r Human Brain Mapping 33:75–88 (2012) r

Direct Optic Nerve Pulvinar Connections definedby Diffusion MR Tractography in Humans:

Implications for Photophobia

Nasim Maleki,1 Lino Becerra,1,2 Jaymin Upadhyay,1 Rami Burstein,3

and David Borsook1*

1P.A.I.N. Group, Brain Imaging Center, McLean Hospital, Harvard Medical School, Belmont, MA, USA2Martinos Center, Massachusetts General Hospital, Charlestown, Massachusetts

3Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center,Harvard Medical School, Boston, MA, USA

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Abstract: The pathway that underlies exacerbation of migraine headache by light has not been eluci-dated in the human brain but has recently been reported in a rodent model. We employ diffusionweighted imaging and probabilistic tractography to map connectivity of direct pathways from the opticnerve to the pulvinar implicated with whole-body allodynia during migraine. Nine healthy subjectswere recruited to the study and underwent scanning on a 3T magnet. We were able to define well-known image-forming (optic nerve -> lateral geniculate -> visual cortex) as well as a less known non-image forming visual pathway from the optic chiasm to the pulvinar, and from the pulvinar to severalassociative cortical brain regions. Such pathway may allow photic signals to converge on a thalamicregion we described recently to be selectively activated during migraine headache. Consistent with phys-iological and anatomical studies in rats, the data provide an anatomical substrate for exacerbation ofmigraine headache by light in the human. Hum Brain Mapp 33:75–88, 2012. VC 2011 Wiley Periodicals, Inc.

Keywords: tractography; nonimage forming pathway; visual pathway; thalamus; central sensitization;migraine; pain

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INTRODUCTION

Photophobia is described by patients suffering fromheadaches of intracranial origin such as migraine, menin-gitis, and subdural hemorrhage. The type of photophobia,defined as exacerbation of headache by light, seems to

involve direct retinal projections to a posterior region ofthe thalamus containing trigeminovascular neurons[Noseda et al., 2010]. In the human, these thalamic regionsinclude the pulvinar and the centromedian nuclei, areasthat receive inputs from dura-sensitive spinal trigeminalnucleus neurons and believed to play a role in whole-body allodyia during migraine [Burstein et al., 2010].

The projections of retinal ganglion cells to the posteriorthalamic nuclei in the rat have led us to determinewhether such connections exist in humans. The aim of thestudy was to differentiate classic visual from nonvisualpathways in humans using diffusion weighted imaging(DWI) and probabilistic tensor-based tractography. Thedefinition of a nonvisual forming pathway from the opticnerve to the posterior thalamus (pulvinar) in humanswould correlate with the pathway defined in rats (see pre-vious) and provide a basis for light induced pain in

Contract grant sponsor: NINDS; Contract grant numbers: R01NS056195, K24 NS064050.

*Correspondence to: David Borsook, P.A.I.N. Group, Brain Imag-ing Center, McLean Hospital, 115 Mill Street, Belmont, MA 02478.E-mail: dborsook@partners.org

Received for publication 18 August 2010; Accepted 29 September2010

DOI: 10.1002/hbm.21194Published online 17 February 2011 in Wiley Online Library(wileyonlinelibrary.com).

VC 2011 Wiley Periodicals, Inc.

migraine. Probabilistic tensor-based tractography is a well-established technique to map anatomical pathways,[Basser and Pierpaoli, 1996; Behrens et al., 2003a,b; 2007]and we used it to map visual and direct optic nerve to tha-lamic regions pathways originating in the optic chiasm.Specifically, we evaluated specific inputs to the thalamus(pulvinar and centromedial nucleus) that were independ-ent of the classic optic nerve -> lateral geniculate -> visualcortex connectivity. We also evaluated pulvinar-corticalconnectivity to a number of regions that may be affectedby migraine, including the pulvinar-olfactory cortex, pulvi-nar-motor cortex and pulvinar-visual cortex. The results ofthese studies support results that have been found in non-human models [Trojanowski and Jacobson, 1976] and pro-vide a basis to evaluate specific brain abnormalities thatmay correlate with altered structure and function in theseregions in future studies.

MATERIAL AND METHODS

Subjects

A total of nine healthy subjects (3 females, 6 males; 31.1� 12.5 years old) with no history of migraine or anychronic headache were recruited for this study. All sub-jects gave informed consent prior to the scanning session.This study was approved by the McLean Hospital Institu-tional Review Board.

Data Acquisition

Imaging was carried out on a 3T Trio MR scanner (Sie-mens, Erlangen, Germany) using an eight-channel phasedarray head coil. For DWI, a single shot-twice refocusedecho planar imaging (EPI) pulse sequence was used. Theimaging parameters were as following: TR ¼ 7900 msec,TE ¼ 92 msec, 5/8 partial Fourier, three-fold SENSE accel-eration, Resolution ¼ 1.75 � 1.75 � 2.5 mm3, and total of50 axial slices to cover the entire cortex and cerebellum.A single nondiffusion weighted (b ¼ 0 sec/mm2) volumewas collected, while 72 distinct diffusion-weighted vol-umes were collected at b ¼ 1000 sec/mm2 (acquisitiontime �10 mins). Also T1-weighted structural images wereacquired using a 3D magnetization-prepared rapid gradi-ent echo (MPRAGE) with the following imaging parame-ters: TR ¼ 2100 msec, TE ¼ 2.74 msec, TI ¼ 1100 msec, FA¼ 12�, Resolution ¼ 1 � 1 � 1 mm3, and 128 sagittal slices[Mugler and Brookeman, 1990].

