Dynamic reconfigurations of brain networks in depressive and anxiety disorders: The influence of antidepressants.

Major Depressive Disorder (MDD) and anxiety disorders are highly comorbid recurrent psychiatric disorders. Reduced dynamic reconfiguration of brain regions across subnetworks may play a critical role underlying these deficits, with indications of normalization after treatment with antidepressants. This study investigated dynamic reconfigurations in controls and individuals with a current MDD and/or anxiety disorder including antidepressant users and non-users in a large sample (N = 207) of adults. We quantified the number of subnetworks a region switched to (promiscuity) as well as the total number of switches (flexibility). Average whole-brain (i.e., global) values and subnetwork-specific values were compared between diagnosis and antidepressant groups. No differences in reconfiguration dynamics were found between individuals with a current MDD (N = 49), anxiety disorder (N = 46), comorbid MDD and anxiety disorder (N = 55), or controls (N = 57). Global and sensorimotor network (SMN) promiscuity and flexibility were higher in antidepressant users (N = 49, regardless of diagnosis) compared to non-users (N = 101) and controls. Dynamic reconfigurations were considerably higher in antidepressant users relative to non-users and controls, but not significantly altered in individuals with a MDD and/or anxiety disorder. The increase in antidepressant users was apparent across the whole brain and in the SMN when investigating subnetworks. These findings help disentangle how antidepressants improve symptoms.

Sleep as a window to target traumatic memories.

Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder in which traumatic memories result in flashbacks and nightmares. With one-third of patients not responding to standard exposure-based psychotherapy, new treatment strategies are needed. Sleep offers a unique time window to enhance therapeutic efficacy. Traumatic memories that are neutralized in therapy need to be stored back into memory (consolidated) during sleep to solidify the treatment effect. New basic research shows that memory consolidation can be enhanced by presenting sounds or scents that were linked to the memory at encoding, again during sleep. This procedure, termed targeted memory reactivation (TMR), has, despite its clinical potential, not been tested in (PTSD) patients. In this narrative review, we explore the potential of TMR as a new sleep-based treatment for PTSD. First we provide the necessary background on the memory and sleep principles underlying PTSD as well as the present applications and conditional factors of TMR. Then, we will discuss the outstanding questions and most promising experimental avenues when testing TMR to treat traumatic memories.

Associations between sex hormones, sleep problems and depression: A systematic review.

Sleep problems and depression are both common and have a high impact on quality of life. They are also strongly associated and commonly occur together. During the reproductive age, both sleep problems and depression are almost twice as common in women than men. Epidemiological studies show that women experience more sleep problems and depressive symptoms around times when sex hormones change, such as puberty and menopause, but it is unclear what effect sex hormones have on sleep problems and depression. This systematic review aims to summarize and evaluate studies that investigated the relationship between sex hormones, sleep and depression. Systematic search resulted in 2895 articles, of which 13 met inclusion criteria. Depressed patients showed worse sleep than controls, but no significant difference in endogenous hormone levels was found. Additionally, higher endogenous estrogen was associated with better sleep in controls, but associations between endogenous sex hormones and depressive symptoms were inconclusive. More research on the effect of sex hormones on sleep and depression is necessary.

[Anxiety, depression and sleep disorders in Parkinson's disease: a complex interaction between body and mind]. / Angst, depressie en slaapproblemen bij de ziekte van Parkinson: een complexe interactie tussen lichaam en geest.

BACKGROUND: Anxiety and depression in Parkinson's disease (PD) are often unrecognized, partially due to a complex relationship with sleep disorders and other PD-related symptoms.
AIM: To gain more insight in anxiety, depression and sleep disorders in PD, their reciprocal interaction and relationship with other (non)motor symptoms.
METHOD: With three epidemiological studies in this thesis article we describe: the symptom dimensions of anxiety, motor symptoms and autonomic failure; predictors of the course of anxiety; and the temporal relationship between anxiety, depression and insomnia in PD.
RESULTS: Anxiety in PD has one affective and various somatic symptom dimensions. There is a symptomatic overlap between anxiety and symptoms of motor and autonomic dysfunctions. Anxiety, depression and impulsive-compulsive behaviors in de novo PD show a parallel course. Cognitive dysfunctions and REM-sleep behaviour disorder are risk factors for anxiety in PD patients. The relationship between insomnia and anxiety and depression is bi-directional.
CONCLUSION: There is an overlap, co-morbidity and interaction between anxiety, depression, sleep disorders and (non)motor symptoms, which warrants a multi-disciplinary approach to PD. Sleep disorders and cognitive dysfunctions may provide starting points for treatment and preventions of anxiety in PD.

