Functional connectivity in the brain estimated by analysis of gamma events.

It is known that gamma activity is generated by local networks. In this paper we introduced a new approach for estimation of functional connectivity between neuronal networks by measuring temporal relations between peaks of gamma event amplitudes. We have shown in freely moving rats that gamma events recorded between electrodes 1.5 mm apart in the majority of cases, are generated by different neuronal modules interfering with each other. The map of functional connectivity between brain areas during the resting state, created based on gamma event temporal relationships is in agreement with anatomical connections and with maps described by fMRI methods during the resting state. The transition from the resting state to exploratory activity is accompanied by decreased functional connectivity between most brain areas. Our data suggest that functional connectivity between interhemispheric areas depends on GABAergic transmission, while intrahemispheric functional connectivity is kainate receptor dependent. This approach presents opportunities for merging electrographic and fMRI data on brain functional connectivity in normal and pathological conditions

Functional connectivity in the brain estimated by analysis of gamma events.

It is known that gamma activity is generated by local networks. In this paper we introduced a new approach for estimation of functional connectivity between neuronal networks by measuring temporal relations between peaks of gamma event amplitudes. We have shown in freely moving rats that gamma events recorded between electrodes 1.5 mm apart in the majority of cases, are generated by different neuronal modules interfering with each other. The map of functional connectivity between brain areas during the resting state, created based on gamma event temporal relationships is in agreement with anatomical connections and with maps described by fMRI methods during the resting state. The transition from the resting state to exploratory activity is accompanied by decreased functional connectivity between most brain areas. Our data suggest that functional connectivity between interhemispheric areas depends on GABAergic transmission, while intrahemispheric functional connectivity is kainate receptor dependent. This approach presents opportunities for merging electrographic and fMRI data on brain functional connectivity in normal and pathological conditions

Correlation of multiunit discharges in the entorhinal cortex with local and remote gamma events during the RS.

<p>A. Matrix of rat #159 showing that gamma events in the left posterior dentate gyrus (LPD) and in the left entorhinal cortex (LEC) have the highest connectivity index. Calibration bar for the connectivity matrix values is presented on the right. B. Examples of gamma activity in the LPD and LEC and multiunit activity in the LEC. C. Perievent histogram of gamma events recorded in the LEC versus 1500 of the LPD gamma wavelets. The average of these events is shown at the top. D and E. Perievent histograms of multiunit activity recorded in the LEC versus gamma events correspondingly in the LPD and LEC.</p

Correlation of multiunit discharges in the entorhinal cortex with local and remote gamma events during the RS.

<p>A. Matrix of rat #159 showing that gamma events in the left posterior dentate gyrus (LPD) and in the left entorhinal cortex (LEC) have the highest connectivity index. Calibration bar for the connectivity matrix values is presented on the right. B. Examples of gamma activity in the LPD and LEC and multiunit activity in the LEC. C. Perievent histogram of gamma events recorded in the LEC versus 1500 of the LPD gamma wavelets. The average of these events is shown at the top. D and E. Perievent histograms of multiunit activity recorded in the LEC versus gamma events correspondingly in the LPD and LEC.</p

Radar graph illustrating the average connectivity index between different brain areas during the Resting state (n = 11).

<p>The green circles indicates the highest (>0.5) values of the connectivity index, which is between RAD-CA3 and RPD-CA3. They correspond to morphological data of high connectivity within the hippocampal circuitry. The red circle indicates the lowest (<0.2) value of the connectivity index, which is between the right CA3 area and ipsilateral entorhinal cortex. The green thick line outlines the connectivity index between recording pairs in the right hemisphere, yellow in the left, and blue in the interhemispheric recording pairs.</p

Distribution of the synchronicity Index (S-index) ranked from high to low values for zero time lag gamma in the neocortex (open diamonds) and hippocampus (filled circles) for 16 animals (n = 128 pairs).

<p>The recording sites were separated 1.5– a probability of distribution of the S-indexes. The blue line indicates the median of the data (0.42) and the dashed box outlines the area between 5^th and 95^th percentiles. <b>a</b>, <b>b</b>, and <b>c</b> – examples of perievent histograms for the S-index equal correspondingly 1.0; 0.73 and 0.05. The red line is the normalized shape of a gamma event.</p

Investigating PSMA-Targeted Radioligand Therapy Efficacy as a Function of Cellular PSMA Levels and Intratumoral PSMA Heterogeneity.

PurposeProstate-specific membrane antigen (PSMA) targeting radioligands deliver radiation to PSMA-expressing cells. However, the relationship between PSMA levels and intralesion heterogeneity of PSMA expression, and cytotoxic radiation by radioligand therapy (RLT) is unknown. Here we investigate RLT efficacy as function of PSMA levels/cell, and the fraction of PSMA+ cells in a tumor.Experimental designRM1 cells expressing different levels of PSMA (PSMA-, PSMA+, PSMA++, PSMA+++; study 1) or a mix of PSMA+ and PSMA- RM1 (study 2, 4) or PC-3/PC-3-PIP (study 3) cells at various ratios were injected into mice. Mice received 177Lu- (studies 1-3) or 225Ac- (study 4) PSMA617. Tumor growth was monitored. Two days post-RLT, tumors were resected in a subset of mice. Radioligand uptake and DNA damage were quantified.Results177Lu-PSMA617 efficacy increased with increasing PSMA levels (study 1) and fractions of PSMA positive cells (studies 2, 3) in both, the RM1 and PC-3-PIP models. In tumors resected 2 days post-RLT, PSMA expression correlated with 177Lu-PSMA617 uptake and the degree of DNA damage. Compared with 177Lu-PSMA617, 225Ac-PSMA617 improved overall antitumor effectiveness and tended to enhance the differences in therapeutic efficacy between experimental groups.ConclusionsIn the current models, both the degree of PSMA expression and the fraction of PSMA+ cells correlate with 177Lu-/225Ac-PSMA617 tumor uptake and DNA damage, and thus, RLT efficacy. Low or heterogeneous PSMA expression represents a resistance mechanism to RLT.See related commentary by Ravi Kumar and Hofman, p. 2774