Toward a brighter constellation: multiorgan neuroimaging of neural and vascular dynamics in the spinal cord and brain.

Significance: Pain comprises a complex interaction between motor action and somatosensation that is dependent on dynamic interactions between the brain and spinal cord. This makes understanding pain particularly challenging as it involves rich interactions between many circuits (e.g., neural and vascular) and signaling cascades throughout the body. As such, experimentation on a single region may lead to an incomplete and potentially incorrect understanding of crucial underlying mechanisms. Aim: We aimed to develop and validate tools to enable detailed and extended observation of neural and vascular activity in the brain and spinal cord. The first key set of innovations was targeted to developing novel imaging hardware that addresses the many challenges of multisite imaging. The second key set of innovations was targeted to enabling bioluminescent (BL) imaging, as this approach can address limitations of fluorescent microscopy including photobleaching, phototoxicity, and decreased resolution due to scattering of excitation signals. Approach: We designed 3D-printed brain and spinal cord implants to enable effective surgical implantations and optical access with wearable miniscopes or an open window (e.g., for one- or two-photon microscopy or optogenetic stimulation). We also tested the viability for BL imaging and developed a novel modified miniscope optimized for these signals (BLmini). Results: We describe "universal" implants for acute and chronic simultaneous brain-spinal cord imaging and optical stimulation. We further describe successful imaging of BL signals in both foci and a new miniscope, the "BLmini," which has reduced weight, cost, and form-factor relative to standard wearable miniscopes. Conclusions: The combination of 3D-printed implants, advanced imaging tools, and bioluminescence imaging techniques offers a coalition of methods for understanding spinal cord-brain interactions. Our work has the potential for use in future research into neuropathic pain and other sensory disorders and motor behavior.

A Bioluminescent Activity Dependent (BLADe) Platform for Converting Neuronal Activity to Photoreceptor Activation.

We developed a platform that utilizes a calcium-dependent luciferase to convert neuronal activity into activation of light sensing domains within the same cell. The platform is based on a Gaussia luciferase variant with high light emission split by calmodulin-M13 sequences that depends on influx of calcium ions (Ca2+) for functional reconstitution. In the presence of its luciferin, coelenterazine (CTZ), Ca2+ influx results in light emission that drives activation of photoreceptors, including optogenetic channels and LOV domains. Critical features of the converter luciferase are light emission low enough to not activate photoreceptors under baseline condition and high enough to activate photosensing elements in the presence of Ca2+ and luciferin. We demonstrate performance of this activity-dependent sensor and integrator for changing membrane potential and driving transcription in individual and populations of neurons in vitro and in vivo.

Multi-finger receptive field properties in primary somatosensory cortex: A revised account of the spatiotemporal integration functions of area 3b.

The leading view in the somatosensory system indicates that area 3b serves as a cortical relay site that primarily encodes (cutaneous) tactile features limited to individual digits. Our recent work argues against this model by showing that area 3b cells can integrate both cutaneous and proprioceptive information from the hand. Here, we further test the validity of this model by studying multi-digit (MD) integration properties in area 3b. In contrast to the prevailing view, we show that most cells in area 3b have a receptive field (RF) that extends to multiple digits, with the size of the RF (i.e., the number of responsive digits) increasing across time. Further, we show that MD cells' orientation angle preference is highly correlated across digits. Taken together, these data show that area 3b plays a larger role in generating neural representations of tactile objects, as opposed to just being a "feature detector" relay site.

Towards a Brighter Constellation: Multi-Organ Neuroimaging of Neural and Vascular Dynamics in the Spinal Cord and Brain.

