Anatomical brain connectivity and positive symptoms of schizophrenia: A diffusion tensor imaging study

Structural brain changes in schizophrenia are well documented in the neuroimaging literature. The classical morphometric analyses of magnetic resonance imaging (MRI) data have recently been supplemented by diffusion tensor imaging (DTI), which mainly assesses changes in white matter (WM). DTI increasingly provides evidence for abnormal anatomical connectivity in schizophrenia, most often using fractional anisotropy (FA) as an indicator of the integrity of WM tracts. To better understand the clinical significance of such anatomical changes, we studied FA values in a whole-brain analysis comparing paranoid schizophrenic patients with a history of auditory hallucinations and matched healthy controls. The relationship of WM changes to psychopathology was assessed by correlating FA values with PANSS scores (positive symptoms and severity of auditory hallucinations) and with illness duration. Schizophrenic patients showed FA reductions indicating WM integrity disturbance in the prefrontal regions, external capsule, pyramidal tract, occipitofrontal fasciculus, superior and inferior longitudinal fasciculi, and corpus callosum. The arcuate fasciculus was the only tract which showed increased FA values in patients. Increased FA values in this region correlated with increased severity of auditory hallucinations and length of illness. Our results suggest that local changes in anatomical integrity of WM tracts in schizophrenia may be related to patients' clinical presentation.     

White Matter Development in Adolescence: Diffusion Tensor Imaging and Meta-Analytic Results

Background

In light of the evidence for brain white matter (WM) abnormalities in schizophrenia, study of normal WM maturation in adolescence may provide critical insights relevant to the neurodevelopment of the disorder. Voxel-wise diffusion tensor imaging (DTI) studies have consistently demonstrated increases in fractional anisotropy (FA), a putative measure of WM integrity, from childhood into adolescence. However, the WM tracts that show FA increases have been variable across studies. Here, we aimed to assess which WM tracts show the most pronounced changes across adolescence.

Methods

DTI was performed in 78 healthy subjects aged 8–21 years, and voxel-wise analysis conducted using tract-based spatial statistics (TBSS). In addition, we performed the first meta-analysis of TBSS studies on WM development in adolescence.

Results

In our sample, we observed bilateral increases in FA with age, which were most significant in the left superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and anterior thalamic radiation. These findings were confirmed by the meta-analysis, and FA increase in the bilateral SLF was the most consistent finding across studies. Moreover, in our sample, FA of the bilateral SLF showed a positive association with verbal working memory performance and partially mediated increases in verbal fluency as a function of increasing age.

Conclusions

These data highlight increasing connectivity in the SLF during adolescence. In light of evidence for compromised SLF integrity in high-risk and first-episode patients, these data suggest that abnormal maturation of the SLF during adolescence may be a key target in the neurodevelopment of schizophrenia.     

Emotional prosodic processing in auditory hallucinations

Deficits in emotional prosodic processing, the expression of emotions in voice, have been widely reported in patients with schizophrenia, not only in comprehending emotional prosody but also expressing it. Given that prosodic cues are important in memory for voice and speaker identity, Cutting has proposed that prosodic deficits may contribute to the misattribution that appears to occur in auditory hallucinations in psychosis. The present study compared hallucinating patients with schizophrenia, non-hallucinating patients and normal controls on an emotional prosodic processing task. It was hypothesised that hallucinators would demonstrate greater deficits in emotional prosodic processing than non-hallucinators and normal controls. Participants were 67 patients with a diagnosis of schizophrenia or schizoaffective disorder (hallucinating = 38, non-hallucinating = 29) and 31 normal controls. The prosodic processing task used in this study comprised a series of semantically neutral sentences expressed in happy, sad and neutral voices which were rated on a 7-point Likert scale from sad (− 3) through neutral (0) to happy (+ 3). Significant deficits in the prosodic processing tasks were found in hallucinating patients compared to non-hallucinating patients and normal controls. No significant differences were observed between non-hallucinating patients and normal controls. In the present study, patients experiencing auditory hallucinations were not as successful in recognising and using prosodic cues as the non-hallucinating patients. These results are consistent with Cutting's hypothesis, that prosodic dysfunction may mediate the misattribution of auditory hallucinations.     

Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging

BACKGROUND: Perceptions of speech in the absence of an auditory stimulus (auditory verbal hallucinations) are a cardinal feature of schizophrenia. Functional neuroimaging provides a powerful means of measuring neural activity during auditory hallucinations, but the results from previous studies have been inconsistent. This may reflect the acquisition of small numbers of images in each subject and the confounding effects of patients actively signaling when hallucinations occur. METHODS: We examined 6 patients with schizophrenia who were experiencing frequent auditory hallucinations, using a novel functional magnetic resonance imaging method that permitted the measurement of spontaneous neural activity without requiring subjects to signal when hallucinations occurred. Approximately 50 individual scans were acquired at unpredictable intervals in each subject while they were intermittently hallucinating. Immediately after each scan, subjects reported whether they had been hallucinating at that instant. Neural activity when patients were and were not experiencing hallucinations was compared in each subject and the group as a whole. RESULTS: Auditory hallucinations were associated with activation in the inferior frontal/insular, anterior cingulate, and temporal cortex bilaterally (with greater responses on the right), the right thalamus and inferior colliculus, and the left hippocampus and parahippocampal cortex (P<.0001). CONCLUSIONS: Auditory hallucinations may be mediated by a distributed network of cortical and subcortical areas. Previous neuroimaging studies of auditory hallucinations may have identified different components of this network.     

Impaired verbal source monitoring in schizophrenia: An intermediate trait vulnerability marker?

Patients with schizophrenia, particularly those with positive symptoms show impaired verbal source monitoring. Specific cognitive deficits have been observed during both active and remission phases of the illness as well as in groups of unaffected first degree relatives of patients with schizophrenia. This type of schizophrenia vulnerability marker may precede the onset of frank psychotic symptoms and contribute to their developments. The aim of this study was first to determine if unaffected siblings were impaired in discriminate internal vs. external generated events when compared to their remitted schizophrenics relatives and healthy subjects. Performances of healthy subjects were then compared with results from previous studies with acute hallucinating patients, acute non-hallucinating patients and patients with resistant auditory verbal hallucinations. Compared with healthy subjects, unaffected siblings are impaired (effect size, ES=0.7), remitted or acute non-hallucinating patients are more impaired than siblings (ES=1.4); patients with verbal auditory hallucinations (acute or resistant) are even more impaired than non-hallucinating patients (ES=2.1). Our results suggest that a source monitoring deficit could be considered as an intermediate vulnerability marker of schizophrenia.     

Source monitoring deficits in hallucinating compared to non-hallucinating patients with schizophrenia.

In two source memory tests, hallucinating patients with schizophrenia (N=30), compared to non-hallucinating (N=31), are impaired in recognizing internal self-generated items and misattribute them to an external event. They are not impaired in recognizing events from two internal sources. Results support a selective source-monitoring deficit in the occurrence of auditory hallucinations.     

Cortical activation associated with the experience of auditory hallucinations and perception of human speech in schizophrenia: a PET correlation study

A [H(2)(15)O] PET correlation analysis technique was employed to correlate brain activations associated with self-reports of auditory hallucinations in hallucinating patients (n=8) and perception of transient, random human speech in non-hallucinating (n=7) patients and normal control subjects (n=8). Perception of externally generated human speech amongst the non-hallucinating and normal control participants was associated with a consistent pattern of extensive bilateral auditory cortex activation (Brodmann areas 40/41/42/22). Hallucinating participants demonstrated a network of cortical activations including bilateral auditory cortex, left limbic regions, right medial frontal and right prefrontal regions. The observed pattern of activation is consistent with models of auditory hallucinations as mis-remembered episodic memories of speech.     

White matter abnormalities in children with and at risk for bipolar disorder

OBJECTIVES: Diffusion tensor magnetic resonance imaging (DT-MRI) assesses the integrity of white matter (WM) tracts in the brain. Children with bipolar disorder (BPD) may have WM abnormalities that precede illness onset. To more fully examine this possibility, we scanned children with DSM-IV BPD and compared them to healthy peers and children at risk for BPD (AR-BPD), defined as having a first-degree relative with the disorder. METHODS: Ten children with BPD, eight healthy controls (HC), and seven AR-BPD, similar in age, had MRI scans on a 1.5 Tesla GE scanner, including a standard DT-MRI sequence (T2-EPI) with 25 axial slices. Fractional anisotropy (FA) values were compared between groups to determine regions of significant difference (p < 0.05). RESULTS: Compared to HC, children with BPD had decreased FA in right and left superior frontal tracts, including the superior longitudinal fasciculus I (SLF I) and the cingulate-paracingulate WM (CG-PAC(WM)). In addition, the BPD group had reduced FA in left orbital frontal WM and the right corpus callosum body. Compared to AR-BPD, children with BPD showed reduced FA in the right and left CG-PAC(WM). Both the BPD and AR-BPD groups showed reduced FA relative to HC in bilateral SLF I. CONCLUSIONS: The bilateral SLF I finding in both the BPD and AR-BPD groups may represent a trait-based marker or endophenotype of the disorder. The finding of decreased FA in the right and left CG-PAC(WM) in children with BPD compared to the other two groups may represent a disease-state related finding.     

