title: Brain neuroplastic changes accompany anxiety and memory deficits in a model of complex regional pain syndrome.
abstract: BACKGROUND
  Complex regional pain syndrome (CRPS) is a painful condition with approximately 50,000 annual new cases in the United States. It is a major cause of work-related disability, chronic pain after limb fractures, and persistent pain after extremity surgery. Additionally, CRPS patients often experience cognitive changes, anxiety, and depression. The supraspinal mechanisms linked to these CRPS-related comorbidities remain poorly understood.
  
  
  METHODS
  The authors used a previously characterized mouse model of tibia fracture/cast immobilization showing the principal stigmata of CRPS (n = 8 to 20 per group) observed in humans. The central hypothesis was that fracture/cast mice manifest changes in measures of thigmotaxis (indicative of anxiety) and working memory reflected in neuroplastic changes in amygdala, perirhinal cortex, and hippocampus.
  
  
  RESULTS
  The authors demonstrate that nociceptive sensitization in these mice is accompanied by altered thigmotactic behaviors in the zero maze but not open field assay, and working memory dysfunction in novel object recognition and social memory but not in novel location recognition. Furthermore, the authors found evidence of structural changes and synaptic plasticity including changes in dendritic architecture and decreased levels of synaptophysin and brain-derived neurotrophic factor in specific brain regions.
  
  
  CONCLUSIONS
  The study findings provide novel observations regarding behavioral changes and brain plasticity in a mouse model of CRPS. In addition to elucidating some of the supraspinal correlates of the syndrome, this work supports the potential use of therapeutic interventions that not only directly target sensory input and other peripheral mechanisms, but also attempt to ameliorate the broader pain experience by modifying its associated cognitive and emotional comorbidities.
authors.affiliation: From the Veterans Affairs Palo Alto Health Care System, Palo Alto, California (M.T., P.S., W.L., H.K., J.D.C.); Department of Anesthesiology, Stanford University School of Medicine, Stanford, California (M.T., P.S., W.L., J.D.C.); Palo Alto Institute of Research and Education, Palo Alto, California (M.T., D.L., Y.Z., H.K., V.H.); Department of Neurology and Neurological Sciences, Stanford University, Stanford, California (Y.Z., T.T.H.); Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California (W.K.); Geriatrics Research Education and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, California (D.L., Y.Z., V.H., T.T.H.); and P.A.I.N. Group, Departments of Anesthesia and Psychiatry, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts (L.B.).
authors.forename: Maral
authors.initials: M
authors.lastname: Tajerian
authors.forename: David
authors.initials: D
authors.lastname: Leu
authors.forename: Yani
authors.initials: Y
authors.lastname: Zou
authors.forename: Peyman
authors.initials: P
authors.lastname: Sahbaie
authors.forename: Wenwu
authors.initials: W
authors.lastname: Li
authors.forename: Hamda
authors.initials: H
authors.lastname: Khan
authors.forename: Vivian
authors.initials: V
authors.lastname: Hsu
authors.forename: Wade
authors.initials: W
authors.lastname: Kingery
authors.forename: Ting Ting
authors.initials: TT
authors.lastname: Huang
authors.forename: Lino
authors.initials: L
authors.lastname: Becerra
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
mesh_terms: D000818:Animals; D001007:Anxiety / Q000473:pathology* / Q000523:psychology; D001921:Brain / Q000473:pathology* / Q000502:physiology; D020918:Complex Regional Pain Syndromes / Q000473:pathology* / Q000523:psychology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology; D008297:Male; D008569:Memory Disorders / Q000473:pathology* / Q000523:psychology; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000502:physiology; D011897:Random Allocation; D013978:Tibial Fractures / Q000473:pathology* / Q000523:psychology
references.citation: Pain. 2011 Apr;152(4):809-817
references.pmid: 21295405
