Diffusion Tensor Imaging in Psychiatric Disorders : Topics in Magnetic Resonance Imaging

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Diffusion Tensor Imaging in Psychiatric Disorders

White, Tonya MD*†‡; Nelson, Miranda BA; Lim, Kelvin O. MD*†‡

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Topics in Magnetic Resonance Imaging: April 2008 - Volume 19 - Issue 2 - p 97-109
doi: 10.1097/RMR.0b013e3181809f1e
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Abstract

The advent of magnetic resonance imaging (MRI) has resulted in the exponential growth in studies using these techniques to study the biological basis of psychiatric disorders. Initial studies focused on structural MRI, but with the discovery of sequences that measure changes in blood flow, such as functional MRI, and diffusion weighted imaging, such as diffusion tensor imaging (DTI), there is now the ability to study the structure, microstructure, and function of the brain using MRI techniques.

The combination of the ability of DTI to measure the microstructural integrity of neuronal tracts coupled with a major hypothesis of schizophrenia being a disruption of neural connectivity1,2 resulted in the early application of DTI to clinical populations involving patients with a diagnosis of schizophrenia.3,4 Since then, the use of DTI has been used to study nearly all of the major psychiatric disorders, including major depression, bipolar affective disorder (BPAD), anxiety disorders, autism, attention deficit hyperactivity disorder (ADHD), substance use disorders, and personality disorders.

With nearly 100 published reports of the use of DTI in psychiatric populations, this review summarizes the major findings for each of the major psychiatric disorders. Differences in methodologies, scanner sequences, and image processing algorithms provide a challenge to interpreting results of these studies. In addition, because there are few studies that compare and contrast different clinical populations, little is known regarding the specificity of the findings. Nevertheless, the consistency of findings in the putative networks associated with each of the disorders contributes evidence for disruption of neural networks in many of the major psychiatric disorders.

MATERIALS AND METHODS

Properties of DTI

Diffusion tensor imaging has properties that allow for high-resolution in vivo measurements of the coherence and direction of neuronal fiber tracts.5 Diffusion tensor imaging is based on the self-diffusion properties of water.6 At temperatures greater than absolute zero, water molecules undergo random movement known as Brownian motion. The higher the temperature, the faster the diffusion of the molecules. To provide an example of the speed of this diffusion, in 1 second, a water molecule will travel, on average, 2.45 μm at body temperature. With the length of a water molecule approximately 14 Å, it is displaced approximately 1750 times its length each second. This distance, in relation to size, is the equivalent to a jet traveling from London to Los Angeles in a mere 76 seconds.

The property of water molecules diffusing freely, unrestricted in any direction, is termed isotropic diffusion. However, when boundaries exist that limit the diffusion of water molecules in certain directions, the diffusion properties of water change to what is termed anisotropic diffusion. Thus, axons, which have a cylindrical morphology, allow for greater diffusion along the length of the axon, and diffusion is hindered by the cell membrane.7 Consequently, axonal fiber bundles provide a mechanism for anisotropic diffusion, whereas cerebrospinal fluid (CSF), which is essentially a spatially unbounded fluid-filled cavity, allows for isotropic diffusion. Because water diffusion in gray matter (GM) is reduced as a result of macromolecules and lipid membranes, its overall diffusion is less than water in CSF.

Diffusion tensor imaging captures the diffusion properties of water by applying strong magnetic gradients in at least 6 noncollinear directions. Strong bipolar diffusion gradients are applied sequentially along the multiple directions, typically during a spin echo sequence. Protons that diffuse will experience a change in their cumulative magnetic field exposure that is based on the distance diffused. This movement results in an alteration in the phase the proton, which provides a means to measure the amount of diffusion experienced by the proton.5 By acquiring at least 2 images of different bipolar diffusion gradient strengths, an apparent diffusion coefficient (ADC) map of the brain can be generated. Using this technique, it is possible to measure the microstructure of regions surrounding water molecules.8 This allows for the observation of regions in the brain that demonstrate high anisotropy, such as the visualization of specific white matter (WM) tracts.7

