Hostname: page-component-78c5997874-8bhkd Total loading time: 0 Render date: 2024-11-04T19:33:56.281Z Has data issue: false hasContentIssue false

Neural correlates of visuospatial working memory in the ‘at-risk mental state’

Published online by Cambridge University Press:  10 March 2010

M. R. Broome*
Affiliation:
Psychosis Clinical Academic Group, Institute of Psychiatry, King's College London, UK Health Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry, UK
P. Fusar-Poli
Affiliation:
Psychosis Clinical Academic Group, Institute of Psychiatry, King's College London, UK Department of Applied and Psychobehavioural Health Sciences, University of Pavia, Italy
P. Matthiasson
Affiliation:
Psychosis Clinical Academic Group, Institute of Psychiatry, King's College London, UK
J. B. Woolley
Affiliation:
Psychosis Clinical Academic Group, Institute of Psychiatry, King's College London, UK
L. Valmaggia
Affiliation:
Psychosis Clinical Academic Group, Institute of Psychiatry, King's College London, UK Department of Psychiatry and Neuropsychology, Maastricht University, The Netherlands
L. C. Johns
Affiliation:
Psychosis Clinical Academic Group, Institute of Psychiatry, King's College London, UK
P. Tabraham
Affiliation:
Psychosis Clinical Academic Group, Institute of Psychiatry, King's College London, UK
E. Bramon
Affiliation:
Psychosis Clinical Academic Group, Institute of Psychiatry, King's College London, UK
S. C. R. Williams
Affiliation:
Neuroimaging Research Group, Department of Neurology, Institute of Psychiatry, King's College London, UK
M. J. Brammer
Affiliation:
Brain Image Analysis Unit, Department of Biostatistics and Computing, Institute of Psychiatry, King's College London, UK
X. Chitnis
Affiliation:
Brain Image Analysis Unit, Department of Biostatistics and Computing, Institute of Psychiatry, King's College London, UK
F. Zelaya
Affiliation:
Neuroimaging Research Group, Department of Neurology, Institute of Psychiatry, King's College London, UK
P. K. McGuire
Affiliation:
Psychosis Clinical Academic Group, Institute of Psychiatry, King's College London, UK
*
*Address for correspondence: Dr M. R. Broome, Warwick Medical School, University of Warwick, Gibbet Hill, Coventry CV4 7AL, UK. (Email: [email protected])

Abstract

Background

Impaired spatial working memory (SWM) is a robust feature of schizophrenia and has been linked to the risk of developing psychosis in people with an at-risk mental state (ARMS). We used functional magnetic resonance imaging (fMRI) to examine the neural substrate of SWM in the ARMS and in patients who had just developed schizophrenia.

Method

fMRI was used to study 17 patients with an ARMS, 10 patients with a first episode of psychosis and 15 age-matched healthy comparison subjects. The blood oxygen level-dependent (BOLD) response was measured while subjects performed an object–location paired-associate memory task, with experimental manipulation of mnemonic load.

Results

In all groups, increasing mnemonic load was associated with activation in the medial frontal and medial posterior parietal cortex. Significant between-group differences in activation were evident in a cluster spanning the medial frontal cortex and right precuneus, with the ARMS groups showing less activation than controls but greater activation than first-episode psychosis (FEP) patients. These group differences were more evident at the most demanding levels of the task than at the easy level. In all groups, task performance improved with repetition of the conditions. However, there was a significant group difference in the response of the right precuneus across repeated trials, with an attenuation of activation in controls but increased activation in FEP and little change in the ARMS.

Conclusions

Abnormal neural activity in the medial frontal cortex and posterior parietal cortex during an SWM task may be a neural correlate of increased vulnerability to psychosis.

