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Changes of Functional and Effective Connectivity in Smoking Replenishment on Deprived Heavy Smokers: A Resting-State fMRI Study

Identifieur interne : 002261 ( Pmc/Curation ); précédent : 002260; suivant : 002262

Changes of Functional and Effective Connectivity in Smoking Replenishment on Deprived Heavy Smokers: A Resting-State fMRI Study

Auteurs : Xiaoyu Ding [Corée du Sud] ; Seong-Whan Lee [Corée du Sud]

Source :

RBID : PMC:3602016

Abstract

Previous researches have explored the changes of functional connectivity caused by smoking with the aid of fMRI. This study considers not only functional connectivity but also effective connectivity regarding both brain networks and brain regions by using a novel analysis framework that combines independent component analysis (ICA) and Granger causality analysis (GCA). We conducted a resting-state fMRI experiment in which twenty-one heavy smokers were scanned in two sessions of different conditions: smoking abstinence followed by smoking satiety. In our framework, group ICA was firstly adopted to obtain the spatial patterns of the default-mode network (DMN), executive-control network (ECN), and salience network (SN). Their associated time courses were analyzed using GCA, showing that the effective connectivity from SN to DMN was reduced and that from ECN/DMN to SN was enhanced after smoking replenishment. A paired t-test on ICA spatial patterns revealed functional connectivity variation in regions such as the insula, parahippocampus, precuneus, anterior cingulate cortex, supplementary motor area, and ventromedial/dorsolateral prefrontal cortex. These regions were later selected as the regions of interest (ROIs), and their effective connectivity was investigated subsequently using GCA. In smoking abstinence, the insula showed the increased effective connectivity with the other ROIs; while in smoking satiety, the parahippocampus had the enhanced inter-area effective connectivity. These results demonstrate our hypothesis that for deprived heavy smokers, smoking replenishment takes effect on both functional and effective connectivity. Moreover, our analysis framework could be applied in a range of neuroscience studies.


Url:
DOI: 10.1371/journal.pone.0059331
PubMed: 23527165
PubMed Central: 3602016

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PMC:3602016

Le document en format XML

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<p>Previous researches have explored the changes of functional connectivity caused by smoking with the aid of fMRI. This study considers not only functional connectivity but also effective connectivity regarding both brain networks and brain regions by using a novel analysis framework that combines independent component analysis (ICA) and Granger causality analysis (GCA). We conducted a resting-state fMRI experiment in which twenty-one heavy smokers were scanned in two sessions of different conditions: smoking abstinence followed by smoking satiety. In our framework, group ICA was firstly adopted to obtain the spatial patterns of the default-mode network (DMN), executive-control network (ECN), and salience network (SN). Their associated time courses were analyzed using GCA, showing that the effective connectivity from SN to DMN was reduced and that from ECN/DMN to SN was enhanced after smoking replenishment. A paired
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<div1 type="bibliography">
<listBibl>
<biblStruct>
<analytic>
<author>
<name sortKey="Upadhyay, J" uniqKey="Upadhyay J">J Upadhyay</name>
</author>
<author>
<name sortKey="Maleki, N" uniqKey="Maleki N">N Maleki</name>
</author>
<author>
<name sortKey="Potter, J" uniqKey="Potter J">J Potter</name>
</author>
<author>
<name sortKey="Elman, I" uniqKey="Elman I">I Elman</name>
</author>
<author>
<name sortKey="Rudrauf, D" uniqKey="Rudrauf D">D Rudrauf</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Kelly, C" uniqKey="Kelly C">C Kelly</name>
</author>
<author>
<name sortKey="Zuo, Xn" uniqKey="Zuo X">XN Zuo</name>
</author>
<author>
<name sortKey="Gotimer, K" uniqKey="Gotimer K">K Gotimer</name>
</author>
<author>
<name sortKey="Cox, Cl" uniqKey="Cox C">CL Cox</name>
</author>
<author>
<name sortKey="Lynch, L" uniqKey="Lynch L">L Lynch</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Tomasi, D" uniqKey="Tomasi D">D Tomasi</name>
</author>
<author>
<name sortKey="Volkow, Nd" uniqKey="Volkow N">ND Volkow</name>
</author>
<author>
<name sortKey="Wang, R" uniqKey="Wang R">R Wang</name>
</author>
<author>
<name sortKey="Carrillo, Jh" uniqKey="Carrillo J">JH Carrillo</name>
</author>
<author>
<name sortKey="Maloney, T" uniqKey="Maloney T">T Maloney</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Ma, N" uniqKey="Ma N">N Ma</name>
</author>
<author>
<name sortKey="Liu, Y" uniqKey="Liu Y">Y Liu</name>
</author>
<author>
<name sortKey="Fu, Xm" uniqKey="Fu X">XM Fu</name>
</author>
<author>
<name sortKey="Li, N" uniqKey="Li N">N Li</name>
</author>
<author>
<name sortKey="Wang, Cx" uniqKey="Wang C">CX Wang</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Yuan, K" uniqKey="Yuan K">K Yuan</name>
</author>
<author>
<name sortKey="Qin, W" uniqKey="Qin W">W Qin</name>
</author>
<author>
<name sortKey="Dong, M" uniqKey="Dong M">M Dong</name>
</author>
<author>
<name sortKey="Liu, J" uniqKey="Liu J">J Liu</name>
</author>
<author>
<name sortKey="Sun, J" uniqKey="Sun J">J Sun</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Diekhof, Ek" uniqKey="Diekhof E">EK Diekhof</name>
</author>
<author>
<name sortKey="Falkai, P" uniqKey="Falkai P">P Falkai</name>
</author>
<author>
<name sortKey="Gruber, O" uniqKey="Gruber O">O Gruber</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Sutherland, Mt" uniqKey="Sutherland M">MT Sutherland</name>
</author>
<author>
<name sortKey="Mchugh, Mj" uniqKey="Mchugh M">MJ McHugh</name>
</author>
<author>
<name sortKey="Pariyadath, V" uniqKey="Pariyadath V">V Pariyadath</name>
</author>
<author>
<name sortKey="Stein, Ea" uniqKey="Stein E">EA Stein</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="David, Sp" uniqKey="David S">SP David</name>
</author>
<author>
<name sortKey="Munaf, Mr" uniqKey="Munaf M">MR Munafò</name>
</author>
<author>
<name sortKey="Johansen Berg, H" uniqKey="Johansen Berg H">H Johansen-Berg</name>
</author>
<author>
<name sortKey="Smith, Sm" uniqKey="Smith S">SM Smith</name>
</author>
<author>
<name sortKey="Rogers, Rd" uniqKey="Rogers R">RD Rogers</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Janes, Ac" uniqKey="Janes A">AC Janes</name>
</author>
<author>
<name sortKey="Pizzagalli, Da" uniqKey="Pizzagalli D">DA Pizzagalli</name>
</author>
<author>
<name sortKey="Richardt, S" uniqKey="Richardt S">S Richardt</name>
</author>
<author>
<name sortKey="Frederick Bde, B" uniqKey="Frederick Bde B">B Frederick Bde</name>
</author>
<author>
<name sortKey="Holmes, Aj" uniqKey="Holmes A">AJ Holmes</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Dagher, A" uniqKey="Dagher A">A Dagher</name>
</author>
<author>
<name sortKey="Tannenbaum, B" uniqKey="Tannenbaum B">B Tannenbaum</name>
</author>
<author>
<name sortKey="Hayashi, T" uniqKey="Hayashi T">T Hayashi</name>
</author>
<author>
<name sortKey="Pruessner, Jc" uniqKey="Pruessner J">JC Pruessner</name>
</author>
<author>
<name sortKey="Mcbride, D" uniqKey="Mcbride D">D McBride</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Hong, Le" uniqKey="Hong L">LE Hong</name>
</author>
<author>
<name sortKey="Gu, H" uniqKey="Gu H">H Gu</name>
</author>
<author>
<name sortKey="Yang, Y" uniqKey="Yang Y">Y Yang</name>
</author>
<author>
<name sortKey="Ross, Tj" uniqKey="Ross T">TJ Ross</name>
</author>
<author>
<name sortKey="Salmeron, Bj" uniqKey="Salmeron B">BJ Salmeron</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Wang, Z" uniqKey="Wang Z">Z Wang</name>
</author>
<author>
<name sortKey="Faith, M" uniqKey="Faith M">M Faith</name>
</author>
<author>
<name sortKey="Patterson, F" uniqKey="Patterson F">F Patterson</name>
</author>
<author>
<name sortKey="Tang, K" uniqKey="Tang K">K Tang</name>
</author>
<author>
<name sortKey="Kerrin, K" uniqKey="Kerrin K">K Kerrin</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Janes, Ac" uniqKey="Janes A">AC Janes</name>
</author>
<author>
<name sortKey="Nickerson, Ld" uniqKey="Nickerson L">LD Nickerson</name>
</author>
<author>
<name sortKey="Frederick, Bd" uniqKey="Frederick B">BD Frederick</name>
</author>
<author>
<name sortKey="Kaufman, Mj" uniqKey="Kaufman M">MJ Kaufman</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Tanabe, J" uniqKey="Tanabe J">J Tanabe</name>
</author>
<author>
<name sortKey="Nyberg, E" uniqKey="Nyberg E">E Nyberg</name>
</author>
<author>
<name sortKey="Martin, Lf" uniqKey="Martin L">LF Martin</name>
</author>
<author>
<name sortKey="Martin, J" uniqKey="Martin J">J Martin</name>
</author>
<author>
<name sortKey="Cordes, D" uniqKey="Cordes D">D Cordes</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Cole, Dm" uniqKey="Cole D">DM Cole</name>
</author>
<author>
<name sortKey="Beckmann, Cf" uniqKey="Beckmann C">CF Beckmann</name>
</author>
<author>
<name sortKey="Long, Cj" uniqKey="Long C">CJ Long</name>
</author>
<author>
<name sortKey="Matthews, Pm" uniqKey="Matthews P">PM Matthews</name>
</author>
<author>
<name sortKey="Durcan, Mj" uniqKey="Durcan M">MJ Durcan</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Hahn, B" uniqKey="Hahn B">B Hahn</name>
</author>
<author>
<name sortKey="Ross, Tj" uniqKey="Ross T">TJ Ross</name>
</author>
<author>
<name sortKey="Yang, Y" uniqKey="Yang Y">Y Yang</name>
</author>
<author>
<name sortKey="Kim, I" uniqKey="Kim I">I Kim</name>
</author>
<author>
<name sortKey="Huestis, Ma" uniqKey="Huestis M">MA Huestis</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Ettinger, U" uniqKey="Ettinger U">U Ettinger</name>
</author>
<author>
<name sortKey="Williams, Sc" uniqKey="Williams S">SC Williams</name>
</author>
<author>
<name sortKey="Patel, D" uniqKey="Patel D">D Patel</name>
</author>
<author>
<name sortKey="Michel, Tm" uniqKey="Michel T">TM Michel</name>
</author>
<author>
<name sortKey="Nwaigwe, A" uniqKey="Nwaigwe A">A Nwaigwe</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Kim, Dy" uniqKey="Kim D">DY Kim</name>
</author>
<author>
<name sortKey="Lee, Jh" uniqKey="Lee J">JH Lee</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Seeley, Ww" uniqKey="Seeley W">WW Seeley</name>
</author>
<author>
<name sortKey="Menon, V" uniqKey="Menon V">V Menon</name>
</author>
<author>
<name sortKey="Schatzberg, Af" uniqKey="Schatzberg A">AF Schatzberg</name>
</author>
<author>
<name sortKey="Keller, J" uniqKey="Keller J">J Keller</name>
</author>
<author>
<name sortKey="Glover, Gh" uniqKey="Glover G">GH Glover</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Friston, Kj" uniqKey="Friston K">KJ Friston</name>
</author>
<author>
<name sortKey="Buechel, C" uniqKey="Buechel C">C Buechel</name>
</author>
<author>
<name sortKey="Fink, Gr" uniqKey="Fink G">GR Fink</name>
</author>
<author>
<name sortKey="Morris, J" uniqKey="Morris J">J Morris</name>
</author>
<author>
<name sortKey="Rolls, E" uniqKey="Rolls E">E Rolls</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Biswal, B" uniqKey="Biswal B">B Biswal</name>
</author>
<author>
<name sortKey="Yetkin, Fz" uniqKey="Yetkin F">FZ Yetkin</name>
</author>
<author>
<name sortKey="Haughton, Vm" uniqKey="Haughton V">VM Haughton</name>
</author>
<author>
<name sortKey="Hyde, Js" uniqKey="Hyde J">JS Hyde</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Mckeown, Mj" uniqKey="Mckeown M">MJ McKeown</name>
</author>
<author>
<name sortKey="Makeig, S" uniqKey="Makeig S">S Makeig</name>
</author>
<author>
<name sortKey="Brown, Gg" uniqKey="Brown G">GG Brown</name>
</author>
<author>
<name sortKey="Jung, Tp" uniqKey="Jung T">TP Jung</name>
</author>
<author>
<name sortKey="Kindermann, Ss" uniqKey="Kindermann S">SS Kindermann</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Beckmann, Cf" uniqKey="Beckmann C">CF Beckmann</name>
</author>
<author>
<name sortKey="Deluca, M" uniqKey="Deluca M">M DeLuca</name>
</author>
<author>
<name sortKey="Devlin, Jt" uniqKey="Devlin J">JT Devlin</name>
</author>
<author>
<name sortKey="Smith, Sm" uniqKey="Smith S">SM Smith</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Esposito, F" uniqKey="Esposito F">F Esposito</name>
</author>
<author>
<name sortKey="Aragri, A" uniqKey="Aragri A">A Aragri</name>
</author>
<author>
<name sortKey="Pesaresi, I" uniqKey="Pesaresi I">I Pesaresi</name>
</author>
<author>
<name sortKey="Cirillo, S" uniqKey="Cirillo S">S Cirillo</name>
</author>
<author>
<name sortKey="Tedeschi, G" uniqKey="Tedeschi G">G Tedeschi</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Goebel, R" uniqKey="Goebel R">R Goebel</name>
</author>
<author>
<name sortKey="Roebroeck, A" uniqKey="Roebroeck A">A Roebroeck</name>
</author>
<author>
<name sortKey="Kim, Ds" uniqKey="Kim D">DS Kim</name>
</author>
<author>
<name sortKey="Formisano, E" uniqKey="Formisano E">E Formisano</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Demirci, O" uniqKey="Demirci O">O Demirci</name>
</author>
<author>
<name sortKey="Stevens, Mc" uniqKey="Stevens M">MC Stevens</name>
</author>
<author>
<name sortKey="Andreasen, Nc" uniqKey="Andreasen N">NC Andreasen</name>
</author>
<author>
<name sortKey="Michael, A" uniqKey="Michael A">A Michael</name>
</author>
<author>
<name sortKey="Liu, J" uniqKey="Liu J">J Liu</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Stevens, Mc" uniqKey="Stevens M">MC Stevens</name>
</author>
<author>
<name sortKey="Pearlson, Gd" uniqKey="Pearlson G">GD Pearlson</name>
</author>
<author>
<name sortKey="Calhoun, Vd" uniqKey="Calhoun V">VD Calhoun</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Sridharan, D" uniqKey="Sridharan D">D Sridharan</name>
</author>
<author>
<name sortKey="Levitin, Dj" uniqKey="Levitin D">DJ Levitin</name>
</author>
<author>
<name sortKey="Menon, V" uniqKey="Menon V">V Menon</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Jiao, Q" uniqKey="Jiao Q">Q Jiao</name>
</author>
<author>
<name sortKey="Lu, G" uniqKey="Lu G">G Lu</name>
</author>
<author>
<name sortKey="Zhang, Z" uniqKey="Zhang Z">Z Zhang</name>
</author>
<author>
<name sortKey="Zhong, Y" uniqKey="Zhong Y">Y Zhong</name>
</author>
<author>
<name sortKey="Wang, Z" uniqKey="Wang Z">Z Wang</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Heatherton, Tf" uniqKey="Heatherton T">TF Heatherton</name>
</author>
<author>
<name sortKey="Kozlowski, Lt" uniqKey="Kozlowski L">LT Kozlowski</name>
</author>
<author>
<name sortKey="Frecker, Rc" uniqKey="Frecker R">RC Frecker</name>
</author>
<author>
<name sortKey="Fagerstrom, Ko" uniqKey="Fagerstrom K">KO Fagerström</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Calhoun, Vd" uniqKey="Calhoun V">VD Calhoun</name>
</author>
<author>
<name sortKey="Adali, T" uniqKey="Adali T">T Adali</name>
</author>
<author>
<name sortKey="Pearlson, Gd" uniqKey="Pearlson G">GD Pearlson</name>
</author>
<author>
<name sortKey="Pekar, Jj" uniqKey="Pekar J">JJ Pekar</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Bell, Aj" uniqKey="Bell A">AJ Bell</name>
</author>
<author>
<name sortKey="Sejnowski, Tj" uniqKey="Sejnowski T">TJ Sejnowski</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Li, Yo" uniqKey="Li Y">YO Li</name>
</author>
<author>
<name sortKey="Adali, T" uniqKey="Adali T">T Adali</name>
</author>
<author>
<name sortKey="Calhoun, Vd" uniqKey="Calhoun V">VD Calhoun</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Himberg, J" uniqKey="Himberg J">J Himberg</name>
