Stefano Marenco

Comprehensive Approach for Correction of Motion and Distortion in Diffusion-Weighted MRI

Patient motion and image distortion induced by eddy currents cause artifacts in maps of diffusion parameters computed from diffusion‐weighted (DW) images. A novel and comprehensive approach to correct for spatial misalignment of DW imaging (DWI) volumes acquired with different strengths and orientations of the diffusion sensitizing gradients is presented. This approach uses a mutual information‐based registration technique and a spatial transformation model containing parameters that correct for eddy current‐induced image distortion and rigid body motion in three dimensions. All parameters are optimized simultaneously for an accurate and fast solution to the registration problem. The images can also be registered to a normalized template with a single interpolation step without additional computational cost. Following registration, the signal amplitude of each DWI volume is corrected to account for size variations of the object produced by the distortion correction, and the b‐matrices are properly recalculated to account for any rotation applied during registration. Both qualitative and quantitative results show that this approach produces a significant improvement of diffusion tensor imaging (DTI) data acquired in the human brain. Magn Reson Med 51:103–114, 2004. Published 2003 Wiley‐Liss, Inc.

The neurodevelopmental hypothesis of schizophrenia: Following a trail of evidence from cradle to grave

This is a critical review of the literature related to the neurodevelopmental hypothesis of schizophrenia which posits that the illness is related to abnormal brain development. The review focuses on data deriving from clinical studies, and it is organized according to the life phase from which the data were collected: conception and birth, infancy and childhood up to the onset of the illness, after illness onset, and postmortem. The neurodevelopmental hypothesis is supported by several pieces of evidence, including increased frequency of obstetric complications in patients with schizophrenia: the presence of minor physical anomalies; the presence of neurological, cognitive, and behavioral dysfunction long before illness onset; a course and outcome of the illness itself that is incompatible in most cases with a degenerative illness; the stability of brain structural measures over time; and the absence of postmortem evidence of neurodegeneration. A historical perspective on how this research accumulated and a section addressing important areas of future investigation are also provided. We conclude that schizophrenia is certainly not a degenerative brain disorder, and that it is likely that a brain insult in utero or at birth plays a role in its expression. Current evidence cannot completely exclude the role of environmental variables after birth. In addition, it is possible that other psychiatric disorders may also have a neurodevelopmental component.

Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk

The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions. We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain (AKT1, BDNF, CAPON, CHRNA7, COMT, DTNBP1, GAD1, GRM3, NOTCH4, NRG1, PRODH, RGS4, TNF-α) interacted with serious obstetric complications to influence risk for schizophrenia. A family-based study of transmission disequilibrium was conducted in 116 trios. Twenty-nine probands had at least one serious obstetric complication (OC) using the McNeil-Sjostrom Scale, and many of the OCs reported were associated with the potential for fetal hypoxia. Analyses were conducted using conditional logistic regression and a likelihood ratio test (LRT) between nested models was performed to assess significance. Of the 13 genes examined, four (AKT1 (three SNPs), BDNF (two SNPs), DTNBP1 (one SNP) and GRM3 (one SNP)) showed significant evidence for gene-by-environment interaction (LRT P-values ranged from 0.011 to 0.037). Although our sample size was modest and the power to detect interactions was limited, we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia.

Functional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome.

Williams syndrome (WS), caused by microdeletion of some 21 genes on chromosome 7q11.23, is characterized by dysmorphic features, mental retardation or learning difficulties, elastin arteriopathy, and striking neurocognitive and social-behavioral abnormalities. Recent studies of murine knockouts of key genes in the microdeleted region, LIM kinase 1 (LIMK1) and cytoplasmatic linker protein 2 (CYLN2), demonstrated significant functional and metabolic abnormalities, but grossly normal structure, in the hippocampal formation (HF). Furthermore, deficits in spatial navigation and long-term memory, major cognitive domains dependent on hippocampal function, have been described in WS. We used multimodal neuroimaging to characterize hippocampal structure, function, and metabolic integrity in 12 participants with WS and 12 age-, sex-, and IQ-matched healthy controls. PET and functional MRI studies showed profound reduction in resting blood flow and absent differential response to visual stimuli in the anterior HF in WS. Spectroscopic measures of N-acetyl aspartate, considered a marker of synaptic activity, were reduced. Hippocampal size was preserved, but subtle alterations in shape were present. These data demonstrate abnormalities in HF in WS in agreement with murine models, implicate LIMK1 and CYLN2 in human hippocampal function, and suggest that hippocampal dysfunction may contribute to neurocognitive abnormalities in WS.

