RESEARCH: Data‐driven identification of subtypes of executive function across typical development, ADHD, and ASD (2020)

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POST SUMMARY
This study looks at the executive function (EF) and brain scans of ADHD, autistic, or neurotypical children between the ages of 8-17 to find EF subgroups. They have found three: those that struggled most with (1) flexibility & emotional regulation; (2) inhibitory control and impulsivity; and (3) working memory, organizing, and planning. All three groups of children were spread out over all three subtypes, and in the brain scans there were more differences within same diagnoses than there were within these cross-diagnostic EF subtypes. This is important because treatments such as stimulants, cognitive training, or cognitive behavioral therapy each differently target the three subtypes.

Data‐driven identification of subtypes of executive function across typical development, attention deficit hyperactivity disorder, and autism spectrum disorders (2020)

  • Vaidya, C.J., You, X., Mostofsky, S., Pereira, F., Berl, M.M. and Kenworthy, L., Journal of Child Psychology and Psychiatry
ABSTRACT

Background: Impairment of executive function (EF), the goal‐directed regulation of thoughts, actions, and emotions, drives negative outcomes and is common across neurodevelopmental disorders including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). A primary challenge to its amelioration is heterogeneity in symptom expression within and across disorders. Parsing this heterogeneity is necessary to attain diagnostic precision, a goal of the NIMH Research Domain Criteria Initiative. We aimed to identify transdiagnostic subtypes of EF that span the normal to impaired spectrum and establish their predictive and neurobiological validity.

Methods: Community detection was applied to clinical parent‐report measures in 8–14‐year‐old children with and without ADHD and ASD from two independent cohorts (discovery N = 320; replication N = 692) to identify subgroups with distinct behavioral profiles. Support vector machine (SVM) classification was used to predict subgroup membership of unseen cases. Preliminary neurobiological validation was obtained with existing functional magnetic resonance imaging (fMRI) data on a subsample (N = 84) by testing hypotheses about sensitivity of EF subgroups versus DSM categories.

Results: We observed three transdiagnostic EF subtypes characterized by behavioral profiles that were defined by relative weakness in: (a) flexibility and emotion regulation; (b) inhibition; and (c) working memory, organization, and planning. The same tripartite structure was also present in the typically developing children. SVM trained on the discovery sample and tested on the replication sample classified subgroup membership with 77.0% accuracy. Split‐half SVM classification on the combined sample (N = 1,012) yielded 88.9% accuracy (this SVM is available for public use). As hypothesized, frontal‐parietal engagement was better distinguished by EF subtype than DSM diagnosis and the subgroup characterized with inflexibility failed to modulate right IPL activation in response to increased executive demands.

Conclusions: The observed transdiagnostic subtypes refine current diagnostic nosology and augment clinical decision‐making for personalizing treatment of executive dysfunction in children.

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Article Highlights:

  • “Impairment of executive function (EF), the goal-directed regulation of thoughts, actions, and emotions, drives negative outcomes and is common across neurodevelopmental disorders…”
    • One of the main difficulties in figuring out how to help executive dysfunction (EDf) is that EDf varies so much, both within and across conditions
  • “We observed three trans-diagnostic EF subtypes characterized by behavioral profiles that were defined by relative weakness in:”
    • “(a) behavioral flexibility and emotion regulation (FLEX- EMOT);
    • (b) hyperactivity/impulsivity and inhibition (INHIBIT); and
    • (c) working memory, organizing, and planning (METACOG).”
  • Even the TD [typically developing/neurotypical] children fell into these three categories, suggesting that the link between these certain EFs are normal in children and that “disordered EF is nested within normal variability.”

ADHD & Autism

  • “A large proportion of autistic children meet criteria for ADHD (41%–78%…).”
    • “Furthermore, 1 in 5 children diagnosed with ASD have a pre-existing ADHD diagnosis”
  • “Comorbid ADHD exacerbates ASD social symptoms… and relates to worse:
    • adaptive function…
    • quality of life…
    • and intervention outcomes…”
  • “Furthermore, impairment is progressive, increasing from childhood to adolescence…
    • persistent, continuing despite amelioration of core ASD symptoms…
    • and drives negative outcomes…”

Participants:

  • Participants were two cohorts of mostly males (62.5% and 67.9%, respectively) between 8-17 years old with IQs > 70 and no medical diagnoses. Between the two groups there were 240 autistic, 307 ADHD, and 465 TD participants.

