Noninvasive Measurement of the Cerebral Blood Flow Response in Human Lateral Geniculate Nucleus With Arterial Spin Labeling fmri

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1 Human Bain Mapping 29: (2008) TECHNICAL REPORT Noninvasive Measuement of the Ceebal Blood Flow Response in Human Lateal Geniculate Nucleus With Ateial Spin Labeling fmri Kun Lu, 1,2 * Joanna E. Pethen, 1,2 Robet O. Duncan, 3 Linda M. Zangwill, 3 and Thomas T. Liu 1,2 1 Cente fo Functional MRI, Univesity of Califonia San Diego, La Jolla, Califonia 2 Depatment of Radiology, Univesity of Califonia San Diego, La Jolla, Califonia 3 Hamilton Glaucoma Cente, Univesity of Califonia San Diego, La Jolla, Califonia Abstact: To date, functional magnetic esonance imaging (fmri) studies of the lateal geniculate nucleus (LGN) have pimaily focused on measues of the blood oxygenation level dependent (BOLD) signal. Ateial spin labeling (ASL) is an MRI method that can povide diect measues of functional ceebal blood flow (CBF) changes. Because CBF is a well-defined physiological quantity that contibutes to BOLD contast, CBF measues can be used to impove the quantitative intepetation of fmri studies. Howeve, due in pat to the low intinsic signal-to-noise atio of the ASL method, measues of functional CBF changes in the LGN ae challenging and have not peviously been epoted. In this study, we demonstate the feasibility of using ASL fmri to measue the CBF esponse of the LGN to visual stimulation on a 3 T MRI system. The use of backgound suppession and physiological noise eduction techniques allowed eliable detection of LGN activation in all five subjects studied. The measued pecent CBF esponse duing activation anged fom 40 to 100%, assuming no inteaction between the left and ight LGN. Hum Bain Mapp 29: , VC 2007 Wiley-Liss, Inc. Key wods: lateal geniculate nucleus; ateial spin labeling; functional magnetic esonance imaging; backgound suppession; physiological noise eduction INTRODUCTION The lateal geniculate nucleus (LGN) is a subdivision of gay matte in the thalamus that is esponsible fo elaying Contact gant sponso: NIH; Contact gant numbe: 5R01EY *Coespondence to: Kun Lu, Ph.D., UCSD Cente fo Functional MRI, 9500 Gilman Dive, MC 0677, La Jolla, CA kunlu@ucsd.edu Received fo publication 2 June 2006; Revised 4 June 2007; Accepted 28 June 2007 DOI: /hbm Published online 21 August 2007 in Wiley InteScience (www. intescience.wiley.com). visual infomation fom the etina to the pimay visual cotex. Noninvasive imaging of the LGN can povide impotant infomation to aid ou undestanding of the visual system in both healthy and diseased states. Fo example, neuodegeneation associated with pimay open angle glaucoma is not esticted to the etinal ganglion cells, but athe extends to the taget neuons in the LGN [Lutha et al., 2005; Yucel et al., 2000, 2001, 2003]. Studies of functional changes in the LGN may theefoe aid in the detection and undestanding of neuodegeneation in glaucoma. Compaed to visual cotex studies, functional imaging of the LGN is technically challenging because of the LGN s elatively small size ( mm 3 [Andews et al., 1997]) and subcotical location. Pevious functional magnetic VC 2007 Wiley-Liss, Inc.

