Altered basal ganglia output during self-restraint.

Suppressing actions is essential for flexible behavior. Multiple neural circuits involved in behavioral inhibition converge upon a key basal ganglia output nucleus, the substantia nigra pars reticulata (SNr). To examine how changes in basal ganglia output contribute to self-restraint, we recorded SNr neurons during a proactive behavioral inhibition task. Rats responded to Go! cues with rapid leftward or rightward movements, but also prepared to cancel one of these movement directions on trials when a Stop! cue might occur. This action restraint - visible as direction-selective slowing of reaction times - altered both rates and patterns of SNr spiking. Overall firing rate was elevated before the Go! cue, and this effect was driven by a subpopulation of direction-selective SNr neurons. In neural state space, this corresponded to a shift away from the restrained movement. SNr neurons also showed more variable inter-spike intervals during proactive inhibition. This corresponded to more variable state-space trajectories, which may slow reaction times via reduced preparation to move. These findings open new perspectives on how basal ganglia dynamics contribute to movement preparation and cognitive control.

Improved inference in coupling, encoding, and decoding models and its consequence for neuroscientific interpretation.

BACKGROUND: A central goal of systems neuroscience is to understand the relationships amongst constituent units in neural populations, and their modulation by external factors, using high-dimensional and stochastic neural recordings. Parametric statistical models (e.g., coupling, encoding, and decoding models), play an instrumental role in accomplishing this goal. However, extracting conclusions from a parametric model requires that it is fit using an inference algorithm capable of selecting the correct parameters and properly estimating their values. Traditional approaches to parameter inference have been shown to suffer from failures in both selection and estimation. The recent development of algorithms that ameliorate these deficiencies raises the question of whether past work relying on such inference procedures have produced inaccurate systems neuroscience models, thereby impairing their interpretation. NEW METHOD: We used algorithms based on Union of Intersections, a statistical inference framework based on stability principles, capable of improved selection and estimation. COMPARISON: We fit functional coupling, encoding, and decoding models across a battery of neural datasets using both UoI and baseline inference procedures (e.g., ℓ1-penalized GLMs), and compared the structure of their fitted parameters. RESULTS: Across recording modality, brain region, and task, we found that UoI inferred models with increased sparsity, improved stability, and qualitatively different parameter distributions, while maintaining predictive performance. We obtained highly sparse functional coupling networks with substantially different community structure, more parsimonious encoding models, and decoding models that relied on fewer single-units. CONCLUSIONS: Together, these results demonstrate that improved parameter inference, achieved via UoI, reshapes interpretation in diverse neuroscience contexts.

Globus pallidus dynamics reveal covert strategies for behavioral inhibition.

Flexible behavior requires restraint of actions that are no longer appropriate. This behavioral inhibition critically relies on frontal cortex - basal ganglia circuits. Within the basal ganglia, the globus pallidus pars externa (GPe) has been hypothesized to mediate selective proactive inhibition: being prepared to stop a specific action, if needed. Here we investigate population dynamics of rat GPe neurons during preparation-to-stop, stopping, and going. Rats selectively engaged proactive inhibition towards specific actions, as shown by slowed reaction times (RTs). Under proactive inhibition, GPe population activity occupied state-space locations farther from the trajectory followed during normal movement initiation. Furthermore, the state-space locations were predictive of distinct types of errors: failures-to-stop, failures-to-go, and incorrect choices. Slowed RTs on correct proactive trials reflected starting bias towards the alternative action, which was overcome before progressing towards action initiation. Our results demonstrate that rats can exert cognitive control via strategic adjustments to their GPe network state.

Oscillation patterns of local field potentials in the dorsal striatum and sensorimotor cortex during the encoding, maintenance, and decision stages for the ordinal comparison of sub- and supra-second signal durations.

Ordinal comparison of successively presented signal durations requires (a) the encoding of the first signal duration (standard), (b) maintenance of temporal information specific to the standard duration in memory, and (c) timing of the second signal duration (comparison) during which a comparison is made of the first and second durations. Rats were first trained to make ordinal comparisons of signal durations within three time ranges using 0.5, 1.0, and 3.0-s standard durations. Local field potentials were then recorded from the dorsal striatum and sensorimotor cortex in order to investigate the pattern of neural oscillations during each phase of the ordinal-comparison process. Increased power in delta and theta frequency ranges was observed during both the encoding and comparison stages. Active maintenance of a selected response, "shorter" or "longer" (counter-balanced across left and right levers), was represented by an increase of theta and delta oscillations in the contralateral striatum and cortex. Taken together, these data suggest that neural oscillations in the delta-theta range play an important role in the encoding, maintenance, and comparison of signal durations.

