Ysbrand D. van der Werf

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.

Presupplementary Motor Area Hyperactivity During Response Inhibition: A Candidate Endophenotype of Obsessive-Compulsive Disorder

OBJECTIVE Endophenotype studies of obsessive-compulsive disorder (OCD) may uncover heritable traits that are related to genetic susceptibility to OCD. Deficient response inhibition is a promising endophenotype of OCD, although its functional neural correlates have not been extensively studied. The authors sought to determine the functional neural correlates of response inhibition in a large sample of medication-free OCD patients and their unaffected siblings. METHOD Forty-one OCD patients, 17 of their siblings, and 37 matched healthy comparison subjects performed a stop-signal task during 3-T functional MRI. The stop-signal reaction time provided a behavioral measure of response inhibition. The neural correlates of response inhibition were assessed in a region-of-interest analysis that included the presupplementary motor area, inferior frontal gyrus, subthalamic nucleus, and inferior parietal cortex. RESULTS Patients with OCD had greater stop-signal reaction times relative to healthy comparison subjects. The numerical stop-signal reaction time difference between siblings and comparison subjects failed to reach significance. Both patients with OCD and their siblings showed greater activity in the left presupplementary motor area during successful inhibition relative to comparison subjects. Relative to both the comparison subjects and the siblings, patients with OCD showed decreased activity in the right inferior parietal cortex and inferior frontal gyrus. In patients and siblings, presupplementary motor area activity correlated negatively with stop-signal reaction time. CONCLUSIONS These findings suggest that presupplementary motor area hyperactivity is a neurocognitive endophenotype of OCD that is possibly related to inefficient neural processing within the presupplementary motor area itself. Patients with OCD further showed a state-dependent deficit in recruiting right inferior parietal cortex and inferior frontal gyrus, which may contribute to their inhibition deficit.

Thalamic volume predicts performance on tests of cognitive speed and decreases in healthy aging. A magnetic resonance imaging-based volumetric analysis.

Recent studies have indicated a role for the thalamus in attention, arousal and the capacity to perform tasks of speeded information processing. The present study evaluated the role of the thalamus in age-related cognitive decline by investigating the correlations between thalamic volume, cognition and age. This was done in 57 healthy subjects ranging from 21 to 82 years of age. All subjects underwent neurocognitive testing with information processing tests and structural magnetic resonance imaging. A significant decrease in volume of the thalamus with increasing age was found, relatively stronger than and independent of the decrease of total brain volume. The decrease of thalamic volume was apparent before the onset of loss of volume of the total brain. Over the age-span studied, the thalamic decrease in volume correlated with the diminished performance on tests of cognitive speed. Additionally, in young and middle-aged, but not in old subjects, the size of the thalamus predicted performance on tasks that require cognitive speed.

Frontal–striatal abnormalities underlying behaviours in the compulsive–impulsive spectrum

In this paper, we tentatively bring together the psychiatric, neurological and addiction perspectives on the impulsive-compulsive spectrum of neuropsychiatric disorders, in order to understand the pathophysiology of impulse control disorders (ICDs) in Parkinsons disease. In an attempt to try to pool the various levels of information we will therefore focus on three disorders within the impulse-compulsive spectrum, i.e., obsessive-compulsive disorder (OCD), ICDs in Parkinsons disease, and cocaine seeking behaviour. Whereas there are large differences between these three domains, each with their own nomenclature, hypotheses and study results, they share the focus on an imbalance within and between the frontal-striatal circuits as underlying substrate for the behaviours. For each disorder, we summarize the results from recent studies in order to describe in which way alterations in the frontal-striatal circuits contribute to the phenotype. The phenomenological overlap between ICDs in Parkinsons disease, addiction and OCD needs further investigation, since better understanding of the overlapping and differentiating characteristics will contribute to our understanding of the pathophysiology of the disturbances and treatment alternatives.

Parkinson's disease-related disorders in the impulsive-compulsive spectrum.

