Rapid eye movement (REM) sleep consists of a dreaming state in which there is activation of the cortical and hippocampal electroencephalogram (EEG), rapid eye movements, and loss of muscle tone. Although REM sleep was discovered more than 50 years ago, the neuronal circuits responsible for switching between REM and non-REM (NREM) sleep remain poorly understood. Here we propose a brainstem flip–flop switch, consisting of mutually inhibitory REM-off and REM-on areas in the mesopontine tegmentum. Each side contains GABA (γ-aminobutyric acid)-ergic neurons that heavily innervate the other. The REM-on area also contains two populations of glutamatergic neurons. One set projects to the basal forebrain and regulates EEG components of REM sleep, whereas the other projects to the medulla and spinal cord and regulates atonia during REM sleep. The mutually inhibitory interactions of the REM-on and REM-off areas may form a flip–flop switch that sharpens state transitions and makes them vulnerable to sudden, unwanted transitions—for example, in narcolepsy. Rapid eye movement (REM) sleep is a dreaming state in which the brain is highly active. The mechanism responsible for switching between REM and non-REM sleep (also called slow-wave sleep, when cortical activity is slow) is poorly understood. Now, based on detailed anatomy and lesion experiments, Lu et al. have identified brainstem regions that control the transition from REM to non-REM sleep. The REM-off and REM-on areas are mutually inhibitory. This appears to produce a flip-flop switch relationship that could explain many of the properties of the abrupt switching into and out of REM states seen in sleep disorders such as narcolepsy.

A putative flip–flop switch for control of REM sleep

Hallucinations, mainly of a visual nature, are considered to affect about one-quarter of patients with Parkinson's disease. They are commonly viewed as a side-effect of antiparkinsonian treatment, but other factors may be involved. The aim of this study was to determine the phenomenology, prevalence and risk factors of hallucinations in Parkinson's disease. Two-hundred and sixteen consecutive patients fulfilling clinical criteria for Parkinson's disease were studied. Demographic and clinical variables were recorded, including motor and cognitive status, depressive symptoms and sleep-wake disturbances. Patients with and without hallucinations were compared using non-parametric tests, and logistic regression was applied to significant data. Hallucinations had been present during the previous 3 months in 39.8% of the patients, and fell into three categories: minor forms, consisting of a sensation of a presence (person), a sideways passage (commonly of an animal) or illusions were present in 25.5% of the patients (an isolated occurrence in 14.3%), formed visual hallucinations were present in 22.2% (isolated in 9.3%) and auditory hallucinations were present in 9.7% (isolated in 2.3%). Patients with minor hallucinations had a higher depression score than non-hallucinators but did not differ in other respects. Logistic regression analysis identified three factors independently predictive of formed visual hallucinations: severe cognitive disorders, daytime somnolence and a long duration of Parkinson's disease. These findings indicate that, when minor hallucinations are included, the total prevalence is much higher than previously reported. A simple side-effect of dopaminergic treatment is not sufficient to explain the occurrence of all visual hallucinations. The main risk factor in treated patients is cognitive impairment, although sleep-wake cycle disturbances, and possibly other factors related to the duration of the disease, act as cofactors.

/pdf/hallucinations-in-parkinson-s-disease-prevalence-3d2uc6a357.pdf

Hallucinations in Parkinson's disease: prevalence, phenomenology and risk factors.

Psychopharmacology: The Fourth Generation of Progress.