ROI Mask Definition

To define the masks that were used in the fiber trackingmore precisely, the masks were created from the automaticsegmentation of the cortical and subcortical structures ofthe brain using the volumetric T1-weighted MPRAGEimages for each subject individually. Cortical parcellation

and subcortical segmentation was performed using Free-surfer (http://surfer.nmr.mgh.harvard.edu/). The approachhas the major advantage that each mask is defined accordingto the specific anatomical characteristics of each subject,which alleviates the problem of errors due to imperfect regis-tration when a seed is defined in the standard space andthen transformed to each subject’s anatomical space.

Masks for Tracking Visual and

Nonimage-Forming Pathways

For each subject the following ROIs/masks were defined(Fig. 2): (1) Optic chiasm mask: which was created foreach subject in its anatomical space using Freesurfer. Themask included the optic chiasm and some portion of theoptic tract beyond the chiasm; (2) Thalamus mask: whichwas defined for each subject individually using the Free-surfer automatic segmentation tools; (3) Pulvinar mask:which was defined for each subject in the anatomical spaceby combining the following information: subcortical seg-mentation of the Thalamus using Freesurfer, the Talairach-atlas-derived pulvinar nucleus mask in the MNI space thatwas then nonlinearly registered to each subject’s anatomi-cal space, and also a digital atlas of the human brain,BrainNavigator (http://www.thehumanbrain.net/naviga-tor, version 2.06); (4) Thalamus minus pulvinar maskwhich was easily created by subtracting the pulvinar fromthe thalamus. This mask was used in the validation step;(5) Primary visual cortex (V1) mask: The V1 mask for eachsubject was defined by registration of the subjects’ corticesto a common spherical atlas on which the V1 area wasdefined (provided by Freesurfer), and the corticallydefined masks where then transformed to volumetricmasks in 2D; (6) LGN mask: The LGN mask was definedusing Juelich Histological atlas. A probability of P > 5%was chosen to define the location of the LGN. Next, anonlinear transformation was used to transform this mapfrom the MNI space to each subject’s anatomical space.For more accurate results the registration wasinitiated with the affine transform coefficients for thistransformation.

Masks for Tracking Pulvinar-Cortical Pathways

In order to track the pulvinar-cortical pathways, in addi-tion to the V1 mask, the following masks were used: (1)Primary motor cortex (M1) mask: which consisted of ante-rior and posterior Brodmann area 4 and was defined fol-lowing the same procedure as the V1 mask as describedearlier; (2) Olfactory mask, which was defined for individ-ual subjects using the Freesurfer automatic segmentationtools similar to Thalamus mask. Finally a trigeminal nu-cleus (SpV) mask was created to assess the pulvinar-brain-stem connectivity. The SpV mask was created by initiallysegmenting the spinal trigeminal (STr), anterolateral (AL),

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trigeminal lemniscus (TL), and medial lemniscus (ML)tracts for each subject [Upadhyay et al., 2008]. Once thelocation of these specific brainstem pathways were identi-fied, the spinal trigeminal nucleus, which is just medial tothe tracts was defined using an online brainstem atlas(https://www.msu.edu/~brains/brains/human/brainstem)

Tractography Analysis

Diffusion analysis was carried out using FMRIB Soft-ware Library (FSL) (www.fmrib.ax.ac.uk/fsl), version4.1.3. Diffusion MR tractography in FSL is performed bymodeling the distributions of fiber orientations or principaldiffusion direction within each voxel, by using a Markovchain Monte Carlo sampling method [Behrens et al., 2007].This model is then used to describe the measured diffu-sion weighted signal in each voxel, from which the proba-bility density functions (PDFs) of each voxel for the modelparameters are derived.

The prestatistical processing for each subject consistedof skull stripping, eddy current distortion correction andhead motion correction [Jenkinson and Smith, 2001; Jen-kinson et al., 2002]. For each individual subject, the DWIdataset was initially corrected for eddy current distortionand head motion. For both eddy current distortion andhead motion corrections, an automated affine registrationalgorithm was employed using FMRIB’s Linear ImageRegistration Tool (FLIRT, www.fmrib.ox.ac.uk/fsl/flirt) inwhich the skull-stripped nondiffusion weighted volumewas used as the reference volume [Jenkinson and Smith,2001, Jenkinson et al., 2002, Smith, 2002]. A diffusion ten-sor for each voxel was calculated using a least squares fitof the tensor model to the diffusion data. From the diffu-sion tensors, the eigenvalues of each tensor, which repre-sent the magnitude of the three main diffusion directions,and fractional anisotropy (FA) values, were calculated foreach voxel. FA maps were created for each subject. Tominimize the confounds such as partial volume effectspresent near gray matter-white matter or ventricle-whitematter borders, a minimum FA threshold of 0.2 was usedto threshold the data.

Diffusion modeling and probabilistic tractography werecarried out using the FMRIB Diffusion Toolbox(www.fmrib.ox.ac.uk/fsl/fdt), which allows estimating themost probable pathways from a seed mask to anywhere inthe brain or a particular defined location (waypoint mask)using a Bayesian estimation technique.

