed above [20, 28, 35], whereas others ruled out the possibility that psychotropic medication confounded the results [18, 22, 23, 27, 29-31, 33]. However, Hassel and colleagues (2009) showed that increased medication load was associated with decreased activity of the dorsolateral prefrontal cortex while directing attention away from fearful faces and increased activity of the ventral striatum while focusing attention away from the emotional content of happy faces.
In summary, it seems very interesting that although ‘pure’ attentional deficits in bipolar disorder seem to be related to hypo-activity in the ventral prefrontal cortex and anterior cingulate cortex, this pattern is likely to be reversed to hyper-activation in both structures in the presence of emotional distractors. On a cautious note, first results indicate that this change might be related to altered connectivity of these structures with the amygdala [18, 31], which showed hyper-activation in response to emotional distractors. As the striatum displayed rather robust hyper-activity in the presence of emotional distractors, altered connectivity between the striatum and frontal brain regions might also be of relevance and needs to be investigated in the future. Nevertheless, existing results underline that there is not one disturbed network in bipolar disorder, but that the task-dependent interaction between networks is of great interest and relevance.
Future studies should compare patients in different symptomatic states. This seems especially interesting, as it has been suggested that both mood states of bipolar disorder are associated with a mood- congruent attentional bias. And indeed, some behavioral studies have reported a mood-congruent attentional bias in manic and depressed bipolar patients [36, 37] that might even persist during remission [38-40]. Although, there are also reports indicating a mood-congruent cognitive bias only for depressed bipolar patients  and mood-incongruent bias in manic and depressed patients .
2.2. Affective response and evaluation
With respect to the emotional response and appraisal of emotional stimuli, studies on bipolar disorder have mostly focused on the recognition of emotions and the reaction to emotional stimuli. As previous studies have demonstrated that neural responses to emotional stimuli are dependent upon the nature of the task performed during stimulus presentation and the valence of the emotional material used [43-46], we will review the existing literature grouped according to the involvement of cognitive processes and appraisal and valence of emotional stimuli.
Firstly, we will present results from passive viewing tasks instructing the participants to view the stimuli without drawing any cognitive interference. Independent of the valence of the emotional stimuli used, this task is known to activate networks involving the medial prefrontal cortex and the anterior cingulate cortex . Secondly, results from affect matching tasks demanding to choose one out of two pictures matching the emotional valence of a target picture will be reviewed. This is a perceptual task with rather low involvement of cognitive appraisal known to activate the amygdala, the thalamus, and the fusiform gyrus . Finally, evidence derived from affect recognition tasks asking participants to label emotional pictures will be discussed. In contrast to the other two paradigms, this task involves cognitive appraisal and was shown to deactivate the amygdala and to activate the prefrontal and temporal cortices [43, 45, 46]. For this task, we will differentiate between different emotional valence such as happiness, sadness, fear, and disgust.
2.2.1. Passive viewing
Bipolar disorder patients display hypo-activation of the ventrolateral prefrontal cortex during mania [47, 48], euthymia , and depression [48, 50] when passively viewing pictures of negative emotional valence. With regard to the amygdala, hyper-activation during mania , euthymia , depression  and in a mixed sample  have been reported. However, hypo-activation during mania and euthymia , and no alterations during mania  have also been reported. Further reports include increased activity of the anterior cingulate during mania when viewing fearful faces , euthymia when viewing angry and happy faces , and in a mixed sample when viewing happy faces . Also, striatal hyper-activity during mania when viewing fearful faces  and in a mixed sample when viewing happy faces  was observed. Hyper-activation of the prefrontal cortex, superior temporal gyrus, thalamus, and hypothalamus when viewing pictures of negative valence and increased activity of the prefrontal cortex, superior temporal gyrus, fusiform gyrus, parahippocampal gyrus, and thalamus when viewing pictures of positive valence have been reported in depressed bipolar disorder patients . Unfortunately, none of the studies using passive viewing of emotional pictures in bipolar disorder patients examined the effects of psychotropic medication. Nevertheless, hypo-activation of the ventrolateral orbitofrontal cortex is a very robust finding in bipolar disorder patients during passive viewing of emotional stimuli. In addition, hyper-activation of the anterior cingulate cortex and the striatum have been frequently and consistently reported across mood states.
2.2.2. Face matching tasks
Interestingly, both manic [54, 55] and depressed  patients showed hypo-activation of the ventrolateral prefrontal cortex during this task, but during euthymia, hyper-activation of the lateral prefrontal cortex was observed, although anticonvulsants showed some normalizing effect . When manic bipolar disorder patients were asked to match facial expressions, they displayed hyper-activation of the amygdala [54, 55]. Euthymic patients did not show any hyper-activation of the amygdala, which might be attributed to antidepressants . Furthermore, increased activity of the thalamus and the ventral anterior cingulate cortex during mania , and increased activity of the dorsolateral prefrontal cortex during depression  have been observed. However, as only four studies used this paradigm to investigate bipolar disorder patients, it is difficult to draw any clear and valid conclusions. Although the possible influence of psychotropic medication has not been frequently tested, hypo-activation of the ventrolateral prefrontal cortex has been repeatedly shown across mood states during this task [54-56].
2.2.3. Affect recognition tasks
When asked to recognize happy facial expressions, neuronal activity in manic , euthymic , and depressive  bipolar disorder patients did not differ from controls. However, others reported hypo-activation of the parahippocampal gyrus during euthymia  and depression  but hyper-connectivity between parahippocampal gyrus and subgenual anterior cingulate cortex during euthymia . Further, depressed bipolar disorder patients showed hyper-activity of the striatum, ventral prefrontal cortex [42, 60], superior frontal gyrus, middle temporal gyrus, visual cortex, thalamus, and dorsal and posterior cingulate gyrus , and they showed hypo-activation of the thalamus and amygdala  while recognizing positive affect. Thus, altered activation during appraisal of positive stimuli appears to be rather state dependent in bipolar disorder.
When asked to recognize sad facial expressions, manic bipolar disorder patients showed hyper-activity in the posterior cingulate cortex, nucleus caudate, posterior insula, temporal cortex , and fusiform gyrus , but they showed hypo-activation in the subgenual anterior cingulate and parahippocampal gyrus . Euthymic bipolar disorder patients displayed hypo-activation in the prefrontal and cingulate cortex but hyper-activation in the parahippocampal gyrus . Depressed bipolar disorder patients showed increased activity of the amygdala [58, 59], hippocampus, and ventral prefrontal cortex  but decreased activation of the orbitofrontal cortex, putamen, and dorsolateral prefrontal cortex . Further, connectivity between the amygdala and the orbitofrontal cortex was increased in depressed bipolar disorder patients during recognition of a sad facial expression . However, no altered brain activation was also reported for euthymic  and depressed  bipolar disorder patients. Similarly to reports concerning appraisal of happiness, altered brain activation in response to appraisal of sadness also seems to be rather state dependent.
When labeling fearful facial expression, manic, euthymic, and depressed bipolar disorder patients showed hyper-activation of the parahippocampal gyrus and the temporal cortex [42, 63]. Further, hyper-activity of the prefrontal cortex, nucleus caudate, putamen, thalamus, and brainstem was observed during mania and depression . There are also reports of increased activity in the amygdala in depressed bipolar disorder patients [58, 60] and hyper-activity of the hippocampus, the parietal cortex, and lingual cortex as well as hypo-activity of the precentral gyrus in euthymic bipolar disorder patients . However, no alterations were also reported for manic  and euthymic  bipolar disorder patients. Comparable to reports for happy and sad affect, altered brain activation in response to fear appraisal seems to be rather state dependent in bipolar disorder except, potentially, hyper-activation of the parahippocampal gyrus, which has been reported to be hyper-active across mood states.
Labeling disgust has only been investigated in euthymic bipolar disorder patients. Disgust appraisal was reported to be associated with increased activity of the nucleus caudate, hippocampus , occipital cortex, and lingual cortex . Furthermore, hypo-activity of the prefrontal cortex [63, 64], anterior cingulate cortex, thalamus , insula, fusiform gyrus, and precuneus was observed .
Studies combining different emotions during data analysis also showed rather heterogeneous results of hyper-activity in the orbitofrontal cortex and in the nucleus caudate during mania , and hyper-activity of the amygdala, hippocampus, orbitofrontal cortex, and insula during euthymia . Further, in a sample of mixed states, hyper-activation of the dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, insula, and superior temporal gyrus when labeling negative pictures also occurred . When recognizing positive pictures, hyper-activation of the medial prefrontal cortex, anterior cingulate cortex, nucleus caudate, thalamus, and precuneus was observed .
Regarding appraisal of affective stimuli, no clear pattern of hyper- and / or hypo-activation has emerged so far. Reports are especially inconsistent for frontal brain regions. During all mood states, hyper-activity of the prefrontal brain regions [42, 55, 65] but also no altered activity in the prefrontal cortex [36, 58, 59, 62, 67] has been reported. Furthermore, there are also reports of hypo-activity in the prefrontal cortex during mania and euthymia [55, 63, 64]. When ignoring the valence of the emotional stimuli, hyper-activation of the striatum [36, 42, 64-66] and amygdala [55, 58, 59, 65] are most consistently found across mood states. However, one has to keep in mind that many studies also reported no activation differences for the striatum [55, 58, 59, 62, 63, 67] and amygdala [36, 42, 62, 63, 67].
In part, medication effects might explain heterogeneity of the results. Unfortunately, many authors did not test whether there was a significant influence of psychotropic medication [36, 42, 55, 63, 64, 66]. Whereas some studies ruled out such influence [59, 65, 67], others reported negative correlation between medication load and amygdala activation  and an influence of psychotropic medication on the functional connectivity between the amygdala and orbitofrontal cortex  during labeling of sad affect.
Interestingly, when tasks like passive viewing and stimulus matching, which do not explicitly ask for appraisal of emotional stimuli, are used, hypo-activity of the ventrolateral prefrontal cortex independent of the emotional valence of the stimuli is consistently observed across mood states. Furthermore, abnormal activity of the anterior cingulate cortex has been frequently reported for ‘appraisal-free’ tasks, although it seems that hypo- or hyper-activity of this region is more related to current mood state and psychotropic medication. However, when using affect recognition tasks, which ask for appraisal of emotional stimuli, a different picture evolves. In case of appraisal, which always implicates a certain personal relevance, hyper-activity of the ventral striatum is the most robust finding across mood states. Although altered activity of the prefrontal brain regions, parahippocampus / hippocampus, insula, and thalamus has also be repeatedly observed, it seems to depend on mood states and medication. It is also important to note that, independent of the mood state, hyper-activation of the amygdala has been consistently observed during both ‘appraisal-free’ and ‘appraisal-demanding’ tasks.
2.3. Emotion regulation
The inability to effectively regulate emotions within an adequate range and to adapt to the respective context has been proposed to be at the core of bipolar disorder [1, 8]. Until now, however, neural correlates of voluntary emotion regulation have not been investigated in bipolar disorder. One major problem in emotion regulation research in general is a very heterogeneous conceptualization of emotion regulation and, consequently, diverse operationalization in experimental research.
According to Gross and Thompson (2007), emotion regulation refers to the process of increasing or decreasing current affect. Such a process may occur consciously or unconsciously on a continuum from effortless and automatic (unconscious) to effortful and controlled regulation (conscious). Within their model of emotion regulation, the authors  differentiate five types of emotion regulation strategies which can be broadly divided into (1) antecedent-focused strategies, occurring before full-blown emotional responses are elicited (situation selection, situation modification, attentional deployment, and cognitive change), and (2) response-focused strategies, occurring after emotional responses are generated (response modulation). In experimental emotion regulation, research focus has been placed on the investigation of a few strategies, particularly on distraction as an example for attentional deployment, on reappraisal as an example for cognitive change, and on suppression as an example for response modulation. Whereas distraction refers to redirecting attention away from the emotional features of the situation to different, potentially non-emotional aspects of the situation, reappraisal refers to changing the meaning of a situation or how we think about a situation in order to alter its emotional significance.
In a way, some of the studies reviewed in the section of early emotional processes might also be considered to have examined deployment of attention as participants were asked to ignore emotional distractors and focus on the task. These studies most consistently showed hyper-activity of the striatum and the amygdala during distraction, yet there is a difference between emotional distractors presented during a cognitive task and conscious perception of an emotional stimulus followed by the ‘decision’ to redirect attention in order to prevent in depth processing of this stimulus.
Recently, our research group completed a study on the neural correlates of two different voluntary emotion regulation strategies, namely distraction and reappraisal in patients with bipolar-I disorder (unpublished manuscript). Bipolar disorder patients showed impaired down-regulation of amygdala activity in response to positive and negative stimuli during reappraisal when compared to healthy controls, but not during distraction. This impaired amygdala down-regulation was mediated by a relatively reduced negative connectivity between the amygdala and the lateral orbitofrontal cortex. These first results concerning emotion regulation mechanisms in bipolar disorder underline the importance of appraisal mechanisms for understanding emotional disturbances in bipolar disorder. However, more studies are needed to draw further conclusions.
