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Density values (B max ) of the five 5-HT targets in FreeSurfer defined brain regions. Median raphe is not reported for 5-HTT due the irreversible kinetic of the TACs (see Material and Methods).
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Significance statement:
We present a high-resolution PET and MR-based human brain atlas of important serotonin receptors and the transporter. The regional PET-derived binding measures correlate strongly with the corresponding autoradiography protein levels. The strong correlation enables the transformation of the PET-derived human brain atlas into...
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Context 1
... slope estimates of the regression were used to transform the BP ND atlases into B max atlases (Figs. 2, ), allowing for a direct comparison across targets. The regional densities are presented in Figure 4. No global or regional significant effect of age, gender, or their interaction was found. ...
Similar publications
Study objective:
Numerous medications interact at serotonin (5-hydroxytryptamine [5-HT]) receptors directly or through off-target interactions, causing mild to severe serotonergic adverse drug events (ADEs), particularly among older adults. Our objective was to develop a novel molecular-based toxicity scoring system to assess serotonergic burden r...
Citations
... The copyright holder for this preprint (which this version posted June 8, 2024. ; https://doi.org/10.1101/2024.06.08.597884 doi: bioRxiv preprint HT1b (Beliveau et al., 2017); (15) 5-HT2a (Beliveau et al., 2017); (16) 5-HT4 (Beliveau et al., 2017); (17) 5-HT6 (Radhakrishnan et al., 2018); (18) serotonin transporter (5-HTT) (Beliveau et al., 2017). To determine the statistical significance, we used the spin test with 10000 permutations (Alexander-Bloch et al., 2018). ...
... The copyright holder for this preprint (which this version posted June 8, 2024. ; https://doi.org/10.1101/2024.06.08.597884 doi: bioRxiv preprint HT1b (Beliveau et al., 2017); (15) 5-HT2a (Beliveau et al., 2017); (16) 5-HT4 (Beliveau et al., 2017); (17) 5-HT6 (Radhakrishnan et al., 2018); (18) serotonin transporter (5-HTT) (Beliveau et al., 2017). To determine the statistical significance, we used the spin test with 10000 permutations (Alexander-Bloch et al., 2018). ...
... The copyright holder for this preprint (which this version posted June 8, 2024. ; https://doi.org/10.1101/2024.06.08.597884 doi: bioRxiv preprint HT1b (Beliveau et al., 2017); (15) 5-HT2a (Beliveau et al., 2017); (16) 5-HT4 (Beliveau et al., 2017); (17) 5-HT6 (Radhakrishnan et al., 2018); (18) serotonin transporter (5-HTT) (Beliveau et al., 2017). To determine the statistical significance, we used the spin test with 10000 permutations (Alexander-Bloch et al., 2018). ...
Developing neural indicators of pain sensitivity is crucial for revealing the neural basis of individual differences in pain and advancing individualized treatment of pain. However, it still remains elusive whether pain-evoked neural responses can encode pain sensitivity. To address this issue, we analyzed five large functional magnetic resonance imaging (fMRI) datasets (total N = 1010), where healthy participants received painful and nonpainful tactile, auditory, and visual stimuli, and different pain treatments, including placebo and transcutaneous electrical neural stimulation. We systematically (1) investigated the correlation between pain-evoked fMRI responses and pain sensitivity, (2) evaluated the correlation's replicability in independent datasets and generalizability across different types of pain, (3) examined whether the correlation between fMRI responses and sensory sensitivity is unique to pain, and (4) how sample sizes affect the relationship between fMRI responses and pain sensitivity. We found that, with a sufficiently large sample size, there were replicable and generalizable correlations between pain-evoked fMRI responses and pain sensitivity across individuals for laser heat, contact heat, and mechanical pains. Despite lacking pain selectivity, fMRI signals exhibited larger correlations with pain sensitivity than with tactile, auditory, and visual sensitivity. Importantly, we developed a machine learning model that could accurately predict not only pain sensitivity to laser heat, contact heat, and mechanical stimuli, but also pain relief from pain treatments. Notably, our findings were influenced considerably by sample sizes, requiring >200 for univariate correlation analysis to reveal the relationship between pain sensitivity and fMRI responses, and >150 for multivariate analysis to decode pain sensitivity with fMRI responses. Altogether, given an enormous sample size, we convincingly showed the validity to decode pain sensitivity and predict analgesic effects using pain-evoked fMRI responses, which holds significant clinical promise in tailoring individualized pain treatments.
