Decreased amplitude of auditory event-related delta responses in Alzheimer's disease
Introduction
Alzheimer's disease (AD) is a slowly progressive disorder, with insidious onset and progressive impairment of episodic memory; instrumental signs include aphasia, apraxia, and agnosia. In the past 100 years the study of Alzheimer's disease has shed light on many crucial issues, ranging from the symptomatic presentation of the disease (Grady et al., 1988, Hodges and Patterson, 1995, Perry and Hodges, 1999) to the underlying neuropathology and its progression (Braak and Braak, 1995).
Many issues, however, are at present unresolved and in need of attention (Hodges, 2006). Ability to detect AD at early stages of the disease may be crucial especially given that much of the pathology may well be present in the absence of clear cognitive symptoms (Fox et al., 1996). Therefore, new biomarkers would be of great value as diagnostic tools, both for the clinical diagnosis of Alzheimer's disease and the prediction of incipient Alzheimer's disease in mild cognitive impairment cases.
The EEG consists of the activity of a pool of generators whose oscillations produce a rhythmic activity in several frequency ranges. These generators are active apparently in a random way. However, by application of sensory stimulation these electric sources are coupled and act together in a coherent way. This synchronization and enhancement of EEG activity gives rise to “evoked” or “induced rhythms”.
The expression “event-related” is generally used to define that every evoked potential is triggered also by an event. A simple auditory or visual stimulation is in a number of cases an “event” carrying also cognitive inputs to the CNS, and every stimulation is not just a physical excitation, it is an event. The term “oscillation” replaces the expression “rhythm”: a rhythm is an oscillatory behavior with some duration. The evoked oscillations usually have a damped oscillatory character lasting for 500 ms (which may be extended to approximately 1 s in the case of the P300 delta response). Nowadays, the use of the expression “event-related oscillations” is more tenable from the physiological and cognitive viewpoints. Event-related oscillations (with a defined temporal relation to a sensory or cognitive event) are classified as “evoked” or “induced” oscillations (the former being phase-locked to the event, the latter not). (Başar and Karakaş, 1998).
The oscillations that followed the stimulation are considered real responses of the brain and, also, are classified according to the “natural frequencies” of the brain (delta, theta, alpha, and gamma) (Başar et al., 2001).
Recently, increased interest has been paid on the frequency EEG responses in different frequency bands. First, event-related responses can provide additional information about sensory and cognitive functions during stimulus and task evaluation (Başar, 1992, Başar et al., 1997). Second, EEG frequency responses provide in physiologically-oriented approach to study brain functioning that is strictly related to natural rhythmic activities in the EEG. In other words, it seems that ERPs features arise from the above mentioned “super-positioned neuroelectric oscillations” modulated o produced by sensory and cognitive processes set into the dynamics of ongoing EEG rhythms (Başar-Eroglu et al., 1992, Başar-Eroglu and Demiralp, 2001, Demiralp et al., 2001, Karakaş et al., 2000a, Karakaş et al., 2000b, Klimesch et al., 2004, Schürmann et al., 2001, Yordanova and Kolev, 1996, Yordanova and Kolev, 1998).
Since the pioneering work by Goodin et al. (1978), the first question has been tackled in ERPs research by measuring delays of P3 latency in the “oddball” task. Such delays have been found reliably (Polich, 1991) when patients were more than mildly demented, but not in cases of mild to very mild dementia (Kraiuhin et al., 1990, Verleger et al., 1992, Polich et al., 1986), although it is precisely in the latter cases where there is a real need for diagnostic information that would complement neuropsychological testing. Also, is still controversial whether P3 amplitude is attenuated in AD patients. Some studies reported that P3 amplitude is not significantly attenuated (Ball et al., 1989, Kazmerski and Friedman, 1998, Verleger et al., 1992, Onofri et al., 1991), whilst others found a significant reduction in AD patients (Polich and Pitzer, 1999, Ford et al., 1996, Holt et al., 1995).
