Publications by authors named "Craig A Branch"

36 Publications

Associations of Maternal Prenatal Drug Abuse With Measures of Newborn Brain Structure, Tissue Organization, and Metabolite Concentrations.

JAMA Pediatr 2020 09;174(9):831-842

Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California.

Importance: Increasing rates of illicit drug use during pregnancy may be associated with risk for long-term health problems in prenatally exposed children.

Objective: To identify the associations of prenatal exposure to illicit drugs with organization of the newborn brain.

Design, Setting, And Participants: For this cohort study, a volunteer sample of 210 illicit drug-using and nonusing mothers and their newborns was enrolled from prenatal clinics and drug abuse treatment programs in New York, New York. Enrollment, scanning, and long-term follow-up occurred from September 2004 through February 2012, and image processing and statistical analyses continued through fall 2018. In addition to 26 participants with incomplete data, a total of 64 mothers were lost to follow-up during pregnancy, and 13 newborns were lost to follow-up at birth because of perinatal complications.

Exposures: Newborns were assigned to 1 of 4 primary exposure groups based on the history of most frequent maternal drug use: marijuana, cocaine, methadone maintenance, and/or heroin. Unexposed newborns were controls.

Main Outcomes And Measures: Unsedated magnetic resonance imaging (MRI) of newborn brains was performed shortly after birth. Infant neurodevelopmental outcomes were assessed at age 12 months. MRI modalities included anatomical imaging, diffusion tensor imaging, T2 relaxometry, and magnetic resonance spectroscopic imaging. Infant neurodevelopmental outcomes included Bayley scales of infant development-III and Vineland Adaptive Behavior Scales. Statistical analyses were performed with results represented on the brain images.

Results: Of 118 mothers, 42 (35%) were in the control group (mean [SD] age, 25.9 [6.1] years), 29 (25%) were in the cocaine group (mean [SD] age, 29.0 [6.1] years), 29 (25%) were in the marijuana group (mean [SD] age, 24.3 [5.5] years), and 18 (15%) were in the methadone and/or heroin group (mean [SD] age, 30.9 [5.7] years). Not all newborns could be scanned successfully; therefore, usable MRIs were acquired for 118 newborns from predominantly minority groups and with economically disadvantaged mothers. Anatomic abnormalities were detected in similar locations across all 3 drug exposures and included smaller volumes in the dorsal, medial, and ventral surfaces of the frontal lobe and dose-related increases in volumes in the lateral temporal lobe, dorsal parietal lobe, and superior frontal gyrus. Dose-related increases in diffusion tensor measures of tissue organization, decreases in T2 relaxometry times, and increases in spectroscopy metabolite concentrations were similar across exposures. These associations of exposures with brain measures were similar to the associations of newborn age with brain measures. The anatomic and diffusion tensor imaging measures suppressively mediated the associations of prenatal exposure with poorer 12-month infant outcomes.

Conclusions And Relevance: The findings suggest that prenatal drug exposure is associated with measures of newborn brain tissue in patterns that may indicate that exposures accelerated normal fetal brain maturation, which in turn mediated the associations with poorer 12-month infant outcomes.
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http://dx.doi.org/10.1001/jamapediatrics.2020.1622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296459PMC
September 2020

Diffusion Tensor Imaging of the Evolving Response to Mild Traumatic Brain Injury in Rats.

J Exp Neurosci 2019 5;13:1179069519858627. Epub 2019 Jul 5.

The Gruss Magnetic Resonance Research Center, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA.

Mild traumatic brain injury (mTBI), also known as concussion, is a serious public health challenge. Although most patients recover, a substantial minority suffers chronic disability. The mechanisms underlying mTBI-related detrimental effects remain poorly understood. Although animal models contribute valuable preclinical information and improve our understanding of the underlying mechanisms following mTBI, only few studies have used diffusion tensor imaging (DTI) to study the evolution of axonal injury following mTBI in rodents. It is known that DTI shows changes after human concussion and the role of delineating imaging findings in animals is therefore to facilitate understanding of related mechanisms. In this work, we used a rodent model of mTBI to investigate longitudinal indices of axonal injury. We present the results of 45 animals that received magnetic resonance imaging (MRI) at multiple time points over a 2-week period following concussive or sham injury yielding 109 serial observations. Overall, the evolution of DTI metrics following concussive or sham injury differed by group. Diffusion tensor imaging changes within the white matter were most noticeable 1 week following injury and returned to baseline values after 2 weeks. More specifically, we observed increased fractional anisotropy in combination with decreased radial diffusivity and mean diffusivity, in the absence of changes in axial diffusivity, within the white matter of the genu corpus callosum at 1 week post-injury. Our study shows that DTI can detect microstructural white matter changes in the absence of gross abnormalities as indicated by visual screening of anatomical MRI and hematoxylin and eosin (H&E)-stained sections in a clinically relevant animal model of mTBI. Whereas additional histopathologic characterization is required to better understand the neurobiological correlates of DTI measures, our findings highlight the evolving nature of the brain's response to injury following concussion.
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http://dx.doi.org/10.1177/1179069519858627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613065PMC
July 2019

Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice.

Geroscience 2019 04 10;41(2):185-208. Epub 2019 May 10.

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer Bldg, Rm 236, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.

Disruptions in growth hormone/insulin-like growth factor-1 (GH/IGF-1) signaling have been linked to improved longevity in mice and humans. Nevertheless, while IGF-1 levels are associated with increased cancer risk, they have been paradoxically implicated with protection from other age-related conditions, particularly in the brain, suggesting that strategies aimed at selectively increasing central IGF-1 action may have favorable effects on aging. To test this hypothesis, we generated inducible, brain-specific (TRE-IGF-1 × Camk2a-tTA) IGF-1 (bIGF-1) overexpression mice and studied effects on healthspan. Doxycycline was removed from the diet at 12 weeks old to permit post-development brain IGF-1 overexpression, and animals were monitored up to 24 months. Brain IGF-1 levels were increased approximately twofold in bIGF-1 mice, along with greater brain weights, volume, and myelin density (P < 0.05). Age-related changes in rotarod performance, exercise capacity, depressive-like behavior, and hippocampal gliosis were all attenuated specifically in bIGF-1 male mice (P < 0.05). However, chronic brain IGF-1 failed to prevent declines in cognitive function or neurovascular coupling. Therefore, we performed a short-term intranasal (IN) treatment of either IGF-1 or saline in 24-month-old male C57BL/6 mice and found that IN IGF-1 treatment tended to reduce depressive (P = 0.09) and anxiety-like behavior (P = 0.08) and improve motor coordination (P = 0.07) and unlike transgenic mice improved motor learning (P < 0.05) and visuospatial and working memory (P < 0.05). These data highlight important sex differences in how brain IGF-1 action impacts healthspan and suggest that translational approaches that target IGF-1 centrally can restore cognitive function, a possibility that should be explored as a strategy to combat age-related cognitive decline.
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http://dx.doi.org/10.1007/s11357-019-00065-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544744PMC
April 2019

Animal models of closed-skull, repetitive mild traumatic brain injury.

