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Selective Estrogen Receptor Modulation Increases Hippocampal Activity during Probabilistic Association Learning in Schizophrenia.

Kindler J, Weickert CS, Skilleter AJ, Catts SV, Lenroot R, Weickert TW - Neuropsychopharmacology (2015)

Bottom Line: A separate region of interest confirmatory analysis in 21 patients vs 36 healthy controls showed a positive association between parahippocampal neural activity and learning in patients, but no such relationship in the parahippocampal gyrus of healthy controls.Thus, selective estrogen receptor modulation by raloxifene concurrently increases activity in the parahippocampal gyrus and improves probabilistic association learning in schizophrenia.These results support a role for estrogen receptor modulation of mesial temporal lobe neural activity in the remediation of learning disabilities in both men and women with schizophrenia.

View Article: PubMed Central - PubMed

Affiliation: 1] School of Psychiatry, University of New South Wales, Randwick, NSW, Australia [2] Neuroscience Research Australia, Randwick, NSW, Australia [3] Department of Psychiatric Neurophysiology, University of Bern, Bern, Switzerland.

ABSTRACT
People with schizophrenia show probabilistic association learning impairment in conjunction with abnormal neural activity. The selective estrogen receptor modulator (SERM) raloxifene preserves neural activity during memory in healthy older men and improves memory in schizophrenia. Here, we tested the extent to which raloxifene modifies neural activity during learning in schizophrenia. Nineteen people with schizophrenia participated in a twelve-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of the SERM raloxifene administered orally at 120 mg daily to assess brain activity during probabilistic association learning using functional magnetic resonance imaging (fMRI). Raloxifene improved probabilistic association learning and significantly increased fMRI BOLD activity in the hippocampus and parahippocampal gyrus relative to placebo. A separate region of interest confirmatory analysis in 21 patients vs 36 healthy controls showed a positive association between parahippocampal neural activity and learning in patients, but no such relationship in the parahippocampal gyrus of healthy controls. Thus, selective estrogen receptor modulation by raloxifene concurrently increases activity in the parahippocampal gyrus and improves probabilistic association learning in schizophrenia. These results support a role for estrogen receptor modulation of mesial temporal lobe neural activity in the remediation of learning disabilities in both men and women with schizophrenia.

No MeSH data available.


Related in: MedlinePlus

Overlay of the increase of hippocampal/parahippocampal activity in the raloxifene treatment group (x, y, z=27, −16, −24, yellow area, raloxifene treatment) and the peak activation based on the regression of blood oxygenation level-dependent (BOLD) signal during probabilistic association learning on the learning slope in people with schizophrenia relative to healthy controls in the confirmatory analysis, (x, y, z=27, −9, −17, T=4.25, Z=3.52, family-wise error rate (FWE), small volume corrected, sphere 15 mm, at p<0.05, red area, confirmatory analysis), orange represents areas of overlap.
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fig4: Overlay of the increase of hippocampal/parahippocampal activity in the raloxifene treatment group (x, y, z=27, −16, −24, yellow area, raloxifene treatment) and the peak activation based on the regression of blood oxygenation level-dependent (BOLD) signal during probabilistic association learning on the learning slope in people with schizophrenia relative to healthy controls in the confirmatory analysis, (x, y, z=27, −9, −17, T=4.25, Z=3.52, family-wise error rate (FWE), small volume corrected, sphere 15 mm, at p<0.05, red area, confirmatory analysis), orange represents areas of overlap.

Mentions: The two-sample t-test analysis comparing brain activity in healthy controls and people with schizophrenia within the ROI yielded significantly increased BOLD activity in people with schizophrenia in the bilateral parahippocampal gyrus (T=2.5, p=0.008, small volume corrected; see Supplementary Figure S1 and Supplementary Table S5). The regression analysis based on the slope of the probabilistic association learning curve and parameter estimates from the parahippocampal gyrus ROI showed a significant relationship in patients (T=1.86, p=0.04, n=21) but not in healthy controls (T=−0.63, p=0.73, n=36) (see Supplementary Figure S2 for the Pearson's correlation analysis results). The peak voxel activation based on the regression analysis was detected in the right parahippocampal gyrus in the patients, which was in close proximity and slightly overlapping with the area reported in the treatment trial (x, y, z=27, −9, −17, T=4.25, Z=3.52, small volume FWE corrected, p<0.05; see Figure 4). Results of the Fisher r-to-z transformation analysis showed that the correlations between learning and brain activity were significantly different between the two diagnostic groups (z=1.81, p=0.04).


