Apnea produces excitotoxic hippocampal synapses and neuronal apoptosis
Obstructive sleep apnea (OSA) results in the degeneration of neurons in the hippocampus that eventuates in neurocognitive deficits. We were therefore interested in determining the effects of apnea on monosynaptic excitatory processes in a hippocampal pathway (cornu ammonis 3–cornu ammonis 1, CA3–CA1...
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| Veröffentlicht in: | Experimental neurology 2012-12, Vol.238 (2), p.107-113 |
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| creator | Fung, Simon J. Xi, MingChu Zhang, JianHua Sampogna, Sharon Chase, Michael H. |
| description | Obstructive sleep apnea (OSA) results in the degeneration of neurons in the hippocampus that eventuates in neurocognitive deficits. We were therefore interested in determining the effects of apnea on monosynaptic excitatory processes in a hippocampal pathway (cornu ammonis 3–cornu ammonis 1, CA3–CA1) that has been shown to mediate the processing of cognitive information. In addition, to substantiate an anatomical basis for the cognitive dysfunction that occurs in OSA patients, we examined the effects of apnea with respect to neurodegenerative changes (apoptosis) in the same hippocampal pathway.
In order to determine the effects of apnea, an automated system for the generation and analysis of single and recurrent periods of apnea was developed. Utilizing this system, the field excitatory postsynaptic potential (fEPSP) generated by pyramidal neurons in the CA1 region of the hippocampus was monitored in α-chloralose anesthetized rats following stimulation of glutamatergic afferents in the CA3 region. A stimulus–response (input–output) curve for CA3–CA1 synaptic activity was determined. In addition, a paired-pulse paradigm was employed to evaluate, electrophysiologically, the presynaptic release of glutamate. Changes in the synaptic efficacy were assessed following single episodes of apnea induced by ventilatory arrest (60 to 80s duration, mean=72s; mean oxygen desaturation was 53% of normoxia level).
Apnea resulted in a significant potentiation of the amplitude (mean=126%) and slope (mean=117%) of the baseline CA1 fEPSP. This increase in the fEPSP was accompanied by a significant decrease in the amplitude (71%) and slope (81%) of normalized paired-pulse facilitation (PPF) ratios. Since the potentiation of the fEPSP is inversely proportional to changes in PPF ratio, the potentiated fEPSP accompanied by the reduced PPF reveals that apnea produces an abnormal increase in the preterminal release of glutamate that results in the over-activation (and calcium overloading) of hippocampal CA1 neurons. Thus, we conclude that individual episodes of apnea result in the development of excitotoxic processes in the hippocampal CA3–CA1 pathway that is critically involved in the processing of cognitive information. Morphologically, the deleterious effect of recurrent apnea was substantiated by the finding of apoptosis in CA1 neurons of apneic (but not normoxic) animals.
► An Automated Apnea Program was developed to induce episodes of apnea. ► A rat model was employed to study |
| doi_str_mv | 10.1016/j.expneurol.2012.08.006 |
| format | Article |
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In order to determine the effects of apnea, an automated system for the generation and analysis of single and recurrent periods of apnea was developed. Utilizing this system, the field excitatory postsynaptic potential (fEPSP) generated by pyramidal neurons in the CA1 region of the hippocampus was monitored in α-chloralose anesthetized rats following stimulation of glutamatergic afferents in the CA3 region. A stimulus–response (input–output) curve for CA3–CA1 synaptic activity was determined. In addition, a paired-pulse paradigm was employed to evaluate, electrophysiologically, the presynaptic release of glutamate. Changes in the synaptic efficacy were assessed following single episodes of apnea induced by ventilatory arrest (60 to 80s duration, mean=72s; mean oxygen desaturation was 53% of normoxia level).
Apnea resulted in a significant potentiation of the amplitude (mean=126%) and slope (mean=117%) of the baseline CA1 fEPSP. This increase in the fEPSP was accompanied by a significant decrease in the amplitude (71%) and slope (81%) of normalized paired-pulse facilitation (PPF) ratios. Since the potentiation of the fEPSP is inversely proportional to changes in PPF ratio, the potentiated fEPSP accompanied by the reduced PPF reveals that apnea produces an abnormal increase in the preterminal release of glutamate that results in the over-activation (and calcium overloading) of hippocampal CA1 neurons. Thus, we conclude that individual episodes of apnea result in the development of excitotoxic processes in the hippocampal CA3–CA1 pathway that is critically involved in the processing of cognitive information. Morphologically, the deleterious effect of recurrent apnea was substantiated by the finding of apoptosis in CA1 neurons of apneic (but not normoxic) animals.
