Falsely positive heparin-induced thrombocytopenia antibody testing in severe hyperbilirubinemia.

Heparin-induced thrombocytopenia (HIT) is a life-threatening pathologic reaction to heparin-based products. Diagnosis of this condition can be confounded by other comorbidities or by acute illness-oftentimes presenting challenging clinical dilemmas, particularly in critically ill patients. A 67-year-old woman was admitted with liver failure and severe hyperbilirubinemia. She developed thrombocytopenia after prophylactic heparin exposure. Subsequent quantitative latex immunoturbidimetric assay (LIA) HIT antibody testing was intermediately positive. Confirmatory serotonin release assay testing subsequently returned negative. Platelet factor4-dependent P-selectin expression assay also returned negative, suggesting false positivity of the initial LIA tests. Concern was raised that hyperbilirubinemia (total bilirubin, 55.5 mg/dL) interfered with the original assay. Further testing with a separate HIT ELISA assay, which includes multiple washes and dilutions of the serum in order to effectively remove bilirubin, returned negative. Medical providers must consider the possibility of false-positive LIA testing when evaluating for HIT in the setting of severe hyperbilirubinemia.

Coupling between motor cortex and striatum increases during sleep over long-term skill learning.

The strength of cortical connectivity to the striatum influences the balance between behavioral variability and stability. Learning to consistently produce a skilled action requires plasticity in corticostriatal connectivity associated with repeated training of the action. However, it remains unknown whether such corticostriatal plasticity occurs during training itself or 'offline' during time away from training, such as sleep. Here, we monitor the corticostriatal network throughout long-term skill learning in rats and find that non-rapid-eye-movement (NREM) sleep is a relevant period for corticostriatal plasticity. We first show that the offline activation of striatal NMDA receptors is required for skill learning. We then show that corticostriatal functional connectivity increases offline, coupled to emerging consistent skilled movements, and coupled cross-area neural dynamics. We then identify NREM sleep spindles as uniquely poised to mediate corticostriatal plasticity, through interactions with slow oscillations. Our results provide evidence that sleep shapes cross-area coupling required for skill learning.

High density carbon fiber arrays for chronic electrophysiology, fast scan cyclic voltammetry, and correlative anatomy.

OBJECTIVE: Multimodal measurements at the neuronal level allow for detailed insight into local circuit function. However, most behavioral studies focus on one or two modalities and are generally limited by the available technology. APPROACH: Here, we show a combined approach of electrophysiology recordings, chemical sensing, and histological localization of the electrode tips within tissue. The key enabling technology is the underlying use of carbon fiber electrodes, which are small, electrically conductive, and sensitive to dopamine. The carbon fibers were functionalized by coating with Parylene C, a thin insulator with a high dielectric constant, coupled with selective re-exposure of the carbon surface using laser ablation. MAIN RESULTS: We demonstrate the use of this technology by implanting 16 channel arrays in the rat nucleus accumbens. Chronic electrophysiology and dopamine signals were detected 1 month post implant. Additionally, electrodes were left in the tissue, sliced in place during histology, and showed minimal tissue damage. SIGNIFICANCE: Our results validate our new technology and methods, which will enable a more comprehensive circuit level understanding of the brain.

Cellular-scale silicon probes for high-density, precisely localized neurophysiology.

Neural implants with large numbers of electrodes have become an important tool for examining brain functions. However, these devices typically displace a large intracranial volume compared with the neurons they record. This large size limits the density of implants, provokes tissue reactions that degrade chronic performance, and impedes the ability to accurately visualize recording sites within intact circuits. Here we report next-generation silicon-based neural probes at a cellular scale (5 × 10 µm cross section), with ultra-high-density packing (as little as 66 µm between shanks) and 64 or 256 closely spaced recording sites per probe. We show that these probes can be inserted into superficial or deep brain structures and record large spikes in freely behaving rats for many weeks. Finally, we demonstrate a slice-in-place approach for the precise registration of recording sites relative to nearby neurons and anatomical features, including striatal µ-opioid receptor patches. This scalable technology provides a valuable tool for examining information processing within neural circuits and potentially for human brain-machine interfaces.NEW & NOTEWORTHY Devices with many electrodes penetrating into the brain are an important tool for investigating neural information processing, but they are typically large compared with neurons. This results in substantial damage and makes it harder to reconstruct recording locations within brain circuits. This paper presents high-channel-count silicon probes with much smaller features and a method for slicing through probe, brain, and skull all together. This allows probe tips to be directly observed relative to immunohistochemical markers.

The Degree of Nesting between Spindles and Slow Oscillations Modulates Neural Synchrony.

Spindles and slow oscillations (SOs) both appear to play an important role in memory consolidation. Spindle and SO "nesting," or the temporal overlap between the two events, is believed to modulate consolidation. However, the neurophysiological processes modified by nesting remain poorly understood. We thus recorded activity from the primary motor cortex of 4 male sleeping rats to investigate how SO and spindles interact to modulate the correlation structure of neural firing. During spindles, primary motor cortex neurons fired at a preferred phase, with neural pairs demonstrating greater neural synchrony, or correlated firing, during spindle peaks. We found a direct relationship between the temporal proximity between SO and spindles, and changes to the distribution of neural correlations; nesting was associated with narrowing of the distribution, with a reduction in low- and high-correlation pairs. Such narrowing may be consistent with greater exploration of neural states. Interestingly, after animals practiced a novel motor task, pairwise correlations increased during nested spindles, consistent with targeted strengthening of functional interactions. These findings may be key mechanisms through which spindle nesting supports memory consolidation.SIGNIFICANCE STATEMENT Our analysis revealed changes in cortical spiking structure that followed the waxing and waning of spindles; firing rates increased, spikes were more phase-locked to spindle-band local field potential, and synchrony across units peaked during spindles. Moreover, we showed that the degree of nesting between spindles and slow oscillations modified the correlation structure across units by narrowing the distribution of pairwise correlations. Finally, we demonstrated that engaging in a novel motor task increased pairwise correlations during nested spindles. These phenomena suggest key mechanisms through which the interaction of spindles and slow oscillations may support sensorimotor learning. More broadly, this work helps link large-scale measures of population activity to changes in spiking structure, a critical step in understanding neuroplasticity across multiple scales.