Restorative Neurology and Neuroscience xx (20xx) x–xx 1

DOI 10.3233/RNN-139007
IOS Press

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Bipolar disorder: A neural network

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2 perspective on a disorder of emotion and

motivation

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3

Michèle Wessaa,∗ , Philipp Kanskeb and Julia Linkea

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6 University Hospital Heidelberg, Heidelberg, Germany or

a Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry,

b Department of Social Neuroscience, Max Planck Institute for Human Cognitive and Brain Sciences,
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8 Leipzig, Germany
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9 Abstract. Bipolar disorder (BD) is a severe, chronic disease with a heritability of 60–80%. BD is frequently misdiagnosed
10 due to phenomenological overlap with other psychopathologies, an important issue that calls for the identification of biological
11 and psychological vulnerability and disease markers. Altered structural and functional connectivity, mainly between limbic and
12 prefrontal brain areas, have been proposed to underlie emotional and motivational dysregulation in BD and might represent
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13 relevant vulnerability and disease markers. In the present laboratory review we discuss functional and structural neuroimaging
14 findings on emotional and motivational dysregulation from our research group in BD patients and healthy individuals at risk
15 to develop BD. As a main result of our studies, we observed altered orbitofrontal and limbic activity and reduced connectivity
16 between dorsal prefrontal and limbic brain regions, as well as reduced integrity of fiber tracts connecting prefrontal and subcortical
17 brain structures in BD patients and high-risk individuals. Our results provide novel insights into pathophysiological mechanisms
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18 of bipolar disorder. The current laboratory review provides a specific view of our group on altered brain connectivity and
19 underlying psychological processes in bipolar disorder based on our own work, integrating relevant findings from others.
20 Thereby we attempt to advance neuropsychobiological models of BD.

21 Keywords: Vulnerability, behavioral activation system, emotion regulation, amygdala, orbitofrontal cortex, reward, connectivity
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22 1. Introduction to alternating phases of mania and depression with 30

interspersed periods of euthymia. Key symptoms of

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23 Bipolar disorder is a severe and chronic mental dis- mania include euphoric or irritable mood, flight of 32

24 order that is one of the leading causes of disability ideas, pressure of speech, increased energy, and hyper- 33

25 worldwide, whose lifetime costs were estimated to be activity with an emphasis on pleasurable activities, 34

26 in excess of $45 billion in the US alone (Wyatt & even if they lead to negative consequences. In contrast, 35

27 Henter, 1995). Among the several subtypes of bipolar during depressive episodes patients report depressed 36

28 spectrum disorders, bipolar I disorder is character- mood, lack of energy and loss of interests, pessimistic 37

29 ized by recurrent prominent mood swings that lead thoughts, and reduced perception of and response to 38

positive stimuli. 39
∗ Corresponding author: Michèle Wessa, Ph.D., Section for To date, the diagnosis of bipolar disorder is based on 40
Experimental Psychopathology and Neuroimaging, Department of
the description of behavioral manifestations. However, 41
General Psychiatry, Center for Psychosocial Medicine, Heidelberg
University, Voßstr. 4, 69115 Heidelberg, Germany. Tel.: +49 6221 due to its overlap with other psychopathological con- 42

56 7163; E-mail: michele.wessa@med.uni-heidelberg.de. ditions, such as unipolar depression, schizophrenia or 43

0922-6028/13/$27.50 © 2013 – IOS Press and the authors. All rights reserved
 2 M. Wessa et al. / Bipolar disorder: A neural network perspective

44 impulse control disorders (Matza et al., 2005; Meyer & an emotional state (Keener & Phillips, 2007). It is 94

45 Meyer, 2009; Mitchell et al., 2010), initial misdiagno- assumed that an imbalance and decreased connectivity 95

sis is common. This often leads to detrimental effects between these two systems, particularly the ventrolat-

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47 on the course of this disease (Findling, 2009; Stens- eral prefrontal cortex and the amygdala, accounts for 97

48 land et al., 2008; Stensland et al., 2010) with a more mood instability, motivational dysregulation and cog- 98

49 severe and chronic progression in patients with late nitive deficits observed in patients with bipolar disorder 99

50 or misleading diagnosis. Therefore, research aiming (Cahill et al., 2009; Kurtz & Gerraty, 2009; Strakowski 100

51 at the identification of vulnerability markers of bipo- et al., 2012a; Wessa & Linke, 2009). 101

lar disorder that allow an early and valid diagnosis Most recently, it has been proposed that impaired

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53 is particularly important. An even more serious con- white matter development in early life might pre- 103

54 dition is that in neither of the previously mentioned cede the onset of bipolar disorder. In more detail, it 104

55 psychopathologies causal therapy is available. As an has been hypothesized that the impaired development 105