The 2 most common quantitative scalar measures used in DTI are termed mean diffusivity (MD) and fractional anisotropy (FA).9 Mean diffusivity is calculated as the sum of the eigenvalues (being a measure of the magnitude of diffusion in a specific direction) for the 3 orthogonal tensors divided by 3. Although MD provides an average measure of diffusion, it cannot differentiate the contribution of each direction to the total measure. To provide a rotationally invariant measure of anisotropy, FA was introduced. 10 As implied in its name, FA is a measure of the fraction of the diffusion tensors that contribute to anisotropic diffusion. If the diffusion tensors are equal in all directions, then FA is zero, whereas if the magnitude of the tensor is in only 1 direction, then FA equals 1. An additional term, the ADC, describes the a measure of the actual water diffusion within different tissue compartments. Thus, ADC is lower in GM than in CSF due to the presence of proteins and other macromolecules within GM.

White Matter Microstructure and DTI

White matter consists primarily of myelinated neuronal fibers that provide high-speed communication between brain regions. The microstructure of WM consists of millions of individual neurons wrapped within a compact, multilayered lipid and protein sheath.11 The sheath is formed by oligodendrocytes within the central nervous system. This sheath prevents an action potential from taking place except for set locations or gaps along the neuron.12 It is the combination of the lipid membrane of the neurons and the myelin sheath that restricts water diffusion.

The myelinated, high-speed connections between brain regions play a role in both the efficiency and timing of brain activity. Myelinated nerve fibers typically travel together in tracts, and it is these tracts that are identified using DTI. Because the typical voxel size for low- to medium-field DTI imaging (1.5-3 T) tend to be approximately 2 mm isotropic, the fiber bundle size needs to approximate or exceed this size to yield the best measure of the vector properties of the fiber bundle. This resolution, however, allows for the identification of many of the principle fiber tracts.13

Most myelination takes place within the first 4 years of life14; however, the development of WM has been shown to progress into early adulthood in frontal and temporal association cortices.14,15 The development of cortical myelination, although complex and heterogeneous, tend to follow a regional progression with posterior regions undergoing myelination before anterior regions.16-19

Analysis Methodologies in DTI

There are several preprocessing steps that are important before analyzing individual or group differences in DTI images. Images should initially undergo visual inspection to assess for the presence of subject-, sequence-, or equipment-related artifacts. Subject motion and the circulatory effects of the cardiac and respiratory cycle during DTI can result in artifacts.20 Rigid body transformations can correct a portion of the subject motion; however, physiological noise from the cardiac or respiratory cycle can be problematic and difficult to correct.20 Rapid cycling of the gradients can result in eddy current artifacts. These can be partially corrected using eddy current correction algorithms.21-23 Magnetic susceptibility artifacts occur primarily at the interface between tissue and air such as near the sinuses and ear canals.24 These susceptibility artifacts result in either a loss or a spatial shifting of the signal. Whereas artifacts due to spatial shifting can be partially corrected for using field maps in the preprocessing stream, lost signal cannot be restored. Unfortunately, the predominance of susceptibility-related signal loss occurs in regions such as the orbitofrontal cortex, amygdala, hippocampus, and other structures within the anterior temporal lobe. Thus, susceptibility artifacts impact regions that are implicated in the pathogenesis of a number of psychiatric disorders. Finally, equipment-related artifacts such as gradient spiking due to low humidity may result in images that are unusable.

Once the preprocessing steps have been completed, there are a number of different approaches to analyze group differences in diffusion tensor images, although they fall under the rubric of 4 general categories. A more time-intensive approach involves manually generating individual regions of interest (ROIs) and comparing the values of FA between groups.4 An advantage of the ROI approach is that regions can be obtained based on the individual anatomy, thus reducing intersubject variability.

