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Open AccePrimary researchDiffusion tensor imaging of frontal lobe white matter tracts in schizophreniaMonte S Buchsbaum*1, Peter Schoenknecht2, Yuliya Torosjan1, Randall Newmark1, King-Wai Chu1, Serge Mitelman1, Adam M Brickman3, Lina Shihabuddin1, M Mehmet Haznedar1, Erin A Hazlett1, Shabeer Ahmed1 and Cheuk Tang4

Address: 1Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA, 2Department of Psychiatry, University Hospital Heidelberg, Ruprecht-Karls-University, Heidelberg, Germany, 3Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons. Columbia University, New York, New York, USA and 4Department of Radiology, Mount Sinai School of Medicine, New York, New York, USA

Email: Monte S Buchsbaum* - monte.buchsbaum@mssm.edu; Peter Schoenknecht - Peter.Schoenknecht@med.uni-heidelberg.de; Yuliya Torosjan - yuliya.torosjan@mssm.edu; Randall Newmark - randall_newmark@hotmail.com; King-Wai Chu - kingwai.chu@mssm.edu; Serge Mitelman - simitelman@pol.net; Adam M Brickman - ambrickman@gmail.com; Lina Shihabuddin - linashihabuddin@comcast.net; M Mehmet Haznedar - Mehmet.Haznedar@mssm.edu; Erin A Hazlett - erin.hazlett@mssm.edu; Shabeer Ahmed - shabeer88@hotmail.com; Cheuk Tang - Cheuk.Tang@mssm.edu

* Corresponding author

AbstractWe acquired diffusion tensor and structural MRI images on 103 patients with schizophrenia and 41age-matched normal controls. The vector data was used to trace tracts from a region of interestin the anterior limb of the internal capsule to the prefrontal cortex. Patients with schizophrenia hadtract paths that were significantly shorter in length from the center of internal capsule to prefrontalwhite matter. These tracts, the anterior thalamic radiations, are important in frontal-striatal-thalamic pathways. These results are consistent with findings of smaller size of the anterior limb ofthe internal capsule in patients with schizophrenia, diffusion tensor anisotropy decreases in frontalwhite matter in schizophrenia and hypothesized disruption of the frontal-striatal-thalamic pathwaysystem.

BackgroundThe hypothesis that schizophrenia is an illness arisingfrom disconnection or misconnections of circuits con-necting prefrontal cortex with the thalamus and striatumhas received support from studies of post-mortem brains[1,2], imaging [3-5], and electrophysiology[6]. The thala-mus has been viewed as a key element in potential schiz-ophrenia-related deficits in this circuit because of thereciprocal circuitry between the prefrontal lobe and the

medial dorsal nucleus [7-9]. The thalamus comprisesmultiple nuclei that relay and filter sensory and higherorder inputs to and from the cerebral cortex and limbicstructures; thus, deficits are consistent with behavioralabnormalities in schizophrenia [10]. The medial dorsalnucleus (MDN) of the thalamus, important in attentionas reviewed elsewhere [11], has interconnections with thedorsolateral prefrontal cortex [12]. The connections of theMDN have been used to define the prefrontal cortex [13],

Published: 28 November 2006

Annals of General Psychiatry 2006, 5:19 doi:10.1186/1744-859X-5-19

Received: 17 February 2006Accepted: 28 November 2006

This article is available from: http://www.annals-general-psychiatry.com/content/5/1/19

© 2006 Buchsbaum et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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a key area of functional and structural alteration in schiz-ophrenia (reviewed by: [14]. Since deficits in the frontallobes, the thalamus, and the striatum have been found inschizophrenia with both structural and functional imag-ing as reviewed elsewhere [14,15], the white matter con-nections between the thalamus and prefrontal cortex areof special interest.

The anterior limb of the internal capsule contains fronto-thalamic and thalamo-frontal pathways, the cortico-pon-tine pathways, and a lesser number of caudate/pallidumfibers, while the posterior section of the anterior limb ofthe internal capsule has primarily corticopontine fibers[16] Reduction in the size of the internal capsules inpatients with schizophrenia [17-20] would be consistentwith diminished corticothalamic and corticostriatal con-nectivity and with previous reports of schizophrenia-asso-ciated abnormalities in the striatum [21,22] and thalamus[4,5,23,24].

