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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

(a) Effects of raloxifene relative to placebo on probabilistic association learning in people with schizophrenia. Cumulative percentage correct at each functional magnetic resonance imaging (fMRI) trial block is shown during probabilistic association learning in the placebo (blue line) and raloxifene (green line) conditions. (b) Effects of raloxifene relative to placebo on neural activity during probabilistic association learning in people with schizophrenia. Raloxifene>placebo, (x, y, z=27, −16, −24), T=8.29, z=5.18, family-wise error rate (FWE) corrected (whole brain), p=0.009, parahippocampal gyrus/hippocampus. Yellow areas show significantly increased blood oxygenation level-dependent (BOLD) signal during raloxifene treatment relative to placebo. The corresponding cluster information is provided in Supplementary Table S1.
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fig2: (a) Effects of raloxifene relative to placebo on probabilistic association learning in people with schizophrenia. Cumulative percentage correct at each functional magnetic resonance imaging (fMRI) trial block is shown during probabilistic association learning in the placebo (blue line) and raloxifene (green line) conditions. (b) Effects of raloxifene relative to placebo on neural activity during probabilistic association learning in people with schizophrenia. Raloxifene>placebo, (x, y, z=27, −16, −24), T=8.29, z=5.18, family-wise error rate (FWE) corrected (whole brain), p=0.009, parahippocampal gyrus/hippocampus. Yellow areas show significantly increased blood oxygenation level-dependent (BOLD) signal during raloxifene treatment relative to placebo. The corresponding cluster information is provided in Supplementary Table S1.

Mentions: For demographics of the patients in the raloxifene treatment trial, see Table 1a. All patients were chronically ill, treated with antipsychotic medication (95% receiving second-generation antipsychotics), and displayed mild-to-moderate symptom severity based on their PANSS scores. In relation to probabilistic association learning (see Figure 2a), there was a significant main effect of treatment with patients showing significantly better overall performance during raloxifene (mean=59.4; SD=2.1) relative to placebo (mean=53.0; SD=2.9), F1,102.0=8.0, p=0.006; however, there was no trial block by treatment condition interaction (F7,59.7=0.96, p=0.47). Additionally, there was no significant difference between placebo and raloxifene treatment groups in relation to PANSS positive, negative, or total symptom severity scores or mean daily CPZ dose (see Table 1a).


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)

(a) Effects of raloxifene relative to placebo on probabilistic association learning in people with schizophrenia. Cumulative percentage correct at each functional magnetic resonance imaging (fMRI) trial block is shown during probabilistic association learning in the placebo (blue line) and raloxifene (green line) conditions. (b) Effects of raloxifene relative to placebo on neural activity during probabilistic association learning in people with schizophrenia. Raloxifene>placebo, (x, y, z=27, −16, −24), T=8.29, z=5.18, family-wise error rate (FWE) corrected (whole brain), p=0.009, parahippocampal gyrus/hippocampus. Yellow areas show significantly increased blood oxygenation level-dependent (BOLD) signal during raloxifene treatment relative to placebo. The corresponding cluster information is provided in Supplementary Table S1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: (a) Effects of raloxifene relative to placebo on probabilistic association learning in people with schizophrenia. Cumulative percentage correct at each functional magnetic resonance imaging (fMRI) trial block is shown during probabilistic association learning in the placebo (blue line) and raloxifene (green line) conditions. (b) Effects of raloxifene relative to placebo on neural activity during probabilistic association learning in people with schizophrenia. Raloxifene>placebo, (x, y, z=27, −16, −24), T=8.29, z=5.18, family-wise error rate (FWE) corrected (whole brain), p=0.009, parahippocampal gyrus/hippocampus. Yellow areas show significantly increased blood oxygenation level-dependent (BOLD) signal during raloxifene treatment relative to placebo. The corresponding cluster information is provided in Supplementary Table S1.
Mentions: For demographics of the patients in the raloxifene treatment trial, see Table 1a. All patients were chronically ill, treated with antipsychotic medication (95% receiving second-generation antipsychotics), and displayed mild-to-moderate symptom severity based on their PANSS scores. In relation to probabilistic association learning (see Figure 2a), there was a significant main effect of treatment with patients showing significantly better overall performance during raloxifene (mean=59.4; SD=2.1) relative to placebo (mean=53.0; SD=2.9), F1,102.0=8.0, p=0.006; however, there was no trial block by treatment condition interaction (F7,59.7=0.96, p=0.47). Additionally, there was no significant difference between placebo and raloxifene treatment groups in relation to PANSS positive, negative, or total symptom severity scores or mean daily CPZ dose (see Table 1a).

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