Recently, studies exploring time course of the event-related changes underlying the target stimulus evaluation suggest that delta oscillations contribute considerably and mainly to the P300 component (Stampfer and Başar, 1985, Başar-Eroglu et al., 1992, Schürmann et al., 1995, Demiralp et al., 1999). Also, Karakaş et al., 2000a, Karakaş et al., 2000b showed that it is the “interplay” between the theta and delta oscillations that mostly produces the waveform and the amplitude of the P300, and, at a less extent, also the N200 component. Hence, the maximal delta response during the target stimulus evaluation significantly contributes to the expression of the time domain P300 component.
From a neurophysiological point of view, Ball et al. (1977) suggested that this delta activity is the epiphenomenon of sequences of excitatory and inhibitory processes of cortical neurons.
Time-frequency ERP analysis has shown that delta frequency component may contribute to P300 expression of human response to a target auditory stimulus (Duncan-Johnson and Donchin, 1979, Stampfer and Başar, 1985, Yordanova and Kolev, 1997), and this delta response can be considered as “real brain response“ with precise functional correlates. This was demonstrated in a study using an auditory oddball paradigm (Başar-Eroglu et al., 1992). Standard auditory EPs (delta response amplitude set to 100%) were compared with responses to oddball stimuli showing that the normalized delta amplitude was approximately 600%. This remarkable increase is paradigmatic of a major change in the frequency contents of an EP. The same conclusion was drawn from a study employing the same paradigm with a visual stimuli (Schürmann et al., 1995). Taking into account the cognitive foundation of the P300 paradigm, this hints at cognitive processing as a functional correlate of the delta response. In particular, in an active oddball paradigm (as in our study), subjects have to manage two types of tasks. Firstly, they have to focalize attention, and secondly, they have to make a decision following the signal detection. The decision consists in the differentiation of the target rare tones from the frequent ones. If the subject's decision regarding the target tone is successful, an increase in the response in the delta frequency range is recorded. Accordingly, it is hypothesised that the delta response is related to signal detection and decision-making generated by a distributed network system (Başar-Eroglu et al., 1992, Başar et al., 1999, Schürmann et al., 2001).
A different paradigm for the investigation of delta response was proposed by Parnefjord and Basar (1995): auditory EPs were recorded in several sessions with decreasing stimulus intensities; stimuli close to subjective hearing threshold elicited nearly pure delta responses. At the threshold level decision-making and increased attention are processes interwoven with the sensory processes. On the one hand, not every sensory stimulation attracts our attention. On the other hand, a very low intensity sensory stimulation puts the individuals into a state of focused attention and readiness to achieve “decision-making”. These delta responses were interpreted as correlates of decision-making (Başar, 1999).
Therefore it is reasonable that individuals with suppressed delta responses are likely to show deficits in executive functions (decision-making, signal matching) which are mediated by this oscillatory process.
As far as AD cognitive profile is concerned, there is ample neuropsychological evidence that support the view that the initial deficit manifests as an amnesic syndrome which may progress very gradually for many years before impairment in other cognitive domains, such as language, semantic memory and visuo-spatial functions, becomes apparent (McKhann et al., 1984, Grady et al., 1988, Hodges and Patterson, 1995). Clinical observation of Alzheimer's disease patients reveals that they often have great difficulty in performing everyday tasks at a relatively early stage in the disease when formal testing of non-memory functions show little or no deficit. These observations have led to speculation that Alzheimer's disease patients may have executive deficit that underlie these difficulties with the everyday activities and that these deficits may be early and still underestimated features of the disease.
Therefore, given the functional role of delta response (decision-making, signal matching), we aimed to demonstrate that measuring delta responses in AD patients could be of relevance might reveal specific insights into the mechanisms underlying cognitive processes of this dementing illness, especially at an initial stage of the disease when executive functions are usually the first non-memory domain to be involved. We use the single sweep method because it has been shown to reflect specific aspects of stimulus information processing that can be obscured by the averaging procedure which implies a loss of information also related to trial to trial variability (Ford et al., 1994, Unsal and Segalowitz, 1995, Yordanova and Kolev, 1996). Moreover, changes in degree of fatigue, habituation, or level of attention of the subject can affect the ERPs. As reported above, the EEG frequency responses are proposed to originate from the reorganization of spontaneous EEG. Therefore, single sweep delta response parameters reflecting the stimulus-related changes in the ongoing EEG are regarded as particularly relevant for analysis. Such parameters are the amplitude changes in the post-stimulus epoch and the response phase-coupling to stimulus (Kalcher and Pfurtscheller, 1995). These amplitude and phase-locking effects cannot be discriminated separately in the averaged ERPs (Ruchkin, 1988).
