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![Dorsal raphe nucleus (DRN) 5-HT 1A availability was positively associated with the degree of modulation induced by citalopram infusion in the amygdala. (a) PET [ 11 C]CUMI-101-binding estimates demonstrated a functionally lateralized positive association with activity in the left amygdala between the response to fearful faces and DRN 5-HT 1A availability (red) and the right amygdala showing an association with happy faces (yellow). (b and c) Citalopram (CITA) minus placebo (PBO) differences show that individuals with greater DRN 5-HT 1A availability have reduced citalopraminduced modulation of the amygdala to happy (yellow) and fearful (red) faces in the right and left hemispheres, respectively. (d and e) Same as panels (b and c) but with citalopram and placebo data presented separately. Whereas individuals with less DRN 5-HT 1A availability show heightened amygdala responses during placebo infusions (cyan), the association largely disappears with citalopram (magenta), suggesting that individual differences in the response of the amygdala to emotional content is associated with differences in DRN 5-HT 1A availability. A full color version of this figure is available at the Neuropsychopharmacology journal online.](profile/Paul-Faulkner-3/publication/318911273/figure/fig2/AS:669148728283157@1536548897748/Dorsal-raphe-nucleus-DRN-5-HT-1A-availability-was-positively-associated-with-the-degree.png)
Dorsal raphe nucleus (DRN) 5-HT 1A availability was positively associated with the degree of modulation induced by citalopram infusion in the amygdala. (a) PET [ 11 C]CUMI-101-binding estimates demonstrated a functionally lateralized positive association with activity in the left amygdala between the response to fearful faces and DRN 5-HT 1A availability (red) and the right amygdala showing an association with happy faces (yellow). (b and c) Citalopram (CITA) minus placebo (PBO) differences show that individuals with greater DRN 5-HT 1A availability have reduced citalopraminduced modulation of the amygdala to happy (yellow) and fearful (red) faces in the right and left hemispheres, respectively. (d and e) Same as panels (b and c) but with citalopram and placebo data presented separately. Whereas individuals with less DRN 5-HT 1A availability show heightened amygdala responses during placebo infusions (cyan), the association largely disappears with citalopram (magenta), suggesting that individual differences in the response of the amygdala to emotional content is associated with differences in DRN 5-HT 1A availability. A full color version of this figure is available at the Neuropsychopharmacology journal online.
Source publication
A subset of patients started on a selective serotonin reuptake inhibitor (SSRI) initially experience increased anxiety, which can lead to early discontinuation before therapeutic effects are manifest. The neural basis of this early SSRI effect is not known. Presynaptic dorsal raphe neuron (DRN) 5-HT1A receptors are known to play a critical role in...
Contexts in source publication
Context 1
... structural MRIs were seg- mented (into gray/white matter/cerebrospinal fluid) using the segmentation tool in SPM (www.fil.ion.ucl.ac.uk/spm) and were re-sliced (1 × 1 × 1 mm 3 ) and co-registered to the corresponding subject's denoised, head movement-corrected, and summed PET image using SPM5. Amygdala, postsy- naptic cortical regions, and cerebellum were defined using a probabilistic brain atlas template (Hammers et al, 2003). The atlas was spatially normalized to the coregistered individual MRI scans with deformation parameters obtained from the normalization to the standard MNI T1 template in SPM. ...
Context 2
... to the possible presence of an outlier (ie, DRN [ 11 C]CUMI-101 BND42.4 SD of mean; q.v., Figure 2b and c), these analyses were repeated with FEAT's outlier deweighting tool. Statistical results were identical. ...
Context 3
... CITA = 5.29, SD CITA = 35.19), r AMYG (10) = 0.38, Z = 2.51, p = 0.027 (FWE-corrected) (Figure 2a, c and e). There was a smaller positive association between DRN [ 11 C]CUMI-101 binding and the citalopram vs placebo difference in response to fearful vs neutral faces in the right amygdala (k = 1, peak MNI coordinates: (x = 24, y = − 10, z = − 14); M PBO = 4.51, SD PBO = 27.91, ...
