Individual spindle detection and analysis in high-density recordings across the night and in thalamic stroke

Sleep spindles are thalamocortical oscillations associated with several behavioural and clinical phenomena. In clinical populations, spindle activity has been shown to be reduced in schizophrenia, as well as after thalamic stroke. Automatic spindle detection algorithms present the only feasible way to systematically examine individual spindle characteristics. We took an established algorithm for spindle detection, and adapted it to high-density EEG sleep recordings. To illustrate the detection and analysis procedure, we examined how spindle characteristics changed across the night and introduced a linear mixed model approach applied to individual spindles in adults (n = 9). Next we examined spindle characteristics between a group of paramedian thalamic stroke patients (n = 9) and matched controls. We found a high spindle incidence rate and that, from early to late in the night, individual spindle power increased with the duration and globality of spindles; despite decreases in spindle incidence and peak-to-peak amplitude. In stroke patients, we found that only left-sided damage reduced individual spindle power. Furthermore, reduction was specific to posterior/fast spindles. Altogether, we demonstrate how state-of-the-art spindle detection techniques, applied to high-density recordings, and analysed using advanced statistical approaches can yield novel insights into how both normal and pathological circumstances affect sleep

Utilization of TREC and KREC quantification for the monitoring of early T- and B-cell neogenesis in adult patients after allogeneic hematopoietic stem cell transplantation

BACKGROUND: After hematopoietic stem cell transplantation (HSCT) T- and B-cell reconstitution from primary lymphoid organs are a prerequisite for an effective early lymphocyte reconstitution and a long-term survival for adult patients suffering from acute leukemia. Here, we asked whether quantification of T cell receptor excision circle, (TREC) and kappa-deleting recombination excision circle (KREC) before and within six month after allogeneic HSCT could be used to measure the thymic and bone marrow outputs in such patients. METHODS: We used a duplex real time PCR assay to quantify the absolute copy counts of TREC and KREC, and correlated the data with absolute cell counts of CD3+CD4+ T-cell and CD19+ B-cell subsets determined by flow cytometry, respectively. RESULTS: By comparing two recently proposed naive T cell subsets, CD31+ naive and CD31- naive T cells, we found a better correlation for the CD31+ subset with TREC level post alloHSCT, in line with the assumption that it contained T cells recently derived from the thymus, indicating that TREC levels reflected real thymic de novo production. Transitional as well as naive B cells highly correlated with KREC levels, which suggested an association of KREC levels with ongoing bone marrow B cell output. CD45RO+ memory T cells and CD27+ memory B cells were significantly less correlated with TREC and KREC recovery, respectively. CONCLUSION: We conclude that simultaneous TREC/ KREC quantification is as a suitable and practicable method to monitor thymic and bone marrow output post alloHSCT in adult patients diagnosed with acute leukemia

Sleep as a model to understand neuroplasticity and recovery after stroke : observational, perturbational and interventional approaches

Our own experiences with disturbances to sleep demonstrate its crucial role in the recovery of cognitive functions. This importance is likely enhanced in the recovery from stroke; both in terms of its physiology and cognitive abilities. Decades of experimental research have highlighted which aspects and mechanisms of sleep are likely to underlie these forms of recovery. Conversely, damage to certain areas of the brain, as well as the indirect effects of stroke, may disrupt sleep. However, only limited research has been conducted which seeks to directly explore this bidirectional link between both the macro and micro-architecture of sleep and stroke. Here we describe a series of semi-independent approaches that aim to establish this link through observational, perturbational, and interventional experiments. Our primary aim is to describe the methodology for future clinical and translational research needed to delineate competing accounts of the current data. At the observational level we suggest the use of high-density EEG recording, combined analysis of macro and micro-architecture of sleep, detailed analysis of the stroke lesion, and sensitive measures of functional recovery. The perturbational approach attempts to find the causal links between sleep and stroke. We promote the use of transcranial magnetic stimulation combined with EEG to examine the cortical dynamics of the peri-infarct stroke area. Translational research should take this a step further using optogenetic techniques targeting more specific cell populations. The interventional approach focuses on how the same clinical and translational perturbational techniques can be adapted to influence long-term recovery of function

Synaptic and transcriptionally downregulated genes are associated with cortical thickness differences in autism.

Differences in cortical morphology-in particular, cortical volume, thickness and surface area-have been reported in individuals with autism. However, it is unclear what aspects of genetic and transcriptomic variation are associated with these differences. Here we investigate the genetic correlates of global cortical thickness differences (ΔCT) in children with autism. We used Partial Least Squares Regression (PLSR) on structural MRI data from 548 children (166 with autism, 295 neurotypical children and 87 children with ADHD) and cortical gene expression data from the Allen Institute for Brain Science to identify genetic correlates of ΔCT in autism. We identify that these genes are enriched for synaptic transmission pathways and explain significant variation in ΔCT. These genes are also significantly enriched for genes dysregulated in the autism post-mortem cortex (Odd Ratio (OR) = 1.11, Pcorrected  10-14), driven entirely by downregulated genes (OR = 1.87, Pcorrected  10-15). We validated the enrichment for downregulated genes in two independent data sets: Validation 1 (OR = 1.44, Pcorrected = 0.004) and Validation 2 (OR = 1.30; Pcorrected = 0.001). We conclude that transcriptionally downregulated genes implicated in autism are robustly associated with global changes in cortical thickness variability in children with autism

