I can't make heads or tails if this did something useful, so go ask your competent? doctor. If useful your competent? doctor needs to get testing on us unhealthy stroke survivors.
Effects of four-week intranasal oxytocin administration on large-scale brain networks in older adults
Introduction
The neuropeptide oxytocin (OT) acts as a neuromodulator on social cognition and social behavior (Meyer-Lindenberg et al., 2011). OT is synthesized in the hypothalamus and processed along axonal projections for posterior pituitary and dendritic release into extracellular space, resulting in both local action and diffusion to distant brain regions, such as the amygdala and insula (Meyer-Lindenberg et al., 2011). One of the most well-documented roles of OT is its involvement in maternal and infant bonding. Additionally, OT is implicated in numerous physiological effects, such as reducing free cortisol levels, lowering blood pressure, inducing analgesia, and promoting wound healing (IsHak et al., 2011).
OT can be administered via diverse routes including intranasal, oral, and intravenous (Phung et al., 2021; Zhuang et al., 2022), but intranasal OT administration (IN-OT) circumvents the blood-brain barrier and is well-suited for the investigation of OT effects on human behavior and brain function (Burmester, Higgs, & Terry, 2018; Quintana, Smerud, Andreassen, & Djupesland, 2018). The majority of current research on IN-OT brain modulation, however, considers activity in isolated regions during a task (Koch, van Zuiden, et al., 2016; Riem et al., 2011; Zhao et al., 2016). Little is known about IN-OT effects on resting-state functional connectivity (rs-FC), i.e., temporal correlations in spontaneous fluctuations of blood oxygen level-dependent (BOLD) signals at rest, providing valuable insights into the inherent functional organization of the brain (Cabral et al., 2011). Further, the few existing IN-OT functional connectivity studies are mostly limited to coupling between two regions (amygdala and insula, De Cagna et al., 2019, nasal administration of 24 International Units (IUs), amygdala and medial prefrontal cortex, Ebner et al., 2016, nasal administration of 24 IUs; thalamus and amygdala, Koch et al., 2019, nasal administration of 40 IUs; but see Bethlehem et al., 2017, nasal administration of 24 IUs; Brodmann et al., 2017, nasal administration of 24 IUs).
Complex brain function, however, is subserved by large-scale brain networks (Bellec et al., 2006), such as the salience network (Menon, 2015), the default mode network (Andrews-Hanna et al., 2014), and the basal ganglia–thalamus network (Haber & Calzavara, 2009; Luo et al., 2012). These networks support social function (Di Simplicio et al., 2009; Grimm et al., 2009; Ince et al., 2023; Kirkpatrick et al., 2014), rendering them particularly likely and effective targets of IN-OT modulation. However, a large-scale network approach (both regarding within as well as between network coupling) to the study of IN-OT brain modulation is nascent (for a recent summary see Liu, Lin, Feifel, & Ebner, 2022, nasal administration of 24 IUs) and IN-OT’s wider-ranging brain mechanisms of action are still insufficiently understood.
Furthermore, previous IN-OT functional connectivity studies exclusively focused on young and middle-aged adults, despite increasing evidence of age-differential effects of IN-OT on both human brain and behavior (Ebner, Maura, MacDonald, Westberg, & Fischer, 2013; Horta, Pehlivanoglu, & Ebner, 2020; Sannino, Chini, & Grinevich, 2017). One exception is Liu et al. (2022) which comprised young and older participants and found that acute (i.e., single-dose) IN-OT decreased rs-FC of the right insula with the salience network in both age groups as well as of the left amygdala with the salience network in older adults. Acute IN-OT also decreased rs-FC between the angular gyrus and the default mode network in both young and older adults. Note that Liu et al. did not examine effects in the basal ganglia–thalamus network, despite evidence of enhanced rs-FC within this network after acute IN-OT in young adults (Bethlehem et al., 2017; Rocchetti et al., 2014).
Finally, only two studies to date have investigated effects of chronic (i.e., repeated) IN-OT on brain activity (Kou et al., 2022, nasal administration for 3 or 5 days with 24 IUs per day) and rs-FC (Watanabe et al., 2015, nasal administration for 6 weeks with 24 IUs twice a day for a total of 48 IUs per day) in humans, and none in aging. To probe IN-OT’s treatment potential, however, determination of chronic IN-OT effects on brain functional connectivity, including among older adults, is warranted (Horta et al., 2020 1).
To fill these research gaps, the present study examined effects of a four-week chronic IN-OT on both within- and between-network rs-FC of the salience network, the default mode network, and the basal ganglia–thalamus network in a sample of generally healthy older adults. Building on Liu et al. (2022), we also directly compared effects from chronic relative to acute IN-OT on within- and between-network connectivity in older adults; as chronic administration of any bioactive drug may produce either more pronounced or less pronounced (tolerance) effects compared to acute administration (Brusa et al., 2007). Chronic IN-OT’s effects may be pronounced over acute effects due to Chronic IN-OT’s potential for prolonged exposure to the OT (Peters et al., 2014), increased receptor sensitivity (Zanos et al., 2014), and/or neuroplastic changes linked to a decrease in epigenetic methylation of the OT receptor and an increase in OT receptor expression (Alaerts et al., 2023, nasal administration for 28 days with 12 IUs twice a day for a total of 24 IUs per day).
We expected chronic IN-OT to modulate within- (Hypothesis 1a) and between- (Hypothesis 1b) network rs-FC for all three networks (i.e., salience network, default mode network, and basal ganglia–thalamus network). We further hypothesized more pronounced effects of chronic than acute IN-OT effects on both within- (Hypothesis 2a) and between- (Hypothesis 2b) network rs-FC for all three networks. Beyond delineation of the effects of chronic IN-OT on a single specific brain network (within-network) or interaction between two brain networks (between-network), we also explored chronic IN-OT effects on resting-state functional coupling between all three networks using selective rs-FC, a comparatively novel metric referring to specific brain networks displaying stronger connections with distinct networks compared to others, indicative of more specialized, efficient network communication (Simmons et al., 2013; Chan et al., 2014). We did not formulate hypotheses for this outcome measure, however, given the lack of prior literature on this variable in OT and aging.
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