Context 4
... CITA = − 12.60, SD CITA = 40.37), r AMYG (10) = 0.21, Z = 2.33, p = 0.032, (FWE-cor- rected) (Figure 2a, b and d), and again, a smaller effect in the left amygdala (k = 1, peak MNI coordinates: (x = − 16, y = − 10, z = − 14); M PBO = − 13.53, SD PBO = 60.41, M CITA = − 7.38, SD CITA = 32.36), ...
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Background
The majority of treatment research on obsessive-compulsive disorder (OCD) has focused on emotional processing theory (EPT)-based exposure-based interventions. Despite the outcomes of EPT-based exposure and response prevention (ERP), a sizeable percentage of patients do not respond whereas 50%–60% of those who respond experience at least...
Citations
... Also, results revealed that suppressing the 5-HT 1A receptor in the left BLA (in the left and bilateral sides of the BLA reduced distance traveling, rearing and grooming) is more responsible for anxiety-like behavior compared to the right BLA. Lateralization of 5-HT 1A serotonin receptor function in the amygdala in processing emotional stimuli has been observed in some previous studies (Selvaraj et al. 2018). Moreover, some previous studies have pointed to asymmetry in the distribution of the serotonin transporter in the hemispheres (Kranz et al. 2014). ...
Behavioral and functional studies describe hemispheric asymmetry in anxiety and metabolic behaviors in responses to stress. However, no study has reported serotonergic receptor (the 5-HT1A receptor) lateralization in the basolateral amygdala (BLA) in vivo on anxiety and metabolic behaviors under stress. In the present study, the effect of unilateral and bilateral suppression of the 5-HT1A receptor in the BLA on anxiety, and metabolic responses to chronic restraint stress was assessed. Male Wistar rats 7 days after cannulation into the BLA received chronic restraint stress for 14 consecutive days. 20 minutes before induction of stress, WAY-100–635 (selective 5-HT1A antagonist) or sterile saline (vehicle) was administered either uni- or bi-laterally into the BLA. Behavioral (elevated plus maze; EPM, and open field test), and metabolic parameter studies were performed. Results showed that stress causes a significant increase in weight gain compared to control. In the non-stress condition, the left and bilaterally, and in the stress condition the right, left, and both sides, inhibition of 5-HT1A in the BLA reduced weight gain. In the restraint stress condition, only inhibition of the 5-HT1A receptor in the left BLA led to decreased food intake compared to the control group. In stress conditions, inhibition of the 5-HT1A receptor on the right, left, and bilateral BLA increased water intake compared to the stress group. Inhibition of the 5-HT1A receptor on the left side of the BLA by WAY-100–635 induced anxiety-like behaviors in stressed rats. Similarly, WAY-100–635 on the left BLA effectively caused anxiety-like behaviors in both EPM and open field tests in the control animals. In conclusion, it seems that 5-HT1A receptors in the left BLA are more responsible for anxiety-like behaviors and metabolic changes in responses to stress.
... Combining SSRI administration with functional Magnetic Resonance Imaging (fMRI) is a strategy to investigate serotonergic modulation of relevant brain function. fMRI studies of healthy individuals evaluating the effects of acute (i.e., within hours) and short-term (i.e., 7-10 days) intake of SSRIs compared to placebo have generally reported an altered amygdala response to emotional stimuli [36][37][38][39] , with the majority reporting reduced amygdala response to threat [40][41][42][43][44][45] . Effects of short-term SSRI intake on emotional face processing have also been observed in other brain regions, for example, in the frontal cortex 46 . ...
