Personalized exposure and experience sampling method feedback versus exposure as usual for obsessive-compulsive disorder: a study protocol for a randomized controlled trial.

BACKGROUND: Patients with obsessive-compulsive disorder (OCD) suffer from repetitive fearful intrusions which they try to neutralize by performing compulsions. OCD is considered to be the most resistant anxiety disorder with a remission rate of only 53% after a year of an evidence-based treatment. Therefore, it remains an obligation to develop and investigate more effective treatment interventions. This study aims to compare personalized exposure with response prevention (ERP) using experience sampling methodology-based feedback to ERP as usual in patients with OCD. Personalized exposure will be provided screen-to-screen in an ecologically valid (real time and real place) context by means of a smartphone application. This app will also be used to collect both objective and subjective data by means of experience sampling methodology (ESM). This ESM data will be used to identify triggers and protective factors for symptom severity, provide personalized feedback and optimize the effect of ERP. The primary goal of this RCT is to compare the effectiveness of personalized ERP to ERP as usual in the traditional context of a therapist's room in patients with OCD in OCD symptom severity, as well as differences in quality of life, depressive symptoms and anxiety states. Since both self-efficacy and experiential avoidance are known to influence symptom severity in OCS, a secondary goal is to examine if a possible treatment effect is mediated by self-efficacy or experiential avoidance. METHODS: This study involves a randomized controlled trial with 20 weekly sessions by 2 groups (ERP as usual versus personalized ERP), repeated measurements at baseline (T0), 5 weeks of treatment (T1), 10 weeks of treatment (T2), 15 weeks of treatment (T3), posttest at 20 weeks (T4), 6 weeks follow-up (T5), 3 months follow-up (T6), 6 months follow-up (T7) and a year follow-up (T8). A hundred and sixty patients with an OCD diagnosis according to DSM-5 criteria will participate. Half of the group will receive exposure with response prevention as usual, the other half will receive personalized exposure with response prevention with a smartphone application and personalized feedback sessions based on experience sampling data. Multilevel mixed modelling analysis will be used to investigate differences in treatment effect, as well as differences in quality of life, depressive symptoms and anxiety states. We will use the macro of Preacher and Hayes and apply bootstrapping methods to assess the possible mediating effect of changes in self-efficacy and experiential avoidance on subsequent treatment effects. DISCUSSION: This randomized controlled trial is the first to assess the influence of delivering ERP through video-calling and the use of an ESM intervention on the symptom severity of OCD. Since the global pandemic COVID-19, the use of video-calling to deliver psychological treatments has become more common, increasing the relevance of this study. TRIAL REGISTRATION: ICTRP Trial NL8254. Registered on 2019-12-24.

Permutation Entropy as a Universal Disorder Criterion: How Disorders at Different Scale Levels Are Manifestations of the Same Underlying Principle.

What do bacteria, cells, organs, people, and social communities have in common? At first sight, perhaps not much. They involve totally different agents and scale levels of observation. On second thought, however, perhaps they share everything. A growing body of literature suggests that living systems at different scale levels of observation follow the same architectural principles and process information in similar ways. Moreover, such systems appear to respond in similar ways to rising levels of stress, especially when stress levels approach near-lethal levels. To explain such communalities, we argue that all organisms (including humans) can be modeled as hierarchical Bayesian controls systems that are governed by the same biophysical principles. Such systems show generic changes when taxed beyond their ability to correct for environmental disturbances. Without exception, stressed organisms show rising levels of 'disorder' (randomness, unpredictability) in internal message passing and overt behavior. We argue that such changes can be explained by a collapse of allostatic (high-level integrative) control, which normally synchronizes activity of the various components of a living system to produce order. The selective overload and cascading failure of highly connected (hub) nodes flattens hierarchical control, producing maladaptive behavior. Thus, we present a theory according to which organic concepts such as stress, a loss of control, disorder, disease, and death can be operationalized in biophysical terms that apply to all scale levels of organization. Given the presumed universality of this mechanism, 'losing control' appears to involve the same process anywhere, whether involving bacteria succumbing to an antibiotic agent, people suffering from physical or mental disorders, or social systems slipping into warfare. On a practical note, measures of disorder may serve as early warning signs of system failure even when catastrophic failure is still some distance away.

