David Clewett

Structural foundations of resting-state and task-based functional connectivity in the human brain

Magnetic resonance imaging enables the noninvasive mapping of both anatomical white matter connectivity and dynamic patterns of neural activity in the human brain. We examine the relationship between the structural properties of white matter streamlines (structural connectivity) and the functional properties of correlations in neural activity (functional connectivity) within 84 healthy human subjects both at rest and during the performance of attention- and memory-demanding tasks. We show that structural properties, including the length, number, and spatial location of white matter streamlines, are indicative of and can be inferred from the strength of resting-state and task-based functional correlations between brain regions. These results, which are both representative of the entire set of subjects and consistently observed within individual subjects, uncover robust links between structural and functional connectivity in the human brain.

Increased functional coupling between the left fronto‐parietal network and anterior insula predicts steeper delay discounting in smokers

In previous work, smokers showed steeper devaluation of delayed rewards than non‐smokers. While the neural correlates of this link between nicotine dependence and delay of discounting are not established, altered activity in executive networks may relate to impaired delayed gratification. The goal of this study was to examine neural correlates of discounting and their relation to nicotine dependence. Thirty‐nine smokers and 33 non‐smokers completed a functional magnetic resonance imaging (fMRI) intertemporal choice task in which they made individualized Hard (similarly valued), easy (dissimilarly valued), and control monetary choices. FMRI data were analyzed using a group independent component analysis and dual regression. Smokers discounted more steeply than non‐smokers, although this difference was only significant among severely dependent smokers. Intertemporal choices recruited distinct left‐ and right‐lateralized fronto‐parietal networks. A group‐by‐difficulty interaction indicated that smokers, relative to non‐smokers, exhibited less difficulty‐sensitivity in the right fronto‐parietal network. In contrast, smokers showed greater functional connectivity between the left fronto‐parietal network and the left fronto‐insular cortex. Moreover, the degree of functional connectivity between the left fronto‐parietal network and left fronto‐insular cortex was significantly correlated with individual differences in discounting. Thus, greater functional coupling between the anterior insula and left fronto‐parietal network is a candidate neural substrate linking smoking and impulsivity. Given the anterior insulas role in interfacing cognitive and interoceptive processing, this altered functional connectivity may relate to an addiction‐related bias towards immediate rewards. Hum Brain Mapp 35:3774–3787, 2014.

Neuromelanin marks the spot: identifying a locus coeruleus biomarker of cognitive reserve in healthy aging

Leading a mentally stimulating life may build up a reserve of neural and mental resources that preserve cognitive abilities in late life. Recent autopsy evidence links neuronal density in the locus coeruleus (LC), the brains main source of norepinephrine, to slower cognitive decline before death, inspiring the idea that the noradrenergic system is a key component of reserve (Robertson, I. H. 2013. A noradrenergic theory of cognitive reserve: implications for Alzheimers disease. Neurobiol. Aging. 34, 298-308). Here, we tested this hypothesis using neuromelanin-sensitive magnetic resonance imaging to visualize and measure LC signal intensity in healthy younger and older adults. Established proxies of reserve, including education, occupational attainment, and verbal intelligence, were linearly correlated with LC signal intensity in both age groups. Results indicated that LC signal intensity was significantly higher in older than younger adults and significantly lower in women than in men. Consistent with the LC-reserve hypothesis, both verbal intelligence and a composite reserve score were positively associated with LC signal intensity in older adults. LC signal intensity was also more strongly associated with attentional shifting ability in older adults with lower cognitive reserve. Together these findings link in vivo estimates of LC neuromelanin signal intensity to cognitive reserve in normal aging.

Age-related reduced prefrontal-amygdala structural connectivity is associated with lower trait anxiety.

OBJECTIVE A current neuroanatomical model of anxiety posits that greater structural connectivity between the amygdala and ventral prefrontal cortex (vPFC) facilitates regulatory control over the amygdala and helps reduce anxiety. However, some neuroimaging studies have reported contradictory findings, demonstrating a positive rather than negative association between trait anxiety and amygdala-vPFC white matter integrity. To help reconcile these findings, we tested the regulatory hypothesis of anxiety circuitry using aging as a model of white matter decline in the amygdala-vPFC pathway. METHODS We used probabilistic tractography to trace connections between the amygdala and vPFC in 21 younger, 18 middle-aged, and 15 healthy older adults. The resulting tract estimates were used to extract 3 indices of white-matter integrity: fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). The relationship between these amygdala-vPFC structural connectivity measures and age and State-Trait Anxiety Inventory (STAI) scores were assessed. RESULTS The tractography results revealed age-related decline in the FA (p = .005) and radial diffusivity (p = .002) of the amygdala-vPFC pathway. Contrary to the regulatory hypothesis, we found a positive rather than negative association between trait anxiety and right amygdala-vPFC FA (p = .01). CONCLUSION These findings argue against the notion that greater amygdala-vPFC structural integrity facilitates better anxiety outcomes in healthy adults. Instead, our results suggest that white matter degeneration in this network relates to lower anxiety in older adults.

