Distinct neural signatures detected for ADHD subtypes after controlling for micro-movements in resting state functional connectivity MRI data

The quote only partly states this claim.

With mean FD as a covariate (Procedure 5), the ability to make age predictions rose slightly from the original estimate (Procedure 1) to R2 = 0.39.

“Interestingly, while the short-long range effect was reduced, the ability to make age predictions in the data rose slightly from the original estimate (i.e. Procedure 1) with the movement correction procedures (R2 = 0.39).”

• AssumptionThe authors state this as an assumption: Movement affects the BOLD signal similarly for any age group.

May combine two claims.

Node strength analysis for Procedures 5, 8, and 10 reveals a distributed pattern of connectivity predictive of age, with several subcortical structures highly predictive; connections that get stronger with age are within networks, and those that get weaker are between networks.

“The figure shows a distributed pattern of connectivity with several subcortical structures being highly predictive. Connections that tended to get stronger with age appeared to be within networks, and connections that got weaker with age were between networks.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Findings for Procedure 8 were consistent across individual sites.

“[Note: findings were consistent across individual sites (Figure A2)].”

May combine two claims.

Adding frame-to-frame displacement (FDi) or frame-to-frame 6 motion parameters as covariates in partial correlation estimates only modestly alters the distinction between short- and long-range connections' relationships with age, while maintaining age prediction ability.

“As can be observed in Figures A1 and 4, the distinction between short- and long-range connections in terms of their relationships with age was only modestly altered by these additional correction procedures, while the ability to make age predictions was maintained.”

May combine two claims.

In simulation, the distance between original and simulated correlation matrices is low when few frames are removed, but the tight relationship degrades as the fraction of frames removed approaches 1.

“As can be seen, the distance is low when few frames are removed; however, the tight relationship degrades as the fraction of frames removed approaches 1.”

• AssumptionRests on an assumption: The correlation matrix calculated from subjects with little to no movement represents the true correlation structure.

May combine two claims.

Combining volume censoring with mean FD matching (Procedure 8) reduces short- and long-range relationships but shows a slight decline in age classification ability (R2 = 0.34).

“This combined method also reduces the short- and long-range relationships (Figures 2 and 4), but shows a slight decline in the ability to make age classifications in individuals (R2 = 0.34).”

May combine two claims.

Volume censoring with FDi > 0.2 mm (Procedure 7) reduces but does not completely remove the distinction between short- and long-range connectivity in their relationships with age.

“While age-relationships were not completely removed, we once again see a reduction in the distinction noted between short- and long-range connectivity (Figures 2 and 4).”

The quote only partly states this claim.

With subject matching based on mean FDi (Procedure 6), the ability to make age predictions increased to R2 = 0.42.

“The ability to make age predictions increased (R2 = 0.42) (Figure 3).”

May combine two claims.

In typically developing children, functional connections that become stronger with increasing age tend to link distant regions (long-range), while connections that become weaker with age are primarily between proximal regions (short-range).

“we found that connections that became stronger with increasing age, or “grew-up,” tended to link distant regions (i.e., long-range connections). Connections that became weaker with increasing age, or “grew-down,” were primarily found between proximal regions (i.e., short-range connections) (see Figures 2 and 4; p < 0.0001).”

May combine two claims.

With r-value correction using polynomial regression (Procedure 10), short- and long-range distinctions in age relationships were significantly reduced, while age prediction ability remained (R2 = 0.40).

“As with the other procedures, the short- and long-range distinctions in terms of age were significantly reduced, yet the ability to make age predictions remained (R2 = 0.40; Figure 3).”

May combine two claims.

There is a positive but non-linear relationship between frame-to-frame motion parameters (FD) and changes in the whole brain BOLD signal.

“while the relationship of frame-to-frame motion parameters (i.e., FD) and changes in the whole brain signal is positive, there is still a non-linear relationship (Figure 1B).”

May combine two claims. The quote only partly states this claim.

