Neural correlates of working memory in Temporal Lobe Epilepsy--an fMRI study.

It has traditionally been held that the hippocampus is not part of the neural substrate of working memory (WM), and that WM is preserved in Temporal Lobe Epilepsy (TLE). Recent imaging and neuropsychological data suggest this view may need revision. The aim of this study was to investigate the neural correlates of WM in TLE using functional MRI (fMRI). We used a visuo-spatial 'n-back' paradigm to compare WM network activity in 38 unilateral hippocampal sclerosis (HS) patients (19 left) and 15 healthy controls. WM performance was impaired in both left and right HS groups compared to controls. The TLE groups showed reduced right superior parietal lobe activity during single- and multiple-item WM. No significant hippocampal activation was found during the active task in any group, but the hippocampi progressively deactivated as the task demand increased. This effect was bilateral for controls, whereas the TLE patients showed progressive unilateral deactivation only contralateral to the side of the hippocampal sclerosis and seizure focus. Progressive deactivation of the posterior medial temporal lobe was associated with better performance in all groups. Our results suggest that WM is impaired in unilateral HS and the underlying neural correlates of WM are disrupted. Our findings suggest that hippocampal activity is progressively suppressed as the WM load increases, with maintenance of good performance. Implications for understanding the role of the hippocampus in WM are discussed

Disrupted segregation of working memory networks in temporal lobe epilepsy

Working memory is a critical building block for almost all cognitive tasks, and impairment can cause significant disruption to daily life routines. We investigated the functional connectivity (FC) of the visuo-spatial working memory network in temporal lobe epilepsy and its relationship to the underlying white matter tracts emanating from the hippocampus. Fifty-two patients with unilateral hippocampal sclerosis (HS) (30 left) and 30 healthy controls underwent working memory functional MRI (fMRI) and Diffusion Tensor Imaging (DTI). Six seed regions were identified for FC analysis; 4 within a task-positive network (left and right middle frontal gyri and superior parietal lobes), and 2 within a task-negative network (left and right hippocampi). FC maps were created by extracting the time-series of the fMRI signal in each region in each subject and were used as regressors of interest for additional GLM fMRI analyses. Structural connectivity (SC) corresponding to areas to which the left and right hippocampi were connected was determined using tractography, and a mean FA for each hippocampal SC map was calculated. Both left and right HS groups showed atypical FC between task-positive and task-negative networks compared to controls. This was characterised by co-activation of the task-positive superior parietal lobe ipsilateral to the typically task-negative sclerosed hippocampus. Correlational analysis revealed stronger FC between superior parietal lobe and ipsilateral hippocampus, was associated with worse performance in each patient group. The SC of the hippocampus was associated with the intra-hemispheric FC of the superior parietal lobe, in that greater SC was associated with weaker parieto-frontal FC. The findings suggest that the segregation of the task-positive and task-negative FC networks supporting working memory in TLE is disrupted, and is associated with abnormal structural connectivity of the sclerosed hippocampus. Co-activation of parieto-temporal regions was associated with poorer working memory and this may be associated with working memory dysfunction in TLE

Persistent and reversible consequences of combat stress on the mesofrontal circuit and cognition

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Alcohol Use Disorders and an fMRI Stress Task: A Connectivity Analysis

Little research has been conducted on neuronal stress processing in individuals with alcohol dependence (AD). The present study examined neural stress response in AD individuals compared to controls using an fMRI stress task, assessing amygdala activation and its connectivity to the medial prefrontal cortex (mPFC). Further, the study analyzed the impact of hormone levels and subjective stress on frontal-limbic connectivity patterns. Ten abstinent AD individuals and 11 controls were recruited. Subjects participated in an fMRI stress task. A region of interest (amygdala) analysis was conducted using area-under-the-curve. This activation was then examined in a whole brain functional connectivity analysis. Follow-up analyses investigated whether brain activation could be predicted by cortisol, ACTH, and subjective stress. As hypothesized, the present study found increased amygdala activation in the AD group in comparison to controls, as well as decreased bilateral amygdala connectivity with the mPFC, as well as fronto-temporal and cerebellar regions. Hormone levels collected a year prior, but not subjective stress, predicted activation and connectivity

Lost in Time and Space: States of High Arousal Disrupt Implicit Acquisition of Spatial and Sequential Context Information

