Elsevier

NeuroImage

Volume 27, Issue 2, 15 August 2005, Pages 387-392
NeuroImage

Cholinergic modulation of preattentive auditory processing in aging

https://doi.org/10.1016/j.neuroimage.2005.04.018Get rights and content

Abstract

Auditory event-related potential (ERP) components P50 and N100 are thought to index preattentive auditory processing underlying stimulus detection, whereas a subsequent component termed mismatch negativity (MMN) has been proposed to reflect comparison of incoming stimuli to a short-lived sensory memory trace of preceding sounds. Existing evidence suggests impairment of preattentive auditory processing in aging, which appears to be accompanied by decline of cholinergic activity. Previous studies indicate that scopolamine, which is a centrally acting muscarinic receptor antagonist, modulates preattentive auditory processing in young subjects. It has remained elusive, however, to which extent scopolamine affects preattentive auditory processing in aged subjects. We measured auditory responses simultaneously with electroencephalogram (EEG) and magnetoencephalogram (MEG) from nine non-demented elderly subjects after intravenous injection of scopolamine or glycopyrrolate, the latter being a peripherally acting cholinergic antagonist, using a double blind protocol. Scopolamine significantly delayed electric P50, both electric and magnetic N100 responses, whereas subsequent MMN and P200 responses were not altered by scopolamine. Our results indicate that the cholinergic system modulates auditory processing underlying stimulus detection in aging. In addition, auditory evoked responses appear to have different age-related sensitivity to cholinergic modulation. The combined MEG/EEG measurements using particularly auditory N100 response might offer an objective tool to monitor cholinergic activity in aging and Alzheimer's disease (AD).

Introduction

Normal aging is associated with gradual deterioration of cognitive abilities, particularly declining speed of performance, impairments in memory and problem solving (Daffner, 2000). In addition to higher order cognitive functions, aging appears to impact preceding preattentive auditory processing that can be studied noninvasively using electroencephalography (EEG) or magnetoencephalography (MEG).

Abrupt sounds elicit event-related potential (ERP) components P50 and N100 about 50 and 100 ms after stimulus presentation, respectively, and specifically N100 response is proposed to index preconscious stimulus evaluation underlying stimulus detection (Parasuraman and Beatty, 1980). Several EEG and MEG studies have found age-related amplitude increase of P50 (Amenedo and Diaz, 1998, Azumi et al., 1995, Pfefferbaum et al., 1979) and P50m (Pekkonen et al., 1995), a magnetic counterpart to electric P50, suggesting age-associated functional alteration of inhibitory neural structures related to P50 generators. Further, N100 (Iragui et al., 1993) and N100m (Pekkonen et al., 1995), a magnetic counterpart to electric N100, responses are delayed with aging. Interestingly, in Alzheimer's disease (AD), which is characterized by depletion of cholinergic activity, attenuated P50 response (Buchwald et al., 1989, Green et al., 1992, Green et al., 1997) and delayed N100m have been reported (Pekkonen et al., 1999).

In addition to P50 and N100 responses, deviant tones embedded in a sequence of frequent standard tones elicit a specific ERP component termed mismatch negativity (MMN), which appears to the deviant tones irrespective whether attention is paid to the sounds (Näätänen, 1992). Hence MMN appears to represent preconscious, memory-based comparison process, and accordingly, MMN attenuation with long stimulus intervals is regarded to index memory trace decay in the auditory cortex (Näätänen, 1992). Several EEG and MEG studies have reported no or only slight age-related alterations of MMN to frequency changes, whereas reduced MMN to duration (for review, see Pekkonen, 2000) and gap (Bertoli et al., 2002) changes has been consistently reported when relatively short ISIs are employed. In contrast, MMN to frequency and duration change appears not to be attenuated in early stage of AD (for review, see Pekkonen, 2000). These findings suggest that aging and AD have a partly different impact on the neuronal encoding of the frequency and time domains of auditory stimuli.

Studies based on biochemical measurements have revealed considerable decline of cholinergic cortical activity in AD, and similar, albeit modest, depletion of cortical cholinergic innervation related to aging (Geula and Mesulam, 1999). Tetrahydroaminoacridine (Riekkinen et al., 1997), which is a cholinesterase inhibitor, and nicotine (Engeland et al., 2002), a cholinergic agonist, have been found to modulate MMN in patients with AD. Several studies have consistently found that scopolamine, which temporarily blocks muscarinic cholinergic receptors in the brain, modulates electric and magnetic P50, N100, and MMN responses in young healthy subjects (Buchwald et al., 1991, Callaway et al., 1991, Jaaskelainen et al., 1999, Pekkonen et al., 2001), indicating cholinergic contribution to preattentive auditory processes underlying stimulus- and stimulus-change detection. Based on age-related changes of the cholinergic system in the brain, the scopolamine administration in elderly subjects may cause different modulations to auditory processing compared with young subjects. This information is essential if evoked responses are intended to be use in clinical trials, which investigate, e.g., the efficacy of cholinergic drug intervention in AD. Scopolamine studies in elderly subjects with combined EEG/MEG measurements have not been done previously, and therefore possible age-related effects of temporary cholinergic blockade on preconscious auditory processing have remained ambiguous.

We recorded auditory responses from healthy elderly subjects with simultaneous MEG/EEG measurements accompanied by neuropsychological test battery using a double-blind paradigm in order to investigate the effects of scopolamine and glycopyrrolate, the latter being a peripheral cholinergic antagonist, on preattentive auditory processing.

Section snippets

Methods

Ten healthy elderly subjects originally participated, and nine subjects successfully accomplished the study. Accordingly, the ERP/AEF (auditory evoked field) measurements of nine subjects (range 59–85 years, 6 females) finally underwent the data analysis. All subjects gave their written informed consent before participating in the study, and the study was accepted by the National Agency for Medicines and local Ethics Committee of the hospital. Scopolamine hydrobromide (0.3 mg) or glycopyrrolate

P50 and P50m responses

P50 was significantly delayed by scopolamine (F(1,8) = 7.92, P = 0.023, repeated-measures ANOVA), and subsequent paired t test showed a significant P50 delay only at the 500-ms condition (Table 1). The scopolamine effect on P50m latency failed to reach significance (F(1,8) = 1.29). The main drug effects for P50 amplitude (F(1,8) = 4.04, ANOVA) and P50m did not reach significance, although P50 (placebo 1.1 μV, scopolamine 2.1 μV, 0.5-s ISI) and P50m (scopolamine 46 fT/cm, glycopyrrolate 32

Discussion

Our results indicate that preattentive auditory processing underlying stimulus detection and subsequent memory-based comparison process are differently modulated by scopolamine in elderly subjects. Scopolamine, which is a cholinergic antagonist, significantly delayed electric and magnetic N100 responses without clear effect on subsequent MMN and P200 responses. The electric P50, but not magnetic P50, was significantly delayed by scopolamine. Based on insignificant AEF/ERP amplitude and dipole

Acknowledgments

This work was supported by the Helsinki University Central Hospital Research Funds and Academy of Finland.

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