To investigate white matter circuitry of these frontal-tha-lamic connections, we applied diffusion tensor magneticresonance imaging (MRI) to a small group of patientswith schizophrenia (n = 5) and found reduced organiza-tion of white matter, as inferred from anisotropy, in thefrontal lobe and anterior limb of the internal capsule [25],a finding replicated by Lim and collaborators [26]. Frontaldecreases in anisotropy in schizophrenia have been con-firmed and extended in other reports [27-32]. In somereports, frontal lobe and fronto-temporal tracts includingthe arcuate fasciculus [33], anterior cingulum bundle[34,35], uncinate fasciculus [36,37] and superior longitu-dinal fasciculus [36] were found to show low anisotropy;by contrast, no white matter area emerged as significantlylow in studies of 14 [38] and 10 schizophrenic patients[39].

An alternative viewpoint to the possibility of misroutingor specific tract deficits in white matter in schizophrenia isa global deficit in myelin [40] (and see review [41]). Thismight produce a pattern of distributed multiregional ani-sotropy deficits compatible with the complex, not clearlylocalizing, behavioral and cognitive disorganization inschizophrenia. Alteration in number, distribution, andultrastructural integrity of oligodendrocytes, key whitematter components, has recently been reported in the pre-frontal cortex in schizophrenia [42-45].

One approach to differentiating a global myelin deficitfrom specific tract deficits is to examine statistical para-metric mapping, which has tended to show deficits infrontal white matter, as reviewed above. This issue canalso be approached by tracing the path of diffusion fromvoxel to voxel, termed tract tracing, to make inferencesabout the course of axon bundles. The fronto-thalamic

connections can be explored by tracing tracts between theanterior limb of the internal capsule forward to the pre-frontal cortex.

Anisotropy analysis is limited to a single number express-ing the directionality of water diffusion at a single voxelwith high values indicating all diffusion in one directionand low values indicating diffusion in all directions. Dif-fusion tensor analysis also yields the 3D vector expressedas the component of the x, y, and z dimensions of the dif-fusion. The ending point of a tract (the xyz location) andlength of the tract are estimated [46]. This method pro-ceeds from a starting voxel and locates an adjacent voxelas part of the tract if the anisotropy exceeds a presetthreshold and if the solid angle of the vector is no greaterthan 30 degrees. Thus a tract can be traced from an out-lined area in the internal capsule moving toward the pre-frontal cortex. If myelin deficits are general, tract tracingwould terminate in a shorter distance from the startingvoxel than expected. However, if the tract terminated in adifferent position or had a different length, then a miswir-ing deficit would be supported. Thus, if we hypothesize ageneral myelin deficit, short tracts might be widespread.Alternatively, we might hypothesize patients with schizo-phrenia to have more poorly organized fibers, fanning outto the cortex irregularly with less topographic precisionand perhaps earlier in their course. Such patterns havebeen observed in cortical dysplasia in elegant single casediffusion tensor tract tracing examples [47]. Their illustra-tions suggested that tract length might be a useful measurein examining deficits in the cortex in schizophrenia.

MethodsSubjectsThe schizophrenia group consisted of 103 patients (83men, 20 women) recruited from inpatient, outpatient,day treatment and vocational rehabilitation services atMount Sinai Hospital (New York, N.Y.), Pilgrim Psychiat-ric Center (W. Brentwood, N.Y.), Bronx VA MedicalCenter (Bronx, N.Y.), Hudson Valley Veterans AffairsMedical Center (Montrose, N.Y.), and Queens HospitalCenter (Jamaica, N.Y.) following approvals by each insti-tutional review board and informed consent obtainedfrom each subject. The 41 matched normal control sub-jects (28 men, 13 women) were recruited through adver-tisement. All schizophrenia patients met DSM-IVdiagnostic criteria for schizophrenia (n = 92) or schizoaf-fective disorder (n = 11). Diagnosis was determined by astructured clinical interview with the ComprehensiveAssessment of Symptoms and History (CASH; [48].Patients were moderately ill (positive and negative syn-drome scale scores (PANSS; [49] for positive, negative andtotal were 18.9 ± 6.6, range 8–38; 18.9 ± 7.8, range 0–41;37.0 ± 9.9, range 19–73 respectively, obtained on n = 97).The Mini-Mental Status Examination scores were 26.9 ±

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2.7, range 16–30, obtained on n = 91). Patients were forthe first time administered neuroleptics as ascertained bymedical records by the age of 24.9 ± 9.1, indicating thatthe average patient had received some treatment over aperiod of 19 years. At the time of the scan we examinedrecords covering the preceding three years and identifiedthe predominant treatment: 11 were unmedicated, 20were on conventional neuroleptics, 37 on atypical neu-roleptics, 16 on both, and the remainder were on otherpsychoactive medications in addition to neuroleptics orthe history of the last period was poorly documented.

