Transcranial direct current stimulation's effect on novice versus experienced learning.

Transcranial direct current stimulation (TDCS) is a non-invasive form of brain stimulation applied via a weak electrical current passed between electrodes on the scalp. In recent studies, TDCS has been shown to improve learning when applied to the prefrontal cortex (e.g., Kincses et al. in Neuropsychologia 42:113-117, 2003; Clark et al. Neuroimage in 2010). The present study examined the effects of TDCS delivered at the beginning of training (novice) or after an hour of training (experienced) on participants' ability to detect cues indicative of covert threats. Participants completed two 1-h training sessions. During the first 30 min of each training session, either 0.1 mA or 2.0 mA of anodal TDCS was delivered to the participant. The anode was positioned near F8, and the cathode was placed on the upper left arm. Testing trials immediately followed training. Accuracy in classification of images containing and not-containing threat stimuli during the testing sessions indicated: (1) that mastery of threat detection significantly increased with training, (2) that anodal TDCS at 2 mA significantly enhanced learning, and (3) TDCS was significantly more effective in enhancing test performance when applied in novice learners than in experienced learners. The enhanced performance following training with TDCS persisted into the second session when TDCS was delivered early in training.

The neural networks underlying auditory sensory gating.

One of the most consistent electrophysiological deficits reported in the schizophrenia literature is the failure to inhibit, or properly gate, the neuronal response to the second stimulus of an identical pair (i.e., sensory gating). Although animal and invasive human studies have consistently implicated the auditory cortex, prefrontal cortex and hippocampus in mediating the sensory gating response, localized activation in these structures has not always been reported during non-invasive imaging modalities. In the current experiment, event-related FMRI and a variant of the traditional gating paradigm were utilized to examine how the gating network differentially responded to the processing of pairs of identical and non-identical tones. Two single-tone conditions were also presented so that they could be used to estimate the HRF for paired stimuli, reconstructed based on actual hemodynamic responses, to serve as a control non-gating condition. Results supported an emerging theory that the gating response for both paired-tone conditions was primarily mediated by auditory and prefrontal cortex, with potential contributions from the thalamus. Results also indicated that the left auditory cortex may play a preferential role in determining the stimuli that should be inhibited (gated) or receive further processing due to novelty of information. In contrast, there was no evidence of hippocampal involvement, suggesting that future work is needed to determine what role it may play in the gating response.

The effect of face inversion on activity in human neural systems for face and object perception.

The differential effect of stimulus inversion on face and object recognition suggests that inverted faces are processed by mechanisms for the perception of other objects rather than by face perception mechanisms. We investigated the face inversion using functional magnetic resonance imaging (fMRI). The principal effect of face inversion on was an increased response in ventral extrastriate regions that respond preferentially to another class of objects (houses). In contrast, house inversion did not produce a similar change in face-selective regions. Moreover, stimulus inversion had equivalent, minimal effects for faces in in face-selective regions and for houses in house-selective regions. The results suggest that the failure of face perception systems with inverted faces leads to the recruitment of processing resources in object perception systems, but this failure is not reflected by altered activity in face perception systems.

Multimodal Neuroimaging in Schizophrenia: Description and Dissemination.

In this paper we describe an open-access collection of multimodal neuroimaging data in schizophrenia for release to the community. Data were acquired from approximately 100 patients with schizophrenia and 100 age-matched controls during rest as well as several task activation paradigms targeting a hierarchy of cognitive constructs. Neuroimaging data include structural MRI, functional MRI, diffusion MRI, MR spectroscopic imaging, and magnetoencephalography. For three of the hypothesis-driven projects, task activation paradigms were acquired on subsets of ~200 volunteers which examined a range of sensory and cognitive processes (e.g., auditory sensory gating, auditory/visual multisensory integration, visual transverse patterning). Neuropsychological data were also acquired and genetic material via saliva samples were collected from most of the participants and have been typed for both genome-wide polymorphism data as well as genome-wide methylation data. Some results are also presented from the individual studies as well as from our data-driven multimodal analyses (e.g., multimodal examinations of network structure and network dynamics and multitask fMRI data analysis across projects). All data will be released through the Mind Research Network's collaborative informatics and neuroimaging suite (COINS).

Effects of spatial cuing on luminance detectability: psychophysical and electrophysiological evidence for early selection.