Pharmacol Ther 2019 06 26;198:109-122. Epub 2019 Feb 26.

The Gruss Magnetic Resonance Research Center, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10641, USA; Department of Radiology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, USA; Departments of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, USA; The Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, USA. Electronic address:

The underlying mechanisms that result in neurophysiological changes and cognitive sequelae in the context of repetitive mild traumatic brain injury (rmTBI) remain poorly understood. Animal models provide a unique opportunity to examine cellular and molecular responses using histological assessment, which can give important insights on the neurophysiological changes associated with the evolution of brain injury. To better understand the potential cumulative effects of multiple concussions, the focus of animal models is shifting from single to repetitive head impacts. With a growing body of literature on this subject, a review and discussion of current findings is valuable to better understand the neuropathology associated with rmTBI, to evaluate the current state of the field, and to guide future research efforts. Despite variability in experimental settings, existing animal models of rmTBI have contributed to our understanding of the underlying mechanisms following repeat concussion. However, how to reconcile the various impact methods remains one of the major challenges in the field today.
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http://dx.doi.org/10.1016/j.pharmthera.2019.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536340PMC
June 2019

The neurobiological effects of repetitive head impacts in collision sports.

Neurobiol Dis 2019 03 21;123:122-126. Epub 2018 Jun 21.

The Gruss Magnetic Resonance Imaging Center, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA; Departments of Radiology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA; Departments of Psychiatry & Behavioral Sciences, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA; The Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.

It is now recognized that repetitive head impacts (RHI) in sport have the potential for long-term neurological impairments. In order to identify targets for intervention and/or pharmacological treatment, it is necessary to characterize the neurobiological mechanisms associated with RHI. This review aims to summarize animal and human studies that specifically address Blood Brain Barrier (BBB) dysfunction, abnormal neuro-metabolic and neuro-inflammatory processes as well as Tau aggregation associated with RHI in collision sports. Additionally, we examine the influence of physical activity and genetics on outcomes of RHI, discuss methodological considerations, and provide suggestions for future directions of this burgeoning area of research.
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http://dx.doi.org/10.1016/j.nbd.2018.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453577PMC
March 2019

Brain neurochemical and hemodynamic findings in the NY1DD mouse model of mild sickle cell disease.

NMR Biomed 2017 May 10;30(5). Epub 2017 Feb 10.

Gruss Magnetic Resonance Research Center, Albert Einstein College of Medicine, Bronx, New York, USA.

To characterize the cerebral profile associated with sickle cell disease (SCD), we used in vivo proton MRI and MRS to quantify hemodynamics and neurochemicals in the thalamus of NY1DD mice, a mild model of SCD, and compared them with wild-type (WT) control mice. Compared with WT mice, NY1DD mice at steady state had elevated cerebral blood flow (CBF) and concentrations of N-acetylaspartate (NAA), glutamate (Glu), alanine, total creatine and N-acetylaspartylglutamate. Concentrations of glutathione (GSH) at steady state showed a negative correlation with BOLD signal change in response to 100% oxygen, a marker for oxidative stress, and mean diffusivity assessed using diffusion-tensor imaging, a marker for edematous inflammation. In NY1DD mice, elevated basal CBF was correlated negatively with [NAA], but positively with concentration of glutamine ([Gln]). Immediately after experimental hypoxia (at reoxygenation after 18 hours of 8% O ), concentrations of NAA, Glu, GSH, Gln and taurine (Tau) increased only in NY1DD mice. [NAA], [Glu], [GSH] and [Tau] all returned to baseline levels two weeks after the hypoxic episode. The altered neurochemical profile in the NY1DD mouse model of SCD at steady state and following experimental hypoxia/reoxygenation suggests a state of chronic oxidative stress leading to compensatory cerebral metabolic adjustments.
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http://dx.doi.org/10.1002/nbm.3692DOI Listing
May 2017

Two step Gaussian mixture model approach to characterize white matter disease based on distributional changes.

J Neurosci Methods 2016 09 29;270:156-164. Epub 2016 Apr 29.

The Gruss Magnetic Resonance Research Center, Radiology, The Albert Einstein College of Medicine, Bronx, NY, USA; Department of Psychiatry and Behavioral Sciences, The Albert Einstein College of Medicine, Bronx, NY, USA; The Dominick P Purpura Department of Neuroscience, The Albert Einstein College of Medicine, Bronx, NY, USA; Department of Radiology, The Montefiore Medical Center, Bronx, NY, USA. Electronic address:

Background: Magnetic resonance imaging reveals macro- and microstructural correlates of neurodegeneration, which are often assessed using voxel-by-voxel t-tests for comparing mean image intensities measured by fractional anisotropy (FA) between cases and controls or regression analysis for associating mean intensity with putative risk factors. This analytic strategy focusing on mean intensity in individual voxels, however, fails to account for change in distribution of image intensities due to disease.

New Method: We propose a method that aims to facilitate simple and clear characterization of underlying distribution. Our method consists of two steps: subject-level (Step 1) and group-level or a specific risk-level density function estimation across subjects (Step 2).

Results: The proposed method was demonstrated with a simulated data set and real FA data sets from two white matter tracts, where the proposed method successfully detected any departure of the FA distribution from the normal state by disease: p<0.001 for simulated data; p=0.047 for the posterior limb of internal capsule; p=0.06 for the posterior thalamic radiation.

Comparison With Existing Method(s): The proposed method found significant disease effect (p<0.001) while conventional 2-group t-test focused only on mean intensity did not (p=0.61) in a simulation study. While significant age effects were found for each white matter tract from conventional linear model analysis with real FA data, the proposed method further confirmed that aging also triggers distribution-wide change.

Conclusion: Our proposed method is powerful for detection of risk factors associated with any type of microstructural neurodegenerations with brain imaging data.
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http://dx.doi.org/10.1016/j.jneumeth.2016.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683897PMC
September 2016

A simple method for determining the coagulation threshold temperature of transparent tissue-mimicking thermal therapy gel phantoms: Validated by magnetic resonance imaging thermometry.

