Faculty Bibliography

We are sad to report that Professor Jacob (Jack) Nachmias passed away on March 2, 2019. Nachmias was born in Athens, Greece, on June 9, 1928. To escape the Nazis, he and his family came to the United States in 1939. He received his undergraduate degree from Cornell University and then an MA from Swarthmore College, where he worked with Hans Wallach and Wolfgang Kohler; his PhD in Psychology was from Harvard University. Nachmias spent the majority of his career as a Professor of Psychology at the University of Pennsylvania. He made fundamental contributions to our understanding of vision, most notably through the study of eye movements, the development of signal detection theory and forced-choice psychophysical methods, and the psychophysical characterization of spatial-frequency-selective visual channels. Nachmias' work was recognized by his election to the National Academy of Sciences and receipt of the Optical Society's Tillyer Award.

The role of the thalamus in cortical sensory transmission is well known, but its broader role in cognition is less appreciated. Recent studies have shown thalamic engagement in dynamic regulation of cortical activity in attention, executive control, and perceptual decision-making, but the circuit mechanisms underlying such functionality are unknown. Because the thalamus is composed of excitatory neurons that are devoid of local recurrent excitatory connectivity, delineating long-range, input-output connectivity patterns of single thalamic neurons is critical for building functional models. We discuss this need in relation to existing organizational schemes such as core versus matrix and first-order versus higher-order relay nuclei. We propose that a new classification is needed based on thalamocortical motifs, where structure naturally informs function. Overall, our synthesis puts understanding thalamic organization at the forefront of existing research in systems and computational neuroscience, with both basic and translational applications.

GABAergic interneurons have many important functions in cortical circuitry, a reflection of their cell diversity. The developmental origins of this diversity are poorly understood. Here, we identify rostral-caudal regionality in Wnt exposure within the interneuron progenitor zone delineating the specification of the two main interneuron subclasses. Caudally situated medial ganglionic eminence (MGE) progenitors receive high levels of Wnt signaling and give rise to somatostatin (SST)-expressing cortical interneurons. By contrast, parvalbumin (PV)-expressing basket cells originate mostly from the rostral MGE, where Wnt signaling is attenuated. Interestingly, rather than canonical signaling through β-catenin, signaling via the non-canonical Wnt receptor Ryk regulates interneuron cell-fate specification in vivo and in vitro. Indeed, gain of function of Ryk intracellular domain signaling regulates SST and PV fate in a dose-dependent manner, suggesting that Ryk signaling acts in a graded fashion. These data reveal an important role for non-canonical Wnt-Ryk signaling in establishing the correct ratios of cortical interneuron subtypes.

Altered metabolic function is common in stressed immune cells, but alteration in brain microglia during neurodegeneration is not understood. In this issue, Baik et al. (2019) provide insight into microglial metabolism. They demonstrate a switch from oxidative phosphorylation to glycolysis following interaction with amyloid beta acutely, and breakdown in both pathways chronically.

Vision relies on both specific knowledge of visual attributes, such as object categories, and general brain states, such as those reflecting arousal. We hypothesized that these phenomena independently influence recognition of forthcoming stimuli through distinct processes reflected in spontaneous neural activity. Here, we recorded magnetoencephalographic (MEG) activity in participants (N = 24) who viewed images of objects presented at recognition threshold. Using multivariate analysis applied to sensor-level activity patterns recorded before stimulus presentation, we identified two neural processes influencing subsequent subjective recognition: a general process, which disregards stimulus category and correlates with pupil size, and a specific process, which facilitates category-specific recognition. The two processes are doubly-dissociable: the general process correlates with changes in criterion but not in sensitivity, whereas the specific process correlates with changes in sensitivity but not in criterion. Our findings reveal distinct mechanisms of how spontaneous neural activity influences perception and provide a framework to integrate previous findings.

Two-photon (2P) optogenetic stimulation is currently the only method for precise, fast, and non-invasive cellular excitation deep inside brain tissue; it is typically combined with holographic wavefront-shaping techniques to generate distributed light patterns and target them to multiple specific cells in the brain. During propagation in the brain, these light patterns undergo severe distortion, mainly due to scattering, which leads to a discrepancy between the desired and actual light distribution. However, despite its importance, measurement of these tissue-induced distortions and their effects on the light patterns has yet to be demonstrated in situ. To this end, holographic optogenetics confocally unraveled sculpting (HOCUS), a system for real-time in situ evaluation of holographic light patterns, based on confocally descanning the stimulation light's reflection from the brain, is developed. HOCUS measures both tissue and wave propagation properties and enables the real-time measurement and correction of the dimensions and positions of holographic spots relative to neurons targeted for stimulation. It can also be used to measure tissue attenuation length, and thus should facilitate future attempts to optimize the generated hologram to pre-compensate for tissue-induced distortions, thereby improving the reliability of 2P holographic stimulation experiments.

