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Original Article |

Pathways That Make Voices:  White Matter Changes in Auditory Hallucinations FREE

Daniela Hubl, MD; Thomas Koenig, PhD; Werner Strik, MD; Andrea Federspiel, PhD; Roland Kreis, PhD; Chris Boesch, MD, PhD; Stephan E. Maier, PhD; Gerhard Schroth, MD; Karl Lovblad, MD; Thomas Dierks, MD
[+] Author Affiliations

From the Department of Psychiatric Neurophysiology, University Hospitalof Clinical Psychiatry, Bern, Switzerland (Drs Hubl, Koenig, Strik, Federspiel,and Dierks); the Departments of Magnetic Resonance Spectroscopy and Methodology(Drs Kreis and Boesch) and Neuroradiology (Drs Schroth and Lovblad), Universityof Bern, Bern; and the Department of Radiology, Brigham and Women's Hospital,Harvard Medical School, Boston, Mass (Dr Maier).


Arch Gen Psychiatry. 2004;61(7):658-668. doi:10.1001/archpsyc.61.7.658.
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Background  The origin of auditory hallucinations, which are one of the core symptoms of schizophrenia, is still a matter of debate. It has been hypothesized that alterations in connectivity between frontal and parietotemporal speech-related areas might contribute to the pathogenesis of auditory hallucinations. These networks are assumed to become dysfunctional during the generation and monitoring of inner speech. Magnetic resonance diffusion tensor imaging is a relatively new in vivo method to investigate the directionality of cortical white matter tracts.

Objective  To investigate, using diffusion tensor imaging, whether previously described abnormal activation patterns observed during auditory hallucinations relate to changes in structural interconnections between the frontal and parietotemporal speech-related areas.

Methods  A 1.5 T magnetic resonance scanner was used to acquire twelve 5-mm slices covering the Sylvian fissure. Fractional anisotropy was assessed in 13 patients prone to auditory hallucinations, in 13 patients without auditory hallucinations, and in 13 healthy control subjects. Structural magnetic resonance imaging was conducted in the same session. Based on an analysis of variance, areas with significantly different fractional anisotropy values between groups were selected for a confirmatory region of interest analysis. Additionally, descriptive voxel-based t tests between the groups were computed.

Results  In patients with hallucinations, we found significantly higher white matter directionality in the lateral parts of the temporoparietal section of the arcuate fasciculus and in parts of the anterior corpus callosum compared with control subjects and patients without hallucinations. Comparing patients with hallucinations with patients without hallucinations, we found significant differences most pronounced in the left hemispheric fiber tracts, including the cingulate bundle.

Conclusion  Our findings suggest that during inner speech, the alterations of white matter fiber tracts in patients with frequent hallucinations lead to abnormal coactivation in regions related to the acoustical processing of external stimuli. This abnormal activation may account for the patients' inability to distinguish self-generated thoughts from external stimulation.

Figures in this Article

Auditory hallucinations (AH), one of the most common psychiatric symptoms,elude a compelling explanation. They have been discussed in nearly every conceivablecontext, ranging from a very private experience to abnormal brain functionin the frame of schizophrenia. In 1838, Esquirol1 wasthe first to formulate the concept of a brain-based origin of hallucinations.Although AH occur with a lifetime prevalence of 10% to 15% in persons withoutneuropsychiatric diseases,2 they are most commonin schizophrenia, with an average prevalence of 60%.3 Therefore,recent models of AH were generally based on results gained from investigationsof patients with schizophrenia.46 Neuropathologic,7,8 structural magnetic resonance imaging(MRI)912 andfunctional MRI1319 studiessuggest that the superior temporal lobe is altered in patients with AH, creatingdysfunctions within brain regions that are important for language and auditoryprocessing.

The present hypotheses of the generation of AH, considering recent neuroimagingfindings, propose that AH derive from inner speech misidentified as externalby means of defective self-monitoring.15 Functionalimaging studies in schizophrenic AH revealed involvement of the frontal motorand premotor speech areas (the Broca area and supplementary motor area) andtemporoparietal speech areas (the Wernicke area) that are necessary for thedecoding and encoding of language.15 Additionalregions described as involved in AH were the primary13 andhigher-order auditory and association cortex located in the temporal lobe,mainly in the left hemisphere.1318 Inright-handed individuals, the speech-relevant areas are predominantly locatedin the left hemisphere,20 which may be relatedto the fact that the left hemisphere also appears to be more functionallyinvolved in the generation of AH than the right hemisphere.4,5 Fornormal speech functions, intact connections between speech-relevant regionsare necessary,20 but recent functional MRI21 and electroencephalography22 studiesapplying language tasks suggest dysfunctional interactions between frontal,parietal, and temporal brain regions in patients with AH. This finding supportsthe more general theories that schizophrenia involves disturbed frontoparietotemporalconnectivity.2325 Themicrostructural foundation of these connections was not yet investigated becauseof a lack of methodical feasibility. Magnetic resonance diffusion tensor imaging(DTI) assesses the directionality of water diffusion (anisotropy), which isrestricted by boundaries such as white matter (WM) fibers. The amount of anisotropycorrelates with the directionality and coherence of fiber tracts.26 Thus, a loss of WM directionality or disruption ofthe microstructure is reflected in reduced anisotropy values.27 Ofthe relatively few studies published using DTI in schizophrenia, the majorityreported reduced anisotropy in subjects with schizophrenia,2834 whereasthe minority did not find differences between patients and control subjects.3537 However, these studiesvary widely in terms of MRI methods and analysis strategies and are not directlycomparable among each other. The more recent studies32,34 focusedon the WM fiber tracts connecting the frontal with the temporal and parietalcortex. Both studies demonstrated pathologic features in schizophrenia; alack of normal left-greater-than-right asymmetry in the uncinate fasciculusin patients with schizophrenia32 respectivelydecreased WM integrity in the left hemispheric arcuate and uncinate fasciclulus.34 Those studies provide in vivo support of the aforementionedneuroanatomical and neurofunctional reports of disruption of the frontal andtemporal brain regions.

In an earlier functional MRI study, we demonstrated an increase of neuronalactivity in the primary auditory cortex and language-related areas duringhallucinations in patients with schizophrenia;13 however,the relation to structural cerebral alterations remained unclear. In thisstudy, we investigate whether altered neuronal activity during AH may be mediatedby altered WM connections in patients with schizophrenia with a history offrequent AH in comparison with patients with schizophrenia who reported neverhaving perceived AH and healthy control subjects. We expected the most prominenthallucination-related differences in the arcuate fasciculus. This frontoparietotemporalfiber tract connects important language-related areas38 thatwere reported to be most affected in schizophrenia in studies of structuraland functional imaging.

