Published in final edited form as: Neuron 77(6), 997–999. doi: http://dx.doi.org/10.1016/j.neuron.2013.02.033
Thalamocortical Synchronization and Cognition: Implications for Schizophrenia?
Peter J. Uhlhaas1, 2, 3, *, Frederic Roux4, Wolf Singer2, 3, 5
1 Institute of Neuroscience and Psychology, University of Glasgow, Hillead St. 58, Glasgow, G12 8QB, UK 2 Department of Neurophysiology, Max Planck Institute for Brain Research, Deutschordenstr. 46, Frankfurt
3 Ernst-Strüngmann Institute (ESI) for Neuroscience, in Cooperation with the Max Planck Society,
Deutschordenstr. 46, Frankfurt am Main 60528, Germany
4 Basque Center on Cognition, Brain and Language (BCBL), 20009 San Sebastian -Donostia, Spain 5 Frankfurt Institute for Advanced Studies, Johann Wolfgang Goethe University, Max-von-Laue-St. 1,
* Correspondence: [email protected]
Cognitive deficits are a core dysfunction in schizophrenia. In this issue of Neuron, Parnaudeau et al. (2013)
investigated synchronization in thalamocortical pathways in an animal model to address the disconnection
between brain regions as a mechanism for working memory impairments in the disorder.
Uhlhaas, P. J., Roux, F., Singer, W. (2013) Thalamocortical Synchronization and Cognition: Implications for Schizophrenia? Neuron 77(6), 997-999. doi: http://dx.doi.org/10.1016/j.neuron.2013.02.033 Schizophrenia is a severe psychiatric disorder with a lifetime risk of about 1% that frequently leads to enduring disability for the majority of patients. In addition to the core clinical symptoms of psychosis (delusions, hallucinations, and thought disorder), schizophrenia is associated with a wide range of impairments in cognition, which include working memory (WM), executive control, attention, and dysfunctional sensory processing. Importantly, these dysfunctions are largely immune to current antipsychotic treatments and, as a result, constitute a major determinant for psychosocial functioning and outcome (Green, 1996). The identification of the causes of dysfunctional cognition is, therefore, a prerequisite for the developmental of novel and more effective interventions. The search for the underlying pathophysiological processes has thus far focused on anatomical and functional abnormalities in circumscribed brain regions. This approach has yielded a large body of evidence implicating various brain areas in cognitive deficits, but the precise circuits and mechanisms underlying these dysfunctions have remained elusive. An alternative approach has been the focus on the role of impaired communication between regions in the pathophysiology of schizophrenia, which most likely involves a disconnection of functional networks (Friston, 1998). This hypothesis has received support through findings from noninvasive studies using electro- and magneto-encephalography (EEG/MEG) that demonstrate impaired amplitude and synchrony of neural oscillations at low- and high-frequency ranges in patients with schizophrenia (Uhlhaas and Singer, 2010). This is of particular relevance because a large body of evidence suggests that the functional networks underlying perception, attention, and executive processes rely on dynamic coordination through the phase locking of synchronized oscillations (Varela et al., 2001). Accordingly, impairments in this mechanism could lead to a transient failure in the establishment of functional interactions between brain regions, thereby affecting the associated cognitive processes. In this issue of Neuron, Parnaudeau et al. (2013) investigated the hypothesis that thalamocortical synchronization, in this case, between frontal brain regions and the mediodorsal (MD) thalamus, might play an important role in WM and that disturbed synchrony in this circuit might be responsible for WM impairments in schizophrenia. Thalamic functions have recently received renewed interest in systems neuroscience because of their crucial role in gating communication between cortical areas through the synchronization of neuronal responses (Saalmann et al., 2012). Because anatomical and functional abnormalities have been repeatedly demonstrated in the thalamus of patients with schizophrenia (Ronenwett and Csernansky, 2010), abnormal synchronization in thalamocortical pathways could represent an intriguing pathophysiological mechanism for cognitive impairments. To test this hypothesis, the authors employed a novel pharmacogenetic approach (designer receptors exclusively activated by designer drugs [DREADD]) (Armbruster et al., 2007) that allowed the subtle manipulation of neuronal activity in the MD thalamus, a nuclear complex that projects to the prefrontal cortex and is involved in working memory (Watanabe and Funahashi, 2012). Through the transfection of MD neurons with a mutated muscarinic G protein-coupled receptor, 48% of these neurons could be selectively inhibited by the inert pharmacological compound clozapine-N-oxide (CNO). To examine the effects of reduced responsiveness of MD neurons on thalamocortical synchrony, the authors recorded local field potentials (LFPs) and single units from MD and LFPs from the medial prefrontal cortex (mPFC) and
