Sien Hu

Global resting-state functional magnetic resonance imaging analysis identifies frontal cortex, striatal, and cerebellar dysconnectivity in obsessive-compulsive disorder.

BACKGROUND Obsessive-compulsive disorder (OCD) is associated with regional hyperactivity in cortico-striatal circuits. However, the large-scale patterns of abnormal neural connectivity remain uncharacterized. Resting-state functional connectivity studies have shown altered connectivity within the implicated circuitry, but they have used seed-driven approaches wherein a circuit of interest is defined a priori. This limits their ability to identify network abnormalities beyond the prevailing framework. This limitation is particularly problematic within the prefrontal cortex (PFC), which is large and heterogeneous and where a priori specification of seeds is therefore difficult. A hypothesis-neutral, data-driven approach to the analysis of connectivity is vital. METHODS We analyzed resting-state functional connectivity data collected at 3T in 27 OCD patients and 66 matched control subjects with a recently developed data-driven global brain connectivity (GBC) method, both within the PFC and across the whole brain. RESULTS We found clusters of decreased connectivity in the left lateral PFC in both whole-brain and PFC-restricted analyses. Increased GBC was found in the right putamen and left cerebellar cortex. Within regions of interest in the basal ganglia and thalamus, we identified increased GBC in dorsal striatum and anterior thalamus, which was reduced in patients on medication. The ventral striatum/nucleus accumbens exhibited decreased global connectivity but increased connectivity specifically with the ventral anterior cingulate cortex in subjects with OCD. CONCLUSIONS These findings identify previously uncharacterized PFC and basal ganglia dysconnectivity in OCD and reveal differentially altered GBC in dorsal and ventral striatum. Results highlight complex disturbances in PFC networks, which could contribute to disrupted cortical-striatal-cerebellar circuits in OCD.

Neural processes of preparatory control for stop signal inhibition

This study investigated the preparatory control of motor inhibition and motor execution using a stop signal task (SST) and functional magnetic resonance imaging (fMRI). In the SST, a frequent “go” signal triggered a prepotent response and a less frequent “stop” signal prompted the inhibition of this response. Preparatory control of motor inhibition and execution in the stop signal trials were examined by contrasting brain activation between stop success and stop error trials during the fore‐period, in which participants prepared to respond to go or to stop. Results from 91 healthy adults showed greater activation in the right prefrontal cortex and inferior parietal lobule during preparatory motor inhibition. Preparatory motor execution activated bilateral putamen, primary motor cortices, posterior cingulate cortex, ventromedial prefrontal cortex, and superior temporal/intraparietal sulci. Furthermore, the extents of these inhibition and execution activities were inversely correlated across subjects. On the basis of a median split of the stop signal reaction time (SSRT), subjects with short SSRT showed greater activity in the right orbital frontal cortex during preparatory inhibition. These new findings suggest that the go and stop processes interact prior to target presentation in the SST, in accord with recent computational models of stop signal inhibition. Hum Brain Mapp, 2012.

Decreased saliency processing as a neural measure of Barratt impulsivity in healthy adults

Cognitive control is necessary to navigating through an uncertain world. With the stop signal task (SST), we measure how cognitive control functions in a controlled environment. There has been conflicting evidence on whether trait impulsivity might reflect differences in cognitive control during the SST. While some studies find that trait impulsivity relates to measures of response inhibition, such as the stop signal reaction time (SSRT), other studies do not. Here, in 92 young adult participants (58 females; age 25 ± 4 years), we examined whether trait impulsivity, measured by the Barratt impulsivity scale (BIS-11), is associated with differences in performance and regional brain activations for the component processes of cognitive control during the SST. Across participants, trait impulsivity showed a trend-level correlation with SSRT (F(1.90)=3.18, p<.07; Pearson regression). In simple regressions, activation of the right anterior dorsal insula and middle frontal cortex (MFC) during stop as compared to go trials negatively correlated with motor and non-planning impulsivity score. Using the generalized form of psychophysiological interaction (gPPI), we showed that functional connectivity of the right insula and MFC with the left dorsolateral prefrontal cortex and bilateral visual areas were also negatively correlated with impulsivity. None of the other component processes of cognitive control, including response inhibition, error processing, post-error slowing, were significantly related to Barratt impulsivity. These results suggest that trait impulsivity as measured by BIS-11 may have distinct effects on saliency processing in adult individuals.