PARTICIPANTS

We investigated 13 patients with acute schizophrenia (International Classification of Diseases, 10th Revision diagnosis criteria)39 with frequent AH (group H), 13 patients with acuteschizophrenia who reported that they had never perceived AH (group N), and13 healthy control subjects (group C). All patients were patients of the UniversityHospital for Clinical Psychiatry in Bern, Switzerland. The groups were matchedfor age and sex, and all subjects were right-handed (Table 1). None of the patients reported substance abuse before hospitalizationexcept sporadic cannabis consumption by 4 patients (3 in group N; 1 in groupH). Only patients and subjects without relevant medical disorders (exceptschizophrenia) were included based on medical history and medical and neurologicalexamination. All patients but 2 received typical or atypical antipsychotictreatment in conventional dosages, in both patient groups. The investigationwas conducted in accordance with the Declaration of Helsinki and approvedby the local ethics committee. Before the investigation began, all patientsand healthy control subjects gave their written informed consent to participatein the study.

CLINICAL MEASURES

To assign each individual patient to 1 subtype of symptom (trait), anextensive semistructured interview concerning medical history, with a specialfocus on the perception of AH, was assessed before scanning. Furthermore,the files of every patient were studied to add missing data. The group withouthallucinations included only patients who had never experienced AH, neitherat the time of this investigation nor at any time in their previous history.The patients prone to hallucinations experienced verbal AH at the time ofthe present hospitalization as well as during all the prior exacerbationsof their disease.

The Oulis et al40 AH rating scale wasused to document the character of AH. The hallucinations fulfilled the criteriaof the Schneiderian first-rank symptoms of comment or dialog voices in allpatients with AH. Eight of 13 patients reported that the voices were comingfrom outside their heads, whereas 3 of 13 experienced voices coming from insideand outside the head. Eight of 13 patients perceived the voices to be as loudas real voices, and 3 of 13 perceived them to be quieter or like a whisperingvoice. All patients were convinced that the voices were real. Two patientsrefused the interview for the hallucination assessment.

The Positive and Negative Syndrome Scale41 andClinical Global Impressions Scale42 were usedto assess psychopathologic symptoms and the severity and acuity of the disease(state). The Positive and Negative Syndrome Scale did not differ significantlybetween the patient groups for the total score and the negative subscore.The positive subscore was significantly higher in the group with AH (P≤.05). Higher values were because of higher scoreson the hallucination and delusion subscore (Table 2).

Table Graphic Jump LocationTable 2. Assessment of Clinical Measures*
MAGNETIC RESONANCE IMAGING

A 1.5 T Signa MR system (version 5.8, equipped with echospeed gradientsof 22 mT/m; General Electric Medical Systems, Milwaukee, Wis) was used forthe investigations. In 1 session, 3-dimensional structural images and diffusiontensors were assessed. Individual whole brain 3-dimensional anatomy was measuredwith a 3-dimensional gradient echo sequence, providing 124 axial slices with1.2-mm thickness, 240 mm × 240- mm field of view, and 256 × 128-pixelresolution. Further scanning parameters were as follows: repetition time,22 milliseconds; echo time, 8 milliseconds; and flip angle, 45°. The originalvoxel size of 0.94 × 1.88 × 1.20 mm3 was interpolatedto a voxel size of 1 × 1 × 1 mm3 with BrainVoyager2000software (BrainInnovation, Maastricht, the Netherlands). Total 3-dimensionalscan time was 9.04 minutes.

Diffusion tensor imaging was realized with a line-scan technique43 that provides a line-by-line spin-echo sampling ofeach slice. In contrast to the more widespread echo planar (ie, gradient echo)method, this technique is less sensitive to susceptibility-related distortionsand, as with single-shot echo planar imaging, it is fairly motion insensitive,which is favorable when imaging is done on patients with schizophrenia. Eddycurrent–related distortions are also very small, in particular afteran eddy-current correction of the DTIs, which is based on cross-correlationwith T2-weighted images. In the line-scan technique, patient motion does notlead to ringing artifacts in phase direction but rather to discontinuitiesthat can be detected and eliminated in postprocessing. This leads to robustnesswith respect to patient motion. The reliability of the apparent diffusioncoefficient determined by line scanning was found to be very high in healthysubjects and patients who had had strokes.44 Similarly,the fractional anisotropy (FA)45 values aremore reproducible with the line-scan technique than with echo planar imagingsequences (S.E.M., unpublished data, November 2003). Twelve axial slices (parallelto the anatomical data set) with 5-mm slice thickness and 1-mm interslicedistance were measured. This volume covered a region around the Sylvian fissure,including the inferior frontal gyrus up to the angular gyrus (Figure 1). For each slice, 6 images with high diffusion weighting(β = 1000 s/mm2) in 6 different directions and 2 images withlow diffusion weighting (β = 5 s/mm2) were collected. Thefield of view was 220 mm × 165 mm; scan matrix, 128 × 96 pixels,interpolated to a final image size of 256 × 256 pixels; repetition time,3360 milliseconds; echo time, 90 milliseconds; and interpolated DTI voxelsize, 0.86 × 0.64 × 5.00 mm3. Scanning time for thecomplete diffusion tensor sequences was 16.34 minutes. Total magnetic resonancescanning time including the localizer scan was about 30 minutes.

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Figure 1.

Localization of 12 acquired axialslices. Measured volume was optimized to cover regions known to be importantin the generation of auditory hallucinations, such as the inferior frontalgyrus, the superior temporal gyrus, and the Wernicke area.

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DATA PROCESSING AND ANALYSIS

After reconstruction of the DTIs, eigenvalues and eigenvectors of thediffusion tensor were determined. Fractional anisotropy values were calculatedfor each image. The 2-dimensional diffusion maps were incorporated into the3-dimensional anatomy data sets through interpolation to the same resolution(voxel size, 1 mm3). This allowed us to superimpose 3-dimensionalstatistical maps onto the 3-dimensional anatomical data sets for visualizationof statistical differences. The 2-dimensional diffusion images and 3-dimensionalstructural measurement were aligned using position files of the magnetic resonancescanner. For confirmation of the coregistration accuracy, a structural 2-dimensionaldata set was obtained by reslicing the 3-dimensional data and compared visuallywith the DTI data in each individual. For each subject, the structural datasets were transformed into Talairach space, following the transformation procedurepublished elsewhere.13 On the basis of theparameters for importing the 2-dimensional DTI slices into the 3-dimensionaldata and on the parameters for transforming the 3-dimensional data sets intoTalairach space, the complete DTI data set of each subject was also transformedinto Talairach space. The study focused on alterations in WM fiber tracts.Therefore, after the individual anatomical data sets at the gray matter–WMboundary were segmented,46 the analysis wasrestricted to voxels identified as WM. Because the segmentation in the regionof the basal ganglia was inconsistent across subjects, this region was excludedfrom analysis. To avoid spurious effects, group statistics were computed onlywhere there was a significant (P≤ .10) preponderanceof WM over gray matter as assessed by χ2 statistics acrosssubjects (Figure 2).