In summary, consideration of appraisal might be essential in understanding altered brain activation in response to emotional stimuli in bipolar disorder. If the task does not ask for appraisal of the emotional stimuli but allows emotional content without assigning any meaning to it (passive viewing: “just look what is there”; face matching: “compare whether you see the same”), hypo-activity of the ventrolateral prefrontal cortex is observed independent of the emotional valence of the stimuli or the current mood state. However, as soon as the task labels the emotional content as important with either a positive (affect recognition: “correct labeling of emotion means mastering the task”) or negative (emotional distractors: “affect is an information that might prevent the person from mastering the task”) connotation, hyper-activity of the striatum implicated in learning and evaluation  is the most consistent finding across mood states. Further, in case of negative appraisal, the ventral prefrontal cortex known to encode behavioral significance  and the anterior cingulate cortex shown to process choice predictions and prediction errors  have been reported to be rather hyper-active. In contrast, positive appraisal of emotional content is not clearly associated with hyper- or hypoactivation of ventral prefrontal structures or anterior cingulate cortex.
Interestingly, hyper-activation of the amygdala has been reported during both ‘appraisal-free’ and ‘appraisal-demanding’ tasks independent of the mood state. Further, euthymic bipolar disorder patients also showed hyper-activation of amygdala activity during reappraisal of positive and negative stimuli. Further, there are several reports of altered functional connectivity between the amygdala and various regions such as the lateral orbitofrontal cortex , the dorsal anterior cingulate cortex , the perigenual anterior cingulate cortex , the posterior cingulate cortex, and the parahippocampal cortex , which itself has been shown to be differentially connected to the subgenual anterior cingulate cortex in bipolar disorder . However, only a few studies have examined functional connectivity during emotion processing in bipolar disorder, so definite conclusions cannot be drawn.
It would be interesting to see the results of a meta-analysis that considers the proposed differentiation between ‘appraisal-free’ and ‘appraisal-demanding’ tasks. To date, meta-analyses included tasks using emotional stimuli irrespective of the task given to the patients. Results of recent meta-analyses consistently showed hypo-activation of the ventrolateral prefrontal cortex during emotional processes [72-74]. Further, meta-analyses showed hyper-activity of the parahippocampal gyrus [72-74], striatum [73, 74], and amygdala [72, 73] in bipolar disorder patients compared to healthy controls. However, a recent review on emotion processing and regulation in bipolar disorder concluded that amygdala activation is rather likely to vary as a function of mood state .
These results have already been incorporated in a ‘condensed’ neurobiological model of bipolar disorder suggesting that impaired prefrontal-limbic modulation in two networks: (1) a network originating in the ventrolateral prefrontal cortex and (2) a network starting from ventromedial prefrontal cortex underlies bipolar disorder . Both networks are thought to be similarly organized, building iterative feedback loops that process information and modulate activity of the amygdala, the ventral striatum, and the thalamus. Whereas the first network is assumed to be involved in the modulation of external emotional cues such as emotional faces, the second network supposedly regulates internal emotional states [77, 78]. Although the simplicity of this hypothesis is rather intriguing, it remains unclear how complex processes of appraisal and reappraisal might be integrated in this model. Further, this model does not account for motivational aspects of the bipolar symptomatology.
3. Motivational processes
In general, motivation is defined as the process of initiating, controlling, and maintaining behavior with the goal of maximizing pleasant outcomes [79; see Figure 2]. Thus, motivation has been closely linked to the human reward network , whose key structures are the midbrain dopamine neurons, the ventral striatum representing reward anticipation , the orbitofrontal cortex embodying the value of possible outcomes, and the anterior cingulate cortex coding the value of actions to guide future behavior . However, information about the incentive value alone is not sufficient to actually receive the reward but must be combined with planning, decision-making, troubleshooting, learning, and the overcoming of strong habitual responses. Consequently, other structures, including the dorsolateral prefrontal cortex guiding the allocation of attentional resources and the learning of stimulus-response contingencies , the habenula and the amygdala involved in the devaluation of previously rewarding stimuli [82, 83], and the thalamus integrating information about reward from different brain areas are involved in motivation regulation .
Most of the structures comprising neurobiological models of bipolar disorder are innervated by dopaminergic projections ascending from the ventral tegmental area to the mesolimbic system, including the ventral striatum, the amygdala, and the hippocampus, as well as the mesocortical system, which includes, among others, the dorsomedial prefrontal cortex, the anterior cingulate cortex, and the orbitofrontal cortex . These dopamine-irrigated structures are the neural correlate of the behavioral activation system, which mediates individual differences in sensitivity and reactivity to appetitive stimuli. High behavioral activation system sensitivity is associated with enhanced appetitive stimuli processing and approach-motivation as well as the diminished processing of aversive stimuli. However, the behavioral activation system might also facilitate active avoidance when safety is perceived as a reward and aggression when reward acquisition is blocked . Thus, hypersensitivity of the behavioral activation system refers to extreme reactions of this system in response to motivationally relevant stimuli also depending on the pre-event state of the behavioral activation system [2, 84, 86]. Extreme fluctuations in activation and deactivation of the behavioral activation system are then reflected in such bipolar symptoms as “excessive involvement in pleasurable activities that have a high potential for painful consequences e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments” during mania and “markedly diminished... pleasure in all, or almost all, activities” during depression .
Whereas the reaction to primary emotional stimuli such as fear, anger, disgust, and happiness has been extensively investigated in bipolar disorder patients, neuroimaging studies on reward processes and motivation in patients with bipolar disorder are extremely rare, although altered reward processing has recently been hypothesized to represent an important mechanism of the alternating phases of mania and depression . On a behavioral level, a reduced and delayed response bias towards more frequently rewarded stimuli was reported in euthymic patients with bipolar disorder . In addition, previous studies have shown that euthymic bipolar disorder patients need more time when the consequence of a decision leads to reward or punishment [90-92]. This might indicate a general deficit in responding to motivationally relevant stimuli in bipolar disorder patients.
3.1. Anticipation of positive and negative consequences
In general, anticipation of positive consequences (reward) has been linked to the concept of incentive motivation . The most important brain structures involved in the anticipation of reward are dopaminergic and include midbrain regions (substantia nigra, ventral tegmental area) projecting to the striatum (nucleus caudatus, putamen, nucleus accumbens) and the frontal cortex [94, 95].
To date, only three studies have examined the anticipation of positive and negative consequences in bipolar disorder patients. During a delayed-incentive paradigm, no differences were observed in a small sample of twelve manic patients in response to expected rewards compared to healthy controls and schizophrenic patients . In a second study, manic patients showed increased activation of the orbitofrontal cortex when expecting increasing gain and decreased responses of the orbitofrontal cortex when expecting increasing loss, which normalized in a subsample of seven patients after remission . In the third study, greater activation in the right ventral striatum and the right lateral orbitofrontal cortex was observed in euthymic bipolar disorder patients compared to healthy controls during reward anticipation. However, no significant group differences were observed during anticipation of loss . All studies tested whether results were influenced by psychotropic medication, but this was not the case.
As there are only a few studies with conflicting results, no definite conclusions can be drawn. However, first evidence suggests that the orbitofrontal cortex is especially relevant for alterations in reward anticipation in bipolar disorder.
3.2. Delivery of positive and negative consequences
Similarly, only a few studies have investigated the neural correlates of reward and punishment delivery. During a delayed-incentive paradigm, manic patients showed significantly decreased activation of the nucleus accumbens in response to the receipt or omission of expected rewards, which was interpreted as deficits in prediction error processing . However, other studies have failed to replicate this result in a different sample of manic patients . Errors made during a behavioural task with changing reward contingencies correlated negatively with activity in orbitofrontal and striatal brain regions in bipolar disorder patients when measured during a separate language-processing task . In addition, increased activation in the frontal polar region close to the orbitofrontal cortex was reported in manic patients during reward processing . However, in euthymic pediatric bipolar disorder patients applying the same task with changing reward contingencies, increased activation in parietal and frontal brain regions, but not in the orbitofrontal cortex, have been reported . Further, adding more inconsistency, a study comparing a small sample of twelve depressed bipolar disorder patients to healthy controls observed no difference in neuronal activations during the same task . Furthermore, decreased activation of the ventral prefrontal cortex and increased activation of the anterior cingulate cortex in response to the receipt of reward during a gambling task were reported for euthymic bipolar disorder patients . In a recent study of our group, greater activation in response to reward and decreased deactivation in response to reversal of reward contingencies were observed in the medial orbitofrontal cortex in euthymic bipolar patients . Further, activation of the amygdala in response to reversal of reward contingencies was increased. In response to reward, there was a significant negative correlation between medication and amygdala activation in bipolar disorder patients. Heightened activation of the medial orbitofrontal cortex and the amygdala during wins was interpreted as heightened sensitivity toward reward, whereas greater activation of the amygdala and reduced deactivation of the medial orbitofrontal cortex during rule reversal was suggested to represent an attenuated prediction error signal. Interestingly, heightened reward sensitivity and reduced prediction error signal, as coded by the medial orbitofrontal cortex, was significantly correlated with the score of the behavioral activation system scale, lending further support to the behavioral system dysregulation model . Last but not least, increased activity in the lateral orbitofrontal cortex, the dorsal anterior cingulate cortex, and the putamen in response to changing reward contingencies was also observed; it was suggested that this might represent a compensatory mechanism that aids in suppressing previously rewarded responses, thus allowing adequate performance during euthymia . Interestingly, despite the significant negative correlation between amygdala response and psychotropic medication observed by Linke and coworkers (2012), no influence of psychotropic medication on brain responses upon delivery of reward or punishment have been observed in other studies [96, 97, 99, 101].
To sum up, in bipolar disorder, the orbitofrontal cortex seems to react differently upon delivery and omission of reward in a way that suggests a heightened reward sensitivity and deficient prediction error signal of this brain structure, which might even be a vulnerability factor for bipolar disorder. Furthermore, other key structures of the human reward system, namely the ventral striatum, the anterior cingulate cortex, and amygdala, seem to react differently upon reward delivery in bipolar disorder patients compared to healthy controls. However, the connection between these alterations needs to be investigated in more depth in the future.
In patients with bipolar disorder and individuals with an increased risk to develop bipolar disorder, reward anticipation and reward delivery seems to elicit a more pronounced response in the orbitofrontal cortex, which is known to code the positive value an individual places on rewards . Furthermore, if a previously rewarding stimulus has lost its rewarding properties, it will still be more likely to elicit a response in the medial OFC, similar to the response upon reward in euthymic bipolar disorder patients and high-risk individuals. This combination of heightened reward sensitivity and attenuated prediction-error signals in response to changing reward contingencies might facilitate the pursuit of immediate rewards despite the negative consequences in the medium or long term. Further, increased motivation to approach rewarding, or at least formerly rewarding, stimuli is likely to be present before the onset of bipolar disorder and could therefore be a vulnerability factor for this disease.
4. Structural alterations in networks associated with emotion and motivation
4.1. Gray matter alterations
In bipolar disorder, regional abnormalities of gray matter volume have been reported for all regions involved in the described emotional and motivational networks. But, as most studies have been performed on heterogeneous samples with respect to illness subtype, medication status, comorbidity, and mood state, they have produced conflicting findings.
Results have been especially inconsistent for the ventral striatum, the amygdala, the anterior cingulate cortex, the thalamus, and the hippocampus. Studies have reported larger caudate volumes in males  and in both affected and unaffected monozygotic bipolar twins  compared to controls. However, other studies have found no differences in the caudate of bipolar disorder patients [107-113] or decreased caudate volume . Similarly, putamen enlargement was reported [112, 115, 116], but other studies found no differences in the putamen [105, 107, 113] or decreased volume . Studies also showed reduced volume in the nucleus accumbens [118, 119]. With respect to the amygdala, findings indicate an enlargement of this structure [120-124], but reductions of amygdala volume have also been reported [118, 125-129]. There were also frequent reports of enlargement of the anterior cingulate cortex [130-133]; however, other studies found volume reductions of the anterior cingulate cortex . Studies reported increased volume of the thalamus [123, 131], while others showed no differences  or reduced volume of the thalamus [119, 135]. Regarding the hippocampus, some studies reported increased volume  as well as decreased volume [119, 137]. By contrast, reports of gray matter abnormalities for dorsolateral prefrontal cortex [118, 134, 138-140] and the habenula  have been infrequent but show a more consistent pattern of reduced volume. For the orbitofrontal cortex, decreased volume [117, 134, 142] and neuronal size reduction  have been reported, in addition to no alterations .
