Understanding the mystery of schizophrenia requires the interpretation of clues. When multiple clues point to the same culprit, there is increased hope that the mystery will be solved. A recently published paper provides one clue that the thalamus may be of special importance in schizophrenia (Ferrarelli et al., 2010). This paper reports abnormalities in EEG spindles in schizophrenia. Spindles are high-voltage thalamocortical oscillations in the 10-15 Hz range that wax and wane in about a second and occur during Stage 2 sleep. Ferrarelli et al. found that, in schizophrenia patients, these spindles are reduced in number, amplitude, and duration. Importantly, this reduction was relative to a control group that received neuroleptics, making it likely that the spindle abnormality is due to the disease rather than the treatment. The authors found correlations between the spindle properties and symptoms of the disease. For example, spindle number negatively correlates with hallucinations, conceptual disorganization, and stereotyped thinking.

What part of the brain might underlie the abnormality in spindles? There has been substantial work in animal models demonstrating that spindles are generated in the thalamus and are then transmitted to cortex (Steriade et al., 1987). Furthermore, spindle generation in the thalamus arises from the bidirectional connections between specialized inhibitory cells of the thalamic nucleus reticularis and the relay cells of thalamic nuclei (these are the cells that communicate with cortex) (von Krosigk et al., 1993). Ferrarelli et al. thus speculate that the culprit in schizophrenia may lie in the nucleus reticularis.

Our studies of rats provide a second clue pointing to the nucleus reticularis, albeit by a totally different logic (Zhang et al., 2009; Lisman et al., 2010). The starting point of our work was the observation that antagonists of the NMDA receptor (NMDAR) can induce many of the symptoms of schizophrenia in normal subjects (Krystal et al., 1994). We and many others have therefore sought to understand the cellular processes induced by NMDAR antagonists. At first pass, one might expect an antagonist of an excitatory amino acid transmitter to quiet the brain, but early work showed that, to the contrary, large slow waves (in the delta frequency range; 1-4 Hz) in the thalamic EEG could be excited by NMDAR antagonist (Miyasaka and Domino, 1968; Buzsaki, 1991). Our recent work (Zhang et al., 2009) suggests how this happens. The nucleus reticularis contains an unusual NMDAR subunit, NR2C, which is not blocked by Mg²⁺ at resting potential. Thus, ambient glutamate can produce an inward current in these cells at resting potential. When this inward current is blocked by NMDAR antagonist, the resting potential hyperpolarizes. Hyperpolarization has long been known to excite thalamic cells because it removes inactivation from T-type Ca²⁺ channels; these channels then produce Ca²⁺ spikes at delta frequency (Llinas and Jahnsen, 1982). Indeed, we found that blocking NMDARs produces rhythmic Ca²⁺ spikes (Zhang et al., 2009) in the nucleus reticularis. These spikes occurred in the delta frequency range similar to the delta oscillations that occur during slow-wave sleep.

According to the thalamocortical dysrhythmia hypothesis (Llinas et al., 1999), mental abnormalities occur when sleep-like delta oscillations are generated in the awake state in particular subparts of thalamocortical system (Jeanmonod et al., 2003). Because the oscillations occur in the awake state, they interfere with normal function. Exactly which parts of the system are affected determines the particular disease that is produced. In schizophrenia, a large number of studies show that there is enhanced delta frequency EEG power in frontal and midline cortical areas (Boutros et al., 2008). At the level of the thalamus, NMDAR antagonist has particularly strong effects (measured by cFOS) on midline thalamic nuclei (Vaisanen et al., 2004). There is thus reason to believe that only parts of the thalamocortical system are activated by NMDAR antagonist.

Among the midline thalamic nuclei activated by NMDAR antagonist, the nucleus reuniens is notable because it innervates the hippocampus, medial prefrontal, and entorhinal cortex—structures that are implicated in schizophrenia on other grounds. Thus, activation of the reuniens would be expected to activate the hippocampus. In a recent theoretical paper (Lisman et al., 2010), we pointed to the literature demonstrating that activation of the hippocampus can trigger dopamine release and that dopamine can further promote delta oscillations in the thalamus. Thus, a loop involving the thalamus (reticularis/reuniens), the hippocampus, and the VTA has the potential for positive feedback. We speculated that the transition to positive feedback might underlie the psychotic break at the onset of schizophrenia.