Tracking the Image-forming Visual Pathways

The human visual system consists of the eye (especiallythe retina), optic nerve, optic chiasm, lateral geniculate nu-cleus (LGN), superior colliculus, optic radiation, visualcortex (V1) and visual association cortex (V2). The visualsystem is schematically depicted in Figure 1. In order to

test the accuracy of the defined seeding masks and thequality of the diffusion weighted images for tracking thedesired pathways, we aimed to first track the known vis-ual pathway. In Figure 1, three known components of thevisual pathway are also depicted schematically. Thesecomponents include: optic nerve to LGN pathway whichconnects the optic nerve to the LGN, optic radiation (LGNto V1) which connects the LGN to the visual cortex (V1)and finally LGN-Colliculi pathway which connects theLGN to the superior colliculi. Fiber tracking was initiatedfrom all voxels within the optic chiasm seed mask to gen-erate 25,000 streamline samples, with a step length of 0.5mm, maximum number of steps of 2,000 and a curvaturethreshold of 0.2. Tracking was constrained by the frac-tional anisotropy that was measured in each pixel. Track-ing was performed in two steps: first, the optic chiasmmask was used as the seeding mask and the LGN as thewaypoint mask, and the first portion of the pathway wasreconstructed. In the second step the LGN mask was usedas a seeding mask and the V1 mask as the waypoint maskin order to track the optic radiation.

Tracking the Non–image forming Visual

Pathways

Non–image forming system in humans is a specializedsystem that originates from intrinsically photosensitiveganglion cells (ipRCGs) and is involved in the control ofcircadian rhythms and sleep, Figure 1. Some pathwayssend information via the retinohypothalamic tract to struc-tures including the habenula [Qu et al., 1996], pineal [Fal-con et al., 2009] and suprachiasmatic nucleus [Mai et al.,1981]. The pathway has also more recently been shown tohave projections to the posterior thalamus (pulvinar)[Nakagawa and Tanaka, 1984; Burstein et al., 2010]. Basedon this latter finding, in order to track the non–imageforming pathway, first the optic chiasm mask was definedas the seed mask and the pulvinar as the waypoint mask.Fiber tracking was initiated from all voxels within theoptic chiasm seed mask to generate 25,000 streamline sam-ples, with a step length of 0.5 mm, maximum number ofsteps of 2,000 and a curvature threshold of 0.2. Trackingwas constrained by the fractional anisotropy that wasmeasured in each pixel. Then, to classify and also validatedifferent components of the tracked pathways from opticchiasm to the pulvinar, LGN mask and V1 mask wereused as exclusion masks separately to determine if there isa direct pathway from the optic chiasm to the pulvinar nu-cleus that does not go through the LGN or project to thevisual cortex. Also a second mask was created for deter-mining the specificity of our results for the nonvisual path-way that consisted of thalamus minus pulvinar. For thisanalysis pulvinar and LGN were used as exclusion masksto determine the specificity of the tracked pathway to seeif the tracked pathway goes exclusively to the pulvinar orto the other nuclei of the thalamus as well.

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Pulvinar-Cortical Pathways

In the next level, the connectivity of the pulvinar nu-cleus to the M1 cortical area, primary visual cortex andthe olfactory cortex were assessed. The tracking was per-formed from the pulvinar mask to each of these targetsseparately for each subject. Fiber tracking was initiatedfrom all voxels within the pulvinar seed mask to generate5,000 streamline samples, with a step length of 0.5 mm,maximum number of steps as 2,000 and a curvaturethreshold of 0.2. Tracking was constrained by the frac-

tional anisotropy that was measured in each pixel. The

probabilistic tractography results were then thresholded

equivalently in all subjects based on the total streamlines

sent out from the seed mask in each subject: In each sub-

ject, we thresholded each of the probablistic tracts to

include only those voxels that received at least 5 � 10�6

percent of the total streamlines sent out from the ROI

masks used to trace that tract (5 � 10�6 times 25,000 times

the number of voxels in the mask) [Rilling et al., 2008].

The subjects’ thresholded pathways were then normalized

Figure 1.

Schematic Pathways. (a) Image-forming visual pathway. This sys-

tem includes the eye, optic nerve, optic chiasm, lateral genicu-

late body (LGN), optic radiation, and visual cortex (V1). The

pathway starts from the retina of both eyes. The optic nerves of

both eyes travel through the optic chiasm to the lateral genicu-

late nucleus (LGN) of the thalamus (optic tract). From the LGN,

a few fibers pass on to the superior colliculus and the rest, optic

radiations, continue their way to the occipital lobe terminating

in the visual cortex.(b) Nonimage forming Pathway. A specialized

pathway involved in nonimage forming functions (entrainment of

the biological clock, adaptation of the pupil size to light). This

pathway starts from the retina of both eyes as well. The optic

nerve fibers project via the retinohypothalamic tract to the

suprachiasmatic nucleus (SCN) of the hypothalamus and then

project to the habenula and the pineal gland (see text). SCN: Su-

pra-Chiasmatic Nucleus, LGN: Lateral Geniculate Nucleus.

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to the total number of estimated pathways in each subjectso that values are comparable across subjects.

