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Clinical Gastroenterology and Hepatology 2015;-:--

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5 Acute Anxiety and Anxiety Disorders Are Associated 63
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7 With Impaired Gastric Accommodation in Patients With 65
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9
Functional Dyspepsia 67
10 Q28 68
Huynh Giao Ly,*,a Nathalie Weltens,*,a Jan Tack,*,b and Lukas Van Oudenhove*,,b
11 69
12Q2Q3 70
*Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, University of
13 Leuven, Leuven, Belgium; Psychiatry, University Psychiatric Centre KU Leuven, University Hospitals Leuven, Leuven, Belgium 71
14 72
15 Q10 BACKGROUND & AIMS: Functional dyspepsia (FD) is associated with impaired gastric accommodation, as well as 73
16 gastric hypersensitivity, delayed emptying, and psychosocial comorbidities. In healthy people, 74
17 acute anxiety impairs gastric accommodation, measured as the average increase in gastric 75
18 volume after a meal over 1 hour. This measurement approach does not address the complex 76
19 time course of the gastric accommodation response to a meal. We modeled gastric accommo- 77
20 dation in patients with FD as a function of postprandial time, to investigate whether it is 78
21 associated with psychosocial factors (state anxiety, anxiety disorder, depression) and gastric 79
22 sensorimotor function (sensitivity, emptying). 80
23 81
24 METHODS: We studied gastric sensorimotor function in 259 consecutive patients diagnosed with FD based 82
on Rome II at the University Hospitals Leuven from January 2002 through February 2009.
25 83
Subjects underwent a gastric barostat and breath test; psychosocial status was assessed by
26 84
questionnaires. Subjects completed the State-Trait Anxiety Inventory to measure levels of state
27 anxiety immediately before and after gastric barostat analysis. The time course of the accom- 85
28 modation response was analyzed using mixed models. Psychological and sensorimotor vari- 86
29 ables were added to the model as continuous (state anxiety) or dichotomous (gastric sensitivity 87
30 and emptying, anxiety disorders, depression) covariates, including their interaction with the 88
31 time effects. 89
32 90
33 RESULTS: In subjects with FD, delayed emptying (b [ 50.3 15.9; P [ .002) and lower state anxiety (b [ 91
34 -1.7 0.7; P [ .012) were associated with an upward shift of the accommodation curve. There 92
35 was a signicant interaction between comorbid anxiety disorder and linear (b [ 8.2 3.5; P [ 93
36 .02), quadratic (b [ -0.4 0.1; P [ .004), and cubic (b [ 0.005 0.002; P [ .002) effects of 94
37 time: patients with a comorbid anxiety disorder had signicantly slower initial increases in 95
gastric volume to a lower maximum, and a slower return to baseline, compared with patients
38 96
without anxiety disorder. Depression and gastric sensitivity were not associated signicantly
39 97
with gastric accommodation.
40 98
41 99
CONCLUSIONS: In patients with FD, state anxiety and comorbid anxiety disorders are associated with impaired
42 accommodation; gastric emptying also is associated with accommodation in these patients. 100
43 These ndings help elucidate the complex interactions between psychological processes and 101
44 disorders, gastric sensorimotor dysfunction, and symptom reporting in patients with FD. 102
45 103
46 Keywords: Psychology; Postprandial Distress; Epigastric Pain; Functional Gastrointestinal Disorders. 104
47 105
48 106
49Q11Q13Q12 unctional dyspepsia (FD) is dened by Rome III 107
50 F criteria as the presence of symptoms thought to 108
51 originate in the gastroduodenal region in the absence of 109
52 110
a
structural or metabolic disease that explains these Authors share co-rst authorship. bAuthors share co-senior authorship.

53 symptoms.1 FD is a syndrome with a multifactorial Abbreviations used in this paper: ANS, autonomic nervous system; DSS, 111
dyspepsia symptom severity; EPS, epigastric pain syndrome; FD, func-
54 etiology and pathogenesis that likely results from in- tional dyspepsia; GI, gastrointestinal; HC, healthy control; PDS, post- 112
55 teractions between biological, psychological, and social prandial distress syndrome. 113
56 factors.24 First, FD is associated with gastric sensori- 114
2015 by the AGA Institute
57 motor dysfunction (impaired gastric accommodation to a 1542-3565/$36.00 115
58 meal, hypersensitivity to gastric distension, and delayed http://dx.doi.org/10.1016/j.cgh.2015.03.032 116

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2 Ly et al Clinical Gastroenterology and Hepatology Vol. -, No. -