► An Automated Apnea Program was developed to induce episodes of apnea. ► A rat model was employed to study the synaptic and anatomical changes due to apnea. ► Apnea resulted in the development of excitotoxic synaptic activity in hippocampal CA1 neurons. ► Apnea also reduced the paired-pulse facilitation of hippocampal CA3–CA1 synapses. ► Recurrent apnea produced hyperactive synapses that led to apoptosis of hippocampal CA1 neurons.</description><identifier>ISSN: 0014-4886</identifier><identifier>EISSN: 1090-2430</identifier><identifier>DOI: 10.1016/j.expneurol.2012.08.006</identifier><identifier>PMID: 22921462</identifier><identifier>CODEN: EXNEAC</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>Animals ; Apnea - pathology ; Apoptosis - physiology ; Biological and medical sciences ; Biophysics ; CA1 ; Cognitive processes ; Disease Models, Animal ; Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes ; DNA, Single-Stranded - metabolism ; Electric Stimulation ; Excitatory Postsynaptic Potentials - drug effects ; Excitatory Postsynaptic Potentials - physiology ; Excitotoxicity ; fEPSP ; Hippocampus - pathology ; Hippocampus - physiopathology ; Hypoxia ; Male ; Medical sciences ; Nervous system (semeiology, syndromes) ; Neurodegeneration ; Neurology ; Neurons - physiology ; Obstructive sleep apnea ; Plasticity ; Rat model ; Rats ; Rats, Sprague-Dawley ; Synapses - physiology</subject><ispartof>Experimental neurology, 2012-12, Vol.238 (2), p.107-113</ispartof><rights>2012 Elsevier Inc.</rights><rights>2014 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c401t-67b8ec1264071fcdbcca579483cb6f5e2593b359e8b002337a4d3efb64e161d73</citedby><cites>FETCH-LOGICAL-c401t-67b8ec1264071fcdbcca579483cb6f5e2593b359e8b002337a4d3efb64e161d73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.expneurol.2012.08.006$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26684596$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22921462$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fung, Simon J.</creatorcontrib><creatorcontrib>Xi, MingChu</creatorcontrib><creatorcontrib>Zhang, JianHua</creatorcontrib><creatorcontrib>Sampogna, Sharon</creatorcontrib><creatorcontrib>Chase, Michael H.</creatorcontrib><title>Apnea produces excitotoxic hippocampal synapses and neuronal apoptosis</title><title>Experimental neurology</title><addtitle>Exp Neurol</addtitle><description>Obstructive sleep apnea (OSA) results in the degeneration of neurons in the hippocampus that eventuates in neurocognitive deficits. We were therefore interested in determining the effects of apnea on monosynaptic excitatory processes in a hippocampal pathway (cornu ammonis 3–cornu ammonis 1, CA3–CA1) that has been shown to mediate the processing of cognitive information. In addition, to substantiate an anatomical basis for the cognitive dysfunction that occurs in OSA patients, we examined the effects of apnea with respect to neurodegenerative changes (apoptosis) in the same hippocampal pathway.
In order to determine the effects of apnea, an automated system for the generation and analysis of single and recurrent periods of apnea was developed. Utilizing this system, the field excitatory postsynaptic potential (fEPSP) generated by pyramidal neurons in the CA1 region of the hippocampus was monitored in α-chloralose anesthetized rats following stimulation of glutamatergic afferents in the CA3 region. A stimulus–response (input–output) curve for CA3–CA1 synaptic activity was determined. In addition, a paired-pulse paradigm was employed to evaluate, electrophysiologically, the presynaptic release of glutamate. Changes in the synaptic efficacy were assessed following single episodes of apnea induced by ventilatory arrest (60 to 80s duration, mean=72s; mean oxygen desaturation was 53% of normoxia level).
Apnea resulted in a significant potentiation of the amplitude (mean=126%) and slope (mean=117%) of the baseline CA1 fEPSP. This increase in the fEPSP was accompanied by a significant decrease in the amplitude (71%) and slope (81%) of normalized paired-pulse facilitation (PPF) ratios. Since the potentiation of the fEPSP is inversely proportional to changes in PPF ratio, the potentiated fEPSP accompanied by the reduced PPF reveals that apnea produces an abnormal increase in the preterminal release of glutamate that results in the over-activation (and calcium overloading) of hippocampal CA1 neurons. Thus, we conclude that individual episodes of apnea result in the development of excitotoxic processes in the hippocampal CA3–CA1 pathway that is critically involved in the processing of cognitive information. Morphologically, the deleterious effect of recurrent apnea was substantiated by the finding of apoptosis in CA1 neurons of apneic (but not normoxic) animals.