Determinants of occurrence and recovery from hallucinations in daily life

Background Data related to the dynamics of hallucinatory experiences of patients suffering from schizophrenia are scarce. Detecting antecedent conditions and coping strategies may aid development of targeted psychological interventions. Method We studied hallucinating and non-hallucinating patients suffering from schizophrenia spectrum disorder (n = 57), and non-schizophrenic severe mentally ill patients with depression (n = 37). Data were collected using the Experience Sampling Method (ESM) over a period of 1 week. Contingent on a randomly signalling beep, subjects filled in reports of ongoing hallucinations as well as thought, mood, current activity, social circumstances and places frequented. Results More subjects suffering from schizophrenia reported hallucinations, but for all hallucinating subjects the qualities of hallucination episodes were quite similar. More subjects reported visual hallucinations at least once. In contrast, the intensity of auditory hallucinations was higher. Anxiety was the most prominent emotion during hallucinations and reports of anxiety intensity exceeded baseline levels before the first report of auditory hallucinations. Context modified hallucination intensity over the course of an episode. Social withdrawal resulted in a decrease of hallucinatory intensity (AH > VH), while social engagement slightly raised intensity levels (VH > AH). Doing nothing (VH > AH) and work activities (AH > VH) led to decreases in intensity levels over time, while passive leisure activities (watching TV) resulted in increases in intensity levels of hallucinations (AH > VH). Conclusion The results suggest that hallucinating experiences are subject to a host of contextual influences. Understanding variation offers useful insights for therapy. Accepted: 14 December 2001     

Aberrations in the arcuate fasciculus are associated with auditory verbal hallucinations in psychotic and in non‐psychotic individuals

The pathophysiology of auditory verbal hallucinations (AVH) is still unclear. Cognitive as well as electrophysiological studies indicate that a defect in sensory feedback (corollary discharge) may contribute to the experience of AVH. This could result from disruption of the arcuate fasciculus, the major tract connecting frontal and temporo‐parietal language areas. Previous diffusion tensor imaging studies indeed demonstrated abnormalities of this tract in schizophrenia patients with AVH. It is, however, difficult to disentangle specific associations with AVH in this patient group as many other factors, such as other positive and negative symptoms, medication or halted education could likewise have affected tract integrity. We therefore investigated AVH in relative isolation and studied a group of non‐psychotic individuals with AVH as well as patients with AVH and non‐hallucinating matched controls. We compared tract integrity of the arcuate fasiculus and of three other control tracts, between 35 non‐psychotic individuals with AVH, 35 schizophrenia patients with AVH, and 36 controls using diffusion tensor imaging and magnetization transfer imaging. Both groups with AVH showed an increase in magnetization transfer ratio (MTR) in the arcuate fasciculus, but not in the other control tracts. In addition, a general decrease in fractional anisotropy (FA) for almost all bundles was observed in the patient group, but not in the non‐psychotic individuals with AVH. As increased MTR in the arcuate fasciculus was present in both hallucinating groups, a specific association with AVH seems plausible. Decreases in FA, on the other hand, seem to be related to other disease processes of schizophrenia. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Brain structural changes in schizophrenia patients with persistent hallucinations

Schizophrenia is characterised by the presence of a heterogeneous range of symptoms. Although there is a consensus regarding ventricular enlargement and regional grey matter deficits, the brain structural correlates of specific symptoms, such as auditory hallucinations, are not clearly defined. We used an automated voxel-wise analysis of dual-echo spin-echo MRI data from 28 patients with schizophrenia characterised by persistent hallucinations and 32 healthy controls. Patients demonstrated grey matter (GM) volume decrements in the insula bilaterally, and in the right superior temporal and fusiform gyri, and left inferior temporal gyrus. With the exception of the insula, these GM volume losses were correlated with severity of auditory hallucinations. GM excesses were observed in the right caudate nucleus and middle temporal gyrus. White matter deficits were observed adjacent to the left superior temporal gyrus, in the right internal capsule and inferior longitudinal fasciculus. These findings support the proposition that there are structural changes in the neural circuits underlying broader processing of affect-laden information in patients with schizophrenia prone to experiencing auditory hallucinations. Such deficits may obscure important cues for recognition of internal speech, contributing to failures of self-monitoring.     