The Persistence of Memory: How the Brain Encodes Time in Memory.

Time and memory are inextricably linked, but it is far from clear how event durations and temporal sequences are encoded in memory. In this review, we focus on resource allocation models of working memory which suggest that memory resources can be flexibly distributed amongst several items such that the precision of working memory decreases with the number of items to be encoded. This type of model is consistent with human performance in working memory tasks based on visual, auditory as well as temporal stimulus patterns. At the neural-network level, we focus on excitatory-inhibitory oscillatary processes that are able to encode both interval timing and working memory in a coupled excitatory-inhibitory network. This modification of the striatal beat-frequency model of interval timing shows how memories for multiple time intervals are represented by neural oscillations and can also be used to explain the mechanisms of resource allocation in working memory.

Oscillatory multiplexing of neural population codes for interval timing and working memory.

Interval timing and working memory are critical components of cognition that are supported by neural oscillations in prefrontal-striatal-hippocampal circuits. In this review, the properties of interval timing and working memory are explored in terms of behavioral, anatomical, pharmacological, and neurophysiological findings. We then describe the various neurobiological theories that have been developed to explain these cognitive processes - largely independent of each other. Following this, a coupled excitatory - inhibitory oscillation (EIO) model of temporal processing is proposed to address the shared oscillatory properties of interval timing and working memory. Using this integrative approach, we describe a hybrid model explaining how interval timing and working memory can originate from the same oscillatory processes, but differ in terms of which dimension of the neural oscillation is utilized for the extraction of item, temporal order, and duration information. This extension of the striatal beat-frequency (SBF) model of interval timing (Matell and Meck, 2000, 2004) is based on prefrontal-striatal-hippocampal circuit dynamics and has direct relevance to the pathophysiological distortions observed in time perception and working memory in a variety of psychiatric and neurological conditions.

Dedicated clock/timing-circuit theories of time perception and timed performance.

Scalar Timing Theory (an information-processing version of Scalar Expectancy Theory) and its evolution into the neurobiologically plausible Striatal Beat-Frequency (SBF) theory of interval timing are reviewed. These pacemaker/accumulator or oscillation/coincidence detection models are then integrated with the Adaptive Control of Thought-Rational (ACT-R) cognitive architecture as dedicated timing modules that are able to make use of the memory and decision-making mechanisms contained in ACT-R. The different predictions made by the incorporation of these timing modules into ACT-R are discussed as well as the potential limitations. Novel implementations of the original SBF model that allow it to be incorporated into ACT-R in a more fundamental fashion than the earlier simulations of Scalar Timing Theory are also considered in conjunction with the proposed properties and neural correlates of the "internal clock".

Altered brain activation in ventral frontal-striatal regions following a 16-week pharmacotherapy in unmedicated obsessive-compulsive disorder.

Recent studies have reported that cognitive inflexibility associated with impairments in a frontal-striatal circuit and parietal region is a core cognitive deficit of obsessive-compulsive disorder (OCD). However, few studies have examined progressive changes in these regions following clinical improvement in obsessive-compulsive symptoms. To determine if treatment changes the aberrant activation pattern associated with task switching in OCD, we examined the activation patterns in brain areas after treatment. The study was conducted on 10 unmedicated OCD patients and 20 matched controls using event-related functional magnetic resonance imaging. Treatment improved the clinical symptoms measured by the Yale-Brown Obsessive Compulsive Scale and behavioral flexibility indicated by the switching cost. At baseline, OCD showed significantly less activation in the dorsal and ventral frontal-striatal circuit and parietal regions under the task-switch minus task-repeat condition compared with controls. After treatment, the neural responses in the ventral frontal-striatal circuit in OCD were partially normalized, whereas the activation deficit in dorsal frontoparietal regions that mediate shifting attention or behavioral flexibility persisted. It is suggested that altered brain activation in ventral frontal-striatal regions in OCD patients is associated with their cognitive flexibility and changes in these regions may underlie the pathophysiology of OCD.