rTMS affects working memory performance, brain activation and functional connectivity in patients with multiple sclerosis.

OBJECTIVE: To investigate the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the right dorsolateral prefrontal cortex (DLPFC) on working memory performance, while measuring task-related brain activation and task-related brain connectivity in patients with multiple sclerosis (MS). METHODS: 17 patients with MS and 11 healthy controls (HCs) underwent 3 experimental sessions (baseline, real-rTMS, sham-rTMS), all including an N-back task (3 task loads: N1, N2, N3; control condition: N0) inside the MR scanner. Prior to imaging, real-rTMS (10 Hz) was applied to the right DLPFC. The stimulation site was defined based on individually assessed N-back task activation at baseline and located using neuronavigation. Changes in whole brain functional activation and functional connectivity with the right DLPFC were calculated. RESULTS: N-back task accuracy (N2 and N3) improved after real-rTMS (and not after sham-rTMS) compared with baseline (p=0.029 and p=0.015, respectively), only in patients. At baseline, patients with MS, compared with HCs, showed higher task-related frontal activation (left DLPFC, N2>N0), which disappeared after real-rTMS. Task-related (N1>N0) functional connectivity between the right DLPFC and the right caudate nucleus and bilateral (para)cingulate gyrus increased in patients after real-rTMS when compared with sham stimulation. CONCLUSIONS: In patients with MS, N-back accuracy improved while frontal hyperactivation (seen at baseline relative to HCs) disappeared after real-rTMS. Together with the changes in functional connectivity after real-rTMS in patients, these findings may represent an rTMS-induced change in network efficiency in patients with MS, shifting patients' brain function towards the healthy situation. This implicates a potentially relevant role for rTMS in cognitive rehabilitation in MS.

The role of sleep on cognition and functional connectivity in patients with multiple sclerosis.

Sleep disturbances are common in multiple sclerosis (MS), but its impact on cognition and functional connectivity (FC) of the hippocampus and thalamus is unknown. Therefore, we investigated the relationship between sleep disturbances, cognitive functioning and resting-state (RS) FC of the hippocampus and thalamus in MS. 71 MS patients and 40 healthy controls underwent neuropsychological testing and filled out self-report questionnaires (anxiety, depression, fatigue, and subjective cognitive problems). Sleep disturbances were assed with the five-item version of the Athens Insomnia Scale. Hippocampal and thalamic volume and RS FC of these regions were determined. Twenty-three patients were categorized as sleep disturbed and 48 as normal sleeping. No differences were found between disturbed and normal sleeping patients concerning cognition and structural MRI. Sleep disturbed patients reported more subjective cognitive problems, and displayed decreased FC between the thalamus and middle and superior frontal gyrus, inferior frontal operculum, anterior cingulate cortex, inferior parietal gyrus, precuneus, and angular gyrus compared to normal sleeping patients. We conclude that sleep disturbances in MS are not (directly) related to objective cognitive functioning, but rather to subjective cognitive problems. In addition, sleep disturbances in MS seem to coincide with a specific pattern of decreased thalamic FC.

Emotion regulation before and after transcranial magnetic stimulation in obsessive compulsive disorder.

BACKGROUND: Impaired emotion regulation may underlie exaggerated emotional reactivity in patients with obsessive compulsive disorder (OCD), yet instructed emotion regulation has never been studied in the disorder. METHOD: This study aimed to assess the neural correlates of emotion processing and regulation in 43 medication-free OCD patients and 38 matched healthy controls, and additionally test if these can be modulated by stimulatory (patients) and inhibitory (controls) repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (dlPFC). Participants performed an emotion regulation task during functional magnetic resonance imaging before and after a single session of randomly assigned real or sham rTMS. Effect of group and rTMS were assessed on self-reported distress ratings and brain activity in frontal-limbic regions of interest. RESULTS: Patients had higher distress ratings than controls during emotion provocation, but similar rates of distress reduction after voluntary emotion regulation. OCD patients compared with controls showed altered amygdala responsiveness during symptom provocation and diminished left dlPFC activity and frontal-amygdala connectivity during emotion regulation. Real v. sham dlPFC stimulation differentially modulated frontal-amygdala connectivity during emotion regulation in OCD patients. CONCLUSIONS: We propose that the increased emotional reactivity in OCD may be due to a deficit in emotion regulation caused by a failure of cognitive control exerted by the dorsal frontal cortex. Modulatory rTMS over the left dlPFC may influence automatic emotion regulation capabilities by influencing frontal-limbic connectivity.

Novelty processing and memory formation in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is characterized by a degeneration of nigrostriatal dopaminergic cells, resulting in dopamine depletion. This depletion is counteracted through dopamine replacement therapy (DRT). Dopamine has been suggested to affect novelty processing and memory, which suggests that these processes are also implicated in PD and that DRT could affect them. OBJECTIVE: To investigate word learning and novelty processing in patients with PD as indexed by the P2 and P3 event-related potential components, and the role of DRT in these processes. METHODS: 21 patients with PD and 21 matched healthy controls were included. Patients with PD were tested on and off DRT in two sessions in a counterbalanced design, and healthy controls were tested twice without intervention. Electroencephalogram (EEG) was measured while participants performed a word learning Von Restorff task. RESULTS: Healthy controls showed the typical Von Restorff effect, with better memory for words that were presented in novel fonts, than for words presented in standard font. Surprisingly, this effect was reversed in the patients with PD. In line with the behavioral findings, the P3 was larger for novel than for standard font words in healthy controls, but not in patients with PD. For both groups the P2 and P3 event-related components were larger for recalled versus forgotten words. DRT did not affect these processes. CONCLUSIONS: Learning of novel information is compromised in patients with PD. Likewise, the P2 and P3 components that predict successful memory encoding are reduced in PD patients. This was true both on and off DRT, suggesting that these findings reflect abnormalities in learning and memory in PD that are not resolved by dopaminergic medication.

Gray matter differences contribute to variation in cognitive performance in Parkinson's disease.

BACKGROUND AND PURPOSE: A substantial proportion of patients with Parkinson's disease (PD) suffer from cognitive deficits, although there is a large variability in the severity of these impairments. Whilst the cognitive deficits are often attributed to monoaminergic changes, there is evidence that alterations in structural brain volume also play a role. The aim of our study was to gain more insight into the variability of cognitive performance amongst PD patients by examining the relation between regional gray matter (GM) volume and cognitive performance. METHODS: Linear regression analyses were performed between task performance and GM volume for six neuropsychological tasks within a group of 93 PD patients; they were additionally compared at a group level with matched healthy controls, using voxel-based morphometry. RESULTS: Our most important findings were positive correlations between GM volume and cognitive performance for (i) parahippocampal gyrus and verbal memory, (ii) medial temporal lobe and putamen and visuospatial memory, and (iii) middle temporal gyrus and frontal lobe and verbal fluency. In addition, decreased GM volume was found in the frontal, parietal and temporal cortices of PD patients compared with matched healthy controls. CONCLUSIONS: It is argued that the large variability in cognitive function across PD patients is partly mediated by GM volume differences in the implicated areas. Volume differences in these brain regions do not discriminate between patients and controls but explain cognitive variation within the patient population.

Slow brain oscillations of sleep, resting state, and vigilance.