How higher goals are constructed and collapse under stress: A hierarchical Bayesian control systems perspective.

In this paper, we show that organisms can be modeled as hierarchical Bayesian control systems with small world and information bottleneck (bow-tie) network structure. Such systems combine hierarchical perception with hierarchical goal setting and hierarchical action control. We argue that hierarchical Bayesian control systems produce deep hierarchies of goal states, from which it follows that organisms must have some form of 'highest goals'. For all organisms, these involve internal (self) models, external (social) models and overarching (normative) models. We show that goal hierarchies tend to decompose in a top-down manner under severe and prolonged levels of stress. This produces behavior that favors short-term and self-referential goals over long term, social and/or normative goals. The collapse of goal hierarchies is universally accompanied by an increase in entropy (disorder) in control systems that can serve as an early warning sign for tipping points (disease or death of the organism). In humans, learning goal hierarchies corresponds to personality development (maturation). The failure of goal hierarchies to mature properly corresponds to personality deficits. A top-down collapse of such hierarchies under stress is identified as a common factor in all forms of episodic mental disorders (psychopathology). The paper concludes by discussing ways of testing these hypotheses empirically.

Can we predict the direction of sudden shifts in symptoms? Transdiagnostic implications from a complex systems perspective on psychopathology.

Recently, there has been renewed interest in the application of assumptions from complex systems theory in the field of psychopathology. One assumption, with high clinical relevance, is that sudden transitions in symptoms may be anticipated by rising instability in the system, which can be detected with early warning signals (EWS). Empirical studies support the idea that this principle also applies to the field of psychopathology. The current manuscript discusses whether assumptions from complex systems theory can additionally be informative with respect to the specific symptom dimension in which such a transition will occur (e.g. whether a transition towards anxious, depressive or manic symptoms is most likely). From a complex systems perspective, both EWS measured in single symptom dynamics and network symptom dynamics at large are hypothesized to provide clues regarding the direction of the transition. Challenging research designs are needed to provide empirical validation of these hypotheses. These designs should be able to follow sudden transitions 'live' using frequent observations of symptoms within individuals and apply a transdiagnostic approach to psychopathology. If the assumptions proposed are supported by empirical studies then this will signify a large improvement in the possibility for personalized estimations of the course of psychiatric symptoms. Such information can be extremely useful for early intervention strategies aimed at preventing specific psychiatric problems.

Draining the pond and catching the fish: Uncovering the ecosystem of auditory verbal hallucinations.

The various models proposed for the mediation of auditory verbal hallucinations (AVH) implicate a considerable number of brain areas and mechanisms. To establish which of those mechanisms are actually involved in the mediation of AVH, we developed a novel method to analyze functional MRI data, which allows for the detection of the full network of mutually interacting brain states, and the identification of those states that are relevant to the mediation of AVH, while applying a minimum number of preconceived assumptions. This method is comparable to the draining of a pond to lay bare the full ecosystem that affects the presence of a particular fish species. We used this model to analyze the fMRI data of 85 psychotic patients experiencing AVH. The data were decomposed into 98 independent components (ICs) representing all major functions active in the brain during scanning. ICs involved in mediating AVH were identified by associating their time series with the hallucination time series as provided by subjects within the scanner. Using graph theory, a network of interacting ICs was created, which was clustered into IC modules. We used causal reasoning software to determine the direction of links in this network, and discover the chain of events that leads to the conscious experience of hallucinations. Hallucinatory activity was linked to three of the seven IC clusters and 11 of the 98 ICs. ICs with the most influential roles in producing AVH-related activity were those within the so-called salience network (comprising the anterior cingulate gyrus, right insula, Broca's homologue, premotor cortex, and supramarginal gyrus). Broca's area and the cerebellar regions were significantly, but more distantly involved in the mediation of AVH. These results support the notion that AVH are largely mediated by the salience network. We therefore propose that the mediation of AVH in the context of schizophrenia spectrum disorders involves the attribution of an excess of negative salience by anterior-cingulate areas to linguistic input from Broca's right homologue, followed by subsequent processing errors in areas further 'downstream' the causal chain of events. We provide a detailed account of the origin of AVH for this patient group, and make suggestions for selective interventions directed at the most relevant brain areas.

