title: Neural correlates of working memory training in HIV patients: study protocol for a randomized controlled trial.
abstract: BACKGROUND
  Potent combined antiretroviral therapy decreased the incidence and severity of HIV-associated neurocognitive disorders (HAND); however, no specific effective pharmacotherapy exists for HAND. Patients with HIV commonly have deficits in working memory and attention, which may negatively impact many other cognitive domains, leading to HAND. Since HAND may lead to loss of independence in activities of daily living and negative emotional well-being, and incur a high economic burden, effective treatments for HAND are urgently needed. This study aims to determine whether adaptive working memory training might improve cognitive functions and neural network efficiency and possibly decrease neuroinflammation. This study also aims to assess whether subjects with the LMX1A-rs4657412 TT(AA) genotype show greater training effects from working memory training than TC(AG) or CC(GG)-carriers.
  
  
  METHODS
  60 HIV-infected and 60 seronegative control participants will be randomized to a double-blind active-controlled study, using adaptive versus non-adaptive Cogmed Working Memory Training® (CWMT), 20-25 sessions over 5-8 weeks. Each subject will be assessed with near- and far-transfer cognitive tasks, self-reported mood and executive function questionnaires, and blood-oxygenation level-dependent functional MRI during working memory (n-back) and visual attention (ball tracking) tasks, at baseline, 1-month, and 6-months after CWMT. Furthermore, genotyping for LMX1A-rs4657412 will be performed to identify whether subjects with the TT(AA)-genotype show greater gain or neural efficiency after CWMT than those with other genotypes. Lastly, cerebrospinal fluid will be obtained before and after CWMT to explore changes in levels of inflammatory proteins (cytokines and chemokines) and monoamines.
  
  
  CONCLUSIONS
  Improving working memory in HIV patients, using CWMT, might slow the progression or delay the onset of HAND. Observation of decreased brain activation or normalized neural networks, using fMRI, after CWMT would lead to a better understanding of how neural networks are modulated by CWMT. Moreover, validating the greater training gain in subjects with the LMX1A-TT(AA) genotype could lead to a personalized approach for future working memory training studies. Demonstrating and understanding the neural correlates of the efficacy of CWMT in HIV patients could lead to a safe adjunctive therapy for HAND, and possibly other brain disorders.
  
  
  BACKGROUND
  ClinicalTrial.gov, NCT02602418.
authors.affiliation: Department of Medicine, John A. Burns School of Medicine, The Queen's Medical Center, University of Hawaii at Manoa, 1356 Lusitana Street, 7th Floor UH Tower, Honolulu, HI, USA. lchang@hawaii.edu.
authors.forename: L
authors.initials: L
authors.lastname: Chang
authors.affiliation: Department of Pediatrics, Sørlandet Hospital, Arendal, Norway. gro.lohaugen@sshf.no.|Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway. gro.lohaugen@sshf.no.
authors.forename: G C
authors.initials: GC
authors.lastname: Løhaugen
authors.affiliation: Department of Medicine, John A. Burns School of Medicine, The Queen's Medical Center, University of Hawaii at Manoa, 1356 Lusitana Street, 7th Floor UH Tower, Honolulu, HI, USA. douet@hawaii.edu.
authors.forename: V
authors.initials: V
authors.lastname: Douet
authors.affiliation: UCLA Psychiatry and Biobehavioral Sciences, Los Angeles, CA, USA. emiller@ucla.edu.
authors.forename: E N
authors.initials: EN
authors.lastname: Miller
authors.affiliation: Department of Pediatrics, Sørlandet Hospital, Arendal, Norway. jon.skranes@ntnu.no.|Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway. jon.skranes@ntnu.no.
authors.forename: J
authors.initials: J
authors.lastname: Skranes
authors.affiliation: Department of Medicine, John A. Burns School of Medicine, The Queen's Medical Center, University of Hawaii at Manoa, 1356 Lusitana Street, 7th Floor UH Tower, Honolulu, HI, USA. tmernst@hawaii.edu.