... This toolbox allowed the estimation of spatial correlations between our PCA rs-fMRI-derived maps and neurotransmitter receptor distribution maps obtained through nuclear imaging techniques These neurotransmitter receptors' linearly rescaled maps are derived from different studies that report the average receptor maps observed in groups of healthy participants. Overall, the following neurotransmitter and neuromodulatory systems were investigated: gamma-aminobutyric acid type A (GABA) (Dukart et al. 2018) serotonin 5-hydroxytryptamine receptor subtype 1a (5-HT1a) (Hansen et al. 2022;Savli et al. 2012) and 1b (Beliveau et al. 2017;Savli et al. 2012) serotonin transporter (SERT) (Beliveau et al. 2017;Savli et al. 2012), dopamine D2 (D2) (Alakurtti et al. 2015), dopamine transporter (DAT) (Dukart et al. 2018), noradrenaline transporter (NAT) (Hesse et al. 2017), and opioid (MU and KappaOp) (Hansen et al. 2022;Kantonen et al. 2020;Shokri-Kojori et al. 2022). ...
... This toolbox allowed the estimation of spatial correlations between our PCA rs-fMRI-derived maps and neurotransmitter receptor distribution maps obtained through nuclear imaging techniques These neurotransmitter receptors' linearly rescaled maps are derived from different studies that report the average receptor maps observed in groups of healthy participants. Overall, the following neurotransmitter and neuromodulatory systems were investigated: gamma-aminobutyric acid type A (GABA) (Dukart et al. 2018) serotonin 5-hydroxytryptamine receptor subtype 1a (5-HT1a) (Hansen et al. 2022;Savli et al. 2012) and 1b (Beliveau et al. 2017;Savli et al. 2012) serotonin transporter (SERT) (Beliveau et al. 2017;Savli et al. 2012), dopamine D2 (D2) (Alakurtti et al. 2015), dopamine transporter (DAT) (Dukart et al. 2018), noradrenaline transporter (NAT) (Hesse et al. 2017), and opioid (MU and KappaOp) (Hansen et al. 2022;Kantonen et al. 2020;Shokri-Kojori et al. 2022). ...
Objective
Despite the promising results of neurofeedback with real-time functional magnetic resonance imaging (rt-fMRI-NF) in the treatment of various psychiatric and neurological disorders, few studies have investigated its effects in acute and chronic pain and with mixed results. The lack of clear neuromodulation targets, rooted in the still poorly understood neurophysiopathology of chronic pain, has probably contributed to these inconsistent findings. In contrast, functional neurosurgery (funcSurg) approaches targeting specific brain regions have been shown to reduce pain in a considerable number of patients with chronic pain, however, their invasiveness limits their use to patients in critical situations. In this work, we sought to redefine, in an unbiased manner, rt-fMRI-NF future targets informed by the long tradition of funcSurg approaches.
Methods
using independent systematic reviews, we identified the targets of the rt-fMRI-NF (in acute and chronic pain) and funcSurg (in chronic pain) studies and characterized their underlying functional networks using a subset of high spatial resolution resting-state fMRI data (7T MRI data from the Human Connectome Project). After applying principal component analysis to reduce the number of identified networks, we performed a quantitative functional and anatomical annotation of these networks with a large-scale meta-analytic approach. Finally, we characterized the functional networks, defining their degree of overlap with canonical intrinsic brain networks (default mode, salience, and somatosensory) and their neurotransmitter profile.
Results
As expected, the rt-fMRI-NF and funcSurg targets were different, except for the middle cingulate cortex, and showed different characteristics in terms of their functional connectivity. Our findings indicate that targets of rt-fMRI-NF primarily encompass hubs within the default mode network and, to a lesser extent, within the salience network. In contrast, funcSurg targets predominantly involve hubs within the sensorimotor system (primarily the motor system), with less robust involvement of the salience network. Notably, 3 out of 4 derived funcSurg rs-fMRI networks correlated significantly with the distribution map of noradrenaline transporters, further supporting the functional relevance of the funcSurg networks as targets for the treatment of chronic pain.
Conclusion
Key hubs of the sensorimotor networks, in particular the motor system, may represent promising targets for the therapeutic application of rt-fMRI-NF in chronic pain in particular in neuropathic pain patients. Our results also suggest that the antinociceptive effects of the funcSurg approaches could be, at least partially, linked to the restoration of abnormal noradrenergic system activation.
... Regions of interest (ROI) for the 5-HTT LVM were chosen based on 5-HTT distribution in the human brain [55] and comprised caudate, amygdala, hippocampus, putamen, thalamus, midbrain and neocortex. Similarly, ROIs for the 5-HT 4 LVMs include caudate, putamen, hippocampus and neocortex, reflecting brain regions across low, moderate to high density of 5-HT 4 receptor in these areas [55] and aligning with previous findings investigating the 5HT 4 receptor system and MDD [32,56]. ...
... Regions of interest (ROI) for the 5-HTT LVM were chosen based on 5-HTT distribution in the human brain [55] and comprised caudate, amygdala, hippocampus, putamen, thalamus, midbrain and neocortex. Similarly, ROIs for the 5-HT 4 LVMs include caudate, putamen, hippocampus and neocortex, reflecting brain regions across low, moderate to high density of 5-HT 4 receptor in these areas [55] and aligning with previous findings investigating the 5HT 4 receptor system and MDD [32,56]. ...
... Thus, assuming similar DNA methylation levels between the two tissues, it is not known whether SLC6A4 or TPH2 expression would be affected in the brain in the same way that it is known to be affected in peripheral blood [13,26,27,63]. Third, gene expression does not always directly correspond to protein levels as post-transcriptional and post-translational modifications can affect protein levels and function, and this notion seems to be true for both genes [55,[64][65][66][67]. This might also help explain why we did not observe any association between 5-HTTLPR or TPH2 rs4570625, which are polymorphisms known to affect SLC6A4 and TPH2 expression, and 5-HTT or 5-HT 4 levels, which is in line with former studies [50,68]. ...
Background
Methylation of serotonin-related genes has been proposed as a plausible gene-by-environment link which may mediate environmental stress, depressive and anxiety symptoms. DNA methylation is often measured in blood cells, but little is known about the association between this peripheral epigenetic modification and brain serotonergic architecture. Here, we evaluated the association between whole-blood-derived methylation of four CpG sites in the serotonin transporter (SLC6A4) and six CpG sites of the tryptophan hydroxylase 2 (TPH2) gene and in-vivo brain levels of serotonin transporter (5-HTT) and serotonin 4 receptor (5-HT4) in a cohort of healthy individuals (N = 254) and, for 5-HT4, in a cohort of unmedicated patients with depression (N = 90). To do so, we quantified SLC6A4/TPH2 methylation using bisulfite pyrosequencing and estimated brain 5-HT4 and 5-HTT levels using positron emission tomography. In addition, we explored the association between SLC6A4 and TPH2 methylation and measures of early life and recent stress, depressive and anxiety symptoms on 297 healthy individuals.
Results
We found no statistically significant association between peripheral DNA methylation and brain markers of serotonergic neurotransmission in patients with depression or in healthy individuals. In addition, although SLC6A4 CpG2 (chr17:30,236,083) methylation was marginally associated with the parental bonding inventory overprotection score in the healthy cohort, statistical significance did not remain after accounting for blood cell heterogeneity.