Selective Estrogen Receptor Modulation Increases Hippocampal Activity during Probabilistic Association Learning in Schizophrenia.

Kindler J, Weickert CS, Skilleter AJ, Catts SV, Lenroot R, Weickert TW - Neuropsychopharmacology (2015)

Overlay of the increase of hippocampal/parahippocampal activity in the raloxifene treatment group (x, y, z=27, −16, −24, yellow area, raloxifene treatment) and the peak activation based on the regression of blood oxygenation level-dependent (BOLD) signal during probabilistic association learning on the learning slope in people with schizophrenia relative to healthy controls in the confirmatory analysis, (x, y, z=27, −9, −17, T=4.25, Z=3.52, family-wise error rate (FWE), small volume corrected, sphere 15 mm, at p<0.05, red area, confirmatory analysis), orange represents areas of overlap.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4538353&req=5

fig4: Overlay of the increase of hippocampal/parahippocampal activity in the raloxifene treatment group (x, y, z=27, −16, −24, yellow area, raloxifene treatment) and the peak activation based on the regression of blood oxygenation level-dependent (BOLD) signal during probabilistic association learning on the learning slope in people with schizophrenia relative to healthy controls in the confirmatory analysis, (x, y, z=27, −9, −17, T=4.25, Z=3.52, family-wise error rate (FWE), small volume corrected, sphere 15 mm, at p<0.05, red area, confirmatory analysis), orange represents areas of overlap.
Mentions: The two-sample t-test analysis comparing brain activity in healthy controls and people with schizophrenia within the ROI yielded significantly increased BOLD activity in people with schizophrenia in the bilateral parahippocampal gyrus (T=2.5, p=0.008, small volume corrected; see Supplementary Figure S1 and Supplementary Table S5). The regression analysis based on the slope of the probabilistic association learning curve and parameter estimates from the parahippocampal gyrus ROI showed a significant relationship in patients (T=1.86, p=0.04, n=21) but not in healthy controls (T=−0.63, p=0.73, n=36) (see Supplementary Figure S2 for the Pearson's correlation analysis results). The peak voxel activation based on the regression analysis was detected in the right parahippocampal gyrus in the patients, which was in close proximity and slightly overlapping with the area reported in the treatment trial (x, y, z=27, −9, −17, T=4.25, Z=3.52, small volume FWE corrected, p<0.05; see Figure 4). Results of the Fisher r-to-z transformation analysis showed that the correlations between learning and brain activity were significantly different between the two diagnostic groups (z=1.81, p=0.04).

Bottom Line: A separate region of interest confirmatory analysis in 21 patients vs 36 healthy controls showed a positive association between parahippocampal neural activity and learning in patients, but no such relationship in the parahippocampal gyrus of healthy controls.Thus, selective estrogen receptor modulation by raloxifene concurrently increases activity in the parahippocampal gyrus and improves probabilistic association learning in schizophrenia.These results support a role for estrogen receptor modulation of mesial temporal lobe neural activity in the remediation of learning disabilities in both men and women with schizophrenia.

View Article: PubMed Central - PubMed

Affiliation: 1] School of Psychiatry, University of New South Wales, Randwick, NSW, Australia [2] Neuroscience Research Australia, Randwick, NSW, Australia [3] Department of Psychiatric Neurophysiology, University of Bern, Bern, Switzerland.

ABSTRACT
People with schizophrenia show probabilistic association learning impairment in conjunction with abnormal neural activity. The selective estrogen receptor modulator (SERM) raloxifene preserves neural activity during memory in healthy older men and improves memory in schizophrenia. Here, we tested the extent to which raloxifene modifies neural activity during learning in schizophrenia. Nineteen people with schizophrenia participated in a twelve-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of the SERM raloxifene administered orally at 120 mg daily to assess brain activity during probabilistic association learning using functional magnetic resonance imaging (fMRI). Raloxifene improved probabilistic association learning and significantly increased fMRI BOLD activity in the hippocampus and parahippocampal gyrus relative to placebo. A separate region of interest confirmatory analysis in 21 patients vs 36 healthy controls showed a positive association between parahippocampal neural activity and learning in patients, but no such relationship in the parahippocampal gyrus of healthy controls. Thus, selective estrogen receptor modulation by raloxifene concurrently increases activity in the parahippocampal gyrus and improves probabilistic association learning in schizophrenia. These results support a role for estrogen receptor modulation of mesial temporal lobe neural activity in the remediation of learning disabilities in both men and women with schizophrenia.

No MeSH data available.


Related in: MedlinePlus