Mahlon R. DeLong

A reappraisal of the functions of the nucleus basalis of Meynert

Abstract The nucleus basalis of Meynert (NBM) has recently been identified as the primary source of acetylcholine (ACh) in the cerebral cortex. Damage to the NBM in Alzheimers disease appears to account for the consistent loss of cholinergic markers in cortex associated with this disease. These findings have drawn attention to the possible functions of the NBM and the other components of the basal forebrain cholinergic system. Cholinergic neurotransmission has long been thought to be involved in memory and arousal, and current research has provided new insights into the specific role of the NBM in these processes. Recent findings have also led to new concepts of how the NBM may interact with other neural structures. This review discusses some of the recent hypotheses of the functions of the NBM, particularly its possible role in learning.

Electrophysiological Studies of the Functions of the Nucleus Basalis in Primates

In summary, the studies reviewed here have indicated which neural functions might be directly influenced by the nucleus basalis. Basalis neurons do not appear to be directly involved in trial-specific memory because, in memory tasks, they have non-differential responses that do not correspond to the information being remembered by the monkey. Similarly, basalis neurons do not appear to be related to movements because, in a go/no-go task, similar neuronal responses occur whether the animal moves or does not move, and, in a delayed response task, different neuronal responses occur during the same arm movement made under different conditions. Basalis neurons also respond differently to the same sensory stimuli presented under different conditions, which indicates that the nucleus basalis is not involved in basic sensory perception. The responses of basalis neurons therefore appear to be strongly influenced by the context or behavioral significance of stimuli. Many basalis neurons respond to appetitive stimuli. In trained animals, the most frequently observed responses have been to a water reward or to stimuli that consistently precede the reward. In naive, thirsty animals, a large proportion of basalis neurons respond to the delivery of water. However, a large number of neurons also respond to an aversive air puff, which indicates that the nucleus basalis cannot be exclusively related to appetitive stimuli. Although some basalis neurons apparently respond only to the appetitive stimulus and others respond only to the aversive stimulus, the majority appear to respond similarly to both stimuli. In particular, almost all of the neurons whose response magnitudes covary with the volume of the water respond similarly to the air puff. Hence, the neurons that appear most likely to be related to the appetitive component of the water are also responsive to an aversive stimulus. Basalis neurons may therefore be related to some common characteristic of aversive and appetitive stimuli, such as the arousing quality of these stimuli. The hypothesis that most basalis neurons are particularly responsive to arousing stimuli could account for the abundance of responses to rewards and stimuli associated with rewards. These phasic responses of basalis neurons are hypothesized to be related to a transient increase in the cortical activation component of arousal, just as the tonic activity of basalis neurons appears to be related to sustained cortical activation.

Basal forebrain neurons provide major cholinergic innervation of primate neocortex

In 3 monkeys, lesions were made in the basal forebrain by microinjections of ibotenic acid into the nucleus basalis. Bilateral samples of multiple neocortical gyri were assayed for the activity of choline acetyltransferase. Compared to control hemispheres, enzyme activity was reduced up to 69% in the neocortex ipsilateral to the lesion; in addition, acetylcholinesterase staining was decreased at the lesioned site and in the ipsilateral cortex. These results support the concept that the principal cholinergic innervation of the primate neocortex is derived from axons and nerve terminals of neurons whose perikarya are located in the basal forebrain, particularly the nucleus basalis.

A personal computer-based spike detector and sorter : implementation and evaluation

Many studies of neuronal activity require isolation of the extracellular wave form (spike) of a single neuron from the potentials generated by nearby cells. A variety of methods for spike sorting exists, but most are expensive and require specialized hardware and software. Moreover, there is no easy and objective way for evaluating and comparing the performance of spike sorting devices. We describe here a system for on-line spike sorting that is implemented on an IBM PC/AT computer using commercially available hardware and C-language software. Spikes are detected after crossing an amplitude threshold and are sorted or rejected by template matching. The templates are constructed in a learning phase, using a fast manual sorting of all detected spikes. Later, each detected spike is matched against all defined templates. A detected spike which does not match any template, or matches more than one, is rejected. A continuous display of the wave forms of the last 256 sorted, double-matched, and rejected spikes is used as the main tool for parameter adjustment and error detection. Also described is a new and highly versatile tool for generating appropriate wave forms for critical evaluation of sorter performance. Using the same hardware and software tools, a simulation program mimics the extra-cellular activity of several neurons by linear combination of two vectors and added random noise. The size, shape and the variability of the action potential, as well as its firing pattern, can be adjusted. Comparison of the sorter output with the known simulated activity is used to examine the sorter performance and limitations.

