Table IV:
Imaging genetics studies in ADHD case-control samples and ADHD candidate genes studies in the healthy population (for selection of candidate genes see Table I).
| Gene | Variant | Imaging modality | Imaging/cognitive phenotype | Genotype groups compared | Samples size (mean age in years) | Primary results (main effect of genotype) | Reference |
|---|---|---|---|---|---|---|---|
| DRD2 | DRD2/ANKK1-Taq1a (rs1800497, T allele = A1 allele) | sMRI (VBM) | Global GM volume | A1- carriers vs. A2/A2-carriers | 70 HC (30.7) | A1- carriers: ↓ part of midbrain, encompassing substantia nigra bilaterally | (Cerasa et al. 2009) |
| sMRI (VBM) | GM and WM volume | A1- carriers vs. A2/A2-carriers | 25 HC (25) | A1-carriers: ↓ Volume in cerebellar cluster | (Wiener et al. 2014) | ||
| fMRI | Temporal or color discrimination task | A1-carriers: ↑ Activation in striatum and right dorsolateral PFC | |||||
| Reward anticipation paradigm | A1- carriers vs. A2/A2-carriers | 24 HC (25.7) | ↑ Nucleus accumbens activation in three-way interaction analysis from placebo to bromocriptine (D2 receptor agonist); ↑ performance under bromocriptine in A1- carriers. | (Kirsch et al. 2006) | |||
| Striatal activation in response to receiving palatable food (2 fMRI paradigms) | A1- carriers vs. A2/A2-carriers | fMRI 1: 43 HC (20.4) † fMRI 2: 33 HC (15.7) † |
↑ Negative relation between striatal response to food receipt and BMI. A1-non-carriers : striatal activation in response to food intake was positively related to weight gain (negatively related to weight gain for A1- carriers). | (Stice et al. 2008) | |||
| Emotional face task | A1/A1-carriers vs. A1/A2-carriers vs. A2/A2-carriers | 45 HC (23.2)†§ | TaqIA genotype modifies activations in putamen, ACC, and amygdala in response to negative facial stimuli (higher signal intensity in homozygous groups (A1/A1 + A2/A2) than in heterozygous group (A1/A2)). | (Lee et al. 2011) | |||
| Flanker task with a motivation manipulation | A1- carriers vs. A2/A2-carriers | 32 HC (22.9) | A1- carriers: ↓ Interference effects to reward alone (as compared to reward + punishment) and ↑ anterior insula activation | (Richter et al. 2013) | |||
| Task-switching paradigm | A1-non-carriers vs. A1-carriers | 48 HC (22) | A1 non-carriers: ↑ Task-switching costs, ↑ prefrontal switching activity in inferior frontal junction area, and ↑ functional connectivity in dorsal frontostriatal circuits | (Stelzel et al. 2010) | |||
| Feedback-based reversal learning task | A1- carriers vs. A2/A2-carriers | 22 HC (age range 20-31) | A1- carriers in placebo condition: ↓ neural responses to positive feedback; cabergoline: ↑neural reward responses in medial OFC, cingulate cortex, and striatum, but ↓task performance and frontostriatal functional connectivity | (Cohen et al. 2007) | |||
| Probabilistic reversal learning task | A1- carriers vs. A2/A2-carriers | 28 HC (26.1)‡ | A1- carriers: no graded increase in RCZ activity to preceding negative feedback; ↓ recruitment of right VS and right lateral OFC during reversals. | (Jocham et al. 2009) | |||
| “Wug” test (knowledge of grammar, opposed to vocabulary) | A2/A2-carriers vs. A1- carriers | 22 HC (22) | A2/A2-carriers: ↑ At concatenative (but not analogical) grammar learning; ↑ striatal responses | (Wong et al. 2013) | |||
| DRD4 | exon 3 VNTR | sMRI | Superior frontal, middle frontal, anterior cingulate, and cerebellum cortices volumes | ADHD 7R-carriers vs. non 7R-carriers | 24 ADHD (38.1) 19 ADHD+BPD (35.8) 20 HC (33.2) |
7R- carriers: ↓ volumes of superior frontal cortex and cerebellum cortex compared to non-carriers. No effects in ADHD+BPD or HC. | (Monuteaux et al. 2008) |
