Regional Brain Volume Reduction Research Articles

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2-6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5-5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4-10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32-4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23-11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification. UK Research and Innovation and National Institute for Health Research.

P.63 Comparison of brain volume reduction in boys with Duchenne muscular dystrophy treated with different corticosteroid regimes

Recent studies show lower gray matter volumes and altered white matter networks in boys with Duchenne Muscular Dystrophy (DMD) compared with healthy controls, suggesting a lack of dystrophin impacts brain structures. However, the majority of boys with DMD are chronically treated with corticosteroids (CS), which are known to cross the blood-brain barrier and cause brain atrophy. Unraveling the impact of CS treatment on the brain of boys with DMD is key to understand brain involvement in this disease. This study compared two groups of DMD boys treated with a different CS regimen with 2 healthy control groups. 3D T1-weighted images were obtained on a 3T Philips system at two different sites. Scans from 20 DMD patients (13.0±3.1y) on a 10 days on/10 days off prednisolone schedule and 20 age-matched controls (13.2±1.8y) were obtained at the LUMC Leiden, the Netherlands. Additionally scans of 20 age-matched DMD patients (12.8±3.0y) on a daily deflazacort regime and 20 age-matched controls (13.1±3.2y) were acquired at the UZ Leuven, Belgium. All 80 scans were processed using FSL software to calculate intracranial (ICV), total brain (TBV), grey matter (GMV), white matter (WMV) and CSF volumes. In addition, volumes of the hippocampus, amygdala, thalamus, nucleus accumbens, caudate nucleus, globus pallidus and putamen were calculated. To control for intracranial volume differences, relative volumes were compared between controls and DMD per center using univariate analyses of variances in SPSS and considered significant at p<0.05. Both DMD groups showed a significant lower relative GMV, and higher relative CSF volume compared to their control groups. Interestingly, a significantly lower relative WMV (33.81% vs 35.45%, p=.002) and relative volume of the globus pallidus (0.25% vs 0.22%, p<.001) was found in the deflazacort group compared with their control group, but not in the prednisolone group. This study suggest that different CS regimes lead to different regional brain volume reductions in patients with DMD.

Regional brain volume reductions in major depressive disorder and bipolar disorder: An analysis by voxel-based morphometry.

The present study investigated the usefulness of evaluating the existence of volume reduction in brain regions using voxel-based morphometry (VBM) to dissociate major depressive disorder (MDD) from bipolar disorder (BD). This study enrolled 92 individuals with MDD, 32 individuals with BD, and 43 healthy controls (HCs). We focused on gray matter volume (GMV) of the subgenual anterior cingulate cortex (sgACC), subcallosal area (SCA), and hippocampus. The degree of volume reduction in these brain regions was calculated as the z score, and the differences of z scores in these regions were investigated among the MDD, BD, and HC groups. We then performed a receiver operating characteristic curve analysis to dissociate the individuals with MDD and BD from the HCs based on the z scores in the GMV of these brain regions. While there were no significant differences in the z scores of the hippocampus among the three groups, the z score of the sgACC was significantly higher in the MDD group than in the BD and HC groups, and the SCA z score was significantly higher in the MDD and BD groups than in the HC group. Our findings suggest that VBM evaluation of GMV reduction in the sgACC may be useful as an objective adjunctive tool to distinguish between MDD and BD.

Regional brain volume reduction and cognitive outcomes in preterm children at low risk at 9years of age.

