@article {2268, title = {Adaptive integration of self-motion and goals in posterior parietal cortex.}, journal = {Cell Rep}, volume = {38}, year = {2022}, month = {2022 Mar 08}, pages = {110504}, abstract = {

Rats readily switch between foraging and more complex navigational behaviors such as pursuit of other rats or prey. These tasks require vastly different tracking of multiple behaviorally significant variables including self-motion state. To explore whether navigational context modulates self-motion tracking, we examined self-motion tuning in posterior parietal cortex neurons during foraging versus visual target pursuit. Animals performing the pursuit task demonstrate predictive processing of target trajectories by anticipating and intercepting them. Relative to foraging, pursuit yields multiplicative gain modulation of self-motion tuning and enhances self-motion state decoding. Self-motion sensitivity in parietal cortex neurons is, on average, history dependent regardless of behavioral context, but the temporal window of self-motion integration extends during target pursuit. Finally, many self-motion-sensitive neurons conjunctively track the visual target position relative to the animal. Thus, posterior parietal cortex functions to integrate the location of navigationally relevant target stimuli into an ongoing representation of past, present, and future locomotor trajectories.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2022.110504}, author = {Alexander, Andrew S and Tung, Janet C and Chapman, G William and Conner, Allison M and Shelley, Laura E and Hasselmo, Michael E and Nitz, Douglas A} } @article {2188, title = {Discovery of genomic loci of the human cerebral cortex using genetically informed brain atlases.}, journal = {Science}, volume = {375}, year = {2022}, month = {2022 02 04}, pages = {522-528}, abstract = {

To determine the impact of genetic variants on the brain, we used genetically informed brain atlases in genome-wide association studies of regional cortical surface area and thickness in 39,898 adults and 9136 children. We uncovered 440 genome-wide significant loci in the discovery cohort and 800 from a post hoc combined meta-analysis. Loci in adulthood were largely captured in childhood, showing signatures of negative selection, and were linked to early neurodevelopment and pathways associated with neuropsychiatric risk. Opposing gradations of decreased surface area and increased thickness were associated with common inversion polymorphisms. Inferior frontal regions, encompassing Broca{\textquoteright}s area, which is important for speech, were enriched for human-specific genomic elements. Thus, a mixed genetic landscape of conserved and human-specific features is concordant with brain hierarchy and morphogenetic gradients.

}, keywords = {Adult, Aged, Aged, 80 and over, Cerebral Cortex, Child, Chromatin, Cohort Studies, Female, Gene Ontology, Genetic Association Studies, Genetic Loci, Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Male, Mental Disorders, Middle Aged, Molecular Sequence Annotation, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid}, issn = {1095-9203}, doi = {10.1126/science.abe8457}, author = {Makowski, Carolina and van der Meer, Dennis and Dong, Weixiu and Wang, Hao and Wu, Yan and Zou, Jingjing and Liu, Cin and Rosenthal, Sara B and Hagler, Donald J and Fan, Chun Chieh and Kremen, William S and Andreassen, Ole A and Jernigan, Terry L and Dale, Anders M and Zhang, Kun and Visscher, Peter M and Yang, Jian and Chen, Chi-Hua} } @article {2179, title = {Valence opponency in peripheral olfactory processing.}, journal = {Proc Natl Acad Sci U S A}, volume = {119}, year = {2022}, month = {2022 Feb 01}, abstract = {

A hallmark of complex sensory systems is the organization of neurons into functionally meaningful maps, which allow for comparison and contrast of parallel inputs via lateral inhibition. However, it is unclear whether such a map exists in olfaction. Here, we address this question by determining the organizing principle underlying the stereotyped pairing of olfactory receptor neurons (ORNs) in sensory hairs, wherein compartmentalized neurons inhibit each other via ephaptic coupling. Systematic behavioral assays reveal that most paired ORNs antagonistically regulate the same type of behavior. Such valence opponency is relevant in critical behavioral contexts including place preference, egg laying, and courtship. Odor-mixture experiments show that ephaptic inhibition provides a peripheral means for evaluating and shaping countervailing cues relayed to higher brain centers. Furthermore, computational modeling suggests that this organization likely contributes to processing ratio information in odor mixtures. This olfactory valence map may have evolved to swiftly process ethologically meaningful odor blends without involving costly synaptic computation.

