Mental fatigue correlates with depression of task-related network and augmented DMN activity but spares the reward circuit.

Long-lasting and demanding cognitive activity typically leads to mental fatigue (MF). Indirect evidence suggests that MF may be caused by altered motivational processes. Here, we hypothesized that if MF consists in an alteration of motivational states, brain functional changes induced by MF could specifically affect the brain motivation circuit. In order to test this hypothesis, we devised a functional neuroimaging protocol to detect altered brain activity in reward-related brain regions in relation to cognitively induced mental fatigue. Twenty-five healthy participants underwent a FATIGUE and a CONTROL session on different days. In the FATIGUE session, MF was induced by performing a demanding cognitive task (adapted Stroop task) during 90 min, whereas in the CONTROL session, participants were asked to read magazines for the same period of time. We measured the neural consequences of the MF induction during a working memory task (Missing Number task) while modulating extrinsic motivation with block-wise variations in monetary reward. We also tracked participants' momentary fatigue, anxiety state and intrinsic motivation prior to and following the MF inducement and measurement. Accuracy on the Missing Number Task was lower in the FATIGUE than in the CONTROL condition. Furthermore, subjective MF, but not its behavioral manifestations, was associated with hypoactivity of the task-evoked neural responses. Importantly, activity in regions modulated by reward showed no differences between FATIGUE and CONTROL sessions. In parallel, subjective MF correlated with increased on-task activity and resting-state functional connectivity in the default mode network. These results indicate that subjective mental fatigue is not associated with altered activity in the brain motivation circuit but rather with hypoactivity in task-specific brain regions as well as relative increases of activity and connectivity in the default mode network during and after the task.

Effect of Distracting Background Speech in an Auditory Brain-Computer Interface.

Studies so far have analyzed the effect of distractor stimuli in different types of brain-computer interface (BCI). However, the effect of a background speech has not been studied using an auditory event-related potential (ERP-BCI), a convenient option when the visual path cannot be adopted by users. Thus, the aim of the present work is to examine the impact of a background speech on selection performance and user workload in auditory BCI systems. Eleven participants tested three conditions: (i) auditory BCI control condition, (ii) auditory BCI with a background speech to ignore (non-attentional condition), and (iii) auditory BCI while the user has to pay attention to the background speech (attentional condition). The results demonstrated that, despite no significant differences in performance, shared attention to auditory BCI and background speech required a higher cognitive workload. In addition, the P300 target stimuli in the non-attentional condition were significantly higher than those in the attentional condition for several channels. The non-attentional condition was the only condition that showed significant differences in the amplitude of the P300 between target and non-target stimuli. The present study indicates that background speech, especially when it is attended to, is an important interference that should be avoided while using an auditory BCI.

Insomnia does not affect heart rate changes when young adults watch humorous films: An exploratory study.

Emotional reactivity in insomnia is affected both subjectively and on a physiological level for negative emotional material, but little is known about reactions to positive stimuli. We here investigated whether in younger adult insomnia patients, presentation of short humorous films would lead to heart rate decreases during and after film viewing, as compared to heart rate changes when falling asleep. Investigating 20 participants with DSM-5-diagnosed insomnia and 18 participants without insomnia, we found that heart rate decreased when falling asleep, increased when watching humorous films and returned to normal values afterwards for all participants. Film-related heart rate increases were strongly related to humour ratings of the films. No differences were found between those with and without insomnia on subjective ratings of the films, film-related heart rate changes or when falling asleep. We conclude that the experience of positive daily life stimuli in younger adults is not affected by insomnia in our study, despite insomnia having a known more profound effect on negative stimuli. Future studies exploring insomnia-related autonomous nervous system responses combining different neurophysiological modalities should confirm our findings.

Application of Machine Learning to Arterial Spin Labeling in Mild Cognitive Impairment and Alzheimer Disease.