Uhlhaas, P. J., Roux, F., Singer, W. (2013) Thalamocortical Synchronization and Cognition: Implications for Schizophrenia? Neuron 77(6), 997-999. doi: http://dx.doi.org/10.1016/j.neuron.2013.02.033 dorsal hippocampus. These signals were examined for phase relationships in oscillation frequencies in the theta (4–12 Hz), beta (13–30 Hz), and gamma (40–60 Hz) ranges. In control animals treated with saline, there was an increase of phase locking of MD units with beta-band oscillations in the mPFC during the choice phase of a T-maze task, which requires the online maintenance of information. The specific relationship between WM and enhanced thalamocortical synchronization was demonstrated in a second experiment during which mice passively explored the T-maze. Here, no increase in beta synchronization between MD and mPFC was observed. Additional analyses of phase lags suggested that MD activity modulated mPFC activity. In CNO-treated mice, a decrease of MD-mPFC beta-band synchronization occurred with impaired WM performance at longer delays, whereas power spectra in both MD and mPFC were not changed. Moreover, decreased MD activity also resulted in delayed task acquisition. As task performance improved, functional connectivity between MD and mPFC progressively increased. These findings suggest that thalamocortical synchronization at beta frequencies is functionally related to WM and that a reduction in MD activity reduces connectivity between these two brain regions, leading to impaired task acquisition and maintenance of WM-related information. The study by Parnaudeau et al. (2013) addresses a number of important issues that will be useful for guiding future research on thalamocortical synchronization and its relationship to cognitive functions and dysfunctions. The current data add to the growing body of evidence for an involvement of the thalamus in the synchronization of cortical structures and the importance of temporal coordination for cognitive processes (Saalmann and Kastner, 2011). The frequencies at which these interactions occur are of particular interest. Although previously long-range synchronization during WM between cortical and subcortical structures has been observed at theta-band frequencies (Sigurdsson et al., 2010), increased theta-band synchronization in the current study was only observed during task acquisition and not during the delay phase. Although the precise computational role of beta-band oscillations during WM needs to be elucidated, it is important to note that beta-band-mediated long-range synchronization has been implicated in the maintenance of visuo-spatial WM items (Salazar et al., 2012). Furthermore, long-range synchronization at beta frequencies is prominently impaired in schizophrenia patients (Uhlhaas et al., 2006), highlighting the potential importance of beta-band synchronization during both normal and abnormal cognition. An important aspect of the study by Parnaudeau et al. (2013) is the application of the DREADD approach toward fundamental questions in systems neuroscience. Previous studies that tested the relationship between thalamic and cortical functions relied on lesioning entire thalamic nuclei. The selective downregulation of MD units through a targeted pharmacogenetic manipulation represents a significant advance in the determination of causal relations between the activity of defined neuron groups and behavioral functions. Thus, DREADD provides a complimentary technique to optogenetic approaches that have been successfully applied to test the role of neural synchronization in both normal and abnormal physiological states (Yizhar et al., 2011). The involvement of thalamocortical synchronization in cognitive functions raises a number of interesting issues that are relevant for schizophrenia research. In addition to pronounced impairments in higher
Uhlhaas, P. J., Roux, F., Singer, W. (2013) Thalamocortical Synchronization and Cognition: Implications for Schizophrenia? Neuron
77(6), 997-999. doi: http://dx.doi.org/10.1016/j.neuron.2013.02.033
cognitive functions, schizophrenia is also associated with marked abnormalities in basic sensory processing
(Javitt, 2009). Because of the crucial role of the thalamus in gating sensory responses and attention
(Saalmann and Kastner, 2011), it appears promising to also investigate the impact of abnormal thalamic
activity on basic perceptual processes and the associated modulation of neural synchrony. Such
investigations ideally should be combined with noninvasive measurements in patient populations, because
this would allow for the testing of specific pathophysiological hypotheses and the validation of findings
from animal models. However, EEG/MEG measurements of thalamocortical interactions remain
In conclusion, the authors have provided convincing support for a concept that attributes the impairment of
cognitive functions in schizophrenia to the disconnection of functional networks through impaired neural
synchronization. The established links with related findings from patient samples should encourage efforts
to further explore the underlying causes of abnormal synchronization. These are likely to be heterogeneous,
but, once identified, it is likely that more effective therapeutic interventions can be designed.
