Associations between early childhood sleep, memory function, and brain development across the nap transition

Preschool-age children often distribute their sleep across a midday nap and overnight sleep. Skipping the nap is suggested to increase the duration and depth of deep sleep (i.e., slow wave activity; SWA). Moreover, missing the midday nap has been shown to impair learning processes. This may be because children’s brains at this point in development are immature, necessitating the intervening nap period to strengthen memories before they are forgotten. Nonetheless, at some point during the preschool years, many children begin transitioning naturally out of napping. It is unclear whether the memory benefits of overnight SWA after a skipped nap depend on children’s baseline nap frequency. To this end, Chapter 2 of my dissertation sought to examine how the consolidation of memory over nocturnal sleep changes across the nap transition. Habitually and non-habitually napping children were taught a declarative task in the afternoon, and memory was probed following a polysomnography-monitored nap and following an equivalent period of wake. Memory was also examined 24-hours later in the afternoon following polysomnography-monitored overnight sleep. While children performed better over overnight sleep had they been awake during nap time the day prior, performance was not related to overnight SWA. However, when SWA was divided into slow and fast SWA, both measures were negatively associated with performance following overnight sleep. While it is known that children transition out of naps, the mechanism behind this transition is unclear. Considering that early childhood is a time of significant changes in both sleep and the brain, it is possible that the cessation of napping may have to do with brain development. To this end, Chapter 3 examined the relations between changes in SWA and hippocampal body volume longitudinally. Hippocampal body volume decreased over time, for both habitual nappers and those who transitioned out of the nap. However, SWA decreased over time only for children who transitioned out of naps. Collectively, the results of this dissertation suggest that the transition out of napping may be indicative of more mature brains (Chapter 3) and therefore a single overnight bout of sleep may be efficient for the consolidation of memories (Chapter 2)

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

Diffusion tensor imaging and resting state functional connectivity as advanced imaging biomarkers of outcome in infants with hypoxic-ischaemic encephalopathy treated with hypothermia

Therapeutic hypothermia confers significant benefit in term neonates with hypoxic-ischaemic encephalopathy (HIE). However, despite the treatment nearly half of the infants develop an unfavourable outcome. Intensive bench-based and early phase clinical research is focused on identifying treatments that augment hypothermic neuroprotection. Qualified biomarkers are required to test these promising therapies efficiently. This thesis aims to assess advanced magnetic resonance imaging (MRI) techniques, including diffusion tensor imaging (DTI) and resting state functional MRI (fMRI) as imaging biomarkers of outcome in infants with HIE who underwent hypothermic neuroprotection. FA values in the white matter (WM), obtained in the neonatal period and assessed by tract-based spatial statistics (TBSS), correlated with subsequent developmental quotient (DQ). However, TBSS is not suitable to study grey matter (GM), which is the primary site of injury following an acute hypoxic-ischaemic event. Therefore, a neonatal atlas-based automated tissue labelling approach was applied to segment central and cortical grey and whole brain WM. Mean diffusivity (MD) in GM structures, obtained in the neonatal period correlated with subsequent DQ. Although the central GM is the primary site of injury on conventional MRI following HIE; FA within WM tissue labels also correlated to neurodevelopmental performance scores. As DTI does not provide information on functional consequences of brain injury functional sequel of HIE was studied with resting state fMRI. Diminished functional connectivity was demonstrated in infants who suffered HIE, which associated with an unfavourable outcome. The results of this thesis suggest that MD in GM tissue labels and FA either determined within WM tissue labels or analysed with TBSS correlate to subsequent neurodevelopmental performance scores in infants who suffered HIE treated with hypothermia and may be applied as imaging biomarkers of outcome in this population. Although functional connectivity was diminished in infants with HIE, resting state fMRI needs further study to assess its utility as an imaging biomarker following a hypoxic-ischaemic brain injury.Open Acces

Implication de la connectivité anatomique dans les caractéristiques des fuseaux de sommeil