An integrated network model of psychotic symptoms.

The full body of research on the nature of psychosis and its determinants indicates that a considerable number of factors are relevant to the development of hallucinations, delusions, and other positive symptoms, ranging from neurodevelopmental parameters and altered connectivity of brain regions to impaired cognitive functioning and social factors. We aimed to integrate these factors in a single mathematical model based on network theory. At the microscopic level this model explains positive symptoms of psychosis in terms of experiential equivalents of robust, high-frequency attractor states of neural networks. At the mesoscopic level it explains them in relation to global brain states, and at the macroscopic level in relation to social-network structures and dynamics. Due to the scale-free nature of biological networks, all three levels are governed by the same general laws, thereby allowing for an integrated model of biological, psychological, and social phenomena involved in the mediation of positive symptoms of psychosis. This integrated network model of psychotic symptoms (INMOPS) is described together with various possibilities for application in clinical practice.

A network view on psychiatric disorders: network clusters of symptoms as elementary syndromes of psychopathology.

INTRODUCTION: The vast number of psychopathological syndromes that can be observed in clinical practice can be described in terms of a limited number of elementary syndromes that are differentially expressed. Previous attempts to identify elementary syndromes have shown limitations that have slowed progress in the taxonomy of psychiatric disorders. AIM: To examine the ability of network community detection (NCD) to identify elementary syndromes of psychopathology and move beyond the limitations of current classification methods in psychiatry. METHODS: 192 patients with unselected mental disorders were tested on the Comprehensive Psychopathological Rating Scale (CPRS). Principal component analysis (PCA) was performed on the bootstrapped correlation matrix of symptom scores to extract the principal component structure (PCS). An undirected and weighted network graph was constructed from the same matrix. Network community structure (NCS) was optimized using a previously published technique. RESULTS: In the optimal network structure, network clusters showed a 89% match with principal components of psychopathology. Some 6 network clusters were found, including "Depression", "Mania", "Anxiety", "Psychosis", "Retardation", and "Behavioral Disorganization". Network metrics were used to quantify the continuities between the elementary syndromes. CONCLUSION: We present the first comprehensive network graph of psychopathology that is free from the biases of previous classifications: a 'Psychopathology Web'. Clusters within this network represent elementary syndromes that are connected via a limited number of bridge symptoms. Many problems of previous classifications can be overcome by using a network approach to psychopathology.

The auditory dorsal stream plays a crucial role in projecting hallucinated voices into external space.

INTRODUCTION: Verbal auditory hallucinations (VAHs) are experienced as spoken voices which seem to originate in the extracorporeal environment or inside the head. Animal and human research has identified a 'where' pathway for sound processing comprising the planum temporale, the middle frontal gyrus and the inferior parietal lobule. We hypothesize that increased activity of that 'where' pathway mediates the exteriorization of VAHs. METHODS: The fMRI scans of 52 right-handed psychotic patients experiencing frequent VAHs were compared with the reported location of hallucinations, as rated with the aid of the PSYRATS-AHRS. For each subject, a unique VAH activation model was created based on the VAH timings, and subsequently convolved with a gamma function to model the hemodynamic response. In order to examine the neurofunctional equivalents of perceived VAH location, second-level group effects of subjects experiencing either internal (n = 24) or external (n = 28) VAHs were contrasted within planum temporale, middle frontal gyrus, and inferior parietal lobule regions of interest (ROIs). RESULTS: Three ROIs were tested for increased activity in relation with the exteriorization of VAHs. The analysis revealed a left-sided medial planum temporale and a right-sided middle frontal gyrus cluster of increased activity. No significant activity was found in the inferior parietal lobule. CONCLUSIONS: Our study indicates that internal and external VAHs are mediated by a fronto-temporal pattern of neuronal activity while the exteriorization of VAHs stems from additional brain activity in the auditory 'where' pathway, comprising the planum temporale and prefrontal regions.