Three experiments were conducted to determine whether attention-related changes in luminance detectability reflect a modulation of early sensory processing. Experiments 1 and 2 used peripheral cues to direct attention and found substantial effects of cue validity on target detectability; these effects were consistent with a sensory-level locus of selection but not with certain memory- or decision-level mechanisms. In Experiment 3, event-related brain potentials were recorded in a similar paradigm using central cues, and attention was found to produce changes in sensory-evoked brain activity beginning within the 1st 100 ms of stimulus processing. These changes included both an enhancement of sensory responses to attended stimuli and a suppression of sensory responses to unattended stimuli; the enhancement and suppression effects were isolated to different neural responses, indicating that they may arise from independent attentional mechanisms.

Parametrically dissociating speech and nonspeech perception in the brain using fMRI.

Candidate brain regions constituting a neural network for preattentive phonetic perception were identified with fMRI and multivariate multiple regression of imaging data. Stimuli contrasted along speech/nonspeech, acoustic, or phonetic complexity (three levels each) and natural/synthetic dimensions. Seven distributed brain regions' activity correlated with speech and speech complexity dimensions, including five left-sided foci [posterior superior temporal gyrus (STG), angular gyrus, ventral occipitotemporal cortex, inferior/posterior supramarginal gyrus, and middle frontal gyrus (MFG)] and two right-sided foci (posterior STG and anterior insula). Only the left MFG discriminated natural and synthetic speech. The data also supported a parallel rather than serial model of auditory speech and nonspeech perception.

Impact of tDCS on performance and learning of target detection: interaction with stimulus characteristics and experimental design.

We have previously found that transcranial direct current stimulation (tDCS) over right inferior frontal cortex (RIFC) enhances performance during learning of a difficult visual target detection task (Clark et al., 2012). In order to examine the cognitive mechanisms of tDCS that lead to enhanced performance, here we analyzed its differential effects on responses to stimuli that varied by repetition and target presence, differences related to expectancy by comparing performance in single- and double-blind task designs, and individual differences in skin stimulation and mood. Participants were trained for 1h to detect target objects hidden in a complex virtual environment, while anodal tDCS was applied over RIFC at 0.1 mA or 2.0 mA for the first 30 min. Participants were tested immediately before and after training and again 1h later. Higher tDCS current was associated with increased performance for all test stimuli, but was greatest for repeated test stimuli with the presence of hidden-targets. This finding was replicated in a second set of subjects using a double-blind task design. Accuracy for target detection discrimination sensitivity (d'; Z(hits)-Z(false alarms)) was greater for 2.0 mA current (1.77) compared with 0.1 mA (0.95), with no differences in response bias (ß). Taken together, these findings indicate that the enhancement of performance with tDCS is sensitive to stimulus repetition and target presence, but not to changes in expectancy, mood, or type of blinded task design. The implications of these findings for understanding the cognitive mechanisms of tDCS are discussed.

Antipsychotic dose and diminished neural modulation: a multi-site fMRI study.

BACKGROUND: The effect of antipsychotics on the blood oxygen level dependent signal in schizophrenia is poorly understood. The purpose of the present investigation is to examine the effect of antipsychotic medication on independent neural networks during a motor task in a large, multi-site functional magnetic resonance imaging investigation. METHODS: Seventy-nine medicated patients with schizophrenia and 114 comparison subjects from the Mind Clinical Imaging Consortium database completed a paced, auditory motor task during functional magnetic resonance imaging (fMRI). Independent component analysis identified temporally cohesive but spatially distributed neural networks. The independent component analysis time course was regressed with a model time course of the experimental design. The resulting beta weights were evaluated for group comparisons and correlations with chlorpromazine equivalents. RESULTS: Group differences between patients and comparison subjects were evident in the cortical and subcortical motor networks, default mode networks, and attentional networks. The chlorpromazine equivalents correlated with the unimotor/bitemporal (rho=-0.32, P=0.0039), motor/caudate (rho=-0.22, P=0.046), posterior default mode (rho=0.26, P=0.020), and anterior default mode networks (rho=0.24, P=0.03). Patients on typical antipsychotics also had less positive modulation of the motor/caudate network relative to patients on atypical antipsychotics (t(77)=2.01, P=0.048). CONCLUSION: The results suggest that antipsychotic dose diminishes neural activation in motor (cortical and subcortical) and default mode networks in patients with schizophrenia. The higher potency, typical antipsychotics also diminish positive modulation in subcortical motor networks. Antipsychotics may be a potential confound limiting interpretation of fMRI studies on the disease process in medicated patients with schizophrenia.

Identification of imaging biomarkers in schizophrenia: a coefficient-constrained independent component analysis of the mind multi-site schizophrenia study.