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ultimate goal it appears therefore essential to determine
biological and psychological markers that are common
to different pathologies or specific for a certain illness
or
of white matter results in impaired prefrontal-limbic
modulation in two networks: (1) a network originat-
ing in the ventrolateral prefrontal cortex and (2) a
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59 in order to develop tailored treatments. Further, mark- network starting from ventromedial prefrontal cor- 109

60 ers that change during the course of the disease might tex. Both networks are similarly organized building 110

61 show potential for improvement under treatment and iterative feedback loops that process information and 111

62 are therefore important to be identified. modulate activity of the amygdala, the ventral striatum 112

As family and twin studies showed a high heritabil- and the thalamus. Whereas the first network is assumed
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63 113

64 ity of bipolar disorder of 60–80% (McGuffin et al., to be involved in the modulation of external emotional 114

65 2003), biological vulnerability factors seem to be of cues such as emotional faces, the second network sup- 115

66 special importance for this disease. The diathesis-stress posedly regulates internal emotional states (Schneider 116

67 model, therefore, poses a good framework to develop et al., 2012; Strakowski et al., 2012a). 117

68 etiological models that incorporate biological and psy- Although, the simplicity of this hypothesis is 118
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69 chological factors associated with the development and rather intriguing, we would like to point out that it 119

70 maintenance of bipolar disorder. In general, such mod- neglects motivational aspects of bipolar symptomatol- 120

71 els assume that the interplay of biological vulnerability ogy despite the fact that both emotion and motivation 121

72 factors (Greek: diathesis) with environmental factors are related. Whereas the focus on emotion implies 122

(stress) determines the onset and course of the disorder a certain state of feeling, the emphasis of motiva-
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73 123

74 (Jones, 2004). tion relates to a certain state of goal pursuit like the 124

75 In bipolar disorder, neurobiological abnormalities achievement of pleasant and the avoidance of unpleas- 125

76 on different levels have been identified, using various ant feelings. 126

77 methods ranging from techniques examining intracel- Yet, to date, most of the existing studies in patients 127
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78 lular and molecular mechanisms to neuroimaging of with bipolar disorder have focused on the neural 128

79 neural networks (Langan & McDonald, 2009). Neu- correlates of aberrant emotion processing, mainly 129

80 robiological models of bipolar disorder (Phillips et al., operationalized by paradigms that use emotionally 130
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81 2008) generally assume a hypoactive dorsal neural sys- evocative stimuli (e.g., words, faces) during pas- 131

82 tem including the dorsolateral prefrontal, ventrolateral sive viewing, implicit and explicit labeling tasks and 132

83 prefrontal, and dorsal anterior cingulate cortex as well response inhibition tasks (Houenou et al., 2011). How- 133

84 as the hippocampus. This dorsal system is relevant ever, although tightly linked to emotion processing, 134

85 for selective attention, planning, performance mon- the investigation of motivational processes, such as 135

86 itoring and voluntary regulation of emotional states the anticipation of positive (reward) and negative con- 136

87 in bipolar disorder. It has been hypothesized that the sequences (punishment) and the response to their 137

88 hypoactive dorsal system interacts with a hyperac- delivery has received little attention in the field. Yet, 138

89 tive ventral brain system comprising amygdala, insula, the evaluation of stimuli as appetitive (reward) or aver- 139

90 ventral striatum, ventral anterior cingulate cortex and sive (punishment) facilitates approach or avoidance 140

91 medial orbitofrontal cortex implicated in the detection motivation and behavior (Alloy & Abramson, 2010). 141

92 of emotionally salient stimuli, mediation of autonomic Indeed, motivational dysregulation and altered reward 142

93 responses to emotional stimuli and the generation of processing have been hypothesized as important 143
 M. Wessa et al. / Bipolar disorder: A neural network perspective 3

144 mechanisms of the alternating phases of mania and 2005; Rich et al., 2005) were reported, suggesting a 191

145 depression and as an endophenotype of bipolar disor- general deficit in responding to motivationally relevant 192

der (Hasler et al., 2006). stimuli in bipolar disorder patients.

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147 In the present laboratory review we will provide a However, our own results show a more differenti- 194

148 specific view of our group on the structural and func- ated pattern of reward and punishment processing in 195

149 tional neural mechanisms underlying emotional and bipolar disorder. In euthymic bipolar disorder patients, 196

150 motivational dysregulation in bipolar disorder based we observed differential learning from positive and 197

151 on our own work. By additionally integrating relevant negative consequences depending on the last illness 198

findings from other group we attempt to contribute to phase of the patients (Linke et al., 2011). Interest-

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153 a further development of neurobiological models of ingly, currently euthymic bipolar patients who last 200

154 bipolar disorder. experienced a manic episode showed a bias towards 201

positive consequences, whereas bipolar patients who 202

155 2. Motivational processes or

last experienced a depressive episode showed a bias
towards negative consequences. This effect occurred
even though patients had been euthymic for up to
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156 Most of the structures comprised in neurobiolog- sixty months. To explain this carry-over effect from 206

