Ellemarije Altena

Sleep benefits subsequent hippocampal functioning

Sleep before learning benefits memory encoding through unknown mechanisms. We found that even a mild sleep disruption that suppressed slow-wave activity and induced shallow sleep, but did not reduce total sleep time, was sufficient to affect subsequent successful encoding-related hippocampal activation and memory performance in healthy human subjects. Implicit learning was not affected. Our results suggest that the hippocampus is particularly sensitive to shallow, but intact, sleep.

Reduced Orbitofrontal and Parietal Gray Matter in Chronic Insomnia: A Voxel-Based Morphometric Study

BACKGROUND Brain mechanisms of chronic insomnia, a highly prevalent condition, have barely been investigated. We demonstrate here a decrease in orbitofrontal gray matter (GM) volume that strongly correlates with the severity of complaints. METHODS In a case-control study, optimized voxel-based morphometry was used to compare the regional brain volumes of 24 medication-free chronic primary insomnia patients (age range 52-74 years, 17 women), carefully selected to exclude psychiatric comorbidity, with those of 13 matched control subjects without sleep problems (age range 50-76 years, 9 women). Additionally, the correlation of regional volumes with insomnia severity was investigated. RESULTS Patients had a smaller volume of GM in the left orbitofrontal cortex, strongly correlating (r = -.71) with the subjective severity of insomnia. Furthermore, reduced GM volume was found in the anterior and posterior precuneus. Patients did not show increased GM volume in any area. No group differences were found for white matter volume. CONCLUSIONS This is the first voxel-based morphometry study showing structural brain correlates of insomnia and their relation with insomnia severity. Functional roles of the affected areas in decision-making and stimulus processing might better guide future research into the poorly understood condition of insomnia.

Sleep loss affects vigilance: effects of chronic insomnia and sleep therapy

Although complaints of impaired daytime functioning are essential to the diagnosis of primary insomnia, objective evidence for cognitive dysfunction has been hard to establish. A prerequisite for understanding the neurocognitive consequences of primary insomnia is to establish task paradigms that robustly differentiate insomniacs from well‐sleeping subjects. We hypothesized that the decline in performance that typically occurs with an increasing cognitive demand would provide a more sensitive measure than performance on a single task version. The hypothesis was tested, first, by assessing the performance on two vigilance tasks with different cognitive demands in 25 elderly patients with primary insomnia and 13 healthy well‐sleeping age‐matched subjects. Secondly, we investigated the performance response to sleep therapy using a waiting‐list controlled design. Sleep therapy consisted of a multi‐component intervention including sleep restriction, cognitive behavioral therapy, bright‐light therapy, structured physical activity and body temperature manipulations. The results show that insomniacs differed markedly from controls in their reaction times across tasks with different cognitive demands: patients responded faster on the ‘simple’ vigilance task, yet slower on the ‘complex’ vigilance task. Sleep therapy effectively restored normal performance: patients became significantly slower on the ‘simple’ task and faster on the ‘complex’ task, returning to the performance levels of control subjects. These findings indicate that the performance decline associated with increasing cognitive demands is possibly the first sensitive and robust measure of the neurocognitive sequelae of insomnia. We suggest that future studies on cognition in primary insomnia should apply a design that varies task demands.

White matter pathology in Parkinson's disease: The effect of imaging protocol differences and relevance to executive function

Diffusion magnetic resonance imaging is increasingly used as a non-invasive method to investigate white matter structure in neurological and neuropsychiatric disease. However, many options are available for the acquisition sequence and analysis method. Here we used Parkinsons disease as a model neurodegenerative disorder to compare imaging protocols and analysis options. We investigated fractional anisotropy and mean diffusivity of white matter in patients and age-matched controls, comparing two datasets acquired with different imaging protocols. One protocol prioritised the number of b value acquisitions, whilst the other prioritised the number of gradient directions. The dataset with more gradient directions was more sensitive to reductions in fractional anisotropy in Parkinsons disease, whilst the dataset with more b values was more sensitive to increases in mean diffusivity. Moreover, the areas of reduced fractional anisotropy were highly similar to areas of increased mean diffusivity in PD patients. Next, we compared two widely used analysis methods: tract-based spatial statistics identified reduced fractional anisotropy and increased mean diffusivity in Parkinsons disease in many of the major white matter tracts in the frontal and parietal lobes. Voxel-based analyses were less sensitive, with similar patterns of white matter pathology observed only at liberal statistical thresholds. We also used tract-based spatial statistics to identify correlations between a test of executive function (phonemic fluency), fractional anisotropy and mean diffusivity in prefrontal white matter in both Parkinsons disease patients and controls. These findings suggest that in Parkinsons disease there is widespread pathology of cerebral white matter, and furthermore, pathological white matter in the frontal lobe may be associated with executive dysfunction. Diffusion imaging protocols that prioritised the number of directions versus the number of b values were differentially sensitive to alternative markers of white matter pathology, such as fractional anisotropy and mean diffusivity.

Selective serotonin reuptake inhibition modulates response inhibition in Parkinson’s disease

Impulsivity is common in Parkinson’s disease. In a double-blind, placebo-controlled study with multi-modal imaging, Ye et al. reveal improved response inhibition in some patients receiving the SSRI citalopram, including those with advanced disease. Improvements correlated with preserved frontostriatal structural connectivity and drug-induced prefrontal activity, highlighting the need for patient stratification in trials.

