Project Summary/Abstract
Persons with HIV (PWH) living in the western world have a life expectancy near that of the general population,
but remain at a significantly elevated risk of developing cognitive impairments. Such impairments are the most
common neurological complication of HIV disease, and research targeting these comorbidities is one of four
overarching priorities identified by the Office of AIDS Research (NOT-OD-20-018). Substance use disorders
(SUD) are also more prevalent in PWH, yet their contribution to the increased rate of cognitive impairment in this
group remains poorly understood. A major barrier to progress has been the historic lack of diagnostic tests and
biomarkers that can precisely assess the neurological complications of HIV-infection, which has all but precluded
quantification of the additive impact of SUD comorbidity. This lack of tests and markers is at least partially
attributable to the field’s limited consensus on the key neuropathological features of HIV-infection. For example,
whether HIV-related cognitive decline is primarily attributable to cortical or subcortical circuits remains widely
debated, despite literally hundreds of neuroimaging studies over the past 20 years.
We recently received a NIH S10 High-End Instrumentation award from the Office of the Director to acquire a
next-generation magnetoencephalography (MEG) system. This $3M instrument was the third such unit installed
in the United States and remains the only one being used for HIV and/or SUD research. This award follows on
the heels of several remarkable discoveries in our ongoing effort to develop quantitative neuro-metrics that can
distinguish impaired from unimpaired PWH. Briefly, these findings revealed highly specific cortical oscillatory
deficits in PWH, which generated significant excitement and were published in a series of high-impact papers.
Most recently, we have shown that regular cannabis use is associated with a normalization of these oscillatory
deficits in PWH. While remarkable, all of this work was based on MEG measurements acquired with a previous
generation system (circa 2008), which was far more sensitive to cortical versus subcortical neural responses. Of
note, this greater sensitivity to cortical activity is true of many modern neuroimaging tools and consequently the
extensive evidence supporting cortical aberrations in virally suppressed PWH could be mistaken. Our new next-
generation MEG system provides an unprecedented opportunity to quantify human brain dynamics with
enhanced precision across multiple parameters, including far greater sensitivity to subcortical brain responses.
Thus, through this project we will determine whether HIV-related deficits in cortical oscillatory and spontaneous
activity are a primary or secondary neural abnormality in PWH, and whether the apparently beneficial effects of
cannabis use on neuronal dynamics in PWH are primarily attributable to modulation of cortical or subcortical
neurophysiological activity. While the pathological spontaneous and oscillatory neural activity observed in PWH
could arise from increased subcortical drive from the thalamus, we hypothesize that these cortical deficits will be
independent of any subcortical aberrations and that the beneficial effects of cannabis will be limited to the cortex.