Interestingly, there has been evidence suggesting that abnormal gray matter volumes in the amygdala, hippocampus, thalamus, anterior cingulate cortex, and orbitofrontal cortex are not pervasive characteristics of bipolar disorder but may instead be associated with specific clinical features. Mood-stabilizers, such as lithium, were shown to increase the gray matter volume of the amygdala, hippocampus, and anterior cingulate cortex in bipolar disorder [116, 145-149]. In contrast, antipsychotics and anticonvulsants do not seem to influence gray matter volume of structures involved in emotional and motivational processes . In addition, a longer duration of illness has been associated with increased gray matter in the basal ganglia, the anterior cingulate cortex, and the amygdala  as well as loss of hippocampal gray matter . Further, depressive episodes have been associated with gray matter density increases in the orbitofrontal cortex and gray matter density decreases in the prefrontal cortex and anterior cingulate cortex .
Based solely on the empirical evidence reviewed above, it is difficult to draw conclusions about potential morphological alterations associated with emotional and motivational circuits as there is either insufficient data on volumetric alterations (habenula, dorsolateral prefrontal cortex) or the results are too heterogenic (striatum, amygdala, thalamus, hippocampus, and orbitofrontal cortex). However, on an important note, a meta-analysis of gray matter alterations in bipolar disorder revealed gray matter reductions in the rostral anterior cingulate cortex , which, in addition, seems to be specific to bipolar disorder but not schizophrenia . Hence, gray matter loss in the anterior cingulate cortex, which was also shown in a recent meta-analysis , might be the most promising correlate of aberrant emotional and motivational processes emerging from volumetric studies of gray matter alterations.
4.2. White matter alterations
The different gray matter regions constituting networks related to emotional and motivational processes are connected through white matter, which is composed of axons. Deviation from normal axonal organization can be investigated using diffusion tensor imaging, a technique that quantifies the restricted diffusion of water in white matter through scalars, such as fractional anisotropy (FA). Fractional anisotropy is known to be positively correlated with the directionality and coherence of white matter bundles . Although studies of bipolar disorder using diffusion tensor imaging lag behind other psychiatric diseases such as schizophrenia, the existing body of evidence strongly suggests that the loss of white matter integrity in fronto-limbic and cortical-striatal-thalamic circuits is a biological vulnerability factor for bipolar disorder . In more detail, it has been hypothesized that impaired development of white matter, such as altered prefrontal pruning, leads to decreased connectivity within emotional and motivational networks. This is further thought to result in impaired top-down and bottom-up modulation of prefrontal-limbic circuits eventually leading to symptoms of bipolar disorder [76, 156].
With regard to motivation, the integrity of the anterior corpus callosum providing interhemispheric connections between the left and right ventral prefrontal cortex and the anterior limb of the internal capsule, which contains fibers interconnecting the thalamus, striatum, amygdala, hippocampus, anterior cingulate cortex, orbitofrontal cortex, and dorsolateral prefrontal cortex [157, 158], seems to be of particular relevance. In more detail, risky decision-making has been shown to be negatively correlated with the integrity in the corpus callosum [159-161] and the integrity of the anterior limb of the internal capsule . Interestingly, pathological gambling was also negatively related to the integrity of the anterior limb of the internal capsule itself and the uncinate fasciculus . On an important note, the integrity of the uncinate fasciulus is also positively associated with recognition of fearful facial expression , harm avoidance , and neuroticism , pointing towards its relevance for emotional processes.
During depression, mania, and euthymia, reduced white matter integrity, especially in the anterior corpus callosum in children and adolescents [167-170] as well as in adults [171-177] suffering from bipolar disorder, has been described. Interestingly, a normalizing effect of lithium on the volume of the corpus callosum has been observed , and a study of euthymic bipolar disorder patients even reported increased integrity of the corpus callosum . Furthermore, all but one  tractography study showed reduced white matter integrity in the anterior thalamic radiation [181-183], which passes through the anterior limb of the internal capsule  in depressed, euthymic, and manic patients. In line, reduced white matter integrity in the anterior limb of the internal capsule has also been repeatedly observed in bipolar patients [173, 185, 186]. Similar, reduced integrity of the uncinate fasciculus, which interconnects the amygdala with the orbitofrontal cortex and the anterior cingulate cortex , has also been frequently observed in depressed and euthymic bipolar disorder patients [173, 180, 182, 183, 188, 189]. Although, increased white matter integrity and increased number of fibers have also been reported for the uncinate fasciculus [180, 190]. On an important note, the integrity of the uncinate fasciculus was shown to influence functional coupling between the anterior cingulate cortex and the amygdala . Reports of reduced white matter integrity of the orbitofrontal cortex [191, 192], which were shown to be related to impulsivity and suicide attempts , are of further interest for the understanding of neurobiological underpinnings of emotional and motivation processes in bipolar disorder.
The effect of psychotropic medication on white matter integrity has been less thoroughly investigated than its influence on gray matter integrity. There are some studies stating that psychotropic medication such as lithium, antidepressants, or antipsychotics do not affect the corpus callosum [167, 173, 176, 177, 179, 192-195], although thickening of the corpus callosum has also been observed after lithium treatment . Similarly, the white matter integrity of the anterior limb of the internal capsule and the uncinate fasciculus were not influenced by psychotropic medication [173, 180, 183].
Based on the empirical findings reviewed above, we conclude that white matter tracts connecting emotional and motivational circuits are disturbed in bipolar disorder. Thus it is very likely that this reduced structural connectivity underlies functional alterations, particularly in the orbitofrontal cortex and amygdala, and emotional and motivational symptoms in bipolar disorder. However, to date, association between impaired white matter integrity in the corpus callosum, the anterior limb of the internal capsule, or the uncinate fasciculus and altered early emotional processes, disturbed generation of an emotional response, or emotional and motivational dysregulation has not been shown.
5. The chicken or the egg
So far, empirical data provide evidence that bipolar disorder is a disorder of emotion and motivation. Furthermore, disturbances in these tightly linked but distinct psychological processes are related to impairments in similar neural networks involving prefrontal brain regions such as the orbitofrontal cortex and the anterior cingulate cortex and subcortical structures like the amygdala and the ventral striatum. However, it appears that neural networks associated with emotional and motivational disturbances in bipolar disorder are not uniformly hypo- or hyperactive. Instead, the ongoing psychological process (e.g. early emotional processes, emotion regulation, motivation) and the current mood state crucially interact with neural activation patterns. In addition, psychotropic medication was also repeatedly reported to influence the neural correlates of emotional and motivational processes in bipolar disorder on a structural and functional level (for review see ). Therefore, it is difficult to distinguish whether the neural abnormalities in emotional and motivational networks represent biological vulnerability factors for bipolar disorder or a consequence of the disease. Despite the lack of longitudinal studies, this issue might in part be clarified by studies examining healthy persons at high risk of developing bipolar disorder, such as first-degree relatives of patients with bipolar disorder.
5.1. Early emotional processes
Using the emotional Stroop task on a behavioral level, an increased emotional interference effect that was specifically associated to disease-related words was reported for first-degree relatives of bipolar disorder patients compared to healthy controls , whereas the ‘regular’ Stroop task did not reveal any deficits in relatives of bipolar disorder patients [198, 199]. However, on a neural level, relatives of bipolar disorder patients displayed reduced activity in the parietal cortex; unaffected relatives also displayed this reduced activity in the nucleus caudate during the Stroop task . In addition, relatives also showed significantly reduced functional connectivity between the ventrolateral prefrontal cortex and the insula compared to healthy controls during the Stroop task . On a descriptive level, connectivity between the ventrolateral prefrontal cortex and the ventral anterior cingulate cortex appeared to be weaker in relatives. Further, connectivity between the ventrolateral prefrontal cortex and the nucleus caudatus appeared weaker in relatives suffering from major depression but not in healthy relatives of bipolar disorder patients, who showed a negative coupling between ventrolateral prefrontal cortex and dorsolateral prefrontal cortex, which was absent in healthy controls and was interpreted as a compensational mechanism . Interestingly, when directing attention away from fearful and happy faces, hyper-activation of the amygdala, the medial prefrontal cortex, and by trend also of the putamen but only during presentation of fearful faces as distractors was also reported in adolescent relatives of bipolar disorder patients . Despite the interesting results of this first imaging study examining early emotional processes in relatives of bipolar disorder patients, no conclusions can be drawn concerning the question whether abnormal early emotional processes constitute a vulnerability or a consequence of bipolar disorder. Thus, future studies should examine these processes in relatives of bipolar disorder patients preferably using imaging techniques.
5.2. Affective response and evaluation
Fortunately, the generation of an emotional response has been studied more extensively in relatives of bipolar disorder patients. On a behavioral level, relatives of bipolar disorder patients showed significant deficits in recognizing and labeling emotional faces correctly [201-203], yet no difference in emotional responsiveness operationalized by choosing the emotion that would best fit the description of a real-life situation was observed . While rating their fear of fearful faces, unaffected subjects at-risk for bipolar disorder exhibited amygdala hyperactivity . After induction of a sad mood, siblings of bipolar disorder patients showed hyper-activity in the dorsal anterior cingulate cortex and the anterior insula but hypo-activation in the orbitofrontal cortex . Interestingly, siblings also showed hyper-activity in the medial prefrontal cortex, which distinguished this group from bipolar disorder patients and was hence interpreted as protective compensatory mechanism . It is difficult to draw any conclusions based on the existing evidence as both imaging studies in relatives of bipolar disorder used very different paradigms – rating of emotion intensity and mood induction through recall of autobiographical life events. Thus, inconsistencies are likely to be related to different experimental operationalization. Further studies are, therefore, needed examining the neurobiological correlates of affective response and evaluation in relatives of bipolar disorder patients.
5.3. Emotion regulation
Similar to early emotional processes, emotion regulation has been rarely studied in first-degree relatives of bipolar disorder. One behavioral study investigated the use of different emotion regulation strategies and reported more frequent use of maladaptive strategies such as catastrophizing and self-blame among relatives, which correlated with higher scores in measures of depression, anxiety, and hypomanic personality . Concerning the mechanisms underlying this preference of mal-adaptive emotion regulation strategies, our workgroup recently observed impaired down-regulation of amygdala activity in response to positive and negative stimuli during reappraisal, but not during distraction in first-degree relatives of bipolar disorder patients, when compared to healthy controls (unpublished manuscript). Similar to the results already reported for bipolar disorder patients, this impaired amygdala down-regulation was mediated by a relatively reduced negative connectivity between the amygdala and the lateral orbitofrontal cortex. These results are the first evidence that deficits in emotion regulation through reappraisal might be a vulnerability marker for bipolar disorder. The underlying neural mechanisms include impaired control of amygdala reactivity in response to emotional stimuli and dysfunctional connectivity of the amygdala and regulatory control regions in the orbitofrontal cortex. Such impaired functional connectivity might result from impaired white matter development disturbing fronto-limbic circuits [76, 207].
Thus, reports of aberrant emotion regulation in first-degree relatives of bipolar disorder patients need to be replicated and imaging studies investigating the neural basis of these alterations are warranted.
To the best of our knowledge, anticipation of reward or punishment has not been studied so far in healthy individuals to develop bipolar disorder. However, there is one study investigating the neural responses to the delivery of reward and punishment in healthy first-degree relatives of bipolar disorder patients. Similar to bipolar disorder patients, the authors observed greater activation in response to reward in the medial prefrontal cortex and the amygdala, which was interpreted as heightened reward sensitivity . Further, in response to negative feedback, which was followed by a change in behavior (reversal of reward contingencies), decreased deactivation in the medial orbitofrontal cortex and increased activation in the amygdala was observed, which is thought to represent an attenuated prediction error signal. This attenuated prediction error signal was particularly pronounced during negative feedback that was not followed by a behavioral change. It was speculated that this might be the underlying mechanism of a behavior frequently observed in manic bipolar patients: the pursuit of immediate rewards despite negative consequences because on a neural level, they are not coded as punishment. Furthermore, heightened reward sensitivity and reduced prediction error signal as coded by the medial orbitofrontal cortex were significantly correlated with the score of the behavioral activation system scale in the healthy relatives of bipolar disorder patients.
Although results need to be replicated, existing empirical evidence from bipolar disorder patients and their relatives suggests that hyper-activation of the amygdala and the medial orbitofrontal cortex in the context of motivational processes constitute a vulnerability for bipolar disorder. This idea is further supported by another study that showed increased amygdala activation in response to reward in carriers of the risk allele of
5.5. Gray matter alterations in networks associated with emotional and motivational processes
Similar to the results in bipolar disorder patients, the literature is very inconsistent with respect to alterations of gray matter volume in relatives of bipolar disorder patients. Although gray matter reduction in the anterior cingulate cortex appeared to be the most robust finding in bipolar disorder patients , the picture is less clear in their relatives as there are both reports of reduced volume  and no volumetric alterations [210, 211]. Other cortical regions, which were investigated in relatives of bipolar disorder patients, are the medial prefrontal cortex where the volume was found to be reduced  and the insula with conflicting results of decreased  and increased volume [213, 214].
