Browsing by Subject "Locus coeruleus"

Now showing 1 - 6 of 6
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    Attentional Disengagement and the Locus Coeruleus – Norepinephrine System in Children With Autism Spectrum Disorder
    (Frontiers Media, 2021-08-31) Keehn, Brandon; Kadlaskar, Girija; Bergmann, Sophia; McNally Keehn, Rebecca; Francis, Alexander; Pediatrics, School of Medicine
    Background: Differences in non-social attentional functions have been identified as among the earliest features that distinguish infants later diagnosed with autism spectrum disorder (ASD), and may contribute to the emergence of core ASD symptoms. Specifically, slowed attentional disengagement and difficulty reorienting attention have been found across the lifespan in those at risk for, or diagnosed with, ASD. Additionally, the locus coeruleus-norepinephrine (LC-NE) system, which plays a critical role in arousal regulation and selective attention, has been shown to function atypically in ASD. While activity of the LC-NE system is associated with attentional disengagement and reorienting in typically developing (TD) individuals, it has not been determined whether atypical LC-NE activity relates to attentional disengagement impairments observed in ASD. Objective: To examine the relationship between resting pupil diameter (an indirect measure of tonic LC-NE activation) and attentional disengagement in children with ASD. Methods: Participants were 21 school-aged children with ASD and 20 age- and IQ-matched TD children. The study consisted of three separate experiments: a resting eye-tracking task and visual and auditory gap-overlap paradigms. For the resting eye-tracking task, pupil diameter was monitored while participants fixated a central crosshair. In the gap-overlap paradigms, participants were instructed to fixate on a central stimulus and then move their eyes to peripherally presented visual or auditory targets. Saccadic reaction times (SRT), percentage of no-shift trials, and disengagement efficiency were measured. Results: Children with ASD had significantly larger resting pupil size compared to their TD peers. The groups did not differ for overall SRT, nor were there differences in SRT for overlap and gap conditions between groups. However, the ASD group did evidence impairments in disengagement (larger step/gap effects, higher percentage of no-shift trials, and reduced disengagement efficiency) compared to their TD peers. Correlational analyses showed that slower, less efficient disengagement was associated with increased pupil diameter. Conclusion: Consistent with prior reports, children with ASD show significantly larger resting pupil diameter, indicative of atypically elevated tonic LC-NE activity. Associations between pupil size and measures of attentional disengagement suggest that atypically increased tonic activation of the LC-NE system may be associated with poorer attentional disengagement in children with ASD.
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    Effects of Reducing Norepinephrine Levels via DSP4 Treatment on Amyloid-β Pathology in Female Rhesus Macaques (Macaca Mulatta)
    (IOS Press, 2019) Duffy, Kara B.; Ray, Balmiki; Lahiri, Debomoy K.; Tilmont, Edward M.; Tinkler, Gregory P.; Herbert, Richard L.; Greig, Nigel H.; Ingram, Donald K.; Ottinger, Mary Ann; Mattison, Julie A.; Psychiatry, School of Medicine
    The degeneration in the locus coeruleus associated with Alzheimer's disease suggests an involvement of the noradrenergic system in the disease pathogenesis. The role of depleted norepinephrine was tested in adult and aged rhesus macaques to develop a potential model for testing Alzheimer's disease interventions. Monkeys were injected with the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) or vehicle at 0, 3, and 6 months; brains were harvested at 9 months. Reduced norepinephrine in the locus coeruleus was accompanied by decreased dopamine β-hydroxylase staining and increased amyloid-β load in the aged group, and the proportion of potentially toxic amyloid-β42 peptide was increased. Immunohistochemistry revealed no effects on microglia or astrocytes. DSP4 treatment altered amyloid processing, but these changes were not associated with the induction of chronic neuroinflammation. These findings suggest norepinephrine deregulation is an essential component of a nonhuman primate model of Alzheimer's disease, but further refinement is necessary.
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    Elevated and Accelerated: Locus Coeruleus Activity and Visual Search Abilities in Autistic Children
    (Elsevier, 2023) Keehn, Brandon; Kadlaskar, Girija; McNally Keehn, Rebecca; Pediatrics, School of Medicine
    Background: Autistic individuals excel at visual search, however, the neural mechanism(s) underlying this advantage remain unclear. The locus coeruleus-norepinephrine (LC-NE) system, which plays a critical role in sensory perception and selective attention, has been shown to function in a persistently elevated state in individuals on the spectrum. However, the relationship between elevated tonic LC-NE activity and accelerated search in autism has not been explored. Objective: To examine the relationship between visual search abilities and resting pupil diameter (an indirect measure of tonic LC-NE activation) in autistic and neurotypical children. Methods: Participants were 24 school-aged autistic children and 24 age- and IQ-matched neurotypical children aged 8-15 years. Children completed two tasks: a resting eye-tracking task and a visual search paradigm. For the resting eye-tracking task, pupil diameter was monitored while participants fixated a central crosshair. For the visual search paradigm, participants were instructed to find the target (vertical line) embedded within an array of tilted (10°) distractor lines. The target was present on 50% of trials, and displayed within set sizes of 18, 24, and 36 items. Results: Consistent with previous studies, autistic children had significantly larger resting pupil size and searched faster and more efficiently compared to their neurotypical peers. Eye-tracking findings revealed that accelerated search was associated with fewer, not shorter, fixations in the autism group. Autistic children also showed reduced leftward search bias. Larger resting pupil size, indicative of increased tonic activation of the LC-NE system, was associated with greater search efficiency, longer fixation durations, and reduced leftward bias. Finally, within both groups reduced leftward bias was associated with increased autism symptomatology. Discussion: Together, these findings add to the existing body of research highlighting superior search in autism, suggest that elevated tonic LC-NE activity may contribute to more efficient search, and link non-social visual-spatial processing strengths to autism symptoms.