The voxel-based approach to DTI is the most common analysis used, likely owing to less manual processing time required for each scan. Voxel-based approach to DTI requires that each scan is normalized to a standard space, spatially filtered,25 and voxel-wide statistical analyses are applied to determine regions of significant difference between groups. Voxel-based approaches rely on an accurate registration between brain scans. Misregistration due to either the registration algorithm or, more likely, to anatomical differences can create the appearance of FA differences. For example, the larger ventricles associated with schizophrenia may occupy WM voxels found in controls, resulting in a decrease in FA in patients compared with controls. This FA measure may reflect ventricular enlargement, rather than WM changes. Techniques used to circumvent these problems include the use of WM masks to restrict the analyses to only those voxels that have been defined as WM by the structural images. Even voxels designated as WM, however, may contain a small percentage of GM or CSF. This combination of tissue components within a voxel is termed partial voluming, and the smaller the voxel size, the less the partial voluming. Alternative approaches to correct for anatomical differences in DTI registration include nonlinear or WM skeleton techniques to register the DTI images.26

The ability to use DTI to quantify specific fiber tracts, or DTI tractography, is still a relatively new phenomenon,27-31 and new algorithms to map WM tracts are developing rapidly. The approaches to reconstruct the WM pathways can be subsumed under 2 major categories, streamline and probabilistic tractography.30,32 Streamline techniques use line propagation algorithms that use information from 1 voxel to determine the most probable next step in the fiber pathway.27-29,31 Both FA and the principle diffusion direction are used to determine the path of the fiber as it propagates from voxel to neighboring voxels. Specific criteria result in a termination of the propagating fiber track such as FA less than or curvature greater than a defined threshold. Whereas line propagation approaches can resolve a number of major fiber pathways, limitations emerge with fiber pathways that cross, diverge, converge, or undergo sharp curvature.6,33 Techniques that use more diffusion directions coupled to higher-order processing algorithms (q-space techniques) are currently being advanced to resolve these limitations.32,34,35

The second set of tractography techniques is based on algorithms that produce a global minimum energy for the system or the minimum energy to connect 2 brain regions.30,36-38 These probabilistic tractography algorithms create probability maps of the likelihood of pathways from a specified ROI to other brain regions.38 Although the fiber pathways identified have restrictions in the detail of the anatomy, applied algorithms are able to show reasonable anatomic consistency with WM tracts such as the geniculocalcarine visual pathway,28 corticocortical connections within the parietal lobe,28 and branches in the corona radiata and optic radiations.37

One limitation of DTI is the inability, at least at present, to define connectivity or the size of the fiber tract at high spatial resolution.39 Typical voxel dimensions used in DTI are on the order of millimeters, whereas a single axon is on the scale of micrometers. Intersections of fiber tracks, for example, result in a decrease in the level of anisotropy and a reduction in the directional sensitivity of the vector. Reducing the volume of voxel size will produce greater directional information, but with a decrease in the signal-to-noise ratio. Increasing the signal-to-noise ratio can be accomplished by using higher field strengths, longer acquisition times, optimized sequences, and state-of-the-art MRI hardware.37 As is true with echo planar sequences used in functional MRI, DTI is also prone to susceptibility artifacts due to the boundary between brain and the air in the sinuses. These susceptibility artifacts are especially pronounced in the anterior temporal and orbitofrontal regions of the brain. Further advances in hardware, sequence design, and image processing algorithms will continue to improve DTI and enhance its clinical use.

RESULTS

DTI in Clinical Populations

Schizophrenia

Owing to hypotheses of disrupted connectivity as a potential etiology of schizophrenia,1 most of the published DTI literature involve the study of schizophrenia. To date, there are more than 55 publications that include schizophrenia and either DTI alone4,40-87 or DTI in combination with other imaging methodologies,3,77,88-93 clinical correlates,51-53,64-67,72,78,82,86 or cognitive function.50,58,62,63,70,71,87,94 There are considerable challenges in integrating the findings due to differences in imaging sequences, resolution, number of diffusion directions, and postprocessing algorithms. However, considering the property of regression to the mean for findings, together, they provide a reasonable indication that WM tracts are disrupted in schizophrenia. To better understand the presentation of schizophrenia, the literature will be parsed into studies of chronic and first-episode (FE) or early-onset schizophrenia (EOS; Table 1).

