A New Case for Thalamic Dysfunction in Schizophrenia
20 March 2012. Despite the current emphasis on identifying genetic lesions in schizophrenia, there are still researchers asking, Where in the brain is schizophrenia? A University of Wisconsin-Madison study, published online March 5 in the Archives of General Psychiatry, presents evidence that the reticular nucleus of the thalamus is one site that exhibits abnormal activity in people with schizophrenia.
As with other brain regions involved directly or indirectly in higher cognitive functions, the thalamus has periodically come under scrutiny in schizophrenia research. However, most findings that thalamic nuclei are structurally different or functionally abnormal in schizophrenia have been inconclusive or indirectly assessed.
In their new study, Yelena Guller and colleagues circumvent the methodological limitations of these earlier studies. Healthy controls and schizophrenia subjects received single-pulse transcranial magnetic stimulation (spTMS) to the precentral gyrus and concurrent functional magnetic resonance imaging (fMRI) to measure the response in the thalamus, medial superior frontal cortex, and insula. Subjects with schizophrenia showed reduced response in the thalamus and the cortical regions compared with controls. The functional anatomy of the thalamus suggests that the source of the abnormal response is the thalamic reticular nucleus, write the authors.
Troubled sleep in the inner chamber
The thalamus (Greek for "inner chamber" or "bedroom") acts as a relay center between subcortical areas and the cortex, plays a role in sleep regulation, arousal, and attention, and may act as a “filter” of salient and non-salient information. There is some support from disparate fields for a role of the thalamus and thalamus-related networks in the neurobiology of schizophrenia (see, e.g., Lisman, 2011). For example, Guller and colleagues note that some neuroimaging studies have reported both structural and functional differences in the thalamus between groups of people with schizophrenia and controls. Also, some studies of sensory gating, thought to involve the thalamus, find aberrant responses in people with schizophrenia.
The current research grows out of studies by coauthor Giulio Tononi, who has found that people with schizophrenia have fewer and smaller sleep spindles, waxing and waning oscillations on EEG that are initiated by the thalamic reticular nucleus (TRN) and regulated by TRN-thalamus and thalamocortical circuits (see Ferrarelli et al., 2010 and comments by Lisman, Zhang, and Otmakhova and Gottesmann). However, Guller and colleagues acknowledge that these studies, as with the imaging and sensory gating research, are limited by their inferential nature—they either do not directly assess thalamic function (or dysfunction), or they assume that the brains of people with schizophrenia perform behavioral tasks in the same way as control subjects.
Simple and direct brings results
To get around these limitations, Guller and colleagues designed an experiment in which they stimulated the cortex directly using spTMS during concurrent fMRI to measure any resulting effect on thalamus and downstream cortical areas. Unlike repetitive TMS, the authors write, spTMS “transiently excites discrete cortical patches without producing prolonged changes in cortical excitability or function.”
Although they are measuring the activity of multiple thalamic regions with fMRI, Guller and colleagues argue that one can presume to be measuring, to a great extent, TRN activity when stimulating cortex and recording in thalamus. TRN synaptic excitation makes up a very large portion of overall excitatory activity in thalamus in response to cortical stimulation.
Guller and colleagues tested 14 psychiatrically healthy subjects and 14 sex- and age-matched subjects with chronic, stable schizophrenia. As for choice of TMS stimulation target, the researchers selected the precentral gyrus, which is not known to be dysfunctional in schizophrenia.
Responses of schizophrenia subjects and healthy controls to spTMS at the cortical stimulation site (precentral gyrus) did not differ. However, thalamic responses were smaller (F1,26 = 80.79; P = 1.86 x 10-9; π2 = 0.762) and earlier peaking (F1,26 = 4.39; P = 0.05; π2 = 0.14) for schizophrenia subjects compared with healthy controls. Likewise, schizophrenia subjects showed a smaller magnitude of responses in a cortical region that was activated by the precentral gyrus stimulation, the medial superior frontal gyrus (mSFG; F1,26 = 6.56; P = 0.02; π2 = 0.20). Guller and colleagues explored possible factors underlying this difference and found schizophrenia subjects to have reduced functional connectivity between the thalamus and mSFG ((F1,26 = 32.00; P = 6.0 x 10-5; π2 = 0.55) relative to control subjects. The researchers found similar results in another activated cortical area, the insula.