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    Locus coeruleus tau is linked to successive cortical tau accumulation
    (Wiley, 2025) Yi, Dahyun; Byun, Min Soo; Jung, Joon Hyung; Jung, Gijung; Ahn, Hyejin; Chang, Yoon Young; Keum, Musung; Lee, Jun-Young; Lee, Yun-Sang; Kim, Yu Kyeong; Kang, Koung Mi; Sohn, Chul-Ho; Risacher, Shannon L.; Saykin, Andrew J.; Lee, Dong Young; KBASE Research Group; Radiology and Imaging Sciences, School of Medicine
    Introduction: We investigated the hypothesis that tau burden in the locus coeruleus (LC) correlates with tau accumulation in cortical regions according to the Braak stages and examined whether the relationships differed according to cortical amyloid beta (Aβ) deposition. Methods: One hundred and seventy well-characterized participants from an ongoing cohort were included. High-resolution T1, tau positron emission tomography (PET), and amyloid PET were obtained. Results: LC tau burden was significantly linked to global tau in neocortical regions, as was tau in both early Braak stage (stage I/II) and later Braak stage areas. This relationship was significant only in Aβ-positive individuals. While LC tau did not directly impact memory, it was indirectly associated with delayed memory through mediation or moderation pathways. Discussion: The findings from living human brains support the idea that LC tau closely relates to subsequent cortical tau accumulation, particularly among individuals with pathological Aβ accumulation, and identify LC tau burden as a promising indicator of cognitive trajectories of AD. Highlights: Tau burden in the LC was significantly associated with cortical tau accumulation. Tau burden in SN or PPN showed no association with cortical tau accumulation. LC tau burden was serially associated with Braak stages. The tau-LC and cortical tau relationship was significant only in the Aβ-positive group. Cortical amyloid's impact on memory worsens with higher tau accumulation in the LC.
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    Measures of tonic and phasic activity of the locus coeruleus-norepinephrine system in children with autism spectrum disorder: An event-related potential and pupillometry study
    (Wiley, 2022) Kim, Yesol; Kadlaskar, Girija; McNally Keehn, Rebecca; Keehn, Brandon; Pediatrics, School of Medicine
    A growing body of research suggests that locus coeruleus‐norepinephrine (LC‐NE) system may function differently in individuals with autism spectrum disorder (ASD). Understanding the dynamics of both tonic (resting pupil diameter) and phasic (pupil dilation response [PDR] and event‐related potential [ERP]) indices may provide meaningful insights about the nature of LC‐NE function in ASD. Twenty‐four children with ASD and 27 age‐ and nonverbal‐IQ matched typically developing (TD) children completed two experiments: (1) a resting eye‐tracking task to measure tonic pupil diameter, and (2) a three‐stimulus oddball paradigm to measure phasic responsivity using PDR and ERP. Consistent with prior reports, our results indicate that children with ASD exhibit increased tonic (resting pupil diameter) and reduced phasic (PDR and ERP) activity of the LC‐NE system compared to their TD peers. For both groups, decreased phasic responsivity was associated with increased resting pupil diameter. Lastly, tonic and phasic LC‐NE indices were primarily related to measures of attention‐deficit/hyperactivity disorder (ADHD), and not ASD, symptomatology. These findings expand our understanding of neurophysiological differences present in ASD and demonstrate that aberrant LC‐NE activation may be associated with atypical arousal and decreased responsivity to behaviorally‐relevant information in ASD.
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    The role of anterior insula-brainstem projections and alpha-1 noradrenergic receptors for compulsion-like and alcohol-only drinking
    (Springer Nature, 2021) De Oliveira Sergio, Thatiane; Lei, Kelly; Kwok, Claudina; Ghotra, Shahbaj; Wegner, Scott A.; Walsh, Margaret; Waal, Jaclyn; Darevsky, David; Hopf, Frederic W.; Psychiatry, School of Medicine
    Compulsion-like alcohol drinking (CLAD), where consumption continues despite negative consequences, is a major obstacle to treating alcohol use disorder. The locus coeruleus area in the brainstem and norepinephrine receptor (NER) signaling in forebrain cortical regions have been implicated in adaptive responding under stress, which is conceptually similar to compulsion-like responding (adaptive responding despite the presence of stress or conflict). Thus, we examined whether anterior insula (aINS)-to-brainstem connections and alpha-1 NERs regulated compulsion-like intake and alcohol-only drinking (AOD). Halorhodopsin inhibition of aINS-brainstem significantly reduced CLAD, with no effect on alcohol-only or saccharin intake, suggesting a specific aINS-brainstem role in aversion-resistant drinking. In contrast, prazosin inhibition of alpha-1 NERs systemically reduced both CLAD and AOD. Similar to systemic inhibition, intra-aINS alpha-1-NER antagonism reduced both CLAD and AOD. Global aINS inhibition with GABAR agonists also strongly reduced both CLAD and AOD, without impacting saccharin intake or locomotion, while aINS inhibition of calcium-permeable AMPARs (with NASPM) reduced CLAD without impacting AOD. Finally, prazosin inhibition of CLAD and AOD was not correlated with each other, systemically or within aINS, suggesting the possibility that different aINS pathways regulate CLAD versus AOD, which will require further study to definitively address. Together, our results provide important new information showing that some aINS pathways (aINS-brainstem and NASPM-sensitive) specifically regulate compulsion-like alcohol consumption, while aINS more generally may contain parallel pathways promoting CLAD versus AOD. These findings also support the importance of the adaptive stress response system for multiple forms of alcohol drinking.