In typically developing children, SVR-based MVPA using rs-fcMRI provides robust age predictions, with Von Bertalanffy's growth curve model fitting brain maturity (R2 = 0.36).

“We also saw robust age-predictions for the TDC group. Von Bertalanffy's growth curve model ([a•(1 − e−bx)]) provided a significant fit for predicting brain maturity (Figure 3A) (R2 = 0.36).”

May combine two claims.

The effect of FD on DVARS is similar across all ages (no strongly discernible relationship between movement effect on BOLD and age).

“Because there appears to be no strongly discernible relationships between the effect of movement on the BOLD signal and age (i.e., the effect of FD on DVARS is similar for all ages—Figure 5)”

May combine two claims.

Regional brain contributions associated with age or ADHD status were not equally distributed throughout the cortex, with some regions having many connections that strongly correlated with age or differentiated TDC from ADHD subjects and others having few or none.

“Regional brain contributions associated with age or ADHD status were not equally distributed throughout the cortex.”

• Also stated in: § Visualizing regional brain contributions · plain

  “Some regions had many connections that strongly correlated with age (or differentiated TDC from ADHD subjects), while others had few or none.”

May combine two claims.

Nodes most strongly differentiating ADHD-C from TDC were distributed across the cortex, most prominent in medial prefrontal and posterior parietal nodes of the default network, with other atypical regions in sensorimotor, visual, and cingulo-opercular systems.

“Nodes most strongly differentiating ADHD-C and TDC were distributed across the cortex (Figure 8), but were most prominent in the medial prefrontal and posterior parietal nodes of the default network. Other atypical regions included nodes of the sensorimotor, visual, and cingulo-opercular systems.”

May combine two claims.

Many developmental principles identified previously are still present even after stringent motion correction, while others are not.

“Similar to a recent report (Satterthwaite et al., 2012), our findings show that many of the developmental principles identified previously are still present even after stringent motion correction, while others are not.”

• cites Satterthwaite et al., 2012Not checked yet

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May combine two claims.

Network configuration appears similar to that of adults, even in younger ages, though not identical.

“Network configuration, while not identical, appears to be similar to that of adults, even in our younger ages, as shown in Figure A7 and in Power et al. (2012a).”

• cites Power et al. (2012a)Not checked yet

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May combine two claims.

Age-related growth curves were improved with several motion correction procedures, with the strongest age-related effects when using DVARS and matching as the surrogate measure for frame removal.

“Age-related growth curves were improved with several of the motion correction procedures, with the strongest age-related effects occurring when using DVARS and matching as the surrogate measure for frame removal (Figure 3).”

May combine two claims.

For ADHD-I, consensus features were largely distributed across systems including prominent sensorimotor features, similar to ADHD-C, but the patterns between subtypes were distinct.

“Findings with regard to consensus features and ADHD-I were similar to those of ADHD-C in that they were largely distributed across systems including prominent features in the sensorimotor systems; however, the patterns between the subtypes were also quite distinct.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Procedures 8 and 10 revealed largely consistent findings with regard to overall patterns (Figure A4).

“As can be seen in Figure A4, procedures 8 and 10 revealed largely consistent findings with regard to overall patterns.”

May combine two claims.

Findings for both ADHD subtypes were relatively distributed, with each affecting only a subset of regions in any one network.

“Findings for both subtypes were relatively distributed, with each affecting only a subset of regions in any one network.”

May combine two claims.

Simulations suggest that correlation structure can be altered with frame removal, but the concern appears largest only after significant portions of frames are removed.

“Our simulations suggest that the correlation structure can be altered with frame removal; however, the concern appears to be largest only after significant portions of the frames are removed.”

• AssumptionRests on an assumption: The correlation matrix calculated from subjects with little to no movement represents the true correlation structure.

May combine two claims.

While both subtypes revealed largely distributed atypical connectivity, findings for ADHD-C were more prominent in the default network.

“While both subtypes revealed largely distributed atypical connectivity, findings for the ADHD-C were more prominent in the default network.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Age-related predictions are still possible and were even improved with motion correction procedures.