| TBV, PFC, cerebellum, CN and pallidum volume | 7R-carriers vs. non-7R-carriers | 41 ADHD (9.7) 56 HC (17.6) |
No volumetric differences between 7R-carriers and non-7R-carriers. No group × genotype interactions. | (Castellanos et al. 1998) ‡ | |||
| DTI | WM integrity | 5R- carriers vs. non 5R-carriers | 765 HC (20.7) § | 5R-carriers : ↑ MD in widespread GM and WM areas of cerebral cortex, and subcortical areas | (Takeuchi et al. 2015) | ||
| fMRI | Activity related to N-back paradigm | 5R-carriers : ↓ Task-induced deactivation in precuneus areas in both attention-demanding working memory task and sensorimotor task; similar patterns were observed in posterior cingulate cortex and areas around midbrain and hippocampus. | |||||
| fMRI | MID task | 7R-carriers vs. non 7R-carriers | 78 HC (16.3) |
DRD4 status moderated relation between Behavioral Inhibition (BI) and activation in CN. 7R-carriers: ↑ striatal response to incentive cues. DRD4 genotype influenced relations among neural response to incentives, early childhood BI and anxiety. |
(Perez-Edgar et al. 2014) | ||
| Emotional rating task | 4R/7R-carriers vs. 4R/4R-carriers | 26 HC (23.3) | 4R/7R-carriers: ↑ activity in response to unpleasant images compared to neutral images in right temporal lobe. | (Gehricke et al. 2015) | |||
| Go/No-go task | 7R-carriers vs. non 7R-carriers | 62 HC (18) | 7R-carriers “No-Go” trials:, ↓ activation in right anterior PFC/IFG, left premotor cortex, and right occipital/ cerebellar areas (7-repeat status accounted for ca. 5-6% of variance in BOLD response during “No-Go” trials). | (Mulligan et al. 2014) | |||
| Combined stimulus-response Incompatibility Task (IC) and Time Discrimination Task (TT) | 7R-non-carriers vs. 7R-carriers | 26 HC (11.4) | 7R-non-carriers: ↑activation of left middle and IFG in IC and ↑cerebellar activation in TT; ↑functional connectivity between left IFG and ACC during IC and between cerebellar activation and IFG and ACC during TT. | (Gilsbach et al. 2012) | |||
| NOS1 | Exon 1f-VNTR | fMRI | Reward anticipation task/ modified MID task | SS-carriers vs. SL/LL-carriers | 63 ADHD (38.3) 41 HC (38.0) |
SS-carriers: ↑ in VS. No group × genotype interactions. | (Hoogman et al. 2011) |
| SLC6A3/DAT1 | 3’UTR and intron 8 VNTR haplotype | sMRI | Bilateral striatal volumes (nucleus accumbens, CN, and putamen) | Three DAT1 alleles (10/10 genotype, and the haplotypes 10-6 and 9-6) | 118 ADHD (35.9) 111 HC (37) 301 ADHD (17.2) 186 HC (16.6) 1718 HC (26.1) |
Adult ADHD 9-6 haplotype carriers ↑ 5.9 % larger striatum volume relative to participants not carrying this haplotype (in adult ADHD patients only). Effect was not replicated in adolescent case-control and adult population-based cohort. |
(Onnink et al. 2016) |
| 3’ UTR VNTR | sMRI | CN volume | 9R-carriers vs. 10R/10R-carriers | 33 ADHD (10.5) 26 HC (10.6) |
9R-carriers: ↑ volumes of CN. | (Shook et al. 2011) | |
| 3’UTR and intron 8 VNTR haplotype | fMRI | VS and CN activity during reward-predicting cues | SLC6A3 10-6 dosage (2 copies vs. <2 copies) | 29 ADHD (combined type; 15.8)‡ 30 HC (15.6)‡ |
ADHD: Activation in CN ↓ as number of copies ↑, but in control group reverse was found. | (Paloyelis et al. 2012) | |
| Striatal activity during reward anticipation task | 9-6 haplotype carriers vs. non 9-6 haplotype carriers | 87 ADHD (38.3) 77 HC (38) |
No differences in striatal activity compared with non 9-6 haplotype carriers nor 9R- and 10R/10R-carriers. | (Hoogman et al. 2013) | |||
| 9-6 haplotype carriers vs. non 9-6 haplotype carriers | 87 ADHD (38.3) 77 HC (38); same as above |
