Theresa M. Marschall

Introduction Parkinson's disease (PD) is a multifactorial disorder, affecting multiple neurotransmitter systems, including the cholinergic system. Cholinergic denervation is heterogeneous across patients and difficult to predict based on clinical presentation. In this study, we assessed the sensitivity of structural MRI (sMRI) and functional MRI (fMRI) to cholinergic degeneration related to PD and to cognitive functioning in PD. We compared our results to results from previously reported [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV) PET imaging, which is considered the gold standard for cholinergic imaging. Methods 34 PD patients and 10 healthy controls underwent structural T1-weighted MRI. A subset of 14 patients and 9 controls also underwent resting-state fMRI. We extracted the bilateral volumes of the nucleus basalis of Meynert (NBM) from the sMRI images. Functional connectivity (FC) from the NBM to the cortex (NBM-FC) was determined using fMRI data. Principal component analysis (PCA) was applied to reduce the dimensionality of the NBM-FC images. We assessed performances for NBM-FC in distinguishing patients from controls using stepwise logistic regression. Similarly, NBM volume was used using logistic regression. Furthermore, the relation between these measures and cognitive function in several domains was investigated with (stepwise) linear regression. Leave-one-out cross validation (LOOCV) and bootstrapping was performed to assess robustness of the results. Results NBM-FC was well able to discriminate patients from controls with an AUC of 0.84 (95% CI: 0.62-1). NBM volume showed lower performance, but was still better than chance: AUC: 0.75 (95% CI: 0.57-0.93). Significant correlations were found between 1) cognition in the attentional domain and NBM-FC (r=0.63; p=.015) and 2) global cognition and NBM volume (r=0.55, p=.001). These results were inferior to those previously reported using [18F]FEOBV tracer uptake (see Chapter 6). Bootstrapping revealed that NBM volume of only the left hemisphere was stably related to PD diagnosis and global cognition in PD patients. We found that a lower NBM-FC in specific brain areas, including the fusiform gyrus, supramarginal gyrus and dorsolateral prefrontal cortex, was related to PD diagnosis. Bootstrapping revealed no stable NBM-FC pattern related to attention. Conclusion Although MRI results were slightly inferior to [18F]FEOBV PET data, MRI may provide a cheaper and more widely available alternative for cholinergic imaging. We recommend testing the utility of MRI as predictor and monitor of cholinergic treatment effect in a longitudinal study.

Hallucinations can have rather heterogeneous aetiology and presentation. This inspired the concept of different subtypes based on symptom profiles, especially in the field of auditory hallucinations. As many people experience hallucinations in more than one sensory modality, it seems important to investigate potential hallucination subtypes across different sensory modalities. We assessed the content of hallucinations as part of a large survey among the general Dutch population (n = 10,448) using the Questionnaire for Psychotic Experiences. Based on their descriptions, thematic categories were created in a data-driven cluster analysis. 2594 participants who experienced hallucinations over the past week that contained at least 2 different thematic categories were selected. Clustering of their hallucination content was performed with the HDBSCAN method. We identified 4 clusters, i.e., subtypes, which can be typified as 1. hallucinations of foul odors, 2. complex visual scenes, 3. a vast variety of rather common hallucinations possibly related to heightened alertness, and 4. possibly bereavement hallucinations. The bereavement subtype showed an increase in emotional loneliness and the presence of delusions. Our findings suggest that the content of hallucinations can be informative, especially when investigated across sensory modalities. Such subtypes may help to better understand their underlying mechanisms.

Patients with hearing impairment (HI) may experience hearing sounds without external sources, ranging from random meaningless noises (tinnitus) to music and other auditory hallucinations (AHs) with meaningful qualities. To ensure appropriate assessment and management, clinicians need to be aware of these phenomena. However, sensory impairment studies have shown that such clinical awareness is low. An online survey was conducted investigating awareness of AHs among clinicians and their opinions about these hallucinations. In total, 125 clinicians (68.8% audiologists; 18.4% Ear-Nose-Throat [ENT] specialists) across 10 countries participated in the survey. The majority (96.8%) was at least slightly aware of AHs in HI. About 69.6% of participants reported encountering patients with AHs less than once every 6 months in their clinic. Awareness was significantly associated with clinicians’ belief that patients feel anxious about their hallucinations (β = .018, t(118) = 2.47, P < .01), their belief that clinicians should be more aware of these hallucinations (β =.018, t(118) = 2.60, P < .01), and with confidence of clinicians in their skills to assess them (β = .017, t(118) = 2.63, P < .01). Clinicians felt underequipped to treat AHs (Median = 31; U = 1838; P_FDRadj < .01). Awareness of AHs among the surveyed clinicians was high. Yet, the low frequency of encounters with hallucinating patients and their belief in music as the most commonly perceived sound suggest unreported cases. Clinicians in this study expressed a lack of confidence regarding the assessment and treatment of AHs and welcome more information.