2 Lu et al. esonance imaging (fmri) studies have used the blood oxygenation level dependent (BOLD) signal to measue functional activation in human LGN [Chen and Zhu, 2001; Chen et al., 1998a,b; Fujita et al., 2001; Kastne et al., 2004; Miki et al., 2001a,b, 2003, 2004, 2005; O Conno et al., 2002] and to map the etinotopic oganization of this stuctue [Chen et al., 1999; Schneide et al., 2004]. Although BOLD fmri povides good sensitivity and spatial esolution, the quantitative intepetation of the BOLD signal is not always staightfowad because of its complex dependence on a numbe of physiological vaiables, such as ceebal blood flow (CBF), the ceebal metabolic ate of oxygen, and ceebal blood volume [Buxton et al., 2004; Kwong et al., 1992; Ogawa et al., 1990]. Intepetation of the BOLD signal is especially poblematic in clinical populations in which changes in the ceebovascula system due to factos such as disease, medication, and age, can significantly alte the BOLD signal [Behzadi and Liu, 2005; D Esposito et al., 2003]. Ateial spin labeling (ASL) is a noninvasive MRI method that can povide quantitative measues of CBF, which is a well-defined physiological quantity [Dete et al., 1992; Williams et al., 1992]. As compaed to BOLD, measues of functional changes in CBF have been shown to exhibit less intesubject vaiability and to be moe obust in the face of baseline vascula changes [Aguie et al., 2002; Bown et al., 2003; Stefanovic et al., 2006; Tjanda et al., 2005; Wang et al., 2003]. It also has been suggested that the CBF signal may be moe localized to bain paenchyma than BOLD [Kim, 1995; Luh et al., 2000]. In addition, CBF measues can be combined with BOLD measues to yield quantitative estimates of changes in oxidative metabolism [Davis et al., 1998; Hoge et al., 1999]. Although ASL has been widely applied to fmri studies of the visual cotex, its application to the study of the LGN has not been peviously epoted, due in pat to its low intinsic signal-tonoise atio (SNR) compaed to BOLD. In a pio study fom ou laboatoy, we showed that the use of etospective physiological noise eduction methods can significantly impove the SNR of the ASL signal in the visual cotex and hippocampal egion [Restom et al., 2006]. Backgound suppession methods have been shown to educe the standad deviation of baseline ASL images, but thei impact on the SNR of functional scans has not been well established [St Lawence et al., 2005; Ye et al., 2000]. In this study, we show that the combination of physiological noise eduction and backgound suppession methods is citical fo the obust detection of functional CBF activation in the LGN. HUMAN SUBJECTS AND EQUIPMENT Five healthy adult subjects (two male) with nomal vision, aged yeas, paticipated in the study. Witten infomed consent was obtained accoding to an Institutional Review Boad appoval fom the Univesity of Califonia, San Diego. All expeiments wee pefomed using a Geneal Electic 3.0-T EXCITE system, with an eight-channel eceive-only head coil. Physiological (cadiac and espiatoy) fluctuations wee ecoded using a pulse oximete (INVIVO Magnitude 3150M patient monito, Olando, Floida) and a espiatoy effot tansduce (TSD201, BioPac Systems, Goleta, CA), espectively. The visual stimulus used in the study was geneated using the Psychophysics Toolbox [Bainad, 1997; Pelli, 1997] fo Matlab (Mathwoks, Natick, MA) on a PoweBook G3 compute (Apple, Cupetino, CA), and was pojected onto a back pojection sceen placed inside the scanne boe using an NEC Solutions (Itasca, IL) LT 157 liquid cystal display pojecto. The geneal specifications of the visual pesentation system wee as follows: viewing distance 5 60 cm; field of view H V; maximum luminance cd/m 2 ; esolution H V; 60-Hz efesh ate. EXPERIMENTAL PROTOCOL Data Acquisition Functional data wee acquied using a quantitative pulsed ASL sequence (PICORE QUIPSS II) [Wong et al., 1998] with single-shot spial eadout. Five contiguous axial slices, each 5-mm thick, wee acquied at the level of the LGN and pimay visual cotex. A tagging slab of width 200 mm was placed 10 mm below the most infeio slice. The QUIPSS II paametes TI1 and TI2 wee chosen to satisfy the following two citeia [Wong et al., 1998]: (1) TI1 is less than the natual tempoal bolus width d and (2) TI2- TI1 is geate than the longest tansit delay Dt. We used measues of the ASL signal ove a ange of invesion times to estimate the bolus width and tansit delays and detemined that TI ms and TI2 5 1,400 ms wee consistent with the QUIPSS II equiements [Buxton et al., 1998]. A total of 80 images (inteleaved tag and contol) pe un wee acquied. Othe paametes wee as follows: TE 3.2 ms, matix size , FOV 22 cm, flip angle 908, TR 3.0 s. Backgound suppession was used to educe the static tissue components [Ye et al., 2000]. It consisted of a pesatuation pulse tain with two 908 