Bayesian Constraint-based Causal Discovery (BCCD) algorithm confirmed that there is no evidence of a direct link between DAT1 genetic variability and brain activation, but suggested an indirect link mediated through inattention symptoms and diagnostic status of ADHD | (Sokolova et al. 2015) | ||||
| 3’ UTR VNTR | fMRI | Working memory task | 9R-carriers vs. 10R/10R-carriers | 53 ADHD (35.7) 38 HC (31.2) |
9R-carriers: ↓ left medial PFC activation compared to 10R/10R-carriers. Group × genotype interaction showed that 10R/10R-ADHD patients had ↑ activity in pre-SMA/dorsal ACC compared to HC. | (Brown et al. 2011) | |
| Go/No-go task | 10R/10R carriers vs. 9R-carriers | 20 ADHD (14.1) 38 HC (13.12) |
10R/10R carriers: ↑ activity in frontal, medial, and parietal regions during response inhibition compared to 9R-carriers; ↓error response in the parahippocampal gyrus | (Braet et al. 2011) | |||
| 10R/10R carriers vs. 9R-carriers | 33 ADHD (11.1) | 10R/10R carriers: ↑ activity in left striatum, right dorsal premotor cortex, and temporoparietal cortical junction compared to 9R-carriers. | (Bedard et al. 2010) | ||||
| 9R-carriers vs. 10R/10R carriers | 10 ADHD (14.6)‡ 10 unaffected siblings (14.8)‡ 9 HC (15.3)‡ |
9R-carriers: ↑ activity in CN and ↓ in cerebellar vermis compared to 10R/10R-carriers. Group × genotype interaction: effect in CN is observed in ADHD and unaffected siblings, but not HC. | (Durston et al. 2008) | ||||
| Multi-source interference task | 10R/10R carriers vs. 9R-carriers | 42 ADHD (35.4) | 9R-carriers: ↓ activity in dorsal ACC compared to 10R/10R-carriers. | (Brown et al. 2010) | |||
| 3’ UTR VNTR | rs-fMRI | Striatal FC | 9R/10R-carriers vs. 10R/10R carriers | 50 HC (20.4) | 9R/10R-carriers: stronger connectivity between dorsal CN and insula, dorsal anterior cingulate, and dorsolateral prefrontal regions, as well as between VS and ventrolateral PFC, compared with 10R/10R-carriers. | (Gordon et al. 2015) | |
| fMRI | Modified version of the MID task | 10R/10R-carriers vs. 9R carriers | 53 HC (29) | 10R/10R-carriers: strong positive correlation between reward sensitivity and reward-related VS activity (relationship is absent in 9R-carriers). | (Hahn et al. 2011) | ||
| Exposure to threatening faces | 10R/10R-carriers vs. 9R-carriers | 85 HC (45.2) | 9R-carriers: ↑ amygdala reactivity compared with 10R/10R-carriers. | (Bergman et al. 2014) | |||
| Go/No-Go task under influence of 40 mg MPH or placebo | 9R-carriers vs. 10R/10R- carriers | 50 HC (23.7)‡ | 9R-carriers: MPH induced ↑ activation during successful no-go trials compared with oddball trials in thalamocortical network 10R/10R-carriers: ↓ activation in thalamocortical network. Same pattern was observed in CN and IFG (successful no-go trials compared with successful go trials). | (Kasparbauer et al. 2015) | |||
| Pre-cued task-switching task | 9R-carriers vs. 10R/10R- carriers | 20 HC (21.6) | 9R-carriers: ↑ventromedial striatum activation during reward anticipation compared with 10R/10R-carriers; ↑ influence of anticipated reward on switch costs, and ↑activity in dorsomedial striatum during task switching in anticipation of high reward relative to low reward in 9R-carriers. | (Aarts et al. 2010) | |||
| Verbal n-back task | 9R/10R-carriers vs. 10R/10R-carriers | 20 HC (10.4) | 9R/10R-carriers: ↑ performance accuracy, ↑ activation in frontalstriatal-parietal regions in high but not low runs compared with 10R/10R-carriers. Genotype × load interaction in right CN. 9R/10R-carriers: ↑ activation in striatal and parietal regions under high compared to low load, and genotype differences (9R/10R>10R/10R) were evident only under high load. 10R/10R-carriers: ↑ activation of substantial nigra/subthalamic nuclei under low than high load and genotype differences (10R/10R>9R/10R) were evident only under low load. |