More information is needed on "low-risk" preterm infants' neurological outcome so that they can be included in follow-up programs. A prospective study was performed to examine the regional brain volume changes compared to term children and to assess the relationship between the regional brain volumes to cognitive outcome of the low-risk preterm children at 9years of age. Subjects comprised 22 preterm children who were determined to be at low risk for neurodevelopmental deficits with a gestational age between 28 and 33weeks without a major neonatal morbidity in the neonatal period and 24 age-matched term control children term and matched for age, sex, and parental educational and occupational status. Regional volumetric analysis was performed for cerebellum, hippocampus, and corpus callosum area. Cognitive outcomes of both preterm and control subjects were assessed by Weschler Intelligence Scale for Children Revised (Turkish version), and attention and executive functions were assessed by Wisconsin Card Sorting Test and Stroop Test TBAG version. Low-risk preterm children showed regional brain volume reduction in cerebellum, hippocampus, and corpus callosum area and achieved statistical significance when compared with term control. When the groups were compared for all WISC-R subscale scores, preterm children at low risk had significantly lower scores on information, vocabulary, similarities, arithmetics, picture completion, block design, object assembly, and coding compared to children born at term. Preterm and term groups were compared on the Stroop Test for mistakes and corrections made on each card, the time spent for completing each card, and total mistakes and corrections. In the preterm group, we found a positive correlation between regional volumes with IQ, attention, and executive function scores. Additionally, a significant correlation was found between cerebellar volume and attention and executive function scores in the preterm group. Low-risk preterm children achieve lower scores in neurophysiological tests than children born at term. Preterm birth itself has a significant impact on regional brain volumes and cognitive outcome of children at 9years of age. It is a risk factor for regional brain volume reductions in preterm children with low risk for neurodevelopmental deficits. The significant interaction between cerebellar volume reduction and executive function and attention may suggest that even in preterm children at low risk can have different trajectories in the growth and development of overall brain structure.

Common and distinct structural network abnormalities in major depressive disorder and borderline personality disorder

Major depressive disorder (MDD) and borderline personality disorder (BPD) show substantial overlap in both affective symptom expression and in regional brain volume reduction. To address the specificity of structural brain change for the respective diagnostic category, we investigated structural networks in MDD and BPD to identify shared and distinct patterns of abnormal brain volume associated with these phenotypically related disorders. Using magnetic resonance imaging at 3T, we studied 22 females with MDD, 17 females with BPD and without comorbid posttraumatic stress disorder, and 22 age-matched female healthy controls. We used “source-based morphometry” (SBM) to investigate naturally grouping patterns of gray matter volume variation (i.e. “structural networks”) and the magnitude of their expression between groups. SBM identified three distinct structural networks which showed a significant group effect (p<0.05, FDR-corrected). A bilateral frontostriatal network showed reduced volume in MDD compared to both controls and BPD patients. A medial temporal/medial frontal network was found to be significantly reduced in BPD compared to both controls and MDD patients. Decreased cingulate and lateral prefrontal volume was found in both MDD and BPD when compared to healthy individuals. In MDD significant relationships were found between depressive symptoms and a cingulate/lateral prefrontal structural pattern. In contrast, overall BPD symptoms and impulsivity scores were significantly associated with medial temporal/medial frontal network volume. The data suggest both distinct and common patterns of abnormal brain volume in MDD and BPD. Alterations of distinct structural networks differentially modulate clinical symptom expression in these disorders.

Severe Congenital Heart Defects Are Associated with Global Reduction of Neonatal Brain Volumes

To determine neonatal global and regional brain volumes in infants with congenital heart disease (CHD) in comparison with healthy controls and to determine brain growth. Prospective cohort study in infants undergoing open-heart surgery for complex CHD. Global and regional volumetric measurements on preoperative cerebral magnetic resonance imaging were manually segmented in children without overt brain lesions. Preoperative brain volumetry of 19 patients demonstrates reduction in total and regional brain volumes, without any specific regional predilection compared with 19 healthy control infants (total brain volume reduction: 21%, regional brain volume reduction 8%-28%, all P < .001). Infants with CHD undergoing bypass surgery have smaller brain volumes prior to surgery without a specific regional predilection. This suggests a fetal origin of reduced brain growth.

Pulse pressure and systolic blood pressure associated with hippocampal volume by apolipoprotein (APO) carriers and Alzheimer disease status: Alzheimer’s disease neuroimaging initiative (ADNI) study