</author>
<author>
<name sortKey="Hyv Rinen, A" uniqKey="Hyv Rinen A">A Hyvärinen</name>
</author>
<author>
<name sortKey="Esposito, F" uniqKey="Esposito F">F Esposito</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Seth, Ak" uniqKey="Seth A">AK Seth</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Schwarz, G" uniqKey="Schwarz G">G Schwarz</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Seth, Ak" uniqKey="Seth A">AK Seth</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Smith, Sm" uniqKey="Smith S">SM Smith</name>
</author>
<author>
<name sortKey="Miller, Kl" uniqKey="Miller K">KL Miller</name>
</author>
<author>
<name sortKey="Salimi Khorshidi, G" uniqKey="Salimi Khorshidi G">G Salimi-Khorshidi</name>
</author>
<author>
<name sortKey="Webster, M" uniqKey="Webster M">M Webster</name>
</author>
<author>
<name sortKey="Beckmann, Cf" uniqKey="Beckmann C">CF Beckmann</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Deshpande, G" uniqKey="Deshpande G">G Deshpande</name>
</author>
<author>
<name sortKey="Hu, X" uniqKey="Hu X">X Hu</name>
</author>
<author>
<name sortKey="Stilla, R" uniqKey="Stilla R">R Stilla</name>
</author>
<author>
<name sortKey="Sathian, K" uniqKey="Sathian K">K Sathian</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Naqvi, Nh" uniqKey="Naqvi N">NH Naqvi</name>
</author>
<author>
<name sortKey="Bechara, A" uniqKey="Bechara A">A Bechara</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Hong, Le" uniqKey="Hong L">LE Hong</name>
</author>
<author>
<name sortKey="Hodgkinson, Ca" uniqKey="Hodgkinson C">CA Hodgkinson</name>
</author>
<author>
<name sortKey="Yang, Y" uniqKey="Yang Y">Y Yang</name>
</author>
<author>
<name sortKey="Sampath, H" uniqKey="Sampath H">H Sampath</name>
</author>
<author>
<name sortKey="Ross, Tj" uniqKey="Ross T">TJ Ross</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Bierut, Lj" uniqKey="Bierut L">LJ Bierut</name>
</author>
<author>
<name sortKey="Stitzel, Ja" uniqKey="Stitzel J">JA Stitzel</name>
</author>
<author>
<name sortKey="Wang, Jc" uniqKey="Wang J">JC Wang</name>
</author>
<author>
<name sortKey="Hinrichs, Al" uniqKey="Hinrichs A">AL Hinrichs</name>
</author>
<author>
<name sortKey="Grucza, Ra" uniqKey="Grucza R">RA Grucza</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Hasselmo, Me" uniqKey="Hasselmo M">ME Hasselmo</name>
</author>
<author>
<name sortKey="Mcgaughy, J" uniqKey="Mcgaughy J">J McGaughy</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Bishop, S" uniqKey="Bishop S">S Bishop</name>
</author>
<author>
<name sortKey="Duncan, J" uniqKey="Duncan J">J Duncan</name>
</author>
<author>
<name sortKey="Brett, M" uniqKey="Brett M">M Brett</name>
</author>
<author>
<name sortKey="Lawrence, Ad" uniqKey="Lawrence A">AD Lawrence</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Omvik, P" uniqKey="Omvik P">P Omvik</name>
</author>
</analytic>
</biblStruct>
</listBibl>
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</TEI>
<pmc article-type="research-article">
<pmc-dir>properties open_access</pmc-dir>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">PLoS One</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plosone</journal-id>
<journal-title-group>
<journal-title>PLoS ONE</journal-title>
</journal-title-group>
<issn pub-type="epub">1932-6203</issn>
<publisher>
<publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">23527165</article-id>
<article-id pub-id-type="pmc">3602016</article-id>
<article-id pub-id-type="publisher-id">PONE-D-12-33424</article-id>
<article-id pub-id-type="doi">10.1371/journal.pone.0059331</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v2">
<subject>Biology</subject>
<subj-group>
<subject>Neuroscience</subject>
<subj-group>
<subject>Neuroimaging</subject>
<subj-group>
<subject>Fmri</subject>
</subj-group>
</subj-group>
<subj-group>
<subject>Neural Networks</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v2">
<subject>Computer Science</subject>
<subj-group>
<subject>Algorithms</subject>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v2">
<subject>Medicine</subject>
<subj-group>
<subject>Anatomy and Physiology</subject>
<subj-group>
<subject>Neurological System</subject>
</subj-group>
</subj-group>
<subj-group>
<subject>Mental Health</subject>
<subj-group>
<subject>Psychology</subject>
<subj-group>
<subject>Behavior</subject>
<subj-group>
<subject>Habits</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group>
<subject>Pulmonology</subject>
<subj-group>
<subject>Smoking Related Disorders</subject>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Changes of Functional and Effective Connectivity in Smoking Replenishment on Deprived Heavy Smokers: A Resting-State fMRI Study</article-title>
<alt-title alt-title-type="running-head">Changes of Connectivity in Smoking Replenishment</alt-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Ding</surname>
<given-names>Xiaoyu</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Lee</surname>
<given-names>Seong-Whan</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="corresp" rid="cor1">
<sup>*</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1">
<label>1</label>
<addr-line>Department of Computer Science and Engineering, Korea University, Anam-dong, Seongbuk-ku, Seoul, Republic of Korea</addr-line>
</aff>
<aff id="aff2">
<label>2</label>
<addr-line>Department of Brain and Cognitive Engineering, Korea University, Anam-dong, Seongbuk-ku, Seoul, Republic of Korea</addr-line>
</aff>
<contrib-group>
<contrib contrib-type="editor">
<name>
<surname>Vanni</surname>
<given-names>Simo</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1">
<addr-line>Aalto University, School of Science, Finland</addr-line>
</aff>
<author-notes>
<corresp id="cor1">* E-mail:
<email>swlee@image.korea.ac.kr (SWL)</email>
</corresp>
<fn fn-type="conflict">
<p>
<bold>Competing Interests: </bold>
The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con">
<p>Conceived and designed the experiments: XD SWL. Performed the experiments: XD. Analyzed the data: XD. Contributed reagents/materials/analysis tools: SWL. Wrote the paper: XD SWL.</p>
</fn>
</author-notes>
<pub-date pub-type="collection">
<year>2013</year>
</pub-date>
<pub-date pub-type="epub">
<day>19</day>
<month>3</month>
<year>2013</year>
</pub-date>
<volume>8</volume>
<issue>3</issue>
<elocation-id>e59331</elocation-id>
<history>
<date date-type="received">
<day>29</day>
<month>10</month>
<year>2012</year>
</date>
<date date-type="accepted">
<day>13</day>
<month>2</month>
<year>2013</year>
</date>
</history>
<permissions>
<copyright-year>2013</copyright-year>
<copyright-holder>Ding, Lee</copyright-holder>
<license>
<license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p>
</license>
</permissions>
<abstract>
<p>Previous researches have explored the changes of functional connectivity caused by smoking with the aid of fMRI. This study considers not only functional connectivity but also effective connectivity regarding both brain networks and brain regions by using a novel analysis framework that combines independent component analysis (ICA) and Granger causality analysis (GCA). We conducted a resting-state fMRI experiment in which twenty-one heavy smokers were scanned in two sessions of different conditions: smoking abstinence followed by smoking satiety. In our framework, group ICA was firstly adopted to obtain the spatial patterns of the default-mode network (DMN), executive-control network (ECN), and salience network (SN). Their associated time courses were analyzed using GCA, showing that the effective connectivity from SN to DMN was reduced and that from ECN/DMN to SN was enhanced after smoking replenishment. A paired
<italic>t</italic>
-test on ICA spatial patterns revealed functional connectivity variation in regions such as the insula, parahippocampus, precuneus, anterior cingulate cortex, supplementary motor area, and ventromedial/dorsolateral prefrontal cortex. These regions were later selected as the regions of interest (ROIs), and their effective connectivity was investigated subsequently using GCA. In smoking abstinence, the insula showed the increased effective connectivity with the other ROIs; while in smoking satiety, the parahippocampus had the enhanced inter-area effective connectivity. These results demonstrate our hypothesis that for deprived heavy smokers, smoking replenishment takes effect on both functional and effective connectivity. Moreover, our analysis framework could be applied in a range of neuroscience studies.</p>
</abstract>
<funding-group>
<funding-statement>This work was supported in part by the World Class University (WCU) Program through the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology, under grant R31-10008; and in part by the Korea Science and Engineering Foundation (KOSEF) Grant funded by the Ministry of Education, Science, and Technology, under grant 2012-005741. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts>
<page-count count="12"></page-count>
</counts>
</article-meta>
</front>
<body>
<sec id="s1">
<title>Introduction</title>
<p>Drug addiction is a complex brain disorder characterized by the compulsive consumption of a deleterious drug, the fundamental mechanisms of which are now studied in the neuroscience field. With the aid of fMRI, researchers have explored the underlying impact on brain functions caused by multiple addiction drugs including opium
<xref ref-type="bibr" rid="pone.0059331-Upadhyay1">[1]</xref>
, cocaine
<xref ref-type="bibr" rid="pone.0059331-Kelly1">[2]</xref>
<xref ref-type="bibr" rid="pone.0059331-Tomasi1">[3]</xref>
, heroin
<xref ref-type="bibr" rid="pone.0059331-Ma1">[4]</xref>
<xref ref-type="bibr" rid="pone.0059331-Yuan1">[5]</xref>
and more. Among these, smoking addiction is also commonly researched due to the wide range of tobacco users and the public sale of cigarettes. fMRI experiments within the study of drug addiction can be typically categorized into two types according to their experimental design: task-related experiments
<xref ref-type="bibr" rid="pone.0059331-Diekhof1">[6]</xref>
, and the so-called “resting-state” experiments
<xref ref-type="bibr" rid="pone.0059331-Sutherland1">[7]</xref>
.</p>
<p>In a task-related experiment, fMRI data are acquired while participants are performing a certain task. A widely used task in smoking research is the visual cue-exposure task, in which smoking-related visual cues and neutral cues are presented to participants during scanning
<xref ref-type="bibr" rid="pone.0059331-David1">[8]</xref>
<xref ref-type="bibr" rid="pone.0059331-Dagher1">[10]</xref>
. Although this type of study is essential for delineating the acute effects of smoking on circumscribed brain areas, the existence of intrinsic and spontaneous hemodynamic activity in resting-state may reveal the inherent mechanisms of smoking on brain functions more efficaciously. Compared to the task-related design, the resting-state experiment design has a prominent advantage in that the data collection is relatively quick and straight-forward. The participants lie passively without any cognitive or behavioral tasks during scanning. Moreover, identified resting-state neural mechanism features are less likely to be confounded by subtle differences in specific task designs. For these reasons, a resting-state experiment design has been widely adopted in smoking studies
<xref ref-type="bibr" rid="pone.0059331-Hong1">[11]</xref>
<xref ref-type="bibr" rid="pone.0059331-Janes2">[13]</xref>
.</p>
<p>Two types of dissociable large-scale brain networks have been explored in terms of the effect caused by smoking in both task-related and resting-state conditions
<xref ref-type="bibr" rid="pone.0059331-Tanabe1">[14]</xref>
<xref ref-type="bibr" rid="pone.0059331-Ettinger1">[17]</xref>
. One is the “default-mode network” (DMN), which is a “task-negative” network (TNN) that shows activity increases during resting-state condition. This contains two parts: the anterior DMN (aDMN), e.g., within the medial/superior frontal areas and anterior cingulate cortex (ACC), and the posterior DMN (pDMN), e.g., within the posterior cingulate cortex (PCC) along with the precuneus and inferior parietal lobe
<xref ref-type="bibr" rid="pone.0059331-Kim1">[18]</xref>
. The other type is termed the “task-positive” network (TPN), which exhibits increased activity in performing tasks. In the absence of explicit task demands, two distinct TPNs appear to exist: one is the “salience network” (SN) within the anterior insula and ACC, the other is the “executive control network” (ECN) which comprises the lateral prefrontal and parietal regions
<xref ref-type="bibr" rid="pone.0059331-Seeley1">[19]</xref>
.</p>
<p>These brain networks appear in such a way that they contain some remote neuronal circuitries which show high temporal correlations across each other. In neuroscience studies, this kind of temporal correlation between spatially remote neurophysiological events is defined as functional connectivity
<xref ref-type="bibr" rid="pone.0059331-Friston1">[20]</xref>
. To examine functional connectivity using resting-state fMRI data, one solution is the “seed voxel” approach
<xref ref-type="bibr" rid="pone.0059331-Biswal1">[21]</xref>
: a voxel together with its surrounding small region of interest (ROI) is chosen as the seed, whose average time-series then serves as a reference for calculating the temporal correlation with the signal in each voxel. An inherent limitation of this method is that the obtained activity map depends highly on the selection of the seed voxel. In order to obviate the interference caused by the selection of seed voxel, independent component analysis (ICA)
<xref ref-type="bibr" rid="pone.0059331-McKeown1">[22]</xref>
, which is a blind source separation method under the assumption that the extracted components are statistically independent, has been introduced and widely applied to analyze functional connectivity in resting-state fMRI data
<xref ref-type="bibr" rid="pone.0059331-Beckmann1">[23]</xref>
<xref ref-type="bibr" rid="pone.0059331-Esposito1">[24]</xref>
. The ICA method results in spatially independent patterns together with their corresponding time courses.</p>
<p>Corresponding to functional connectivity, another ensemble called effective connectivity is defined as the causal influence from one neuronal system to another
<xref ref-type="bibr" rid="pone.0059331-Goebel1">[25]</xref>
. Granger causality analysis (GCA), which is equivalent to a correlation-based method
<xref ref-type="bibr" rid="pone.0059331-Davey1">[26]</xref>
, has been proposed for estimating the causal interactions of information flows. Previous fMRI studies used the GCA approach to explore the interactions among brain networks
<xref ref-type="bibr" rid="pone.0059331-Demirci1">[27]</xref>
<xref ref-type="bibr" rid="pone.0059331-Stevens1">[28]</xref>
or brain regions
<xref ref-type="bibr" rid="pone.0059331-Sridharan1">[29]</xref>
<xref ref-type="bibr" rid="pone.0059331-Jiao1">[30]</xref>
identified by ICA during task-related or resting-state fMRI experiments.</p>