(Stollstorff et al. 2010) | |||
| SLC6A4/5HTT | 5-HTTLPR | sMRI (VBM) | GM volume | S-carriers vs. LL | 291 ADHD 78 subthreshold ADHD 332 HC; Average age: 17 years |
S-carriers: stress exposure is associated with ↓ GM volume in precentral gyrus, middle and superior frontal gyri, frontal pole, and cingulated gyrus. Association of G × E interaction with ADHD symptom count was mediated by GM volume in frontal pole and anterior cingulated gyrus only. | (van der Meer et al. 2015) |
| 5-HTTLPR | sMRI | Amygdala | SS vs. SL vs. LL | 138 HC (41.2) | SS-carriers × anxiety: ↑ right amygdala volume (only in females) | (Cerasa et al. 2014) | |
| Hippocampus | S-carriers vs. LL | 56 HC (71) | ↓ Hippocampal volume in interaction with increased waking cortisol levels | (O’Hara et al. 2007) | |||
| SS/SL vs. LL | 357 HC (24.3) | S-carriers: ↓ hippocampal volume (females only); ↓ hippocampal volume correlated with severe CA (males only) | (Everaerd et al. 2012) | ||||
| S-carriers vs. LL | 51 HC (∼21) | ↑ Left hippocampal volumes in woman ↓ Left hippocampal volumes in men |
(Price et al. 2013) | ||||
| LL vs. SS/SL | 159 HC (69.5) | LL-carriers × stress: ↓ hippocampal volume | (Zannas et al. 2013) | ||||
| Multiple regions | S-carriers vs. LL | 113 HC (37.6) | ↓ GM volume of right IFG, left anterior cingulate, and superior temporal gyrus | (Selvaraj et al. 2011) | |||
| 5-HTTLPR, rs25531 | sMRI | Total GM volume | SS vs. LL, S’ vs. L’ | 58 HC (18.5) | No significant association with total GM volume | (Walsh et al. 2014) | |
| 5-HTTLPR, rs25531, AluJb methylation of promoter | sMRI (VBM) | Hippocampus, amygdala, insula, anterior cingulated gyrus | S’ vs. L’ quantitative methylation score | Sample 1: 94 HC (36.9) Sample 2: 95 HC (34.2) |
No significant association of genotype. Strong association of methylation and hippocampal GM volume; amygdala, insula, and CN showed similar associations, genotype-independent. |
(Dannlowski et al. 2014) | |
| 5-HTTLPR | sMRI (VBM) | GM volume | S-carriers vs. LL | sMRI: 114 HC (32.8) fMRI: 94 HC (31.3) (26 included in both) |
S-carriers (VBM): ↓GM volume in limbic regions, particularly perigenual ACC and medial amygdala. | (Pezawas et al. 2005) | |
| fMRI | perceptual processing of fearful stimuli | S-carriers (fMRI): ↓ of amygdala- perigenual ACC connectivity, particularly in rostral ACC; ↓ structural covariance between amygdala and rostral ACC | |||||
| GM volume, attentional interference task | S-carriers vs. LL | 41 HC (adults) | S-carriers (VBM): ↑ volume in left cerebellum LL (VBM): ↑ volume in left superior and medial frontal gyri, left anterior cingulated, and right IFG S-carriers (fMRI): ↑ activation in response to negative, relative to neutral, words in right amygdala (driven by ↓ activation to neutral stimuli, rather than ↑ activation to negative stimuli); for negative-neutral contrast ↑ activation most prominent in insula, putamen, and CN |
(Canli et al. 2005) | |||
| sMRI (VBM) | Hippocampus, amygdala | S-carriers vs. LL, interaction with SLEs | 48 HC (24.7); | S-carriers: no correlation of hippocampus and amygdala volume with SLEs. LL-carriers: positive correlation in GM volume with SLEs. |
(Canli et al. 2006) | ||
| fMRI | Face-stimuli | Negative correlation between SLEs and amygdala and hippocampus activation in response to face stimuli in S-carriers; positive correlation in LL-carriers. | |||||
| rs-fMRI | FC between amygdala and hippocampus; absolute CBF at rest | 21 HC for perfusion scan | GxE effect altered FC between hippocampus and putamen. Interaction effect of 5-HTTLPR genotype and life stress on resting level activation in amygdala and hippocampus (positive correlation in S-group and negative correlation in L-group). |
