Resting-state thalamic dysconnectivity in schizophrenia and relationships with symptoms.

BACKGROUND: Schizophrenia (SZ) is a severe neuropsychiatric disorder associated with disrupted connectivity within the thalamic-cortico-cerebellar network. Resting-state functional connectivity studies have reported thalamic hypoconnectivity with the cerebellum and prefrontal cortex as well as thalamic hyperconnectivity with sensory cortical regions in SZ patients compared with healthy comparison participants (HCs). However, fundamental questions remain regarding the clinical significance of these connectivity abnormalities. METHOD: Resting state seed-based functional connectivity was used to investigate thalamus to whole brain connectivity using multi-site data including 183 SZ patients and 178 matched HCs. Statistical significance was based on a voxel-level FWE-corrected height threshold of p < 0.001. The relationships between positive and negative symptoms of SZ and regions of the brain demonstrating group differences in thalamic connectivity were examined. RESULTS: HC and SZ participants both demonstrated widespread positive connectivity between the thalamus and cortical regions. Compared with HCs, SZ patients had reduced thalamic connectivity with bilateral cerebellum and anterior cingulate cortex. In contrast, SZ patients had greater thalamic connectivity with multiple sensory-motor regions, including bilateral pre- and post-central gyrus, middle/inferior occipital gyrus, and middle/superior temporal gyrus. Thalamus to middle temporal gyrus connectivity was positively correlated with hallucinations and delusions, while thalamus to cerebellar connectivity was negatively correlated with delusions and bizarre behavior. CONCLUSIONS: Thalamic hyperconnectivity with sensory regions and hypoconnectivity with cerebellar regions in combination with their relationship to clinical features of SZ suggest that thalamic dysconnectivity may be a core neurobiological feature of SZ that underpins positive symptoms.

Effects of alfaxalone, propofol and isoflurane on cerebral blood flow and cerebrovascular reactivity to carbon dioxide in dogs: A pilot study.

Propofol total intravenous anesthesia is a common choice to anesthetize patients with increased intracranial pressure, reducing cerebral blood flow while maintaining cerebrovascular reactivity to CO2. Propofol and alfaxalone are commonly used for total intravenous anesthesia in dogs, but the effects of alfaxalone on cerebral blood flow and cerebrovascular reactivity to CO2 are unknown. Our hypothesis was that alfaxalone would not be significantly different to propofol, while isoflurane would increase cerebral blood flow and decrease cerebrovascular reactivity to CO2. Six healthy hound dogs were evaluated in this randomized crossover trial. Dogs were anesthetized with 7.5 mg/kg propofol, 3 mg/kg alfaxalone or 8 % sevoflurane, mechanically ventilated and maintained with propofol (400 µg/kg/min), alfaxalone (150 µg/kg/min) or 1.7 % end-tidal isoflurane, respectively, with one week washout between treatments. Cerebral blood flow and cerebrovascular reactivity to CO2 during hypercapnic and hypocapnic challenges were measured using arterial spin labelling and blood oxygen level-dependent magnetic resonance imaging sequences, respectively. Median (interquartile range, IQR) normocapnic cerebral blood flow was significantly lower (P = 0.016) with alfaxalone compared to isoflurane, in the whole brain 15.39 mL/min/100 g (14.90-19.90 mL/min/100 g) vs. 34.10 mL/min/100 g (33.35-43.17 mL/min/100 g), the grey matter 14.57 mL/min/100 g (13.66-18.72 mL/min/100 g) vs. 32.37 mL/min/100 g (31.03-42.99 mL/min/100 g), the caudal brain 15.47 mL/min/100 g (13.37-21.45 mL/min/100 g) vs. 36.85 mL/min/100 g (32.50-47.18 mL/min/100 g) and the temporal lobe grey matter 18.80 mL/min/100 g (15.89-20.84 mL/min/100 g) vs. 43.32 (36.07-43.58 mL/min/100 g). Median (IQR) hypocapnic cerebrovascular reactivity to CO2 was significantly higher (P = 0.016) for alfaxalone compared to isoflurane 8.85 %S/mm Hg (6.92-10.44 %S/mm Hg) vs. 3.90 %S/mm Hg (3.80-4.33 %S/mm Hg). Alfaxalone maintained lower cerebral blood flow and higher hypocapnic cerebrovascular reactivity to CO2 than isoflurane.