157 ical models of bipolar disorder are innervated by symptomatic to euthymic phases, we proposed that 207

158 dopaminergic projections ascending from the ventral affective episodes might represent learning experi- 208

159 tegmental area to the mesolimbic system, includ- ences during which patients perceive and experience 209

ing ventral striatum, amygdala and hippocampus and outcomes (failure vs. success) and consequences
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161 to the mesocortical system comprising, among oth- (reward vs. punishment) mostly in a mood-congruent 211

162 ers, the dorsolateral prefrontal, anterior cingulate and manner which shapes their perception of self-efficacy 212

163 orbitofrontal cortex (Depue & Iacono, 1989). These as well as their action-outcome expectancies and 213

164 dopamine-irrigated structures represent the neural cor- outcome-consequence expectancies persisting beyond 214

165 relate of the behavioral activation system that mediates the symptomatic phases. The influence of action- 215
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166 individual differences in the sensitivity and reactivity outcome and outcome-consequence expectancies on 216

167 to appetitive stimuli. High sensitivity of the behavioral personality constructs of generalized self-referential 217

168 activation system is associated with enhanced appet- cognitions like control orientations and subjective 218

169 itive stimulus processing and approach-motivation as knowledge (Krampen, 1988) further explains the 219

well as the diminished processing of aversive stimuli. endurance of these biases, which might only be
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171 However, the behavioral activation system might also changed by very powerful learning experiences like 221

172 facilitate active avoidance responses, when safety is the next affective episode or psychotherapy. These 222

173 perceived as reward, and aggressive behavior, when results correspond to the theoretical framework of the 223

174 reward acquisition is blocked (Gray, 1987). In the con- dysregulation model of the behavioral activation sys- 224
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175 text of bipolar disorder, dysregulation model of the tem (Urosévic et al., 2008) suggesting that altered 225

176 behavioral activation system suggests a hypersensi- expectancies and beliefs influence the appraisal as well 226

177 tive behavioral activation system as vulnerability factor as the creation and selection of events relevant for the 227
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178 (Alloy & Abramson, 2010; Depue & Iacono, 1989; behavioral activation system and thus interact with the 228

179 Urosévic et al., 2008). Extreme fluctuations in acti- dysregulation of that system. 229

180 vation and deactivation of the behavioral activation Furthermore, there is some evidence on brain func- 230

181 system might be reflected in bipolar symptoms like tion and structure underlying this motivational bias. 231

182 “excessive involvement in pleasurable activities that Altered activity of and changed connectivity between 232

183 have a high potential for painful consequences” dur- brain regions like the orbitofrontal cortex, rostral cin- 233

184 ing mania and “markedly diminished... pleasure in all, gulate cortex, amygdala and striatum that are involved 234

185 or almost all, activities” during depression (American in motivation (Diekhof et al., 2008; Ernst et al., 2004) 235

186 Psychiatric Association, 2000). On a behavioral level, have been reported in patients with bipolar disorder 236

187 reduced and delayed responses to more frequently (for reviews see Blond et al., 2012; Strakowski et 237

188 rewarded stimuli (Pizzagalli et al., 2008) as well as al., 2012b) and might constitute the neuronal corre- 238

189 longer reaction times for decisions that lead to reward late of differential responses to positive and negative 239

190 or punishment (Gorrindo et al., 2005; McClure et al., feedback. 240

 4 M. Wessa et al. / Bipolar disorder: A neural network perspective

241 Indeed, in a recent study, we observed decreased sion we did not observe significant correlations with 291

242 deactivation in the medial orbitofrontal cortex and medication load, which of course does not rule out that 292

greater activation of the amygdala in response to rever- medication has some effect or that it has a more specific

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243 293

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244 sal of reward contingencies in euthymic patients with effect than we were able to detect with a rather global 294

245 bipolar-I disorder and unaffected first-degree relatives measure like the composite medication load score. 295

246 of bipolar I disorder patients (Linke et al., 2012a). Fur- Another explanation refers to the fact that bipolar dis- 296

247 ther, patients and relatives showed greater activation of order patients in our study were chronic patients with a 297

248 the medial orbitofrontal cortex in response to reward history of multiple manic and depressive episodes and 298

delivery, whereas only in unaffected first-degree rel- ideally, during psychotherapy, they already acquired

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250 atives of bipolar patients (Linke et al., 2012a) and some strategies to regulate their initially increased 300

251 in healthy individuals carrying a genetic risk variant sensitivity to immediate reward and impulsivity. 301

252 (CACNA1C rs1006737) for bipolar disorder (Wessa The convergent results in patients with bipolar dis- 302

