Hallucinations- Synchronisation of thalamocortical γ oscillations underconstrained by sensory input

Consciousness and Cognition Consciousness and Cognition 12 (2003) 413451
www.elsevier.com/locate/concog
Hallucinations: Synchronisation of thalamocortical c oscillations underconstrained by sensory input

R.P. Behrendt
MRCPsych, Longley Centre, Norwood Grange Drive, Sheeld S5 7JT, UK Received 8 October 2002
Abstract What we perceive is the product of an intrinsic process and not part of external physical reality. This notion is consistent with the philosophical position of transcendental idealism but also agrees with physiological ndings on the thalamocortical system. c-Frequency rhythms of discharge activity from thalamic and cortical neurons are facilitated by cholinergic arousal and resonate in thalamocortical networks, thereby transiently forming assemblies of coherent c oscillations under constraints of sensory input and prefrontal attentional mechanisms. Perception and conscious experience may be based on such assemblies and sensory input to thalamic nuclei plays merely a constraining role in their formation. In schizophrenia, the ability of sensory input to modulate self-organisation of thalamocortical c activity may be generally reduced. If during arousal thalamocortical self-organisation is underconstrained by sensory input, then attentional mechanisms alone may determine the content of perception and hallucinations may arise. 2003 Elsevier Science (USA). All rights reserved.
Keywords: Perception; Thalamocortical system; c Oscillations; Hallucinations; Schizophrenia
E-mail address: rp.behrendt@btinternet.com. 1053-8100/$ - see front matter 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S1053-8100(03)00017-5
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R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451
1. Introduction In the rst half of the last century, Gestalt psychologists argued that perceptual experience cannot be broken down into primitive sensations, or, in the case of visual perception, into patterns of stimulation and excitation at the retina. Perception, they maintained, is an active achievement of the nervous system and not a derivative of the richness of stimulation in the external world (Koehler, 1940; reviewed in Kelso, 1995). The intrinsic organisation of perceptual experience that was stressed by Gestalt psychologists was thought to reect principles of autonomous creation of order in the nervous system. Koehler (1940) and other Gestalt psychologists viewed the brain as a dynamic system that spontaneously converges toward equilibrium in an energy function. Perception is the dynamic outcome of interaction of external constraints provided by sensory stimulation with brain structure and function, with no special agent necessary to produce it (Koehler, 1940; reviewed in Kelso, 1995). Llinas and Pare (1991) suggested that conscious perception is subserved by intrinsic activity in thalamocortical circuits, involving cortical pyramidal neurons and specic thalamic nuclei. They pointed out that most of the connectivity in thalamocortical circuits is geared to the generation of internal functional modes, which can principally operate in the presence or absence of sensory input. Only a relatively minor part of thalamocortical connectivity is devoted to the transfer of sensory input. Cells in thalamocortical circuits are intrinsically active and sensory input may only modulate their activity. Llinas and Pare (1991) viewed consciousness as a closed-loop property of the thalamocortical system, and not a by-product of sensory input. Accordingly, they regarded wakefulness and paradoxical sleep as fundamentally equivalent states. The main dierence between perception in wakefulness and dream imagery in paradoxical sleep would lie in the weight given to sensory aerents. In the state of wakefulness, but not in paradoxical sleep, the intrinsic functional mode underlying consciousness is modulated by sensory input (Llinas & Pare, 1991). Picton and Stuss (1994) argued that the brain generates an internal model of the world to t incoming sensory information; and what is being experienced is this model rather than sensory information. These views are consistent with a philosophical position of idealism and call for a re-appraisal of the relationship between perception and sensory information. There are two principle positions on the nature of the world that we perceive around us. The prevailing position, which can be referred to as realism, holds that what we see, hear or feel around us is an objective material reality that exists independently of our mind. The alternative position holds that the perceived world is not independent of the mind but a product and even part of our mind. This position is called idealism. Idealism can be absolute or transcendental. Absolute idealism, or solipsism, denies the very existence of an objective physical world. Transcendental idealism, a term introduced by Kant, emphasises that an objective physical world does exist, although we do not and cannot perceive it. The world that we perceive around us is a mental creation that is fundamentally subjective; its assumed objectivity is illusory (Fig. 1).
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Fig. 1. According to transcendental idealism, a crucial distinction has to be made between the world that we perceive around us and the external physical world with which we interact. What we perceive as being around us is not equivalent to the external physical world; instead, it is a part of our mind that is projected outside. In order to be adaptive, the subjective image of the world has to be constrained by the external physical reality, which is achieved by sensory input. This means that in the state of normal wakefulness, there is a relationship between the external physical world and the world that we perceive, but, again, it is not the physical world that we see.
To understand the concept of transcendental idealism more intuitively, it may be helpful to compare normal perception to dream imagery and consider the role of nocturnal stimuli in dreaming. During the state of dreaming, we regard the images that we perceive as real and objective, despite sometimes gross violations of logic. Sometimes we notice that the ow of dream imagery has been inuenced by strong nocturnal stimuli. What we perceive under the inuence of a strong nocturnal stimulus is primarily consistent with the theme of the dream and concerns of the dreamer and does not represent the stimulus as it turns out to be upon awakening. This models the relationship between wakeful perception and external physical reality. What we perceive in the context of current needs, concerns and behavioural goals is constrained by external physical factors but it does not represent or depict physical reality. From a perspective of transcendental idealism, there is no fundamental dierence between wakeful perception, dream imagery and hallucinations; conscious experience is internally created and fundamentally subjective in any case. Transcendental idealism predicts that hallucinations, normal perception and dream imagery dier only with respect to the degree with which they are constrained by the external physical reality. These forms of conscious experience are principally manifestations of the same internal physiological process. To understand how dream imagery and hallucinations are produced we have to consider how perception is normally constrained by sensory input representing the physical world and how these constraints can be disrupted.
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2. Resonance in thalamocortical networks Projection neurons in specic and non-specic thalamic nuclei and inhibitory neurons in the adjacent reticular thalamic nucleus form neuronal circuits with interneurons and pyramidal neurons in the cerebral cortex. In specic thalamocortical circuits, thalamic relay cells send axons to interneurons in cortical layer IV, which connect to pyramidal neurons in layer VI of the cortex. Cortical activity re-enters the thalamus via corticofugal projections from pyramidal neurons (reviewed in Llinas & Ribary, 1993). These projections are glutamatergic and exert a direct excitatory inuence on thalamic relay cells, as well as an indirect inhibitory inuence mediated by the reticular thalamic nucleus. The reticular thalamic nucleus, which forms a sheet along the outer surface of the thalamus, plays an important part in thalamocortical connectivity. It consists of GABAergic inhibitory neurons that project to all other thalamic nuclei in a topographically organised manner and receive collateral terminals from both thalamocortical and re-entrant corticofugal axons passing through the nucleus (reviewed in Saper, 2000). Sensory relay plays only a minor role in the activity of thalamocortical circuits compared with re-entrant activity from the cortex and reverberating activity (Sherman & Koch, 1986). Thalamic relay neurons and inhibitory neurons in the reticular nucleus can be in one of two electrophysiological modes: a tonic ring mode in which cells are partly depolarised and respond to aerent stimulation with ring of single action potentials, and a burst-ring mode in which cells are hyperpolarized and respond with bursts of action potentials. In tonic mode, thalamic relay cells re in a manner related to aerent sensory input, whereas in burst-ring mode sensory information is not transmitted effectively (McCormick & Feeser, 1990). During wakefulness, thalamic relay neurons are predominantly in tonic mode; burst-ring mode becomes more prevalent in states of inattentiveness and drowsiness and predominates in slow-wave sleep. Thalamic and cortical neurons in thalamocortical circuits have intrinsic resonance rhythmicity around 40 Hz (Steriade, Curro Dossi, Pare, & Oakson, 1991). In the depolarised state corresponding to the tonic ring mode, the membrane potential of these cells exhibits subthreshold oscillations around 40 Hz, predisposing them to re at 40-Hz rhythms in response to synaptic excitation. Rhythmic discharges can entrain oscillatory activity in connected neurons, whereby resonance occurs at a preferred frequency of synaptic input. Synchronised ring of several neurons will elicit temporally overlapping excitatory postsynaptic potentials in other cells in the network and increase their chance of ring too. Thus, networks containing single cell oscillators and the conduction time of the intervening pathways can resonate to generate large functional states in the thalamocortical system (Llinas & Ribary, 1993). Coherent ring by local populations of thalamic and cortical cells can manifest in fast oscillations of electrical local eld potentials recorded over the cortex. 2.1. Depolarisation and membrane potential oscillations Subthreshold c oscillations of membrane potential depend on partial membrane depolarisation, which was demonstrated in cortical neurons (Nunez, Amzica, & Steriade, 1992; Steriade, Amzica, & Contreras, 1996) and thalamic projection
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neurons (Steriade et al., 1991; Steriade, Curro Dossi, & Contreras, 1993). Partial depolarisation also enables tonic ring of action potentials. With further depolarisation, subthreshold membrane potential oscillations can give rise to spikes or spikebursts of action potentials recurring at c rhythms (Steriade et al., 1993). Thus, subthreshold oscillations of membrane potential may predispose cortical and thalamic neurons to re at c frequencies and synchronously in response to sensory input during wakefulness or internal input during paradoxical sleep (Steriade et al., 1996). Depolarising inputs to cortical pyramidal neurons or relay cells in specic thalamic nuclei can be specic or non-specic. Aerent sensory stimulation may impose specic patterns of depolarisation on specic thalamic nuclei. Similarly, prefrontal activity, reecting attention, recent memories and current behavioural goals, may induce specic patterns of depolarisation in postrolandic cortical networks via longdistance corticocortical projections. Ascending brainstem systems, on the other hand, would modulate neural activity in thalamocortical circuits in a non-specic or global manner (Fig. 2). In particular, cholinergic activation induces sustained muscarinic depolarisation in thalamic relay cells and cortical neurons, which contributes to their predisposition to participate in resonant fast oscillations (Steriade & Amzica, 1996). 2.2. Burst-ring mode When thalamic relay cells or neurons of the reticular thalamic nucleus are hyperpolarized, excitatory postsynaptic potentials can open low-threshold calcium channels in these cells (McCormick & Feeser, 1990). Opening of these special calcium channels produces a calcium current that leads to a large depolarisation spike, bringing the membrane potential above ring threshold and generating a burst of action potentials. Action potentials produce further calcium channel openings, until enough calcium has entered the cell to trigger a potassium current that hyperpolarizes the cell and resets it for another cycle of burst ring (reviewed in Saper, 2000). Burst ring in large populations of thalamic neurons can synchronise during slowwave sleep, producing waves of depolarisation in dendrites of cortical neurons, which manifest in slow oscillations in the electroencephalogram. In the partly depolarised state (tonic ring mode), low-threshold calcium channels are inactivated. Thalamic relay cells switch from the tonic to the burst-ring mode through accumulation of inhibitory postsynaptic potentials. The neurotransmitter GABA, which is released from presynaptic terminals of interneurons and reticular thalamic neurons, activates GABA-B receptors on thalamic relay cells. This triggers a slow potassium current that produces a prolonged inhibitory postsynaptic potential (Wallenstein, 1994). Inhibitory potentials hyperpolarize the neuron and reverse the inactivation of low-threshold calcium channels, allowing the generation of rhythmic bursts of action potentials. 2.3. Neocortical c oscillations c Oscillations of electrical or magnetic eld potentials that can be recorded over the neocortex are under the control of ascending cholinergic pathways from the
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Fig. 2. Specic and non-specic factors that determine the pattern of activation in the thalamocortical system: Attentional mechanisms activate neurons in cortical sensory areas and via corticothalamic projections contribute to depolarisation of thalamic relay cells. Sensory input complements activation of thalamic relay cells. Mediated by muscarinic receptor activation, cholinergic input during arousal enhances sensory evoked activity of thalamic relay cells, but also increases their spontaneous background activity. To maintain the signal-tonoise ratio of activity in specic thalamic nuclei, activation of relay cells during arousal is balanced by specic inhibition, which is mediated by nicotinic receptor activation.
