David N. Guilfoyle

Magnocellular pathway impairment in schizophrenia: evidence from functional magnetic resonance imaging.

Sensory processing deficits in schizophrenia have been documented for several decades, but their underlying neurophysiological substrates are still poorly understood. In the visual system, the pattern of pathophysiology reported in several studies is suggestive of dysfunction within the magnocellular visual pathway beginning in early sensory cortex or even subcortically. The present study used functional magnetic resonance imaging to investigate further the neurophysiological bases of visual processing deficits in schizophrenia and in particular the potential role of magnocellular stream dysfunction. Sinusoidal gratings systematically varying in spatial frequency content were presented to subjects at low and high levels of contrast to differentially bias activity in magnocellular and parvocellular pathways based on well established differences in neuronal response profiles. Hemodynamic responses elicited by different spatial frequencies were mapped over the occipital lobe and then over the entire brain. Retinotopic mapping was used to localize the occipital activations with respect to the boundaries of visual areas V1 and V2, which were demarcated in each subject. Relative to control subjects, schizophrenia patients showed markedly reduced activations to low, but not high, spatial frequencies in multiple regions of the occipital, parietal, and temporal lobes. These findings support the hypothesis that schizophrenia is associated with impaired functioning of the magnocellular visual pathway and further suggest that these sensory processing deficits may contribute to higher-order cognitive deficits in working memory, executive functioning, and attention.

Impaired visual object processing across an occipital-frontal-hippocampal brain network in schizophrenia: an integrated neuroimaging study.

CONTEXT Perceptual closure is the ability to identify objects based on partial information and depends on the function of a distributed network of brain regions that include the dorsal and the ventral visual streams, prefrontal cortex (PFC), and hippocampus. OBJECTIVE To evaluate network-level interactions during perceptual closure in schizophrenia using parallel event-related potential (ERP), functional magnetic resonance imaging (fMRI), and neuropsychological assessment. DESIGN Case-control study. SETTING Inpatient and outpatient facilities associated with the Nathan Kline Institute for Psychiatric Research. Patients Twenty-seven patients with schizophrenia or schizoaffective disorder and 23 healthy controls. Intervention Event-related potentials were obtained from 24 patients and 20 healthy volunteers in response to fragmented (closeable) and control-scrambled (noncloseable) line drawings. Functional MRI was performed in 11 patients and 12 controls. Main Outcome Measure Patterns of between-group differences for predefined ERP components and fMRI regions of interest were determined using both analysis of variance and structural equation modeling. Global neuropsychological performance was assessed using standard neuropsychological batteries. RESULTS Patients showed impaired generation of event-related components reflecting early sensory and later closure-related activity. In fMRI, patients showed impaired activation of the dorsal and ventral visual regions, PFC, and hippocampus. Impaired activation of dorsal stream visual regions contributed significantly to impaired PFC activation, which contributed significantly to impaired activation of the hippocampus and ventral visual stream. Impaired ventral stream and hippocampal activation contributed significantly to deficits on neuropsychological measures of perceptual organization. CONCLUSIONS Schizophrenia is associated with severe activation deficits across a distributed network of sensory and higher order cognitive regions. Deficit in early visual processing within the dorsal visual stream contributes significantly to impaired frontal activation, which, in turn, leads to dysregulation of the hippocampus and ventral visual stream. Dysfunction within this network underlies deficits in more traditional neurocognitive measures, supporting distributed models of brain dysfunction in schizophrenia.

Limbic dysregulation is associated with lowered heart rate variability and increased trait anxiety in healthy adults

We tested whether dynamic interaction between limbic regions supports a control systems model of excitatory and inhibitory components of a negative feedback loop, and whether dysregulation of those dynamics might correlate with trait differences in anxiety and their cardiac characteristics among healthy adults.

Quantitative measurements of proton spin-lattice (T1) and spin-spin (T2) relaxation times in the mouse brain at 7.0 T.

The goal of this work is to provide regional T1 and T2 values at a field strength of 7 T for the normal mouse brain at 6 weeks and 1 year old. A novel segmented snapshot FLASH sequence was used to measure T1 in the hippocampus, corpus callosum, and the retrosplenial granular (RSG) cortex; T2 measurements were made in the same regions using a single spin echo sequence repeated at six separate echo times. Both T1 and T2 measurements were validated with phantom measurements. Magn Reson Med 49:576–580, 2003.

Histological correlation of diffusional kurtosis and white matter modeling metrics in cuprizone-induced corpus callosum demyelination.

The cuprizone mouse model is well established for studying the processes of both demyelination and remyelination in the corpus callosum, and it has been utilized together with diffusion tensor imaging (DTI) to investigate myelin and axonal pathology. Although some underlying morphological mechanisms contributing to the changes in diffusion tensor (DT) metrics have been identified, the understanding of specific associations between histology and diffusion measures remains limited. Diffusional kurtosis imaging (DKI) is an extension of DTI that provides metrics of diffusional non‐Gaussianity, for which an associated white matter modeling (WMM) method has been developed. The main goal of the present study was to quantitatively assess the relationships between diffusion measures and histological measures in the mouse model of cuprizone‐induced corpus callosum demyelination. The diffusional kurtosis (DK) and WMM metrics were found to provide additional information that enhances the sensitivity to detect the morphological heterogeneity in the chronic phase of the disease process in the rostral segment of the corpus callosum. Specifically, in the rostral segment, axonal water fraction (d = 2.6; p < 0.0001), radial kurtosis (d = 2.0; p = 0.001) and mean kurtosis (d = 1.5; p = 0.005) showed the most sensitivity between groups with respect to yielding statistically significant p values and high Cohens d values. These results demonstrate the ability of DK and WMM metrics to detect white mater changes and inflammatory processes associated with cuprizone‐induced demyelination. They also validate, in part, the application of these new WMM metrics for studying neurological diseases, as well as helping to elucidate their biophysical meaning. Copyright

In Vivo MRI identifies cholinergic circuitry deficits in a Down syndrome model

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 Alzheimers disease-relevant cholinergic changes in animal models of DS and characterizing the selective vulnerability of cholinergic neuron subpopulations.