117 gastric emptying).4 Second, FD is associated with psy- gastrointestinal [GI] or GI motility clinic at the University 175
118 chological status alterations (including depressive and Hospitals Leuven, or at a recent secondary care gastro- 176
119 anxiety disorders comorbidity).3 enterologist visit that lead to referral to our center) were 177
120 Gastric accommodation is a vago-vagal reex initiated recruited between January 2002 and February 2009. The 178
121 by the arrival of nutrients in the stomach and duodenum patient sample of the present study partially overlapped 179
122 and resulting in fundus relaxation (decreased proximal with recent studies from our group.79 However, the 180
123 stomach tone), which creates storage capacity for food hypotheses tested in the present study were novel and 181
124 without pressure increase, thereby enabling the gastric the results have not been reported elsewhere. 182
125 fundus to exert its reservoir function.5 Healthy volunteers who participated in gastric baro- 183
126 Gastric accommodation commonly is measured using stat studies in which no drugs were administered were 184
127 a gastric barostat, and quantied as the difference in used as controls. 185
128 intraballoon volume 30 minutes before and 60 minutes Details on patients and healthy controls are provided 186
129 after a standardized liquid meal at xed intraballoon in the Supplementary Methods section. Q14 187
130 pressure.5 Based on this quantication method, approx- 188
131 imately 40% of FD patients have impaired accommoda- 189
132 tion,5 which has been associated consistently with the Gastric Barostat Protocol 190
133 postprandial distress symptoms (postprandial fullness, 191
134 early satiation) of the FD syndrome.2,5 However, this Gastric sensitivity to distension and gastric accom- 192
135 approach ignores the complex time course of the gastric modation were studied using a gastric barostat. Details 193
136 accommodation response, which may result in low sta- are provided in the Supplementary Methods section. 194
137 tistical power to detect differences between groups or 195
138 relationships with other relevant etiopathogenetic fac- 196
Gastric Emptying Measurement
139 tors within the heterogeneous FD group. Even without 197
140 taking these methodologic issues into consideration, 198
Gastric half-emptying time for solids was calculated
141 research on how other gastric sensorimotor processes 199
using the 14C octanoic acid breath test. The validated cut-
142 and psychosocial comorbidity may be associated with 200
off time of 109 minutes was used to dene delayed
143 gastric accommodation in FD is virtually nonexistent. 201
emptying.10
144 However, we previously showed that experimentally 202
145 induced anxiety signicantly impairs gastric accommo- 203
146 dation in healthy volunteers, providing proof of concept Psychometric Questionnaires 204
147 for central inuences on this vago-vagal reex.6 205
148 Therefore, our primary aim was to model the time On the day of the barostat investigation, FD patients 206
149 course of the gastric accommodation response and use lled out the following self-report questionnaires. 207
150 this approach to investigate the putative association be- Dyspepsia Symptom Severity Scale. The severity of 208
151 tween gastric accommodation and other key gastric dyspeptic symptoms was evaluated using the Dyspepsia 209
152 sensorimotor functions (sensitivity, emptying) as well as Symptom Severity (DSS) scale, consisting of Likert 210
153 psychosocial status (state anxiety, comorbid depressive scales (range, 03: absent, mild, moderate, or severe) 211
154 and anxiety disorders). Based on our study in healthy on the intensity of 9 dyspeptic symptoms during the past 212
155 volunteers,6 we hypothesized an association between 3 months. The DSS is calculated as the sum of all 9 213
156 increasing state anxiety as well as the presence of co- items.11 214
157 morbid anxiety disorders and impaired accommodation Because patient recruitment started years before the 215
158 (downward shift or lower maximum of the initial post- introduction of the Rome III criteria in 2006, no data on 216
159 prandial volume increase). Given the lack of prior evi- the subdivision of FD in the Epigastric Pain Syndrome 217
160 dence, no specic a priori hypotheses were formulated (EPS) and/or Postprandial Distress Syndrome (PDS) are 218
161 for gastric sensitivity, emptying, and presence of co- available. However, to test the association between the 219
162 morbid depressive disorder. Our secondary aim was to time course of the accommodation response and EPS and 220
163 apply this analysis method to conrm differences in PDS symptom levels, EPS symptom severity was quan- 221
164 gastric accommodation between healthy controls and FD tied by calculating the sum of the epigastric pain and 222
165 patients, and an association between postprandial epigastric burning items of the DSS; PDS symptom 223
166 distress symptom levels and impaired accommodation. severity was calculated as the sum of the postprandial 224
167 fullness and early satiation items. For analysis purposes, 225
168 the resulting ordinal variables (06) were dichotomized 226
169 Methods by median split. 227
170 State-Trait Anxiety Inventory, state scale. The state 228
171 Participants scale of the State-Trait Anxiety Inventory12,13 was lled 229
172 out twice, immediately before and after the barostat 230
173 Consecutive Dutch-speaking Rome II FD patients with investigation (with the latter rating referring retrospec- 231
174 a recent diagnosis (either at their visit to the general tively to the period during the barostat investigation). 232

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233 The mean of these 2 scores was used as a measure for Table 1. Descriptive Patients Characteristics 291
234 Q15 state anxiety during the investigation. 292
N (%)
235 Patient Health Questionnaire. The depression and 293
Mean  SD or positive/above
236 anxiety disorder modules of the Patient Health Ques- Q25
294
Patient characteristic median (IQR) cut-off level
237 tionnaire were completed to screen for comorbid major 295
238 depressive disorder and anxiety disorders,14 using their Gastric sensorimotor function 296
239 validated algorithms.15 Gastric discomfort threshold 9.9  3.6 mm Hg 108 (42.3%)a 297
240 Gastric half-emptying time 90.9  53.5 min 36/173 (20.8%)b 298
solids
241 Statistical Analysis Psychological state
299
242 State anxiety (STAI) 42.3  8.9 - 300
243 SAS 9.4 (SAS Institute, Cary, NC) was used to analyze Depression (PHQ-9) 8.4  5.2 76 (29.3%) 301
244 the data, which are expressed as means  standard er- Anxiety disorder (PHQ) N/A 30 (12.4%) 302
245 Dyspepsia symptoms 303
ror. Signicance was set at a P value of .05 (P < .10 Dyspepsia symptom severity 13.4  4.8 -
246 represents a trend). Postprandial distress 4 (34) -
304
247 To analyze the time course of the accommodation symptoms 305
248 response, the intraballoon volume data recorded by the Epigastric pain symptoms 2 (24) - 306
249 barostat device rst were divided into 5-minute time Comorbid irritable bowel - 142 (56.8%) 307
250 syndrome 308
bins by averaging the data within each time bin. Next, the
251 average preprandial volume (over all 6 preprandial 309
252 5-minute time bins) was subtracted from the volume in PHQ, Patient Health Questionnaire; STAI, State-Trait Anxiety Inventory. 310
253 each of the 12 postprandial time bins, resulting in a value
a
b
Hypersensitive patients. 311
Patients with delayed emptying, emptying data were available only in a sub-
254 reecting volume increase compared with the average group (n 173).
312
255 preprandial volume for each of these postprandial time 313
256 Q16 bins. The resulting change in volume variable was used 314
257 as the dependent variable in linear mixed-model ana- postprandial volume increase), with the quadratic effect 315
258 lyses with linear, quadratic, cubic, and fourth-order ef- representing the turn around the maximum volume in- 316
259 fects of time as continuous independent variables. To crease of the accommodation response and the higher- 317
260 test the putative association of sensorimotor and psy- order effects mostly corresponding to the decrease in 318
261 chosocial variables with the time course of the accom- volume toward the end of the 1-hour postprandial period. 319
262 Healthy controls. A similarly parameterized model 320
modation response, main effects for the respective
263 including signicant linear (b 43.87  3.74; P < 321
independent variables (either continuous or categoric) as
264 .0001), quadratic (b -2.33  0.24; P < .0001), cubic 322
well as their interactions with the time effects were
265 (b 0.047  0.0059; P < .0001), and fourth-order (b 323
added to the model. Details are provided in the
266 -0.00033  0.00005; P < .0001) effects of time, which 324
Supplementary Methods section.
267 also tted the HC data best. Q18
325
268 326
269
Results 327
270 328
271 Participants 329
272 330
273 Table 1 shows relevant patient characteristics. 331
274 Supplementary Figure 1 shows a patient owchart; de- 332
275 tails are provided in the Supplementary Methods section. 333
276 Forty-six historical healthy controls (HCs) (18 women 334
277 [39%]; mean age, 24.1  3.6 y) were included. Both sex 335
278
Q17 (c2[1] 24.25; P <.0001) and age (t[165.9], 15.12; P < 336
279 .0001) were signicantly different between both groups. 337
280 338
281 339
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Time Course of the Accommodation Response