In Parkinson’s disease (PD), there is increasing evidence for disorders in the impulsive-compulsive spectrum, related to the disease itself, to the pharmacological management of this disease or to both. These disorders comprise dopamine deficiency syndrome (with immediate reward seeking behaviour), dopamine dependency syndrome (with addictive behaviour), dopamine dysregulation syndrome (with both addictive behaviour and stereotyped behaviour) and impulse control disorders (such as pathological gambling, compulsive shopping, binge eating and hypersexuality). These disorders are especially seen in PD patients with young age of onset, higher doses of antiparkinsonian drugs, pre-existent or current depression, pre-existing recreational drug or alcohol use, and high novelty seeking personality traits.Dopamine is not only implicated in voluntary movement control but also plays a significant role in the brain’s reward system and the modulation of behaviours. Therefore, most if not all drugnaïve PD patients will suffer dysphoria, leading to mild immediate reward seeking behaviour as a consequence of the striatal dopaminergic denervation. In some of these patients, during treatment, this may even lead to the intake of increasing quantities of levodopa, above those required to adequately treat motor parkinsonism, with all characteristics of a dopamine dependence syndrome. These patients may develop plastic changes in the striatal matrix leading to hyperkinesia, caused by extracellular striatal dopaminergic fluctuations due to pulsatile dopamine replacement therapy. As soon as these changes are also seen in the striatal striosomes, in the framework of a dopamine dysregulation syndrome, stereotyped behaviours (punding) may occur (supposedly due to dorsal versus ventral striatal overactivity). Finally, impulse control disorders are suggested as being pure adverse side-effects of dopamine replacement therapy. Obsessive-compulsive behaviour (caused by ventral to dorsal overactivity) so far has not been described in PD patients.Treatment of impulse control disorders is related to the underlying pathology. In the case of an intrinsic dopamine deficiency syndrome, treatment with dopamine replacement therapy, especially levodopa, will help. In the multifactorial (intrinsic and extrinsic) dopamine dependency and dysregulation syndromes, addictive behaviour might best be helped by psychosocial strategies, and punding by continuous dopaminergic receptor stimulation (or amantadine), hypothesized to reduce the plastic changes-induced hypersensitization. The extrinsic impulse control disorders might be best treated by reducing or replacing dopamine receptor agonists.

Compensatory Frontoparietal Activity During Working Memory: An Endophenotype of Obsessive- Compulsive Disorder

BACKGROUND Subtle deficits in executive functioning are present in patients with obsessive-compulsive disorder (OCD) and their first-degree relatives, suggesting involvement of the frontoparietal circuits. The neural correlates of working memory may be a neurocognitive endophenotype of OCD. METHODS Forty-three unmedicated OCD patients, 17 unaffected siblings, and 37 matched comparison subjects performed a visuospatial n-back task, with a baseline condition (N0) and three working memory load levels (N1, N2, N3) during functional magnetic resonance imaging. Task-related brain activity was compared between groups in frontoparietal regions of interest. Generalized psychophysiological interaction analyses were used to study task-related changes in functional connectivity. RESULTS Obsessive-compulsive disorder patients, compared with comparison subjects and siblings, showed increased error rates at N3. Compared with comparison subjects, OCD patients showed task-related hyperactivation in left dorsal frontal areas and left precuneus associated with better task performance. Siblings exhibited hyperactivation in a bilateral frontoparietal network. Increased task load was associated with increased task-related brain activity, but in OCD patients and siblings this increase was smaller from load N2 to N3 than in comparison subjects. Obsessive-compulsive disorder patients, compared with siblings and comparison subjects, showed increased task-related functional connectivity between frontal regions and bilateral amygdala. CONCLUSIONS These findings indicate that compensatory frontoparietal brain activity in OCD patients and their unaffected relatives preserves task performance at low task loads but is insufficient to maintain performance at high task loads. Frontoparietal dysfunction may constitute a neurocognitive endophenotype for OCD, possibly reflecting limbic interference with and neural inefficiency within the frontoparietal network.

Functional adaptive changes within the hippocampal memory system of patients with multiple sclerosis

Memory deficits are highly prevalent in multiple sclerosis (MS). As the hippocampus is crucial to memory processing, a functional magnetic resonance imaging (fMRI) task was used to investigate changes in hippocampal function in MS patients with and without cognitive decline. Fifty patients with MS, (34 cognitively preserved (CP) and 16 cognitively impaired (CI)) and 30 healthy controls completed an episodic memory fMRI task (encoding and retrieval) that was used to specifically activate the hippocampus. During encoding of correctly remembered items, increased brain activation was seen in the parahippocampal areas bilaterally and in the left anterior cingulate gyrus in the CP patients compared to the controls (unclustered, Z ≥ 3.1, P ≤ 0.001). No brain areas showed less activation. In CI patients the right (para)hippocampal areas and the prefrontal cortex showed less brain activation compared to controls (cluster‐corrected, P < 0.05). The posterior cingulate gyrus and the left precuneus showed increased activation in CI patients when compared to controls (unclustered Z ≥ 3.1, P ≤ 0.001). No significant differences were found on structural MRI measures between the CP and CI patients. These results suggest the presence of functional adaptation in the memory network before cognitive decline becomes evident in MS, as displayed by the increased brain activation in the hippocampal‐cingulate memory system in CP patients. Interestingly, CI patients showed less activation in the hippocampal network during correct encoding. These findings are important for future cognitive therapeutic studies, since cognitive intervention might be most effective before cognitive impairment is present and when adaptive changes of the brain are most prominent. Hum Brain Mapp 33:2268–2280, 2012.

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.