Conclusions
We suggest that findings on peripheral DNA methylation in the context of brain serotonin-related features should be interpreted with caution. More studies are needed to rule out a role of SLC6A4 and TPH2 methylation as biomarkers for environmental stress, depressive or anxiety symptoms.
... Human studies using 5-HT 2A R ligand Positron Emission Tomography (PET) tracers show binding to regions throughout the cortex [42][43][44]. Studies in rodents, including our prior RNAscope in situ hybridization results, as well as previous radioactive in situ hybridization and antibody staining studies, have shown that both Htr2a mRNA, which encodes the 5-HT 2A R, as well as the receptor protein itself, display an anteroposterior gradient throughout the cortex [45][46][47][48]. ...
Serotonin 2A receptors (5-HT 2A Rs) mediate the effects of psychedelic drugs. 5-HT 2A R agonists, such as (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), that produce a psychedelic experience in humans induce a head-twitch response (HTR) behavior in rodents. However, it is unknown whether the activity of 5-HT 2A R expressing neurons is sufficient to produce the HTR in the absence of an agonist, or in which brain region 5-HT 2A Rs control the HTR. Here, we use an optogenetic approach to examine whether activation of 5-HT 2A R expressing neurons in the mouse prefrontal cortex (PFC) is sufficient to induce HTRs alone, or may augment the HTR produced by DOI, and if inhibition of these neurons prevents DOI-induced HTRs in mice. We crossed Htr2a -Cre mice to Cre-dependent optogenetic lines Ai32 (channelrhodopsin) and Ai39 (halorhodopsin) to selectively activate and inhibit (respectively) 5-HT 2A R-expressing neurons in the PFC of adult mice. We found that optogenetic stimulation of PFC 5-HT 2A R expressing neurons in the absence of an agonist does not increase HTRs in mice. In both male and female Ai32 mice that received vehicle, there was no difference in HTRs in mice that expressed Htr2a -Cre compared with control mice, indicating that optogenetic activation of 5-HT 2A R+ cells in the PFC was not sufficient to produce HTRs in the absence of an agonist. In female mice, activation of PFC 5-HT 2A R expressing neurons augmented the HTR produced by DOI. However, this result was not seen in male mice. In contrast, inhibition of 5-HT 2A R expressing neurons in the PFC prevented the increase in HTR produced by DOI in male, but not in female, mice. Together, these findings suggest that activation of 5-HT 2A Rs in the PFC is not sufficient to induce HTRs in the absence of a 5-HT 2A R agonist but is necessary for induction of HTRs by a 5-HT 2A R agonist in a sex-dependent manner.
... Receptor densities of dopamine [107], acetylcholine [108], serotonin [109], norepinephrine [110], and glutamate [111]; Structural measures obtained from the Human Connectome Project S1200 release [112], including group average cortical myelin that was quantified using MRI T1-weighted/T2-weighted ratio [113] and cortical thickness; Electrophysiological MEG power distributions from 6 frequency bands, also obtained from the Human Connectome Project S1200 release [112], including alpha (8-12 Hz), beta (15-29 Hz), delta (2)(3)(4), low gamma (30-59 Hz), high gamma (60-90 Hz), and theta (5-7 Hz); And a representation of evolutionary expansion, based on the cortical surface area expansion from macaque to human [114]. ...
Human neuroimaging studies consistently show multimodal patterns of variability along a key principle of macroscale cortical organization - the sensorimotor-association (S-A) axis. However, little is known about day-to-day fluctuations in functional activity along this axis within an individual, including sex-specific neuroendocrine factors contributing to such transient changes. We leveraged data from two densely sampled healthy young adults, one female and one male, to investigate intra-individual daily variability along the S-A axis, which we computed as our measure of functional cortical organization by reducing the dimensionality of functional connectivity matrices. Daily variability was greatest in temporal limbic and ventral prefrontal regions in both participants, and was more strongly pronounced in the male subject. Next, we probed local- and system-level effects of steroid hormones and self-reported perceived stress on functional organization. Our findings revealed modest effects that differed between participants, hinting at subtle -potentially sex-specific- associations between neuroendocrine fluctuations and intra-individual variability along the S-A axis. In sum, our study points to neuroendocrine factors as possible modulators of intra-individual variability in functional brain organization, highlighting the need for further research in larger samples.