Med Phys 2016 Mar;43(3):1167-74

Institute for Onco-Physics, Albert Einstein College of Medicine, Bronx, New York 10461 and Department of Radiation Oncology, Montefiore Medical Center, Bronx, New York 10461.

Purpose: Tissue-mimicking thermal therapy phantoms that coagulate at specific temperatures are valuable tools for developing and evaluating treatment strategies related to thermal therapy. Here, the authors propose a simple and efficient method for determining the coagulation threshold temperature of transparent thermal therapy gel phantoms.

Methods: The authors used a previously published gel phantom recipe with 2% (w/v) of bovine serum albumin as the temperature-sensitive protein. Using the programmable heating settings of a polymerase chain reaction (PCR) machine, the authors heated 50 μl gel samples to various temperatures for 3 min and then imaged them using the BioRad Gel Doc system to determine the coagulation temperature using an opacity quantification method. The estimated coagulation temperatures were then validated for gel phantoms prepared with different pH levels using high-intensity focused ultrasound (HIFU) heating and magnetic resonance imaging (MRI) thermometry methods on a clinical MR-HIFU system.

Results: The PCR heating method produced consistent and reproducible coagulation of gel samples in precise correlation with the set incubation temperatures. The resulting coagulation threshold temperatures for gel phantoms of varying pH levels were found to be 44.1 ± 0.1, 53.4 ± 0.9, and 60.3 ± 0.9 °C for pH levels of 4.25, 4.50, and 4.75, respectively. This corresponded well with the coagulation threshold temperatures determined by MR-thermometry, with coagulation defined as a 95% decrease in T2 relaxation time, which were estimated at 53.6 ± 1.9 and 62.9 ± 2.4 °C for a pH of 4.50 and 4.75, respectively.

Conclusions: The opacity quantification method provides a fast and reproducible estimate of the coagulation threshold temperature of transparent temperature-sensitive gel phantoms. The temperatures determined using this method were well within the range of temperatures estimated using MR-thermometry. Due to the specific heating capabilities of the PCR machine, and the robust determination of coagulation threshold temperatures based on the statistically significant increase in the opacity of gel samples, coagulation temperatures can be determined more precisely and with less variability compared to MRI-based methods.
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http://dx.doi.org/10.1118/1.4941361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752546PMC
March 2016

AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas.

Proc Natl Acad Sci U S A 2016 Mar 16;113(9):2466-71. Epub 2016 Feb 16.

University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131

Patients with inoperable or unresectable pancreatic neuroendocrine tumors (NETs) have limited treatment options. These rare human tumors often express somatostatin receptors (SSTRs) and thus are clinically responsive to certain relatively stable somatostatin analogs, such as octreotide. Unfortunately, however, this tumor response is generally short-lived. Here we designed a hybrid adeno-associated virus and phage (AAVP) vector displaying biologically active octreotide on the viral surface for ligand-directed delivery, cell internalization, and transduction of an apoptosis-promoting tumor necrosis factor (TNF) transgene specifically to NETs. These functional attributes of AAVP-TNF particles displaying the octreotide peptide motif (termed Oct-AAVP-TNF) were confirmed in vitro, in SSTR type 2-expressing NET cells, and in vivo using cohorts of pancreatic NET-bearing Men1 tumor-suppressor gene KO mice, a transgenic model of functioning (i.e., insulin-secreting) tumors that genetically and clinically recapitulates the human disease. Finally, preclinical imaging and therapeutic experiments with pancreatic NET-bearing mice demonstrated that Oct-AAVP-TNF lowered tumor metabolism and insulin secretion, reduced tumor size, and improved mouse survival. Taken together, these proof-of-concept results establish Oct-AAVP-TNF as a strong therapeutic candidate for patients with NETs of the pancreas. More broadly, the demonstration that a known, short, biologically active motif can direct tumor targeting and receptor-mediated internalization of AAVP particles may streamline the potential utility of myriad other short peptide motifs and provide a blueprint for therapeutic applications in a variety of cancers and perhaps many nonmalignant diseases as well.
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http://dx.doi.org/10.1073/pnas.1525709113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780640PMC
March 2016

In vivo (1)H MRS and (31)P MRSI of the response to cyclocreatine in transgenic mouse liver expressing creatine kinase.

NMR Biomed 2015 Dec 9;28(12):1634-44. Epub 2015 Oct 9.

Gruss Magnetic Resonance Research Center, Albert Einstein College of Medicine, Bronx, NY, USA.

Hepatocyte transplantation has been explored as a therapeutic alternative to liver transplantation, but a means to monitor the success of the procedure is lacking. Published findings support the use of in vivo (31)P MRSI of creatine kinase (CK)-expressing hepatocytes to monitor proliferation of implanted hepatocytes. Phosphocreatine tissue level depends upon creatine (Cr) input to the CK enzyme reaction, but Cr measurement by (1)H MRS suffers from low signal-to-noise ratio (SNR). We examine the possibility of using the Cr analog cyclocreatine (CCr, a substrate for CK), which is quickly phosphorylated to phosphocyclocreatine (PCCr), as a higher SNR alternative to Cr. (1)H MRS and (31)P MRSI were employed to measure the effect of incremental supplementation of CCr upon PCCr, γ-ATP, pH and Pi /ATP in the liver of transgenic mice expressing the BB isoform of CK (CKBB) in hepatocytes. Water supplementation with 0.1% CCr led to a peak total PCCr level of 17.15 ± 1.07 mmol/kg wet weight by 6 weeks, while adding 1.0% CCr led to a stable PCCr liver level of 18.12 ± 3.91 mmol/kg by the fourth day of feeding. PCCr was positively correlated with CCr, and ATP concentration and pH declined with increasing PCCr. Feeding with 1% CCr in water induced an apparent saturated level of PCCr, suggesting that CCr quantization may not be necessary for quantifying expression of CK in mice. These findings support the possibility of using (31)P MRS to noninvasively monitor hepatocyte transplant success with CK-expressing hepatocytes.
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http://dx.doi.org/10.1002/nbm.3391DOI Listing
December 2015

Subcortical structure alterations impact language processing in individuals with schizophrenia and those at high genetic risk.

Schizophr Res 2015 Dec 18;169(1-3):76-82. Epub 2015 Sep 18.

New York University Medical School, NY, United States; VA Boston Healthcare System, Harvard Medical School, Brockton, MA, United States.