Control of lens epithelial cell survival.

We have studied the survival requirements of developing lens epithelial cells to test the hypothesis that most cells are programmed to kill themselves unless they are continuously signaled by other cells not to do so. The lens cells survived for weeks in both explant cultures and high-density dissociated cell cultures in the absence of other cells or added serum or protein, suggesting that they do not require signals from other cell types to survive. When cultured at low density, however, they died by apoptosis, suggesting that they depend on other lens epithelial cells for their survival. Lens epithelial cells cultured at high density in agarose gels also survived for weeks, even though they were not in direct contact with one another, suggesting that they can promote one another's survival in the absence of cell-cell contact. Conditioned medium from high density cultures promoted the survival of cells cultured at low density, suggesting that lens epithelial cells support one another's survival by secreting survival factors. We show for the first time that normal cell death occurs within the anterior epithelium in the mature lens, but this death is strictly confined to the region of the anterior suture.

Nerve terminal remodeling visualized in living mice by repeated examination of the same neuron.

The distribution of presynaptic endings on the surfaces of autonomic ganglion cells was mapped in living mice after intravenous administration of a styryl pyridinium dye. The staining and imaging techniques did not appear to damage the ganglion cells, or the synapses on them; these procedures could therefore be repeated after an arbitrary period. Observations of the same neurons at intervals of up to 3 weeks indicate that the pattern of preganglionic terminals on many of these nerve cells gradually changes.

fMRI activity correlated with auditory hallucinations during performance of a working memory task: data from the FBIRN consortium study.

INTRODUCTION: Auditory hallucinations are a hallmark symptom of schizophrenia. The neural basis of auditory hallucinations was examined using data from a working memory task. Data were acquired within a multisite consortium and this unique dataset provided the opportunity to analyze data from a large number of subjects who had been tested on the same procedures across sites. We hypothesized that regions involved in verbal working memory and language processing would show activity that was associated with levels of hallucinations during a condition where subjects were rehearsing the stimuli. METHODS: Data from the Sternberg Item Recognition Paradigm, a working memory task, were acquired during functional magnetic resonance imaging procedures. The data were collected and preprocessed by the functional imaging biomedical informatics research network consortium. Schizophrenic subjects were split into nonhallucinating and hallucinating subgroups and activity during the probe condition (in which subjects rehearsed stimuli) was examined. Levels of activation from contrast images for the probe phase (collapsed over levels of memory load) of the working memory task were also correlated with levels of auditory hallucinations from the Scale for the Assessment of Positive Symptoms scores. RESULTS: Patients with auditory hallucinations (relative to nonhallucinating subjects) showed decreased activity during the probe condition in verbal working memory/language processing regions, including the superior temporal and inferior parietal regions. These regions also showed associations between activity and levels of hallucinations in a correlation analysis. DISCUSSION: The association between activation and hallucinations scores in the left hemisphere language/working memory regions replicates the findings of previous studies and provides converging evidence for the association between superior temporal abnormalities and auditory hallucinations.

Differentiation and morphogenesis in pellet cultures of developing rat retinal cells.

We previously developed a reaggregate cell culture system (pellet cultures) in which retinal neuroepithelial cells proliferate and give rise to rod photoreceptor cells (rods) in vitro (Watanabe and Raff, 1990, Neuron 4:461-467). In the present study, we analyzed cell differentiation and morphogenesis in pellet cultures by using both cell-type-specific markers with immunofluorescence and electron microscopy. We demonstrated that, in addition to rods, the other major retinal cell types, including amacrine cells, bipolar cells, Müller cells, and ganglion cells were all present in the pellets, where most were able to develop from dividing precursor cells in vitro. The different cell types in the pellets became organized into two distinct structures: dark rosettes and pale rosettes. The cellular composition of these structures indicated that the dark rosettes correspond to the outer nuclear layer and the pale rosettes to the inner nuclear layer of the normal retina. Ultrastructural studies have indicated that the thin layer of neuronal processes surrounding the dark rosettes correspond to the outer plexiform layer, and the central region of the pale rosettes correspond to the inner plexiform layer of the normal retina. Other features of normal retinal development also occurred in the pellets, including programmed cell death and the formation of inner and outer rod cell segments and synapses. Thus, pellet cultures provide a convenient way to study different aspects of retinal development where one can control the size and the cellular composition of the initial reaggregate.

