Effects of early life stress on depression, cognitive performance and brain morphology.

BACKGROUND: Childhood early life stress (ELS) increases risk of adulthood major depressive disorder (MDD) and is associated with altered brain structure and function. It is unclear whether specific ELSs affect depression risk, cognitive function and brain structure. METHOD: This cross-sectional study included 64 antidepressant-free depressed and 65 never-depressed individuals. Both groups reported a range of ELSs on the Early Life Stress Questionnaire, completed neuropsychological testing and 3T magnetic resonance imaging (MRI). Neuropsychological testing assessed domains of episodic memory, working memory, processing speed and executive function. MRI measures included cortical thickness and regional gray matter volumes, with a priori focus on the cingulate cortex, orbitofrontal cortex (OFC), amygdala, caudate and hippocampus. RESULTS: Of 19 ELSs, only emotional abuse, sexual abuse and severe family conflict independently predicted adulthood MDD diagnosis. The effect of total ELS score differed between groups. Greater ELS exposure was associated with slower processing speed and smaller OFC volumes in depressed subjects, but faster speed and larger volumes in non-depressed subjects. In contrast, exposure to ELSs predictive of depression had similar effects in both diagnostic groups. Individuals reporting predictive ELSs exhibited poorer processing speed and working memory performance, smaller volumes of the lateral OFC and caudate, and decreased cortical thickness in multiple areas including the insula bilaterally. Predictive ELS exposure was also associated with smaller left hippocampal volume in depressed subjects. CONCLUSIONS: Findings suggest an association between childhood trauma exposure and adulthood cognitive function and brain structure. These relationships appear to differ between individuals who do and do not develop depression.

BDNF Val66Met genotype and 6-month remission rates in late-life depression.

Although not observed in younger adult cohorts, in older individuals the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with major depressive disorder (MDD) risk. It is further associated with subjective social support and magnetic resonance imaging (MRI) hyperintense lesions, clinical features independently related to MDD. We examined the relationship between this polymorphism and antidepressant remission rates in an elderly sample with MDD, while also testing for mediation effects of social support and hyperintensities. A total of 229 elderly Caucasian subjects with MDD completed baseline assessments, 1.5 T MRI, and BDNF genotyping. They received antidepressant medication under a structured treatment algorithm and were evaluated for remission at 3 and 6 months. At the 3-month evaluation, BDNF Val66Met genotype was not associated with remission (Wald's χ²=2.51, P=0.1131). When not controlling for multiple comparisons, Met66 allele carriers were more likely to be remitted at 6 months (χ²=4.32, P=0.0377) with an odds ratio of 1.82 (95% CI: 1.04, 3.22). This effect persisted after controlling for lesion volume and social support, neither of which mediated this relationship. Thus in this exploratory analysis, the Met66 allele may be associated with increased odds of remission in older subjects, but also with increased time to remission as there was no 3-month effect.

Angiotensin receptor gene polymorphisms and 2-year change in hyperintense lesion volume in men.

This longitudinal study examined the relationship between 2-year change in white matter hyperintense lesion (WML) volume and polymorphisms in genes coding for the angiotensin-II type 1 and type 2 receptors, AGTR1 A1166C and AGTR2 C3123A, respectively. 137 depressed and 94 non-depressed participants aged >or=60 years were enrolled. Standard clinical evaluations were performed on all participants and blood samples obtained for genotyping. 1.5-T MRI (magnetic resonance imaging) data were obtained at baseline and approximately 2 years later. These scans were processed using a semi-automated segmentation process, which allowed for the calculation of WML volume at each time point. Statistical models were tested for the relationship between change in WML volume and genotype, while also controlling for age, sex, diagnostic strata, baseline WML volume and comorbid cerebrovascular risk factors. In men, AGTR1 1166A allele homozygotes exhibited significantly less change in WML volume than 1166C carriers. We also found that men reporting hypertension (HTN) with the AGTR2 3123C allele exhibit less change in WML volume than hypertensive men with the 3123A allele, or men without HTN. There were no significant relationships between these polymorphisms and change in WML volume in women. No significant gene-gene or gene-depression interactions were observed. Our results parallel earlier observed gender differences of the relationship between other renin-angiotensin system polymorphisms and HTN. Further work is needed to determine whether these observed relationships are secondary to polymorphisms affecting response to antihypertensive medication, and whether antihypertensive medications can slow WML progression and lower the risk of morbidity associated with WMLs.