A number of recent studies have combined multiple experimental paradigms and modalities to find relevant biological markers for schizophrenia. In this study, we extracted fMRI features maps from the analysis of three experimental paradigms (auditory oddball, Sternberg item recognition, sensorimotor) for a large number (n=154) of patients with schizophrenia and matched healthy controls. We used the general linear model (GLM) and independent component analysis (ICA) to extract feature maps (i.e. ICA component maps and GLM contrast maps), which were then subjected to a coefficient-constrained independent component analysis (CCICA) to identify potential neurobiological markers. A total of 29 different feature maps were extracted for each subject. Our results show a number of optimal feature combinations that reflect a set of brain regions that significantly discriminate between patients and controls in the spatial heterogeneity and amplitude of their feature signals. Spatial heterogeneity was seen in regions such as the superior/middle temporal and frontal gyri, bilateral parietal lobules, and regions of the thalamus. Most strikingly, an ICA feature representing a bilateral frontal pole network was consistently seen in the ten highest feature results when ranked on differences found in the amplitude of their feature signals. The implication of this frontal pole network and the spatial variability which spans regions comprising of bilateral frontal/temporal lobes and parietal lobules suggests that they might play a significant role in the pathophysiology of schizophrenia.

Spatial selective attention affects early extrastriate but not striate components of the visual evoked potential.

Abstract The effects of spatial selective attention on sensory processing in visual cortical areas were investigated by means of visual evoked potential (VEP) recordings and source localization techniques. Patterned stimuli were rapidly presented in random order to the left and right visual fields while subjects maintained central fixation and attended to one visual field at a time. Attended stimuli evoked enhanced P1 (100-130 msec) and N1 (120-200 msec) components of the VEP, whereas no effects of attention were observed on the C1 (50-100 msec) or P2 (200-240 msec) components. Spatiotemporal dipole modeling of the early VEP sources was carried out in relation to MRI-defined cortical anatomy. The dipolar generator of the C1 component was found to lie in calcarine cortex, the human homologue of area V1, whereas the attention-sensitive P1 generator was localized to ventral-lateral occipital cortex, within extrastriate area 19. These results support the hypothesis that spatial attention does not affect the initial activity evoked in area V1 but rather produces an enhancement within extrastriate visual areas of sensory signals arising from stimuli at attended locations.

Paradigm-dependent modulation of event-related fMRI activity evoked by the oddball task.

We have previously shown that event-related functional magnetic resonance imaging (ER-fMRI) may be used to record responses to the rapid, interleaved presentation of stimuli in the three-stimulus oddball task. The present study examined the sensitivity of ER-fMRI responses to variations in the range of inter-stimulus intervals (ISIs, calculated as the time from the offset of one stimulus to the onset of the next stimulus) and the type of behavioral response task used. ISIs were varied between a wide ISI range (550-2,050 msec) and a narrow ISI range (800-1,200 msec), while maintaining a similar mean ISI (approximately 1 stimulus per sec) between experiments. The response task was varied between button press and subvocal target counting. Gradient echo, echo planar images were acquired for each of three experiments (wide ISI with button press, narrow ISI with button press, and wide-ISI with counting) in five subjects. Target stimuli generated increased fMRI signal in a wide range of brain regions. The use of a narrow ISI range generated a greater volume of subcortical activity and a reduced volume of cortical activity relative to a wide ISI range. The counting task generated a larger amplitude and longer lasting evoked response in brain regions that responded during all three experiments. Rare distractor stimuli evoked fMRI signal change primarily in orbitofrontal, ventral-medial prefrontal and superior parietal cortex. These results illustrate that although ER-fMRI is relatively insensitive as a technique to small variations in the timing of stimulus-evoked responses, it is remarkably sensitive to consequences such variations have for the topographic location and amplitude of neural responses to stimuli.

In vivo myeloarchitectonic analysis of human striate and extrastriate cortex using magnetic resonance imaging.

A primary goal of investigations into the organization of human cerebral cortex is to determine the functional specificity of architectonic regions. This includes the correlation of neurobehavioral deficits with neuropathological data for clinical diagnosis and treatment, and the identification of active brain regions using functional neural imaging techniques, such as positron emission tomography, electroencephalographic and magnetoencephalographic (EEG and MEG) source localization algorithms, and direct cortical stimulation. Currently, the architectonic classification of a cortical region identified by these methods is inferred from the comparison of its cerebral topographic position to cytoarchitectonic brain atlases. However, substantial intersubject variability in the position of cytoarchitectonic regions with respect to cerebral topographic landmarks may lead to errors in this procedure. An alternative method is presented here, which uses magnetic resonance (MR) imaging to identify myeloarchitectonic regions of isocortex directly by estimating the relative concentration of myelin within cortical laminae. This high-resolution MR protocol is used to identify striate cortex (Brodmann's area 17) and extrastriate cortex in vivo. Correspondence of MR signal intensity with myeloarchitectonic data from a postmortem brain confirms this identification. As MR imaging technology improves, this noninvasive method has the potential to identify and discriminate among at least 50 cortical regions in the living human brain.

fMRI study of face perception and memory using random stimulus sequences.