T1-4
TABLE 1:
Diffusion Tensor Imaging Results in Patients With Schizophrenia

Most DTI studies are in adults with chronic schizophrenia.3,4,40-46,48-53,55-58,60,62-74,76-80,83,84,86,89-93 Of the current 36 nonoverlapping studies evaluating patients with chronic schizophrenia, there is a striking amount of heterogeneity in the findings (Fig. 1). The finding that has been identified in multiple studies is a decrease in FA in the cingulate,51 a structure that is involved in error checking, attention, and serves as a link between limbic and higher cortical functions. Lower FA in patients has been shown in the left,67,70 right,64 or bilateral cingulate,50,58,68,78,80,83,91 and lower FA has been shown to correlate with poorer performance in orienting of attention70 and with increased saccadic latency.64

F1-4
FIGURE 1:
Regions indicating lower FA in patients with chronic schizophrenia. The red dots indicate the general brain region, rather than the exact location. The raw MRI scan was obtained from the Whole Brain Atlas (http://www.med.harvard.edu/AANLIB/cprt.html) courtesy of Keith A. Johnson and J. Alex Becker (used with permission).

The corpus callosum (CC), a WM structure involved in the interhemispheric transfer of neural signals, has 8 independent studies that demonstrate a decrease in FA.40-42,48,53,67,78,91 The location of the FA decrease within the CC varies to some extent between studies, with reports of decrease globally in the CC,41,43,53,67,91 decreases in only the genu,78 and others showing a decrease in the splenium.40,48

The frontal lobe is reported to demonstrate lower FA in chronic patients with schizophrenia4,41,43,65,77; however, lower FA values have also been seen in the temporal lobes,4,65,77,93 parietal lobes,4,41,65 and the occipital lobes.4,41,65 In addition, multiple WM tracts that provide for intralobar and interlobar transfer of neural signals have also been shown to have lower FA in patients with schizophrenia. These include the superior longitudinal fasciculus,67,78 fronto-occipital longitudinal fasciculi,67 uncinate fasciculi,68 frontal longitudinal fasciculus,42,67,95 and the arcuate fasciculus.44,53,95

Whereas the cingulate, CC, and the frontal lobe have been identified most often as showing lower FA in patients with chronic schizophrenia, a number of other brain structures have been evaluated and shown to have a reduced FA. These include the cerebellar peduncles,71,72 the fornix,60,95 the hippocampus and parahippocampal gyrus,41 and the thalamic67 and optic radiations.45,67 To summarize the DTI findings in adults with chronic schizophrenia, the most consistent findings emerge in the cingulate, CC, and frontal lobes; however, even these findings are not present in all studies, and there is a considerable amount of heterogeneity in the findings, including several studies that do not report any FA differences in patients with schizophrenia.49,55,57,84,92

First-Episode and Early-Onset Schizophrenia

Although there are some differences in the definition of FE schizophrenia, studies of FE populations are typically within the first 1 to 2 years of illness. Early-onset schizophrenia is defined as onset of the illness before the age of 18 years. The FE and EOS groups are combined in this description because they share many commonalities. These commonalities include being early in the course of their illness, being relatively young, and not having been treated long term with medication. These populations can be difficult to study, and, thus, there are fewer DTI studies in this population.