The literature also remains inconsistent for subcortical structures. Comparable to patient data, there is also evidence of decreased caudate volume in relatives of bipolar disorder patients [209, 215]. However, increased volume  and no alterations  in caudate volume have also been reported. Whereas there seem to be no volumetric alterations in the amygdala of relatives of patients with bipolar disorder [217, 218], there are reports of reduced hippocampal volume  and also reports of no apparent alterations in the hippocampus . Furthermore, one study observed reduced thalamic volumes in relatives of bipolar disorder patients .
Due to the heterogeneity of the gray matter alterations in bipolar disorder patients and their unaffected relatives, no final conclusion whether alterations are the cause or the consequence of the disease can be drawn. However, considering the variance of the obtained results, it seems more likely that gray matter alterations are more related to certain endophenotypes like altered early emotional processes, impulsivity, working-memory, or reward processing than the illness itself. If at all, the volume of the anterior cingulate cortex seems to be the most promising candidate for a vulnerability factor of bipolar disorder.
5.6. White matter alterations in networks associated with emotional and motivational processes
Similar to the results obtained in patients, decreased integrity of the corpus callosum was also reported for adult and adolescent first-degree relatives of patients with bipolar disorder [186, 219, 220], although others observed no differences in the corpus callosum of relatives of bipolar disorder patients [193, 196]. Also corresponding to the abnormalities reported in patients, unaffected relatives displayed reduced integrity of the internal capsule [186, 220], even though not all research groups replicated this finding . Interestingly, white matter integrity in the anterior limb of the internal capsule was also inversely related to cyclothymic temperament . To date, we are not aware of any study replicating the finding of decreased integrity of the uncinate fasciculus observed in bipolar disorder patients in unaffected relatives of bipolar disorder patients.
The empirical findings of reduced inter-hemispheric and prefrontal-subcortical connectivity in children, adolescents, and adults that are independent of the current mood state and are also observable in unaffected first-degree relatives of bipolar disorder patients support the hypothesis that impaired development in white matter precedes functional alterations in networks relevant for emotion and motivation. Although causality still needs to be proven, there is notable evidence suggesting that impaired white matter integrity in the corpus callosum, the anterior limb of the internal capsule, and the uncinate fasciculus might be biological vulnerability factors of bipolar disorder. However, enthusiasm for this assumption has been limited by the fact that reductions of white matter integrity, especially of the corpus callosum [221-228], the anterior limb of the internal capsule, and the uncinate fasciculus, have also been reported for schizophrenia and unipolar depression [173, 183, 229-233]. Thus, reported white matter abnormalities might not be a vulnerability specific to bipolar disorder, but they seem linked to clinical features like impulsivity, psychosis, and depressive mood as well. Consequently, impaired development of inter-hemispheric and prefrontal-subcortical connectivity seems to be a necessary but not a sufficient condition for the development of bipolar disorder.
Supporting the view that impaired white matter development in early life might precede the onset of bipolar disorder , reduced white matter integrity in the corpus callosum and the anterior limb of the internal capsule was observed in children, adolescents, and adults suffering from bipolar disorder as well as in unaffected first-degree relatives of bipolar disorder patients. Further, it has been hypothesized that the impaired development of white matter results in impaired prefrontal-limbic modulation in two networks comprising either the ventrolateral or ventromedial prefrontal cortex as well as the amygdala, ventral striatum, and thalamus . And, indeed, hyper-activation of the amygdala has also been observed during early emotional processes , generation of an affective response , emotion regulation (unpublished manuscript of our group), and motivational processes  in unaffected relatives. Thus, we conclude that both impaired white matter of the corpus callosum and the anterior limb of the internal capsule likely disturb fronto-limbic feedback- and feedforward-loops, leading to hyper-activity of the amygdala that precede bipolar symptoms. Further, abnormalities in prefrontal brain regions such as hyper-activity of the medial prefrontal cortex in response to emotional distractors  and sad mood , hyper-activity of the anterior cingulate cortex , hyper-activity of the orbitofrontal cortex in response to reward and omission of reward , and reduced functional connectivity between the lateral orbitofrontal cortex and the amygdala (unpublished manuscript of our group) have been observed. However, results are rather inconsistent, implying that these abnormalities might be either protective  or risk factors . However, it might be of great interest to examine potential alterations in frontal brain regions in more detail in unaffected relatives. This is especially true as white matter alterations were shown to be not specific for a certain mental disorder, raising the question which neurobiological alterations make the difference between uni- and bipolar affective disorder or bipolar disorder and schizophrenia. However, we like to emphasize that these reflections are rather speculative and that more studies examining emotional and motivational processes in relatives of bipolar disorder patients as well as longitudinal studies are warranted in order to definitely clarify the question which neurobiological abnormalities are risks or consequences of the disease.
6. Conclusion and future perspectives
The interpretation of the above-reviewed results is hampered by a large heterogeneity of results, which is likely to arise from the investigation of heterogenic samples with respect to (1) current symptomatic states, (2) main diagnosis of bipolar I, bipolar II, or bipolar spectrum disorder, (3) psychotropic medication, and (4) life time as well as current psychiatric comorbidities. In the past years, authors started to investigate effects of psychotropic medication more regularly and it seems that functional magnetic resonance imaging and diffusion tensor imaging is rather not influenced by medication . However, the effect of current symptomatology and especially of comorbidity has not been investigated in depth. Thus, future research should address how current symptomatology and comorbidity influences emotional and motivational processes. Further, it would be of great interest to compare patients of bipolar I, bipolar II, and bipolar spectrum disorder.
Despite all heterogeneity, the presented synopsis of empirical results on the neural underpinnings of emotional and motivational processes in bipolar disorder show that bipolar disorder clearly is a disorder of emotion and motivation. As Figure 3 shows, these two psychological processes are closely interrelated and cannot be separated when studying the psychological and neurobiological mechanisms underlying bipolar disorder. This notion is underlined by the fact that emotional and motivational disturbances in bipolar disorder partly share one neural basis. Several structures that are part of the emotion-motivation circuit (ventral prefrontal/orbitofrontal cortex, dorsolateral prefrontal cortex, anterior cingulate cortex, parietal cortex, amygdala, striatum, thalamus, hippocampus) show deviant activation patterns in bipolar patients compared to healthy controls; however, the direction of deviance (hyper- or hypo-activity) depends on the underlying ongoing psychological process. One example is the ventral prefrontal/orbitofrontal cortex: this structure appears to be (1) hypo-active during passive perception of emotions without being asked to actively deal with the emotional content (e.g., correct labeling of emotion) and (2) hyper-active during reward anticipation and reward delivery. From a systems neuroscience perspective, bipolar disorder might therefore be well described on the basis of a neural network dysfunction mainly originating from the amygdala and the ventral prefrontal/orbitofrontal cortex . However, from a psychological and psychotherapeutic perspective, the reviewed results also imply that the underlying psychological processes are the crucial determinants of neural dysfunctions on the one side and of bipolar symptoms during mania and depression on the other. Integrating the systems neuroscience and psychological perspective suggest that alterations in the described emotional and motivational processes, for example, through psychotherapy would accordingly result in neural changes. Thus, in the case of successful therapy, behavioral modifications should result in normalization of disturbed functioning of the emotion-motivation brain network. Consequently, research on modifications of emotional and motivational processes in bipolar patients with neuroimaging methods would be worthwhile and timely.
Finally, although existing data clearly show that a neural network of several brain structures and not single structures on their own forms the pathophysiological basis of bipolar disorder symptoms, more studies on altered functional connectivity during emotion and motivation processing combined with and related to measures of structural connectivity are warranted.
We thoroughly thank Tracy Netemeyer for language editing.
Phillips M. L. Ladouceur C. D. Drevets W. C. A neural model of voluntary and automatic emotion regulation: implications for understanding the pathophysiology and neurodevelopment of bipolar disorderMol Psychiatry. 2008
Alloy L. B. Abramson L. Y. The Role of the Behavioral Approach System (BAS) in Bipolar Spectrum DisordersCurr Dir Psychol Sci. 2010 19 3 189 94Epub 2010/07/08.
Ogawa S. Lee T. M. Kay A. R. Tank D. W. Brain magnetic resonance imaging with contrast dependent on blood oxygenation.Proc Natl Acad Sci U S A. 1990 87 24 9868 72Epub 1990/12/01.
Ogawa S. Lee T. M. Nayak A. S. Glynn P. Oxygenation-sensitive contrast in magnetic resonance image of rodent brain at high magnetic fieldsMagn Reson Med. 1990 14 1 68 78Epub 1990/04/01.
Logothetis N. K. Pfeuffer J. On the nature of the BOLD fMRI contrast mechanismMagn Reson Imaging. 2004 22 10 1517 31Epub 2005/02/15.
Logothetis N. K. What we can do and what we cannot do with fMRI. 2008 453 7197 869 78Epub 2008/06/13.
Keener M. T. Phillips M. L. Neuroimaging in bipolar disorder: a critical review of current findings. 2007 9 6 512 20
Phillips M. Drevets W. Rauch S. Lane R. Neurobiology of emotion perception II: Implications for major psychiatric disordersBiol Psychiatry. 2003 54 5 515 28
Fox R. K. Currie S. L. Evans J. Wright T. L. Tobler L. Phelps B. et al Hepatitis C virus infection among prisoners in the California state correctional system.Clin Infect Dis. 2005 41 2 177 86Epub 2005/06/29.
Wessa M. Linke J. Emotional processing in bipolar disorder: behavioural and neuroimaging findings.Int Rev Psychiatry. 2009 21 4 357 67Epub 2009/01/01.
Anderson A. K. Phelps E. A. Is the human amygdala critical for the subjective experience of emotion? Evidence of intact dispositional affect in patients with amygdala lesions.J Cogn Neurosci. 2002 14 5 709 20Epub 2002/08/09.
How brains beware: neural mechanisms of emotional attention. Trends Cogn Sci. Vuilleumier P. 2005 9 12 585 94Epub 2005/11/18.
Blumberg H. P. Leung H. C. Skudlarski P. Lacadie C. M. Fredericks C. A. Harris B. C. et al A functional magnetic resonance imaging study of bipolar disorder: state- and trait-related dysfunction in ventral prefrontal cortices.Arch Gen Psychiatry. 2003 60 6 601 9
Kronhaus D. M. Lawrence N. S. Williams A. M. Frangou S. Brammer M. J. Williams S. C. et al Stroop performance in bipolar disorder: further evidence for abnormalities in the ventral prefrontal cortexBipolar Disord. 2006 8 1 28 39
Pompei F. Jogia J. Tatarelli R. Girardi P. Rubia K. Kumari V. et al Familial and disease specific abnormalities in the neural correlates of the Stroop Task in Bipolar Disorder. 2011 56 3 1677 84Epub 2011/03/01.
DelBello MP, Eliassen JC. Strakowski S. M. Adler C. M. Holland S. K. Mills N. P. Abnormal FMRI brain activation in euthymic bipolar disorder patients during a counting Stroop interference task.Am J Psychiatry. 2005 162 9 1697 705
Phelps J. Prenatal PAH exposure causes genetic changes in newborns. 2005 A237 EOFEpub 2005/04/15.
Mullin B. C. Perlman S. B. Versace A. De Almeida J. R. Labarbara E. J. Klein C. et al An fMRI study of attentional control in the context of emotional distracters in euthymic adults with bipolar disorder.Psychiatry Res. 2012 201 3 196 205Epub 2012/04/19.
DelBello MP, et al. Fleck D. E. Eliassen J. C. Durling M. Lamy M. Adler C. M. Functional MRI of sustained attention in bipolar mania.Mol Psychiatry. 2012 17 3 325 36Epub 2010/10/27.
Wessa M. Houenou J. Paillere-martinot M. L. Berthoz S. Artiges E. Leboyer M. et al Fronto-striatal overactivation in euthymic bipolar patients during an emotional go/nogo task.Am J Psychiatry. 2007 164 4 638 46
Pavuluri M. N. Passarotti A. M. Harral E. M. Sweeney J. A. An fMRI study of the neural correlates of incidental versus directed emotion processing in pediatric bipolar disorder.Journal of the American Academy of Child Adolescent Psychiatry. 2009 48 3 308 19
Surguladze S. A. Marshall N. Schulze K. Hall M. H. Walshe M. Bramon E. et al Exaggerated neural response to emotional faces in patients with bipolar disorder and their first-degree relatives. 2010 53 1 58 64
Strakowski S. M. Eliassen J. C. Lamy M. Cerullo M. A. Allendorfer J. B. Madore M. et al Functional magnetic resonance imaging brain activation in bipolar mania: evidence for disruption of the ventrolateral prefrontal-amygdala emotional pathwayBiol Psychiatry. 2011 69 4 381 8Epub 2010/11/06.