253

254

255
et al., 2010) the amygdala appeared hyperactive in
response to reward. However, in euthymic patients with
bipolar-I disorder, hyper-activation of amygdala was
or
order, unaffected first-degree relatives of patients with
bipolar disorder (Linke et al., 2012a) and carriers
of a genome-wide supported genetic risk variant for
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304

305
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256 normalized by psychotropic medication as indicated by bipolar disorder (CACNA1C rs1006737, Wessa et al., 306

257 a significant negative correlation between medication 2010) strongly suggest that alterations in the medial 307

258 load and amygdala activation to reward delivery. orbitofrontal cortex and amygdala represent a trait 308

259 Differential activation patterns in medial marker for bipolar disorder. On a cautious note, these 309

orbitofrontal cortex during reward delivery and abnormalities might also contribute to increased ill-
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260 310

261 reversal of reward contingencies in BD patients and ness vulnerability, a proposition that is in line with the 311

262 first-degree relatives of bipolar disorder patients might above-mentioned dysregulation theory of the behav- 312

263 represent different underlying mechanisms: whereas ioral activation system (Alloy & Abramson, 2010). 313

264 heightened activation of the medial orbitofrontal cortex This theory suggests that a hypersensitive behavioral 314

265 (and amygdala) in response to reward is interpreted as activation system, which regulates approach motiva- 315
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266 heightened reward sensitivity, reduced deactivation of tion and goal-directed behavior and depends (amongst 316

267 the medial orbitofrontal cortex and hyper-activation of other structures) on the orbitofrontal cortex (Depue 317

268 the amygdala during reversal of reward contingencies, and Iacono, 1989), mediates vulnerability for bipo- 318

269 observed in both patients with bipolar disorder and lar disorder. Indeed, further analyses of our data 319

healthy relatives of bipolar disorder patients represents revealed moderate and significantly positive correla-
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271 an attenuated prediction error signal. Such an attenu- tions between the score on the behavioral activation 321

272 ated prediction error signal was particularly prominent system scale (Carver & White, 1994) and neural acti- 322

273 in unaffected relatives when negative feedback was vation in the medial orbitofrontal cortex in response to 323

274 not followed by a behavioral change, which reminds reward and reversal of reward contingencies in bipo- 324
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275 of clinical symptoms in manic bipolar patients, who lar disorder patients and their relatives. The behavior 325

276 continue to pursue immediate rewards despite nega- activation system scale measures dispositional sensi- 326

277 tive consequences (American Psychiatric Association tivity to the behavioral activation system (Carver & 327
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278 2000). Interestingly, in a very recent neuropsycholog- White, 1994) and is calculated from questionnaire 328

279 ical study (Wessa et al., unpublished manuscript) we items loading high on the dimensions ‘Drive’, ‘Reward 329

280 observed increased delay aversion scores in healthy Responsiveness’ and ‘Fun Seeking’. 330

281 first-degree relatives of bipolar disorder patients, Despite the evidence from our studies, the question 331

282 which reflect an impulsive behavior, i.e., the inability whether alterations in the medial orbitofrontal cortex 332

283 to delay and inhibit responses in the context of reward- and amygdala in response to reward delivery and rever- 333

284 related decision-making. However, no such effect sal of reward contingencies represent a vulnerability 334

285 was present in bipolar disorder patients themselves. marker for bipolar disorder has to be further evaluated 335

286 This even higher sensitivity to immediate rewards and in longitudinal studies considering conversion rates 336

287 impulsive behavior in healthy individuals at risk to in high-risk individuals, particularly at young age, to 337

288 develop bipolar disorder compared to bipolar patients bipolar disorder or other psychopathologies. 338

289 might be related to medication effects. However, with In addition to these potential vulnerability mark- 339

290 respect to the prediction error signal and delay aver- ers for bipolar disorder, we also identified increased 340
 M. Wessa et al. / Bipolar disorder: A neural network perspective 5

341 activity in the ventral putamen and lateral orbitofrontal In general, hyper-activation in ventral-limbic brain 387

342 cortex during reversal of reward contingencies. As areas in bipolar disorder patients has been related to 388

described earlier, these structures have been subsumed diminished top-down control, which is supported by

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344 under an external emotional control network in a studies showing reduced negative or even increased 390

345 recently published neurobiological consensus model functional connectivity between the ventrolateral 391

346 of bipolar disorder (Strakowski et al., 2012b). Further- prefrontal cortex/anterior cingulate cortex and the 392

347 more, increased activity in lateral orbitofrontal cortex amygdala in manic (Cerullo et al., 2012; Foland et 393

348 seems to signal punishment and could thus repre- al., 2008), euthymic (Wang et al., 2009) and depressed 394

sent a compensatory mechanism in bipolar patients patients (Versace et al., 2010b). In addition to these

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349 395

350 that aides to suppress previously rewarded responses task-related abnormal connectivity patterns, a rela- 396