brainstem (Steriade et al., 1991) and are more likely to occur in states of increased alertness and focused attention (Bouyer, Montaron, & Rougeul, 1981; HerculanoHouzel, Munk, Neuenschwander, & Singer, 1999). They are also characteristic of paradoxical sleep (Llinas & Pare, 1991; Llinas & Ribary, 1993) and have been observed in association with hallucinations (Baldeweg, Spence, Hirsch, & Gruzelier, 1998). Neocortical c oscillations are generated by fast reverberating activity in thalamocortical circuits (Ribary et al., 1991). Oscillating local eld potentials represent the synchronisation of neuronal discharges in local populations of interconnected thalamic and cortical neurons and can, in turn, be correlated with oscillations of local eld potentials at other cortical sites. Synchronization of neuronal c activity may serve as a mechanism that transiently integrates distributed neural activity into functional assemblies. Neocortical c rhythms have been implicated in the binding of visual features into unitary percepts (Engel, Konig, Kreiter, Schillen, & Singer, 1992). Resetting and enhancement of neocortical 40-Hz oscillations in response to sensory stimulation may represent
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integration of cortical activity centred on the activated sensory area (Ribary et al., 1991). During paradoxical sleep, fast neocortical oscillations and their synchronisation over widespread cortical areas may underlie dream imagery (Amzica & Steriade, 1996; Llinas & Ribary, 1993). Joliot, Ribary, and Llinas (1994) provided evidence for an association between 40Hz neocortical oscillatory activity and auditory perception. The authors recorded magnetic cerebral activity from subjects who were required to identify separate auditory clicks that were presented at varying interstimulus intervals. At interstimulus intervals shorter than 1215 ms, only one 40-Hz oscillatory magnetic response was recorded to the rst click. At longer intervals, a second 40-Hz response was observed, which coincided with the subjects perception of a second distinct auditory stimulus (Joliot et al., 1994). Rodriguez et al. (1999) record electrical brain activity from subjects who were viewing ambiguous visual stimuli that were perceived either as faces or as meaningless shapes. Face perception was accompanied by a consistent pattern of long-distance synchronization in the c range between occipital, parietal and frontal areas. This synchrony was absent when faces were presented upside down and therefore not recognised (Rodriguez et al., 1999). 2.4. Edge eect Recordings from thalamic neurons in patients receiving stereotactical medial thalamotomy for chronic neurogenic pain, tinnitus, abnormal movements and other neurological positive symptoms, revealed that most of these cells were unresponsive to sensory stimuli (Jeanmonod, Magnin, & Morel, 1996). Nearly half of the unresponsive cells showed rhythmic or random burst-ring activity, which was related to low-threshold calcium spikes and cell membrane hyperpolarisation that normally characterise slow-wave sleep. Jeanmonod et al. (1996) suggested that neurological positive symptoms might be caused by these pathological burst patterns. Using magnetoencephalography, Llinas, Ribary, Jeanmonod, Kronberg, and Mitra (1999) demonstrated ongoing low-frequency rhythmic activity with large-scale coherence in patients with Parkinsons disease, neurogenic pain, tinnitus and major depression. Recognising that slow oscillatory activity in thalamocortical networks cannot be correlated with perception, the authors attributed positive signs and symptoms in these patients to ectopic c activity that may be generated as an edge eect in surrounding areas of excitation. Symptoms would thus be conditioned by the primary lesion (Llinas et al., 1999). This model is applicable to neuropsychiatric conditions such as psychosis that develops secondary to temporal lobe damage or epilepsy, but there may be no primary lesions in patients with schizophrenia or major aective disorders who occasionally experience hallucinations. Hallucinations in these patients appear to be conditioned at least in part by psychological factors (see below). Sustained hyperpolarisation of thalamic relay cells is central to the model proposed by Llinas et al. (1999): Hyperpolarized cells generate low-threshold spike bursts that lock thalamocortical circuits in low-frequency resonance, and it is the interaction of low-frequency circuits with adjacent high-frequency ones that produces the edge eect and neurological symptoms. Alternatively, it is proposed here that random activation of thalamic relay cells in the context of general facilitation of
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high-frequency resonance in the thalamocortical system is responsible for hallucinations. 2.5. Non-specic thalamocortical circuits Llinas and Ribary (1993) suggested that conscious experience may be based on coherent 40-Hz co-activation of specic and non-specic thalamocortical circuits. Non-specic thalamocortical circuits consist of intralaminar thalamic neurons that project to layer I of the cerebral cortex and pyramidal cells of cortical layers V and VI that project back to intralaminar nuclei both directly and indirectly via collaterals to the reticular thalamic nucleus (Llinas & Ribary, 1993). Neurons of intralaminar nuclei have a particularly strong intrinsic 40-Hz rhythmicity that may entrain neurons in specic thalamocortical circuits. While the content of consciousness may lie in specic thalamocortical circuits (Llinas & Pare, 1991; Llinas & Ribary, 1993), in which neurons are depolarised and activated by sensory input and attentional mechanisms, it may be the role of non-specic thalamocortical circuits to enable the temporary binding of specic thalamocortical circuits, thereby creating a unitary conscious experience (Llinas & Pare, 1991; Llinas & Ribary, 1993). c Oscillations recorded from the neocortex during wakefulness or paradoxical sleep show a coherent rostrocaudal phase shift from the frontal to the occipital pole of the hemisphere (Llinas & Ribary, 1993; Ribary et al., 1991). Intralaminar nuclei project to supercial layers of all neocortical areas in a spatially continuous manner and are organised as a circular mass, which may allow the propagation of internal waves of neural activity and explain the generation of the rostrocaudal phase shift on the cortical level (Llinas & Ribary, 1993). Both, the generation of rostrocaudal sweeps of activation and the particularly strong capacity of intralaminar neurons to discharge at frequencies around 40 Hz may contribute to the synchronisation of fast oscillatory activity in specic thalamocortical circuits (Llinas & Ribary, 1993). If specic thalamocortical circuits provide the content of conscious experience, then the role of non-specic circuits is possibly the same in perception and hallucinations. Activation of non-specic thalamocortical circuits will enable temporal binding of activity in specic thalamocortical circuits whether or not the latter have been activated in a manner that is related to sensory input, i.e., regardless of the nature of thalamic relay cell activation. However, non-specic thalamocortical circuits are predominantly under cholinergic control (see below) and strong cholinergic activation (in states of hyperarousal) could theoretically lead to entrainment of specic thalamocortical circuits that are insuciently activated by sensory input, thereby generally increasing the likelihood of underconstrained perception. 2.6. Self-organisation in the thalamocortical system Following activation by arousal mechanisms, populations of neurons synchronise their c-frequency discharge activity through reciprocal interaction via re-entrant loops. Oscillatory activity self-organises into transient neuronal assemblies and the thalamocortical system as a whole converges towards a state of transient stability, an attractor state (Singer, 2001). The attractor state is determined by the current
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Fig. 3. Perception cannot be reduced to sensory information; instead it emerges from intrinsic self-organisation of c oscillations in the thalamocortical system. c-Frequency activity in the thalamocortical system is facilitated by arousal mechanisms and self-organises into coherent assemblies under constraints of attentional mechanisms (based on prefrontal cortex, limbic system and nucleus basalis) and aerent sensory input (to specic thalamic nuclei). If sensory constraints are relatively weak, attentional mechanisms may become dominant and hallucinations may arise.
constellation of external and endogenous constraints imposed on the system, which in sensory areas are determined by the pattern of sensory input, on the one hand, and prefrontal cortical and limbic system input, on the other. Neuronal assemblies that emerge under a particular constellation of such constraints may represent the set of features that dene a particular perceptual experience (Singer, 2001). Attractors themselves change owing to changes in external and endogenous constraints, reecting changing patterns of sensory stimulation and emergence of new memories and behavioural goals. Large-scale synchronous networks emerge and disappear in waves that last 100300 ms (Varela, Lachaux, Rodriguez, & Martinerie, 2001). The transient nature of synchronisation emphasises that the thalamocortical system behaves in a metastable fashion, rather than following stable attractors. To Varela et al. (2001) the brain appeared as a resourceful complex system that satises simultaneously the exogenous and endogenous constraints that arise at each moment by transiently settling in a globally consistent state. If transient assemblies of coherently ring cortical and thalamic neurons underlie perception and other conscious events, then perception may be more of an outward manifestation of self-organising processes than the outcome of directed or purposeful sensory information processing. Sensory input may merely be a factor that externally restricts intrinsic brain dynamics (Fig. 3).