The Posteromedial Region of the Default Mode Network Shows Attenuated Task-Induced Deactivation in Psychopathic Prisoners

OBJECTIVE Psychopathy is a personality disorder with symptoms that include lack of empathy or remorse, antisocial behavior, and excessive self-focus. Previous neuroimaging studies have linked psychopathy to dysfunction in the default mode network (DMN), a brain network that deactivates during externally focused tasks and is more engaged during self-referential processing. Specifically, the DMN has been found to remain relatively active in individuals with psychopathic tendencies during externally focused tasks, suggesting a failure to properly deactivate. However, the exact extent and nature of task-induced DMN dysfunction is poorly understood, including (a) the degree to which specific DMN subregions are affected in criminal psychopaths, and (b) how activity in these subregions relates to affective/interpersonal and antisocial/lifestyle traits of psychopathy. METHOD We performed a group independent component analysis to assess DMN activation during a Go/NoGo task in a group of 22 high-psychopathy and 22 low-psychopathy prisoners. The identified group-level DMN was parcellated into 6 subregions, and group differences in task-induced activity were examined. RESULTS In general, DMN subregions failed to deactivate beneath baseline in the high-psychopathy group. A group comparison with the low-psychopathy group localized this attenuated task-induced deactivation to the posteromedial cortical (mPC) region of the DMN. Moreover, multiple regression analyses revealed that activity in the mPC was associated with affective/interpersonal traits of psychopathy. CONCLUSION These findings suggest that attenuated deactivation of the mPC subregion of the DMN is intrinsic to psychopathy, and is a pattern that may be more associated with affective psychopathic traits, including lack of concern for others.

Maintaining a cautious state of mind during a recognition test: A large-scale fMRI study

Decision criterion is an important factor in recognition memory, determining the amount of evidence required to judge an item as previously encountered. For a typical recognition memory test involving the prior study of a set of items, a conservative criterion establishes a higher standard of evidence for recognition and designates fewer items as previously studied. In contrast, a liberal criterion establishes a lower standard of evidence and designates more items as previously studied. Therefore, the hit rate and the correct rejection rate on a recognition memory test can be affected by both the memory strength of the studied items and the criterion used to make that judgment. Yet most neuroimaging studies of the successful retrieval effect (a contrast between hits and correct rejections) fail to measure or consider decision criterion. The goal of the current fMRI study with ninety-five participants was to directly manipulate decision criteria on two tests of recognition memory by varying the likelihood of an items prior occurrence. Our results indicate that regions of the lateral prefrontal and parietal cortex associated with successful retrieval are significantly more active when using conservative criteria than liberal criteria. Furthermore, our results reveal that activity in these regions associated with successful retrieval can be accounted for by individual differences in the conservativeness of the decision criterion above and beyond any differences in memory strength. These results expound on the role of cognitive control in recognition memory and the neural mechanisms that mediate this processing.

Higher locus coeruleus MRI contrast is associated with lower parasympathetic influence over heart rate variability

Abstract The locus coeruleus (LC) is a key node of the sympathetic nervous system and suppresses parasympathetic activity that would otherwise increase heart rate variability. In the current study, we examined whether LC‐MRI contrast reflecting neuromelanin accumulation in the LC was associated with high‐frequency heart rate variability (HF‐HRV), a measure reflecting parasympathetic influences on the heart. Recent evidence indicates that neuromelanin, a byproduct of catecholamine metabolism, accumulates in the LC through young and mid adulthood, suggesting that LC‐MRI contrast may be a useful biomarker of individual differences in habitual LC activation. We found that, across younger and older adults, greater LC‐MRI contrast was negatively associated with HF‐HRV during fear conditioning and spatial detection tasks. This correlation was not accounted for by individual differences in age or anxiety. These findings indicate that individual differences in LC structure relate to key cardiovascular parameters. HighlightsWe measured locus coeruleus neuromelanin MRI contrast (LC‐MRI).Participants with higher LC‐MRI had lower high‐frequency heart rate variability.This relationship was not due to individual differences in age or anxiety.

