Reduced Functional Connectivity of Default Mode and Set-Maintenance Networks in Ornithine Transcarbamylase Deficiency

Ileana Pacheco-Colón, Stuart D Washington, Courtney Sprouse, Guy Helman, Andrea L Gropman, John W VanMeter, Ileana Pacheco-Colón, Stuart D Washington, Courtney Sprouse, Guy Helman, Andrea L Gropman, John W VanMeter

Abstract

Background and purpose: Ornithine transcarbamylase deficiency (OTCD) is an X-chromosome linked urea cycle disorder (UCD) that causes hyperammonemic episodes leading to white matter injury and impairments in executive functioning, working memory, and motor planning. This study aims to investigate differences in functional connectivity of two resting-state networks--default mode and set-maintenance--between OTCD patients and healthy controls.

Methods: Sixteen patients with partial OTCD and twenty-two control participants underwent a resting-state scan using 3T fMRI. Combining independent component analysis (ICA) and region-of-interest (ROI) analyses, we identified the nodes that comprised each network in each group, and assessed internodal connectivity.

Results: Group comparisons revealed reduced functional connectivity in the default mode network (DMN) of OTCD patients, particularly between the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) node and bilateral inferior parietal lobule (IPL), as well as between the ACC/mPFC node and the posterior cingulate cortex (PCC) node. Patients also showed reduced connectivity in the set-maintenance network, especially between right anterior insula/frontal operculum (aI/fO) node and bilateral superior frontal gyrus (SFG), as well as between the right aI/fO and ACC and between the ACC and right SFG.

Conclusion: Internodal functional connectivity in the DMN and set-maintenance network is reduced in patients with partial OTCD compared to controls, most likely due to hyperammonemia-related white matter damage. Because several of the affected areas are involved in executive functioning, it is postulated that this reduced connectivity is an underlying cause of the deficits OTCD patients display in this cognitive domain.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. DMN.
Fig 1. DMN.
The default mode network of both subject groups is composed of an ACC/mPFC node, a PCC/precuneus node, and bilateral IPL nodes.
Fig 2. ROI Analyses Results.
Fig 2. ROI Analyses Results.
A) Z-scores reflecting degree of functional connectivity between pairs of ROIs in the Control group. B) Z-scores reflecting degree of functional connectivity between pairs of ROIs in OTCD patient group. C) Controls have significantly greater DMN functional connectivity than OTCD patients between ACC/mPFC node and bilateral IPL.
Fig 3. Set-Maintenance Network.
Fig 3. Set-Maintenance Network.
The set-maintenance network is composed of A) ACC and bilateral SFG, and B) bilateral aI/fO.
Fig 4. ROI Analyses Results.
Fig 4. ROI Analyses Results.
A) Z-scores reflecting degree of functional connectivity between pairs of ROIs in the Control group. B) Z-scores reflecting degree of functional connectivity between pairs of ROIs in OTCD patient group. C) Controls have significantly greater set-maintenance functional connectivity than OTCD patients between ACC node and bilateral SFG.