3. Attentional modulation of thalamocortical activity Endogenous activity from the prefrontal cortex or limbic system, reecting attention, current behavioural goals and recent memories, modulates cortical activity in primary and secondary sensory areas (reviewed in Varela et al., 2001). Selective attention, for instance, was shown to modulate rates and synchrony of neuronal
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ring in primary and secondary sensory cortices (Roelfsema, Lamme, & Spekreijse, 1998; Steinmetz et al., 2000). The prefrontal cortex was suggested to organise anticipatory attention by activating corticocortical circuits to sensory areas and thalamocortical circuits, thereby setting sensory areas to respond to the presentation of an expected stimulus (Brunia, 1999). The prefrontal cortex has also been implicated in short-term memory and sustained behavioural interaction with the environment. Prefrontal cortex neurons can sustain their activity for short periods of time despite ongoing behaviour and changes in sensory stimulation (Bodner, Kroger, & Fuster, 1996; Fuster, 1991), thus imposing endogenous constraints on cortical self-organisation in posterior sensory areas. 3.1. Attentional modulation of regional cerebral activity in sensory systems Using positron emission tomography, OLeary et al. (1996) measured regional cerebral blood ow in normal subjects as they listened to auditory stimuli that were presented either binaurally or dichotically. In the dichotic condition, dierent sounds were presented to dierent ears and subjects were asked to focus on either their left ear or right ear. Regional cerebral blood ow in superior temporal gyri was increased contralateral and decreased ipsilateral to the attended ear, as compared to binaural conditions (OLeary et al., 1996), suggesting that attentional mechanisms operate at the level of primary auditory cortex. Using functional magnetic resonance imaging, Woodru et al. (1996) found that selectively attending to either visual or auditory stimuli that were presented simultaneously modulated activity in the corresponding sensory cortices. The authors concluded that attention acts during early stages of sensory processing (Woodru et al., 1996). Shulman et al. (1997) compared blood ow responses measured with positron emission tomography during passive viewing of visual stimuli with those obtained during discrimination tasks involving the same visual stimuli and found signicant task-dependent modulation of activity in the early visual cortex in the medial occipital lobe. Attention modulates activity even in parts of sensory systems believed to subserve the earliest stages of sensory processing. Vanduel, Tootell, and Orban (2000) measured regional changes of metabolic activity in the macaque visual system during two tasks with identical visual stimulation but dierent attentional demands. They found attention-dependent changes in metabolic activity in parts of the lateral geniculate nucleus of the thalamus and parts of the retinotopically organised striate cortex (Vanduel et al., 2000). Woldor et al. (1993) recorded evoked magnetic elds from subjects who were asked to listen selectively to sequences of tones presented to one ear while ignoring sequences of dierent tones presented to the other ear. Attention-sensitive interhemispheric dierences in evoked magnetic brain responses occurred as early as 2050 and 80130 ms poststimulus (Woldor et al., 1993). Woldor et al. (1993) suggested that an early selection mechanism regulates auditory input before initial stages of cortical analysis. These ndings show that activity in early sensory systems is largely dependent on attention and is not just a function of external sensory input. They are evidence against the notion implicit in information-processing accounts of perception that sensory information is rst analysed to create a representation of the world from
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which attentional mechanisms then select relevant stimuli. In other words, it does not appear that the focus of attention shifts in or selects from a pre-processed meaningful representation of the world. If this were the case, then activation in early sensory systems would depend more clearly on the pattern of external stimulation. Instead of being derived from hierarchically processed sensory information, perception appears to be created in the very focus of attention. Attentional mechanisms and sensory input may complement each other in activation of cortical and thalamic sensory areas. Hypothetically, if the set of thalamocortical circuits that are pre-activated by prefrontal attentional mechanisms is matched by the pattern of sensory input to specic thalamic nuclei, then sustained thalamocortical activation and perception may ensue. In hallucinations and dream imagery, attentional mechanisms alone may produce sustained assemblies of thalamocortical activation, regardless of the pattern of sensory input. In sensory imagery, which is a non-substantial and eeting experience, attentional mechanisms may initiate patterns of thalamocortical resonance that would normally lead to perception but quickly disappear in the absence of supporting sensory information. Indeed, activity in early sensory processing areas during sensory imagery resembled that observed during selective attention (reviewed in Frith & Dolan, 1997), again emphasising the importance of attention in the modulation of sensory systems. 3.2. Corticofugal control of relay cells Numerically the largest input to thalamic nuclei does not derive from sensory organs but from layer VI of the cerebral cortex. Cortical neurons establish abundant excitatory synaptic connections with both thalamic relay cells and neurons in the reticular thalamic nucleus. In the lateral geniculate nucleus, only 1020% of synapses on thalamic relay cells stem from the retina, about one third of synapses are from inhibitory terminals of local interneurons or neurons in the perigeniculate section of the reticular thalamic nucleus, and roughly half of all synapses are from neurons in cortical layer VI (reviewed in Sherman & Koch, 1986). Via these abundant corticothalamic projections, neuronal activity in specic thalamic nuclei may be adjusted as a function of cortical activity, thus supporting selective ltering of sensory input at the thalamic level (Villa et al., 1991). Through corticofugal (corticothalamic) projections, the cortex can trigger and synchronise rhythmic discharges in the thalamus. Sillito, Jones, Gerstein, and West (1994) observed that, during presentation of a moving contour, cortical feedback to the thalamus induced correlated ring patterns in relay cells of the lateral geniculate nucleus, with synchronised ring occurring in those groups of relay cells that project to cortical areas sensitive to the particular orientation of the moving contour. Steriade (1997) reported that cortical pyramidal neurons discharging at 3040 Hz rhythms are eective in synchronizing c oscillations in thalamocortical networks. Enhanced excitability of cortical pyramidal cells, which can be induced by noradrenaline or acetylcholine, may increase the spatiotemporal coherence of oscillatory activity in the thalamus (Destexhe, Contreras, & Steriade, 1999). As proposed by Destexhe et al. (1999), a more excitable cortex may generate a more powerful feedback onto the thalamus, resulting in highly coherent oscillations.
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Sensory information may only play an adjuvant role in thalamocortical activation. The excitatory eect of cortical input to thalamic relay cells may be similar to that of aerent sensory input (Destexhe, 2000). If thalamic relay cells are in tonic ring mode, corticothalamic excitatory postsynaptic potentials may contribute to depolarisation of relay cells alongside with accumulating sensory-induced excitatory potentials, until the ring threshold is reached. In this manner, corticofugal input may complement or predict aerent sensory input (Destexhe, 2000). It is therefore conceivable that strong corticofugal input in combination with increased spontaneous activity pre-existing for various reasons can induce fast rhythmic discharges in relay cells despite insucient or absent sensory input to these cells. As part of the physiological basis for some forms of attention, Sherman and Koch (1986) suggested that corticothalamic input modulates thalamocortical sensory transmission by altering the electrophysiological state of thalamic relay cells. McCormick and von Krosigk (1992) showed that activation of glutamatergic corticothalamic bres induced slow depolarisation in thalamic relay cells in the lateral geniculate nucleus of the guinea pig. This could switch the electrophysiological state of relay cells from burst-ring to tonic mode, thus facilitating thalamocortical transmission (McCormick & von Krosigk, 1992). Excitatory corticofugal input to thalamic relay cells is balanced by inhibitory input from GABAergic neurons of the reticular thalamic nucleus. Reticular thalamic neurons establish synaptic connections primarily with dendrites of thalamic relay cells and to a lesser extent with inhibitory interneurons (Liu, Warren, & Jones, 1995). Inhibitory input from the reticular thalamic nucleus can hyperpolarize thalamic relay cells, thus switching their response mode back to burst ring and preventing them from reaching the ring threshold in accordance with accumulating sensory inputs. 3.3. The reticular thalamic nucleus The reticular thalamic nucleus is involved in selective attention. McAlonan, Brown, and Bowman (2000) showed that, in rats, sectors of the reticular thalamic nucleus associated with an attended stimulus were activated more than sectors associated with an unattended stimulus. Montero (2000) reported that the visual sector of the reticular thalamic nucleus in rats was activated by attentional exploration of a new environment and that this activation depended on corticofugal inputs from the primary visual cortex. Montero (2000) argued that attentional modulation of thalamocortical transmission is a major function of corticofugal projections to the thalamus. According to Monteros (2000) hypothesis, a focus of attention in the primary visual cortex generates a column of increased thalamocortical sensory transmission by (i) corticofugal glutamatergic activation of thalamic relay cells in conjunction with (ii) input to the reticular thalamic nucleus mediating the inhibition of surrounding relay cells. An assembly of columns of thalamocortical circuits may be pre-activated in this manner and matching this assembly with the pattern of sensory input would be what ultimately determines the pattern of thalamocortical activity. Instead of being transmitted to the cortex for analysis, sensory input may be matched to a limited set of columns that are prepared by cortical attentional mechanisms.
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Destexhe (2000) suggested that attentional mechanisms might involve control of the electrophysiological response mode of reticular thalamic neurons. In hyperpolarized reticular thalamic neurons, excitatory postsynaptic potentials induced by glutamatergic cortical input can trigger a low-threshold calcium current that produces a depolarisation spike and a burst of action potentials. Burst ring in reticular thalamic neurons leads to hyperpolarisation of thalamic relay cells, causing them to enter burst-ring mode themselves (Destexhe, 2000). Partly depolarised reticular thalamic neurons, on the other hand, do not generate bursts of action potentials in response to corticothalamic excitatory postsynaptic potentials. Hence, thalamic relay cells remain in tonic-ring mode (Destexhe, 2000), allowing them to accumulate corticothalamic excitatory postsynaptic potentials. In Destexhes (2000) model, corticofugal input can either promote or inhibit thalamocortical sensory transmission, depending on the functional state of reticular thalamic neurones. 3.4. The nucleus basalis The nucleus basalis of Meynert may contribute to specic activation in postrolandic cortical sensory areas alongside corticocortical connections from prefrontal and limbic cortices. The nucleus basalis represents the sole source of cholinergic input to the cerebral cortex and projects to all cortical areas. It also sends cholinergic input to intralaminar thalamic nuclei, the medial part of the mediodorsal thalamic nucleus and the reticular thalamic nucleus. In turn, the nucleus basalis receives terminals from the cholinergic pedunculopontine and laterodorsal tegmental nuclei in the mesopontine tegmentum (as well as from intralaminar thalamic nuclei, limbic cortex, amygdala and other structures) (reviewed in Smythies, 1997). Arousal is associated with increased tonic ring of nucleus basalis neurons and release of acetylcholine to the cortex (reviewed in Smythies, 1997). Activation of muscarinic cholinergic receptors on cortical neurons leads to increased neuronal excitability and facilitation of synaptic transmission from thalamic projections (Metherate & Ashe, 1993), thus enhancing cortical sensory-evoked activity. The nucleus basalis is involved in shifting attention to environmental stimuli that are behaviourally signicant, e.g., in predicting a reward (Wenk, 1997). For this purpose, the nucleus basalis receives information about the behavioural signicance and reinforcement value of stimuli via aerents from the limbic system. Cholinergic projections from the nucleus basalis, in turn, modulate cortical excitability appropriately in order to facilitate perception of the signicant stimulus (Wenk, 1997). Apart from sending direct excitatory projections to the cortex, the nucleus basalis may modulate thalamocortical activity via projections to the reticular thalamic nucleus. Unlike most other thalamic nuclei, the reticular nucleus receives a substantial cholinergic innervation from the basal forebrain (Heckers, Geula, & Mesulam, 1992).