“For example, age-related predictions are still possible and were even improved with motion correction procedures (Dosenbach et al., 2010).”

• cites Dosenbach et al., 2010Not checked yet

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Both populations showed atypical nodes in primary sensorimotor systems, supporting previous work implicating this system in ADHD.

“Both populations showed atypical nodes in primary sensorimotor systems, supporting previous work implicating this system in ADHD (Mostofsky et al., 2006).”

• cites Mostofsky et al., 2006Not checked yet

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May combine two claims.

Despite potential differences across centers, there are brain features related to the presence of ADHD and ADHD subtype that are robust to this variation.

“Our findings suggest that despite potential differences across centers, there are brain features related to the presence of ADHD and ADHD subtype that are robust to this variation.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Abrupt head displacement typically manifests as signal loss in echo-planar imaging.

“This measure is based on the fact that abrupt head displacement typically manifests as signal loss in echo-planar imaging (Smyser et al., 2010).”

• cites Smyser et al., 2010Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The modules used to categorize regions had a high quality index (Q) and were the most resistant to perturbation by randomization, measured by variation of information (VOI).

“The modules (i.e., communities) used to categorize regions had a high quality index (Q) and were the most resistant to perturbation by randomization, measured by variation of information (VOI) (Karrer et al., 2008).”

• cites Karrer et al., 2008Not checked yet

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Classified as probably not a substantial claim.

These preprocessing steps are thought to reduce spurious variance unlikely to reflect neuronal activity.

“These preprocessing steps are thought to reduce spurious variance unlikely to reflect neuronal activity (Fox and Raichle, 2007).”

• cites Fox and Raichle, 2007Not checked yet

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May combine two claims.

Motion can artificially produce or obscure ADHD-related differences in rs-fcMRI metrics.

“As a prototypical hyperkinetic disorder, ADHD presents exceptional challenges for fMRI-based research, due to importance of addressing the increased prevalence of motion in this population, which can artificially produce or obscure ADHD-related differences in rs-fcMRI metrics (Power et al., 2012a; Satterthwaite et al., 2012; Van Dijk et al., 2012).”

• cites Power et al., 2012aNot checked yet

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• cites Satterthwaite et al., 2012Not checked yet

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• cites Van Dijk et al., 2012Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

rs-fcMRI results are remarkably reliable across imaging centers.

“and rs-fcMRI results are remarkably reliable across imaging centers (Biswal et al., 2010).”

• cites Biswal et al., 2010Not checked yet

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Classified as probably not a substantial claim.

Subsample size was matched to avoid biasing the classifier group.

“To avoid biasing our classifier group, subsample size was matched (see Table 3).”

Probably not a substantial claim: may not pass S3 (load-bearing).

rs-fcMRI yields consistent results across subjects, scans, and days.

“it yields consistent results across subjects, scans, and days (van de Ven et al., 2004; Damoiseaux et al., 2006; Shehzad et al., 2009; Van Dijk et al., 2010),”

• cites van de Ven et al., 2004Not checked yet

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• cites Damoiseaux et al., 2006Not checked yet

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• cites Shehzad et al., 2009Not checked yet

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May combine two claims.

Replacing traditional movement parameters with frame-to-frame motion parameters in linear regression preprocessing will assist but likely not fully account for movement artifact.

“These data suggest that simply replacing traditional movement parameters with frame-to-frame motion parameters in traditional preprocessing steps (i.e., linear regression) will assist, but likely not fully account for potential movement artifact.”

May combine two claims.

The continued association between age and mean FD after volume censoring is likely due to a small increase in movement in younger subjects for remaining frames and a small relationship between DVARS and FD even under the 0.2 mm cutoff.

“This observation is likely due to a small increase in movement in younger subjects for the remaining frames and what can be observed as a small relationship of frame-to-frame changes in BOLD (i.e., DVARS) and FD even under this 0.2 mm cutoff (Figure 1).”