windowed sinc pulses, with cushe gadients to satuate the imaging slab immediately pio to the application of the ASL tagging pulse and two adiabatic invesion pulses placed at 233 and 833 ms afte the pesatuation pulse tain. The timing of the invesion pulses was optimized to achieve a theoetical attenuation of at least 95% in all imaging slices, assuming typical T1 values of 1,331, 832, and 3,900 ms at 3.0 T fo gay matte, white matte, and CSF, espectively [Luh et al., 2000; Wansapua et al., 1999]. The numbe of invesion pulses was limited to 2 in ode to minimize the losses in the pefusion signal because of the impefections of the pulses and magnetization tansfe effects [Gacia et al., 2005b; Talagala et al., 2004; Ye et al., 2000]. The emaining tissue signal component in the LGN aea aveaged among the five subjects afte suppession was found 1208

3 Pefusion Activation in Human LGN expeimentally to be 6, 10, and 12% in the LGN slices (slices 2, 3, and 4, espectively). Fo each subject, two 4-min backgound-suppessed ASL uns wee acquied. In addition to the backgound-suppessed ASL uns, two additional 4-min uns using the ASL sequence without backgound suppession wee acquied. In these uns, a dual-echo single-shot spial acquisition (TE 5 3.2, 25 ms) was used. Duing all fou functional expeiments, cadiac and espiatoy activities wee ecoded. A high-esolution stuctual scan was also acquied using an invesion-pepaed fast spoiled gadient echo pulse sequence, with an invesion delay of 450 ms, 124 axial slices (1-mm thick), FOV 25 cm, matix size , TR 7.9 ms, TE 3.1 ms, flip angle 128, and bandwidth khz. Duing each functional un, the subjects wee instucted to passively view a visual stimulus with a cental fixation point. The visual stimulus consisted of contast-evesing (8 Hz) checkeboad pattens (100% contast, 258 hoizontal and 158 vetical apetue) that altenated between the left and ight visual fields in a block design (left visual field fist, 30 s left, 30 s ight, a total of fou epeats fo each visual field, total time 4 min). The cental fixation point (0.68) was visible thoughout the expeiment. Data Analysis The fist fou images of each scan wee excluded fom data analysis to allow the MRI signal to each steady state. All functional uns wee motion-coected and then egisteed to the fist functional un using AFNI softwae [Cox, 1996]. The anatomical volume was egisteed to the functional volume with an in-house MATLAB pogam that utilizes the scanne coodinates of each volume. The accuacy of this egistation pogam was veified on phantoms, using high-esolution inteleaved spial images obtained with the same spial pulse sequence used fo the functional studies. Functional CBF esponses wee computed fom the suound subtaction of the contol and tag image seies in the backgound-suppessed data. If odd indices coespond to contol images and even indices coespond to tag images, then the suound subtaction ove an image acquisition time seies y[n], n 5 0, 1, 2,... poduces the pefusion weighted time seies: {y[1] 2 (y[0] 1 y[2])/2, (y[1] 1 y[3])/2 2 y[2],...} [Liu and Wong, 2005]. Functional BOLD esponses wee computed fom the unning aveage (aveage of each image with the mean of its two neaest neighbos) of the second echo (TE 5 25 ms) nonbackgound-suppessed data [Liu and Wong, 2005]. CBF esponses wee also fomed fom the fist echo (TE 5 3 ms) of the nonbackgound-suppessed data, but as shown in the Results section, the SNR of these data was too low to povide eliable detection of LGN activation, even afte physiological noise coection. Statistical analysis of the data was pefomed using a geneal linea model (GLM) appoach fo the analysis of ASL data [Restom et al., 2006]. The stimulus-elated egesso in the GLM was assumed to be a vecto, obtained by convolving the stimulus patten with a gamma density function of the fom hðtþ ¼ðsn!Þ 1 ððt DtÞ=sÞ n expð ðt DtÞ=sÞ fo t Dt and 0 othewise, with s 5 1.2, n 5 3, and Dt 5 1 [Boynton et al., 1996]. The measued cadiac and espiatoy fluctuation data wee included in the GLM as egessos to model the physiological modulation of the ASL signal. In addition, a constant and a linea tem wee included as nuisance egessos. The data fom the two uns (eithe two backgound suppessed o two nonbackgound suppessed uns) wee concatenated pio to analysis with an expanded GLM (cf. Eq. (10) in Restom et al. [2006]). As descibed in Restom et al. [2006], the expanded GLM allowed fo diffeent physiological and nuisance egessos fo each un. The estimated physiological noise components wee emoved fom the oiginal data to fom the noise-coected CBF and BOLD time seies. Pobability values (P values) wee calculated on a pe-voxel basis using the methods descibed in Restom et al. [2006]. A Sattethwaite appoximation was used to account fo the noise covaiance intoduced by the ASL suound subtaction pocess [Kiebel et al., 2003; Restom