Abstract
Objective
The purpose of this paper was to determine whether antiretroviral medications, especially the nucleoside analogue reverse transcriptase inhibitors, lead to altered brain activation due to their potential neurotoxic effects in patients with human immunodeficiency virus (HIV) infection.
Methods
Forty-two right-handed men were enrolled in three groups: seronegative controls (SN, n = 18), HIV subjects treated with antiretroviral medications (HIV+ARV, n = 12), or not treated with antiretroviral medications (HIV+NARV, n = 12). Each subject performed a set of visual attention tasks with increasing difficulty or load (tracking two, three or four balls) during functional magnetic resonance imaging.
Results
HIV subjects, both groups combined, showed greater load-dependent increases in brain activation in the right frontal regions compared to SN (p-corrected = 0.006). HIV+ARV additionally showed greater load-dependent increases in activation compared to SN in bilateral superior frontal regions (p-corrected = 0.032) and a lower percent accuracy on the performance of the most difficult task (tracking four balls). Region of interest analyses further demonstrated that SN showed load-dependent decreases (with repeated trials despite increasing difficulty), while HIV subjects showed load-dependent increases in activation with the more difficult tasks, especially those on ARVs.
Interpretation
These findings suggest that chronic ARV treatments may lead to greater requirement of the attentional network reserve and hence less efficient usage of the network and less practice effects in these HIV patients. As the brain has a limited reserve capacity, exhausting the reserve capacity in HIV+ARV would lead to declined performance with more difficult tasks that require more attention.
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References
Avison MJ, Nath A, Greene-Avison R, Schmitt FA, Greenberg RN, Berger JR (2004) Neuroimaging correlates of HIV-associated BBB compromise. J Neuroimmunol 157:140–6
Carey CL, Woods SP, Gonzalez R, Conover E, Marcotte TD, Grant I et al (2004) Predictive validity of global deficit scores in detecting neuropsychological impairment in HIV infection. J Clin Exp Neuropsychol 26:307–319
Chang L, Ernst T, Leonido-Yee M, Witt M, Speck O, Walot I et al (1999) Highly active antiretroviral therapy reverses brain metabolite abnormalities in mild HIV dementia. Neurology 53:782–789
Chang L, Ernst T, Witt M, Ames N, Walot I, Jovicich J et al (2003) Persistent brain abnormalities in antiretroviral-naïve HIV patients three-months after HAART. Antivir Ther 8:17–26
Chang L, Speck O, Miller E, Braun A, Jovicich J, Koch C et al (2001) Neural correlates of attention and working memory deficits in HIV patients. Neurology 57:1001–1007
Chang L, Tomasi D, Yakupov R, Lozar C, Arnold S, Caparelli E et al (2004) Adaptation of the attention network in human immunodeficiency virus brain injury. Ann Neurol 56:259–272
Culham JC, Brandt SA, Cavanagh P, Kanwisher NG, Dale AM, Tootell RBH (1998) Cortical fMRI activation produced by attentive tracking of moving targets. J Neurophysiol 80:2657–2670
Cysique LA, Maruff P, Brew BJ (2006) Variable benefit in neuropsychological function in HIV-infected HAART-treated patients. Neurology 66:1447–1450
Dalakas MC (2001) Peripheral neuropathy and antiretroviral drugs. J Peripher Nerv Syst 6:14–20
Dore GJ, McDonald A, Li Y, Kaldor JM, Brew BJ (2003) Marked improvement in survival following AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 17:1539–1545
Ernst T, Chang L, Arnold S (2003) Increased glial markers predict increased working memory network activation in HIV patients. NeuroImage 19:1686–1693
Ernst T, Chang L, Jovicich J, Ames N, Arnold S (2002) Abnormal brain activation on functional MRI in cognitively asymptomatic HIV patients. Neurology 59:1343–1349
Folstein MF, Folstein SE, McHugh PR (1975) Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198
Friston KJ, Holmes AP, Price CJ, Buchel C, Worsley KJ (1999) Multisubject fMRI studies and conjunction analyses. NeuroImage 10:385–396