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Figure 2.

Three-dimensional anatomical data(A) were analyzed, and coregistered fractional anisotropy maps were rotated,normalized, and transformed to Talairach space (D). Individually, anatomywas segmented at the gray–white-matter (WM) boundary (B). Ninety percentWM probability was estimated using χ2 distribution (C). Fractionalanisotropy analysis was restricted to the WM volume (E). Voxelwise analysisof variance and t test comparisons were computedbetween groups, and significant results were fused with the anatomical datafor better orientation (F).

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In a first step, a voxel-based 1-way analysis of variance (ANOVA) restrictedto WM volume was performed with the factor "group" (C, H, and N) as a singlefactor. To avoid potential registration errors and disease-related misalignmentsin Talairach space, a region of interest (ROI) analysis based on the ANOVAwas computed. The WM tracts identified as significantly different betweengroups by the ANOVA were selected in each study subject by using the individualcoregistered T1 and DTIs. The mean FA values of each ROI were used for a 3-wayANOVA (factors were "group" [C, H, and N], "hemisphere" [left, right], and"ROI" [lateral and medial arcuate fasciculus]). Post hoc unpaired t tests were computed between the groups where appropriate.

Subsequently, for further descriptive statistics, 3-dimensional statisticalmaps (using a voxelwise, 2-tailed, unpaired t test)were computed, comparing the FA values between healthy control subjects andpatients, between the 2 patient groups (H vs N), and between each patientgroup and control subjects (H vs C and N vs C). To identify the most involvedregions and to reduce the problem of multiple testing, clusters containingmore than 99 neighboring voxels (100 mm3) with differences of P≤.05 were identified. For each cluster, FA values wereaveraged and tabulated (Table 3 and Table 4). Further, the Talairach47 coordinates of the center of gravity were noted.Clusters were assigned to the underlying WM fiber tracts using 3-dimensionalanatomical data. Data analysis and visualization were realized with BrainVoyagerand in-house software.

Table Graphic Jump LocationTable 3a. Analysis of Significant Clusters for Comparison Between 13Healthy Control Subjects (Group C) and 26 Patients (Group P)*
Table Graphic Jump LocationTable 3b. Analysis of Significant Clusters for Comparison Between 13Healthy Control Subjects (Group C) and 26 Patients (Group P)*
Table Graphic Jump LocationTable 4a. Analysis of Significant Clusters for Comparison Between 13Patients With Hallucinations (Group H) and 13 Patients Without Hallucinations(Group N) and 13 Healthy Control Subjects (Group C)*
Table Graphic Jump LocationTable 4b. Analysis of Significant Clusters for Comparison Between 13Patients With Hallucinations (Group H) and 13 Patients Without Hallucinations(Group N) and 13 Healthy Control Subjects (Group C)*

In the voxel-based 1-way ANOVA, several significant clusters in longassociation and commissural fiber tracts were found. As we focused on speech-and language-related brain regions, the subsequent confirmatory ROI analysis(3-way ANOVA) included values for the medial and lateral arcuate fasciculusof both hemispheres (Figure 3A).The ANOVA demonstrated a significant main effect of hemisphere and a significantinteraction of group × hemisphere (Table 5). Post hoc t tests (P≤.05) showed that (1) FA values were higher in the right than inthe left hemisphere, (2) patients with AH had higher FA values in the leftlateral arcuate fascicle than did both patients without AH and healthy controlsubjects, and (3) control subjects had higher FA values in the medial arcuatefascicle than did patients with AH and patients without AH (Table 5) (Figure 3B).

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Figure 3.

A, Significant voxels resultingfrom a 1-way analysis of variance comparing healthy control subjects (n =13), patients with hallucinations (n = 13), and patients without hallucinations(n = 13). B, On the basis of this analysis of variance, a confirmatory regionof interest analysis was calculated for 4 regions, including the medial (lefthemisphere, mean [SD] Talairach coordinates x, y, z, respectively, −32[1], −42 [2], and 25 [2]; right hemisphere, 22 [2], −42 [2], and34 [2]) and lateral arcuate fasciculus (left hemisphere, −42 [2],−38[8], 4 [3]; right hemisphere, 38 [2], −43 [1], and 17 [2]). Mean (SD)fractional anisotropy values and post hoc results are presented. Asteriskindicates P≤.05.

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Table Graphic Jump LocationTable 5. Repeated Measures Analysis of Variance*
COMPARISON OF FA VALUES BETWEEN HEALTHY CONTROL SUBJECTS AND ALL PATIENTSWITH SCHIZOPHRENIA

In the voxelwise t tests, FA values were lowerin patients with schizophrenia in many parts of the WM. The identificationof voxel clusters and the corresponding WM tracts yielded 17 significant regions(Table 3), 8 clusters in the leftand 9 in the right hemisphere. Significantly higher FA values in the voxel-basedanalysis for control subjects were observed in the long anterior-to-posteriorassociation fibers in large parts of the arcuate fasciculus (superior longitudinalfasciculus), the uncinate fasciculus, and the inferior longitudinal fasciculusin both hemispheres (Figure 4).Further, higher FA values were observed in control subjects in parts of thecorpus callosum (CC) (Figure 4).There were no clusters with higher values in patients with schizophrenia.

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Figure 4.

Voxelwise comparison between healthycontrol subjects (n = 13) and all patients with schizophrenia (n = 26). Patientswith schizophrenia show lower fractional anisotropy values in wide parts ofvarious white matter tracts. In this axial slice, the lower fractional anisotropyvalues in patients are shown at the level of the corpus callosum and the inferiorlongitudinal fasciculus. The region of the basal ganglia, which was excludedfrom the analysis because of inconsistent segmentation, is indicated by thedotted gray line. NS indicates not significant.

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COMPARISON OF FA VALUES BETWEEN PATIENTS WITH SCHIZOPHRENIA WITH ANDWITHOUT HALLUCINATIONS

Patients with AH showed voxels with significant higher FA values inmany parts of the WM (Figure 5A). A total of 12 clusters were located in the left hemisphereand 5 in the right. There were 15 clusters with higher FA values in patientswith AH compared with patients without AH and only 2 clusters with higherFA values in patients without AH compared with patients with AH. The mostimportant differences for the 2 patient groups could be observed in the arcuatefasciculus (10 of 17 clusters), with a slight dominance of the left hemisphere(6 of 10 clusters). The significantly higher FA clusters in patients withAH were distributed from prefrontal WM passing the parietal WM down into thetemporal lobe part of the arcuate fasciculus. The largest cluster (402 voxels)was located in the left temporoparietal section of the arcuate fasciculus(Figure 5A). Furthermore in theleft cingulate bundle, part of the limbic system, patients with AH had higherFA values compared with patients without AH. Finally, there were higher FAvalues in the anterior and posterior parts of the interhemispherical commissuralfibers of the CC (Figure 5 A). Theclusters with higher FA values in patients without AH were located in theleft inferior longitudinal fasciculus.