et al., 2006; Wosley and Fiston, 1995]. Because of the low SNR of the CBF measues, detection of functional CBF activation was confined to an anatomical egion of inteest (ROI) encompassing the LGN egion. This ROI was defined on the stuctual images based on anatomical landmaks suounding the LGN (the hippocampal fomation and optical adiation [Fujita et al., 2001]). The size of the ROI (22 30 voxels pe hemisphee) was chosen to be lage than the actual size of the LGN to allow fo patial-voluming and image-bluing effects. A pe-voxel theshold of P < (coesponding to P < 0.05 afte coection fo multiple compaisons) with a neaest neighbo clusteing citeia was used to define voxels with significant functional CBF activation. Coection fo multiple compaisons was pefomed using the AFNI pogam AlphaSim [Cox, 1996; Foman et al., 1995; Xiong et al., 1995], with a minimum cluste size of two and inplane full-width half maximum (FWHM) of 5.8 mm mm. To maintain the same P-value theshold acoss subjects, the lagest ROI size (30 voxels) was used. Estimates of the FWHM wee obtained fom Bloch simulations of the spial acquisition pocess with an assumed T2* 5 30 ms, which was measued fom the dual echo data. Fo detection of BOLD activation, we used the same anatomical ROI and pe-voxel theshold as fo the functional CBF detection. In addition, to facilitate compaison with pio studies, we also consideed a moe stingent pevoxel theshold of P < , coesponding to P < afte coection fo multiple compaisons within the anatomical ROI. Fo each subject and each hemisphee, aveage CBF and BOLD time couses wee obtained by aveaging the individual noise-coected time couses acoss activated CBF and BOLD voxels, espectively. Pecent change CBF and BOLD esponses wee calculated by dividing the espective time couse by its baseline, which is defined as the 1209

4 Lu et al. mean signal duing the off peiod of the visual stimulus fo each LGN. The tempoal vaiation of the pefusion measuements was assessed in the active voxels of the left and ight LGN by calculating the standad deviation of the esidual noise estimated fom the GLM. Without physiological noise coection, the esidual noise included the cadiac and espiatoy induced vaiations; wheeas with physiological noise coection, estimates of the cadiac and espiatoy vaiations wee emoved fom the esidual noise. To compensate fo the highe eceive gains used in the backgound suppessed uns, the standad deviations of the backgound suppessed esidual noise components wee scaled down by the elative diffeence in the eceive gains to achieve the same effective gain fo all the noise tems. RESULTS Bilateal CBF and BOLD activation within the LGN was detected in all subjects. Figue 1A shows an example CBF activation map fom Subject 1, who demonstated activation in both the left and ight LGN and visual cotex. Figue 1B shows the CBF time couses aveaged ove the active CBF voxels fo the left and ight LGN. Both aveage time couses ae highly coelated with thei espective stimulus pattens ( > 0.8). Table I summaizes the pecent CBF and BOLD esponses on a pe subject basis. The pecent change in CBF esponse anged fom 40 to 100%, with the exception of the esponse in Subject 5 s left LGN, which had a physiologically unlikely pecent CBF change (400%). An examination of Subject 5 s data evealed a low CBF estimate duing the baseline peiod in the left LGN aea, as compaed to the ight LGN. The low baseline CBF estimate was in tun due to the pesence of lage negative values in the CBF time seies duing two out of the fou baseline peiods. As the CBF time couse is obtained fom the suound subtaction of the contol and tag images, the pesence of esidual image noise components that ae not emoved by backgound suppession o physiological noise coection can give ise to anomalous negative values due to the diffeencing of the noise components. The numbe of active CBF voxels pe hemisphee anged fom two to fou among the five subjects, coesponding to activation volumes of mm 3. The measued activation volume hee is simila to the peviously epoted BOLD-based activation volumes of mm 3 [Chen et al., 1999; Kastne et al., 2004], and agee easonably with the epoted anatomical volume mm 3 [Andews et al., 1997]. At a theshold of P < 0.05 (same as the theshold used fo the CBF with coection fo multiple compaisons), the measued pecent BOLD esponse anged fom 0.47% to Figue 1. A: Subject 1 s CBF activation map (P < 0.05 coected fo multiple compaisons) supeimposed on the anatomical image. Activation within the pimay visual cotex and the LGN (indicated by the aows) can be seen. B: CBF time couses aveaged ove active voxels within the left (blue) and ight (ed) LGN functional ROIs. The blue and ed bas below the gaph indicate the peiods of visual stimulation pesented to the contalateal visual fields. [Colo figue can be viewed in the online issue, which is available at

