{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T01:26:50Z","timestamp":1791336410330,"version":"4.3.1"},"reference-count":37,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5500","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2000,12,22]]},"abstract":"<jats:p>Using functional magnetic resonance imaging, we investigated the mechanism by which cholinergic enhancement improves working memory. We studied the effect of the cholinesterase inhibitor physostigmine on subcomponents of this complex function. Cholinergic enhancement increased the selectivity of neural responses in extrastriate cortices during visual working memory, particularly during encoding. It also increased the participation of ventral extrastriate cortex during memory maintenance and decreased the participation of anterior prefrontal cortex. These results indicate that cholinergic enhancement improves memory performance by augmenting the selectivity of perceptual processing during encoding, thereby simplifying processing demands during memory maintenance and reducing the need for prefrontal participation.<\/jats:p>","DOI":"10.1126\/science.290.5500.2315","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T09:47:44Z","timestamp":1027763264000},"page":"2315-2319","source":"Crossref","is-referenced-by-count":258,"title":["Cholinergic Enhancement and Increased Selectivity of Perceptual Processing During Working Memory"],"prefix":"10.1126","volume":"290","author":[{"given":"Maura L.","family":"Furey","sequence":"first","affiliation":[{"name":"Laboratory of Brain and Cognition, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Pietrini","sequence":"additional","affiliation":[{"name":"Department of Human and Environmental Sciences, University of Pisa, Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James V.","family":"Haxby","sequence":"additional","affiliation":[{"name":"Laboratory of Brain and Cognition, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1080\/14640748608401616","volume":"38","author":"Baddeley A.","year":"1986","unstructured":"Baddeley A., Logie R., Bressi S., Della Sala S., Spinnler H., Q. 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L.","year":"1997","unstructured":"Furey M. L., et al., Proc. Natl. Acad. Sci. U.S.A. 94, 6512 (1997);","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_1_10_3","unstructured":". Physostigmine and other cholinesterase inhibitors enhance cholinergic function by prolonging the action of endogenously released acetylcholine."},{"key":"e_1_3_1_11_2","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0361-9230(99)00219-1","volume":"51","author":"Furey M. L.","year":"2000","unstructured":"Furey M. L., et al., Brain Res. Bull. 51, 213 (2000).","journal-title":"Brain Res. Bull."},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1006\/nimg.1996.0247"},{"key":"e_1_3_1_13_2","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/(SICI)1097-0193(1996)4:4<227::AID-HBM1>3.0.CO;2-5","volume":"4","author":"Grady C. L.","year":"1996","unstructured":"Grady C. L., et al., Hum. Brain Mapp. 4, 227 (1996).","journal-title":"Hum. Brain Mapp."},{"key":"e_1_3_1_14_2","unstructured":"All participants (two male five female) gave written informed consent. Gradient echo echo planar imaging (repetition time 3 s echo time 40 ms flip angle 90) was used on a GE Signa 1.5-T scanner (Milwaukee WI). Whole-brain volumes composed of 24 contiguous 5-mm-thick axial slices were obtained in 12 series of 92 scans as each subject performed the WM for faces and control tasks. All subjects received an intravenous infusion of physostigmine at a rate of 1 mg\/hour according to the following procedure: A 10-min loading dose (1.93 mg\/hour) to quickly achieve desired blood plasma levels followed by a maintenance drip (0.816 mg\/hour) to maintain stable drug levels to completion of the study. Infusions continued for 30 min before the beginning of the task to obtain stable drug effects (14). To minimize peripheral side effects glycopyrrolate (0.2 mg) was given intravenously before the physostigmine infusion. Glycopyrrolate is a cholinergic antagonist that does not cross the blood-brain barrier and thus acts as a peripheral blocker of physostigmine effects. The same infusion schedule was used with saline on the placebo infusion day. Blood pressure and ECG were monitored throughout the study on both days in all subjects."},{"key":"e_1_3_1_15_2","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/S0091-3057(00)00186-6","volume":"66","author":"Furey M. L.","year":"2000","unstructured":"Furey M. L., et al., Pharmacol. Biochem. Behav. 66, 475 (2000).","journal-title":"Pharmacol. Biochem. Behav."},{"key":"e_1_3_1_16_2","unstructured":"Time series data were analyzed on a voxel-by-voxel basis using multiple regression (5 35) and were done separately for the two experimental days for each subject. Hemodynamic delays were estimated on a voxel-by-voxel basis from the time series data based on a Fourier analysis of the phase delays of the principal frequencies in the experimental paradigm. Regressors in the multiple regression model were designed to identify responses to different subcomponents within the experimental design: (i) the response during face encoding (ii) activity during the memory delay (iii) the response during recognition memory testing (iv) the response to the scrambled stimulus at the beginning of control items (v) activity during the control item delay (vi) the response to the pair of scrambled pictures that ended each control item (vii) the intertrial interval that preceded each memory item and (viii) the intertrial interval that preceded each control item. Selected contrasts between responses to different subcomponents were calculated as effects of interest: (i) responses to visual stimuli minus responses to a blank screen (nonselective visual response) (ii) responses to faces (including both encoding and recognition testing stimuli) minus responses to control stimuli (face-selective visual response) (iii) the response during face encoding minus the response during face retrieval (encoding-selective visual response) and (iv) activity during the memory delay minus activity during the control delay (memory delay