Visual attention deficits in schizophrenia can arise from inhibitory dysfunction in thalamus or cortex

Schizophrenia is associated with diverse cognitive deficits, including disorders of attention-related oculomotor behavior. At the structural level, schizophrenia is associated with abnormal inhibitory control in the circuit linking cortex and thalamus. We developed a spiking neural network model that demonstrates how dysfunctional inhibition can degrade attentive gaze control. Our model revealed that perturbations of two functionally distinct classes of cortical inhibitory neurons, or of the inhibitory thalamic reticular nucleus, disrupted processing vital for sustained attention to a stimulus, leading to distractibility. Because perturbation at each circuit node led to comparable but qualitatively distinct disruptions in attentive tracking or fixation, our findings support the search for new eye movement metrics that may index distinct underlying neural defects. Moreover, because the cortico-thalamic circuit is a common motif across sensory, association, and motor systems, the model and extensions can be broadly applied to study normal function and the neural bases of other cognitive deficits in schizophrenia.R01 MH057414 - NIMH NIH HHS; R01 MH101209 - NIMH NIH HHS; R01 NS024760 - NINDS NIH HHSPublished versio

The emotional gatekeeper: a computational model of attentional selection and suppression through the pathway from the amygdala to the inhibitory thalamic reticular nucleus

In a complex environment that contains both opportunities and threats, it is important for an organism to flexibly direct attention based on current events and prior plans. The amygdala, the hub of the brain's emotional system, is involved in forming and signaling affective associations between stimuli and their consequences. The inhibitory thalamic reticular nucleus (TRN) is a hub of the attentional system that gates thalamo-cortical signaling. In the primate brain, a recently discovered pathway from the amygdala sends robust projections to TRN. Here we used computational modeling to demonstrate how the amygdala-TRN pathway, embedded in a wider neural circuit, can mediate selective attention guided by emotions. Our Emotional Gatekeeper model demonstrates how this circuit enables focused top-down, and flexible bottom-up, allocation of attention. The model suggests that the amygdala-TRN projection can serve as a unique mechanism for emotion-guided selection of signals sent to cortex for further processing. This inhibitory selection mechanism can mediate a powerful affective 'framing' effect that may lead to biased decision-making in highly charged emotional situations. The model also supports the idea that the amygdala can serve as a relevance detection system. Further, the model demonstrates how abnormal top-down drive and dysregulated local inhibition in the amygdala and in the cortex can contribute to the attentional symptoms that accompany several neuropsychiatric disorders.R01MH057414 - NIMH NIH HHS; R01 MH057414 - NIMH NIH HHS; R01 MH101209 - NIMH NIH HHS; R01NS024760 - NINDS NIH HHS; R01MH101209 - NIMH NIH HHS; R01 NS024760 - NINDS NIH HH

Distinction of Neurons, Glia and Endothelial Cells in the Cerebral Cortex: An Algorithm Based on Cytological Features

The estimation of the number or density of neurons and types of glial cells and their relative proportions in different brain areas are at the core of rigorous quantitative neuroanatomical studies. Unfortunately, the lack of detailed, updated, systematic, and well-illustrated descriptions of the cytology of neurons and glial cell types, especially in the primate brain, makes such studies especially demanding, often limiting their scope and broad use. Here, following extensive analysis of histological materials and the review of current and classical literature, we compile a list of precise morphological criteria that can facilitate and standardize identification of cells in stained sections examined under the microscope. We describe systematically and in detail the cytological features of neurons and glial cell types in the cerebral cortex of the macaque monkey and the human using semithin and thick sections stained for Nissl. We used this classical staining technique because it labels all cells in the brain in distinct ways. In addition, we corroborate key distinguishing characteristics of different cell types in sections immunolabeled for specific markers counterstained for Nissl and in ultrathin sections processed for electron microscopy. Finally, we summarize the core features that distinguish each cell type in easy-to-use tables and sketches, and structure these key features in an algorithm that can be used to systematically distinguish cellular types in the cerebral cortex. Moreover, we report high inter-observer algorithm reliability, which is a crucial test for obtaining consistent and reproducible cell counts in unbiased stereological studies. This protocol establishes a consistent framework that can be used to reliably identify and quantify cells in the cerebral cortex of primates as well as other mammalian species in health and disease

The intercalated nuclear complex of the primate amygdala

Published in final edited form as: Neuroscience. 2016 August 25; 330: 267–290. doi:10.1016/j.neuroscience.2016.05.0.The organization of the inhibitory intercalated cell masses (IM) of the primate amygdala is largely unknown despite their key role in emotional processes. We studied the structural, topographic, neurochemical and intrinsic connectional features of IM neurons in the rhesus monkey brain. We found that the intercalated neurons are not confined to discrete cell clusters, but form a neuronal net that is interposed between the basal nuclei and extends to the dorsally located anterior, central, and medial nuclei of the amygdala. Unlike the IM in rodents, which are prominent in the anterior half of the amygdala, the primate inhibitory net stretched throughout the antero-posterior axis of the amygdala, and was most prominent in the central and posterior extent of the amygdala. There were two morphologic types of intercalated neurons: spiny and aspiny. Spiny neurons were the most abundant; their somata were small or medium size, round or elongated, and their dendritic trees were round or bipolar, depending on location. The aspiny neurons were on average slightly larger and had varicose dendrites with no spines. There were three non-overlapping neurochemical populations of IM neurons, in descending order of abundance: (1) Spiny neurons that were positive for the striatal associated dopamine- and cAMP-regulated phosphoprotein (DARPP-32+); (2) Aspiny neurons that expressed the calcium-binding protein calbindin (CB+); and (3) Aspiny neurons that expressed nitric oxide synthase (NOS+). The unique combinations of structural and neurochemical features of the three classes of IM neurons suggest different physiological properties and function. The three types of IM neurons were intermingled and likely interconnected in distinct ways, and were innervated by intrinsic neurons within the amygdala, or by external sources, in pathways that underlie fear conditioning and anxiety.We thank Dr. Alan Peters for EM consultation, Dr. John Fiala for assistance in adapting the free 3D-reconstruction software he developed, Drs. Ron Killiany, Maria Medalla and Clare Timbie for MRI and surgical assistance, Drs. Paul Greengard and Jean-Antoine Girault for their generous gift of the DARPP-32 antibody, and Mrs. Marcia Feinberg for exceptional technical assistance and imaging at the electron microscope. Supported by grants from NIH (BZ: R01 MH101209, HB: R01 MH057414, R01 NS024760) and NSF CELEST (YJ, HB, BZ: 0835976). (R01 MH101209 - NIH; R01 MH057414 - NIH; R01 NS024760 - NIH; 0835976 - NSF CELEST)Accepted manuscrip

Mirror trends of plasticity and stability indicators in primate prefrontal cortex

Published in final edited form as: Eur J Neurosci. 2017 October ; 46(8): 2392–2405. doi:10.1111/ejn.13706.Research on plasticity markers in the cerebral cortex has largely focused on their timing of expression and role in shaping circuits during critical and normal periods. By contrast, little attention has been focused on the spatial dimension of plasticity–stability across cortical areas. The rationale for this analysis is based on the systematic variation in cortical structure that parallels functional specialization and raises the possibility of varying levels of plasticity. Here, we investigated in adult rhesus monkeys the expression of markers related to synaptic plasticity or stability in prefrontal limbic and eulaminate areas that vary in laminar structure. Our findings revealed that limbic areas are impoverished in three markers of stability: intracortical myelin, the lectin Wisteria floribunda agglutinin, which labels perineuronal nets, and parvalbumin, which is expressed in a class of strong inhibitory neurons. By contrast, prefrontal limbic areas were enriched in the enzyme calcium/calmodulin-dependent protein kinase II (CaMKII), known to enhance plasticity. Eulaminate areas have more elaborate laminar architecture than limbic areas and showed the opposite trend: they were enriched in markers of stability and had lower expression of the plasticity-related marker CaMKII. The expression of glial fibrillary acidic protein (GFAP), a marker of activated astrocytes, was also higher in limbic areas, suggesting that cellular stress correlates with the rate of circuit reshaping. Elevated markers of plasticity may endow limbic areas with flexibility necessary for learning and memory within an affective context, but may also render them vulnerable to abnormal structural changes, as seen in neurologic and psychiatric diseases.This work was supported by the National Institutes of Health (National Institute of Neurological Disorders and Stroke, grant number R01NS024760; National Institute of Mental Health, grant numbers R01MH057414 and R01MH101209); and by the Center of Excellence for Learning in Education, Science and Technology (CELEST), a National Science Foundation Science of Learning Center (grant number NSF SBE-0354378). M. A. Garcia-Cabezas was the recipient of a 2014 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation (grant number 22777, P&S Fund Investigator). (R01NS024760 - National Institutes of Health (National Institute of Neurological Disorders and Stroke); R01MH057414 - National Institute of Mental Health; R01MH101209 - National Institute of Mental Health; NSF SBE-0354378 - Center of Excellence for Learning in Education, Science and Technology (CELEST), a National Science Foundation Science of Learning Center; 22777 - NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation)Accepted manuscrip

An Organizational-Level Program of Intervention for AKI: A Pragmatic Stepped Wedge Cluster Randomized Trial

Background Variable standards of care may contribute to poor outcomes associated with AKI. We evaluatedwhether a multifaceted intervention (AKI e-alerts, an AKI care bundle, and an education program)would improve delivery of care and patient outcomes at an organizational level.Methods A multicenter, pragmatic, stepped-wedge cluster randomized trial was performed in five UK hospitals,involving patients with AKI aged$18 years. The intervention was introduced sequentially across fixed three-monthperiods according to a randomly determined schedule until all hospitals were exposed. The primary outcome was30-day mortality,withpre-specifiedsecondaryendpointsandanestedevaluationof careprocessdelivery.Thenatureof the intervention precluded blinding, but data collection and analysiswere independent of project delivery teams.Results We studied 24,059 AKI episodes, finding an overall 30-day mortality of 24.5%, with no differencebetween control and intervention periods. Hospital length of stay was reduced with the intervention(decreases of 0.7, 1.1, and 1.3 days at the 0.5, 0.6, and 0.7 quantiles, respectively). AKI incidence increasedand was mirrored by an increase in the proportion of patients with a coded diagnosis of AKI. Our assessmentof process measures in 1048 patients showed improvements in several metrics including AKI recognition,medication optimization, and fluid assessment.Conclusions A complex, hospital-wide intervention to reduce harm associated with AKI did not reduce30-day AKImortality but did result in reductions in hospital length of stay, accompanied by improvementsin in quality of care. An increase in AKI incidence likely reflected improved recognitio

Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: r(g) = 0.098, p = 2.3 x 10(-8)) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: r(g) = 0.137, p = 2.0 x 10(-12)). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis