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Study Objectives: Emotional reactivity to negative stimuli has been investigated in insomnia, but little is known about emotional reactivity to positive stimuli and its neural representation., Methods: We used 3 Tesla functional magnetic resonance imaging (fMRI) to determine neural reactivity during the presentation of standardized short, 10- to 40-seconds, humorous films in patients with insomnia (n = 20, 18 females, aged 27.7 +/- 8.6 years) and age-matched individuals without insomnia (n = 20, 19 females, aged 26.7 +/- 7.0 years) and assessed humor ratings through a visual analog scale. Seed-based functional connectivity was analyzed for the left and right amygdalas (lAMYG and rAMYG, respectively) networks: group-level mixed-effects analysis (FLAME; FMRIB Software Library [FSL]) was used to compare amygdala connectivity maps between groups., Results: fMRI seed-based analysis of the amygdala revealed stronger neural reactivity in patients with insomnia than in controls in several brain network clusters within the reward brain network, without humor rating differences between groups (p = 0.6). For lAMYG connectivity, cluster maxima were in the left caudate (Z = 3.88), left putamen (Z = 3.79), and left anterior cingulate gyrus (Z = 4.11), whereas for rAMYG connectivity, cluster maxima were in the left caudate (Z = 4.05), right insula (Z = 3.83), and left anterior cingulate gyrus (Z = 4.29). Cluster maxima of the rAMYG network were correlated with hyperarousal scores in patients with insomnia only., Conclusions: The presentation of humorous films leads to increased brain activity in the neural reward network for patients with insomnia compared with controls, related to hyperarousal features in patients with insomnia, in the absence of humor rating group differences. These novel findings may benefit insomnia treatment interventions., Clinical Trial: The Sleepless Brain: Neuroimaging Support for a Differential Diagnosis of Insomnia (SOMNET). ClinicalTrials.gov identifier: NCT02821234; https://clinicaltrials.gov/ct2/show/NCT02821234., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

While there is an extensive literature on predisposing, precipitating, coping, and perpetuating factors in those with chronic insomnia, very little work has been undertaken to evaluate these factors over the early developmental course of insomnia. The present aim was to determine whether several hypothesized factors in each domain (predisposing, precipitating, coping, and perpetuating), assessed during an episode of acute insomnia (AI), are related to its persistence or remission to normal sleep. Participants comprised n = 140 people with AI and n = 737 normal sleepers (NS) recruited from the general public. Participants completed measures assessing predisposing characteristics (personality traits, arousal predisposition, and insomnia vulnerability), precipitating events and outcomes (life events, perceived stress, anxiety, and depression), coping styles (thought control strategies and coping styles), and perpetuating factors (sleep preoccupation, pre-sleep arousal, dysfunctional beliefs, and fatigue). Additionally, insomnia status (from AI at baseline to its persistence or natural remission [NR]) was assessed 1 month later (n = 129). Baseline differences between NS and individuals with AI were observed in each domain with increasing age, lower openness to experience and conscientiousness, higher insomnia severity, levels of anxiety, and affective sleep preoccupation significantly predicting AI status. Further, a previous episode of insomnia, higher depression scores, and affective sleep preoccupation scores significantly predicted its persistence, as opposed to its NR. Results are discussed with reference to the conceptualization of insomnia and how the findings may influence the design of preventative interventions to circumvent the transition from acute to chronic insomnia., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Study Objectives: The study objectives were to examine accidental risks associated with insomnia or hypnotic medications, and how these risk factors interact with sex and age., Methods: A population-based sample of 3,413 adults (Mage = 49.0 years old; 61.5% female), with or without insomnia, were surveyed annually for five consecutive years about their sleep patterns, sleep medication usage, and road collisions., Results: There was a significant risk of reporting road collisions associated with insomnia (hazard ratio [HR] = 1.20; 95% confidence interval [CI] = 1.00-1.45) and daytime fatigue (HR = 1.21; 95% CI = 1.01-1.47). Insomnia and its daytime consequences were perceived to have played some contributory role in 40% of the reported collisions. Both chronic (HR = 1.50; 95% CI = 1.17-1.91) and regular use of sleep medications (HR = 1.58; 95% CI = 1.16-2.14) were associated with higher accidental risks, as well as being young female with insomnia and reporting excessive daytime sleepiness., Conclusions: Both insomnia and use of sleep medications are associated with significant risks of road collisions, possibly because of or in association with some of their residual daytime consequences (i.e. fatigue and poor concentration). The findings also highlight a new group of at-risk patients, i.e. young women reporting insomnia and excessive daytime sleepiness., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Impulsivity is common in Parkinson's disease even in the absence of impulse control disorders. It is likely to be multifactorial, including a dopaminergic 'overdose' and structural changes in the frontostriatal circuits for motor control. In addition, we proposed that changes in serotonergic projections to the forebrain also contribute to response inhibition in Parkinson's disease, based on preclinical animal and human studies. We therefore examined whether the selective serotonin reuptake inhibitor citalopram improves response inhibition, in terms of both behaviour and the efficiency of underlying neural mechanisms. This multimodal magnetic resonance imaging study used a double-blind randomized placebo-controlled crossover design with an integrated Stop-Signal and NoGo paradigm. Twenty-one patients with idiopathic Parkinson's disease (46-76 years old, 11 male, Hoehn and Yahr stage 1.5-3) received 30 mg citalopram or placebo in addition to their usual dopaminergic medication in two separate sessions. Twenty matched healthy control subjects (54-74 years old, 12 male) were tested without medication. The effects of disease and drug on behavioural performance and regional brain activity were analysed using general linear models. In addition, anatomical connectivity was examined using diffusion tensor imaging and tract-based spatial statistics. We confirmed that Parkinson's disease caused impairment in response inhibition, with longer Stop-Signal Reaction Time and more NoGo errors under placebo compared with controls, without affecting Go reaction times. This was associated with less stop-specific activation in the right inferior frontal cortex, but no significant difference in NoGo-related activation. Although there was no beneficial main effect of citalopram, it reduced Stop-Signal Reaction Time and NoGo errors, and enhanced inferior frontal activation, in patients with relatively more severe disease (higher Unified Parkinson's Disease Rating Scale motor score). The behavioural effect correlated with the citalopram-induced enhancement of prefrontal activation and the strength of preserved structural connectivity between the frontal and striatal regions. In conclusion, the behavioural effect of citalopram on response inhibition depends on individual differences in prefrontal cortical activation and frontostriatal connectivity. The correlation between disease severity and the effect of citalopram on response inhibition may be due to the progressive loss of forebrain serotonergic projections. These results contribute to a broader understanding of the critical roles of serotonin in regulating cognitive and behavioural control, as well as new strategies for patient stratification in clinical trials of serotonergic treatments in Parkinson's disease.