EF Subtypes across ADHD & ASD

  • The results showed that there are more similarities in the frontal-parietal recruitment of the brains of people in the same EF subtype, regardless of whether the brains belonged to someone who was TD, ASD, or ADHD, than there were between scans of people with the same diagnosis.
  • “EF profiles spanned the normal to impaired spectrum,” “manifested as dispositional traits at the normative end and psychopathology at the maladaptive end.”
    • The TD children were fairly evenly distributed among all three subgroups, however:
    • the FLEX-EMOT subgroup had more ASD participants
    • the INHIBIT subgroup had more ADHD participants.
  • These findings are important for getting people the appropriate treatment as “[m]any evidence- based treatments for EF in children with developmental disabilities target specific ‘subtypes’ of EF deficit, for example:
    • central stimulants are evidence- based for inhibition, working memory and attention deficits,
    • while the computer-based treatment Cogmed improves working memory specifically…
    • and the cognitive-behavioral treatment Unstuck and On Target improves flexibility…”

EF Subtypes & rethinking diagnostic criteria

  • The results showed the insufficiency of the current diagnostic criteria for ADHD in the DSM.
    • Because, while “INHIBIT maps to Hyperactivity/Impulsivity”
    • Different groups of children being tested had differing levels of inattention between the INHIBIT and METACOG groups,
      • suggesting that focusing on a patient’s level of inattention has “limited utility as a distinguishing feature.”
    • In addition, 19% of ADHD children were in the FLEX-EMOT group, which is not explained by the current DSM diagnostic criteria or subtypes,
      • “…community detection applied to temperamental traits in ADHD revealed segregation by positive and negative emotion regulation problems…which suggests that FLEX- EMOT profile may be further segregated upon deeper phenotyping.”
  • Importantly, among ASD children “only half of the samples in each cohort showed the FLEX-EMOT profile, which challenges the often held notion of cognitive inflexibility as the hallmark EF comorbidity in ASD”

Future Research:

  • “Further, deeper phenotyping would be helpful to parse the type of difficulties in regulating externalizing behaviors (e.g., rule-breaking vs. aggression) that are associated with disinhibition or inflexibility.”
  • “Future neuroimaging studies can identify the ‘signatures’ of activation and connectivity patterns that signify EF subtype, with AUC values [severity] serving as a continuous dimension to probe the EF profile spectrum.”
  • “Additionally, whether the observed tripartite structure is stable developmentally and generalizes beyond ADHD and ASD diagnoses and in a broader age range needs to be tested in future work,” as does establishing “the clinical importance of the observed tripartite structure by testing predictive validity for outcomes (e.g., treatment efficacy)”

CITATION

Vaidya, C.J., You, X., Mostofsky, S., Pereira, F., Berl, M.M. and Kenworthy, L. (2020), Data‐driven identification of subtypes of executive function across typical development, attention deficit hyperactivity disorder, and autism spectrum disorders. J Child Psychol Psychiatr, 61: 51-61. doi:10.1111/jcpp.13114

RESEARCH: Increasing Extrinsic Motivation Improves Time-Based Prospective Memory in Adults with Autism: Relations with Executive Functioning and Mentalizing (2019)

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POST SUMMARY
This article is about how “time-based prospective memory” (TBPM- which, when impaired, is often referred to as “time blindness” or “time numbness”) is at least in part reduced in autistics (and we here at EDRA think the same would go if ADHDers, and perhaps other folks with prioritization difficulty) due to not encoding tasks with the same level of importance that neurotypicals do. When explicitly instructed to prioritize the TBPM tasks, autistics’ performance increased significantly, almost matching those of the NT controls. So, this paper suggests that for some, impaired TBPM can improve by being explicitly told what time-related tasks should be prioritized.

