Elsevier

Biological Psychiatry

Volume 53, Issue 6, 15 March 2003, Pages 511-519
Biological Psychiatry

Neuronal substrates of sensory gating within the human brain

https://doi.org/10.1016/S0006-3223(02)01673-6Get rights and content

Abstract

Background

For the human brain, habituation to irrelevant sensory input is an important function whose failure is associated with behavioral disturbances. Sensory gating can be studied by recording the brain’s electrical responses to repeated clicks: the P50 potential is normally reduced to the second of two paired clicks but not in schizophrenia patients. To identify its neural correlates, we recorded electrical traces of sensory gating directly from the human hippocampus and neocortex.

Methods

Intracranial evoked potentials were recorded using hippocampal depth electrodes and subdural strip and grid electrodes in 32 epilepsy patients undergoing invasive presurgical evaluation.

Results

We found evidence of sensory gating only in the hippocampus, the temporo-parietal region (Brodmann’s areas 22 and 2), and the prefrontal cortex (Brodmann’s areas 6 and 24); however, whereas neocortical habituating responses to paired clicks were peaking around 50 msec, responses within the hippocampus proper had a latency of about 250 msec.

Conclusions

Consistent with data from animal studies, our findings show that the hippocampus proper contributes to sensory gating, albeit during a time window following neocortical habituation processes. Thus, sensory gating may be a multistep process, with an early phase subserved by the temporo-parietal and prefrontal cortex and a later phase mediated by the hippocampus.

Introduction

Habituation of repetitive, irrelevant sensory input is an essential protective function of the central nervous system and has been demonstrated in studies with both human and nonhuman animals Fruhstorfer et al 1970, Gale and Edward 1986. Deficits of sensory habituation could lead to impairment of the brain’s capacity to select, process, and store information (Braff and Geyer 1990) and have been associated with the development of severe behavioral aberration (Freedman et al 1991). One important aspect of habituation is the so-called “sensory gating” or “P50 effect”: the P50 is a positive wave peaking between 15 and 80 msec following stimulus presentation. It is the earliest component of the midlatency auditory evoked responses (MLAERs) that habituates to stimulus repetition. At this early stage of information processing attentional influences are minimal, thus making the P50 (P1) component ideal for examination of preattentive sensory habituation mechanisms.

The P50 and the N100 (a negative component peaking between 75 and 150 msec) have been used to examine the brain’s ability to inhibit irrelevant sensory input in healthy and psychopathological populations (e.g., Adler et al 1982, Boutros and Belger 1999a. Indeed, failure of this fundamental mechanism has been hypothesized to represent a core physiologic dysfunction of the entire schizophrenia spectrum of disorders (Cadenhead et al 2000); however, the anatomical structures mediating sensory gating in humans are not known. Therefore, identification of the different brain structures mediating sensory gating in the auditory system could significantly add to our understanding of the neural mechanisms subserving this important protective function. Subsequently, informed hypotheses regarding the relationship between the different physiologic aberrations of this neural system and the different psychopathological conditions could be developed. At present, animal studies have strongly implicated the hippocampus as an essential mediator of sensory gating (Freedman et al 1996).

The occasional need to implant intracranial electrodes during the presurgical evaluation of patients with medically intractable focal epilepsies makes it possible to record event-related potentials (ERPs) directly from the human hippocampal formation and cerebral cortex. In patients in whom hippocampal depth electrodes were necessary, limbic ERP recordings have identified a medial temporal lobe P300 component generated by the hippocampus proper Grunwald et al 1999b, Halgren et al 1980, McCarthy et al 1989, Meador et al 1987, Puce et al 1989, Smith et al 1986. Anterior medial temporal lobe N400 potentials have been found to be related to the processing of words and pictures in memory and language tasks (e.g., Halgren et al 1994, McCarthy et al 1995, Puce et al 1991, Smith et al 1986. Nobre and McCarthy (1995) demonstrated that this potential is sensitive to semantic priming and word class and that it is not elicited by nonwords. We found that anterior medial temporal lobe N400s are an index of verbal memory capacity (Elger et al 1997), that their amplitudes correlate with the density of pyramidal cells within the hippocampal CA1 subsector, and that they depend on the activation of N-methyl-d-aspartate receptors (Grunwald et al 1999a). Moreover, we found that memory formation is associated with distinct but interrelated ERP differences within the rhinal cortex and the hippocampus arising after about 300 and 500 msec, respectively (Fernández et al 1999) and that they are accompanied by a rhinal–hippocampal γ-band synchronization (Fell et al 2001).

Neocortical ERPs have been recorded intracranially in oddball paradigms (e.g., Baudena et al 1995, Halgren et al 1995a, Halgren et al 1995b and in face and word processing tasks (e.g., Elger et al 1997, Guillem et al 1995); however, with the exception of one single-case study (Freedman et al 1994), no P50 potentials in a paired-click condition have yet been systematically recorded for the purpose of examining the neural correlates of sensory gating.

We used the unique opportunity of depth recordings to examine whether the human hippocampus does indeed contribute to sensory gating. To this end, we recorded hippocampal responses in a paired-click paradigm, in which the first click is thought to generate a memory trace to which the second is compared upon arrival. Processing of the second click is then actively inhibited, as this repetition contains no new information. After 8 sec the memory trace has fully decayed, and the neuronal pool is ready for another “new” pair of clicks (Zouridakis and Boutros 1993). Moreover, we recorded neocortically evoked responses in patients who had subdural strip or grid electrodes either alone or in addition to hippocampal depth electrodes. These latter recordings were considered with the aim of identifying different regions of the human neocortex that participate in sensory gating.

Section snippets

Methods and materials

Thirty-two patients with pharmacoresistant (symptomatic or kryptogenic) focal epilepsies (14 women, 18 men; age [mean ± SD] 32.1 ± 9.2 years; duration of epilepsy 19.5 ± 9.9 years, see Table 1) participated in the study. All patients were right hand dominant (self-reported) and underwent invasive presurgical evaluation because the localization of the primary epileptogenic area could not be determined by noninvasive procedures. None of them had a history of psychotic symptoms. The patients’

Results

We found no P50-like activity within the hippocampus in any of our subjects. By contrast, first clicks (S1) elicited pronounced negative field potentials peaking after approximately 250 msec within the hippocampus proper in each of the 21 patients implanted with hippocampal depth electrodes. These responses to S1 were always recorded within the hippocampus proper but not with immediately adjacent parahippocampal contacts (see Figure 2). Neural responses elicited by second clicks (S2) were very

Discussion

In the healthy brain, attenuation or habituation of incoming irrelevant sensory input (sensory gating) is an important process for the selection of relevant and inhibition of irrelevant information. Surface electroencephalogram recordings of early (P50/P1) and later (“N100” and “mismatch negativity”) sensory gating indices suggest that this function is subserved by a multistage system (Boutros et al 1999). Abnormal sensory gating has been associated with several psychiatric conditions, such as

Acknowledgements

This study was supported by grant No. 1 RO1 MH63476–01A1 (National Institutes of Health, National Institute of Mental Health) and the Department of Veterans Affairs.

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