► An Automated Apnea Program was developed to induce episodes of apnea. ► A rat model was employed to study the synaptic and anatomical changes due to apnea. ► Apnea resulted in the development of excitotoxic synaptic activity in hippocampal CA1 neurons. ► Apnea also reduced the paired-pulse facilitation of hippocampal CA3–CA1 synapses. ► Recurrent apnea produced hyperactive synapses that led to apoptosis of hippocampal CA1 neurons.</description><subject>Animals</subject><subject>Apnea - pathology</subject><subject>Apoptosis - physiology</subject><subject>Biological and medical sciences</subject><subject>Biophysics</subject><subject>CA1</subject><subject>Cognitive processes</subject><subject>Disease Models, Animal</subject><subject>Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes</subject><subject>DNA, Single-Stranded - metabolism</subject><subject>Electric Stimulation</subject><subject>Excitatory Postsynaptic Potentials - drug effects</subject><subject>Excitatory Postsynaptic Potentials - physiology</subject><subject>Excitotoxicity</subject><subject>fEPSP</subject><subject>Hippocampus - pathology</subject><subject>Hippocampus - physiopathology</subject><subject>Hypoxia</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Nervous system (semeiology, syndromes)</subject><subject>Neurodegeneration</subject><subject>Neurology</subject><subject>Neurons - physiology</subject><subject>Obstructive sleep apnea</subject><subject>Plasticity</subject><subject>Rat model</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Synapses - physiology</subject><issn>0014-4886</issn><issn>1090-2430</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1v1DAQhi0EotuPvwC5IPWSMP6I7RxXVUuRKnGBs-U4E-FVNjZ2grb_Hm93KUdOI42e953RQ8hHCg0FKj_vGjzEGdcUpoYBZQ3oBkC-IRsKHdRMcHhLNgBU1EJreUEuc94BQCeYek8uGOsYFZJtyMO21NgqpjCsDnOFB-eXsISDd9VPH2Nwdh_tVOXn2cZcADsP1cvhuWxtDHEJ2edr8m60U8ab87wiPx7uv9891k_fvny92z7VTgBdaql6jY4yKUDR0Q29c7ZVndDc9XJskbUd73nboe4BGOfKioHj2EuBVNJB8Stye-otD_9aMS9m77PDabIzhjUbShXVSvOOFVSdUJdCzglHE5Pf2_RsKJijRLMzrxLNUaIBbYrEkvxwPrL2exxec3-tFeDTGbDZ2WlMdnY-_-Ok1KLtjkXbE4dFyW-PyWTncXY4-IRuMUPw_33mD34AlWg</recordid><startdate>20121201</startdate><enddate>20121201</enddate><creator>Fung, Simon J.</creator><creator>Xi, MingChu</creator><creator>Zhang, JianHua</creator><creator>Sampogna, Sharon</creator><creator>Chase, Michael H.</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20121201</creationdate><title>Apnea produces excitotoxic hippocampal synapses and neuronal apoptosis</title><author>Fung, Simon J. ; Xi, MingChu ; Zhang, JianHua ; Sampogna, Sharon ; Chase, Michael H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c401t-67b8ec1264071fcdbcca579483cb6f5e2593b359e8b002337a4d3efb64e161d73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Apnea - pathology</topic><topic>Apoptosis - physiology</topic><topic>Biological and medical sciences</topic><topic>Biophysics</topic><topic>CA1</topic><topic>Cognitive processes</topic><topic>Disease Models, Animal</topic><topic>Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes</topic><topic>DNA, Single-Stranded - metabolism</topic><topic>Electric Stimulation</topic><topic>Excitatory Postsynaptic Potentials - drug effects</topic><topic>Excitatory Postsynaptic Potentials - physiology</topic><topic>Excitotoxicity</topic><topic>fEPSP</topic><topic>Hippocampus - pathology</topic><topic>Hippocampus - physiopathology</topic><topic>Hypoxia</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Nervous system (semeiology, syndromes)</topic><topic>Neurodegeneration</topic><topic>Neurology</topic><topic>Neurons - physiology</topic><topic>Obstructive sleep apnea</topic><topic>Plasticity</topic><topic>Rat model</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Synapses - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fung, Simon J.</creatorcontrib><creatorcontrib>Xi, MingChu</creatorcontrib><creatorcontrib>Zhang, JianHua</creatorcontrib><creatorcontrib>Sampogna, Sharon</creatorcontrib><creatorcontrib>Chase, Michael H.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Experimental neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fung, Simon J.