Of the 10 FE and EOS studies, the results tend to also display a similar amount of heterogeneity as seen in studies of chronic patients. Decreases in FA have been found in many of the regions identified in the chronic studies, including the anterior cingulate,96 frontal lobe,54,59,81,82,96 parietal lobe,61,96 cerebellar peduncle,61 hippocampus,85 and perihippocampal gyrus.81,96 Interestingly, 1 FE study found no FE patient and control differences in the CC, although women with schizophrenia were shown to have reduced FA in genu.75

Cognitive and Symptom Correlates of DTI With Schizophrenia

In addition to studies that probe differences between patients and controls using DTI, recent studies have evaluated the relationships between DTI measures and targeted cognitive domains or clinical symptoms. For example, higher FA in the right cingulate bundle has been shown to be associated with better performance on orienting of attention using the anterior nucleus of the thalamus task.70 Leitman et al62 demonstrated that lower FA values in regions including the CC were associated with poorer performance in tasks measuring emotion comprehension.

Evaluating the relationship between DTI measures and clinical symptoms, studies have shown a relationship between CC FA and auditory hallucinations.53,78 In addition, decreased FA in the inferior fronto-occipital fasciculus has also shown to be associated with an increased severity of hallucinations and delusions.82 Finally, Hoptman et al97 found that lower FA in fronto-temporo-limbic circuits was associated with greater impulsivity in patients with schizophrenia.

Mood Disorders

Major depressive disorder (MDD) and BPAD are the 2 mood disorders that have been principally studied using DTI (Table 2). Although the primary symptoms of BPAD, being depression and mania, are distinct from symptoms found in schizophrenia, overlap can occur in symptoms of hallucinations, delusions, which are typically mood congruent, and thought disorders.

T2-4
TABLE 2:
Diffusion Tensor Imaging Results in Patients with Mood Disorders

There are 5 studies to date that assess the neurobiology of BPAD using DTI. Adolescents in their FE of mania had a reduction in FA in superior frontal WM regions.98 In adults with BPAD, the frontal findings are mixed, with studies demonstrating a decrease in FA in frontal WM superior to the anterior commissure,99 no patient control differences,100 and an increase in frontal lobe FA.101 Patients with BPAD also demonstrated global increases in the ADC compared with controls in the orbitofrontal cortex and the superior and middle frontal gyri, although these regions did not show a statistically significant decrease in FA.102

Major depressive disorder is perhaps the most common psychiatric disorder, affecting 1 in 5 women and 1 in 10 men during their lifetime. Most studies of MDD to date evaluate the illness in later life, individuals older than 60 years. Older patients with MDD have been shown to demonstrate lower FA in the dorsolateral prefrontal cortex,103 the anterior cingulate,103 and diffuse frontal104-106 and temporal regions.105 Lower FA in regions lateral to the anterior cingulate was associated with lower rates of remission in geriatric depression.107 Interestingly, after electroconvulsive therapy (ECT), depressed geriatric patients had an increase in frontal FA associated with their improvement in clinical symptoms.108 There were no changes post-ECT in the temporal lobe WM regions.

A study of medication naive young adults with MDD found decreases in FA in the right middle frontal gyrus, left occipitotemporal gyrus, and the subgyral and angular gyri of the right parietal lobe.109 Finally, whereas Steele et al110 did not find any differences in brainstem FA between patients with MDD and controls, their post hoc analysis found decreases in FA in the right lateral temporal lobe and the left uncinate fasciculus.

Anxiety Disorders

Patients with obsessive-compulsive disorder (OCD) experience ego-dystonic intrusive thoughts that they attempt to neutralize to repetitive, compulsive behavior. Although the cingulum has long been implicated in the pathogenesis of OCD, DTI studies of this structure are mixed. The left cingulum bundle has shown both an increase111 and decrease in FA,112 whereas 2 studies have demonstrated a reduction in FA in the right cingulum.111,112 In addition, increased FA has been shown in the internal capsule and CC111,113 and decreases in the parietal lobes, supramarginal gyri, and the left lingual gyrus in the occipital lobe.112 In addition, Yoo et al113 demonstrated that after treatment with citalopram, the FA measures had decreased in the patients such that after 12 weeks of treatment, there were no longer significant differences between the OCD and control groups (Table 3).