Classified as probably not a substantial claim.

Spontaneous neural activity is associated with correlated low-frequency (<~0.1 Hz) BOLD signal fluctuations in functionally related brain regions at rest.

“rs-fcMRI is based on the discovery that spontaneous neural activity (Biswal et al., 1995; Leopold et al., 2003; Nir et al., 2006; Scholvinck et al., 2010) is associated with correlated low-frequency (<~0.1 Hz) blood oxygen level-dependent (BOLD) signal fluctuations in functionally related brain regions at rest (Biswal et al., 1995).”

• cites Biswal et al., 1995Not checked yet

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• cites Leopold et al., 2003Not checked yet

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• cites Nir et al., 2006Not checked yet

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Classified as probably not a substantial claim.

Frame-to-frame changes in signal intensity related to movement are significantly greater than those caused by neurophysiologic changes in the BOLD signal.

“Because frame-to-frame changes in signal intensity related to movement are significantly greater than those caused by neurophysiologic changes in the BOLD signal, this measure provides a natural parameter with which to directly examine the relationship of movement measurements and the BOLD response (Smyser et al., 2010).”

• cites Smyser et al., 2010Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

rs-fcMRI can be used during sleep as well as during sedation.

“Importantly, rs-fcMRI can be used during sleep as well as during sedation (Fukunaga et al., 2006, 2008; Vincent et al., 2007; Greicius, 2008; Horovitz et al., 2008);”

• cites Fukunaga et al., 2006, 2008Not checked yet

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• cites Vincent et al., 2007Not checked yet

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• cites Greicius, 2008Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

As data for this investigation were aggregated retrospectively, slightly different ADHD assessment protocols were used across institutions.

“As data for this investigation were aggregated retrospectively (as a large collaborative effort), slightly different ADHD assessment protocols were used across institutions.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The large sample size in this study afforded the ability to examine conservative motion correction approaches, but other samples may not support the same opportunity.

“The large sample size here afforded us the ability to examine these conservative approaches, but other samples may not support the same opportunity.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

These approaches perform respectably for reducing artifact induced by changes in head position, but more robust procedures are likely to emerge.

“It should be emphasized, however, that while these approaches appear to perform respectably for reducing artifact induced by changes in head position, work in this area is currently ongoing and even more robust procedures are likely to emerge.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Recent theories suggest the default network is associated with remembering the past, as well as planning for, and anticipating future events.

“Recent theories suggest the default network is associated with remembering the past, as well as planning for, and anticipating future events (Buckner and Carroll, 2007; Buckner et al., 2008).”

• cites Buckner and Carroll, 2007Not checked yet

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• cites Buckner et al., 2008Not checked yet

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Classified as probably not a substantial claim.

The fronto-parietal network is believed to be an important system for task level control.

“The fronto-parietal network is believed to be an important system for task level control (Dosenbach et al., 2008).”

• cites Dosenbach et al., 2008Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Children with ADHD show increased variability during performance of simple motor skills and during motor adaptation.

“Furthermore, in parallel with numerous recent studies showing ADHD-associated increases in intrasubject response time variability (Castellanos et al., 2005; Vaurio et al., 2009; Epstein et al., 2011), children with ADHD show increased variability during performance of simple motor skills and during motor adaptation (Izawa et al., 2012).”

• cites Izawa et al., 2012Not checked yet

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Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

Our findings demonstrate the potential utility of functional MRI approaches in characterizing clinical heterogeneity in ADHD, which should be similarly useful with other psychiatric disorders.

“In summary, our findings demonstrate the potential utility of functional MRI approaches in characterizing clinical heterogeneity in ADHD, which should be similarly useful with other psychiatric disorders.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Lower SICI is robustly correlated with parent ratings of more severe hyperactive/impulsive and inattentive behavior.

“To that end, recent studies of motor cortex physiology using Transcranial Magnetic Stimulation (TMS) reveal that subjects with ADHD show reduced Short Interval Cortical Inhibition (SICI) and that lower SICI is robustly correlated with parent ratings of more severe hyperactive/impulsive and inattentive behavior (Gilbert et al., 2006).”

