Table 4.
Details of neuroimaging studies of candidate monitoring/response biomarkers.
| Authors, year | Country | N ADHD | N Controls | Age | % Male | % White | Design | Candidate biomarker(s) | Key findings |
|---|---|---|---|---|---|---|---|---|---|
| Alegria et al. [28] | UK | 31 (24 receiving stable medication) | 0 | M = 13.90 SD = 1.58 | 100% | Not reported | 2-week real-time fMRI neurofeedback of the right IFG vs. a control para-hippocampal region. Single-blind RCT. | Neurofeedback transfer effect (IFG upregulation in the absence of feedback) and brain activation during inhibitory control task | Improvements in ADHD symptoms over 2 weeks were observed in both groups, but only the active IFG-neurofeedback group showed transfer effects (increased IFG activation during transfer session), which correlated with clinical improvements assessed using the CPRS‐R ADHD index scale. |
| An et al. [25] | China | 23 (medication free for >1 month) | 32 | M = 12.09 SD = 1.8 | 100% | Not reported | Single-blind, counter balanced cross-over, placebo-controlled RCT, comparing MPH to placebo | ReHo |
MPH decreased ReHo in the right lingual gyrus and right postcentral gyrus, and increased ReHo in left IFG and right orbitofrontal cortex. ReHo decreases in the right postcentral gyrus and superior parietal lobe following a single dose of MPH were negatively associated with changes in ADHD symptoms at the 8th week, as assessed using the ADHD RS-IV (examined in a subgroup of N = 7 with follow-up symptom data). |
| Criaud et al. [30] | UK | 31 (24 receiving stable medication) | 0 | M = 13.90 SD = 1.58 | 100% | Not reported | 2-week real-time fMRI neurofeedback of the right IFG vs. a control para-hippocampal region. Single-blind RCT | Changes in brain activation during error-monitoring associated with right IFC and control neurofeedback | Increases in left insula/IFG/putamen activation during error trials was associated with improvements in ADHD symptoms assessed using the ADHD-RS-IV in the right IFG feedback group. |
| Cubillo et al. [152] | UK | 20 (all medication naïve) | 20 | Range = 10–17 years old | 100% | Not reported | Double-blind, placebo-controlled, crossover RCT comparing single-dose MPH, ATX, and placebo | Task-related brain activation, assessed on and off single doses of MPH and ATX | In the working memory task, drugs increased fronto-temporo-striatal activation and deactivated the default-mode network. However, ATX alone increased and normalized right DLPFC activation, while MPH upregulated left IFG activation. |
| Cubillo et al. [152] | UK | 19 (all medication naïve) | 29 | Range = 10–17 years old | 100% | Not reported | Double-blind, placebo-controlled, crossover RCT comparing single-dose MPH, ATX, and placebo | Task-related brain activation, assessed on and off single doses of MPH and ATX. | During the stop task, both drugs significantly normalized left IFG underactivation observed under placebo. MPH also upregulated and normalized activation in right IFG. |
| Kowalczyk et al. [75] | UK | 14 (all medication naïve) | :27 | Range = 10–17 years old | 100% | Not reported | Double-blind, placebo-controlled, crossover RCT comparing single-dose MPH, ATX, and placebo | Task-related brain activation, assessed on and off single doses of MPH and ATX | During sustained attention, both drugs enhanced activation of right middle/superior temporal cortex, PCC, and precuneus relative to placebo. Only MPH upregulated left IFG/superior temporal lobe activation. |
| Liddle et al. [78] | UK | 18 (all undergoing MPH treatment) | 18 | Not reported (9- to 15-year-old range) | Not reported | Not reported | Non-blinded study of chronically medicated MPH responders with ADHD, in which subjects were scanned on and off MPH | Default mode deactivation on and off MPH, assessed during a go/no-go task | MPH normalized default mode deactivation relative to controls. |