A new functional magnetic resonance imaging (fMRI) method was used to investigate the functional neuroanatomy of face perception and memory. Whole-brain fMRI data were acquired while four types of stimuli were presented sequentially in an unpredictable pseudorandom order at a rate of 0.5 Hz. Stimulus types were a single repeated memorized target face, unrepeated novel faces, nonsense scrambled faces, and a blank screen. Random stimulus sequences were designed to generate a functional response to each stimulus type that was uncorrelated with responses to other stimuli. This allowed fMRI responses to each stimulus type to be examined separately using multiple regression. Signal increases were found for all stimuli in ventral posterior cortex. Responses to intact faces extended to more anterior locations of occipitotemporal cortex than did responses to scrambled faces, consistent with previous studies of face perception. Responses evoked by novel faces were in regions of ventral occipitotemporal cortex medial to regions in which significant responses were evoked by the target face. The repeated target face stimulus also evoked activity in widely distributed regions of frontal and parietal cortex. These results demonstrate that cortical hemodynamic responses to interleaved novel and repeated stimuli can be distinguished and measured using fMRI with appropriate stimulus sequences and data analysis methods. This method can now be used to examine the neural systems involved in cognitive tasks that were previously impossible to study using positron emission tomography or fMRI.

Dissociation of saccade-related and pursuit-related activation in human frontal eye fields as revealed by fMRI.

The location of the human frontal eye fields (FEFs) underlying horizontal visually guided saccadic and pursuit eye movements was investigated with the use of functional magnetic resonance imaging in five healthy humans. Execution of both saccadic and pursuit eye movements induced bilateral FEF activation located medially at the junction of the precentral sulcus and the superior frontal sulcus and extending laterally to the precentral gyrus. These findings extend previous functional imaging studies by providing the first functional imaging evidence of a specific activation in the FEF during smooth pursuit eye movements in healthy humans. FEF activation during smooth pursuit performance was smaller than during saccades. This finding, which may reflect the presence of a smaller pursuit-related region area in human FEF than the saccade-related region, is consistent with their relative size observed in the monkey. The mean location of the pursuit-related FEF was more inferior and lateral than the location of the saccade-related FEF. These results provide the first evidence that there are different subregions in the human FEF that are involved in the execution of two different types of eye movements, namely saccadic and pursuit eye movements. Moreover, this study provides additional evidence that the human FEF is located in Brodmann's area 6, unlike the monkey FEF which is located in the posterior part of Brodmann's area 8.

Responses to rare visual target and distractor stimuli using event-related fMRI.

Previous studies have found that the P300 or P3 event-related potential (ERP) component is useful in the diagnosis and treatment of many disorders that influence CNS function. However, the anatomic locations of brain regions involved in this response are not precisely known. In the present event-related functional magnetic resonance imaging (fMRI) study, methods of stimulus presentation, data acquisition, and data analysis were optimized for the detection of brain activity in response to stimuli presented in the three-stimulus oddball task. This paradigm involves the interleaved, pseudorandom presentation of single block-letter target and distractor stimuli that previously were found to generate the P3b and P3a ERP subcomponents, respectively, and frequent standard stimuli. Target stimuli evoked fMRI signal increases in multiple brain regions including the thalamus, the bilateral cerebellum, and the occipital-temporal cortex as well as bilateral superior, medial, inferior frontal, inferior parietal, superior temporal, precentral, postcentral, cingulate, insular, left middle temporal, and right middle frontal gyri. Distractor stimuli evoked an fMRI signal change bilaterally in inferior anterior cingulate, medial frontal, inferior frontal, and right superior frontal gyri, with additional activity in bilateral inferior parietal lobules, lateral cerebellar hemispheres and vermis, and left fusiform, middle occipital, and superior temporal gyri. Significant variation in the amplitude and polarity of distractor-evoked activity was observed across stimulus repetitions. No overlap was observed between target- and distractor-evoked activity. These event-related fMRI results shed light on the anatomy of responses to target and distractor stimuli that have proven useful in many ERP studies of healthy and clinically impaired populations.

Sources of attention-sensitive visual event-related potentials.