• cites Gilbert et al., 2006Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Studies of gray matter thickness and connectivity measurements have shown that many of the same regions correspond to various forms of impulsivity measures.

“Studies of gray matter thickness (Shaw et al., 2007) and connectivity measurements (Shannon et al., 2011) have shown that many of these same regions correspond to various forms of impulsivity measures, supporting this claim.”

• cites Shaw et al., 2007Not checked yet

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• cites Shannon et al., 2011Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

While significant changes occur throughout development, the general network structure appears intact at early ages.

“Thus, while significant changes do occur throughout development, the general network structure appears to be intact at early ages.”

May combine two claims.

Changes in short- and long-range connectivity remain but are significantly reduced after motion correction procedures, indicating that the distance between connections that get weaker with age and those that get stronger overlap more than previously appreciated.

“However, while the changes in short- and long-range connectivity appear to remain, this phenomena is significantly reduced after motion correction procedures (and becomes only weakly significant for some procedures)—highlighting that the distance between those connections that get weaker with age and those that get stronger overlap more than was previously appreciated.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Recent studies of motor cortex physiology using TMS reveal that subjects with ADHD show reduced Short Interval Cortical Inhibition (SICI).

“To that end, recent studies of motor cortex physiology using Transcranial Magnetic Stimulation (TMS) reveal that subjects with ADHD show reduced Short Interval Cortical Inhibition (SICI) and that lower SICI is robustly correlated with parent ratings of more severe hyperactive/impulsive and inattentive behavior (Gilbert et al., 2006).”

• cites Gilbert et al., 2006Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Impairments in incentive salience, motivation, and reward processing are increasingly appreciated in ADHD.

“In particular, impairments in incentive salience, motivation, and reward processing are increasingly appreciated in ADHD.”

• cites Sagvolden et al., 2005Not checked yet

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• cites Musser et al., 2011Not checked yet

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• cites Nigg and Casey (2005)Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Children with ADHD often demonstrate difficulties with motor control, paralleling difficulties with higher-order executive control.

“Children with ADHD often demonstrate difficulties with motor control, paralleling difficulties with higher-order executive control (Pennington and Ozonoff, 1996; Mostofsky et al., 2003).”

• cites Pennington and Ozonoff, 1996Not checked yet

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• cites Mostofsky et al., 2003Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

These findings for ADHD-C are consistent with a growing body of studies implicating the default network in ADHD.

“These findings for ADHD-C are consistent with a growing body of studies implicating the default network in ADHD (Castellanos et al., 2008; Fassbender et al., 2009; Fair et al., 2010)”

• cites Castellanos et al., 2008Not checked yet

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• cites Fassbender et al., 2009Not checked yet

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• cites Fair et al., 2010Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

A consistent characteristic of children with ADHD is that they fail to meet age-norms on timed repetitive and sequential movements and manifest a greater amount of motor overflow than age-matched controls.

“A consistent characteristic of children with ADHD is that they fail to meet age-norms on timed repetitive and sequential movements and manifest a greater amount of motor overflow than age-matched controls (Denckla and Rudel, 1978; Mostofsky et al., 2003).”

• cites Denckla and Rudel, 1978Not checked yet

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• cites Mostofsky et al., 2003Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Both overflow and variability in motor execution have been found to be related to ADHD-associated impairments at the behavioral level.

“Both overflow and variability in motor execution have been found to be related to ADHD-associated impairments at the behavioral level (Mostofsky et al., 2003).”

• cites Mostofsky et al., 2003Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The dorsolateral prefrontal and cerebellar nodes have been empirically linked to fronto-parietal systems by community detection methods.

“These particular nodes (see Figure A6) have been empirically linked with community detection methods to fronto-parietal systems (black/yellow) (Dosenbach et al., 2010)”

• cites Dosenbach et al., 2010Not checked yet

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Probably not a substantial claim: may not pass S2 (checkable).

