Combined in vivo MRI assessment of locus coeruleus and nucleus basalis of Meynert integrity in amnestic Alzheimer's disease, suspected-LATE and frontotemporal dementia.

BACKGROUND: The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls. METHODS: Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy. RESULTS: We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients. CONCLUSIONS: The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.

With an eye on uncertainty: Modelling pupillary responses to environmental volatility.

Living creatures must accurately infer the nature of their environments. They do this despite being confronted by stochastic and context sensitive contingencies-and so must constantly update their beliefs regarding their uncertainty about what might come next. In this work, we examine how we deal with uncertainty that evolves over time. This prospective uncertainty (or imprecision) is referred to as volatility and has previously been linked to noradrenergic signals that originate in the locus coeruleus. Using pupillary dilatation as a measure of central noradrenergic signalling, we tested the hypothesis that changes in pupil diameter reflect inferences humans make about environmental volatility. To do so, we collected pupillometry data from participants presented with a stream of numbers. We generated these numbers from a process with varying degrees of volatility. By measuring pupillary dilatation in response to these stimuli-and simulating the inferences made by an ideal Bayesian observer of the same stimuli-we demonstrate that humans update their beliefs about environmental contingencies in a Bayes optimal way. We show this by comparing general linear (convolution) models that formalised competing hypotheses about the causes of pupillary changes. We found greater evidence for models that included Bayes optimal estimates of volatility than those without. We additionally explore the interaction between different causes of pupil dilation and suggest a quantitative approach to characterising a person's prior beliefs about volatility.

In vivo MRI assessment of the human locus coeruleus along its rostrocaudal extent in young and older adults.

The locus coeruleus (LC), a major origin of noradrenergic projections in the central nervous system (CNS), may serve a critical role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). As such, there is considerable interest to develop magnetic resonance imaging (MRI) techniques to assess the integrity of the LC in vivo. The high neuromelanin content of the LC serves as an endogenous contrast for MRI but existing protocols suffer from low spatial resolution along the rostrocaudal axis of the LC rendering it difficult to differentiate its integrity in caudal and rostral portions. This study presents a novel approach to investigate the human LC in vivo using T1-weighted Fast Low Angle Shot (FLASH) MRI at 3 T (T). Using high-resolution isotropic imaging to minimise the effect of low spatial resolution in the slice direction, this study aimed to characterise the rostrocaudal distribution of LC signal intensity attributed to neuromelanin from 25 young (22-30) and 57 older (61-80) adults. We found a significant age-related increase in maximum but not median signal intensity, indicating age-related differences were not homogenous. Instead, they were confined to the rostral third of the LC with relative sparing of the caudal portion. The findings presented demonstrate in vivo T1-weighted FLASH imaging may be used to characterise signal intensity changes across the entire rostrocaudal length of the LC (a corresponding standardised LC map is available for download), which may help to identify how the human LC is differentially affected in aging and neurodegenerative disease.

A novel approach for integrative studies on neurodegenerative diseases in human brains.

Despite a massive research effort to elucidate Alzheimer's disease (AD) in recent decades, effective treatment remains elusive. This failure may relate to an oversimplification of the pathogenic processes underlying AD and also lack of understanding of AD progression during its long latent stages. Although evidence shows that the two specific neuropathological hallmarks in AD (neuronal loss and protein accumulation), which are opposite in nature, do not progress in parallel, the great majority of studies have focused on only one of these aspects. Furthermore, research focusing on single structures is likely to render an incomplete picture of AD pathogenesis because as AD involves complete brain networks, potential compensatory mechanisms within the network may ameliorate impairment of the system to a certain extent. Here, we describe an approach for enabling integrative analysis of the dual-nature lesions, simultaneously, in all components of one of the brain networks most vulnerable to AD. This approach is based on significant development of methods previously described mainly by our group that were optimized and complemented for this study. It combines unbiased stereology with immunohistochemistry and immunofluorescence, making use of advanced graphics computing for three-dimensional (3D) volume reconstructions. Although this study was performed in human brainstem and focused in AD, it may be applied to the study of any neurological disease characterized by dual-nature lesions, in humans and animal models. This approach does not require a high level of investment in new equipment and a significant number of specimens can be processed and analyzed within a funding cycle.

In vivo electrophysiological assessment of the putative antidepressant Wf-516 in the rat raphe dorsalis, locus coeruleus and hippocampus.