Short-term intake of selective serotonin reuptake inhibitors (SSRIs) modulates threat-related amygdala responses in healthy individuals. However, how SSRI intake over a clinically relevant time period modulates threat-related amygdala responses is less clear. In a semi-randomised, double-blind, placebo-controlled study of 64 healthy individuals (SSRI n = 32, placebo n = 32), we examined the effect of 3–5 weeks of SSRI escitalopram (20 mg daily) on brain response to angry, fearful and neutral faces using BOLD fMRI. Data was analysed using a whole-brain region-wise approach extracting standardised effects (i.e., Cohen’s D). The study was conducted at the Copenhagen University Hospital. A priori, we hypothesised that SSRI would attenuate amygdala responses to angry and fearful faces but not to neutral ones. Whether SSRI modulates correlations between amygdala responses to emotional faces and negative mood states was also explored. Compared to placebo, 3–5 weeks of SSRI intake did not significantly affect the amygdala response to angry, fearful, or neutral faces (|Cohen’s D|< 0.2, PFWER = 1). Whole-brain, region-wise analyses revealed significant differences in frontal (|Cohen’s D|< 0.6, PFWER < .01) and occipital regions (|Cohen’s D|< 0.5, PFWER < .01). SSRI did not modulate correlations between amygdala responses to emotional faces and negative mood states. Our findings indicate that a 3–5 week SSRI intake impacts cortical responses to emotional stimuli, an effect possibly involved in SSRI’s therapeutic efficacy.
Trial registration Clinical Trials NCT04239339.
... Studies suggest that the 5-HT 1A receptor subtype plays a pivotal role in learning, memory, and anxiety-like behaviors (Stiedl et al., 2015). Some studies have shown that the 5-HT 1A receptors in the left and right amygdala work differently in emotion processing (Selvaraj et al., 2018). ...
The serotonin-1A receptors (5-HT1A) in the two cerebral hemispheres are differentially involved in memory. The distribution of 5-HT1A receptors in the left and right amygdala is different. Furthermore, evidence shows that the 5-HT1A receptors in the left and right amygdala work differently in memory function. The basolateral amygdala (BLA) also regulates hippocampal long-term potentiation (LTP) during stress. However, which BLA structure in each hemisphere underlies such lateralized function is unclear. The present research investigated the possible involvement of 5-HT1A lateralization in the BLA on stress-induced memory impairment. 5-HT1A receptor antagonist (Way-100-635) was injected into the left, right, or bilateral BLA twenty minutes before chronic restraint stress (CRS) for 14 consecutive days. Results indicated that suppression of 5HT1A-receptors in the BLA plays an essential role in reducing the acquisition of passive avoidance in the shuttle box test and spatial memory in the Barnes maze test in the stress animals. This decrease was significant in the CRS animals with left and bilateral suppressed 5HT1A-receptors in the BLA. Field potential recording results showed that the left, right, and bilateral injection of Way-100-635 into the BLA significantly reduced the slope and amplitude of fEPSP in the CA1 area of the hippocampus in stressed rats. No significant difference was observed in neuronal arborization in the CA1 area of the hippocampus. In conclusion, the 5-HT1A receptor in the left and right sides of BLA nuclei play a different role in memory consolidation in the hippocampus under stress.
... Multimodal brain imaging integrating PET and fMRI provides a powerful framework for establishing associations between specific neurotransmitter signaling pathways and distributed functional neural activity [29]. Previous such studies have shown that brain serotonergic signaling (for instance, via 5HT 1A and 5HT 2A receptors) modulate neural responses to emotional stimuli [30][31][32][33][34]. In healthy individuals, changes in brain 5-HT 4 R binding in response to a 3-week intervention with SSRI are associated with corresponding changes in amygdala reactivity [35]. ...