Purpose To investigate whether multivariate pattern recognition analysis of arterial spin labeling (ASL) perfusion maps can be used for classification and single-subject prediction of patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) and subjects with subjective cognitive decline (SCD) after using the W score method to remove confounding effects of sex and age. Materials and Methods Pseudocontinuous 3.0-T ASL images were acquired in 100 patients with probable AD; 60 patients with MCI, of whom 12 remained stable, 12 were converted to a diagnosis of AD, and 36 had no follow-up; 100 subjects with SCD; and 26 healthy control subjects. The AD, MCI, and SCD groups were divided into a sex- and age-matched training set (n = 130) and an independent prediction set (n = 130). Standardized perfusion scores adjusted for age and sex (W scores) were computed per voxel for each participant. Training of a support vector machine classifier was performed with diagnostic status and perfusion maps. Discrimination maps were extracted and used for single-subject classification in the prediction set. Prediction performance was assessed with receiver operating characteristic (ROC) analysis to generate an area under the ROC curve (AUC) and sensitivity and specificity distribution. Results Single-subject diagnosis in the prediction set by using the discrimination maps yielded excellent performance for AD versus SCD (AUC, 0.96; P < .01), good performance for AD versus MCI (AUC, 0.89; P < .01), and poor performance for MCI versus SCD (AUC, 0.63; P = .06). Application of the AD versus SCD discrimination map for prediction of MCI subgroups resulted in good performance for patients with MCI diagnosis converted to AD versus subjects with SCD (AUC, 0.84; P < .01) and fair performance for patients with MCI diagnosis converted to AD versus those with stable MCI (AUC, 0.71; P > .05). Conclusion With automated methods, age- and sex-adjusted ASL perfusion maps can be used to classify and predict diagnosis of AD, conversion of MCI to AD, stable MCI, and SCD with good to excellent accuracy and AUC values. © RSNA, 2016.

Impact of APOE-ɛ4 and family history of dementia on gray matter atrophy in cognitively healthy middle-aged adults.

The apolipoprotein E ε4 allele (APOE4) and family history of dementia (FH) are well-known risk factors for the development of sporadic Alzheimer's disease. We assessed the effects of these risk factors on gray matter (GM) volume in 295 cognitively healthy middle-aged community-dwelling subjects. Voxel-based morphometry was used to study GM volume differences between high- and low-risk subjects, based on APOE4 carriership (n = 74), first-degree FH (n = 228), or both (n = 62). No significant results were found using a corrected p value. Using a more lenient threshold (p < 0.001 and minimum cluster size of 100 voxels), APOE4 carriers had reduced GM in the striatum compared to noncarriers. Subjects with FH had reduced GM in right precuneus compared to subjects without FH. Maternal and paternal FH provided similar atrophy patterns. APOE4 carriers with FH had GM reductions in bilateral insula compared to subjects with neither APOE4 nor FH. We conclude that a family history of dementia and APOE4 carriership are both associated with regional GM decreases in cognitively healthy middle-aged subjects, with differential effects on brain regions typically affected in Alzheimer's disease.

Information Flow Between Resting-State Networks.

UNLABELLED: The resting brain dynamics self-organize into a finite number of correlated patterns known as resting-state networks (RSNs). It is well known that techniques such as independent component analysis can separate the brain activity at rest to provide such RSNs, but the specific pattern of interaction between RSNs is not yet fully understood. To this aim, we propose here a novel method to compute the information flow (IF) between different RSNs from resting-state magnetic resonance imaging. After hemodynamic response function blind deconvolution of all voxel signals, and under the hypothesis that RSNs define regions of interest, our method first uses principal component analysis to reduce dimensionality in each RSN to next compute IF (estimated here in terms of transfer entropy) between the different RSNs by systematically increasing k (the number of principal components used in the calculation). When k=1, this method is equivalent to computing IF using the average of all voxel activities in each RSN. For k≥1, our method calculates the k multivariate IF between the different RSNs. We find that the average IF among RSNs is dimension dependent, increasing from k=1 (i.e., the average voxel activity) up to a maximum occurring at k=5 and to finally decay to zero for k≥10. This suggests that a small number of components (close to five) is sufficient to describe the IF pattern between RSNs. Our method--addressing differences in IF between RSNs for any generic data--can be used for group comparison in health or disease. To illustrate this, we have calculated the inter-RSN IF in a data set of Alzheimer's disease (AD) to find that the most significant differences between AD and controls occurred for k=2, in addition to AD showing increased IF w.r.t. CONTROLS: The spatial localization of the k=2 component, within RSNs, allows the characterization of IF differences between AD and controls.

Reading networks in children with dyslexia compared to children with ocular motility disturbances revealed by fMRI.

Key PointsDyslexia is a neurological disorder with a genetic origin, but the underlying biological and cognitive causes are still being investigated.This study compares the brain activation pattern while reading in Spanish, a semitransparent language, in three groups of children: typically developing readers, dyslexic readers and readers with functional monocular vision.Based on our results Dyslexia would be a neurological disorder not related to vision impairments and would require a multidisciplinary treatment based on improving phonological awareness and language development. Developmental dyslexia is a neurological disorder the underlying biological and cognitive causes of which are still being investigated, a key point, because the findings will determine the best therapeutic approach to use. Using functional magnetic resonance imaging, we studied the brain activation pattern while reading in the language-related cortical areas from the two reading routes, phonological and orthographic, and the strength of their association with reading scores in 66 Spanish-speaking children aged 9-12 years divided into three groups: typically developing readers (controls), dyslexic readers and readers with monocular vision due to ocular motility disorders but with normal reading development, to assess whether (or not) the neuronal network for reading in children with dyslexia has similarities with that in children with impaired binocular vision due to ocular motility disorders. We found that Spanish-speaking children with dyslexia have a brain circuit for reading that differs from that in children with monocular vision. Individuals with dyslexia tend to hypoactivate some of the language-related areas in the left hemisphere engaged by the phonological route, especially the visual word form area and left Wernicke's area, and try to compensate this deficit by activating language-related areas related to the orthographic route, such as the anterior part of the visual word form area and the posterior part of both middle temporal gyri. That is, they seem to compensate for impairment in the phonological route through orthographic routes of both hemispheres. Our results suggest that ocular motility disturbances do not play a causal role in dyslexia. Dyslexia seems to be a neurological disorder that is unrelated to vision impairments and requires early recognition and multidisciplinary treatment, based on improving phonological awareness and language development, to achieve the best possible outcome.

Amyloid and its association with default network integrity in Alzheimer's disease.

The purpose of this study was to investigate the association between functional connectivity and ß-amyloid depositions in the default mode network (DMN) in Alzheimer's disease (AD), patients with mild cognitive impairment (MCI), and healthy elderly. Twenty-five patients with AD, 12 patients with MCI, and 18 healthy controls were included in the study. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in the DMN. In parallel, amyloid burden was measured in the same subjects using positron emission tomography with carbon-11-labeled Pittsburgh Compound-B as amyloid tracer. Functional connectivity of the DMN and amyloid deposition within the DMN were not associated across all subjects or within diagnostic groups. Longitudinal studies are needed to examine if amyloid depositions precede aberrant functional connectivity in the DMN.

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

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.

Functional segmentation of the hippocampus in the healthy human brain and in Alzheimer's disease.

In this study we segment the hippocampus according to functional connectivity assessed from resting state functional magnetic resonance images in healthy subjects and in patients with Alzheimer's disease (AD). We recorded the resting FMRI signal from 16 patients and 22 controls. We used seed-based functional correlation analyses to calculate partial correlations of all voxels in the hippocampus relative to characteristic regional signal changes in the thalamus, the prefrontal cortex (PFC) and the posterior cingulate cortex (PCC), while controlling for ventricular CSF and white matter signals. Group comparisons were carried out controlling for age, gender, hippocampal volume and brain volume. The strength of functional connectivity in each region also was correlated with neuropsychological measures. We found that the hippocampus can be segmented into three distinct functional subregions (head, body, and tail), according to the relative connectivity with PFC, PCC and thalamus, respectively. The AD group showed stronger hippocampus-PFC and weaker hippocampus-PCC functional connectivity, the magnitudes of which correlated with MMSE in both cases. The results are consistent with an adaptive role of the PFC in the context of progression of dysfunction in PCC during earlier stages of AD. Extension of our approach could integrate regional volume measures for the hippocampus with their functional connectivity patterns in ways that should increase sensitivity for assessment of AD onset and progression.