Objective: Cortical structural and functional anomalies have been found to associate with language impairments in both schizophrenia patients and genetic high risk individuals for developing schizophrenia. However, subcortical structures that contribute to language processing haven't been well studied in this population, and thus became the main objective of this study.

Method: We examined structural MRI data from 20 patients with schizophrenia, 21 individuals at genetic high risk, and 48 controls. Surface shape and volume differences of 6 subcortical structures that are involved in language processing, including nuclei pallidum, putamen, caudate, amygdala, thalamus, and hippocampus from both hemispheres, were compared between groups. Performance scores of language-associated cognitive tests were obtained to identify relationships of subcortical structures to language-related behaviors.

Results: Significantly reduced volumes of both the left and right side caudate nuclei, thalami and right side amygdala were shown in patients when compared with controls. Very interestingly, the high risk group demonstrated significantly increased correlations between volumes of left side pallidum nucleus and bilateral thalami and language-related cognitive test scores when compared to controls.

Conclusions: This study furthers our understanding of subcortical structural alterations in schizophrenia and high risk individuals, and suggests the contribution of subcortical structures to the language impairments that may serve as an early sign for impending development of schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2015.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681604PMC
December 2015

Phenotypic characterization of a Csf1r haploinsufficient mouse model of adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP).

Neurobiol Dis 2015 Feb 9;74:219-28. Epub 2014 Dec 9.

Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address:

Mutations in the colony stimulating factor-1 receptor (CSF1R) that abrogate the expression of the affected allele or lead to the expression of mutant receptor chains devoid of kinase activity have been identified in both familial and sporadic cases of ALSP. To determine the validity of the Csf1r heterozygous mouse as a model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) we performed behavioral, radiologic, histopathologic, ultrastructural and cytokine expression studies of young and old Csf1r+/- and control Csf1r+/+ mice. Six to 8-month old Csf1r+/- mice exhibit cognitive deficits, and by 9-11 months develop sensorimotor deficits and in male mice, depression and anxiety-like behavior. MRIs of one year-old Csf1r+/- mice reveal lateral ventricle enlargement and thinning of the corpus callosum. Ultrastructural analysis of the corpus callosum uncovers dysmyelinated axons as well as neurodegeneration, evidenced by the presence of axonal spheroids. Histopathological examination of 11-week-old mice reveals increased axonal and myelin staining in the cortex, increase of neuronal cell density in layer V and increase of microglial cell densities throughout the brain, suggesting that early developmental changes contribute to disease. By 10-months of age, the neuronal cell density normalizes, oligodendrocyte precursor cells increase in layers II-III and V and microglial densities remain elevated without an increase in astrocytes. Also, the age-dependent increase in CSF-1R+ neurons in cortical layer V is reduced. Moreover, the expression of Csf2, Csf3, Il27 and Il6 family cytokines is increased, consistent with microglia-mediated inflammation. These results demonstrate that the inactivation of one Csf1r allele is sufficient to cause an ALSP-like disease in mice. The Csf1r+/- mouse is a model of ALSP that will allow the critical events for disease development to be determined and permit rapid evaluation of therapeutic approaches. Furthermore, our results suggest that aberrant activation of microglia in Csf1r+/- mice may play a central role in ALSP pathology.
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http://dx.doi.org/10.1016/j.nbd.2014.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323933PMC
February 2015

In vivo proton MR spectroscopy of pancreatic neuroendocrine tumors in a multiple endocrine neoplasia type 1 conditional knockout mouse model.

Magn Reson Med 2015 Nov 13;74(5):1221-6. Epub 2014 Nov 13.

Department of Surgery, Albert Einstein College of Medicine, Bronx, New York, USA.

Purpose: MR spectroscopy (MRS) can improve diagnosis and follow treatment in cancer. However, no study has yet reported application of in vivo (1)H-MRS in malignant pancreatic lesions. This study quantitatively determined whether in vivo (1)H-MRS on multiple endocrine neoplasia type 1 (Men1) conditional knockout (KO) mice and their wild type (WT) littermates could detect differences in total choline (tCho) levels between tumor and control pancreas.

Methods: Relative tCho levels in pancreatic tumors or pancreata from KO and WT mice were determined using in vivo (1)H-MRS at 9.4 T. The levels of Cho-containing compounds were also quantified using in vitro (1)H-NMR on extracts of pancreatic tissues from KO and WT mice, respectively, and on extracts of pancreatic tissues from patients with pancreatic neuroendocrine tumors (PNETs).

Results: tCho levels measured by in vivo (1)H-MRS were significantly higher in PNETs from KO mice compared to the normal pancreas from WT mice. The elevated choline-containing compounds were also identified in pancreatic tumors from KO mice and tissues from patients with PNETs via in vitro (1)H-NMR.

Conclusion: These results indicate the potential use of tCho levels estimated via in vivo (1)H-MRS in differentiating malignant pancreatic tumors from benign tumors.
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http://dx.doi.org/10.1002/mrm.25529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430461PMC
November 2015

A gaussian mixture model approach for estimating and comparing the shapes of distributions of neuroimaging data: diffusion-measured aging effects in brain white matter.

Front Public Health 2014 14;2:32. Epub 2014 Apr 14.

Department of Radiology, The Gruss Magnetic Resonance Research Center, Albert Einstein College of Medicine , Bronx, NY , USA ; Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine , Bronx, NY , USA ; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine , Bronx, NY , USA ; Department of Radiology, Montefiore Medical Center , Bronx, NY , USA.

Neuroimaging signal intensity measures underlying physiology at each voxel unit. The brain-wide distribution of signal intensities may be used to assess gross brain abnormality. To compare distributions of brain image data between groups, t-tests are widely applied. This approach, however, only compares group means and fails to consider the shapes of the distributions. We propose a simple approach for estimating both subject- and group-level density functions based on the framework of Gaussian mixture modeling, with mixture probabilities that are testable between groups. We demonstrate this approach by application to the analysis of fractional anisotropy image data for assessment of aging effects in white matter.
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http://dx.doi.org/10.3389/fpubh.2014.00032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995036PMC
April 2014

Soccer heading is associated with white matter microstructural and cognitive abnormalities.

Radiology 2013 Sep 11;268(3):850-7. Epub 2013 Jun 11.

Gruss Magnetic Resonance Research Center, Department of Radiology, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Ave, Bronx, NY 10461, USA.

Purpose: To investigate the association of soccer heading with subclinical evidence of traumatic brain injury.

Materials And Methods: With institutional review board approval and compliance with HIPAA guidelines, 37 amateur soccer players (mean age, 30.9 years; 78% [29] men, 22% [eight] women) gave written informed consent and completed a questionnaire to quantify heading in the prior 12 months and lifetime concussions. Diffusion-tensor magnetic resonance (MR) imaging at 3.0 T was performed (32 directions; b value, 800 sec/mm(2); 2 × 2 × 2-mm voxels). Cognitive function was measured by using a computerized battery of tests. Voxelwise linear regression (heading vs fractional anisotropy [FA]) was applied to identify significant regional associations. FA at each location and cognition were tested for a nonlinear relationship to heading by using an inverse logit model that incorporated demographic covariates and history of concussion.

Results: Participants had headed 32-5400 times (median, 432 times) over the previous year. Heading was associated with lower FA at three locations in temporo-occipital white matter with a threshold that varied according to location (885-1550 headings per year) (P < .00001). Lower levels of FA were also associated with poorer memory scores (P < .00001), with a threshold of 1800 headings per year. Lifetime concussion history and demographic features were not significantly associated with either FA or cognitive performance.

Conclusion: Heading is associated with abnormal white matter microstructure and with poorer neurocognitive performance. This relationship is not explained by a history of concussion.
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http://dx.doi.org/10.1148/radiol.13130545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750422PMC
September 2013

Whole brain approaches for identification of microstructural abnormalities in individual patients: comparison of techniques applied to mild traumatic brain injury.

PLoS One 2013 26;8(3):e59382. Epub 2013 Mar 26.

The Gruss Magnetic Resonance Research Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA.

Purpose: Group-wise analyses of DTI in mTBI have demonstrated evidence of traumatic axonal injury (TAI), associated with adverse clinical outcomes. Although mTBI is likely to have a unique spatial pattern in each patient, group analyses implicitly assume that location of injury will be the same across patients. The purpose of this study was to optimize and validate a procedure for analysis of DTI images acquired in individual patients, which could detect inter-individual differences and be applied in the clinical setting, where patients must be assessed as individuals.

Materials And Methods: After informed consent and in compliance with HIPAA, 34 mTBI patients and 42 normal subjects underwent 3.0 Tesla DTI. Four voxelwise assessment methods (standard Z-score, "one vs. many" t-test, Family-Wise Error Rate control using pseudo t-distribution, EZ-MAP) for use in individual patients, were applied to each patient's fractional anisotropy (FA) maps and tested for its ability to discriminate patients from controls. Receiver Operating Characteristic (ROC) analyses were used to define optimal thresholds (voxel-level significance and spatial extent) for reliable and robust detection of mTBI pathology.

Results: ROC analyses showed EZ-MAP (specificity 71%, sensitivity 71%), "one vs. many" t-test and standard Z-score (sensitivity 65%, specificity 76% for both methods) resulted in a significant area under the curve (AUC) score for discriminating mTBI patients from controls in terms of the total number of abnormal white matter voxels detected while the FWER test was not significant. EZ-MAP is demonstrated to be robust to assumptions of Gaussian behavior and may serve as an alternative to methods that require strict Gaussian assumptions.

Conclusion: EZ-MAP provides a robust approach for delineation of regional abnormal anisotropy in individual mTBI patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059382PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608654PMC
September 2013

Unique topology of language processing brain network: a systems-level biomarker of schizophrenia.

Schizophr Res 2012 Nov 21;141(2-3):128-36. Epub 2012 Aug 21.

Gruss Magnetic Resonance Research Center, Albert Einstein College of Medicine, Bronx, NY, USA.

Objective: Schizophrenia is a severe and heritable brain disorder. Language impairment has been hypothesized to spur its onset and underlie the characteristic symptoms. In this study, we investigate whether altered topological pattern of the language processing brain network exists and could be a potential biomarker of schizophrenia. We hypothesized that both patients with schizophrenia and the genetic high risk population would show significantly weakened efficiencies of the network hubs for normal language processing, especially at left inferior frontal and bilateral temporal lobes.

Method: Language task-based fMRI data from 21 patients with schizophrenia, 22 genetic high risk subjects and 36 controls were analyzed. Graph theoretic and post hoc analyses of the fMRI data, and correlations between the functional network features and scores of language tests were carried out.

Results: Compared to controls, patients with schizophrenia and the high risk subjects showed significantly weakened network hubs in left inferior frontal and right fusiform gyri. A unique topology of super active and intercommunicating network hubs at left fusiform gyrus and right inferior/middle frontal gyri, which were associated with the behavioral language impairment was found in the patient group, compared to the high risk and control groups.

Conclusions: Aberrant systems-level topology of language processing network, especially significantly weakened network hubs in left inferior frontal and right fusiform gyri, may serve as a candidate biomarker of schizophrenia. Supported by existing findings, the hyperactive left fusiform gyrus communicating with right frontal lobe might be the key neurophysiological component causing hallucinations in schizophrenia. These findings provided a new systems-level diagnostic target for the disorder.
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http://dx.doi.org/10.1016/j.schres.2012.07.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463735PMC
November 2012

Robust detection of traumatic axonal injury in individual mild traumatic brain injury patients: intersubject variation, change over time and bidirectional changes in anisotropy.

Brain Imaging Behav 2012 Jun;6(2):329-42

The Gruss Magnetic Resonance Research Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, USA.

To identify and characterize otherwise occult inter-individual spatial variation of white matter abnormalities across mild traumatic brain injury (mTBI) patients. After informed consent and in compliance with Health Insurance Portability and Accountability Act (HIPAA), Diffusion tensor imaging (DTI) was performed on a 3.0 T MR scanner in 34 mTBI patients (19 women; 19-64 years old) and 30 healthy control subjects. The patients were imaged within 2 weeks of injury, 3 months after injury, and 6 months after injury. Fractional anisotropy (FA) images were analyzed in each patient. To examine white matter diffusion abnormalities across the entire brain of individual patients, we applied Enhanced Z-score Microstructural Assessment for Pathology (EZ-MAP), a voxelwise analysis optimized for the assessment of individual subjects. Our analysis revealed areas of abnormally low or high FA (voxel-wise P-value < 0.05, cluster-wise P-value < 0.01(corrected for multiple comparisons)). The spatial pattern of white matter FA abnormalities varied among patients. Areas of low FA were consistent with known patterns of traumatic axonal injury. Areas of high FA were most frequently detected in the deep and subcortical white matter of the frontal, parietal, and temporal lobes, and in the anterior portions of the corpus callosum. The number of both abnormally low and high FA voxels changed during follow up. Individual subject assessments reveal unique spatial patterns of white matter abnormalities in each patient, attributable to inter-individual differences in anatomy, vulnerability to injury and mechanism of injury. Implications of high FA remain unclear, but may evidence a compensatory mechanism or plasticity in response to injury, rather than a direct manifestation of brain injury.
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http://dx.doi.org/10.1007/s11682-012-9175-2DOI Listing
June 2012

Structural abnormalities in language circuits in genetic high-risk subjects and schizophrenia patients.