}, issn = {1091-6490}, doi = {10.1073/pnas.2120134119}, author = {Wu, Shiuan-Tze and Chen, Jen-Yung and Martin, Vanessa and Ng, Renny and Zhang, Ye and Grover, Dhruv and Greenspan, Ralph J and Aljadeff, Johnatan and Su, Chih-Ying} } @article {1805, title = {Neurally driven synthesis of learned, complex vocalizations}, journal = {Current Biology}, year = {2021}, abstract = {

Summary Brain machine interfaces (BMIs) hold promise to restore impaired motor function and serve as powerful tools to study learned motor skill. While limb-based motor prosthetic systems have leveraged nonhuman primates as an important animal model,1, 2, 3, 4 speech prostheses lack a similar animal model and are more limited in terms of neural interface technology, brain coverage, and behavioral study design.5, 6, 7 Songbirds are an attractive model for learned complex vocal behavior. Birdsong shares a number of unique similarities with human speech,8, 9, 10 and its study has yielded general insight into multiple mechanisms and circuits behind learning, execution, and maintenance of vocal motor skill.11, 12, 13, 14, 15, 16, 17, 18 In addition, the biomechanics of song production bear similarity to those of humans and some nonhuman primates.19, 20, 21, 22, 23 Here, we demonstrate a vocal synthesizer for birdsong, realized by mapping neural population activity recorded from electrode arrays implanted in the premotor nucleus HVC onto low-dimensional compressed representations of song, using simple computational methods that are implementable in real time. Using a generative biomechanical model of the vocal organ (syrinx) as the low-dimensional target for these mappings allows for the synthesis of vocalizations that match the bird{\textquoteright}s own song. These results provide proof of concept that high-dimensional, complex natural behaviors can be directly synthesized from ongoing neural activity. This may inspire similar approaches to prosthetics in other species by exploiting knowledge of the peripheral systems and the temporal structure of their output.

}, keywords = {bioprosthetics, birdsong, brain machine interfaces, Electrophysiology, neural networks, nonlinear dynamics, Speech}, issn = {0960-9822}, doi = {https://doi.org/10.1016/j.cub.2021.05.035}, url = {https://www.sciencedirect.com/science/article/pii/S0960982221007338}, author = {Ezequiel M. Arneodo and Shukai Chen and Daril E. Brown and Vikash Gilja and Timothy Q. Gentner} } @article {1648, title = {Fast near-whole-brain imaging in adult Drosophila during responses to stimuli and behavior.}, journal = {PLoS Biol}, volume = {17}, year = {2019}, month = {2019 Feb}, pages = {e2006732}, abstract = {

Whole-brain recordings give us a global perspective of the brain in action. In this study, we describe a method using light field microscopy to record near-whole brain calcium and voltage activity at high speed in behaving adult flies. We first obtained global activity maps for various stimuli and behaviors. Notably, we found that brain activity increased on a global scale when the fly walked but not when it groomed. This global increase with walking was particularly strong in dopamine neurons. Second, we extracted maps of spatially distinct sources of activity as well as their time series using principal component analysis and independent component analysis. The characteristic shapes in the maps matched the anatomy of subneuropil regions and, in some cases, a specific neuron type. Brain structures that responded to light and odor were consistent with previous reports, confirming the new technique{\textquoteright}s validity. We also observed previously uncharacterized behavior-related activity as well as patterns of spontaneous voltage activity.

}, issn = {1545-7885}, doi = {10.1371/journal.pbio.2006732}, author = {Aimon, Sophie and Katsuki, Takeo and Jia, Tongqiu and Grosenick, Logan and Broxton, Michael and Deisseroth, Karl and Sejnowski, Terrence J and Greenspan, Ralph J} } @article {1669, title = {Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.}, journal = {Transl Psychiatry}, volume = {9}, year = {2019}, month = {2019 01 17}, pages = {24}, abstract = {

SETD5, a gene linked to intellectual disability (ID) and autism spectrum disorder (ASD), is a member of the SET-domain family and encodes a putative histone methyltransferase (HMT). To date, the mechanism by which SETD5 haploinsufficiency causes ASD/ID remains an unanswered question. Setd5 is the highly conserved mouse homolog, and although the Setd5 null mouse is embryonic lethal, the heterozygote is viable. Morphological tracing and multielectrode array was used on cultured cortical neurons. MRI was conducted of adult mouse brains and immunohistochemistry of juvenile mouse brains. RNA-Seq was used to investigate gene expression in the developing cortex. Behavioral assays were conducted on adult mice. Setd5 cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology. A specific subpopulation of fetal Setd5 cortical neurons showed altered gene expression of neurodevelopment-related genes. Setd5 animals manifested several autism-like behaviors, including hyperactivity, cognitive deficit, and altered social interactions. Anatomical differences were observed in Setd5 adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain. Our data converge on a picture of abnormal neurodevelopment driven by Setd5 haploinsufficiency, consistent with a highly penetrant risk factor.