“Time blindness” or “time numbness” is a common experience for many people with executive dysfunction, especially autistics and ADHDers. This paper adds to the amount of evidence supporting the role that the executive function of prioritization plays in our ability to manage our time efficiently, which will hopefully lead to more interventions to help folks improve these skills.

Increasing Extrinsic Motivation Improves Time-Based Prospective Memory in Adults with Autism: Relations with Executive Functioning and Mentalizing

  • 2019; Julia Landsiedel and David M. Williams; Journal of Autism and Developmental Disorders
ABSTRACT
Time-based prospective memory (PM) is diminished under various task demands in individuals with autism spectrum disorder (ASD). However, it is still unclear what underpins their impairment or how it could be remediated. This study explored whether instructions to prioritise one element of a PM task over another improved performance in adults with ASD (compared to a group of matched neurotypical adults), and how that is related to cognitive abilities. Results indicated that importance instructions significantly improved the PM performance of participants with ASD. Moreover, the extent of the benefit was associated significantly with objectively-measured executive set-shifting ability and self-reported inhibitory control ability (the poorer the set-shifting/inhibitory control, the greater the benefit). Implications for future research and clinical practice are discussed.
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Article Highlights:

  • Prospective memory (PM) is “the ability to remember to carry out a delayed intention or plan at the appropriate moment in the future“
  • Time-based prospective memory (TBPM) is when that delayed intention or plan must “be carried out at a particular future time point.” This includes both
    • “remembering to carry out an action after a certain time delay (e.g., taking medication 30 min after eating),”
    • “or at a specific time point (e.g., taking medication at 7 pm).”

TBPM & Executive Function

  • “It is thought that several elements of executive functioning (EF) work together to support this process.”
    • “Working memory supports the maintenance of the time-based intention while participants complete the ongoing task and track the passage of time…”
    • “Inhibitory control, as well as cognitive flexibility, are required to interrupt attention to the ongoing task… and either initiate a time-check… or to execute the PM intention…”

Intention Importance

  • When we create an intention to do something, our brains encode the activity’s importance along with it. So, “an intention’s importance will be a crucial determinant of successful PM performance in everyday life.”
    • “For example, collecting lifesaving medication for one’s child is likely to be undertaken regardless of the costs to one’s ongoing activities (e.g., even if it makes one late for work),
    • whereas collecting one’s dry-cleaned clothes may not be important enough to disrupt one’s ongoing daily activities for.”
  • The relative importance of an intention (i.e., how important one intention is relative to other intentions to do other actions) “affects PM performance by increasing extrinsic motivation (doing something for external incentives/driving factors).”
    • “This leads to changes in the strategic allocation of attentional resources towards the completion of the intended action, even if it is at the expense of other ongoing activities”

Importance in TBPM for Autistics

  • When researchers emphasized the TBPM task over the ongoing task before the autistic participants started (“PM high importance”), their overall PM performance increased significantly, with only a “small to medium” score difference from controls
    • When the task was “PM low importance,” autistics had a statistically large difference (lower performance) than the neurotypical (NT) controls.
  • So, the autistics had a much larger benefit (increase in performance) than the NTs when they were explicitly told when the PM task was more important than the ongoing task.
    • It appears that it helped them “remember to carry out the planned action at the appropriate time…while they were successfully completing the ongoing task.”
  • It appeared that “the more difficulties the participants had with cognitive flexibility and shifting mindset, the more they benefitted from the emphasised instructions”

“Overall, then, the results imply that supporting executive control processes by giving explicit instructions can positively support TBPM among people with ASD.”

  • “This could be particularly useful in employment settings to alleviate communication and interactional difficulties…when individuals with ASD are required to manage multi-tasking demands (e.g., finishing a work report and being on time for a work meeting).”

Future Research:

  • “Finally, it would be important to explore whether the execution of self-generated compared to other-generated (family, work colleague, experimenter) intentions differs in ASD. Related to this, future research should also explore how self-rated (personal) importance of intentions… affects PM performance.”
  • “Exploration of these factors would provide further important insight into how to tailor task instructions in order to maximally benefit task performance of individuals with ASD.”