These data highlight the need to take careful consideration of movement-related artifact in all connectivity studies, particularly during classification of clinical samples.

“Most importantly, however, these data in aggregate highlight the need to take careful consideration of movement related artifact in all connectivity studies, particularly during classification of clinical samples as noted below.”

May combine two claims.

Procedure 10 cannot completely resolve the issues of frame removal; it still relies on a valid estimate of the correlation structure after removing frames and requires participant removal when a high degree of motion is present.

“The results were promising, but the method is not able to completely resolve the issues noted by frame removal. The method still relies on a valid estimate of the correlation structure after removing frames, and thus still requires participant removal when a high degree of motion is present.”

May combine two claims.

Several motion correction methods appeared relatively robust at controlling for motion artifact in the BOLD signal, and all reduced the distinction between short- and long-range connections in their relationships with age.

“we found several methods that appeared relatively robust at controlling for motion artifact in the BOLD signal. All of these additional approaches reduced the distinction between short- and long-range connections in terms of their relationships with age.”

May combine two claims.

Frame-to-frame measurements (FD) also share a non-linear relationship with the BOLD signal, so simple linear regression of these measurements provides only limited improvement for motion artifacts.

“while frame-to-frame measurements (i.e., FD), appear to be superior with relation to the assumption of linearity, they too share a non-linear relationship with the BOLD signal. Thus, simple linear regression of these measurements from the BOLD signal also provides only limited improvement with regard to motion artifacts (Figure 4).”

May combine two claims.

Frame removal approaches reduce sample size due to matching or effectively removing subjects, thus reducing statistical power.

“In particular, the approaches reduce sample size due to “matching” (i.e., subject exclusion) or, effectively removing subjects due to the high percentage of frames removed. Thus, statistical power is reduced.”

Probably not a substantial claim: may not pass S3 (load-bearing).

This work does not consider the possibility that the differences noted here could be unique to the effort required to remain still in the ADHD population.

“Last, we mention that this work does not consider the possibility that the differences noted here could be unique to the effort required to remain still in the ADHD population.”

May combine two claims.

These results suggest that ADHD-I has distributed atypical connectivity, with prominent findings in control systems, which may underlie the prominent inattentive symptoms in this population.

“Taken together, these results suggest that ADHD-I has distributed atypical connectivity, with prominent findings in control systems, which may underlie the prominent inattentive symptoms in this population.”

• AssumptionRests on an assumption: ADHD-I subtype symptoms are predominantly those of inattention.

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

While the study's movement correction procedures were carefully considered, there is still room for improvement in controlling for the movement confound.

“Notably, while our movement correction procedures were carefully considered, there is still room for improvement in controlling for this confound.”

May combine two claims.

ADHD-C also shows distributed atypical connectivity, with prominent findings in systems such as the default network, which may mark for an inability to exert top-down attentional control-perhaps in the context of an inability to integrate contextual information supported by default mode processing.

“ADHD-C also shows distributed atypical connectivity, with prominent findings in systems such as the default network, which may mark for an inability to exert top-down attentional control—perhaps in the context of an inability to integrate contextual information supported by default mode processing.”

May combine two claims.

These findings point to potential distinct connectivity patterns underlying ADHD subtypes, but also emphasize the vast heterogeneity in these populations.

“These findings point to potential distinct connectivity patterns underlying ADHD subtypes, but also emphasizes the vast heterogeneity in these populations, which will need to be considered in future clinical investigations of ADHD.”

May combine two claims.

The findings presented here highlight the translational potential of rs-fcMRI for developmental neuropsychiatric disorders in general by demonstrating the ability of SVM-based MVPA to classify individuals with the disorder using rs-fcMRI.

“Beyond a simple characterization of the neural signatures of ADHD subtypes, the findings presented here highlight the translational potential of rs-fcMRI for developmental neuropsychiatric disorders in general by demonstrating the ability of SVM-based MVPA to classify individuals with the disorder using the rs-fcMRI.”