References

    1. Nagata N, Matsuda I, Oyanagi K (1991) Estimated frequency of urea cycle enzymopathies in Japan. Am. J. Med. Genet. 18: 228–9.
    1. Applegarth DA, Toone JR, Lowry RB (2000) Incidence of inborn errors of metabolism in British Columbia. Pediatrics 105: 1969–96.
    1. Caldovic L, Morizono H, Gracia Panglao M, Gallegos R, Yu X, Shi D, et al. (2002) Cloning and expression of the human N-acetylglutamate synthase gene. Biochem. Biophys. Res. Commun. 299: 581–6.
    1. Caldovic L, Morizono H, Gracia Panglao M, Cheng SF, Packman S, Tuchman M (2003) Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia. Hum. Genet.: 112: 364–8.
    1. Dionisi-Vici C, Rizzo C, Burlina AB, Caruso U, Sabetta G, Uziel G, et al. (2002) Inborn errors of metabolism in the Italian pediatric population: a national retrospective survey. J. Pediatr. 140: 321–7.
    1. Brusilow SW, Maestri NE (1973) Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv. Pediatr. 1996: 43: 127–70.
    1. Kang ES, Snodgrass PJ, Gerald PS (1973) Ornithine transcarbamylase deficiency in the newborn infant. J. Pediatr. 82: 642–9.
    1. McCullough BA, Yudkoff M, Batshaw ML, Wilson JM, Raper SE, Tuchman M (2000) Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. Am. J. Med. Genet. 93: 313–9.
    1. Gropman AL, Batshaw ML (2004) Cognitive outcome in urea cycle disorders. Mol. Genet. Metab. 81: Suppl 1: S58–62.
    1. Msall M, Monahan PS, Chapanis N, Batshaw ML (1984) Neurologic outcome in children with inborn errors of urea synthesis: outcome of urea-cycle enzymopathies. N Engl J Med. 310 (23): 1500–5.
    1. Nicolaides P, Liebsch D, Dale N, Leonard J, Surtees R (2002) Neurological outcome of patients with ornithine carbamoyltransferase deficiency. Arch. Dis. Child. 86: 54–6.
    1. Batshaw ML, Msall M, Beaudet AL, Trojak J (1986) Risk of serious illness in heterozygotes for ornithine transcarbamylase deficiency. J. Pediatr. 108: 236–41.
    1. Batshaw ML, Roan Y, Jung AL, Rosenberg LA, Brusilow SW (1980) Cerebral dysfunction in asymptomatic carriers of ornithine transcarbamylase deficiency. N. Engl. J. Med. 302: 482–5.
    1. Gropman AL, Gertz B, Shattuck K, Kahn IL, Seltzer R, Krivistsky L, et al. (2010) Diffusion tensor imaging detects areas of abnormal white matter microstructure in patients with partial ornithine transcarbamylase deficiency. AJNR Am. J. Neuroradiol. 31: 1719–23. 10.3174/ajnr.A2122
    1. Gyato K, Wray J, Huang ZJ, Yudkoff M, Batshaw ML (2004) Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency. Ann. Neurol. 55: 80–6.
    1. Biswal BB, Mennes M, Zuo XN, Gohel S, Kelly C, Smith SM, et al. (2010) Toward discovery science of human brain function. Proc. Natl. Acad. Sci. U. S. A. 107: 4734–9. 10.1073/pnas.0911855107
    1. Buckner RL, Andrews-Hanna JR, Schacter DL (2008) The brain’s default network: anatomy, function, and relevance to disease. Ann. N. Y. Acad. Sci. 1124: 1–38. 10.1196/annals.1440.011
    1. Damoiseaux JS, Rombouts SARB, Barkhof F, Scheltens P, Stam CJ, Smith SM, et al. (2006) Consistent resting-state networks across healthy subjects. Proc. Natl. Acad. Sci. U. S. A. 103: 13848–53.
    1. Greicius MD, Srivastava G, Reiss AL, Menon V (2004) Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: Evidence from functional MRI. Proc. Natl. Acad. Sci. U. S. A. 101: 4637–42.
    1. Gusnard DA, Raichle ME, Raichle ME (2001) Searching for a baseline: functional imaging and the resting human brain. Nat. Rev. Neurosci. 2: 685–94.
    1. Uddin LQ, Kelly AM, Biswal BB, Castellanos FX, Milham MP (2009) Functional connectivity of default mode network components: correlation, anticorrelation, and causality. Hum. Brain Mapp. 30: 627–35.
    1. Addis DR, Wong AT, Schacter DL (2007) Remembering the past and imagining the future: common and distinct neural substrates during event construction and elaboration. Neuropsychologia 45: 1363–77.
    1. Greicius MD, Krasnow B, Reiss AL, Menon V (2003) Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc. Natl. Acad. Sci. U. S. A. 100, 253–8.
    1. Kim H (2010) Dissociating the roles of the default-mode, dorsal, and ventral networks in episodic memory retrieval. NeuroImage 50: 1648–57. 10.1016/j.neuroimage.2010.01.051
    1. Saxe R, Kanwisher N (2003) People thinking about thinking people: the role of the temporo-parietal junction in ‘theory of mind’. NeuroImage 19: 1835–42.
    1. Spreng RN, Grady CL (2010) Patterns of brain activity supporting autobiographical memory, prospection, and theory of mind, and their relationship to the default mode network. J. Cogn. Neurosci. 22: 1112–23. 10.1162/jocn.2009.21282
    1. Dosenbach NUF, Fair DA, Miezin FM, Cohen AL, Wenger KK, Dosenbach RA, et al. (2007) Distinct brain networks for adaptive and stable task control in humans. Proc. Natl. Acad. Sci. 104: 11073–8.
    1. Dosenbach NUF, Fair DA, Cohen AL, Schlaggar BL, Petersen SE (2008) A dual-networks architecture of top-down control. Trends Cogn. Sci. 12: 99–105. 10.1016/j.tics.2008.01.001
    1. Friston KJ, Frith CD, Liddle PF, Frackowiak RSJ (1993) Functional connectivity: The principal-component analysis of large (PET) data sets. J. Cereb. Blood Flow Metab. 13: 5–14.