Multi-level comparison of empathy in schizophrenia: an fMRI study of a cartoon task.

Empathy deficits might play a role in social dysfunction in schizophrenia. However, few studies have investigated the neuroanatomical underpinnings of the subcomponents of empathy in schizophrenia. This study investigated the hemodynamic responses to three subcomponents of empathy in patients with schizophrenia (N=15) and healthy volunteers (N=18), performing an empathy cartoon task during functional magnetic resonance imaging. The experiment used a block design with four conditions: cognitive, emotional, and inhibitory empathy, and physical causality control. Data were analyzed by comparing the blood-oxygen-level-dependent (BOLD) signal activation between the two groups. The cognitive empathy condition activated the right temporal pole to a lesser extent in the patient group than in comparison subjects. In the emotional and inhibitory conditions, the patients showed greater activation in the left insula and in the right middle/inferior frontal cortex, respectively. These findings add to our understanding of the impaired empathy in patients with schizophrenia by identifying a multi-level cortical dysfunction that underlies a deficit in each subcomponent of empathy and highlighting the importance of the fronto-temporal cortical network in ability to empathize.

Integration of cross-modal emotional information in the human brain: an fMRI study.

The interaction of information derived from the voice and facial expression of a speaker contributes to the interpretation of the emotional state of the speaker and to the formation of inferences about information that may have been merely implied in the verbal communication. Therefore, we investigated the brain processes responsible for the integration of emotional information originating from different sources. Although several studies have reported possible sites for integration, further investigation using a neutral emotional condition is required to locate emotion-specific networks. Using functional magnetic resonance imaging (fMRI), we explored the brain regions involved in the integration of emotional information from different modalities in comparison to those involved in integrating emotionally neutral information. There was significant activation in the superior temporal gyrus (STG); inferior frontal gyrus (IFG); and parahippocampal gyrus, including the amygdala, under the bimodal versus the unimodal condition, irrespective of the emotional content. We confirmed the results of previous studies by finding that the bimodal emotional condition elicited strong activation in the left middle temporal gyrus (MTG), and we extended this finding to locate the effects of emotional factors by using a neutral condition in the experimental design. We found anger-specific activation in the posterior cingulate, fusiform gyrus, and cerebellum, whereas we found happiness-specific activation in the MTG, parahippocampal gyrus, hippocampus, claustrum, inferior parietal lobule, cuneus, middle frontal gyrus (MFG), IFG, and anterior cingulate. These emotion-specific activations suggest that each emotion uses a separate network to integrate bimodal information and shares a common network for cross-modal integration.

BOLD response during visual perception of biological motion in obsessive-compulsive disorder : an fMRI study using the dynamic point-light animation paradigm.

OBJECTIVE: Although research has shown that deficits in various cognitive functions may underlie obsessive-compulsive disorder (OCD), studies have not yet clarified the specificity and etiology of perception processing, particularly the perception of biological motion that is correlated with social cognition. We used functional magnetic resonance imaging (fMRI) to investigate neural activity associated with the perception of biological motion in OCD patients. METHODS: The subjects were 15 patients with OCD and 15 age- and IQ-matched healthy volunteers. All subjects participated in a biological motion task in which they performed a one-back task signaling a repeated stimulus with a key press in each block condition to obligate attention to both types of stimuli. RESULTS: The biological motion versus scrambled motion contrast revealed that both OCD patients and healthy controls exhibited increased activation of the superior and middle temporal gyrus, the regions implicated in processing of biological motion, which is consistent with previous studies. However, direct comparison between OCD subjects and healthy controls indicated that patients with OCD exhibited increased activation in the right superior and middle temporal gyrus and the left inferior temporal and fusiform gyrus, and reduced activation in the right postcentral gyrus (BA 40) compared to healthy subjects. OCD patients exhibited increased activation in the ventral visual system, including the inferior temporal and fusiform gyrus. DISCUSSION: We observed a differential pattern of activity between OCD patients and healthy controls, indicating that OCD patients have functional differences related to the perception of biological motion. The differential activation between OCD patients and healthy subjects might contribute to the pathophysiological understanding of obsessive compulsive disorder.

Structural abnormalities of the right inferior colliculus in schizophrenia.

