Behavior modulates effective connectivity between cortex and striatum.

It has been notoriously difficult to understand interactions in the basal ganglia because of multiple recurrent loops. Another complication is that activity there is strongly dependent on behavior, suggesting that directional interactions, or effective connections, can dynamically change. A simplifying approach would be to examine just the direct, monosynaptic projections from cortex to striatum and contrast this with the polysynaptic feedback connections from striatum to cortex. Previous work by others on effective connectivity in this pathway indicated that activity in cortex could be used to predict activity in striatum, but that striatal activity could not predict cortical activity. However, this work was conducted in anesthetized or seizing animals, making it impossible to know how free behavior might influence effective connectivity. To address this issue, we applied Granger causality to local field potential signals from cortex and striatum in freely behaving rats. Consistent with previous results, we found that effective connectivity was largely unidirectional, from cortex to striatum, during anesthetized and resting states. Interestingly, we found that effective connectivity became bidirectional during free behaviors. These results are the first to our knowledge to show that striatal influence on cortex can be as strong as cortical influence on striatum. In addition, these findings highlight how behavioral states can affect basal ganglia interactions. Finally, we suggest that this approach may be useful for studies of Parkinson's or Huntington's diseases, in which effective connectivity may change during movement

Non-parametric Granger causality during spontaneous behavior.

<p>Granger causality derived directly from the Fourier transform of LFPs gathered during alertness (A), exploration (B), and rearing (C). Note the substantial similarity between these estimates of Granger causality and those obtained using a regression model. The agreement between these measures lends credence to our analysis and rules out model fitting as a source of error.</p

Coherence and causality spectra during multiple behaviors.

<p>Coherence spectra (A–E) and Granger causality (F–J) based on data recorded during anesthesia (row 1), sleep (row 2), immobile alertness (row 3), exploration (row 4), and rearing (row 5). Gray shaded regions indicate a non-Gaussian approximation of +/−1 standard deviation based on resampling (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089443#s2" target="_blank">methods</a>). Bars above each peak indicates the range over frequency over which GC exceeds a 0.005 cutoff based upon permutation analysis; solid lines denote frequency regimes over which corticostriatal causality is above chance, and dashed lines denote regimes over which striatocortical causality is above chance. Note the dominance of cortical drive during both anesthesia and sleep, as well as the complete lack of causality peaks in the striatocortical direction during sleep. Also note the refined information revealed by Granger causality. The coherence spectra are similar among the three behaviors; however, the relative contribution of information flow in the corticostriatal and striatocortical directions varies substantially among behaviors.</p

Time-frequency content of LFPs recorded in M1 during anesthesia in all rats showing consistent spectral content in multiple signals recorded in multiple animals.

<p>This figure was generated by wavelet transforming each epoch using multiwavelet estimation and estimating the average squared amplitude. The resulting single-trial spectrograms were concatenated to form the image shown. The color bar gives the averaged squared amplitude of the wavelet coefficients at each point in time-frequency space. Note the concentration of power in the 1–3 Hz range across all epochs of anesthesia.</p

Peak Granger causality for each behavior (shown in bold) with the 95% intersubject confidence interval, determined by a bootstrapping procedure described in the methods.

<p>The second column shows the number of realizations used to generate the ensemble average, and the duration of each realization in parentheses. Model order refers to the number of parameters used to generate the regression model, using data from all animals engaged in a particular behavior.</p

A representative histology section.

<p>Asterisks indicate the location of electrode tips, as revealed by metal ion deposits marked by ferrocyanide.</p

f Power spectral densities generated using LFPs recorded in M1 (A–E) and dStr (F–J) during anesthesia (row 1), sleep (row 2), immobile alertness (row 3), exploration (row 4), and rearing (row 5).

<p>Power in both M1 (A) and dStr (F) was higher during anesthesia than during sleep (B,D). Quantile ranges for some data are too narrow to be discernable in this figure. Gray shaded regions indicate a non-Gaussian approximation of +/−1 standard deviation based on resampling (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089443#s2" target="_blank">methods</a>). Note the variation in contributions to total power from oscillations in the 1–5 Hz and 7–12 Hz ranges across the three spontaneous behaviors.</p

Enhanced infection prophylaxis reduces mortality in severely immunosuppressed HIV-infected adults and older children initiating antiretroviral therapy in Kenya, Malawi, Uganda and Zimbabwe: the REALITY trial

Meeting abstract FRAB0101LB from 21st International AIDS Conference 18–22 July 2016, Durban, South Africa. Introduction: Mortality from infections is high in the first 6 months of antiretroviral therapy (ART) among HIV‐infected adults and children with advanced disease in sub‐Saharan Africa. Whether an enhanced package of infection prophylaxis at ART initiation would reduce mortality is unknown. Methods: The REALITY 2×2×2 factorial open‐label trial (ISRCTN43622374) randomized ART‐naïve HIV‐infected adults and children >5 years with CD4 <100 cells/mm3. This randomization compared initiating ART with enhanced prophylaxis (continuous cotrimoxazole plus 12 weeks isoniazid/pyridoxine (anti‐tuberculosis) and fluconazole (anti‐cryptococcal/candida), 5 days azithromycin (anti‐bacterial/protozoal) and single‐dose albendazole (anti‐helminth)), versus standard‐of‐care cotrimoxazole. Isoniazid/pyridoxine/cotrimoxazole was formulated as a scored fixed‐dose combination. Two other randomizations investigated 12‐week adjunctive raltegravir or supplementary food. The primary endpoint was 24‐week mortality. Results: 1805 eligible adults (n = 1733; 96.0%) and children/adolescents (n = 72; 4.0%) (median 36 years; 53.2% male) were randomized to enhanced (n = 906) or standard prophylaxis (n = 899) and followed for 48 weeks (3.8% loss‐to‐follow‐up). Median baseline CD4 was 36 cells/mm3 (IQR: 16–62) but 47.3% were WHO Stage 1/2. 80 (8.9%) enhanced versus 108(12.2%) standard prophylaxis died before 24 weeks (adjusted hazard ratio (aHR) = 0.73 (95% CI: 0.54–0.97) p = 0.03; Figure 1) and 98(11.0%) versus 127(14.4%) respectively died before 48 weeks (aHR = 0.75 (0.58–0.98) p = 0.04), with no evidence of interaction with the two other randomizations (p > 0.8). Enhanced prophylaxis significantly reduced incidence of tuberculosis (p = 0.02), cryptococcal disease (p = 0.01), oral/oesophageal candidiasis (p = 0.02), deaths of unknown cause (p = 0.02) and (marginally) hospitalisations (p = 0.06) but not presumed severe bacterial infections (p = 0.38). Serious and grade 4 adverse events were marginally less common with enhanced prophylaxis (p = 0.06). CD4 increases and VL suppression were similar between groups (p > 0.2). Conclusions: Enhanced infection prophylaxis at ART initiation reduces early mortality by 25% among HIV‐infected adults and children with advanced disease. The pill burden did not adversely affect VL suppression. Policy makers should consider adopting and implementing this low‐cost broad infection prevention package which could save 3.3 lives for every 100 individuals treated