To determine the common/average pathway among allof the subjects in this analysis, the following procedurewas employed: a nonlinear registration was performed inorder to coregister or align all FA images from all subjectsto a predefined FA template image. The FSL-based FAtemplate or target image was derived from an averageddataset of 58 FA maps from healthy male and female sub-jects. The FA template was also in the standard 1 � 1 � 1mm3 MNI152 space. Using the tract-based spatial statistics(TBSS) tool (www.fmrib.ox.ac.uk/fsl/TBSS), the calculatednonlinear transformation was applied to the estimatedpathways for each individual subject to coregister all ofthe subjects to the standard 1 � 1 � 1 mm3 MNI152 spaceand perform group level analysis. These maps were thenbinarized. The thresholded, normalized and nonlinearlywarped and binarized maps were then summed across thesubjects to produce a group average probability map.

A second set of analysis was performed with the aim offurther assessing the connectivity of the pulvinar to thecortical ROIs that were mentioned. The probability mapswere calculated for each subject and similar to the previ-ous analysis. Moreover, the pulvinar voxels were classified

according to the probability of connection to a correspond-ing cortical ROI. These probability maps were then thresh-olded and averaged across subjects.

Brain Stem-Pulvinar Pathways

Given that nociceptive inputs from the trigeminovascu-lar system to the pulvinar have been described [Bursteinet al., 2010] we wished to assess connectivity betweenregions of the brainstem that included the trigeminal nu-cleus (the region that peripheral trigeminal nerve fiberssynapse with second order fibers). To assess the connectiv-ity of the pulvinar nucleus to the SpV nucleus in the brainstem, the pulvinar mask was used as the seed mask andthe SpV mask (based on our earlier work; see Upadhyayet al., 2008), as the waypoint mask. Fiber tracking was per-formed following the same procedure that was used fortracking the pulvinar-cortical pathways.

RESULTS

Segmentation

The thalamus and pulvinar segmentation results for onesubject in three views are presented in Figure 2b. The

Figure 2.

Masks for tracking visual and nonimage forming pathways. (a)

For each subject the following masks were defined to be used in

tracking the visual or the nonimage forming pathway: ON: optic

nerve mask, V1: Primary visual cortex, LGN: Lateral geniculate

nucleus, pulvinar and thalamus. ON mask was used as the seed-

ing mask and the rest of the masks were used as target or

exclusion masks. (b) thalamus and pulvinar segmentation results

in one subject along with the group average results of the left

and right thalamic and pulvinar volumes (graph). The average

pulvinar volume was found to be approximately one-third that

of the thalamus. Th: Thalamus, P: Pulvinar, L: Left, and R: Right

(example: P-L: Left Pulvinar)

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group average results of the thalamic and pulvinar volumesare also presented. The average volume of the pulvinar wasfound to be approximately one-third that of the thalamus,which is consistent with figures reported in the literature[Sherman and Guillery, 2002; Sherman, 2007]. There wereno significant differences in the volumes of the thalamus orpulvinar in both hemispheres as determined by univariateanalysis of variance controlling for the effect of age and cra-nium size (estimated using Freesurfer) of the subjects.

Image-forming Visual Pathway

The visual pathways connecting the optic chiasm to theLGN and projecting from LGN to the primary visual cor-tex and the colliculi were found consistently in both hemi-spheres bilaterally in all subjects. The reconstructedpathways are shown for one subject in Figure 3a.The threedistinct components of the visual pathways are labeledwithin this figure. To obtain the results seen in Figure 3a,the tracking was done in two steps: first ON-LGN path-way and LGN-Colliculi pathways were reconstructed byusing the optic chiasm mask as the seeding mask and theLGN as the target. The LGN mask was next defined as theseed and V1 as the target for reconstructing the optic radi-ation. In Figure 3b, the visual pathway of another subjectis shown in axial, sagittal and coronal views with ON-LGN, LGN-Colliculi and LGN-V1 pathway components.

Nonimage-forming Visual Pathway

The results for tracking the non–image forming visualpathway are presented in Figure 4a,b. The pathway in Figure4a is a pathway connecting optic chiasm to the pulvinarwhere any pathway from the optic chiasm to the pulvinarthat passes through the LGN has been excluded. These exclu-sions therefore qualify the shown pathway as nonvisual.

In Figure 4b results of our validation approach for deter-mining the nonvisual nature of the detected pathway (4b-i) and its specificity (4b-ii) are reported. In Figure 4b-I asingle axial slice in one subject is shown and the delinea-tion of the pathways are color-coded. Three pathways areshown in Figure 4b-I: The green is the LGN-Colliculi Path-way, the blue is the optic radiation and the red is the path-way that connects ON and Pulvinar directly, which wasalso shown in Figure 4a. Optic radiation, ON-Pulvinarpathways and LGN-Colliculi are all shown in one slice. Byexcluding the LGN-V1 projections (optic radiation) theON-Pulvinar pathway and LGN-Colliculi pathway remain(ii).By excluding the LGN-Colliculi pathway (as describedearlier) the sole pathway that remains is the ON-Pulvinar(iii), which directly connects the ON and Pulvinar and isshown in red-yellow in both figures.