Significance: Pain is comprised of a complex interaction between motor action and somatosensation that is dependent on dynamic interactions between the brain and spinal cord. This makes understanding pain particularly challenging as it involves rich interactions between many circuits (e.g., neural and vascular) and signaling cascades throughout the body. As such, experimentation on a single region may lead to an incomplete and potentially incorrect understanding of crucial underlying mechanisms. Aim: Here, we aimed to develop and validate new tools to enable detailed and extended observation of neural and vascular activity in the brain and spinal cord. The first key set of innovations were targeted to developing novel imaging hardware that addresses the many challenges of multi-site imaging. The second key set of innovations were targeted to enabling bioluminescent imaging, as this approach can address limitations of fluorescent microscopy including photobleaching, phototoxicity and decreased resolution due to scattering of excitation signals. Approach: We designed 3D-printed brain and spinal cord implants to enable effective surgical implantations and optical access with wearable miniscopes or an open window (e.g., for one- or two-photon microscopy or optogenetic stimulation). We also tested the viability for bioluminescent imaging, and developed a novel modified miniscope optimized for these signals (BLmini). Results: Here, we describe novel 'universal' implants for acute and chronic simultaneous brain-spinal cord imaging and optical stimulation. We further describe successful imaging of bioluminescent signals in both foci, and a new miniscope, the 'BLmini,' which has reduced weight, cost and form-factor relative to standard wearable miniscopes. Conclusions: The combination of 3D printed implants, advanced imaging tools, and bioluminescence imaging techniques offers a new coalition of methods for understanding spinal cord-brain interactions. This work has the potential for use in future research into neuropathic pain and other sensory disorders and motor behavior.

Comparison of Scalp ERP to Faces in Macaques and Humans.

Face recognition is an essential activity of social living, common to many primate species. Underlying processes in the brain have been investigated using various techniques and compared between species. Functional imaging studies have shown face-selective cortical regions and their degree of correspondence across species. However, the temporal dynamics of face processing, particularly processing speed, are likely different between them. Across sensory modalities activation of primary sensory cortices in macaque monkeys occurs at about 3/5 the latency of corresponding activation in humans, though this human simian difference may diminish or disappear in higher cortical regions. We recorded scalp event-related potentials (ERPs) to presentation of faces in macaques and estimated the peak latency of ERP components. Comparisons of latencies between macaques (112 ms) and humans (192 ms) suggested that the 3:5 ratio could be preserved in higher cognitive regions of face processing between those species.

Miniaturized Devices for Bioluminescence Imaging in Freely Behaving Animals.

In vivo fluorescence miniature microscopy has recently proven a major advance, enabling cellular imaging in freely behaving animals. However, fluorescence imaging suffers from autofluorescence, phototoxicity, photobleaching and non- homogeneous illumination artifacts. These factors limit the quality and time course of data collection. Bioluminescence provides an alternative kind of activity-dependent light indicator. Bioluminescent calcium indicators do not require light input, instead generating photons through chemiluminescence. As such, limitations inherent to the requirement for light presentation are eliminated. Further, bioluminescent indicators also do not require excitation light optics: the removal of these components should make a lighter and lower cost microscope with fewer assembly parts. While there has been significant recent progress in making brighter and faster bioluminescence indicators, the advances in imaging hardware have not yet been realized. A hardware challenge is that despite potentially higher signal-to-noise of bioluminescence, the signal strength is lower than that of fluorescence. An open question we address in this report is whether fluorescent miniature microscopes can be rendered sensitive enough to detect bioluminescence. We demonstrate this possibility in vitro and in vivo by implementing optimizations of the UCLA fluorescent miniscope v3.2. These optimizations yielded a miniscope (BLmini) which is 22% lighter in weight, has 45% fewer components, is up to 58% less expensive, offers up to 15 times stronger signal and is sensitive enough to capture spatiotemporal dynamics of bioluminescence in the brain with a signal-to-noise ratio of 34 dB.

The BioLuminescent-OptoGenetic in vivo response to coelenterazine is proportional, sensitive, and specific in neocortex.