||||
| sMRI | GM volume resting CBF | SS vs. LL | 26 HC (20.3) | SS-carriers: No effect on amygdala and ventromedial PFC volume | (Rao et al. 2007) | ||
| rs-fMRI | SS-carriers: ↑ resting CBF in amygdala and ↓ CBF in ventromedial PFC | ||||||
| DTI | WM integrity | L-carriers vs. SS | 233 HC (22.7) § | L-carriers: ↓ anatomical connectivity between amygdala and PFC through uncinate fasciculus. | (Long et al. 2013) | ||
| rs-fMRI | TC | L-carriers: ↓ FC between right amygdala and right frontal pole. | |||||
| 5-HTTLPR, rs25531 | DTI | Structural connectivity | S’-carriers × SLE vs. L’L’ × SLE | 34 HC (25.6) † | ↑ Structural connectivity between hippocampus and putamen (seed-based). | (Favaro et al. 2014) | |
| rs-fMRI | FC | ↑ Positive correlation of co-activation of right parahippocampus and posterior cingulate cortex with SLEs (seed-based). | |||||
| 5-HTTLPR | rs-fMRI | Task-free activity | SS vs. LL | 30 HC (20.3) | ↑ Negative correlation of right amygdala activity and depressive symptoms | (Gillihan et al. 2011) | |
| FC | SS vs. L-carriers | 200 HC (22.1) ‡§ | SS-carriers: ↑ fractional amplitude of low-frequency fluctuation in amygdala; ↓ rsFC between amygdala and various regions (including insula, Heschl’s gyrus, lateral occipital cortex, superior temporal gyrus, hippocampus) and ↑ rsFC between amygdala and various regions (including supramarginal gyrus and middle frontal gyrus) | (Zhang et al. 2015) | |||
| 5-HTTLPR, rs25531 | rs-fMRI | FC | S’S’ vs. S’L’ vs. L’L’ | 39 HC (14.8) | ↓ Superior medial frontal cortex connectivity ↓ Age-related increase in FC between posterior hub and superior medial frontal cortex |
(Wiggins et al. 2012) | |
| 5-HTTLPR | fMRI | Sadness induction - regulation to normal emotion | SS vs. LL | 30 HC (20.3) | ↑ Amygdala activity during mood recovery. | (Gillihan et al. 2010) | |
| Emotion regulation task | S-carriers vs. LL | 37 HC (22.6) † | ↑ Right amygdala reactivity to fearful faces. ↑ Signal reductions in right amygdala during regulation of fear. ↑ Modulatory influence of cognitive regulation on FC between amygdala and bilateral ventrolateral PFC, left medial OFC, subgenual ACC and rostral ACC. |
(Schardt et al. 2010) | |||
| SS vs. LL | 30 HC (20.3), same sample as above | ↑Anti-correlation between amygdala and posterior cingulate cortex/precuneus during mood recovery. | (Fang et al. 2013) | ||||
| 5-HTTLPR, rs25531 | fMRI | Emotion regulation task | S’S’ vs. L’L’ | 30 HC (20.5) | ↓ Posterior insula and prefrontal brain activation during passive perception of negative emotional information. ↑ Prefrontal activation and anterior insula activation during down- and upregulation of negative emotional responses. |
(Firk et al. 2013) | |
| 5-HTTLPR | fMRI | Mood induction, sadness (film) | S-carriers vs. LL | 48 HC (8.3) | ↑ Right putamen, right CN, right rostro-ventral ACC, left CN, and left putamen in sad mood. | (Fortier et al. 2010) | |
| S-carriers vs. LL | 49 HC (12) † | ↑ Earlier rise of left amygdala activation as sad mood increases. | (Furman et al. 2011) | ||||
| 5-HTTLPR | rs-fMRI | FC | LL vs. SS | 38 HC (20.4) § | ↑ Regional homogeneity in right amygdala; no effects on FC of right amygdala. | (Li et al. 2012) | |
| fMRI | Emotional processing | No difference in amygdala activity in response to negative stimuli. | |||||
| 5-HTTLPR, rs25531 | fMRI | Emotion processing task | S’S’ vs. S’L’ vs. L’L’ (treatment with escitalopram) | 36 HC (25.1) † | ↑Left amygdala activation with escitalopram treatment linearly related to 5-HTTLPR S’ allele load for negative stimuli increased. | (Outhred et al. 2014) | |