Astrocytes are essential for central nervous system health, regulating homeostasis, metabolism, and synaptic transmission. In addition to these and many other physiological roles, the pathological impact of astrocytes ('reactive astrocytes') in acute trauma and chronic disease like Alzheimerêž‹s disease (AD) is well established. Growing evidence supports a fundamental and active role of astrocytes in multiple neurodegenerative diseases. With a growing interest in normal astrocyte biology, and countless studies on changes in astrocyte function in the context of disease, it may be a surprise that no therapies exist incorporating astrocytes as key targets. Here, we examine unintentional effects of current AD therapies on astrocyte function and theorise how astrocytes may be intentionally targeted for more efficacious therapeutic outcomes. Given their integral role in normal neuronal functioning, incorporating astrocytes as key criteria for AD drug development can only lead to more effective therapies for the millions of AD sufferers worldwide.

Determining the cause of unexplained death in all age groups, including infants, is a priority in forensic medicine. The triple risk model proposed for sudden infant death syndrome involves the intersection of three risks: (1) a critical developmental period in homeostatic control (2), exogenous stressors, and (3) a vulnerable infant. Even though sex and age factor into some forms of inherited arrhythmogenic deaths in young individuals and adults, more appropriate a dual-risk disease model for adults involves exogenous stressors and a vulnerable individual. The vulnerability aspect clearly has a genetic component as underscored by a number of recent large-scale and high-throughput genetic testing studies performed in attempt to define the causes of sudden unexplained death. These studies often focus on 'cardiac' and channelopathy genes. Genetic testing often identify lists of rare or ultra-rare nonsynonymous variants, classified according to the ACMG guidelines as 'pathogenic' or 'likely pathogenic', which may form the basis of diagnostic decisions and/or family counseling. However, computer algorithms used to categorize gene variants are not completely accurate and these variants are often not functionally tested to determine their pathogenicity. Due to conflicting computational predictions, a large number of variants are labeled as 'variants of uncertain significance' or VUS. Functional testing of these VUS can greatly assist to reclassify these VUS as 'likely benign' or 'likely pathogenic'. However, functional testing has its limits and by itself cannot be used to determine cause of death. Going forward, computer algorithms must be improved to take account of variants across multiple genes and efforts must be expanded to obtain clinical, familial and segregation data. Forensic genetic testing needs to be held to the same rigorous standards as defined by the NIH Clinical Genome Resource Consortium, where functional evaluation of a channelopathy variant is only one (but important) aspect of the overall picture.

BACKGROUND:Late-onset Pompe disease (LOPD) is a rare, metabolic disease primarily affecting the musculoskeletal and respiratory systems. Forced vital capacity (FVC) is commonly used to measure pulmonary function; however, associations between FVC and other LOPD outcomes remain unclear. METHODS:A systematic literature review was conducted on November 2015, updated September 2016 and supplemented with clinical trial data from the sponsor. Outcomes included: 6-min walk test distance (6MWT), FVC, maximal inspiratory/expiratory pressure (MIP/MEP), Medical Research Council-skeletal muscle strength score (MRC), 36-item short-form survey-physical component score (SF-36), Rotterdam Handicap Scale (RHS), Fatigue Severity Scale (FSS) and survival. Individual patient data meta-analysis was used for cross-sectional analyses and longitudinal analyses to determine associations between percent of predicted FVC and LOPD measures and outcomes. RESULTS:Fifteen studies were selected. From cross-sectional analyses, FVC and MRC were most strongly associated. Specifically, patients with 10% higher FVC (a round number for illustrative purposes only) were associated with a 4.72% (95% confidence interval [CI]: 3.37, 6.07) higher MRC score, indicating a positive association. Similarly, slopes for the 6MWT and SF-36 relative to a 10% higher FVC were estimated at 33.2 meters (95% CI 24.0, 42.4) and 1.2% (95% CI 0.24, 2.16%), respectively. From longitudinal analyses, a 10% incremental increase in predicted FVC was associated with an average increase of 4.12% in MRC score (95% CI 1.29, 6.95), 35.6 m in the 6MWT (95% CI 19.9, 51.6), and 1.34% in SF-36 (95% CI 0.08, 2.60). There was insufficient data to conduct analyses for RHS, FSS and survival. CONCLUSIONS:FVC is positively associated with LOPD measures and outcomes across multiple domains. Additionally, longitudinal changes in FVC are positively associated with changes in the 6MWT, MRC and SF-36.