Childhood Trauma and Premenstrual Symptoms: The Role of Emotion Regulation.

BACKGROUND: Women with Premenstrual Dysphoric Disorder (PMDD) are more likely to have a history of childhood trauma, and may experience more severe premenstrual symptomatology. However, the pathway in which childhood trauma affects the prevalence and severity of premenstrual symptoms remains largely unclear. OBJECTIVE: To determine whether childhood trauma is associated with increased premenstrual symptoms, and if so, whether emotional dysregulation mediates or moderates this relationship. PARTICIPANTS AND SETTINGS: A total of 112 women were recruited for the study among students at the Hebrew University of Jerusalem. METHODS: Participants completed the Premenstrual Symptoms Screening Tool (PSST), the Childhood Trauma Questionnaire (CTQ) and the Difficulties in Emotion Regulation Scale (DERS). To test the mediation hypothesis, direct and indirect effects of childhood trauma on premenstrual symptoms were calculated. To test moderation, we performed multiple regression, including the interaction term between childhood trauma and emotion dysregulation RESULTS: Twenty-two women (18.6%) met criteria for premenstrual syndrome (PMS) and sixteen (13.6 %) for PMDD. The number and severity of premenstrual symptoms increased with more childhood trauma (r = .282), and this relationship was completely mediated by emotion regulation difficulties. Specifically, exposure to Sexual abuse (r = .243) and Emotional neglect (r = .198) were significantly associated with premenstrual symptoms. Abuse predicted greater emotion dysregulation (r = .33), whereas, neglect did not. CONCLUSIONS: This study contributes to the current knowledge on the long-term effects of childhood trauma. Promoting use of adaptive emotion regulation strategies for women with a history of childhood trauma, could improve their capability to confront and adapt to premenstrual changes.

Alterations in the expression of a neurodevelopmental gene exert long-lasting effects on cognitive-emotional phenotypes and functional brain networks: translational evidence from the stress-resilient Ahi1 knockout mouse.

Many psychiatric disorders are highly heritable and may represent the clinical outcome of early aberrations in the formation of neural networks. The placement of brain connectivity as an 'intermediate phenotype' renders it an attractive target for exploring its interaction with genomics and behavior. Given the complexity of genetic make up and phenotypic heterogeneity in humans, translational studies are indicated. Recently, we demonstrated that a mouse model with heterozygous knockout of the key neurodevelopmental gene Ahi1 displays a consistent stress-resilient phenotype. Extending these data, the current research describes our multi-faceted effort to link early variations in Ahi1 expression with long-term consequences for functional brain networks and cognitive-emotional phenotypes. By combining behavioral paradigms with graph-based analysis of whole-brain functional networks, and then cross-validating the data with robust neuroinformatic data sets, our research suggests that physiological variation in gene expression during neurodevelopment is eventually translated into a continuum of global network metrics that serve as intermediate phenotypes. Within this framework, we suggest that organization of functional brain networks may result, in part, from an adaptive trade-off between efficiency and resilience, ultimately culminating in a phenotypic diversity that encompasses dimensions such as emotional regulation and cognitive function.

Reduced connectivity and inter-hemispheric symmetry of the sensory system in a rat model of vulnerability to developing depression.

Defining the markers corresponding to a high risk of developing depression in humans would have major clinical significance; however, few studies have been conducted since they are not only complex but also require homogeneous groups. This study compared congenital learned helpless (cLH) rats, selectively bred for high stress sensitivity and learned helplessness (LH) behavior, to congenital non-learned helpless (cNLH) rats that were bred for resistance to uncontrollable stress. Naïve cLH rats show some depression-like behavior but full LH behavior need additional stress, making this model ideal for studying vulnerability to depression. Resting-state functional connectivity obtained from seed correlation analysis was calculated for multiple regions that were selected by anatomy AND by a data-driven approach, independently. Significance was determined by t-statistic AND by permutation analysis, independently. A significant reduction in functional connectivity was observed by both analyses in the cLH rats in the sensory, motor, cingulate, infralimbic, accumbens and the raphe nucleus. These reductions corresponded primarily to reduced inter-hemispheric connectivity. The main reduction however was in the sensory system. It is argued that reduced connectivity and inter-hemispheric connectivity of the sensory system reflects an internal convergence state which may precede other depressive symptomatology and therefore could be used as markers for vulnerability to the development of depression.

Functional connectivity in prenatally stressed rats with and without maternal treatment with ladostigil, a brain-selective monoamine oxidase inhibitor.