The most important quest of cognitive neuroscience may be to unravel the mechanisms by which the brain selects, links, consolidates, and integrates new information into its neuronal network, while preventing saturation to occur. During the past decade, neuroscientists working within several disciplines have observed an important involvement of the specific types of brain oscillations that occur during sleep--the cortical slow oscillations; during the resting state--the fMRI resting state networks including the default-mode network (DMN); and during task performance--the performance modulations that link as well to modulations in electroencephalography or magnetoencephalography frequency content. Understanding the role of these slow oscillations thus appears to be essential for our fundamental understanding of brain function. Brain activity is characterized by oscillations occurring in spike frequency, field potentials or blood oxygen level-dependent functional magnetic resonance imaging signals. Environmental stimuli, reaching the brain through our senses, activate or inactivate neuronal populations and modulate ongoing activity. The effect they sort is to a large extent determined by the momentary state of the slow endogenous oscillations of the brain. In the absence of sensory input, as is the case during rest or sleep, brain activity does not cease. Rather, its oscillations continue and change with respect to their dominant frequencies and coupling topography. This chapter briefly introduces the topics that will be addressed in this dedicated volume of Progress in Brain Research on slow oscillations and sets the stage for excellent papers discussing their molecular, cellular, network physiological and cognitive performance aspects. Getting to know about slow oscillations is essential for our understanding of plasticity, memory, brain structure from synapse to DMN, cognition, consciousness, and ultimately for our understanding of the mechanisms and functions of sleep and vigilance.

Dynamics underlying spontaneous human alpha oscillations: a data-driven approach.

Although the cognitive and clinical correlates of spontaneous human alpha oscillations as recorded with electroencephalography (EEG) or magnetoencephalography (MEG) are well documented, the dynamics underlying these oscillations is still a matter of debate. This study proposes a data-driven method to reveal the dynamics of these oscillations. It demonstrates that spontaneous human alpha oscillations as recorded with MEG can be viewed as noise-perturbed damped harmonic oscillations. This provides evidence for the hypothesis that these oscillations reflect filtered noise and hence do not possess limit-cycle dynamics. To illustrate the use of the model, we apply it to two data-sets in which a decrease in alpha power can be observed across conditions. The associated differences in the estimated model parameters show that observed decreases in alpha power are associated with different kinds of changes in the dynamics. Thus, the model parameters are useful dynamical biomarkers for spontaneous human alpha oscillations.

Common limbic and frontal-striatal disturbances in patients with obsessive compulsive disorder, panic disorder and hypochondriasis.

BACKGROUND: Direct comparisons of brain function between obsessive compulsive disorder (OCD) and other anxiety or OCD spectrum disorders are rare. This study aimed to investigate the specificity of altered frontal-striatal and limbic activations during planning in OCD, a prototypical anxiety disorder (panic disorder) and a putative OCD spectrum disorder (hypochondriasis). METHOD: The Tower of London task, a 'frontal-striatal' task, was used during functional magnetic resonance imaging measurements in 50 unmedicated patients, diagnosed with OCD (n=22), panic disorder (n=14) or hypochondriasis (n=14), and in 22 healthy subjects. Blood oxygen level-dependent (BOLD) signal changes were calculated for contrasts of interest (planning versus baseline and task load effects). Moreover, correlations between BOLD responses and both task performance and state anxiety were analysed. RESULTS: Overall, patients showed a decreased recruitment of the precuneus, caudate nucleus, globus pallidus and thalamus, compared with healthy controls. There were no statistically significant differences in brain activation between the three patient groups. State anxiety was negatively correlated with dorsal frontal-striatal activation. Task performance was positively correlated with dorsal frontal-striatal recruitment and negatively correlated with limbic and ventral frontal-striatal recruitment. Multiple regression models showed that adequate task performance was best explained by independent contributions from dorsolateral prefrontal cortex (positive correlation) and amygdala (negative correlation), even after controlling for state anxiety. CONCLUSIONS: Patients with OCD, panic disorder and hypochondriasis share similar alterations in frontal-striatal brain regions during a planning task, presumably partly related to increased limbic activation.