According to the researchers, discriminant analysis showed that spTMS correctly identified members of the two groups (Χ2 = 36.0; P = 1.95 x 10-9; sensitivity = 85.7 percent; specificity = 100 percent; overall classification accuracy = 92.9 percent). Sham TMS showed the results could not be attributed to TMS coil discharge, and control analyses using chronicity, medication, and education factors did not predict any of the results.
The possibility that physiological abnormality of the stimulated cortical tissue accounted for the results was dismissed by Guller and colleagues, because there was no response difference between the groups at the placement of the spTMS. They also note that deficient corticothalamic signal propagation was unlikely because thalamus-precentral gyrus connectivity did not differ between the groups. “The most likely interpretation, therefore," the researchers write, "is that our results reflect aberrant functioning of the thalamus itself….”, and they suggest that future studies should examine whether this deficit more specifically stems from TRN dysfunction.—J. Meggin Hollister and Hakon Heimer.
Guller Y, Ferrarelli F, Shackman AJ, Sarasso S, Peterson MJ, Langheim FJ, Meyerand ME, Tononi G, Postle BR. Probing Thalamic Integrity in Schizophrenia Using Concurrent Transcranial Magnetic Stimulation and Functional Magnetic Resonance Imaging. Arch Gen Psychiatry . 2012 Mar 5. Abstract
Comments on News and Primary Papers
Primary Papers: Probing Thalamic Integrity in Schizophrenia Using Concurrent Transcranial Magnetic Stimulation and Functional Magnetic Resonance Imaging.Comment by: Zoran Vukadinovic
Submitted 23 March 2012
Posted 23 March 2012
I recommend this paper
In their recent article, Guller et al. demonstrated that, in individuals with schizophrenia, TMS stimulation of the precentral gyrus results in reduced activation of the thalamus, and, subsequently, of certain cortical regions (medial superior frontal cortex and insula) as measured by fMRI. This finding is consistent with earlier reports by the same group (Ferrarelli et al., 2007; 2010) that sleep spindles are reduced in this illness. Namely, sleep spindles are a brain rhythm seen in stages 2 and 3 of non-rapid eye movement sleep that is initiated by high-frequency discharges of cortical cells during “up” states of the slow cortical oscillations in slow-wave sleep (Steriade, 2006). The generation of sleep spindles subsequently involves the thalamic reticular nucleus (TRN) and the rest of the thalamus, and further thalamocortical interactions as the spindle activity spreads. In summary, sleep spindles constitute a form of trans-thalamic cortico-cortical interaction, and their reduction in schizophrenia suggests an impairment in these interactions (see Vukadinovic, 2011; Vukadinovic and Rosenzweig, 2012). This is in agreement with the findings of Guller et al.
Importantly, Sherman and Guillery (2006) have pointed out that some parts of the thalamus, the so-called higher-order (HO) nuclei, are concerned with relay of cortical signals to other cortical areas, and to describe the potential importance of the HO nuclei in the thalamus, they have coined the term "trans-thalamic cortico-cortical interactions." Moreover, this suggests a role for the thalamus in internal motor monitoring, which has been proposed to be impaired in schizophrenia (Feinberg, 2011). All of these findings together raise the possibility that thalamic abnormalities in schizophrenia (see also Byne et al., 2009)—the reported sleep abnormalities as well as proposed internal motor monitoring deficits—are related and involve impaired trans-thalamic cortico-cortical interactions in this illness. The Guller et al. study lends further evidence to this hypothesis. It is interesting that in schizophrenia, the HO thalamic nuclei have been found to be affected to a greater extent compared to first-order nuclei, which are primarily concerned with the relay of sensory inputs (see Byne et al., 2009).