activity). Regions of interest were defined as those showing a significant signal change (Z > 4.0 P < 0.0001) for the overall experimental effect with a minimum of five contiguous significant voxels. Within these regions showing a significant overall experimental effect subregions were identified that had significant contrasts for the individual effects of interest (Z > 3.09 P < 0.001). Mean echoplanar brain scans from each experimental session were created and registered to a location midway between the locations of the scans in their original image volumes. Maps of the regions of interest from the two scanning sessions were resampled into this common reference frame. The same regions from the two sessions were combined to create a single region in the common space that contained all voxels that showed a significant effect on either day. Thus these regions were defined in a way that was not biased toward greater effects for either day. These significance maps were superimposed onto a structural MRI for each individual subject to identify their anatomical locations (16). Mean time series associated with these regions of interest were determined for each subject and for each experimental session. Multiple regression then was performed on each individual region of interest time series to calculate the magnitude of the effects of interest as differences in percent signal change (nonselective visual face-selective encoding-selective and activity during the memory delay). Contrast magnitudes were analyzed using repeated measures ANOVA (analysis of variance) to test the significance of changes in response contrasts between placebo and drug sessions."},{"key":"e_1_3_1_17_2","unstructured":"Regions of interest were defined as voxels showing significant effects (15) in the following locations as defined by anatomical landmarks that were identified on structural MRI scans (with Talairach coordinates of mean center of gravity): ventral occipital cortex including the lateral occipital sulcus the inferior occipital gyrus and inferior part of the middle occipital gyrus and the posterior part of the fusiform gyrus (left \u221224 \u221277 and \u221214; right 18 \u221279 and \u221215); ventral temporal cortex including the inferior and fusiform gyri (left \u221228 \u221252; and \u221212; right 27 \u221255 and \u221216); dorsal occipital cortex including the superior occipital gyrus and the intraoccipital sulcus (left \u221232 \u221272; and 12 right 26 \u221274 and 12); intraparietal sulcus (left \u221228 \u221260; and 31 right 28 \u221259 and 31); inferior prefrontal cortex including the inferior frontal gyrus and anterior insular cortex (left \u201331 40 and 1; right 39 38 and \u20134); anterior middle frontal gyrus (left -27 39 and 26; right 36 39 and 21); posterior middle frontal gyrus (left \u201341 11 and 23; right 36 13 and 27); superior frontal gyrus (left \u22129 31 and 45; right 17 35 and 37)."},{"key":"e_1_3_1_18_2","unstructured":"Although the improvement in WM performance with cholinergic enhancement was a nonsignificant trend in the current study ( P = 0.07) in a previous study (9) with a larger sample ( n = 13) the effect was highly significant ( P < 0.001). In the current study we analyzed RT data for six of our seven subjects because the behavioral data for one subject were unavailable due to a computer failure. The difference in the significance of the two findings is simply a result of the difference in sample sizes. A power analysis shows that the size of the RT difference and variability in the current sample would yield a significant result ( P = 0.01) with a sample size of 13. During the memory trials mean RT was 1180 ms during placebo and 1119 ms during physostigmine. During the control trials mean RT was 735 ms during placebo and 709 ms during physostigmine a difference that did not approach significance ( P = 0.24) suggesting that the effect of cholinergic enhancement on WM performance is not due to a nonspecific increase in arousal."},{"key":"e_1_3_1_19_2","unstructured":"Matched-pair t tests (two-tailed) were used to test the significance of drug-related changes in the volume of regions of interest that showed significant response contrasts."},{"key":"e_1_3_1_20_2","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1152\/jn.1987.58.4.765","volume":"55","author":"Sato H.","year":"1987","unstructured":"Sato H., Hata Y., Masui H., Tsumoto T., J. Neurophysiol. 55, 765 (1987).","journal-title":"J. Neurophysiol."},{"key":"e_1_3_1_21_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0166-4328(94)00113-T","volume":"67","author":"Hasselmo M. E.","year":"1995","unstructured":"Hasselmo M. E., Behav. 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S., Science 217, 408 (1985).","journal-title":"Science"},{"key":"e_1_3_1_35_2","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1001\/jama.280.20.1777","volume":"280","author":"Qizilbash N.","year":"1998","unstructured":"Qizilbash N., et al., JAMA 280, 1777 (1998).","journal-title":"JAMA"},{"key":"e_1_3_1_36_2","unstructured":"J. V. Haxby J. Ma. Maisog S. M. Courtney in Mapping and Modeling the Human Brain P. Fox J. Lancaster K. Friston Eds. (Wiley New York in press)."},{"key":"e_1_3_1_37_2","unstructured":"We express our appreciation to S. Courtney R. Desimone Y. Jiang S. Kastner L. Latour A. Martin L. Pessoa and L. Ungerleider for careful and critical review of the manuscript. We also thank M. B. Schapiro and S. I. Rapoport for input during early stages of this project. This research was supported by the National Institute on Mental Health and National Institute on Aging Intramural Research Programs."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.290.5500.2315","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T09:58:07Z","timestamp":1705139887000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.290.5500.2315"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,12,22]]},"references-count":37,"journal-issue":{"issue":"5500","published-print":{"date-parts":[[2000,12,22]]}},"alternative-id":["10.1126\/science.290.5500.2315"],"URL":"https:\/\/doi.org\/10.1126\/science.290.5500.2315","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,12,22]]}}}