It is increasingly evident that high blood pressure (BP) levels may be associated with brain volume reduction. A few studies have shown that high BP levels are associated with global and regional brain volume reduction with preferential localization in hippocampus and prefrontal cortex. We examined the relationship of blood pressure to hippocampal volume (HV) by Apolipoprotein (APO) carrier status from the Alzheimer's Disease Neuroimaging Initiative (ADNI) data. ADNI data in this analysis was downloaded on October 12, 2012. 1308 subjects were isolated: Alzheimer's disease (AD = 237), late mild cognitive impairment (LMCI = 454), early mild cognitive impairment (EMCI = 254) and control group (CN = 365). Subjects were reexamined at 6, 12, and 24 months, with 460 remaining at the last exam. Univariate analysis was conducted to examine data distribution and validate assumption for normality. Proc Mixed Effects Model was used to elucidate the relationships of HV to BP according to APO ε4 carriers and AD status while accounting for the effects of education, gender, history of hypertension, ethnicity and body mass index. Baseline characteristics of participants by AD status showed a mean age of 74.6±7.9 (AD); 73.3±7.5 (LMCI); 70.8±7.2 (EMCI) and 74.4±5.6 (CN). Females ranged from 39.4% – 49.6% by AD status. As anticipated AD subjects had lower HV: 5726.54±1003.26 (AD), 6491.91±1107.01 (LMCI), 7308.37±1027.11 (EMCI), 7361.12±920.69 (CN). Increased diastolic blood pressure was significantly associated with decreased HV among the controls who were non-APO ε4 carrier (β = -9.40, SE = 3.51, p = 0.008). EMCI non-APO ε4 carriers with high diastolic blood pressure had significantly higher HV (β = 17.10, SE = 7.94, p = 0.03). Increasing pulse pressure (PP) was positively associated with HV (p = 0.002) in EMCI non-APO ε4 carriers. In these ADNI data, a statistically significant association of diastolic BP and PP was observed with HV in non-APO ε4 carriers with EMCI, suggesting a possible role for elevated BP and PP in amyloid mediated early cognitive decline. This observation supports the view that CVD risk may promote amyloid-mediated early cognitive decline. This hypothesis should be examined in other studies.

Brain volumes predict neurodevelopment in adolescents after surgery for congenital heart disease

Patients with complex congenital heart disease are at risk for neurodevelopmental impairments. Evidence suggests that brain maturation can be delayed and pre- and postoperative brain injury may occur, and there is limited information on the long-term effect of congenital heart disease on brain development and function in adolescent patients. At a mean age of 13.8 years, 39 adolescent survivors of childhood cardiopulmonary bypass surgery with no structural brain lesions evident through conventional cerebral magnetic resonance imaging and 32 healthy control subjects underwent extensive neurodevelopmental assessment and cerebral magnetic resonance imaging. Cerebral scans were analysed quantitatively using surface-based and voxel-based morphometry. Compared with control subjects, patients had lower total brain (P = 0.003), white matter (P = 0.004) and cortical grey matter (P = 0.005) volumes, whereas cerebrospinal fluid volumes were not different. Regional brain volume reduction ranged from 5.3% (cortical grey matter) to 11% (corpus callosum). Adolescents with cyanotic heart disease showed more brain volume loss than those with acyanotic heart disease, particularly in the white matter, thalami, hippocampi and corpus callosum (all P-values < 0.05). Brain volume reduction correlated significantly with cognitive, motor and executive functions (grey matter: P < 0.05, white matter: P < 0.01). Our findings suggest that there are long-lasting cerebral changes in adolescent survivors of cardiopulmonary bypass surgery for congenital heart disease and that these changes are associated with functional outcome.

Blood pressure levels and brain volume reduction

High blood pressure (BP) levels may be associated with brain volume reduction and may contribute to brain atrophy in key brain regions involved in cognition and susceptible to neurodegeneration in Alzheimer's disease. The purpose of this work was to systematically review and quantitatively synthesize the association of BP levels with brain volume reduction in humans. An English Medline, Cochrane Library and PsycINFO search was conducted in June 2012 using the Medical Subject Heading terms 'Blood pressure', 'Hypertension', 'Brain mapping' and 'Brain atrophy'. Of the 609 screened abstracts, 28 studies (4.6%) were included in the qualitative analysis. Twenty-six studies (92.9%) showed a significant association of higher BP levels and/or hypertension with total and/or regional brain volume reduction, the frontal and temporal lobes being particularly affected. In addition, four other studies reported an association between lower BP levels and brain volume reduction. Due to the heterogeneity of methodology and outcomes, random-effects meta-analyses of the mean difference of brain volume could be performed on only seven studies, with a total of 709 cases with hypertension and 1001 controls without hypertension. The findings showed no between-group difference regarding the whole-gray matter volume (summary mean difference = 2.42 cm [95% confidence interval (CI): -2.13 to 6.96]). Conversely, cases with hypertension exhibited lower hippocampus volume compared with controls [summary mean difference = -0.10 cm (95% CI: -0.17 to -0.02)]. These findings provide evidence that high BP levels lead to brain volume reduction, specifically in hippocampus, and may be an important factor that contributes to neurodegeneration in Alzheimer's disease.