references.citation: Biol Psychiatry. 2011 Nov 15;70(10):946-53
references.pmid: 21890110
references.citation: J Pain. 2006 Aug;7(8):544-55
references.pmid: 16885011
references.citation: J Neurosci. 2012 May 16;32(20):6795-807
references.pmid: 22593049
references.citation: Pain. 1999 Mar;80(1-2):171-7
references.pmid: 10204729
references.citation: J Neurosci. 2006 Jan 4;26(1):126-37
references.pmid: 16399679
references.citation: Behav Brain Funct. 2013 Jun 07;9:22
references.pmid: 24025218
references.citation: Prog Neurobiol. 2014 Jan;112:80-99
references.pmid: 24211850
references.citation: Behav Brain Res. 2002 May 14;132(2):215-26
references.pmid: 11997151
references.citation: Clin J Pain. 2012 May;28(4):355-63
references.pmid: 22001668
references.citation: Eur J Pain. 2007 Nov;11(8):903-9
references.pmid: 17451979
references.citation: PLoS One. 2013 Jun 21;8(6):e65483
references.pmid: 23805183
references.citation: Clin J Pain. 1997 Jun;13(2):116-37
references.pmid: 9186019
references.citation: J Neurosci. 2011 May 18;31(20):7540-50
references.pmid: 21593339
references.citation: Neuroscience. 2008 Jan 24;151(2):558-63
references.pmid: 18065152
references.citation: J Neurocytol. 1996 Dec;25(12):821-8
references.pmid: 9023727
references.citation: Psychosom Med. 2002 Sep-Oct;64(5):773-86
references.pmid: 12271108
references.citation: Arch Clin Neuropsychol. 2007 Aug;22(6):719-29
references.pmid: 17611073
references.citation: PLoS One. 2013;8(3):e57205
references.pmid: 23526938
references.citation: Behav Brain Res. 2001 Nov 1;125(1-2):269-77
references.pmid: 11682118
references.citation: J Neurosci. 2011 Sep 7;31(36):12889-99
references.pmid: 21900567
references.citation: Neuropsychopharmacology. 2011 Apr;36(5):979-92
references.pmid: 21289602
references.citation: Mol Pain. 2013 Aug 08;9:40
references.pmid: 23924076
references.citation: Neuron. 2005 Oct 20;48(2):175-87
references.pmid: 16242399
references.citation: Anesth Analg. 2007 Jun;104(6):1570-7, table of contents
references.pmid: 17513660
references.citation: Neuroscience. 2011 Oct 27;194:282-90
references.pmid: 21723920
references.citation: Arthritis Rheum. 2013 Jun;65(6):1494-503
references.pmid: 23460087
references.citation: Neurosci Lett. 2009 Sep 29;463(1):98-102
references.pmid: 19631256
references.citation: Mol Pain. 2007 Oct 31;3:32
references.pmid: 17974009
references.citation: J Neuroimmune Pharmacol. 2013 Jun;8(3):547-63
references.pmid: 23188523
references.citation: Arch Phys Med Rehabil. 1981 Nov;62(11):549-54
references.pmid: 6172092
references.citation: Learn Mem. 2002 Mar-Apr;9(2):49-57
references.pmid: 11992015
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 5;101(40):14515-20
references.pmid: 15452348
references.citation: Neuropsychopharmacology. 2014 Feb;39(3):614-24
references.pmid: 24008352
references.citation: Pain. 2004 Jun;109(3):214-224
references.pmid: 15157681
references.citation: J Neurosci. 2012 Apr 25;32(17):5747-56
references.pmid: 22539837
references.citation: J Pain. 2011 Apr;12(4):436-43
references.pmid: 21146463
references.citation: Physiol Rev. 2010 Apr;90(2):419-63
references.pmid: 20393190
references.citation: J Neurosci Methods. 1994 Jul;53(1):55-63
references.pmid: 7990513
references.citation: J Int Neuropsychol Soc. 2010 May;16(3):566-73
references.pmid: 20298641
references.citation: Mol Pain. 2012 Apr 26;8:32
references.pmid: 22537768
references.citation: Eur J Pain. 2008 Nov;12(8):970-9
references.pmid: 18304847
references.citation: J Pain Symptom Manage. 2001 May;21(5):392-6
references.pmid: 11369160
references.citation: Nat Rev Neurosci. 2012 Oct;13(10):713-26
references.pmid: 22992647
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1710-5
references.pmid: 18227507
references.citation: Prog Neurobiol. 2005 Jun;76(2):99-125
references.pmid: 16099088
references.citation: J Clin Psychol Med Settings. 2013 Jun;20(2):247-54
references.pmid: 22961122
references.citation: Neuroscience. 2005;133(4):999-1006
references.pmid: 15964488
references.citation: Pain. 2003 Nov;106(1-2):127-33
references.pmid: 14581119
references.citation: Pain. 2014 Jan;155(1):53-59