[Impulse control disorders in Parkinson's disease]. / Impulscontrolestoornissen bij de ziekte van Parkinson en de relatie tot andere stoornissen binnen het impulsieve-compulsieve spectrum.

BACKGROUND: Parkinson's disease is characterised not only by the classic triad of bradykinesia, rigidity and tremor, but also by the frequent occurrence of various non-motor symptoms such as the impulse control disorders (pathological gambling, hypersexuality, compulsive buying, binge eating, punding and dopamine dependency). AIM: To increase insight into the clinical presentation, risk factors, treatment and the underlying pathophysiological mechanisms of impulse control disorders in Parkinson's disease. METHOD: Relevant literature was reviewed. RESULTS: Impulse control disorders belong to an important group of neuropsychiatric disorders that occur at some point in 5-10% of patients with Parkinson's disease. They generally occur in conjunction with dopaminergic medication and can have a marked social, relational and/ or financial impact. CONCLUSION: Early recognition of impulse control disorders in Parkinson's disease is important and a close collaboration between the neurologist and the psychiatrist is essential in order to ensure correct diagnosis and the best possible treatment. Impulse control disorders in Parkinson's disease show considerable phenomenological overlap with other repetitive behaviours within the impulsive-compulsive spectrum of disorders to which the obsessive-compulsive disorders and addiction disorders belong. The overlap can possibly be explained by a shared pathophysiological mechanism involving an imbalance between the direct and indirect pathways of the dorsal and ventral frontal-striatal circuits.

Observations on the cortical silent period in Parkinson's disease.

Transcranial magnetic stimulation is a tool in the neurosciences to study motor functions and nervous disorders, amongst others. Single pulses of TMS applied over the primary motor cortex lead to a so-called cortical silent period in the recording from the corresponding muscle, i.e. a period of approximately 100ms with no muscle activity. We here show that in Parkinson's disease (PD), this cortical silent period in some cases is interrupted by short bursts of EMG activity. We describe in detail these interruptions in two patients with PD. These interruptions may number up to 3 per cortical silent period and show a consistent frequency across trials and hemispheres within a given patient; the two patients described here do differ, however, in the time-delay of the interruptions and hence the induced frequency. For one patient, the frequency of the interruptions proved to be around 13 Hz, the other patient showed a frequency of around 17 Hz. The results corroborate earlier findings of cortical oscillations elicited by pulses of TMS and may be related to abnormal oscillatory activity found in the cortical-subcortical motor system in PD.

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.

Neuropsychology of infarctions in the thalamus: a review.

From a review of the literature on the consequences of thalamic infarctions, it may be concluded that memory problems taking the form of an amnesic syndrome are dependent upon the integrity of the mammillo-thalamic tract (MTT). Memory problems incompatible with an amnesic syndrome however, appear to result from thalamic infarctions involving other areas of the thalamus but which leave MTT intact. In contrast, executive dysfunctions could not be shown so readily to depend upon a single structure of the thalamus. The results indicate that damage to the mediodorsal nucleus of the thalamus, the midline nuclei or the intralaminar nuclei, or a combined lesion of these structures may be responsible for deficits of executive functioning.

Brain correlates of memory dysfunction in alcoholic Korsakoff's syndrome.

OBJECTIVES: To investigate the relation between anterograde amnesia and atrophy of brain structures involved in memory processing in alcoholic Korsakoff's syndrome. METHODS: The volume of brain structures involved in memory processing was measured with MRI from 13 subjects with Korsakoff's syndrome, 13 subjects with chronic alcoholism without Korsakoff's syndrome, and 13 control subjects. The brain structures analysed were the hippocampus, the parahippocampal gyrus, the mamillary bodies, the third ventricle, and the thalamus. Brain volumes were correlated with the delayed recall of a verbal learning test. RESULTS: Compared with subjects with chronic alcoholism and control subjects, subjects with Korsakoff's syndrome had a reduced volume of the hippocampus, the mamillary bodies, and the thalamus, and enlargement of the third ventricle. The impairment of delayed recall correlated with the volume of the third ventricle (r=-0.55, p=0.05) in the Korsakoff group. CONCLUSIONS: Anterograde amnesia in alcoholic Korsakoff's syndrome is associated with atrophy of the nuclei in the midline of the thalamus, but not with atrophy of the mamillary bodies, the hippocampus, or the parahippocampal gyrus.