authors.forename: T
authors.initials: T
authors.lastname: Ernst
mesh_terms: D002985:Clinical Protocols; D003071:Cognition; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000503:physiopathology* / Q000523:psychology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term; D009483:Neuropsychological Tests; D017063:Outcome Assessment, Health Care
references.citation: J Clin Exp Neuropsychol. 1994 Apr;16(2):173-82
references.pmid: 8021304
references.citation: PLoS One. 2009;4(6):e6102
references.pmid: 19564918
references.citation: Disabil Rehabil. 2012;34(21):1848-52
references.pmid: 22458375
references.citation: Front Hum Neurosci. 2012 Mar 27;6:63
references.pmid: 22470330
references.citation: J Pediatr. 2011 Apr;158(4):555-561.e4
references.pmid: 21130467
references.citation: Nat Rev Neurosci. 2007 Jan;8(1):21-32
references.pmid: 17180160
references.citation: Neuropsychol Rev. 2009 Jun;19(2):152-68
references.pmid: 19462243
references.citation: Acta Neurol Scand Suppl. 2003;179:94-9
references.pmid: 12603255
references.citation: J Int Neuropsychol Soc. 1997 Sep;3(5):451-6
references.pmid: 9322404
references.citation: Neurology. 2000 Jan 11;54(1):233-5
references.pmid: 10636157
references.citation: J Immunol. 2010 Jan 15;184(2):746-56
references.pmid: 19966207
references.citation: Sleep. 1991 Dec;14(6):540-5
references.pmid: 1798888
references.citation: Psychol Med. 2001 Oct;31(7):1279-91
references.pmid: 11681554
references.citation: J Cogn Neurosci. 1995 Fall;7(4):497-510
references.pmid: 23961907
references.citation: J Int Neuropsychol Soc. 2001 Jan;7(1):20-6
references.pmid: 11253838
references.citation: J Int Neuropsychol Soc. 2002 May;8(4):532-8
references.pmid: 12030306
references.citation: Ann Neurol. 2006 Feb;59(2):419-23
references.pmid: 16437575
references.citation: J Am Geriatr Soc. 2012 Jan;60(1):136-41
references.pmid: 22150209
references.citation: Neuroimage. 2004 Dec;23(4):1414-21
references.pmid: 15589105
references.citation: Neurology. 2009 Dec 8;73(23):1975-81
references.pmid: 19890073
references.citation: AIDS Behav. 2007 Mar;11(2):185-94
references.pmid: 16897351
references.citation: J Pers Assess. 1998 Aug;71(1):114-28
references.pmid: 9807231
references.citation: J Magn Reson Imaging. 2010 Nov;32(5):1045-53
references.pmid: 21031507
references.citation: Neuroimage. 2011 Oct 15;58(4):1110-20
references.pmid: 21757013
references.citation: J Clin Exp Neuropsychol. 2002 Sep;24(6):781-91
references.pmid: 12424652
references.citation: J Neuroimmune Pharmacol. 2008 Jun;3(2):95-104
references.pmid: 18247124
references.citation: J Cogn Neurosci. 2001 Aug 15;13(6):730-43
references.pmid: 11564318
references.citation: Spat Vis. 1988;3(3):179-97
references.pmid: 3153671
references.citation: Neurology. 2001 Sep 25;57(6):1001-7
references.pmid: 11571324
references.citation: AIDS. 2016 Feb 20;30(4):543-52
references.pmid: 26558720
references.citation: Ann Neurol. 2010 Jun;67(6):699-714
references.pmid: 20517932
references.citation: AIDS. 1994 Jan;8(1):67-71
references.pmid: 8011238
references.citation: Physiol Behav. 2007 Sep 10;92(1-2):186-92
references.pmid: 17597168
references.citation: Neurology. 2007 Sep 25;69(13):1314-21
references.pmid: 17652642
references.citation: Neuroimage. 2008 Aug 15;42(2):869-78
references.pmid: 18579413
references.citation: Science. 1999 Mar 5;283(5407):1538-41
references.pmid: 10066177
references.citation: Dev Biol. 2010 Mar 1;339(1):101-13
references.pmid: 20035737
references.citation: Science. 2009 Feb 6;323(5915):800-2
references.pmid: 19197069
references.citation: Brain Inj. 2007 Jan;21(1):21-9
references.pmid: 17364516
references.citation: Trials. 2014;15:156
references.pmid: 24886034
references.citation: Sex Health. 2011 Dec;8(4):541-50
references.pmid: 22127041
references.citation: Nat Neurosci. 2004 Jan;7(1):75-9
references.pmid: 14699419
references.citation: Neuropsychologia. 2011 Jun;49(7):1938-42
references.pmid: 21435346
references.citation: J Cogn Neurosci. 2001 Nov 15;13(8):1048-58
references.pmid: 11784443