4. Non-specic regulation of thalamocortical activity Thalamic relay cells and reticular thalamic neurons are under non-specic control by cholinergic, noradrenergic and serotonergic systems ascending from the brain-
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stem. While specic control exerted by the cortex over thalamic relay cell activity may reect attentional mechanisms, non-specic regulatory input appears to be related to arousal and sleep-wake cycle control. During wakefulness, brainstem regulatory systems globally facilitate or inhibit fast oscillatory and resonance capabilities of thalamic neurons and modulate their responsiveness to aerent sensory input. Thus, aerents from brainstem neurotransmitter centres adjust the impact of sensory information on resonance in the thalamocortical system or, in other words, regulate the capacity of specic thalamic nuclei to transmit sensory information from the sensory organ to the cortex. The neuromodulatory eects of serotonergic, noradrenergic and cholinergic input on spontaneous and evoked activity of thalamic relay cells have been studied mostly in the dorsal lateral geniculate nucleus of the cat. Experiments involved ionophoretic application of the neurotransmitter to the lateral geniculate nucleus and electrical stimulation of the respective brainstem centre. It was demonstrated that noradrenaline released from bres originating in the locus coeruleus produces a delayed enhancement of spontaneous ring in lateral geniculate relay cells and enhances their responsiveness to aerent synaptic excitation (Rogawski & Aghajanian, 1980). Serotonin released from terminals of dorsal raphe nucleus neurons induces a delayed and prolonged suppression of spontaneous ring in lateral geniculate relay cells (Kayama, Shimada, Hishikawa, & Ogawa, 1989). It also suppresses responses of lateral geniculate neurons to weak retinal stimulation (Kemp, Roberts, & Sillito, 1982). Serotonergic suppression of relay cell activity is associated with augmentation of slow waves in the EEG (Kayama et al., 1989). 4.1. Cholinergic control of discharge activity of thalamic cells The laterodorsal tegmental nucleus and the pedunculopontine nucleus in the mesopontine region of the brainstem are the main cholinergic nuclei that project to the thalamus. Mesopontine cholinergic neurons are active during both wakefulness and paradoxical sleep and much less so during slow-wave sleep (Williams, Comisarow, Day, Fibiger, & Reiner, 1994). Acetylcholine released in the thalamus plays a crucial role in electroencephalographic activation during wakefulness and the generation of paradoxical sleep. In the lateral geniculate nucleus, acetylcholine from cholinergic brainstem centres exerts a strong facilitatory inuence over the transfer of visual information. At times of increased alertness, relay cells in the lateral geniculate nucleus of the cat show enhanced visually evoked responses (McCormick & Pape, 1988). Apart from facilitation of visually evoked responses, acetylcholine (experimentally released by electrical stimulation of cholinergic brainstem centres or applied directly by ionophoresis) increases the spontaneous discharge activity of lateral geniculate relay cells (Francesconi, Muller, & Singer, 1988). Acetylcholine activates thalamic relay cells in the lateral geniculate nucleus both directly and indirectly, the indirect eect being mediated by activation of muscarinic receptors on local GABAergic inhibitory neurons (McCormick & Pape, 1988; Francesconi et al., 1988). In particular, M2 muscarinic receptors on inhibitory interneurons have been implicated, which by mediating a reduction in the release of GABA play an important role in increasing the ecacy of signal transmission in
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states of arousal and increased attention (Carden & Bickford, 1999). M2 muscarinic receptors are metabotropic receptors that are negatively coupled via the G-i protein to adenylate cyclase; they produce slow responses. Neurons in the reticular thalamic nucleus express M2 muscarinic receptors too (Carden & Bickford, 1999) and muscarinic inhibition of these neurons may contribute to general activation of thalamic relay cells. On the other hand, reticular thalamic neurons are particularly characterised by high concentrations of nicotinic cholinergic receptors, specically those with the a-7 subunit (Agulhon, Abitbol, Bertrand, & Malafosse, 1999; Quik et al., 2000; Spurden et al., 1997). In contrast to muscarinic receptors, nicotinic receptors are excitatory ionotropic receptors that allow rapid responses. Cholinergic input to the thalamus not only produces general excitation and disinhibition of thalamic relay cells, thus facilitating the transfer of sensory information, but also preserves or enhances short-lasting inhibitory processes that are necessary for signal discrimination. Ionophoretic application of acetylcholine to the cat lateral geniculate nucleus was shown by Sillito, Kemp, and Berardi (1983) to excite thalamic relay cells and facilitate their responses to optimal sensory stimuli; responses to non-optimal stimuli were not facilitated to the same extent or even suppressed. These stimulus-specic inhibitory eects in thalamic relay cells were thought to have arisen from action of acetylcholine on presynaptic terminals from inhibitory neurons (Sillito et al., 1983). Specically, cholinergic activation of GABAergic terminals from the reticular thalamic nucleus may be responsible for stimulus-specic inhibition of thalamic relay cells. Murphy, Uhlrich, Tamamaki, and Sherman (1994) found that cholinergic input from the brainstem inhibited spontaneous activity of neurons in the perigeniculate sector of the reticular thalamic nucleus, leading to disinhibition of lateral geniculate relay neurons. However, when brainstem stimulation was paired with visual stimulation, responses of perigeniculate reticular neurons were facilitated with the use of certain patterns of stimulation, which indicated that reticular thalamic neurons in the perigeniculate sector can produce stimulus-specic inhibition of relay cells (Murphy et al., 1994). Lena and Changeux (1997) suggested that nicotinic activation of presynaptic GABAergic terminals improves the signal-to-noise ratio of sensory transmission during arousal. They showed that activation of presynaptic nicotinic receptors on GABAergic terminals leads to an increase in spontaneous and electrically evoked release of GABA, which increases the frequency of postsynaptic inhibitory potentials in thalamic relay cells (Lena & Changeux, 1997). Nicotinic receptors are expressed particularly on reticular thalamic neurons. While activation of nicotinic receptors may mediate phasic release of GABA, which produces phasic inhibition of thalamic relay cells, activation of M2 muscarinic receptors would reduce the release of GABA more tonically, causing tonic disinhibition of thalamic relay cells. The reticular nucleus is among the thalamic nuclei with the highest density of cholinergic input (Heckers et al., 1992) and activation of its nicotinic and muscarinic cholinergic receptors may increase the ecacy and specicity of thalamic sensory-related activity in states of arousal and increased attention (Fig. 2). The reticular thalamic nucleus assists in organising activity in specic thalamic nuclei according to characteristics of sensory input and attentional demands. In the auditory modality for example, the reticular nucleus participates in time-dependent
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analysis of the auditory input, with dierent neurons of the auditory part of the reticular nucleus being sensitive to dierent latencies of stimulus presentation (Villa, 1990). Dysfunction of the reticular thalamic nucleus would lead to loss sensoryspecic inhibition in specic thalamic nuclei and impairment of the signal-to-noise ratio. This may be the case particularly at times of arousal when thalamic relay cells exhibit increased spontaneous activity. Then, noise may predominate over stimulusspecic activity and relay cells may become recruited into thalamocortical reverberations without receiving adequate sensory input. 4.2. Cholinergic facilitation of c oscillations Stimulation of mesopontine cholinergic nuclei in the cat increases neocortical 40Hz oscillations in the electroencephalogram (Curro Dossi, Pare, & Steriade, 1991; Steriade et al., 1991). This is mediated by cholinergic projections to the thalamus where acetylcholine, acting on muscarinic receptors (Steriade et al., 1991), induces delayed and prolonged membrane depolarisation in thalamic projection neurons (after initial nicotinic depolarisation) (Curro Dossi et al., 1991). Prolonged depolarisation of thalamic neurons can release or enhance intrinsic fast oscillations of membrane potential, which predispose cells to generate action potentials at 40-Hz rhythms. Resonance in thalamocortical networks then produces waves of excitatory postsynaptic potentials in dendrites of cortical neurons that manifest as c oscillations in local eld potentials and the electroencephalogram. This explains the observation by Curro Dossi et al. (1991) that prolonged muscarinic depolarisation in thalamic projection neurons (as elicited by brainstem cholinergic stimulation) was accompanied by simultaneous electroencephalographic activation. Herculano-Houzel et al. (1999) reported that cortical response synchronisation is particularly eective during states of arousal. Stimulation of the mesencephalic reticular formation in the cat caused electroencephalographic activation (characterised by high power in the c-frequency range) and at the same time increased the degree of synchronisation of stimulus-induced neuronal activity in the visual cortex (Herculano-Houzel et al., 1999; Munk, Roelfsema, Konig, Engel, & Singer, 1996). Cholinergic arousal also facilitates synchronisation in thalamocortical circuits. Steriade and Amzica (1996) demonstrated that stimulation of the pedunculopontine tegmental nucleus increased the coherence between neuronal activities in reciprocally connected cortical and intralaminar thalamic sites, again in conjunction with facilitation of fast neocortical rhythms. Intralaminar thalamic nuclei distribute 40-Hz rhythms over the cerebral neocortex during paradoxical sleep and in states of increased attention and arousal (Steriade et al., 1993). Thereby, they may facilitate the synchronisation of activity in specic thalamocortical circuits and enable the creation of a unitary conscious experience (Llinas & Pare, 1991; Llinas & Ribary, 1993). The centrolateral and paracentral intralaminar nuclei of the thalamus receive input from the mesencephalic reticular formation, as well as from other structures including the nucleus basalis and raphe nuclei. Acting through intralaminar nuclei, the mesencephalic reticular formation may set the level of arousal in the neocortex; during slow-wave sleep, these nuclei are inactive (reviewed in Smythies, 1997).