Type
Original Articles
Copyright
Copyright © Cambridge University Press 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Ananth, H, Popescu, I, Critchley, HD, Good, CD, Frackowiak, RS, Dolan, RJ (2002). Cortical and subcortical gray matter abnormalities in schizophrenia determined through structural magnetic resonance imaging with optimized volumetric voxel-based morphometry. American Journal of Psychiatry 159, 14971505.CrossRefGoogle ScholarPubMed
Barnett, JH, Sahakian, BJ, Werners, U, Hill, KE, Brazil, R, Gallagher, O, Bullmore, ET, Jones, PB (2005). Visuospatial learning and executive function are independently impaired in first-episode psychosis. Psychological Medicine 35, 10311041.CrossRefGoogle ScholarPubMed
Boyer, P, Phillips, JL, Rousseau, FL, Ilivitsky, S (2007). Hippocampal abnormalities and memory deficits: new evidence of a strong pathophysiological link in schizophrenia. Brain Research Reviews 54, 92–112.CrossRefGoogle Scholar
Brammer, M, Bullmore, E, Simmons, A, Williams, S, Grasby, PM, Howard, RJ, Woodruff, PW, Rabe-Hesketh, S (1997). Generic brain activation mapping in functional magnetic resonance imaging: a nonparametric approach. Magnetic Resonance Imaging 15, 763770.CrossRefGoogle ScholarPubMed
Brewer, WJ, Francey, SM, Wood, SJ, Jackson, HJ, Pantelis, C, Phillips, LJ, Yung, AR, Anderson, VA, McGorry, PD (2005). Memory impairments identified in people at ultra-high risk for psychosis who later develop first-episode psychosis. American Journal of Psychiatry 162, 7178.CrossRefGoogle ScholarPubMed
Broome, MR, Johns, LC, Valli, I, Woolley, JB, Tabraham, P, Brett, C, Valmaggia, L, Peters, E, Garety, PA, McGuire, PK (2007). Delusion formation and reasoning biases in those at clinical high risk for psychosis. British Journal of Psychiatry 191, s38s42.CrossRefGoogle Scholar
Broome, MR, Matthiasson, P, Fusar-Poli, P, Woolley, JB, Johns, LC, Tabraham, P, Bramon, E, Valmaggia, L, Williams, SCR, Brammer, MJ, Chitnis, X, McGuire, PK (2009). Neural correlates of executive function and working memory in the ‘at-risk mental state’. British Journal of Psychiatry 194, 2533.CrossRefGoogle ScholarPubMed
Broome, MR, Woolley, JB, Johns, LC, Valmaggia, LR, Tabraham, P, Gafoor, R, Bramon, E, McGuire, PK (2005 a). Outreach and support in South London (OASIS): implementation of a clinical service for prodromal psychosis and the at risk mental state. European Psychiatry 20, 372378.CrossRefGoogle ScholarPubMed
Broome, MR, Woolley, JB, Tabraham, P, Johns, LC, Bramon, E, Murray, GK, Pariante, C, McGuire, PK, Murray, RM (2005 b). What causes the onset of psychosis? Schizophrenia Research 79, 2334.CrossRefGoogle ScholarPubMed
Bullmore, E, Long, C, Suckling, J, Fadili, J (2001). Coloured noise and computational inference in neurophysiological (fMRI) series analysis: resampling methods in time and wavelet domains. Human Brain Mapping 12, 6178.3.0.CO;2-W>CrossRefGoogle ScholarPubMed
Bullmore, ET, Suckling, J, Overmeyer, S, Rabe-Hesketh, S, Taylor, E, Brammer, MJ (1999 a). Global, voxel and cluster tests, by theory and permutation, for a difference between two groups of structural MR images of the brain. Transcranial Medical Imaging 18, 3242.CrossRefGoogle ScholarPubMed
Bullmore, ET, Brammer, MJ, Rabe-Hesketh, S, Curtis, VA, Morris, RG, Williams, SC, Sharma, T, McGuire, PK (1999 b). Methods for diagnosis and treatment of stimulus-correlated motion in generic brain activation studies using fMRI. Human Brain Mapping 7, 3848.3.0.CO;2-Q>CrossRefGoogle ScholarPubMed
