Although HIV-infected patients in the western world have a life expectancy near that of the general population, they are at a significantly elevated risk of developing HIV-associated neurocognitive disorders (HAND). Such disorders are the most common neurological complication of HIV disease, with prevalence estimates ranging from 35-70% of all HIV-infected patients, and research targeting such comorbidities has been identified as a top priority by the Office of AIDS Research (NOT-OD-15-137). While the mechanisms that underlie HAND are not well understood, numerous human neuroimaging studies have examined the brain regions that may be involved, and overall these studies have been largely successful in identifying the critical hubs and large-scale networks. However, many questions remain regarding basic circuit dysfunction within these brain regions, and consequently there is a clear and common need to further investigate the key physiological parameters that may underlie the development and progression of HAND, especially in the context of aging. It is well known that human cortical neurons exhibit spontaneous firing in the absence of incoming exogenous and endogenous input. Across a neuronal population, these discharges summate with local dendritic currents and synaptic potentials to produce cortical rhythmic activity, which is often referred to as ?spontaneous activity.? Such spontaneous rhythms are ubiquitous throughout the human brain, but their role in modulating cognition is only beginning to be understood. Recently, we used magnetoencephalography (MEG) to show that the strength of spontaneous activity directly affects neural oscillatory activity in the same cortical area, and in-turn modulates real time task performance in controls and HIV-infected adults. Additionally, we have shown that spontaneous activity in multiple brain regions increases with advancing age, that this increase is deleterious to performance, and that these effects are accentuated in patients with HAND. In fact, our preliminary data suggests that the level of spontaneous activity in specific brain regions may distinguish age-matched HIV-infected patients with and without HAND. In this project, we will quantify the trajectory of age-related elevations in spontaneous cortical activity in a large group of HIV-infected adults and demographically-matched controls. We will then evaluate how the strength of such spontaneous activity affects local neural oscillations and real time cognitive performance. Based on extensive preliminary data, we hypothesize that spontaneous activity will increase with age in both groups, and that the slope of this increase will be steeper in HIV-infected adults relative to controls, and further accentuated in those with HAND. Importantly, we also hypothesize that these increases will be associated with proportional changes in the strength of the neural oscillations underlying cognition, and behavioral performance indices such as accuracy and reaction time. Finally, in Aim 3, we will utilize deep learning methods to classify our sample into groups based on the neurophysiological metrics derived from MEG, with the gold standard being their overall neuropsychological profile.

Public Health Relevance

HIV-infection has become a chronic manageable condition with a life expectancy that approaches that of the general population, but affected patients remain at a significantly elevated risk of developing cognitive disorders. Previous neuroimaging studies have mapped the brain regions that may be involved in these HIV-associated neurocognitive disorders(HAND), and while these studies have been largely successful, many questions persist about the inherent physiology in these regions, and how it might differ in patients with HAND. In the current study, we use an advanced dynamic functional brain mapping approach to evaluate the role of two novel neurophysiological parameters, previously shown to be implicated in aging, in the pathophysiology of HAND.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH116782-02
Application #
9662844
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Brouwers, Pim
Project Start
2018-04-01
Project End
2023-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Neurology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Wiesman, Alex I; Mills, Mackenzie S; McDermott, Timothy J et al. (2018) Polarity-dependent modulation of multi-spectral neuronal activity by transcranial direct current stimulation. Cortex 108:222-233
Spooner, Rachel K; Wiesman, Alex I; Mills, Mackenzie S et al. (2018) Aberrant oscillatory dynamics during somatosensory processing in HIV-infected adults. Neuroimage Clin 20:85-91
Embury, Christine M; Wiesman, Alex I; McDermott, Timothy J et al. (2018) The impact of type 1 diabetes on neural activity serving attention. Hum Brain Mapp :
Lew, Brandon J; McDermott, Timothy J; Wiesman, Alex I et al. (2018) Neural dynamics of selective attention deficits in HIV-associated neurocognitive disorder. Neurology 91:e1860-e1869
Wiesman, Alex I; Groff, Boman R; Wilson, Tony W (2018) Frontoparietal Networks Mediate the Behavioral Impact of Alpha Inhibition in Visual Cortex. Cereb Cortex :
McDermott, Timothy J; Wiesman, Alex I; Mills, Mackenzie S et al. (2018) tDCS modulates behavioral performance and the neural oscillatory dynamics serving visual selective attention. Hum Brain Mapp :