Resting-state brain networks in type 1 diabetic patients with and without microangiopathy and their relation to cognitive functions and disease variables.

Cognitive functioning depends on intact brain networks that can be assessed with functional magnetic resonance imaging (fMRI) techniques. We hypothesized that cognitive decrements in type 1 diabetes mellitus (T1DM) are associated with alterations in resting-state neural connectivity and that these changes vary according to the degree of microangiopathy. T1DM patients with (MA(+): n = 49) and without (MA(-): n = 52) microangiopathy were compared with 48 healthy control subjects. All completed a neuropsychological assessment and resting-state fMRI. Networks were identified using multisubject independent component analysis; specific group differences within each network were analyzed using the dual-regression method, corrected for confounding factors and multiple comparisons. Relative to control subjects, MA(-) patients showed increased connectivity in networks involved in motor and visual processes, whereas MA(+) patients showed decreased connectivity in networks involving attention, working memory, auditory and language processing, and motor and visual processes. Better information-processing speed and general cognitive ability were related to increased degree of connectivity. T1DM is associated with a functional reorganization of neural networks that varies, dependent on the presence or absence of microangiopathy.

Resting-state networks in awake five- to eight-year old children.

During the first 6-7 years of life children undergo a period of major neurocognitive development. Higher-order cognitive functions such as executive control of attention, encoding and retrieving of stored information and goal-directed behavior are present but less developed compared to older individuals. There is only very limited information from functional magnetic resonance imaging (fMRI) studies about the level of organization of functional networks in children in the early school period. In this study we perform continuous resting-state functional connectivity MRI in 5- to 8-year-old children in an awake state to identify and characterize resting-state networks (RSNs). Temporal concatenation independent component analysis (ICA) approach was applied to analyze the data. We identified 14 components consisting of regions known to be involved in visual and auditory processing, motor function, attention control, memory, and the default mode network (DMN). Most networks, in particular those supporting basic motor function and sensory related processing, had a robust functional organization similar to mature adult patterns. In contrast, the DMN and other RSNs involved in higher-order cognitive functions had immature characteristics, revealing incomplete and fragmented patterns indicating less developed functional connectivity. We therefore conclude that the DMN and other RSNs involved in higher order cognitive functioning are detectable, yet in an immature state, at an age when these cognitive abilities are mastered.

Gender-related differences in functional connectivity in multiple sclerosis.

BACKGROUND: Gender effects are strong in multiple sclerosis (MS), with male patients showing a worse clinical outcome than female patients. Functional reorganization of neural activity may contribute to limit disability, and possible gender differences in this process may have important clinical implications. OBJECTIVES: The aim of this study was to explore gender-related changes in functional connectivity and network efficiency in MS patients. Additionally, we explored the association of functional changes with cognitive function. METHODS: Sixty subjects were included in the study, matched for age, education level and intelligence quotient (IQ). Male and female patients were matched for disability, disease duration and white matter lesion load. Two cognitive domains often impaired in MS, i.e. visuospatial memory and information processing speed, were evaluated in all subjects. Functional connectivity between brain regions and network efficiency was explored using resting-state functional magnetic resonance imaging and graph analysis. Differences in cognitive and functional characteristics between groups, and correlations with cognitive performance, were examined. RESULTS: Male patients showed worse performance on cognitive tests than female and male controls, while female patients were cognitively normal. Decreases in functional connectivity and network efficiency, observed in male patients, correlated with reduced visuospatial memory (r = -0.6 and r = -0.5, respectively). In the control group, no cognitive differences were found between genders, despite differences in functional connectivity between healthy men and women. CONCLUSIONS: Functional connectivity differences were found in male patients only and were related to impaired visuospatial memory. These results underline the importance of gender in MS and require further investigation in larger and longitudinal studies.