Schizophrenia patients were divided into good-outcome(non-Kraepelinian, n = 51) and poor-outcome(Kraepelinian, n = 52) subgroups based on published cri-teria [50]. Poor-outcome patients met the following crite-ria for at least the five years prior to study contact: 1)continuous hospitalization, or, if living outside the hospi-tal, complete dependence on others for food, clothing,and shelter; 2) no useful work or employment; and 3) noevidence of symptom remission. All other schizophreniapatients were considered good-outcome, or non-Kraepelinian.

There was no significant difference in age between schizo-phrenia patients (mean age 43.0 ± 12.4) and normal con-trols (mean age 44.1 ± 14.7) (t (142) = -0.47, p = 0.64)and sex distribution (χ2(1) = 1.86, p = 0.17). MRI volu-metric data from participants in the current study havepreviously been reported in studies of the thalamus, stria-tum, and Brodmann areas of the cortex [51-54].

Image acquisitionThe diffusion tensor sequence acquired fourteen axial 7.5-mm-thick slices (TR = 10 s, TE = 99 ms, TI = 2.2 s, b = 750s/mm, δ = 31 ms, Δ = 73 ms, NEX = 5, voxel 1.8 × 1.8 × 7.5mm, FOV = 230 mm) and the SPGR (spoiled gradientrecalled acquisition in steady state) anatomical sequenceacquired 124 1.2-mm-thick slices (TR = 24 ms, echo time= 5 ms, flip angle = 40°). This sequence was chosenbecause of its data-acquisition speed, an important con-sideration when imaging schizophrenia patients. It alsoallows us to perform signal averaging to improve the sig-nal-to-noise ratio (SNR). Before the diffusion EPIsequence, a Turbo Spin Echo (TSE) is also acquired toobtain a localizing anatomical image.

To assess the degree of diffusion anisotropy in each voxel,we used fractional anisotropy (FA). This quantity is ameasure of the degree of anisotropy in a voxel, the degreeto which the diffusivity is biased along the fiber axis asopposed to perpendicular to it. In order to solve for thecomponents of the diffusion tensor, seven diffusion EPIimages were then obtained: six with different non-col-linear gradient weightings and one with no diffusion gra-

dient applied. Five acquisitions were then obtained andaveraged to improve the SNR. The diffusion tensor wasthen obtained by solving the seven simultaneous signalequations relating the measured signal intensity to the dif-fusion tensor. We then obtained a tensor for every voxel ina slice. We then computed the eigenvectors and eigenval-ues for every tensor, which form the basic raw data set thatwas analyzed subsequently. The eigenvector associatedwith the largest eigenvalue or principal diffusivity indi-cates the direction along which the apparent diffusivity isat a maximum, which in normal white matter corre-sponds to the orientation of the axis of an axonal bundle,and allowed us to obtain information about the orienta-tion of maximum diffusion, which in normal white mat-ter would correspond to the axis of an axonal bundle.

We also determined that images were processed with theaveraging for 5 NEX done in the Matlab routine for thefirst subjects and using GE software for the later subjects.Although visual inspection of the anisotropy imagesrevealed no apparent differences in the earlier or laterscans, statistical analysis of whole brain white matter FAshowed small but significant differences between the twosets of data. We are not specifically able to identify thesources of variation. No subjects were scanned with bothvariants of the method. Therefore we first corrected forpotential variation over time by dividing by the whole-brain average fractional anisotropy. This is quite analo-gous to correcting BOLD or FDG PET values to wholebrain activity levels as is widely done and also controlsunwanted drift effects over time.

Anatomical MRIs were resectioned to standard Talairach-Tournoux position using the algorithm of Woods et al.[55] and a 6-parameter rigid-body transformation. Theanisotropy images from each subject were then aligned tosubject's own standard-position anatomical images usingthe same 6-parameter rigid-body transformation. Notethat both the structural and diffusion tensor imagesremained in their original dimensions and were onlyaligned using the 6-parameter alignment.

We tested the extent of error of coregistration and poten-tial distortion of the diffusion tensor images from the lessdistorted structural MRI and the diffusion tensor anisot-ropy images as described in detail elsewhere [56]. Themedian difference of the absolute image frame coordi-nates of the anterior and posterior brain edges betweenstructural and anisotropy images was 0.0 and 1.78 mmrespectively and the median difference in brain length was2.23 mm, just above 1%. The mean absolute value in mmof the differences between the diffusion tensor and MRIlocations in the anterior and posterior brain edges was+2.14 and +2.71 mm respectively. No difference between

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images collected with the different nex averaging methodswas statistically significant.