282 340
283 Functional dyspepsia. A model including signicant 341
284 linear (b 27.84  2.00; P < .0001), quadratic (b -1.63 342
285  0.14; P < .0001), cubic (b 0.036  0.0034; 343
286 P < .0001), and fourth-order (b -0.00028  0.000029; 344
287 P < .0001) effects of time tted the data best, without Figure 1. Observed and modeled curves reecting the time 345
course of the gastric accommodation response averaged more
288 further improvement in t by adding the fth order effect than 259 functional dyspepsia patients. The curve is modeled 346
289 of time (Figure 1). The linear effect represents the slope optimally by a combination of signicant linear, quadratic, 347
290 of the initial linear increase of the curve (early cubic, and fourth-order effects of time (all P < .0001). 348

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349 Comparison of the Time Course of the 407


350 Accommodation Response Between 408
351 Functional Dyspepsia and Healthy Controls 409
352 410
353 Signicant interactions between group on the one 411
354 hand and the linear, quadratic, and cubic effects of time 412
355 on the other hand were found, indicating a different time 413
356 course of the accommodation reex in FD vs HC, with FD 414
357 patients showing an impaired response (Figure 2). The 415
358 signicant group-by-time interaction (b 14.48  3.03; 416
359 P < .0001) represents a steeper initial linear increase of 417
360 the curve to a higher maximum in HC (timeHC b 42.60 418
361  3.20; P < .0001) compared with FD (timeFD b 28.12 419
362  1.96; P < .0001). The signicant group-by-time2 420
363 interaction (b -0.50  0.12; P < .0001) represents a 421
364 sharper turn around a higher maximum in HC (time2HC 422
365 b -2.16  0.16; P < .0001) compared with FD (time2FD 423
366 b -1.66  0.13; P < .0001). Finally, the signicant 424
367 group-by-time3 interaction (b 0.0049  0.0013; 425
368 P .0002) is owing to a different time course of the 426
369 return to baseline in the later postprandial phase in HC 427
370 (time3HC b 0.042  0.0033; P < .0001) compared with 428
371 FD (time3FD b 0.037  0.0031; P < .0001). 429
372 The effect of sex was not signicant (b -12.22  430
373 11.40; P .28), but a signicant effect of age (b -0.92 431
374  0.42; P .030) was found. 432
375 433
376 434
377 Symptom Pattern and Time Course of 435

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378 the Accommodation Response in 436
379 Functional Dyspepsia 437
380 438
381 Postprandial distress symptoms. Signicant in- 439
382 teractions between PDS symptom level (high/low) and 440
383 the linear and quadratic effects of time were found 441
Figure 3. Observed gastric accommodation curves in func-
384 (Figure 3A). The signicant PDS symptoms-by-time tional dyspepsia patients with high vs low symptom levels. (A) 442
385 interaction (b 3.37  1.16; P .0042) represents a Postprandial distress symptom levels. Signicant PDS-by- 443
386 steeper initial linear increase of the curve to a slightly time and PDS-by-time2 interaction effects were found (both 444
387 higher maximum volume in patients with low PDS P < .02). (B) Epigastric pain symptom levels. No EPS main 445
388 effect or EPS-by-time interaction effects were found. The 446
slightly lower sample sizes compared with the total sample
389 (n 259) indicate that a small fraction of the patients had 447
390 incomplete symptom data. 448
391 449
392 450
393 symptom levels (timelow PDS symptoms b 30.26  2.17; P 451
394 < .0001) compared with patients with high PDS symp- 452
395 tom levels (timehigh PDS symptoms b 26.90  2.13; P < 453
396 .0001). The signicant PDS-by-time2 interaction (b 454
397 -0.046  0.019; P .016) is attributable to a sharper 455
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398 turn around a lower maximum followed by a faster 456


399 decrease in volume in patients with high PDS symptom 457
400 levels (time2high PDS symptoms b -1.64  0.14; P < .0001) 458
401 compared with patients with low PDS symptom levels 459
402 (time2low PDS symptoms b -1.69  0.14; P < .0001). This 460
403 conrms an impaired gastric accommodation response in 461
Figure 2. Observed gastric accommodation curves in func-
404 tional dyspepsia patients and healthy controls. Signicant patients with high vs low PDS symptom levels. 462
405 group-by-time, group-by-time,2 and group-by-time3 interac- Epigastric pain symptoms. No signicant main effect 463
406 tion effects were found (all P < .0005). or any interactions with time were found for EPS 464