Functional organization of activation patterns in children: whole brain fMRI imaging during three different cognitive tasks.

1. Patterns of brain activation were measured with whole brain echo-planar functional magnetic resonance imaging (fMRI) at 3.0 Tesla in healthy children (N = 6) and in one child with a left-hemisphere encephalomalacic lesion as sequellae from early stroke. 2. Three cognitive tasks were used: auditory sentence comprehension, verb generation to line drawings, and mental rotation of alphanumeric stimuli. 3. There was evidence for significant bilateral activation in all three cognitive tasks for the healthy children. Their patterns of activation were consistent with previous functional imaging studies with adults. 4. The child with a left-hemisphere stroke showed evidence of homologous organization in the non-damaged hemisphere.

Functional MR imaging using a visually guided saccade paradigm for comparing activation patterns in patients with probable Alzheimer's disease and in cognitively able elderly volunteers.

BACKGROUND AND PURPOSE: Alzheimer's disease is associated with progressive visuospatial dysfunction. This study used functional MR (fMR) imaging with an eye movement paradigm to investigate differences in visuospatial cognition between patients with probable Alzheimer's disease (pAD) and cognitively able elderly volunteers. METHODS: Using established, although imperfect, clinical criteria, patients with pAD (n = 18) and cognitively able elderly volunteers (n = 10) were selected for study. All patients underwent echo-planar fMR imaging at 1.5 T. The visually guided saccade paradigm consisted of alternating periods (30 s) of central fixation and visually guided saccades to a target appearing randomly along the horizontal meridian. Activation maps were derived using a voxelwise t test, comparing the signal intensities between the two steady-state conditions. The activation patterns were characterized by Talairach coordinates, activation volumes, and laterality ratios (LRs). RESULTS: Statistically significant differences existed between the activation patterns of the patients with pAD and those of the volunteers. In contrast to the control group, a left-dominant parietal activation pattern and enhanced prefrontal cortical activation were observed in most patients with pAD. CONCLUSION: Within the limitations of the imperfect clinical standard of reference, the reduction in right parietal activation producing the left-dominant LR for the intraparietal sulcus may reflect the progressive dysfunction in spatial attention associated with Alzheimer's disease, considering the known parietal lobe involvement in this function and the disease. The high specificity of a positive intraparietal sulcal LR measured by fMR imaging may have a role in detecting and monitoring Alzheimer's disease.

Developmental and lesion effects in brain activation during sentence comprehension and mental rotation.

The development of neurocognitive networks was examined in 2 cognitive paradigms: auditory sentence comprehension and mental rotation of alphanumeric stimuli. Patterns of brain activation were measured with whole brain echoplanar functional magnetic resonance imaging at 3 Tesla in 5 adults (20-28 years old), 7 children (9-12 years old), and 6 pediatric patients (9-12 years old) with perinatal strokes or periventricular hemorrhages. Healthy children and adults activated similar neurocognitive networks, but there were developmental differences in the distribution of activity across these networks. In the sentence task, children showed more activation in the inferior visual area suggesting an imagery strategy rather than a linguistic strategy for sentence processing. Furthermore, consistent use of a sentence comprehension strategy, whether correct or incorrect as compared to chance performance, was associated with greater activation in the inferior frontal area (Broca's) in both children and pediatric patients. In the mental rotation task, healthy adults showed more activation in the superior parietal and middle frontal areas and less activation in the supramarginal gyrus, suggesting adults were primarily engaged in visual-spatial manipulation and less engaged in the recognition of noncanonical views of stimuli. The pediatric patients showed patterns of activation consistent with organization of cognitive processing into homologous areas of the contralateral hemisphere.

Development and regulation of dendrites in the rat superior cervical ganglion.