Resting state functional connectivity of the basal nucleus of Meynert in humans: In comparison to the ventral striatum and the effects of age

The basal nucleus of Meynert (BNM) provides the primary cholinergic inputs to the cerebral cortex. Loss of neurons in the BNM is linked to cognitive deficits in Alzheimers disease and other degenerative conditions. Numerous animal studies described cholinergic and non-cholinergic neuronal responses in the BNM; however, work in humans has been hampered by the difficulty of defining the BNM anatomically. Here, on the basis of a previous study that delineated the BNM of post-mortem human brains in a standard stereotaxic space, we sought to examine functional connectivity of the BNM, as compared to the nucleus accumbens (or ventral striatum, VS), in a large resting state functional magnetic resonance imaging data set. The BNM and VS shared but also showed a distinct pattern of cortical and subcortical connectivity. Compared to the VS, the BNM showed stronger positive connectivity with the putamen, pallidum, thalamus, amygdala and midbrain, as well as the anterior cingulate cortex, supplementary motor area and pre-supplementary motor area, a network of brain regions that respond to salient stimuli and orchestrate motor behavior. In contrast, compared to the BNM, the VS showed stronger positive connectivity with the ventral caudate and medial orbitofrontal cortex, areas implicated in reward processing and motivated behavior. Furthermore, the BNM and VS each showed extensive negative connectivity with visual and lateral prefrontal cortices. Together, the distinct cerebral functional connectivities support the role of the BNM in arousal, saliency responses and cognitive motor control and the VS in reward related behavior. Considering the importance of BNM in age-related cognitive decline, we explored the effects of age on BNM and VS connectivities. BNM connectivity to the visual and somatomotor cortices decreases while connectivity to subcortical structures including the midbrain, thalamus, and pallidum increases with age. These findings of age-related changes of cerebral functional connectivity of the BNM may facilitate research of the neural bases of cognitive decline in health and illness.

Ventromedial prefrontal cortex and the regulation of physiological arousal

Neuroimaging studies show a correlation between activity of the ventromedial prefrontal cortex (vmPFC) and skin conductance measurements. However, little is known whether this brain region plays a causal role in regulating physiological arousal. To address this question, we employed Granger causality analysis (GCA) to establish causality between cerebral blood oxygenation level-dependent and skin conductance signals in 24 healthy adults performing a cognitive task during functional magnetic resonance imaging. The results showed that activity of the vmPFC not only negatively correlated with skin conductance level (SCL) but also Granger caused SCL, thus establishing the direction of influence. Importantly, across participants, the strength of Granger causality was negatively correlated to phasic skin conductance responses elicited by external events during the behavioral task. In contrast, activity of the dorsal anterior cingulate cortex positively correlated with SCL but did not show a causal relationship in GCA. These new findings indicate that the vmPFC plays a causal role in regulating physiological arousal. Increased vmPFC activity leads to a decrease in skin conductance. The findings may also advance our understanding of dysfunctions of the vmPFC in mood and anxiety disorders that involve altered control of physiological arousal.

Cerebral gray matter volumes and low-frequency fluctuation of BOLD signals in cocaine dependence: Duration of use and gender difference ☆

BACKGROUND Magnetic resonance imaging has provided a wealth of information on altered brain activations and structures in individuals addicted to cocaine. However, few studies have considered the influence of age and alcohol use on these changes. METHODS We examined gray matter volume with voxel based morphometry (VBM) and low frequency fluctuation (LFF) of BOLD signals as a measure of cerebral activity of 84 cocaine dependent (CD) and 86 healthy control (HC) subjects. We performed a covariance analysis to account for the effects of age and years of alcohol use. RESULTS Compared to HC, CD individuals showed decreased gray matter (GM) volumes in frontal and temporal cortices, middle/posterior cingulate cortex, and the cerebellum, at p<0.05, corrected for multiple comparisons. The GM volume of the bilateral superior frontal gyri (SFG) and cingulate cortices were negatively correlated with years of cocaine use, with women showing a steeper loss in the right SFG in association with duration of use. In contrast, the right ventral putamen showed increased GM volume in CD as compared to HC individuals. Compared to HC, CD individuals showed increased fractional amplitude of LFF (fALFF) in the thalamus, with no significant overlap with regions showing GM volume loss. CONCLUSIONS These results suggested that chronic cocaine use is associated with distinct changes in cerebral structure and activity that can be captured by GM volume and fALFF of BOLD signals.