5 Pefusion Activation in Human LGN TABLE I. Summay of the measued CBF and BOLD esponses duing LGN activation CBF (P < 0.05) BOLD (P < 0.05) BOLD (P < ) Subject no. No. of voxels % change No. of voxels % change Ovelap with CBF (no. of voxels) No. of voxels % change Ovelap with CBF (no. of voxels) 1 L R L R L R L R n/a 0 5 L a R L, left LGN; R, ight LGN. a This lage pecent CBF incease is discussed futhe in the text. 0.97%, and the numbes of active BOLD voxels anged fom 2 to 14 coesponding to activation volumes of mm 3. Ovelap of the activated CBF and BOLD voxels was obseved in all but two of the LGN (Table I). When using the lowe coected theshold of P < , the detected numbe of active BOLD voxels anged fom 2 to 7 coesponding to LGN volumes of mm 3, except in Subject 4 s ight LGN, whee no BOLD activation was found. When using this lowe theshold, ovelap between the BOLD and CBF activation egions was found in only 4 of the 10 LGN. Figue 2A compaes the numbe of activated CBF voxels with and without the use of backgound suppession and physiological noise coection. In the absence of backgound suppession and physiological noise coection, no active LGN voxels wee found in any of the five subjects. Afte applying physiological noise coection to the nonbackgound-suppessed data, one subject showed discenable activation. With backgound suppession alone, two subjects showed significant activation. The use of both physiological noise coection and backgound suppession esulted in the lagest impovement in the SNR of the ASL data, with the detection of LGN activation in all five subjects. Figue 2B compaes the standad deviation of the esidual noise component of the GLM in the LGN voxels with and without the use of backgound suppession and physiological noise coection. A eduction of 61 75% in the standad deviation was obseved afte backgound suppession. Applying physiological noise coection to the backgound suppessed data povided an additional eduction of 6 18%. The combination of the two methods educed the standad deviation of the esidual noise by 75 89% in the five subjects. DISCUSSION We have shown that CBF activation within the LGN can be measued using ASL fmri. To ou knowledge, this is the fist quantitative measue of the functional CBF esponse in the human LGN. Despite the SNR gains achieved with the use of physiological noise eduction and backgound suppession methods, ASL is still an inheently low SNR technique and necessitates the use of lage voxels than those typically used in BOLD fmri studies. The voxel size used hee (3.44 mm mm 3 5 mm) Figue 2. A: Numbe of activated voxels detected in each subject (sum of the left and ight LGN voxels) and B: Standad deviation of the estimated esidual noise in LGN voxels when no coection methods wee applied (fist goup on left), only physiological noise eduction was applied (2nd goup), only backgound suppession (BGS) was applied (3d goup), and both physiological noise eduction and BGS wee applied (4th goup). The lagest impovement in the sensitivity of the detection occued when both BGS and physiological noise eduction wee used. A value lowe than 1 in (A) indicates no active voxels wee found. [Colo figue can be viewed in the online issue, which is available at

6 Lu et al. was chosen afte pefoming peliminay expeiments with slice thicknesses of 3 and 4 mm, but the SNR using these smalle voxels was too low to povide obust detection of CBF activation in the LGN. The use of lage voxels is likely to have caused undeestimation of the pecentage signal change duing activation. Indeed, the measued BOLD pecent change of 0.47% 0.97% is smalle than the 1.2% measued by Kastne et al. [2004] at 3 T using 3.17 mm mm mm voxels. Othe ecently published epots indicate pecent BOLD changes of 1.63% 3.09% at 1.5 T fo 3.17 mm mm 3 3 mm voxels [Fujita et al., 2001] and 2.2% at 4 T fo 1.56 mm mm 3 3 mm voxels [Chen et al., 1999]. When using the same theshold (pe-voxel P < coesponding to P < 0.05 afte coection fo multiple compaisons) to detect active CBF and BOLD voxels, the numbe of active BOLD voxels (2 14) was geate than the numbe of active CBF voxels (2 4), eflecting in pat the lowe SNR of the CBF measues. Both the pe-voxel and coected P- values ae highe than the coesponding P-values used in pio BOLD studies of the LGN. The use of a highe coected theshold and a elatively small anatomical ROI in this study was motivated by the low SNR of the CBF measues. The thesholds used in pio BOLD studies have vaied geatly depending on the study design and magnetic field stength, with coected P-values of at 4 T, 0.01 at 3 T, and 0.05 at 1.5 T [Chen et al., 1998b, 1999; Fujita et al., 2001; Kastne et al., 2004]. In addition, as compaed to the cuent study, the pio studies used a lage ROI (typically 1,000 2,000 voxels) when coecting fo multiple compaisons, esulting in lage