}, keywords = {Animals, Autism Spectrum Disorder, Behavior, Animal, Brain, Female, Genetic Predisposition to Disease, Haploinsufficiency, Heterozygote, Magnetic Resonance Imaging, Male, Methyltransferases, Mice, Mice, Knockout, Mutation, Neurons}, issn = {2158-3188}, doi = {10.1038/s41398-018-0344-y}, author = {Moore, Spencer M and Seidman, Jason S and Ellegood, Jacob and Gao, Richard and Savchenko, Alex and Troutman, Ty D and Abe, Yohei and Stender, Josh and Lee, Daehoon and Wang, Sicong and Voytek, Bradley and Lerch, Jason P and Suh, Hoonkyo and Glass, Christopher K and Muotri, Alysson R} } @article {1696, title = {Multiplexed oscillations and phase rate coding in the basal forebrain.}, journal = {Sci Adv}, volume = {4}, year = {2018}, month = {2018 08}, pages = {eaar3230}, abstract = {

Complex behaviors demand temporal coordination among functionally distinct brain regions. The basal forebrain{\textquoteright}s afferent and efferent structure suggests a capacity for mediating this coordination at a large scale. During performance of a spatial orientation task, synaptic activity in this region was dominated by four amplitude-independent oscillations temporally organized by the phase of the slowest, a theta-frequency rhythm. Oscillation amplitudes were also organized by task epoch and positively correlated to the task-related modulation of individual neuron firing rates. For many neurons, spiking was temporally organized through phase precession against theta band field potential oscillations. Theta phase precession advanced in parallel to task progression, rather than absolute spatial location or time. Together, the findings reveal a process by which associative brain regions can integrate independent oscillatory inputs and transform them into sequence-specific, rate-coded outputs that are adaptive to the pace with which organisms interact with their environment.

}, keywords = {Animals, Basal Forebrain, Male, Models, Neurological, Neurons, Rats, Rats, Long-Evans, Space Perception, Theta Rhythm}, issn = {2375-2548}, doi = {10.1126/sciadv.aar3230}, author = {Tingley, David and Alexander, Andrew S and Quinn, Laleh K and Chiba, Andrea A and Nitz, Douglas} } @article {1686, title = {Spatial fine-mapping for gene-by-environment effects identifies risk hot spots for schizophrenia.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 12 13}, pages = {5296}, abstract = {

Spatial mapping is a promising strategy to investigate the mechanisms underlying the incidence of psychosis. We analyzed a case-cohort study (n = 24,028), drawn from the 1.47 million Danish persons born between 1981 and 2005, using a novel framework for decomposing the geospatial risk for schizophrenia based on locale of upbringing and polygenic scores. Upbringing in a high environmental risk locale increases the risk for schizophrenia by 122\%. Individuals living in a high gene-by-environmental risk locale have a 78\% increased risk compared to those who have the same genetic liability but live in a low-risk locale. Effects of specific locales vary substantially within the most densely populated city of Denmark, with hazard ratios ranging from 0.26 to 9.26 for environment and from 0.20 to 5.95 for gene-by-environment. These findings indicate the critical synergism of gene and environment on the etiology of schizophrenia and demonstrate the potential of incorporating geolocation in genetic studies.

}, keywords = {Chromosome Mapping, Denmark, Environment, Genetic Predisposition to Disease, Geography, Humans, Proof of Concept Study, Risk Factors, Schizophrenia}, issn = {2041-1723}, doi = {10.1038/s41467-018-07708-7}, author = {Fan, Chun Chieh and McGrath, John J and Appadurai, Vivek and Buil, Alfonso and Gandal, Michael J and Schork, Andrew J and Mortensen, Preben Bo and Agerbo, Esben and Geschwind, Sandy A and Geschwind, Daniel and Werge, Thomas and Thompson, Wesley K and Pedersen, Carsten B{\o}cker} } @article {1674, title = {Peripheral inflammation related to lower fMRI activation during a working memory task and resting functional connectivity among older adults: a preliminary study.}, journal = {Int J Geriatr Psychiatry}, volume = {32}, year = {2017}, month = {2017 Mar}, pages = {341-349}, abstract = {

OBJECTIVE: Peripheral inflammation has been associated with adverse effects on cognition and brain structure in late life, a process called {\textquoteright}inflammaging.{\textquoteright} Identifying biomarkers of preclinical cognitive decline is critical in the development of preventative therapies, and peripheral inflammation may be able to serve as an indicator of cognitive decline. However, little is known regarding the relationship between peripheral inflammation and brain structure and function among older adults.