Resting-State Functional Connectivity of the Locus Coeruleus in Humans: In Comparison with the Ventral Tegmental Area/Substantia Nigra Pars Compacta and the Effects of Age

The locus coeruleus (LC) provides the primary noradrenergic inputs to the cerebral cortex. Despite numerous animal studies documenting the functions of the LC, research in humans is hampered by the small volume of this midbrain nucleus. Here, we took advantage of a probabilistic template, explored the cerebral functional connectivity of the LC with resting-state fMRI data of 250 healthy adults, and verified the findings by accounting for physiological noise in another data set. In addition, we contrasted connectivities of the LC and the ventral tegmental area/substantia nigra pars compacta. The results highlighted both shared and distinct connectivity of these 2 midbrain structures, as well as an opposite pattern of connectivity to bilateral amygdala, pulvinar, and right anterior insula. Additionally, LC connectivity to the fronto-parietal cortex and the cerebellum increases with age and connectivity to the visual cortex decreases with age. These findings may facilitate studies of the role of the LC in arousal, saliency responses and cognitive motor control and in the behavioral and cognitive manifestations during healthy and disordered aging. Although the first to demonstrate whole-brain LC connectivity, these findings need to be confirmed with high-resolution imaging.

Neural Processes of an Indirect Analog of Risk Taking in Young Nondependent Adult Alcohol Drinkers-An fMRI Study of the Stop Signal Task

BACKGROUND Alcohol abuse and dependence are common problems in the United States that stem from a variety of factors, one of which may be a period of high level social drinking during college and early adulthood. Extant study implicates risk taking as a cognitive factor that contributes to habitual and heavy drinking. We sought to examine the neural processes of risk taking in young, nondependent drinkers. METHODS We compared 20 young adult social drinkers with a high level of alcohol use (AH), as defined by number of drinks per month, and 21 demographically matched drinkers with low to moderate alcohol use (ALM) in a functional magnetic resonance imaging study of the stop signal task. By contrasting risk taking (speeded) to risk aversion (slowed) trials, we examined the neural correlates of risk taking. Brain imaging data were analyzed with Statistical Parametric Mapping. Regions of interest were identified and corresponding effect sizes were examined for correlations with self-reported alcohol use. RESULTS The results showed that, compared with ALM, AH demonstrated decreased activation in right superior frontal gyrus and left caudate nucleus when contrasting risk taking and risk aversion trials at p < 0.001, uncorrected. Furthermore, examination of the effect size data showed that the extent of these decreased regional activations correlated with frequency of drinking in women, but not men. CONCLUSIONS These findings suggest a neural analog of nondependent, high level drinking. Specifically, high level social drinking is associated with altered activation of the caudate and superior frontal cortex, an association that appears to be stronger in women than in men and is strongly tied to the frequency of drinking. These results are relevant in understanding risk taking behavior in social drinking as well as in examining the potential path from high level social use in young adults to dangerous alcohol consumption later in life.

Cerebral correlates of skin conductance responses in a cognitive task.

Changes in physiological arousal frequently accompany cognitive performance. Many studies sought to identify the neural correlates of heightened arousal as indexed by skin conductance responses (SCR). However, the observed regional activations may be confounded by task events. We addressed this issue by recording SCR in 25 adults performing a stop signal task (SST) during functional magnetic resonance imaging. We compared only go trials with high and low SCR in order to isolate the event-independent processes. Furthermore, we distinguished go trials that followed another go, a stop success, or a stop error trial to examine whether the neural activities are contingent on the local context in which changes in SCR occurred. The results showed that the supplementary motor area responded to increased SCR irrespective of the preceding trial. The dorsal anterior cingulate cortex increased activation to heightened arousal most significantly in response to stop errors. The medial prefrontal cortex increased activation to SCR following a stop error but decreased activation following a go or stop success trial. These new findings specify the regional activations that accompany changes in physiological arousal during the SST and support distinct processes for the changes that occur under different local contexts. In particular, the MPFC shows opposing responses by increasing activation to changes in arousal evoked by salient stimuli and decreasing activation to the control of arousal.

Anticipating conflict: Neural correlates of a Bayesian belief and its motor consequence.

Previous studies have examined the neural correlates of proactive control using a variety of behavioral paradigms; however, the neural network relating the control process to its behavioral consequence remains unclear. Here, we applied a dynamic Bayesian model to a large fMRI data set of the stop signal task to address this issue. By estimating the probability of the stop signal - p(Stop) - trial by trial, we showed that higher p(Stop) is associated with prolonged go trial reaction time (RT), indicating proactive control of motor response. In modeling fMRI signals at trial and target onsets, we distinguished activities of proactive control, prediction error, and RT slowing. We showed that the anterior pre-supplementary motor area (pre-SMA) responds specifically to increased stop signal likelihood, and its activity is correlated with activations of the posterior pre-SMA and bilateral anterior insula during prolonged response times. This directional link is also supported by Granger causality analysis. Furthermore, proactive control, prediction error, and time-on-task are each mapped to distinct areas in the medial prefrontal cortex. Together, these findings dissect regional functions of the medial prefrontal cortex in cognitive control and provide system level evidence associating conflict anticipation with its motor consequence.