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Jones (1998) suggested that intralaminar thalamic nuclei are not the only source of diuse thalamocortical projections that allow the spread of activity across wide cortical areas. This function may extend beyond the intralaminar nuclei to all cells with immunoreactivity for calbindin distributed throughout the thalamus. Calbindin-positive cells project to supercial layers of the cortex across area boundaries. By diusing activity across the cortex, they again may facilitate the engagement of multiple cortical areas in the creation of a unitary conscious experience (Jones, 1998). 4.3. Modulation of response properties of relay cells Apart from the release of subthreshold oscillations of membrane potential, other cellular mechanisms may be involved in activation of thalamic relay cells. In the rodent thalamus, acetylcholine and noradrenaline selectively depress the ecacy of corticothalamic synapses for low-frequency inputs from the cortex, thus enabling high-pass ltering of corticothalamic activity during arousal (Castro-Alamancos & Calcagnotto, 2001). In this way, acetylcholine and noradrenaline may facilitate reverberations of fast rhythms in thalamocortical networks. Moreover, acetylcholine and noradrenaline can increase the excitability of relay cells by blocking a phenomenon called after-hyperpolarisation (reviewed in Sherman & Koch, 1986). Following the generation of an action potential, thalamic neurons show a phase of after-hyperpolarisation, which down-regulates the discharge frequency in response to sustained supra-threshold stimulation (reviewed in Sherman & Koch, 1986). If afterhyperpolarisation is blocked, thalamic cells can generate more frequent discharges, which again may enable their participation in fast thalamocortical oscillations. General anaesthetics induce an unconscious state possibly by disrupting intrinsic oscillatory capabilities of neurons in thalamocortical circuits, thereby preventing fast thalamocortical resonance that characterises conscious states. Tennigkeit, Ries, Schwarz, and Puil (1997) investigated the eects of the volatile anaesthetic isourane on frequency preferences of thalamic neurons in the medial geniculate nucleus. Under isourane anaesthesia, they found a decreased tendency of the membrane potential to oscillate or generate resonant responses, as expressed in a at band-pass lter function. This may disrupt interneuronal resonance and corrupt the transfer of sensory information (Tennigkeit et al., 1997).
5. Paradoxical sleep To briey summarise, during arousal evoked and spontaneous activity of thalamic relay cells is enhanced and fast rhythmic discharges and their synchronisation in thalamocortical networks are facilitated. Normally, increased spontaneous activity of relay cells is accompanied by an increase in stimulus- or attention-specic inhibition, so that the signal-to-noise ratio of neuronal activity in specic thalamic nuclei does not deteriorate. A disturbance in mechanisms that maintain stimulusspecic inhibition despite generally increased excitability during cholinergic activation would increase the level of noise in specic thalamic nuclei, thereby masking
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patterns of sensory input. The constellation of increased excitability of thalamic relay cells, as observed during arousal, and dysfunction of the reticular thalamic nucleus could lead to activation of thalamocortical circuits and the formation of coherent assemblies of c oscillations independently of aerent sensory information, potentially giving rise to underconstrained perception, such as hallucinations or dream imagery. 5.1. Cholinergic activation Physiological events that accompany paradoxical (rapid-eye-movement) sleep are at least partially caused by disinhibition of mesopontine cholinergic cells following the cessation of ring from inhibitory serotonergic neurons in dorsal raphe nuclei (Steriade, 1992). Acetylcholine is released in the thalamus from terminals of mesopontine cholinergic neurons during paradoxical sleep (similarly to wakefulness) but much less so during slow-wave sleep (Carden & Bickford, 1999). During slow-wave sleep, neurons of the lateral geniculate nucleus of the thalamus are hyperpolarized and participate in slow thalamocortical reverberations that synchronise and generate slow oscillations in the electroencephalogram. During paradoxical sleep, when their membranes are depolarised, lateral geniculate neurons exhibit tonically increased background ring (Steriade, Pare, Bouhassira, Deschenes, & Oakson, 1989). 5.1.1. Ponto-geniculo-occipital waves Ponto-geniculo-occipital waves are spiky electrical eld potentials that occur in the brainstem, thalamus and cerebral cortex during paradoxical sleep (and just prior to it). They are generated in the mesopontine tegmental area of the brainstem and transferred to the thalamus via cholinergic aerents. Although usually being recorded from the lateral geniculate nucleus and visual cortex, ponto-geniculo-occipital waves involve virtually all thalamic nuclei and appear as synchronous eld potentials over widespread neocortical areas (Amzica & Steriade, 1996). The appearance of ponto-geniculo-occipital potentials over the neocortex is followed by c oscillations of cortical eld potentials, the synchronization of which over widespread cortical areas may underlie dreaming (Amzica & Steriade, 1996). Hu, Steriade, and Deschenes (1989) proposed that ponto-geniculo-occipital potentials during paradoxical sleep correspond to orienting reactions elicited by sensory stimuli in the waking state. Ponto-geniculo-occipital potentials recorded from the lateral geniculate nucleus reect nicotinic depolarisation of relay cells and simultaneous muscarinic inhibition of neurons in the perigeniculate sector of the reticular thalamic nucleus (Hu et al., 1989). During paradoxical sleep (but not just before it), lateral geniculate relay cells discharge only a train of spikes in response to ponto-geniculo-occipital waves that only slightly exceeds their tonically increased background ring (Steriade et al., 1989). Perigeniculate neurons, however, always discharge bursts of action potentials in response to ponto-geniculo-occipital waves (Steriade et al., 1989). This suggests that while thalamic relay cells are tonically active during paradoxical sleep, reticular thalamic neurons continue to be hyperpolarized rendering the reticular nucleus functionally inactive.
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5.2. Responsiveness to sensory stimulation Edeline, Manunta, and Hennevin (2000) investigated properties of frequency receptive elds of neurons in the auditory thalamus of guinea pigs during wakefulness, paradoxical sleep and slow-wave sleep. During slow-wave sleep and to a lesser extent during paradoxical sleep, thalamic neurons exhibited decreased rates of evoked ring and reduced receptive eld sizes; during both paradoxical sleep and slow-wave sleep, they showed delayed latencies of evoked responses and increased acoustic thresholds (Edeline et al., 2000). It was concluded that, in paradoxical sleep, and to a greater extent in slow-wave sleep, reactivity of auditory thalamic neurons to sensory stimuli is attenuated, but not abolished (Edeline et al., 2000). While evoked responses of thalamic relay cells may be attenuated compared to wakefulness, their spontaneous activity is not, leading to impairment in the signal-to-noise ratio during paradoxical sleep. Satoh, Eguchi, Watabe, Harada, and Hotta (1980) considered impairment of the signal-to-noise ratio in neuronal networks as one of the characteristics of paradoxical sleep, which they supported by ndings in cats of attenuated responses of thalamic neurons to tooth-pulp stimulation during paradoxical sleep, but not during slow-wave sleep or wakefulness. 5.2.1. Failure to reset cortical c oscillations Forty-Hertz thalamocortical resonance occurs during both wakefulness and paradoxical sleep, giving rise to very similar global properties of cortical activity in these states. Neocortical 40-Hz oscillations recorded magnetoencephalographically during paradoxical sleep are similar in distribution, phase shift and amplitude compared to those recorded during wakefulness (Llinas & Ribary, 1993). Llinas and Ribary (1993) showed that auditory stimuli produced well-dened 40-Hz magnetic oscillations during wakefulness, whereas during paradoxical sleep, random bursts of 40-Hz oscillations occurred in a manner unrelated to sensory stimulation. The fact that during paradoxical sleep 40-Hz oscillations cannot be reset by sensory stimulation was suggested to represent the central dierence between wakefulness and paradoxical sleep (Llinas & Ribary, 1993). Cortical 40-Hz oscillations and conscious experience are generated during both wakefulness and paradoxical sleep, but the external world is mostly excluded from conscious experience during paradoxical sleep (Llinas & Ribary, 1993). Nevertheless, as Llinas and Ribary (1993) pointed out, the thalamocortical system is still accessible to sensory stimulation as indicated by evoked potentials that can be recorded during paradoxical sleep. This may allow strong and persistent nocturnal stimuli to reset c oscillations and thereby inuence dream imagery. In a paired stimulus paradigm (S1S2), van Luijtelaar, Miller, Coenen, Drinkenburg, and Ellenbroek (1998) observed an increase in the S2/S1 ratio of cortical auditory evoked potentials in rats during paradoxical sleep compared to wakefulness but not during slow-wave sleep. An increase in the S2/S1 ratio of mid-latency auditory evoked potentials was also demonstrated repeatedly in schizophrenia and may indicate an impaired signal-to-noise ratio of neuronal activity in specic thalamic nuclei (see below), consistent with the hypothesis by Llinas and Ribary (1993) that a
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similar mechanism may be involved in paradoxical sleep and conditions that are accompanied by hallucinations. 5.3. Hypothetical role of the reticular thalamic nucleus Hyperpolarisation of reticular thalamic neurons may explain the impaired signalto-noise ratio of thalamic activity and the reduced impact of sensory stimulation on thalamocortical c oscillations during paradoxical sleep. While thalamic relay cells are tonically active during paradoxical sleep, allowing them to participate in reverberations of fast oscillations similarly to wakefulness, reticular thalamic neurons are inhibited with the consequence of a lack of stimulus-specic inhibition in specic thalamic nuclei. In the context of increased spontaneous activity in specic thalamic nuclei during cholinergic brainstem activation, this may give rise to thalamocortical activation that is underconstrained by sensory input. Only strong sensory stimuli would be able to inuence patterns of fast thalamocortical activity and, thus, conscious experience in dreaming. Corticofugal attentional mechanisms would be largely unrestricted by sensory input in their recruitment of thalamic relay cells into activated thalamocortical assemblies. As Llinas and Pare (1991) have suggested, dreaming may be a state of increased attentiveness that is relatively unperturbed by sensory stimulation.