Cannon, TD, Huttunen, MO, Lonnqvist, J, Tuulio-Henriksson, A, Pirkola, T, Glahn, D, Finkelstein, J, Hietanen, M, Kaprio, J, Koskenvuo, M (2000). The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. American Journal of Human Genetics 67, 369382.CrossRefGoogle ScholarPubMed
Cavanna, AE, Trimble, MR (2006). The precuneus: a review of its functional anatomy and behavioural correlates. Brain 129, 564583.CrossRefGoogle ScholarPubMed
Chakos, MH, Schobel, SA, Gu, H, Gerig, G, Bradford, D, Charles, C, Lieberman, JA (2005). Duration of illness and treatment effects on hippocampal volume in male patients with schizophrenia. British Journal of Psychiatry 186, 2631.CrossRefGoogle ScholarPubMed
Chung, GH, Han, YM, Jeong, SH, Jack, CR Jr. (2005). Functional heterogeneity of the supplementary motor area. American Journal of Neuroradiology 26, 18191823.Google ScholarPubMed
Curtis, CE (2006). Prefrontal and parietal contributions to spatial working memory. Neuroscience 139, 173180.CrossRefGoogle ScholarPubMed
Dazzan, P, Morgan, KD, Orr, K, Hutchinson, G, Chitnis, X, Suckling, J, Fearon, P, McGuire, PK, Mallett, RM, Jones, PB, Leff, J, Murray, RM (2005). Different effects of typical and atypical antipsychotics on grey matter in first episode psychosis: the AESOP study. Neuropsychopharmacology 30, 765774.CrossRefGoogle ScholarPubMed
Exner, C, Weniger, G, Schmidt-Samoa, C, Irle, E (2006). Reduced size of the pre-supplementary motor cortex and impaired motor sequence learning in first-episode schizophrenia. Schizophrenia Research 84, 386396.CrossRefGoogle ScholarPubMed
Farmer, CM, O'Donnell, BF, Niznikiewicz, MA, Voglmaier, MM, McCarley, RW, Shenton, ME (2000). Visual perception and working memory in schizotypal personality disorder. American Journal of Psychiatry 157, 781788.CrossRefGoogle ScholarPubMed
Fleming, K, Goldberg, TE, Binks, S, Randolph, C, Gold, JM, Weinberger, DR (1997). Visuospatial working memory in patients with schizophrenia. Biological Psychiatry 41, 4349.CrossRefGoogle ScholarPubMed
Francey, SM, Jackson, HJ, Phillips, LJ, Wood, SJ, Yung, AR, McGorry, PD (2005). Sustained attention in young people at high risk of psychosis does not predict transition to psychosis. Schizophrenia Research 79, 127136.CrossRefGoogle Scholar
Friman, O, Borga, P, Lundberg, P (2003). Adaptive analysis of fMRI data. NeuroImage 19, 837845.CrossRefGoogle ScholarPubMed
Fusar-Poli, P, Broome, MR, Matthiasson, P, Woolley, JB, Mechelli, A, Johns, LC, Tabraham, P, Bramon, E, Valmaggia, L, Williams, S, McGuire, P (2009). Prefrontal response during executive functioning directly related to twelve months clinical outcome in people at ultra high risk of psychosis. Schizophrenia Bulletin. Published online: 7 August 2009. doi:10.1093/schbul/sbp074.Google Scholar
Fusar-Poli, P, Perez, J, Broome, M, Borgwardt, S, Placentino, A, Caverzasi, E, Cortesi, M, Veggiotti, P, Politi, P, Barale, F, McGuire, P (2007). Neurofunctional correlates of vulnerability to psychosis: a systematic review and meta-analysis. Neuroscience and Biobehavioral Reviews 31, 465484.CrossRefGoogle ScholarPubMed
Glahn, DC, Ragland, JD, Abramoff, A, Barrett, J, Laird, AR, Bearden, CE, Velligan, DI (2005). Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia. Human Brain Mapping 25, 6069.CrossRefGoogle ScholarPubMed
Goldstein, LH, Canavan, AG, Polkey, CE (1988). Verbal and abstract designs paired associate learning after unilateral temporal lobectomy. Cortex 24, 4152.CrossRefGoogle ScholarPubMed