Medial orbital frontal lesions in late-onset depression.

BACKGROUND: Early studies using magnetic resonance (MR) imaging suggested that subcortical vascular changes are more prevalent in late-life depression and that they may play a role in the pathophysiology of depression. Studying the location of the lesion relative to the occurrence of depression could be critical in delineating the neuroanatomic substrates of depression. Our purpose was to characterize these lesions in terms of location by development of statistical parametric maps of lesions that differentiate patients from control subjects. METHODS: Magnetic resonance images were acquired on 88 elderly depressed subjects ("patients," unipolar major depression assessed using the Duke Depression Evaluation Schedule, age range 63-80 years) enrolled in the Duke University Clinical Research Center for the Study of Late-Life Depression and 47 age- and gender-matched nondepressed subjects ("control subjects"). The MR protocol includes a volumetric, dual-contrast fast spin-echo pulse sequence. A statistical parametric map was formed from a two-group t test to test for differences in lesion density between patients and control subjects. Additional testing was performed to evaluate whether there were regions that correlated with the severity of depression using the 17-item Hamilton Depression rating. RESULTS: The statistical parametric mapping analysis between groups showed two major regions of increased lesion density in the patients in the medial orbital prefrontal white matter. Severity of depression among depressed patients was correlated with lesions in the medial orbital region. CONCLUSIONS: This study supports recent evidence implicating the medial orbital frontal cortex in depression.

Evidence of white matter tract disruption in MRI hyperintensities.

BACKGROUND: Diffusion tensor imaging (DTI) of brain tissue measures the apparent diffusion coefficient (ADC), or isotropic diffusion, and anisotropy, or diffusion as influenced by tissue structure. We hypothesized that hyperintensities, when compared with normal tissue by DTI, would show evidence of damage through an increased ADC and decreased anisotropy. We also hypothesized that DTI changes in hyperintensities would be similar between depressed subjects and control subjects. METHODS: Fourteen depressed geriatric patients and nineteen control subjects received DTI. The ADC and aniso-tropy of normal tissue from standard regions were compared with hyperintensities from these regions. The Students' t test compared individual regions and averaged white matter results. RESULTS: Hyperintensities showed higher ADC and lower anisotropy than normal regions. Gray matter exhibited similar trends. There was no significant difference in diffusion characteristics of hyperintensities between subjects and control subjects. CONCLUSIONS: Hyperintensities damage the structure of brain tissue, and do so comparably in depressed subjects and control subjects.

Hippocampal volume in geriatric depression.

BACKGROUND: There is a growing literature on the importance of hippocampal volume in geriatric depression. METHODS: We examined hippocampal volume in a group of elderly depressed patients and a group of elderly control subjects (N = 66 geriatric depressed patients and 18 elderly nondepressed control subjects) recruited through Duke's Mental Health Clinical Research Center for the Study of Depression in the Elderly. The subjects received a standardized evaluation, including a magnetic resonance imaging scan of the brain. Patients had unipolar major depression and were free of comorbid major psychiatric illness and neurologic illness. Differences were assessed using t tests and linear regression modeling. RESULTS: Accounting for the effects of age, gender, and total brain volume, depressed patients tended to have smaller right hippocampal volume (p =.014) and left hippocampal volume (p =.073). Among depressed patients, age of onset was negatively but not significantly related to right hippocampal volume (p =.052) and to left hippocampal volume (p =.062). We noted that among subjects with either right or left hippocampal volume of 3 mL or less, the vast majority were patients rather than control subjects. CONCLUSIONS: These results support a role for hippocampal dysfunction in depression, particularly in late-age onset depression. Longitudinal studies examining both depressive and cognitive outcomes are needed to clarify the relationships between the hippocampus, depression, and dementia.