Disrupted cerebral metabolite levels and lower nadir CD4+ counts are linked to brain volume deficits in 210 HIV-infected patients on stable treatmentpatients on stable treatment

Cognitive impairment and brain injury are common in people with HIV/AIDS, even when viral replication is effectively suppressed with combined antiretroviral therapies (cART). Metabolic and structural abnormalities may promote cognitive decline, but we know little about how these measures relate in people on stable cART. Here we used tensor-based morphometry (TBM) to reveal the 3D profile of regional brain volume variations in 210 HIV + patients scanned with whole-brain MRI at 1.5 T (mean age: 48.6 ± 8.4 years; all receiving cART). We identified brain regions where the degree of atrophy was related to HIV clinical measures and cerebral metabolite levels assessed with magnetic resonance spectroscopy (MRS). Regional brain volume reduction was linked to lower nadir CD4 + count, with a 1–2% white matter volume reduction for each 25-point reduction in nadir CD4 +. Even so, brain volume measured by TBM showed no detectable association with current CD4 + count, AIDS Dementia Complex (ADC) stage, HIV RNA load in plasma or cerebrospinal fluid (CSF), duration of HIV infection, antiretroviral CNS penetration-effectiveness (CPE) scores, or years on cART, after controlling for demographic factors, and for multiple comparisons. Elevated glutamate and glutamine (Glx) and lower N-acetylaspartate (NAA) in the frontal white matter, basal ganglia, and mid frontal cortex — were associated with lower white matter, putamen and thalamus volumes, and ventricular and CSF space expansion. Reductions in brain volumes in the setting of chronic and stable disease are strongly linked to a history of immunosuppression, suggesting that delays in initiating cART may result in imminent and irreversible brain damage.

Regional brain volume reductions relate to facial dysmorphology and neurocognitive function in fetal alcohol spectrum disorders

Regional brain volume reductions relate to facial dysmorphology and neurocognitive function in fetal alcohol spectrum disorders

Regional brain volume reductions relate to facial dysmorphology and neurocognitive function in fetal alcohol spectrum disorders

Individuals with heavy prenatal alcohol exposure can experience significant deficits in cognitive and psychosocial functioning and alterations in brain structure that persist into adulthood. In this report, data from 99 participants collected across three sites (Los Angeles and San Diego, California, and Cape Town, South Africa) were analyzed to examine relationships between brain structure, neurocognitive function, facial morphology, and maternal reports of quantities of alcohol consumption during the first trimester. Across study sites, we found highly significant volume reductions in the FASD group for all of the brain regions evaluated. After correcting for scan location, age, and total brain volume, these differences remained significant in some regions of the basal ganglia and diencephalon. In alcohol-exposed subjects, we found that smaller palpebral fissures were significantly associated with reduced volumes in the ventral diencephalon bilaterally, that greater dysmorphology of the philtrum predicted smaller volumes in basal ganglia and diencephalic structures, and that lower IQ scores were associated with both smaller basal ganglia volumes and greater facial dysmorphology. In subjects from South Africa, we found a significant negative correlation between intracranial volume and total number of drinks per week in the first trimester. These results corroborate previous reports that prenatal alcohol exposure is particularly toxic to basal ganglia and diencephalic structures. We extend previous findings by illustrating relationships between specific measures of facial dysmorphology and the volumes of particular subcortical structures, and for the first time show that continuous measures of maternal alcohol consumption during the first trimester relates to overall brain volume reduction.