In their report, Guller et al. also raise the possibility that a defect in the TRN may account for the observed reduced thalamic activation in response to cortical TMS stimulation. As the TRN is also important for the generation of sleep spindles, is there an abnormality that is associated with schizophrenia that could provide clues to what the specific defect in the TRN may be? In a recent review (Vukadinovic and Rosenzweig, 2012), Rosenzweig and I raised the possibility that recently reported overexpression of the KCNH2-3.1 isoform of the ether-a-go-go (ERG) potassium channel in schizophrenia (Huffaker et al., 2009) may be behind the reduction in sleep spindles, and also possibly behind the proposed reduced ability of the thalamus in schizophrenia to support the trans-thalamic cortico-cortical communication. Namely, the overexpressed isoform of the ERG channel results in reduced outward potassium channels that enable sustained hyperpolarization following periods of intense excitatory neuronal stimulation (Shepard et al., 2007). In the case of the TRN neurons, which have been found to express the ERG channels, KCNH2-3.1 overexpression would result in reduced ability to remain hyperpolarized, and, consequently, also in reduced post-inhibitory rebound burst firing, which is important for spindle initiation (see Vukadinovic, 2012). This same firing mode in the thalamus may also be important for the trans-thalamic cortico-cortical communication (Ramcharan et al., 2005). More specifically, the burst firing mode in the thalamus involves opening of T-type calcium channels, which tend to open at more negative membrane potentials, and, therefore, impaired ability to remain hyperpolarized would also be expected to lead to reduced opening of these channels.
Thus, in summary, the recent evidence provides further insights into an old idea that schizophrenia may be a disconnection syndrome. Importantly, we are now in the position to make hypotheses about the brain regions involved (i.e., higher-order thalamic nuclei) as well as about the specific genes involved (KCNH2-3.1 overexpression).
Byne W, Hazlett EA, Buchsbaum MS, Kemether E. The thalamus and schizophrenia: current status of research. Acta Neuropathol . 2009 Apr ; 117(4):347-68. Abstract
Feinberg I. Corollary discharge, hallucinations, and dreaming. Schizophr Bull . 2011 Jan ; 37(1):1-3. Abstract
Ferrarelli F, Huber R, Peterson MJ, Massimini M, Murphy M, Riedner BA, Watson A, Bria P, Tononi G. Reduced sleep spindle activity in schizophrenia patients. Am J Psychiatry . 2007 Mar ; 164(3):483-92. Abstract
Ferrarelli F, Peterson MJ, Sarasso S, Riedner BA, Murphy MJ, Benca RM, Bria P, Kalin NH, Tononi G. Thalamic dysfunction in schizophrenia suggested by whole-night deficits in slow and fast spindles. Am J Psychiatry . 2010 Nov ; 167(11):1339-48. Abstract
Guller Y, Ferrarelli F, Shackman AJ, Sarasso S, Peterson MJ, Langheim FJ, Meyerand ME, Tononi G, Postle BR. Probing Thalamic Integrity in Schizophrenia Using Concurrent Transcranial Magnetic Stimulation and Functional Magnetic Resonance Imaging. Arch Gen Psychiatry . 2012 Mar 5. Abstract
Huffaker SJ, Chen J, Nicodemus KK, Sambataro F, Yang F, Mattay V, Lipska BK, Hyde TM, Song J, Rujescu D, Giegling I, Mayilyan K, Proust MJ, Soghoyan A, Caforio G, Callicott JH, Bertolino A, Meyer-Lindenberg A, Chang J, Ji Y, Egan MF, Goldberg TE, Kleinman JE, Lu B, Weinberger DR. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nat Med . 2009 May ; 15(5):509-18. Abstract
Ramcharan EJ, Gnadt JW, Sherman SM. Higher-order thalamic relays burst more than first-order relays. Proc Natl Acad Sci U S A . 2005 Aug 23 ; 102(34):12236-41. Abstract
Shepard PD, Canavier CC, Levitan ES. Ether-a-go-go-related gene potassium channels: what's all the buzz about? Schizophr Bull . 2007 Nov ; 33(6):1263-9. Abstract
Sherman S.M., Guillery R.W., Exploring the Thalamus and Its Role in Cortical Function, 2nd ed., The MIT Press, Cambridge MA, 2006.