The caudate: a key node in the neuronal network imbalance of insomnia?

Although insomnia is common and disabling, its neural correlates remain enigmatic. Stoffers et al. use structural and functional MRI to demonstrate that hyperarousal, its clearest characteristic, involves reduced recruitment and connectivity of the left caudate that may predispose to insomnia and perpetuate it.

Improving Response Inhibition in Parkinson's Disease with Atomoxetine

Background Dopaminergic drugs remain the mainstay of Parkinson’s disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm. Methods This pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging. Results Patients with Parkinson’s disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity. Conclusions This study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinson’s disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson’s disease.

Is Disturbed Intracortical Excitability a Stable Trait of Chronic Insomnia? A Study Using Transcranial Magnetic Stimulation Before and After Multimodal Sleep Therapy

BACKGROUND Chronic insomnia is a poorly understood disorder. Risk factors for developing chronic insomnia are largely unknown, yet disturbances in brain indexes of arousal seem to accompany the disorder. We here investigate whether insomnia patients and control participants differ with respect to brain responses to direct stimulation, i.e., cortical excitability. Transcranial magnetic stimulation (TMS) offers a method to directly investigate the excitability level of the human cerebral cortex in psychiatric and neurological disease. METHODS We investigated cortical excitability in 16 insomnia patients and 14 carefully matched control participants using absolute and relative amplitudes of motor evoked potentials in response to single- and paired-pulse stimulation using TMS. RESULTS Nonmedicated insomnia patients showed, first, an exaggerated absolute response to both suprathreshold single- and paired-pulse stimulation compared with control participants and second, a reduced relative response to paired-pulse stimulation at long interpulse intervals (i.e., a reduced intracortical facilitation). The abnormal excitability persisted despite sleep therapy that effectively improved sleep quality as well as behavioral and neuroimaging indexes of brain function. CONCLUSIONS The results suggest that a subtly disturbed intracortical excitability characterizes patients with chronic insomnia: a relatively reduced intracortical facilitation in the context of a globally increased absolute excitability. The findings do not resemble TMS findings after sleep deprivation or in sleep apnea and thus seem specific to insomnia. They may offer diagnostic value and implications for assessment of risk to develop this common and disabling disorder.

The medial frontal-prefrontal network for altered awareness and control of action in corticobasal syndrome

The volitional impairments of alien limb and apraxia are a defining feature of the corticobasal syndrome, but a limited understanding of their neurocognitive aetiology has hampered progress towards effective treatments. Here we combined several key methods to investigate the mechanism of impairments in voluntary action in corticobasal syndrome. We used a quantitative measure of awareness of action that is based on well-defined processes of motor control; structural and functional anatomical information; and evaluation against the clinical volitional disorders of corticobasal syndrome. In patients and healthy adults we measured ‘intentional binding’, the perceived temporal attraction between voluntary actions and their sensory effects. Patients showed increased binding of the perceived time of actions towards their effects. This increase correlated with the severity of alien limb and apraxia, which we suggest share a core deficit in motor control processes, through reduced precision in voluntary action signals. Structural neuroimaging analyses showed the behavioural variability in patients was related to changes in grey matter volume in pre-supplementary motor area, and changes in its underlying white matter tracts to prefrontal cortex. Moreover, changes in functional connectivity at rest between the pre-supplementary motor area and prefrontal cortex were proportional to changes in binding. These behavioural, structural and functional results converge to reveal the frontal network for altered awareness and control of voluntary action in corticobasal syndrome, and provide candidate markers to evaluate new therapies.

Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures

Recent studies indicate that selective noradrenergic (atomoxetine) and serotonergic (citalopram) reuptake inhibitors may improve response inhibition in selected patients with Parkinsons disease, restoring behavioral performance and brain activity. We reassessed the behavioral efficacy of these drugs in a larger cohort and developed predictive models to identify patient responders. We used a double‐blind randomized three‐way crossover design to investigate stopping efficiency in 34 patients with idiopathic Parkinsons disease after 40 mg atomoxetine, 30 mg citalopram, or placebo. Diffusion‐weighted and functional imaging measured microstructural properties and regional brain activations, respectively. We confirmed that Parkinsons disease impairs response inhibition. Overall, drug effects on response inhibition varied substantially across patients at both behavioral and brain activity levels. We therefore built binary classifiers with leave‐one‐out cross‐validation (LOOCV) to predict patients’ responses in terms of improved stopping efficiency. We identified two optimal models: (1) a “clinical” model that predicted the response of an individual patient with 77–79% accuracy for atomoxetine and citalopram, using clinically available information including age, cognitive status, and levodopa equivalent dose, and a simple diffusion‐weighted imaging scan; and (2) a “mechanistic” model that explained the behavioral response with 85% accuracy for each drug, using drug‐induced changes of brain activations in the striatum and presupplementary motor area from functional imaging. These data support growing evidence for the role of noradrenaline and serotonin in inhibitory control. Although noradrenergic and serotonergic drugs have highly variable effects in patients with Parkinsons disease, the individual patients response to each drug can be predicted using a pattern of clinical and neuroimaging features. Hum Brain Mapp 37:1026–1037, 2016.