elative diffeences between the coected and pe-voxel thesholds. Because of the highe thesholds used in this study, we found that the numbe of active BOLD voxels was geate than the peviously epoted values. When the coected theshold in this study was educed to , the pe-voxel theshold deceased to a value of , which is oughly compaable to the epoted pe-voxel theshold of used by Chen et al. [1999]. At this lowe theshold, the measued BOLD activation volume ( mm 3 ) was found to be compaable to peviously epoted values [Chen et al., 1998b, 1999; Fujita et al., 2001; Kastne et al., 2004]. A compaison of the active BOLD and CBF egions showed a patial ovelap of the two egions, with the CBF egion typically confined to the paenchyma of the thalamus, wheeas the BOLD egion consistently extended towad the lateal infeio o posteio infeio edge of the thalamus. In addition, the amount of ovelap deceased as the theshold on the BOLD activation became moe stingent. These findings ae consistent with those of a pevious study of moto cotex activation by Luh et al. [2000], which concluded that the CBF signal is pimaily localized to the bain paenchyma, wheeas the BOLD signal is moe weighted to the venous compatment. Ou esults indicate that backgound suppession and physiological noise coection ae citical fo the detection of functional CBF changes in the LGN. The eduction of noise components (e.g. due to espiation-induced motion and magnetic field fluctuations) with backgound suppession was sufficient to allow fo detection of activation in Subjects 1 and 2, who exhibited smalle esidual noise levels pio to suppession. Fo Subjects 3 though 5, who exhibited highe initial esidual noise levels, the combination of backgound suppession and physiological noise coection was necessay to educe the esidual noise to levels that allowed fo detection of activation. The futhe eduction of the esidual noise by applying physiological noise coection to the backgound suppessed data most likely eflects the pesence of fluctuations in the CBF signal, such as espiatoy modulation of CBF though changes in cabon dioxide [Wise et al., 2004] and cadiac modulations of the tag bolus (discussed late and in Wu and Wong [2006]). Since these factos diectly affect the CBF signal, they ae unlikely to be educed by the attenuation of the static tissue component that is achieved by backgound suppession. Ou esults also indicate that even with the application of backgound suppession and physiological noise eduction methods the SNR of the CBF measues is still significantly lowe than that of the BOLD measues. Othe methods, such as singleshot 3D acquisitions [Gunthe et al., 2005; Talagala et al., 2004], may pove to be useful fo attaining futhe SNR inceases fo functional CBF measues. In addition, Wu et al. [2007] ecently demonstated that pseudocontinuous ASL [Gacia et al., 2005a] with optimized paametes offes highe tagging efficiency and SNR than pulsed ASL fo baseline CBF measues. Futhe studies to detemine whethe pseudocontinuous ASL can povide bette detection of functional CBF changes in the LGN would be useful. It has been ecently demonstated that the CBF signal measued with a PICORE QUIPSS II ASL acquisition depends on the elative position of the tag and QUIPSS II satuation pulses within the cadiac cycle [Wu and Wong, 2006]. The obseved dependence most likely eflects vaiations in the size of the tagged bolus ceated by the QUIPSS II appoach because of cadiac-induced vaiations in blood velocity. The esultant vaiability in the CBF signal can be educed by using cadiac gating of the sequence. Howeve, because the acquisition is no longe synchonized with the stimulus, the gains achieved may be offset by deceases in statistical powe because of the need to esample the data. Futhe wok compaing the elative advantages of cadiac gating vesus physiological noise coection would be useful. Altenatively, the use of a longe TI1 paamete in the ode of about 1 s would decease the sensitivity of the bolus size to cadiac fluctuations. Howeve, the use of a longe TI1 paamete would be inconsistent with the QUIPSS II equiements fo CBF quantification (see Data Acquisition section). In futue wok, it would be useful to detemine whethe a continuous ASL appoach with a tagging duation of 1 s could povide bette pefomance than the pulsed ASL appoach used hee. In this study, the baseline CBF in each LGN was estimated by aveaging the signal measued duing the off peiod (e.g. lack of hemispheic stimulus) fo that LGN. This 1212