Exploring the relationship between personality and regional brain volume in healthy aging

Aging is characterized by a reduction in regional brain volumes, particularly in prefrontal and medial temporal regions. Recent evidence suggests that personality may be related to neuroanatomical integrity. The present investigation explored whether the three targeted personality traits of neuroticism, conscientiousness, and extraversion moderated cross-sectional age-related decline in measures of neural integrity. Estimates of the personality traits and volumes of cerebral gray and white matter, prefrontal and medial temporal regions were obtained in a sample of 79 healthy adults aged 44-88. Higher neuroticism was associated with smaller regional volumes and greater decreases in volume with increasing age. Higher conscientiousness was related to larger regional volumes and less decline with advancing age. These results suggest that personality may not only relate to, but may also moderate age-related cross-sectional decline in prefrontal and medial temporal regions.

Magnetic resonance microscopy defines ethanol-induced brain abnormalities in prenatal mice: effects of acute insult on gestational day 8.

Magnetic resonance microscopy (MRM), magnetic resonance imaging (MRI) at microscopic levels, provides unprecedented opportunities to aid in defining the full spectrum of ethanol's insult to the developing brain. This is the first in a series of reports that, collectively, will provide an MRM-based atlas of developmental stage-dependent structural brain abnormalities in a Fetal Alcohol Spectrum Disorders (FASD) mouse model. The ethanol exposure time and developmental stage examined for this report is gestational day (GD) 8 in mice, when the embryos are at early neurulation stages; stages present in humans early in the fourth week postfertilization. For this study, pregnant C57Bl/6J mice were administered an ethanol dosage of 2.8 g/kg intraperitoneally at 8 days, 0 hour and again at 8 days, 4 hours postfertilization. On GD 17, fetuses that were selected for MRM analyses were immersion fixed in a Bouin's/Prohance solution. Control fetuses from vehicle-treated dams were stage-matched to those that were ethanol-exposed. The fetal mice were scanned ex vivo at 7.0 T and 512 x 512 x 1024 image arrays were acquired using 3-D spin warp encoding. The resulting 29 microm (isotropic) resolution images were processed using ITK-SNAP, a 3-D segmentation/visualization tool. Linear and volume measurements were determined for selected brain, head, and body regions of each specimen. Comparisons were made between control and treated fetuses, with an emphasis on determining (dis)proportionate changes in specific brain regions. As compared with controls, the crown-rump lengths of stage-matched ethanol-exposed GD 17 fetuses were significantly reduced, as were brain and whole body volumes. Volume reductions were notable in every brain region examined, with the exception of the pituitary and septal region, and were accompanied by increased ventricular volumes. Disproportionate regional brain volume reductions were most marked on the right side and were significant for the olfactory bulb, hippocampus, and cerebellum; the latter being the most severely affected. Additionally, the septal region and the pituitary were disproportionately large. Linear measures were consistent with those of volume. Other dysmorphologic features noted in the MR scans were choanal stenosis and optic nerve coloboma. This study demonstrates that exposure to ethanol occurring in mice at stages corresponding to the human fourth week postfertilization results in structural brain abnormalities that are readily identifiable at fetal stages of development. In addition to illustrating the utility of MR microscopy for analysis of an FASD mouse model, this work provides new information that confirms and extends human clinical observations. It also provides a framework for comparison of structural brain abnormalities resulting from ethanol exposure at other developmental stages and dosages.

Voxel-based morphometry study on brain structure in children with high-functioning autism

Earlier studies have suggested abnormal brain volumes in autism, but inconsistencies exist. Using voxel-based morphometry, we compared global and regional brain volumes in 17 high-functioning autistic children with 15 matched controls. We identified significant reduction in left white matter volume and white/gray matter ratio in autism. Regional brain volume reductions were detected for right anterior cingulate, left superior parietal lobule white matter volumes, and right parahippocampal gyrus gray matter volume, whereas enlargements in bilateral supramarginal gyrus, right postcentral gyrus, right medial frontal gyrus, and right posterior lobe of cerebellum gray matter in autism. Our findings showed global and regional brain volumes abnormality in high-functioning autism.

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

BackgroundCurrent 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 hypothesisWe 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 hypothesisMulti-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 Ca2+), as well as astrocyte function (α1, α2 and β-adrenoceptors, dopamine D1 receptors) and myelin synthesis (lactate transporter, Lingo-1, Quaking homolog, leukemia inhibitory factor, and Transferrin).Implications of the hypothesisThe 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.