Le sommeil est un état de conscience distinct de l’éveil et nécessaire à diverses fonctions du cerveau allant de la métabolisation des déchets dans le système nerveux central jusqu’à la plasticité cérébrale, la mémoire et la performance cognitive. Les fuseaux de sommeil (FS), ces oscillations fusiformes ayant une fréquence qui varie entre 12 et 16 Hz, constituent un marqueur de synchronie neuronale principalement observé dans le sommeil lent. Ils font partie de ces oscillations qui ont été associées à la préservation du sommeil, la consolidation en mémoire et à l’intelligence. Les FS montrent une très grande variabilité intra- et interindividuelle quant à leurs caractéristiques, celles-ci étant d’ailleurs influencées par des facteurs tels que l’âge et le sexe. Les mécanismes neurophysiologiques impliqués dans ces variations demeurent toutefois méconnus à ce jour. Il a été démontré que la génération et la propagation des FS dépendent de la communication entre le thalamus et le cortex et reposeraient sur les fibres de matière blanche (MB) du cerveau. Le but de cette thèse est donc d’investiguer l’implication de la connectivité anatomique par l’analyse de la MB du cerveau, dans la variabilité interindividuelle des caractéristiques des FS. Nous évaluerons également si les différences d’âge et de sexe dans les caractéristiques des FS peuvent être expliquées par la MB. La première étude a évalué si l’intégrité de la MB du cerveau pouvait expliquer les changements d’amplitude et de densité des FS au cours du vieillissement. Une meilleure intégrité de la MB dans les principaux faisceaux connectant le thalamus au cortex frontal a été associée à une plus grande amplitude des FS et de l’activité électroencéphalographique dans la bande de fréquences sigma. Ces résultats ont été observés exclusivement chez les sujets jeunes, suggérant que d’autres facteurs pourraient expliquer les changements de FS au cours du vieillissement. La deuxième étude avait, quant à elle, pour but d’évaluer si la longueur des faisceaux de fibres thalamo-corticales (TC) prédisait la variation interindividuelle de la fréquence et de l’amplitude des FS. Il a été démontré que de plus courts faisceaux de fibres entre le thalamus et les régions frontales prédisaient une fréquence des FS plus rapide. De plus, une analyse de médiation a permis de démontrer que la différence sexuelle observée pour la fréquence des FS était complètement expliquée par l’effet indirect du sexe sur la longueur des faisceaux de fibres de MB. Nos résultats suggèrent donc que l’amplitude et la fréquence des FS reflèteraient des aspects spécifiques des projections de MB sous-jacentes à la boucle TC. De fait, l’amplitude des FS a été associée à l’intégrité des connexions neuronales et à la synchronie des décharges électriques alors que la fréquence des FS a été associée au temps requis à l’influx nerveux pour parcourir la boucle TC et à des mesures quantitatives des projections entre le thalamus et le cortex cérébral. Cette thèse propose donc une première hypothèse neuroanatomique tentant d’expliquer les variations interindividuelles et sexuelles des caractéristiques des FS.Sleep is a state of consciousness distinct from waking and necessary in multiple brain functions ranging from the metabolism of waste products in the central nervous system to brain plasticity, memory, and cognition. Sleep spindles (SS), these fusiform oscillations with a frequency which varies between 12 and 16 Hz, constitute a marker of neuronal synchrony prominently observed during non-rapid eye movement sleep. SS are one of these brain oscillations associated with sleep maintenance, memory consolidation, and intelligence. SS characteristics show an important intra- and inter-individual variability, and are known to be affected by factors such as age and sex. However, the neurophysiological mechanisms implicated in this variability are yet to be discovered. The generation and the propagation of SS depend on the communication between the thalamus and the cerebral cortex which rely on white matter (WM) fibre bundles. The goal of this thesis is to investigate the implication of the anatomical connectivity as assessed through WM, in the inter-individual variability of SS characteristics. We will also evaluate whether the age and sex differences in SS characteristics could be explained by the WM. The first study evaluated whether WM integrity could explain age-related changes in SS amplitude and density. Increased WM integrity in the main WM tracts connecting the thalamus to the frontal cortex was associated with an increased SS amplitude and electroencephalographic signal power in the sigma frequency band. These results were observed exclusively in young subjects suggesting that other factors could explain age-related changes in SS. The second study aimed at evaluating whether the length of the thalamo-cortical (TC) fiber bundles would predict the inter-individual variability of SS frequency and amplitude. We found that shorter fiber bundles between the thalamus and the frontal regions of the brain predicted a faster SS frequency. Moreover, a mediation analysis showed that the sex-related differences in SS frequency was completely explained by the indirect effect of sex on the length of the WM fiber bundles. Our results suggest that SS amplitude and frequency reflect specific aspect of the WM projections underlying the TC loop. Indeed, SS amplitude was associated with the integrity of neuronal connections and the synchrony of nerve impulses, whereas SS frequency was associated with the timing of the nerve impulses in the TC loop and to quantitative measures of WM projections between the thalamus and the cerebral cortex. This thesis therefore brings a first neuroanatomical hypothesis in explaining the inter-individual and sex-related variability of SS characteristics

