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Pinault D. The thalamic reticular nucleus: structure, function and concept. Brain Res Brain Res Rev. 2004 Aug ; 46(1):1-31. Pubmed Abstract

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Related News: A New Case for Thalamic Dysfunction in Schizophrenia

Comment 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.

References:
Behrendt RP (2006) Dysregulation of thalamic sensory "transmission" in schizophrenia: neurochemical vulnerability to hallucinations. J Psychopharmacol 20:356-372. Abstract

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

Cronenwett WJ, Csernansky J (2010) Thalamic pathology in schizophrenia. Curr Top Behav Neurosci 4:509-528. 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

Guillery RW, Sherman SM (2002) Thalamic relay functions and their role in corticocortical communication: generalizations from the visual system. Neuron 33:163-175. Abstract

Guller Y, Ferrarelli F, Shackman AJ, Sarasso S, Peterson MJ, Langheim FJ, Meyerand ME, Tononi G, Postle BR (2012) Probing Thalamic Integrity in Schizophrenia Using Concurrent Transcranial Magnetic Stimulation and Functional Magnetic Resonance Imaging. Arch Gen Psychiatry (published online March 5, 2012). Abstract

Hakami T, Jones NC, Tolmacheva EA, Gaudias J, Chaumont J, Salzberg M, O'Brien TJ, Pinault D (2009) NMDA receptor hypofunction leads to generalized and persistent aberrant gamma oscillations independent of hyperlocomotion and the state of consciousness. PLoS One 4:e6755. Abstract

Harms MP, Wang L, Mamah D, Barch DM, Thompson PA, Csernansky JG (2007) Thalamic shape abnormalities in individuals with schizophrenia and their nonpsychotic siblings. J Neurosci 27:13835-13842. Abstract

Ibrahim HM, Hogg AJ, Jr., Healy DJ, Haroutunian V, Davis KL, Meador-Woodruff JH (2000) Ionotropic glutamate receptor binding and subunit mRNA expression in thalamic nuclei in schizophrenia. Am J Psychiatry 157:1811-1823. Abstract

Insel TR (2010) Rethinking schizophrenia. Nature 468:187-193. Abstract

Jones EG (2007) The Thalamus. 2nd ed. Cambridge, England: Cambridge University Press.

Kulikova S, Gaudias J, Tolmacheva EA, Brendan EA, Zheng T, Pinault D (2011) Disruption of the thalamocortical signal-to-noise ratio in the pathogenesis of psychoses. Abstract

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Pinault D (2004) The thalamic reticular nucleus: structure, function and concept. Brain Res Rev 46:1-31. Abstract

Pinault D, Slezia A, Acsady L (2006) Corticothalamic 5-9 Hz oscillations are more pro-epileptogenic than sleep spindles in rats. J Physiol 574:209-227. Abstract

Pinault D (2008) N-methyl d-aspartate receptor antagonists ketamine and MK-801 induce wake-related aberrant gamma oscillations in the rat neocortex. Biol Psychiatry 63:730-735. Abstract

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