Brain serotonergic (5-HT) signaling is posited to modulate neural responses to emotional stimuli. Dysfunction in 5-HT signaling is implicated in major depressive disorder (MDD), a disorder associated with significant disturbances in emotion processing. In MDD, recent evidence points to altered 5-HT4 receptor (5-HT4R) levels, a promising target for antidepressant treatment. However, how these alterations influence neural processing of emotions in MDD remains poorly understood. This is the first study to examine the association between 5-HT4R binding and neural responses to emotions in patients with MDD and healthy controls. The study included one hundred and thirty-eight participants, comprising 88 outpatients with MDD from the NeuroPharm clinical trial (ClinicalTrials.gov identifier: NCT02869035) and 50 healthy controls. Participants underwent an [¹¹C]SB207145 positron emission tomography (PET) scan to quantify 5-HT4R binding (BPND) and a functional magnetic resonance imaging (fMRI) scan during which they performed an emotional face matching task. We examined the association between regional 5-HT4R binding and corticolimbic responses to emotional faces using a linear latent variable model, including whether this association was moderated by depression status. We observed a positive correlation between 5-HT4R BPND and the corticolimbic response to emotional faces across participants (r = 0.20, p = 0.03). This association did not differ between groups (parameter estimate difference = 0.002, 95% CI = −0.008: 0.013, p = 0.72). Thus, in the largest PET/fMRI study of associations between serotonergic signaling and brain function, we found a positive association between 5-HT4R binding and neural responses to emotions that appear unaltered in MDD. Future clinical trials with novel pharmacological agents targeting 5-HT4R are needed to confirm whether they ameliorate emotion processing biases in MDD.
... Correspondingly, pharmacological treatment of depression and anxiety disorders involve serotonergic agents, and selective serotonin reuptake inhibitors (SSRI) are firstline treatment options in most cases (28). Escitalopram, an antidepressant of the SSRI class, blocks the serotonin transporter in axon terminals increasing serotonin levels in the synaptic cleft (29), although the net effect on serotonin concentrations in the projection areas is also mitigated by activation of 5-HT auto-receptors (30)(31)(32)(33)(34). Patients treated with SSRIs generally respond within 4-12 weeks after the start of treatment (35), but a substantial number report increased anxiety and blunted emotions as early side effect of treatment (36). ...
... Besides their broad clinical application, SSRIs in conjunction with brain imaging are also frequently used as pharmacological probes to gauge the role of serotonin in emotion induction and regulation. Hemodynamic activity of prefrontal cortex (PFC) and amygdala has thus been shown to be affected by changes in the serotonergic transmission (38)(39)(40), but the direction of modulation seems to vary with task and brain region and both increased and decreased activations have been reported (32,41). For example, hemodynamic activity in amygdala has been found to increase or decrease during facial emotion recognition tasks after ingestion of SSRI (42)(43)(44)(45)(46). Similarly, there are reports of increased and decreased activations of PFC areas after intake of SSRI (30,43,(46)(47)(48). ...
... For example, hemodynamic activity in amygdala has been found to increase or decrease during facial emotion recognition tasks after ingestion of SSRI (42)(43)(44)(45)(46). Similarly, there are reports of increased and decreased activations of PFC areas after intake of SSRI (30,43,(46)(47)(48). More specifically, single dose SSRI was associated with increased startle responses (32,(49)(50)(51), and enhanced detection of facial expressions of fear and happiness without affecting that of anger, sadness and disgust (52). Murphy, Norbury (42) reported that single dose SSRI decreased recognition of disgust and amygdala response to fear, while Outhred, Das (53) using escitalopram reported reduced activation of right inferior frontal gyrus during emotion induction (54). ...
Introduction
Adaptive and successful emotion regulation, the ability to flexibly exert voluntary control over emotional experience and the ensuing behavior, is vital for optimal daily functioning and good mental health. In clinical settings, pharmacological and psychological interventions are widely employed to modify pathological emotion processing and ameliorate its deleterious consequences.
Methods
In this study, we investigated the acute effects of single-dose escitalopram on the induction and regulation of fear and disgust in healthy subjects. Furthermore, we compared these pharmacological effects with psychological emotion regulation that utilized a cognitive strategy with reappraisal. Emotion induction and regulation tasks were performed before and 4 h after ingestion of placebo or 10 mg escitalopram in a randomized, double-blind design. The International Affective Picture System (IAPS) was used as a source of images, with threat-related pictures selected for fear and disease and contamination-related pictures for disgust. Behavioral data, electrodermal activity (EDA), and functional near-infrared spectroscopy (fNIRS) recordings were collected.