... Since the binding of psychedelics to the 5-HT2A (serotonin-2A) receptor is known to meditate their hallucinogenic effects, we measured the correlation between regional irreversibility and 5-HT2A receptor expression. To quantify spatial patterns of 5-HT2A receptor expression, we used three existing PET maps (Beliveau et al., 2017;Savli et al., 2012;Talbot et al., 2012) and one average of those maps (Hansen et al., 2022). We hypothesised that 5-HT2A receptor expression would be more strongly associated with regional irreversibility than that of other serotonin receptors, which may not be essential for the characteristic behavioral effects of psychedelics. ...
... We hypothesised that 5-HT2A receptor expression would be more strongly associated with regional irreversibility than that of other serotonin receptors, which may not be essential for the characteristic behavioral effects of psychedelics. Therefore, we also correlated regional irreversibility with 5-HT1A and 5-HT1B receptor expression, using existing PET maps (Beliveau et al., 2017;Gallezot et al., 2010;Hansen et al., 2022;Savli et al., 2012). ...
Psychedelics are serotonergic drugs that profoundly alter consciousness, yet their neural mechanisms are not fully understood. A popular theory, RElaxed Beliefs Under pSychedelics (REBUS), posits that psychedelics flatten the hierarchy of information flow in the brain. Here, we investigate hierarchy based on the imbalance between sending and receiving brain signals, as determined by directed functional connectivity. We measure directed functional hierarchy in a magnetoencephalography (MEG) dataset of 16 healthy human participants who were administered a psychedelic dose (75 micrograms, intravenous) of lysergic acid diethylamide (LSD) under four different conditions. LSD diminishes the asymmetry of directed connectivity when averaged across time. Additionally, we demonstrate that machine learning classifiers distinguish between LSD and placebo more accurately when trained on one of our hierarchy metrics than when trained on traditional measures of functional connectivity. Taken together, these results indicate that LSD weakens the hierarchy of directed connectivity in the brain by increasing the balance between senders and receivers of neural signals.
... At the circuit level, 5HT 2A receptor signalling is thought to enhance neural plasticity [8] and increases cortical glutamate and thalamic GABA levels [9]. The receptor is expressed throughout the cortex but especially in regions related to sensorimotor integration [10] and the so-called default mode network responsible for "self " and "other" processing [11]. Thus, through these key processes that shape neuronal architecture and neurotransmission, serotonin influences lower-order systems (e.g. ...
... We have shown that SSVEPs during this task are altered in autism [21]. 5HT 2A receptors are particularly highly expressed in the primary visual cortex [11], and their agonism alters visual response amplitudes and surround suppression in mouse primary visual cortex [43]. In humans, we expect visual processing to be altered by 5HT 2A receptor activation given that the marked visual perceptual changes robustly induced with higher doses of psychedelics are blocked by pretreatment with the 5HT 2 receptor antagonist, ketanserin [44]. ...
Background
The underlying neurobiology of the complex autism phenotype remains obscure, although accumulating evidence implicates the serotonin system and especially the 5HT2A receptor. However, previous research has largely relied upon association or correlation studies to link differences in serotonin targets to autism. To directly establish that serotonergic signalling is involved in a candidate brain function our approach is to change it and observe a shift in that function.
We will use psilocybin as a pharmacological probe of the serotonin system in vivo. We will directly test the hypothesis that serotonergic targets of psilocybin – principally, but not exclusively, 5HT2A receptor pathways—function differently in autistic and non-autistic adults.
Methods
The ‘PSILAUT’ “shiftability” study is a case–control study autistic and non-autistic adults. How neural responses ‘shift’ in response to low doses (2 mg and 5 mg) of psilocybin compared to placebo will be examined using multimodal techniques including functional MRI and EEG. Each participant will attend on up to three separate visits with drug or placebo administration in a double-blind and randomized order.