Consensus opinion characterizes dementia with Lewy bodies (DLB) as a progressive dementing illness, with significant fluctuations in cognition, visual hallucinations and/or parkinsonism. When parkinsonism is an early dominant feature, consensus opinion recommends that dementia within the first year is necessary for a diagnosis of DLB. If dementia occurs later, a diagnosis of Parkinson's disease with dementia (PDD) is recommended. While many previous studies have correlated the neuropathology in DLB with dementia and parkinsonism, few have analysed the relationship between fluctuating cognition and/or well-formed visual hallucinations and the underlying neuropathology in DLB and PDD. The aim of the present study was to determine any relationship between these less-studied core clinical features of DLB, and the distribution and density of cortical Lewy bodies (LB). The brains of 63 cases with LB were obtained over 6 years following population-based studies of dementia and parkinsonian syndromes. Annual, internationally standardized, clinical assessment batteries were reviewed to determine the presence and onset of the core clinical features of DLB. The maximal density of LB, plaques and tangles in the amygdala, parahippocampal, anterior cingulate, superior frontal, inferior temporal, inferior parietal and visual cortices were determined. Current clinicopathological diagnostic criteria were used to classify cases into DLB (n = 29), PDD (n = 18) or parkinsonism without dementia (n = 16) groups. Predictive statistics were used to ascertain whether fluctuating cognition or visual hallucinations predicted the clinicopathological group. Analysis of variance and regressions were used to identify any significant relationship(s) between the presence and severity of neuropathological and clinical features. Cognitive fluctuations and/or visual hallucinations were not good predictors of DLB in pathologically proven patients, although the absence of these features early in the disease course was highly predictive of PDD. Cases with DLB had higher LB densities in the inferior temporal cortex than cases with PDD. There was no association across groups between any neuropathological variable and the presence or absence of fluctuating cognition. However, there was a striking association between the distribution of temporal lobe LB and well-formed visual hallucinations. Cases with well-formed visual hallucinations had high densities of LB in the amygdala and parahippocampus, with early hallucinations relating to higher densities in parahippocampal and inferior temporal cortices. These temporal regions have previously been associated with visual hallucinations in other disorders. Thus, our results suggest that the distribution of temporal lobe LB is more related to the presence and duration of visual hallucinations in cases with LB than to the presence, severity or duration of dementia.

/pdf/visual-hallucinations-in-lewy-body-disease-relate-to-lewy-708lea3pvi.pdf

Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe.

Seeking antemortem markers to distinguish Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), we examined brain glucose metabolism of DLB and AD. Eleven DLB patients (7 Lewy body variant of AD [LBVAD] and 4 pure diffuse Lewy body disease [DLBD]) who had antemortem position emission tomography imaging and autopsy confirmation were compared to 10 autopsy-confirmed pure AD patients. In addition, 53 patients with clinically-diagnosed probable AD, 13 of whom later fulfilled clinical diagnoses of DLB, were examined. Autopsy-confirmed AD and DLB patients showed significant metabolic reductions involving parietotemporal association, posterior cingulate, and frontal association cortices. Only DLB patients showed significant metabolic reductions in the occipital cortex, particularly in the primary visual cortex (LBVAD -23% and DLBD -29% vs AD -8%), which distinguished DLB versus AD with 90% sensitivity and 80% specificity. Multivariate analysis revealed that occipital metabolic changes in DLB were independent from those in the adjacent parietotemporal cortices. Analysis of clinically diagnosed probable AD patients showed a significantly higher frequency of primary visual metabolic reduction among patients who fulfilled later clinical criteria for DLB. In these patients, occipital hypometabolism preceded some clinical features of DLB. Occipital hypometabolism is a potential antemortem marker to distinguish DLB versus AD.

/pdf/alzheimer-s-disease-versus-dementia-with-lewy-bodies-1qgwpfniuk.pdf

Alzheimer's disease versus Dementia with Lewy bodies : Cerebral metabolic distinction with autopsy confirmation

Complex visual hallucinations may affect some normal individuals on going to sleep and are also seen in pathological states, often in association with a sleep disturbance. The content of these hallucinations is striking and relatively stereotyped, often involving animals and human figures in bright colours and dramatic settings. Conditions causing these hallucinations include narcolepsy-cataplexy syndrome, peduncular hallucinosis, treated idiopathic Parkinson's disease, Lewy body dementia without treatment, migraine coma, Charles Bonnet syndrome (visual hallucinations of the blind), schizophrenia, hallucinogen-induced states and epilepsy. We describe cases of hallucinosis due to several of these causes and expand on previous hypotheses to suggest three mechanisms underlying complex visual hallucinations. (i) Epileptic hallucinations are probably due to a direct irritative process acting on cortical centres integrating complex visual information. (ii) Visual pathway lesions cause defective visual input and may result in hallucinations from defective visual processing or an abnormal cortical release phenomenon. (iii) Brainstem lesions appear to affect ascending cholinergic and serotonergic pathways, and may also be implicated in Parkinson's disease. These brainstem abnormalities are often associated with disturbances of sleep. We discuss how these lesions, outside the primary visual system, may cause defective modulation of thalamocortical relationships leading to a release phenomenon. We suggest that perturbation of a distributed matrix may explain the production of similar, complex mental phenomena by relatively blunt insults at disparate sites.

/pdf/complex-visual-hallucinations-clinical-and-neurobiological-1bolma3rfh.pdf

M Manford

Papers

Complex visual hallucinations. Clinical and neurobiological insights.

Further advances in epilepsy.