Tract tracingWe followed the technique of [46] beginning with everypixel in the internal capsule at each slice level. The crite-rion for continuing the path was a relative anisotropyvalue of 0.7, interpolated steps of 0.3 mm and a change ofless than 30 degrees from voxel to voxel. Note that this isa value relative to whole brain. Each tract length is meas-ured from the individual voxel location in the internalcapsule region of interest along the tract to its termina-tion.

Manual tracing of the anterior limb of the internal capsulesThe left and right anterior internal capsules were manuallytraced in the axial plane on five dorsal-to-ventral equidis-tant levels [18]. The five slices were determined based onanatomy of the striatum, following Buchsbaum and col-leagues [52]. Briefly, the most ventral and most dorsalslices containing the putamen were selected. The mostventral aspect was defined as the first slice in which thecaudate and putamen were no longer merged. The mostdorsal slice was defined as the first slice in which the puta-men was no longer visible. The number of slices betweenthe most dorsal and most ventral slices was divided by 6to yield an increment accurate to two decimal places. Thisincrement was added to the bottom slice number fivetimes and the result rounded to yield five equally and pro-portionately spaced slices for tracing. The internal capsulewas traced on the five slices corresponding to the fiveequidistant spaced slices of putamen.

The tracing protocol was developed after consultationwith a neuroanatomist, expert in cerebral white matter,with the intent of maximizing consistent measurementsacross subjects while capturing fibers restricted to theanterior limb of the internal capsule region. Four manu-ally-inserted landmarks were used to create the "corners"of a polygon containing the fibers of the internal capsule.For each hemisphere, a landmark was placed on the mostlateral anterior part of the caudate nucleus to define theanterior medial corner of the internal capsules. A land-mark was placed on the most medial anterior part of theputamen to define the anterior lateral corner of the inter-nal capsule. For the more posterior medial and lateral cor-ners, a landmark was placed on the most posterior part ofthe caudate nucleus, and one was placed on the mostmedial aspect of the putamen, respectively. An automaticboundary-finding method, based on the Sobel-gradientfilter allowed for maximization of grey/white matter con-trast for accurate placement of landmarks on the bordersbetween the striatum and internal capsules. Figure 1 dis-plays an example of placement of landmarks on the five

equidistant slices. To determine interrater reliability, tensubjects were chosen randomly and traced by two inde-pendent operators and total volumes, across hemisphere,were compared between the two. The intraclass correla-tion (ICC) was 0.74, which is consistent with other stud-ies that have examined the tracer reliability of smallstructures. An automatic computer program developed byMSB was used to compute the area of the internal capsuleat each slice, which was contained in a polygon formed bythe four landmarks.

In a second step, we located the anterior corpus callosumon an axial slice at the dorsoventral level of the third outof five internal capsule levels (vertical center) and deter-mined the brain midline (x) and most anterior border ofcorpus callosum white matter (y). We used this positionto further standardize the xy coordinates of the anteriorlimb of the internal capsule and termination of tracts inthe frontal lobe as it was symmetrically in the midline anddetermined in exact reference to our traced volume of theinternal capsule. This reduced the variation which wasintroduced by using the Woods algorithm brain standard-ization which yielded some residual dorsoventral varia-tion at this level.

We examined both raw tract length and tract lengthadjusted for brain size. Since the major tract length differ-ences were in the axial plane, we first determined the mid-line of each axial slice, defined as 90 degrees. We then

Axial MRI with four corner markers of the internal capsule placedFigure 1Axial MRI with four corner markers of the internal capsule placed.

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determined the angle from the midline formed by the linejoining the centroid of the internal capsule with the cen-troid of the tract end and the length and width of thebrain. We divided the tract length by the brain length mul-tiplied by a correction for brain proportion (the anglebetween the midline and the tract angle divided by 90 ;e.g. if the brain length was 200 and the brain width 100

and the angle of the tract end 45 degrees from the midline,then the correction factor for brain size was 200 minus((200 minus 100) × ((90–45)/90)) or 200 minus 50which is 150. We then divided the tract length by 150, themeasure of axial brain size.