Gould, RL, Brown, RG, Owen, AM, ffytche, DH, Howard, RJ (2003). fMRI BOLD response to increasing task difficulty during successful paired associates learning. NeuroImage 20, 10061019.CrossRefGoogle ScholarPubMed
Honey, GD, Sharma, T, Suckling, J, Giampietro, V, Soni, W, Williams, SC, Bullmore, ET (2003). The functional neuroanatomy of schizophrenic subsyndromes. Psychological Medicine 33, 10071018.CrossRefGoogle ScholarPubMed
Joyce, E, Huddy, V (2004). Defining the cognitive impairment in schizophrenia. Psychological Medicine 34, 11511155.CrossRefGoogle ScholarPubMed
Kay, SR (1990). Positive-negative symptom assessment in schizophrenia: psychometric issues and scale comparison. Psychiatry Quarterly 61, 163178.CrossRefGoogle ScholarPubMed
Keshavan, MS, Diwadkar, VA, Spencer, SM, Harenski, KA, Luna, B, Sweeney, JA (2002). A preliminary functional magnetic resonance imaging study in offspring of schizophrenic parents. Progress in Neuropsychopharmacology and Biological Psychiatry 26, 11431149.CrossRefGoogle ScholarPubMed
Krause, BJ, Schmidt, D, Mottaghy, FM, Taylor, J, Halsband, U, Herzog, H, Tellmann, L, Muller-Gartner, HW (1999). Episodic retrieval activates the precuneus irrespective of the imagery content of word pair associates. A PET study. Brain 122, 255263.CrossRefGoogle ScholarPubMed
Kuperberg, GR, Broome, MR, McGuire, PK, David, AS, Eddy, M, Ozawa, F, Goff, D, West, WC, Williams, SC, van der Kouwe, AJ, Salat, DH, Dale, AM, Fischl, B (2003). Regionally localized thinning of the cerebral cortex in schizophrenia. Archives of General Psychiatry 60, 878888.CrossRefGoogle ScholarPubMed
LaBar, KS, Gitelman, DR, Parrish, TB, Mesulam, MM (1999). Neuroanatomic overlap of working memory and spatial attention networks: a functional MRI comparison within subjects. NeuroImage 10, 695704.CrossRefGoogle ScholarPubMed
Lencz, T, Smith, CW, McLaughlin, D, Auther, A, Nakayama, E, Hovey, L, Cornblatt, BA (2006). Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biological Psychiatry 59, 863871.CrossRefGoogle ScholarPubMed
Lieberman, J, Chakos, M, Wu, H, Alvir, J, Hoffman, E, Robinson, D, Bilder, R (2001). Longitudinal study of brain morphology in first episode schizophrenia. Biological Psychiatry 49, 487499.CrossRefGoogle ScholarPubMed
Lieberman, JA (1999). Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological perspective. Biological Psychiatry 46, 729739.CrossRefGoogle ScholarPubMed
McCarthy, G, Puce, A, Constable, T, Krystal, JH, Gore, JC, Goldman-Rakic, P (1996). Activation of human prefrontal cortex during spatial and nonspatial working memory tasks measured by functional MRI. Cerebral Cortex 6, 600611.CrossRefGoogle ScholarPubMed
McGuffin, P, Farmer, A, Harvey, I (1991). A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. Archives of General Psychiatry 48, 764770.CrossRefGoogle ScholarPubMed
Miller, TJ, McGlashan, TH, Rosen, JL, Somjee, L, Markovich, PJ, Stein, K, Woods, SW (2002). Prospective diagnosis of the initial prodrome for schizophrenia based on the Structured Interview for Prodromal Syndromes: preliminary evidence of interrater reliability and predictive validity. American Journal of Psychiatry 159, 863865.CrossRefGoogle ScholarPubMed
Morey, RA, Inan, S, Mitchell, TV, Perkins, DO, Lieberman, JA, Belger, A (2005). Imaging frontostriatal function in ultra-high-risk, early, and chronic schizophrenia during executive processing. Archives of General Psychiatry 62, 254262.CrossRefGoogle ScholarPubMed
Muller, NG, Knight, RT (2006). The functional neuroanatomy of working memory: contributions of human brain lesion studies. Neuroscience 139, 5158.CrossRefGoogle ScholarPubMed