| 5-HTTLPR | fMRI | Emotional face task | S-carriers vs. LL | 28 HC | S-carriers: ↑ right amygdala activity | (Hariri et al. 2002) | |
| S-carriers vs. LL | 92 HC (30.5) | S-carriers: ↑ right amygdala activity | (Hariri et al. 2005) | ||||
| S-carriers vs. LL | 29 HC (40) ‡ | S-carriers: ↑ activation of amygdala and ↑ coupling between amygdala and ventromedial PFC. | (Heinz et al. 2005) | ||||
| SS vs. SL vs. LL | 29 HC (37.5) | ↑ Activity in right fusiform gyrus to fearful faces. ↑Positive FC between amygdala and fusiform gyrus and between right fusiform gyrus and right ventrolateral PFC. |
(Surguladze et al. 2008) | ||||
| S-carriers vs. LL | 21 HC (15) | ↑ Left amygdala activation in response to anger. | (Battaglia et al. 2012) | ||||
| 5-HTTLPR, rs25531 | fMRI | Emotional face task | S’-carriers vs. L’L’ | 44 HC (30.3) | ↑ Right amygdala responses to sad faces. | (Dannlowski et al. 2010) | |
| L’L’ vs. S’S’ | 30 HC (26.6) | No association with amygdala reactivity. ↓ Subgenual cingulate cortex activation in response to fearful faces. |
(O’Nions et al. 2011) | ||||
| sMRI | Amygdala volume | S’-carriers vs. L’L’ | 54 HC (41.6) | ↓ Amygdala volume Path analysis suggests effects on left amygdala volume are mediated by right amygdala volume but not through (midbrain) 5-HTT availability. |
(Kobiella et al. 2011) | ||
| PET | 5-HTT availability | No genotype effect on (midbrain) 5-HTT availability. | |||||
| fMRI | Amygdala activation | ↑ Left amygdala activation in response to emotional stimuli. | |||||
| S’S’ vs. L’L | 67 HC (18.6) | ↑ Left amygdala reactivity in multivariate analysis; additive effects of recent SLEs. | (Walsh et al. 2012) | ||||
| S’S’ vs. L’-carriers, interaction with SLEs | 44 HC (26.8) ‡ | ↑ Bilateral amygdala activation in response to fearful faces. Interaction with SLEs: highest activity in S’S with SLEs for fearful faces in bilateral amygdala. |
(Alexander et al. 2012) | ||||
| rs-fMRI | S’S’ vs. L’-carriers | 48 HC (14.8) | ↓ Connectivity between right amygdala and ventromedial PFC with age. | (Wiggins et al. 2014) | |||
| fMRI | ↑ Amygdala activation with age (age range 9-19 years) | ||||||
| S’-carriers vs. L’L’ (bright-light intervention) | 30 HC (24.3)‡ | Bright-light dose positively associated with intra-prefrontal (medial PFC coupling with medial PFC seed) functional coupling only in S’-carriers. | (Fisher et al. 2014) | ||||
| 5-HTTLPR | fMRI | Perceptual task of threatening stimuli | S-carriers vs. LL | 14 HC phobic-prone (32.7) 14 HC eating disorders prone (34.3) |
S-carriers: ↑ activity in right amygdala | (Bertolino et al. 2005) | |
| fMRI | Emotional face task with approach-avoidance | S-carriers vs. LL | 48 HC (22.5) ‡ | ↑ Amygdala activity originating from reduced prefrontal inhibitory regulation. | (Volman et al. 2013) | ||
| Emotional face-emotional word conflict task | S-carriers vs. LL | 26 HC (70.5) | ↓ Connectivity between dorsal ACC and pregenual ACC for incongruent face-word combination. | (Waring et al. 2014) | |||
| 5-HTTLPR, rs25531 | fMRI | Emotional face task with self-referential and emotion labeling conditions | S-carriers vs. LL, SLE interaction | 45 HC (23.3) | ↑ Amygdala activation and ↓ FC of amygdala with subgenual ACC in self-referential processing vs. emotion labeling. Negative correlation of bilateral amygdala activation during self-referential with SLEs in S-carriers; positive correlation in LL; pattern opposite during emotion labeling. |
(Lemogne et al. 2011) | |