Reduction of Pavlovian bias in schizophrenia: Enhanced effects in clozapine-administered patients

The negative symptoms of schizophrenia (SZ) are associated with a pattern of reinforcement learning (RL) deficits likely related to degraded representations of reward values. However, the RL tasks used to date have required active responses to both reward and punishing stimuli. Pavlovian biases have been shown to affect performance on these tasks through invigoration of action to reward and inhibition of action to punishment, and may be partially responsible for the effects found in patients. Forty-five patients with schizophrenia and 30 demographically-matched controls completed a four-stimulus reinforcement learning task that crossed action ("Go" or "NoGo") and the valence of the optimal outcome (reward or punishment-avoidance), such that all combinations of action and outcome valence were tested. Behaviour was modelled using a six-parameter RL model and EEG was simultaneously recorded. Patients demonstrated a reduction in Pavlovian performance bias that was evident in a reduced Go bias across the full group. In a subset of patients administered clozapine, the reduction in Pavlovian bias was enhanced. The reduction in Pavlovian bias in SZ patients was accompanied by feedback processing differences at the time of the P3a component. The reduced Pavlovian bias in patients is suggested to be due to reduced fidelity in the communication between striatal regions and frontal cortex. It may also partially account for previous findings of poorer "Go-learning" in schizophrenia where "Go" responses or Pavlovian consistent responses are required for optimal performance. An attenuated P3a component dynamic in patients is consistent with a view that deficits in operant learning are due to impairments in adaptively using feedback to update representations of stimulus value

Humor as a Reward Mechanism: Event-Related Potentials in the Healthy and Diseased Brain

Humor processing involves distinct processing stages including incongruity detection, emotional response, and engagement of mesolimbic reward regions. Dysfunctional reward processing and clinical symptoms in response to humor have been previously described in both hypocretin deficient narcolepsy-cataplexy (NC) and in idiopathic Parkinson disease (PD). For NC patients, humor is the strongest trigger for cataplexy, a transient loss of muscle tone, whereas dopamine-deficient PD-patients show blunted emotional responses to humor. To better understand the role of reward system and the various contributions of hypocretinergic and dopaminergic mechanisms to different stages of humor processing we examined the electrophysiological response to humorous and neutral pictures when given as reward feedback in PD, NC and healthy controls. Humor compared to neutral feedback demonstrated modulation of early ERP amplitudes likely corresponding to visual processing stages, with no group differences. At 270 ms post-feedback, conditions showed topographical and amplitudinal differences for frontal and left posterior electrodes, in that humor feedback was absent in PD patients but increased in NC patients. We suggest that this effect relates to a relatively early affective response, reminiscent of increased amygdala response reported in NC patients. Later ERP differences, corresponding to the late positive potential, revealed a lack of sustained activation in PD, likely due to altered dopamine regulation in reward structures in these patients. This research provides new insights into the temporal dynamics and underlying mechanisms of humor detection and appreciation in health and disease

Slow waves promote sleep-dependent plasticity and functional recovery after stroke.

Functional recovery after stroke is associated with a remapping of neural circuits. This reorganization is often associated with low frequency high amplitude oscillations in the peri-infarct zone in both rodents and humans. These oscillations are reminiscent of sleep slow waves (SW) and suggestive of a role for sleep in brain plasticity that occur during stroke recovery, however, direct evidence is missing. Using a stroke model in male mice, we showed that stroke was followed by a transient increase in NREM sleep accompanied by reduced amplitude and slope of ipsilateral NREM sleep SW. We next used 5 ms optical activation of Channelrhodopsin 2-expressing pyramidal neurons, or 200 ms silencing of Archeorhodopsin T-expressing pyramidal neurons, to generate local cortical UP, or DOWN, states, respectively, both sharing similarities with spontaneous NREM SW in freely-moving mice. Importantly, we found that single optogenetically-evoked SW (SWopto) in the peri-infarct zone, randomly distributed during sleep, significantly improved fine motor movements of the limb corresponding to the sensorimotor stroke lesion site, as compared to spontaneous recovery and control conditions, while motor strength remained unchanged. In contrast, SWopto during wakefulness had no effect. Furthermore, chronic SWopto during sleep were associated with local axonal sprouting as revealed by the increase of anatomical pre- and post-synaptic markers in the peri-infarct zone and corresponding contra-lesional areas to cortical circuit reorganization during stroke recovery. These results support a role for sleep SW in cortical circuit plasticity and sensorimotor recovery after stroke and provide a clinically-relevant framework for rehabilitation strategies using neuromodulation during sleep.SIGNIFICANCE STATEMENTBrain stroke is one of the leading causes of death and major disabilities in elderly worldwide. A better understanding of the pathophysiological mechanisms underlying spontaneous brain plasticity after stroke, together with an optimization of rehabilitative strategies, are essential to improve stroke treatments. Here, we investigate the role of optogenetically-induced sleep slow waves in an animal model of ischemic stroke and identify sleep as a window for post-stroke intervention that promotes neuroplasticity and facilitates sensorimotor recovery