Neuroimaging markers of human immunodeficiency virus infection in South Africa

Previous studies have reported cognitive deficits among HIV-positive individuals infected with clade C virus. However, no study has examined whether individuals predominately infected with clade C virus exhibit brain atrophy relative to healthy controls. This study examined volumetric differences between 28 HIV+ individuals and 23 HIV- controls from South Africa. Volumetric measures were obtained from six regions of interest -- caudate, thalamus, corpus callosum, total cortex, total gray matter, and total white matter. HIV+ participants had significantly lower volumes in the total white matter (p<0.01), thalamus (p<0.01) and total gray matter (inclusive of cortical and subcortical regions, p<0.01). This study is the first to provide evidence of brain atrophy among HIV+ individuals in South Africa, where HIV clade C predominates. Additional research that integrates neuroimaging, comprehensive neuropsychological testing, genetic variance in clade-specific proteins, and the impact of treatment with Antiretrovirals (ARV) are necessary to understand the development of HIV-related neurocognitive disorders in South Africa.     

Continuous Arterial Spin Labeled Perfusion Magnetic Resonance Imaging in Patients before and after Carotid Endarterectomy

Continuous arterial spin labeling perfusion magnetic resonance imaging (CASL-pMRI) uses magnetically labeled arterial blood water as a tracer to obtain quantifiable measurements of cerebral blood flow (CBF) (mL/100 g-1/min-1). CASL-pMRI was used to assess CBF changes in major vascular distributions in patients (n = 10) prior to and 3 months after carotid endarterectomy (CEA). No significant change in the global baseline CBF before and after CEA was observed in the group as a whole (P = .81). In patients with reduced CBF prior to CEA (< 50 ml/100 g/min), a significant increase in global CBF following CEA was observed. An inverse relationship existed between percent change in CBF after CEA versus baseline CBF within the anterior circulation (r = -.78, P < .05) but not in the posterior distribution (r = .25, P = .63). CASL-pMRI may provide a convenient, inexpensive, noninvasive method for identifying CEA patients at risk for hyperperfusion following carotid revascularization.     

Functional connectivity and graph theory in preclinical Alzheimer's disease

Alzheimer's disease (AD) has a long preclinical phase in which amyloid and tau cerebral pathology accumulate without producing cognitive symptoms. Resting state functional connectivity magnetic resonance imaging has demonstrated that brain networks degrade during symptomatic AD. It is unclear to what extent these degradations exist before symptomatic onset. In this study, we investigated graph theory metrics of functional integration (path length), functional segregation (clustering coefficient), and functional distinctness (modularity) as a function of disease severity. Further, we assessed whether these graph metrics were affected in cognitively normal participants with cerebrospinal fluid evidence of preclinical AD. Clustering coefficient and modularity, but not path length, were reduced in AD. Cognitively normal participants who harbored AD biomarker pathology also showed reduced values in these graph measures, demonstrating brain changes similar to, but smaller than, symptomatic AD. Only modularity was significantly affected by age. We also demonstrate that AD has a particular effect on hub-like regions in the brain. We conclude that AD causes large-scale disconnection that is present before onset of symptoms.     

Coupling of neural activation to blood flow in the somatosensory cortex of rats is time-intensity separable, but not linear.

Changes in cerebral blood flow (CBF) because of functional activation are used as a surrogate for neural activity in many functional neuroimaging studies. In these studies, it is often assumed that the CBF response is a linear-time invariant (LTI) transform of the underlying neural activity. By using a previously developed animal model system of electrical forepaw stimulation in rats (n = 11), laser Doppler measurements of CBF, and somatosensory evoked potentials, measurements of neural activity were obtained when the stimulus duration and intensity were separately varied. These two sets of time series data were used to assess the LTI assumption. The CBF data were modeled as a transform of neural activity (N1-P2 amplitude of the somatosensory evoked potential) by using first-order (linear) and second-order (nonlinear) components. Although a pure LTI model explained a large amount of the variance in the data for changes in stimulus duration, our results demonstrated that the second-order kernel (i.e., a nonlinear component) contributed an explanatory component that is both statistically significant and appreciable in magnitude. For variations in stimulus intensity, a pure LTI model explained almost all of the variance in the CBF data. In particular, the shape of the CBF response did not depend on intensity of neural activity when duration was held constant (time-intensity separability). These results have important implications for the analysis and interpretation of neuroimaging data.     

The effects of graded hypercapnia on the activation flow coupling response due to forepaw stimulation in α-chloralose anesthetized rats

Activation flow coupling (AFC), changes in cerebral blood flow (CBF) due to changes in neural activity with functional stimulation, provides the physiological basis of many neuroimaging techniques. Hypercapnia leads to an increase in CBF while neural activity remains unaffected. Laser Doppler (LD) flowmetry was used to measure CBF changes (LD_CBF) in the somatosensory cortex due to periodic electrical forepaw stimulation (4 s in duration) before and during graded hypercapnia (3% CO₂, 5% CO₂ and 10% CO₂). With increasing CO₂ concentrations, the baseline LD_CBF progressively increased. The peak height (PH) of the LD_CBF response, expressed as a percent change from the observed baseline for each hypercapnic state, significantly decreased (P<0.05) with increasing CO₂ concentrations. However, the absolute magnitude of the LD_CBF change was independent of CO₂ concentration. The temporal dynamics of the LD_CBF response during hypercapnia were significantly prolonged compared to baseline conditions (P<0.05).     

Effects of aging on cerebral blood flow, oxygen metabolism, and blood oxygenation level dependent responses to visual stimulation

Calibrated functional magnetic resonance imaging (fMRI) provides a noninvasive technique to assess functional metabolic changes associated with normal aging. We simultaneously measured both the magnitude of the blood oxygenation level dependent (BOLD) and cerebral blood flow (CBF) responses in the visual cortex for separate conditions of mild hypercapnia (5% CO(2)) and a simple checkerboard stimulus in healthy younger (n = 10, mean: 28-years-old) and older (n = 10, mean: 53-years-old) adults. From these data we derived baseline CBF, the BOLD scaling parameter M, the fractional change in the cerebral metabolic rate of oxygen consumption (CMRO(2)) with activation, and the coupling ratio n of the fractional changes in CBF and CMRO(2). For the functional activation paradigm, the magnitude of the BOLD response was significantly lower for the older group (0.57 +/- 0.07%) compared to the younger group (0.95 +/- 0.14%), despite the finding that the fractional CBF and CMRO(2) changes were similar for both groups. The weaker BOLD response for the older group was due to a reduction in the parameter M, which was significantly lower for older (4.6 +/- 0.4%) than younger subjects (6.5 +/- 0.8%), most likely reflecting a reduction in baseline CBF for older (41.7 +/- 4.8 mL/100 mL/min) compared to younger (59.6 +/- 9.1 mL/100 mL/min) subjects. In addition to these primary responses, for both groups the BOLD response exhibited a post-stimulus undershoot with no significant difference in this magnitude. However, the post-undershoot period of the CBF response was significantly greater for older compared to younger subjects. We conclude that when comparing two populations, the BOLD response can provide misleading reflections of underlying physiological changes. A calibrated approach provides a more quantitative reflection of underlying metabolic changes than the BOLD response alone.