351 (Cools et al., 2002) and potentially enables adequate tively reduced negative correlation and decreased low 397

352 performance during euthymia. Such compensatory frequency BOLD fluctuations between ventral pre- 398

353

354

355
recruitment of orbitofrontal structures was previously
reported by our group for euthymic bipolar disorder
patients during the inhibition of responses to emotional
or
frontal/anterior cingulate cortex and amygdala activity
at rest was reported in bipolar disorder patients as
compared to healthy controls (Anand et al., 2009;
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400

401
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356 compared to neutral faces (Wessa et al., 2007). Chepenik et al., 2010). Among other regions (e.g. 402

357 Taken as a whole, our results support neurobiolog- medial prefrontal cortex, parietal cortex), the dorsal, 403

358 ical models of bipolar disorder, highlighting the role anterior cingulate and ventrolateral prefrontal cortices 404

359 of the ventral prefrontal cortex and the amygdala as have been found to underlie voluntary emotion reg- 405

key structures in the development and maintenance ulation through attentional control (e.g. distraction)
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360 406

361 of bipolar disorder (Blond et al., 2012; Strakowski et or cognitive change (e.g. reappraisal) (Kanske et al., 407

362 al., 2012). Our findings add to the existing models 2011; McRae et al., 2010). In bipolar disorder patients, 408

363 in identifying abnormal amygdala and ventral pre- hypo-activation of prefrontal structures and reduced 409

364 frontal cortex functioning in response to reward as negative functional connectivity between ventral pre- 410

365 potential vulnerability marker for bipolar disorder. Fur- frontal and limbic brain areas might therefore lead to 411
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366 thermore, our data extend previous results by showing a deficit in voluntarily down-regulating exaggerated 412

367 that heightened emotional reactivity in bipolar disorder emotional responses. 413

368 is not limited to primary emotional cues but also occurs Until now, however, very few studies have investi- 414

369 for positive and negative feedback probably leading to gated neural correlates of voluntary emotion regulation 415

motivational dysregulation. in bipolar disorder although theoretical models, empir-

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370 416

ical data and clinical observations strongly suggest 417

such regulation deficits (Phillips et al., 2008). One 418

371 3. Emotional processing major problem in emotion regulation research in 419

bipolar disorder is a very heterogeneous conceptualiza- 420

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372 As pointed out, the majority of neuroimaging stud- tion of emotion regulation, and consequently diverse 421

373 ies in bipolar disorder investigated the recognition of or operationalization in experimental research. Emotion 422

374 reaction to emotional stimuli, such as emotional faces regulation is part of a broader concept of emotional 423
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375 or words. In line with the clinical observation of an processing, including a pre-attentive stage, attention 424

376 emotional instability and emotional hyper-reactivity allocation, sensory perception, transient and automatic 425

377 in patients with bipolar disorder, an emotion-specific emotional responses, experience and expression of 426

378 hyperactivity of ventral-limbic brain structures such emotion, higher-level appraisal of emotional stim- 427

379 as the amygdala, the insula, the anterior cingulate cor- uli, and finally the regulation of emotions (Wessa 428

380 tex and the orbitofrontal cortex has been repeatedly & Linke, 2009). From an experimental and clinical 429

381 reported in adult depressed and euthymic bipolar dis- neuroscience perspective it is important to make a dis- 430

382 order patients (Altshuler et al., 2005; Lawrence et al., tinction between these sub-processes in order to be 431

383 2004; Malhi et al., 2004; Wessa et al., 2007; Yurgelun- able to validly characterize disturbed or maladaptive 432

384 Todd et al., 2000). During mania, results are more con- processes in psychopathology. 433

385 flicting with a number of studies reporting decreased According to Gross & Thompson (2007) regula- 434

386 rather than increased amygdala activity (Chen et al., tion of emotions refers to the process of increasing 435

2010; Hulvershorn et al., 2012; Lennox, 2004). or decreasing current affect. Such a process may 436
 6 M. Wessa et al. / Bipolar disorder: A neural network perspective

437 occur consciously or unconsciously on a continuum responses to neutral faces (Elliott et al., 2004; Wessa 487

438 from effortless and automatic (unconscious) to effort- et al., 2007). Two more recent studies investigated 488

ful and controlled regulation (conscious). Within their working memory performance during either mood

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439 489

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440 model of emotion regulation, Gross & Thompson induction (Deckersbach et al., 2008) or concurrently 490

441 (2007), differentiate five types of emotion regula- presented emotional faces (Bertocci et al., 2012). In 491

442 tion strategies which can be broadly divided into depressed bipolar disorder patients, Deckersbach et 492

443 (1) antecedent-focused strategies, occurring before al. (2008) reported increased activation in dorsal ante- 493

444 full-blown emotional responses are elicited (situation rior cingulate and dorsolateral prefrontal cortices while 494

selection, situation modification, attentional deploy- performing the working memory task under sad mood