6. Schizophrenia From the philosophical position of transcendental idealism, normal perception, dream imagery and hallucinations dier only with respect to the degree to which they are constrained by external sensory stimulation. Hallucinations may be conceptualised as perceptual experiences in the state of wakefulness that are underconstrained by sensory input and it is suggested that in schizophrenia this can be caused by peripheral sensory impairment or increased random neural activity in specic thalamic nuclei. Otherwise, there should be no dierence: hallucinations arise in the focus of attention, just like any other perception, and they should involve activity in the same physiological systems that subserve normal perception. In hallucinations (as in dream imagery), attentional factors determine the content of conscious experience in a manner that is unrestricted by external sensory stimulation. Schizophrenia is characterised by episodes of hallucinations and other psychotic symptoms in clear consciousness that are usually accompanied by a lack of insight and occur in the absence of a primary mood disturbance or identiable brain disease. Gruzelier (1999) suggested that schizophrenia might be a partial disorder of consciousness involving dysregulation in specic and non-specic thalamocortical systems. It is suggested here that the biological core disturbance in schizophrenia may be a failure of sensory input to modulate intrinsic thalamocortical activity, which may predispose to hallucinations at times of arousal and heightened attention. Hallucinations in the auditory modality and particularly verbal hallucinations appear to prevail in schizophrenia and aective psychoses. Nevertheless, visual hallucinations are not uncommon in schizophrenia; in contrast to some organic
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conditions, they typically occur without prodromata and in a psychological setting of intense aect (Asaad & Shapiro, 1986). Tactile, kinaesthetic, olfactory and gustatory hallucinations are also reported in schizophrenia. Asaad and Shapiro (1986) suggested that the development of hallucinations in mental illness might represent a nal common pathway involving biological vulnerability and psychological inuences. While biological vulnerability factors are likely to be indiscriminate of perceptual modality (aecting either all modalities or aecting them randomly), it may be that psychological factors can explain the apparent predominance of verbal hallucinations in mental illness. First, human communication and interpersonal relationships are largely mediated by language, and verbal hallucinations may reect social experiences or full defensive functions in people with enduring social anxiety and problems in relating to others. Verbal hallucinations may be employed unconsciously to project social fears, conrm suspicions or full social desires, bypassing open interaction with the social environment. Second, subvocal speech may provide a mechanism to unconsciously modulate and maintain the experience of verbal hallucinations once they have started to develop. It is argued here that in schizophrenia, the development of hallucinations and possibly other psychotic symptoms represents the outcome of a general biological predisposition towards hallucinations that interacts with psychological distress or anxiety arising from dierent constellations of personality problems, limited social coping skills and current interpersonal conicts or social problems. 6.1. Impaired response synchronisation The electroencephalogram synchronizes to the frequency of periodic sensory stimulation, with preferred resonance occurring at 40 Hz (Kwon et al., 1999). When 40-Hz auditory click trains were presented to schizophrenic patients, Kwon et al. (1999) noticed a delayed onset of entrainment of the electroencephalogram (EEG) and delayed return to desynchronisation after cessation of the click train. This was interpreted by the authors as a failure in schizophrenia to entrain intrinsic c-frequency oscillators. Delays in onset of synchronisation and return to desynchronisation of the EEG suggest that intrinsic c oscillations in patients with schizophrenia are less modiable by sensory stimulation. This is consistent with the prediction by Llinas and Ribary (1993) that impaired resetting of 40-Hz oscillations by sensory stimulation characterises conditions that are accompanied by hallucinations. Hallucinatory experiences may be subserved by coherent c-band oscillations in the same way as normal perception in wakefulness or dream imagery in paradoxical sleep. In electroencephalographic recordings from a patient with recurrent somatic hallucinations, Baldeweg et al. (1998) observed c oscillations that occurred at the same time as the hallucinations. It appears that, on the one hand, sustained patterns of fast thalamocortical resonance can occur in the absence of sensory input and give rise to hallucinations; on the other hand, thalamocortical rhythms are less modiable by external sensory input in schizophrenia. The notion of increased random activity or noise in specic thalamic nuclei may explain this apparent paradox. Increased noise in specic thalamic nuclei could both mask changes in sensory input and, particularly at times of arousal, facilitate the recruitment of thalamic relay cells by
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cortical attentional mechanisms into assemblies of coherently activated thalamocortical circuits regardless of their sensory input. Thus, not only would an impaired signal-to-noise ratio dampen the impact of sensory input on thalamocortical activity and perception, it would also predispose to hallucinations. More intensive or prolonged sensory stimulation would be necessary to induce or modulate patterns of coherent thalamocortical oscillations, with the consequence of reduced perceptual responsiveness to changes in sensory input. This may manifest in elevated thresholds for tone discrimination (Rabinowicz, Silipo, Goldman, & Javitt, 2000) and reduced auditory acuity (Mathew, Gruzelier, & Liddle, 1993) that were demonstrated in patients with schizophrenia. 6.1.1. Visual backward masking In visual backward masking tasks, detection of a briey presented target stimulus is prevented by a mask stimulus that is presented shortly after the target (at interstimulus intervals of less than 100 ms). Compared to normal subjects, patients with schizophrenia require longer interstimulus intervals between the presentation of target and mask to be able to identify the target stimulus. In other words, target identication by schizophrenic patients is disrupted more easily by an early masking stimulus. Poor performance in visual backward masking procedures is related more to negative than positive symptoms of schizophrenia (Cadenhead et al., 1997). Visual backward masking performance decits were demonstrated in schizophrenic patients who were in clinical remission (Green, Nuechterlein, Breitmeyer, & Mintz, 1999) and unaected siblings of schizophrenic patients (Green, Nuechterlein, & Breitmeyer, 1997), suggesting that these decits are a marker of predisposition to schizophrenia rather than the presence of active illness (Green et al., 1999). When analysing visually evoked potentials that were recorded during a visual backward masking procedure, Patterson, Spohn, and Hayes (1987) concluded that visual backward masking decits in patients with schizophrenia may be due to a failure of initial target stimulus registration within the time allowed rather than abnormal gating mechanisms. Even without early interference, patients with schizophrenia require longer stimulus presentation to visually recognise a stimulus (increased critical stimulus duration) (Cadenhead et al., 1997; Schwartz, Evans, Sautter, & Winstead, 1992), independently of attentional demands (Schwartz et al., 1992). Green et al. (1999) related visual backward masking decits in patients with schizophrenia to a failure to establish cortical oscillations in the c range. Findings on critical stimulus duration and visual backward masking suggest that sensory stimulation has to be more persistent and followed by a longer interferencefree interval to allow establishment of sustained thalamocortical synchronisation in the c range that underlies stimulus perception. In other words, the ability of sensory stimulation to modulate processes of thalamocortical resonance and perception may be reduced in schizophrenia. 6.1.2. Mid-latency auditory evoked potentials The amplitude of the P50 component of auditory evoked potentials tends to be reduced in patients with schizophrenia, which, as pointed out by Gruzelier (1999), is associated with the presence of auditory hallucinations. c Activity in the
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electroencephalogram was shown to signicantly contribute to the formation of P30 and P50 auditory evoked potentials (Basar, Rosen, Basar-Eroglu, & Greitschus, 1987). This led to the suggestion that mid-latency evoked potentials (generally 30 80 ms poststimulus) reect the transient synchronisation of the electroencephalogram to an external stimulus (Basar, Basar-Eroglu, Rahn, & Schurmann, 1991). Data obtained by Clementz, Blumenfeld, and Cobb (1997) are also consistent with the notion that the auditory evoked P50 is a subcomponent of the 40-Hz synchronised response that may underlie feature binding and stimulus perception. Therefore, smaller amplitudes of mid-latency evoked potentials may reect impaired synchronisation of thalamocortical c activity in response to sensory stimulation. 6.1.3. S2 P50 amplitude suppression In experiments that involve repeated presentation of paired auditory stimuli and averaging of the electroencephalographic responses, most normal subjects show an amplitude reduction of mid-latency evoked-potential components such as P50 in response to the second stimulus S2 as compared to the response to rst stimulus S1. This amplitude reduction of the P50 response to S2 in auditory paired-stimulus paradigms is absent in most schizophrenic patients, as expressed in an increase of their P50 S2/S1 amplitude ratio (so-called gating ratio). Lack of suppression of S2 P50 can be found both in acutely psychotic and medicated clinically stable patients (Adler et al., 1990; Freedman, Adler, Waldo, Pachtman, & Franks, 1983) and is also present in many relatives of schizophrenic patients (Adler, Hoer, Grith, Waldo, & Freedman, 1992; Clementz, Geyer, & Bra, 1998). Decreased suppression of the S2 P50 amplitude (increased P50 S2/S1 amplitude ratio) in auditory paired-stimulus paradigms is usually interpreted as evidence for impaired sensory gating in schizophrenia (e.g., Freedman, Waldo, Bickford-Wimer, & Nagamoto, 1991). However, patients with schizophrenia who show an increased P50 S2/S1 amplitude ratio also tend to have smaller P50 amplitudes to S1 (Boutros, Zouridakis, & Overall, 1991; Clementz et al., 1998), which can partly explain the relative lack of S2 P50 suppression. Moreover, evoked potentials are averaged from electroencephalographic recordings of many individual trials and their amplitudes can be aected by the temporal variability of the evoked response. Analysing individual trial data, Jin et al. (1997) and Patterson et al. (2000) found that in patients with schizophrenia the temporal variability of the P50 response to S1 was increased, while the P50 response to S2 showed the same temporal variability in patients and control subjects. Correction for temporal variability eliminated the signicant difference between patients and control subjects in S1 P50 amplitudes (Jin et al., 1997) and P50 S2/S1 amplitude ratios (Patterson et al., 2000). Thus, increased temporal variability of the evoked response to S1 importantly contributes to the reduction of S1 P50 amplitudes and the lack of S2 P50 suppression that are consistently seen in averaged evoked potentials. Assuming that the P50 is part of c response synchronisation, Clementz et al. (1997) suggested that suppression of the P50 amplitude in response to S2 that is normally observed in paired-stimulus paradigms might be a proxy for suppression of the c-band response to S2. Zouridakis, Boutros, and Jansen (1997) established impaired response synchronisation of the electroencephalogram to S2 in both normal