Intracellular injection of HRP was used to study the postnatal development of dendrites in the rat superior cervical ganglion (SCG). This study had 2 goals: to describe the growth of dendrites during normal development and to determine the influence of preganglionic innervation on dendritic growth. At birth, ganglion cell morphology is relatively simple; cells have few dendritic branches and an average total dendritic length under 300 micron. In the first postnatal month there is a 4-fold increase in dendritic length and a marked increase in the complexity of branching. Dendrites continue to grow into adulthood; at each age studied (up to 16 months old), the dendritic geometries of SCG cells became progressively more extensive and complex. The influence of innervation on the development of dendrites was assessed by cutting the cervical sympathetic trunk (CST) within a day of birth; reinnervation was prevented by ligating and displacing the proximal end of the CST. During the first postnatal month, the cells in denervated ganglia showed an increase in dendritic length indistinguishable from that seen in unoperated control ganglia. The rate of growth after 1 month was somewhat slower in experimental animals than in controls; nevertheless, the dendrites of cells in denervated ganglia showed progressively larger arbors at each time point measured. These results indicate that in the SCG the majority of dendritic growth occurs postnatally, dendrites continue to grow in adult rats, and dendritic growth is largely independent of the presence of preganglionic innervation. The significance of these findings for the regulation of innervation in this part of the nervous system is discussed.

Target size regulates calibre and myelination of sympathetic axons.

Axons in vertebrate peripheral nerves are ensheathed by Schwann cells. For some axons, this sheath consists of a single layer of glial cell cytoplasm and plasma membranes; for other axons, Schwann cells form multilayered myelin. Whether or not a Schwann cell makes myelin is determined by a signal from the axon, but the nature of this signal is not known. Here I show that sympathetic postganglionic axons, which are normally not myelinated, become myelinated when their calibre is increased as a result of increasing the size of the peripheral target they innervate. This result implies that axon calibre, which is known to be correlated with myelination, is in fact the crucial determinant of whether an axon becomes myelinated. Furthermore, the finding that increasing or decreasing target size causes corresponding increases or decreases in axon size indicates that axon calibre is itself regulated by retrograde signals from peripheral target tissues.

Peripheral target regulation of dendritic geometry in the rat superior cervical ganglion.

Dendritic arborizations of neurons in the adult rat superior cervical ganglion were measured in control ganglia and in ganglia innervating peripheral targets that were relatively larger or smaller than normal. The relative size of the target--the submandibular gland in these experiments--was manipulated during development by changing the ratio between the amount of target tissue and the number of innervating ganglion cells. Thus, ligating the submandibular salivary duct reduced the size of the gland, whereas partially denervating the gland produced a relatively larger target by making a smaller number of ganglion cells innervate a gland of normal size. Neurons innervating targets that were smaller than normal had significantly smaller dendritic arborizations and cell bodies than control cells. Conversely, neurons projecting to relatively larger than normal targets had larger dendritic arborizations and cell bodies, and more primary dendritic branches. Such cells were also innervated by a larger than normal number of preganglionic inputs. A similar change in dendritic geometry was observed when relative target size was increased after cutting the cervical sympathetic trunk, showing that target regulation of dendritic geometry is not dependent on ganglion cell activity or the presence of presynaptic innervation. Dendrites in the superior cervical ganglion normally grow in parallel with body size throughout life (Purves et al., 1986a; Voyvodic, 1987a). The present results imply that an important aspect of dendritic growth is an ongoing responsiveness of ganglion cells to feedback signals arising from the peripheral targets they innervate.

Real-time fMRI paradigm control, physiology, and behavior combined with near real-time statistical analysis.

This study presents an integrated approach to on-line fMRI data processing that combines real-time paradigm control and real-time MR image statistical analysis with nearly real-time integration of fMRI behavioral and physiological data. The real-time paradigms involve accurate timing control of multiple independent processing streams for stimulus presentation, physiological monitoring, behavioral response recording, and scanner synchronization. The real-time image analysis provides high resolution MR image reconstruction, head motion detection, translational motion correction, and t test statistical activation maps for either block design or single-trial based paradigms. The near real-time analysis allows physiological and behavioral data collected during a paradigm to be combined with the MR time series and provides extended data filtering and statistical processing within a few minutes after the end of the scan. This integrated approach improves fMRI reliability for both clinical and research studies.

Dynamic changes in the dendritic geometry of individual neurons visualized over periods of up to three months in the superior cervical ganglion of living mice.