Investigation of Anatomical Thalamo-Cortical Connectivity and fMRI Activation in Schizophrenia

The purpose of this study was to examine measures of anatomical connectivity between the thalamus and lateral prefrontal cortex (LPFC) in schizophrenia and to assess their functional implications. We measured thalamocortical connectivity with diffusion tensor imaging (DTI) and probabilistic tractography in 15 patients with schizophrenia and 22 age- and sex-matched controls. The relationship between thalamocortical connectivity and prefrontal cortical blood-oxygenation-level-dependent (BOLD) functional activity as well as behavioral performance during working memory was examined in a subsample of 9 patients and 18 controls. Compared with controls, schizophrenia patients showed reduced total connectivity of the thalamus to only one of six cortical regions, the LPFC. The size of the thalamic region with at least 25% of model fibers reaching the LPFC was also reduced in patients compared with controls. The total thalamocortical connectivity to the LPFC predicted working memory task performance and also correlated with LPFC BOLD activation. Notably, the correlation with BOLD activation was accentuated in patients as compared with controls in the ventral LPFC. These results suggest that thalamocortical connectivity to the LPFC is altered in schizophrenia with functional consequences on working memory processing in LPFC.

Effects of image distortions originating from susceptibility variations and concomitant fields on diffusion MRI tractography results.

In this work we investigate the effects of echo planar imaging (EPI) distortions on diffusion tensor imaging (DTI) based fiber tractography results. We propose a simple experimental framework that would enable assessing the effects of EPI distortions on the accuracy and reproducibility of fiber tractography from a pilot study on a few subjects. We compare trajectories computed from two diffusion datasets collected on each subject that are identical except for the orientation of phase encode direction, either right-left (RL) or anterior-posterior (AP). We define metrics to assess potential discrepancies between RL and AP trajectories in association, commissural, and projection pathways. Results from measurements on a 3 Tesla clinical scanner indicated that the effects of EPI distortions on computed fiber trajectories are statistically significant and large in magnitude, potentially leading to erroneous inferences about brain connectivity. The correction of EPI distortion using an image-based registration approach showed a significant improvement in tract consistency and accuracy. Although obtained in the context of a DTI experiment, our findings are generally applicable to all EPI-based diffusion MRI tractography investigations, including high angular resolution (HARDI) methods. On the basis of our findings, we recommend adding an EPI distortion correction step to the diffusion MRI processing pipeline if the output is to be used for fiber tractography.

Comparison of Cognitive Performances During a Placebo Period and an Atypical Antipsychotic Treatment Period in Schizophrenia: Critical Examination of Confounds

Although previous studies report cognitive improvement following atypical antipsychotic administration in schizophrenia (SC), few placebo-controlled within-subject studies with examination of confounds (symptom reduction, cooperation, learning, and outliers) have been reported. The present study examines the effects of atypicals and confounds upon cognition in SC. The hypothesis tested was that relative to placebo, atypicals as a general class of medication would elicit cognitive improvement in SC. In all, 19 patients with SC (15 males) completed the double-blind, counterbalanced, randomized within-subject study of the effects of atypical antipsychotics (risperidone, clozapine, olanzapine, or quetiapine) vs placebo administration upon cognitive performance in the domains of executive function, attention, memory, language, visual perception, and general intellect. Significant cognitive improvement during atypical antipsychotic administration relative to placebo withdrawal occurred in most cognitive domains with robust improvements in intelligence (p=0.001), memory (p=0.0009), and fluency (p<0.002) even after outliers and unmotivated performances were excluded. These findings suggest that relative to placebo withdrawal, atypicals improve cognitive performance in SC. However, this finding may not be specific to atypicals, since analogous studies of typicals have not been performed.