Do informal caregivers of people with dementia mirror the cognitive deficits of their demented patients?:A pilot study

Recent research suggests that informal caregivers of people with dementia (ICs) experience more cognitive deficits than noncaregivers. The reason for this is not yet clear. Objective: to test the hypothesis that ICs ‘mirror' the cognitive deficits of the demented people they care for. Participants and methods: 105 adult ICs were asked to complete three neuropsychological tests: letter fluency, category fluency, and the logical memory test from the WMS-III. The ICs were grouped according to the diagnosis of their demented patients. One-sample ttests were conducted to investigate if the standardized mean scores (t-scores) of the ICs were different from normative data. A Bonferroni correction was used to correct for multiple comparisons. Results: 82 ICs cared for people with Alzheimer's dementia and 23 ICs cared for people with vascular dementia. Mean letter fluency score of the ICs of people with Alzheimer's dementia was significantly lower than the normative mean letter fluency score, p = .002. The other tests yielded no significant results. Conclusion: our data shows that ICs of Alzheimer patients have cognitive deficits on the letter fluency test. This test primarily measures executive functioning and it has been found to be sensitive to mild cognitive impairment in recent research. Our data tentatively suggests that ICs who care for Alzheimer patients also show signs of cognitive impairment but that it is too early to tell if this is cause for concern or not

Activation of the pro-resolving receptor Fpr2 attenuates inflammatory microglial activation

Poster number: P-T099 Theme: Neurodegenerative disorders & ageing Activation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activation Authors: Edward S Wickstead - Life Science & Technology University of Westminster/Queen Mary University of London Inflammation is a major contributor to many neurodegenerative disease (Heneka et al. 2015). Microglia, as the resident immune cells of the brain and spinal cord, provide the first line of immunological defence, but can become deleterious when chronically activated, triggering extensive neuronal damage (Cunningham, 2013). Dampening or even reversing this activation may provide neuronal protection against chronic inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced inflammation could be abrogated through activation of the receptor Fpr2, known to play an important role in peripheral inflammatory resolution. Immortalised murine microglia (BV2 cell line) were stimulated with LPS (50ng/ml) for 1 hour prior to the treatment with one of two Fpr2 ligands, either Cpd43 or Quin-C1 (both 100nM), and production of nitric oxide (NO), tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) were monitored after 24h and 48h. Treatment with either Fpr2 ligand significantly suppressed LPS-induced production of NO or TNFα after both 24h and 48h exposure, moreover Fpr2 ligand treatment significantly enhanced production of IL-10 48h post-LPS treatment. As we have previously shown Fpr2 to be coupled to a number of intracellular signaling pathways (Cooray et al. 2013), we investigated potential signaling responses. Western blot analysis revealed no activation of ERK1/2, but identified a rapid and potent activation of p38 MAP kinase in BV2 microglia following stimulation with Fpr2 ligands. Together, these data indicate the possibility of exploiting immunomodulatory strategies for the treatment of neurological diseases, and highlight in particular the important potential of resolution mechanisms as novel therapeutic targets in neuroinflammation. References Cooray SN et al. (2013). Proc Natl Acad Sci U S A 110: 18232-7. Cunningham C (2013). Glia 61: 71-90. Heneka MT et al. (2015). Lancet Neurol 14: 388-40

12th World Congress on Controversies in Neurology

Warszawa, 22–25 marca 2018 rok