We describe a means of visualizing the same neuron in the superior cervical ganglion of young adult mice over intervals of up to 3 months. The dendrites of these neurons change during this interval; some branches retract, others elongate, and still others appear to form de novo. Thus, neuronal dendrites in this part of the nervous system are subject to continual change beyond what is usually considered the developmental period. The remodeling of postsynaptic processes further implies that the synaptic connections made onto these cells undergo substantial rearrangement well into adulthood.

Trophic regulation of nerve cell morphology and innervation in the autonomic nervous system.

A remarkable feature of nerve cells is the complex and variable pattern of their axonal and dendritic branches. Quantitative studies of a simple part of the nervous system in mammals provide evidence that neuronal geometry and innervation are regulated by long-term trophic interactions between neurons and their targets. This trophic linkage may explain how nerve cells adjust their function to the needs of bodies that vary markedly in size and form.

Quantification of normal cell death in the rat retina: implications for clone composition in cell lineage analysis.

Naturally occurring cell death complicates the analysis of cell lineage studies by making the surviving members of a clone appear more closely related than they actually are. Here we ask how much normal cell death occurs during rat retinal development, and whether that amount of death is sufficient to confuse the analysis of cell lineage relationships. We measure total cell death in the retina by combining relative counts of dead cells with absolute measurements of total cell loss. For most cell types, but not rods, we find that half of the cells generated die during normal retinal development. We use a computer model to quantify the effects of different amounts of cell death in a simulated lineage study. The simulation indicates that 50% cell death means that clonal variability analysed after the cell death period is not necessarily a good indicator of how much variability actually occurs in the underlying lineage.

High-resolution echo-planar fMRI of human visual cortex at 3.0 tesla.

Known specialized properties of the human visual cortex have been used to investigate the role of spatial resolution on fMRI using blood oxygenation level dependent (BOLD) echo-planar MRI at 3.0 tesla. The magnitude of BOLD signal changes has been examined at low (3.1 x 3.1 x 3.0 mm3) and high (0.8 x 1.6 x 3.0 mm3) resolution using both gradient-echo and spin-echo EPI. Paradigms were designed to activate primary visual cortex (V1/V2) and more specialized areas associated with detection of color (V4) and motion (V5). Sensitivity of activation maps increased at higher resolution despite the decreased total signal intensity at the smaller voxel size, presumably from reduced partial volume averaging. The greater microvascular selectivity of high-resolution spin-echo imaging enabled distinct activation patterns sensitive to motion to be detected in V1/V2 that were not apparent with gradient-echo imaging. The spatial resolution at 3.0 tesla was constrained by the size of physiological head motion relative to the voxel dimensions rather than SNR or the hemodynamic response of BOLD contrast. The higher spatial resolution at 3.0 tesla with more selective spin-echo EPI can further refine functional mapping within the cerebral cortex.

Cell death in the oligodendrocyte lineage.

We have recently found that about 50% of newly formed oligodendrocytes normally die in the developing rat optic nerve. When purified oligodendrocytes or their precursors are cultured in the absence of serum or added signalling molecules, they die rapidly with the characteristics of programmed cell death. This death is prevented either by the addition of medium conditioned by cultures of their normal neighboring cells in the developing optic nerve, or by the addition of platelet-derived growth factor (PDGF) or insulin-like growth factors (IGFs). Increasing PDGF in the developing optic nerve decreases normal oligodendrocyte death by up to 90% and doubles the number of oligodendrocytes, suggesting that this normally occurring glial cell death might result from a competition for limiting amounts of survival signals. These results suggest that competition for limiting amounts of survival factors is not confined to developing neurons, and raise the possibility that a similar mechanism may be responsible for some naturally occurring cell deaths in nonneural tissues.

Cell death and control of cell survival in the oligodendrocyte lineage.

Dead cells are observed in many developing animal tissues, but the causes of these normal cell deaths are mostly unknown. We show that about 50% of oligodendrocytes normally die in the developing rat optic nerve, apparently as a result of a competition for limiting amounts of survival signals. Both platelet-derived growth factor and insulin-like growth factors are survival factors for newly formed oligodendrocytes and their precursors in culture. Increasing platelet-derived growth factor in the developing optic nerve decreases normal oligodendrocyte death by up to 90% and doubles the number of oligodendrocytes in 4 days. These results suggest that a requirement for survival signals is more general than previously thought and that some normal cell deaths in nonneural tissues may also reflect competition for survival factors.