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Figure 5.

The medial part of the arcuatefasciculus contains long fibers connecting the frontal with the temporal cortex,whereas the lateral part, with its shorter U-shaped fibers, connects, forexample, the language-related regions in the frontal and parietotemporal lobes.The main differences between patients with hallucinations (n = 13) and healthycontrol subjects (n = 13) as well as patients without hallucinations (n =13) were located in the lateral fibers of the arcuate fasciculus (1) and theanterior corpus callosum (3). NS indicates not significant.

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COMPARISON OF FA VALUES BETWEEN PATIENTS WITH SCHIZOPHRENIA WITH HALLUNICATIONSAND HEALTHY CONTROL SUBJECTS

There were 16 significant clusters in the comparison of patients withschizophrenia with AH vs healthy control subjects. Thirteen demonstrated lowervalues in patients with schizophrenia with AH whereas 3 showed higher valuesin patients with schizophrenia with AH (Table 4B). These regions in which patients with AH had significantlyhigher FA values compared with control subjects were located in the lateralleft and right temporoparietal section of the arcuate fasciculus close tothe posterior end of the Sylvian fissure—where the Wernicke area islocated—and close to the auditory regions (Figure 5B). Patients with AH showed generally higher FA values inthe lateral part of the arcuate fasciculus whereas control subjects showedgenerally higher FA values in the medial parts of the arcuate fasciculus.Further, patients with AH did have higher FA values in the left anterior CCcompared with control subjects (Figure 5B).

In 13 clusters (6 in the left, 7 in the right hemisphere), lower FAvalues were observed in patients with AH in comparison with control subjects.These clusters were distributed in the prefrontal to the temporal arcuatefasciculus (medial), in the uncinate fasciculus, and in the inferior longitudinalfasciculus. Further clusters were located in the more ventral part of theanterior CC (Figure 5B).

COMPARISON OF FA VALUES BETWEEN PATIENTS WITH SCHIZOPHRENIA WITHOUTAH AND HEALTHY CONTROL SUBJECTS

In all 21 clusters with significant differences, patients with schizophreniawithout AH had lower FA values compared with control subjects (Table 3). Eleven of the 21 clusters were located in the left hemisphere.Significant clusters were located in the frontotemporal arcuate fasciculus(Figure 5C), the uncinate fasciculus,and the inferior longitudinal fasciculus as well as in the anterior and medialsections of the CC (Figure 5C).

In 1919, Kraepelin48 had already postulatedthat AH were a result of temporal lobe abnormalities. This hypothesis wassupported by severe abnormalities in the left temporal lobe in the brainsof patients with schizophrenia, found post mortem or in structural imagingstudies49; these abnormalities were thoughtto be related to AH. In 1900, Wernicke50 hypothesizedthat a pathologic activation of the primary acoustic cortex was the basisof the experience of external sensory stimulation during AH. In fact, a dysfunctionof temporal cortical areas, in particular of the primary auditory cortex,and of frontal speech areas was reported in AH, suggesting an associationwith impaired auditory and language-processing networks.19 However,it remained unclear to what degree WM alterations in fiber tracts constitutingparts of these functional networks were involved in the pathogenesis of AH.

In the present study, we investigated the integrity of WM fiber tractsin patients with schizophrenia with frequent AH, patients who had never experiencedhallucinations, and healthy control subjects. Using a line-scan DTI sequence,43 we obtained FA data in a 3-dimensional volume coveringthe Sylvian fissure. The arcuate fasciculus contains—among others—fibersconnecting the frontal, parietal, and temporal language and auditory areas.Compared with healthy control subjects, patients with a history of AH demonstrated,especially in the left hemisphere, an imbalance in directionality of the arcuatefasciculus, with higher directionality in the lateral part of the arcuatefasciculus and decreased directionality of WM fibers in the medial part ofthe arcuate fasciculus. This pattern could not be demonstrated for patientswithout AH. The arcuate fasciculus is divided into (1) a medial part thatcontains longer fibers connecting the lateral frontal cortex with the dorsolateralparietal and temporal cortex and (2) a lateral part, with shorter U-shapedfibers connecting the frontoparietal, parietooccipital, and parietotemporalcortex51; fibers originate in the prefrontaland premotor gyri (mainly the Broca area) and project among others posteriorto the Wernicke area. Thus, the lateral part of the arcuate fasciculus providesa pathway by which frontal speech-production areas can influence auditoryand speech perception areas during overt and inner speech. The importanceof the arcuate fasciculus in language is underlined by results from neurologicalfindings in aphasia research. A disruption of the arcuate fasciculus leadsto a disturbance of the neuronal connections from the frontal Broca area tothe temporal Wernicke area, which results in a disturbance of the stream ofspeech.52 One link between AH and inner speechis the common clinical observation that the content of AH is often closelyrelated to the content of the patient's own thought and sometimes is evenreported as thoughts becoming loud. The exact neurobiological functional correlateof alterations of FA remains unclear; however, most in vivo human and animalstudies investigating FA values during neuronal development and functionaldisturbances in neuropsychiatric diseases suggest that an increase of FA valuesis related to an increase of connectivity in WM bundles.53 Therefore,it can be hypothesized that high WM directionality in the lateral part ofthe arcuate fasciculus in AH is associated with high connectivity betweendistributed language and auditory areas. This may facilitate the dysfunctionalcoactivation of the primary auditory cortex and language-related areas thathas been previously described during AH.13 Inthe medial part of the arcuate fasciculus, both patient groups showed smallerdirectionality than did control subjects, which is in accordance with a recentreport observing reduced left hemispherical FA values in the arcuate fasciclein schizophrenia.34 This might provide a structuralalteration associated with disrupted frontotemporal processing.2325 Themore pronounced alterations in the left hemisphere, the same hemisphere reportedlymore affected in schizophrenia, may be related to language dominance.54 The fiber tracts found to be affected here coincidewith those that show the strongest developmental changes during childhoodand adolescence.55 This allows speculationabout a developmental origin of the aforementioned alterations of the arcuatefasciculus in patients with AH and suggests a relation between AH and WM aberrance.

The CC carries most of the commissural fibers in the cerebrum, interconnectingleft with the correspondent right hemispheric regions,38 mediatinginterhemispheric communication. It was argued56 thatthe deficit in information processing in schizophrenia might be related toalterations in the CC. Many studies on the size of the CC have shown smallervolumes in schizophrenia; however, these findings are not unequivocal.49,57 Even if no concluding macrostructuralresults were obvious, behavioral experiments gave evidence for a specificexcessive callosal transfer in schizophrenia.58 However,a recent study searching for a specific relation between AH and the CC failedto show clear volumetric differences.59 Inthe present study, we report higher directionality in the anterior part ofthe CC, including fibers that connect the left with the right frontal speech-relatedareas. This gives—on a microstructural level—support to the earlierassumption of higher callosal transfer in patients with schizophrenia withAH.