Psychiatry Res 2012 Mar 16;201(3):182-9. Epub 2012 Apr 16.

Department of Radiology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA.

Schizophrenia is a severe psychiatric disorder with a strong genetic predisposition. Structural and functional brain deficits throughout the cerebral cortex, particularly in the language-processing associated brain regions, are consistently reported. Recently, increasing evidence from magnetic resonance imaging (MRI) studies suggests that healthy relatives of schizophrenia patients also show structural brain abnormalities in cortical gray matter (GM) volume and thickness, suggesting that this may be associated with an unexpressed genetic liability for the disorder. Unfortunately, the findings are not consistent, which may be caused by different age ranges of the cohorts studied. In the present study, we examined the voxel-based whole brain cortical thickness, area, GM volume densities, and regional cortical thickness-related laterality indices in 14 bilateral regions of interest (ROIs) from known language-processing circuits in 20 schizophrenia patients, 21 young non-psychotic subjects with heightened genetic risk for schizophrenia at the peak ages for development of the disorder, and 48 matched controls. The results showed widespread significant reductions in cortical thickness, cortical GM volume density, and scattered decreases in cortical surface area in the schizophrenia patients compared with those in the high-risk subjects and normal controls. Moreover, the genetic high-risk subjects showed significantly increased regional cortical thickness in 7 of the 14 ROIs in the language-processing pathway when compared with controls. They also had increased GM volume density in scattered regions associated with language-processing when compared with the normal controls. Laterality analyses showed that the spatial distribution of abnormal cortical thickness in the schizophrenia patients, as well as in the high-risk subjects, contributes to a decrease of the normal left-greater-than-right anatomical asymmetry in the inferior orbital frontal area, and a increased left-greater-than-right pattern in the inferior parietal and occipital regions. Together with the existing findings in the literature, the results of the present study suggest that developmental disruption of the anatomical differentiation of the hemispheres provides a basis for understanding the language impairment and symptoms of psychosis, and that these may arise because of abnormal left-right hemispherical communications that interrupt the normal flow of information processing. The early structural deficits in language-processing circuits may precede the appearance of psychotic symptoms and may be an indicator of an increased risk of developing schizophrenia.
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http://dx.doi.org/10.1016/j.pscychresns.2011.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3361621PMC
March 2012

Interactions within the hand representation in primary somatosensory cortex of primates.

J Neurosci 2010 Nov;30(47):15895-903

The Gruss Magnetic Resonance Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Previous studies indicate that primary somatosensory cortical area 3b in macaques contains a somatotopic map of the hand, encompassing representations of each digit. However, numerous observations including recent findings in anesthetized New World monkeys indicate that that the digit representations within the map are not discrete. We assessed the generality and spatial extent of these effects in awake macaques. We show that, within a given digit representation, (1) there is response to stimulation of all other digits tested, extending across most or all of the digit map, and (2) response to stimulation of the locally preferred digit is modulated by concurrent stimulation of each of the other digits. Control experiments rule out effects of attention and mechanical spread of stimulation. We thus confirm that, even at the first level of somatosensory cortical processing, inputs from potentially all of the digits frame the context within which the input to a single digit is represented.
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http://dx.doi.org/10.1523/JNEUROSCI.4765-09.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073563PMC
November 2010

Disturbed functional connectivity of cortical activation during semantic discrimination in patients with schizophrenia and subjects at genetic high-risk.

Brain Imaging Behav 2010 Mar 17;4(1):109-20. Epub 2010 Feb 17.

Department of Radiology, Albert Einstein College of Medicine, Yeshiva University, 1300 Morris Park Avenue, Gruss 204, Bronx, NY 10461, USA.

Schizophrenia has a strong genetic component that is relevant to the understanding of the pathophysiology of the syndrome. Thus, recent investigations have shifted from studies of diagnosed patients with schizophrenia to examining their unaffected relatives. Previous studies found that during language processing, relatives thought to be at genetic high-risk for the disorder exhibit aberrant functional activation in regions of language processing, specifically in the left inferior frontal gyrus (Broca's area). However, functional connectivity among the regions involved in language pathways is not well understood. In this study, we examined the functional connectivity between a seed located in Broca's area and the remainder of the brain during a visual lexical decision task, in 20 schizophrenia patients, 21 subjects at genetic high risk for the disorder and 21 healthy controls. Both the high-risk subjects and patients showed significantly reduced activation correlations between seed and regions related to visual language processing. Compared to the high-risk subjects, the schizophrenia patients showed even fewer regions that were correlated with the seed regions. These results suggest that there is aberrant functional connectivity within cortical language circuitry in high-risk subjects and patients with schizophrenia. Broca's area, which is one of the important regions for language processing in healthy controls, had a significantly reduced role in the high-risk subjects and patients with schizophrenia. Our findings are consistent with the existence of an underlying biological disturbance that begins in genetically at risk individuals and progresses to a greater extent in those who eventually develop schizophrenia.
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http://dx.doi.org/10.1007/s11682-010-9090-3DOI Listing
March 2010

The contributions of myelin and axonal caliber to transverse relaxation time in shiverer and neurofilament-deficient mouse models.

Neuroimage 2010 Jul 11;51(3):1098-105. Epub 2010 Mar 11.

Center for Dementia Research, Nathan Kline Institute Orangeburg, New York 10962, USA.