Wf-516 is a potential novel antidepressant. It has high affinity for serotonin (5-hydroxytryptamine; 5-HT) transporters, 5-HT(1A) and 5-HT(2A) receptors. In the present study, the pharmacologic properties of Wf-516 were thus assessed using in vivo electrophysiology in the rat dorsal raphe nucleus (DRN), locus coeruleus (LC) and hippocampus. Glass microelectrodes were lowered into the DRN, LC or hippocampus, and neurons were recorded and tested using systemic or microiontophoretic injections of drugs. In the DRN, cumulative doses of 0.5 mg/kg of Wf-516 were injected intravenously and total inhibition of 5-HT neurons firing was obtained with 2.8 +/- 0.3 mg/kg. The administration of 1 mg/kg of Wf-516, which by itself did not induce a change in the firing of 5-HT neurons, markedly attenuated the inhibitory effect of the 5-HT(1A) autoreceptor agonist LSD, indicating that Wf-516 is a 5-HT(1A) autoreceptor antagonist. In the LC, 1 mg/kg of Wf-516 dampened the inhibitory effect of the preferential 5-HT(2A) agonist DOI on norepinephrine (NE) neurons, indicating that Wf-516 is also a 5-HT(2A) receptor antagonist. In the hippocampus, cumulative intravenous doses of Wf-516 significantly increased the recovery time of firing activity of CA(3) pyramidal neurons after 5-HT applications, indicating an inhibitory effect on 5-HT reuptake. Unlike the 5-HT(1A) antagonist WAY100635, Wf-516 did not block the inhibitory effect of microiontophoretic application of 5-HT, indicating that this drug is devoid of 5-HT(1A) receptor antagonistic activity in this postsynaptic structure. These properties of WF-516 define the transporter/receptorial profile of an antidepressant with superior effectiveness.

Gabrb3 gene deficient mice exhibit increased risk assessment behavior, hypotonia and expansion of the plexus of locus coeruleus dendrites.

Gabrb3 gene deficient (gabrb3(-/-)) mice, control littermates (gabrb3(+/+)) and their progenitor strains C57Bl/6J and 129/SvJ were assessed for changes in the morphology of the main noradrenergic nuclei, the locus coeruleus (LC) and LC-associated behaviors including anxiety and muscle tone. While the area defined by the cell bodies of the LC was found not to differ between gabrb3(-/-) mice and controls, the pericoerulear dendritic zone of the LC was found to be significantly enlarged in gabrb3(-/-) mice. Relative to controls, gabrb3(-/-) mice were also found to be hypotonic, as was indicated by poor performance on the wire hanging task. Gabrb3(-/-) mice also exhibited a significant increase in stretch-attend posturing, a form of risk assessment behavior associated with anxiety. However, in the plus maze, a commonly used behavioral test for assessing anxiety, no significant difference was observed between gabrb3(-/-) and control mice. Lastly, relative to controls, gabrb3(-/-) mice exhibited significantly less marble burying behavior, a method commonly used to assess obsessive-compulsive behavior. However, the poor marble burying performance of the gabrb3(-/-) mice could be associated with the hypotonic condition exhibited by these mice. In conclusion, the results of this study indicate that the gabrb3 gene contributes to LC noradrenergic dendrite development with the disruption of this gene in mice resulting in an enlarged plexus of LC dendrites with a concurrent reduction in muscle tone and marble burying behavior, an increase in risk assessment behavior but no change in the plus maze parameters that are commonly used for assessing anxiety.

The physiology and processing of pain: a review.

Despite the many advances in our understanding of the mechanisms underlying pain processing, pain continues to be a major healthcare problem in the United States. Each day, millions of Americans are affected by both acute and chronic pain conditions, costing in excess of $100 billion for treatment-related costs and lost work productivity. Thus, it is imperative that better treatment strategies be developed. One step toward improving pain management is through increased knowledge of pain physiology. Within the nervous system, there are several pathways that transmit information about pain from the periphery to the brain. There is also a network of pathways that carry modulatory signals from the brain and brainstem that alter the incoming flow of pain information. This article provides a review to the physiology and processing of pain.

A hidden Markov model approach to neuron firing patterns.

Analysis and characterization of neuronal discharge patterns are of interest to neurophysiologists and neuropharmacologists. In this paper we present a hidden Markov model approach to modeling single neuron electrical activity. Basically the model assumes that each interspike interval corresponds to one of several possible states of the neuron. Fitting the model to experimental series of interspike intervals by maximum likelihood allows estimation of the number of possible underlying neuron states, the probability density functions of interspike intervals corresponding to each state, and the transition probabilities between states. We present an application to the analysis of recordings of a locus coeruleus neuron under three pharmacological conditions. The model distinguishes two states during halothane anesthesia and during recovery from halothane anesthesia, and four states after administration of clonidine. The transition probabilities yield additional insights into the mechanisms of neuron firing.

Noradrenergic terminal fields as determinants of seizure predisposition in GEPR-3s: a neuroanatomic assessment with intracerebral microinjections of 6-hydroxydopamine.