BioLuminescent (BL) light production can modulate neural activity and behavior through co-expressed OptoGenetic (OG) elements, an approach termed "BL-OG." Yet, the relationship between BL-OG effects and bioluminescent photon emission has not been characterized in vivo. Further, the degree to which BL-OG effects strictly depend on optogenetic mechanisms driven by bioluminescent photons is unknown. Crucial to every neuromodulation method is whether the activator shows a dynamic concentration range driving robust, selective, and nontoxic effects. We systematically tested the effects of four key components of the BL-OG mechanism (luciferin, oxidized luciferin, luciferin vehicle, and bioluminescence), and compared these against effects induced by the Luminopsin-3 (LMO3) BL-OG molecule, a fusion of slow burn Gaussia luciferase (sbGLuc) and Volvox ChannelRhodopsin-1 (VChR1). We performed combined bioluminescence imaging and electrophysiological recordings while injecting specific doses of Coelenterazine (substrate for sbGluc), Coelenteramide (CTM, the oxidized product of CTZ), or CTZ vehicle. CTZ robustly drove activity in mice expressing LMO3, with photon production proportional to firing rate. In contrast, low and moderate doses of CTZ, CTM, or vehicle did not modulate activity in mice that did not express LMO3. We also failed to find bioluminescence effects on neural activity in mice expressing an optogenetically nonsensitive LMO3 variant. We observed weak responses to the highest dose of CTZ in control mice, but these effects were significantly smaller than those observed in the LMO3 group. These results show that in neocortex in vivo, there is a large CTZ range wherein BL-OG effects are specific to its active chemogenetic mechanism.

Functional consequences of experience-dependent plasticity on tactile perception following perceptual learning.

Continuous training enhances perceptual discrimination and promotes neural changes in areas encoding the experienced stimuli. This type of experience-dependent plasticity has been demonstrated in several sensory and motor systems. Particularly, non-human primates trained to detect consecutive tactile bar indentations across multiple digits showed expanded excitatory receptive fields (RFs) in somatosensory cortex. However, the perceptual implications of these anatomical changes remain undetermined. Here, we trained human participants for 9 days on a tactile task that promoted expansion of multi-digit RFs. Participants were required to detect consecutive indentations of bar stimuli spanning multiple digits. Throughout the training regime we tracked participants' discrimination thresholds on spatial (grating orientation) and temporal tasks on the trained and untrained hands in separate sessions. We hypothesized that training on the multi-digit task would decrease perceptual thresholds on tasks that require stimulus processing across multiple digits, while also increasing thresholds on tasks requiring discrimination on single digits. We observed an increase in orientation thresholds on a single digit. Importantly, this effect was selective for the stimulus orientation and hand used during multi-digit training. We also found that temporal acuity between digits improved across trained digits, suggesting that discriminating the temporal order of multi-digit stimuli can transfer to temporal discrimination of other tactile stimuli. These results suggest that experience-dependent plasticity following perceptual learning improves and interferes with tactile abilities in manners predictive of the task and stimulus features used during training.

Neural mechanisms of selective attention in the somatosensory system.

Selective attention allows organisms to extract behaviorally relevant information while ignoring distracting stimuli that compete for the limited resources of their central nervous systems. Attention is highly flexible, and it can be harnessed to select information based on sensory modality, within-modality feature(s), spatial location, object identity, and/or temporal properties. In this review, we discuss the body of work devoted to understanding mechanisms of selective attention in the somatosensory system. In particular, we describe the effects of attention on tactile behavior and corresponding neural activity in somatosensory cortex. Our focus is on neural mechanisms that select tactile stimuli based on their location on the body (somatotopic-based attention) or their sensory feature (feature-based attention). We highlight parallels between selection mechanisms in touch and other sensory systems and discuss several putative neural coding schemes employed by cortical populations to signal the behavioral relevance of sensory inputs. Specifically, we contrast the advantages and disadvantages of using a gain vs. spike-spike correlation code for representing attended sensory stimuli. We favor a neural network model of tactile attention that is composed of frontal, parietal, and subcortical areas that controls somatosensory cells encoding the relevant stimulus features to enable preferential processing throughout the somatosensory hierarchy. Our review is based on data from noninvasive electrophysiological and imaging data in humans as well as single-unit recordings in nonhuman primates.