Magnetic resonance thermometry during hyperthermia for human high-grade sarcoma.

PURPOSE: To determine the feasibility of measuring temperature noninvasively with magnetic resonance imaging during hyperthermia treatment of human tumors. METHODS: The proton chemical shift detected using phase-difference magnetic resonance imaging (MRI) was used to measure temperature in phantoms and human tumors during treatment with hyperthermia. Four adult patients having high-grade primary sarcoma tumors of the lower leg received 5 hyperthermia treatments in the MR scanner using an MRI-compatible radiofrequency heating applicator. Prior to each treatment, an average of 3 fiberoptic temperature probes were invasively placed into the tumor (or phantom). Hyperthermia was applied concurrent with MR thermometry. Following completion of the treatment, regions of interest (ROI) were defined on MR phase images at each temperature probe location, in bone marrow, and in gel standards placed outside the heated region. The median phase difference (compared to pretreatment baseline images) was calculated for each ROI. This phase difference was corrected for phase drift observed in standards and bone marrow. The observed phase difference, with and without corrections, was correlated with the fiberoptic temperature measurements. RESULTS: The phase difference observed with MRI was found to correlate with temperature. Phantom measurements demonstrated a linear regression coefficient of 4.70 degrees phase difference per degree Celsius, with an R2 = 0.998. After human images with artifact were excluded, the linear regression demonstrated a correlation coefficient of 5.5 degrees phase difference per degree Celsius, with an R2 = 0.84. In both phantom and human treatments, temperature measured via corrected phase difference closely tracked measurements obtained with fiberoptic probes during the hyperthermia treatments. CONCLUSIONS: Proton chemical shift imaging with current MRI and hyperthermia technology can be used to monitor and control temperature during treatment of large tumors in the distal lower extremity.

Temperature-dependent changes in physiologic parameters of spontaneous canine soft tissue sarcomas after combined radiotherapy and hyperthermia treatment.

PURPOSE: The objectives of this study were to evaluate effects of hyperthermia on tumor oxygenation, extracellular pH (pHe), and blood flow in 13 dogs with spontaneous soft tissue sarcomas prior to and after local hyperthermia. METHODS AND MATERIALS: Tumor pO2 was measured using an Eppendorf polarographic device, pHe using interstitial electrodes, and blood flow using contrast-enhanced magnetic resonance imaging (MRI). RESULTS: There was an overall improvement in tumor oxygenation observed as an increase in median pO2 and decrease in hypoxic fraction (% of pO2 measurements <5 mm Hg) at 24-h post hyperthermia. These changes were most pronounced when the median temperature (T50) during hyperthermia treatment was less than 44 degrees C. Tumors with T50 > 44 degrees C were characterized by a decrease in median PO2 and an increase in hypoxic fraction. Similar thermal dose-related changes were observed in tumor perfusion. Perfusion was significantly higher after hyperthermia. Increases in perfusion were most evident in tumors with T50 < 44 degrees C. With T50 > 44 degrees C, there was no change in perfusion after hyperthermia. On average, pHe values declined in all animals after hyperthermia, with the greatest reduction seen for larger T50 values. CONCLUSION: This study suggests that hyperthermia has biphasic effects on tumor physiologic parameters. Lower temperatures tend to favor improved perfusion and oxygenation, whereas higher temperatures are more likely to cause vascular damage, thus leading to greater hypoxia. While it has long been recognized that such effects occur in rodent tumors, this is the first report to tie such changes to temperatures achieved during hyperthermia in the clinical setting. Furthermore, it suggests that the thermal threshold for vascular damage is higher in spontaneous tumors than in more rapidly growing rodent tumors.

Accuracy of registration of PET, SPECT and MR images of a brain phantom.