ResultsTract lengthAverage tract path lengths in mm from the internal cap-sule voxel to the tract termination centroids entered intoin a four-way ANOVA with group as an independentmeasure and length, ventrodorsal level, and hemisphereas repeated measures revealed that in the left hemispherepatients with schizophrenia revealed shorter tracts in allventrodorsal levels and in four of five right hemisphereventrodorsal levels (Figure 4), and differences were great-est in the left hemisphere at ventral levels (group × ventro-dorsal level × hemisphere F = 2.65, df = 4,568, p = 0.032;MANOVA Wilks 0.92, F = 3.01, df = 4,139, p = 0.020; cor-rected for brain size: group × ventrodorsal level × hemi-sphere F = 2.53, df = 4,568, p = 0.040; multivariate F =2.79, df = 4,139, p = 0.029). Post-hoc t-tests were not sig-nificant.

Both good and poor outcome patients had shorter tractlengths than normal controls at ventral levels, but goodoutcome patients had shorter tracts than normal controlsor poor outcome patients at dorsal levels; they lacked thenormal ventrodorsal gradient (group × ventrodorsal level× hemisphere interaction F = 3.38, df = 8,564, p = 0.0084)(Figure 5).

AnisotropyPatients with schizophrenia had lower anisotropy withinthe tracts ventrally but not dorsally compared to the con-trols (group × ventrodorsal level × hemisphere interactionF = 3.20, df = 4,568, p = 0.013; but multivariate F 2.31, p= 0.061) Although patients and normals were wellmatched for age, we carried out ANCOVA to remove ageeffects and the result remained significant (F = 3.14, df =4, 564, p = 0.014).

Tract path termination locationsWe separately examined the x, y, and z coordinates of thecentroids of tracts termination positions, for the tracts ineach subject that originated anterior limb of the internalcapsule. Three-way ANOVAs separately performed on xand z directions, with diagnosis as an independent groupdimension and dorsoventral level and hemisphere asrepeated measures revealed no significant main effects orgroup interactions. An ANOVA performed on the y-coor-dinate of the centroid of tracts' terminations revealed thatin the left hemisphere the tracts of normal controls termi-nated more anteriorly than the tracts of patients withschizophrenia for all ventrodorsal levels except level 4,

Top: Enlarged view of internal capsule with four corners markedFigure 2Top: Enlarged view of internal capsule with four corners marked. Bottom: Sobel gradient filtered image with enhanced edges of caudate and putamen marked.

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where there was no difference between the normals andthe patients (1 = most ventral, 5 = most dorsal). In theright hemisphere, the tracts terminations are practicallythe same for the ventral levels 1 and 2 in normals andschizophrenics, but in level 3 the schizophrenics are moreanterior in their tract termination than the controls. Forthe dorsal levels 4 and 5 in the right hemisphere, the pat-tern resembles the left hemisphere with the normals hav-ing more anterior points of tract termination as indicatedby the more anterior y-coordinate of their centroids(group × ventrodorsal level × hemisphere interaction, F =2.725, df = 4,568, p = .029; Wilks 0.92, F = 2.97, df =4,139, p = 0.022).

Internal capsule size and tract lengthIn normals, there were no significant correlations betweensize of the internal capsule and tract length at any of thefive levels in either hemisphere. For patients, only the leftmost ventral level showed a correlation (r = -0.21) indicat-ing that smaller internal capsules were associated with

greater length. Thus, internal capsule size does not appearto be a major determinant of tract length.

Number of starting locations for tractsThe number of starting locations at the ventralmost inter-nal capsule (left and right combined for normal controls(151 ± 22) and patients (147 ± 28) did not differ (t = -.72,df = 142, p = 0.47). Only the dorsalmost level differedwith normals (227 ± 45) higher than patients (209 ± 43)differed significantly (t = -2.26, df = 1,142, p = 0.026).

DiscussionThe finding of shorter tract lengths between the anteriorlimb of the internal capsule and the prefrontal cortex isconsistent with an abnormality in thalamo-cortical andcortico-thalamic connectivity, with findings of reducedsize of the anterior limb of the internal capsule in schizo-phrenia, postmortem and MRI findings of smaller medialdorsal nucleus volume in schizophrenia and with the per-ceptual and cognitive abnormalities in schizophrenia.

Location of average tract endingsFigure 3Location of average tract endings. White oval has center placed at mean xyz location of the centroid of each tract ending loca-tion across all normal subjects and the width and length of the ellipse are equal to one standard deviation of the x and y coor-dinates. The black oval portrays the same data for patients with schizophrenia

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Mean tract length at five ventrodorsal internal capsule positions for normal controls and patients with schizophreniaFigure 4Mean tract length at five ventrodorsal internal capsule positions for normal controls and patients with schizophrenia. In the left hemisphere, the patients' tracts were shorter than normal volunteers at all five levels but the difference was most marked at the ventralmost levels. For the right hemisphere the difference was present only for the most dorsal two levels (group × ven-trodorsal level × hemisphere interaction, F = 2.65, df = 4,568, p = 0.032; Wilks 0.92, F = 3.01, df = 4,139, p = 0.02).