Concerning our research, it was designed to evaluate the delta response amplitude within the temporal window of the P300 wave to the auditory target in mild AD patients and healthy subjects.
The primary purpose of the present study was how single delta response amplitude relative to pre-stimulus activity differs between AD patients and healthy age-matched controls. We hypothesise that delta response amplitude might differentiate the groups, thereby adding this measure as a new biomarker, especially in the early phase of the disease when the episodic memory impairment dominates the syndrome and the other cognitive domains seem to be relatively spared by the pathological process, and when the averaged event-related potentials do not efficaciously discriminate patients from healthy individuals. Also, because of a major distribution of delta response to auditory stimuli is at the level of fronto-central regions (Schürmann et al., 1995, Başar, 1999), our hypothesis is that in AD patients this delta response reactivity is not functionally sensitive and cannot be involved upon processing demands as efficiently as in controls, especially at the frontal location. Although in this study the main emphasis is addressed on single sweep analysis, averaged ERPs were also obtained to enable comparison with results from the single sweep analysis and with literature data. In particular, we hypothesise that single sweep maximal delta amplitude might better discriminate between the two groups than P300 amplitude of the averaged potentials.
Section snippets
Methods and materials
All patients were in charge of our outpatients' neurological department for the diagnosis and therapy of dementing diseases. Healthy subjects were recruited from the hospital personnel or were the husbands/wives of patients who entered the study. For each subject (both controls and AD patients), all demographic, clinical and pharmacological data were formally collected in a detailed case history. Healthy controls and AD patients were matched for age, sex, handedness, and educational level to
Results
At conventional visual analysis, all subjects showed an electroencephalogram that was judged as normal by two expert electroencephalographers, each in two different sessions, respectively.
Discussion
Major results of the study can be summarized as follows: (i) Concerning the time domain averaged evoked ERPs, no significant group differences were observed for N100 and P200 components (both latency and amplitude); also, N200 and P300 amplitude did not differ between groups, whilst N200 and P300 latency were significantly prolonged in AD patients. (ii) Concerning the delta frequency component of the averaged ERPs, no significant differences between groups were obtained for the delta response
Conclusion
In an active oddball paradigm eliciting event-related potentials, patients with Alzheimer's disease did not show significant reactivity of delta response upon stimulus processing. Rather, a significant enhancement of delta reactivity was observed only in healthy controls, especially at frontal location.
This is a novel observation. Yet it is not conclusive whether the delta response change is specific for AD: future researches should analyze other frequency components (theta, alpha, beta, gamma)
Acknowledgments
The authors are thankful to the anonymous reviewers for their most helpful criticisms and suggestions.
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2020, International Journal of PsychophysiologyCitation Excerpt :While the spontaneous EEG (Babiloni et al., 2004, 2016; Huang et al., 2000) and ERP markers of AD (Polich and Corey-Bloom, 2005) have been investigated in a number of studies (for a review see Horvath et al., 2018), Başar and coworkers focused on the use of EROs as possible biomarkers of cognitive decline in AD and MCI (Yener and Başar, 2010, 2013; Başar, 2013; Başar and Güntekin, 2013; Başar et al., 2013). They have shown in parallel to other research groups (Polikar et al., 2007; Caravaglios et al., 2008; Deiber et al., 2009; Nguyen et al., 2017) that EROs provide a promising methodology to detect abnormalities of cognitive processes in MCI and AD (Yener et al., 2007, 2008, 2009, 2012, 2013, 2014; Başar et al., 2016, 2017). EROs are divided into “evoked” and “induced” components in terms of the phase relationship of the oscillations with the event.