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subjects and patients with schizophrenia. In normal subjects, this is due to phase opposition with response synchronisation elicited by S1 (Zouridakis et al., 1997). In patients with schizophrenia, synchronisation of the electroencephalogram is impaired not only in response to S2 but also in response to S1 (Zouridakis et al., 1997), which may explain their reduced S1 P50 amplitudes and increased S2/S1 P50 amplitude ratios. Recognising that neuronal synchrony can be aected when the rate of background ring is too high, Patterson et al. (2000) hypothesised that increased temporal variability of S1 P50 in schizophrenic patients may be the result of erratic neuronal ring in a hyperactive nervous system. Increased random neuronal activity could mask stimulus-specic activity, leading to decient synchronisation in response to sensory stimulation or greater instability of the synchronised response. This would manifest in reduced mid-latency evoked potentials and an increased S2/S1 P50 ratio. Rather than reecting sensory gating decits, lack of suppression of S2 P50 may therefore indicate an increase in random neuronal activity and corresponding loss of stimulus-specic activity in schizophrenia. 6.2. Implication of the reticular thalamic nucleus Administration of nicotine to schizophrenic smokers after a night of abstinence transiently restored their amplitude suppression of P50 in response to S2 (Adler, Hoer, Wiser, & Freedman, 1993). Administration of nicotine to non-smoking relatives (of schizophrenic patients) who had an abnormal P50 S2/S1 amplitude ratio transiently restored their S2 P50 suppression too (Adler et al., 1992). These ndings implicated nicotinic cholinergic receptors in schizophrenia. S2 P50 amplitude suppression normalised in schizophrenic patients after brief periods of slow-wave sleep (Grith, Waldo, Adler, & Freedman, 1993), suggesting that nicotinic receptors might undergo abnormally rapid desensitisation during cholinergic arousal and resensitise only after a period of absence of cholinergic stimulation (Grith et al., 1998). In a pedigree study, Waldo et al. (1991) demonstrated a familial association between an increased P50 S2/S1 ratio (i.e., lack of S2 P50 suppression) and schizophrenia. Genetic linkage analysis by Freedman et al. (1997) established that the increase in the P50 S2/S1 amplitude ratio in patients with schizophrenia and their relatives was linked to a polymorphic marker at chromosome locus 15q13-14, which is the site encoding the a-7 subunit of the nicotinic cholinergic receptor. Altered expression or function of the a-7 nicotinic receptor may therefore be responsible for failure to suppress the auditory-evoked P50 response to the second of paired auditory stimuli in patients with schizophrenia and their relatives. Nicotinic cholinergic receptors with the a-7 subunit are particularly concentrated in the reticular thalamic nucleus (Agulhon et al., 1999; Quik et al., 2000; Spurden et al., 1997). Interestingly, expression of a-7 nicotinic receptors was found to be moderately reduced in the reticular thalamic nucleus in post-mortem tissue from patients with schizophrenia (Court et al., 1999). Activation of nicotinic receptors on terminals from reticular thalamic neurons facilitates GABAergic transmission in the thalamus, which may contribute to an increase in the signal-to-noise ratio of neural
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activity in specic thalamic nuclei during arousal (Lena & Changeux, 1997). Rapid desensitisation and/or reduced expression of a-7 nicotinic receptors on reticular thalamic neurons would therefore result in decreased stimulus-specic inhibition and increased random activity in specic thalamic nuclei. This is consistent with the hypothesis by Patterson et al. (2000) that greater temporal variability of auditory evoked responses reects erratic neuronal activity in schizophrenia. As a consequence of increased noise and reduced sensory-specic activity, longer or more intensive sensory stimulation would be necessary to induce sustained assemblies of fast thalamocortical oscillations underlying stimulus perception. Moreover, during arousal, when background activity of thalamic relay cells is further increased and c oscillations in the thalamocortical system are facilitated, attentional mechanisms would be less restricted by the pattern of sensory input in their attempts to recruit thalamic relay cells into assemblies of activated thalamocortical circuits. 6.3. Dopaminergic hyperactivity Lack of amplitude suppression of P50 in response to the second of paired auditory stimuli (i.e., increased P50 S2/S1 amplitude ratio) appears to be more related to a predisposition to schizophrenia rather than the presence of active illness. Waldo et al. (1994) suggested that an increase in the P50 S2/S1 amplitude ratio might be a necessary factor but not in itself sucient to cause schizophrenia. For schizophrenia to become clinically manifest, a pre-existing increase in the P50 S2/S1 ratio may have to be complemented by other abnormalities, such as diminished hippocampal volume or increased dopamine metabolism (Waldo et al., 1994). Dopamine may activate D2 and D4 dopamine receptors on neurons in the reticular thalamic nucleus (Khan et al., 1998). D2 and D4 are metabotropic receptors that are negatively coupled to adenylate cyclase. Among other eects, their activation on reticular thalamic neurons may reduce the expression or activation of glutamic acid decarboxylase (GAD), which is the rate-limiting enzyme in the synthesis of GABA. If this were the case, then dopaminergic hyperactivity would result in decreased release of GABA upon nicotinic receptor activation and excessive disinhibition in specic thalamic nuclei. Excessive thalamic disinhibition, in turn, would impair thalamocortical c response synchronization, which would manifest in increased temporal variability of mid-latency evoked potentials (with a reduction in averaged amplitudes and elevation of S2/S1 ratios). Indeed, the use of indirectly acting dopamine agonists, such as cocaine and amphetamine, was associated with amplitude reduction of the auditory-evoked P50 (Boutros, Zouridakis, Rustin, Peabody, & Warner, 1993) and a failure to reduce P50 in response to the second of paired stimuli (Light et al., 1999). In patients with schizophrenia, the amplitude reduction of evoked potentials that is observed during exacerbation of schizophrenia may similarly be mediated by excessive dopamine (Adler et al., 1990). There is evidence to suggest that antipsychotic drugs may reduce the predisposition to hallucinations by preventing this hypothetical sequence of events. D2 and D4 receptors are common targets for antipsychotic drugs. By blocking these receptors on reticular thalamic nucleus neurons, antipsychotics may increase the
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synthesis of GABA and restore its release onto thalamic relay cells (upon nicotinic receptor activation). Indeed, dopamine receptor blockade with dierent antipsychotic drugs was demonstrated in Sprague Dawley rats to increase the expression of GAD particularly in the reticular thalamic nucleus (Sakai, Gao, Hashimoto, & Tamminga, 2001). Chronic administration of the antipsychotic drug haloperidol was reported to increase inhibition of relay neurons in the ventrolateral thalamic nucleus (Lukhanina, 1989). Furthermore, treatment with antipsychotics can normalize the amplitude reduction of P50 in patients with schizophrenia (Boutros et al., 1993). These ndings are consistent with the hypothesis that the action of antipsychotics may ultimately involve facilitation of the GABAergic function of the reticular thalamic nucleus and reversal of excessive disinhibition in specic thalamic nuclei. Clozapine, which is known to be particularly eective in the treatment of symptoms of schizophrenia, is characterized by a high anity for the D4 receptor. Interestingly, D4 receptors are expressed particularly on GABAergic neurons (including those in the reticular thalamic nucleus) suggesting that the antipsychotic eect of clozapine may be achieved by modulation of GABAergic transmission (Mrzljak et al., 1996). Nicotinic receptor abnormalities in patients with schizophrenia, which are related to an increase in the P50 S2/S1 amplitude ratio, and dopaminergic hyperactivity may be additive in causing a decrease in the release of GABA onto thalamic relay cells and a corresponding decrease in the signal-to-noise ratio of thalamic sensory transmission. An increased P50 S2/S1 amplitude ratio, which is a relatively enduring abnormality independent of clinical state (Adler et al., 1990), may indicate an elevated baseline level of random thalamic activity in schizophrenia, and this may be increased further by episodic dopaminergic hyperactivity, which is know to be associated with active psychosis. Conventional antipsychotics do not reduce the increased P50 S2/S1 ratio in patients with schizophrenia, however clozapine (reviewed in Gruzelier, 1999) and risperidone (Yee, Nuechterlein, Morris, & White, 1998) can do so, consistent with the superior eectiveness that is attributed to these atypical antipsychotics. A similar mechanism to the one proposed for excess dopamine and dopaminergic agonists, i.e., (i) inhibition of reticular thalamic neurons, (ii) reduction of the release of GABA onto thalamic relay cells, (iii) disinhibition of thalamic relay cells and (iv) pathological activation of thalamocortical circuits, was suggested by Tomitaka, Tomitaka, Tolliver, and Sharp (2000) and Sharp, Tomitaka, Bernaudin, and Tomitaka (2001) to underlie the capacity of non-competitive NMDA (N-methyl-D -aspartate) receptor antagonists, such as phencyclidine and ketamine, to cause psychosis in humans. This suggestion was based on the observation that non-competitive NMDA receptor antagonists produce over-excitation and injury of cortical pyramidal cells in rats via the blockade of NMDA receptors on GABAergic neurons of the reticular thalamic nucleus (Tomitaka et al., 2000). Antipsychotic drugs can prevent NMDA-antagonist-induced pyramidal cell injury presumably by blocking dopamine receptors on reticular thalamic neurons (reviewed in Sharp et al., 2001). In schizophrenia, excessive disinhibition of thalamic relay cells alone may not produce psychotic symptoms. Corticofugal attentional mechanisms may be involved in the formation of assemblies of pathologically activated thalamocortical circuits by providing additional specic depolarisation to cortical neurons. Under conditions of
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excessive disinhibition of thalamic relay cells, strong corticofugal input may recruit thalamic relay cells into assemblies of coherent thalamocortical c oscillations in a manner that is unrestricted by the pattern of sensory input. Such assemblies of pathologically activated thalamocortical circuits may underlie hallucinations and other psychotic symptoms. 6.4. Peripheral sensory impairment Noise, to some extent, is normally inherent in the ow of sensory information. For instance, retinal dark discharge, which is the maintained discharge of retinal ganglion cells, constitutes the background noise from which the visual signal must be discriminated. The proportion of noise in sensory input would be expected to increase as a result of peripheral sensory impairment. Hypothetically, thalamic relay cell excitability may be up-regulated in an attempt to enhance or recover lost information. Such compensatory up-regulation or indeed simply up-regulation by cholinergic mechanisms during arousal would amplify random activity in specic thalamic nuclei. There is a well-established association between hearing loss and late paraphrenia (Almeida, Howard, Levy, & David, 1995; Cooper, Curry, Kay, Garside, & Roth, 1974; Howard, Almeida, & Levy, 1994; Pearlson et al., 1989), a form of schizophrenia that develops in later life and is characterised by prominent paranoid delusions and auditory hallucinations. Chronic hearing loss in patients with paranoidhallucinatory psychoses of later life usually starts well before the onset of illness, suggesting that hearing impairment plays an important role in causing late-life psychosis (Cooper et al., 1974; Cooper, Garside, & Kay, 1976; Kay, Cooper, Garside, & Roth, 1976). Patients with late-onset psychotic disorder are also more likely to have chronic visual impairment (Cooper & Porter, 1976; Pearlson et al., 1989) and this was found to be associated with the presence of visual hallucinations (Howard et al., 1994). Similarly, hearing impairment in childhood or early adulthood is a risk factor for later development of schizophrenia (David, Malmberg, Lewis, Brandt, & Allbeck, 1995; ONeal & Robins, 1958). Schizophrenia has been linked to middle ear disease (Mason & Winton, 1995) and is associated with impaired conduction through auditory pathways in the brainstem, as revealed by reduced amplitudes and missing peaks in brainstem auditory-evoked potentials (i.e., potentials occurring within 10 ms of auditory stimulus presentation) (Hayashida et al., 1986; Igata, Ohta, Hayashida, & Abe, 1994; Lindstrom, Klockho, Svedberg, & Bergstrom, 1987). Lindstrom et al. (1987) suggested that interference with auditory brainstem pathways might be causally related to auditory hallucinations in schizophrenia. Auditory hallucinations, particularly musical hallucinations, can occur in hearing impairment without associated psychopathology (Berrios, 1990; Hammeke, McQuillen, & Cohen, 1983) and are not uncommon in the general population (Tien, 1991). Psychosis may develop only if the person fails to gain early insight into the abnormal nature of these experiences. An anxious or paranoid person may attribute the source of a sudden noise or unusual voice to the social environment more readily. Lack of insight would ensure that he or she continues to pay attention to utterances
