Faculty Bibliography

Clinical data suggest that optic neuropathy and retinal ganglion cell loss are the main cause of visual decline in patients with familial dysautonomia, but this has not previously been confirmed by pathological analyses. We studied retinas and optic nerves in 6 eyes from 3 affected patients obtained at autopsy. Analyses included routine neurohistology and immunohistochemistry for neurofilaments, cytochrome c oxidase (COX), and melanopsin-containing ganglion cells. We observed profound axon loss in the temporal portions of optic nerves with relative preservation in the nasal portions; this correlated with clinical and optical coherence tomography findings in 1 patient. Retinal ganglion cell layers were markedly reduced in the central retina, whereas melanopsin-containing ganglion cells were relatively spared. COX staining was reduced in the temporal portions of the optic nerve indicating reduced mitochondrial density. Axonal swelling with degenerating lysosomes and mitochondria were observed by electron microscopy. These findings support the concept that there is a specific optic neuropathy and retinopathy in patients with familial dysautonomia similar to that seen in other optic neuropathies with mitochondrial dysfunction. This raises the possibility that defective expression of the IkB kinase complex-associated protein (IKAP) resulting from mutations in IKBKAP affects mitochondrial function in the metabolism-dependent retinal parvocellular ganglion cells in this condition.

Adolescents are generally characterized as impulsive. However, impulsivity is a multi-dimensional construct that involves multiple component processes. Which of these components contribute to adolescent impulsivity is currently unclear. This study focused on the neural mechanisms underlying individual differences in distinct components of temporal discounting (TD), i.e., the preference for smaller immediate rewards over larger delayed rewards. Participants were 58 adolescents (12-16 years-old) who performed an fMRI TD task with both monetary and snack rewards. Using mixed-effects modeling, we determined participants' average impatience, and further decomposed TD choices into: 1) amount sensitivity (unique contribution of the magnitude of the immediate reward); and 2) delay sensitivity (unique contribution of delay duration). Adolescents' average impatience was positively correlated with frontoparietal and ventral striatal activity during delayed reward choices, and with ventromedial prefrontal cortex activity during immediate reward choices. Adolescents' amount sensitivity was positively associated with ventral striatal and dorsal anterior cingulate cortex activity during immediate reward choices. Delay sensitivity was positively correlated with inferior parietal cortex activity during delayed reward choices. As expected, snacks were discounted more steeply than money, and TD of both reward types was associated with overlapping activation in the inferior parietal cortex. Exploring whether testosterone or estradiol were associated with TD and its neural correlates revealed no significant associations. These findings indicate that distinct components contribute uniquely to TD choice and that individual differences in amount sensitivity are uniquely associated with activation of reward valuation areas, while individual differences in delay sensitivity are uniquely associated with activation of cognitive control areas.

OBJECTIVES: The aim of this study was to assess the applicability of Dixon radial volumetric encoding (Dixon-RAVE) for comprehensive dynamic contrast-enhanced 3D magnetic resonance imaging (MRI) of the breast using a combination of radial sampling, model-based fat/water separation, compressed sensing, and parallel imaging. MATERIALS AND METHODS: In this Health Insurance Portability and Accountability Act-compliant prospective study, 24 consecutive patients underwent bilateral breast MRI, including both conventional fat-suppressed and non-fat-suppressed precontrast T1-weighted volumetric interpolated breath-hold examination (VIBE). Afterward, 1 continuous Dixon-RAVE scan was performed with the proposed approach while the contrast agent was injected. This scan was immediately followed by the acquisition of 4 conventional fat-saturated VIBE scans. From the comprehensive Dixon-RAVE data set, different image contrasts were reconstructed that are comparable to the separate conventional VIBE scans.Two radiologists independently rated image quality, conspicuity of fibroglandular tissue from fat (FG), and degree of fat suppression (FS) on a 5-point Likert-type scale for the following 3 comparisons: precontrast fat-suppressed (pre-FS), precontrast non-fat-suppressed (pre-NFS), and dynamic fat-suppressed (dyn-FS) images. RESULTS: When scores were averaged over readers, Dixon-RAVE achieved significantly higher (P < 0.001) degree of fat suppression compared with VIBE, for both pre-FS (4.25 vs 3.67) and dyn-FS (4.10 vs 3.46) images. Although Dixon-RAVE had lower image quality score compared with VIBE for the pre-FS (3.56 vs 3.67, P = 0.490), the pre-NFS (3.54 vs 3.88, P = 0.009), and the dyn-FS images (3.06 vs 3.67, P < 0.001), acceptable or better diagnostic quality was achieved (score >/= 3). The FG score for Dixon-RAVE in comparison to VIBE was significantly higher for the pre-FS image (4.23 vs 3.85, P = 0.044), lower for the pre-NFS image (3.98 vs 4.25, P = 0.054), and higher for the dynamic fat-suppressed image (3.90 vs 3.85, P = 0.845). CONCLUSIONS: Dixon-RAVE can serve as a one-stop-shop approach for comprehensive T1-weighted breast MRI with diagnostic image quality, high spatiotemporal resolution, reduced overall scan time, and improved fat suppression compared with conventional imaging.