The network structure of human personality according to the NEO-PI-R: matching network community structure to factor structure.

INTRODUCTION: Human personality is described preferentially in terms of factors (dimensions) found using factor analysis. An alternative and highly related method is network analysis, which may have several advantages over factor analytic methods. AIM: To directly compare the ability of network community detection (NCD) and principal component factor analysis (PCA) to examine modularity in multidimensional datasets such as the neuroticism-extraversion-openness personality inventory revised (NEO-PI-R). METHODS: 434 healthy subjects were tested on the NEO-PI-R. PCA was performed to extract factor structures (FS) of the current dataset using both item scores and facet scores. Correlational network graphs were constructed from univariate correlation matrices of interactions between both items and facets. These networks were pruned in a link-by-link fashion while calculating the network community structure (NCS) of each resulting network using the Wakita Tsurumi clustering algorithm. NCSs were matched against FS and networks of best matches were kept for further analysis. RESULTS: At facet level, NCS showed a best match (96.2%) with a 'confirmatory' 5-FS. At item level, NCS showed a best match (80%) with the standard 5-FS and involved a total of 6 network clusters. Lesser matches were found with 'confirmatory' 5-FS and 'exploratory' 6-FS of the current dataset. Network analysis did not identify facets as a separate level of organization in between items and clusters. A small-world network structure was found in both item- and facet level networks. CONCLUSION: We present the first optimized network graph of personality traits according to the NEO-PI-R: a 'Personality Web'. Such a web may represent the possible routes that subjects can take during personality development. NCD outperforms PCA by producing plausible modularity at item level in non-standard datasets, and can identify the key roles of individual items and clusters in the network.

An Increase of the Character Function of Self-Directedness Is Centrally Involved in Symptom Reduction during Remission from Major Depression.

Background. Studies with the Temperament and Character Inventory (TCI) in depressive disorders have shown changes (Δ) of the character of Self-Directedness (SD) and the temperament of Harm Avoidance (HA). The central question of this study is which of these two changes is most proximally related to the production of depressive symptoms. Methods. The start and endpoint data from a two-year followup of 58 depressed patients were reanalyzed. We used the ΔHA and ΔSD scores as well as the Δ scores on three dimensions of psychopathology, called Emotional Dysregulation (ED), Retardation (RET), and Anxiety (ANX). The presence of the main relation between personality and psychopathology was tested in all patients and in four subcategories. The data were analyzed by MANCOVA and Structural Equation Modelling (SEM). Results. ΔHA and ΔSD correlated negatively, and only ΔSD was related (negatively) to ΔED. This pattern was found in all subcategories. SEM showed ΔHA and ΔSD had an ambiguous causal interrelationship, while ΔSD, ΔRET, and ΔANX had unidirectional effects on ΔED. Conclusion. The results correspond with a central pathogenetic role for a state-related deficit at the character level in depression. This may have important consequences for investigations of endophenotypes and clinical treatment.

Treatment of Alice in Wonderland syndrome and verbal auditory hallucinations using repetitive transcranial magnetic stimulation: a case report with fMRI findings.