In most parts of the CC, however, patients demonstrated smaller FA valuescompared with control subjects. Results on FA values in the CC of previousDTI studies are not fully consistent, even though most showed reduced FA valuesin schizophrenia.30,31 However,1 group failed to replicate their own findings in a second study.36

The uncinate fasciculus connects the temporal pole with the orbitofrontalcortex. It includes projection fibers from the somatosensory cortex and auditorycortex.38 In the present study, the directionalityin the uncinate fasciculus was significantly smaller in both groups with schizophreniacompared with healthy subjects, and there was no difference between patientswith and without hallucinations. Thus, compared with the arcuate fasciculus,the uncinate fasciculus appears less important for the generation of AH. Ingeneral, our results agree with previously found reduced FA values in theleft uncinate fascicle, although we found reduced values in both hemispheres.34 Although we found reduced anisotropy in the uncinatefasciculus in schizophrenia, we could not confirm the previously reportedrelated loss of normal left-higher-than-right FA asymmetry,32 aphysiological asymmetry that might indirectly relate to specialized, lateralizedfunctions such as language to AH. Kubicki et al32 raisedthe issue of whether their findings were restricted to the uncinate fascicleor a general phenomenon in schizophrenia. Our results show various fasciculito be affected in schizophrenia and a differential involvement of the WM tractsdepending on psychopathologic features (in this study, AH).

The third important frontotemporal fiber tract besides the arcuate anduncinate fasciculus is the cingulate bundle. It is, in contrast to the arcuateand uncinate fasciculus, part of the limbic system. The cingulated gyrus isdiscussed as an "interface between emotion and cognition,"60(p107) and impairment is found in several psychiatric disorders suchas schizophrenia,61 obsessive-compulsive disorder,62 and major depression.63 Inthe cingulate bundle, we demonstrated a reduced anisotropy in patients withouthallucinations compared with patients who had hallucinations, but restrictedto the left hemisphere. This difference was not obvious in the comparisonof either patient group with control subjects. This is in accordance withthe earlier studies that also did not find differences of FA values in thecingulate bundle when comparing patients with schizophrenia without respectto psychopathologic features.34 From functionalimaging studies, there is evidence of the involvement of the anterior6466 and of the left-sidedposterior regions67 of the cingulate gyrusin the generation of AH. Our finding of higher FA values in AH is locatedin the left medioposterior part of the cingulate bundle and may be relatedon a microstructural level to reports of pathologic, high activation shownin imaging studies.

In conclusion, those WM fibers that we found to be most altered in patientswho had AH constitute the most important connections between language-relatedfrontal and temporal regions. These alterations may have a developmental originand may contribute to an understanding of how internally generated languageis perceived to be generated externally. The aberrant connections may leadto abnormal activation in regions that normally process external acousticaland language stimuli. That accounts for these patients' inability to distinguishself-generated thoughts from external stimulation.

Correspondence: Daniela Hubl, MD, Department of Psychiatric Neurophysiology,University Hospital of Clinical Psychiatry, Bolligenstrasse 111, CH-3000 Bern60, Switzerland (hubl@puk.unibe.ch).

Submitted for publication September 29, 2002; final revision receivedJune 4, 2003; accepted February 6, 2004.

This study was supported by grants 3200-059077.99 (Dr Dierks) and 31-59082.99(Dr Kreis) from the Swiss National Science Foundation, Bern.

We thank Karin Zwygart for performing the magnetic resonance imagingmeasurements.