<p>To the best of our knowledge, no previous study has explored the effect of smoking on effective connectivity. This study therefore aims to investigate the influence of smoking on both functional and effective connectivity, and it is exploratory in nature. We hypothesized that the effect of smoking replenishment on deprived heavy smokers would influence both functional and effective connectivity. Considering effective connectivity, we further hypothesized that the causal interactions among TNNs (i.e., aDMN and pDMN) and TPNs (i.e., ECN and SN), as well as those among the crucial brain regions as revealed by functional connectivity analysis, would be changed significantly. For this purpose, we conducted a resting-state fMRI experiment with conditions of smoking abstinence followed by conditions of smoking satiety on heavy smokers. We propose an analysis framework combining ICA and GCA so as to give attention to both functional connectivity and effective connectivity, including brain networks and crucial brain regions. In our framework, we first investigate the functional connectivity of TNNs and TPNs using group ICA followed by a paired
<italic>t</italic>
-test on the ICA resulted spatial patterns. The corresponding time courses are used as inputs to GCA to reveal the causal interactions among brain networks. Several ROIs are selected based on the previous paired
<italic>t</italic>
-test results, and their causal relationships are also explored using GCA.</p>
<p>The rest of this paper is organized as follows: in the following section we describe the resting-state fMRI experiment and our analysis framework in detail. We then present the experimental results together with related analysis. We later discuss several interesting aspects of our findings and form a conclusion.</p>
</sec>
<sec sec-type="materials|methods" id="s2">
<title>Materials and Methods</title>
<sec id="s2a">
<title>Ethics Statement</title>
<p>This study was approved by the Institutional Review Board of Korea University. All participants provided written informed consent and received monetary compensation for their participation.</p>
</sec>
<sec id="s2b">
<title>Participants</title>
<p>Twenty-one right-handed male smokers (mean age = 25.86 years ±2.10, range = 22∼30 years) were enrolled as participants in this study. All participants were heavy smokers (>5 years, >15 cigarettes/day). They were firstly interviewed to verify they had no history of neurological or psychiatric illness, and were also examined to confirm no recent alcohol consumption or other recreational drug use. All participants completed the Fagerström Test for Nicotine Dependence (FTND)
<xref ref-type="bibr" rid="pone.0059331-Heatherton1">[31]</xref>
during initial screening (mean score = 6.19±0.93, range = 5∼8). Each participant was deemed free of structural abnormalities following review of anatomical MRI scans.</p>
</sec>
<sec id="s2c">
<title>Procedure</title>
<p>All participants were scanned for two resting-state sessions
<xref ref-type="bibr" rid="pone.0059331-Ding1">[32]</xref>
. In the first session, the participants had abstained from smoking for more than twelve hours, and the levels of exhaled carbon monoxide (CO) were measured using Bedfont smokerlyzer piCO
<sup>+</sup>
(mean = 9.62 ppm ±3.53, range = 4∼15). They took the resting-state scanning with eyes closed. After the first session, they were allowed to smoke until they felt satisfied. The levels of exhaled CO were measured again (mean = 22.86 ppm ±8.05, range = 11∼42), which showed a distinct increase for each participant compared to that measured in the first session (see
<xref ref-type="table" rid="pone-0059331-t001">Table 1</xref>
). They then took the second session resting-state scanning still with their eyes closed. In the remaining part of this paper, the first and second session will be denoted as “RS_abs” and “RS_sat” respectively.</p>
<table-wrap id="pone-0059331-t001" orientation="portrait" position="float">
<object-id pub-id-type="doi">10.1371/journal.pone.0059331.t001</object-id>
<label>Table 1</label>
<caption>
<title>The FTND score, as well as the CO-levels tested in RS_abs and RS_sat for each subject.</title>
</caption>
<alternatives>
<graphic id="pone-0059331-t001-1" xlink:href="pone.0059331.t001"></graphic>
<table frame="hsides" rules="groups">
<colgroup span="1">
<col align="left" span="1"></col>
<col align="center" span="1"></col>
<col align="center" span="1"></col>
<col align="center" span="1"></col>
</colgroup>
<thead>
<tr>
<td align="left" rowspan="1" colspan="1">Subject ID</td>
<td align="left" rowspan="1" colspan="1">FTND</td>
<td align="left" rowspan="1" colspan="1">CO (RS_abs)</td>
<td align="left" rowspan="1" colspan="1">CO (RS_sat)</td>
</tr>
</thead>
<tbody>
<tr>
<td align="left" rowspan="1" colspan="1">001</td>
<td align="left" rowspan="1" colspan="1">5</td>
<td align="left" rowspan="1" colspan="1">14</td>
<td align="left" rowspan="1" colspan="1">28</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">002</td>
<td align="left" rowspan="1" colspan="1">6</td>
<td align="left" rowspan="1" colspan="1">15</td>
<td align="left" rowspan="1" colspan="1">42</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">003</td>
<td align="left" rowspan="1" colspan="1">8</td>
<td align="left" rowspan="1" colspan="1">11</td>
<td align="left" rowspan="1" colspan="1">24</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">004</td>
<td align="left" rowspan="1" colspan="1">6</td>
<td align="left" rowspan="1" colspan="1">13</td>
<td align="left" rowspan="1" colspan="1">26</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">005</td>
<td align="left" rowspan="1" colspan="1">6</td>
<td align="left" rowspan="1" colspan="1">12</td>
<td align="left" rowspan="1" colspan="1">25</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">006</td>
<td align="left" rowspan="1" colspan="1">6</td>
<td align="left" rowspan="1" colspan="1">11</td>
<td align="left" rowspan="1" colspan="1">26</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">007</td>
<td align="left" rowspan="1" colspan="1">6</td>
<td align="left" rowspan="1" colspan="1">7</td>
<td align="left" rowspan="1" colspan="1">21</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">008</td>
<td align="left" rowspan="1" colspan="1">5</td>
<td align="left" rowspan="1" colspan="1">8</td>
<td align="left" rowspan="1" colspan="1">17</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">009</td>
<td align="left" rowspan="1" colspan="1">7</td>
<td align="left" rowspan="1" colspan="1">8</td>
<td align="left" rowspan="1" colspan="1">21</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">010</td>
<td align="left" rowspan="1" colspan="1">6</td>
<td align="left" rowspan="1" colspan="1">6</td>
<td align="left" rowspan="1" colspan="1">15</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">011</td>
<td align="left" rowspan="1" colspan="1">6</td>
<td align="left" rowspan="1" colspan="1">11</td>
<td align="left" rowspan="1" colspan="1">21</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">012</td>
<td align="left" rowspan="1" colspan="1">8</td>
<td align="left" rowspan="1" colspan="1">15</td>
<td align="left" rowspan="1" colspan="1">42</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">013</td>
<td align="left" rowspan="1" colspan="1">8</td>
<td align="left" rowspan="1" colspan="1">5</td>
<td align="left" rowspan="1" colspan="1">26</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">014</td>
<td align="left" rowspan="1" colspan="1">6</td>
<td align="left" rowspan="1" colspan="1">4</td>
<td align="left" rowspan="1" colspan="1">11</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">015</td>
<td align="left" rowspan="1" colspan="1">6</td>
<td align="left" rowspan="1" colspan="1">13</td>
<td align="left" rowspan="1" colspan="1">23</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">016</td>
<td align="left" rowspan="1" colspan="1">7</td>
<td align="left" rowspan="1" colspan="1">12</td>
<td align="left" rowspan="1" colspan="1">26</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">017</td>
<td align="left" rowspan="1" colspan="1">6</td>
<td align="left" rowspan="1" colspan="1">7</td>
<td align="left" rowspan="1" colspan="1">19</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">018</td>
<td align="left" rowspan="1" colspan="1">6</td>
<td align="left" rowspan="1" colspan="1">6</td>
<td align="left" rowspan="1" colspan="1">13</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">019</td>
<td align="left" rowspan="1" colspan="1">5</td>
<td align="left" rowspan="1" colspan="1">5</td>
<td align="left" rowspan="1" colspan="1">13</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">020</td>
<td align="left" rowspan="1" colspan="1">5</td>
<td align="left" rowspan="1" colspan="1">7</td>
<td align="left" rowspan="1" colspan="1">17</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">021</td>
<td align="left" rowspan="1" colspan="1">6</td>
<td align="left" rowspan="1" colspan="1">12</td>
<td align="left" rowspan="1" colspan="1">24</td>
</tr>
</tbody>
</table>
</alternatives>
</table-wrap>
</sec>
<sec id="s2d">
<title>Data Acquisition and Preprocessing</title>
<p>Blood oxygenation level-dependent (BOLD) contrast, single-shot, T
<sub>2</sub>
<sup>*</sup>
-weighted, gradient-echo planar imaging (EPI) data were acquired in an interleaved multi-slice mode using a 3T clinical scanner (MAGNETOM Trio Tim, Siemens) with a 12-channel head coil. Each scan session contained 155 volumes of the whole brain in 36 axial slice acquisition (TR = 2000 ms, TE = 30 ms, flip angle = 90°, field of view = 240×240 mm
<sup>2</sup>
, voxel size = 3.8×3.8×4.0 mm
<sup>3</sup>
). The first 5 volumes were discarded from further analysis to allow for magnetic equilibration. Additional high-resolution T
<sub>1</sub>
-weighted anatomical MRI scans (MPRAGE) were acquired with a 32-channel head coil for each participant (TR = 1900 ms, TE = 2.32 ms, flip angle = 9°, field of view = 240×240 mm
<sup>2</sup>
, voxel size = 0.9×0.9×0.9 mm
<sup>3</sup>
, 192 slices).</p>
<p>Raw EPI data were preprocessed using the SPM5 toolbox (
<ext-link ext-link-type="uri" xlink:href="http://www.fil.ion.ucl.ac.uk/spm">http://www.fil.ion.ucl.ac.uk/spm</ext-link>
). Slice timing differences were corrected for each volume. The functional volumes were realigned to the first volume for head movement correction, and then normalized into standard MNI (Montreal Neurological Institute) space with 3×3×3 mm
<sup>3</sup>
voxels. After linear trends were removed, these data were band-pass filtered (0.01–0.08 Hz) to reduce the effect of low-frequency drift and high-frequency physiological noise
<xref ref-type="bibr" rid="pone.0059331-Jiao1">[30]</xref>
. Finally, they were smoothed with a 8×8×8 mm
<sup>3</sup>
full width at half-maximum (FWHM) Gaussian kernel.</p>
</sec>
<sec id="s2e">
<title>Overview of Analysis Framework</title>
<p>An overview of the proposed analysis framework is illustrated in
<xref ref-type="fig" rid="pone-0059331-g001">Fig. 1</xref>
. After preprocessing the raw EPI data, a group ICA method was applied on the temporally concatenated dataset of each participant in each session. Decomposed brain networks of TNNs (i.e., aDMN and pDMN) and TPNs (i.e., ECN and SN) were selected for further analysis. Their spatial patterns were examined using a paired t-test to investigate the changes of functional connectivity caused by smoking replenishment. The corresponding time courses were used as inputs to GCA to reveal the causal interactions among the selected brain networks. Several ROIs were selected based on the result of previous paired
<italic>t</italic>
-tests, and their BOLD time series were analyzed using GCA to explore the effect of smoking on causal interactions among critical brain regions. The following parts will describe this framework in detail part by part.</p>
<fig id="pone-0059331-g001" orientation="portrait" position="float">
<object-id pub-id-type="doi">10.1371/journal.pone.0059331.g001</object-id>
<label>Figure 1</label>
<caption>
<title>An overview of the proposed analysis framework.</title>
</caption>
<graphic xlink:href="pone.0059331.g001"></graphic>
</fig>
</sec>
<sec id="s2f">
<title>Independent Component Analysis (ICA)</title>
<p>We adopted a group ICA
<xref ref-type="bibr" rid="pone.0059331-Calhoun1">[33]</xref>
method to execute the ICA approach. Group ICA is commonly used for making group inferences from fMRI data of multiple subjects. In our study, this was carried out using the GIFT toolbox (
<ext-link ext-link-type="uri" xlink:href="http://icatb.sourceforge.net">http://icatb.sourceforge.net</ext-link>
) for not only estimating individual spatial patterns but also facilitating investigation of group differences under the same study condition. The individual datasets were temporally concatenated (datasets of RS_abs followed by datasets of RS_sat) and reduced for computational feasibility through three stages of principal component analysis to obtain a dimension reduced final dataset, which was then decomposed by ICA (Infomax algorithm
<xref ref-type="bibr" rid="pone.0059331-Bell1">[34]</xref>
) into twenty-three spatially independent components. Here, the number of components was estimated using the minimum description length criteria
<xref ref-type="bibr" rid="pone.0059331-Li1">[35]</xref>
, and also accordant with the common settings in previous ICA-GCA researches
<xref ref-type="bibr" rid="pone.0059331-Demirci1">[27]</xref>
<xref ref-type="bibr" rid="pone.0059331-Jiao1">[30]</xref>
. The Infomax algorithm was repeated twenty times with randomly initialized decomposition matrices and the same convergence threshold using ICASSO approach
<xref ref-type="bibr" rid="pone.0059331-Himberg1">[36]</xref>
in GIFT toolbox. After clustering the obtained components, centrotype-based components were selected and considered as the stable decomposition result. The individual spatial patterns and time courses were obtained through a back reconstruction process.</p>
</sec>
<sec id="s2g">
<title>Functional Connectivity Analysis</title>
<p>Brain networks of TNNs (i.e., aDMN and pDMN) and TPNs (i.e., ECN and SN) were visually selected from all subjects in both sessions. The individual spatial maps were normalized into
<italic>z</italic>
-score images, and were fed into the random-effect analysis using a one-sample
<italic>t</italic>
-test to infer the group-level activation pattern of each brain network in the two separate sessions. The differences in the functional connectivity of each network between the two sessions were explored using a paired
<italic>t</italic>
-test. A complete diagram of how functional connectivity was analyzed is illustrated in
<xref ref-type="fig" rid="pone-0059331-g002">Fig. 2</xref>
.</p>
<fig id="pone-0059331-g002" orientation="portrait" position="float">
<object-id pub-id-type="doi">10.1371/journal.pone.0059331.g002</object-id>
<label>Figure 2</label>
<caption>
<title>Flow diagram of functional connectivity analysis approach.</title>
</caption>
<graphic xlink:href="pone.0059331.g002"></graphic>
</fig>
</sec>
<sec id="s2h">
<title>Granger Causality Analysis (GCA)</title>
<p>Analysis of effective connectivity was facilitated by using GCA, which models one directional causality among multiple time series based on a VAR model
<xref ref-type="bibr" rid="pone.0059331-Seth1">[37]</xref>
. The bivariate VAR model can be expressed mathematically as follows:
<disp-formula id="pone.0059331.e001">
<graphic xlink:href="pone.0059331.e001"></graphic>
<label>(1)</label>
</disp-formula>
</p>
<p>Here,
<bold>x</bold>
<sub>1</sub>
(
<italic>t</italic>
) and
<bold>x</bold>
<sub>2</sub>
(
<italic>t</italic>
) are the time series at time point
<italic>t</italic>
. Matrix
<italic>A</italic>
contains the regression coefficients, e.g., coefficient
<italic>A
<sub>12,j</sub>
</italic>
denotes the causal influence of
<bold>x</bold>
<sub>2</sub>
(
<italic>t-j</italic>
) on the prediction of
<bold>x</bold>
<sub>1</sub>
(
<italic>t</italic>
).