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TABLE 3:
Diffusion Tensor Imaging Results in Patients With Anxiety Disorders

A subgroup of individuals who experience traumatic events such as those who witness the horrific acts of terror occurring on a daily basis in parts of the world develop posttraumatic stress disorder (PTSD). The symptoms of PTSD include a desire to avoid situations or places that bring memories of the trauma and an increased state of hypervigilance. Comparing survivors of the Tokyo subway sarin attack who either had or did not have PTSD, Abe et al114 found a significant increase in FA in the left anterior cingulum (AC). In an ROI exploration of the AC in a group who survived a traumatic subway fire, Kim et al115 found a reduction in FA in the left rostral, subgenual, and dorsal cingulum bundle. The lower FA was lateralized to the left, and FA values on the right were no different than the control group.

Panic disorder is characterized by sudden, often nonprecipitated, intense fear. Patients will often experience sweating, shaking, palpitations, chest pains as intense as a heart attack, and, not uncommonly, a fear that they will soon die. The fear can be so intense that people avoid crowded places and may be afraid to leave their home. Interestingly, similar to the studies of previously listed anxiety spectrum disorders, patients show increased FA values in the left anterior and right posterior cingulum.116 Thus, many of the anxiety disorders show alterations of the cingulum bundle, although there are discordant findings with respect to increases or decreases in FA.

Substance Use Disorders

The substance of abuse most studied with DTI is chronic alcoholism, which is not surprising considering that alcohol use disorders affect approximately 18 million (8%) of the adult population in the United States.117 Both men and women with chronic alcoholism show a decrease in FA in the genu of the CC and the centrum semiovale,118-120 and men also show FA decreases in the splenium of the CC.118,120 The decrease in FA in the genu was associated with decreased area of both the genu and the body of the CC,121 and decreases in FA have been shown to correlate with the amount of alcohol consumption119 and with comorbid human immunodeficiency syndrome infection.122 In addition, lower FA tend to be greater in men with chronic alcoholism (Table 4).123

T4-4
TABLE 4:
Diffusion Tensor Imaging Results in Patients With Substance Abuse

Marijuana (cannabis) is the most commonly used illegal drug of abuse in the United States, with more than 94 million (40%) having used the substance at least once.124 Recent studies have found a gene/environment interaction between the use of marijuana during adolescence and the later development of schizophrenia.125 This finding, coupled with the high prevalence of cannabis abuse and dependence, provides the impetus to evaluate the potential for microstructural brain changes associated with cannabis use. Oddly, there are only 2 studies evaluating cannabis use with DTI.126,127 Gruber and Yugelun-Todd126 found no differences in frontal, AC, or corpus callosal FA in marijuana smokers compared with controls; however, the average diffusivity (AD) was elevated in these regions. Delisi et al127 found higher FA in regions of the right and left frontal WM, right inferior parietal gyrus, and right and left cingulate in a group who began cannabis use before the age of 18 years and who had used at least 21 times in any single year.

Cocaine is a highly addictive drug that can be snorted, sniffed, injected, or smoked with an estimate of abuse or dependence in 1.5 million (2.7%) of the adult US population.128 Cocaine use can result in a number of neurological complications, including headaches, seizures, and strokes. Diffusion tensor imaging may be useful to uncover microstructural effects of cocaine that would not be uncovered using traditional structural MRI techniques. Studies of cocaine use disorders include a decrease in frontal FA129,130 and the genu and rostral body of the CC.131 The FA measures in the CC were inversely correlated with impulsivity,130,131 and there is evidence that cocaine adversely disrupts the myelin sheaths.132

There is only 1 study using DTI to evaluate 3,4-methylenedioxymethamphetamine or ecstasy abuse.133 Ecstasy is a combined stimulant and psychedelic drug that has been shown to be neurotoxic to serotonin neurons.134 Low-dose 3,4-methylenedioxymethamphetamine resulted in an increase in centrum semiovale FA and decreased thalamic ADC.133