Corpus callosum area and functioning in schizophrenic patients with auditory--verbal hallucinations

Auditory--verbal hallucinations (AVH) are a characteristic feature of schizophrenia. Patients with AVHs have been found to differ from non-hallucinating patients in volumes of certain asymmetrical brain structures on MRI, and on certain neuropsychological measures. There is also evidence of corpus callosum (CC) abnormalities in schizophrenia, and it has been proposed that abnormalities of inter-hemispheric transmission may underlie hallucinations and other symptoms. The aim of this study was to examine whether patients with AVHs have smaller corpora callosa than those without AVH, and whether CC size is related to performance on neuropsychological tests of functional cerebral asymmetry. Seventy-one DSM-IV male schizophrenics were recruited on the basis of their hallucination history plus 33 matched normal controls. Twenty-nine patients had no history of AVH, and 42 had a strong history of AVH. The mid-sagittal surface area and longitudinal length of the CC were measured from T(1)-weighted spin echo images. Callosal area was divided into four sections. There were no significant differences in any of the measurements between the two patient groups, or between patients with schizophrenia and controls. There was no association between CC measures and handedness, or performance on dichotic listening or finger tapping tasks. The results of this study do not lend support for there being a major morphological abnormality of the corpus callosum in schizophrenic patients, or for a specific relationship to AVH. However, a significant association between CC area and overall grey and white matter volumes was noted in the hallucinating patients and, to a lesser extent, in the non-hallucinators, which may point to differing influences on brain development or degeneration in such patients compared with normal controls.     

Brain structure associations with phonemic and semantic fluency in typically-developing children

Verbal fluency is the ability to retrieve lexical knowledge quickly and efficiently and develops during childhood and adolescence. Few studies have investigated associations between verbal fluency performance and brain structural variation in children. Here we examined associations of verbal fluency performance with structural measures of frontal and temporal language-related brain regions and their connections in 73 typically-developing children aged 7–13 years. Tract-based spatial statistics was used to extract fractional anisotropy (FA) from the superior longitudinal fasciculus/arcuate fasciculus (SLF/AF), and the white matter underlying frontal and temporal language-related regions. FreeSurfer was used to extract cortical thickness and surface area. Better semantic and phonemic fluency performance was associated with higher right SLF/AF FA, and phonemic fluency was also modestly associated with lower left SLF/AF FA. Explorative voxelwise analyses for semantic fluency suggested associations with FA in other fiber tracts, including corpus callosum and right inferior fronto-occipital fasciculus. Overall, our results suggest that verbal fluency performance in children may rely on right hemisphere structures, possibly involving both language and executive function networks, and less on solely left hemisphere structures as often is observed in adults. Longitudinal studies are needed to clarify whether these associations are mediated by maturational processes, stable characteristics and/or experience.     

Abnormal brain response during the auditory emotional processing in schizophrenic patients with chronic auditory hallucinations

OBJECTIVE: Few neuroimaging studies have been conducted regarding clinical associations between auditory hallucinations (AHs) and affective disturbances in patients with schizophrenia. This study aimed to elucidate the neurobiological basis of emotional disturbances in schizophrenic patients with persisting AHs. METHODS: Using functional magnetic resonance imaging (fMRI), the cortical responsiveness during the processing of laughing and crying sounds was measured and compared between 14 hallucinating schizophrenic patients, 14 nonhallucinating schizophrenic patients and 28 normal controls. RESULTS: The hallucinating patients showed differential neural activities in various areas including the amygdala, the hippocampus, the cingulate, the prefrontal cortex, and the parietal cortex, compared with the nonhallucinating patients and the normal controls. In particular, compared with the nonhallucinators, the hallucinators revealed reduced activation in the left amygdala and the bilateral hippocampus during the processing of crying sounds. CONCLUSION: Our findings suggest that the persistence of AHs in schizophrenia may induce functional disturbances of the emotion-related interconnected neural networks, including reduced responsiveness in the amygdala and hippocampus to negative stimuli.     