The genetically epilepsy-prone rat (GEPR) and other mammals with genetically based epilepsy are characterized by an innate predisposition to seizures evoked by a wide variety of stimuli (including those of endogenous origin). The present investigation was undertaken to identify the anatomical location of the noradrenergic terminal fields responsible for regulation of seizure predisposition. In this study, audiogenic seizure severity was used as the index of seizure predisposition. The effect of widespread destruction of noradrenergic terminal fields was compared with the effect of destroying regionally distinct terminal fields. These lesions were produced by microinfusion of 6-hydroxydopamine (6-OHDA) into the locus ceruleus, the A1 noradrenergic area, the noradrenergic dorsal bundle, the cerebellar peduncles and spinal intrathecal space. Selective depletion of norepinephrine in the forebrain, the cerebellum, or the spinal cord failed to alter audiogenic seizure severity. An increase in seizure severity was always associated with marked depletion of norepinephrine in the midbrain excluding the inferior colliculus. Also a significant correlation existed between the seizure intensification and reduction of norepinephrine in this structure in all instances where a seizure intensification was observed. An association of seizure intensification also existed in all cases except one with depletion in the pons/medulla. The present findings support the hypothesis that the noradrenergic terminal fields of the midbrain excluding the inferior colliculus are determinants of seizure predisposition. Inasmuch as audiogenic seizures are a type of brainstem seizure, the present findings do not a priori pertain to the noradrenergic regulation of forebrain seizures.

Favored patterns in spontaneous spike trains.

By using the modified detection method, favored patterns can be detected in a total of 44 spontaneous spike trains. Among these the 'periodical burst' discharge of one sympathetic preganglionic neuron and the 'fast-slow' alternative discharge of some hypothalamic neurons have visible characteristics, hence we use them to test the reliability of our method by comparing the detected patterns with the non-sequential interval histograms and oscillograms of the spike trains. The comparisons show that our method is reliable. The spike trains of nucleus raphe magnus (NRM) and the locus coeruleus (LC) have no visible characteristics; from these the following results have been observed: (1) all spike trains have one or more favored patterns; (2) some spike trains from neurons in the same nucleus have common fragments of favored patterns; (3) the favored patterns in spike trains recorded from different nuclei are different from each other; (4) some favored patterns in spike trains of the NRM neurons remain unchanged from beginning to end in 35-min records and their repetitions are relatively stable; and (5) microinjection of normal saline or normal serum into the LC has no significant influence on the occurrence of favored patterns in 35-min records of spike trains of the LC neurons. The above results indicate that the favored patterns in spike trains are objective and regular phenomena with relative stability. It seems likely that favored pattern may be used (as an index of the neuronal activity) in combination with the microinjection technique, etc., for various studies including studies on neural coding.

Distribution and ultrastructure of Alzheimer's neurofibrillary tangles in postencephalitic Parkinsonism of Economo type.

The distribution and ultrastructure of Alzheimer's neurofibrillary tangles (ANT) in the brain stem, hypothalamus, and Ammon's horn were studied in four patients with postencephalitic parkinsonism of Economo type (PEPE). The distribution of ANT was as previously reported; the pattern of distribution resembled to that of amine-containing nerve cells. Ultrastructurally, ANT revealed twisted tubules (TT), but straight tubules (ST) of 150 A width were also found in the locus ceruleus of three cases; sometimes, TT and ST were mixed in a single neuron. Whether the coexistence of TT and ST in the locus ceruleus is a characteristic ultrastructural feature of ANT in PEPE or a regional peculiarity could not be determined. Ultrastructurally, ANT in PEPE were identical to those found in the brains of patients with Alzheimer's disease or senile dementia.

Assessment of the effects of neonatal subcutaneous 6-hydroxydopamine on noradrenergic and dopaminergic innervation of the cerebral cortex.

Female rats, treated at birth with 6-hydroxydopamine (3 x 100 mg/kg s.c. at 24 h intervals) or vehicle, were subjected at 112 days of age to unilateral electrolytic lesions of the locus coeruleus. Two weeks later regions of the telencephalon, both ipsi- and contralateral to the lesion, were simultaneously assayed for norepinephrine (NE) and dopamine (DA) content, and for tyrosine hydroxylase (TOH) and dopamine-beta-hydroxylase (DBH) activities. In the vehicle-treated rats the lesion resulted in at least an 80% reduction of NE and DBH on the ipsilateral side, relative to the contralateral side. TOH was reduced to a similar extent only in the parietal cortex and hippocampus. In the prefrontal cortex and cingulate gyrus TOH was decreased by only 31% and 64% respectively; the remainder was interpreted to be associated with projections of the mesocortical dopamine system. From this data it was possible to calculate that the ratio of TOH to DA in dopaminergic terminals is about 10-fold greater than the ratio of TOH to NE in noradrenergic terminals. Neonatal 6-hydroxydopamine treatment resulted in practically total elimination of noradrenergic terminals throughout the telencephalon, and the locus coeruleus lesion had no additional effect. The drug treatment produced no significant change in DA content or in the TOH to DA ratio in the prefrontal cortex and cingulate gyrus, indicating complete sparing of the mesocortical DA projections.