Stress during pregnancy in humans is known to be a risk factor for neuropsychiatric disorders in the offspring. Prenatal stress in rats caused depressive-like behavior that was restored to that of controls by maternal treatment with ladostigil (8.5 mg/kg per day), a brain-selective monoamine oxidase (MAO) inhibitor that prevented increased anxiety-like behavior in stressed mothers. Ladostigil inhibited maternal striatal MAO-A and -B by 45-50% at the time the pups were weaned. Using resting state-functional connectivity magnetic resonance imaging on rat male offspring of control mothers, and mothers stressed during gestation with and without ladostigil treatment, we identified neuronal connections that differed between these groups. The percentage of significant connections within a predefined predominantly limbic network in control rats was 23.3 within the right and 22.0 within the left hemisphere. Prenatal stress disturbed hemispheric symmetry, resulting in 30.2 and 21.6%, significant connections in the right and left hemispheres, respectively, but this was fully restored in the maternal ladostigil group to 24.6% in both hemispheres. All connections that were modified in prenatally stressed rats and restored by maternal drug treatment were associated with the dopaminergic system. Specifically, we observed that restoration of the connections of the right nucleus accumbens shell with frontal areas, the cingulate, septum and motor and sensory cortices, and those of the right globus pallidus with the infra-limbic and the dentate gyrus, were most important for prevention of depressive-like behavior.

Neural mechanisms underlying stress resilience in Ahi1 knockout mice: relevance to neuropsychiatric disorders.

The Abelson helper integration site 1 (AHI1) gene has a pivotal role in brain development. Studies by our group and others have demonstrated association of AHI1 with schizophrenia and autism. To elucidate the mechanism whereby alteration in AHI1 expression may be implicated in the pathogenesis of neuropsychiatric disorders, we studied Ahi1 heterozygous knockout (Ahi1(+/-)) mice. Although their performance was not different from wild-type mice on tests that model classical schizophrenia-related endophenotypes, Ahi1(+/-) mice displayed an anxiolytic-like phenotype across different converging modalities. Using behavioral paradigms that involve exposure to environmental and social stress, significantly decreased anxiety was evident in the open field, elevated plus maze and dark-light box, as well as during social interaction in pairs. Assessment of core temperature and corticosterone secretion revealed a significantly blunted response of the autonomic nervous system and the hypothalamic-pituitary-adrenal axis in Ahi1(+/-) mice exposed to environmental and visceral stress. However, response to centrally acting anxiogenic compounds was intact. On resting-state functional MRI, connectivity of the amygdala with other brain regions involved in processing of anxiogenic stimuli and inhibitory avoidance learning, such as the lateral entorhinal cortex, ventral hippocampus and ventral tegmental area, was significantly reduced in the mutant mice. Taken together, our data link Ahi1 under-expression with a defect in the process of threat detection. Alternatively, the results could be interpreted as representing an anxiety-related endophenotype, possibly granting the Ahi1(+/-) mouse relative resilience to various types of stress. The current knockout model highlights the contribution of translational approaches to understanding the genetic basis of emotional regulation and its associated neurocircuitry, with possible relevance to neuropsychiatric disorders.

Osteonecrosis in a chemically induced rat model of human hemolytic disorders associated with thrombosis--a new model for avascular necrosis of bone.

Bone injury occurs in human hemolytic disorders associated with thrombosis, such as beta-thalassemia and sickle cell disease. Exposure of rats to 2-butoxyethanol (BE) has been associated with hemolytic anemia, disseminated thrombosis, and infarction in multiple organs including bone. This rat model apparently mimics acute hemolysis and thrombosis in humans. To elucidate the extent of bone injury, male and female Fischer F344 rats were given 4 daily doses of 250 mg BE/5 ml water/kg of body weight. Tail vertebrae were studied by histopathology and magnetic resonance imaging (MRI). Thrombosis and infarction were seen in both sexes, but females were more severely affected. Lesions were characterized by extensive medullary fat necrosis, granulomatous inflammation, fibroplasia, growth plate degeneration, and new woven bone formation adjacent to necrotic bone trabeculae. MRI mean and standard deviation tissue-density data for both sexes indicated a significant (P < or = 0.05) decrease following 4-days treatment and a significant increase (P < or = 0.05) following an additional 24 days without treatment. Thus, MRI was useful in revealing BE-induced bone injury, which was predominantly necrotic initially and subsequently regenerative with proliferation of connective tissue and bone following postischemia recovery.

Fast 3D T(2)-weighted MRI with Hadamard encoding in the slice select direction.