BACKGROUND: Alice in Wonderland syndrome (AIWS) is a rare cluster of CNS symptoms characterized by visual distortions (i.e. metamorphopsias), body image distortions, time distortions, and déjà experiences. Verbal auditory hallucinations (VAHs) are the most prevalent type of hallucination in adults with or without a history of psychiatric illness. Here, we report the case of a woman with AIWS, long-lasting VAHs, and various additional perceptual and mood symptoms. METHODS: Semi-structured interviews were used to assess symptoms, and functional MRI (fMRI) was employed to localize cerebral activity during self-reported VAHs. Treatment consisted of repetitive transcranial magnetic stimulation (rTMS) at a frequency of 1 Hz at T3P3, overlying Brodmann's area 40. RESULTS: Activation during VAHs was observed bilaterally in the basal ganglia, the primary auditory cortex, the association auditory cortex, the temporal poles, and the anterior cingulated gyrus. The left and right inferior frontal gyri (Broca's area and its contralateral homologue) were involved, along with the dorsolateral prefrontal cortex. Interestingly, synchronized activation was observed in the primary visual cortex (areas V1 and V2), and the bilateral dorsal visual cortex. The higher visual association cortex also showed significant, but less prominent, activation. During the second week of rTMS treatment, not only the VAHs, but also the other sensory deceptions/distortions and mood symptoms showed complete remission. The patient remained free of any symptoms during a 4-month follow-up phase. After 8 months, when many of the original symptoms had returned, a second treatment phase with rTMS was again followed by complete remission. CONCLUSIONS: This case indicates that VAHs and metamorphopsias in AIWS are associated with synchronized activation in both auditory and visual cortices. It also indicates that local rTMS treatment may have global therapeutic effects, suggesting an effect on multiple brain regions in a distributed network. Although a placebo effect cannot be ruled out, this case warrants further investigation of the effects of rTMS treatment in AIWS.

Can low-frequency repetitive transcranial magnetic stimulation really relieve medication-resistant auditory verbal hallucinations? Negative results from a large randomized controlled trial.

BACKGROUND: Several studies have applied low-frequency repetitive transcranial magnetic stimulation (rTMS) directed at the left temporoparietal area (TP) for the treatment of auditory verbal hallucinations (AVH), but findings on efficacy are inconsistent. Furthermore, recent functional magnetic resonance imaging (fMRI) studies indicate that the left TP is not a general focus of activation during the experience of AVH. The aims of this study are twofold: to investigate the effects of rTMS on AVH in a double blind, randomized, sham-controlled study; and to investigate whether the efficacy can be improved when rTMS is guided by individual fMRI scans of hallucinatory activation. METHODS: Sixty-two patients with medication-resistant AVH were randomized over three conditions: rTMS targeted at the area of maximal hallucinatory activation calculated from individual fMRI scans during AVH, rTMS directed at the left TP, and sham treatment. Repetitive TMS was applied during 15 sessions of 20 min each, at 1 Hz and 90% of the individual motor threshold. The severity of AVH and other psychotic symptoms were monitored during treatment and 3-month follow-up, with the Auditory Hallucination Rating Scale, the Positive and Negative Syndrome Scale, and the Psychotic Symptom Rating Scales. RESULTS: The effects of fMRI-guided rTMS and left TP rTMS on the severity of AVH were comparable to those of sham treatment. No differences in severity of general psychotic symptoms were found among the three treatment conditions. CONCLUSIONS: Low-frequency rTMS administered to the left TP or to the site of maximal hallucinatory activation is not more effective for medication-resistant AVH than sham treatment.

Deactivation of the parahippocampal gyrus preceding auditory hallucinations in schizophrenia.

