Locus coeruleus degeneration is associated with disorganized functional topology in Parkinson’s disease

Zhou, Cheng; Guo, Tao; Bai, Xueqin; Wu, Jingjing; Gao, Ting; Guan, Xiaojun; Liu, Xiaocao; Gu, Luyan; Huang, Peiyu; Xuan, Min; Gu, Quanquan; Xu, Xiaojun; Zhang, Baorong; Zhang, Minming

doi:10.1016/j.nicl.2021.102873

Cited by 11 publications

(6 citation statements)

References 68 publications

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“…Its widespread noradrenergic projections modulate cortical, subcortical, cerebellar, brainstem and spinal cord circuits, which makes it well suited to rapidly and globally modulate brain function in response to changes in the environment (e.g., stressful stimuli) [ 32 ]. Moreover, locus coeruleus noradrenaline contributes to the reconfiguration of functional communication between distributed brain regions [ 33 ]. It is part of the ascending arousal pathway, and plays a major role in attentional and arousal response to threat [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Modulating arousal to overcome gait impairments in Parkinson’s disease: how the noradrenergic system may act as a double-edged sword

Tosserams

Bloem

Martens

et al. 2023

Transl Neurodegener

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In stressful or anxiety-provoking situations, most people with Parkinson’s disease (PD) experience a general worsening of motor symptoms, including their gait impairments. However, a proportion of patients actually report benefits from experiencing—or even purposely inducing—stressful or high-arousal situations. Using data from a large-scale international survey study among 4324 people with PD and gait impairments within the online Fox Insight (USA) and ParkinsonNEXT (NL) cohorts, we demonstrate that individuals with PD deploy an array of mental state alteration strategies to cope with their gait impairment. Crucially, these strategies differ along an axis of arousal—some act to heighten, whereas others diminish, overall sympathetic tone. Together, our observations suggest that arousal may act as a double-edged sword for gait control in PD. We propose a theoretical, neurobiological framework to explain why heightened arousal can have detrimental effects on the occurrence and severity of gait impairments in some individuals, while alleviating them in others. Specifically, we postulate that this seemingly contradictory phenomenon is explained by the inherent features of the ascending arousal system: namely, that arousal is related to task performance by an inverted u-shaped curve (the so-called Yerkes and Dodson relationship). We propose that the noradrenergic locus coeruleus plays an important role in modulating PD symptom severity and expression, by regulating arousal and by mediating network-level functional integration across the brain. The ability of the locus coeruleus to facilitate dynamic ‘cross-talk’ between distinct, otherwise largely segregated brain regions may facilitate the necessary cerebral compensation for gait impairments in PD. In the presence of suboptimal arousal, compensatory networks may be too segregated to allow for adequate compensation. Conversely, with supraoptimal arousal, increased cross-talk between competing inputs of these complementary networks may emerge and become dysfunctional. Because the locus coeruleus degenerates with disease progression, finetuning of this delicate balance becomes increasingly difficult, heightening the need for mental strategies to self-modulate arousal and facilitate shifting from a sub- or supraoptimal state of arousal to improve gait performance. Recognition of this underlying mechanism emphasises the importance of PD-specific rehabilitation strategies to alleviate gait disability.

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Section: Discussionmentioning

confidence: 99%

Modulating arousal to overcome gait impairments in Parkinson’s disease: how the noradrenergic system may act as a double-edged sword

Tosserams

Bloem

Martens

et al. 2023

Transl Neurodegener

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“…In fact, the LC is among the first brain regions to be affected in PD [24], with the loss of neurons in the LC beginning prior to, and to a greater extent, than that observed within the SN [20,24]. This depletion of LC neurons disrupts the supply of NA to regions such as the pre-frontal cortex (PFC), which is thought to contribute to various non-motor symptoms experienced by PD patients, including cognitive impairment, depression, and anxiety [8,[25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Long-Term Impact of Diffuse Traumatic Brain Injury on Neuroinflammation and Catecholaminergic Signaling: Potential Relevance for Parkinson’s Disease Risk