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465 symptom level (high/low), indicating no difference in the volume increase in patients with delayed gastric 523
466 time course of the accommodation response between emptying over the entire 1-hour measurement period, 524
467 patients with high and low EPS symptom levels albeit most pronounced during the rst 30 minutes 525
468 (Figure 3B) (details not shown). (Figure 4B). No signicant interactions between gastric 526
469 emptying and any of the time effects were found, indi- 527
470 cating that the overall shape of the accommodation curve 528
Gastric Sensorimotor Function and Time
471 does not differ signicantly between both patient groups. 529
472 Course of the Accommodation Response in 530
473 Functional Dyspepsia 531
Psychological State and Time Course of
474 the Accommodation Response in 532
475 Gastric sensitivity. No signicant main effect of 533
sensitivity or signicant interaction effects with time Functional Dyspepsia
476 534
477 were found. However, trends were found for the sensi- 535
tivity-by-time2 (b -0.15  0.09; P .096) and sensi- State anxiety. A signicant state anxiety main effect
478 was found (b -1.71  0.68; P .012). This indicates 536
479 tivity-by-time3 (b -0.15  0.09; P .096) interactions, 537
representing a sharper turn around a higher maximum, that the average postprandial volume increase over the
480 entire 1-hour measurement period decreased with, on 538
481 followed by a faster return to baseline in hypersensitive 539
compared with normosensitive patients (Figure 4A). average, 1.71 mL per point increase on the State-Trait
482 Anxiety Inventory state scale (range, 2080) 540
Gastric emptying. A signicant main effect of gastric
483 541
484 emptying (delayed/normal) was found (b 50.29  (Figure 5A). No signicant interactions between state
542
485 15.85; P .0018), representing a higher postprandial anxiety and any of the time effects were found. Details
543
about the effect of anxiety before vs during/after the
486 barostat investigation are provided in the Supplementary 544
487 Methods section. 545
488 Depression. No signicant main effect was found, or 546
489 signicant interactions with any of the time effects. 547
490 Anxiety disorder. Signicant interactions between 548
491 anxiety disorder comorbidity and the linear, quadratic, 549
492 and cubic time effects were found (Figure 5B). The sig- 550
493 nicant anxiety-by-time interaction (b 8.24  3.52; 551
494 P .02) represents a steeper initial linear increase of the 552
495 curve to a higher maximum volume in patients without 553
496 comorbid anxiety disorder (b 28.46  2.11; P < .0001) 554
497 compared with patients with such comorbidity (b 555
498 20.22  3.71; P < .0001). The signicant anxiety-by- 556
499 time2 interaction (b -0.40  0.14; P .0038) is owing 557
500 to a sharper turn around a higher maximum in patients 558
501 without comorbid anxiety disorder (b -1.65  0.14; 559
502 P < .0001) compared with patients with such comor- 560
503 bidity (b -1.25  0.18; P < .0001). Finally, the signif- 561
504 icant anxiety-by-time3 interaction (b 0.0048  0.0015; 562
505 P .0016) is owing to a different shape of the volume 563
506 decrease in the later postprandial phase in patients 564
507 without comorbid anxiety disorder (b 0.036  0.0036; 565
508 P < .0001) compared with patients with such comor- 566
509 bidity (b 0.031  0.0038; P < .0001). Taken together, 567
510 these effects indicate impaired accommodation in FD 568
511 569
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patients with vs without comorbid anxiety disorder


512 (Figure 5B). 570
513 571
514 572
515 Discussion 573
516 574
517 Figure 4. Observed gastric accommodation curves in func- Gastric accommodation impairment, other gastric 575
518 tional dyspepsia patients according to gastric sensitivity and sensorimotor abnormalities, and psychosocial factors are 576
519 gastric emptying status. (A) Gastric sensitivity status. Trends involved in FD, but the interactions between these 577
were found for the sensitivity-by-time2 and sensitivity-by-
520 Q24 time3 interaction effects (both <.10). (B) Gastric emptying pathogenetic factors remain understudied. Specically, it 578
521 status. A signicant main effect of gastric emptying status is unknown whether psychosocial status, gastric sensi- 579
522 was found (P < .002). tivity, or emptying are associated with impaired gastric 580

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581 response (early increase in volume, later return to 639


582 baseline, and so forth) primarily are altered. Conversely, 640
583 we found associations with anxiety that we did not 641
584 pick up previously (at least for panic disorder) using 642
585 the simplied approach.17 This may indicate that the 643
586 current method is more sensitive to detect associations 644
587 between relevant factors and alterations in gastric 645
588 accommodation. 646
589 The association between both (anticipatory) state 647
590 anxiety and the presence of comorbid anxiety disorders 648
591 (which inherently are chronic) on the one hand, and an 649
592 impaired gastric accommodation response (altered 650
593 height and/or shape of the accommodation curve) on the 651
594 other, represents the most novel nding of this study. 652
595 The effect of state anxiety is relatively limited in size 653
596 (although the difference between the 2 ends of the range 654
597 corresponds to more than 100 mL gastric accommoda- 655
598 tion impairment), whereas the association between co- 656
599 morbid anxiety disorders and impaired accommodation 657
600 is more pronounced. This may indicate that chronic 658
601 anxiety may have a cumulative effect over time, resulting 659
602 in increased accommodation impairment. The present 660
603 study was cross-sectional and observational and hence 661
604 662
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did not allow us to draw conclusions about temporal