Accuracy of a surface-fitting algorithm for three-dimensional image registration of single photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance (MR) images was tested using a three-dimensional, water-fillable brain phantom. Multislice or volume image sets were acquired for each modality. Small fiducial markers were attached to assess accuracy of surface fitting and provide an alternate fitting technique. A maximum gradient technique was found to work well for SPECT and PET edge detection. Transformation parameters for translation, rotation and scaling were determined by surface fit to match each SPECT and PET scan with MR images. Using the markers, overall translation errors were found to be < 2 mm in each direction and rotational errors < 2 degrees in every case. Errors for specific internal regions were also determined to be < 2 mm for most regions, with only a few fits resulting in errors > 3 mm for some cortical regions. Results indicate surface fitting to be sufficiently accurate for visual comparison of registered images and for enhanced SPECT and PET region of interest (ROI) determination and image reconstruction.

Contrast and accuracy of relaxation time measurements in acquired and synthesized multislice magnetic resonance images.

The effects of interslice spacing, the number of data points and other factors on the accuracy of relaxation time measurements and contrast have been investigated for both acquired and synthesized multislice MR images using experiments and computer simulations. The cross-excitation between adjacent slices in multislice imaging affects both contrast and derived relaxation times. Such measurements also are affected by the T1 and T2 of the materials imaged, the pulse sequence timing parameters, and the number of data points used to estimate the relaxation times. Errors in T1 and T2 may be severe, particularly for slice spacings less than 0.5 slice thickness and for long T1 and T2 materials. Consequently, the difference in signal intensities between two materials with different relaxation times also varies with slice spacing and between acquired and synthetic images, particularly for strongly T1-weighed images.

Thick-section, single breath-hold magnetic resonance pulmonary angiography.

RATIONALE AND OBJECTIVES: Approaches to performing magnetic resonance angiography (MRA) of the pulmonary vasculature are described using very fast (repetition time [TR] less than 13 mseconds) radiofrequency (rf)-spoiled, gradient-recalled pulse sequences and the standard quadrature body imaging coil of a commercial 1.5-T MR imaging system. METHODS AND RESULTS: Signal-to-noise (SNR) is improved by signal averaging (Nex greater than or equal to 4) in a two-dimensional, single thick-section approach and by volume acquisition (Nex = 1) in a three-dimensional approach. Blood signal loss is minimized by using short, asymmetric echoes (echo time [TE] less than or equal to 2.7 mseconds). Respiratory motion is eliminated by keeping the scan time short enough (approximately 15 seconds) for image acquisition within a single breath-hold. Cardiac motion artifacts are reduced with section orientations that avoid intersecting the heart and/or use of small flip angle (alpha less than or equal to 25 degrees). CONCLUSIONS: Images of healthy volunteers showed that while single thick sections have superior SNR, the three-dimensional approach appears to produce better visualization of the peripheral vascular segments and offers improved ability to process the images to remove overlapping structures.

Clot-blood contrast in fast gradient-echo magnetic resonance imaging.

RATIONALE AND OBJECTIVES: Contrast between clot and blood in magnetic resonance imaging (MRI) at 1.5T using fast gradient-echo pulse sequences (fast GRE), with 8 ms < TR < 20 mseconds was studied both in vitro and in clinical human deep venous thrombosis (DVT) to assess whether good contrast could be obtained at such short repetition times and at clinically relevant flow rates. METHODS: In vitro studies used an apparatus that contained flowing MnCl2[aq] (water adjusted with manganese chloride to have T1, T2 similar to blood) and an immobilized clot (T1, T2 similar to those in DVT) for flow velocities between 0 and 16.5 cm/sec. Seven patients with DVT were imaged with the fast GRE sequences to observe the clot-blood contrast in vivo. RESULTS: Peak contrast-to-noise ratio (CNR) was achieved using flip angles between 20 degrees and 40 degrees (increasing with flow velocity) with or without radiofrequency "spoiling," consistent with a natural spoiling effect of flow. The CNR between MnCI2[aq] and clot decreased less than 10% as TR was reduced 56% from 18 mseconds to 8 mseconds (30 degrees flip angle). In four patients with nonocclusive DVT, fast GRE imaging provided good contrast while in occlusive cases (three patients) the contrast was not as good as conventional GRE sequences with longer TR values (TR = 33 mseconds). CONCLUSION: A fast GRE sequence with TR = 8 mseconds, TE = 3 mseconds, and a flip angle = 40 degrees is a promising approach to speeding up the detection of nonocclusive clinical DVT.