A fast method to obtain 3-dimensional (3D) magnetic resonance imaging with long repetition times is presented. It can be used to obtain fast 3D MRI with for example T(2) or diffusion weighted imaging. The method uses a 3D multiple thin slab sequence with radio frequency encoding, preferably Hadamard encoding, in the slice select direction. The point-spread function of the Hadamard-encoded slices is close to ideal even at low encoding numbers. This allows the acquisition of 3D data volumes with tolerable image quality up to four times faster than is possible using Fourier phase encoding. The scope of the method includes both longitudinal and transverse encoding. Longitudinal encoding provides a better point spread function than transverse encoding, at the expense of having to discard one slice per slab. The method is demonstrated experimentally for 4th order longitudinal Hadamard encoding to obtain 3D T(2)-weighted images.

Complex denoising of MR data via wavelet analysis: application for functional MRI.

A fast post-processing method for noise reduction of MR images, termed complex-denoising, is presented. The method is based on shrinking noisy discrete wavelet transform coefficients via thresholding, and it can be used for any MRI data-set with no need for high power computers. Unlike previous wavelet application to MR images, the denoising algorithm is applied, separately, to the two orthogonal sets of the complex MR image. The norm of the combined data are used to construct the image. With this method, signal-noise decoupling and Gaussian white noise assumptions used in the wavelet noise suppression scheme, are better fulfilled. The performance of the method is tested by carrying out a qualitative and quantitative comparison of a single-average image, complex-denoised image, multiple-average images, and a magnitude-denoised image, of a standard phantom. The comparison shows that the complex-denoising scheme improves the signal-to-noise and contrast-to-noise ratios more than the magnitude-denoising scheme, particularly in low SNR regions. To demonstrate the method strength, it is applied to fMRI data of somatosensory rat stimulation. It is shown that the activation area in a cross-correlation analysis is approximately 63% larger in the complex-denoised versus original data sets when equal threshold value is used. Application of the method of Principal Component Analysis to the complex-denoised, magnitude-denoised, and original data sets results in a similar but higher variance of the first few principal components obtained from the former data set as compared to those obtained from the later two sets.

Hadamard encoding with surface coils for high SNR MR spectroscopy.

The advantages of Hadamard over phase encoding in magnetic resonance spectroscopy (MRS) applied with surface coils in the direction perpendicular to the coil are demonstrated experimentally. With the recently introduced, time-shifted adiabatic pulses, the application of Hadamard encoding with surface coils results with almost ideal point spread function for pixels up to a distance of a radius from the coil. Comparison to phase encoding with equal region of interest size shows the significant advantage of Hadamard encoding in slice sharpness, overlapping, and spatial contamination. In addition, since there is no aliasing in Hadamard space, the total experimental time for the same region of interest is much shorter. We conclude that the hybrid of Hadamard encoding in the direction perpendicular to the coil and phase encoding in other directions is the method of choice to obtain reliable high signal to noise ratio MRS in vivo.

3D multivoxel proton spectroscopy of human brain using a hybrid of 8th-order Hadamard encoding with 2D chemical shift imaging.

Multivoxel 3D localized proton spectroscopy using a hybrid of 1D 8th-order transverse Hadamard spectroscopic imaging (HSI) with 2D chemical shift imaging (CSI) is demonstrated in human brain. The spatially selective HSI pulse incorporates naturally into the PRESS sequence (TE = 135 ms), which then both excites an 8 x 8 x 6 cm parallelepiped volume of interest (VOI) and subdivides it into eight slices. The planes of these slices are further partitioned into 16 x 16 voxel arrays using 2D CSI to yield 8 x 8 x 8 voxels within the VOI. Simultaneous 3D coverage yields good voxel signal-to-noise (8, 12, and 22 for choline, creatine, and N-acetylaspartate, respectively) from these 0.75-ml voxels, in approximately 45 min. The high spatial isolation allows localization to within less than 1 cm from the skull without fat contamination.

3D localized in vivo 1H spectroscopy of human brain by using a hybrid of 1D-Hadamard with 2D-chemical shift imaging.

We report acquisition of 3D image-guided localized proton spectroscopy (1H-MRS) in the human brain on a standard clinical imager. 3D coverage is achieved with a hybrid of chemical shift imaging (CSI) and transverse Hadamard spectroscopic imaging (HSI). 16 x 16 x 4 arrays of 3.5 and 1 ml voxels were obtained in 27 min. The spatially selective HSI 90 degrees pulses incorporate naturally into a PRESS double spin-echo sequence to subdivide the VOI into four partitions along its short axis. 2D CSI (16 x 16) is performed along the other long axes. Because the hybrid excites the spins in the entire VOI, a square-root-N signal-to-noise-ratio (SNR) gain per given examination time is realized compared with sequentially interleaving N 2D slices. A two-fold gain in sensitivity is demonstrated in the brain for N = 4.

Two methods for peak RF power minimization of multiple inversion-band pulses.