605 precedence or direction, let alone causality. However, 663
606 these ndings conrmed our a priori hypothesis on the 664
607 role of anxiety, which was based on our previous work in 665
608 which we showed that experimentally induced state 666
609 anxiety impairs gastric accommodation in HCs,6,16 667
Figure 5. Relationship between anxiety and time course of
610 rendering the interpretation that anxiety is implicated 668
the gastric accommodation response in functional dyspepsia
611 patients. (A) Modeled gastric accommodation curves causally in gastric accommodation impairment in FD 669
612 showing the effect of a linear increase in state anxiety. A plausible. However, further conrmation of this inter- 670
613 signicant main effect of state anxiety was found. The effect pretation would require a longitudinal study in FD pa- 671
614 of an increase with 2 SDs is shown for illustration purposes. tients with both anxiety disorders and impaired 672
(B) Observed gastric accommodation curves in patients with
615 accommodation, with repeat testing, to determine 673
and without comorbid anxiety disorders. Signicant anxiety
616 comorbidity-by-time, anxiety comorbidity-by-time,2 and whether resolution of the anxiety disorder is associated 674
617 anxiety comorbidity-by-time3 interaction effects were found with an increase in gastric accommodation. Alternatively, 675
618 (all P < .025). STAI, State-Trait Anxiety Inventory. one could study accommodation in anxiety disorder pa- 676
619 tients without FD, although this would be difcult from 677
620 an ethical and/or recruitment perspective. 678
621 accommodation, or whether each of these mechanisms An association between anxiety disorders and FD has 679
622 contributes independently to FD symptom generation. been reported consistently, mostly based on epidemio- 680
623 We showed that other gastric sensorimotor dysfunctions logic studies.3,18 However, the mechanisms by which 681
624 (delayed gastric emptying and, to a lesser extent, gastric anxiety exerts its effect on FD symptom generation 682
625 hypersensitivity), state anxiety, and comorbid anxiety largely have remained elusive, although evidence has 683
626 disorders are associated with altered gastric accommo- been found for an inuence of anxiety on gastric sensi- 684
627 dation. To investigate these associations, we used mixed tivity,19 potentially through altered emotional modula- 685
628 models to model the time course of the gastric accom- tion of visceral afferent input.20 Taken together with the 686
629 modation response accurately as a linear, quadratic, cu- association between impaired accommodation and 687
630 bic, and fourth-order function of postprandial time. By postprandial symptom severity, which we conrm here 688
631 using this approach, we conrmed ndings obtained using our novel approach, our present study may identify 689
632 earlier with a simplied approach, including differences a novel mechanism by which anxiety inuences (post- 690
633 in accommodation between HC and FD,16 as well as an prandial) symptom generation in FD, namely through 691
634 association of impaired accommodation with post- impairment of gastric accommodation, although we 692
635 prandial symptoms16 and a lack of association of should remain careful with causal interpretations. These 693
636 depression with impaired accommodation17 in FD. This results also may have clinical relevance in that it may be 694
637 validates our novel approach, which, in addition, allowed helpful to screen for and treat comorbid anxiety disor- 695
638 us to identify which phases of the accommodation ders in FD patients who present with impaired 696

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697 accommodation, rather than exclusively focusing on pe- found because this would involve additional measure- 755
698 ripheral mechanisms in an attempt to restore their ments of the ANS, stress hormones, or other (psycho) 756
699 gastric accommodation response. physiological functions. Finally, because recruitment 757
700 Furthermore, the mechanisms underlying the associ- started 4 years before the introduction of the Rome III 758
701 ation between acute and chronic anxiety and gastric ac- criteria, Rome II criteria were used. Although we believe 759
702 commodation in FD cannot be identied based on this this is unlikely to have inuenced our results strongly, 760
703 study. However, efferent brain-gut pathways, including strictly speaking, these cannot be generalized to FD 761
704 the autonomic nervous system (ANS), and the stress samples diagnosed according to Rome III criteria. 762
705 hormone system are the prime candidates, with central Furthermore, the use of Rome II criteria did not allow 763
706 and peripheral corticotrophin-releasing factor as an us to subdivide the patient sample into EPS or PDS. 764
707 important neurotransmitter. This is conceivable based on Strengths of the study, however, included the large 765
708 several lines of evidence: gastric accommodation is sample size of well-characterized FD patients, both in 766
709 mediated vago-vagally, the ANS and stress hormone terms of gastric sensorimotor function and psychologi- 767
710 system respond to acute anxiety and are altered in cal characteristics, as well as the use of advanced sta- 768
711 anxiety disorders21,22 and functional gastrointestinal tistics to model the time course of the gastric 769
712 disorders,23 and corticotrophin-releasing factor specif- accommodation response more accurately compared 770
713 ically has effects on GI motor function.24 with the simplied approach used previously, which 771
714 Q19 Furthermore, we found a trend for an association may have hampered the detection of the associations 772
715 between gastric sensitivity and an altered time course of, we found using our novel approach. 773
716 in particular, the later part of the accommodation In summary, we modeled the time course of the Q22 774
717 Q20 response. By using a similar approach, we recently re- gastric accommodation response accurately, and we used 775
718 ported an association between rectal sensitivity and this approach to show that (anticipatory) state anxiety as 776
719 postprandial rectal tone in irritable bowel syndrome.25 well as comorbid anxiety disorders are associated with 777
720 The mechanisms underlying this association cannot be impaired gastric accommodation in FD. In addition, we 778
721 inferred from this study, but it is conceivable that ab- showed an association between delayed gastric emptying Q23 779
722 normalities in afferent visceral sensory signaling path- and increased accommodation, as well as a trend for an 780
723 ways along the entire gutbrain axis, which presumably association between gastric sensitivity and accommoda- 781
724 carry the afferent signal for the vago-vagal gastric ac- tion. Taken together, these ndings are relevant to the 782
725 commodation reex and gastric sensitivity, may be pathophysiology of FD because they indicate that it is 783
726 involved. important not to study the different processes that are 784
727 We investigated the association between gastric believed to be involved in the pathophysiology of FD in 785
728 Q21 emptying and gastric accommodation in FD. We found isolation, but rather look at their interaction to optimize 786
729 that in FD patients with delayed gastric emptying, the diagnosis and, hence, treatment of this heterogeneous 787
730 entire gastric accommodation curve is shifted upward, and poorly understood condition. 788
731 without signicantly changing its time course. Again, the 789
732 mechanisms underlying this association cannot be 790
733 determined from this study, but the increase in gastric Supplementary Material 791
734 accommodation may represent a compensatory mecha- 792
735 nism that allows the proximal stomach to exert its Note: To access the supplementary material accom- 793
736 reservoir function when more food remains in the panying this article, visit the online version of Clinical 794
737 stomach for a longer period of time owing to a failure of Gastroenterology and Hepatology at www.cghjournal.org, 795
738 the distal stomachs emptying mechanism. Alternatively, and at http://dx.doi.org/10.1016/j.cgh.2015.03.032. 796
739 a lower neuromuscular (cholinergic) tone in both the 797
740 distal and the proximal stomach may generate delayed References 798
741 emptying as well as enhanced gastric relaxation upon 1. Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal 799
disorders. Gastroenterology 2006;130:14661479.
742 food intake. 800
2. Carbone F, Tack J. Gastroduodenal mechanisms underlying
743 This study had a number of limitations. First, this 801
functional gastric disorders. Dig Dis 2014;32:222229.
744 was a cross-sectional study, which implies that no def- 802
3. Van Oudenhove L, Aziz Q. The role of psychosocial factors and
745 inite conclusion about the direction or causality of the 803
psychiatric disorders in functional dyspepsia. Nat Rev Gastro-
746 associations can be drawn. However, we previously enterol Hepatol 2013;10:158167.
804
747 showed that anxiety induction impairs gastric accom- 4. Vanheel H, Farre R. Changes in gastrointestinal tract function
805
748 modation in healthy HCs, rendering a causal interpre- and structure in functional dyspepsia. Nat Rev Gastroenterol 806
749 tation of the association between anxiety and impaired Hepatol 2013;10:142149. 807
750 accommodation in the present study plausible. Second, 5. Bisschops R, Tack J. Dysaccommodation of the stomach: 808
751 our tertiary care ndings are not necessarily general- therapeutic nirvana? Neurogastroenterol Motil 2007;19:8593. 809
752 izable to primary care or population-based FD samples. 6. Geeraerts B, Vandenberghe J, Van Oudenhove L, et al. Inuence 810
753 Third, we cannot draw nal conclusions on the (patho) of experimentally induced anxiety on gastric sensorimotor 811
754 physiological mechanisms underlying the associations function in man. Gastroenterology 2005;129:14371444. 812

