Neurophysiological signature(s) of visual hallucinations across neurological and perceptual:and non-invasive treatment with physical exercise

Hallucinations are common and stressful in many psychiatric, neurologic and perceptual disorders disturbing daily life, and increasing mortality, while current treatment of hallucinations is far from optimal. In current clinical practice, treatment with medication is selected in accordance with guidelines for the underlying diagnostic entity, not on the underlying mechanism of hallucinations per se. Understanding the pathophysiological mechanism of (subtypes of) hallucinations may provide new opportunities for treatment and enable rational choice of pharmacotherapy in a personalized manner increasing treatment efficacy and safety. In part I of this dissertation, we found common neurophysiological mechanism(s) underlying visual hallucinations (VH) across disorders. Although the hypothesis of altered attention in VH is not new and has been proposed in several individual disorders, its neurophysiological signature(s) have never been investigated and compared as such across a variety of disorders. This dissertation shows that VH across disorders are quite similar with regard to an underlying neurophysiological mechanism. This finding may aid the discovery of treatment options that could effectively alleviate these hallucinations across disorders, as it suggests that treatment effective for VH in one disorder may be beneficial for VH in another disorder too. In part II of this dissertation, we found evidence for the efficacy of physical exercise (PE) as an add-on treatment for clinical symptoms in schizophrenia spectrum disorder, but also for quality of life, depressive symptoms, and cognitive impairment in the chronic brain disorders Alzheimer’s disease, Huntington’s disease, Multiple Sclerosis, Parkinson’s disease, Schizophrenia, and Unipolar Depression

Understanding hallucinations in probable Alzheimer's disease:Very low prevalence rates in a tertiary memory clinic

Introduction: Averaging at 13.4%, current literature reports widely varying prevalence rates of hallucinations in patients with probable Alzheimer's disease (AD), and is still inconclusive on contributive factors to hallucinations in AD. Methods: This study assessed prevalence, associated factors and clinical characteristics of hallucinations in 1227 patients with probable AD, derived from a tertiary memory clinic specialized in early diagnosis of dementia. Hallucinations were assessed with the Neuropsychiatric Inventory. Results: Hallucination prevalence was very low, with only 4.5% (n = 55/1227) affected patients. Hallucinations were mostly visual (n = 40/55) or auditory (n = 12/55). Comorbid delusions were present in over one-third of cases (n = 23/55). Hallucinations were associated with increased dementia severity, neuropsychiatric symptoms, and a lifetime history of hallucination-evoking disease (such as depression and sensory impairment), but not with age or gender. Discussion: In the largest sample thus far, we report a low prevalence of hallucinations in probable AD patients, comparable to rates in non-demented elderly. Our results suggest that hallucinations are uncommon in early stage AD. Clinicians that encounter hallucinations in patients with early AD should be sensitive to hallucination-evoking comorbidity

Author Correction:Functional connectome differences in individuals with hallucinations across the psychosis continuum (Scientific Reports, (2021), 11, 1, (1108), 10.1038/s41598-020-80657-8)

The Supplementary Information published with this Article contained an error, where an old version of Figure S5 was used. This error has now been corrected in the Supplementary Information file that accompanies the original Article. The corrected Supplementary Information file is also linked to this correction notices.</p

Author Correction:Functional connectome differences in individuals with hallucinations across the psychosis continuum (Scientific Reports, (2021), 11, 1, (1108), 10.1038/s41598-020-80657-8)

The Supplementary Information published with this Article contained an error, where an old version of Figure S5 was used. This error has now been corrected in the Supplementary Information file that accompanies the original Article. The corrected Supplementary Information file is also linked to this correction notices

Functional connectome differences in individuals with hallucinations across the psychosis continuum