Antinuclear antibody testing: discordance between commercial laboratories.

Antinuclear antibody (ANA) test results frequently affect the course of patients' evaluations, diagnosis, and treatment, but different laboratory centers may yield conflicting results. This study investigated the degree of agreement between laboratory results in a group of subjects who had ANA testing performed at two commercial laboratories. This was a chart review study, in which all ANA tests ordered by the authors from one commercial laboratory over a 4-year period were queried. Corresponding patient charts were reviewed, and if ANA testing had also been performed at the second commercial laboratory, subjects were entered into the study. The primary measurement was agreement between paired ANA results, and we performed sensitivity analysis using varying criteria defining agreement (criteria A to criteria D [strictest to most lenient definition of agreement]). Other data captured included relevant data obtained through the course of evaluation (e.g., presenting complaints, exam findings, other laboratory data) and final diagnoses. Of 101 paired ANA tests, there was 18 % agreement according to the strictest criteria and 42 % according to the most lenient. Of the seven subjects with ANA-associated rheumatic disease, none of the paired tests were in agreement according to criteria A (two agreed according to criteria D). Our findings demonstrate poor agreement between paired ANA tests performed at two commercial laboratories. The low level of agreement may have far-reaching clinical implications. Specifically, this finding calls into question the reliability of ANA testing as it is currently performed and suggests that results may in part depend upon the laboratory center to which patients are referred.

Keeping in touch with the visual system: spatial alignment and multisensory integration of visual-somatosensory inputs.

Correlated sensory inputs coursing along the individual sensory processing hierarchies arrive at multisensory convergence zones in cortex where inputs are processed in an integrative manner. The exact hierarchical level of multisensory convergence zones and the timing of their inputs are still under debate, although increasingly, evidence points to multisensory integration (MSI) at very early sensory processing levels. While MSI is said to be governed by stimulus properties including space, time, and magnitude, violations of these rules have been documented. The objective of the current study was to determine, both psychophysically and electrophysiologically, whether differential visual-somatosensory (VS) integration patterns exist for stimuli presented to the same versus opposite hemifields. Using high-density electrical mapping and complementary psychophysical data, we examined multisensory integrative processing for combinations of visual and somatosensory inputs presented to both left and right spatial locations. We assessed how early during sensory processing VS interactions were seen in the event-related potential and whether spatial alignment of the visual and somatosensory elements resulted in differential integration effects. Reaction times to all VS pairings were significantly faster than those to the unisensory conditions, regardless of spatial alignment, pointing to engagement of integrative multisensory processing in all conditions. In support, electrophysiological results revealed significant differences between multisensory simultaneous VS and summed V + S responses, regardless of the spatial alignment of the constituent inputs. Nonetheless, multisensory effects were earlier in the aligned conditions, and were found to be particularly robust in the case of right-sided inputs (beginning at just 55 ms). In contrast to previous work on audio-visual and audio-somatosensory inputs, the current work suggests a degree of spatial specificity to the earliest detectable multisensory integrative effects in response to VS pairings.

Multimodal Interactions between Proprioceptive and Cutaneous Signals in Primary Somatosensory Cortex.

The classical view of somatosensory processing holds that proprioceptive and cutaneous inputs are conveyed to cortex through segregated channels, initially synapsing in modality-specific areas 3a (proprioception) and 3b (cutaneous) of primary somatosensory cortex (SI). These areas relay their signals to areas 1 and 2 where multimodal convergence first emerges. However, proprioceptive and cutaneous maps have traditionally been characterized using unreliable stimulation tools. Here, we employed a mechanical stimulator that reliably positioned animals' hands in different postures and presented tactile stimuli with superb precision. Single-unit recordings in SI revealed that most neurons responded to cutaneous and proprioceptive stimuli, including cells in areas 3a and 3b. Multimodal responses were characterized by linear and nonlinear effects that emerged during early (∼20 ms) and latter (> 100 ms) stages of stimulus processing, respectively. These data are incompatible with the modality specificity model in SI, and provide evidence for distinct mechanisms of multimodal processing in the somatosensory system.