Steriade M. Grouping of brain rhythms in corticothalamic systems. Neuroscience . 2006 ; 137(4):1087-106. Abstract
Vukadinovic Z. Sleep abnormalities in schizophrenia may suggest impaired trans-thalamic cortico-cortical communication: towards a dynamic model of the illness. Eur J Neurosci . 2011 Oct ; 34(7):1031-9. Abstract
Vukadinovic Z, Rosenzweig I. Abnormalities in thalamic neurophysiology in schizophrenia: could psychosis be a result of potassium channel dysfunction? Neurosci Biobehav Rev . 2012 Feb ; 36(2):960-8. Abstract
Vukadinovic Z., Similarities between cortical up states during slow wave sleep and wakefulness: the implications for schizophrenia, Translational Neuroscience, 2012, 3(1), 51-55.
View all comments by Zoran VukadinovicComment by: Didier Pinault
Submitted 28 March 2012
Posted 1 April 2012
I recommend the Primary Papers
Schizophrenia and Thalamus Dysfunction
The pathophysiology of schizophrenia still conceals many secrets (Meyer-Lindenberg, 2010; Insel, 2010), which is the reason why the neurobiology of schizophrenia is the relentless object of experimental and clinical investigations. These point out that schizophrenia is a complex, multifunctional disorder involving dysfunctional networks.
Guller and colleagues recently published, in the Archives of General Psychiatry (published online March 5, 2012), clinical data in favor of the hypothesis of thalamic dysfunction in schizophrenia. The authors’ objective was to test the hypothesis that the thalamus of patients with schizophrenia responds abnormally to cortical activation. The authors used fMRI to record in healthy subjects and patients with schizophrenia the vascular response in their cerebral cortex (medial superior frontal cortex [mSFC] and insula) and thalamus following a single pulse TMS (spTMS) of the precentral gyrus. The authors recorded a reduced hemodynamic response in the thalamus, mSFC, and insula in the patients. Taken together, these results reveal abnormal decreases in thalamus-mSFC and thalamus-insula functional connectivity. The authors conclude that the thalamus contributes to the patterns of aberrant connectivity, a central feature of schizophrenia. This interesting study opens up new vistas, leaving a certain number of questions open.
What are the corticothalamic (CT)-induced neural mechanisms underlying the thalamic hemodynamic response?
No definitive answer can be given since the TMS-induced effects depend on many factors, including TMS protocol, the cortical target, and state, as previously demonstrated by the same research team (Massimini et al., 2007; 2010). The subjects of the study by Guller et al. were awake with open eyes. During wakefulness, TMS evokes a time-locked high-frequency (20-35 Hz) sustained EEG oscillation during the first 100 ms (Massimini et al., 2010). Such a cortically evoked, short-lasting oscillation is expected to reflect simultaneous waves of excitation and inhibition in the CT/thalamocortical (TC) systems. On the other hand, the neural mechanisms underlying the slowness of the BOLD neuro-glio-vascular response remain elusive.