Nagahama, Y, Okada, T, Katsumi, Y, Hayashi, T, Yamauchi, H, Sawamoto, N, Toma, K, Nakamura, K, Hanakawa, T, Konishi, J, Fukuyama, H, Shibasaki, H (1999). Transient neural activity in the medial superior frontal gyrus and precuneus time locked with attention shift between object features. NeuroImage 10, 193199.CrossRefGoogle ScholarPubMed
Narberhaus, A, Lawrence, E, Allin, MP, Walshe, M, McGuire, P, Rifkin, L, Murray, R, Nosarti, C (2009). Neural substrates of visual paired associates in young adults with a history of very preterm birth: alterations in fronto-parieto-occipital networks and caudate nucleus. NeuroImage 47, 18841893.CrossRefGoogle ScholarPubMed
Paillere-Martinot, M, Caclin, A, Artiges, E, Poline, JB, Joliot, M, Mallet, L, Recasens, C, Attar-Levy, D, Martinot, JL (2001). Cerebral gray and white matter reductions and clinical correlates in patients with early onset schizophrenia. Schizophrenia Research 50, 1926.CrossRefGoogle ScholarPubMed
Pantelis, C, Velakoulis, D, McGorry, PD, Wood, SJ, Suckling, J, Phillips, LJ, Yung, AR, Bullmore, ET, Brewer, W, Soulsby, B, Desmond, P, McGuire, PK (2003). Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet 361, 281288.CrossRefGoogle ScholarPubMed
Park, S, Holzman, PS (1992). Schizophrenics show spatial working memory deficits. Archives of General Psychiatry 49, 975982.CrossRefGoogle ScholarPubMed
Park, S, Holzman, PS, Lenzenweger, MF (1995). Individual differences in spatial working memory in relation to schizotypy. Journal of Abnormal Psychology 104, 355363.CrossRefGoogle ScholarPubMed
Pollmann, S, von Cramon, DY (2000). Object working memory and visuospatial processing: functional neuroanatomy analyzed by event-related fMRI. Experimental Brain Research 133, 1222.CrossRefGoogle ScholarPubMed
Postle, BR (2006). Working memory as an emergent property of the mind and brain. Neuroscience 139, 2338.CrossRefGoogle ScholarPubMed
Postle, BR, Berger, JS, Taich, AM, D'Esposito, M (2000). Activity in human frontal cortex associated with spatial working memory and saccadic behavior. Journal of Cognitive Neuroscience 12, 2–14.CrossRefGoogle ScholarPubMed
Pukrop, R, Ruhrmann, S, Schultze-Lutter, F, Bechdolf, A, Brockhaus-Dumke, A, Klosterkotter, J (2007). Neurocognitive indicators for a conversion to psychosis: comparison of patients in a potentially initial prodromal state who did or did not convert to a psychosis. Schizophrenia Research 92, 116125.CrossRefGoogle Scholar
Rapoport, JL, Giedd, JN, Blumenthal, J, Hamburger, S, Jeffries, N, Fernandez, T, Nicolson, R, Bedwell, J, Lenane, M, Zijdenbos, A, Paus, T, Evans, A (1999). Progressive cortical change during adolescence in childhood-onset schizophrenia. A longitudinal magnetic resonance imaging study. Archives of General Psychiatry 56, 649654.CrossRefGoogle ScholarPubMed
Rushworth, MF, Walton, ME, Kennerley, SW, Bannerman, DM (2004). Action sets and decisions in the medial frontal cortex. Trends in Cognitive Science 8, 410417.CrossRefGoogle ScholarPubMed
Rypma, B, Prabhakaran, V, Desmond, JE, Glover, GH, Gabrieli, JDE (1999). Load-dependent roles of frontal brain regions in the maintenance of working memory. NeuroImage 9, 216226.CrossRefGoogle ScholarPubMed
Saperstein, AM, Fuller, RL, Avila, MT, Adami, H, McMahon, RP, Thaker, GK, Gold, JM (2006). Spatial working memory as a cognitive endophenotype of schizophrenia: assessing risk for pathophysiological dysfunction. Schizophrenia Bulletin 32, 498506.CrossRefGoogle ScholarPubMed