JA. Pavuluri M. N. O. Connor M. M. Harral E. M. Sweeney An fMRI study of the interface between affective and cognitive neural circuitry in pediatric bipolar disorder.Psychiatry Res. 2008 162 3 244 55Epub 2008/02/26.
Shah M. P. Wang F. Kalmar J. H. Chepenik L. G. Tie K. Pittman B. et al Role of variation in the serotonin transporter protein gene (SLC6A4) in trait disturbances in the ventral anterior cingulate in bipolar disorder.Neuropsychopharmacology. 2009 34 5 1301 10
Hassel S. Almeida J. R. Frank E. Versace A. Nau S. A. Klein C. R. et al Prefrontal cortical and striatal activity to happy and fear faces in bipolar disorder is associated with comorbid substance abuse and eating disorder.J Affect Disord. 2009 19 EOF 27 EOF
Hassel S. Almeida J. R. Kerr N. Nau S. Ladouceur C. D. Fissell K. et al Elevated striatal and decreased dorsolateral prefrontal cortical activity in response to emotional stimuli in euthymic bipolar disorder: no associations with psychotropic medication loadBipolar Disord. 2008 10 8 916 27
Malhi G. S. Lagopoulos J. Sachdev P. S. Ivanovski B. Shnier R. An emotional Stroop functional MRI study of euthymic bipolar disorderBipolar Disord. 2005Suppl 5 58 69Epub 2005/10/18.
Kalmar J. H. Wang F. Chepenik L. G. Womer F. Y. Jones M. M. Pittman B. et al Relation between amygdala structure and function in adolescents with bipolar disorder.J Am Acad Child Adolesc Psychiatry. 2009 48 6 636 42
Rich B. A. Vinton D. T. Roberson-nay R. Hommer R. E. Berghorst L. H. Mcclure E. B. et al Limbic hyperactivation during processing of neutral facial expressions in children with bipolar disorderProc Natl Acad Sci U S A. 2006 103 23 8900 5
Wang F. Kalmar J. H. He Y. Jackowski M. Chepenik L. G. Edmiston E. E. et al Functional and structural connectivity between the perigenual anterior cingulate and amygdala in bipolar disorderBiol Psychiatry. 2009 66 5 516 21
Rich B. A. Fromm S. J. Berghorst L. H. Dickstein D. P. Brotman M. A. Pine D. S. et al Neural connectivity in children with bipolar disorder: impairment in the face emotion processing circuitJ Child Psychol Psychiatry. 2008 49 1 88 96
Brotman M. A. Rich B. A. Guyer A. E. Lunsford J. R. Horsey S. E. Reising M. M. et al Amygdala activation during emotion processing of neutral faces in children with severe mood dysregulation versus ADHD or bipolar disorder.Am J Psychiatry. 2010 167 1 61 9
Liu X. Akula N. Skup M. Brotman M. A. Leibenluft E. Mcmahon F. J. A genome-wide association study of amygdala activation in youths with and without bipolar disorderJ Am Acad Child Adolesc Psychiatry. 2010 49 1 33 41Epub 2010/03/11.
Elliott R. Ogilvie A. Rubinsztein J. S. Calderon G. Dolan R. J. Sahakian B. J. Abnormal ventral frontal response during performance of an affective go/no go task in patients with maniaBiol Psychiatry. 2004 55 12 1163 70
Lennox B. R. Jacob R. Calder A. J. Lupson V. Bullmore E. T. Behavioural and neurocognitive responses to sad facial affect are attenuated in patients with mania. 2004 34 795 8
Murphy F. C. Rubinsztein J. S. Michael A. Rogers R. D. Robbins T. W. Paykel E. S. et al Decision-making cognition in mania and depression. 2001 31 679 93
Jongen E. M. Smulders F. T. Ranson S. M. Arts B. M. Krabbendam L. Attentional bias and general orienting processes in bipolar disorderJ Behav Ther Exp Psychiatry. 2007 38 2 168 83
Todd R. M. Cunningham W. A. Anderson A. K. Thompson E. Affect-biased attention as emotion regulation.Trends Cogn Sci. 2012 16 7 365 72Epub 2012/06/22.
Linke J. Sonnekes C. Wessa M. Sensitivity to positive and negative feedback in euthymic patients with bipolar I disorder: the last episode makes the difference.Bipolar Disord. 2011 638 EOF 50 EOFEpub 2011/11/17.
Farb N. A. Anderson A. K. Segal Z. V. The mindful brain and emotion regulation in mood disorders.Can J Psychiatry. 2012 57 2 70 7Epub 2012/02/22.
Chen C. Lennox B. R. Jacob R. Calder A. Lupson V. Bisbrown-chippendale R. et al Explicit and implicit facial affect recognition in manic and depressed states of bipolar disorder: A functional magnetic resonance imaging study 2006 59 1 31 9
Lumen N. Fonteyne V. De Meerleert G. Ost P. Villeirs G. Mottrie A. et al Population screening for prostate cancer: an overview of available studies and meta-analysis. 2012 19 2 100 8Epub 2011/11/23.
Teasdale J. D. Howard R. J. Cox S. G. Ha Y. Brammer M. J. Williams S. C. et al Functional MRI study of the cognitive generation of affect.Am J Psychiatry. 1999 156 2 209 15Epub 1999/02/16.
2 9 93 105 Critchley H, Daly E, Phillips M, Brammer M, Bullmore E, Williams S, et al. Explicit and implicit neural mechanisms for processing of social information from facial expressions: a functional magnetic resonance imaging study. Hum Brain Mapp. 2000;9(2):93-105. Epub 2000/02/19
Lange K. Williams L. M. Young A. W. Bullmore E. T. Brammer M. J. Williams S. C. et al Task instructions modulate neural responses to fearful facial expressionsBiol Psychiatry. 2003 53 3 226 32
15 19 1523 7 Killgore WD, Gruber SA, Yurgelun-Todd DA. Abnormal corticostriatal activity during fear perception in bipolar disorder. Neuroreport. 2008;19(15):1523-7. Epub 2008/09/18
Trait and state dependent functional impairments in bipolar disorder. Psychiatry Res. Van Der Schot A. Kahn R. Ramsey N. Nolen W. Vink M. 2010 184 3 135 42Epub 2010/11/06.
JA. Pavuluri M. N. O. Connor M. M. Harral E. Sweeney Affective neural circuitry during facial emotion processing in pediatric bipolar disorderBiol Psychiatry. 2007 62 2 158 67
Malhi G. S. Lagopoulos J. Ward P. B. Kumari V. Mitchell P. B. Parker G. B. et al Cognitive generation of affect in bipolar depression: an fMRI studyEur J Neurosci. 2004 19 3 741 54
Bermpohl F. Dalanay U. Kahnt T. Sajonz B. Heimann H. Ricken R. et al A preliminary study of increased amygdala activation to positive affective stimuli in mania.Bipolar Disord. 2009 11 1 70 5Epub 2009/01/13.
Blumberg H. P. Donegan N. H. Sanislow C. A. Collins S. Lacadie C. Skudlarski P. et al Preliminary evidence for medication effects on functional abnormalities in the amygdala and anterior cingulate in bipolar disorderBerl). 2005 183 3 308 13
Neural activation during encoding of emotional faces in pediatric bipolar disorder. Dickstein D. P. Rich B. A. Roberson-nay R. Berghorst L. Vinton D. Pine D. S. et al 2007 9 7 679 92
A, et al. Altshuler L. Bookheimer S. Proenza M. A. Townsend J. Sabb F. Firestine Increased Amygdala Activation during Mania:A functional magnetic resonance imaging study.Journal Psychiatry. 2005 162 6 1211 3
Foland L. C. Altshuler L. L. Bookheimer S. Y. Eisenberger N. Townsend J. Thompson P. M. Evidence for deficient modulation of amygdala response by prefrontal cortex in bipolar mania.Psychiatry Res. 2008 162 1 27 37
6 10 708 17 Altshuler L, Bookheimer S, Townsend J, Proenza MA, Sabb F, Mintz J, et al. Regional brain changes in bipolar I depression: a functional magnetic resonance imaging study. Bipolar Disord. 2008;10(6):708-17. Epub 2008/10/08
2 164 106 13 Robinson JL, Monkul ES, Tordesillas-Gutierrez D, Franklin C, Bearden CE, Fox PT, et al. Fronto-limbic circuitry in euthymic bipolar disorder: evidence for prefrontal hyperactivation. Psychiatry Res. 2008;164(2):106-13. Epub 2008/10/22
Almeida J. R. Versace A. Hassel S. Kupfer D. J. Phillips M. L. Elevated amygdala activity to sad facial expressions: a state marker of bipolar but not unipolar depressionBiol Psychiatry. 2010 67 5 414 21Epub 2009/11/26.
Almeida J. R. Versace A. Mechelli A. Hassel S. Quevedo K. Kupfer D. J. et al Abnormal amygdala-prefrontal effective connectivity to happy faces differentiates bipolar from major depression.Biol Psychiatry. 2009 66 5 451 9
Lawrence N. S. Williams A. M. Surguladze S. Giampietro V. Brammer M. J. Andrew C. et al Subcortical and ventral prefrontal cortical neural responses to facial expressions distinguish patients with bipolar disorder and major depression 2004 55 6 578 87
Jogia J. Haldane M. Cobb A. Kumari V. Frangou S. Pilot investigation of the changes in cortical activation during facial affect recognition with lamotrigine monotherapy in bipolar disorderBr J Psychiatry. 2008 192 3 197 201Epub 2008/03/04.
Versace A. Thompson W. K. Zhou D. Almeida J. R. Hassel S. Klein C. R. et al Abnormal left and right amygdala-orbitofrontal cortical functional connectivity to emotional faces: state versus trait vulnerability markers of depression in bipolar disorderBiol Psychiatry. 2010; 67 5 422 31Epub 2010
Is a lack of disgust something to fear? A functional magnetic resonance imaging facial emotion recognition study in euthymic bipolar disorder patients. Bipolar Disord. Malhi G. S. Lagopoulos J. Sachdev P. S. Ivanovski B. Shnier R. Ketter T. 2007 9 4 345 57
Lagopoulos J. Malhi G. Impairments in "top-down" processing in bipolar disorder: a simultaneous fMRI-GSR study.Psychiatry Res. 2011; 192 2 100 8Epub 2011/04/16.
Chen C. H. Suckling J. Ooi C. Jacob R. Lupson V. Bullmore E. T. et al A longitudinal fMRI study of the manic and euthymic states of bipolar disorder.Bipolar Disord. 2010; 12 3 344 7Epub 2010
Chang K. Adleman N. E. Dienes K. Simeonova D. I. Menon V. Reiss A. Anomalous prefrontal-subcortical activation in familial pediatric bipolar disorder: a functional magnetic resonance imaging investigation. 2004 61 8 781 92
Almeida J. R. Mechelli A. Hassel S. Versace A. Kupfer D. J. Phillips M. L. Abnormally increased effective connectivity between parahippocampal gyrus and ventromedial prefrontal regions during emotion labeling in bipolar disorder.Psychiatry Res. 2009 174 3 195 201
Emotion Regulation: Conceptual Foundations. In: Gross JJ, editor. Gross J. J. Thompson A. J. Handbook of Emotion RegulationNew York: Guilford Press; 2007 3 24
12 11 11692 716 Chobtang J, de Boer IJ, Hoogenboom RL, Haasnoot W, Kijlstra A, Meerburg BG. The need and potential of biosensors to detect dioxins and dioxin-like polychlorinated biphenyls along the milk, eggs and meat food chain. Sensors (Basel). 2011;11(12):11692-716. Epub 2012/01/17
Sakagami M. Pan X. Functional role of the ventrolateral prefrontal cortex in decision making.Curr Opin Neurobiol. 2007 17 2 228 33Epub 2007/03/14.
Wallis J. D. Kennerley S. W. Heterogeneous reward signals in prefrontal cortex.Curr Opin Neurobiol. 2010 20 2 191 8Epub 2010/03/23.
Chen C. H. Suckling J. Lennox B. R. Ooi C. Bullmore E. T. A quantitative meta-analysis of fMRI studies in bipolar disorder.Bipolar Disord. 2011 13 1 1 15Epub 2011/02/16.
Delvecchio G. Fossati P. Boyer P. Brambilla P. Falkai P. Gruber O. et al Common and distinct neural correlates of emotional processing in Bipolar Disorder and Major Depressive Disorder: a voxel-based meta-analysis of functional magnetic resonance imaging studiesEur Neuropsychopharmacol. 2012 22 2 100 13Epub 2011/08/09.