Two novel methods to minimize peak RF power for high order longitudinal Hadamard encoding are described and demonstrated experimentally. The first method uses the fact that the choice of a reference phase in an inversion process does not affect the final frequency response. In this method, the different single inversion-band pulses are added together, each with a different reference phase. For a proper phase choice, minimization of the peak RF power is obtained. Scaling laws are defined allowing the use of a given phase-set in multiple cases. In the second method, single inversion-band pulses are added together, each partially shifted in time. This results in a significant reduction in peak power with only a moderate increase in pulse length. Theoretical conditions outlining the optimal addition order are defined. Experimental results verify the theoretical conditions and demonstrate that the frequency response is not affected by the peak power minimization process. With the new low peak RF power, longitudinal Hadamard encoding of 8TH (or 16TH) order can be performed in any clinical setting.

Hybrid three dimensional (1D-Hadamard, 2D-chemical shift imaging) phosphorus localized spectroscopy of phantom and human brain.

A hybrid of two localized spectroscopy techniques, chemical shift imaging (CSI) and Hadamard spectroscopic imaging (HSI), is used to obtain an array of 16 x 16 x 4 (3 x 3 x 3 cm3 voxels) proton-decoupled phosphorus (31P) spectra of human brain. For equal spatial resolution, this organ's oblate shape requires fewer axial than coronal or sagittal slices. These different spatial requirements are well suited to 1D, 4th order, transverse HSI in the axial direction, combined with 2D 16 x 16 CSI in the other two orientations. The reduced localization matrix (16 x 16 x 4 over just the brain versus a cubic-16 x 16 x 16 matrix of equal resolution, over the entire head) may proportionally shorten data acquisition if the voxel size is not signal-to-noise limited. In addition, the use of Hadamard encoding can improve the intervoxel spectral isolation.

Fast Hadamard spectroscopic imaging techniques.

Fast Hadamard spectroscopic imaging (HSI) techniques are presented. These techniques combine transverse and longitudinal encoding to obtain multiple-volume localization. The fast techniques are optimized for nuclei with short T2 and long T1 relaxation times and are therefore suitable for in vivo 31P spectroscopy. When volume coils are used in fast HSI techniques, the signal-to-noise ratio per unit time (SNRT) is equal to the SNRT in regular HSI techniques. When surface coils are used, fast HSI techniques give significant improvement of SNRT over conventional HSI. Several fast techniques which are different in total experimental time and pulse demands are presented. When the number of acquisitions in a single repetition time is not higher than two, fast HSI techniques can be used with surface coils and the B1 inhomogeneity does not affect the localization. Surface-coil experiments on phantoms and on human calf muscles in vivo are presented. In addition, it is shown that the localization obtained by the HSI techniques are independent of the repetition times.

pH heterogeneity during exercise in localized spectra from single human muscles.

We investigated whether pH heterogeneity in skeletal muscle during exercise, observed with 31P nuclear magnetic resonance, represents muscle fiber type heterogeneity. Localized spectra were simultaneously acquired from the soleus, medial, and lateral gastrocnemius using a multivolume localization technique, the Hadamard spectroscopic imaging (HSI) technique. Contamination of nonselected regions to the localized volumes was < 5%. HSI-localized spectra were obtained from the calf muscles of untrained subjects and a small group of athletes. Two plantar flexion exercise protocols were implemented: a "maximal" high frequency protocol and a "steady-state" protocol at low contraction frequency (0.25 Hz). pH heterogeneity was observed in localized spectra of single muscles during both exercise protocols, as indicated by the large Pi line width. During maximal exercise the Pi line width was up to three times wider than the phosphocreatine line width, covering an entire pH unit. During the steady-state exercise, in three subjects the Pi peak clearly resolved into two distinct peaks, one at low pH and one at high pH. As pH heterogeneity was observed in localized spectra of single muscles during both exercise protocols, it most likely reflects the metabolic heterogeneity between fiber types.

Spectral localization of arbitrarily shaped regions of interest (SLASH) using single voxel signals.

A method for obtaining localized spectra from arbitrarily shaped regions of interest is described. When a sample consists of homogeneous compartments or domains, spectra localized in each compartment can be obtained from signals of single voxels with regular shapes by solving a set of simultaneous linear equations. Experimental demonstrations on a phantom and on human brain in vivo for a two compartment, two voxel case are presented. The issue of signal-to-noise ratio is also discussed.

Hadamard spectroscopic imaging technique as applied to study human calf muscles.

In vivo results obtained by the B1 insensitive Hadamard spectroscopic imaging multivolume technique used with a surface coil are shown. The functional behavior of different human calf muscles during exercise was determined and the Pi/PCr ratio in each calf muscle, during steady-state conditions, was measured as a function of work level. Different levels of metabolic and physical activity were observed at the three calf muscles.