7 Pefusion Activation in Human LGN analysis implicitly assumes that the left and ight LGN do not inteact with each othe duing activation, e.g. an incease in CBF in one LGN will not affect CBF in the othe. Depatues fom this assumption can cause bias in the estimates of baseline CBF, which in tun lead to bias in the estimates of the pecent change in CBF. In futue studies, the inclusion of contol peiods duing which neithe LGN is stimulated would be useful fo minimizing these potential biases. The pesent study is an initial demonstation of the feasibility of detecting functional CBF esponses in the LGN with ASL fmri. Because CBF is a fundamental physiological quantity, measues of functional CBF in the LGN may pove useful fo futheing ou undestanding of neuodegeneative diseases of the visual system such as glaucoma. Additional studies to efine the pefomance of ASL methods and demonstate thei application in clinical populations would be useful. REFERENCES Aguie GK, Dete JA, Zaahn E, Alsop DC (2002): Expeimental design and the elative sensitivity of BOLD and pefusion fmri. Neuoimage 15: Andews TJ, Halpen SD, Puves D (1997): Coelated size vaiations in human visual cotex, lateal geniculate nucleus, and optic tact. J Neuosci 17: Behzadi Y, Liu TT (2005): An ateiola compliance model of the ceebal blood flow esponse to neual stimulus. Neuoimage 25: Boynton GM, Engel SA, Glove GH, Heege DJ (1996): Linea systems analysis of functional magnetic esonance imaging in human V1. J Neuosci 16: Bainad DH (1997): The psychophysics toolbox. Spatial Vis 10: Bown GG, Eyle Zoilla LT, Geogy B, Kindemann SS, Wong EC, Buxton RB (2003): BOLD and pefusion esponse to fingethumb apposition afte acetazolamide administation: Diffeential elationship to global pefusion. J Ceeb Blood Flow Metab 23: Buxton RB, Fank LR, Wong EC, Siewet B, Waach S, Edelman RR (1998): A geneal kinetic model fo quantitative pefusion imaging with ateial spin labeling. Magn Reson Med 40: Buxton RB, Uludag K, Dubowitz DJ, Liu TT (2004): Modeling the hemodynamic esponse to bain activation. Neuoimage 23 (Suppl 1):S220 S233. Chen W, Zhu XH (2001): Coelation of activation sizes between lateal geniculate nucleus and pimay visual cotex in humans. Magn Reson Med 45: Chen W, Kato T, Zhu XH, Ogawa S, Tank DW, Ugubil K (1998a): Human pimay visual cotex and lateal geniculate nucleus activation duing visual imagey. Neuoepot 9: Chen W, Kato T, Zhu XH, Stupp J, Ogawa S, Ugubil K (1998b): Mapping of lateal geniculate nucleus activation duing visual stimulation in human bain using fmri. Magn Reson Med 39: Chen W, Zhu XH, Thulbon KR, Ugubil K (1999): Retinotopic mapping of lateal geniculate nucleus in humans using functional magnetic esonance imaging. Poc Natl Acad Sci USA 96: Cox RW (1996): AFNI: Softwae fo analysis and visualization of functional magnetic esonance neuoimages. Comput Biomed Res 29: Davis TL, Kwong KK, Weisskoff RM, Rosen BR (1998): Calibated functional MRI: Mapping the dynamics of oxidative metabolism. Poc Natl Acad Sci USA 95: D Esposito M, Deouell LY, Gazzaley A (2003): Alteations in the BOLD fmri signal with ageing and disease: A challenge fo neuoimaging. Nat Rev Neuosci 4: Dete JA, Leigh JS, Williams DS, Koetsky AP (1992): Pefusion imaging. Magn Reson Med 23: Foman SD, Cohen JD, Fitzgeald M, Eddy WF, Mintun MA, Noll DC (1995): Impoved assessment of significant activation in functional magnetic esonance imaging (fmri): Use of a cluste-size theshold. Magn Reson Med 33: Fujita N, Tanaka H, Takanashi M, Hiabuki N, Abe K, Yoshimua H, Nakamua H (2001): Lateal geniculate nucleus: Anatomic and functional identification by use of MR imaging. AJNR Am J Neuoadiol 22: Gacia DM, de Bazelaie C, Alsop DC (2005a): Pseudo-continuous flow diven adiabatic invesion fo ateial spin labeling. Poceedings of the 13th Scientific Meeting of the Int Soc Magn Reson Med 13:37. Gacia DM, Duhamel G, Alsop DC (2005b): Efficiency of invesion pulses fo backgound suppessed ateial spin labeling. Magn Reson Med 54: Gunthe M, Oshio K, Feinbeg DA (2005): Single-shot 3D imaging techniques impove ateial spin labeling pefusion measuements. Magn Reson Med 54: Hoge RD, Atkinson J, Gill B, Celie GR, Maett S, Pike GB (1999): Investigation of BOLD signal dependence on ceebal blood flow and oxygen consumption: The deoxyhemoglobin dilution model. Magn Reson Med 42: Kastne S, O Conno DH, Fukui MM, Fehd HM, Hewig U, Pinsk MA (2004): Functional imaging of the human lateal geniculate nucleus and pulvina. J Neuophysiol 91: Kiebel SJ, Glase DE, Fiston KJ (2003): A heuistic fo the degees of feedom of statistics based on multiple vaiance paametes. Neuoimage 20: Kim SG (1995): Quantification of elative ceebal blood flow change by flow-sensitive altenating invesion ecovey (FAIR) technique: Application to functional mapping. Magn Reson Med 34: Kwong KK, Belliveau JW, Chesle DA, Goldbeg IE, Weisskoff RM, Poncelet BP, Kennedy DN, Hoppel BE, Cohen MS, Tune R, et al. (1992): Dynamic magnetic esonance imaging of human bain activity duing pimay sensoy stimulation. Poc Natl Acad Sci USA 89: Liu TT, Wong EC (2005): A signal pocessing model fo ateial spin labeling functional MRI. Neuoimage 24: Luh WM, Wong EC, Bandettini PA, Wad BD, Hyde JS (2000): Compaison of simultaneously measued pefusion and BOLD signal inceases duing bain activation with T(1)-based tissue identification. Magn Reson Med 44: Lutha A, Gupta N, Kaufman PL, Weineb RN, Yucel YH (2005): Oxidative injuy by peoxynitite in neual and vascula tissue of the lateal geniculate nucleus in expeimental glaucoma. Exp Eye Res 80: Miki A, Liu GT, Englande SA, van Ep TG, Bonhomme GR, Aleman DO, Liu CS, Haselgove JC (2001a): Functional magnetic esonance imaging of eye dominance at 4 tesla. Ophthalmic Res 33: Miki A, Liu GT, Raz J, Englande SA, Bonhomme GR, Aleman DO, Modestino EJ, Liu CS, Haselgove JC (2001b): Visual acti- 1213