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813 7. Van Oudenhove L, Vandenberghe J, Vos R, et al. Risk factors for population: the Kalixanda study. Gastroenterology 2009; 871
814 impaired health-related quality of life in functional dyspepsia. 137:94100. 872
815 Aliment Pharmacol Ther 2010;33:261274. 19. Van Oudenhove L, Vandenberghe J, Geeraerts B, et al. Rela- 873
816 8. Van Oudenhove L, Vandenberghe J, Vos R, et al. Factors tionship between anxiety and gastric sensorimotor function in 874
associated with co-morbid irritable bowel syndrome and chronic functional dyspepsia. Psychosom Med 2007;69:455463.
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fatigue-like symptoms in functional dyspepsia. Neuro- 20. Van Oudenhove L, Vandenberghe J, Dupont P, et al. Abnormal
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gastroenterol Motil 2011;23:524e202. regional brain activity during rest and (anticipated) gastric
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9. Jones MP, Coppens E, Vos R, et al. A multidimensional model distension in functional dyspepsia and the role of anxiety: a
820 of psychobiological interactions in functional dyspepsia: a 15
H2 O-PET study. Am J Gastroenterol 2010;105:913924.
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821 structural equation modelling approach. Gut 2013;62: 21. Friedman BH. An autonomic exibilityneurovisceral integration
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822 15731580. model of anxiety and cardiac vagal tone. Biol Psychol 2007; 880
823 10. Ghoos YF, Maes BD, Geypens BJ, et al. Measurement of gastric 74:185199. 881
824 emptying rate of solids by means of a carbon-labeled octanoic 22. Binder EB, Nemeroff CB. The CRF system, stress, depression 882
825 acid breath test. Gastroenterology 1993;104:16401647. and anxietyinsights from human genetic studies. Mol Psy- 883
826 11. Cuomo R, Sarnelli G, Grasso R, et al. Functional dyspepsia chiatry 2010;15:574588. 884
827 symptoms, gastric emptying and satiety provocative test: 23. Fukudo S. Stress and visceral pain: focusing on irritable bowel 885
828 analysis of relationships. Scand J Gastroenterol 2001;36: syndrome. Pain 2013;154(Suppl 1):S63S70. 886
829 10301036. 24. Tache Y, Bonaz B. Corticotropin-releasing factor receptors and 887
830 12. Van der Ploeg H. Handleiding bij de zelf-beoordelings vragenlijst stress-related alterations of gut motor function. J Clin Invest 888
831 [Manual for the Dutch adaptation of the STAI-Y]. 2nd ed. Lisse: 2007;117:3340. 889
Swets & Zeitlinger, 2000.
832 25. Trnblom H, Van Oudenhove L, Tack J, et al. Interaction be- 890
13. Spielberger C, Gorsuch R, Lushene R, et al. Manual for
833 tween preprandial and postprandial rectal sensory and motor 891
the StateTrait Anxiety Inventory (form Y Self-evaluation abnormalities in IBS. Gut 2014;63:14411449.
834 892
Questionnaire). Palo Alto, CA: Consulting Psychologists Press,
835 1983.
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836 14. Kroenke K, Spitzer RL, Williams JBW. The PHQ-9. Validity of a
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Reprint requests
837 brief depression severity measure. J Gen Intern Med 2001; Address requests for reprints to: Lukas Van Oudenhove, MD, PhD, Trans- 895
838 16:606613.
lational Research Center for Gastrointestinal Disorders, KU Leuven, Onderwijs 896
and Navorsing I, Room 07.330, Herestraat 49, Box 701, B-3000 Leuven,
839 15. Spitzer RL, Kroenke K, Williams JBW, et al. Validation and utility Belgium. e-mail: lukas.vanoudenhove@med.kuleuven.be; fax: (32) 16-345939. Q4 897
840 of a self-report version of PRIME-MD: the PHQ primary care 898
841 study. JAMA 1999;282:17371744. Acknowledgments Q5 899
The authors wish to thank Rita Vos for skillfully performing all the barostat
842 16. Tack J, Piessevaux H, Coulie B, et al. Role of impaired gastric investigations reported in this study and Lieselot Holvoet for invaluable help in 900
843 accommodation to a meal in functional dyspepsia. Gastroen- patient recruitment. 901
844 terology 1998;115:13461352. 902
Conicts of interest
845 17. Van Oudenhove L, Vandenberghe J, Vos R, et al. Abuse history,
The authors disclose no conicts. Q6 903
846 depression, and somatization are associated with gastric 904
847 sensitivity and gastric emptying in functional dyspepsia. Psy- Funding 905
chosom Med 2011;73:648655. Supported by a Methusalem grant of the KU Leuven Special Research Fund
848 (BOF) (H.G.L and J.T.); a research grant from the Research-Foundation Flan- 906
18. Aro P, Talley NJ, Storskrubb T, et al. Associations with unin-
849 ders (FWO-Vlaanderen) (N.W., J.T., and L.V.O.); and the KU Leuven Special 907
vestigated and functional dyspepsia (Rome III) in a random adult Research Fund (Bijzonder Onderzoeksfonds, BOF) (L.V.O.). Q7Q8
850 Q9 908
851 909
852 910
853 911
854 912
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929 Supplementary Methods (80 ) and the trunk upright in a specically designed 987
930 bed. After a 30-minute adaptation period, minimal dis- 988
931 Participants tending pressure was determined by increasing intra- 989
932 balloon pressure by 1 mm Hg every 3 minutes. The rst 990
933 All patients underwent history taking and clinical pressure level at which the intraballoon volume excee- 991
934 examination, upper GI endoscopy, routine biochemistry, ded 30 mL equilibrated the intra-abdominal pressure 992
935 and abdominal ultrasound. Before inclusion, all patients (minimal distending pressure). Subsequently, isobaric 993