<bold>e</bold>
<sub>1</sub>
(
<italic>t</italic>
) and
<bold>e</bold>
<sub>2</sub>
(
<italic>t</italic>
) are the residual error at the time
<italic>t</italic>
. The model order
<italic>p</italic>
that represents the maximum time lag can be estimated using the Bayesian Information Criterion (BIC)
<xref ref-type="bibr" rid="pone.0059331-Schwarz1">[38]</xref>
. When the residual error reaches the minimum, an
<italic>F</italic>
-test is used to estimate the statistical significance of the estimated model based on the residual error. A higher
<italic>F</italic>
-score means a stronger prediction of Granger causality between the two time series.</p>
<p>To investigate the effective connectivity among brain networks as well as among multiple brain regions, a MATLAB toolbox for GCA approach
<xref ref-type="bibr" rid="pone.0059331-Seth2">[39]</xref>
was adopted to enable further analysis of the causal relations based on previous results from the functional connectivity analysis.</p>
</sec>
<sec id="s2i">
<title>Analysis of the Effective Connectivity among Brain Networks</title>
<p>For each individual in each session, the time courses corresponding to the brain networks (i.e., aDMN, pDMN, ECN, and SN) were obtained from the back-reconstruction process in group ICA. Then they were band-pass filtered (0.01–0.08 Hz), and normalized into zero mean and unit variance. The resulted time courses were concatenated across twenty-one subjects and served as the inputs for the GCA so as to reveal the causal interactions among brain networks in RS_abs and RS_sat.</p>
</sec>
<sec id="s2j">
<title>Definition of Regions of Interest (ROIs)</title>
<p>In previous studies of smoking addiction using resting-state fMRI
<xref ref-type="bibr" rid="pone.0059331-Sutherland1">[7]</xref>
,
<xref ref-type="bibr" rid="pone.0059331-Wang1">[12]</xref>
<xref ref-type="bibr" rid="pone.0059331-Cole1">[15]</xref>
, brain regions such as the insula, para−/hippocampus, caudate, thalamus, pre−/cuneus, anterior cingulate cortex (ACC), posterior cingulate cortex, supplementary motor area (SMA), ventromedial prefrontal cortex (vmPFC, equivalent to Brodmann area 10) and dorsolateral prefrontal cortex (dlPFC, roughly equivalent to Brodmann areas 9 and 46) were found to be highly influenced by smoking, and can thus be treated as the critical smoking-related brain regions. In our framework, if the afore mentioned brain regions showed significant changes by previous paired
<italic>t</italic>
-test in the functional connectivity analysis, their peak
<italic>t</italic>
-value related voxels would be picked out. A selected peak voxel together with its surrounding 26 voxels (i.e., 27 voxels, 9×9×9 mm
<sup>3</sup>
) were defined as an ROI.</p>
</sec>
<sec id="s2k">
<title>Analysis of Effective Connectivity among ROIs</title>
<p>The average BOLD time series within each ROI was calculated from the fMRI data of each subject in each session, and shifted to zero-mean in order to facilitate the concatenation across subjects. The GCA was applied on the concatenated time series to explore the causal relations among smoking related brain regions in the two sessions separately. To describe the interactions between ROIs in the causal network, we additionally used the following described out-in degree metrics in traditional graph-theoretic analysis
<xref ref-type="bibr" rid="pone.0059331-Seth1">[37]</xref>
: (1) Out-degree of a node is the number of causal out-flow connections from the node to any other nodes. (2) In-degree of a node is the number of causal in-flow connections to the node from any other nodes. (3) Out-In degree is then defined as the difference between out-degree and in-degree. A node with a high positive out-in degree is regarded as a causal source, while a node with a high negative out-in degree is considered as a causal target.</p>
</sec>
</sec>
<sec id="s3">
<title>Results</title>
<sec id="s3a">
<title>Functional Connectivity Analysis</title>
<p>The brain networks of TNNs (i.e., aDMN and pDMN) and TPNs (i.e., ECN and SN), indicated through one-sample
<italic>t</italic>
-test on back-reconstructed individual spatial maps, are shown in
<xref ref-type="fig" rid="pone-0059331-g003">Fig. 3</xref>
(FDR corrected
<italic>p</italic>
<0.01). For TNNs, the aDMN mainly located in the ACC, and the medial and superior PFC; while the pDMN located in the PCC along with the precuneus and inferior parietal lobe. For TPNs, the ECN mainly contained parts of the anterior and medial PFC, as well as the superior parietal lobe; and the SN contained areas of the insula, ACC and anterior PFC.</p>
<fig id="pone-0059331-g003" orientation="portrait" position="float">
<object-id pub-id-type="doi">10.1371/journal.pone.0059331.g003</object-id>
<label>Figure 3</label>
<caption>
<title>TNNs and TPNs via one-sample
<italic>t</italic>
-test of RS_abs and RS_sat separately (FDR corrected
<italic>p</italic>
<0.01).</title>
</caption>
<graphic xlink:href="pone.0059331.g003"></graphic>
</fig>
<p>The changes of functional connectivity revealed by paired
<italic>t</italic>
-test are listed in
<xref ref-type="table" rid="pone-0059331-t002">Table 2</xref>
(uncorrected
<italic>p</italic>
<0.005). In the resting-state of smoking abstinence, enhanced functional connectivity in both the aDMN and pDMN was indicated. In these two TNNs, hemodynamic responses were increased in the dorsal/rostral ACC (dACC/rACC), SMA and dlPFC, as well as the middle occipital gyrus and inferior frontal/temporal gyrus in the condition of smoking abstinence; while after replenishment, the hemodynamic responses were enhanced in regions of the precuneus and postcentral gyrus. For the two TPNs (i.e., ECN and SN), the parahippocampus, insula, as well as the inferior occipital gyrus and precentral gyrus showed the increased hemodynamic responses under the deprivation condition; whereas in smoking satiety, the hemodynamic responses were enhanced in regions such as the vmPFC.</p>
<table-wrap id="pone-0059331-t002" orientation="portrait" position="float">
<object-id pub-id-type="doi">10.1371/journal.pone.0059331.t002</object-id>
<label>Table 2</label>
<caption>
<title>Changes of functional connectivity in each networks revealed by paired
<italic>t</italic>
-test at uncorrected
<italic>p</italic>
<0.005.</title>
</caption>
<alternatives>
<graphic id="pone-0059331-t002-2" xlink:href="pone.0059331.t002"></graphic>
<table frame="hsides" rules="groups">
<colgroup span="1">
<col align="left" span="1"></col>
<col align="center" span="1"></col>
<col align="center" span="1"></col>
<col align="center" span="1"></col>
<col align="center" span="1"></col>
<col align="center" span="1"></col>
</colgroup>
<thead>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Anatomical location</td>
<td align="left" rowspan="1" colspan="1">NmVx</td>
<td align="left" rowspan="1" colspan="1">Peak
<italic>t</italic>
-value</td>
<td align="left" rowspan="1" colspan="1">MNI coordinates</td>
</tr>
</thead>
<tbody>
<tr>
<td align="left" rowspan="1" colspan="1">
<bold>aDMN</bold>
</td>
<td align="left" rowspan="1" colspan="1">RS_abs>RS_sat</td>
<td align="left" rowspan="1" colspan="1">L Inferior frontal gyrus</td>
<td align="left" rowspan="1" colspan="1">28</td>
<td align="left" rowspan="1" colspan="1">4.836</td>
<td align="left" rowspan="1" colspan="1">(−54, 27, −3)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">L Superior temporal gyrus</td>
<td align="left" rowspan="1" colspan="1">62</td>
<td align="left" rowspan="1" colspan="1">4.804</td>
<td align="left" rowspan="1" colspan="1">(−54, −33, 18)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">R Middle occipital gyrus</td>
<td align="left" rowspan="1" colspan="1">36</td>
<td align="left" rowspan="1" colspan="1">5.115</td>
<td align="left" rowspan="1" colspan="1">(45, −81, 15)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">R Middle cingulate cortex</td>
<td align="left" rowspan="1" colspan="1">28</td>
<td align="left" rowspan="1" colspan="1">4.344</td>
<td align="left" rowspan="1" colspan="1">(15, 21, 30)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">
<italic>L Anterior cingulate cortex(dACC)</italic>
</td>
<td align="left" rowspan="1" colspan="1">32</td>
<td align="left" rowspan="1" colspan="1">4.181</td>
<td align="left" rowspan="1" colspan="1">(−6, 21, 30)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">R Middle cingulate cortex</td>
<td align="left" rowspan="1" colspan="1">46</td>
<td align="left" rowspan="1" colspan="1">4.889</td>
<td align="left" rowspan="1" colspan="1">(3, −39, 48)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">
<italic>L Supplementary motor area</italic>
</td>
<td align="left" rowspan="1" colspan="1">34</td>
<td align="left" rowspan="1" colspan="1">4.161</td>
<td align="left" rowspan="1" colspan="1">(−3, 12, 69)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">RS_sat>RS_abs</td>
<td align="left" rowspan="1" colspan="1">L Postcentral gyrus</td>
<td align="left" rowspan="1" colspan="1">35</td>
<td align="left" rowspan="1" colspan="1">4.196</td>
<td align="left" rowspan="1" colspan="1">(−57, −15, 18)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">L Angular gyrus</td>
<td align="left" rowspan="1" colspan="1">43</td>
<td align="left" rowspan="1" colspan="1">5.116</td>
<td align="left" rowspan="1" colspan="1">(−42, −69, 45)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">
<bold>pDMN</bold>
</td>
<td align="left" rowspan="1" colspan="1">RS_abs>RS_sat</td>
<td align="left" rowspan="1" colspan="1">L Cerebellum posterior lobe</td>
<td align="left" rowspan="1" colspan="1">37</td>
<td align="left" rowspan="1" colspan="1">4.225</td>
<td align="left" rowspan="1" colspan="1">(−27, −66, −45)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">L Cerebellum anterior lobe</td>
<td align="left" rowspan="1" colspan="1">22</td>
<td align="left" rowspan="1" colspan="1">4.208</td>
<td align="left" rowspan="1" colspan="1">(−27, −42, −33)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">L Inferior temporal gyrus</td>
<td align="left" rowspan="1" colspan="1">27</td>
<td align="left" rowspan="1" colspan="1">3.586</td>
<td align="left" rowspan="1" colspan="1">(−42, −15, −27)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">
<italic>R Anterior cingulate cortex(rACC)</italic>
</td>
<td align="left" rowspan="1" colspan="1">38</td>
<td align="left" rowspan="1" colspan="1">5.077</td>
<td align="left" rowspan="1" colspan="1">(6, 27, 15)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">
<italic>R Middle frontal gyrus (dlPFC)</italic>
</td>
<td align="left" rowspan="1" colspan="1">171</td>
<td align="left" rowspan="1" colspan="1">5.787</td>
<td align="left" rowspan="1" colspan="1">(42, 36, 42)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">L Middle frontal gyrus</td>
<td align="left" rowspan="1" colspan="1">27</td>
<td align="left" rowspan="1" colspan="1">5.643</td>
<td align="left" rowspan="1" colspan="1">(−27, −6, 57)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">RS_sat>RS_abs</td>
<td align="left" rowspan="1" colspan="1">R Vermis</td>
<td align="left" rowspan="1" colspan="1">57</td>
<td align="left" rowspan="1" colspan="1">5.089</td>
<td align="left" rowspan="1" colspan="1">(3, −57, −12)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">L Supramarginal gyrus</td>
<td align="left" rowspan="1" colspan="1">37</td>
<td align="left" rowspan="1" colspan="1">3.802</td>
<td align="left" rowspan="1" colspan="1">(−48, −45, 24)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">
<italic>L Precuneus</italic>
</td>
<td align="left" rowspan="1" colspan="1">20</td>
<td align="left" rowspan="1" colspan="1">3.432</td>
<td align="left" rowspan="1" colspan="1">(−12, −57, 42)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">
<bold>ECN</bold>
</td>
<td align="left" rowspan="1" colspan="1">RS_abs>RS_sat</td>
<td align="left" rowspan="1" colspan="1">L Cerebellum posterior lobe</td>
<td align="left" rowspan="1" colspan="1">24</td>
<td align="left" rowspan="1" colspan="1">5.202</td>
<td align="left" rowspan="1" colspan="1">(−15, −90, −27)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">
<italic>R Parahippocampus</italic>
</td>
<td align="left" rowspan="1" colspan="1">44</td>
<td align="left" rowspan="1" colspan="1">4.521</td>
<td align="left" rowspan="1" colspan="1">(21, −15, −18)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">R Inferior occipital gyrus</td>
<td align="left" rowspan="1" colspan="1">25</td>
<td align="left" rowspan="1" colspan="1">4.614</td>
<td align="left" rowspan="1" colspan="1">(36, −78, −3)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">R Supramarginal gyrus</td>
<td align="left" rowspan="1" colspan="1">38</td>
<td align="left" rowspan="1" colspan="1">3.985</td>
<td align="left" rowspan="1" colspan="1">(66, −27, 39)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">L Superior frontal gyrus</td>
<td align="left" rowspan="1" colspan="1">56</td>
<td align="left" rowspan="1" colspan="1">3.880</td>
<td align="left" rowspan="1" colspan="1">(−9, 39, 45)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">R Precentral gyrus</td>
<td align="left" rowspan="1" colspan="1">40</td>
<td align="left" rowspan="1" colspan="1">4.175</td>
<td align="left" rowspan="1" colspan="1">(45, 0, 42)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">RS_sat>RS_abs</td>
<td align="left" rowspan="1" colspan="1">L Superior temporal gyrus</td>
<td align="left" rowspan="1" colspan="1">20</td>
<td align="left" rowspan="1" colspan="1">3.971</td>
<td align="left" rowspan="1" colspan="1">(−54, −24, 6)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">R Middle cingulate cortex</td>
<td align="left" rowspan="1" colspan="1">94</td>
<td align="left" rowspan="1" colspan="1">4.590</td>
<td align="left" rowspan="1" colspan="1">(3, 30, 30)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">R Middle frontal gyrus</td>
<td align="left" rowspan="1" colspan="1">25</td>
<td align="left" rowspan="1" colspan="1">4.146</td>
<td align="left" rowspan="1" colspan="1">(24, 36, 33)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">R Superior frontal gyrus</td>
<td align="left" rowspan="1" colspan="1">84</td>
<td align="left" rowspan="1" colspan="1">5.133</td>
<td align="left" rowspan="1" colspan="1">(27, 30, 54)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">
<bold>SN</bold>
</td>
<td align="left" rowspan="1" colspan="1">RS_abs>RS_sat</td>
<td align="left" rowspan="1" colspan="1">R Middle temporal pole</td>
<td align="left" rowspan="1" colspan="1">31</td>
<td align="left" rowspan="1" colspan="1">4.855</td>
<td align="left" rowspan="1" colspan="1">(42, 15, −33)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">L Cerebellum posterior lobe</td>