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445 495

446 ment, and cognitive change), and (2) response-focused as compared to no mood induction. This might be 496

447 strategies, occurring after emotional responses are gen- interpreted as a greater demand for executive control 497

448 erated (response modulation). In experimental emotion to perform the cognitive task when being in a sad 498

449

450

451
regulation research, a focus has been placed on the
investigation of a few strategies, particularly on dis-
traction as an example for attentional deployment,
or
mood. Whereas Bertocci et al. (2012) did not find such
compensatory activity in bipolar disorder patients,
but reported elevated activity in the dorsal anterior
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500

501
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452 reappraisal as an example for cognitive change and cingulate cortex during high working memory-load 502

453 suppression as an example for response modulation. and concurrently presented neutral faces in depressed 503

454 Whereas distraction refers to directing attention away patients with unipolar depression, suggesting compen- 504

455 from the emotional features of the situation to differ- sational recruitment of brain regions belonging to the 505

ent, potentially non-emotional aspects of the situation, attentional control network.

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456 506

457 reappraisal means to change the connotation of a situ- Interestingly, our group could show a similar effect 507

458 ation or how we think about a situation in order to alter in patients with unipolar depression not only for dis- 508

459 its emotional significance. traction but also for reappraisal (Kanske et al., 2012). 509

460 Previous studies in bipolar disorder employed exper- Activity in the regulating control-network includ- 510

461 imental paradigms that included cognitive tasks (e.g., ing anterior cingulate cortex and lateral orbitofrontal 511
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462 response inhibition, n-back task) with concurrently cortex was increased during both distraction and reap- 512

463 presented emotional stimuli (e.g., Bertocci et al., 2012; praisal. In contrast, patients with unipolar depression 513

464 Deckersbach et al., 2008; Elliott et al., 2004; Wessa showed a selective deficit in down-regulating amyg- 514

465 et al., 2007). To assure successful task performance, dala responses to negative emotional stimuli using 515

study participants had to direct their attention away reappraisal. This down-regulation of amygdala activ-
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466 516

467 from the concurrently presented emotional stimulus ity was strongest in participants with high habitual 517

468 and to focus on the cognitive task. Likewise, these use of reappraisal measured with the Cognitive Emo- 518

469 studies might also be seen as investigating atten- tion Regulation Questionnaire (CERQ; Garnefski & 519

470 tional deployment as one emotion regulation strategy. Kraaij, 2007) that assesses the regular use of reap- 520
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471 However, in their analyses the authors mainly investi- praisal or suppression as emotion regulation strategy 521

472 gated the distracting influence of emotion on cognitive during every-day life. These data are in line with previ- 522

473 processes, for example by contrasting brain activity ous studies on cognitive control of emotions in patients 523
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474 associated with the task during the presentation of dis- with unipolar depression, suggesting a deficit in the 524

475 tracting emotional stimuli versus neutral stimuli. Yet, ability to down-regulate amygdala activity to nega- 525

476 to determine the neural correlates of the influence of tive emotional stimuli (Beauregard et al., 2006), and 526

477 cognitive task performance on emotional responses, altered connectivity between the amygdala and pre- 527

478 and thus emotion regulation, a comparison between the frontal control regions (Erk et al., 2010; Johnstone et 528

479 ‘task + emotion’ condition and ‘emotion-only’ condi- al., 2007). 529

480 tion would be necessary. To overcome the described gap in voluntary emo- 530

481 Previously, two studies investigated the impact tion regulation research in bipolar disorder patients, 531

482 of disturbing emotional information on response we recently completed a study on the neural corre- 532

483 inhibition in manic and euthymic bipolar disorder lates of two different voluntary emotion regulation 533

484 patients, revealing increased ventral prefrontal activ- strategies, i.e., distraction and reappraisal, in patients 534

485 ity in bipolar patients when trying to inhibit responses with bipolar-I disorder and their unaffected first-degree 535

486 to emotional faces compared to the inhibition of relatives (Kanske et al., unpublished manuscript). 536
 M. Wessa et al. / Bipolar disorder: A neural network perspective 7

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Fig. 1. Illustration of heightened reward sensitivity and reduced prediction error signal in the medial orbitofrontal cortex as observed in Linke et
al., 2012 a. (A) Depiction of significant greater activation in patients with bipolar-I disorder (n = 19) compared to healthy controls (n = 19) and
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(B) of significant greater activation in relatives of bipolar-I patients (n = 22) compared to healthy controls (n = 22). Sagittal slices are overlaid on
the MRIcron ch2 template. Activation is thresholded at p < 0.05 corrected for family-wise error rates within the orbitofrontal cortex as defined
by the aal template.