Neuropsychological correlates of a right unilateral lacunar thalamic infarction.

OBJECTIVES: To report on a patient with a lacunar infarction in the right intralaminar nuclei of the thalamus. The role of the thalamic intralaminar nuclei in cognitive function is as yet insufficiently known. The patient described has shown signs of apathy and loss of initiative, in combination with cognitive deficits, which have persisted essentially unaltered up to the present day since an abrupt onset 17 years ago. METHODS: High resolution MRI was performed to show the extent of the lesion; a combination of published and experimental neuropsychological techniques was administered to show the nature of the cognitive defects; Single photon emission computed tomography (SPECT) was employed to obtain a measure of cortical perfusion. RESULTS: Brain MRI disclosed an isolated lacunar infarction in the dorsal caudal intralaminar nuclei of the thalamus. Neuropsychological evaluation indicated problems with attention and concentration, executive disturbances, and memory deficits both in the visual and verbal domains. The memory deficits could not be attributed to problems in the early stages of information processing, and are hence regarded as resulting from a failure of retrieval rather than encoding or storage. Brain SPECT disclosed a hypoperfusion of the right frontal cortex. CONCLUSION: The data indicate that the cognitive profile is the result of a dysfunction of executive functions. This is corroborated by the finding of decreased blood flow in the right frontal cortex, and by evidence from the neuroanatomical literature. Thus the dysexecutive symptoms are thought to be caused by disconnection of the prefrontal cortex from the brainstem activating nuclei through the strategic localisation of the right thalamic infarction.

Altered expression of the cell cycle regulatory protein cyclin D1 in the rat dentate gyrus after adrenalectomy-induced granular cell loss.

The loss of dentate gyrus (DG) granular cells after removal of the rat adrenal glands (ADX) is mediated by a process that is apoptotic in nature. The present study was initiated to compare changes in the immunocytochemical distribution of the cell-cycle regulatory protein cyclin D1, which has been implicated in apoptosis, with the loss of DG granular cells after ADX. Our data indicate that cyclin D1-immunoreactivity (cyclin D1-ir) is enhanced in the rat dentate gyrus after adrenalectomy. The enhanced cyclin D1-ir shows a close relationship, both in time and space, with granular cell loss in the rat dentate gyrus that occurs after adrenalectomy. However, the enhanced cyclin D1-immunoreactivity was present in microglia and radial glia rather than in the dentate gyrus granular cells. This suggests that cyclin D1 is not directly involved in apoptosis of granular cells in the rat dentate gyrus after adrenalectomy.

The immune system mediates blood-brain barrier damage; possible implications for pathophysiology of neuropsychiatric illnesses.

In this investigation the effects of immune activation on the brain are characterized. In order to study this, we used a model for chronic immune activation, the myocardial infarction, and intravenous injections with the pro-inflammatory cytokine Tumour Necrosis Factor alpha (TNF-α). The incentive for this study is the observation that myocardial infarction is accompanied by behavioural and neuronal abnormalities. The effects of myocardial infarction on the brain and its functioning are widespread. In order to examine the mechanism through which this interaction occurs, a group of rats underwent an experimentally induced myocardial infarction whereafter immunohistochemistry was performed on slices of the brain. This experiment revealed regional serum protein extravasation, pointing to leakage of the blood-brain barrier. This process occurred in certain cortical, subcortical and hindbrain areas in discrete patches. The leakage was co-localized with the expression of the immune activation marker ICAM-1. A second group of rats was therefore injected with TNF-α, a major pro-inflammatory cytokine, to assess the involvement of the immune system in the effects shown. This procedure rendered the same results. It is concluded that myocardial infarction may interfere with the integrity of the blood-brain barrier and possibly with brain functioning through activation of the immune system. The relevance for pathophysiological processes is discussed.