METHODS: Twenty-four older adults (mean age = 78) underwent a functional magnetic resonance imaging (fMRI) resting state functional connectivity scan, and a subset (n = 14) completed the n-Back working memory task in the scanner. All participants completed a blood draw, and inflammation was measured with interleukin 6 (IL-6) and C-Reactive Protein (CRP).

RESULTS: Surprisingly, age was unrelated to measures of inflammation (IL-6, CRP) or brain function (default mode network (DMN) connectivity; working memory performance; blood oxygenation level dependent (BOLD) activation with higher working memory load). However, lower functional connectivity between the left parietal seed and all other DMN regions was associated with higher levels of IL-6 and CRP. Additionally, greater plasma concentration of IL-6 was associated with lower BOLD activation in the left middle frontal gyrus in response to increased working memory load.

CONCLUSIONS: These preliminary findings support the importance of IL-6 and CRP in brain function among older adults. Frontal and parietal regions may be particularly sensitive to the effects of inflammation. Additionally, these findings provide preliminary evidence of inflammatory contributions to level of neural activity, even after accounting for vascular risk factors.

}, keywords = {Aged, Brain Mapping, C-Reactive Protein, Cognition, Cognitive Dysfunction, Female, Frontal Lobe, Humans, Inflammation, Interleukin-6, Magnetic Resonance Imaging, Male, Memory, Short-Term, Parietal Lobe, Rest}, issn = {1099-1166}, doi = {10.1002/gps.4482}, author = {Dev, Sheena I and Moore, Raeanne C and Soontornniyomkij, Benchawanna and Achim, Cristian L and Jeste, Dilip V and Eyler, Lisa T} } @article {127, title = {Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder.}, journal = {Nature}, volume = {527}, year = {2015}, month = {2015 Nov 5}, pages = {95-9}, abstract = {

Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15\% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

}, keywords = {Action Potentials, Antipsychotic Agents, Bipolar Disorder, Calcium Signaling, Dentate Gyrus, Endophenotypes, Humans, Induced Pluripotent Stem Cells, Lithium Compounds, Male, Mitochondria, Neurons, Patch-Clamp Techniques}, issn = {1476-4687}, doi = {10.1038/nature15526}, author = {Mertens, Jerome and Wang, Qiu-Wen and Kim, Yongsung and Yu, Diana X and Pham, Son and Yang, Bo and Zheng, Yi and Diffenderfer, Kenneth E and Zhang, Jian and Soltani, Sheila and Eames, Tameji and Schafer, Simon T and Boyer, Leah and Marchetto, Maria C and Nurnberger, John I and Calabrese, Joseph R and {\O}degaard, Ketil J and McCarthy, Michael J and Zandi, Peter P and Alda, Martin and Alba, Martin and Nievergelt, Caroline M and Mi, Shuangli and Brennand, Kristen J and Kelsoe, John R and Gage, Fred H and Yao, Jun} } @article {129, title = {Primate-specific ORF0 contributes to retrotransposon-mediated diversity.}, journal = {Cell}, volume = {163}, year = {2015}, month = {2015 Oct 22}, pages = {583-93}, abstract = {

LINE-1 retrotransposons are fast-evolving mobile genetic entities that play roles in gene regulation, pathological conditions, and evolution. Here, we show that the primate LINE-1 5{\textquoteright}UTR contains a primate-specific open reading frame (ORF) in the antisense orientation that we named ORF0. The gene product of this ORF localizes to promyelocytic leukemia-adjacent nuclear bodies. ORF0 is present in more than 3,000 loci across human and chimpanzee genomes and has a promoter and a conserved strong Kozak sequence that supports translation. By virtue of containing two splice donor sites, ORF0 can also form fusion proteins with proximal exons. ORF0 transcripts are readily detected in induced pluripotent stem (iPS) cells from both primate species. Capped and polyadenylated ORF0 mRNAs are present in the cytoplasm, and endogenous ORF0 peptides are identified upon proteomic analysis. Finally, ORF0 enhances LINE-1 mobility. Taken together, these results suggest a role for ORF0 in retrotransposon-mediated diversity.

}, keywords = {5{\textquoteright} Untranslated Regions, Amino Acid Sequence, Animals, Base Sequence, Cytoplasm, Humans, Long Interspersed Nucleotide Elements, Molecular Sequence Data, Nuclear Proteins, Open Reading Frames, Pan troglodytes, Retroelements, Ribosomes, RNA Processing, Post-Transcriptional, RNA, Antisense, RNA, Messenger, Sequence Alignment}, issn = {1097-4172}, doi = {10.1016/j.cell.2015.09.025}, author = {Denli, Ahmet M and Narvaiza, I{\~n}igo and Kerman, Bilal E and Pena, Monique and Benner, Christopher and Marchetto, Maria C N and Diedrich, Jolene K and Aslanian, Aaron and Ma, Jiao and Moresco, James J and Moore, Lynne and Hunter, Tony and Saghatelian, Alan and Gage, Fred H} } @article {178, title = {Atypical right hemisphere specialization for object representations in an adolescent with specific language impairment.}, journal = {Front Hum Neurosci}, volume = {8}, year = {2014}, month = {2014}, pages = {82}, abstract = {