Biased cognition during high arousal states is a relevant phenomenon in a variety of topics: from the development of post-traumatic stress disorders or stress-triggered addictive behaviors to forensic considerations regarding crimes of passion. Recent evidence indicates that arousal modulates the engagement of a hippocampus-based “cognitive” system in favor of a striatum-based “habit” system in learning and memory, promoting a switch from flexible, contextualized to more rigid, reflexive responses. Existing findings appear inconsistent, therefore it is unclear whether and which type of context processing is disrupted by enhanced arousal. In this behavioral study, we investigated such arousal-triggered cognitive-state shifts in human subjects. We validated an arousal induction procedure (three experimental conditions: violent scene, erotic scene, neutral control scene) using pupillometry (Preliminary Experiment, n = 13) and randomly administered this method to healthy young adults to examine whether high arousal states affect performance in two core domains of contextual processing, the acquisition of spatial (spatial discrimination paradigm; Experiment 1, n = 66) and sequence information (learned irrelevance paradigm; Experiment 2, n = 84). In both paradigms, spatial location and sequences were encoded incidentally and both displacements when retrieving spatial position as well as the predictability of the target by a cue in sequence learning changed stepwise. Results showed that both implicit spatial and sequence learning were disrupted during high arousal states, regardless of valence. Compared to the control group, participants in the arousal conditions showed impaired discrimination of spatial positions and abolished learning of associative sequences. Furthermore, Bayesian analyses revealed evidence against the null models. In line with recent models of stress effects on cognition, both experiments provide evidence for decreased engagement of flexible, cognitive systems supporting encoding of context information in active cognition during acute arousal, promoting reduced sensitivity for contextual details. We argue that arousal fosters cognitive adaptation towards less demanding, more present-oriented information processing, which prioritizes a current behavioral response set at the cost of contextual cues. This transient state of behavioral perseverance might reduce reliance on context information in unpredictable environments and thus represent an adaptive response in certain situations

Attention in the Brain Under Conditions of Sub-Optimal Alertness: Neurobiological Effects and Individual Differences

Sleep deprivation (SD) is a prevalent problem in modern society, and one that can have serious adverse consequences for health and safety. Critically, even short periods of SD can lead to relatively large decrements in attention, which may in turn cause an individual to neglect important environmental stimuli. In this thesis, I report the results of three experiments designed to investigate the neural bases of attentional declines under conditions of sleep loss and mental fatigue. In two experiments using arterial spin labeled fMRI, a technique that enables the quantification of absolute levels of cerebral blood flow (CBF), it was found that CBF patterns in the resting brain differed significantly based on arousal levels (Study #1) and prior cognitive workload (Study #2). These findings are a departure from prior neuroimaging studies, which have typically taken neural activity during non-task periods as static and inseparable baseline. In a test of sustained attention, performance declines were observed both following SD (Study #1) and when performing the task for an extended period of time while well-rested (Study #2). These decrements were primarily mediated by hypoactivation in a fronto-parietal attentional circuit. Furthermore, resting baseline levels of cerebral blood flow in the thalamus and prefrontal cortex before the start of the task were predictive of interindividual differences in subsequent performance decline (Study #2). In Study #3, an experiment using standard BOLD fMRI, it was found that performance declines in a test of selective attention following SD were accompanied by reduced functional connectivity between top-down control areas and regions of ventral visual cortex, as well as reductions in activation to targets in object-selective areas. Taken together, these results further our understanding of the neural basis of attention under conditions when this system is taxed beyond its normal limits

An Investigation of the Neural Mechanism by which the Prefrontal Cortex Facilitates Anti-saccade Task Performance

Cognitive control enables us to guide our behaviour in an appropriate manner, such as rapid eye movements (saccades) toward a location or object of interest. A well-established test of cognitive control is the anti-saccade task, which instructs subjects to look away from a suddenly-appearing stimulus. The dorsolateral prefrontal cortex (dlPFC) and anterior cingulate cortex (ACC) are part of a cortical saccade control network that influences the superior colliculus (SC), which sends saccade commands to the brainstem saccade generator. To compare and contrast the roles of the dlPFC and ACC in saccade control, the cryoloop method of reversible cryogenic deactivation was used to identify the effects of dlPFC and ACC deactivation on pro-saccades and anti-saccades. Both dlPFC and ACC deactivation increased the incidence of ipsilateral saccades, but only dlPFC deactivation impaired contralateral saccades. An inhibitory model of prefrontal function has been proposed by which the prefrontal cortex suppresses the activity of SC saccade neurons on anti-saccade trials, to inhibit an unwanted saccade toward the stimulus. A direct test of this inhibitory model was performed by deactivating the dlPFC and recording the activity of SC saccade neurons. Unilateral dlPFC deactivation delayed the onset of saccade-related activity in the SC ipsilateral to deactivation, which suggests that the dlPFC has an excitatory influence on SC saccade neurons. There was also an increase of activity in the contralateral SC, which suggests that unilateral dlPFC deactivation caused a neural imbalance at the SC. Bilateral dlPFC deactivation, on the other hand, should not cause a neural imbalance, and thus was used to identify the effects of dlPFC deactivation that were caused by cognitive control impairments. Bilateral dlPFC deactivation increased the stimulus-related activity, and decreased the saccade-related activity, of SC saccade neurons. An increase of anti-saccade errors was more substantial in a “rule memorized” condition, which suggests that the dlPFC plays an important role in rule maintenance. Given an excitatory influence of the dlPFC on SC saccade neurons, I propose that the dlPFC facilitates anti-saccade task performance by first maintaining the relevant rule in working memory, then implementing the rule by enhancing the saccade-generating signal at the SC