references.pmid: 24012953
references.citation: Pain. 2012 Aug;153(8):1657-1663
references.pmid: 22664319
references.citation: Pain. 2006 Nov;125(1-2):89-97
references.pmid: 16750298
references.citation: J Neurosci. 2004 Nov 17;24(46):10410-5
references.pmid: 15548656
references.citation: Neurosci Lett. 2012 Nov 7;529(2):103-7
references.pmid: 22999928
references.citation: J Neurosci. 2010 May 5;30(18):6282-90
references.pmid: 20445054
references.citation: Neuroscientist. 2004 Jun;10(3):221-34
references.pmid: 15155061
references.citation: Exp Neurol. 2009 Sep;219(1):223-7
references.pmid: 19477176
references.citation: Radiology. 2013 Jul;268(1):170-80
references.pmid: 23533286
references.citation: Hippocampus. 2001;11(1):61-71
references.pmid: 11261774
references.citation: Neuroscience. 2013 Aug 29;246:230-42
references.pmid: 23660193
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9385-90
references.pmid: 10430952
references.citation: J Neurosci. 2011 Jul 20;31(29):10721-31
references.pmid: 21775615
references.citation: Pain. 2010 Dec;151(3):870-876
references.pmid: 20965657
references.citation: Pain. 2004 Nov;112(1-2):94-105
references.pmid: 15494189
references.citation: Cereb Cortex. 2013 Sep;23(9):2190-203
references.pmid: 22784608
references.citation: Anesth Analg. 2007 Dec;105(6):1820-9, table of contents
references.pmid: 18042888
references.citation: Anesthesiology. 2008 Aug;109(2):297-307
references.pmid: 18648239
references.citation: PLoS One. 2013;8(1):e55259
references.pmid: 23383129
references.citation: Mol Pain. 2013 Apr 18;9:21
references.pmid: 23597049
references.citation: Exp Neurol. 1973 Aug;40(2):491-504
references.pmid: 4730268
references.citation: Neurosci Lett. 2013 Apr 29;541:275-80
references.pmid: 23415758
references.citation: Clin J Pain. 1997 Jun;13(2):163-70
references.pmid: 9186024
references.citation: Pain. 2004 Mar;108(1-2):95-107
references.pmid: 15109512
references.citation: Pain. 2013 Aug;154(8):1181-96
references.pmid: 23707355
references.citation: Eur J Pain. 2013 Feb;17(2):158-73
references.pmid: 23042687
references.citation: Learn Mem. 2003 Mar-Apr;10(2):86-98
references.pmid: 12663747
references.citation: Neuroscience. 1992;46(1):1-8
references.pmid: 1594095
references.citation: Pain. 2013 Jul;154(7):972-7
references.pmid: 23473784
references.citation: Behav Neurosci. 2002 Jun;116(3):494-7
references.pmid: 12049331
references.citation: Neurol Sci. 2013 Aug;34(8):1355-65
references.pmid: 23187788
references.citation: Pain. 2004 Mar;108(1-2):129-36
references.pmid: 15109516
references.citation: Trends Neurosci. 2000 Dec;23(12):639-45
references.pmid: 11137155
references.citation: Pain. 2013 Feb;154(2):204-212
references.pmid: 23141478
references.citation: Exp Neurol. 2006 Apr;198(2):401-15
references.pmid: 16443221
references.citation: AJNR Am J Neuroradiol. 2009 Aug;30(7):1279-84
references.pmid: 19386737
references.citation: Behav Brain Res. 2012 Mar 17;228(2):328-32
references.pmid: 22197296
references.citation: Neural Plast. 2012;2012:640259
references.pmid: 22530157
references.citation: Eur J Pharmacol. 2003 Feb 28;463(1-3):3-33
references.pmid: 12600700
references.citation: Behav Brain Res. 2008 Mar 5;187(2):207-20
references.pmid: 17983671
references.citation: Hippocampus. 2000;10(1):47-56
references.pmid: 10706216
references.citation: Psychopharmacology (Berl). 1994 Sep;116(1):56-64
references.pmid: 7862931
references.citation: Mol Pain. 2012 Nov 28;8:85
references.pmid: 23191958
references.citation: Pain. 2007 May;129(1-2):12-20
references.pmid: 17084977
references.citation: Brain Res. 2013 Nov 20;1539:73-86
references.pmid: 24096214
references.citation: Neuron. 2008 Jun 12;58(5):662-71
references.pmid: 18549779
references.citation: Clin J Pain. 1995 Jun;11(2):103-11
references.pmid: 7549165
references.citation: Rheumatology (Oxford). 2011 Oct;50(10):1739-50
references.pmid: 21712368
references.citation: Acta Neurol Scand. 2000 Apr;101(4):262-9
references.pmid: 10770524
references.citation: Neuroscience. 2013 Jun 14;240:147-54
references.pmid: 23466809
references.citation: Pain. 2014 Feb;155(2):377-387
references.pmid: 24211726