Individuals with a diagnosis of specific language impairment (SLI) show abnormal spoken language occurring alongside normal non-verbal abilities. Behaviorally, people with SLI exhibit diverse profiles of impairment involving phonological, grammatical, syntactic, and semantic aspects of language. In this study, we used a multimodal neuroimaging technique called anatomically constrained magnetoencephalography (aMEG) to measure the dynamic functional brain organization of an adolescent with SLI. Using single-subject statistical maps of cortical activity, we compared this patient to a sibling and to a cohort of typically developing subjects during the performance of tasks designed to evoke semantic representations of concrete objects. Localized patterns of brain activity within the language impaired patient showed marked differences from the typical functional organization, with significant engagement of right hemisphere heteromodal cortical regions generally homotopic to the left hemisphere areas that usually show the greatest activity for such tasks. Functional neuroanatomical differences were evident at early sensoriperceptual processing stages and continued through later cognitive stages, observed specifically at latencies typically associated with semantic encoding operations. Our findings show with real-time temporal specificity evidence for an atypical right hemisphere specialization for the representation of concrete entities, independent of verbal motor demands. More broadly, our results demonstrate the feasibility and potential utility of using aMEG to characterize individual patient differences in the dynamic functional organization of the brain.

}, issn = {1662-5161}, doi = {10.3389/fnhum.2014.00082}, author = {Brown, Timothy T and Erhart, Matthew and Avesar, Daniel and Dale, Anders M and Halgren, Eric and Evans, Julia L} } @article {173, title = {California can lead the way on brain research}, year = {2014}, url = {http://www.sacbee.com/opinion/op-ed/article2606601.html}, author = {Greenspan, RJ and Alivisatos, AP} } @article {214, title = {Covariate-modulated local false discovery rate for genome-wide association studies.}, journal = {Bioinformatics}, volume = {30}, year = {2014}, month = {2014 Aug 1}, pages = {2098-104}, abstract = {

MOTIVATION: Genome-wide association studies (GWAS) have largely failed to identify most of the genetic basis of highly heritable diseases and complex traits. Recent work has suggested this could be because many genetic variants, each with individually small effects, compose their genetic architecture, limiting the power of GWAS, given currently obtainable sample sizes. In this scenario, Bonferroni-derived thresholds are severely underpowered to detect the vast majority of associations. Local false discovery rate (fdr) methods provide more power to detect non-null associations, but implicit assumptions about the exchangeability of single nucleotide polymorphisms (SNPs) limit their ability to discover non-null loci.

METHODS: We propose a novel covariate-modulated local false discovery rate (cmfdr) that incorporates prior information about gene element-based functional annotations of SNPs, so that SNPs from categories enriched for non-null associations have a lower fdr for a given value of a test statistic than SNPs in unenriched categories. This readjustment of fdr based on functional annotations is achieved empirically by fitting a covariate-modulated parametric two-group mixture model. The proposed cmfdr methodology is applied to a large Crohn{\textquoteright}s disease GWAS.

RESULTS: Use of cmfdr dramatically improves power, e.g. increasing the number of loci declared significant at the 0.05 fdr level by a factor of 5.4. We also demonstrate that SNPs were declared significant using cmfdr compared with usual fdr replicate in much higher numbers, while maintaining similar replication rates for a given fdr cutoff in de novo samples, using the eight Crohn{\textquoteright}s disease substudies as independent training and test datasets. Availability an implementation: https://sites.google.com/site/covmodfdr/

CONTACT: : wes.stat@gmail.com

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

}, keywords = {Analysis of Variance, Bayes Theorem, Computational Biology, False Positive Reactions, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btu145}, author = {Zablocki, Rong W and Schork, Andrew J and Levine, Richard A and Andreassen, Ole A and Dale, Anders M and Thompson, Wesley K} } @article {208, title = {Inhibitory motor control based on complex stopping goals relies on the same brain network as simple stopping.}, journal = {Neuroimage}, volume = {103}, year = {2014}, month = {2014 Dec}, pages = {225-34}, abstract = {