936 were diagnosed with FD according to Rome II criteria1 by distensions were performed in stepwise increments of 2 994
937 a single gastroenterologist with extensive experience in mm Hg starting from the minimal distending pressure, 995
938 functional GI and motility disorders. Rome II criteria each lasting 2 minutes, while the corresponding intra- 996
939 were used because recruitment of this patient cohort gastric volume was recorded. Patients were instructed to 997
940 started 4 years before the introduction of Rome III score their perception of upper abdominal sensations at 998
941 criteria. However, analyses of our own patient cohort the end of every distending step using a graphic rating 999
942 showed that only 11 of 708 patients who fullled Rome scale with verbal descriptors on a scale graded from 0 to 1000
943 II FD criteria did not fulll Rome III criteria (unpublished 6. The end point of each sequence of distensions was 1001
944 analyses of cohort reported by Tack et al2). In addition, established at an intraballoon volume of 1000 mL or 1002
945 dyspeptic symptoms had to be present for at least 3 days when the patients reported discomfort or pain (score, 5 1003
946 per week, with 2 or more symptoms scored as relevant or 6). After a 30-minute adaptation period with the 1004
947 or severe on a symptom questionnaire (see later). balloon completely deated, the pressure level was set at 1005
948 Exclusion criteria were the presence of esophagitis, the minimal distending pressure 2 mm Hg during 90 Q26 1006
949 gastric atrophy, erosive gastroduodenal lesions on minutes and the corresponding intraballoon volume was 1007
950 endoscopy, heartburn as a predominant symptom, a recorded by the barostat device to quantify gastric tone. 1008
951 history of peptic ulcer, major abdominal surgery, and the After 30 minutes, a liquid meal (200 mL, 300 kcal, 13% 1009
952 use of nonsteroidal anti-inammatory drugs, steroids, or proteins, 48% carbohydrates, and 39% lipids; Nutri- 1010
953 drugs affecting gastric acid secretion. Comorbid irritable drink; Nutricia, Bornem, Belgium) was administered. 1011
954 bowel syndrome was not an exclusion criterion. All drugs Intraballoon volume (ie, gastric tone) measurement 1012
955 potentially affecting gastric function (including antide- continued for 60 minutes after the meal. 1013
956 pressants) were discontinued at least 1 week before the 1014
957 barostat investigation. The protocol was approved by the 1015
958 Statistical Analysis 1016
Medical Ethics Committee of the University Hospitals
959 Leuven before the start of the study. Patients were not 1017
960 paid for their participation.
Demographic characteristics were compared between 1018
961 All volunteers were free of medical or psychiatric
groups using the unpaired Student t test for continuous 1019
962 disorders, were studied in the same period as the FD
variables and the Pearson chi-square test for categoric 1020
963 patients, did not take any medication on a regular basis,
variables. 1021
964 and were paid a small fee for their participation.
First, in the FD group, linear, quadratic, cubic, and 1022
965 fourth-order effects of time (middle of each time bin in 1023
966 minutes, relative to the start of the nutrient ingestion) 1024
967 Gastric Barostat Protocol (time, time2, time3, and time4, respectively) were 1025
968 included as independent xed-effects variables in the 1026
969 All barostat investigations were performed by a sin- model. Plotting of the observed data vs the estimated 1027
970 gle experienced clinical laboratory technician in both the data based on the regression equations showed that the 1028
971 FD and control cohorts. After an overnight fast of at least estimated curve closely matched the observed curve 1029
972 12 hours, a double-lumen polyvinyl tube (Salem sump when the effect of time was modeled up to the fourth 1030
973 tube 14 Ch; Sherwood Medical, Petit Rechain, Belgium) order, with only marginal improvement when the fth- 1031
974 with an adherent nely folded plastic balloon (1200-mL order effect was added. This was conrmed further by 1032
975 capacity; 17-cm maximal diameter), was introduced comparing the t statistics of the models (Akaikes in- 1033
976 through the mouth and secured to the subjects chin with formation criterion) as well as by chi-square difference 1034
977 adhesive tape. The correct position of the balloon in the tests. These both indicated a signicant improvement of 1035
978 gastric fundus was checked uoroscopically. The poly- t when the fourth-order term was added to the cubic 1036
979 vinyl tube then was connected to a programmable model, but no signicant further improvement over the 1037
980 barostat device (Visceral Stimulator; Synectics, Stock- fourth-order model when the fth-order effect of time 1038
981 holm, Sweden). To unfold the balloon, it was inated was added. Therefore, models were limited to the fourth- 1039
982 with a xed volume of 300 mL of air for 2 minutes with order effect of time for reasons of parsimony. 1040
983 the patient in a recumbent position, after which it was Second, both groups were pooled in one analysis to 1041
984 deated completely. The patients then were positioned test a putative main effect of group (FD vs controls), as 1042
985 in a comfortable sitting position with the knees bent well as putative interaction effects between group on the 1043
986 1044