Functional Implications of Tonic and Phasic Activity Changes in Nucleus Basalis Neurons

The basal forebrain cholinergic system (BFCS) has become a focus of research in many laboratories over the past decade. Current interest in this system began in the mid-1970s when a population of neurons in the basal forebrain was discovered to project to cerebral cortex (Divac, 1975; Kievit and Kuypers, 1975). It was later established that the neurotransmitter for the cortically projecting neurons was acetylcholine (ACh) (Mesulam et al., 1983; Rye et al., 1984) and that these neurons provided the major source of cholinergic input to cortex (Lehmann et al., 1980; Wenk et al., 1980; Johnston et al., 1981; Struble et al., 1986). Also in the mid-1970s, ACh became strongly implicated in Alzheimer’s disease (AD) because cholinergic markers were found to be severely reduced in the brains of AD patients (Davies and Maloney, 1976; Perry et al., 1977; Spillane et al., 1977). By the early 1980s, the nucleus basalis, the largest component of the BFCS, was shown to have a substantial loss of neurons in patients with AD (Whitehouse et al., 1982). The depletion of nucleus basalis neurons was hypothesized to account for the decrease in cortical cholinergic markers which could possibly lead to the cognitive deterioration of AD (Bartus et al., 1982; Coyle et al., 1983). These findings stimulated a great deal of interest in the anatomical and physiological properties of the BFCS in an effort to understand its role in normal brain function and dementia.

Responses of Nucleus Basalis of Meynert Neurons in Behaving Monkeys

Cholinergic systems have long been implicated in memory processes since anticholinergic drugs disrupt performance on memory tasks in both human (Drachman, 1977; Mewaldt and Ghoneim, 1979) and nonhuman primates (Bartus, 1978; Ridley et al., 1984) and other species (Buresova et al., 1964; Deutsch, 1971; Squire et al., 1971). The source of cholinergic afferents to cerebral cortex has recently been found to lie primarily in the nucleus basalis of Meynert (NBM) (Lehman et al., 1980; Johnston et al., 1981; Mesulam et al., 1983; Pearson et al., 1983). Moreover, both the number of neurons in the NBM (Whitehouse et al., 1982; Arendt et al., 1983; Rogers et al., 1985) and the levels of cholinergic markers in cortex (Davies and Maloney, 1976; Perry et al., 1977; White et al., 1977) have consistently been found to be reduced in patients with Alzheimer’s disease. These findings have led to the hypothesis that the NBM may play an important role in learning and memory.

Brain Mechanisms in Alzheimer's Disease

A clear connection between specific neuropathology and impaired brain function has recently been established in Alzheimers disease and in a closely related form of senile dementia. Although therapy and prophylaxis remain remote, mechanisms now being investigated may eventually facilitate palliative management and also shed some light on normal brain function.

Magnetic resonance planned thalamotomy followed by X-ray/CT-guided thalamotomy.

Magnetic resonance imaging (MRI) is currently the optimal neuroradiologic technique for visualizing the anterior and posterior commissure for defining the AC-PC line. CT is the optimal technique for electrode and probe guidance during stereotactic thalamotomy. Various possibilities of transferring or overlying MRI and CT are outlined which in some future might result in more refined methods of CT-MRI guidance for stereotactic surgery.

Microphysiological Recordings at CT Gantry Site during Stereotactic Thalamotomy

Neural unit recording was performed during CT-guided stereotactic thalamotomy in 2 patients referred for severe cerebellar ataxia and dysmetric movements. Periodic CT scanning was performed during the recording in order to verify probe location and trajectory. Our experience with electrophysiological recordings at the CT gantry site demonstrates the feasibility of acquiring satisfactory neural unit recordings in spite of the high-voltage environment.