Houenou J. Frommberger J. Carde S. Glasbrenner M. Diener C. Leboyer M. et al Neuroimaging-based markers of bipolar disorder: evidence from two meta-analysesJ Affect Disord. 2011 132 3 344 55Epub 2011/04/08.
Townsend J. Altshuler L. L. Emotion processing and regulation in bipolar disorder: a review.Bipolar Disord. 2012 14 4 326 39Epub 2012/05/29.
Strakowski S. M. Adler C. M. Almeida J. Altshuler L. L. Blumberg H. P. Chang K. D. et al The functional neuroanatomy of bipolar disorder: a consensus model.Bipolar Disord. 2012; 14 4 313 25Epub 2012
Schneider M. R. Delbello M. P. Mcnamara R. K. Strakowski S. M. Adler C. M. Neuroprogression in bipolar disorder. 2012 14 4 356 74Epub 2012/05/29.
Strakowski S. M. Adler C. M. Almeida J. Altshuler L. L. Blumberg H. P. Chang K. D. et al The functional neuroanatomy of bipolar disorder: a consensus model. 14 4 313 25Epub 2012
Does psychology make a significant difference in our lives? Am Psychol. Zimbardo P. G. 2004 59 5 339 51
Haber S. N. Knutson B. The reward circuit: linking primate anatomy and human imaging.Neuropsychopharmacology. 2010 35 1 4 26Epub 2009/10/09.
JP. O. Doherty Reward representations and reward-related learning in the human brain: insights from neuroimaging.Curr Opin Neurobiol. 2004 14 6 769 76Epub 2004/12/08.
Baxter M. G. Murray E. A. The amygdala and rewardNat Rev Neurosci. 2002; 3 7 563 73Epub 2002
10 23 4308 14 Ullsperger M, von Cramon DY. Error monitoring using external feedback: specific roles of the habenular complex, the reward system, and the cingulate motor area revealed by functional magnetic resonance imaging. J Neurosci. 2003;23(10):4308-14. Epub 2003/05/24
Depue R. A. Iacono W. G. Neurobehavioral aspects of affective disorders.Ann Rev Psychol. 1989 40 457 92
Gray J. A. The psychology of fear and stressCambridge: Cambridge University Press; 1987
Urosévic S. Abramson L. Harmon-jones E. Alloy L. Dysregulation of the behavioral approach system (BAS) in bipolar spectrum disorders: Review of theory and evidenceClin Psychol Rev. 2008 28 7 1188 205
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Health Disorders. 4 ed: Text Revision ed. Washington, D.C.: American Psychiatric Press; 2000.
Hasler G. Drevets W. C. Gould T. D. Gottesman I. I. Manji H. K. Toward constructing an endophenotype strategy for bipolar disordersBiol Psychiatry. 2006 60 2 93 105
Pizzagalli D. A. Goetz E. Ostacher M. Iosifescu D. V. Perlis R. H. Euthymic patients with bipolar disorder show decreased reward learning in a probabilistic reward taskBiol Psychiatry. 2008 64 2 162 8
Gorrindo T. Blair R. Budhani S. Dickstein D. Pine D. Leibenluft E. Deficits on a probabilistic response-reversal task in patients with pediatric bipolar disorder.Am J Psychiatry. 2005 162 10 1975 7
Mcclure E. B. Treland J. E. Snow J. Schmajuk M. Dickstein D. P. Towbin K. E. et al Deficits in social cognition and response flexibility in pediatric bipolar disorder.Am J Psychiatry. 2005 162 9 1644 51
The impact of reward, punishment, and frustration on attention in pediatric bipolar disorder. Biol Psychiatry. Rich B. A. Schmajuk M. Perez-edgar K. E. Pine D. S. Fox N. A. Leibenluft E. 2005 58 7 532 9
Reinforcement, expectancy, and learning. Psychol Rev. Bolles R. C. 1972 79 394 409
Riggs L. Mcquiggan D. A. Farb N. Anderson A. K. Ryan J. D. The role of overt attention in emotion-modulated memory.Emotion. 2011 11 4 776 85Epub 2011/04/27.
Steidl S. Razik F. Anderson A. K. Emotion enhanced retention of cognitive skill learning.Emotion. 2011 11 1 12 9Epub 2010/11/10.
Abler B. Greenhouse I. Ongur D. Walter H. Heckers S. Abnormal reward system activation in mania.Neuropsychopharmacology. 2008 33 2217 27
Bermpohl F. Kahnt T. Dalanay U. Hagele C. Sajonz B. Wegner T. et al Altered representation of expected value in the orbitofrontal cortex in mania.Hum Brain Mapp. 2010; 31 7 958 69Epub 2009
Nusslock R. Almeida J. R. Forbes E. E. Versace A. Frank E. Labarbara E. J. et al Waiting to win: elevated striatal and orbitofrontal cortical activity during reward anticipation in euthymic bipolar disorder adults.Bipolar Disord. 2012 14 3 249 60Epub 2012/05/03.
Mcintosh A. M. Whalley H. C. Mckirdy J. Hall J. Sussmann J. E. Shankar P. et al Prefrontal function and activation in bipolar disorder and schizophrenia.Am J Psychiatry. 2008 165 3 378 84
Decision-making in mania: a PET study. Brain. Rubinsztein J. S. Fletcher P. C. Rogers R. D. Ho L. W. Aigbirhio F. I. Paykel E. S. et al 2001Pt 12):2550-63.
Dickstein D. P. Finger E. C. Skup M. Pine D. S. Blair J. R. Leibenluft E. Altered neural function in pediatric bipolar disorder during reversal learning.Bipolar Disord. 2010 12 7 707 19
Taylor Tavares JVClark L, Furey ML, Williams GB, Sahakian BJ, Drevets WC. Neural basis of abnormal response to negative feedback in unmedicated mood disorders. 2008 42 3 1118 26
Jogia J. Dima D. Kumari V. Frangou S. Frontopolar cortical inefficiency may underpin reward and working memory dysfunction in bipolar disorder.World J Biol Psychiatry. 2011Epub 2011/08/05.
Linke J. King A. V. Rietschel M. Strohmaier J. Hennerici M. Gass A. et al Increased medial orbitofrontal and amygdala activation: evidence for a systems-level endophenotype of bipolar I disorder.Am J Psychiatry. 2012 169 3 316 25Epub 2012/01/24.
Aylward E. H. Roberts-twillie J. V. Barta P. E. Kumar A. J. Harris G. J. Geer M. et al Basal ganglia volumes and white matter hyperintensities in patients with bipolar disorder.Am J Psychiatry. 1994; 151 5 687 93Epub 1994
Noga J. T. Vladar K. Torrey E. F. A volumetric magnetic resonance imaging study of monozygotic twins discordant for bipolar disorder.Psychiatry Res. 2001 106 1 25 34Epub 2001/03/07.
Brambilla P. Harenski K. Nicoletti M. A. Mallinger A. G. Frank E. Kupfer D. J. et al Anatomical MRI study of basal ganglia in bipolar disorder patients.Psychiatry Res. 2001; 106 2 65 80Epub 2001
DelBello MP, Keck PE, Jr., Hawkins JM. Sax K. W. Strakowski S. M. Zimmerman M. E. Frontosubcortical neuroanatomy and the continuous performance test in mania.Am J Psychiatry. 1999 156 1 139 41
Dolan R. J. Poynton A. M. Bridges P. K. Trimble M. R. Altered magnetic resonance white-matter T1 values in patients with affective disorder.Br J Psychiatry. 1990 157 107 10Epub 1990/07/01.
Dupont R. M. Jernigan T. L. Heindel W. Butters N. Shafer K. Wilson T. et al Magnetic resonance imaging and mood disorders. Localization of white matter and other subcortical abnormalities.Arch Gen Psychiatry. 1995 52 9 747 55Epub 1995/09/01.
Strakowski S. M. Wilson D. R. Tohen M. Woods B. T. Douglass A. W. Stoll A. L. Structural brain abnormalities in first-episode mania.Biol Psychiatry. 1993 602 EOF 9 EOFEpub 1993/04/01.
DelBello MP, Zimmerman ME, Getz GE, Mills NP, Ret J, et al. Strakowski S. M. Ventricular and periventricular structural volumes in first- versus multiple-episode bipolar disorder.Am J Psychiatry. 2002 159 11 1841 7
nd, Andreasen NC, Alliger RJ, Yuh WT, Ehrhardt JC. Swayze V. W. Subcortical and temporal structures in affective disorder and schizophrenia: a magnetic resonance imaging study.Biol Psychiatry. 1992 31 3 221 40Epub 1992/02/01.
MacFall J, et al. Beyer J. L. Kuchibhatla M. Payne M. Moo-young M. Cassidy F. Caudate volume measurement in older adults with bipolar disorder.Int J Geriatr Psychiatry. 2004; 19 2 109 14Epub 2004
DelBello MPZimmerman ME, Mills NP, Getz GE, Strakowski SM. Magnetic resonance imaging analysis of amygdala and other subcortical brain regions in adolescents with bipolar disorderBipolar Disord. 2004 6 1 43 52Epub 2004/03/06.
Hallahan B. Newell J. Soares J. C. Brambilla P. Strakowski S. M. Fleck D. E. et al Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient dataBiol Psychiatry. 2011; 69 4 326 35Epub 2010
Almeida J. R. Akkal D. Hassel S. Travis M. J. Banihashemi L. Kerr N. et al Reduced gray matter volume in ventral prefrontal cortex but not amygdala in bipolar disorder: significant effects of gender and trait anxiety.Psychiatry Res. 2009 171 1 54 68
D, S, et al. Dickstein D. P. Milham M, P. Nugent A, C. Drevets W, C. Charney D, S. Pine Frontotemporal alterations in pediatric bipolar disorder: results of a voxel-based morphometry study. 2005 62 7 734 41
Jr., Pung CJ, et al. Rimol L. M. Hartberg C. B. Nesvag R. Fennema-notestine C. Hagler D. J. Cortical thickness and subcortical volumes in schizophrenia and bipolar disorder.Biol Psychiatry. 2010 68 1 41 50Epub 2010/07/09.
Altshuler L. L. Bartzokis G. Grieder T. Curran J. Jimenez T. Leight K. et al An MRI study of temporal lobe structures in men with bipolar disorder or schizophreniaBiol Psychiatry. 2000 48 2 147 62Epub 2000/07/21.
Altshuler L. L. Bartzokis G. Grieder T. Curran J. Mintz J. Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia: an MRI study demonstrating neuroanatomic specificityArch Gen Psychiatry. 1998 55 7 663 4Epub 1998/07/22.
Brambilla P. Harenski K. Nicoletti M. Sassi R. B. Mallinger A. G. Frank E. et al MRI investigation of temporal lobe structures in bipolar patientsJ Psychiatr Res. 2003; 37 4 287 95Epub 2003
DelBello MP, Sax KW, Zimmerman ME, Shear PK, Hawkins JM, et al. Strakowski S. M. Brain magnetic resonance imaging of structural abnormalities in bipolar disorder.Arch Gen Psychiatry. 1999 56 3 254 60Epub 1999/03/17.
Velakoulis D. Wood S. J. Wong M. T. Mcgorry P. D. Yung A. Phillips L. et al Hippocampal and amygdala volumes according to psychosis stage and diagnosis: a magnetic resonance imaging study of chronic schizophrenia, first-episode psychosis, and ultra-high-risk individuals.Arch Gen Psychiatry. 2006 63 2 139 49Epub 2006/02/08.
Blumberg H. P. Kaufman J. Martin A. Whiteman R. Zhang J. H. Gore J. C. et al Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder.Arch Gen Psychiatry. 2003 60 12 1201 8
Ziskind-Somerfeld Research Award 1996. Pearlson G. D. Barta P. E. Powers R. E. Menon R. R. Richards S. S. Aylward E. H. et al Medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorderBiol Psychiatry. 1997; 41 1 1 14Epub 1997
Rosso I. M. Killgore W. D. Cintron C. M. Gruber S. A. Tohen M. Yurgelun-todd D. A. Reduced amygdala volumes in first-episode bipolar disorder and correlation with cerebral white matterBiol Psychiatry. 2007 61 6 743 9Epub 2006/11/25.