Results
Escitalopram significantly reduced emotion intensity for both fear and disgust during emotion induction, albeit with differing electrodermal and hemodynamic activity patterns for the two negative emotions. At rest, i.e., in the absence of emotive stimuli, escitalopram increased sympathetic activity during the fear but not during the disgust experiments. For both fear and disgust, emotion regulation with reappraisal was more effective in reducing emotion intensity compared to pharmacological intervention with escitalopram or placebo.
Discussion
We concluded that emotion regulation with reappraisal and acute administration of escitalopram, but not placebo, reduce emotion intensity for both fear and disgust, with cognitive regulation being significantly more efficient compared to pharmacological regulation under the conditions of this study. Results from the fNIRS and EDA recordings support the concept of differential mechanisms of emotion regulation that could be emotion-specific.
... Studies employing negative emotional scenes reported that citalopram did not decrease activity in cortico-limbic regions ( Brühl et al., 2011 ;Brühl et al., 2010 ). However, there are also reports of increased, rather than decreased, amygdala activation in response to negative emotional stimuli after citalopram intake ( Bigos et al., 2008 ;Di Simplicio et al., 2014 ;Klomp et al., 2013 ;Selvaraj et al., 2018 ). Contradictory findings may be due to heterogeneity of fMRI paradigms, but also to different dosing regimen (i.e. ...
Abnormal emotional processing in major depressive disorder (MDD) has been associated with increased activation to negative stimuli in cortico-limbic brain regions. The authors investigated whether treatment with BI 1358894, a small-molecule inhibitor of the transient receptor potential cation channel subfamily C leads to attenuated activity in these areas in MDD patients. 73 MDD patients were randomized to receive a single oral dose of BI 1358894 (100 mg), citalopram (20 mg), or matching placebo. Brain responses to emotional faces and scenes were investigated using functional magnetic resonance imaging. Primary endpoints were BOLD signal changes in response to negative faces in cortico-limbic brain regions, i.e. bilateral amygdala (AMY), dorsolateral prefrontal cortex, anterior insula (AI), and anterior cingulate cortex. Secondary endpoints were BOLD signal changes in response to negative scenes. For each region, separate ANOVA models were computed for the comparison of treatments (BI 1358894 or citalopram) vs. placebo. The adjusted treatment differences in the % BOLD signal changes in the faces task showed that BI 1358894 induced signal reduction in bilateral AMY and left AI. In the scenes task, BI 1358894 demonstrated significant signal reduction in bilateral AMY, AI, anterior cingulate cortex and left dorsolateral prefrontal cortex. Citalopram failed to induce any significant reductions in BOLD signal in both tasks. BI 1358894-mediated inhibition of the transient receptor potential cation channel subfamily resulted in strong signal reduction in cortico-limbic brain regions, thereby supporting development of this mechanism of action for MDD patients.
... For example, SSRI administration has been found to alter connectivity within and with the Default Mode Network (DMN) [12][13][14][15][16], which has frequently been associated with rumination in depression [17]. Furthermore, task-based studies using emotion recognition paradigms, have frequently found altered activation in the limbic system in response to SSRIs [18][19][20][21], which has been implicated in aberrant emotion regulation in depressed patients [22]. However, how engagement of 5-HT molecular targets, including the 5-HTT and 5-HT1AR, might contribute to these circuit-level effects remains poorly understood. ...
... Moreover, Hahn et al. [23] emphasized the importance of 5-HT1AR in regulating DMN connectivity by demonstrating diverse and areaspecific patterns of associations between the FC of the PCC, a core node of the DMN, and 5-HT1A autoreceptor and local heteroreceptor binding. Noteworthy, 5-HT1AR has also been hypothesized to be a key modulator of the engagement of neural circuits underlying emotional processing in taskbased fMRI studies, as evidenced by associations between DRN 5-HT1AR binding and (changes in) amygdala activation during facial emotion processing [20,24]. However, given the prominent role of 5-HT1AR in regulating the 5-HT system, dissecting the pharmacodynamics of SSRIs in the human brain and its correspondent interindividual variability should incorporate concomitant investigations of how post-drug increases in 5-HT might relate to subsequent modulations of neural circuits associated with specific 5-HT receptor subtypes, such as 5-HT1AR. ...
