Cholinergic modulation of preattentive auditory processing in aging
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.
References (33)
- et al.
Aging and cholinergic modulation of the transient magnetic 40-Hz auditory response
NeuroImage
(2002) - et al.
Effects of aging on middle-latency auditory evoked potentials: a cross-sectional study
Biol. Psychiatry
(1998) - et al.
Temporal resolution in young and elderly subjects as measured by mismatch negativity and a psychoacoustic gap detection task
Clin. Neurophysiol.
(2002) - et al.
Midlatency auditory evoked responses: differential abnormality of P1 in Alzheimer's disease
Electroencephalogr. Clin. Neurophysiol.
(1989) - et al.
Midlatency auditory evoked responses: differential effects of a cholinergic agonist and antagonist
Electroencephalogr. Clin. Neurophysiol.
(1991) - et al.
Clonidine and scopolamine: differences and similarities in how they change human information processing
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
(1991) - et al.
Acute nicotine effects on auditory sensory memory in tacrine-treated and nontreated patients with Alzheimer's disease: an event-related potential study
Pharmacol. Biochem. Behav.
(2002 May) - et al.
Scopolamine enhances middle-latency auditory evoked magnetic fields
Neurosci. Lett.
(1999) - et al.
Increased cognitive sensitivity to scopolamine with age and a perspective on the scopolamine model
Brain Res. Brain Res. Rev.
(1992) - et al.
Preserved acetylcholinesterase activity in aged cerebral cortex
Lancet
(1998)
Impaired preconscious auditory processing and cognitive functions in Alzheimer's disease
Clin. Neurophysiol.
Auditory sensory memory and the cholinergic system: implications for Alzheimer's disease
NeuroImage
Event-related potential changes in healthy aged females
Electroencephalogr. Clin. Neurophysiol.
Ageing-related changes in the processing of attended and unattended standard stimuli
NeuroReport
Aging effects on auditory middle latency responses
Electromyogr. Clin. Neurophysiol.
Current approaches to the clinical diagnosis of Alzheimer's disease
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2017, Behavioural Brain ResearchCitation Excerpt :The auditory MMN is considered to be an index of sound-discrimination accuracy and auditory sensory memory [47]. Previous EEG studies in which a passive oddball task was used have found inconsistent results on the MMN after using scopolamine [16,48]. After the administration of biperiden the MMN was not affected [20].