Changes in resting-state functional brain activity are associated with waning cognitive functions in HIV-infected children

Delayed brain development in perinatally HIV-infected children may affect the functional brain activity and subsequently cognitive function. The current study evaluated the functional brain activity in HIV-infected children by quantifying the amplitude of low frequency fluctuations (ALFF) and functional connectivity (FC). Additionally, correlation of ALFF and FC with cognitive measures was performed. Twenty-six HIV-infected children and 20 control children underwent neuropsychological (NP) assessment and resting-state functional magnetic resonance imaging (rs-fMRI). ALFF and FC maps were generated and group differences were analyzed using two-sample t-test. Furthermore, ALFF and FC showing significant group differences were correlated with NP scores using Pearson's correlation. Significantly lower ALFF in the left middle temporal gyrus, precentral and post central gyrus was observed in HIV-infected children compared to controls. FC was significantly reduced in the right inferior parietal, vermis, middle temporal and left postcentral regions, and significantly increased in the right precuneus, superior parietal and left middle frontal regions in HIV-infected children as compared to control. HIV-infected children showed significantly lower NP scores in various domains including closure, exclusion, memory, verbal meaning, quantity and hidden figure than controls. These waning cognitive functions were significantly associated with changes in ALFF and FC in HIV-infected children. The findings suggest that abnormal ALFF and FC may responsible for cognitive deficits in HIV-infected children. ALFF and FC in association with cognitive evaluation may provide a clinical biomarker to evaluate functional brain activity and to plan neurocognitive intervention in HIV-infected children undergoing standard treatment.

[1]  P. Stewart,et al.  Neurodevelopmental Trajectory of HIV-Infected Children Accessing Care in Kinshasa, Democratic Republic of Congo , 2009, Journal of acquired immune deficiency syndromes.

[2]  K. Hertogs,et al.  Delayed central nervous system virus suppression during highly active antiretroviral therapy is associated with HIV encephalopathy, but not with viral drug resistance or poor central nervous system drug penetration , 2003, AIDS.

[3]  Y. Zang,et al.  Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI , 2007, Brain and Development.

[4]  J. Lurito,et al.  Multiple sclerosis: low-frequency temporal blood oxygen level-dependent fluctuations indicate reduced functional connectivity initial results. , 2002, Radiology.

[5]  Chunshui Yu,et al.  Altered functional connectivity of primary visual cortex in early blindness , 2008, Human brain mapping.

[6]  Florence Rémy,et al.  Verbal episodic memory impairment in Alzheimer's disease: a combined structural and functional MRI study , 2005, NeuroImage.

[7]  R. Leighty,et al.  Effects of Perinatal HIV Infection and Associated Risk Factors on Cognitive Development Among Young Children , 2006, Pediatrics.

[8]  H. Alkadhi,et al.  Localization of the motor hand area to a knob on the precentral gyrus. A new landmark. , 1997, Brain : a journal of neurology.

[9]  K. Robertson,et al.  Impact of HAART and CNS-penetrating antiretroviral regimens on HIV encephalopathy among perinatally infected children and adolescents , 2009, AIDS.

[10]  T. Benzinger,et al.  Weighted brain networks in disease: centrality and entropy in human immunodeficiency virus and aging , 2015, Neurobiology of Aging.

[11]  P A Robinson,et al.  Determination of effective brain connectivity from functional connectivity with application to resting state connectivities. , 2014, Physical review. E, Statistical, nonlinear, and soft matter physics.

[12]  Gregory R. Kirk,et al.  Regional cortical thinning associated with detectable levels of HIV DNA. , 2012, Cerebral cortex.

[13]  S. Du Plessis,et al.  Review of functional MRI in HIV: effects of aging and medication , 2016, Journal of NeuroVirology.

[14]  M. Maschke,et al.  Structural gray and white matter changes in patients with HIV , 2011, Journal of Neurology.

[15]  C. Peckham,et al.  Mother-to-child transmission of the human immunodeficiency virus. , 1995, The New England journal of medicine.

[16]  Piet Van Mieghem,et al.  A Mapping Between Structural and Functional Brain Networks , 2016, Brain Connect..

[17]  E. Bullmore,et al.  Impaired long distance functional connectivity and weighted network architecture in Alzheimer's disease. , 2014, Cerebral cortex.

[18]  Yingli Lu,et al.  Regional homogeneity approach to fMRI data analysis , 2004, NeuroImage.

[19]  Zhenchao Tang,et al.  Gray and white matter alterations in early HIV‐infected patients: Combined voxel‐based morphometry and tract‐based spatial statistics , 2016, Journal of magnetic resonance imaging : JMRI.

[20]  M. V. van Gerven,et al.  Resting-state subcortical functional connectivity in HIV-infected patients on long-term cART , 2016, Brain Imaging and Behavior.

[21]  Chantal E. Stern,et al.  Compromised fronto-striatal functioning in HIV: An fMRI investigation of semantic event sequencing , 2008, Behavioural Brain Research.

[22]  F. Marincola,et al.  Altered structural brain changes and neurocognitive performance in pediatric HIV , 2017, NeuroImage: Clinical.

[23]  L. D. de Sonneville,et al.  Neurocognitive function profile in HIV-infected school-age children. , 2008, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[24]  Axel Wismüller,et al.  Alteration of brain network topology in HIV-associated neurocognitive disorder: A novel functional connectivity perspective , 2017, NeuroImage: Clinical.

[25]  G. Rees,et al.  Comparing the temporal relationship of structural and functional connectivity changes in different adult human brain networks: a single-case study , 2018 .