537 Bipolar disorder patients and their first-degree relatives trol (Kochunov et al., 2010). Deviation from normal 561

538 when compared to healthy controls showed impaired axonal organization can be investigated by means of 562
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539 down-regulation of amygdala activity in response diffusion tensor imaging. This technique allows the 563

540 to positive and negative stimuli during reappraisal, visualization of white matter tracts in the brain and 564

541 but not during distraction. This impaired amygdala the quantification of diffusion characteristics of water 565

542 down-regulation was mediated by a relatively reduced in white matter (e.g., fractional anisotropy) which 566

negative connectivity between the amygdala and the gives an estimate of the directionality and coher-
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543 567

544 lateral orbitofrontal cortex in bipolar disorder patients ence of white matter bundles (Basser et al., 1994). 568

545 and their relatives compared to healthy controls. Children and adolescents with bipolar disorder show 569

546 These results suggest that deficits in emotion regu- decreased fractional anisotropy in the corpus callosum, 570

547 lation through reappraisal are a vulnerability factor the cingulate-paracingulate white matter, the fornix, 571
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548 for bipolar disorder. The underlying neural mecha- and the superior longitudinal fasciculus (Schneider 572

549 nisms include impaired control of amygdala reactivity et al., 2012). In adult patients with bipolar disor- 573

550 in response to emotional stimuli and dysfunctional der, a loss of white matter integrity in fronto-limbic 574

connectivity of the amygdala and regulatory control and cortical-striatal-thalamic circuits has been rela-
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551 575

552 regions in the orbitofrontal cortex. Such impaired func- tively consistently observed and has been proposed to 576

553 tional connectivity might result from impaired white represent a biological vulnerability factor for bipolar 577

554 matter development disturbing fronto-limbic circuits disorder (Heng et al., 2010). 578

555 (Schneider et al., 2012; Strakowski et al., 2012). In a recent study, we found decreased white mat- 579

ter integrity, as indicated by decreased fractional 580

anisotropy in the anterior limb of the internal cap- 581

556 4. Structural connectivity sule in patients with bipolar-I disorder and in healthy 582

first-degree relatives of patients with bipolar-I disor- 583

557 The brain regions related to disturbed motivational der (Linke et al., unpublished manuscript) as well as 584

558 and emotional processes in bipolar disorder are con- in a healthy sample of carriers of a genetic risk vari- 585

559 nected through white matter, which is composed of ant of bipolar disorder (ANK3 rs10994336; Linke et 586

560 axons and was shown to be under strong genetic con- al., 2012b). The anterior limb of the internal capsule 587
 8 M. Wessa et al. / Bipolar disorder: A neural network perspective

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Fig. 2. Illustration of the anterior thalamic radiation (orange) and the uncinate fasciulus (light blue) in healthy relatives of bipoar-I patients
compared to controls. Results of probabilistic tractography show fiber pathways that connect thalamus (pink), amygdala (blue) or nucleus
accumbens (yellow) with the prefrontal cortex via clusters showing significant group differences in the anterior limb of the internal capsule
rre

(brown) and the uncinate fasciculus (turquoise). These connections are thresholded to include at least 70 % of the persons in each group (n = 22).
Connections between subcortical seed regions and prefrontal cortex are overlapped. Masks and fiber pathways are overlaid on the MNI template
in radiological convention.

588 contains fibers that interconnect thalamus, striatum, orbitofrontal cortex passing through the anterior limb 605
co

589 amygdala, hippocampus, anterior cingulate cortex, of the internal capsule. Our results are in line with 606

590 orbitofrontal cortex, and dorsolateral prefrontal cor- previous reports, consistently showing reduced white 607

591 tex (Livingston & Escobar 1971; Papez, 1995). In matter integrity in the anterior limb of the internal 608

our study, probabilistic fiber tracking from the clus- capsule in bipolar patients (Haznedar et al., 2005,
Un

592 609

593 ter of significant group differences in the anterior McIntosh et al., 2005, Sussmann et al., 2009) and first- 610

594 limb of the internal capsule were carried out to spec- degree relatives of bipolar disorder patients (Chaddock 611

595 ify which bundles are predominantly affected. We et al., 2009, Sprooten et al., 2011). 612

596 showed that direct connections between the thalamus In our study, bipolar-I disorder patients and their 613

597 as well as the nucleus accumbens and orbitofrontal healthy first-degree relatives additionally showed 614

598 cortex were altered in bipolar patients, healthy first reduced white matter integrity in the uncinate fasci- 615

599 degree relatives of bipolar patients (Linke et al., culus (Linke et al., unpublished manuscript), which 616

600 unpublished manuscript) and risk-allele carriers of interconnects the amygdala with the orbitofrontal and 617

601 ANK3 rs10994336 (Linke et al., 2012b). Consistent anterior cingulate cortex (Petrides & Pandya, 2007). 618

602 with previous studies (Zarei et al., 2010), we observed This finding is also in line with other reports of reduced 619