| Lin and Gau [87] | Taiwan | 24 (all medication naïve) | 24 | M = 30.32 SD = 9.05 | 46% | Not reported | 8-week double-blind randomized controlled trial comparing ATX against placebo | Changes in resting-state connectivity of key nodes of default mode, affective, dorsal attention, ventral attention, and cognitive control networks | ATX-related improvements in ADHD symptoms were related to pre- to post-treatment changes in functional connectivity, predominantly involving inferior frontal and temporo-parietal regions. |
| Mizuno et al. [83] | Japan | 27 (all medication-free for >5 times medication half-lives) | 49 | M = 10.96, SD = 2.14 | 100% | Not reported | Double-blind, placebo-controlled, crossover RCT comparing single-dose MPH, and placebo | Dynamic resting-state functional connectivity | Abnormalities in time-varying connectivity observed under placebo were remediated by MPH. |
| Peterson et al. [21] | USA | 16 (all MPH responders) | 20 | M = 13.71 SD = 2.85 | 69% | 94% | Non-blinded study of chronically medicated psychostimulant responders with ADHD, in which subject were scanned on and off MPH | Brain activation was assessed during a stop task both on and off medication | MPH improved deactivation of default mode network in the ADHD group during the stop task. |
| Rubia et al. [76] | UK | 12 (all medication naïve) | 12 | M = 13, SD = 1 | 100% | Not reported | Double-blind, placebo-controlled, crossover RCT comparing single-dose MPH, and placebo | Task-related brain activation, assessed on and off single doses of MPH | During time discrimination, left IFG/insula and dACC were upregulated by MPH. |
| Rubia et al. [72] | UK | 13 (all medication naïve) | 13 | M = 12.79 SD = 1.5 | 100% | Not reported | Double-blind, placebo-controlled, crossover RCT comparing single-dose MPH, and placebo | Task-related brain activation, assessed on and off single doses of MPH | MPH upregulated right IFG during sustained attention and vmPFC and caudate during rewarded processing. |
| Rubia et al. [77] | UK | 12 (all medication naïve) | 13 | M = 13, SD = 1 | 100% | Not reported | Double-blind, placebo-controlled, crossover RCT comparing single-dose MPH, and placebo | Task-related brain activation, assessed on and off single doses of MPH | MPH upregulated right IFG and premotor cortices during the Simon task. |
| Rubia et al. [153] | UK | 12 (all medication naïve) | 13 | M = 13, SD = 1 | 100% | Not reported | Double-blind, placebo-controlled, crossover RCT comparing single-dose MPH and placebo | Task-related brain activation, assessed on and off single doses of MPH | During error trials on stop task, MPH upregulated bilateral IFG/insula/putamen/caudate and left DLPFC. |
| Rubia et al. [90] | UK | 31 (24 receiving stable medication) | 0 | M = 13.90 SD = 1.58 | 100% | Not reported | 2-week real-time fMRI neurofeedback of the right IFG vs. a control para-hippocampal region. Single-blind RCT. | Changes in functional connectivity assessed during transfer session | Changes in IFG connectivity were specific to the right IFG training group, and correlated with clinical improvements assessed using the CPRS‐R ADHD index scale. |
| Schrantee et al. [80] | Netherlands | 40 children + 48 adults (all medication naïve) | 0 | Children: 11.5 (0.8); adults: 28.6 (4.6) | 100% | Not reported | Subjects scanned before and after a single-dose of MPH | ASL | MPH was associated with reduction widespread cortical CBF reductions in children and adults. CBF reductions within the thalamus were observed only in children. |
| Shang et al. [88] | Taiwan | 38 (all medication naïve) | 0 | 10.5 (2.4) | 83% | Not reported | 12-week open-label RCT of MPH and ATX | fALFF | Pre- to post-treatment increases in fALFF in the left superior temporal gyrus and left inferior parietal lobule (MPH) and in the left lingual gyrus and left inferior occipital gyrus (ATX) were associated with changes in inattention symptoms. Changes in hyperactivity/impulsivity symptoms were associated with increases in fALFF in the MPH group but decreases in fALFF in the ATX group. |