In a study of the neural processes that mediate visual attention in humans, 32-channel recordings of event-related potentials were obtained from 14 normal subjects while they performed a spatial attention task. The generator locations of the early C1, P1, and N1 components of the visual evoked response were estimated by means of topographic maps of voltage and current source density in conjunction with dipole modelling. The topography of the C1 component (ca. 85 ms post-stimulus) was consistent with a generator in striate cortex, and this component was unaffected by attention. In contrast, the P1 and N1 components (ca. 95 and 170 ms) exhibited current density foci at scalp sites overlying lateral extrastriate cortex and were larger for attended stimuli than for unattended stimuli. The voltage topographies in the 75-175 ms latency range were modeled with a 5-dipole configuration consisting of a single striate dipole and left-right pairs of dipoles located in lateral extrastriate and inferior occipito-temporal areas. This model was found to account for the voltage topographies produced by both attended and unattended stimuli with low residual variance. These results support the proposal that visual-spatial attention modulates neural activity in extrastriate visual cortex but does not affect the initial evoked response in striate cortex.

Functional magnetic resonance imaging of human visual cortex during face matching: a comparison with positron emission tomography.

Cortical areas associated with the perception of faces were identified using functional magnetic resonance imaging (fMRI). T2*-weighted gradient echo, echo-planar MR images were obtained using a modified 1.5-T GE Signa MRI. In all nine subjects studied, performance of a face-matching task was associated with a region of significantly increased MR signal in the ventral occipitotemporal cortex, extending from the inferior occipital sulcus to the lateral occipitotemporal sulcus and fusiform gyrus. Smaller and more variable signal increases were found in dorsolateral occipitoparietal cortex near the intraparietal sulcus. Signal decreases were found in the angular gyrus and posterior cingulate cortex. Single-subject fMRI analyses revealed discrete areas of activation with well-defined borders. Group analyses of spatially smoothed fMRI data produced results that replicated most aspects of previous studies of face processing using positron emission tomography (PET). These results show that PET and fMRI identify functional areas with similar anatomical locations. In addition, fMRI reveals interindividual variation in the anatomical location of higher-level processing areas with greater anatomical precision.

Monitoring the visual world: hemispheric asymmetries and subcortical processes in attention.

Abstract Hemispheric specialization and subcortical processes in visual anention were investigated in callosotomy (split-brain) patients by measuring reaction times to lateralized stimuli in a spatial cuing paradigm. Cuing effects were obtained for targets presented to the right hemisphere (left visual hemifield) but not for those presented to the left hemisphere. These cuing effects were manifest as faster reaction times when the cue correctly indicated the location of the subsequent target (valid trials), as compared to trials in which the cue and target appeared in opposite hemifields (invalid trials). This pattern suggests that the right hemisphere allocated attention to cued locations in either visual hemifield, whereas the left hemisphere allocated attention predominantly to the right hemifield. This finding is consistent with a body of evidence from studies in patients with cortical lesions who display different attentional deficits for right versus left hemisphere damage. Because the present pattern occurs in patients whose cerebral hemispheres are separated at the cortical level, it suggests that right hemisphere attentional allocation to events in the ipsilateral visual half-field is mediated in part via intact subcortical systems.

Selective attention to face identity and color studied with f MRI.

Cortical areas associated with selective attention to the color and identity of faces were located using functional magnetic resonance imaging (fMRI). Six subjects performed tasks which required selective attention to face identity or color similarity using the same color-washed face stimuli. Performance of the color attention task but not the face attention task was associated with a region of activity in the collateral sulcus and nearby regions of the lingual and fusiform gyri. Performance of both tasks was associated with a region of activity in ventral occipitotemporal cortex that was lateral to the color responsive area and had a greater spatial extent. These fMRI results converge with results obtained from PET and ERP studies to demonstrate similar anatomical locations of functional areas for face and color processing across studies.

Sentence reading: a functional MRI study at 4 tesla.

In this study, changes in blood oxygenation and volume were monitored while monolingual right-handed subjects read English sentences. Our results confirm the role of the left peri-sylvian cortex in language processing. Interestingly, individual subject analyses reveal a pattern of activation characterized by several small, limited patches rather than a few large, anatomically well-circumscribed centers. Between-subject analyses confirm a lateralized pattern of activation and reveal active classical language areas including Broca's area, Wernicke's area, and the angular gyms. In addition they point to areas only more recently considered as language-relevant including the anterior portion of the superior temporal sulcus. This area has not been reliably observed in imaging studies of isolated word processing. This raises the hypothesis that activation in this area is dependent on processes specific to sentence reading.