... In line with previous findings on FC changes after citalopram, we hypothesized an inverse relationship between 5-HTT availability and 5-HTT-and 5-HT1ARenriched FC post-treatment both at rest and during the task. In accordance with previous studies showing that amygdala activation during emotion recognition is associated with DRN 5-HT1AR binding [20,24], we expected 5-HTT availability in task-dependent FC to be mostly subserved by 5-HT1AR. ...
Background
Selective serotonin reuptake inhibitors (SSRIs) potentiate serotonergic neurotransmission by blocking the serotonin transporter (5-HTT), but the functional brain response to SSRIs involves neural circuits beyond regions with high 5-HTT expression. Currently, it is unclear whether and how changes in 5-HTT availability after SSRI administration modulate brain function of key serotoninergic circuits, including those characterized by high availability of serotonin 1A receptors (5-HT1AR).
Aim
We investigated the association between 5-HTT availability and 5-HTT- and 5-HT1AR-enriched functional connectivity (FC) after an acute citalopram challenge.
Methods
We analyzed multimodal data from a dose-response, placebo-controlled, double-blind study, in which 45 healthy women were randomized into three groups receiving placebo, a low (4 mg), or high (16 mg) oral dose of citalopram. Receptor-Enhanced Analysis of functional Connectivity by Targets was used to estimate 5-HTT- and 5-HT1AR-enriched FC from resting-state and task-based fMRI. 5-HTT availability was determined using [ ¹²³ I]FP-CIT single-photon emission computerized tomography.
Results
5-HTT availability was negatively correlated with resting-state 5-HTT-enriched FC, and with task-dependent 5-HT1AR-enriched FC. Our exploratory analyses revealed lower 5-HT1AR-enriched FC in the low dose group compared to the high dose group at rest and the placebo group during the task.
Conclusions
Taken together, our findings provide evidence for differential links between 5-HTT availability and brain function within 5-HTT and 5-HT1AR pathways and in context- and dose-dependent manner. As such, they support a potential pivotal role of the 5-HT1AR in the effects of citalopram on the brain and add to its potential as a therapeutic avenue for mood and anxiety disturbances.
... 160 In a PET trial with healthy volunteers, [ 11 C]45 was proved to be a versatile radiotracer for imaging high-affinity 5-HT 1A binding in humans. 161,162 In recent years, [ 11 C]45 has been used in clinical PET studies to explore the changes of 5-HT 1A receptor level in various physiological conditions, such as a study about the effect of citalopram (a selective serotonin reuptake inhibitor) on emotion processing in humans 163 and a quantification study of PET data using simultaneous estimation of the input function; 164 as well as pathological conditions like major depressive disorder, 165,166 schizophrenia, 167 lithium treatment response in bipolar depression, 168 and loudness dependence of auditory evoked potentials research in patients with unipolar and bipolar depression. 169 However, PET studies in baboons 170 and healthy participants 171,172 showed that [ 11 C]45 was insufficient in detecting changes in endogenous intrasynaptic serotonin. ...
Serotonin (5-hydroxytryptamine, 5-HT) and 5-HT receptors (5-HTRs) have crucial roles in various neuropsychiatric disorders and neurodegenerative diseases, making them attractive diagnostic and therapeutic targets. Positron emission tomography (PET) is a noninvasive nuclear molecular imaging technique and is an essential tool in clinical diagnosis and drug discovery. In this context, numerous PET ligands have been developed for "visualizing" 5-HTRs in the brain and translated into human use to study disease mechanisms and/or support drug development. Herein, we present a comprehensive repertoire of 5-HTR PET ligands by focusing on their chemotypes and performance in PET imaging studies. Furthermore, this Perspective summarizes recent 5-HTR-focused drug discovery, including biased agonists and allosteric modulators, which would stimulate the development of more potent and subtype-selective 5-HTR PET ligands and thus further our understanding of 5-HTR biology.