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8.e2 Ly et al Clinical Gastroenterology and Hepatology Vol. -, No. -

1045 one hand and the linear, quadratic, cubic, and fourth- Forty-six patients (13.9%) canceled their study visit or 1103
1046 order effect of time on the other. Signicant group-by- did not show up, allowing 280 barostat investigations to 1104
1047 time interaction effects indicated differences in the be performed. In 21 patients (6.4%), the procedure had 1105
1048 shape of the linear, quadratic, cubic, and/or fourth-order to be stopped prematurely because patients did not 1106
1049 parts of the accommodation curve between groups, with tolerate tube insertion or had severe discomfort once the 1107
1050 the b coefcient for the respective interaction effects tube was inserted. Hence, 259 patients (78.5%) 1108
1051 representing the magnitude of this difference. Nonsig- completed the study, 195 of whom (75.3% of the com- 1109
1052 nicant higher-order interaction effects between group pleters) were women; the mean age was 39.5  12.9 1110
1053 and time were eliminated from the full model, resulting years. 1111
1054 in a more parsimonious model to facilitate interpreta- 1112
1055 tion of the lower-order interaction effects or main effect 1113
Psychological State and the Time Course
1056 of group. In the absence of any interaction effects, a 1114
1057 signicant main effect of group indicated a signicant
of the Accommodation Response in 1115
1058 difference in the average change in volume between Functional Dyspepsia 1116
1059 groups independent of time (upward or downward shift 1117
1060 of the whole curve without change in shape of the State anxiety 1118
1061 curve/time course of the accommodation response), 1119
1062 with the b coefcient representing the magnitude of this State anxiety ratings before (46.5  11.7) were 1120
1063 difference. signicantly higher compared with after (38.1  9.3) the 1121
1064 A similar approach was used within the FD group to barostat investigation (the latter were retrospective 1122
1065 test the effects of the level of PDS and EPS symptoms ratings of state anxiety during the investigation) (paired 1123
1066 (high/low based on the median split), gastric hypersen- t test P < .0001, Cohens d 0.74), with a correlation 1124
1067 sitivity (hypersensitive vs normosensitive based on the coefcient of r 0.44 (P < .0001). The signicant dif- 1125
1068 established cut-off values), gastric emptying (delayed vs ference and the fact that the correlation between both 1126
1069 normal based on the established cut-off values), and state anxiety ratings was of only moderate magnitude 1127
1070 comorbid depression or anxiety disorder (both yes/no suggests that these 2 ratings may capture different forms 1128
1071 based on the cut-off values of the respective Patient of state anxiety (anticipatory anxiety vs anxiety induced 1129
1072 Health Questionnaire modules). State anxiety was by gastric stimulation during the barostat investigation). 1130
1073 entered as a continuous rather than a categoric inde- Therefore, we explored whether their association with 1131
1074 pendent variable given the absence of cut-off values for the time course of the gastric accommodation response 1132
1075 Q27 the State-Trait Anxiety Inventory-state. was different. Similar to the results with the mean of 1133
1076 In all models, the variancecovariance structure of both anxiety ratings, a signicant main effect was found 1134
1077 the repeatedly measured data was modeled using a for state anxiety before the barostat investigation was 1135
1078 combination of a random intercept and a random linear signicant (b -1.33  0.47; P .0054). However, the 1136
1079 and quadratic effect of time or using time as a categoric main effect of state anxiety after/during the barostat 1137
1080 repeated variable with an unstructured var- investigation only showed a trend (b -1.06  0.64; P 1138
1081 iancecovariance matrix. The best tting model was .099). This suggests that the effect of state anxiety on the 1139
1082 chosen based on the lowest value for the Akaike infor- time course of the gastric accommodation response is 1140
1083 mation criterion. driven mainly by anticipatory anxiety. 1141
1084 1142
1085 Results 1143
1086 1144
References
1087 Participants 1145
1. Talley NJ, Stanghellini V, Heading RC, et al. Functional gastro-
1088 duodenal disorders. Gut 1999;45:37ii42ii.
1146
1089 A total of 330 FD patients were invited to participate; 2. Tack J, Bisschops R, Sarnelli G. Pathophysiology and treatment
1147
1090 4 (1.2% of the total sample) refused to participate. of functional dyspepsia. Gastroenterology 2004;127:12391255. 1148
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