Silver, H, Feldman, P, Bilker, W, Gur, RC (2003). Working memory deficit as a core neuropsychological dysfunction in schizophrenia. American Journal of Psychiatry 160, 18091816.CrossRefGoogle ScholarPubMed
Smith, CW, Park, S, Cornblatt, B (2006). Spatial working memory deficits in adolescents at clinical high risk for schizophrenia. Schizophrenia Research 81, 211215.CrossRefGoogle ScholarPubMed
Stevens, AA, Goldman-Rakic, PS, Gore, JC, Fulbright, RK, Wexler, BE (1998). Cortical dysfunction in schizophrenia during auditory word and tone working memory demonstrated by functional magnetic resonance imaging. Archives of General Psychiatry 55, 10971103.CrossRefGoogle ScholarPubMed
Suzuki, M, Zhou, SY, Takahashi, T, Hagino, H, Kawasaki, Y, Niu, L, Matsui, M, Seto, H, Kurachi, M (2005). Differential contributions of prefrontal and temporolimbic pathology to mechanisms of psychosis. Brain 128, 21092122.CrossRefGoogle ScholarPubMed
Talairach, J, Tournoux, P (1988). A Co-planar Stereotactic Atlas of the Human Brain. Thieme Medical Publishers: New York.Google Scholar
Thirion, B, Pinel, P, Meriaux, S, Roche, A, Dehaene, S, Poline, J-B (2007). Analysis of a large fMRI cohort: statistical and methodological issues for group analysis. NeuroImage 35, 105120.CrossRefGoogle Scholar
Valmaggia, LR, McCrone, P, Knapp, M, Woolley, JB, Broome, MR, Tabraham, P, Johns, LC, Prescott, C, Bramon, E, Lappin, J, Power, P, McGuire, PK (2009). Economic impact of early intervention in people at high risk of psychosis. Psychological Medicine 39, 16171626.CrossRefGoogle ScholarPubMed
Vance, A, Hall, N, Bellgrove, MA, Casey, M, Karsz, F, Maruff, P (2006). Visuospatial working memory deficits in adolescent onset schizophrenia. Schizophrenia Research 87, 223227.CrossRefGoogle ScholarPubMed
Wagner, AD, Shannon, BJ, Kahn, I, Buckner, RL (2005). Parietal lobe contributions to episodic memory retrieval. Trends in Cognitive Science 9, 445453.CrossRefGoogle ScholarPubMed
Wagner, M, Frommann, I, Jessen, F, Pukrop, R, Bechdolf, A, Ruhrmann, S, Klosterkotter, J, Brinkmeyer, J, Woelwer, W, Decker, P, Maier, W (2006). Cognitive and neurobiological risk indicators in early and late prodromal stages. Schizophrenia Research 86, S35S36.CrossRefGoogle Scholar
Wood, SJ, Pantelis, C, Proffitt, T, Phillips, LJ, Stuart, GW, Buchanan, JA, Mahony, K, Brewer, W, Smith, DJ, McGorry, PD (2003). Spatial working memory ability is a marker of risk-for-psychosis. Psychological Medicine 33, 12391247.CrossRefGoogle ScholarPubMed
Wood, SJ, Proffitt, T, Mahony, K, Smith, DJ, Buchanan, JA, Brewer, W, Stuart, GW, Velakoulis, D, McGorry, PD, Pantelis, C (2002). Visuospatial memory and learning in first-episode schizophreniform psychosis and established schizophrenia: a functional correlate of hippocampal pathology? Psychological Medicine 32, 429438.CrossRefGoogle ScholarPubMed
Yung, AR, Phillips, LJ, McGorry, PD, McFarlane, CA, Francey, S, Harrigan, S, Patton, GC, Jackson, HJ (1998). Prediction of psychosis. A step towards indicated prevention of schizophrenia. British Journal of Psychiatry 172, 1420.CrossRefGoogle ScholarPubMed
Yung, AR, Phillips, LJ, Yuen, HP, Francey, SM, McFarlane, CA, Hallgren, M, McGorry, PD (2003). Psychosis prediction: 12-month follow up of a high-risk (‘prodromal’) group. Schizophrenia Research 60, 2132.CrossRefGoogle ScholarPubMed
Yung, AR, Yuen, HP, Berger, GE, Francey, S, Hung, T-C, McGorry, P (2007). Declining transition rate in ultra high risk (prodromal) services: dilution or reduction of risk? Schizophrenia Bulletin 33, 673681.CrossRefGoogle ScholarPubMed