Let us consider the appealing concept of “grouping of brain rhythms in CT systems” (Steriade, 2006). Indeed, the grouping of brain rhythms in CT/TC systems is the result of interplays between synaptic and intrinsic properties of the corresponding neural excitatory and inhibitory elements. Such functional-anatomic interactions would thus generate state-dependent complex wave sequences, which are readily apparent in spontaneously occurring cortical EEG. Therefore, it is tempting to suggest that every spTMS evoked both excitation and inhibition in the target cortical area with their respective amount and time course, which would subsequently modulate the activity of local and distant structures, including the thalamus potentially inducing the BOLD response. The CT-induced activity pattern depends on the anatomical and electrophysiological properties of the engaged nerve elements. Among the most responsive thalamic elements to CT activation are the GABAergic thalamic reticular nucleus (TRN) neurons (Pinault, 2004). TRN cells can behave like resonators. For instance, in the awake rat, it was demonstrated that, during natural CT 5-9 Hz oscillations, TRN cells start to fire with robust, high-frequency bursts of action potentials in a rhythmic manner and almost always do so before TC neurons (Pinault, 2003). It is worth specifying that the intracellular events underlying CT 5-9 Hz and TC spindle oscillations are distinctively different in thalamic neurons (Pinault et al., 2006). The rodent CT 5-9 Hz oscillation emerges during quiet, immobile wakefulness and is thought to be a sensorimotor rhythm, and it may be the equivalent of the alpha rhythm of the human occipital cortex.
What are the mechanisms underlying the smaller thalamic hemodynamic response in patients with schizophrenia?
Guller and colleagues think that the structural abnormalities observed in the thalamus of patients with schizophrenia and the functional-anatomical properties of the thalamo-reticular (TC-TRN) system account for its dysfunction, reflected in their results by the smaller spTMS-induced vascular response (Guller et al., 2012) and by a deficit in sleep spindles (Ferrarelli et al., 2007; 2010). Moreover, structural, metabolic, and neurochemical changes (Clinton and Meador-Woodruff, 2004; Harms et al., 2007; Popken et al., 2000) and abnormalities in the expression of glutamate receptors (Ibrahim et al., 2000) were observed in the brains of patients with schizophrenia.
Assuming that the functional-anatomical properties of thalamic circuits are severely affected in schizophrenia, the impact would be major. Indeed, one cannot think about the thalamus without thinking about the cerebral cortex and vice versa, since they are reciprocally connected and work in tandem to generate physiological and pathological rhythms (Steriade and Deschenes, 1984; Steriade and Llinas, 1988). Both the neocortex and the thalamus and their related CT/TC circuits are prominently involved in the same global brain operations (consciousness, perception, and cognition). The thalamus also innervates the striatum, amygdala, and hippocampus (Lisman et al., 2010). Postmortem and high-resolution functional-anatomical studies support the hypothesis of dysfunctional CT/TC and basal ganglia networks in patients with schizophrenia (Cronenwett and Csernansky, 2010; Clinton and Meador-Woodruff, 2004).
The thalamus relays sensorimotor and higher-order information to the cerebral cortex and plays a key role in large-scale cortico-cortical communication (Guillery and Sherman, 2002). The thalamus is reciprocally connected not only with the cerebral cortex, but also with the TRN. The TC and CT neurons are glutamatergic and cross the TRN, wherein they give off axon collaterals (Jones, 2007). The TRN contains only GABAergic neurons, which project to the dorsal thalamus (Pinault, 2004). The firing pattern (single-action potential or high-frequency burst of APs) of TC and TRN neurons is state and voltage dependent. Pathological changes in the firing pattern of thalamic neurons might involve, among many other factors (Pinault, 2011), potassium channel dysfunction (Vukadinovic and Rosenzweig, 2012).
The TRN is a thin GABAergic layer interface strategically located between the thalamus and the neocortex. It is more than the mediator of selective attention (Pinault, 2004). It works like a combinatorial matrix since it holds and can combine all functional, sensorimotor, limbic, and cognitive modalities. Furthermore, it is endowed with extraordinary intrinsic oscillatory properties. TRN cells work like integrators under the leading influence of CT inputs. Of importance, although the thalamus and the TRN are reciprocally connected, this anatomical rule does not apply at the cellular level. Indeed, TRN and TC neurons principally form two-neuron, open-loop circuits, meaning that they do not form reciprocal connections (Pinault and Deschenes, 1998). The functioning principle of such open GABAergic-glutamatergic circuits is lateral inhibition, which allows the relaying of relevant streams of information to the neocortex and the deletion of distracting activities during brain operations. Disruption of thalamic lateral inhibition is thought to contribute to a lack of coordination between neuronal assemblies, as observed in schizophrenia (Pinault, 2011).