Alterations of structural and functional connectivity in profound sensorineural hearing loss infants within an early sensitive period: A combined DTI and fMRI study

Due to heightened level of neuroplasticity, there is a sensitive period (2–4 years after birth) that exists for optimal central auditory development. Using diffusion tensor imaging combined with resting-state functional connectivity (rsFC) analysis, this study directly investigates the structural connectivity alterations of the whole brain white matter (WM) and the functional reorganization of the auditory network in infants with sensorineural hearing loss (SNHL) during the early sensitive period. 46 bilateral profound SNHL infants prior to cochlear implantation (mean age, 17.59 months) and 33 healthy controls (mean age, 18.55 months) were included in the analysis. Compared with controls, SNHL infants showed widespread WM alterations, including bilateral superior longitudinal fasciculus, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, right corticospinal tract, posterior thalamic radiation and left uncinate fasciculus. Moreover, SNHL infants demonstrated increased rsFC between left/right primary auditory cortex seeds and right insula and superior temporal gyrus. In conclusion, this study suggests that SNHL in the early sensitive period is associated with diffuse WM alterations that mainly affect the auditory and language pathways. Furthermore, increased rsFC in areas mainly associated with auditory and language networks may potentially reflect reorganization and compensatory activation in response to auditory deprivation during the early sensitive period.     

The right profile: mismatch negativity in schizophrenia with and without auditory hallucinations as measured by a multi-feature paradigm.

ObjectiveTo examine pre-attentive acoustic change detection in schizophrenia patients with and without auditory hallucinations via mismatch negativity (MMN) extracted from a multi-feature paradigm.MethodsThis study examined the electroencephalograph (EEG)-derived MMN, recorded across 32 sites, in 12 hallucinating patients (HPs) with schizophrenia, 12 non-hallucinating patients (NPs) with schizophrenia and 12 healthy controls (HCs). MMN was recorded in response to a multi-feature MMN paradigm [Näätänen, R., et al., 2004. The mismatch negativity (MMN): towards the optimal paradigm. Clin. Neurophys. 115, 140–144] which employs frequency, duration, intensity, location and gap deviants. Differences in source localization were probed using standardized low resolution brain electromagnetic tomography (sLORETA).ResultsHPs showed significantly smaller MMNs to duration deviants compared to HCs and NPs, as well as smaller MMNs to intensity deviants compared to HCs. Regionalized differences between HCs and each of the patient groups were observed in response to frequency deviants. There were no significant group effects for location or gap deviants, or for MMN latency. Source localization using sLORETA showed no significant differences in MMN generator location across groups for any of the deviant stimuli.ConclusionsThe often-reported robust MMN deficit to duration deviants may be specific to schizophrenia patients afflicted with auditory hallucinations. Furthermore, by using symptom-specific groups, novel deficits of pre-attentive auditory processing, such as that observed to intensity deviants in HPs, may be revealed.SignificanceThe differential responding observed between both groups of patients with schizophrenia has implications for automatic processing within the auditory cortex of hallucinating patients and suggests that care must be taken when recruiting participants in studies involving schizophrenia to ensure consistent, replicable results.     

Sustained attention is associated with right superior longitudinal fasciculus and superior parietal white matter microstructure in children

Sustained attention develops during childhood and has been linked to the right fronto‐parietal cortices in functional imaging studies; however, less is known about its relation to white matter (WM) characteristics. Here we investigated whether the microstructure of the WM underlying and connecting the right fronto‐parietal cortices was associated with sustained attention performance in a group of 76 typically developing children aged 7–13 years. Sustained attention was assessed using a rapid visual information processing paradigm. The two behavioral measures of interest were the sensitivity index d′ and the coefficient of variation in reaction times (RT_CV). Diffusion‐weighted imaging was performed. Mean fractional anisotropy (FA) was extracted from the WM underlying right dorsolateral prefrontal (DLPFC) and parietal cortex (PC), and the right superior longitudinal fasciculus (SLF), as well as equivalent anatomical regions‐of‐interest (ROIs) in the left hemisphere and mean global WM FA. When analyzed collectively, right hemisphere ROIs FA was significantly associated with d′ independently of age. Follow‐up analyses revealed that only FA of right SLF and the superior part of the right PC contributed significantly to this association. RT_CV was significantly associated with right superior PC FA, but not with right SLF FA. Observed associations remained significant after controlling for FA of equivalent left hemisphere ROIs or global mean FA. In conclusion, better sustained attention performance was associated with higher FA of WM in regions connecting right frontal and parietal cortices. Further studies are needed to clarify to which extent these associations are driven by maturational processes, stable characteristics and/or experience. Hum Brain Mapp 34:3216–3232, 2013. © 2012 Wiley Periodicals, Inc.     