    1. Zhang L, Qi R, Wu S, Zhong J, Zhong Y, Zhang Z, et al. (2012) Brain default-mode network abnormalities in hepatic encephalopathy: a resting-state functional MRI study. Hum. Brain Mapp. 33: 1384–92. 10.1002/hbm.21295
    1. Uddin LQ, Kelly AM, Biswal BB, Margulies DS, Shehzad Z, Shaw D, et al. (2008) Network homogeneity reveals decreased integrity of default-mode network in ADHD. J. Neurosci. Methods 169: 249–54.
    1. Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED (1988) Cognitive development in children with inborn errors of urea synthesis. Acta Paediatr Jpn 30: 435–41.
    1. Power JD, Barnes KA, Snyder AZ, Schlaggar BL, Petersen SE (2012) Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. NeuroImage 59: 2142–54.
    1. Washington SD, Gordon EM, Brar J, Warburton S, Sawyer AT, Wolfe A, et al. (2013) Dysmaturation of the default mode network in autism. Hum. Brain Mapp. 35: 1284–96.
    1. Beckmann CF, Smith SM (2004) Probabilistic independent component analysis for functional magnetic resonance imaging. IEEE Trans Med Imaging 23: 137–52.
    1. Van Dijk KRA, Hedden T, Venkataraman A, Evans KC, Lazar SW, Buckner RL (2010) Intrinsic functional connectivity as a tool for human connectomics: theory, properties, and optimization. J. Neurophysiol. 103: 297–321. 10.1152/jn.00783.2009
    1. Shirer WR, Ryali S, Rykhlevskaia E, Menon V, Greicius MD (2012) Decoding subject-driven cognitive states with whole-brain connectivity patterns. Cereb. Cortex. 22: 158–65. 10.1093/cercor/bhr099
    1. Leech R, Sharp DJ (2014) The role of the posterior cingulate cortex in cognition and disease. Brain J. Neurol. 137: 12–32.
    1. Nelson SM, Dosenbach NUF, Cohen AL, Wheeler ME, Schlaggar BL, Petersen SE (2010) Role of the anterior insula in task-level control and focal attention. Brain Struct. Funct. 214: 669–80. 10.1007/s00429-010-0260-2
    1. Carter CS, Mintun M, Cohen JD (1995) Interference and facilitation effects during selective attention: an H215O PET study of Stroop task performance. NeuroImage 2: 264–72.
    1. Duncan J, Owen AM (2000) Common regions of the human frontal lobe recruited by diverse cognitive demands. Trends Neurosci 23: 475–83.
    1. Owen AM, McMillan KM, Laird AR, Bullmore E (2005) N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies. Hum. Brain Mapp. 25: 46–59.
    1. Pardo JV, Pardo PJ, Janer KW, Raichle ME (1990) The anterior cingulate cortex mediates processing selection in the Stroop attentional conflict paradigm. Proc. Natl. Acad. Sci. U. S. A. 87: 256–9.
    1. Callicott JH, Mattay VS, Bertolino A, Finn K, Coppola R, Frank JA, et al. (1999) Physiological characteristics of capacity constraints in working memory as revealed by functional MRI. Cereb. Cortex 9: 20–6.
    1. Rämä P, Martinkauppi S, Linnankoski J, Koivisto J, Aronen HJ, Carlson S (2001) Working memory of identification of emotional vocal expressions: an fMRI study. NeuroImage 13: 1090–101.
    1. Cutini S, Scatturin P, Menon E, Bisiacchi PS, Gamberini L, Zorzi M, et al. (2008) Selective activation of the superior frontal gyrus in task-switching: an event-related fNIRS study. NeuroImage 42: 945–55. 10.1016/j.neuroimage.2008.05.013
    1. du Boisgueheneuc F, Levy R, Volle E, Seassau M, Duffau H, Kinkingnehun S, et al. (2006) Functions of the left superior frontal gyrus in humans: a lesion study. Brain J. Neurol. 129: 3315–28.
    1. Sprouse C, King J, Helman G, Pacheco-Colón I, Shattuck K, Breeden A, et al. (2014) Investigating neurological deficits in carriers and affected patients with ornithine transcarbamylase deficiency. Mol. Genet. Metab. 113: 136–41. 10.1016/j.ymgme.2014.05.007
    1. Gropman AL, Shattuck K, Prust MJ, Seltzer RR, Breeden AL, Hailu A, et al. (2013) Altered neural activation in ornithine transcarbamylase deficiency during executive cognition: an fMRI study. Hum. Brain Mapp. 34: 753–61. 10.1002/hbm.21470
    1. Gropman AL, Fricke ST, Seltzer RR, Hailu A, Adeyemo A, Sawyer A, et al. (2008). 1H MRS identifies symptomatic and asymptomatic subjects with partial ornithine transcarbamylase deficiency. Mol Genet Metab 95: 21–30. 10.1016/j.ymgme.2008.06.003
    1. Uddin LQ (2013) Complex relationships between structural and functional brain connectivity. Trends Cogn. Sci. 17: 600–02. 10.1016/j.tics.2013.09.011
    1. Qi R, Xu Q, Zhang LJ, Zhong J, Zheng G, Wu S, et al. (2012) Structural and functional abnormalities of default mode network in minimal hepatic encephalopathy: a study combining DTI and fMRI. PLoS ONE 7: e41376 10.1371/journal.pone.0041376
    1. Honey CJ, Sporns O, Cammoun L, Gigandet X, Thiran JP, Meuli RA (2009) Predicting human resting-state functional connectivity from structural connectivity. Proc. Natl. Acad. Sci. U. S. A. 106: 2035–40. 10.1073/pnas.0811168106
    1. Uddin LQ, Supekar KS, Ryali S, Menon V (2011) Dynamic reconfiguration of structural and functional connectivity across core neurocognitive brain networks with development. J. Neurosci. Off. J. Soc. Neurosci. 31: 18578–89.
    1. Ford JH, Kensinger EA (2014) The relation between structural and functional connectivity depends on age and on task goals. Front. Hum. Neurosci. 8: 307 10.3389/fnhum.2014.00307

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