Faculty Bibliography

In a longitudinal study of recovery of left neglect following stroke using reaction time computerized assessment, we find that lateralized spatial deficits of attention and perception to be more severe than disturbance of action. Perceptual-attention deficits also show the most variability in the course of recovery, making them prime candidates for intervention. In an anatomical analysis of MRI findings, ventral frontal cortex damage was correlated with the most severe neglect, reflecting impaired fronto-parietal communication.

Recent studies have shown that immunotherapy clears amyloid beta (Abeta) plaques and reduces Abeta levels in mouse models of Alzheimer's disease (AD), as well as in AD patients. Tangle pathology is also relevant for the neurodegeneration in AD, and our studies have shown that active immunization with an AD related phospho-tau peptide reduces aggregated tau within the brain and slows the progression of tauopathy-induced behavioral impairments. Thus, clearance of neurofibrillary tangles and/or their precursors may reduce synaptic and neuronal loss associated with AD and other tauopathies. So far the mechanisms involved in antibody-mediated clearance of tau pathology are yet to be elucidated. In this study we have used a mouse brain slice model to examine the uptake and localization of FITC labeled anti-tau antibodies. Confocal microscopy analysis showed that the FITC labeled anti-tau antibody co-stained with phosphorylated tau, had a perinuclear appearance and co-localized with markers of the endosomal/lysosomal pathway. Additionally, tau and FITC-IgG were found together in an enriched lysosome fraction. In summary, antibody-mediated clearance of intracellular tau aggregates appears to occur via the lysosomal pathway

BACKGROUND: Mutations in eukaryotic translation initiation factor 2B (eIF2B) cause Childhood Ataxia with CNS Hypomyelination (CACH), also known as Vanishing White Matter disease (VWM), which is associated with a clinical pathology of brain myelin loss upon physiological stress. eIF2B is the guanine nucleotide exchange factor (GEF) of eIF2, which delivers the initiator tRNA(Met) to the ribosome. We recently reported that a R132H mutation in the catalytic subunit of this GEF, causing a 20% reduction in its activity, leads under normal conditions to delayed brain development in a mouse model for CACH/VWM. To further explore the effect of the mutation on global gene expression in the brain, we conducted a wide-scale transcriptome analysis of the first three critical postnatal weeks. METHODOLOGY/PRINCIPAL FINDINGS: Genome-wide mRNA expression of wild-type and mutant mice was profiled at postnatal (P) days 1, 18 and 21 to reflect the early proliferative stage prior to white matter establishment (P1) and the peak of oligodendrocye differentiation and myelin synthesis (P18 and P21). At each developmental stage, between 441 and 818 genes were differentially expressed in the mutant brain with minimal overlap, generating unique time point-specific gene expression signatures. CONCLUSIONS: The current study demonstrates that a point mutation in eIF2B, a key translation initiation factor, has a massive effect on global gene expression in the brain. The overall changes in expression patterns reflect multiple layers of indirect effects that accumulate as the brain develops and matures. The differentially expressed genes seem to reflect delayed waves of gene expression as well as an adaptation process to cope with hypersensitivity to cellular stress.

Introduction: Spinal cord stimulation (SCS) has been shown to modulate atrial electrophysiology and confer protection against ischemia and ventricular arrhythmias. We hypothesized that SCS may reduce susceptibility to tachypacing (TP) induced atrial fibrillation (AF). Methods: Spinal cord leads (Octrode, St. Jude Medical) were implanted in the upper thoracic spine (T1-T5) of canines and connected to pulse generators (EonC, St. Jude Medical). The AV node was ablated and atrial effective refractory period (AERP) was measured at baseline and with SCS (n=10). In separate animals the AV node was ablated and endocardial RA and RV pacing leads were connected to dual chamber pacemakers for ambulatory AF induction. Custom firmware provided continuous 30s periods of atrial TP followed by 6s sense windows. TP was interrupted by detection of AF (atrial rate >250 bpm) and resumed upon return to sinus rhythm. AF Index was defined as the fraction of time the animal did not receive TP relative to the total allowable TP time. The effect of SCS delivered intermittently for 6 hr/day (SCS ON; n=3) on AF index was followed for 8 weeks and compared to control (SCS OFF; n=3). Results: Right (p=0.002) and left (p=0.009) AERP were significantly longer during SCS (168+/-15.1, 168+/-14.8 ms) compared to baseline (130+/-8.7, 152+/-10.3 ms). AF Index was significantly decreased in the SCS ON compared to SCS OFF (p<0.0001). AF Index was >70% in the SCS OFF group and <5% in the SCS ON animals starting at week 3 (Figure). Conclusions: These data demonstrate that SCS prolongs AERP and prevents TP-induced AE (Graph presented)

Consider the decomposition of a signal into features that undergo transformations drawn from a continuous family. Current methods discretely sample the transformations and apply sparse recovery methods to the resulting finite dictionary. These methods do not exploit the underlying continuous structure, thereby limiting the ability to produce sparse solutions. Instead, we employ interpolation functions which linearly approximate the manifold of scaled and transformed features. Coefficients are interpreted as interpolation weights, and we formulate a convex optimization problem for obtaining them, enforcing both reconstruction accuracy and sparsity. We compare our method, which we call continuous basis pursuit (CBP) with the standard basis pursuit approach on a sparse deconvolution task. CBP yields substantially sparser solutions without sacrificing accuracy, and does so with a smaller dictionary. We conclude that for signals generated by transformation-invariant processes, a representation that explicitly accommodates the transformation(s) can yield sparser and more interpretable decompositions.

In this review, we first provide a historical perspective of inhibitory signaling from the discovery of inhibition through to our present understanding of the diversity and mechanisms by which GABAergic interneuron populations function in different parts of the telencephalon. This is followed by a summary of the mechanisms of inhibition in the CNS. With this as a starting point, we provide an overview describing the variations in the subtypes and origins of inhibitory interneurons within the pallial and subpallial divisions of the telencephalon, with a focus on the hippocampus, somatosensory, paleo/piriform cortex, striatum, and various amygdala nuclei. Strikingly, we observe that marked variations exist in the origin and numerical balance between GABAergic interneurons and the principal cell populations in distinct regions of the telencephalon. Finally we speculate regarding the attractiveness and challenges of establishing a unifying nomenclature to describe inhibitory neuron diversity throughout the telencephalon