Temporal correlation mechanisms and their role in feature selection: a single-unit study in primate somatosensory cortex.

Studies in vision show that attention enhances the firing rates of cells when it is directed towards their preferred stimulus feature. However, it is unknown whether other sensory systems employ this mechanism to mediate feature selection within their modalities. Moreover, whether feature-based attention modulates the correlated activity of a population is unclear. Indeed, temporal correlation codes such as spike-synchrony and spike-count correlations (r(sc)) are believed to play a role in stimulus selection by increasing the signal and reducing the noise in a population, respectively. Here, we investigate (1) whether feature-based attention biases the correlated activity between neurons when attention is directed towards their common preferred feature, (2) the interplay between spike-synchrony and rsc during feature selection, and (3) whether feature attention effects are common across the visual and tactile systems. Single-unit recordings were made in secondary somatosensory cortex of three non-human primates while animals engaged in tactile feature (orientation and frequency) and visual discrimination tasks. We found that both firing rate and spike-synchrony between neurons with similar feature selectivity were enhanced when attention was directed towards their preferred feature. However, attention effects on spike-synchrony were twice as large as those on firing rate, and had a tighter relationship with behavioral performance. Further, we observed increased r(sc) when attention was directed towards the visual modality (i.e., away from touch). These data suggest that similar feature selection mechanisms are employed in vision and touch, and that temporal correlation codes such as spike-synchrony play a role in mediating feature selection. We posit that feature-based selection operates by implementing multiple mechanisms that reduce the overall noise levels in the neural population and synchronize activity across subpopulations that encode the relevant features of sensory stimuli.

Impairments in background and event-related alpha-band oscillatory activity in patients with schizophrenia.

Studies show that patients with schizophrenia exhibit impaired responses to sensory stimuli, especially at the early stages of neural processing. In particular, patients' alpha-band (8-14 Hz) event-related desynchronization (ERD) and visual P1 event-related potential (ERP) component tend to be significantly reduced, with P1 ERP deficits greater for visual stimuli biased towards the magnocellular system. In healthy controls, studies show that pre-stimulus alpha (background alpha) plays a pivotal role in sensory processing and behavior, largely by shaping the neural responses to incoming stimuli. Here, we address whether patients' ERD and P1 deficits stem from impairments in pre-stimulus alpha mechanisms. To address this question we recorded electrophysiological activity in patients with schizophrenia and healthy controls while they engaged in a visual discrimination task with low, medium, and high contrast stimuli. The results revealed a significant decrease in patients' ERDs, which was largely driven by reductions in pre-stimulus alpha. These reductions were most prominent in right-hemispheric areas. We also observed a systematic relationship between pre-stimulus alpha and the P1 component across different contrast levels. However, this relationship was only observed in healthy controls. Taken together, these findings highlight a substantial anomaly in patients' amplitude-based alpha background activity over visual areas. The results provide further support that pre-stimulus alpha activity plays an active role in perception by modulating the neural responses to incoming sensory inputs, a mechanism that seems to be compromised in schizophrenia.

Cross-modal sensory integration of visual-tactile motion information: instrument design and human psychophysics.

Information obtained from multiple sensory modalities, such as vision and touch, is integrated to yield a holistic percept. As a haptic approach usually involves cross-modal sensory experiences, it is necessary to develop an apparatus that can characterize how a biological system integrates visual-tactile sensory information as well as how a robotic device infers object information emanating from both vision and touch. In the present study, we develop a novel visual-tactile cross-modal integration stimulator that consists of an LED panel to present visual stimuli and a tactile stimulator with three degrees of freedom that can present tactile motion stimuli with arbitrary motion direction, speed, and indentation depth in the skin. The apparatus can present cross-modal stimuli in which the spatial locations of visual and tactile stimulations are perfectly aligned. We presented visual-tactile stimuli in which the visual and tactile directions were either congruent or incongruent, and human observers reported the perceived visual direction of motion. Results showed that perceived direction of visual motion can be biased by the direction of tactile motion when visual signals are weakened. The results also showed that the visual-tactile motion integration follows the rule of temporal congruency of multi-modal inputs, a fundamental property known for cross-modal integration.