Much research has modeled action-stopping using the stop-signal task (SST), in which an impending response has to be stopped when an explicit stop-signal occurs. A limitation of the SST is that real-world action-stopping rarely involves explicit stop-signals. Instead, the stopping-system engages when environmental features match more complex stopping goals. For example, when stepping into the street, one monitors path, velocity, size, and types of objects and only stops if there is a vehicle approaching. Here, we developed a task in which participants compared the visual features of a multidimensional go-stimulus to a complex stopping-template, and stopped their go-response if all features matched the template. We used independent component analysis of EEG data to show that the same motor inhibition brain network that explains action-stopping in the SST also implements motor inhibition in the complex-stopping task. Furthermore, we found that partial feature overlap between go-stimulus and stopping-template led to motor slowing, which also corresponded with greater stopping-network activity. This shows that the same brain system for action-stopping to explicit stop-signals is recruited to slow or stop behavior when stimuli match a complex stopping goal. The results imply a generalizability of the brain{\textquoteright}s network for simple action-stopping to more ecologically valid scenarios.

}, keywords = {Adolescent, Adult, Brain, Brain Mapping, Electroencephalography, Female, Goals, Humans, Inhibition (Psychology), Male, Psychomotor Performance, Reaction Time, Young Adult}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2014.09.048}, author = {Wessel, Jan R and Aron, Adam R} } @article {158, title = {Neuroscience. The brain activity map.}, journal = {Science}, volume = {339}, year = {2013}, month = {2013 Mar 15}, pages = {1284-5}, keywords = {Brain Diseases, Brain Mapping, Hippocampus, Humans, Neural Pathways, Neurons}, issn = {1095-9203}, doi = {10.1126/science.1236939}, author = {Alivisatos, A Paul and Chun, Miyoung and Church, George M and Deisseroth, Karl and Donoghue, John P and Greenspan, Ralph J and McEuen, Paul L and Roukes, Michael L and Sejnowski, Terrence J and Weiss, Paul S and Yuste, Rafael} } @article {181, title = {Atypical social referencing in infant siblings of children with autism spectrum disorders.}, journal = {J Autism Dev Disord}, volume = {42}, year = {2012}, month = {2012 Dec}, pages = {2611-21}, abstract = {

Social referencing was investigated in 18-month-old siblings of children with autism spectrum disorders (ASD; "high-risk infants"). Infants were exposed to novel toys, which were emotionally tagged via adults{\textquoteright} facial and vocal signals. Infants{\textquoteright} information seeking (initiation of joint attention with an adult) and their approach/withdrawal behavior toward the toys before versus after the adults{\textquoteright} emotional signals was measured. Compared to both typically developing infants and high-risk infants without ASD, infants later diagnosed with ASD engaged in slower information seeking, suggesting that this aspect of referencing may be an early indicator of ASD. High-risk infants, both those who were and those who were not later diagnosed with ASD, exhibited impairments in regulating their behavior based on the adults{\textquoteright} emotional signals, suggesting that this aspect of social referencing may reflect an endophenotype for ASD.

}, keywords = {Attention, Child, Child Development, Child Development Disorders, Pervasive, Child, Preschool, Emotions, Endophenotypes, Female, Humans, Infant, Infant Behavior, Male, Risk Factors, Siblings, Social Behavior}, issn = {1573-3432}, doi = {10.1007/s10803-012-1518-8}, author = {Cornew, Lauren and Dobkins, Karen R and Akshoomoff, Natacha and McCleery, Joseph P and Carver, Leslie J} } @article {159, title = {The brain activity map project and the challenge of functional connectomics.}, journal = {Neuron}, volume = {74}, year = {2012}, month = {2012 Jun 21}, pages = {970-4}, abstract = {

The function of neural circuits is an emergent property that arises from the coordinated activity of large numbers of neurons. To capture this, we propose launching a large-scale, international public effort, the Brain Activity Map Project, aimed at reconstructing the full record of neural activity across complete neural circuits. This technological challenge could prove to be an invaluable step toward understanding fundamental and pathological brain processes.

}, keywords = {Action Potentials, Brain, Brain Mapping, Humans, Models, Neurological, Nerve Net, Neural Pathways, Neurons}, issn = {1097-4199}, doi = {10.1016/j.neuron.2012.06.006}, author = {Alivisatos, A Paul and Chun, Miyoung and Church, George M and Greenspan, Ralph J and Roukes, Michael L and Yuste, Rafael} } @article {211, title = {Accumulation of neural activity in the posterior insula encodes the passage of time.}, journal = {Neuropsychologia}, volume = {48}, year = {2010}, month = {2010 Aug}, pages = {3110-20}, abstract = {

A number of studies have examined the perception of time with durations ranging from milliseconds to a few seconds, however the neural basis of these processes are still poorly understood and the neural substrates underlying the perception of multiple-second intervals are unknown. Here we present evidence of neural systems activity in circumscribed areas of the human brain involved in the encoding of intervals with durations of 9 and 18s in a temporal reproduction task using event-related functional magnetic resonance imaging (fMRI). During the encoding there was greater activation in more posterior parts of the medial frontal and insular cortex whereas the reproduction phase involved more anterior parts of these brain structures. Intriguingly, activation curves over time show an accumulating pattern of neural activity, which peaks at the end of the interval within bilateral posterior insula and superior temporal cortex when individuals are presented with 9- and 18-s tone intervals. This is consistent with an accumulator-type activity, which encodes duration in the multiple seconds range. Given the close connection between the dorsal posterior insula and ascending internal body signals, we suggest that the accumulation of physiological changes in body states constitutes our experience of time. This is the first time that an accumulation function in the posterior insula is detected that might be correlated with the encoding of time intervals.

}, keywords = {Adult, Analysis of Variance, Brain Mapping, Cerebral Cortex, Factor Analysis, Statistical, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Oxygen, Reaction Time, Time Factors, Time Perception, Young Adult}, issn = {1873-3514}, doi = {10.1016/j.neuropsychologia.2010.06.023}, author = {Wittmann, Marc and Simmons, Alan N and Aron, Jennifer L and Paulus, Martin P} } @article {174, title = {Adult neurogenesis: integrating theories and separating functions.}, journal = {Trends Cogn Sci}, volume = {14}, year = {2010}, month = {2010 Jul}, pages = {325-37}, abstract = {

The continuous incorporation of new neurons in the dentate gyrus of the adult hippocampus raises exciting questions about memory and learning, and has inspired new computational models to understand the function of adult neurogenesis. These theoretical approaches suggest distinct roles for new neurons as they slowly integrate into the existing dentate gyrus network: immature adult-born neurons seem to function as pattern integrators of temporally adjacent events, thereby enhancing pattern separation for events separated in time; whereas maturing adult-born neurons possibly contribute to pattern separation by being more amenable to learning new information, leading to dedicated groups of granule cells that respond to experienced environments. We review these hypothesized functions and supporting empirical research and point to new directions for future theoretical efforts.

}, keywords = {Adult, Adult Stem Cells, Animals, Cell Proliferation, Hippocampus, Humans, Models, Biological, Neurogenesis, Neurons}, issn = {1879-307X}, doi = {10.1016/j.tics.2010.04.003}, author = {Aimone, James B and Deng, Wei and Gage, Fred H} } @article {182, title = {New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?}, journal = {Nat Rev Neurosci}, volume = {11}, year = {2010}, month = {2010 May}, pages = {339-50}, abstract = {

The integration of adult-born neurons into the circuitry of the adult hippocampus suggests an important role for adult hippocampal neurogenesis in learning and memory, but its specific function in these processes has remained elusive. In this article, we summarize recent progress in this area, including advances based on behavioural studies and insights provided by computational modelling. Increasingly, evidence suggests that newborn neurons might be involved in hippocampal functions that are particularly dependent on the dentate gyrus, such as pattern separation. Furthermore, newborn neurons at different maturation stages may make distinct contributions to learning and memory. In particular, computational studies suggest that, before newborn neurons are fully mature, they might function as a pattern integrator by introducing a degree of similarity to the encoding of events that occur closely in time.

}, keywords = {Adult Stem Cells, Animals, Hippocampus, Humans, Learning, Memory, Models, Neurological, Neurogenesis, Neurons}, issn = {1471-0048}, doi = {10.1038/nrn2822}, author = {Deng, Wei and Aimone, James B and Gage, Fred H} } @article {194, title = {Atypical face versus object processing and hemispheric asymmetries in 10-month-old infants at risk for autism.}, journal = {Biol Psychiatry}, volume = {66}, year = {2009}, month = {2009 Nov 15}, pages = {950-7}, abstract = {

BACKGROUND: Previous studies have documented atypicalities in face/object processing in children and adults with autism spectrum disorders (ASDs). To investigate whether such atypicalities may reflect a genetically mediated risk factor present early in development, we measured face/object processing in 10-month-old high-risk infants who carry some of the genes associated with ASD because they have an older sibling diagnosed with the disorder.

METHODS: We employed event-related potentials (ERPs) to measure cortical responses to pictures of faces and objects, the objects being toys. Latencies and amplitudes of four ERP components (P100, N290, P400, and Nc) were compared between 20 high-risk infants and 20 low-risk control subjects (infants with no family history of ASD).

RESULTS: Responses to faces versus objects differed between high- and low-risk infants for the latencies of the N290 and P400. Differences were driven by faster responses to faces than objects in low-risk, but not high-risk, infants (P400) and, conversely, faster responses to objects than faces in high-risk, but not low-risk, infants (N290). Object responses were also faster in high-risk than low-risk infants (both N290 and P400). Left versus right hemisphere responses also differed between high- and low-risk infants for the amplitudes of the P100, N290, and P400; collapsed across faces/objects, low-risk, but not high-risk, infants exhibited hemisphere asymmetries.

CONCLUSIONS: Genetic risk for ASD is associated with atypical face versus object processing and an atypical lack of hemispheric asymmetry early in life. These atypicalities might contribute to development of the disorder.

}, keywords = {Analysis of Variance, Autistic Disorder, Brain, Brain Mapping, Cerebral Cortex, Child, Child, Preschool, Electroencephalography, Evoked Potentials, Face, Female, Fourier Analysis, Functional Laterality, Humans, Infant, Male, Neuropsychological Tests, Pattern Recognition, Visual, Photic Stimulation, Reaction Time, Risk}, issn = {1873-2402}, doi = {10.1016/j.biopsych.2009.07.031}, author = {McCleery, Joseph P and Akshoomoff, Natacha and Dobkins, Karen R and Carver, Leslie J} } @article {175, title = {Computational influence of adult neurogenesis on memory encoding.}, journal = {Neuron}, volume = {61}, year = {2009}, month = {2009 Jan 29}, pages = {187-202}, abstract = {

Adult neurogenesis in the hippocampus leads to the incorporation of thousands of new granule cells into the dentate gyrus every month, but its function remains unclear. Here, we present computational evidence that indicates that adult neurogenesis may make three separate but related contributions to memory formation. First, immature neurons introduce a degree of similarity to memories learned at the same time, a process we refer to as pattern integration. Second, the extended maturation and change in excitability of these neurons make this added similarity a time-dependent effect, supporting the possibility that temporal information is included in new hippocampal memories. Finally, our model suggests that the experience-dependent addition of neurons results in a dentate gyrus network well suited for encoding new memories in familiar contexts while treating novel contexts differently. Taken together, these results indicate that new granule cells may affect hippocampal function in several unique and previously unpredicted ways.

}, keywords = {Age Factors, Algorithms, Animals, Cell Proliferation, Computer Simulation, Dentate Gyrus, Humans, Memory, Nerve Net, Neural Pathways, Neurogenesis, Neuronal Plasticity, Neurons, Stem Cells, Synapses, Time Perception}, issn = {1097-4199}, doi = {10.1016/j.neuron.2008.11.026}, author = {Aimone, James B and Wiles, Janet and Gage, Fred H} } @article {147, title = {Dopaminergic modulation of arousal in Drosophila.}, journal = {Curr Biol}, volume = {15}, year = {2005}, month = {2005 Jul 12}, pages = {1165-75}, abstract = {

BACKGROUND: Arousal levels in the brain set thresholds for behavior, from simple to complex. The mechanistic underpinnings of the various phenomena comprising arousal, however, are still poorly understood. Drosophila behaviors have been studied that span different levels of arousal, from sleep to visual perception to psychostimulant responses.

RESULTS: We have investigated neurobiological mechanisms of arousal in the Drosophila brain by a combined behavioral, genetic, pharmacological, and electrophysiological approach. Administration of methamphetamine (METH) suppresses sleep and promotes active wakefulness, whereas an inhibitor of dopamine synthesis promotes sleep. METH affects courtship behavior by increasing sexual arousal while decreasing successful sexual performance. Electrophysiological recordings from the medial protocerebrum of wild-type flies showed that METH ingestion has rapid and detrimental effects on a brain response associated with perception of visual stimuli. Recordings in genetically manipulated animals show that dopaminergic transmission is required for these responses and that visual-processing deficits caused by attenuated dopaminergic transmission can be rescued by METH.

CONCLUSIONS: We show that changes in dopamine levels differentially affect arousal for behaviors of varying complexity. Complex behaviors, such as visual perception, degenerate when dopamine levels are either too high or too low, in accordance with the inverted-U hypothesis of dopamine action in the mammalian brain. Simpler behaviors, such as sleep and locomotion, show graded responses that follow changes in dopamine level.

}, keywords = {Animals, Animals, Genetically Modified, Arousal, Brain, Dopa Decarboxylase, Dopamine, Dose-Response Relationship, Drug, Drosophila, Drosophila Proteins, Dynamins, Electrophysiology, Methamphetamine, Mutation, Sexual Behavior, Animal, Sleep, Visual Perception}, issn = {0960-9822}, doi = {10.1016/j.cub.2005.05.025}, author = {Andretic, Rozi and van Swinderen, Bruno and Greenspan, Ralph J} }