White matter disorders can involve injury to myelin or axons but the respective contribution of each to clinical course is difficult to evaluate non-invasively. Here, to develop a paradigm for further investigations of axonal pathology by MRI, we compared two genetic mouse models exhibiting relatively selective axonal or myelin deficits using quantitative MRI relaxography of the transverse relaxation times (T2) in vivo and ultrastructural morphometry. In HM-DKO mice, which lack genes encoding the heavy (NF-H) and medium (NF-M) subunits of neurofilaments, neurofilament content of large myelinated axons of the central nervous system (CNS) is markedly reduced in the absence of changes in myelin thickness and volume. In shiverer mutant mice, which lack functional myelin basic protein, CNS myelin sheath formation is markedly reduced but neurofilament content is normal. We observed increases in T2 in nearly all white matter in shiverer mice compared to their wild type, while more subtle increases in T2 were observed in HM-DKO in the corpus callosum. White matter T2 was generally greater in shiverer mice than HM-DKO mice. Ultrastructural morphometry of the corpus callosum, which exhibited the greatest T2 differences, confirmed that total cross-sectional area occupied by axons was similar in the two mouse models and that the major ultrastructural differences, determined by morphometry, were an absence of myelin and larger unmyelinated axons in shiverer mice and absence of neurofilaments in HM-DKO mice. Our findings indicate that T2 is strongly influenced by myelination state and axonal volume, while neurofilament structure within the intra-axonal compartment has a lesser effect upon single compartment T2 estimates.
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http://dx.doi.org/10.1016/j.neuroimage.2010.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862816PMC
July 2010

Diffusion-tensor imaging implicates prefrontal axonal injury in executive function impairment following very mild traumatic brain injury.

Radiology 2009 Sep 30;252(3):816-24. Epub 2009 Jun 30.

Gruss Magnetic Resonance Research Center, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA.

Purpose: To determine whether frontal white matter diffusion abnormalities can help predict acute executive function impairment after mild traumatic brain injury (mTBI).

Materials And Methods: This study had institutional review board approval, included written informed consent, and complied with HIPAA. Diffusion-tensor imaging and standardized neuropsychologic assessments were performed in 20 patients with mTBI within 2 weeks of injury and 20 matched control subjects. Fractional anisotropy (FA) and mean diffusivity (MD) images (imaging parameters: 3.0 T, 25 directions, b = 1000 sec/mm(2)) were compared by using whole-brain voxelwise analysis. Spearman correlation analyses were performed to evaluate associations between diffusion measures and executive function.

Results: Multiple clusters of lower frontal white matter FA, including the dorsolateral prefrontal cortex (DLPFC), were present in patients (P < .005), with several clusters also demonstrating higher MD (P < .005). Patients performed worse on tests of executive function. Lower DLPFC FA was significantly correlated with worse executive function performance in patients (P < .05).

Conclusion: Impaired executive function following mTBI is associated with axonal injury involving the DLPFC.
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http://dx.doi.org/10.1148/radiol.2523081584DOI Listing
September 2009

Language pathway abnormalities in schizophrenia: a review of fMRI and other imaging studies.

Curr Opin Psychiatry 2009 Mar;22(2):131-9

Center for Advanced Brain Imaging, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York 10962, USA.

Purpose Of Review: Schizophrenia is a severe mental disorder with substantial genetic vulnerability. This review discusses recent neuroimaging studies reporting on impairment in brain functioning relevant to language processing in individuals with schizophrenia and those who are at a genetic risk for its development.

Recent Findings: Studies have shown that schizophrenia is associated with deficits in language function, as well as structural and functional abnormalities in brain regions that are involved with language perception and processing. Individuals who are at genetic high risk for schizophrenia also have structural and functional deficits in brain pathways for language processing. These studies consistently suggest that the normal pattern of left hemisphere dominance of language processing is significantly disturbed.

Summary: This review suggests that future studies should examine the underlying mechanism for producing this disturbance in language processing and that prospective studies should be carried out that aim to follow individuals over time to determine whether these anomalies eventually lead to clinical symptoms of schizophrenia.
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http://dx.doi.org/10.1097/YCO.0b013e328324bc43DOI Listing
March 2009

Multifocal white matter ultrastructural abnormalities in mild traumatic brain injury with cognitive disability: a voxel-wise analysis of diffusion tensor imaging.

J Neurotrauma 2008 Nov;25(11):1335-42

Department of Radiology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York 10467, USA.

The purpose of the present study is to identify otherwise occult white matter abnormalities in patients suffering persistent cognitive impairment due to mild traumatic brain injury (TBI). The study had Institutional Review Board (IRB) approval, included informed consent and complied with the U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996. We retrospectively analyzed diffusion tensor MRI (DTI) of 17 patients (nine women, eight men; age range 26-70 years) who had cognitive impairment due to mild TBI that occurred 8 months to 3 years prior to imaging. Comparison was made to 10 healthy controls. Fractional anisotropy (FA) and mean diffusivity (MD) images derived from DTI (1.5 T; 25 directions; b = 1000) were compared using whole brain histogram and voxel-wise analyses. Histograms of white matter FA show an overall shift toward lower FA in patients. Areas of significantly decreased FA (p < 0.005) were found in the subject group in corpus callosum, subcortical white matter, and internal capsules bilaterally. Co-located elevation of mean diffusivity (MD) was found in the patients within each region. Similar, though less extensive, findings were demonstrated in each individual patient. Multiple foci of low white matter FA and high MD are present in cognitively impaired mild TBI patients, with a distribution that conforms to that of diffuse axonal injury. Evaluation of single subjects also reveals foci of low FA, suggesting that DTI may ultimately be useful for clinical evaluation of individual patients.
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http://dx.doi.org/10.1089/neu.2008.0547DOI Listing
November 2008

A DTI study of white matter microstructure in individuals at high genetic risk for schizophrenia.

Schizophr Res 2008 Dec 20;106(2-3):115-24. Epub 2008 Sep 20.

Division of Clinical Research, The Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Bldg. 35, Orangeburg, NY 10962, United States.

Structural brain developmental anomalies, particularly those in frontotemporal white matter pathways, may have a genetic component and place people at increased risk for schizophrenia. The current study employed Diffusion Tensor Imaging (DTI) to measure fractional anisotropy (FA) as a quantitative indicator of white matter integrity. We examined twenty-two participants at high genetic risk for schizophrenia (HR), 23 people with schizophrenia (most of whom were family members of those at HR) and 37 non-psychiatric controls for comparison. In those at HR, reduced FA was observed in the cingulate and angular gyri bilaterally. In a few regions, FA was higher in HR participants than in comparison participants. These regional variations in FA might reflect differences in white matter development from comparison participants. Our data provide some evidence that abnormal white matter integrity may be detectable before the onset of a psychotic illness, although longitudinal studies are necessary to determine whether these individuals at genetic risk with abnormal FA will develop illness and whether these changes are associated with the genetic risk for the disorder.
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http://dx.doi.org/10.1016/j.schres.2008.07.023DOI Listing
December 2008

In vivo MRI identifies cholinergic circuitry deficits in a Down syndrome model.

Neurobiol Aging 2009 Sep 3;30(9):1453-65. Epub 2008 Jan 3.

Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, United States.