The thalamic abnormalities observed in the brains of patients with schizophrenia might cause abnormally excessive, ongoing noisy activities in TC circuits (Behrendt, 2006), which would prominently disrupt thalamic lateral inhibitions (Pinault, 2011) and subsequently impair the ability of TC networks to discriminate relevant information from such ongoing distracting activities (Pinault, 2008; Hakami et al., 2009; Kulikova et al., 2011).
Is the amplitude of the thalamic neuro-glio-vascular response a signature of clinical symptoms?
Guller and colleagues emphasize that the observed changes in sleep spindles (Ferrarelli et al., 2010) and in the amplitude of the thalamic hemodynamic response (Guller et al., 2012) may be related to clinical symptoms, in particular, to positive symptoms. Both the thalamus and the neocortex work under the influence of neuromodulatory inputs from the forebrain and brainstem. Disorders in neuromodulatory transmission might generate excessive TC background activity, subserving, for instance, the emergence of hallucinations (Behrendt, 2006) and impairing information processing in CT/TC circuits. So, one may wonder whether or not schizophrenia-related thalamic anatomo-functional abnormalities are secondary to dysfunctional pre-thalamic (e.g., neuromodulatory) inputs.
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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
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View all comments by Didier Pinault
Primary Papers: Probing Thalamic Integrity in Schizophrenia Using Concurrent Transcranial Magnetic Stimulation and Functional Magnetic Resonance Imaging.
Comment by: John Lisman
Submitted 2 April 2012
Posted 5 April 2012
The recent paper by Guller et al. provides evidence that schizophrenia produces a large and systematic change in the ability of cortical stimulation (by TMS) to increase BOLD activity in the thalamus (Guller et al., 2012). As pointed out by Guller et al., this adds to the growing list of evidence for a thalamic abnormality in schizophrenia. The most direct evidence is the observation of a size abnormality of the thalamus in schizophrenia (Brickman et al., 2004; Konick and Friedman, 2001). In addition, functions such as sensory gating and EEG sleep spindles (Ferrarelli and Tononi, 2011; Krause et al., 2003), which are thought to be regulated by the thalamus, are abnormal in schizophrenia. However, an additional line of evidence not mentioned by Guller et al. is of particular importance. This relates to the often replicated finding that delta oscillations of the sort that normally occur during slow-wave sleep have increased power in schizophrenia (Boutros et al., 2008). These oscillations are produced in subregions of the thalamocortical system. Of particular note, NMDAR antagonists, which mimic many symptoms of schizophrenia, can also mimic the delta oscillation abnormality (Buzsaki, 1991; Zhang et al., 2012). This has now been shown to be due to an action of the NMDAR antagonist on NR2C in the thalamus (Zhang et al., 2009). Given that delta oscillations do not allow either the cortex or thalamus to operate in a way characteristic of the normal awake state, these oscillations may well be on the causal chain to produce the major symptoms of the disease. Consistent with a direct role of delta oscillations in the disease, there is a good correlation of the delta abnormality with the disease itself (Venables et al., 2009). In contrast, most of other measures of the disease (e.g., high-frequency oscillations or prepulse inhibition) are endophenotypes, meaning that they indicate a predisposition to the disease (seen also in unaffected relatives), and thus do not correlate with the disease itself. Given the possible causal role of delta, the involvement of the thalamus in delta generation, and the growing evidence of thalamic abnormality in schizophrenia, identifying drugs that reduce thalamic delta generation appears to be an excellent strategy for finding new treatments for the disease.
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View all comments by John Lisman