Oscillatory sensory selection mechanisms during intersensory attention to rhythmic auditory and visual inputs: a human electrocorticographic investigation.

Oscillatory entrainment mechanisms are invoked during attentional processing of rhythmically occurring stimuli, whereby their phase alignment regulates the excitability state of neurons coding for anticipated inputs. These mechanisms have been examined in the delta band (1-3 Hz), where entrainment frequency matches the stimulation rate. Here, we investigated entrainment for subdelta rhythmic stimulation, recording from intracranial electrodes over human auditory cortex during an intersensory audiovisual task. Audiovisual stimuli were presented at 0.67 Hz while participants detected targets within one sensory stream and ignored the other. It was found that entrainment operated at twice the stimulation rate (1.33 Hz), and this was reflected by higher amplitude values in the FFT spectrum, cyclic modulation of alpha-amplitude, and phase-amplitude coupling between delta phase and alpha power. In addition, we found that alpha-amplitude was relatively increased in auditory cortex coincident with to-be-ignored auditory stimuli during attention to vision. Thus, the data suggest that entrainment mechanisms operate within a delimited passband such that for subdelta task rhythms, oscillatory harmonics are invoked. The phase of these delta-entrained oscillations modulates alpha-band power. This may in turn increase or decrease responsiveness to relevant and irrelevant stimuli, respectively.

Preliminary Evidence of Pre-Attentive Distinctions of Frequency-Modulated Tones that Convey Affect.

Recognizing emotion is an evolutionary imperative. An early stage of auditory scene analysis involves the perceptual grouping of acoustic features, which can be based on both temporal coincidence and spectral features such as perceived pitch. Perceived pitch, or fundamental frequency (F(0)), is an especially salient cue for differentiating affective intent through speech intonation (prosody). We hypothesized that: (1) simple frequency-modulated tone abstractions, based on the parameters of actual prosodic stimuli, would be reliably classified as representing differing emotional categories; and (2) that such differences would yield significant mismatch negativities (MMNs) - an index of pre-attentive deviance detection within the auditory environment. We constructed a set of FM tones that approximated the F(0) mean and variation of reliably recognized happy and neutral prosodic stimuli. These stimuli were presented to 13 subjects using a passive listening oddball paradigm. We additionally included stimuli with no frequency modulation (FM) and FM tones with identical carrier frequencies but differing modulation depths as control conditions. Following electrophysiological recording, subjects were asked to identify the sounds they heard as happy, sad, angry, or neutral. We observed that FM tones abstracted from happy and no-expression speech stimuli elicited MMNs. Post hoc behavioral testing revealed that subjects reliably identified the FM tones in a consistent manner. Finally, we also observed that FM tones and no-FM tones elicited equivalent MMNs. MMNs to FM tones that differentiate affect suggests that these abstractions may be sufficient to characterize prosodic distinctions, and that these distinctions can be represented in pre-attentive auditory sensory memory.

"What" and "where" in auditory sensory processing: a high-density electrical mapping study of distinct neural processes underlying sound object recognition and sound localization.