Tract length in good and poor outcome schizophreniaFigure 5Tract length in good and poor outcome schizophrenia. Note that both good and poor outcome patients have shorter tracts at the ventralmost level.

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Shorter tract lengths might result from a less fully topo-graphically developed fiber tracts (Figure 6).

The findings are also consistent with the appearance ofanisotropy images which show a very marked line run-ning from the internal capsule in an anterior directiontoward the frontal pole. The significant difference in thelength of the tracts is primarily due to the difference in they-component of the distance from the centroid of theinternal capsule to the tract termination, and not to eitherx or z components. We note that both reported ANOVA'son the y component and on the three-dimensional dis-tance in mm reveal similar F-ratio values, indicating theeffect is due to y-dimension (anterior-posterior axis).

The shorter tract length in patients does not seem to beattributable to a different number of tract-tracing startingpositions, since the biggest differences in tract lengthbetween normals and patients are at the ventralmost lev-els where the number of intial tract starting positionswithin the internal capsule are the same in both groups.

Validity of tract tracing, potential confounders, and study limitationsWe oriented the tracing of the vectors from the internalcapsule toward the prefrontal cortex to specifically evalu-ate thalamo-frontal and fronto-thalamic fibers. Note thatthe diffusion tensor data does not differentiate betweenthalamo-frontal and fronto-thalamic directions, but onlyyields the orientation of the water diffusion.

Validity of the tract-tracing algorithm is supported by thesystematic topographic organization of the tract termina-tion location and, as noted above, the marked visibility ofanteroposterior white markings in the y-direction imagesof anisotropy [46]. However the tract tracing is limited bythe resolution of the diffusion tensor images and the rela-tively conservative threshold (0.7) used to terminatetracts. The presence of tracts crossing the anteroposteriorcourse of the thalamocortical fibers, differentiallyincreased head motion in patients with schizophrenia,frontal distortion of diffusion tensor images, and errors inMRI coregistration all affect the accuracy of the results. Wemay also have less power to find z-axis effects since the

Hypothetical arrangements of corona radiate fibers in normals and patients with schizophreniaFigure 6Hypothetical arrangements of corona radiate fibers in normals and patients with schizophrenia. In the normal pattern, tract length would be longer than in the more radial divergence seen in patients with schizophrenia.

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within axial plane (xy) resolution is greater than the z res-olution.

Shorter tracts were not clearly related to lower tract anisot-ropy, since only one of the ten tract tracings (5 levels intwo hemispheres) showed significantly lower anisotropyin the tract itself. Our region of interest was not defined bytract orientation, so it contained a mixture of frontotha-lamic, frontopontine and caudatopallidal fibers[16].While our method of actually outlining the edges of awhite matter area gives it some specificity, Kanaan et al[57] point out the advantages of adding tract directioninformation to determining the roi edge. Note that FA hasbeen found to be reliable across sections [58]

Functional neuroanatomy and schizophrenia functionThe tract lengths terminate before reaching the corticalrim. This may result from the fibers fanning out to reach asector of the cortex earlier in their course (Figure 6) andmay suggest a different geometry of prefrontal connectiv-ity. It may also represent fibers which have a tortuouscourse and are therefore interpreted as terminated by the30 degree criterion or the presence of right to left fiberscrossing the anterior-going paths. Changes in internalcapsule size due to ventricular enlargement might alsoaffect the tract length, perhaps especially within the inter-nal capsule. More detailed analysis of the angles of fibersat the anterior edge of the internal capsule and within theinternal capsule, and correlations with ventricular size,prefrontal and thalamic volumes, and cortical thicknessmay be informative in extending our understanding ofthis finding.

SummaryThe length of tracts from the anterior limb of the internalcapsule to the prefrontal cortex was found to be shorter inpatients with schizophrenia than age- and sex-matchednormal controls. This suggests a deficit in connectivitybetween the association nuclei of the thalamus, especiallythe medial dorsal nucleus, and the executive areas of theprefrontal cortex. Such a deficit might be associated withthe degraded performance on attentional and perceptualtasks widely observed in schizophrenia.

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