Figure 4b-II shows the specificity analysis results. Twotracked pathways are shown in this figure. For both path-ways optic chiasm was used as the seed mask. Red-yellowis the pathway tracked from optic chiasm to the pulvinar

excluding the LGN. Blue represents the pathway trackedfrom the optic chiasm to the thalamus minus pulvinarwhere pulvinar and LGN were used as exclusion masks.As it can be seen in the results when pulvinar and LGNare excluded neither any pathway reaches the pulvinarnor there is any pathway reaching any other nuclei of thethalamus. Diffusion tensor color map of an independentDTI study (Wakana et al, 2004 and http://cmrm.med.jhmi.edu/) is shown in 4b-III.It shows white matter fiberspassing through the same area as the nonvisual pathwaythat was tracked in our study. On color map, red, green,and blue represent fibers running along right-left, anterior-posterior, and superior-inferior axes, respectively.

Brainstem—Pulvinar Connections

The results of tracking the pulvinar-brainstem connect-ing pathway are shown in Figure 5. The pathways werefound in both hemispheres bilaterally in all subjects. Thedata are shown both in a set of consecutive coronal slicesand also sagittal slices at the level of the pathway on theleft and right side. For this analysis the pulvinar was usedas seeding mask and the SpV as the target mask.

Pulvinar—Cortical Connections

After the direct connection between the optic nerve andthe pulvinar was determined, the next step was to assessthe connectivity of the pulvinar to the cortex. We focusedon olfactory cortex, V1, and M1 areas. The ROIs that wereused for this analysis are shown in Figure 6a. The groupprobability maps of reconstructed pathways connectingthe pulvinar to the other cortical areas are shown in Figure6b–c. These results are based on tractography in 9 subjects.The average tract map is thresholded to show the tractsthat are present in at least 50% of the subjects. Yellow rep-resents higher probability that a pathway is present inmore subjects, and red depicts the lower probability (mini-mum 50%). The pathways connecting the pulvinar to theM1 cortical area are shown in Figure 6b. The probabilistictractography method enabled a segmentation of the Supe-rior Thalamic Radiation/Superior Corona Radiata. Path-ways connecting the pulvinar to the olfactory cortex areshown in Figures 6c, where the Anterior Thalamic Radia-tion/Anterior Corona Radiata was segmented.

In addition connectivity of pulvinar with some other cort-ical areas including the primary and secondary auditorycortex, gustatory cortex, and insular cortex were assessed inthis study. However no significant connectivity was foundbetween the pulvinar and these areas after thresholding.

DISCUSSION

In this study we identified optic nerve connections tothe pulvinar in humans using a probabilistic tractographyapproach. We propose that this pathway is suited to carryphotic signals to a thalamic area that is activated during

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migraine [Burstein et al., 2010] and thus, may provide theanatomical substrate for migraine-type photophobia. Inagreement with this notion, we described recently a novelpathway through which photic signals that travel alongthe optic nerve enhance the firing rate of trigeminovascu-lar neurons in the lateral posterior and posterior thalamic

nuclei in the rat and proposed that this pathway mediatesthe exacerbation of headache by light during migraine[Noseda et al., 2010]. In a related study we have reportedimaging data of increased activation in the pulvinar inpatients with central sensitization (during their migraine)compared with their interictal period [Burstein et al.,

Figure 3.

Image forming visual pathway. The tracking results for the visual

system are shown. (a) The pathways connecting the optic nerve

to the LGN, optic radiation to the primary visual cortex and

those projecting from LGN to the superior colliculi are shown

in a single subject. (b) Visual pathway is shown in another sub-

ject in axial, sagittal and coronal views. The course of the visual

pathway can be followed in these slices from where the optic

tract connects the optic nerve to the LGN and then travels to

the superior colliculus or the LGN, and next continues to the

occipital lobe where it terminates in the visual cortex. The

results are consistent with the known visual pathway system.

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2010]. This data correlated with central sensitization ofposterior thalamic neurons in a rat model of migraine.Taken together, these data implicate the pulvinar as a cen-tral site for modulating sensory inputs.

The Pulvinar

The pulvinar is usually grouped as one of the lateralthalamic nuclei, which forms a cushion like prominence

overlying the geniculate bodies. Cytoarchitecture and den-droarchitecture of the pulvinar is similar to that of LateralPosterior (LP) nucleus [Percheron, 2004]. Thus LP is fre-quently linked to pulvinar as ‘‘pulvinar-LP-Complex.’’Lower mammals such as rats do not have a prominentpulvinar or LP. The pulvinar is presumed to have evolvedfrom the LP of lower mammals [Percheron, 2004]. In pri-mates including humans, pulvinar comprises approxi-mately 30–40% of the thalamus [Danos et al., 2003;

Figure 4.

Nonimage forming visual pathway. (a) A direct pathway that

connects the optic nerve to the thalamus. This pathway reaches

the posterior thalamic nucleus that includes the pulvinar nucleus.