603 connections from the amygdala to anterior and pos- fractional anisotropy in the uncinate fasciculus in bipo- 620

604 terior thalamus, but no direct connections to the lar disorder patients (Lin et al., 2011; McIntosh et al., 621
 M. Wessa et al. / Bipolar disorder: A neural network perspective 9

622 2008; Sui et al., 2011; Sussmann et al., 2009; Versace & Cohen, M.S. (2005). Increased amygdala activation during 664

623 et al., 2008; 2010a). Importantly, the integrity of the mania: A functional magnetic resonance imaging study. Am 665
J Psychiatry, 162(6), 1211-1213. 666
uncinate fasciculus was shown to influence functional

f
624
[3] American Psychiatric Association. (2000). Diagnostic and 667

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625 coupling between the anterior cingulate cortex and the Statistical Manual of Mental Health Disorders (4 ed.): Text 668

626 amygdala (Wang et al., 2009). Revision ed. Washington, D.C.: American Psychiatric Press. 669

627 In conclusion, our own data and previous results [4] Anand, A., Li, Y., Wang, Y., Lowe, M.J. & Dzemidizic, M. 670
(2009). Resting state corticolimbic connectivity abnormali- 671
628 support the assumption that altered structural con- ties in unmedicated bipolar disorder and unipolar depression. 672
629 nectivity in networks associated with motivational Psychiatry Res, 171, 189-198. 673

and emotional processes contributes to functional

P
630 [5] Balanzá-Martı́nez, V., Rubio, C., Selva-Vera, G., Martinez- 674

631 abnormalities in these networks. However, studies Aran, A., Sánchez-Moreno, J., Slazar-Fraile, J., Vieta, E. 675
& Tabarés-Seisdedos, R. (2008). Neurocognitive endophe- 676
632 integrating findings from functional and anatomical notypes (endophenocognitypes) from studies of relatives of 677
633 connectivity measures will have to confirm this notion. bipolar disorder subjects: A systematic review. Neurosci

5. Conclusion
[6]

[7]
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Beauregard, M., Paquette, V. & Levesque, J. (2006). Dys-
678
679
680
681
uth
634 682
function in the neural circuitry of emotional self-regulation in 683

635 Results from our own laboratory as well as empiri- major depressive disorder. Neuroreport, 17, 843-846. 684
[8] Bertocci, M.A., Bebko, G.M., Mullin, B.C., Langenecker, 685
636 cal data from other research groups provide evidence S.A., Ladouceur, C.D., Almeida, J.R. & Phillips, M.L. (2012). 686
637 that bipolar disorder is a disorder of emotion and Abnormal anterior cingulate cortical activity during emo- 687

motivation. Interestingly disturbances in these tightly tional n-back task performance distinguishes bipolar from
dA

638 688
unipolar depressed females. Psychol Med, 42(7), 1417-1428. 689
639 related psychological processes appear to ground on
[9] Blond, B.N., Fredericks, C.A. & Blumberg, H.P. (2012). 690
640 impairments in overlapping neural networks with the Functional neuroanatomy of bipolar disorder: Structure, func- 691
641 orbitofrontal cortex and the amygdala playing a partic- tion, and connectivity in an amygdala-anterior paralimbic 692

642 ularly important role. Based on our own and previous neural system. Bipolar Disord, 14(4), 340-355. 693
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643 data we further propose that functional and anatomical
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tion in bipolar disorder and juvenile bipolar disorder. J Can 695

644 alterations in orbitofrontal cortex and amygdala as well Acad Child Adolesc Psychiatry, 18(3), 221-230. 696
645 as the connection between these two regions represents [11] Carver, T. & White, T.L. (1994). Behavioral inhibition, behav- 697

646 a biological vulnerability marker of bipolar disorder. ioral activation, and affective responses to impending reward 698
and punishment: The BIS/BAS scales. J Personality Soc Psy- 699
647 It is noteworthy that in reviewing our own data chol, 67(2), 319-333. 700
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648 and results from other groups, it appears that neural [12] Cerullo, M.A., Fleck, D.E., Eliassen, J.C., Smith, M.S., Del- 701

649 networks involved in the pathophysiology of bipolar Bello, M.P., Adler, C.M. & Strakowski, S.M. (2012). A 702

650 disorder are not either uniformly hypoactive or uni- longitudinal functional connectivity analysis of the amygdala 703
in bipolar I disorder across mood states. Bipolar Disord, 14 704
651 formly hyperactive but that a) the ongoing psycholog- (2), 175-184. 705
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652 706

653 crucially interact with neural activation patterns. M.H., Fern, A., Walshe, M., Bramon, E., Chitnis, X.A., Mur- 707
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657 (We3638/3-1 and SFB 636/C6). F., Jones, M.M., Pittman, B., Skudlarski, P. & Blumberg, H.P. 716
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