references.citation: J Neurovirol. 2011 Feb;17(1):63-9
references.pmid: 21246320
references.citation: AIDS. 2010 Jun 1;24(9):1243-50
references.pmid: 19996937
references.citation: J Int Neuropsychol Soc. 2004 May;10(3):317-31
references.pmid: 15147590
references.citation: Interdiscip Perspect Infect Dis. 2010;2010:678648
references.pmid: 20069120
references.citation: Arch Neurol. 1998 Jan;55(1):41-51
references.pmid: 9443710
references.citation: Science. 2011 Aug 19;333(6045):959-64
references.pmid: 21852486
references.citation: J Neural Transm (Vienna). 2009 Mar;116(3):333-8
references.pmid: 19189040
references.citation: Neurology. 2014 Jun 17;82(24):2213-22
references.pmid: 24850492
references.citation: J Neuroimmune Pharmacol. 2010 Sep;5(3):294-309
references.pmid: 20396973
references.citation: Neuropsychology. 2002 Jul;16(3):400-10
references.pmid: 12146687
references.citation: J Acquir Immune Defic Syndr. 2002 Dec 15;31 Suppl 3:S132-5
references.pmid: 12562036
references.citation: Scand J Occup Ther. 2012 Mar;19(2):176-83
references.pmid: 21843045
references.citation: Science. 2008 Jun 13;320(5882):1510-2
references.pmid: 18556560
references.citation: PLoS One. 2012;7(4):e35653
references.pmid: 22530064
references.citation: J Speech Lang Hear Res. 2011 Aug;54(4):1182-96
references.pmid: 21173394
references.citation: Brain. 2004 Nov;127(Pt 11):2452-8
references.pmid: 15319273
references.citation: J Am Acad Child Adolesc Psychiatry. 2005 Feb;44(2):177-86
references.pmid: 15689731
references.citation: Z Gerontol Geriatr. 2012 Jan;45(1):11-6
references.pmid: 22278001
references.citation: Neurology. 2002 Nov 12;59(9):1343-9
references.pmid: 12427881
references.citation: J Int Neuropsychol Soc. 2000 Jul;6(5):548-55
references.pmid: 10932474
references.citation: Curr Pharm Biotechnol. 2011 Oct;12(10):1707-14
references.pmid: 21466443
references.citation: Antivir Ther. 2003 Feb;8(1):17-26
references.pmid: 12713060
references.citation: Psychol Med. 1995 Nov;25(6):1221-32
references.pmid: 8637952
references.citation: Gerontologist. 1969 Autumn;9(3):179-86
references.pmid: 5349366
references.citation: HIV Clin Trials. 2010 Jan-Feb;11(1):59-67
references.pmid: 20400412
references.citation: AIDS Patient Care STDS. 2008 Apr;22(4):323-35
references.pmid: 18290734
references.citation: Microsc Res Tech. 2000 Oct 1;51(1):54-63
references.pmid: 11002353
references.citation: Neuroimage. 2003 Aug;19(4):1686-93
references.pmid: 12948723
references.citation: Proc Natl Acad Sci U S A. 2009 May 5;106(18):7613-8
references.pmid: 19383789
references.citation: J Neurovirol. 2009 Apr;15(2):176-86
references.pmid: 19306230
references.citation: Neuroimage. 2002 Nov;17(3):1638-48
references.pmid: 12414302
references.citation: J Neurovirol. 2011 Feb;17(1):3-16
references.pmid: 21174240
references.citation: Psychiatry Res. 1989 May;28(2):193-213
references.pmid: 2748771
references.citation: Nat Neurosci. 2000 Dec;3(12):1329-34
references.pmid: 11100155
references.citation: Rev Neurol (Paris). 1998 Dec;154(12):816-29
references.pmid: 9932303
references.citation: Methods Mol Biol. 2011;793:401-15
references.pmid: 21913116
references.citation: Nature. 1995 Sep 14;377(6545):155-8
references.pmid: 7675082
references.citation: Ann Neurol. 2009 Mar;65(3):316-25
references.pmid: 19334060
references.citation: Neurology. 2007 Oct 30;69(18):1789-99
references.pmid: 17914061
references.citation: Qual Life Res. 1997 Aug;6(6):481-93
references.pmid: 9330549
references.citation: J Clin Exp Neuropsychol. 2011 Feb;33(2):200-9
references.pmid: 20694873
references.citation: Neuropsychology. 2015 Mar;29(2):247-54
references.pmid: 24819065
references.citation: AIDS. 2006 Oct 24;20(16):2005-9
references.pmid: 17053346
references.citation: Neurology. 2011 Sep 20;77(12):1135-42
references.pmid: 21900636
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2010 Aug 16;34(6):1094-7
references.pmid: 20570600
references.citation: Ann Neurol. 2004 Aug;56(2):259-72
references.pmid: 15293278
references.citation: Antivir Ther. 2004 Jun;9(3):431-40
references.pmid: 15259906