Loss of 'small-world' networks in Alzheimer's disease: graph analysis of FMRI resting-state functional connectivity.

BACKGROUND: Local network connectivity disruptions in Alzheimer's disease patients have been found using graph analysis in BOLD fMRI. Other studies using MEG and cortical thickness measures, however, show more global long distance connectivity changes, both in functional and structural imaging data. The form and role of functional connectivity changes thus remains ambiguous. The current study shows more conclusive data on connectivity changes in early AD using graph analysis on resting-state condition fMRI data. METHODOLOGY/PRINCIPAL FINDINGS: 18 mild AD patients and 21 healthy age-matched control subjects without memory complaints were investigated in resting-state condition with MRI at 1.5 Tesla. Functional coupling between brain regions was calculated on the basis of pair-wise synchronizations between regional time-series. Local (cluster coefficient) and global (path length) network measures were quantitatively defined. Compared to controls, the characteristic path length of AD functional networks is closer to the theoretical values of random networks, while no significant differences were found in cluster coefficient. The whole-brain average synchronization does not differ between Alzheimer and healthy control groups. Post-hoc analysis of the regional synchronization reveals increased AD synchronization involving the frontal cortices and generalized decreases located at the parietal and occipital regions. This effectively translates in a global reduction of functional long-distance links between frontal and caudal brain regions. CONCLUSIONS/SIGNIFICANCE: We present evidence of AD-induced changes in global brain functional connectivity specifically affecting long-distance connectivity. This finding is highly relevant for it supports the anterior-posterior disconnection theory and its role in AD. Our results can be interpreted as reflecting the randomization of the brain functional networks in AD, further suggesting a loss of global information integration in disease.

Modulating spontaneous brain activity using repetitive transcranial magnetic stimulation.

BACKGROUND: When no specific stimulus or task is presented, spontaneous fluctuations in brain activity occur. Brain regions showing such coherent fluctuations are thought to form organized networks known as 'resting-state' networks, a main representation of which is the default mode network. Spontaneous brain activity shows abnormalities in several neurological and psychiatric diseases that may reflect disturbances of ongoing thought processes. Information about the degree to which such spontaneous brain activity can be modulated may prove helpful in the development of treatment options. We investigated the effect of offline low-frequency rTMS on spontaneous neural activity, as measured with fMRI, using a sequential independent-component-analysis and regression approach to investigate local changes within the default mode network. RESULTS: We show that rTMS applied over the left dorsolateral prefrontal cortex results in distal changes of neural activity, relative to the site of stimulation, and that these changes depend on the patterns of brain network activity during 'resting-state'. CONCLUSIONS: Whereas the proximal changes may reflect the off-line effect of direct stimulation of neural elements, the distal changes likely reflect modulation of functional connectivity.

3-D cytoarchitectonic parcellation of human orbitofrontal cortex correlation with postmortem MRI.