Friston KJ, Worsley KJ, Frackowiak RSJ, Mazziotta JC, Evans AC (1994) Assessing the significance of focal activations using their spatial extent. Hum Brain Mapp 1:214–220
Ghafouri M, Amini S, Khalili K, Sawaya BE (2006) HIV-1 associated dementia: symptoms and causes. Retrovirology 3:28
Jiang B, Hebert VY, Zavecz JH, Dugas TR (2006) Antiretrovirals induce direct endothelial dysfunction in vivo. J Acquir Immune Defic Syndr 42:391–395
Jovicich J, Peters RJ, Koch C, Braun J, Chang L, Ernst T (2001) Brain areas specific for attentional load in a motion tracking task. J Cogn Neurosci 13:1048–1058
Larussa D, Lorenzini P, Cingolani A, Bossolasco S, Grisetti S, Bongiovanni M et al (2006) Highly active antiretroviral therapy reduces the age-associated risk of dementia in a cohort of older HIV-1-infected patients. AIDS Res Hum Retrovir 22:386–392
Letendre SL, McCutchan JA, Childers ME, Woods SP, Lazzaretto D, Heaton RK et al (2004) Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disorders. Ann Neurol 56:416–423
Levin JM, Frederick BB, Ross MH, Fox JF, vonRosenberg HL, Kaufman MJ et al (2001) Influence of baseline hematocrit and hemodilution on BOLD fMRI activation. Magn Reson Imaging 19:1055–1062
Lorenz MW, Stephan C, Harmjanz A, Staszewski S, Buehler A, Bickel M et al (2007) Both long-term HIV infection and highly active antiretroviral therapy are independent risk factors for early carotid atherosclerosis (in press)
Opii WO, Sultana R, Abdul HM, Ansari MA, Nath A, Butterfield DA (2006) Oxidative stress and toxicity induced by the nucleoside reverse transcriptase inhibitor (NRTI)-2′,3′-dideoxycytidine (ddC): Relevance to HIV-dementia. Exp Neurol 204:29–38
Power C, Johnson RT (1995) HIV-1 associated dementia: clinical features and pathogenesis. Can J Neurol Sci 22:92–100
Sacktor N, Nakasujja N, Skolasky R, Robertson K, Wong M, Musisi S, et al (2006) Antiretroviral therapy improves cognitive impairment in HIV+ individuals in sub-Saharan Africa. Neurology 67:311–314
Sacktor N, Skolasky R, Lyles R, Esposito D, Selnes O, McArthur J (2000) Improvement in HIV-associated motor slowing after antiretroviral therapy including protease inhibitors. J Neurovirol 6:84–88
Schweinsburg BC, Taylor MJ, Alhassoon OM, Gonzalez R, Brown GG, Ellis RJ et al (2005) Brain mitochondrial injury in human immunodeficiency virus-seropositive (HIV+) individuals taking nucleoside reverse transcriptase inhibitors. J Neurovirol 11:356–364
Tarasow E, Wiercinska-Drapalo A, Jaroszewicz J, Orzechowska-Bobkiewicz A, Dzienis W, Prokopowicz D et al (2004) Antiretroviral therapy and its influence on the stage of brain damage in patients with HIV-1H MRS evaluation. Med Sci Monit 10 Suppl 3:101–106
Thomas SA, Segal MB (1998) The transport of the anti-HIV drug, 2′,3′-didehydro-3′-deoxythymidine (D4T), across the blood–brain and blood–cerebrospinal fluid barriers. Br J Pharmacol 125:49–54
Tomasi D, Ernst T, Caparelli EC, Chang L (2004) Practice-induced changes of brain function during visual attention: a parametric fMRI study at 4 Tesla. NeuroImage 23:1414–1421
Vion-Dury J, Nicoli F, Salvan A, Confort-Gouny S, Dhiver C, Cozzone P (1995) Reversal of brain metabolic alterations with zidovudine detected by proton localised magnetic resonance spectroscopy. Lancet 345:60–61
Woods RP (1996) Modeling for intergroup comparisons of imaging data. NeuroImage 4:S84–S94
Woods SP, Rippeth JD, Frol AB, Levy JK, Ryan E, Soukup VM et al (2004) Interrater reliability of clinical ratings and neurocognitive diagnoses in HIV. J Clin Exp Neuropsychol 26:759–778
Acknowledgements
We thank our research participants and support by the NIH (2R01MH61427; K24-DA16170; K02-DA16991; 5P20-RR11091; G12-RR003061) and the Office of National Drug Control Policy (ONDCP).
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Chang, L., Yakupov, R., Nakama, H. et al. Antiretroviral Treatment is Associated with Increased Attentional Load-Dependent Brain Activation in HIV Patients. J Neuroimmune Pharmacol 3, 95–104 (2008). https://doi.org/10.1007/s11481-007-9092-0
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DOI: https://doi.org/10.1007/s11481-007-9092-0