8 Lu et al. vation in functional magnetic esonance imaging at vey high field (4 Tesla). J Neuoophthalmol 21:8 11. Miki A, Liu GT, Goldsmith ZG, Liu CS, Haselgove JC (2003): Deceased activation of the lateal geniculate nucleus in a patient with anisometopic amblyopia demonstated by functional magnetic esonance imaging. Ophthalmologica 217: Miki A, Liu CS, Liu GT (2004): Effects of voxel size on detection of lateal geniculate nucleus activation in functional magnetic esonance imaging. Jpn J Ophthalmol 48: Miki A, Liu GT, Modestino EJ, Bonhomme GR, Liu CS, Haselgove JC (2005): Deceased lateal geniculate nucleus activation in etogeniculate hemianopia demonstated by functional magnetic esonance imaging at 4 Tesla. Ophthalmologica 219: O Conno DH, Fukui MM, Pinsk MA, Kastne S (2002): Attention modulates esponses in the human lateal geniculate nucleus. Nat Neuosci 5: Ogawa S, Lee TM, Kay AR, Tank DW (1990): Bain magnetic esonance imaging with contast dependent on blood oxygenation. Poc Natl Acad Sci USA 87: Pelli DG (1997): The VideoToolbox softwae fo visual psychophysics: Tansfoming numbes into movies. Spat Vis 10: Restom K, Behzadi Y, Liu TT (2006): Physiological noise eduction fo ateial spin labeling functional MRI. Neuoimage 31: Schneide KA, Richte MC, Kastne S (2004): Retinotopic oganization and functional subdivisions of the human lateal geniculate nucleus: A high-esolution functional magnetic esonance imaging study. J Neuosci 24: St Lawence KS, Fank JA, Bandettini PA, Ye FQ (2005): Noise eduction in multi-slice ateial spin tagging imaging. Magn Reson Med 53: Stefanovic B, Wanking JM, Rylande KM, Pike GB (2006): The effect of global ceebal vasodilation on focal activation hemodynamics. Neuoimage 30: Talagala SL, Ye FQ, Ledden PJ, Chesnick S (2004): Whole-bain 3D pefusion MRI at 3.0 T using CASL with a sepaate labeling coil. Magn Reson Med 52: Tjanda T, Books JC, Figueiedo P, Wise R, Matthews PM, Tacey I (2005): Quantitative assessment of the epoducibility of functional activation measued with BOLD and MR pefusion imaging: Implications fo clinical tial design. Neuoimage 27: Wang J, Aguie GK, Kimbeg DY, Roc AC, Li L, Dete JA (2003): Ateial spin labeling pefusion fmri with vey low task fequency. Magn Reson Med 49: Wansapua JP, Holland SK, Dunn RS, Ball WS J. (1999): NMR elaxation times in the human bain at 3.0 tesla. J Magn Reson Imaging 9: Williams DS, Dete JA, Leigh JS, Koetsky AP (1992): Magnetic esonance imaging of pefusion using spin invesion of ateial wate. Poc Natl Acad Sci USA 89: Wise RG, Ide K, Poulin MJ, Tacey I (2004): Resting fluctuations in ateial cabon dioxide induce significant low fequency vaiations in BOLD signal. Neuoimage 21: Wong EC, Buxton RB, Fank LR (1998): Quantitative imaging of pefusion using a single subtaction (QUIPSS and QUIPSS II). Magn Reson Med 39: Wosley KJ, Fiston KJ (1995): Analysis of fmri time-seies evisited again. Neuoimage 2: Wu WC, Wong EC (2006): The effect of cadiac pulsation on fmri data analysis. Poceedings of the 14th Scientific Meeting of the Int Soc Mag Reson Med. p Wu WC, Fenandez-Seaa M, Wehli F, Dete J, Wang J (2007): A theoetical and expeimental investigation of the tagging efficiency of pseudo-continuous ateial spin labeling. Poceedings of the Int Soc Magn Reson Med. p 375. Xiong J, Gao J-H, Lancaste JL, Fox PT (1995): Clusteed pixels analysis fo functional MRI activation studies fo the human bain. Hum Bain Mapp 3: Ye FQ, Fank JA, Weinbege DR, McLaughlin AC (2000): Noise eduction in 3D pefusion imaging by attenuating the static signal in ateial spin tagging (ASSIST). Magn Reson Med 44: Yucel YH, Zhang Q, Gupta N, Kaufman PL, Weineb RN (2000): Loss of neuons in magnocellula and pavocellula layes of the lateal geniculate nucleus in glaucoma. Ach Ophthalmol 118: Yucel YH, Zhang Q, Weineb RN, Kaufman PL, Gupta N (2001): Atophy of elay neuons in magno- and pavocellula layes in the lateal geniculate nucleus in expeimental glaucoma. Invest Ophthalmol Vis Sci 42: Yucel YH, Zhang Q, Weineb RN, Kaufman PL, Gupta N (2003): Effects of etinal ganglion cell loss on magno-, pavo-, koniocellula pathways in the lateal geniculate nucleus and visual cotex in glaucoma. Pog Retin Eye Res 22: