@article {2288, title = {Electro-optical mechanically flexible coaxial microprobes for minimally invasive interfacing with intrinsic neural circuits.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 Jun 07}, pages = {3286}, abstract = {

Central to advancing our understanding of neural circuits is developing minimally invasive, multi-modal interfaces capable of simultaneously recording and modulating neural activity. Recent devices have focused on matching the mechanical compliance of tissue to reduce inflammatory responses. However, reductions in the size of multi-modal interfaces are needed to further improve biocompatibility and long-term recording capabilities. Here a multi-modal coaxial microprobe design with a minimally invasive footprint (8-14 {\textmu}m diameter over millimeter lengths) that enables efficient electrical and optical interrogation of neural networks is presented. In the brain, the probes allowed robust electrical measurement and optogenetic stimulation. Scalable fabrication strategies can be used with various electrical and optical materials, making the probes highly customizable to experimental requirements, including length, diameter, and mechanical properties. Given their negligible inflammatory response, these probes promise to enable a new generation of readily tunable multi-modal devices for long-term, minimally invasive interfacing with neural circuits.

}, keywords = {Brain, Optogenetics}, issn = {2041-1723}, doi = {10.1038/s41467-022-30275-x}, author = {Ward, Spencer and Riley, Conor and Carey, Erin M and Nguyen, Jenny and Esener, Sadik and Nimmerjahn, Axel and Sirbuly, Donald J} } @article {2298, title = {Intestinal transgene delivery with native E.~coli chassis allows persistent physiological changes.}, journal = {Cell}, volume = {185}, year = {2022}, month = {2022 Aug 18}, pages = {3263-3277.e15}, abstract = {

Live bacterial therapeutics (LBTs) could reverse diseases by engrafting in the gut and providing persistent beneficial functions in the host. However, attempts to functionally manipulate the gut microbiome of conventionally raised (CR) hosts have been unsuccessful because engineered microbial organisms (i.e., chassis) have difficulty in colonizing the hostile luminal environment. In this proof-of-concept study, we use native bacteria as chassis for transgene delivery to impact CR host physiology. Native Escherichia coli bacteria isolated from the stool cultures of CR mice were modified to express functional genes. The reintroduction of these strains induces perpetual engraftment in the intestine. In addition, engineered native E.\ coli can induce functional changes that affect physiology of and reverse pathology in CR hosts months after administration. Thus, using native bacteria as chassis to "knock in" specific functions allows mechanistic studies of specific microbial activities in the microbiome of CR hosts and enables LBT with curative intent.

}, keywords = {Animals, Bacteria, Escherichia coli, Gastrointestinal Microbiome, Mice, Microbiota, Transgenes}, issn = {1097-4172}, doi = {10.1016/j.cell.2022.06.050}, author = {Russell, Baylee J and Brown, Steven D and Siguenza, Nicole and Mai, Irene and Saran, Anand R and Lingaraju, Amulya and Maissy, Erica S and Dantas Machado, Ana C and Pinto, Antonio F M and Sanchez, Concepcion and Rossitto, Leigh-Ana and Miyamoto, Yukiko and Richter, R Alexander and Ho, Samuel B and Eckmann, Lars and Hasty, Jeff and Gonzalez, David J and Saghatelian, Alan and Knight, Rob and Zarrinpar, Amir} } @article {2291, title = {knockout in excitatory neurons impairs postnatal synapse maturation and increases the repressive histone modification H3K27me3.}, journal = {Elife}, volume = {11}, year = {2022}, month = {2022 May 23}, abstract = {

Two epigenetic pathways of transcriptional repression, DNA methylation and polycomb repressive complex 2 (PRC2), are known to regulate neuronal development and function. However, their respective contributions to brain maturation are unknown. We found that conditional loss of the de novo DNA methyltransferase in mouse excitatory neurons altered expression of synapse-related genes, stunted synapse maturation, and impaired working memory and social interest. At the genomic level, loss of abolished postnatal accumulation of CG and non-CG DNA methylation, leaving adult neurons with an unmethylated, fetal-like epigenomic pattern at ~222,000 genomic regions. The PRC2-associated histone modification, H3K27me3, increased at many of these sites. Our data support a dynamic interaction between two fundamental modes of epigenetic repression during postnatal maturation of excitatory neurons, which together confer robustness on neuronal regulation.

}, keywords = {Animals, Brain, Disease Models, Animal, DNA Methyltransferase 3A, Histone Code, Histones, Mice, Mice, Knockout, Neurons, Polycomb Repressive Complex 2, Synapses}, issn = {2050-084X}, doi = {10.7554/eLife.66909}, author = {Li, Junhao and Pinto-Duarte, Ant{\'o}nio and Zander, Mark and Cuoco, Michael S and Lai, Chi-Yu and Osteen, Julia and Fang, Linjing and Luo, Chongyuan and Lucero, Jacinta D and Gomez-Castanon, Rosa and Nery, Joseph R and Silva-Garcia, Isai and Pang, Yan and Sejnowski, Terrence J and Powell, Susan B and Ecker, Joseph R and Mukamel, Eran A and Behrens, M Margarita} } @article {1693, title = {Asymmetric ephaptic inhibition between compartmentalized olfactory receptor neurons.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 04 05}, pages = {1560}, abstract = {

In the Drosophila antenna, different subtypes of olfactory receptor neurons (ORNs) housed in the same sensory hair (sensillum) can inhibit each other non-synaptically. However, the mechanisms underlying this underexplored form of lateral inhibition remain unclear. Here we use recordings from pairs of sensilla impaled by the same tungsten electrode to demonstrate that direct electrical ("ephaptic") interactions mediate lateral inhibition between ORNs. Intriguingly, within individual sensilla, we find that ephaptic lateral inhibition is asymmetric such that one ORN exerts greater influence onto its neighbor. Serial block-face scanning electron microscopy of genetically identified ORNs and circuit modeling indicate that asymmetric lateral inhibition reflects a surprisingly simple mechanism: the physically larger ORN in a pair corresponds to the dominant neuron in ephaptic interactions. Thus, morphometric differences between compartmentalized ORNs account for highly specialized inhibitory interactions that govern information processing at the earliest stages of olfactory coding.

}, keywords = {Animals, Drosophila, Imaging, Three-Dimensional, Models, Biological, Olfactory Pathways, Olfactory Receptor Neurons, Sensilla, Smell}, issn = {2041-1723}, doi = {10.1038/s41467-019-09346-z}, author = {Zhang, Ye and Tsang, Tin Ki and Bushong, Eric A and Chu, Li-An and Chiang, Ann-Shyn and Ellisman, Mark H and Reingruber, J{\"u}rgen and Su, Chih-Ying} } @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 {1695, title = {High-quality ultrastructural preservation using cryofixation for 3D electron microscopy of genetically labeled tissues.}, journal = {Elife}, volume = {7}, year = {2018}, month = {2018 05 11}, abstract = {

Electron microscopy (EM) offers unparalleled power to study cell substructures at the nanoscale. Cryofixation by high-pressure freezing offers optimal morphological preservation, as it captures cellular structures instantaneously in their near-native state. However, the applicability of cryofixation is limited by its incompatibility with diaminobenzidine labeling using genetic EM tags and the high-contrast staining required for serial block-face scanning electron microscopy (SBEM). In addition, it is challenging to perform correlated light and electron microscopy (CLEM) with cryofixed samples. Consequently, these powerful methods cannot be applied to address questions requiring optimal morphological preservation. Here, we developed an approach that overcomes these limitations; it enables genetically labeled, cryofixed samples to be characterized with SBEM and 3D CLEM. Our approach is broadly applicable, as demonstrated in cultured cells, olfactory organ and mouse brain. This optimization exploits the potential of cryofixation, allowing for quality ultrastructural preservation for diverse EM applications.

}, keywords = {Animal Structures, Animals, Brain, Cryopreservation, Drosophila, Imaging, Three-Dimensional, Mice, Microscopy, Electron, Scanning, Sense Organs}, issn = {2050-084X}, doi = {10.7554/eLife.35524}, author = {Tsang, Tin Ki and Bushong, Eric A and Boassa, Daniela and Hu, Junru and Romoli, Benedetto and Phan, Sebastien and Dulcis, Davide and Su, Chih-Ying and Ellisman, Mark H} } @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 {124, title = {Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders.}, journal = {Stem Cell Reports}, volume = {5}, year = {2015}, month = {2015 Dec 8}, pages = {933-45}, abstract = {

As a group, we met to discuss the current challenges for creating meaningful patient-specific in vitro models to study brain disorders. Although the convergence of findings between laboratories and patient cohorts provided us confidence and optimism that hiPSC-based platforms will inform future drug discovery efforts, a number of critical technical challenges remain. This opinion piece outlines our collective views on the current state of hiPSC-based disease modeling and discusses what we see to be the critical objectives that must be addressed collectively as a field.

}, issn = {2213-6711}, doi = {10.1016/j.stemcr.2015.10.011}, author = {Brennand, Kristen J and Marchetto, M Carol and Benvenisty, Nissim and Br{\"u}stle, Oliver and Ebert, Allison and Izpisua Belmonte, Juan Carlos and Kaykas, Ajamete and Lancaster, Madeline A and Livesey, Frederick J and McConnell, Michael J and McKay, Ronald D and Morrow, Eric M and Muotri, Alysson R and Panchision, David M and Rubin, Lee L and Sawa, Akira and Soldner, Frank and Song, Hongjun and Studer, Lorenz and Temple, Sally and Vaccarino, Flora M and Wu, Jun and Vanderhaeghen, Pierre and Gage, Fred H and Jaenisch, Rudolf} } @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 {1673, title = {Distinct neural correlates of emotional and cognitive empathy in older adults.}, journal = {Psychiatry Res}, volume = {232}, year = {2015}, month = {2015 Apr 30}, pages = {42-50}, abstract = {

Empathy is thought to be a mechanism underlying prosocial behavior across the lifespan, yet little is known about how levels of empathy relate to individual differences in brain functioning among older adults. In this exploratory study, we examined the neural correlates of affective and cognitive empathy in older adults. Thirty older adults (M=79 years) underwent fMRI scanning and neuropsychological testing and completed a test of affective and cognitive empathy. Brain response during processing of cognitive and emotional stimuli was measured by fMRI in a priori and task-related regions and was correlated with levels of empathy. Older adults with higher levels of affective empathy showed more deactivation in the amygdala and insula during a working memory task, whereas those with higher cognitive empathy showed greater insula activation during a response inhibition task. Our preliminary findings suggest that brain systems linked to emotional and social processing respond differently among older adults with more or less affective and cognitive empathy. That these relationships can be seen both during affective and non-emotional tasks of "cold" cognitive abilities suggests that empathy may impact social behavior through both emotional and cognitive mechanisms.

}, keywords = {Affect, Aged, Aged, 80 and over, Aging, Brain, Brain Mapping, Cognition, Emotions, Empathy, Female, Humans, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Social Behavior, Social Perception}, issn = {1872-7123}, doi = {10.1016/j.pscychresns.2014.10.016}, author = {Moore, Raeanne C and Dev, Sheena I and Jeste, Dilip V and Dziobek, Isabel and Eyler, Lisa T} } @article {199, title = {From suffering to caring: a model of differences among older adults in levels of compassion.}, journal = {Int J Geriatr Psychiatry}, volume = {30}, year = {2015}, month = {2015 Feb}, pages = {185-91}, abstract = {

OBJECTIVE: Compassion is an important contributor to pro-social behavior and maintenance of interpersonal relationships, yet little is known about what factors influence compassion in late life. The aim of this study was to test theories about how past and current stressors and emotional functioning, resilience, and demographic indicators of life experiences are related to compassion among older adults.

METHODS: One thousand and six older adults (50-99 years) completed a comprehensive survey including self-report measures of compassion, resilience, past and present stress, and emotional functioning (i.e., stressful life events, perceived stress, and current and prior depression and anxiety), and demographic information. The sample was randomly split, and exploratory and confirmatory regression analyses were conducted testing hypothesized relationships with compassion.

RESULTS: Exploratory stepwise regression analysis (n = 650) indicated that participants who reported higher levels of compassion were more likely to be female, not currently in a married/married-like relationship, reported higher resilience levels, and had experienced more significant life events. Age, income level, past and current mental distress, and interactions between resilience and other predictors were not significantly related to compassion. The associations between greater self-reported compassion and being female, having greater resilience, and having experienced more significant life events were supported by a confirmatory stepwise regression analysis (n = 356).

CONCLUSIONS: Older women report more compassion than older men. Resilience and significant life events, independently, also appear to facilitate a desire to help others, while current stress and past and present emotional functioning are less relevant. Specificity of findings to older adults is not yet known.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Empathy, Female, Humans, Life Change Events, Male, Marital Status, Middle Aged, Regression Analysis, Resilience, Psychological, Sex Factors, Socioeconomic Factors}, issn = {1099-1166}, doi = {10.1002/gps.4123}, author = {Moore, Raeanne C and Martin, A{\textquoteright}verria Sirkin and Kaup, Allison R and Thompson, Wesley K and Peters, Matthew E and Jeste, Dilip V and Golshan, Shahrokh and Eyler, Lisa T} } @article {205, title = {Age-related changes in tissue signal properties within cortical areas important for word understanding in 12- to 19-month-old infants.}, journal = {Cereb Cortex}, volume = {24}, year = {2014}, month = {2014 Jul}, pages = {1948-55}, abstract = {

Recently, our laboratory has shown that the neural mechanisms for encoding lexico-semantic information in adults operate functionally by 12-18 months of age within left frontotemporal cortices (Travis et al., 2011. Spatiotemporal neural dynamics of word understanding in 12- to 18-month-old-infants. Cereb Cortex. 8:1832-1839). However, there is minimal knowledge of the structural changes that occur within these and other cortical regions important for language development. To identify regional structural changes taking place during this important period in infant development, we examined age-related changes in tissue signal properties of gray matter (GM) and white matter (WM) intensity and contrast. T1-weighted surface-based measures were acquired from 12- to 19-month-old infants and analyzed using a general linear model. Significant age effects were observed for GM and WM intensity and contrast within bilateral inferior lateral and anterovental temporal regions, dorsomedial frontal, and superior parietal cortices. Region of interest (ROI) analyses revealed that GM and WM intensity and contrast significantly increased with age within the same left lateral temporal regions shown to generate lexico-semantic activity in infants and adults. These findings suggest that neurophysiological processes supporting linguistic and cognitive behaviors may develop before cellular and structural maturation is complete within associative cortices. These results have important implications for understanding the neurobiological mechanisms relating structural to functional brain development.

}, keywords = {Aging, Brain Mapping, Cerebral Cortex, Comprehension, Female, Humans, Image Processing, Computer-Assisted, Infant, Language Development, Magnetic Resonance Imaging, Male, Vocabulary}, issn = {1460-2199}, doi = {10.1093/cercor/bht052}, author = {Travis, Katherine E and Curran, Megan M and Torres, Christina and Leonard, Matthew K and Brown, Timothy T and Dale, Anders M and Elman, Jeffrey L and Halgren, Eric} } @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 {180, title = {Speech-specific tuning of neurons in human superior temporal gyrus.}, journal = {Cereb Cortex}, volume = {24}, year = {2014}, month = {2014 Oct}, pages = {2679-93}, abstract = {

How the brain extracts words from auditory signals is an unanswered question. We recorded approximately 150 single and multi-units from the left anterior superior temporal gyrus of a patient during multiple auditory experiments. Against low background activity, 45\% of units robustly fired to particular spoken words with little or no response to pure tones, noise-vocoded speech, or environmental sounds. Many units were tuned to complex but specific sets of phonemes, which were influenced by local context but invariant to speaker, and suppressed during self-produced speech. The firing of several units to specific visual letters was correlated with their response to the corresponding auditory phonemes, providing the first direct neural evidence for phonological recoding during reading. Maximal decoding of individual phonemes and words identities was attained using firing rates from approximately 5 neurons within 200 ms after word onset. Thus, neurons in human superior temporal gyrus use sparse spatially organized population encoding of complex acoustic-phonetic features to help recognize auditory and visual words.

}, keywords = {Acoustic Stimulation, Adult, Humans, Male, Neurons, Phonetics, Speech Perception, Temporal Lobe}, issn = {1460-2199}, doi = {10.1093/cercor/bht127}, author = {Chan, Alexander M and Dykstra, Andrew R and Jayaram, Vinay and Leonard, Matthew K and Travis, Katherine E and Gygi, Brian and Baker, Janet M and Eskandar, Emad and Hochberg, Leigh R and Halgren, Eric and Cash, Sydney S} } @article {204, title = {Independence of early speech processing from word meaning.}, journal = {Cereb Cortex}, volume = {23}, year = {2013}, month = {2013 Oct}, pages = {2370-9}, abstract = {

We combined magnetoencephalography (MEG) with magnetic resonance imaging and electrocorticography to separate in anatomy and latency 2 fundamental stages underlying speech comprehension. The first acoustic-phonetic stage is selective for words relative to control stimuli individually matched on acoustic properties. It begins \~{}60 ms after stimulus onset and is localized to middle superior temporal cortex. It was replicated in another experiment, but is strongly dissociated from the response to tones in the same subjects. Within the same task, semantic priming of the same words by a related picture modulates cortical processing in a broader network, but this does not begin until \~{}217 ms. The earlier onset of acoustic-phonetic processing compared with lexico-semantic modulation was significant in each individual subject. The MEG source estimates were confirmed with intracranial local field potential and high gamma power responses acquired in 2 additional subjects performing the same task. These recordings further identified sites within superior temporal cortex that responded only to the acoustic-phonetic contrast at short latencies, or the lexico-semantic at long. The independence of the early acoustic-phonetic response from semantic context suggests a limited role for lexical feedback in early speech perception.

}, keywords = {Adult, Brain, Brain Mapping, Female, Humans, Magnetic Resonance Imaging, Magnetoencephalography, Male, Speech Perception, Young Adult}, issn = {1460-2199}, doi = {10.1093/cercor/bhs228}, author = {Travis, Katherine E and Leonard, Matthew K and Chan, Alexander M and Torres, Christina and Sizemore, Marisa L and Qu, Zhe and Eskandar, Emad and Dale, Anders M and Elman, Jeffrey L and Cash, Sydney S and Halgren, Eric} } @article {192, title = {Language proficiency modulates the recruitment of non-classical language areas in bilinguals.}, journal = {PLoS One}, volume = {6}, year = {2011}, month = {2011}, pages = {e18240}, abstract = {

Bilingualism provides a unique opportunity for understanding the relative roles of proficiency and order of acquisition in determining how the brain represents language. In a previous study, we combined magnetoencephalography (MEG) and magnetic resonance imaging (MRI) to examine the spatiotemporal dynamics of word processing in a group of Spanish-English bilinguals who were more proficient in their native language. We found that from the earliest stages of lexical processing, words in the second language evoke greater activity in bilateral posterior visual regions, while activity to the native language is largely confined to classical left hemisphere fronto-temporal areas. In the present study, we sought to examine whether these effects relate to language proficiency or order of language acquisition by testing Spanish-English bilingual subjects who had become dominant in their second language. Additionally, we wanted to determine whether activity in bilateral visual regions was related to the presentation of written words in our previous study, so we presented subjects with both written and auditory words. We found greater activity for the less proficient native language in bilateral posterior visual regions for both the visual and auditory modalities, which started during the earliest word encoding stages and continued through lexico-semantic processing. In classical left fronto-temporal regions, the two languages evoked similar activity. Therefore, it is the lack of proficiency rather than secondary acquisition order that determines the recruitment of non-classical areas for word processing.

