Corby L. Dale

Toward a neurobiology of temporal cognition: Advances and challenges.

A rich tradition of normative psychophysics has identified two ubiquitous properties of interval timing: the scalar property, a strong form of Webers law, and ratio comparison mechanisms. Finding the neural substrate of these properties is a major challenge for neurobiology. Recently, advances have been made in our understanding of the brain structures important for timing, especially the basal ganglia and the cerebellum. Surgical intervention or diseases of the cerebellum generally result in increased variability in temporal processing, whereas both clock and memory effects are seen for neurotransmitter interventions, lesions and diseases of the basal ganglia. We propose that cerebellar dysfunction may induce deregulation of tonic thalamic tuning, which disrupts gating of the mnemonic temporal information generated in the basal ganglia through striato-thalamo-cortical loops.

Preparatory allocation of attention and adjustments in conflict processing.

Attentional control involves the ability to allocate preparatory attention to improve subsequent stimulus processing and response selection. There is behavioral evidence to support the hypothesis that increased expectancy of stimulus and response conflict may decrease the subsequent experience of conflict during task performance. We used a cued flanker and event-related fMRI design to separate processes involved in preparation from those involved in resolving conflict and to identify the brain systems involved in these processes as well as the association between preparatory activity levels and activity related to subsequent conflict processing. Our results demonstrate that preparatory attentional allocation following a cue to the upcoming level of conflict is mediated by a network involving Dorsolateral Prefrontal Cortex (DLPFC) and the Intraparietal Sulcus (IPS). Informed preparation for conflict processing was associated with decreased Anterior Cingulate Cortex/pre-Supplementary Motor Area (ACC/pre-SMA) and IPS activity during the flanker target presentation, supporting their roles in conflict processing and visuospatial attention during the flanker task. Ventrolateral Prefrontal Cortex/Orbitofrontal Cortex (VLPFC/OFC) was active when specific strategic task rule and outcome information was available.

Timing is everything: Neural response dynamics during syllable processing and its relation to higher-order cognition in schizophrenia and healthy comparison subjects

Successful linguistic processing requires efficient encoding of successively-occurring auditory input in a time-constrained manner, especially under noisy conditions. In this study we examined the early neural response dynamics to rapidly-presented successive syllables in schizophrenia participants and healthy comparison subjects, and investigated the effects of noise on these responses. We used magnetoencephalography (MEG) to reveal the time-course of stimulus-locked activity over bilateral auditory cortices during discrimination of syllable pairs that differed either in voice onset time (VOT) or place of articulation (POA), in the presence or absence of noise. We also examined the association of these early neural response patterns to higher-order cognitive functions. The M100 response, arising from auditory cortex and its immediate environs, showed less attenuation to the second syllable in patients with schizophrenia than healthy comparison subjects during VOT-based discrimination in noise. M100 response amplitudes were similar between groups for the first syllable during all three discrimination conditions, and for the second syllable during VOT-based discrimination in quiet and POA-based discrimination in noise. Across subjects, the lack of M100 attenuation to the second syllable during VOT-based discrimination in noise was associated with poorer task accuracy, lower education and IQ, and lower scores on measures of Verbal Learning and Memory and Global Cognition. Because the neural response to the first syllable was not significantly different between groups, nor was a schizophrenia-related difference obtained in all discrimination tasks, early linguistic processing dysfunction in schizophrenia does not appear to be due to general sensory input problems. Rather, data suggest that faulty temporal integration occurs during successive syllable processing when the signal-to-noise ratio is low. Further, the neural mechanism by which the second syllable is suppressed during noise-challenged VOT discrimination appears to be important for higher-order cognition and provides a promising target for neuroscience-guided cognitive training approaches to schizophrenia.

Dynamic Activation of Frontal, Parietal, and Sensory Regions Underlying Anticipatory Visual Spatial Attention

Although it is well established that multiple frontal, parietal, and occipital regions in humans are involved in anticipatory deployment of visual spatial attention, less is known about the electrophysiological signals in each region across multiple subsecond periods of attentional deployment. We used MEG measures of cortical stimulus-locked, signal-averaged (event-related field) activity during a task in which a symbolic cue directed covert attention to the relevant location on each trial. Direction-specific attention effects occurred in different cortical regions for each of multiple time periods during the delay between the cue and imperative stimulus. A sequence of activation from V1/V2 to extrastriate, parietal, and frontal regions occurred within 110 ms after cue, possibly related to extraction of cue meaning. Direction-specific activations ∼300 ms after cue in frontal eye field (FEF), lateral intraparietal area (LIP), and cuneus support early covert targeting of the cued location. This was followed by coactivation of a frontal–parietal system [superior frontal gyrus (SFG), middle frontal gyrus (MFG), LIP, anterior intraparietal sulcus (IPSa)] that may coordinate the transition from targeting the cued location to sustained deployment of attention to both space and feature in the last period. The last period involved direction-specific activity in parietal regions and both dorsal and ventral sensory regions [LIP, IPSa, ventral IPS, lateral occipital region, and fusiform gyrus], which was accompanied by activation that was not direction specific in right hemisphere frontal regions (FEF, SFG, MFG). Behavioral performance corresponded with the magnitude of attention-related activity in different brain regions at each time period during deployment. The results add to the emerging electrophysiological characterization of different cortical networks that operate during anticipatory deployment of visual spatial attention.