Background Auditory verbal hallucinations (AVH) are often seen as a hallmark of schizophrenia, but can also occur in the general healthy population. While AVH in non-clinical populations might offer an opportunity to study them in isolation, it remains debatable whether the mechanisms underlying AVH are the same in clinical and non-clinical populations. For example, non-clinical populations are reported to attribute lower emotional valence to their AVH. Such differences in phenomenology are hypothesized to arise from differences on the neurobiological level. With the current study, we employ a data-driven approach to define brain networks involved in AVH in clinical and non-clinical subjects, and test whether dynamic differences in network connectivity exist between these groups. Methods Functional magnetic resonance imaging data of 21 non-psychotic individuals and 21 matched psychotic patients with frequent AVH were obtained. During scanning, subjects manually indicated the on- and offset of their AVH. Using independent component (IC) analysis, the data were split into 72 statistically independent spatial maps and their time courses. These time courses were regressed with the AVH time courses. With a one sample t-test on the beta weights, we selected those ICs that related to AVH in both groups for further dynamic functional network connectivity analysis. To identify functional connectivity states, k-means clustering was implemented on correlation matrices acquired using sliding windows. Group differences between these states were determined with two-sample t-tests. Results Both groups experienced AVH during scanning, with a mean number of 24.71 AVH episodes in the clinical and 17.14 episodes in the non-clinical group. We identified seven ICs with time courses significantly related to the occurrence of AVH in both groups. The auditory, sensorimotor, and posterior salience network were positively related to AVH occurrence. The ventral default mode network (DMN), anterior salience network and a network consisting of (para-)hippocampal areas were negatively related to AVH. While in general, networks related to AVH were similar in both groups, a significant difference between the two groups was found in the mean dwell time in states characterized by varying connectivity between these networks. Psychotic patients spent more time in a state of low connectivity (r < 0.055) between all AVH-related networks. Non-psychotic patients dwelled longer in a different state, where some weak correlations between networks were present (.15 > r ≥ .10). Specifically, networks positively related to AVH showed small negative correlations with each other, and a small negative relationship with the DMN. At the same time, the anterior salience network displayed a small positive relationship with the sensorimotor, auditory and posterior salience networks. Discussion Our findings suggest that similar brain networks underlie AVH in non-psychotic and psychotic individuals, but that the groups differ in terms of connectivity between those networks. Among the involved networks are those typically associated with AVH in psychotic patients, such as the DMN and auditory network. During the experience of AVH, psychotic individuals are more likely to show a state defined by segregation of the AVH-related networks. On the contrary, during AVH non-psychotic individuals are in a state defined by more connectivity between the networks. This suggests that a distinction between clinical and non-clinical AVH may have its neurobiological basis in the extend of disruption of involved network connectivity.

Purpose of review: The association between hallucinations and sensory loss, especially vision- and hearing-impairment, has been firmly established over the past years. The deafferentation theory, a decrease of the threshold for activation in the brain and the consequential imbalance between excitatory and inhibitory brain networks, is hypothesized to underly this relationship. Here we review the studies investigating this theory with a focus on the most recent literature to better understand the contribution of sensory loss to hallucinations.Recent findings: A large cross-sectional study has recently confirmed the relationship between auditory impairment and deafferentation. However, the underlying mechanisms of deafferentation are still under debate, with hyperexcitability and deviations in bottom-up and top-down processes being the most likely explanations. Social isolation following sensory impairment increases the risk for hallucinations. Better knowledge and awareness about the contribution of deafferentation and loneliness would benefit diagnosis and treatment of hallucinations.Summary: Studies imply activity in higher order areas, corresponding to the functional mapping of sensory system, and a general state of higher excitability as neurobiological explanation. Auditory deafferentation, tinnitus and other auditory hallucinations, likely lie on a continuum. Social isolation mediates psychotic symptoms in sensory-impaired individuals. Currently, there is no standard treatment for deafferentation hallucinations.