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PubMed
Shergill  SSBullmore  ESimmons  AMurray  RMcGuire  P Functional anatomy of auditory verbal imagery in schizophrenic patientswith auditory hallucinations. Am J Psychiatry. 2000;1571691- 1693
PubMed
Shergill  SSBrammer  MJWilliams  SCMurray  RMMcGuire  PK Mapping auditory hallucinations in schizophrenia using functional magneticresonance imaging. Arch Gen Psychiatry. 2000;571033- 1038
PubMed
Lennox  BRPark  SBMedley  IMorris  PGJones  PB The functional anatomy of auditory hallucinations in schizophrenia. Psychiatry Res. 2000;10013- 20
PubMed
Halligan  PWDavid  AS Cognitive neuropsychiatry: towards a scientific psychopathology. Nat Rev Neurosci. 2001;2209- 215
PubMed
Roland  P Language. Roland  PedBrain Activation. NewYork, NY Wiley-Liss1993;269- 290
Lawrie  SMBuechel  CWhalley  HCFrith  CDFriston  KJJohnstone  EC Reduced frontotemporal functional connectivity in schizophrenia associatedwith auditory hallucinations. Biol Psychiatry. 2002;511008- 1011
PubMed
Ford  JMMathalon  DHWhitfield  SFaustman  WORoth  WT Reduced communication between frontal and temporal lobes during talkingin schizophrenia. Biol Psychiatry. 2002;51485- 492
PubMed
Andreasen  NC Schizophrenia: the fundamental questions. Brain Res Brain Res Rev. 2000;31106- 112
PubMed
Frith  CDFriston  KJHerold  SSilbersweig  DFletcher  PCahill  CDolan  RJFrackowiak  RSLiddle  PF Regional brain activity in chronic schizophrenic patients during theperformance of a verbal fluency task. Br J Psychiatry. 1995;167343- 349
PubMed
Liddle  PF Functional imaging—schizophrenia. Br Med Bull. 1996;52486- 494
PubMed
Basser  PJMattiello  JLeBihan  D MR diffusion tensor spectroscopy and imaging. Biophys J. 1994;66259- 267
PubMed
Le Bihan  DMangin  JFPoupon  CClark  CAPappata  SMolko  NChabriat  H Diffusion tensor imaging: concepts and applications. J Magn Reson Imaging. 2001;13534- 546
PubMed
Buchsbaum  MSTang  CYPeled  SGudbjartsson  HLu  DHazlett  EADownhill  JHaznedar  MFallon  JHAtlas  SW MRI white matter diffusion anisotropy and PET metabolic rate in schizophrenia. Neuroreport. 1998;9425- 430
PubMed
Lim  KOHedehus  MMoseley  Mde Crespigny  ASullivan  EVPfefferbaum  A Compromised white matter tract integrity in schizophrenia inferredfrom diffusion tensor imaging. Arch Gen Psychiatry. 1999;56367- 374
PubMed
Foong  JMaier  MClark  CABarker  GJMiller  DHRon  MA Neuropathological abnormalities of the corpus callosum in schizophrenia:a diffusion tensor imaging study. J Neurol Neurosurg Psychiatry. 2000;68242- 244
PubMed
Agartz  IAndersson  JLSkare  S Abnormal brain white matter in schizophrenia: a diffusion tensor imagingstudy. Neuroreport. 2001;122251- 2254
PubMed
Kubicki  MWestin  CFMaier  SEFrumin  MNestor  PGSalisbury  DFKikinis  RJolesz  FAMcCarley  RWShenton  ME Uncinate fasciculus findings in schizophrenia: a magnetic resonancediffusion tensor imaging study. Am J Psychiatry. 2002;159813- 820
PubMed
Wolkin  AChoi  SJSzilagyi  SSanfilipo  MRotrosen  JPLim  KO Inferior frontal white matter anisotropy and negative symptoms of schizophrenia:a diffusion tensor imaging study. Am J Psychiatry. 2003;160572- 574
PubMed
Burns  JJob  DBastin  MEWhalley  HMacgillivray  TJohnstone  ECLawrie  SM Structural disconnectivity in schizophrenia: a diffusion tensor magneticresonance imaging study. Br J Psychiatry. 2003;182439- 443
PubMed
Steel  RMBastin  MEMcConnell  SMarshall  ICunningham-Owens  DGLawrie  SMJohnstone  ECBest  JJ Diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy(1H MRS) in schizophrenic subjects and normal controls. Psychiatry Res. 2001;106161- 170
PubMed
Foong  JSymms  MRBarker  GJMaier  MMiller  DHRon  MA Investigating regional white matter in schizophrenia using diffusiontensor imaging. Neuroreport. 2002;13333- 336
PubMed
Lim  KOHelpern  JA Neuropsychiatric applications of DTI—a review. NMR Biomed. 2002;15587- 593
PubMed
Nieuwenhuys  RVoogd  Jvan Huijzen  C Lange Assoziationsbahnen und kommissurale Verbindungen. Nieuwenhuys  RVoogd  Jvan Huijzen  CedsDas zentrale Nervensystem des Menschen. 2nd Berlin, Germany Springer-Verlag1978;381- 392
Bramer  GR International statistical classification of diseases and related healthproblems: 10th revision. World Health Stat Q. 1988;4132- 36
PubMed
Oulis  PGMavreas  VGMamounas  JMStefanis  CN Clinical characteristics of auditory hallucinations. Acta Psychiatr Scand. 1995;9297- 102
PubMed
Kay  SRFiszbein  AOpler  LA The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13261- 276
PubMed
National Institute for Mental Health, Clinical global impressions. Guy  WBonato  RedsManual for the ECDEUAssessment Battery. 2nd rev Chevy Chase, Md National Institutefor Mental Health1970;
Mamata  HMamata  YWestin  CFShenton  MEKikinis  RJolesz  FAMaier  SE High-resolution line scan diffusion tensor MR imaging of white matterfiber tract anatomy. AJNR Am J Neuroradiol. 2002;2367- 75
PubMed
Maier  SEGudbjartsson  HPatz  SHsu  LLovblad  KOEdelman  RRWarach  SJolesz  FA Line scan diffusion imaging: characterization in healthy subjects andstroke patients. AJR Am J Roentgenol. 1998;17185- 93
Papadakis  NGXing  DHouston  GCSmith  JMSmith  MIJames  MFParsons  AAHuang  CLHall  LDCarpenter  TA A study of rotationally invariant and symmetric indices of diffusionanisotropy. Magn Reson Imaging. 1999;17881- 892
PubMed
Kriegeskorte  NGoebel  R An efficient algorithm for topologically correct segmentation of thecortical sheet in anatomical MR volumes. Neuroimage. 2001;14329- 346
PubMed
Talairach  JTournoux  P Co-Planar Stereotaxic Atlas of the Human Brain.  Stuttgart, Germany Thieme Medical Publishers1988;
Kraepelin  E Dementia Praecox.  New York, NY Churchill Livingston Inc1919;
Shenton  MEDickey  CCFrumin  MMcCarley  RW A review of MRI findings in schizophrenia. Schizophr Res. 2001;491- 52
PubMed
Wernicke  C Zwanzigste Vorlesung. Wernicke  CedGrundriss der Psychiatrie inklinischen Vorlesungen. Leipzig, Germany Verlag von Georg Thieme1900201
Catani  MHoward  RJPajevic  SJones  DK Virtual in vivo interactive dissection of white matter fasciculi inthe human brain. Neuroimage. 2002;1777- 94
PubMed
Kolb  BWhishaw  I Language. Fundamentals of Human Neuropsychology. 4th New York, NY WH Freeman1996;387- 415
Dong  QWelsh  RCChenevert  TLCarlos  RCMaly-Sundgren  PGomez-Hassan  DMMukherji  SK Clinical applications of diffusion tensor imaging. J Magn Reson Imaging. 2004;196- 18
PubMed
Schultz  SKAndreasen  NC Schizophrenia. Lancet. 1999;3531425- 1430
PubMed
Paus  TZijdenbos  AWorsley  KCollins  DLBlumenthal  JGiedd  JNRapoport  JLEvans  AC Structural maturation of neural pathways in children and adolescents:in vivo study. Science. 1999;2831908- 1911
PubMed
Gruzelier  J Hemispheric imbalance: syndromes of schizophrenia, premorbid personality,and neurodevelopmental influences. Steinhauer  SGruzelier  JZubin  JedsHandbookof Schizophrenia: Neurosychology, Psychophysiology and Information Processing,vol. 5. New York, NY Elsevier1991;599- 650
Innocenti  GMAnsermet  FParnas  J Schizophrenia, neurodevelopment and corpus callosum. Mol Psychiatry. 2003;8261- 274
PubMed
David  AS Callosal transfer in schizophrenia: too much or too little? J Abnorm Psychol. 1993;102573- 579
PubMed
Rossell  SLShapleske  JFukuda  RWoodruff  PWSimmons  ADavid  AS Corpus callosum area and functioning in schizophrenic patients withauditory-verbal hallucinations. Schizophr Res. 2001;509- 17
PubMed
Allman  JMHakeem  AErwin  JMNimchinsky  EHof  P The anterior cingulate cortex: the evolution of an interface betweenemotion and cognition. Ann N Y Acad Sci. 2001;935107- 117
PubMed
Tamminga  CAVogel  MGao  XLahti  ACHolcomb  HH The limbic cortex in schizophrenia: focus on the anterior cingulate. Brain Res Brain Res Rev. 2000;31364- 370
PubMed
Graybiel  AMRauch  SL Toward a neurobiology of obsessive-compulsive disorder. Neuron. 2000;28343- 347
PubMed
Brody  ALBarsom  MWBota  RGSaxena  S Prefrontal-subcortical and limbic circuit mediation of major depressivedisorder. Semin Clin Neuropsychiatry. 2001;6102- 112
PubMed
Cleghorn  JMGarnett  ESNahmias  CBrown  GMKaplan  RDSzechtman  HSzechtman  BFranco  SDermer  SWCook  P Regional brain metabolism during auditory hallucinations in chronicschizophrenia. Br J Psychiatry. 1990;157562- 570
PubMed
Silbersweig  DAStern  EFrith  CCahill  CHolmes  AGrootoonk  SSeaward  JMcKenna  PChua  SESchnorr  LJones  TFrackowiak  RSJ A functional neuroanatomy of hallucinations in schizophrenia. Nature. 1995;378176- 179
PubMed
Lennox  BRPark  SBJones  PBMorris  PGPark  G Spatial and temporal mapping of neural activity associated with auditoryhallucinations. Lancet. 1999;353644
PubMed
Copolov  DLSeal  MLMaruff  PUlusoy  RWong  MTTochon-Danguy  HJEgan  GF Cortical activation associated with the experience of auditory hallucinationsand perception of human speech in schizophrenia: a PET correlation study. Psychiatry Res. 2003;122139- 152
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Localization of 12 acquired axialslices. Measured volume was optimized to cover regions known to be importantin the generation of auditory hallucinations, such as the inferior frontalgyrus, the superior temporal gyrus, and the Wernicke area.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Three-dimensional anatomical data(A) were analyzed, and coregistered fractional anisotropy maps were rotated,normalized, and transformed to Talairach space (D). Individually, anatomywas segmented at the gray–white-matter (WM) boundary (B). Ninety percentWM probability was estimated using χ2 distribution (C). Fractionalanisotropy analysis was restricted to the WM volume (E). Voxelwise analysisof variance and t test comparisons were computedbetween groups, and significant results were fused with the anatomical datafor better orientation (F).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