For this analysis, optic chiasm was used as the seeding mask,

pulvinar as the target and LGN as an exclusion mask to exclude

any visual pathway that goes through the LGN. The pathway

shown in this figure is thus nonvisual. Also seen in this figure is

the optic chiasm-hypothalamic connectivity, which presumably

represents the suprachiasmatic nucleus projections. (b) (I) Delin-

eation of the non–image forming and visual pathways in an axial

slice. The visual and non–image forming pathways are delineated

as follows: (i) the LGN-Colliculi pathway, ON-Pulvinar pathway

and optic radiation are all shown. (ii) Optic-radiation is excluded

by using the V1 mask as an exclusion mask. (iii) The optic radia-

tion and the LGN-Colliculi pathway are excluded by using the

LGN mask and V1 mask as exclusion masks. The green is

the LGN-Colliculi pathway, the blue is the optic radiation and

the red is the pathway that connects ON and pulvinar directly.

(II) Specificity analysis results. Pathways were tracked from the

optic chiasm with pulvinar as the waypoint mask (red-yellow) or

thalamus minus pulvinar as the waypoint mask and pulvinar and

LGN as exclusion masks. No pathway was tracked from optic

chiasm to any other nuclei of the thalamus. (III) Diffusion tensor

color map of an independent DTI study (Wakana et al., 2004

and http://cmrm.med.jhmi.edu/). Arrows refer to fibers passing

through the same area as the nonvisual pathway. Red, green, and

blue represent fibers running along right-left, anterior-posterior,

and superior-inferior axes, respectively.

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Sherman, 2007]. The pulvinar complex have been dividedinto oral (somatosensory), superior and inferior (visual),and medial (visual, multisensory) [Grieve et al., 2000].Vari-ous studies have found extensive projections of the pulvi-nar to several cortical regions including the cingulategyrus, visual association areas, somatosensory, posteriorparietal and prefrontal cortex [Burstein et al., 2010; Glen-denning et al., 1975; Grieve et al., 2000; Raczkowski andDiamond, 1980]. There are also reports of pulvinar projec-tions to subcortical regions including superior colliculusand pretectal area [Tekian and Afifi, 1981].Finally, retino-pulvinar pathways have been described in the cat [Fedor-ova, 1983], tree shrew [Somogyi et al., 1981], in the rat[Burstein et al., 2010] and in primates [O’Brien et al.,2001].No such pathways have been reported in humans.

Visual Image and Nonimage-Forming Pathways

Classic visual pathways include projections from the ret-ina to the LGN and then to the visual cortices. Non–imageforming pathways include those to the habenula [Quet al., 1996], pineal [Falcon et al., 2009] and the suprachias-matic nucleus [Mai et al., 1981] and have projections to theposterior thalamus (pulvinar) [Burstein et al., 2010; Naka-gawa and Tanaka, 1984]. There are also projections to theintergeniculate leaflet(which plays a role in pineal melato-nin suppression) and the olivary pretectal nucleus, which

plays a role in pupillary light response through its connec-tions to Edinger-Westfal nucleus and the ciliary ganglion[Hattar et al., 2002; Panda et al., 2002]. In order to demon-strate the known image-forming visual pathway usingDWI and tractography, we presented data that is consist-ent with prior studies on visual pathway [Iwasawa et al.,1997; Sherbondy et al., 2008; Staempfli et al., 2007; Tripet al., 2006]. In our study both the visual and non–imageforming pathways were tracked reproducibly in all sub-jects and the reconstructed fiber pathways were in agree-ment with the known visual anatomy. Our main findingwas a direct non–image forming tract from the optic nerveto the pulvinar in the posterior thalamus. In addition, thespecificity of our analysis results shows optic chiasmhypothalamic (presumably suprachiasmatic nucleus) pro-jections (Fig. 4a).Our analysis also indicates connectionsfrom trigeminal nuclei to the pulvinar, providing evidencefor this pathway in humans as a means by which nocicep-tive signals that arise in the meninges during migrainemay reach the pulvinar. In addition, connections betweenthe pulvinar and various cortical areas, including themotor cortex (M1), visual cortex (V1) and olfactory cortexwere indicated. These projections may contribute to othermanifestations of the migraine state (e.g., osmophobia).Each of these pathways (optic nerve-pulvinar; trigemino-pulvinar and pulvinar-cortical) is discussed below. Ourmapping of a non–image forming visual pathway that con-nects the optic nerve to the pulvinar, to the best of our

Figure 5.

Pulvinar to brainstem pathway. Pulvinar-brainstem connecting pathway. This pathway connects

the trigeminal nuclei to the pulvinar. This pathway may send nociceptive information originating

in trigeminal afferents during migraine via the trigeminal nuclei to the pulvinar.

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knowledge, is the first systematic approach to study anon–image forming visual pathway with regards to itsconnections to pain processing areas in the human brainusing a diffusion tensor-based tractography approach.

Optic Nerve-Thalamic (Pulvinar) Pathway

Diffusion tensor imaging can quantify the degree anddirection of water diffusion anisotropy in white matterfibers noninvasively in vivo. Water diffuses predominantlyalong the long axis of the white matter fibers. Therefore,

axonal connectivity of different brain areas can then bederived from tracking the properties of the local diffusionprofiles on a voxel-by-voxel basis. In prior MRI studies ofvisual pathways the focus has been on tractography of thevisual pathways [Iwasawa et al., 1997; Sherbondy et al.,2008; Staempfli et al., 2007; Trip et al., 2006].

In some of these studies, an optic nerve-thalamic path-way is shown in the included figures, but this pathway isnot directly evaluated in their reports. While these studieslend support to our findings, the focus has been on image-forming visual pathways rather than the non–image form-ing pathways. Therefore, none of the groups have focused

Figure 6.