The orbitofrontal cortex (OFC) is located on the basal surface of the frontal lobe and is distinguished by its unique anatomical and functional features. Clinical and postmortem studies suggest the involvement of the orbitofrontal cortex in psychiatric disorders. However, the exact parcellation of this cortical region is still a matter of debate. Therefore, the goal of this study is to provide a detailed description of the extent of borders of individual orbitofrontal cortical areas using cytoarchitectonic criteria in a large sample of human brains, which could be applied by independent neuroanatomists. To make this microscopic parcellation useful to neuroimaging studies, magnetic resonance images of postmortem brains in the coronal plane were collected prior to the preparation of coronal histological sections from the same brains. A complete series of coronal sections from 6 normal human brains and partial sections from the frontal cortex of 21 normal human brains were stained with general histological and immunohistochemical methods specific for different cell-types. These sections were examined microscopically by two independent neuroanatomists (HBMU and GR) to achieve reproducible delineations. After the borders were determined, the tissue sections were superimposed on the corresponding magnetic resonance images. Based on our cytoarchitectonical criteria, Brodmann's areas 47 and 11 were included in the human orbitofrontal cortex. Area 47 was further subdivided into three medial (located on the medial, anterior and posterior orbital gyri) and two lateral (located on the lateral orbital gyrus) subareas. In addition, we observed an anterior-posterior gradient in the cytoarchitecture of areas 11 and 47. The transverse orbital sulcus corresponds roughly to the transition between the subregions of the anterior and posterior OFC. Finally, the present delineation is contrasted with an overview of the different published nomenclatures for the OFC parcellation.

Resting state networks change in clinically isolated syndrome.

Task-functional magnetic resonance imaging studies have shown that early cortical recruitment exists in multiple sclerosis, which can partly explain the discrepancy between conventional magnetic resonance imaging and clinical disability. The study of the brain 'at rest' may provide additional information, because task-induced metabolic changes are relatively small compared to the energy use of the resting brain. We therefore questioned whether functional changes exist at rest in the early phase of multiple sclerosis, and addressed this question by a network analysis of no-task functional magnetic resonance imaging data. Fourteen patients with symptoms suggestive of multiple sclerosis (clinically isolated syndrome), 31 patients with relapsing remitting multiple sclerosis and 41 healthy controls were included. Resting state functional magnetic resonance imaging data were brought to standard space using non-linear registration, and further analysed using multi-subject independent component analysis and individual time-course regression. Eight meaningful resting state networks were identified in our subjects and compared between the three groups with non-parametric permutation testing, using threshold-free cluster enhancement to correct for multiple comparisons. Additionally, quantitative measures of structural damage were obtained. Grey and white matter volumes, normalized for head size, were measured for each subject. White matter integrity was investigated with diffusion tensor measures that were compared between groups voxel-wise using tract-based spatial statistics. Patients with clinically isolated syndrome showed increased synchronization in six of the eight resting state networks, including the default mode network and sensorimotor network, compared to controls or relapsing remitting patients. No significant decreases were found in patients with clinically isolated syndrome. No significant resting state synchronization differences were found between relapsing remitting patients and controls. Normalized grey matter volume was decreased and white matter diffusivity measures were abnormal in relapsing remitting patients compared to controls, whereas no atrophy or diffusivity changes were found for the clinically isolated syndrome group. Thus, early synchronization changes are found in patients with clinically isolated syndrome that are suggestive of cortical reorganization of resting state networks. These changes are lost in patients with relapsing remitting multiple sclerosis with increasing brain damage, indicating that cortical reorganization of resting state networks is an early and finite phenomenon in multiple sclerosis.

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.

White matter tract integrity in aging and Alzheimer's disease.

The pattern of degenerative changes in the brain white matter (WM) in aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD) has been under debate. Methods of image analysis are an important factor affecting the outcomes of various studies. Here we used diffusion tensor imaging (DTI) to obtain fractional anisotropy (FA) measures of the WM in healthy young (n = 8), healthy elderly (n = 22), MCI (n = 8), and AD patients (n = 16). We then applied "tract-based spatial statistics" (TBSS) to study the effects of aging, MCI, and AD on WM integrity. Our results show that changes in WM integrity (that is, decreases in FA) are different between healthy aging and AD: in healthy older subjects compared with healthy young subjects decreased FA was primarily observed in frontal, parietal, and subcortical areas whereas in AD, compared with healthy older subjects, decreased FA was only observed in the left anterior temporal lobe. This different pattern of decreased anatomical connectivity in normal aging and AD suggests that AD is not merely accelerated aging.

Prefrontal hypoactivation and recovery in insomnia.

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.