Psychiatric Disorders Presenting During Childhood

Autistic disorder is typically diagnosed within the first 2 years of life and is characterized by stereotypies and profound deficits in social communication and language. Approximately 70% of individuals diagnosed with autism are mentally retarded, and the development of language before 5 years of age is a good prognostic indicator. Occipitofrontal head circumference provides a proxy measure of brain volume, especially in infants before closure of the fontanels. Occipitofrontal head circumference is normal or less than average at birth in autistic individuals but undergoes excessive growth by 2 years of age.135 These changes are reflected by increase growth in both WM and GM within the brain.

Diffusion tensor imaging studies of children with autism have mixed results (Table 5). The earliest study demonstrated more widespread decreases in FA in autistic boys involving the WM adjacent to the ventromedial prefrontal cortices, anterior cingulate gyri, temporoparietal region, regions adjacent to the superior temporal sulcus bilaterally, temporal lobes bilaterally in the region of the amygdala, occipitotemporal tracts, and, finally, reduced FA in the CC.136 Decreased FA in the CC has been replicated in autistic men,137,138 and in high-functioning autistic men, the alterations in FA and diffusivity were associated with decreases in nonverbal intelligence measures.138 Widespread decreases in FA and increases in AD were found in WM of the superior temporal gyrus and temporal stem.139 Finally, FA was shown to be significantly increased in left frontal regions in young children with autism.140

T5-4
TABLE 5:
Diffusion Tensor Imaging Results in Patients With Childhood Psychiatric Disorders

Attention deficit hyperactivity disorder is characterized by inattention with or without hyperactivity and impulsivity. By definition, the symptoms must present before 7 years of age and must impair school, social, or family function. The only study using DTI to evaluate children with ADHD141 found reduced FA in the right striatum, cerebral peduncle, and premotor areas, as well as in the left cerebellum and parieto-occipital WM. A second study evaluating women with comorbid ADHD and borderline personality disorder did not find any WM differences between patients and controls.142

Personality Disorders

The only 2 personality disorders that have been studied using DTI are schizotypal (SPD) and borderline personality disorders (Table 6). Schizotypal personality disorder is considered on a continuum with schizophrenia and has higher rates in families with a family member with schizophrenia. Interestingly, the 2 studies of SPD found decreased FA in the uncinate fasciculus,143,144 a WM structure connecting the temporal and frontal lobes. In addition, greater FA in the uncinate fasciculus predicted the level of extraversion, which may be related to the importance of temporal and prefrontal connections in social communication. Finally, Nakamura et al144 did not find significant differences in the cingulum bundle in SPD individuals.

T6-4
TABLE 6:
Diffusion Tensor Imaging Results in Patients With Personality Disorders

As previously described, the only study evaluating patients with borderline personality disorder also had comorbid ADHD. Although the study found no differences in FA between patients and controls, they did find a relationship of decreased inferior frontal FA in those patients who had a history of depression or who currently had an eating disorder.

Impulse Control Disorders

Kleptomania is a disorder that is associated with the impulse to steal items that are typically of little value to the individual. The stealing is not for monetary gain, but rather as a compulsion, and individuals often have preferences to certain objects. The 1 study that evaluated 10 women with kleptomania compared with a matched control group found lower FA and a concomitant higher MD in frontal brain regions.145 Because lower frontal FA has been shown to be associated with impulsivity in other disorders,52 it may serve as a nonspecific marker for impulsive behaviors.

DISCUSSION

Diffusion tensor imaging is currently the best tool currently available to noninvasively quantify WM microstructure. Since its development more than a decade ago, there has been an exponential growth in its application, especially directed toward psychiatric disorders. Schizophrenia, which of the psychiatric disorders has seen the most research using neuroimaging techniques, was the first disorder to be studied.3 This was followed by mood disorders, autism, and substance use disorders. Finally, there have emerged recent studies of ADHD, anxiety, and personality disorders.