A. Chang K. Karchemskiy A. Barnea-goraly N. Garrett A. Simeonova D. I. Reiss Reduced amygdalar gray matter volume in familial pediatric bipolar disorderJournal American Academy of Child Adolesc Psychiatry. 2005 44 6 565 73
DelBello MP. Pfeifer J. C. Welge J. Strakowski S. M. Adler C. M. Meta-analysis of amygdala volumes in children and adolescents with bipolar disorderJ Am Acad Child Adolesc Psychiatry. 2008 47 11 1289 98
de Azevedo-Marques Perico CDuran FL, Zanetti MV, Santos LC, Murray RM, Scazufca M, et al. A population-based morphometric MRI study in patients with first-episode psychotic bipolar disorder: comparison with geographically matched healthy controls and major depressive disorder subjects. Bipolar Disord. 2011; 13 1 28 40Epub 2011
DelBello MP, Jarvis K, Levine A, Adams J, Strakowski SM. Adler C. M. Voxel-based study of structural changes in first-episode patients with bipolar disorderBiol Psychiatry. 2007 61 6 776 81
DelBello MP, Strakowski SM. Adler C. M. Levine A. D. Changes in gray matter volume in patients with bipolar disorderBiol Psychiatry. 2005 58 2 151 7
Javadapour A. Malhi G. S. Ivanovski B. Chen X. Wen W. Sachdev P. Increased anterior cingulate cortex volume in bipolar I disorder.Aust N Z J Psychiatry. 2007 41 11 910 6
Foland-ross L. C. Thompson P. M. Sugar C. A. Madsen S. K. Shen J. K. Penfold C. et al Investigation of cortical thickness abnormalities in lithium-free adults with bipolar I disorder using cortical pattern matching.Am J Psychiatry. 2011 168 5 530 9Epub 2011/02/03.
Radenbach K. Flaig V. Schneider-axmann T. Usher J. Reith W. Falkai P. et al Thalamic volumes in patients with bipolar disorderEur Arch Psychiatry Clin Neurosci. 2010; 260 8 601 7Epub 2010
Javadapour A. Malhi G. S. Ivanovski B. Chen X. Wen W. Sachdev P. Hippocampal volumes in adults with bipolar disorder.J Neuropsychiatry Clin Neurosci. 2010 22 1 55 62
Jr., Juruena MF, Fainberg J, Domingues RC, et al. Doring T. M. Kubo T. T. Cruz L. C. Evaluation of hippocampal volume based on MR imaging in patients with bipolar affective disorder applying manual and automatic segmentation techniques.J Magn Reson Imaging. 2011; 33 3 565 72Epub 2011
Tost H. Ruf M. Schmal C. Schulze T. G. Knorr C. Vollmert C. et al Prefrontal-temporal gray matter deficits in bipolar disorder patients with persecutory delusionsJ Affect Disord. 2010;120(1-3): 54 EOFEpub 2009
rd, Bonner JC, Rosen AC, Wang PW, Hoblyn JC, Hill SJ, et al. Brooks J. O. Dorsolateral and dorsomedial prefrontal gray matter density changes associated with bipolar depression.Psychiatry Res. 2009; 172 3 200 4Epub 2009
DelBello MP, Zimmerman ME, Schwiers ML, Strakowski SM. Lopez-larson M. P. Regional prefrontal gray and white matter abnormalities in bipolar disorderBiol Psychiatry. 2002 52 2 93 100
Savitz J. B. Nugent A. C. Bogers W. Roiser J. P. Bain E. E. Neumeister A. et al Habenula volume in bipolar disorder and major depressive disorder: a high-resolution magnetic resonance imaging studyBiol Psychiatry. 2011 69 4 336 43Epub 2010/11/26.
Orbitofrontal cortex gray matter volumes in bipolar disorder patients: a region-of-interest MRI study. Bipolar Disord. 2009; Nery F. G. Chen H. H. Hatch J. P. Nicoletti M. A. Brambilla P. Sassi R. B. et al 11 2 145 53Epub 2009/03/10.
Evidence for orbitofrontal pathology in bipolar disorder and major depression, but not in schizophrenia. Bipolar Disord. Cotter D. Hudson L. Landau S. 2005 7 4 358 69Epub 2005/07/20.
Brambilla P. Nicoletti M. A. Harenski K. Sassi R. B. Mallinger A. G. Frank E. et al Anatomical MRI study of subgenual prefrontal cortex in bipolar and unipolar subjects.Neuropsychopharmacology. 2002 27 5 792 9Epub 2002/11/15.
Benedetti F. Radaelli D. Poletti S. Locatelli C. Falini A. Colombo C. et al Opposite effects of suicidality and lithium on gray matter volumes in bipolar depressionJ Affect Disord. 2011
Bora E. Fornito A. Yucel M. Pantelis C. Voxelwise meta-analysis of gray matter abnormalities in bipolar disorderBiol Psychiatry. 2010 67 11 1097 105Epub 2010/03/23.
Foland L. C. Altshuler L. L. Sugar C. A. Lee A. D. Leow A. D. Townsend J. et al Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium. 19 2 221 4Epub 2008
Moore G. J. Cortese B. M. Glitz D. A. Zajac-benitez C. Quiroz J. A. Uhde T. W. et al A longitudinal study of the effects of lithium treatment on prefrontal and subgenual prefrontal gray matter volume in treatment-responsive bipolar disorder patients.J Clin Psychiatry. 2009; 70 5 699 705Epub 2009
Savitz J. Nugent A. C. Bogers W. Liu A. Sills R. Luckenbaugh D. A. et al Amygdala volume in depressed patients with bipolar disorder assessed using high resolution 3T MRI: the impact of medication. 2010 49 4 2966 76Epub 2009/11/26.
Hafeman D. M. Chang K. D. Garrett A. S. Sanders E. M. Phillips M. L. Effects of medication on neuroimaging findings in bipolar disorder: an updated review.Bipolar Disord. 2012 14 4 375 410Epub 2012/05/29.
Moorhead T. W. Mckirdy J. Sussmann J. E. Hall J. Lawrie S. M. Johnstone E. C. et al Progressive gray matter loss in patients with bipolar disorderBiol Psychiatry. 2007 62 8 894 900
rd, Foland-Ross LC, Thompson PM, Altshuler LL. Brooks J. O. Preliminary evidence of within-subject changes in gray matter density associated with remission of bipolar depression.Psychiatry Res. 2011; 193 1 53 5Epub 2011
Ellison-wright I. Bullmore E. Anatomy of bipolar disorder and schizophrenia: a meta-analysis.Schizophr Res. 2010 117 1 1 12Epub 2010/01/15.
LeBihan D. MR diffusion tensor spectroscopy and imaging. Biophys J. Basser P. J. Mattiello J. 1994 66 1 259 67
Heng S. Song A. Sim K. White matter abnormalities in bipolar disorder: insights from diffusion tensor imaging studies.J Neural Transm. 2010 117 5 639 54
Anderson L. Shimamura A. P. Influences of emotion on context memory while viewing film clips 2005 118 3 323 37Epub 2005/11/01.
Papez J. W. A proposed mechanism of emotion.1937.J Neuropsychiatry Clin Neurosci. 1995 7 1 103 12
. Anatomical bias of the limbic system concept. Arch Neurol. , Livingston KE Escobar A 1971; 24 17 21.
Warner T. D. Behnke M. Eyler F. D. Padgett K. Leonard C. Hou W. et al Diffusion tensor imaging of frontal white matter and executive functioning in cocaine-exposed children. 2006 118 2014 24
Moeller F. Steinberg J. Lane S. Buzby M. Swann A. Hasan K. et al Diffusion tensor imaging in MDMA users and controls: association with decision making.Am J Drug Alcohol Abuse. 2007 33 6 777 89
Lane S. D. Steinberg J. L. Ma L. Hasan K. M. Kramer L. A. Zuniga E. A. et al Diffusion Tensor Imaging and Decision Making in Cocaine DependencePLoS One. 2010e11591.
Adams K. Cimino J. E. Arnold R. M. Anderson W. G. Why should I talk about emotion? Communication patterns associated with physician discussion of patient expressions of negative emotion in hospital admission encounters.Epub 2012
Anderson C. J. The psychology of doing nothing: forms of decision avoidance result from reason and emotion.Psychol Bull. 2003 129 1 139 67Epub 2003/01/31.
Anderson C. Moyle W. Mcallister M. Emotion and cardiac technology: an interpretive study. 2002 20 2 27 33Epub 2003/01/23.
Di Russo F. Taddei F. Bultrini A. Spinelli D. Neural correlates of attentional and executive processing in middle-age fencers. 44 6 1057 66Epub 2011
LeJeune J, et al. Bonanno G. A. Keltner D. Noll J. G. Putnam F. W. Trickett P. K. When the face reveals what words do not: facial expressions of emotion, smiling, and the willingness to disclose childhood sexual abuse.J Pers Soc Psychol. 2002 83 1 94 110Epub 2002/06/29.
and corpus callosum aberrations in adolescents with bipolar disorder: a tract-based spatial statistics analysis. Barnea-goraly N. Chang K. D. Karchemskiy A. Howe M, E. Reiss A, L. Limbic 2009 66 3 238 44
Oosterwegel A. Field N. Hart D. Anderson K. The relation of self-esteem variability to emotion variability, mood, personality traits, and depressive tendencies.J Pers. 2001; 69 5 689 708Epub 2001
Pain and emotion: new research directions. J Clin Psychol. Keefe F. J. Lumley M. Anderson T. Lynch T. Studts J. L. Carson K. L. 2001 57 4 587 607Epub 2001/03/20.
Pavuluri M. N. Yang S. Kamineni K. Passarotti A. M. Srinivasan G. Harral E. M. et al Diffusion tensor imaging study of white matter fiber tracts in pediatric bipolar disorder and attention-deficit/hyperactivity disorder.Biol Psychiatry. 2009 65 7 586 93Epub 2008/11/26.
A. Bruno S. Cercignani M. Ron M. White matter abnormalities in bipolar disorder: a voxel-based diffusion tensor imaging study. 2008 10 4 460 8
. Family psychoeducation, social skills training, and maintenance chemotherapy in the aftercare treatment of schizophrenia. I. One-year effects of a controlled study on relapse and expressed emotion. Arch Gen Psychiatry. , Hogarty GE , Anderson CM , Reiss DJ , Kornblith SJ , Greenwald DP , Javna CD et al 1986; 43 7 633 42. Epub 1986/07/01.
Munoz Maniega S, Job D, et al. Sussmann J. E. Lymer G. K. Mckirdy J. Moorhead T. W. White matter abnormalities in bipolar disorder and schizophrenia detected using diffusion tensor magnetic resonance imaging.Bipolar Disord. 2009 11 1 11 8Epub 2009/01/13.
Walterfang M. Malhi G. S. Wood A. G. Reutens D. C. Chen J. Barton S. et al Corpus callosum size and shape in established bipolar affective disorderAust N Z J Psychiatry. 2009; 43 9 838 45Epub 2009
Wang F. Kalmar J. H. Edmiston E. Chepenik L. G. Bhagwagar Z. Spencer L. et al Abnormal corpus callosum integrity in bipolar disorder: a diffusion tensor imaging study.Biol Psychiatry. 2008 64 8 730 3
Macritchie K. A. Lloyd A. J. Bastin M. E. Vasudev K. Gallagher P. Eyre R. et al White matter microstructural abnormalities in euthymic bipolar disorder.Br J Psychiatry. 2010; 196 1 52 8Epub 2010
Benedetti F. Yeh P. H. Bellani M. Radaelli D. Nicoletti M. A. Poletti S. et al Disruption of white matter integrity in bipolar depression as a possible structural marker of illnessBiol Psychiatry. 2011; 69 4 309 17Epub 2010
Anderson C. M. Hogarty G. Bayer T. Needleman R. Expressed emotion and social networks of parents of schizophrenic patients.Br J Psychiatry. 1984 144 247 55Epub 1984/03/01.
P, J. White matter abnormalities observed in bipolar disorder: a diffusion tensor imaging study. Bipolar Disorders. Yurgelun-tood D. A. Silveri M, M. Gruber S, A. Rohan M, L. Pimentel 2007 9 5 504 12
Versace A. Almeida J. Hassel S. Walsh N. Novelli M. Klein C. et al Elevated left and reduced right orbitomedial prefrontal fractional anisotropy in adults with bipolar disorder revealed by tract-based spatial statistics.Arch Gen Psychiatry. 2008 65 9 1041 52
Sui J. Adali T. Pearlson G. D. Calhoun V. D. An ICA-based method for the identification of optimal FMRI features and components using combined group-discriminative techniques. 2009 46 1 73 86
Lin F. Weng S. Xie B. Wu G. Lei H. Abnormal frontal cortex white matter connections in bipolar disorder: a DTI tractography study.J Affect Disord. 2011 299 EOF 306 EOFEpub 2011/01/18.