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from thought-to-be-real people, leading to the perpetuation and elaboration of verbal hallucinations. 6.5. Hyperarousal Tonic electrodermal activity is a measure of autonomic arousal. Electrodermal activity and sweat glands are regulated mostly by cholinergic innervation from the sympathetic nervous system, although adrenergic mechanisms also play a role (reviewed in Boutros & Bra, 1999). Tonic electrodermal hyperactivity was identied as a state indicator of acute psychosis, since tonic electrodermal activity was abnormally elevated during psychotic states but not during remission in patients with schizophrenia (Dawson, Nuechterlein, Schell, Gitlin, & Ventura, 1994). Tonic electrodermal hyperarousal may even precede a psychotic relapse (Dawson, Nuechterlein, & Schell, 1992). Furthermore, in schizophrenic patients with intermittent hallucinations the onset of hallucinatory periods was associated with a substantial increase in the rate of spontaneous uctuations of skin conductance (Cooklin, Sturgeon, & Le, 1983). These ndings may indicate that hyperarousal contributes to the development of psychosis and the production of hallucinations. Cholinergic activation during arousal also leads to electroencephalographic activation with an excess of fast activity. Electroencephalographic recordings from patients with schizophrenia tend to show increased b activity, particularly in postcentral regions, and less a activity, but also excessive slow-wave activity, particularly in frontal areas (Morihisa, Duy, & Wyatt, 1983). On its own, the excess of fast activity in the EEG would indicate hyperarousal (Gruzelier, 1999). Among schizophrenic patients, excessive fast b activity and less a and slow-wave activity in the resting EEG were associated with more orid psychotic symptoms and better response to neuroleptic treatment (Itil, Marasa, Saletu, Davis, & Mucciardi, 1975), further supporting an association between hyperarousal and acute psychosis. Episodic hyperarousal together with enduring vulnerability to hallucinations may be the key components in a biopsychosocial model of psychosis. Asaad and Shapiro (1986) predicted that the neurobiological basis for the vulnerability to hallucinations is also the basis for the vulnerability to schizophrenia. In schizophrenia and late paraphrenia, the biological vulnerability to hallucinations may be given in form of excessive random activity in specic thalamic nuclei, which may be due to dysfunction of the reticular thalamic nucleus or inherent lack of stimulus-specic regularities in input from disordered peripheral sensory organs (Fig. 4). Environmental stressors, such as life events and ongoing social stress, can precipitate psychotic episodes by interacting with pre-existing biological vulnerability factors (Nuechterlein & Dawson, 1984). Premorbid limitations in social competence and coping skills would inuence the likelihood of life events and social problems and thereby determine extent to which the individuals biological vulnerability is stressed. Excessive cholinergic arousal that accompanies psychological stress and anxiety may mediate between environmental stressors and acute psychosis in a predisposed individual. Once hallucinations have started to occur, a vicious circle of anxiety and psychotic defences may develop, with accompanying hyperarousal maintaining thalamic
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Fig. 4. Neurobiological factors suggested to be involved in the generation of hallucinations in schizophrenia: Disruption of sensory constraints may be due to disturbed function of the reticular thalamic nucleus, leading to lack of specic inhibition in specic thalamic nuclei, or peripheral sensory disorder. Reticular thalamic nucleus dysfunction in turn may be caused by nicotinic receptor abnormalities or dopaminergic hyperactivity. During arousal, relay cells in specic thalamic nuclei may then be activated by attentional mechanisms alone and be induced by non-specic thalamocortical circuits to participate in coherent assemblies of thalamocortical c activity that underlie hallucinatory perception.
random background activity at a level compatible with ongoing hallucinations throughout the psychotic episode. Besides stress and anxiety that could contribute to hyperarousal during psychosis, cholinergic brainstem centres in schizophrenia may be inappropriately responsive to normal stress-inducing factors. The number of neurons in the pedunculopontine nucleus was shown to be increased in most schizophrenic patients, which suggested that increased cholinergic output from the midbrain reticular formation could overdrive the thalamus to produce schizophrenic symptoms such as hallucinations (Garcia-Rill et al., 1995). In part this may be achieved by increasing the activation of intralaminar thalamic nuclei and non-specic thalamocortical circuits, allowing the binding of insuciently activated specic thalamocortical circuits into a unitary conscious experience.
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6.6. Psychological factors While a predisposition to hallucinations may be given biologically, content and frequency of hallucinations may depend crucially on psychological factors. Clinical observations suggested that auditory hallucinations are context-dependent (Nayani & David, 1996) and inuenced in their form and content by attentional and intentional factors (Hammeke et al., 1983). On the other hand, attention-commanding properties in stimulation from the environment can suppress hallucinations (Margo, Hemsley, & Slade, 1981). In their content, verbal hallucinations may reect the patients beliefs about his subordination, disparagement and marginalisation in social relationships (Birchwood, Meaden, Trower, Gilbert, & Plaistow, 2000; Linn, 1977). Verbal hallucinations may represent parental authority (Nayani & David, 1996) and reveal psychodynamic inuences such as guilt, wish fullment or gratication of repressed impulses (Asaad & Shapiro, 1986). In short, rather than being symptoms that randomly aict the patient, verbal hallucinations appear to be intricately linked to the patients psychological condition, reecting his experiences, preoccupations and anxieties, both on a conscious and unconscious level. Psychodynamic theory suggests that hallucinations and psychosis develop only when there is already a major impairment of the ego (Asaad & Shapiro, 1986). Personality decits and enduring social anxiety may be core problems that precede symptomatic illness. Premorbid feelings of inferiority can be found in at least a subgroup of patients with schizophrenia (Kendler & Hays, 1982). Poor social adjustment and lack of social condence are common characteristics in children and adolescents who later develop schizophrenia (Jones, Murray, & Rodgers, 1995). Similarly, paranoid personality traits and social isolation are frequent premorbid characteristics of elderly patients with late paraphrenia. If there is an additional biological predisposition to underconstrained perception, hallucinations and other psychotic symptoms may develop at times of insurmountable social stress and rising interpersonal anxiety. Neurobiological and psychological aspects are essential and complementary in understanding the nature of hallucinations in mental illness. In patients with a predisposition to underconstrained perception, verbal hallucinations may develop at times of heightened arousal and increased attention to social stimuli. An already anxious or paranoid person may attribute perceived sounds or primitive voices to the social environment more readily. If the person fails to gain early insight into the abnormality of these experiences, he may increasingly pay attention to what voices say. Misattribution of voices to the social environment ensures that attention remains focused on their presumed external source and this may contribute to the perpetuation of verbal hallucinations. Furthermore, hearing voices may be become increasingly entangled in unconscious defence mechanisms that regulate self-esteem and anxiety in the psychotic patient. Subvocal speech may gradually become involved in the maintenance and elaboration of voices. As the patient with lack of insight realises how his own thoughts can inuence voices from thought-to-be-real people, he may resort to the delusional elaboration that he can inuence other peoples thoughts, that other people can be aware of his thoughts or that his thoughts are being broadcast outside (Behrendt, 1998).
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7. Summary The cerebral cortex and thalamus constitute a unied oscillatory system that displays dierent spontaneous rhythms depending on the state of vigilance (Steriade, 1997). During arousal, cholinergic input to the thalamus from the mesencephalic reticular formation releases c oscillations in thalamic and cortical neurons and facilitates their synchronisation. Under constraints of sensory input and prefrontal and limbic activities (mediating the inuence of anticipation, recent memories, current behavioural goals and aective value), oscillatory c activities in populations of interconnected thalamic and cortical neurons synchronise to form coherent assemblies that underlie perception and conscious events in general. It is important to understand that perception is merely constrained by sensory input. Perception and conscious experience are manifestations of an intrinsic process that can principally operate in the presence or absence of sensory input (Llinas & Pare, 1991; Llinas & Ribary, 1993). Llinas and Ribary (1993) considered dreaming as a state of hyperattentiveness in which sensory input cannot address the machinery that generates conscious experience. They hypothesised that a similar mechanism may be involved in conditions that are accompanied by hallucinations (Llinas & Ribary, 1993). In schizophrenia, dysfunction of the reticular thalamic nucleus may lead to loss of stimulus-specic inhibition and an increase of random activity in specic thalamic nuclei. Peripheral sensory impairment may constitute another cause for increased thalamic random activity. If, during cholinergic arousal, such thalamic noise combines with general activation of relay cells, then, in the context of general facilitation of c range synchronisation, attentional mechanisms alone may recruit thalamic relay cells into resonant assemblies of fast thalamocortical oscillations without contribution from aerent sensory input. When thalamocortical self-organisation that underlies conscious experience is unrestricted by sensory input, attentional mechanisms may dominate the content of perceptual experience. Besides a biological predisposition to underconstrained perception, increased arousal and psychological concerns operating through attentional mechanisms may play an important part in bringing about episodic psychosis in schizophrenia. In conclusion, it is the understanding that even normal perception is a fundamentally subjective experience that is created internally and projected into a virtual space around us that allows us to conceptualise hallucinations and dream imagery as forms of underconstrained perception, thereby providing a perspective from which to integrate neurobiological and clinical ndings on hallucinations.
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Hallucinations- Synchronisation of thalamocortical γ oscillations underconstrained by sensory input

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Hallucinations- Synchronisation of thalamocortical γ oscillations underconstrained by sensory input

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Consciousness and Cognition Consciousness and Cognition 12 (2003) 413451

Hallucinations: Synchronisation of thalamocortical c oscillations underconstrained by sensory input

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

R.P. Behrendt / Consciousness and Cognition 12 (2003) 413451

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