Schizophrenia, with its diverse array of clinical symptoms, has been theorized to be caused by disrupted connectivity between brain regions.1,146,147 Although there is evidence supporting abnormalities of the oligodendroglia and subsequent myelination, there is considerable heterogeneity in the location of reduced FA in schizophrenia. Regions that most consistently show reduced FA include the cingulate bundle, CC, and frontal lobe WM. It is possible that the microstructural abnormalities are subtle, and, thus, the current signal-to-noise ratio of DTI techniques is unable to consistently resolve patient/control differences. Alternatively, there may be actual regional differences that result in similar final common clinical phenotypes. Future work in schizophrenia should evaluate these differences longitudinally, in the context of other psychiatric disorders, and assessing whether specific subgroups emerge depending on the location of the abnormality. Longitudinal studies will also be beneficial to tease apart the effects of illness versus medication on WM microstructure. Mori et al68 found that there was an age-dependent decline in FA in schizophrenia that was correlated with duration of illness, rather than with medication.

Whereas there are fewer studies of mood disorders, the FA findings demonstrate a similar heterogeneity of FA differences as seen in individuals with schizophrenia. Interestingly, FA differences have several regions in common with schizophrenia. These include the cingulate bundle and the frontal and temporal lobes.98,99,101,103-106 In OCD, the cingulum, notably the right cingulum, has been shown to have decreased FA,111,112 whereas the left cingulum FA is reduced in PTSD. This overlap of reduced FA in brain regions in mood disorders, anxiety, and schizophrenia may reflect a more generalized abnormality shared across disorders.

Studies of substance use disorders have found FA reductions in WM structures that are involved in the interhemispheric transfer of information. This was especially true for alcohol use disorders and cocaine abuse.119,131,132 In fact, FA was found to correlate with the amount of alcohol intake.119

Studies using DTI in autism have had mixed results. Autistic individuals have demonstrated widespread reductions in FA136 to more focal findings in temporal lobe WM.139 The findings of lower FA in the CC of autistic individuals have been replicated,136-138 suggesting abnormalities in the interhemispheric transfer of information.

CONCLUSIONS

Future work using DTI in psychiatric disorders would benefit from a multidisciplinary venture involving both the technical and clinical fields. Through further technological advances, including increasing magnet strength, sequence design, and improved processing algorithms, it will be possible to obtain improved information of the structural connectivity between brain regions, which may assist in increasing the specificity of the extent of aberrant connectivity between the different psychiatric disorders. Not only will it be beneficial to assess the specificity of aberrant brain connectivity between the different psychiatric disorders, it will also be important to evaluate differential trajectories of WM connectivity within disorders using longitudinal designs. The study demonstrating a normalization of FA after ECT treatment for depression is intriguing,108 and little is known regarding the impact of medication on WM microstructure for many of the psychiatric disorders.

Improvements in image acquisitions and processing will assist in more precise localization of the microstructural deficits. Because there is considerable heterogeneity in the findings, studies that directly compare different diagnostic groups or clinical phenotypes will be important to determine the specificity of the microstructural abnormalities. Large WM tracts that contain highly packed neuronal fibers (ie, the CC, centrum semiovale) tend to be studied more than smaller or less accessible WM tracts (ie, the fornix or WM tracts in the orbitofrontal cortex that are prone to susceptibility artifacts). This may result in a general bias in the results reported.

Finally, integrating these findings with both genetic data and additional imaging methodologies will assist in the understanding of the genetic contributions to the findings and the functional consequences of the microstructural abnormalities. The combination of methodologies may see future use in diagnoses and prognosis (Table 7).148

T7-4
TABLE 7:
Summary of Studies Showing DTI Differences Between Patients and Controls

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Keywords:

diffusion tensor imaging; psychiatric disorders; schizophrenia; review

© 2008 Lippincott Williams & Wilkins, Inc.