Wee,

Arulsamy,

Corrigan

et al. 2024

Molecules

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Traumatic brain injury (TBI) is associated with an increased risk of developing Parkinson’s disease (PD), though the exact mechanisms remain unclear. TBI triggers acute neuroinflammation and catecholamine dysfunction post-injury, both implicated in PD pathophysiology. The long-term impact on these pathways following TBI, however, remains uncertain. In this study, male Sprague-Dawley rats underwent sham surgery or Marmarou’s impact acceleration model to induce varying TBI severities: single mild TBI (mTBI), repetitive mild TBI (rmTBI), or moderate–severe TBI (msTBI). At 12 months post-injury, astrocyte reactivity (GFAP) and microglial levels (IBA1) were assessed in the striatum (STR), substantia nigra (SN), and prefrontal cortex (PFC) using immunohistochemistry. Key enzymes and receptors involved in catecholaminergic transmission were measured via Western blot within the same regions. Minimal changes in these markers were observed, regardless of initial injury severity. Following mTBI, elevated protein levels of dopamine D1 receptors (DRD1) were noted in the PFC, while msTBI resulted in increased alpha-2A adrenoceptors (ADRA2A) in the STR and decreased dopamine beta-hydroxylase (DβH) in the SN. Neuroinflammatory changes were subtle, with a reduced number of GFAP+ cells in the SN following msTBI. However, considering the potential for neurodegenerative outcomes to manifest decades after injury, longer post-injury intervals may be necessary to observe PD-relevant alterations within these systems.

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“…Therefore, eTNS has the potential to stimulatefrom the bottomupseveral different fronto-cortico-thalamic and fronto-limbic pathways within the central nervous system, many of which are implicated in the symptoms, cognitive functions, and/or related behavioral features observed in several neurological and psychiatric disorders [6,7,[19][20][21][22]. In addition, given that neurotransmitters are implicated in neurological and psychiatric disorders [23,24], eTNS can potentially improve, for example, 1) inattention symptoms and arousal regulation in attention-deficit/hyperactivity disorder (ADHD) or seizure frequency in epilepsy via noradrenaline release [25][26][27], 2) symptoms in major depressive disorder (MDD) or migraine via enhanced noradrenaline and serotonin release [19,28], or 3) cognitive decline and dopaminergic degeneration in Parkinson's disease via modulating the LC-noradrenergic system [11,29,30]. While the evidence so far seems stronger for potential improvements of symptoms in neurological disorders, there is emerging evidence for improvement also of symptoms in psychiatric disorders.…”

Section: Introductionmentioning

confidence: 99%

Clinical and cognitive effects of external trigeminal nerve stimulation (eTNS) in neurological and psychiatric disorders: a systematic review and meta-analysis

Westwood,

Conti,

Tang

et al. 2023

Mol Psychiatry

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This pre-registered (CRD42022322038) systematic review and meta-analysis investigated clinical and cognitive outcomes of external trigeminal nerve stimulation (eTNS) in neurological and psychiatric disorders. PubMed, OVID, Web of Science, Chinese National Knowledge Infrastructure, Wanfang, and VIP database for Chinese technical periodicals were searched (until 16/03/2022) to identify trials investigating cognitive and clinical outcomes of eTNS in neurological or psychiatric disorders. The Cochrane Risk of Bias 2.0 tool assessed randomized controlled trials (RCTs), while the Risk of Bias of Non-Randomized Studies (ROBINS-I) assessed single-arm trials. Fifty-five peer-reviewed articles based on 48 (27 RCTs; 21 single-arm) trials were included, of which 12 trials were meta-analyzed (N participants = 1048; of which ~3% ADHD, ~3% Epilepsy, ~94% Migraine; age range: 10–49 years). The meta-analyses showed that migraine pain intensity (K trials = 4, N = 485; SMD = 1.03, 95% CI[0.84–1.23]) and quality of life (K = 2, N = 304; SMD = 1.88, 95% CI[1.22–2.53]) significantly improved with eTNS combined with anti-migraine medication. Dimensional measures of depression improved with eTNS across 3 different disorders (K = 3, N = 111; SMD = 0.45, 95% CI[0.01–0.88]). eTNS was well-tolerated, with a good adverse event profile across disorders. eTNS is potentially clinically relevant in other disorders, but well-blinded, adequately powered RCTs must replicate findings and support optimal dosage guidance.

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Locus coeruleus degeneration is associated with disorganized functional topology in Parkinson’s disease

Cited by 11 publications

References 68 publications

Modulating arousal to overcome gait impairments in Parkinson’s disease: how the noradrenergic system may act as a double-edged sword

Modulating arousal to overcome gait impairments in Parkinson’s disease: how the noradrenergic system may act as a double-edged sword

Long-Term Impact of Diffuse Traumatic Brain Injury on Neuroinflammation and Catecholaminergic Signaling: Potential Relevance for Parkinson’s Disease Risk

Clinical and cognitive effects of external trigeminal nerve stimulation (eTNS) in neurological and psychiatric disorders: a systematic review and meta-analysis

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