Hallucinations may arise from an imbalance between sensory and higher cognitive brain regions, reflected by alterations in functional connectivity. It is unknown whether hallucinations across the psychosis continuum exhibit similar alterations in functional connectivity, suggesting a common neural mechanism, or whether different mechanisms link to hallucinations across phenotypes. We acquired resting-state functional MRI scans of 483 participants, including 40 non-clinical individuals with hallucinations, 99 schizophrenia patients with hallucinations, 74 bipolar-I disorder patients with hallucinations, 42 bipolar-I disorder patients without hallucinations, and 228 healthy controls. The weighted connectivity matrices were compared using network-based statistics. Non-clinical individuals with hallucinations and schizophrenia patients with hallucinations exhibited increased connectivity, mainly among fronto-temporal and fronto-insula/cingulate areas compared to controls (P < 0.001 adjusted). Differential effects were observed for bipolar-I disorder patients with hallucinations versus controls, mainly characterized by decreased connectivity between fronto-temporal and fronto-striatal areas (P = 0.012 adjusted). No connectivity alterations were found between bipolar-I disorder patients without hallucinations and controls. Our results support the notion that hallucinations in non-clinical individuals and schizophrenia patients are related to altered interactions between sensory and higher-order cognitive brain regions. However, a different dysconnectivity pattern was observed for bipolar-I disorder patients with hallucinations, which implies a different neural mechanism across the psychosis continuum.publishedVersio

Exercise improves clinical symptoms, quality of life, global functioning, and depression in schizophrenia: A systematic review and meta-analysis

Background: Physical exercise may be valuable for patients with schizophrenia spectrum disorders as it may have beneficial effect on clinical symptoms, quality of life and cognition. Methods: A systematic search was performed using PubMed (Medline), Embase, PsychInfo, and Cochrane Database of Systematic Reviews. Controlled and uncontrolled studies investigating the effect of any type of physical exercise interventions in schizophrenia spectrum disorders were included. Outcome measures were clinical symptoms, quality of life, global functioning, depression or cognition. Meta-analyses were performed using Comprehensive Meta-Analysis software. A random effects model was used to compute overall weighted effect sizes in Hedges' g. Results: Twenty-nine studies were included, examining 1109 patients. Exercise was superior to control conditions in improving total symptom severity (k = 14, n = 719: Hedges' g =. 39, P <. 001), positive (k = 15, n = 715: Hedges' g =. 32, P <. 01), negative (k = 18, n = 854: Hedges' g =. 49, P <. 001), and general (k = 10, n = 475: Hedges' g =. 27, P <. 05) symptoms, quality of life (k = 11, n = 770: Hedges' g =. 55, P <. 001), global functioning (k = 5, n = 342: Hedges' g =. 32, P <. 01), and depressive symptoms (k = 7, n = 337: Hedges' g =. 71, P <. 001). Yoga, specifically, improved the cognitive subdomain long-term memory (k = 2, n = 184: Hedges' g =. 32, P <. 05), while exercise in general or in any other form had no effect on cognition. Conclusion: Physical exercise is a robust add-on treatment for improving clinical symptoms, quality of life, global functioning, and depressive symptoms in patients with schizophrenia. The effect on cognition is not demonstrated, but may be present for yoga

Exercise Improves Clinical Symptoms, Quality of Life, Global Functioning, and Depression in Schizophrenia : A Systematic Review and Meta-analysis

BACKGROUND: Physical exercise may be valuable for patients with schizophrenia spectrum disorders as it may have beneficial effect on clinical symptoms, quality of life and cognition. METHODS: A systematic search was performed using PubMed (Medline), Embase, PsychInfo, and Cochrane Database of Systematic Reviews. Controlled and uncontrolled studies investigating the effect of any type of physical exercise interventions in schizophrenia spectrum disorders were included. Outcome measures were clinical symptoms, quality of life, global functioning, depression or cognition. Meta-analyses were performed using Comprehensive Meta-Analysis software. A random effects model was used to compute overall weighted effect sizes in Hedges' g. RESULTS: Twenty-nine studies were included, examining 1109 patients. Exercise was superior to control conditions in improving total symptom severity (k = 14, n = 719: Hedges' g = .39, P < .001), positive (k = 15, n = 715: Hedges' g = .32, P < .01), negative (k = 18, n = 854: Hedges' g = .49, P < .001), and general (k = 10, n = 475: Hedges' g = .27, P < .05) symptoms, quality of life (k = 11, n = 770: Hedges' g = .55, P < .001), global functioning (k = 5, n = 342: Hedges' g = .32, P < .01), and depressive symptoms (k = 7, n = 337: Hedges' g = .71, P < .001). Yoga, specifically, improved the cognitive subdomain long-term memory (k = 2, n = 184: Hedges' g = .32, P < .05), while exercise in general or in any other form had no effect on cognition. CONCLUSION: Physical exercise is a robust add-on treatment for improving clinical symptoms, quality of life, global functioning, and depressive symptoms in patients with schizophrenia. The effect on cognition is not demonstrated, but may be present for yoga