<td align="left" rowspan="1" colspan="1">34</td>
<td align="left" rowspan="1" colspan="1">4.244</td>
<td align="left" rowspan="1" colspan="1">(−30, −78, −21)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">
<italic>R Insula</italic>
</td>
<td align="left" rowspan="1" colspan="1">37</td>
<td align="left" rowspan="1" colspan="1">5.018</td>
<td align="left" rowspan="1" colspan="1">(39, 9, 6)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">R Middle frontal gyrus</td>
<td align="left" rowspan="1" colspan="1">71</td>
<td align="left" rowspan="1" colspan="1">4.851</td>
<td align="left" rowspan="1" colspan="1">(30, 33, 45)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">RS_sat>RS_abs</td>
<td align="left" rowspan="1" colspan="1">
<italic>L Superior frontal gyrus (vmPFC)</italic>
</td>
<td align="left" rowspan="1" colspan="1">21</td>
<td align="left" rowspan="1" colspan="1">4.170</td>
<td align="left" rowspan="1" colspan="1">(−27, 51, 0)</td>
</tr>
</tbody>
</table>
</alternatives>
<table-wrap-foot>
<fn id="nt101">
<label></label>
<p>The cluster information is illustrated using anatomical location, cluster size in number of voxels, peak
<italic>t</italic>
-value and its MNI coordinates. The eight regions marked in italics are our selected ROIs.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<p>According to the ROI selection criteria described in previous section, we picked eight ROIs in total located in the following brain regions: the dACC, SMA, rACC, dlPFC, precuneus, parahippocampus, insula and vmPFC. These regions are displayed in
<xref ref-type="fig" rid="pone-0059331-g004">Fig. 4</xref>
and marked with italic types in
<xref ref-type="table" rid="pone-0059331-t002">Table 2</xref>
.</p>
<fig id="pone-0059331-g004" orientation="portrait" position="float">
<object-id pub-id-type="doi">10.1371/journal.pone.0059331.g004</object-id>
<label>Figure 4</label>
<caption>
<title>Eight ROIs located clusters with functional connectivity variation revealed using paired
<italic>t</italic>
-test (uncorrected
<italic>p</italic>
<0.005).</title>
</caption>
<graphic xlink:href="pone.0059331.g004"></graphic>
</fig>
</sec>
<sec id="s3b">
<title>Effective Connectivity Analysis</title>
<p>
<xref ref-type="fig" rid="pone-0059331-g005">Fig. 5</xref>
shows the causal interactions among the brain networks of the aDMN, pDMN, ECN, and SN (FDR corrected
<italic>p</italic>
<0.01), together with the mean time course of each brain network. When smoking was replenished for the participants after abstinence, causal connection from SN to pDMN was reduced, whereas that from ECN/aDMN to SN was enhanced. Specifically, the ECN showed more active causal interactions with the other three brain networks in satiety condition. In these four causal nodes, the pDMN was a causal target in abstinence condition. After smoking replenishment, the SN turned to be a causal target, and the ECN became a causal source.</p>
<fig id="pone-0059331-g005" orientation="portrait" position="float">
<object-id pub-id-type="doi">10.1371/journal.pone.0059331.g005</object-id>
<label>Figure 5</label>
<caption>
<title>Causal interactions among brain networks.</title>
<p>Causal interactions among aDMN, pDMN, ECN, and SN (FDR corrected
<italic>p</italic>
<0.01) in conditions of (A) smoking abstinence and (B) smoking satiety, together with the mean time course of each brain network. The reciprocal causal flows were revealed using black color, and the nonreciprocal ones were in blue color.</p>
</caption>
<graphic xlink:href="pone.0059331.g005"></graphic>
</fig>
<p>In
<xref ref-type="fig" rid="pone-0059331-g006">Fig. 6</xref>
, (A) and (C) display the causal relationships among eight ROIs before and after smoking (FDR corrected
<italic>p</italic>
<0.001); (B) and (D) are the corresponding significant path weight matrices. The causal degrees measured using
<italic>F</italic>
-score are listed in
<xref ref-type="table" rid="pone-0059331-t003">Table 3</xref>
. For clear illustration,
<xref ref-type="fig" rid="pone-0059331-g006">Fig. 6</xref>
(E) indicates the changed causal paths in the satiety vs. abstinence condition. Overall speaking, the insula and dACC had the increased inter-area causal connection in smoking abstinence, whereas the parahippocampus and rACC showed the enhanced causal interactions with the other ROIs after replenishment. Referring to the out-in degree metrics (
<xref ref-type="table" rid="pone-0059331-t004">Table 4</xref>
), the SMA seemed to be a causal target in deprived state, and the rACC could be regarded as a causal source in satiety condition.</p>
<fig id="pone-0059331-g006" orientation="portrait" position="float">
<object-id pub-id-type="doi">10.1371/journal.pone.0059331.g006</object-id>
<label>Figure 6</label>
<caption>
<title>Causal interactions among selected ROIs.</title>
<p>Causal interactions among selected eight ROIs in conditions of smoking abstinence and smoking satiety: (A) causal relationship of smoking abstinence at FDR corrected
<italic>p</italic>
<0.001, (B) significant path weight matrix of causal interactions in smoking abstinence; (C) causal relationship of smoking satiety at FDR corrected
<italic>p</italic>
<0.001, (D) significant path weight matrix of causal interactions in smoking satiety; (E) matrix indicating the changed causal paths in the satiety vs. abstinence condition. In (A) and (C), the reciprocal causal flows were revealed using black color, and the nonreciprocal ones were in blue color. In (B) and (D), the insignificant path weights are indicated in zero.</p>
</caption>
<graphic xlink:href="pone.0059331.g006"></graphic>
</fig>
<table-wrap id="pone-0059331-t003" orientation="portrait" position="float">
<object-id pub-id-type="doi">10.1371/journal.pone.0059331.t003</object-id>
<label>Table 3</label>
<caption>
<title>The degree of the significant causal interactions in
<xref ref-type="fig" rid="pone-0059331-g006">Fig. 6</xref>
(measured using
<italic>F</italic>
-score).</title>
</caption>
<alternatives>
<graphic id="pone-0059331-t003-3" xlink:href="pone.0059331.t003"></graphic>
<table frame="hsides" rules="groups">
<colgroup span="1">
<col align="left" span="1"></col>
<col align="center" span="1"></col>
<col align="center" span="1"></col>
<col align="center" span="1"></col>
</colgroup>
<thead>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">From</td>
<td align="left" rowspan="1" colspan="1">To</td>
<td align="left" rowspan="1" colspan="1">
<italic>F</italic>
-score</td>
</tr>
</thead>
<tbody>
<tr>
<td align="left" rowspan="1" colspan="1">
<bold>RS_abs</bold>
</td>
<td align="left" rowspan="1" colspan="1">dACC</td>
<td align="left" rowspan="1" colspan="1">SMA</td>
<td align="left" rowspan="1" colspan="1">3.61</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Precuneus</td>
<td align="left" rowspan="1" colspan="1">18.07</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Parahippocampus</td>
<td align="left" rowspan="1" colspan="1">7.18</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Insula</td>
<td align="left" rowspan="1" colspan="1">63.39</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">vmPFC</td>
<td align="left" rowspan="1" colspan="1">36.24</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">rACC</td>
<td align="left" rowspan="1" colspan="1">SMA</td>
<td align="left" rowspan="1" colspan="1">4.99</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Insula</td>
<td align="left" rowspan="1" colspan="1">19.64</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">vmPFC</td>
<td align="left" rowspan="1" colspan="1">13.23</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">dlPFC</td>
<td align="left" rowspan="1" colspan="1">Insula</td>
<td align="left" rowspan="1" colspan="1">7.59</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Precuneus</td>
<td align="left" rowspan="1" colspan="1">dACC</td>
<td align="left" rowspan="1" colspan="1">25.31</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">dlPFC</td>
<td align="left" rowspan="1" colspan="1">7.30</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Insula</td>
<td align="left" rowspan="1" colspan="1">108.81</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">vmPFC</td>
<td align="left" rowspan="1" colspan="1">15.90</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Parahippocampus</td>
<td align="left" rowspan="1" colspan="1">dACC</td>
<td align="left" rowspan="1" colspan="1">4.71</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Insula</td>
<td align="left" rowspan="1" colspan="1">15.00</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Insula</td>
<td align="left" rowspan="1" colspan="1">dACC</td>
<td align="left" rowspan="1" colspan="1">47.97</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">SMA</td>
<td align="left" rowspan="1" colspan="1">43.31</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">rACC</td>
<td align="left" rowspan="1" colspan="1">44.46</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">dlPFC</td>
<td align="left" rowspan="1" colspan="1">22.61</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Precuneus</td>
<td align="left" rowspan="1" colspan="1">70.57</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Parahippocampus</td>
<td align="left" rowspan="1" colspan="1">24.92</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">vmPFC</td>
<td align="left" rowspan="1" colspan="1">62.23</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">vmPFC</td>
<td align="left" rowspan="1" colspan="1">dlPFC</td>
<td align="left" rowspan="1" colspan="1">19.66</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Precuneus</td>
<td align="left" rowspan="1" colspan="1">9.57</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">
<bold>RS_sat</bold>
</td>
<td align="left" rowspan="1" colspan="1">dACC</td>
<td align="left" rowspan="1" colspan="1">rACC</td>
<td align="left" rowspan="1" colspan="1">51.61</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Parahippocampus</td>
<td align="left" rowspan="1" colspan="1">12.65</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">SMA</td>
<td align="left" rowspan="1" colspan="1">Precuneus</td>
<td align="left" rowspan="1" colspan="1">14.23</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Insula</td>
<td align="left" rowspan="1" colspan="1">4.73</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">rACC</td>
<td align="left" rowspan="1" colspan="1">SMA</td>
<td align="left" rowspan="1" colspan="1">8.79</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">dlPFC</td>
<td align="left" rowspan="1" colspan="1">7.96</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Precuneus</td>
<td align="left" rowspan="1" colspan="1">11.61</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Parahippocampus</td>
<td align="left" rowspan="1" colspan="1">3.45</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Insula</td>
<td align="left" rowspan="1" colspan="1">13.98</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">vmPFC</td>
<td align="left" rowspan="1" colspan="1">33.10</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">dlPFC</td>
<td align="left" rowspan="1" colspan="1">rACC</td>
<td align="left" rowspan="1" colspan="1">8.44</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Precuneus</td>
<td align="left" rowspan="1" colspan="1">dlPFC</td>
<td align="left" rowspan="1" colspan="1">4.29</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Parahippocampus</td>
<td align="left" rowspan="1" colspan="1">15.13</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">vmPFC</td>
<td align="left" rowspan="1" colspan="1">4.78</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Parahippocampus</td>
<td align="left" rowspan="1" colspan="1">dACC</td>
<td align="left" rowspan="1" colspan="1">34.03</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">rACC</td>
<td align="left" rowspan="1" colspan="1">11.10</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Insula</td>
<td align="left" rowspan="1" colspan="1">30.47</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">vmPFC</td>
<td align="left" rowspan="1" colspan="1">3.25</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Insula</td>
<td align="left" rowspan="1" colspan="1">dACC</td>
<td align="left" rowspan="1" colspan="1">15.01</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">SMA</td>
<td align="left" rowspan="1" colspan="1">31.32</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Parahippocampus</td>
<td align="left" rowspan="1" colspan="1">75.31</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">vmPFC</td>
<td align="left" rowspan="1" colspan="1">23.08</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">vmPFC</td>
<td align="left" rowspan="1" colspan="1">dACC</td>
<td align="left" rowspan="1" colspan="1">18.12</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Precuneus</td>
<td align="left" rowspan="1" colspan="1">42.16</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Parahippocampus</td>
<td align="left" rowspan="1" colspan="1">6.80</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Insula</td>
<td align="left" rowspan="1" colspan="1">8.92</td>
</tr>
</tbody>
</table>
</alternatives>
</table-wrap>
<table-wrap id="pone-0059331-t004" orientation="portrait" position="float">
<object-id pub-id-type="doi">10.1371/journal.pone.0059331.t004</object-id>
<label>Table 4</label>
<caption>
<title>The out-in degree corresponding to the causal networks in
<xref ref-type="fig" rid="pone-0059331-g006">Fig. 6</xref>
.</title>
</caption>
<alternatives>
<graphic id="pone-0059331-t004-4" xlink:href="pone.0059331.t004"></graphic>
<table frame="hsides" rules="groups">
<colgroup span="1">
<col align="left" span="1"></col>
<col align="center" span="1"></col>
<col align="center" span="1"></col>
<col align="center" span="1"></col>
<col align="center" span="1"></col>
<col align="center" span="1"></col>
<col align="center" span="1"></col>
<col align="center" span="1"></col>
<col align="center" span="1"></col>
</colgroup>
<thead>
<tr>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">dACC</td>
<td align="left" rowspan="1" colspan="1">SMA</td>
<td align="left" rowspan="1" colspan="1">rACC</td>
<td align="left" rowspan="1" colspan="1">dlPFC</td>
<td align="left" rowspan="1" colspan="1">Precuneus</td>
<td align="left" rowspan="1" colspan="1">Parahippocampus</td>
<td align="left" rowspan="1" colspan="1">Insula</td>
<td align="left" rowspan="1" colspan="1">vmPFC</td>
</tr>
</thead>
<tbody>
<tr>
<td align="left" rowspan="1" colspan="1">
<bold>RS_abs</bold>
</td>
<td align="left" rowspan="1" colspan="1">2</td>
<td align="left" rowspan="1" colspan="1">−3</td>
<td align="left" rowspan="1" colspan="1">2</td>
<td align="left" rowspan="1" colspan="1">−2</td>