Insomnia is prevalent, severe and partially heritable. Unfortunately, its neuronal correlates remain enigmatic, hampering the development of mechanistic models and rational treatments. Consistently reported impairments concern fragmented sleep, hyper-arousal and executive dysfunction. Because fronto-striatal networks could well play a role in sleep, arousal regulation and executive functioning, the present series of studies used an executive task to evaluate fronto-striatal functioning in disturbed sleep. Patients with insomnia showed reduced recruitment of the head of the left caudate nucleus during executive functioning, which was not secondary to altered performance or baseline perfusion. Individual differences in caudate recruitment were associated with hyper-arousal severity. Seed-based functional connectivity analysis suggested that attenuated input from a projecting orbitofrontal area with reduced grey matter density contributes to altered caudate recruitment in patients with insomnia. Attenuated caudate recruitment persisted after successful treatment of insomnia, warranting evaluation as a potential vulnerability trait. A similar selective reduction in caudate recruitment could be elicited in participants without sleep complaints by slow-wave sleep fragmentation, providing a model to facilitate investigation of the causes and consequences of insomnia.

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.

We have previously shown that patients with Parkinson's disease (PD) perseverate in their choice of action relative to healthy controls, and that this is affected by dopaminergic medication (Hughes LE, Barker RA, Owen AM, Rowe JB. 2010. Parkinson's disease and healthy aging: Independent and interacting effects on action selection. Hum Brain Mapp. 31:1886-1899). To understand further the neural basis of these phenomena, we used a new task that manipulated the options to repeat responses. Seventeen patients with idiopathic PD were studied both "on" and "off" dopaminergic medication and 18 healthy adults were scanned twice as controls. All subjects performed a right-handed 3-choice button press task, which controlled the availability of repeatable responses. The frequency of choosing to repeat a response (a form of perseveration) in patients was related to dopamine therapy and disease severity as a "U-shaped" function. For repetitive trials, this "U-shaped" relationship was also reflected in the BOLD response in the caudate nuclei and ventrolateral prefrontal cortex. Our results support a U-shaped model of optimized cortico-striatal circuit function and clearly demonstrate that flexibility in response choice is modulated by an interaction of dopamine and disease severity.

Study Objectives: Although subjective complaints about daytime cognitive functioning are an essential symptom of chronic insomnia, abnormalities in functional brain activation have not previously been investigated. This study was designed to investigate functional brain activation differences as a possible result of chronic insomnia, and the reversibility of these differences after nonmedicated sleep therapy., Design: Insomniacs and carefully matched controls underwent functional magnetic resonance imaging (fMRI) scanning during the performance of a category and a letter fluency task. Insomniacs were randomly assigned to either a 6-week period of nonpharmacological sleep therapy or a wait list period, after which fMRI scanning was repeated using parallel tasks. Task-related brain activation and number of generated words were considered as outcome measures., Setting: The outpatient sleep clinic of the VU University Medical Center, Department of Clinical Neurophysiology; fMRI was performed at the Department of Radiology., Participants: Twenty-one patients suffering from chronic insomnia and 12 matched controls., Interventions: Nonpharmacological sleep therapy for 6 weeks, consisting of cognitive behavioral therapy, body temperature and bright light interventions, sleep hygiene, and physical activity counseling., Measurement and Results: Compared to controls, insomnia patients showed hypoactivation of the medial and inferior prefrontal cortical areas (Brodmann Area 9, 44-45), which recovered after sleep therapy but not after a wait list period., Conclusions: Insomnia interferes in a reversible fashion with activation of the prefrontal cortical system during daytime task performance.