</au><au>Xi, MingChu</au><au>Zhang, JianHua</au><au>Sampogna, Sharon</au><au>Chase, Michael H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Apnea produces excitotoxic hippocampal synapses and neuronal apoptosis</atitle><jtitle>Experimental neurology</jtitle><addtitle>Exp Neurol</addtitle><date>2012-12-01</date><risdate>2012</risdate><volume>238</volume><issue>2</issue><spage>107</spage><epage>113</epage><pages>107-113</pages><issn>0014-4886</issn><eissn>1090-2430</eissn><coden>EXNEAC</coden><abstract>Obstructive sleep apnea (OSA) results in the degeneration of neurons in the hippocampus that eventuates in neurocognitive deficits. We were therefore interested in determining the effects of apnea on monosynaptic excitatory processes in a hippocampal pathway (cornu ammonis 3–cornu ammonis 1, CA3–CA1) that has been shown to mediate the processing of cognitive information. In addition, to substantiate an anatomical basis for the cognitive dysfunction that occurs in OSA patients, we examined the effects of apnea with respect to neurodegenerative changes (apoptosis) in the same hippocampal pathway.
In order to determine the effects of apnea, an automated system for the generation and analysis of single and recurrent periods of apnea was developed. Utilizing this system, the field excitatory postsynaptic potential (fEPSP) generated by pyramidal neurons in the CA1 region of the hippocampus was monitored in α-chloralose anesthetized rats following stimulation of glutamatergic afferents in the CA3 region. A stimulus–response (input–output) curve for CA3–CA1 synaptic activity was determined. In addition, a paired-pulse paradigm was employed to evaluate, electrophysiologically, the presynaptic release of glutamate. Changes in the synaptic efficacy were assessed following single episodes of apnea induced by ventilatory arrest (60 to 80s duration, mean=72s; mean oxygen desaturation was 53% of normoxia level).
Apnea resulted in a significant potentiation of the amplitude (mean=126%) and slope (mean=117%) of the baseline CA1 fEPSP. This increase in the fEPSP was accompanied by a significant decrease in the amplitude (71%) and slope (81%) of normalized paired-pulse facilitation (PPF) ratios. Since the potentiation of the fEPSP is inversely proportional to changes in PPF ratio, the potentiated fEPSP accompanied by the reduced PPF reveals that apnea produces an abnormal increase in the preterminal release of glutamate that results in the over-activation (and calcium overloading) of hippocampal CA1 neurons. Thus, we conclude that individual episodes of apnea result in the development of excitotoxic processes in the hippocampal CA3–CA1 pathway that is critically involved in the processing of cognitive information. Morphologically, the deleterious effect of recurrent apnea was substantiated by the finding of apoptosis in CA1 neurons of apneic (but not normoxic) animals.
► An Automated Apnea Program was developed to induce episodes of apnea. ► A rat model was employed to study the synaptic and anatomical changes due to apnea. ► Apnea resulted in the development of excitotoxic synaptic activity in hippocampal CA1 neurons. ► Apnea also reduced the paired-pulse facilitation of hippocampal CA3–CA1 synapses. ► Recurrent apnea produced hyperactive synapses that led to apoptosis of hippocampal CA1 neurons.</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>22921462</pmid><doi>10.1016/j.expneurol.2012.08.006</doi><tpages>7</tpages></addata></record> |
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| subjects | Animals Apnea - pathology Apoptosis - physiology Biological and medical sciences Biophysics CA1 Cognitive processes Disease Models, Animal Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes DNA, Single-Stranded - metabolism Electric Stimulation Excitatory Postsynaptic Potentials - drug effects Excitatory Postsynaptic Potentials - physiology Excitotoxicity fEPSP Hippocampus - pathology Hippocampus - physiopathology Hypoxia Male Medical sciences Nervous system (semeiology, syndromes) Neurodegeneration Neurology Neurons - physiology Obstructive sleep apnea Plasticity Rat model Rats Rats, Sprague-Dawley Synapses - physiology |
| title | Apnea produces excitotoxic hippocampal synapses and neuronal apoptosis |
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