<td align="left" rowspan="1" colspan="1">1</td>
<td align="left" rowspan="1" colspan="1">0</td>
<td align="left" rowspan="1" colspan="1">2</td>
<td align="left" rowspan="1" colspan="1">−2</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">
<bold>RS_sat</bold>
</td>
<td align="left" rowspan="1" colspan="1">−1</td>
<td align="left" rowspan="1" colspan="1">0</td>
<td align="left" rowspan="1" colspan="1">3</td>
<td align="left" rowspan="1" colspan="1">−1</td>
<td align="left" rowspan="1" colspan="1">0</td>
<td align="left" rowspan="1" colspan="1">−1</td>
<td align="left" rowspan="1" colspan="1">0</td>
<td align="left" rowspan="1" colspan="1">0</td>
</tr>
</tbody>
</table>
</alternatives>
</table-wrap>
</sec>
</sec>
<sec id="s4">
<title>Discussion</title>
<p>In this study, in order to investigate the neuronal mechanisms associated with smoking, we conducted a resting-state fMRI experiment in which twenty-one heavy smokers were scanned in two sessions: smoking abstinence followed by smoking satiety. We proposed a novel analysis framework combining ICA and GCA to inspect both functional and effective connectivity, mainly considering the brain networks of TNNs (i.e., aDMN and pDMN) and TPNs (i.e., ECN and SN). The causal interaction from SN to pDMN was reduced, and that from ECN/aDMN to SN was enhanced after smoking replenishment. The experimental results also showed that before and after smoking, both functional and effective connectivity changed in the brain regions of the insula, dACC, rACC, SMA, dlPFC, vmPFC, precuneus and parahippocampus. These findings did not only reflect the effect of smoking/nicotine on brain connectivity, but also could be explained by the presence and absence of withdrawal. Obviously, it demonstrated our hypothesis that the effect of smoking replenishment on deprived heavy smokers would influence both functional and effective connectivity.</p>
<p>Previous studies of smoking or nicotine addiction have mostly focused on functional connectivity in resting-state or task-related environments. Besides functional connectivity, we also paid attention to effective connectivity, which was represented by causal interactions. In our analysis framework, group ICA was applied to identify functionally connected brain networks. The time courses of specific functional networks were analyzed using GCA to reveal the causal relationship among these networks. Changes in functional connectivity were investigated using a paired
<italic>t</italic>
-test on back-reconstructed individual spatial maps and the results enabled selection of the ROIs for further GCA analysis to explore the causal interactions among crucial brain regions. Undeniably, our method was not the first one that combined ICA and GCA in fMRI analysis. However, different from the previous ICA-GCA approaches that measured the effective connectivity using only the network time courses derived from ICA
<xref ref-type="bibr" rid="pone.0059331-Demirci1">[27]</xref>
<xref ref-type="bibr" rid="pone.0059331-Stevens1">[28]</xref>
or only the BOLD time series of peak clusters located in ICA spatial maps
<xref ref-type="bibr" rid="pone.0059331-Sridharan1">[29]</xref>
<xref ref-type="bibr" rid="pone.0059331-Jiao1">[30]</xref>
, our framework seems more systematic and full-scaled as it concerns the effective connectivity with respect to both the large-scale brain networks and the brain regions of varied functional connectivity.</p>
<p>Granger causality analysis, which describes a statistical interpretation of causal interactions between sets of time series, was adopted to measure the effective connectivity in our experiment. Common criticisms regarding GCA for fMRI data are as follows
<xref ref-type="bibr" rid="pone.0059331-Smith1">[40]</xref>
: (1) the spurious influence might be occurred because of the systematic differences across brain regions in hemodynamic delays; and (2) changes in directionality could be caused by the differences in hemodynamic coupling in different regions. However, it seems that the impact of variable hemodynamic delays is not severe when the sampling interval is as long as 2000 ms
<xref ref-type="bibr" rid="pone.0059331-Deshpande1">[41]</xref>
. For the second criticism, we obtained the ROIs from a significant functional connectivity analysis using statistical testing rather than adopting the other atlas-based ROIs. The ROI definition rule was based on the hypothesis that the changes in functional connectivity would be caused together with the variations in effective connectivity, which was also demonstrated by our experiment results.</p>
<p>The four brain networks chosen in our study were aDMN, pDMN, ECN and SN. The first two are anterior and posterior parts of DMN. A previous study
<xref ref-type="bibr" rid="pone.0059331-Sutherland1">[7]</xref>
reviewed the earlier research on resting-state functional connectivity in addiction, and proposed a hypothesized network model of nicotine addiction regarding these selected networks so that abstinence would result in one or more of the following observable changes: (1) enhanced connectivity within the DMN, (2) reduced connectivity within the ECN, (3) enhanced interactions between DMN and SN, and (4) reduced interactions between ECN and SN. Our functional connectivity results directly testified to the validity of the first hypothesis. The GCA result among brain networks could demonstrate the fourth hypothesis.</p>
<p>The ROIs revealed by the paired
<italic>t</italic>
-test were generally in agreement with the results of previous smoking research
<xref ref-type="bibr" rid="pone.0059331-Sutherland1">[7]</xref>
,
<xref ref-type="bibr" rid="pone.0059331-Wang1">[12]</xref>
<xref ref-type="bibr" rid="pone.0059331-Cole1">[15]</xref>
. Particularly, as a part of SN, the insula showed the enhanced hemodynamic responses and increased inter-area causal interactions in abstinent condition, giving the evidence of insula’s interoceptive effects in the addiction cycle that it tracks bodily changes and in turn interacts with other regions rather than acting solely
<xref ref-type="bibr" rid="pone.0059331-Naqvi1">[42]</xref>
. An interesting finding is that the two ACC ROIs (i.e., dACC and rACC), which all showed the enhanced hemodynamic responses in deprived condition, performed differently in causal analysis. The dACC had the enhanced inter-area causal interactions during smoking abstinence, whereas the rACC showed the increased inter-area causal connection in satiety condition. A previous study
<xref ref-type="bibr" rid="pone.0059331-Hong1">[11]</xref>
found that when taking them as seed-voxels, the dACC and rACC revealed the different resting-state whole-brain functional connectivity maps for healthy smokers, which potentially indicated that these two parts might also perform different roles in causal interactions. However, further studies are still needed to ascertain whether the sub-regions of the ACC has different mechanisms in smoking addiction.</p>
<p>Furthermore, neuropharmacological mechanisms could also relate the effect of smoking deprivation and replenishment on functional network activity. Nicotine acts on the nicotine acetylcholine receptors. In low concentrations, nicotine increases the activity of these receptors. It has been found that the nicotine acetylcholine receptors are associated with the dACC involved circuits
<xref ref-type="bibr" rid="pone.0059331-Hong2">[43]</xref>
,
<xref ref-type="bibr" rid="pone.0059331-Bierut1">[44]</xref>
. This may be a neural-level explanation of our experimental result that the dACC exhibited the enhanced hemodynamic responses and causal interactions in abstinent condition. Moreover, acetylcholine performs a role in toggling circuit dynamics between cortico-cortical feed-backward states (low acetylcholine levels) and thalamo-cortical feed-forward states (high acetylcholine levels)
<xref ref-type="bibr" rid="pone.0059331-Hasselmo1">[45]</xref>
, which may reflect in parallel as the smoking induced suppression of DMN and enhancement of ECN activity at the system-level.</p>
<p>In our experiment, the scanning sessions were designed in the order of smoking abstinence followed by satiety, since our goal was to investigate the connectivity variations caused by smoking replenishment on the abstinent state. More specifically, we considered the abstinent state as a reference state of satiety, rather than treating these two states as two disconnected and separate conditions. However, it is possible that order effects such as more anxiety in the first session might have an impact on our findings
<xref ref-type="bibr" rid="pone.0059331-Bishop1">[46]</xref>
. A potential solution is to add one more resting-state session directly before the abstinence session so as to make the participants familiar with the scanning procedure. Moreover, since our experiment was based on measuring changes in blood flow, the elevation of blood pressure caused by smoking
<xref ref-type="bibr" rid="pone.0059331-Omvik1">[47]</xref>
might also confound the results. Exact impact of these factors are waiting for the future researches, and a variety of additional neuroscience measurements will be applied before a firm conclusion can be made about the effect of smoking on human brain functions.</p>
<sec id="s4a">
<title>Conclusion</title>
<p>To investigate the brain connectivity associated with smoking addiction, we conducted a resting-state fMRI experiment and proposed an analysis framework combining ICA and GCA that can inspect both functional and effective connectivity in terms of brain networks and ROIs. The experimental results demonstrated our hypothesis that for deprived heavy smokers, smoking replenishment took effect on both functional connectivity and effective connectivity, involving brain networks such as TNNs and TPNs, as well as some crucial brain regions. Moreover, our proposed analysis framework could be applied across a range of neuroscience studies.</p>
</sec>
</sec>
</body>
<back>
<ack>
<p>We would like to thank Prof. Jong-Hwan Lee for providing us useful assistance and great convenience in data collection part.</p>
</ack>
<ref-list>
<title>References</title>
<ref id="pone.0059331-Upadhyay1">
<label>1</label>
<mixed-citation publication-type="journal">
<name>
<surname>Upadhyay</surname>
<given-names>J</given-names>
</name>
,
<name>
<surname>Maleki</surname>
<given-names>N</given-names>
</name>
,
<name>
<surname>Potter</surname>
<given-names>J</given-names>
</name>
,
<name>
<surname>Elman</surname>
<given-names>I</given-names>
</name>
,
<name>
<surname>Rudrauf</surname>
<given-names>D</given-names>
</name>
,
<etal>et al</etal>
(
<year>2010</year>
)
<article-title>Alternations in brain structure and functional connectivity in prescription opioid-dependent patients</article-title>
.
<source>Brain</source>
<volume>133(7)</volume>
:
<fpage>2098</fpage>
<lpage>2114</lpage>
<pub-id pub-id-type="pmid">20558415</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Kelly1">
<label>2</label>
<mixed-citation publication-type="journal">
<name>
<surname>Kelly</surname>
<given-names>C</given-names>
</name>
,
<name>
<surname>Zuo</surname>
<given-names>XN</given-names>
</name>
,
<name>
<surname>Gotimer</surname>
<given-names>K</given-names>
</name>
,
<name>
<surname>Cox</surname>
<given-names>CL</given-names>
</name>
,
<name>
<surname>Lynch</surname>
<given-names>L</given-names>
</name>
,
<etal>et al</etal>
(
<year>2011</year>
)
<article-title>Reduced interhemispheric resting state functional connectivity in cocaine addiction</article-title>
.
<source>Biol Psychiatry</source>
<volume>69(7)</volume>
:
<fpage>684</fpage>
<lpage>692</lpage>
<pub-id pub-id-type="pmid">21251646</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Tomasi1">
<label>3</label>
<mixed-citation publication-type="journal">
<name>
<surname>Tomasi</surname>
<given-names>D</given-names>
</name>
,
<name>
<surname>Volkow</surname>
<given-names>ND</given-names>
</name>
,
<name>
<surname>Wang</surname>
<given-names>R</given-names>
</name>
,
<name>
<surname>Carrillo</surname>
<given-names>JH</given-names>
</name>
,
<name>
<surname>Maloney</surname>
<given-names>T</given-names>
</name>
,
<etal>et al</etal>
(
<year>2010</year>
)
<article-title>Disrupted functional connectivity with dopaminergic midbrain in cocaine abusers</article-title>
.
<source>PLoS ONE</source>
<volume>5(5)</volume>
:
<fpage>e10815</fpage>
<comment>doi:
<ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1371/journal.pone.0010815">10.1371/journal.pone.0010815</ext-link>
</comment>
<pub-id pub-id-type="pmid">20520835</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Ma1">
<label>4</label>
<mixed-citation publication-type="journal">
<name>
<surname>Ma</surname>
<given-names>N</given-names>
</name>
,
<name>
<surname>Liu</surname>
<given-names>Y</given-names>
</name>
,
<name>
<surname>Fu</surname>
<given-names>XM</given-names>
</name>
,
<name>
<surname>Li</surname>
<given-names>N</given-names>
</name>
,
<name>
<surname>Wang</surname>
<given-names>CX</given-names>
</name>
,
<etal>et al</etal>
(
<year>2011</year>
)
<article-title>Abnormal brain default-mode network functional connectivity in drug addicts</article-title>
.
<source>PLoS ONE</source>
<volume>6(1)</volume>
:
<fpage>e16560</fpage>
<comment>doi:
<ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1371/journal.pone.0016560">10.1371/journal.pone.0016560</ext-link>
</comment>
<pub-id pub-id-type="pmid">21298074</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Yuan1">
<label>5</label>
<mixed-citation publication-type="journal">
<name>
<surname>Yuan</surname>
<given-names>K</given-names>
</name>
,
<name>
<surname>Qin</surname>
<given-names>W</given-names>
</name>
,
<name>
<surname>Dong</surname>
<given-names>M</given-names>
</name>
,
<name>
<surname>Liu</surname>
<given-names>J</given-names>
</name>
,
<name>
<surname>Sun</surname>
<given-names>J</given-names>
</name>
,
<etal>et al</etal>
(
<year>2010</year>
)
<article-title>Gray matter deficits and resting-state abnormalities in abstinent heroin-dependent individuals</article-title>
.
<source>Neurosci Lett</source>
<volume>482(2)</volume>
:
<fpage>101</fpage>
<lpage>105</lpage>
<pub-id pub-id-type="pmid">20621162</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Diekhof1">
<label>6</label>
<mixed-citation publication-type="journal">
<name>
<surname>Diekhof</surname>
<given-names>EK</given-names>
</name>
,
<name>
<surname>Falkai</surname>
<given-names>P</given-names>
</name>
,
<name>
<surname>Gruber</surname>
<given-names>O</given-names>
</name>
(
<year>2008</year>
)
<article-title>Functional neuroimaging of reward processing and decision-making: a review of aberrant motivational and affective processing in addiction and mood disorders</article-title>
.