A, Significant voxels resultingfrom a 1-way analysis of variance comparing healthy control subjects (n =13), patients with hallucinations (n = 13), and patients without hallucinations(n = 13). B, On the basis of this analysis of variance, a confirmatory regionof interest analysis was calculated for 4 regions, including the medial (lefthemisphere, mean [SD] Talairach coordinates x, y, z, respectively, −32[1], −42 [2], and 25 [2]; right hemisphere, 22 [2], −42 [2], and34 [2]) and lateral arcuate fasciculus (left hemisphere, −42 [2],−38[8], 4 [3]; right hemisphere, 38 [2], −43 [1], and 17 [2]). Mean (SD)fractional anisotropy values and post hoc results are presented. Asteriskindicates P≤.05.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Voxelwise comparison between healthycontrol subjects (n = 13) and all patients with schizophrenia (n = 26). Patientswith schizophrenia show lower fractional anisotropy values in wide parts ofvarious white matter tracts. In this axial slice, the lower fractional anisotropyvalues in patients are shown at the level of the corpus callosum and the inferiorlongitudinal fasciculus. The region of the basal ganglia, which was excludedfrom the analysis because of inconsistent segmentation, is indicated by thedotted gray line. NS indicates not significant.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

The medial part of the arcuatefasciculus contains long fibers connecting the frontal with the temporal cortex,whereas the lateral part, with its shorter U-shaped fibers, connects, forexample, the language-related regions in the frontal and parietotemporal lobes.The main differences between patients with hallucinations (n = 13) and healthycontrol subjects (n = 13) as well as patients without hallucinations (n =13) were located in the lateral fibers of the arcuate fasciculus (1) and theanterior corpus callosum (3). NS indicates not significant.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 2. Assessment of Clinical Measures*
Table Graphic Jump LocationTable 3a. Analysis of Significant Clusters for Comparison Between 13Healthy Control Subjects (Group C) and 26 Patients (Group P)*
Table Graphic Jump LocationTable 3b. Analysis of Significant Clusters for Comparison Between 13Healthy Control Subjects (Group C) and 26 Patients (Group P)*
Table Graphic Jump LocationTable 4a. Analysis of Significant Clusters for Comparison Between 13Patients With Hallucinations (Group H) and 13 Patients Without Hallucinations(Group N) and 13 Healthy Control Subjects (Group C)*
Table Graphic Jump LocationTable 4b. Analysis of Significant Clusters for Comparison Between 13Patients With Hallucinations (Group H) and 13 Patients Without Hallucinations(Group N) and 13 Healthy Control Subjects (Group C)*
Table Graphic Jump LocationTable 5. Repeated Measures Analysis of Variance*