Comparison of EPI Distortion Correction Methods in Diffusion Tensor MRI Using a Novel Framework

Diffusion weighted images (DWIs) are commonly acquired with Echo-planar imaging (EPI). B0 inhomogeneities affect EPI by producing spatially nonlinear image distortions. Several strategies have been proposed to correct EPI distortions including B0 field mapping (B0M) and image registration. In this study, an experimental framework is proposed to evaluation the performance of different EPI distortion correction methods in improving DT-derived quantities. A deformable registration based method with mutual information metric and cubic B-spline modeled constrained deformation field (BSP) is proposed as an alternative when B0 mapping data are not available. BSP method is qualitatively and quantitatively compared to B0M method using the framework. Both methods can successful reduce EPI distortions and significantly improve the quality of DT-derived quantities. Overall, B0M was clearly superior in infratentorial regions including brainstem and cerebellum, as well as in the ventral areas of the temporal lobes while BSP was better in all rostral brain regions.

Genetic contributions to white matter architecture revealed by diffusion tensor imaging in Williams syndrome.

Little is known about genetic regulation of the development of white matter. This knowledge is critical in understanding the pathophysiology of neurodevelopmental syndromes associated with altered cognition as well as in elucidating the genetics of normal human cognition. The hemideletion of ≈25 genes on chromosome 7q11.23 that causes Williams syndrome (WS) includes genes that regulate cytoskeletal dynamics in neurons, especially LIMK1 and CYLN2, and therefore offers the opportunity to investigate the role of these genes in the formation of white matter tracts. We used diffusion tensor imaging to demonstrate alteration in white matter fiber directionality, deviation in posterior fiber tract course, and reduced lateralization of fiber coherence in WS. These abnormalities are consistent with an alteration of the late stages of neuronal migration, define alterations of white matter structures underlying dissociable behavioral phenotypes in WS, and provide human in vivo information about genetic control of white matter tract formation.

An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression

Amino-acid neurotransmitter system dysfunction plays a major role in the pathophysiology of major depressive disorder (MDD). We used proton magnetic resonance spectroscopy (¹H-MRS) to investigate whether prefrontal levels of amino-acid neurotransmitters predict antidepressant response to a single intravenous infusion of the N-methyl-D-aspartate (NMDA) antagonist ketamine in MDD patients. Fourteen drug-free patients with MDD were scanned 1-3 d before receiving a single intravenous infusion of ketamine (0.5 mg/kg). We measured gamma aminobutyric acid (GABA), glutamate, and Glx/glutamate ratio (a surrogate marker of glutamine) in the ventromedial prefrontal cortex (VM-PFC) and the dorsomedial/dorsal anterolateral prefrontal cortex (DM/DA-PFC). Correlation analyses were conducted to determine whether pretreatment GABA, glutamate, or Glx/glutamate ratio predicted change in depressive and anxiety symptoms 230 min after ketamine administration. Pretreatment GABA or glutamate did not correlate with improved depressive symptoms in either of the two regions of interest (p>0.1); pretreatment Glx/glutamate ratio in the DM/DA-PFC was negatively correlated with improvement in depressive symptoms [r s(11)=-0.57, p<0.05]. Pretreatment glutamate levels in the VM-PFC were positively correlated with improvement in anxiety symptoms [r s(11)=0.57, p<0.05]. The findings suggest an association between lower Glx/glutamate ratio and greater improvement in response to ketamine treatment. Because glutamine is mainly contained in glia, the decreased Glx/glutamate ratio observed in this study may reflect the reduction in glial cells found in the same regions in post-mortem studies of individuals with MDD, and suggests that the presence of this neuropathological construct may be associated with antidepressant responsiveness to ketamine.