OBJECTIVE: Activation in a network of language-related regions has been reported during auditory verbal hallucinations. It remains unclear, however, how this activation is triggered. Identifying brain regions that show significant signal changes preceding auditory hallucinations might reveal the origin of these hallucinations. METHOD: Twenty-four patients with a psychotic disorder indicated the presence of auditory verbal hallucinations during 3-Tesla functional magnetic resonance imaging by squeezing a handheld balloon. A one-sample t test was performed to reveal groupwise activation during hallucinations. To enable analysis of brain activation 6 to 0 seconds preceding hallucinations, a tailored 'selective averaging' method, without any a priori assumptions concerning the hemodynamic response profile, was performed. To control for motor-related activation, 15 healthy comparison subjects squeezed a balloon at matched time intervals. RESULTS: Groupwise analysis during auditory verbal hallucinations revealed brain activation in bilateral (right more than left) language-related regions and bilateral motor regions. Prominent deactivation preceding these hallucinations was observed in the left parahippocampal gyrus. In addition, significant deactivation preceding hallucinations was found in the left superior temporal, right inferior frontal, and left middle frontal gyri as well as in the right insula and left cerebellum. No significant signal changes were revealed prior to the matched balloon squeezing among the comparison subjects. CONCLUSION: Auditory verbal hallucinations in patients with a psychotic disorder are consistently preceded by deactivation of the parahippocampal gyrus. The parahippocampus has been hypothesized to play a central role in memory recollection, sending information from the hippocampus to the association areas. Dysfunction of this region could trigger inadequate activation of right language areas during auditory hallucinations.

Model-free group analysis shows altered BOLD FMRI networks in dementia.

FMRI research in Alzheimer's disease (AD) and mild cognitive impairment (MCI) typically is aimed at determining regional changes in brain function, most commonly by creating a model of the expected BOLD-response and estimating its magnitude using a general linear model (GLM) analysis. This crucially depends on the suitability of the temporal assumptions of the model and on assumptions about normality of group distributions. Exploratory data analysis techniques such as independent component analysis (ICA) do not depend on these assumptions and are able to detect unknown, yet structured spatiotemporal processes in neuroimaging data. Tensorial probabilistic ICA (T-PICA) is a model free technique that can be used for analyzing multiple subjects and groups, extracting signals of interest (components) in the spatial, temporal, and also subject domain of FMRI data. We applied T-PICA and model-based GLM to study FMRI signal during face encoding in 18 AD, 28 MCI patients, and 41 healthy elderly controls. T-PICA showed activation in regions associated with motor, visual, and cognitive processing, and deactivation in the default mode network. Six networks showed a significantly decreased response in patients. For two networks the T-PICA technique was significantly more sensitive to detect group differences than the standard model-based technique. We conclude that T-PICA is a promising tool to identify and detect differences in (de)activated brain networks in elderly controls and dementia patients. The technique is more sensitive than the commonly applied model-based method. Consistent with other research, we show that networks of activation and deactivation show decreased reactivity in dementia.

Cholinergic challenge in Alzheimer patients and mild cognitive impairment differentially affects hippocampal activation--a pharmacological fMRI study.

Pharmacological functional MRI (phMRI) examines the impact of pharmacologically induced neurochemical changes on brain function at a system level. The current phMRI study directly compared effects of cholinergic stimulation on brain function between patients with Alzheimer's disease and mild cognitive impairment, a disease stage preceding the development of Alzheimer's disease. Brain function during recognition of (un)familiar information was examined for changes after exposure to galantamine, a cholinesterase inhibitor used for treating memory deficits in Alzheimer's disease. Alzheimer patients [n = 18; age 74.5 years +/- 8.2; Mini-Mental State Examination (MMSE) 22.5 +/- 2.4] and patients with mild cognitive impairment (n = 28; mean age 73.6 +/- 7.5; MMSE 27.0 +/- 1.2) were scanned during face recognition under three different conditions: at baseline, and after acute (single dose) and prolonged exposure (5 days) to galantamine. Functional data were analysed in an event-related fashion. In both groups, acute exposure produced strong increases in brain activation (Z > 3.1). Prolonged exposure produced less strong effects that mainly involved decreases in activation (Z > 3.1). In mild cognitive impairment, acute exposure increased activation in posterior cingulate, left inferior parietal, and anterior temporal lobe. Prolonged exposure decreased activation in similar posterior cingulate areas, and in bilateral prefrontal areas. Effects were stronger for positive ('familiar') than for negative ('unfamiliar') decisions, indicating that the effect was specific to memory retrieval. In Alzheimer patients, acute exposure increased activation bilaterally in hippocampal areas, whereas prolonged exposure decreased activation in these areas. Effects were more pronounced for negative than for positive decisions, suggesting a preferential effect on memory encoding. Unique profiles of signal reactivity were found in a number of areas, including left inferior parietal lobe and left hippocampus proper. The reactivity of posterior cingulate and hippocampal structures to cholinergic challenge suggests a key role of the cholinergic system in the functional processes that lead to Alzheimer's disease. The differential response to cholinergic challenge in mild cognitive impairment and Alzheimer patients may reflect a difference in the functional status of the cholinergic system between both groups, which is in line with recent results showing a differential clinical response to cholinergic treatment.