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Shergill  SSBrammer  MJWilliams  SCMurray  RMMcGuire  PK Mapping auditory hallucinations in schizophrenia using functional magneticresonance imaging. Arch Gen Psychiatry. 2000;571033- 1038
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Lennox  BRPark  SBMedley  IMorris  PGJones  PB The functional anatomy of auditory hallucinations in schizophrenia. Psychiatry Res. 2000;10013- 20
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Halligan  PWDavid  AS Cognitive neuropsychiatry: towards a scientific psychopathology. Nat Rev Neurosci. 2001;2209- 215
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Roland  P Language. Roland  PedBrain Activation. NewYork, NY Wiley-Liss1993;269- 290
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PubMed
Ford  JMMathalon  DHWhitfield  SFaustman  WORoth  WT Reduced communication between frontal and temporal lobes during talkingin schizophrenia. Biol Psychiatry. 2002;51485- 492
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Andreasen  NC Schizophrenia: the fundamental questions. Brain Res Brain Res Rev. 2000;31106- 112
PubMed
Frith  CDFriston  KJHerold  SSilbersweig  DFletcher  PCahill  CDolan  RJFrackowiak  RSLiddle  PF Regional brain activity in chronic schizophrenic patients during theperformance of a verbal fluency task. Br J Psychiatry. 1995;167343- 349
PubMed
Liddle  PF Functional imaging—schizophrenia. Br Med Bull. 1996;52486- 494
PubMed
Basser  PJMattiello  JLeBihan  D MR diffusion tensor spectroscopy and imaging. Biophys J. 1994;66259- 267
PubMed
Le Bihan  DMangin  JFPoupon  CClark  CAPappata  SMolko  NChabriat  H Diffusion tensor imaging: concepts and applications. J Magn Reson Imaging. 2001;13534- 546
PubMed
Buchsbaum  MSTang  CYPeled  SGudbjartsson  HLu  DHazlett  EADownhill  JHaznedar  MFallon  JHAtlas  SW MRI white matter diffusion anisotropy and PET metabolic rate in schizophrenia. Neuroreport. 1998;9425- 430
PubMed
Lim  KOHedehus  MMoseley  Mde Crespigny  ASullivan  EVPfefferbaum  A Compromised white matter tract integrity in schizophrenia inferredfrom diffusion tensor imaging. Arch Gen Psychiatry. 1999;56367- 374
PubMed
Foong  JMaier  MClark  CABarker  GJMiller  DHRon  MA Neuropathological abnormalities of the corpus callosum in schizophrenia:a diffusion tensor imaging study. J Neurol Neurosurg Psychiatry. 2000;68242- 244
PubMed
Agartz  IAndersson  JLSkare  S Abnormal brain white matter in schizophrenia: a diffusion tensor imagingstudy. Neuroreport. 2001;122251- 2254
PubMed
Kubicki  MWestin  CFMaier  SEFrumin  MNestor  PGSalisbury  DFKikinis  RJolesz  FAMcCarley  RWShenton  ME Uncinate fasciculus findings in schizophrenia: a magnetic resonancediffusion tensor imaging study. Am J Psychiatry. 2002;159813- 820
PubMed
Wolkin  AChoi  SJSzilagyi  SSanfilipo  MRotrosen  JPLim  KO Inferior frontal white matter anisotropy and negative symptoms of schizophrenia:a diffusion tensor imaging study. Am J Psychiatry. 2003;160572- 574
PubMed
Burns  JJob  DBastin  MEWhalley  HMacgillivray  TJohnstone  ECLawrie  SM Structural disconnectivity in schizophrenia: a diffusion tensor magneticresonance imaging study. Br J Psychiatry. 2003;182439- 443
PubMed
Steel  RMBastin  MEMcConnell  SMarshall  ICunningham-Owens  DGLawrie  SMJohnstone  ECBest  JJ Diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy(1H MRS) in schizophrenic subjects and normal controls. Psychiatry Res. 2001;106161- 170
PubMed
Foong  JSymms  MRBarker  GJMaier  MMiller  DHRon  MA Investigating regional white matter in schizophrenia using diffusiontensor imaging. Neuroreport. 2002;13333- 336
PubMed
Lim  KOHelpern  JA Neuropsychiatric applications of DTI—a review. NMR Biomed. 2002;15587- 593
PubMed
Nieuwenhuys  RVoogd  Jvan Huijzen  C Lange Assoziationsbahnen und kommissurale Verbindungen. Nieuwenhuys  RVoogd  Jvan Huijzen  CedsDas zentrale Nervensystem des Menschen. 2nd Berlin, Germany Springer-Verlag1978;381- 392
Bramer  GR International statistical classification of diseases and related healthproblems: 10th revision. World Health Stat Q. 1988;4132- 36
PubMed
Oulis  PGMavreas  VGMamounas  JMStefanis  CN Clinical characteristics of auditory hallucinations. Acta Psychiatr Scand. 1995;9297- 102
PubMed
Kay  SRFiszbein  AOpler  LA The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13261- 276
PubMed
National Institute for Mental Health, Clinical global impressions. Guy  WBonato  RedsManual for the ECDEUAssessment Battery. 2nd rev Chevy Chase, Md National Institutefor Mental Health1970;
Mamata  HMamata  YWestin  CFShenton  MEKikinis  RJolesz  FAMaier  SE High-resolution line scan diffusion tensor MR imaging of white matterfiber tract anatomy. AJNR Am J Neuroradiol. 2002;2367- 75
PubMed
Maier  SEGudbjartsson  HPatz  SHsu  LLovblad  KOEdelman  RRWarach  SJolesz  FA Line scan diffusion imaging: characterization in healthy subjects andstroke patients. AJR Am J Roentgenol. 1998;17185- 93
Papadakis  NGXing  DHouston  GCSmith  JMSmith  MIJames  MFParsons  AAHuang  CLHall  LDCarpenter  TA A study of rotationally invariant and symmetric indices of diffusionanisotropy. Magn Reson Imaging. 1999;17881- 892
PubMed
Kriegeskorte  NGoebel  R An efficient algorithm for topologically correct segmentation of thecortical sheet in anatomical MR volumes. Neuroimage. 2001;14329- 346
PubMed
Talairach  JTournoux  P Co-Planar Stereotaxic Atlas of the Human Brain.  Stuttgart, Germany Thieme Medical Publishers1988;
Kraepelin  E Dementia Praecox.  New York, NY Churchill Livingston Inc1919;
Shenton  MEDickey  CCFrumin  MMcCarley  RW A review of MRI findings in schizophrenia. Schizophr Res. 2001;491- 52
PubMed
Wernicke  C Zwanzigste Vorlesung. Wernicke  CedGrundriss der Psychiatrie inklinischen Vorlesungen. Leipzig, Germany Verlag von Georg Thieme1900201
Catani  MHoward  RJPajevic  SJones  DK Virtual in vivo interactive dissection of white matter fasciculi inthe human brain. Neuroimage. 2002;1777- 94
PubMed
Kolb  BWhishaw  I Language. Fundamentals of Human Neuropsychology. 4th New York, NY WH Freeman1996;387- 415
Dong  QWelsh  RCChenevert  TLCarlos  RCMaly-Sundgren  PGomez-Hassan  DMMukherji  SK Clinical applications of diffusion tensor imaging. J Magn Reson Imaging. 2004;196- 18
PubMed
Schultz  SKAndreasen  NC Schizophrenia. Lancet. 1999;3531425- 1430
PubMed
Paus  TZijdenbos  AWorsley  KCollins  DLBlumenthal  JGiedd  JNRapoport  JLEvans  AC Structural maturation of neural pathways in children and adolescents:in vivo study. Science. 1999;2831908- 1911
PubMed
Gruzelier  J Hemispheric imbalance: syndromes of schizophrenia, premorbid personality,and neurodevelopmental influences. Steinhauer  SGruzelier  JZubin  JedsHandbookof Schizophrenia: Neurosychology, Psychophysiology and Information Processing,vol. 5. New York, NY Elsevier1991;599- 650
Innocenti  GMAnsermet  FParnas  J Schizophrenia, neurodevelopment and corpus callosum. Mol Psychiatry. 2003;8261- 274
PubMed
David  AS Callosal transfer in schizophrenia: too much or too little? J Abnorm Psychol. 1993;102573- 579
PubMed
Rossell  SLShapleske  JFukuda  RWoodruff  PWSimmons  ADavid  AS Corpus callosum area and functioning in schizophrenic patients withauditory-verbal hallucinations. Schizophr Res. 2001;509- 17
PubMed
Allman  JMHakeem  AErwin  JMNimchinsky  EHof  P The anterior cingulate cortex: the evolution of an interface betweenemotion and cognition. Ann N Y Acad Sci. 2001;935107- 117
PubMed
Tamminga  CAVogel  MGao  XLahti  ACHolcomb  HH The limbic cortex in schizophrenia: focus on the anterior cingulate. Brain Res Brain Res Rev. 2000;31364- 370
PubMed
Graybiel  AMRauch  SL Toward a neurobiology of obsessive-compulsive disorder. Neuron. 2000;28343- 347
PubMed
Brody  ALBarsom  MWBota  RGSaxena  S Prefrontal-subcortical and limbic circuit mediation of major depressivedisorder. Semin Clin Neuropsychiatry. 2001;6102- 112
PubMed
Cleghorn  JMGarnett  ESNahmias  CBrown  GMKaplan  RDSzechtman  HSzechtman  BFranco  SDermer  SWCook  P Regional brain metabolism during auditory hallucinations in chronicschizophrenia. Br J Psychiatry. 1990;157562- 570
PubMed
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