Results
This study will provide the first direct evidence that the serotonin targets of psilocybin function differently in the autistic and non-autistic brain. We will also examine individual differences in serotonin system function.
Conclusions
This work will inform our understanding of the neurobiology of autism as well as decisions about future clinical trials of psilocybin and/or related compounds including stratification approaches.
Trial registration
NCT05651126.
... This agonism results in postsynaptic excitation, which is understood at the level of neuronal populations to lead to desynchronization and thus impaired function. We can start by considering regions of the brain that have densely expressed 5-HT 2A receptors in their neuronal populations (Beliveau et al., 2017). The regions of particular clinical interest are the thalamus, the prefrontal cortex, and the claustrum. ...
Psychedelic therapy has seen a resurgence of interest in the last decade, with promising clinical outcomes for the treatment of a variety of psychopathologies. In response to this success, several theoretical models have been proposed to account for the positive therapeutic effects of psychedelics. One of the more prominent models is “RElaxed Beliefs Under pSychedelics,” which proposes that psychedelics act therapeutically by relaxing the strength of maladaptive high-level beliefs encoded in the brain. The more recent “CANAL” model of psychopathology builds on the explanatory framework of RElaxed Beliefs Under pSychedelics by proposing that canalization (the development of overly rigid belief landscapes) may be a primary factor in psychopathology. Here, we make use of learning theory in deep neural networks to develop a series of refinements to the original CANAL model. Our primary theoretical contribution is to disambiguate two separate optimization landscapes underlying belief representation in the brain and describe the unique pathologies which can arise from the canalization of each. Along each dimension, we identify pathologies of either too much or too little canalization, implying that the construct of canalization does not have a simple linear correlation with the presentation of psychopathology. In this expanded paradigm, we demonstrate the ability to make novel predictions regarding what aspects of psychopathology may be amenable to psychedelic therapy, as well as what forms of psychedelic therapy may ultimately be most beneficial for a given individual.
... The 5-HT 4 receptor (5-HT 4 R) is an excitatory, postsynaptic, G scoupled receptor widely distributed in the brain and strongly expressed in the limbic regions including the striatum (Beliveau et al., 2017). Both human Murphy et al., 2020) and rodent (Hagena and Manahan-Vaughan, 2017) studies have linked 5-HT 4 R signaling to memory functions, and it has been proposed as a key target for both cognitive and mood symptoms in MDD . ...
... In addition, experimental models suggest that 5-HT 4 R levels are sensitive to central 5-HT modulation 11,12 . Positron emission tomography (PET) studies in humans and monkeys have shown high densities of 5-HT 4 R in the dorsal striatum, including in the caudate and putamen [13][14][15] . The strong expression of 5-HT 4 R suggests a potential role of these regions in modulating decisions involving temporal discounting. ...
Temporal discounting, in which the recipient of a reward perceives the value of that reward to decrease with delay in its receipt, is associated with impulsivity and psychiatric disorders such as depression. Here, we investigate the role of serotonin 5-HT 4 receptors (5-HT 4 R) in modulating temporal discounting in the macaque dorsal caudate nucleus (dCDh), the neurons of which have been shown to represent temporally discounted value. We first mapped the 5-HT 4 R distribution in macaque brains using positron emission tomography (PET) imaging and confirmed dense expression of 5-HT 4 R in the dCDh. We then examined the effects of a specific 5-HT 4 R antagonist infused into the dCDh. Blockade of 5-HT 4 R significantly increased error rates in a goal-directed delayed reward task, indicating an increase in the rate of temporal discounting. This increase was specific to the 5-HT 4 R blockade because saline controls showed no such effect. The results demonstrate that 5-HT 4 Rs in the dCDh are involved in reward-evaluation processes, particularly in the context of delay discounting, and suggest that serotonergic transmission via 5-HT 4 R may be a key component in the neural mechanisms underlying impulsive decisions, potentially contributing to depressive symptoms.