<source>Brain Res Rev</source>
<volume>59(1)</volume>
:
<fpage>164</fpage>
<lpage>184</lpage>
<pub-id pub-id-type="pmid">18675846</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Sutherland1">
<label>7</label>
<mixed-citation publication-type="journal">
<name>
<surname>Sutherland</surname>
<given-names>MT</given-names>
</name>
,
<name>
<surname>McHugh</surname>
<given-names>MJ</given-names>
</name>
,
<name>
<surname>Pariyadath</surname>
<given-names>V</given-names>
</name>
,
<name>
<surname>Stein</surname>
<given-names>EA</given-names>
</name>
(
<year>2012</year>
)
<article-title>Resting state functional connectivity in addiction: lessons learned and a road ahead</article-title>
.
<source>Neuroimage</source>
<volume>62(4)</volume>
:
<fpage>2281</fpage>
<lpage>2295</lpage>
<pub-id pub-id-type="pmid">22326834</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-David1">
<label>8</label>
<mixed-citation publication-type="journal">
<name>
<surname>David</surname>
<given-names>SP</given-names>
</name>
,
<name>
<surname>Munafò</surname>
<given-names>MR</given-names>
</name>
,
<name>
<surname>Johansen-Berg</surname>
<given-names>H</given-names>
</name>
,
<name>
<surname>Smith</surname>
<given-names>SM</given-names>
</name>
,
<name>
<surname>Rogers</surname>
<given-names>RD</given-names>
</name>
,
<etal>et al</etal>
(
<year>2005</year>
)
<article-title>Ventral striatum/nucleus accumbens activation to smoking-related pictorial cues in smokers and nonsmokers: a functional magnetic resonance imaging study</article-title>
.
<source>Biol Psychiatry</source>
<volume>58(6)</volume>
:
<fpage>488</fpage>
<lpage>494</lpage>
<pub-id pub-id-type="pmid">16023086</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Janes1">
<label>9</label>
<mixed-citation publication-type="journal">
<name>
<surname>Janes</surname>
<given-names>AC</given-names>
</name>
,
<name>
<surname>Pizzagalli</surname>
<given-names>DA</given-names>
</name>
,
<name>
<surname>Richardt</surname>
<given-names>S</given-names>
</name>
,
<name>
<surname>Frederick Bde</surname>
<given-names>B</given-names>
</name>
,
<name>
<surname>Holmes</surname>
<given-names>AJ</given-names>
</name>
,
<etal>et al</etal>
(
<year>2010</year>
)
<article-title>Neural substrates of attentional bias for smoking-related cues: an fMRI study</article-title>
.
<source>Neuropsychopharmacology</source>
<volume>35(12)</volume>
:
<fpage>2339</fpage>
<lpage>2345</lpage>
<pub-id pub-id-type="pmid">20703221</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Dagher1">
<label>10</label>
<mixed-citation publication-type="journal">
<name>
<surname>Dagher</surname>
<given-names>A</given-names>
</name>
,
<name>
<surname>Tannenbaum</surname>
<given-names>B</given-names>
</name>
,
<name>
<surname>Hayashi</surname>
<given-names>T</given-names>
</name>
,
<name>
<surname>Pruessner</surname>
<given-names>JC</given-names>
</name>
,
<name>
<surname>McBride</surname>
<given-names>D</given-names>
</name>
(
<year>2009</year>
)
<article-title>An acute psychosocial stress enhances the neural response to smoking cues</article-title>
.
<source>Brain Res</source>
<volume>1293</volume>
:
<fpage>40</fpage>
<lpage>48</lpage>
<pub-id pub-id-type="pmid">19632211</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Hong1">
<label>11</label>
<mixed-citation publication-type="journal">
<name>
<surname>Hong</surname>
<given-names>LE</given-names>
</name>
,
<name>
<surname>Gu</surname>
<given-names>H</given-names>
</name>
,
<name>
<surname>Yang</surname>
<given-names>Y</given-names>
</name>
,
<name>
<surname>Ross</surname>
<given-names>TJ</given-names>
</name>
,
<name>
<surname>Salmeron</surname>
<given-names>BJ</given-names>
</name>
,
<etal>et al</etal>
(
<year>2009</year>
)
<article-title>Association of nicotine addiction and nicotine’s actions with separate cingulate cortex functional circuits</article-title>
.
<source>Arch Gen Psychiatry</source>
<volume>66(4)</volume>
:
<fpage>431</fpage>
<lpage>441</lpage>
<pub-id pub-id-type="pmid">19349313</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Wang1">
<label>12</label>
<mixed-citation publication-type="journal">
<name>
<surname>Wang</surname>
<given-names>Z</given-names>
</name>
,
<name>
<surname>Faith</surname>
<given-names>M</given-names>
</name>
,
<name>
<surname>Patterson</surname>
<given-names>F</given-names>
</name>
,
<name>
<surname>Tang</surname>
<given-names>K</given-names>
</name>
,
<name>
<surname>Kerrin</surname>
<given-names>K</given-names>
</name>
,
<etal>et al</etal>
(
<year>2007</year>
)
<article-title>Neural substrates of abstinence-induced cigarette cravings in chronic smokers</article-title>
.
<source>J Neurosci</source>
<volume>27(51)</volume>
:
<fpage>14035</fpage>
<lpage>14040</lpage>
<pub-id pub-id-type="pmid">18094242</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Janes2">
<label>13</label>
<mixed-citation publication-type="journal">
<name>
<surname>Janes</surname>
<given-names>AC</given-names>
</name>
,
<name>
<surname>Nickerson</surname>
<given-names>LD</given-names>
</name>
,
<name>
<surname>Frederick</surname>
<given-names>BD</given-names>
</name>
,
<name>
<surname>Kaufman</surname>
<given-names>MJ</given-names>
</name>
(
<year>2012</year>
)
<article-title>Prefrontal and limbic resting state brain network functional connectivity differs between nicotine dependent smokers and non-smoking controls</article-title>
.
<source>Drug Alcohol Depend</source>
<volume>125(3)</volume>
:
<fpage>252</fpage>
<lpage>259</lpage>
<pub-id pub-id-type="pmid">22459914</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Tanabe1">
<label>14</label>
<mixed-citation publication-type="journal">
<name>
<surname>Tanabe</surname>
<given-names>J</given-names>
</name>
,
<name>
<surname>Nyberg</surname>
<given-names>E</given-names>
</name>
,
<name>
<surname>Martin</surname>
<given-names>LF</given-names>
</name>
,
<name>
<surname>Martin</surname>
<given-names>J</given-names>
</name>
,
<name>
<surname>Cordes</surname>
<given-names>D</given-names>
</name>
,
<etal>et al</etal>
(
<year>2011</year>
)
<article-title>Nicotine effects on default mode network during resting state</article-title>
.
<source>Psychopharmacology</source>
<volume>216(2)</volume>
:
<fpage>287</fpage>
<lpage>295</lpage>
<pub-id pub-id-type="pmid">21331518</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Cole1">
<label>15</label>
<mixed-citation publication-type="journal">
<name>
<surname>Cole</surname>
<given-names>DM</given-names>
</name>
,
<name>
<surname>Beckmann</surname>
<given-names>CF</given-names>
</name>
,
<name>
<surname>Long</surname>
<given-names>CJ</given-names>
</name>
,
<name>
<surname>Matthews</surname>
<given-names>PM</given-names>
</name>
,
<name>
<surname>Durcan</surname>
<given-names>MJ</given-names>
</name>
,
<etal>et al</etal>
(
<year>2010</year>
)
<article-title>Nicotine replacement in abstinent smokers improves cognitive withdrawal symptoms with modulation of resting brain network dynamics</article-title>
.
<source>Neuroimage</source>
<volume>52(2)</volume>
:
<fpage>590</fpage>
<lpage>599</lpage>
<pub-id pub-id-type="pmid">20441798</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Hahn1">
<label>16</label>
<mixed-citation publication-type="journal">
<name>
<surname>Hahn</surname>
<given-names>B</given-names>
</name>
,
<name>
<surname>Ross</surname>
<given-names>TJ</given-names>
</name>
,
<name>
<surname>Yang</surname>
<given-names>Y</given-names>
</name>
,
<name>
<surname>Kim</surname>
<given-names>I</given-names>
</name>
,
<name>
<surname>Huestis</surname>
<given-names>MA</given-names>
</name>
,
<etal>et al</etal>
(
<year>2007</year>
)
<article-title>Nicotine enhances visuospatial attention by deactivating areas of the resting brain default network</article-title>
.
<source>J Neurosci</source>
<volume>27(13)</volume>
:
<fpage>3477</fpage>
<lpage>3489</lpage>
<pub-id pub-id-type="pmid">17392464</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Ettinger1">
<label>17</label>
<mixed-citation publication-type="journal">
<name>
<surname>Ettinger</surname>
<given-names>U</given-names>
</name>
,
<name>
<surname>Williams</surname>
<given-names>SC</given-names>
</name>
,
<name>
<surname>Patel</surname>
<given-names>D</given-names>
</name>
,
<name>
<surname>Michel</surname>
<given-names>TM</given-names>
</name>
,
<name>
<surname>Nwaigwe</surname>
<given-names>A</given-names>
</name>
,
<etal>et al</etal>
(
<year>2009</year>
)
<article-title>Effects of acute nicotine on brain function in healthy smokers and non-smokers: estimation of inter-individual response heterogeneity</article-title>
.
<source>Neuroimage</source>
<volume>45(2)</volume>
:
<fpage>549</fpage>
<lpage>561</lpage>
<pub-id pub-id-type="pmid">19159693</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Kim1">
<label>18</label>
<mixed-citation publication-type="journal">
<name>
<surname>Kim</surname>
<given-names>DY</given-names>
</name>
,
<name>
<surname>Lee</surname>
<given-names>JH</given-names>
</name>
(
<year>2011</year>
)
<article-title>Are posterior default-mode networks more robust than anterior default-mode networks? Evidence from resting-state fMRI data analysis</article-title>
.
<source>Neurosci Lett</source>
<volume>498(1)</volume>
:
<fpage>57</fpage>
<lpage>62</lpage>
<pub-id pub-id-type="pmid">21575682</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Seeley1">
<label>19</label>
<mixed-citation publication-type="journal">
<name>
<surname>Seeley</surname>
<given-names>WW</given-names>
</name>
,
<name>
<surname>Menon</surname>
<given-names>V</given-names>
</name>
,
<name>
<surname>Schatzberg</surname>
<given-names>AF</given-names>
</name>
,
<name>
<surname>Keller</surname>
<given-names>J</given-names>
</name>
,
<name>
<surname>Glover</surname>
<given-names>GH</given-names>
</name>
,
<etal>et al</etal>
(
<year>2007</year>
)
<article-title>Dissociable intrinsic connectivity networks for salience processing and executive control</article-title>
.
<source>J Neurosci</source>
<volume>27(9)</volume>
:
<fpage>2349</fpage>
<lpage>2356</lpage>
<pub-id pub-id-type="pmid">17329432</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Friston1">
<label>20</label>
<mixed-citation publication-type="journal">
<name>
<surname>Friston</surname>
<given-names>KJ</given-names>
</name>
,
<name>
<surname>Buechel</surname>
<given-names>C</given-names>
</name>
,
<name>
<surname>Fink</surname>
<given-names>GR</given-names>
</name>
,
<name>
<surname>Morris</surname>
<given-names>J</given-names>
</name>
,
<name>
<surname>Rolls</surname>
<given-names>E</given-names>
</name>
,
<etal>et al</etal>
(
<year>1997</year>
)
<article-title>Psychophysiological and modulatory interactions in neuroimaging</article-title>
.
<source>Neuroimage</source>
<volume>6(3)</volume>
:
<fpage>218</fpage>
<lpage>229</lpage>
<pub-id pub-id-type="pmid">9344826</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Biswal1">
<label>21</label>
<mixed-citation publication-type="journal">
<name>
<surname>Biswal</surname>
<given-names>B</given-names>
</name>
,
<name>
<surname>Yetkin</surname>
<given-names>FZ</given-names>
</name>
,
<name>
<surname>Haughton</surname>
<given-names>VM</given-names>
</name>
,
<name>
<surname>Hyde</surname>
<given-names>JS</given-names>
</name>
(
<year>1995</year>
)
<article-title>Functional connectivity in the motor cortex of resting human brain using echo-planar MRI</article-title>
.
<source>Magn Reson Med</source>
<volume>34(4)</volume>
:
<fpage>537</fpage>
<lpage>541</lpage>
<pub-id pub-id-type="pmid">8524021</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-McKeown1">
<label>22</label>
<mixed-citation publication-type="journal">
<name>
<surname>McKeown</surname>
<given-names>MJ</given-names>
</name>
,
<name>
<surname>Makeig</surname>
<given-names>S</given-names>
</name>
,
<name>
<surname>Brown</surname>
<given-names>GG</given-names>
</name>
,
<name>
<surname>Jung</surname>
<given-names>TP</given-names>
</name>
,
<name>
<surname>Kindermann</surname>
<given-names>SS</given-names>
</name>
,
<etal>et al</etal>
(
<year>1998</year>
)
<article-title>Analysis of fMRI data by blind separation into independent spatial components</article-title>
.
<source>Hum Brain Mapp</source>
<volume>6(3)</volume>
:
<fpage>160</fpage>
<lpage>188</lpage>
<pub-id pub-id-type="pmid">9673671</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Beckmann1">
<label>23</label>
<mixed-citation publication-type="journal">
<name>
<surname>Beckmann</surname>
<given-names>CF</given-names>
</name>
,
<name>
<surname>DeLuca</surname>
<given-names>M</given-names>
</name>
,
<name>
<surname>Devlin</surname>
<given-names>JT</given-names>
</name>
,
<name>
<surname>Smith</surname>
<given-names>SM</given-names>
</name>
(
<year>2005</year>
)
<article-title>Investigations into resting-state connectivity using independent component analysis</article-title>
.
<source>Philos Trans R Soc Lond B Biol Sci</source>
<volume>360(1457)</volume>
:
<fpage>1001</fpage>
<lpage>1013</lpage>
<pub-id pub-id-type="pmid">16087444</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Esposito1">
<label>24</label>
<mixed-citation publication-type="journal">
<name>
<surname>Esposito</surname>
<given-names>F</given-names>
</name>
,
<name>
<surname>Aragri</surname>
<given-names>A</given-names>
</name>
,
<name>
<surname>Pesaresi</surname>
<given-names>I</given-names>
</name>
,
<name>
<surname>Cirillo</surname>
<given-names>S</given-names>
</name>
,
<name>
<surname>Tedeschi</surname>
<given-names>G</given-names>
</name>
,
<etal>et al</etal>
(
<year>2008</year>
)
<article-title>Independent component model of the default-mode brain function: combining individual-level and population-level analysis in resting-state fMRI</article-title>
.