Memories of experiences are stored in the cerebral cortex. Sleep is critical for the consolidation of hippocampal memory of wake experiences into the neocortex. Understanding representations of neural codes of hippocampal-neocortical networks during sleep would reveal important circuit mechanisms in memory consolidation and provide novel insights into memory and dreams. Although sleep-associated ensemble spike activity has been investigated, identifying the content of memory in sleep remains challenging. Here we revisit important experimental findings on sleep-associated memory (i.e., neural activity patterns in sleep that reflect memory processing) and review computational approaches to the analysis of sleep-associated neural codes (SANCs). We focus on two analysis paradigms for sleep-associated memory and propose a new unsupervised learning framework ('memory first, meaning later') for unbiased assessment of SANCs.

OBJECTIVE: Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Current pain research mostly focuses on molecular and synaptic changes at the spinal and peripheral levels. However, a complete understanding of pain mechanisms requires the physiological study of the neocortex. Our goal is to apply a neural decoding approach to read out the onset of acute thermal pain signals, which can be used for brain-machine interface. APPROACH: We used micro wire arrays to record ensemble neuronal activities from the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC) in freely behaving rats. We further investigated neural codes for acute thermal pain at both single-cell and population levels. To detect the onset of acute thermal pain signals, we developed a novel latent state-space framework to decipher the sorted or unsorted S1 and ACC ensemble spike activities, which reveal information about the onset of pain signals. MAIN RESULTS: The state space analysis allows us to uncover a latent state process that drives the observed ensemble spike activity, and to further detect the 'neuronal threshold' for acute thermal pain on a single-trial basis. Our method achieved good detection performance in sensitivity and specificity. In addition, our results suggested that an optimal strategy for detecting the onset of acute thermal pain signals may be based on combined evidence from S1 and ACC population codes. SIGNIFICANCE: Our study is the first to detect the onset of acute pain signals based on neuronal ensemble spike activity. It is important from a mechanistic viewpoint as it relates to the significance of S1 and ACC activities in the regulation of the acute pain onset.

BACKGROUND: Two genetic variants in SCN5A, encoding the Nav1.5 Na+ channel alpha-subunit, were found in a five month-old girl who died suddenly in her sleep. The first variant is a missense mutation, resulting in an amino acid change (Q1832E), which has been described (but not characterized) in a patient with Brugada syndrome. The second is a nonsense mutation that produces a premature stop codon and a C-terminal truncation (R1944Delta). METHODS AND RESULTS: To investigate their functional relevance with patch clamp experiments in transfected HEK293 cells. The Q1832E mutation drastically reduced Nav1.5 current density. The R1944Delta C-terminal truncation had negligible effects on Nav1.5 current density. Neither of the mutations affected the voltage dependence of steady activation and inactivation or influenced the late Na+ current or the recovery from inactivation. Biochemical and immunofluorescent approaches demonstrated that the Q1832E mutation caused severe trafficking defects. PCR cloning and sequencing the victim's genomic DNA allowed us to determine that the two variants were in trans. We investigated the functional consequences by co-expressing Nav1.5(Q1832E) and Nav1.5(R1944Delta), which led to a significantly reduced current amplitude relative to wild-type. CONCLUSIONS: These SIDS-related variants caused a severely dysfunctional Nav1.5 channel, which was mainly due to trafficking defects caused by the Q1832E mutation. The decreased current density is likely to be a major contributing factor to arrhythmogenesis in Brugada syndrome and the sudden death of this SIDS victim