}, keywords = {Adult, Brain Mapping, Female, Humans, Language, Language Development, Magnetic Resonance Imaging, Magnetoencephalography, Male, Multilingualism, Young Adult}, issn = {1932-6203}, doi = {10.1371/journal.pone.0018240}, author = {Leonard, Matthew K and Torres, Christina and Travis, Katherine E and Brown, Timothy T and Hagler, Donald J and Dale, Anders M and Elman, Jeffrey L and Halgren, Eric} } @article {206, title = {Spatiotemporal neural dynamics of word understanding in 12- to 18-month-old-infants.}, journal = {Cereb Cortex}, volume = {21}, year = {2011}, month = {2011 Aug}, pages = {1832-9}, abstract = {

Learning words is central in human development. However, lacking clear evidence for how or where language is processed in the developing brain, it is unknown whether these processes are similar in infants and adults. Here, we use magnetoencephalography in combination with high-resolution structural magnetic resonance imaging to noninvasively estimate the spatiotemporal distribution of word-selective brain activity in 12- to 18-month-old infants. Infants watched pictures of common objects and listened to words that they understood. A subset of these infants also listened to familiar words compared with sensory control sounds. In both experiments, words evoked a characteristic event-related brain response peaking \~{}400 ms after word onset, which localized to left frontotemporal cortices. In adults, this activity, termed the N400m, is associated with lexico-semantic encoding. Like adults, we find that the amplitude of the infant N400m is also modulated by semantic priming, being reduced to words preceded by a semantically related picture. These findings suggest that similar left frontotemporal areas are used for encoding lexico-semantic information throughout the life span, from the earliest stages of word learning. Furthermore, this ontogenetic consistency implies that the neurophysiological processes underlying the N400m may be important both for understanding already known words and for learning new words.

}, keywords = {Adult, Brain Mapping, Cerebral Cortex, Evoked Potentials, Auditory, Female, Humans, Infant, Language Tests, Learning, Magnetic Resonance Imaging, Magnetoencephalography, Male, Neurons, Speech Perception, Vocabulary}, issn = {1460-2199}, doi = {10.1093/cercor/bhq259}, author = {Travis, Katherine E and Leonard, Matthew K and Brown, Timothy T and Hagler, Donald J and Curran, Megan and Dale, Anders M and Elman, Jeffrey L and Halgren, Eric} } @article {191, title = {Spatiotemporal dynamics of bilingual word processing.}, journal = {Neuroimage}, volume = {49}, year = {2010}, month = {2010 Feb 15}, pages = {3286-94}, abstract = {

Studies with monolingual adults have identified successive stages occurring in different brain regions for processing single written words. We combined magnetoencephalography and magnetic resonance imaging to compare these stages between the first (L1) and second (L2) languages in bilingual adults. L1 words in a size judgment task evoked a typical left-lateralized sequence of activity first in ventral occipitotemporal cortex (VOT: previously associated with visual word-form encoding) and then ventral frontotemporal regions (associated with lexico-semantic processing). Compared to L1, words in L2 activated right VOT more strongly from approximately 135 ms; this activation was attenuated when words became highly familiar with repetition. At approximately 400 ms, L2 responses were generally later than L1, more bilateral, and included the same lateral occipitotemporal areas as were activated by pictures. We propose that acquiring a language involves the recruitment of right hemisphere and posterior visual areas that are not necessary once fluency is achieved.

}, keywords = {Adolescent, Adult, Brain, Brain Mapping, Female, Functional Laterality, Humans, Magnetoencephalography, Male, Multilingualism, Nerve Net, Pattern Recognition, Visual, Reading, Semantics, Young Adult}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2009.12.009}, author = {Leonard, Matthew K and Brown, Timothy T and Travis, Katherine E and Gharapetian, Lusineh and Hagler, Donald J and Dale, Anders M and Elman, Jeffrey L and Halgren, Eric} }