<source>Magn Reson Imaging</source>
<volume>26(7)</volume>
:
<fpage>905</fpage>
<lpage>913</lpage>
<pub-id pub-id-type="pmid">18486388</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Goebel1">
<label>25</label>
<mixed-citation publication-type="journal">
<name>
<surname>Goebel</surname>
<given-names>R</given-names>
</name>
,
<name>
<surname>Roebroeck</surname>
<given-names>A</given-names>
</name>
,
<name>
<surname>Kim</surname>
<given-names>DS</given-names>
</name>
,
<name>
<surname>Formisano</surname>
<given-names>E</given-names>
</name>
(
<year>2003</year>
)
<article-title>Investigating directed cortical interactions in time-resolved fMRI data using vector autoregressive modeling and Granger causality mapping</article-title>
.
<source>Magn Reson Imaging</source>
<volume>21(10)</volume>
:
<fpage>1251</fpage>
<lpage>1261</lpage>
<pub-id pub-id-type="pmid">14725933</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Davey1">
<label>26</label>
<mixed-citation publication-type="other">Davey CE, Grayden DB, Gavrilescu M, Egan GF, Johnston LA (2012) The equivalence of linear gaussian connectivity techniques. Hum Brain Mapp: doi:10.1002/hbm.22043.</mixed-citation>
</ref>
<ref id="pone.0059331-Demirci1">
<label>27</label>
<mixed-citation publication-type="journal">
<name>
<surname>Demirci</surname>
<given-names>O</given-names>
</name>
,
<name>
<surname>Stevens</surname>
<given-names>MC</given-names>
</name>
,
<name>
<surname>Andreasen</surname>
<given-names>NC</given-names>
</name>
,
<name>
<surname>Michael</surname>
<given-names>A</given-names>
</name>
,
<name>
<surname>Liu</surname>
<given-names>J</given-names>
</name>
,
<etal>et al</etal>
(
<year>2009</year>
)
<article-title>Investigation of relationships between fMRI brain networks in the spectral domain using ICA and Granger causality reveals distinct difference between schizophrenia patients and healthy controls</article-title>
.
<source>Neuroimage</source>
<volume>46(2)</volume>
:
<fpage>419</fpage>
<lpage>431</lpage>
<pub-id pub-id-type="pmid">19245841</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Stevens1">
<label>28</label>
<mixed-citation publication-type="journal">
<name>
<surname>Stevens</surname>
<given-names>MC</given-names>
</name>
,
<name>
<surname>Pearlson</surname>
<given-names>GD</given-names>
</name>
,
<name>
<surname>Calhoun</surname>
<given-names>VD</given-names>
</name>
(
<year>2009</year>
)
<article-title>Changes in the interaction of resting-state neural networks from adolescence to adulthood</article-title>
.
<source>Hum Brain Mapp</source>
<volume>30(8)</volume>
:
<fpage>2356</fpage>
<lpage>2366</lpage>
<pub-id pub-id-type="pmid">19172655</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Sridharan1">
<label>29</label>
<mixed-citation publication-type="journal">
<name>
<surname>Sridharan</surname>
<given-names>D</given-names>
</name>
,
<name>
<surname>Levitin</surname>
<given-names>DJ</given-names>
</name>
,
<name>
<surname>Menon</surname>
<given-names>V</given-names>
</name>
(
<year>2008</year>
)
<article-title>A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks</article-title>
.
<source>Proc Natl Acad Sci U S A</source>
<volume>105(34)</volume>
:
<fpage>12569</fpage>
<lpage>12574</lpage>
<pub-id pub-id-type="pmid">18723676</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Jiao1">
<label>30</label>
<mixed-citation publication-type="journal">
<name>
<surname>Jiao</surname>
<given-names>Q</given-names>
</name>
,
<name>
<surname>Lu</surname>
<given-names>G</given-names>
</name>
,
<name>
<surname>Zhang</surname>
<given-names>Z</given-names>
</name>
,
<name>
<surname>Zhong</surname>
<given-names>Y</given-names>
</name>
,
<name>
<surname>Wang</surname>
<given-names>Z</given-names>
</name>
,
<etal>et al</etal>
(
<year>2011</year>
)
<article-title>Granger causal influence predicts BOLD activity levels in the default mode network</article-title>
.
<source>Hum Brain Mapp</source>
<volume>32(1)</volume>
:
<fpage>154</fpage>
<lpage>161</lpage>
<pub-id pub-id-type="pmid">21157880</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Heatherton1">
<label>31</label>
<mixed-citation publication-type="journal">
<name>
<surname>Heatherton</surname>
<given-names>TF</given-names>
</name>
,
<name>
<surname>Kozlowski</surname>
<given-names>LT</given-names>
</name>
,
<name>
<surname>Frecker</surname>
<given-names>RC</given-names>
</name>
,
<name>
<surname>Fagerström</surname>
<given-names>KO</given-names>
</name>
(
<year>1991</year>
)
<article-title>The Fagerström test for nicotine dependence: a revision of the Fagerström tolerance questionnaire</article-title>
.
<source>Br J Addict</source>
<volume>86(9)</volume>
:
<fpage>1119</fpage>
<lpage>1127</lpage>
<pub-id pub-id-type="pmid">1932883</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Ding1">
<label>32</label>
<mixed-citation publication-type="other">Ding X, Lee JH, Lee SW (2012) Investigation of smoking related features in spatio-spectral domain on resting-state fMRI data using nonnegative matrix factorization. Proc of IEEE Int Conf on Systems, Man and Cybernetics (SMC2012), Oct. 14–17, Seoul, Korea: 571–574.</mixed-citation>
</ref>
<ref id="pone.0059331-Calhoun1">
<label>33</label>
<mixed-citation publication-type="journal">
<name>
<surname>Calhoun</surname>
<given-names>VD</given-names>
</name>
,
<name>
<surname>Adali</surname>
<given-names>T</given-names>
</name>
,
<name>
<surname>Pearlson</surname>
<given-names>GD</given-names>
</name>
,
<name>
<surname>Pekar</surname>
<given-names>JJ</given-names>
</name>
(
<year>2001</year>
)
<article-title>A method for making group inferences from functional MRI data using independent component analysis</article-title>
.
<source>Hum Brain Mapp</source>
<volume>14(3)</volume>
:
<fpage>140</fpage>
<lpage>151</lpage>
<pub-id pub-id-type="pmid">11559959</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Bell1">
<label>34</label>
<mixed-citation publication-type="journal">
<name>
<surname>Bell</surname>
<given-names>AJ</given-names>
</name>
,
<name>
<surname>Sejnowski</surname>
<given-names>TJ</given-names>
</name>
(
<year>1995</year>
)
<article-title>An information-maximization approach to blind separation and blind deconvolution</article-title>
.
<source>Neural Comput</source>
<volume>7(6)</volume>
:
<fpage>1129</fpage>
<lpage>1159</lpage>
<pub-id pub-id-type="pmid">7584893</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Li1">
<label>35</label>
<mixed-citation publication-type="journal">
<name>
<surname>Li</surname>
<given-names>YO</given-names>
</name>
,
<name>
<surname>Adali</surname>
<given-names>T</given-names>
</name>
,
<name>
<surname>Calhoun</surname>
<given-names>VD</given-names>
</name>
(
<year>2007</year>
)
<article-title>Estimating the number of independent components for functional magnetic resonance imaging data</article-title>
.
<source>Hum Brain Mapp</source>
<volume>28(11)</volume>
:
<fpage>1251</fpage>
<lpage>1266</lpage>
<pub-id pub-id-type="pmid">17274023</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Himberg1">
<label>36</label>
<mixed-citation publication-type="journal">
<name>
<surname>Himberg</surname>
<given-names>J</given-names>
</name>
,
<name>
<surname>Hyvärinen</surname>
<given-names>A</given-names>
</name>
,
<name>
<surname>Esposito</surname>
<given-names>F</given-names>
</name>
(
<year>2004</year>
)
<article-title>Validating the independent components of neuroimaging time series via clustering and visualization</article-title>
.
<source>Neuroimage</source>
<volume>22(3)</volume>
:
<fpage>1214</fpage>
<lpage>1222</lpage>
<pub-id pub-id-type="pmid">15219593</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Seth1">
<label>37</label>
<mixed-citation publication-type="journal">
<name>
<surname>Seth</surname>
<given-names>AK</given-names>
</name>
(
<year>2005</year>
)
<article-title>Causal connectivity of evolved neural networks during behavior</article-title>
.
<source>Network</source>
<volume>16(1)</volume>
:
<fpage>35</fpage>
<lpage>54</lpage>
<pub-id pub-id-type="pmid">16350433</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Schwarz1">
<label>38</label>
<mixed-citation publication-type="journal">
<name>
<surname>Schwarz</surname>
<given-names>G</given-names>
</name>
(
<year>1978</year>
)
<article-title>Estimating the dimension of a model</article-title>
.
<source>Ann Stat</source>
<volume>6(2)</volume>
:
<fpage>461</fpage>
<lpage>464</lpage>
</mixed-citation>
</ref>
<ref id="pone.0059331-Seth2">
<label>39</label>
<mixed-citation publication-type="journal">
<name>
<surname>Seth</surname>
<given-names>AK</given-names>
</name>
(
<year>2010</year>
)
<article-title>A MATLAB toolbox for Granger causal connectivity analysis</article-title>
.
<source>J Neurosci Methods</source>
<volume>186(2)</volume>
:
<fpage>262</fpage>
<lpage>273</lpage>
<pub-id pub-id-type="pmid">19961876</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Smith1">
<label>40</label>
<mixed-citation publication-type="journal">
<name>
<surname>Smith</surname>
<given-names>SM</given-names>
</name>
,
<name>
<surname>Miller</surname>
<given-names>KL</given-names>
</name>
,
<name>
<surname>Salimi-Khorshidi</surname>
<given-names>G</given-names>
</name>
,
<name>
<surname>Webster</surname>
<given-names>M</given-names>
</name>
,
<name>
<surname>Beckmann</surname>
<given-names>CF</given-names>
</name>
,
<etal>et al</etal>
(
<year>2011</year>
)
<article-title>Network modelling methods for FMRI</article-title>
.
<source>Neuroimage</source>
<volume>54(2)</volume>
:
<fpage>875</fpage>
<lpage>891</lpage>
<pub-id pub-id-type="pmid">20817103</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Deshpande1">
<label>41</label>
<mixed-citation publication-type="journal">
<name>
<surname>Deshpande</surname>
<given-names>G</given-names>
</name>
,
<name>
<surname>Hu</surname>
<given-names>X</given-names>
</name>
,
<name>
<surname>Stilla</surname>
<given-names>R</given-names>
</name>
,
<name>
<surname>Sathian</surname>
<given-names>K</given-names>
</name>
(
<year>2008</year>
)
<article-title>Effective connectivity during haptic perception: a study using Granger causality analysis of functional magnetic resonance imaging data</article-title>
.
<source>Neuroimage</source>
<volume>40(4)</volume>
:
<fpage>1807</fpage>
<lpage>1814</lpage>
<pub-id pub-id-type="pmid">18329290</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Naqvi1">
<label>42</label>
<mixed-citation publication-type="journal">
<name>
<surname>Naqvi</surname>
<given-names>NH</given-names>
</name>
,
<name>
<surname>Bechara</surname>
<given-names>A</given-names>
</name>
(
<year>2010</year>
)
<article-title>The insula and drug addiction: an interoceptive view of pleasure, urges, and decision-making</article-title>
.
<source>Brain Struct Funct</source>
<volume>214(5–6)</volume>
:
<fpage>433</fpage>
<lpage>450</lpage>
</mixed-citation>
</ref>
<ref id="pone.0059331-Hong2">
<label>43</label>
<mixed-citation publication-type="journal">
<name>
<surname>Hong</surname>
<given-names>LE</given-names>
</name>
,
<name>
<surname>Hodgkinson</surname>
<given-names>CA</given-names>
</name>
,
<name>
<surname>Yang</surname>
<given-names>Y</given-names>
</name>
,
<name>
<surname>Sampath</surname>
<given-names>H</given-names>
</name>
,
<name>
<surname>Ross</surname>
<given-names>TJ</given-names>
</name>
,
<etal>et al</etal>
(
<year>2010</year>
)
<article-title>A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction</article-title>
.
<source>Proc Natl Acad Sci U S A</source>
<volume>107(30)</volume>
:
<fpage>13509</fpage>
<lpage>13514</lpage>
<pub-id pub-id-type="pmid">20643934</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Bierut1">
<label>44</label>
<mixed-citation publication-type="journal">
<name>
<surname>Bierut</surname>
<given-names>LJ</given-names>
</name>
,
<name>
<surname>Stitzel</surname>
<given-names>JA</given-names>
</name>
,
<name>
<surname>Wang</surname>
<given-names>JC</given-names>
</name>
,
<name>
<surname>Hinrichs</surname>
<given-names>AL</given-names>
</name>
,
<name>
<surname>Grucza</surname>
<given-names>RA</given-names>
</name>
,
<etal>et al</etal>
(
<year>2008</year>
)
<article-title>Variants in the nicotinic receptors alter the risk for nicotine dependence</article-title>
.
<source>Am J Psychiatry</source>
<volume>165(9)</volume>
:
<fpage>1163</fpage>
<lpage>1171</lpage>
<pub-id pub-id-type="pmid">18519524</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Hasselmo1">
<label>45</label>
<mixed-citation publication-type="journal">
<name>
<surname>Hasselmo</surname>
<given-names>ME</given-names>
</name>
,
<name>
<surname>McGaughy</surname>
<given-names>J</given-names>
</name>
(
<year>2004</year>
)
<article-title>High acetylcholine levels set circuit dynamics for attention and encoding and low acetylcholine levels set dynamics for consolidation</article-title>
.
<source>Prog Brain Res</source>
<volume>145</volume>
:
<fpage>207</fpage>
<lpage>231</lpage>
<pub-id pub-id-type="pmid">14650918</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Bishop1">
<label>46</label>
<mixed-citation publication-type="journal">
<name>
<surname>Bishop</surname>
<given-names>S</given-names>
</name>
,
<name>
<surname>Duncan</surname>
<given-names>J</given-names>
</name>
,
<name>
<surname>Brett</surname>
<given-names>M</given-names>
</name>
,
<name>
<surname>Lawrence</surname>
<given-names>AD</given-names>
</name>
(
<year>2004</year>
)
<article-title>Prefrontal cortical function and anxiety: controlling attention to threat-related stimuli</article-title>
.
<source>Nat Neurosci</source>
<volume>7(2)</volume>
:
<fpage>184</fpage>
<lpage>188</lpage>
<pub-id pub-id-type="pmid">14703573</pub-id>
</mixed-citation>
</ref>
<ref id="pone.0059331-Omvik1">
<label>47</label>
<mixed-citation publication-type="journal">
<name>
<surname>Omvik</surname>
<given-names>P</given-names>
</name>
(
<year>1996</year>
)
<article-title>How smoking affects blood pressure</article-title>
.
<source>Blood Press</source>
<volume>5(2)</volume>
:
<fpage>71</fpage>
<lpage>77</lpage>
<pub-id pub-id-type="pmid">9162447</pub-id>
</mixed-citation>
</ref>
</ref-list>
</back>
</pmc>
</record>

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