... We may have observed our negative findings as a result of a lack of sensitivity of our measures to CBD's effects. Evidence against this possibility is that we selected our measures on the basis of their previous sensitivity to drugrelated effects (Hindocha et al. 2018;Selvaraj et al. 2018) and that each of our measures elicited significant task effects (e.g. differentiation of valence and arousal responses to positive and negative emotional stimuli in the face rating task, increased subjective and cardiovascular stress responses in the mental arithmetic task, see the supplementary materials for full statistical results). ...
Rationale
There is growing interest in the therapeutic potential of cannabidiol (CBD) across a range of psychiatric disorders. CBD has been found to reduce anxiety during experimentally induced stress in anxious individuals and healthy controls. However, the mechanisms underlying the putative anxiolytic effects of CBD are unknown.
Objectives
We sought to investigate the behavioural and neural effects of a single dose of CBD vs. placebo on a range of emotion-related measures to test cognitive-mechanistic models of its effects on anxiety.
Methods
We conducted a randomised, double-blind, placebo-controlled, crossover, acute oral challenge of 600 mg of CBD in 24 healthy participants on emotional processing, with neuroimaging (viewing emotional faces during functional magnetic resonance imaging) and cognitive (emotional appraisal) measures as well as subjective response to experimentally induced anxiety.
Results
CBD did not produce effects on brain responses to emotional faces and cognitive measures of emotional processing, or modulate experimentally induced anxiety, relative to placebo.
Conclusions
Given the rising popularity of CBD for its putative medical benefits, these findings question whether further research is warranted to investigate the clinical potential of CBD for the treatment of anxiety disorders.
... Alternatively, it is also possible we have not adequately interrogated large-scale brain networks related to the neurochemical systems involved in complex higher-order behaviours (Cremers et al., 2017). This may be especially important for the serotonin (5-HT) system which has widespread regulatory effects across brain (Ciranna, 2006), is involved in processing facial emotions (Harmer et al., 2003;Murphy et al., 2006;Selvaraj et al., 2018) and is strongly implicated in ASD (Deutsch and Raffaele, 2019). ...
Background
Alterations in the serotonergic control of brain pathways responsible for facial emotion processing in people with autism spectrum disorder (ASD) may be a target for intervention. However, the molecular underpinnings of autistic-neurotypical serotonergic differences are challenging to access in vivo. Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) has helped define molecular-enriched functional magnetic resonance imaging (fMRI) brain networks based on a priori information about the spatial distribution of neurochemical systems from available PET templates.
Methods
We used REACT to estimate the dominant fMRI signal related to the serotonin (5-HT) transporter (SERT) distribution during processing of aversive facial emotion in adults with and without ASD. We first predicted a group difference in baseline (placebo) functioning of this system. We next used a single 20 mg oral dose of citalopram, a serotonin reuptake inhibitor, to test the hypothesis that network activity in people with and without ASD would respond differently to inhibition of SERT. To confirm the specificity of our findings, we also repeated the analysis with 5-HT1A, 5-HT1B, 5-HT2A and 5-HT4 receptor maps.
Results
Using REACT with the SERT map, we found a baseline group difference in the SERT-enriched response to faces in the ventromedial prefrontal cortex. A single oral dose of citalopram ‘shifted’ the response in the ASD group towards the neurotypical baseline but did not alter response in the control group. Similar differences in SERT-enriched response were observed after controlling for other 5-HT maps.
Conclusions
Our findings suggest that the SERT-enriched functional network is dynamically different in ASD during processing of socially relevant stimuli. Whether this acute neurobiological response to citalopram in ASD translates to a clinical target will be an important next step.