Cortical-Pulvinar Pathways. (a) Cortical masks were defined for

each subject individually including: Primary motor cortex (M1),

olfactory and V1 mask (shown in figure 2a). In Figures 4b–c,

group probability maps of reconstructed pathways connecting

the pulvinar to (b) M1, and (c) Olfactory cortex are presented.

These results are based on tractography in nine subjects. The

average tract map is thresholded to show the tracts that are

present in at least 50% of the subjects. Yellow represents higher

probability of a pathway’s presence in more subjects and red is

for lower probability (minimum 50%).

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on tracking the non–image forming visual pathway interms of its terminal fields or clear delineation of this path-way from the visual pathway. We, on the other hand,focused on the non–image forming visual pathway whereit was clearly defined and delineated from the visual path-way by creating various target masks as described in themethods section to label different components of the path-ways originating from the optic chiasm.

Non–image forming pathways originate in intrinsicallyphotosensitive Retinal Ganglion Cells (ipRGC) and projectvia the optic nerve to the suprachiasmatic nucleus (SCN),intergeniculate leaflet (IGL), habenula, pineal and olivarypretectal nucleus (OPT).In the rat, most retinal projectionsto the posterior and lateral posterior thalamic nuclei thatconverge on dura-sensitive neurons originate in ipRGCs[Burstein et al., 2010]. Thus, our results parallel datareported in rats. As noted in the methods, by defining aseed region in the optic chiasm and a specific target regionin the pulvinar in addition to excluding specific knownvisual pathways, the DWI measure of the tract wouldseem specific for an optic nerve- pulvinar projection inhumans.

Trigeminal–Pulvinar Projection

Pain produced by migraine involves activation ofmeningheal nociceptors that project via the trigeminalnerve to the spinal trigeminal nucleus, and second ordertrigeminovascular neurons that project to more rostralbrain regions including the thalamus. Neurons in thehuman pulvinar may become sensitized with the progres-sion of an attack [Burstein et al., 2010].Direct trigeminovas-cular projections to posterior thalamic nuclei including POand LP have been reported in rats [Burstein et al., 1998;2010]. We believe that this pathway conveys sensory sig-nals from the spinal trigeminal nucleus to the pulvinarsince there are no known projections from the pulvinar tothe spinal trigeminal nucleus. While, brainstem-pulvinarconnections, including trigemino nuclear complex (TNC) -> pulvinar [Burstein et al., 1998] and periaqueductal gray -> pulvinar [Spreafico et al., 1980] have been described ouranalysis only included seeding from the TNC based onour prior human studies [Borsook et al., 2004; DaSilvaet al., 2002; Upadhyay et al., 2008].

Pulvinar-Cortical Projections

Reciprocal Pulvinar-cortical connections have beendescribed in a number of species including nonhuman pri-mates [Raczkowski and Diamond, 1980; Shipp, 2001].Assuch the pulvinar is an associative nucleus [Shipp, 2003]that has connections with a number of cortical regions. Inthe rat study, projections from neurons that were bothlight and dural sensitive projected to a number of corticalregions including motor and olfactory areas [Noseda et al.,2010].Tractography studies of pulvinar connections have

been reported in humans [Leh et al., 2008] with a numberof regions including primary visual areas (Brodmann area17), secondary visual areas (Brodmann areas 18 and 19),visual inferotemporal areas (Brodmann area 20), posteriorparietal association areas (Brodmann area 7), and frontaleye fields and prefrontal areas. The authors did not com-ment on connectivity with specific regions; we focusinstead on the motor cortex, the olfactory cortex and thevisual cortex. These regions could be easily identifiedusing standard brain atlases and reports in the literature[Mai et al., 2008]. The data shown in Figure 6b–c showthis connectivity in our subjects. The ‘‘direction’’ of con-nectivity cannot be ascertained using diffusion tensor-based tractography and it does not permit differentiationof thalamocortical from reciprocal corticothalamic connec-tions. Moreover reciprocal connections have been reportedbetween the pulvinar and for these regions [Grieve et al.,2000; Rouiller et al., 1998]. The specific function of connec-tivity for each of these regions as related to pain processingin migraine may be different. For example, the olfactorycortex may be involved in either precipitating a migrainefrom strong olfactory stimulants such as perfumes [Kelman,2007] in osmophobia. In addition, even during the interictalperiod changes in olfactory acuity [Amery et al., 1988] havebeen evaluated using PET scanning [Demarquay et al.,2008]. Animal studies show that thalamic projections to theorbitofrontal cortex arise from midline and intralaminarnuclei, from the anteromedial nucleus, the medial dorsalnucleus, and the pulvinar nucleus [Morecraft et al., 1992].Motor cortical involvement in migraine may be related tohyperexcitability of this region in the interictal state of mi-graine patients [Antal et al., 2008; Curra et al., 2007;Siniatchkin et al., 2009].During migraine the hyperexcitablestate in this cortical region is reversed to an inhibitory statethat may contribute to motor abnormalities such as slowedspeech or hand clumsiness [Brighina et al., 2009; Ebinger,2006]. Animal studies also confirm pulvinar projections tothe M1 area [Huffman and Krubitzer, 2001; Kultas-Ilinskyet al., 2003]. Both anterograde and retrograde labeling inmedial pulvinar nucleus of the rhesus monkey has alsobeen reported following injections of biotinylated dextranamine (BDA) in different locations of the primary motorcortex [Kultas-Ilinsky et al., 2003].