In vivo quantitative magnetic resonance imaging (MRI) was employed to detect brain pathology and map its distribution within control, disomic mice (2N) and in Ts65Dn and Ts1Cje trisomy mice with features of human Down syndrome (DS). In Ts65Dn, but not Ts1Cje mice, transverse proton spin-spin (T(2)) relaxation time was selectively reduced in the medial septal nucleus (MSN) and in brain regions that receive cholinergic innervation from the MSN, including the hippocampus, cingulate cortex, and retrosplenial cortex. Basal forebrain cholinergic neurons (BFCNs) in the MSN, identified by choline acetyltransferase (ChAT) and nerve growth factor receptors p75(NTR) and TrkA immunolabeling were reduced in Ts65Dn brains and in situ acetylcholinesterase (AChE) activity was depleted distally along projecting cholinergic fibers, and selectively on pre- and postsynaptic profiles in these target areas. T(2) effects were negligible in Ts1Cje mice that are diploid for App and lack BFCN neuropathology, consistent with the suspected relationship of this pathology to increased App dosage. These results establish the utility of quantitative MRI in vivo for identifying Alzheimer's disease-relevant cholinergic changes in animal models of DS and characterizing the selective vulnerability of cholinergic neuron subpopulations.
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http://dx.doi.org/10.1016/j.neurobiolaging.2007.11.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771203PMC
September 2009

fMRI study of language activation in schizophrenia, schizoaffective disorder and in individuals genetically at high risk.

Schizophr Res 2007 Nov 24;96(1-3):14-24. Epub 2007 Aug 24.

Center for Advanced Brain Imaging, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.

Background: Structural and functional abnormalities have been found in language-related brain regions in patients with schizophrenia. We previously reported findings pointing to differences in word processing between people with schizophrenia and individuals who are at high-risk for schizophrenia using a voxel-based (whole brain) fMRI approach. We now extend this finding to specifically examine functional activity in three language related cortical regions using a larger cohort of individuals.

Method: A visual lexical discrimination task was performed by 36 controls, 21 subjects at high genetic-risk for schizophrenia, and 20 patients with schizophrenia during blood oxygenation level dependent (BOLD) fMRI scanning. Activation in bilateral inferior frontal gyri (Brodmann's area 44-45), bilateral inferior parietal lobe (Brodmann's area 39-40), and bilateral superior temporal gyri (Brodmann's area 22) was investigated. For all subjects, two-tailed Pearson correlations were calculated between the computed laterality index and a series of cognitive test scores determining language functioning.

Results: Regional activation in Brodmann's area 44-45 was left lateralized in normal controls, while high-risk subjects and patients with schizophrenia or schizoaffective disorder showed more bilateral activation. No significant differences among the three diagnostic groups in the other two regions of interest (Brodmann's area 22 or areas 39-40) were found. Furthermore, the apparent reasons for loss of leftward language lateralization differed between groups. In high-risk subjects, the loss of lateralization was based on reduced left hemisphere activation, while in the patient group, it was due to increased right side activation. Language ability related cognitive scores were positively correlations with the laterality indices obtained from Brodmann's areas 44-45 in the high-risk group, and with the laterality indices from Brodmann's areas 22 and 44-45 in the patient group.

Conclusions: This study reinforces previous language related imaging studies in high-risk subjects and patients with schizophrenia suggesting that reduced functional lateralization in language related frontal cortex may be a vulnerability marker for schizophrenia. Future studies will determine whether it is predictive of who develops illness.
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http://dx.doi.org/10.1016/j.schres.2007.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2212592PMC
November 2007

An fMRI study of language processing in people at high genetic risk for schizophrenia.

Schizophr Res 2007 Mar 16;91(1-3):62-72. Epub 2007 Feb 16.

The Center for Advanced Brain Imaging at The Nathan S Kline Institute for Psychiatric Research, Orangeburg, New York 10962, United States.

Background: Abnormalities in language processing and the related brain structures have been reported in people with schizophrenia. It has been proposed that the brain pathways for language processing are anomalous in these individuals and form the underlying basis for the positive symptoms of the illness. If language pathway abnormalities can be detected early in people at high-risk for schizophrenia prior to the onset of symptoms, early treatment can ensue.

Methods: Fifteen young adults at high genetic risk for developing schizophrenia were compared with 15 of their siblings with schizophrenia or schizoaffective disorder and 15 age and sex matched individuals at low risk for schizophrenia using a visual lexical decision task during fMRI. The data were analyzed by contrasting activation obtained during a real word-pseudoword discrimination task to activation obtained during a nonlinguistic discrimination task, and the differential activations were examined.

Results: Patterns of brain activation while reading and discriminating between real and pseudowords differed across groups, with more bilateral activation in schizophrenia patients and their high-risk siblings than controls. In control subjects discrimination of words from psuedowords significantly activated Brodmann's area 44 more strongly than when non-linguistic symbols were discriminated. However, high-risk subjects and their siblings with schizophrenia activated this region similarly for both language and non-language tasks.

Conclusions: Normal individuals can be distinguished from subjects at high genetic risk for schizophrenia and patients with schizophrenia by their more lateralized and stronger activation of Brodmann's area 44 to word compared with symbol discrimination tasks. Thus, evaluation of language processing by fMRI may be a valuable tool for use in the prediction of individual risk for developing schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2006.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1978181PMC
March 2007

Magnetization transfer effects on the efficiency of flow-driven adiabatic fast passage inversion of arterial blood.

NMR Biomed 2007 Dec;20(8):733-42

FMRI Laboratory, University of Michigan, Ann Arbor, MI 28109-2108, USA.

Continuous arterial spin labeling experiments typically use flow-driven adiabatic fast passage inversion of the arterial blood water protons. In this article, we measure the effect of magnetization transfer in blood and how it affects the inversion label. We use modified Bloch equations to model flow-driven adiabatic inversion in the presence of magnetization transfer in blood flowing at velocities from 1 to 30 cm/s in order to explain our findings. Magnetization transfer results in a reduction of the inversion efficiency at the inversion plane of up to 3.65% in the range of velocities examined, as well as faster relaxation of the arterial label in continuous labeling experiments. The two effects combined can result in inversion efficiency reduction of up to 8.91% in the simulated range of velocities. These effects are strongly dependent on the velocity of the flowing blood, with 10 cm/s yielding the largest loss in efficiency due to magnetization transfer effects. Flowing blood phantom experiments confirmed faster relaxation of the inversion label than that predicted by T(1) decay alone.
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http://dx.doi.org/10.1002/nbm.1137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867234PMC
December 2007