Mean diffusivity and fractional anisotropy as indicators of disease and genetic liability to schizophrenia

The goals of this study were to first determine whether the fractional anisotropy (FA) and mean diffusivity (MD) of major white matter pathways associate with schizophrenia, and secondly to characterize the extent to which differences in these metrics might reflect a genetic predisposition to schizophrenia. Differences in FA and MD were identified using a comprehensive atlas-based tract mapping approach using diffusion tensor imaging and high-resolution structural data from 35 patients, 28 unaffected first-degree relatives of patients, 29 community controls, and 14 first-degree relatives of controls. Schizophrenia patients had significantly higher MD in the following tracts compared to controls: the right anterior thalamic radiations, the forceps minor, the bilateral inferior fronto-occipital fasciculus (IFO), the temporal component of the left superior longitudinal fasciculus (tSLF), and the bilateral uncinate. FA showed schizophrenia effects and a linear relationship to genetic liability (represented by schizophrenia patients, first-degree relatives, and controls) for the bilateral IFO, the left inferior longitudinal fasciculus (ILF), and the left tSLF. Diffusion tensor imaging studies have previously identified white matter abnormalities in all three of these tracts in schizophrenia; however, this study is the first to identify a significant genetic liability. Thus, FA of these three tracts may serve as biomarkers for studies seeking to identify how genes influence brain structure predisposing to schizophrenia. However, differences in FA and MD in frontal and temporal white matter pathways may be additionally driven by state variables that involve processes associated with the disease.     

An fMRI study of auditory hallucinations in patients with epilepsy

Purpose : The aim of the study was to investigate behavioral and brain activation in nonpsychotic hallucinating individuals. Auditory hallucinations are reported by patients with epilepsy, although less frequent than visual hallucinations are. If behavioral and neuronal activation patterns in hallucinating patients with epilepsy are found to be similar to what has been found in hallucinating patients with schizophrenia, this would support a unique neuronal representation for auditory hallucinations cutting across diagnostic groups. Methods : We report behavioral and functional magnetic resonance imaging (fMRI) data from six epilepsy patients experiencing auditory hallucinations compared with six healthy control subjects. The participants had to report which of two simultaneously presented simple speech sounds they perceived on each trial, using a dichotic stimulus presentation mode. Results : The results showed that the patients failed to show an expected right ear advantage on the task, and they also showed significantly reduced activation in temporal, frontal, and cingulate cortex areas. Discussion : The results are discussed in relation to a view that neuropsychological and functional neuroimaging indices of auditory hallucinations may be orthogonal to diagnostic category and not unique to patients with schizophrenia.     

DTI tractography and white matter fiber tract characteristics in euthymic bipolar I patients and healthy control subjects

With the introduction of diffusion tensor imaging (DTI), structural differences in white matter (WM) architecture between psychiatric populations and healthy controls can be systematically observed and measured. In particular, DTI-tractography can be used to assess WM characteristics over the entire extent of WM tracts and aggregated fiber bundles. Using 64-direction DTI scanning in 27 participants with bipolar disorder (BD) and 26 age-and-gender-matched healthy control subjects, we compared relative length, density, and fractional anisotrophy (FA) of WM tracts involved in emotion regulation or theorized to be important neural components in BD neuropathology. We interactively isolated 22 known white matter tracts using region-of-interest placement (TrackVis software program) and then computed relative tract length, density, and integrity. BD subjects demonstrated significantly shorter WM tracts in the genu, body and splenium of the corpus callosum compared to healthy controls. Additionally, bipolar subjects exhibited reduced fiber density in the genu and body of the corpus callosum, and in the inferior longitudinal fasciculus bilaterally. In the left uncinate fasciculus, however, BD subjects exhibited significantly greater fiber density than healthy controls. There were no significant differences between groups in WM tract FA for those tracts that began and ended in the brain. The significance of differences in tract length and fiber density in BD is discussed.