Raloxifene treatment enhances brain activation during recognition of familiar items: a pharmacological fMRI study in healthy elderly males.

Raloxifene is a selective estrogen receptor modulator that may delay the onset of mild cognitive impairment in elderly women. Effects of raloxifene treatment on mental performance in males remain to be investigated. In a previous functional magnetic resonance imaging (fMRI) study, we showed that raloxifene treatment enhanced brain activation in elderly males during encoding of new information (faces) into memory. The current study used fMRI in the same group of subjects to screen for effects of raloxifene treatment on brain function during face recognition. Healthy elderly males (n=28; mean age 63.6 years, SD 2.4) were scanned at baseline and after 3 months of treatment with either raloxifene 120 mg (n=14) or placebo (n=14) in a randomized, double-blind, placebo-controlled study design. Functional data were analyzed in an event-related fashion with respect to correct hits and correct rejections using FSL software. Performance data were analyzed with respect to recognition accuracy, latency, and response bias. Functional effects of treatment were found on brain activation related to correct hits only. When compared to placebo treatment, raloxifene treatment enhanced brain activation in the left posterior parahippocampal area (Z=3.9) and right inferior prefrontal cortex (Z=3.5). Recognition accuracy scores remained stable in the raloxifene group, whereas the placebo group showed a small but significant decrease in accuracy scores (p=0.02). No significant effects were found on response bias or latency. In conclusion, raloxifene treatment affects brain function during memory performance in a way that may reflect increased arousal during initial encoding, with downstream effects on brain function during retrieval of information. Behaviorally, such neurofunctional effects may actively block decreased memory performance as a result of context-dependency. The validity of these predictions can be tested in large-scale clinical trials.

Altered resting state networks in mild cognitive impairment and mild Alzheimer's disease: an fMRI study.

Activity and reactivity of the default mode network in the brain was studied using functional magnetic resonance imaging (fMRI) in 28 nondemented individuals with mild cognitive impairment (MCI), 18 patients with mild Alzheimer's disease (AD), and 41 healthy elderly controls (HC). The default mode network was interrogated by means of decreases in brain activity, termed deactivations, during a visual encoding task and during a nonspatial working memory task. Deactivation was found in the default mode network involving the anterior frontal, precuneus, and posterior cingulate cortex. MCI patients showed less deactivation than HC, but more than AD. The most pronounced differences between MCI, HC, and AD occurred in the very early phase of deactivation, reflecting the reactivity and adaptation of the network. The default mode network response in the anterior frontal cortex significantly distinguished MCI from both HC (in the medial frontal) and AD (in the anterior cingulate cortex). The response in the precuneus could only distinguish between patients and HC, not between MCI and AD. These findings may be consistent with the notion that MCI is a transitional state between healthy aging and dementia and with the proposed early changes in MCI in the posterior cingulate cortex and precuneus. These findings suggest that altered activity in the default mode network may act as an early marker for AD pathology.

Delayed rather than decreased BOLD response as a marker for early Alzheimer's disease.