According to this view, abnormal loop dynamics should involve delta frequency oscillations; however, Ferrarelli et al. did not observe any change in delta oscillations in their study. But it is important to note that their experiments were restricted to sleep. In contrast, many previous studies have observed an increase in delta power in schizophrenia, but these studies were made on subjects in the awake state (Boutros et al., 2008). Thus, a simple reconciliation is that delta during sleep may be unaffected in schizophrenia, except insofar as there are fewer and smaller spindles. We believe that delta oscillations that occur in the awake state, rather than the spindles that occur during sleep, cause the cognitive problems in schizophrenia.

Although we emphasized here two clues that point to the nucleus reticularis and midline thalamic nuclei as the culprit in schizophrenia, there have been other clues that point more generally to thalamic involvement. Imaging studies have suggested a deficit in circuitry connecting the thalamus, frontal cortex, and cerebellum in schizophrenia (Andreasen, 1997). Postmortem studies have identified abnormalities of glutamate receptors in the thalamus (e.g., reduced expression of AMPA/NMDA receptor) (Clinton and Meador-Woodruff, 2004). Morphometric neuroimaging approaches have revealed some specific thalamic nuclei (anterior thalamus, pulvinar, and others) that have a reduced volume in schizophrenia (Byne et al., 2009). Functional imaging studies found decreased D2-type dopamine receptor ligand binding in thalamus (Buchsbaum et al., 2006), suggesting that D2-type receptors may be already occupied by dopamine.

Given this convergence of clues, further study of the thalamus is warranted. This may shed light on the particular subparts that are most strongly affected and may potentially explain this selectivity. Localizing a core deficit to the thalamus has one silver lining: this is one of the most studied brain regions; many biophysical, pharmacological, and computational studies provide insight into how this brain region works. There is the real possibility that this insight can be used to rationally design drugs that block the abnormal oscillations.

References:

Andreasen NC (1997) The role of the thalamus in schizophrenia. Can J Psychiatry 42:27-33. Abstract

Boutros NN, Arfken C, Galderisi S, Warrick J, Pratt G, Iacono W (2008) The status of spectral EEG abnormality as a diagnostic test for schizophrenia. Schizophr Res 99:225-237. Abstract

Buchsbaum MS, Christian BT, Lehrer DS, Narayanan TK, Shi B, Mantil J, Kemether E, Oakes TR, Mukherjee J (2006) D2/D3 dopamine receptor binding with [F-18]fallypride in thalamus and cortex of patients with schizophrenia. Schizophr Res 85:232-244. Abstract

Buzsaki G (1991) The thalamic clock: emergent network properties. Neuroscience 41:351-364. Abstract

Byne W, Hazlett EA, Buchsbaum MS, Kemether E (2009) The thalamus and schizophrenia: current status of research. Acta Neuropathol 117:347-368. Abstract

Clinton SM, Meador-Woodruff JH (2004) Thalamic dysfunction in schizophrenia: neurochemical, neuropathological, and in vivo imaging abnormalities. Schizophr Res 69:237-253. Abstract

Ferrarelli F, Huber R, Peterson MJ, Massimini M, Murphy M, Riedner BA, Watson A, Bria P, Tononi G (2007) Reduced sleep spindle activity in schizophrenia patients. Am J Psychiatry 164:483-492. Abstract

Ferrarelli F, Peterson MJ, Sarasso S, Riedner BA, Murphy MJ, Benca RM, Bria P, Kalin NH, Tononi G (2010) Thalamic dysfunction in schizophrenia suggested by whole-night deficits in slow and fast spindles. Am J Psychiatry 167:1339-1348. Abstract

Jeanmonod D, Schulman J, Ramirez R, Cancro R, Lanz M, Morel A, Magnin M, Siegemund M, Kronberg E, Ribary U, Llinas R (2003) Neuropsychiatric thalamocortical dysrhythmia: surgical implications. Neurosurg Clin N Am 14:251-265. Abstract

Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB, Jr., Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199-214. Abstract

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Steriade M, Domich L, Oakson G, Deschenes M (1987) The deafferented reticular thalamic nucleus generates spindle rhythmicity. J Neurophysiol 57:260-273. Abstract

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Thalamic reticular nucleus and schizophrenia
Ferrarelli et al. examine the occurrence of slow and fast sleep spindles and slow-wave activity in schizophrenia. The authors clearly observed a general decrease in spindle number, amplitude, duration, and integrated activity that was not related to any pharmacological treatment. No change was observed in slow-wave activity.