Munoz Maniega S, Lymer GK, McKirdy J, Hall J, Sussmann JE, et al. Mcintosh A. M. White matter tractography in bipolar disorder and schizophreniaBiol Psychiatry. 2008 64 12 1088 92
van Zijl PCM. Mori S. Wakana S. Nagae-poetscher L. M. MRI atlas of human white matterAmsterdam: ELSEVIER B. 2005
Mcintosh A. M. Job D. E. Moorhead T. W. Harrison L. K. Lawrie S. M. Johnstone E. C. White matter density in patients with schizophrenia, bipolar disorder and their unaffected relativesBiol Psychiatry. 2005 58 3 254 7
Chaddock C. A. Barker G. J. Marshall N. Schulze K. Hall M. H. Fern A. et al White matter microstructural impairments and genetic liability to familial bipolar I disorderBr J Psychiatry. 2009 194 6 527 34
Petrides M. Pandya D. N. Efferent association pathways from the rostral prefrontal cortex in the macaque monkey.J Neurosci. 2007 27 43 11573 86Epub 2007/10/26.
Sui J. Pearlson G. Caprihan A. Adali T. Kiehl K. A. Liu J. et al Discriminating schizophrenia and bipolar disorder by fusing fMRI and DTI in a multimodal CCA+ joint ICA model. 2011 57 3 839 55Epub 2011/06/07.
Versace A. Almeida J. R. Quevedo K. Thompson W. K. Terwilliger R. A. Hassel S. et al Right orbitofrontal corticolimbic and left corticocortical white matter connectivity differentiate bipolar and unipolar depressionBiol Psychiatry. 2010 68 6 560 7Epub 2010/07/06.
Houenou J. Wessa M. Douaud G. Leboyer M. Chanraud S. Perrin M. et al Increased white matter connectivity in euthymic bipolar patients: diffusion tensor tractography between the subgenual cingulate and the amygdalo-hippocampal complex.Mol Psychiatry. 2007 12 11 1001 10
J, M, et al. Cortical white matter microstructural abnormalities in bipolar disorder. Neuropsychopharmacology. 2005;30(12):2225- 9. , Beyer J L, Taylor Fall J, R, Kuchibhatla M, Payne M, E, Provenzale W, D, Mac
Frazier J. A. Breeze J. L. Papadimitriou G. Kennedy D. N. Hodge S. M. Moore C. M. et al White matter abnormalities in children with and at risk for bipolar disorderBipolar Disord. 2007; 9 8 799 809Epub 2007
Bearden C. E. Van Erp T. G. Dutton R. A. Boyle C. Madsen S. Luders E. et al Mapping corpus callosum morphology in twin pairs discordant for bipolar disorderCereb Cortex. 2011; 21 10 2415 24Epub 2011
Lopez-larson M. Breeze J. L. Kennedy D. N. Hodge S. M. Tang L. Moore C. et al Age-related changes in the corpus callosum in early-onset bipolar disorder assessed using volumetric and cross-sectional measurements.Brain Imaging Behav. 2010;4(3-4): 220 EOF 31 EOFEpub 2010
Haller S. Xekardaki A. Delaloye C. Canuto A. Lovblad K. O. Gold G. et al Combined analysis of grey matter voxel-based morphometry and white matter tract-based spatial statistics in late-life bipolar disorder.J Psychiatry Neurosci. 2011; 36 6 391 401Epub 2011
Walterfang M. Wood A. G. Barton S. Velakoulis D. Chen J. Reutens D. C. et al Corpus callosum size and shape alterations in individuals with bipolar disorder and their first-degree relativesProg Neuropsychopharmacol Biol Psychiatry. 2009; 33 6 1050 7Epub 2009
Pourtois G. Dan E. S. Grandjean D. Sander D. Vuilleumier P. Enhanced extrastriate visual response to bandpass spatial frequency filtered fearful faces: time course and topographic evoked-potentials mapping.Hum Brain Mapp. 2005; 26 1 65 79Epub 2005
Stroop and emotional Stroop interference in unaffected relatives of patients with schizophrenic and bipolar disorders: distinct markers of vulnerability? World J Biol Psychiatry. Besnier N. Richard F. Zendjidjian X. Kaladjian A. Mazzola-pomietto P. Adida M. et al 2009Pt 3):809-18. Epub 2009/08/27.
Kravariti E. Schulze K. Kane F. Kalidindi S. Bramon E. Walshe M. et al Stroop-test interference in bipolar disorder.Br J Psychiatry. 2009 194 3 285 6
Pompei F. Dima D. Rubia K. Kumari V. Frangou S. Dissociable functional connectivity changes during the Stroop task relating to risk, resilience and disease expression in bipolar disorder 2011 57 2 576 82Epub 2011/05/17.
Brotman M. A. Guyer A. E. Lawson E. S. Horsey S. E. Rich B. A. Dickstein D. P. et al Facial emotion labeling deficits in children and adolescents at risk for bipolar disorder.Am J Psychiatry. 2008 165 3 385 9
Brotman M. A. Skup M. Rich B. A. Blair K. S. Pine D. S. Blair J. R. et al Risk for bipolar disorder is associated with face-processing deficits across emotionsJ Am Acad Child Adolesc Psychiatry. 2008 47 12 1455 61
Seidel E. M. Habel U. Finkelmeyer A. Hasmann A. Dobmeier M. Derntl B. Risk or resilience? Empathic abilities in patients with bipolar disorders and their first-degree relativesJ Psychiatr Res. 2012 46 3 382 8Epub 2011/12/03.
Olsavsky A. K. Brotman M. A. Rutenberg J. G. Muhrer E. J. Deveney C. M. Fromm S. J. et al Amygdala hyperactivation during face emotion processing in unaffected youth at risk for bipolar disorder.J Am Acad Child Adolesc Psychiatry. 2012 51 3 294 303Epub 2012/03/01.
Kruger S. Alda M. Young L. T. Goldapple K. Parikh S. Mayberg H. S. Risk and resilience markers in bipolar disorder: brain responses to emotional challenge in bipolar patients and their healthy siblings.Am J Psychiatry. 2006 163 2 257 64Epub 2006/02/02.
Green M. J. Lino B. J. Hwang E. J. Sparks A. James C. Mitchell P. B. Cognitive regulation of emotion in bipolar I disorder and unaffected biological relativesActa Psychiatr Scand. 2011; 124 4 307 16Epub 2011
Schneider M. R. Delbello M. P. Mcnamara R. K. Strakowski S. M. Adler C. M. Neuroprogression in bipolar disorder.Bipolar Disord. 2012 14 4 356 74Epub 2012/05/29.
Wessa M. Linke J. Witt S. H. Nieratschker V. Esslinger C. Kirsch P. et al The CACNA1C risk variant for bipolar disorder influences limbic activity.Mol Psychiatry. 2010 15 12 1126 7Epub 2010/03/31.
Mcdonald C. Bullmore E. T. Sham P. C. Chitnis X. Wickham H. Bramon E. et al Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. 2004 61 10 974 84
Hajek T. Gunde E. Bernier D. Slaney C. Propper L. Grof P. et al Subgenual cingulate volumes in affected and unaffected offspring of bipolar parentsJ Affect Disord. 2008; 108 3 263 9Epub 2007
Hajek T. Novak T. Kopecek M. Gunde E. Alda M. Hoschl C. Subgenual cingulate volumes in offspring of bipolar parents and in sporadic bipolar patients.Eur Arch Psychiatry Clin Neurosci. 2010 260 4 297 304Epub 2009/10/09.
Matsuo K. Kopecek M. Nicoletti M. A. Hatch J. P. Watanabe Y. Nery F. G. et al New structural brain imaging endophenotype in bipolar disorder.Mol Psychiatry. 2012; 17 4 412 20Epub 2011
Frangou S. Brain structural and functional correlates of resilience to Bipolar DisorderFront Hum Neurosci. 2011Epub 2012/03/01.
Kempton M. J. Haldane M. Jogia J. Grasby P. M. Collier D. Frangou S. Dissociable brain structural changes associated with predisposition, resilience, and disease expression in bipolar disorder.J Neurosci. 2009 29 35 10863 8Epub 2009/09/04.
Mcintosh A. M. Job D. E. Moorhead T. W. Harrison L. K. Forrester K. Lawrie S. M. et al Voxel-based morphometry of patients with schizophrenia or bipolar disorder and their unaffected relatives 2004 56 8 544 52
MacQueen G, Duffy A, et al. Hajek T. Gunde E. Slaney C. Propper L. Striatal volumes in affected and unaffected relatives of bipolar patients--high-risk study.J Psychiatr Res. 2009; 43 7 724 9Epub 2008
MacQueen G, Duffy A, et al. Hajek T. Gunde E. Slaney C. Propper L. Amygdala and hippocampal volumes in relatives of patients with bipolar disorder: a high-risk study.Can J Psychiatry. 2009; 54 11 726 33Epub 2009
Subcortical gray matter volume abnormalities in healthy bipolar offspring: potential neuroanatomical risk marker for bipolar disorder? J Am Acad Child Adolesc Psychiatry. Ladouceur C. D. Almeida J. R. Birmaher B. Axelson D. A. Nau S. Kalas C. et al 2008 47 5 532 9
Versace A. Ladouceur C. D. Romero S. Birmaher B. Axelson D. A. Kupfer D. J. et al Altered development of white matter in youth at high familial risk for bipolar disorder: a diffusion tensor imaging studyJ Am Acad Child Adolesc Psychiatry. 2010; 49 12 1249 59e1. Epub 2010
Sprooten E. Sussmann J. E. Clugston A. Peel A. Mckirdy J. William T. et al White Matter Integrity in Individuals at High Genetic Risk of Bipolar DisorderBiol Psychiatry. 2011. Epub 2011
Guo W. B. Liu F. Chen J. D. Xu X. J. Wu R. R. Ma C. Q. et al Altered white matter integrity of forebrain in treatment-resistant depression: A diffusion tensor imaging study with tract-based spatial statisticsProg Neuropsychopharmacol Biol Psychiatry. 2012; 38 2 201 6Epub 2012
Guo W. B. Liu F. Xue Z. M. Gao K. Wu R. R. Ma C. Q. et al Altered white matter integrity in young adults with first-episode, treatment-naive, and treatment-responsive depression.Neurosci Lett. 2012. Epub 2012
Henze R. Brunner R. Thiemann U. Parzer P. Klein J. Resch F. et al White matter alterations in the corpus callosum of adolescents with first-admission schizophrenia.Neurosci Lett. 2012; 513 2 178 82Epub 2012
van de Ven V, Prvulovic D, et al. Interhemispheric hypoconnectivity in schizophrenia: fiber integrity and volume differences of the corpus callosum in patients and unaffected relatives. Neuroimage. 2012; Knochel C. Oertel-knochel V. Schonmeyer R. Rotarska-jagiela A. 59 2 926 34Epub 2011
Kong X. Ouyang X. Tao H. Liu H. Li L. Zhao J. et al Complementary diffusion tensor imaging study of the corpus callosum in patients with first-episode and chronic schizophrenia.J Psychiatry Neurosci. 2011; 36 2 120 5Epub 2010
Kunimatsu N. Aoki S. Kunimatsu A. Abe O. Yamada H. Masutani Y. et al Tract-specific analysis of white matter integrity disruption in schizophrenia.Psychiatry Res. 2012; 201 2 136 43Epub 2012
Wang Q. Deng W. Huang C. Li M. Ma X. Wang Y. et al Abnormalities in connectivity of white-matter tracts in patients with familial and non-familial schizophrenia.Psychol Med. 2011; 41 8 1691 700Epub 2011
S, et al. Whitford T. J. Savadjiev P. Kubicki M. O. Donnell L. J. Terry D. P. Bouix Fiber geometry in the corpus callosum in schizophrenia: evidence for transcallosal misconnectionSchizophr Res. 2011; 132 1 69 74Epub 2011
Federspiel A. Begre S. Kiefer C. Schroth G. Strik W. K. Dierks T. Alterations of white matter connectivity in first episode schizophreniaNeurobiol Dis. 2006 22 3 702 9
Pérez-iglesias R. Tordesillas-gutiérres D. Barker G. J. Mcguire P. K. Roiz-santianez R. Mata I. et al White matter defects in first episode psychosis patients: A voxelwise analysis of diffusion tensor imaging. 2010 49 1 199 204
Muñoz Maniega SLymer GK, Bastian ME, Marjoram D, Job DE, Moorhead TW, et al. A diffusion tenso MRI study of white matter integrity in subjectsat hiegh genetic risk of schizophrenia. Schizophr Res. 2008
Zou K. Huang X. Li T. Gong Q. Li Z. Ou-yang L. et al Alterations of white matter integrity in adults with major depressive disorder: a magnetic resonance imaging studyJ Psychiatry Neurosci. 2008 33 6 525 30
Zhu X. Wang X. Xiao J. Zhong M. Liao J. Yao s. Altered white matter integrity in first-episode, treatment-naive young adults with major depressive disorder: A tract-based spatial statistics studyBrain Res. 2011 1369 223 9