Although structural and functional neuroimaging studies of schizophrenia have suggested that impaired connectivity in the extensive network of cortical and subcortical areas is involved in its pathophysiology, there were no studies have investigated the structural integrity of the lower sensory brain areas including the inferior (IC) and the superior (SC) colliculus. The IC plays an important role in mediating auditory gating processes and inhibitory neural transmission, while the SC is a key structure in a distributed network mediating saccadic eye movements and shifts of attention, both of which have been linked to the pathophysiology of schizophrenia. We compared the morphologies of the IC and SC, which are involved in the early stage processing of visual and auditory stimuli, in patients with schizophrenia (N=28) and healthy controls (N=34) using high-resolution magnetic resonance imaging. Subjects with schizophrenia had a significantly smaller right IC, compared with controls. The reduced IC volume suggests that a structural abnormality of the IC in patients with schizophrenia may be involved in the auditory cognitive dysfunction of schizophrenia.

Objects and their icons in the brain: the neural correlates of visual concept formation.

We are constantly exposed to symbols such as traffic signs, emoticons in internet communication, or other abstract representations of objects as well as, of course, the written words. However, aside from the word reading, little is known about the way our brain responds when we read non-lexical iconic symbols. By using functional MRI, we found that the watching of icons recruited manifold brain areas including frontal and parietal cortices in addition to the temporo-occipital junction in the ventral pathway. Remarkably, the brain response for icons was contrasted with the response for corresponding concrete objects with the pattern of 'hyper-cortical and hypo-subcortical' brain activation. This neural underpinning might be called the neural correlates for visual concept formation.

Artificial shifting of fMRI activation localized by volume- and surface-based analyses.

Spatial smoothing is an important post-processing procedure that is used to increase the signal-to-noise ratio (SNR) of blood oxygenation level-dependent signals (BOLD) in common functional magnetic resonance imaging (fMRI) applications. However, recent studies have shown that smoothing artificially shifts probabilistic local maxima of fMRI activations. In this study, we show shifting of the localization of functional centers in hand motor areas of the cerebral cortex by three-dimensional isotropic Gaussian kernel smoothing or two-dimensional heat kernel smoothing in volume- and surface-based fMRI analyses. Activation maps derived from smoothed echo planar imaging (EPI) data by volume- and surface-based analyses were assigned to the nodes of individual cortical surface models, and local maxima in the primary motor area (M1) and the primary somatosensory cortex (S1) were compared with those derived from non-smoothed risk map analysis, which is commonly used in presurgical applications. For each analysis, the Euclidean and geodesic distances between the correlation coefficients of local maxima derived from smoothed and non-smoothed EPI data were measured. The results show that the correlation coefficients derived from the volume- and surface-based analyses were about 29.4% and 42.9% higher for smoothed than for non-smoothed risk map analyses, and show minimum shifting of localizations by 12.1 mm and 6.9 mm on average in Euclidean distance, respectively, and about 9.5 mm and 5.7 mm on average in geodesic distance, respectively.

Neural correlates of cognitive inflexibility during task-switching in obsessive-compulsive disorder.

A deficit in cognitive flexibility is acknowledged as a cognitive trait for obsessive-compulsive disorder (OCD). However, no investigations to date have used a cognitive activation paradigm to specify the neural correlates of this deficit in OCD. The objective of this study was to clarify how abnormal brain activities relate to cognitive inflexibility in OCD, using a task-switching paradigm. A task-switching paradigm which has two kinds of task-set was applied to 21 patients with OCD and 21 healthy subjects of matching age, IQ and sex, during an event-related functional magnetic resonance imaging experiment. Compared with the healthy subjects, patients with OCD exhibited a significantly higher error rate in task-switch trials (P < 0.05). Healthy controls showed significant activation in various areas, including dorsal frontal-striatal regions, during task-switching, whereas patients with OCD showed no activation in these areas. Significant differences were also observed in the dorsal frontal-striatal regions and ventromedial prefrontal and right orbitofrontal cortexes between patients with OCD and healthy controls. Correlation analysis indicated that the activations of orbitofrontal cortex were related with the performance in both groups and also with the activation of anterior cingulate cortex in the OCD group. These findings replicate previous studies of cognitive inflexibility in OCD and provide neural correlates related to a task-switching deficit in OCD. The results suggest that impaired task-switching ability in OCD patients might be associated with an imbalance in brain activation between dorsal and ventral frontal-striatal circuits.