Our current study combined diffusion tensor Image and graph theory to demonstrate changes in the organization and segregation of structural networks in cART-naïve and cART-treated subjects. Our main findings were as follows: (1) the regional characteristics (nodal efficiency) were altered in cART-naïve and cART-treated subjects preferentially in the frontal cortical regions; (2) alterations in some topological metrics in cART-naïve and cART-treated patients correlated with cognitives performances; (3) reduced network segregation was associated with lower current CD4 T cell counts in cART-naïve patients, indicating that brain network segregation may have been adversely affected by a history of enhanced immunosuppression; (4) Hubs redistributed in HIV subjects especially in cART-treated patients. These findings suggested that WM degeneration altered the structural connectivity pattern of WM network in HIV individuals, and cART failed to reverse the existing disruption of structural topology. However, this may, just slow the progression, so early diagnosis and treatment are imperative.
In our study there were no significant small-worldness among the three groups, which is quite different from extensive studies[20, 21]. This may be due to our limited samples. Global differences in our study also failed to present results like previous studies. It is possible that the average time of infection was too short to present such outcomes.
The regional alterations in cART-treated, cART-naïve and NC networks were detected to have significantly altered nodal characteristics (i.e., betweeness centrality, local efficiency, path length and clustering coefficient) in cortical regions, which were mainly lied in the right hemisphere. We found that betweenness alterations preferentially lied in the prefrontal lobe (e.g., OLF and SFGmed) and temporal lobe (e.g., TPOsup). And previous studies have shown that these frontal regions exhibited HIV-related abnormalities in the WM integrity [22–24] and gray matter morphology. The temporal pole, which includes linguistic integration, emotion, and semantic memory, also verified that there was atrophy and neuronal loss [25–29] in HIV patients and SIV infected rhesus monkeys. We also found that clustering coefficient widely described across occipital, parital, subcortical and prefrontal lobes. In addition, significant local efficiency differences mainly concentrated on the subcortical and prefrontal lobes. Finally, path length changes were all discovered in the pareital lobe.
According to most of the previous studies, a combination of shortest path lengths and high clustering coefficients gave rise to the most optimal network balance between segregation and integration[30]. However, HIV infection can be a disconnection element. Betweenness centrality measures the importance of nodes for information transmission[31]. Our findings of betweeness centrality alterations among cART-treated, cART-naïve and control groups indicated that cART-treated had significantly higher betweenness centrality than the cART-naïve group, which suggested that prescribed cART does improve structual connectivity to some extent, which is inconsistent with previous studies[32]. However, the right SFG and the right TPOsup showed increased betweenness centrality, which is quite opposite to previous research. We speculated that the increase of these nodes may be compensatory for the reduction of OLF centrality.
Clustering coefficient measures network segregation which reflects specialization of discrete brain regions or systems in conducting Specific psychological operations[33]. In our study, the right SFGmed implied an increase in Clustering coefficient in control group compared with cART-naïve and cART-treated group, suggesting a stronger local specialization, which has been verified in several studies[32]. On the other hand, there was an obvious decrease in the Clustering coefficient in the control group than the other two groups. This may be due to a possible compensation for the decrease in SFG.
Local efficiency in the right ICU and the right SFGmed in the control group was significantly higher than that in the cART-treated group, indicating that the efficiency of information transformation was affected by the white matter disruption, which is quite consistent with the previous studies.
Short path lengths in the brain networks ensure efficient transmission or rapid transfer of information between or among remote areas considered to be the basis of cognitive processes[34]. The increase in HIV-related pathways may therefore reflect the disruption of neuronal integration across distant regions associated with impaired cognitive function[35]. These findings indicated that CART may have differential effects on regional variability with regular treatment.
We further examined the relevance between network affairs and cognitive performances. Results suggested that the cART-naïve changes of network metrics were significantly associated with the decrease of cognitive functions, which is in accordance with the previous studies[36]. Meanwhile, for the cART-treated groups, we obtained quite the opposite results. The speculation for this phenomenon may be that the compensatory mechanism is reversed even during the ART era.
We further examined the relevance between network affairs and cognitive performances. Results suggested that the cART-naïve changes of network metrics were significantly associated with the decrease of cognitive functions, which is in accordance with the previous studies[36]. Meanwhile, for the cART-treated groups, we obtained quite the opposite results. The speculation for this phenomenon may be that the compensatory mechanism is reversed even during the ART era.
Among cART-naïve patients, lower current CD4 T cell counts were positively correlated with decreased clustering coefficient (eg, right CAU), indicating that historical immunesuppression plays a key role in brain network segregation. However, lower current CD4 T cell counts were negatively associated with the reduced clustering coefficient (e.g., left POCG). That may be explained by the compensatory mechanism of the neighborhood nodes. While among cART-treated patients current CD4 T cell counts were negatively correlated with right CAU local efficiency, indicative of thereserved compensatory mechanism with the application of ART.
We investigate alterations of hub profile, which plays a crucial role in identifying the most relevant nodes to information traffic. To identify the hub regions, we examined nodal betweenness centrality of each cortical region across the three subject groups (see material and methods). We found that these identified hubs were preferentially located in regions of association cortex (PUT, STG, and MOG), indicating their paramount roles in the structural networks. When hubs among three groups were further analyzed, we interestingly found the phenomenon that hubs in the cART-naïve and cART-treated groups redistributed separately. According to the “hubs overload and failure” theory, brain disease can break down the optimal balance of network, diminishing the information handling of hub nodes. As a result, scenario rerouting and rewiring contributed to hubs overload followed by hub failure[37]. Furthermore, more hubs in cART-treated patients were reproduced from prefrontal to occipital, apart from the cognitive injury resulting from pathological affairs, the cART patients received may also lead to hub redistributed in drugs vulnerable regions, which was suspected of higher metabolic activity from these regions[38]
There are several limitations in our study. In the first place, we constructed the structural network with deterministic tractography which has been widely used in previous studies. While it failed in accurately mapping out such fibers as crossing fibers and long-distance fibers, the sample size was too small to draw an effective conclusion regarding our method, though we found significant regional alterations among the three groups. Moreover, The cross-sectional nature of our study made us unable to confirm progress of HIV and the effect of cART over time. Thereofore, a longitudinal study would be beneficial in future studies.