Functional MRI (fMRI) in established Alzheimer's disease (AD) shows regionally altered blood oxygenation level dependent (BOLD) responses. Mild cognitive impairment (MCI) is thought to represent an intermediate state between health and early Alzheimer's disease. To study this probable early dementia stage pathology, we studied in detail the BOLD response in MCI during visual encoding. 28 MCI patients, 18 AD patients, and 41 healthy elderly controls performed a face encoding task during fMRI scanning. Data were analyzed using orthogonal regressors, each representing different phases of the BOLD response (from slow to fast). Using a mixed effects model, regressor x group interactions were analyzed applying P < 0.05, corrected. In occipital regions, MCI patients could be distinguished significantly better from controls and AD patients with a regressor of the early phase of the (fast) BOLD response than with the regressor of the late (slow) BOLD phase. Occipitally, the early phase BOLD response was significantly diminished in MCI patients compared to controls, and significantly increased when compared to AD. AD patients showed diminished early phase activation in widespread regions throughout the brain when compared to controls. There were no differences in the late (slow) phase of the BOLD response. This study stresses the importance of analyzing early phase BOLD responses and not only using one model of the BOLD response in neurodegenerative diseases. The increasing delay of the BOLD response from controls to MCI to AD may be consistent with the idea that MCI is a transitional state between healthy aging and dementia. Analyzing differences in different phases of the BOLD response introduces new opportunities to understand changes in regional brain dynamics in MCI and how well this may serve as an early marker of AD pathology.

Noradrenaline mediates amygdala activation in men and women during encoding of emotional material.

The amygdala is a pivotal structure in humans for encoding of emotional information, as shown by recent imaging studies. It is unknown which neurotransmitters are specifically involved in the human amygdala, although in animal studies noradrenaline was shown to be essential. In our study, participants received the betablocker propranolol (which blocks the noradrenergic response) or placebo when watching neutral to highly negative arousing pictures. Amygdala activation, monitored with functional magnetic resonance imaging (fMRI), increased with emotional intensity of the pictures under placebo condition. Betablockade selectively decreased amygdala activation for emotional pictures of the second highest category, but not for the highest or lower (neutral) category pictures. Two findings add to the existing knowledge in this area. First, the activation pattern in the amygdala under placebo condition shows a nonlinearity related to the emotional categories of the pictures. Second, propranolol disturbs this activation pattern in the amygdala. Explorations with respect to gender show a similar effect of betablockade on amygdala activation in both men and women, but a difference in its effect on long-term memory for emotional pictures. This study supports the hypothesis that the neurotransmitter noradrenaline also mediates amygdala activity in humans when processing emotional stimuli and that betablockers can disrupt the normal activation pattern in the amygdala.

Challenging the cholinergic system in mild cognitive impairment: a pharmacological fMRI study.

Mild cognitive impairment (MCI) often represents an early form of Alzheimer disease (AD). In both MCI and AD, characteristic cholinergic changes may occur. Functional magnetic resonance imaging (fMRI) may help to examine neurochemical changes in early disease by studying signal reactivity to pharmacological challenge. In this study, MCI patients [n=28; mean age 73.6+/-7.5; mini mental state examination (MMSE) 27.0+/-1.2] were scanned during task performance in a randomized trial under three different medication regimes: at baseline [BL; no galantamine (GAL)], after a single oral dose of GAL (SD), and after prolonged exposure (steady state: SS). Memory tasks included an episodic face-encoding task and a parametric n-letter back working memory (WM) task. Alterations in brain activation patterns before and after treatment were analyzed for both tasks using multilevel statistical analysis. Significant increases in brain activation from BL were observed after prolonged exposure only. For face encoding (n=28), these involved left prefrontal areas, the anterior cingulate gyrus, left occipital areas, and left posterior hippocampus. For working memory (n=28), increased activation was found in right precuneus and right middle frontal gyrus, coinciding with increased accuracy scores after GAL treatment. In conclusion, cholinergic challenge produces alterations in brain activation patterns in elderly MCI patients that can be detected with fMRI. This should encourage further functional imaging studies to examine the status of neurotransmitter systems in disease.