Response variability in Attention-Deficit/Hyperactivity Disorder: a neuronal and glial energetics hypothesis

BACKGROUND: Current concepts of Attention-Deficit/Hyperactivity Disorder (ADHD) emphasize the role of higher-order cognitive functions and reinforcement processes attributed to structural and biochemical anomalies in cortical and limbic neural networks innervated by the monoamines, dopamine, noradrenaline and serotonin. However, these explanations do not account for the ubiquitous findings in ADHD of intra-individual performance variability, particularly on tasks that require continual responses to rapid, externally-paced stimuli. Nor do they consider attention as a temporal process dependent upon a continuous energy supply for efficient and consistent function. A consideration of this feature of intra-individual response variability, which is not unique to ADHD but is also found in other disorders, leads to a new perspective on the causes and potential remedies of specific aspects of ADHD. THE HYPOTHESIS: We propose that in ADHD, astrocyte function is insufficient, particularly in terms of its formation and supply of lactate. This insufficiency has implications both for performance and development: H1) In rapidly firing neurons there is deficient ATP production, slow restoration of ionic gradients across neuronal membranes and delayed neuronal firing; H2) In oligodendrocytes insufficient lactate supply impairs fatty acid synthesis and myelination of axons during development. These effects occur over vastly different time scales: those due to deficient ATP (H1) occur over milliseconds, whereas those due to deficient myelination (H2) occur over months and years. Collectively the neural outcomes of impaired astrocytic release of lactate manifest behaviourally as inefficient and inconsistent performance (variable response times across the lifespan, especially during activities that require sustained speeded responses and complex information processing). TESTING THE HYPOTHESIS: Multi-level and multi-method approaches are required. These include: 1) Use of dynamic strategies to evaluate cognitive performance under conditions that vary in duration, complexity, speed, and reinforcement; 2) Use of sensitive neuroimaging techniques such as diffusion tensor imaging, magnetic resonance spectroscopy, electroencephalography or magnetoencephalopathy to quantify developmental changes in myelination in ADHD as a potential basis for the delayed maturation of brain function and coordination, and 3) Investigation of the prevalence of genetic markers for factors that regulate energy metabolism (lactate, glutamate, glucose transporters, glycogen synthase, glycogen phosphorylase, glycolytic enzymes), release of glutamate from synaptic terminals and glutamate-stimulated lactate production (SNAP25, glutamate receptors, adenosine receptors, neurexins, intracellular Ca(2+)), as well as astrocyte function (α(1), α(2 )and β-adrenoceptors, dopamine D1 receptors) and myelin synthesis (lactate transporter, Lingo-1, Quaking homolog, leukemia inhibitory factor, and Transferrin). IMPLICATIONS OF THE HYPOTHESIS: The hypothesis extends existing theories of ADHD by proposing a physiological basis for specific aspects of the ADHD phenotype – namely frequent, transient and impairing fluctuations in functioning, particularly during performance of speeded, effortful tasks. The immediate effects of deficient ATP production and slow restoration of ionic gradients across membranes of rapidly firing neurons have implications for daily functioning: For individuals with ADHD, performance efficacy would be enhanced if repetitive and lengthy effortful tasks were segmented to reduce concurrent demands for speed and accuracy of response (introduction of breaks into lengthy/effortful activities such as examinations, motorway driving, assembly-line production). Also, variations in task or modality and the use of self- rather than system-paced schedules would be helpful. This would enable energetic demands to be distributed to alternate neural resources, and energy reserves to be re-established. Longer-term effects may manifest as reduction in regional brain volumes since brain areas with the highest energy demand will be most affected by a restricted energy supply and may be reduced in size. Novel forms of therapeutic agent and delivery system could be based on factors that regulate energy production and myelin synthesis. Since the phenomena and our proposed basis for it are not unique to ADHD but also manifests in other disorders, the implications of our hypotheses may be relevant to understanding and remediating these other conditions as well

International AIDS Society global scientific strategy: towards an HIV cure 2016

Antiretroviral therapy is not curative. Given the challenges in providing life-long therapy to a global population of over 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations

International AIDS Society global scientific strategy: towards an HIV cure 2016

Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy

Emerging Developmental Pathways to ADHD: Possible Path Markers in Early Infancy

Sixty-six male infants participating in the Ben-Gurion Infant Development Study of familial risk for attention deficit hyperactivity disorder (ADHD)were assessed at 7 months of age using observational and mother report measures. Risk for ADHD was based on ADHD symptoms in the father. Infants whose fathers had seven or more symptoms formed the ADHD risk group; infants whose fathers had three or less symptoms formed the comparison group. The ADHD risk group significantly differed from the comparison group on measures of interest, anger, and activity level and showed less interest in block play and more anger reactivity but less directed anger in a barrier task. According to mother report, the ADHD risk group had higher levels of activity than the comparison group. Measures of neonatal immaturity and activity were related to behavior at 7 months. The findings suggest that possible developmental pathways to ADHD may be emerging in early infancy

“My Brain Can Stop”: An ERP Study of Longitudinal Prediction of Inhibitory Control in Adolescence

We examined the longitudinal predictors of electrophysiological and behavioral markers of inhibitory control in adolescence. Participants were 63 adolescent boys who have been followed since birth as part of a prospective longitudinal study on the developmental pathways to attention-deficit hyperactivity disorder (ADHD). At 17 years of age, they completed the stop-signal task (SST) while electroencephalography (EEG) was continuously recorded. Inhibitory control was evaluated by the stop-signal reaction time (SSRT) as well as by the amplitude of the event-related potential (ERP) component of N2 during successful inhibition. We found that higher inattention symptoms throughout childhood predicted reduced amplitude (i.e., less negative) of the N2 in adolescence. Furthermore, the N2 amplitude was longitudinally predicted by the early precursors of child familial risk for ADHD and early childhood temperament. Specifically, father’s inattention symptoms (measured in the child’s early infancy) and child’s effortful control at 36 months of age directly predicted the N2 amplitude in adolescence, even beyond the consistency of inattention symptoms throughout development. The SSRT was predicted by ADHD symptoms throughout childhood but not by the early precursors. Our findings emphasize the relevance of early familial and temperamental risk for ADHD to the prediction of a later dysfunction in inhibitory control

“My Brain Can Stop”: An ERP Study of Longitudinal Prediction of Inhibitory Control in Adolescence

We examined the longitudinal predictors of electrophysiological and behavioral markers of inhibitory control in adolescence. Participants were 63 adolescent boys who have been followed since birth as part of a prospective longitudinal study on the developmental pathways to attention-deficit hyperactivity disorder (ADHD). At 17 years of age, they completed the stop-signal task (SST) while electroencephalography (EEG) was continuously recorded. Inhibitory control was evaluated by the stop-signal reaction time (SSRT) as well as by the amplitude of the event-related potential (ERP) component of N2 during successful inhibition. We found that higher inattention symptoms throughout childhood predicted reduced amplitude (i.e., less negative) of the N2 in adolescence. Furthermore, the N2 amplitude was longitudinally predicted by the early precursors of child familial risk for ADHD and early childhood temperament. Specifically, father’s inattention symptoms (measured in the child’s early infancy) and child’s effortful control at 36 months of age directly predicted the N2 amplitude in adolescence, even beyond the consistency of inattention symptoms throughout development. The SSRT was predicted by ADHD symptoms throughout childhood but not by the early precursors. Our findings emphasize the relevance of early familial and temperamental risk for ADHD to the prediction of a later dysfunction in inhibitory control