Auditory Cortical Plasticity Drives Training-Induced Cognitive Changes in Schizophrenia

Schizophrenia is characterized by dysfunction in basic auditory processing, as well as higher-order operations of verbal learning and executive functions. We investigated whether targeted cognitive training of auditory processing improves neural responses to speech stimuli, and how these changes relate to higher-order cognitive functions. Patients with schizophrenia performed an auditory syllable identification task during magnetoencephalography before and after 50 hours of either targeted cognitive training or a computer games control. Healthy comparison subjects were assessed at baseline and after a 10 week no-contact interval. Prior to training, patients (N = 34) showed reduced M100 response in primary auditory cortex relative to healthy participants (N = 13). At reassessment, only the targeted cognitive training patient group (N = 18) exhibited increased M100 responses. Additionally, this group showed increased induced high gamma band activity within left dorsolateral prefrontal cortex immediately after stimulus presentation, and later in bilateral temporal cortices. Training-related changes in neural activity correlated with changes in executive function scores but not verbal learning and memory. These data suggest that computerized cognitive training that targets auditory and verbal learning operations enhances both sensory responses in auditory cortex as well as engagement of prefrontal regions, as indexed during an auditory processing task with low demands on working memory. This neural circuit enhancement is in turn associated with better executive function but not verbal memory.

A novel ANCOVA design for analysis of MEG data with application to a visual attention study

Statistical inference from MEG-based distributed activation maps is well suited to the general linear modeling framework, a standard approach to the analysis of fMRI and PET neuroimaging studies. However, there are important differences from the other neuroimaging modalities related to how observations are created and fitted in GLM models, as well as how subsequent statistical inference is performed. In this paper, we demonstrate how MEG oscillatory components can be analyzed in this framework based on a custom ANCOVA model that takes into account baseline and inter-hemispheric effects, rather than a simpler ANOVA design. We present the methodology using as an example an MEG study of visual spatial attention, since the model design depends on the specific experiment and neuroscience hypotheses being tested. However, the techniques presented here can be readily adapted to accommodate other experimental paradigms. We create statistics that estimate the temporal evolution of attention effects on alpha power in several cortical regions. We present evidence for direction-specific attention effects on alpha activity in occipital and parietal regions and demonstrate the sub-second timing of these effects in each region. The results support a mechanism for anticipatory attentional deployment that dynamically modulates the local alpha synchrony in a network of parietal control and occipital sensory regions.

Transient and sustained brain activity during anticipatory visuospatial attention.

In this study, we determined whether the visuospatial attention network of frontal, parietal, and occipital cortex can be parsed into two different subsets of active regions associated with transient and sustained processes within the same cue-to-target delay period of an endogenously cued visuospatial attention task. We identified regions with early transient activity and regions with later sustained activity during the same trials using a general linear model analysis of event-related BOLD functional MRI data with two timecourse covariates for the same cue-to-target delay period. During the delay between the cue and target, we observed significant transient activity in right frontal eye field and right occipital-parietal junction, and significant sustained activity in right ventral intraparietal sulcus and right dorsolateral and anterior prefrontal cortex.

Imaging of oscillatory behavior in event-related MEG studies

Since event-related components in MEG (magnetoencephalography) studies are often buried in background brain activity and environmental and sensor noise, it is a standard technique for noise reduction to average over multiple stimulus-locked responses or “epochs”. However this also removes event-related changes in oscillatory activity that are not phase locked to the stimulus. To overcome this problem, we combine time-frequency analysis of individual epochs with corticallyconstrained imaging to produce dynamic images of brain activity on the cerebral cortex in multiple time-frequency bands. While the SNR in individual epochs is too low to see any but the strongest components, we average signal power across epochs to find event related components on the cerebral cortex in each frequency band. To determine which of these components are statistically significant within an individual subject, we threshold the cortical images to control for false positives. This involves testing thousands of hypotheses (one per surface element and time-frequency band) for significant experimental effects. To control the number of false positives over all tests, we must therefore apply multiplicity adjustments by controlling the familywise error rate, i.e. the probability of one or more false positive detections across the entire cortex. Applying this test to each frequency band produces a set of cortical images showing significant eventrelated activity in each band of interest. We demonstrate this method in applications to high density MEG studies of visual attention.

Event-related brain potentials isolate the motor component in a tapping task.

Repetitive tapping is used to investigate temporal perception, memory, and reproduction. Intertap intervals and their variability, arise from cognitive and motor processes during the task. We used a measure of readiness potential onset to determine motor component latency during the timed interval. Subjects performed a paced, two-handed tapping task at four target intervals (1.5–2.75 s). Overall latency of production increased with increasing ISI, as did variability across target interval, conforming to a generalized Webers law. In contrast, average motor latency was roughly 0.5 s across ISI. This constant motor latency may also indicate constant variability attributable to motor processing.

EXPLORING HUMAN VISUAL ATTENTION IN AN MEG STUDY OF A SPATIAL CUEING PARADIGM USING A NOVEL ANCOVA DESIGN

Visual attention models postulate that relevant information is selectively extracted by differentially modulating neural activity in the visual cortex to control the response to target and distractor stimuli. To investigate attention bias mechanisms in the brain, we use general linear modeling of cortically constrained images of oscillatory alpha activity extracted from an MEG study of visual attention. By using a novel ANCOVA design, we create statistics that estimate the temporal evolution of attention effects on several cortical regions. We present evidence that the superior parietal lobe and temporal parietal junction have instrumental roles, respectively, in shifting and sustaining attention.