| Schulz et al. [89] | USA | 36 (13 medication naïve, 8 medicated at enrollment prior to washout) | 0 | 11.2 2.71 | 83% | Not reported | 6 to 8-week MPH and ATX double-blind parallel groups RCT | Brain activation during go/no-go task | Improvement in ADHD symptoms under both drugs was associated with decreased bilateral motor cortex activation. Symptomatic improvement was also related to increased activation following treatment for ATX in right IFG, left ACC, and bilateral posterior cingulate cortex, but decreases in activation in the MPH group. |
| Silk et al. [79] | Australia | 16 (10 medication naïve, 6 withdrawn from meds for 48 hours) | 15 | M = 13.37 Range = 12.13 to 15.80 | 100% | Not reported | Double-blind cross-over RCT comparing single doses of MPH, and placebo | Whole-brain resting-state connectivity | MPH was associated with widespread decreases in functional connectivity involving occipital, temporal and subcortical regions. |
| Smith et al. [74] | UK | 20 (all medication naïve) | 20 | Range = 10–17 years old | 100% | Not reported | Double-blind, placebo-controlled, crossover RCT comparing single-dose MPH, ATX and placebo. | Task-related brain activation, assessed on and off single doses of MPH and ATX | Both medications, upregulated right IFG/insula activation during time discrimination. No differences were observed between drugs. |
| van Elst et al. [71] | Germany | 131 at baseline (98 had follow-up data) | 0 | M = 35.40, SD = 9.8 | 52% | 99% | 12-month placebo-controlled RCT of MPH versus placebo | Gray matter volume | MPH was not associated with any significant changes in gray matter volume. Non-significant trends were detected in the cerebellum, which showed increases over time in the MPH group only. |
| Wang et al. [82] | USA | 49 (all medication naïve or medication free for >4 months for children or 12 months for adults) | 46 | M = 13.52 SD = 5.51 | 62.1% | Not reported | 12-week, placebo-controlled RCT of LDEX versus placebo | Dynamic resting-state functional connectivity | LDEX increased static and decreased dynamic FC. However, decreases in dynamic functional connectivity were associated with the therapeutic effects of LDEX. |
| Yang et al. [85] | USA | 19 | 0 | 34.3 (9.3) | 68.75% | Not reported | 3-week RCT of amphetamine-based stimulant medications | Whole-brain resting-state connectivity | Reductions in connectivity between left DLPFC and bilateral ACC and right insula tracked treatment-related improvement in hyperactive/impulsive symptoms, while reductions in connectivity between bilateral medial frontal and left insula were associated with greater overall improvements in ADHD symptoms. |
| Yoo et al. [86] | South Korea | 20 (all medication-naïve) | 27 | 10.09 (2.5) | 74.47% | Not reported | 12-week MPH, open label | ALFF, fALFF, resting-state connectivity assessed using ICA dual regression and graph theory measures of resting-state connectivity | Changes in resting-state connectivity and ALFF could explain the 27.1% variance of symptom improvement measured by the K-ARS total score. The strongest predictor was ALFF within bilateral superior parietal lobe. |
ACC anterior cingulate cortex, ADHD attention deficit hyperactivity disorder, ADHD-RS-IV ADHD Rating Scale-IV, ALFF amplitude of low-frequency fluctuation, ASL Arterial spin labeling, ATX atomoxetine, CPRS-r Conners’ Parent Rating Scale-revised, dACC dorsal anterior cingulate cortex, DICA-IV Diagnostic Interview for Children and Adolescents – IV, DLPFC dorsolateral prefrontal cortex, fALFF fractional amplitude of low-frequency fluctuations, fMRI; functional magnetic resonance imaging, IFG inferior prefrontal gyrus; ICA independent component analysis, K-ARS Korean ADHD Rating Scale, LDEX lisdexamfetamine, MPH methylphenidate; MRI magnetic resonance imaging, PCC posterior cingulate cortex, RCT randomized controlled trial, ReHo regional homogeneity, vmPFC ventromedial prefrontal cortex.