”It is the dialogue between the thalamus and the cortex that generates subjectivity” (p. 532) (Llinas and Paré, 1991). This quotation from 1991 shows that the role of the thalamus in higher integrated processes has been underlined for quite some time, based on sleep-waking research. The paper of Ferrarelli et al. confirms that “sleep offers important advantages for investigating possible dysfunctions in brain circuits in schizophrenia patients” (p. 1) (Ferrarelli et al., 2010). This study of slow-wave sleep features in schizophrenia is paralleled by research devoted to REM sleep. The work by Ferrarelli et al. is very important since it has allowed the identification of an additional possible neurobiological endophenotype of schizophrenia, in continuation of other possible endophenotypes related to REM sleep (Gottesmann, 2006; Gottesmann and Gottesman, 2007) (see also my recent answer to Dr. Sasi’s commentary in the Forum).

Today, it is well established that cortical spindles are of thalamic origin, since now old results have shown that they appear in the thalamus after decortication (Morison and Dempsey, 1943; Morison and Bassett, 1945). More recent studies have determined that the reticular nucleus generates this EEG pattern, since spindles disappear in the thalamus when it is disconnected from the reticular nucleus (Steriade et al., 1985) or by lesion of the latter (Buzsaki et al., 1988). Also, the isolated reticular nucleus generates spindle rhythmicity (Steriade et al., 1987). These spindles spread to other thalamic nuclei and to the cortex. When intracellular recordings are processed in relay nuclei neurons, the spindles occur concomitantly to barrages of inhibitory post-synaptic potentials that occur in synchrony with bursts of action potentials in the neurons of the reticular nucleus (Bal et al., 1995). "The spindle-related spike bursts of reticular nucleus impose rhythmic IPSPs in target thalamic relay neurons, leading to post-inhibitory rebound bursts that are transferred to the cortex." (p. 3293) (Steriade et al., 1993). Inversely, the reticular nucleus is under the influence of ascending influences from the brainstem, of intrathalamic influences, and of influences originating in the cortex and the forebrain basalis nucleus.

The reticular nucleus contains the highest concentration of GABAergic neurons in the brain (Houser et al., 1980; Crunelli and Leresche, 1991). GABA_A and GABA_B receptors are involved in spindle generation and regulation (Krosigk et al., 1993). "The persistence of normal spindle waves despite strong or complete block of GABA_B receptors…indicates that these receptors do not make an essential contribution to the normal generation of spindle waves in thalamic relay cells" (p. 658) (Bal et al., 1995). In contrast, when GABA_A receptors are blocked, the intrinsic frequency of spindles decreases and spike-and-waves are observed; this pattern is similar to that seen in absence epilepsy and is inhibited by cholinergic nucleus basalis stimulation (Buzsaki et al., 1988). GABA_B receptor antagonists suppress this abnormal activity, demonstrating the influence of this receptor on the generation of this pathological rhythm. Indeed, GABA_B receptor antagonists are used as a medication for this disease (Bittiger et al., 1992).

The results of Ferrarelli et al. suggest that the spindle deficit observed in schizophrenic patients is an indication of disinhibitory processes acting in the thalamus. It has already been shown that there is a deficit of sensory gate control in this disease. Indeed, the N₁₀₀ component of the auditory evoked potential shows a disturbed recovery cycle (Kisley et al., 2003), with the prepulse inhibition being decreased. This observation could be directly or indirectly related to the decrease in monoaminergic ascending influences that occurs during sleep (Hobson et al., 1975; McGinty and Harper, 1976; Aston-Jones and Bloom, 1981a; Rasmussen et al., 1984). These influences are mainly inhibitory (Krnjevic and Phillis, 1963; Nelson et al., 1973; Reader et al., 1979; Araneda and Andrade, 1991), although noradrenaline and serotonin are known to increase the signal/noise ratio of neuron activity (Foote et al., 1975; Aston-Jones and Bloom, 1981b; McCormick, 1992). This sensory impairment is known to favor hallucinations (Behrendt and Young, 2005), and a monoaminergic deficit has previously been demonstrated in schizophrenia (Friedman et al., 1999; Silver et al., 2000; Linner et al., 2002; Van Hes et al., 2003).

To conclude, the most important result of this paper is the identification of an additional electroencephalographic deficit in schizophrenia. This deficit could represent a new endophenotype of this mental disease. The future elucidation of the genetic basis of this specific electrophysiological activity could contribute to new methods of curing and possibly preventing the appearance of schizophrenic symptoms, first by pharmacological and then by genetic therapy.

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