EEG-based neurophysiological indicators of hallucinations in Alzheimer's disease : Comparison with dementia with Lewy bodies

We studied neurophysiological indicators of hallucinations in Alzheimer's disease patients with hallucinations (ADhall+), and compared them with nonhallucinating AD (ADhall−) and dementia with Lewy bodies (DLBhall+) patients. Thirty-six matched ADhall+ and 108 ADhall− and 29 DLBhall+ patients were selected from the Amsterdam Dementia Cohort. Electroencephalography (EEG) spectral and functional connectivity (FC) analyses (phase lag index) were performed. Quantitative and visual EEG measures were combined in a random forest algorithm to determine which EEG-based variable(s) play a role in hallucinations. ADhall+ patients showed lower peak frequency (7.26 vs. 7.94 Hz, p < 0.01), α2-and β-power, and α2-FC but higher δ-power compared to ADhall−. ADhall+ showed lower δ-power, higher β-power, and α1-FC than DLBhall+ but did not differ in peak frequency (7.26 vs. 6.95 Hz), θ- or α-power. ADhall+ patients could be differentiated from ADhall− and DLBhall+ with a weighted accuracy of 71% with α1-power and 100% with β-FC, the 2 most differentiating features. In sum, EEG slowing and decrease in α1-and β-band activity form potential neurophysiological indicators of underlying cholinergic deficiency in ADhall+ and DLBhall+

Physical exercise improves quality of life, depressive symptoms, and cognition across chronic brain disorders: a transdiagnostic systematic review and meta-analysis of randomized controlled trials

We performed a meta-analysis to synthesize evidence on the efficacy and safety of physical exercise as an add-on therapeutic intervention for quality of life (QoL), depressive symptoms and cognition across six chronic brain disorders: Alzheimer’s disease, Huntington’s disease, multiple sclerosis, Parkinson’s disease, schizophrenia and unipolar depression. 122 studies ( = k) (n = 7231) were included. Exercise was superior to treatment as usual in improving QoL (k = 64, n = 4334, ES = 0.40, p < 0.0001), depressive symptoms (k = 60, n = 2909, ES = 0.78, p < 0.0001), the cognitive domains attention and working memory (k = 21, n = 1313, ES = 0.24, p < 0.009), executive functioning (k = 14, n = 977, ES = 0.15, p = 0.013), memory (k = 12, n = 994, ES = 0.12, p = 0.038) and psychomotor speed (k = 16, n = 896, ES = 0.23, p = 0.003). Meta-regression showed a dose–response effect for exercise time (min/week) on depressive symptoms (β = 0.007, p = 0.012). 69% of the studies that reported on safety, found no complications. Exercise is an efficacious and safe add-on therapeutic intervention showing a medium-sized effect on QoL and a large effect on mood in patients with chronic brain disorders, with a positive dose–response correlation. Exercise also improved several cognitive domains with small but significant effects

Understanding hallucinations in probable Alzheimer's disease : Very low prevalence rates in a tertiary memory clinic

Introduction: Averaging at 13.4%, current literature reports widely varying prevalence rates of hallucinations in patients with probable Alzheimer's disease (AD), and is still inconclusive on contributive factors to hallucinations in AD. Methods: This study assessed prevalence, associated factors and clinical characteristics of hallucinations in 1227 patients with probable AD, derived from a tertiary memory clinic specialized in early diagnosis of dementia. Hallucinations were assessed with the Neuropsychiatric Inventory. Results: Hallucination prevalence was very low, with only 4.5% (n = 55/1227) affected patients. Hallucinations were mostly visual (n = 40/55) or auditory (n = 12/55). Comorbid delusions were present in over one-third of cases (n = 23/55). Hallucinations were associated with increased dementia severity, neuropsychiatric symptoms, and a lifetime history of hallucination-evoking disease (such as depression and sensory impairment), but not with age or gender. Discussion: In the largest sample thus far, we report a low prevalence of hallucinations in probable AD patients, comparable to rates in non-demented elderly. Our results suggest that hallucinations are uncommon in early stage AD. Clinicians that encounter hallucinations in patients with early AD should be sensitive to hallucination-evoking comorbidity