In Vivo NMR Studies of Neurodegenerative Diseases in Transgenic and Rodent Models

In vivo magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) provide unique quality to attain neurochemical, physiological, anatomical, and functional information noninvasively. These techniques have been increasingly applied to biomedical research and clinical usage in diagnosis and prognosis of diseases. The ability of MRS to detect early yet subtle changes of neurochemicals in vivo permits the use of this technology for the study of cerebral metabolism in physiological and pathological conditions. Recent advances in MR technology have further extended its use to assess the etiology and progression of neurodegeneration. This review focuses on the current technical advances and the applications of MRS and MRI in the study of neurodegenerative disease animal models including amyotrophic lateral sclerosis, Alzheimers, Huntingtons, and Parkinsons diseases. Enhanced MR measurable neurochemical parameters in vivo are described in regard to their importance in neurodegenerative disorders and their investigation into the metabolic alterations accompanying the pathogenesis of neurodegeneration.

Functional connectivity fMRI in mouse brain at 7T using isoflurane.

Although many resting state fMRI human studies have been published, the number of such rodent studies is considerably less. The reason for this is the severe technical challenge of high magnetic field small rodent imaging. Local magnetic field susceptibility changes at air tissue boundaries cause image distortion and signal losses. The current study reports measures of functional connectivity in mice using only isoflurane for the anesthetic. Because all anesthetic agents will alter cerebral blood flow and cerebral metabolism, the impact these changes have on neuronal connectivity has yet to be fully understood, however this work reports for the first time that reliable functional connectivity measures in mouse brain can be obtained with isoflurane.

Selective reduction of cerebral cortex GABA neurons in a late gestation model of fetal alcohol spectrum disorder.

Fetal alcohol spectrum disorders (FASD) are associated with cognitive and behavioral deficits, and decreased volume of the whole brain and cerebral cortex. Rodent models have shown that early postnatal treatments, which mimic ethanol toxicity in the third trimester of human pregnancy, acutely induce widespread apoptotic neuronal degeneration and permanent behavioral deficits. However, the lasting cellular and anatomical effects of early ethanol treatments are still incompletely understood. This study examined changes in neocortex volume, thickness, and cellular organization that persist in adult mice after postnatal day 7 (P7) ethanol treatment. Post mortem brain volumes, measured by both MRI within the skull and by fluid displacement of isolated brains, were reduced 10-13% by ethanol treatment. The cerebral cortex showed a similar reduction (12%) caused mainly by lower surface area (9%). In spite of these large changes, several features of cortical organization showed little evidence of change, including cortical thickness, overall neuron size, and laminar organization. Estimates of total neuron number showed a trend level reduction of about 8%, due mainly to reduced cortical volume but unchanged neuron density. However, counts of calretinin (CR) and parvalbumin (PV) subtypes of GABAergic neurons showed a striking >30% reduction of neuron number. Similar ethanol effects were found in male and female mice, and in C57BL/6By and BALB/cJ mouse strains. Our findings indicate that the cortex has substantial capacity to develop normal cytoarchitectonic organization after early postnatal ethanol toxicity, but there is a selective and persistent reduction of GABA cells that may contribute to the lasting cognitive and behavioral deficits in FASD.

Glutamatergic Transmission Aberration: A Major Cause of Behavioral Deficits in a Murine Model of Down's Syndrome

Trisomy 21, or Downs syndrome (DS), is the most common genetic cause of intellectual disability. Altered neurotransmission in the brains of DS patients leads to hippocampus-dependent learning and memory deficiency. Although genetic mouse models have provided important insights into the genes and mechanisms responsible for DS-specific changes, the molecular mechanisms leading to memory deficits are not clear. We investigated whether the segmental trisomy model of DS, Ts[Rb(12.1716)]2Cje (Ts2), exhibits hippocampal glutamatergic transmission abnormalities and whether these alterations cause behavioral deficits. Behavioral assays demonstrated that Ts2 mice display a deficit in nest building behavior, a measure of hippocampus-dependent nonlearned behavior, as well as dysfunctional hippocampus-dependent spatial memory tested in the object-placement and the Y-maze spontaneous alternation tasks. Magnetic resonance spectra measured in the hippocampi revealed a significantly lower glutamate concentration in Ts2 as compared with normal disomic (2N) littermates. The glutamate deficit accompanied hippocampal NMDA receptor1 (NMDA-R1) mRNA and protein expression level downregulation in Ts2 compared with 2N mice. In concert with these alterations, paired-pulse analyses suggested enhanced synaptic inhibition and/or lack of facilitation in the dentate gyrus of Ts2 compared with 2N mice. Ts2 mice also exhibited disrupted synaptic plasticity in slice recordings of the hippocampal CA1 region. Collectively, these findings imply that deficits in glutamate and NMDA-R1 may be responsible for impairments in synaptic plasticity in the hippocampus associated with behavioral dysfunctions in Ts2 mice. Thus, these findings suggest that glutamatergic deficits have a significant role in causing intellectual disabilities in DS.