[26]  Matthew R. Brier,et al.  Effects of HIV and combination antiretroviral therapy on cortico-striatal functional connectivity , 2015, AIDS.

[27]  M. Hughes,et al.  Neurodevelopmental Functioning in HIV-Infected Infants and Young Children Before and After the Introduction of Protease Inhibitor–Based Highly Active Antiretroviral Therapy , 2007, Pediatrics.

[28]  F. Scaravilli,et al.  Early entry and widespread cellular involvement of HIV-1 DNA in brains of HIV-1 positive asymptomatic individuals. , 1999, Journal of neuropathology and experimental neurology.

[29]  P. Reiss,et al.  Cerebral injury in perinatally HIV-infected children compared to matched healthy controls , 2016, Neurology.

[30]  Masato Taira,et al.  Reading in a Regular Orthography: An fMRI Study Investigating the Role of Visual Familiarity , 2004, Journal of Cognitive Neuroscience.

[31]  B. Ances,et al.  Pathogenesis of HIV in the Central Nervous System , 2010, Current HIV/AIDS reports.

[32]  Chaozhe Zhu,et al.  An improved approach to detection of amplitude of low-frequency fluctuation (ALFF) for resting-state fMRI: Fractional ALFF , 2008, Journal of Neuroscience Methods.

[33]  H. Budka,et al.  Loss of neurons in the frontal cortex in AIDS brains , 2004, Acta Neuropathologica.

[34]  J. Church,et al.  Regional brain gray and white matter changes in perinatally HIV-infected adolescents☆ , 2013, NeuroImage: Clinical.

[35]  Ying Wu,et al.  Structural brain alterations can be detected early in HIV infection , 2012, Neurology.

[36]  J. Becker,et al.  Updated research nosology for HIV-associated neurocognitive disorders , 2007, Neurology.

[37]  Yong He,et al.  Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI. , 2007, Brain & development.

[38]  Xi-Nian Zuo,et al.  REST: A Toolkit for Resting-State Functional Magnetic Resonance Imaging Data Processing , 2011, PloS one.

[39]  A. Van Rie,et al.  Impact of the HIV/AIDS Epidemic on the Neurodevelopment of Preschool-Aged Children in Kinshasa, Democratic Republic of the Congo , 2008, Pediatrics.

[40]  C. Golden,et al.  Neuropsychological consequences of HIV in children: a review of current literature. , 2002, Clinical psychology review.

[41]  Allen W. Song,et al.  Structural connectome differences in HIV infection: brain network segregation associated with nadir CD4 cell count , 2018, Journal of NeuroVirology.

[42]  M. Fox,et al.  Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging , 2007, Nature Reviews Neuroscience.

[43]  Tony W Wilson,et al.  Multimodal neuroimaging evidence of alterations in cortical structure and function in HIV‐infected older adults , 2015, Human brain mapping.

[44]  Yuan Zhou,et al.  Functional dysconnectivity of the dorsolateral prefrontal cortex in first-episode schizophrenia using resting-state fMRI , 2007, Neuroscience Letters.

[45]  Martha J. Holmes,et al.  HIV-associated CD4+/CD8+ depletion in infancy is associated with neurometabolic reductions in the basal ganglia at age 5 years despite early antiretroviral therapy , 2016, AIDS.

[46]  P. Lantos,et al.  Neuronal loss in the frontal cortex in HIV infection , 1991, The Lancet.

[47]  Paige L. Williams,et al.  Default Mode Connectivity in Youth With Perinatally Acquired HIV , 2015, Medicine.

[48]  Ravi S. Menon,et al.  Identification of Optimal Structural Connectivity Using Functional Connectivity and Neural Modeling , 2014, The Journal of Neuroscience.

[49]  N. Jahanshad,et al.  Novel Neuroimaging Methods to Understand How HIV Affects the Brain , 2015, Current HIV/AIDS Reports.

[50]  J. Smirniotopoulos,et al.  From the archives of the AFIP: central nervous system infections associated with human immunodeficiency virus infection: radiologic-pathologic correlation. , 2008, Radiographics : a review publication of the Radiological Society of North America, Inc.

[51]  G. Jackson,et al.  Functional connectivity networks are disrupted in left temporal lobe epilepsy , 2006, Annals of neurology.

[52]  M. Boivin,et al.  Neurodevelopment in perinatally HIV-infected children: a concern for adolescence , 2013, Journal of the International AIDS Society.

[53]  Tianzi Jiang,et al.  Changes in hippocampal connectivity in the early stages of Alzheimer's disease: Evidence from resting state fMRI , 2006, NeuroImage.

[54]  D Louis Collins,et al.  Regionally Specific Brain Volumetric and Cortical Thickness Changes in HIV-Infected Patients in the HAART Era , 2017, Journal of acquired immune deficiency syndromes.

[55]  L. Chang,et al.  Neural correlates of working memory training in HIV patients: study protocol for a randomized controlled trial , 2016, Trials.

[56]  Jianhui Zhong,et al.  Combination antiretroviral therapy improves cognitive performance and functional connectivity in treatment-naïve HIV-infected individuals , 2017, Journal of NeuroVirology.

[57]  M. Newell,et al.  Neurodevelopment in Children Born to HIV-Infected Mothers by Infection and Treatment Status , 2012, Pediatrics.

[58]  A diffusion tensor imaging and neurocognitive study of HIV-positive children who are HAART-naïve “slow progressors” , 2012, Journal of NeuroVirology.

[59]  Bharat B. Biswal,et al.  The oscillating brain: Complex and reliable , 2010, NeuroImage.