Functionally distinct dorsal and ventral auditory pathways for sound localization (WHERE) and sound object recognition (WHAT) have been described in non-human primates. A handful of studies have explored differential processing within these streams in humans, with highly inconsistent findings. Stimuli employed have included simple tones, noise bursts, and speech sounds, with simulated left-right spatial manipulations, and in some cases participants were not required to actively discriminate the stimuli. Our contention is that these paradigms were not well suited to dissociating processing within the two streams. Our aim here was to determine how early in processing we could find evidence for dissociable pathways using better titrated WHAT and WHERE task conditions. The use of more compelling tasks should allow us to amplify differential processing within the dorsal and ventral pathways. We employed high-density electrical mapping using a relatively large and environmentally realistic stimulus set (seven animal calls) delivered from seven free-field spatial locations; with stimulus configuration identical across the "WHERE" and "WHAT" tasks. Topographic analysis revealed distinct dorsal and ventral auditory processing networks during the WHERE and WHAT tasks with the earliest point of divergence seen during the N1 component of the auditory evoked response, beginning at approximately 100 ms. While this difference occurred during the N1 timeframe, it was not a simple modulation of N1 amplitude as it displayed a wholly different topographic distribution to that of the N1. Global dissimilarity measures using topographic modulation analysis confirmed that this difference between tasks was driven by a shift in the underlying generator configuration. Minimum-norm source reconstruction revealed distinct activations that corresponded well with activity within putative dorsal and ventral auditory structures.

The development of multisensory speech perception continues into the late childhood years.

Observing a speaker's articulations substantially improves the intelligibility of spoken speech, especially under noisy listening conditions. This multisensory integration of speech inputs is crucial to effective communication. Appropriate development of this ability has major implications for children in classroom and social settings, and deficits in it have been linked to a number of neurodevelopmental disorders, especially autism. It is clear from structural imaging studies that there is a prolonged maturational course within regions of the perisylvian cortex that persists into late childhood, and these regions have been firmly established as being crucial to speech and language functions. Given this protracted maturational timeframe, we reasoned that multisensory speech processing might well show a similarly protracted developmental course. Previous work in adults has shown that audiovisual enhancement in word recognition is most apparent within a restricted range of signal-to-noise ratios (SNRs). Here, we investigated when these properties emerge during childhood by testing multisensory speech recognition abilities in typically developing children aged between 5 and 14 years, and comparing them with those of adults. By parametrically varying SNRs, we found that children benefited significantly less from observing visual articulations, displaying considerably less audiovisual enhancement. The findings suggest that improvement in the ability to recognize speech-in-noise and in audiovisual integration during speech perception continues quite late into the childhood years. The implication is that a considerable amount of multisensory learning remains to be achieved during the later schooling years, and that explicit efforts to accommodate this learning may well be warranted.

Cognitive control in late-life depression: response inhibition deficits and dysfunction of the anterior cingulate cortex.

OBJECTIVES: Geriatric depression is associated with frontolimbic functional deficits, and this frontal dysfunction may underlie the marked executive control deficits often seen in this population. The authors' goal was to assess the integrity of frontal cortical functioning in geriatric depression, while these individuals performed a standard cognitive control task. The N2 component of the event-related potential (ERP), an evoked response generated within the anterior cingulate cortex (ACC), is significantly enhanced when nondepressed individuals successfully inhibit a response, providing an excellent metric of frontal inhibitory function. DESIGN: The authors used a variant of a demanding Go/NoGo task-switching paradigm that required participants to inhibit response execution during NoGo trials by overcoming a potent response tendency established by frequent Go trials. PARTICIPANTS: The authors compared a cohort of depressed geriatric outpatients (N = 11) with a similarly aged group of nondepressed participants (N = 11). MEASUREMENTS: Reaction times, accuracy, and high-density event-related potential recordings from a 64-channel electrode montage were obtained. RESULTS: A significantly enhanced N2 to NoGo trials was observed in nondepressed elderly participants, with generators localized to the ACC. In contrast, this enhancement was strongly reduced in the depressed sample. Source analysis and topographic mapping pointed to a displacement of N2 generators toward more posterior areas of the middle frontal gyrus in depressed subjects. CONCLUSIONS: Findings confirm previous reports of an inhibitory control deficit in depressed elderly who show significantly increased rates of commission errors (i.e., failures to inhibit responses on NoGo trials). Electrophysiologic data suggest underlying dysfunction in ACC as the basis for this deficit.