Caveats

There are a couple of limitations associated with diffu-sion tensor-based tractography. The most important limita-tion stems from the partial volume averaging of complexfiber structures (such as sharp curves) or fiber combina-tions/interaction (such as crossing fibers, merging fibers)into single voxels where the principal eigenvector of avoxel (which describes the principal diffusion direction inthat voxel) may not correspond to the main fiber direction.Also because of the limitations in feasible resolutions withMR only major fiber tracts can be resolved since the voxel

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size of the MR data is typically many orders of magnitudelarger than the size of a single axon (2–4 mm vs. a fewmicrons). As noted previously, diffusion tensor-based trac-tography does not have the ability to distinguish betweenafferent and efferent pathways. Therefore the directionalityof the observed connections cannot be inferred from ourresults. For this reason, the results of our connectivity anal-yses needed to be validated against known anatomicaldirectionality analyses in tracer studies of animal models.Other limitations relate to the differences in the quality ofthe diffusion data (which depends on issues such as scanquality or head motion) and anatomical variations among agroup of subjects, which makes generating a group averagefor thinner fiber bundles especially difficult. Another aspectof this issue also relates to choosing the appropriate thresh-old for the tracked probabilistic pathways to distinguishbetween the real connections and spurious/artifactual con-nections. In this study we followed an approach [Rillinget al., 2008] for thresholding the pathways that takes intoaccount the anatomical differences among subjects.

Our study parallels known visual pathways mapped innonhuman primates and humans [Iwasawa et al., 1997;Sherbondy et al., 2008; Staempfli et al., 2007; Trip et al.,2006]. With respect to defining the retino-pulvinar pathwayour findings are in agreement with the results shown forthese pathways using electrophysiology and tracing meth-ods [Burstein et al., 2010]. However, we were not able todetermine ipRGC inputs to the intergeniculate leaflet or tospecifically separate the ON-IGL projections from the ON-LGN projections due to proximity of IGL and LGN, the sizeof IGL and our probabilistic approach in deriving the LGNmasks in this study. However, the direct pathway that wefind also connects to the posterior region of the thalamus.Given that this pathway projects to the SCN, pineal andhabenula and ends in the posterior thalamus and sincethere is no known direct visual pathway in that direction, itsuggests that this direct pathway is part of the ipRGC axonprojections that project to the SCN and continue to the pos-terior thalamus. The pathway is also of the same nature andfunction as the ipRGC axon projections that were found inthe rat study by Burstein et al. (2010).

Photophobia and Pulvinar Inputs

In migraine, photophobia results from light acting on anotherwise normal eye/visual system. In other forms of thephotophobia there is an associated alteration in the corneaor other parts of the anterior eye, which may involve thetrigeminal nerve, and activation of its nociceptors in condi-tions such as corneal lesions, dry eye or uveitis. There areprojections from the eye (e.g., cornea) through the trigemi-nal ganglion that are well described in the rat [Marfurtand Del Toro, 1987; Okamoto et al., 2009] and in the mon-key [Marfurt and Echtenkamp, 1988], and recently in sin-gle case human imaging study of photophobia related tocorneal injury [Moulton et al., 2009]. Based on clinical and

preclinical studies, in these nonmigraine conditions noci-cieptor activation travels along trigeminal fibers to thebrainstem. Subsequent changes in higher brain areasincluding the thalamus may take place as a secondaryphenomenon. In addition, photophobia has been associ-ated with chiasmal compression in patients [Kawasaki andPurvin, 2002].This may result from pressure on the dura(dura mater and arachnoid mater) that sheaths the opticnerve/chiasm and is contiguous with the sclera of the eye-ball [Hayreh, 1984]. We are unaware of reports of nocicep-tor presence within the arterial supply of the optic nervealthough the dura that surrounds the optic nerve is inner-vated by C fibers, yet the dura resembles the epineuriumof normal peripheral nerves [Raspanti et al., 1992].If this isthe case, information would travel via the supraorbitalsubdivision of the trigeminal nerve to reach the trigeminalnuclear complex. Photophobia has also been associatedwith blepharospasm and the pulvinar may also mediatethe type of photophobia that is commonly associated withessential blepharospasm. In a study in which photophobiawas not defined clearly (i.e., light-induced ocular pain,abnormal sensitivity to light) and the thalamus was notparcellated, Emoto et al., (2009) observed activation in theposterior thalamus of patient diagnosed with blepharo-spasm. At this time it is unclear whether there is any over-lap in these conditions.

CONCLUSION

In conclusion, we were able to define well-knownimage-forming pathway as well as a direct pathway fromthe optic nerve to the pulvinar, and from the pulvinar toseveral associative cortical brain regions. The importanceof finding this direct pathway is that the direct pathwayfrom optic nerve to the posterior thalamus shows whatmay be a possible mechanism for exacerbation of pain bylight alone (photophobia) in migraine patients where thereis no corneal/ocular damage (photoallodynia).

ACKNOWLEDGMENT

The aurhors thank Lauren Nutile’s assistance in prepa-ration of the manuscript.

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