Muscle activity localization with 31P spectroscopy and calculated T2-weighted 1H images.

Using 31P spectroscopy and magnetic resonance imaging (MRI), the authors studied changes in muscle phosphorous metabolites and T2 with isometric knee extension to evaluate the potential role of T2 images in coil placement for exercise spectroscopy studies. Increased signal intensity was visible in active muscles on T2 images after exercise. Calculated T2-weighted values were elevated immediately after exercise in the quadriceps (P less than .01). T2 increases for individual quadricep muscles varied, with the largest changes in the rectus femoris and the least in the vastus lateralis. 31P spectroscopy studies demonstrated similar findings: percent change in T2 correlated positively with inorganic phosphorus to phosphocreatine ratio (Pi/PCr) (r = 0.89, P less than .01) and negatively with pH (r = -0.88, P less than .01). The correlations between imaging and spectroscopy suggest that T2 images may allow more precise placement of phosphorous coils in exercise studies. The heterogeneity of T2 changes within the quadriceps with exercise suggests that assumptions about muscle activity may be misleading. T2 images may provide muscle activity verification for exercise studies.

Quantification of contrast in clinical MR brain imaging at high magnetic field.

The relative contrast between two tissues in a magnetic resonance (MR) image is shown to be quantifiable for any combination of pulse timing parameters, provided the intrinsic parameters are known. Based on multiple inversion-recovery and spin echo images, a region-of-interest T1, T2 and density analysis was conducted at 1.4T in selected patients with diagnosed neuropathology for various brain tissues. The resulting tissue parameters subsequently served to calculate the contrast-to-noise (C/N) ratio for typical tissue interfaces as a function of the operator-variable pulse timing parameters and the data were compared with the images. Although such calculations may be useful as a protocol selection aid, it is obvious that an optimized pulse protocol can only be established for a single tissue interface. The data also reveal that a T2-discriminating pulse sequence like Carr-Purcell-Meiboom-Gill with long repetition time, generally advocated as clinically most effective, may not always be ideal.

Magnetic resonance imaging using deoxyhemoglobin contrast versus positron emission tomography in the assessment of brain function.

1. Function of the brain can be assessed through radiologic imaging to determine physiology of underlying tissue. 2. Until recently, positron emission tomography has been the standard tool with which to study function. 3. In the past few years, several investigators have attempted to use magnetic resonance imaging, which has better resolution and is less expensive, to provide functional information. 4. A noninvasive technique termed BOLD (blood oxygen level dependent) has become a popular area of research to determine physiologic change that occurs in the brain in resting as well as activated states. 5. This article reviews what information PET has given us with regard to function of the brain, followed by a discussion of the principle of functional MRI of the brain with emphasis on what has been done in this field as well as future application of the technique.

Age and sex effects on brain morphology.

1. Brain morphology can be assessed readily in vivo using magnetic resonance imaging (MRI). 2. In this study, the effects of age and sex on whole-brain morphology were examined using an operator-controlled computer-segmentation protocol. 3. Results indicated that age was associated with gray-matter volume reduction. 4. Brain-size differences between males and females were primarily attributable to white-matter volume. 5. This study confirms the importance of controlling for age and sex in brain-morphology studies.

Poststenotic signal loss in MR angiography: effects of echo time, flow compensation, and fractional echo.