This work was supported by the Max Planck Society and a LOEWE grant from der Neuronale Koordination
Forschungsschwerpunkt Frankfurt. References
Armbruster, B.N., Li, X., Pausch, M.H., Herlitze, S., and Roth, B.L. (2007). Proc. Natl. Acad. Sci. USA 104, 5163–5168.
Friston, K.J. (1998). Schizophr. Res. 30, 115–125. Green, M.F. (1996). Am. J. Psychiatry 153, 321–330.
Javitt, D.C. (2009). Annu. Rev. Clin. Psychol. 5, 249–275.
Parnaudeau, S., O’Neill, P.K.,Bolkan, S.,Ward, R.D., Abbas, A.I.,Roth, B.L.,Balsam, P.,Gordon, J.A., and Kellendonk, C. (2013). Neuron 77, this issue, 1151– 1162.
Ronenwett, W.J., and Csernansky, J. (2010). Curr. Top Behav. Neurosci. 4, 509–528.
Saalmann, Y.B., and Kastner, S. (2011). Neuron 71, 209–223.
Saalmann, Y.B., Pinsk, M.A., Wang, L., Li, X., and Kastner, S. (2012). Science 337, 753–756.
Salazar, R.F., Dotson, N.M., Bressler, S.L., and Gray, C.M. (2012). Science 338, 1097–1100.
Sigurdsson, T., Stark, K.L., Karayiorgou, M., Gogos, J.A., and Gordon, J.A. (2010). Nature 464, 763–767.
Uhlhaas, P.J., and Singer, W. (2010). Nat. Rev. Neurosci. 11, 100–113.
Uhlhaas, P.J., Linden, D.E., Singer, W., Haenschel, C., Lindner, M., Maurer, K., and Rodriguez, E. (2006). J. Neurosci. 26, 8168–8175.
Varela, F., Lachaux, J.P., Rodriguez, E., and Martinerie, J. (2001). Nat. Rev. Neurosci. 2, 229–239.
Watanabe, Y., and Funahashi, S. (2012). Neurosci. Biobehav. Rev. 36, 134–142.
Uhlhaas, P. J., Roux, F., Singer, W. (2013) Thalamocortical Synchronization and Cognition: Implications for Schizophrenia? Neuron 77(6), 997-999. doi: http://dx.doi.org/10.1016/j.neuron.2013.02.033 Yizhar, O., Fenno, L.E., Davidson, T.J., Mogri, M., and Deisseroth, K. (2011). Neuron 71, 9–34.
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FRANCO CORELLI REPERTOIRE AND PERFORMANCE HISTORY This document arranges Corelli’s performance chronology by composer and role. Detailsfor concert and recital appearances have been more difficult to obtain than for completeopera performances, and indeed, the programmes for many recitals are known only becausethey were recorded. The dates of performances that were recorded are indicated in