Sympathetic arousal increases a negative memory bias in young women with low sex hormone levels

Emotionally arousing events are typically better attended to and remembered than neutral ones. Current theories propose that arousal-induced increases in norepinephrine during encoding bias attention and memory in favor of affectively salient stimuli. Here, we tested this hypothesis by manipulating levels of physiological arousal prior to encoding and examining how it influenced memory for emotionally salient images, particularly those that are negative rather than positive in valence. We also tested whether sex steroid hormones interact with noradrenergic activity to influence these emotional memory biases in women. Healthy naturally cycling women and women on hormonal contraception completed one of the following physiological arousal manipulations prior to viewing a series of negative, positive and neutral images: (1) immediate handgrip arousal-isometric handgrip immediately prior to encoding, (2) residual handgrip arousal-isometric handgrip 15min prior to encoding, or (3) no handgrip. Sympathetic arousal was measured throughout the session via pupil diameter changes. Levels of 17β-estradiol and progesterone were measured via salivary samples. Memory performance was assessed approximately 10min after encoding using a surprise free recall test. The results indicated that handgrip successfully increased sympathetic arousal compared to the control task. Under immediate handgrip arousal, women showed enhanced memory for negative images over positive images; this pattern was not observed in women assigned to the residual and no-handgrip arousal conditions. Additionally, under immediate handgrip arousal, both high estradiol and progesterone levels attenuated the memory bias for negative over positive images. Follow-up hierarchical linear models revealed consistent effects when accounting for trial-by-trial variability in normative International Affective Picture System valence and arousal ratings. These findings suggest that heightened sympathetic arousal interacts with estradiol and progesterone levels during encoding to increase the mnemonic advantage of negative over positive emotional material.

Locus coeruleus neuromodulation of memories encoded during negative or unexpected action outcomes

When people experience surprising or sub-optimal performance outcomes, an increase in autonomic arousal helps allocate cognitive resources to adjust behavior accordingly. The locus-coeruleus-norepinephrine (LC-NE) system regulates a central orienting response to behaviorally relevant events, and might therefore signal the need to attend to and learn from performance feedback. Memories of such events also rely on elevated NE, suggesting that LC activity not only responds to salient performance outcomes but also strengthens memory for stimuli associated with their occurrence. In the present study, we used a monetary incentive delay paradigm to determine whether LC functional connectivity during reaction time feedback relates to trial-by-trial memory of preceding photo-objects. We used one psychophysiological interaction (PPI) analysis to examine patterns of LC functional connectivity that were associated with subsequent memory for picture trials in which negative or positive feedback was given, and a second PPI analysis to investigate whether successfully encoded objects from trials with uncertain outcomes were related to distinct patterns of LC functional connectivity across the brain. The PPI results revealed that successfully encoded negative feedback trials (i.e., responses exceeding the response deadline) were uniquely associated with enhanced functional coupling between the LC and left anterior insula. Furthermore, successful memory for objects in low reaction time certainty trials (i.e., responses closest to the response deadline) were linked to positive LC functional coupling with left dorsolateral prefrontal cortex. These findings suggest that noradrenergic influences help facilitate memory encoding during outcome processing via dynamic interactions with regions that process negative or unexpected feedback.

Locus coeruleus activity strengthens prioritized memories under arousal

Recent models posit that bursts of locus ceruleus (LC) activity amplify neural gain such that limited attention and encoding resources focus even more on prioritized mental representations under arousal. Here, we tested this hypothesis in human males and females using fMRI, neuromelanin MRI, and pupil dilation, a biomarker of arousal and LC activity. During scanning, participants performed a monetary incentive encoding task in which threat of punishment motivated them to prioritize encoding of scene images over superimposed objects. Threat of punishment elicited arousal and selectively enhanced memory for goal-relevant scenes. Furthermore, trial-level pupil dilations predicted better scene memory under threat, but were not related to object memory outcomes. fMRI analyses revealed that greater threat-evoked pupil dilations were positively associated with greater scene encoding activity in LC and parahippocampal cortex, a region specialized to process scene information. Across participants, this pattern of LC engagement for goal-relevant encoding was correlated with neuromelanin signal intensity, providing the first evidence that LC structure relates to its activation pattern during cognitive processing. Threat also reduced dynamic functional connectivity between high-priority (parahippocampal place area) and lower-priority (lateral occipital cortex) category-selective visual cortex in ways that predicted increased memory selectivity. Together, these findings support the idea that, under arousal, LC activity selectively strengthens prioritized memory representations by modulating local and functional network-level patterns of information processing. SIGNIFICANCE STATEMENT Adaptive behavior relies on the ability to select and store important information amid distraction. Prioritizing encoding of task-relevant inputs is especially critical in threatening or arousing situations, when forming these memories is essential for avoiding danger in the future. However, little is known about the arousal mechanisms that support such memory selectivity. Using fMRI, neuromelanin MRI, and pupil measures, we demonstrate that locus ceruleus (LC) activity amplifies neural gain such that limited encoding resources focus even more on prioritized mental representations under arousal. For the first time, we also show that LC structure relates to its involvement in threat-related encoding processes. These results shed new light on the brain mechanisms by which we process important information when it is most needed.