CITATION:

Landsiedel, J. & Williams, D.M. J Autism Dev Disord (2019). https://doi.org/10.1007/s10803-019-04340-2

RESEARCH: Druggable genome in attention deficit/hyperactivity disorder and its co-morbid conditions. New avenues for treatment (2019)

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POST SUMMARY
This post shares information from a 2019 scientific article which reports that current ADHD medications do not actually target the genes involved in ADHD, however there are some other medications being used for other (mostly autoimmune or malignant) conditions which do target the some of the genes found in ADHD. These findings will hopefully lead to more potential treatments for ADHD.

Here is an interesting new paper from Molecular Psychiatry on the genetics of ADHD + current medications. As executive dysfunction (EDf) is the defining feature of ADHD, advancements made in the treatment of this condition may hopefully lead to better treatments for people with EDf across diagnosises!

ABSTRACT
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder with only symptomatic care available. Genome-wide association (GWA) studies can provide a starting point in the search for novel drug targets and possibilities of drug repurposing. Here, we explored the druggable genome in ADHD by utilising GWA studies on ADHD and its co-morbid conditions. First, we explored whether the genes targeted by current ADHD drugs show association with the disorder and/or its co-morbidities. Second, we aimed to identify genes and pathways involved in the biological processes underlying ADHD that can be targeted by pharmacological agents. These ADHD-associated druggable genes and pathways were also examined in co-morbidities of ADHD, as commonalities in their aetiology and management may lead to novel pharmacological insights.

Strikingly, none of the genes encoding targets of first-line pharmacotherapeutics for ADHD were significantly associated with the disorder, suggesting that FDA-approved ADHD drugs may act through different mechanisms than those underlying ADHD.

In the examined druggable genome, three loci on chromosomes 1, 4 and 12 revealed significant association with ADHD and contained nine druggable genes, five of which encode established drug targets for malignancies, autoimmune and neurodevelopmental disorders. To conclude, we present a framework to assess the druggable genome in a disorder, exemplified by ADHD. We highlight signal transduction and cell adhesion as potential novel avenues for ADHD treatment. Our findings add to knowledge on known ADHD drugs and present the exploration of druggable genome associated with ADHD, which may offer interventions at the aetiological level of the disorder.

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Tile plot of the association between druggable genes and ADHD (p 
LINK: Druggable genome in attention deficit/hyperactivity disorder and its co-morbid conditions. New avenues for treatment.
(Molecular Psychiatry, 2019)

Article Highlights:

About Specific Genes:

  • “PTPRF…. encodes a tyrosine phosphatase, a signalling molecule involved in a myriad of cellular processes, including cell adhesion, neuronal development and functioning [41, 42]. PTPRF has mainly been studied in the context of cancer. However, its involvement in hyperactivity [42] and axonal growth [43] has also been reported.” (p.9)
  • “Similarly, sarcosine has also been tested as a possible ADHD drug, although the preliminary analyses indicate that its effect may be limited to oppositional symptoms only [46].” (p.9)
  • “…the KCNH3 gene is also interacting with drugs that are FDA-approved or are in clinical trials. This gene encodes a voltage-dependent potassium channel, a selective inhibitor of which was recently described [47]. It is also a non-specific target of blood–brain barrier penetrating drug dalfampridine [48] used to relieve the symptoms of multiple sclerosis and related neurologic disorders [44, 49]. Knocking out KCNH3 in mice has been reported to enhance cognitive skills, including attention, further supporting a potential role of dalfampridine-like drugs in the treatment of ADHD [50].” (p.9)
  • “The aforementioned druggable genes also showed significant association with educational attainment, suggesting that drugs targeting them may have a possible impact on quality of life of ADHD patients.” (p.9)
  • “…LEPRE1 interacts with a number of compounds in clinical trials, such as nutraceutical ascorbate, succinic acid and L-proline. This gene encodes an enzyme needed for collagen synthesis and assembly, which has recently been proposed as a novel therapeutic vista for protection and regeneration of neurons [51].”

CITATION:

Hegvik, T., Waløen, K., Pandey, S.K. et al. Druggable genome in attention deficit/hyperactivity disorder and its co-morbid conditions. New avenues for treatment. Mol Psychiatry (2019) doi:10.1038/s41380-019-0540-z