| Emotional face- word conflict task (Stroop-like task) | S’-carriers vs. L’L’ | 42 HC (∼20) | ↓ Recruitment of prefrontal control regions and superior temporal sulcus during conflict when task-irrelevant information was positively-valenced. ↑ Recruitment of these regions during conflict when task-irrelevant information was negatively-valenced. |
(Stollstorff et al. 2013) | |||
| 5-HTTLPR | fMRI | Pain rating task | LL vs. SS | 50 HC (24.9) † | ↑ Positive linear effect of target pain in posterior cerebellum. | (Laursen et al. 2014) | |
| (un)predictable electric shocks | SS vs. L-carriers | 51 HC (22) † | ↑ Activity of amygdala, hippocampus, anterior insula, thalamus, pulvinar, CN, precuneus, ACC, and mPFC during threat anticipation. ↑ Positive coupling between mPFC activation and anxiety experience; L-carriers show ↑ negative coupling between insula and success of regulating anxiety. |
(Drabant et al. 2012) | |||
| S- carriers vs. LL | 99 HC (21.9)‡ 69 HC (33.4) |
S-carriers: ↑ dorsomedial PFC, anterior insula, bed nucleus of stria terminalis, thalamus and midbrain activation with increasing threat conditions across both samples. | (Klumpers et al. 2014) | ||||
| 5-HTTLPR, rs25531 | fMRI | Modified Flanker task | S’-carriers vs. L’L’ | 33 HC (23.4) | ↑ Error-related rostral ACC activation. ↓ Conflict-related dorsal ACC activation. |
(Holmes et al. 2010) | |
| Decision making task | S’S’ vs. L’L’ | 30 HC (26.6) | ↑ Amygdala activation during decisions made counter to, relative to decisions made in accord with, the frame effect (gain or loss). Anterior cingulate-amygdala coupling during choices to made in counter to, relative to those made in accord with, the frame effect only observed in L’L’. |
(Roiser et al. 2009) | |||
| n-back task | S’S’ vs. S’L’ vs. L’L’ | 33 HC (37) † | ↑ Bilateral prefrontal activation in right and left IFG pars triangularis with increasing S-allele count. | (Jonassen et al. 2012) | |||
| 5-HTTLPR | fMRI | Source memory task | S-carriers vs. LL | 23 HC (66.8) [17 (23.3), not analyzed for genotype effects in fMRI] | ↓ Activity in left IFG, middle frontal gyrus and anterior paracingulate cortex. | (Pacheco et al. 2012) | |
| Food / non-food pictures | LL vs. S-carriers | 28 HC (25.5) | ↑ Left posterior cingulate cortex activity for food pictures. | (Kaurijoki et al. 2008) | |||
| 5-HTTLPR, rs25531 | fMRI | Differential fear conditioning | S’S’ vs. L’-carriers | 47 HC (26.8) ‡ | ↑ Activity in fear network: amygdala (right), insula, thalamus (left) and occipital cortex for conditioned stimulus. Interaction with SLEs: ↑ activity in right insula and left occipital cortex in S’S’. |
(Klucken et al. 2013) | |
ACC = anterior cingulated cortex, ADHD = attention-deficit/hyperactivity disorder, BCCD = Bayesian Constraint-based Causal Discovery, BI = Behavioral Inhibition, BMI = Body mass index, BOLD = blood oxygen level–dependent, BPD = bipolar disorder, CA = childhood adversity, CBF = cerebral blood flow, CN = caudate nucleus, FC = functional connectivity, fMRI = functional magnetic resonance imaging, GM = gray matter, HC = healthy control, IC = Incompatibility Task, IFG = inferior frontal gyrus, MD = mean diffusivity, MID task = monetary incentive delay task, MPH = methylphenidate, OFC = orbitofrontal cortex, PET = positron emission tomography, PFC = prefrontal cortex, RCZ = rostral cingulate zone, rsFC = resting-state functional connectivity, SLE = stressful life events, SMA = supplementary motor area, sMRI = structural magnetic resonance imaging, TBV = total brain volume, TT = Time Discrimination Task, VBM = voxel-based morphometry, VS = ventral striatum, WM = white matter
†
only females
‡
only males
§
Asian sample
S’= functional S-allele (S or LG), L’= functional L’-allele (LA); in gray case-control studies