PURPOSE: To evaluate with steady and pulsatile flow the influence of echo time, gradient strength and duration, and flow compensation on the degree of turbulent signal loss, factors that have been implicated in MR angiography's overestimation of the degree of stenosis. METHODS: We examined poststenotic turbulent flow in two models, one that created a turbulent jet and another that simulated a plaque-like stenosis. The pulse sequence used in these experiments allowed for a single variable (flow compensation, echo time, or gradient strength) to be varied without changing the others. RESULTS: Poststenotic signal loss can lead to overestimation of the degree of a stenosis. The area of signal loss in the turbulent jet was influenced by fractional echo and flow compensation, but not by echo time. We found that the dominant mechanism in poststenotic signal loss is related to the strength and duration of the imaging gradients. CONCLUSIONS: Flow-compensated sequences with reduced gradient strength and duration will reduce poststenotic signal loss and may lead to more accurate estimations of the extent of stenotic lesions.

Cerebral magnetic resonance image synthesis.

The authors previously described magnetic resonance (MR) image synthesis, a process that enables the investigator to manipulate imaging parameters retrospectively and generate or "synthesize" the image that corresponds to various arbitrary scanning factors. They demonstrate the validity and utility of synthetic spin-echo images in cerebral imaging. As a test of their method, spin-echo images are synthesized for echo times identical to those of the original acquired images as well as for alternate values. Subjectively, the quality of synthetic and acquired images is comparable. It is shown quantitatively for several tissue types that the reconstructed synthetic signal matches the acquired signal within the uncertainty of the acquired images. Observed and measured noise levels in the acquired and synthetic images are comparable. Because of a signal-averaging effect, the synthetic images can have a higher signal-to-noise ratio than the source images, thereby providing improved boundary definition. Applications of MR image synthesis are discussed with respect to potential reduction in scanning time. The advantages of image synthesis versus analysis of computed images are discussed.

An analysis of noise propagation in computed T2, pseudodensity, and synthetic spin-echo images.

Methods are reviewed for estimating the transverse relaxation time T2 and the pseudodensity (PD) from spin-echo measurements acquired at an arbitrary set of echo times [TEi]. Least-squares fitting is applied to the logarithmically processed signals for the case in which the weights are proportional to the inverse of the logarithmically transformed signal variances (the minimum variance case). General formulas are derived for the estimated noise levels in the PD and T2 estimates due to the propagation of uncertainties in the original measurements. It is shown that the T2 and PD estimates are anticorrelated. Additionally, an expression is derived for the variance in a synthetic spin-echo signal subsequently formed from the PD and T2 estimates. It is shown that under many circumstances a signal synthesized at some echo time can have a signal-to-noise ratio superior to that in a signal directly acquired at that time. Experimental measurements made on phantoms match the theoretical predictions to a high degree.

1H MRI phase thermometry in vivo in canine brain, muscle, and tumor tissue.

The temperature sensitivity of the chemical shift of water (approximately 0.01 ppm/degree C) provides a potential method to monitor temperature changes in vivo or in vitro through the changes in phase of a gradient-echo magnetic resonance (MR) image. This relation was studied at 1.5 T in gel materials and in vivo in canine brain and muscle tissue, heated with a radio frequency (rf) annular phased array hyperthermia antenna. The rf fields associated with heating (130 MHz) and imaging (64 MHz) were decoupled using bandpass filters providing isolation in excess of 100 dB, thus allowing simultaneous imaging and rf heating without deterioration of the MR image signal-to-noise ratio. In a gel, temperature sensitivity of the MR image phase was observed to be (4.41 +/- 0.02) phase degrees/degree C for Te = 20 ms, which allowed temperature changes of 0.22 degree C to be resolved for a 50-mm3 region in less than 10 s of data acquisition. In vivo, for Te = 20 ms, the temperature sensitivity was (3.2 +/- 0.1) phase degrees/degree C for brain tissue, (3.1 +/- 0.1) phase degrees/degree C for muscle, and (3.0 +/- 0.2) phase degrees/degree C for a muscle tumor (sarcoma), allowing temperature changes of 0.6 degree C to be resolved in a 16-mm3 volume in less than 10 s of data acquisition. We conclude that, while the technique is very sensitive to magnetic field inhomogeneity, stability, and subject motion, it appears to be useful for in vivo temperature change measurement.