- Email: [email protected]
Understanding the role of thalamic circuits in schizophrenia neuropathology
SCHRES-07073; No of Pages 3 Schizophrenia Research xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Invited commentary
Understanding the role of thalamic circuits in schizophrenia neuropathology☆ Alan Anticevic Department of Psychiatry, Yale University, United States Department of Psychology, Yale University, United States
a r t i c l e
i n f o
Article history: Received 24 November 2016 Received in revised form 28 November 2016 Accepted 28 November 2016 Available online xxxx
© 2016 Published by Elsevier B.V.
Guest editorial, The complexity of schizophrenia symptoms has presented a major challenge for delineating neural circuits that may map onto underlying pathophysiological mechanism and in turn developed into viable biomarkers that can track illness risk, disease progression, and ultimately treatment response. It is now generally appreciated that schizophrenia is a ‘dysconnection’ syndrome (Stephan et al., 2009) whereby distributed large-scale neural circuits exhibit altered patterns of information flow (Woodward et al., 2012). Yet, it remains challenging to define any particular set of regions or networks as specifically associated with schizophrenia onset, progression and treatment response. The thalamus has offered a unique translational opportunity to map neural alterations in patients with schizophrenia. Examining functional and structural features of thalamic circuits capitalizes on key properties of this area. First, thalamic nuclei are topographically connected to the entire cortex and striatum (Behrens et al., 2003; Zhang et al., 2010), forming a major element of parallel cortico-thalamic-striatal-cortical (CTSC) loops. Therefore, thalamic circuits may be particularly sensitive to brain-wide disturbances that occur in schizophrenia (Andreasen, 1997). Second, the thalamus contains segregated nuclei, providing a method for probing parallel yet distributed large-scale alterations that may occur along distinct neural systems. Third, thalamic nuclei can be reliably identified using modern neuroimaging technology, allowing detailed functional and structural studies of this structure (Fischl et al.,
☆ DISCLOSURES: Dr. Anticevic is a consultant and a member of the SAB for BlackThorn Therapeutics E-mail address: [email protected].
2002). Finally, thalamic circuits have featured prominently in theoretical models of schizophrenia, given its critical role in both sensory and higher-order cognitive functions (Barch and Ceaser, 2012), as well as their focal interaction with a variety of neurotransmitter systems, such as dopamine, glutamate and γ-Aminobutyric acid (GABA) (Abi-Dargham, 2014; Coyle, 2006; Howes et al., 2015; Krystal et al., 2003). These reasons notwithstanding, neural disturbances in schizophrenia are likely not exclusively confined to thalamic circuits. In fact, there is good evidence that distributed cortical areas and networks are profoundly altered in patients suffering from schizophrenia (Baker et al., 2014). Instead, an alternative perspective could consider the thalamus as a central nexus point of distributed information flow and therefore a preferentially ‘fragile’ brain region that communicates with distributed neural systems, which may consequently be particularly affected in schizophrenia. In line with this hypothesis, several investigations have reported altered thalamo-cortical information flow in chronic SCZ (Anticevic et al., 2014; Klingner et al., 2014; Welsh et al., 2010; Woodward et al., 2012). Similar patterns were replicated in individuals who are at clinically elevated risk for developing psychosis (i.e. the schizophrenia prodrome (Anticevic et al., 2015)), ruling out the possibility that this effect is driven by illness chronicity or long-term medication effects. Similarly, animal models have repeatedly implicated thalamic dysfunction as one central mechanism for occurrence of cognitive deficits (Wells et al., 2016), which are a hallmark feature of schizophrenia spectrum disorders that is closely tied to functional outcome (Glahn et al., 2007; Michalopoulou et al., 2013; Reichenberg and Harvey, 2007; Reichenberg et al., 2009). Collectively, these lines of evidence suggest the importance of understanding the role of thalamic circuits in schizophrenia neuropathology as it may present a sensitive
http://dx.doi.org/10.1016/j.schres.2016.11.044 0920-9964/© 2016 Published by Elsevier B.V.
Please cite this article as: Anticevic, A., , Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.11.044
2
A. Anticevic / Schizophrenia Research xxx (2016) xxx–xxx
point of disruption with rich translational opportunities for developing a family of biomarkers across the schizophrenia spectrum and perhaps other neuropsychiatric conditions (Schmitt and Halassa, 2016). In an attempt to help achieve this goal, the “Pathologies of the Thalamus in Schizophrenia” Special Issue features a combination of empirical and review manuscripts detailing what we consider state-of-the-art understanding of thalamic alterations in schizophrenia. The featured articles span review papers on thalamic neurobiology as well as evidence for its disruption in schizophrenia from a structural, functional and genetic perspective. First, Pratt and colleagues review the central role of the thalamus as a possible window into the origins of schizophrenia by considering its interplay with cortex, its reliance on glutamatergic neurotransmission, and its vital role in generating neural oscillations (Pratt et al., 2016), which are disrupted in schizophrenia (Lisman, 2012; Uhlhaas, 2013; Uhlhaas et al., 2013). Next, Pergola et al. present new evidence for gray matter thalamic volume alterations and associations of such disruptions with familial risk for schizophrenia (Pergola et al., 2016), suggesting a genetic basis for thalamic structural alterations. This is followed by related empirical work from Cobia and colleagues, which details longitudinal structural thalamic alterations that were most prominent for higher order associative thalamic nuclei (Cobia et al., 2016). Dorph-Petersen & Lewis in turn review post-mortem work detailing thalamic structural alterations in schizophrenia (DorphPetersen and Lewis, 2016). Next, Ferrarelli & Tononi consider a key functional property of the thalamus and its particular involvement in schizophrenia – namely the thalamic reticular nucleus (TRN) that forms a layer of GABA cells wrapped around the central thalamic nuclei. Their piece articulates the functional role of the TRN for generating thalamic inhibition and how altered TRN function points to alterations between higher-order thalamic nuclei and prefrontal cortex in schizophrenia (Ferrarelli and Tononi, 2016). Young & Wimmer expand on this topic by considering TRN impairment in schizophrenia in relation to cognitive disturbances and sleep alterations (Young and Wimmer, 2016). Dandash and colleagues discuss the broader role of the thalamus in CSTC circuits, particularly in relation to well-known dopamine disturbances in schizophrenia (Dandash et al., 2016). Giraldo-Chica & Woodward in turn review the recently emerging resting-state functional neuroimaging work that has revealed replicable patterns of widespread thalamo-cortical alterations in schizophrenia (Giraldo-Chica and Woodward, 2016). Richard and colleagues offer a review of recent genetic findings in schizophrenia and how such mounting yet complex genetic evidence could collectively impact thalamic circuits (Richard et al., 2016). Finally, Murray and Anticevic provide a perspective for how forthcoming thalamic neuroimaging studies of schizophrenia in humans could benefit from formal neuroscience theory and computational modeling (Murray and Anticevic, 2016). Here the case is presented that the rich and growing translational empirical base can be leveraged to develop biophysically-based computational models of thalamo-cortical circuits. Such models can in turn generate competing predictions with regard to specific features of thalamic physiology – for instance feed-forward versus feedback thalamo-cortical and cortico-thalamic projections as well as differences between associative versus sensory thalamic nuclei. Incorporating such detail will be vital to obtain a ‘strong inference’ framework (Platt, 1964) whereby future human neuroimaging and electrophysiological studies can rule out some hypotheses while confirming others. Such work can also be combined readily with pharmacological imaging studies that causally, safely and transiently manipulate thalamic circuits (Anticevic et al., 2013). Collectively, this Special Issue combines distinct lines of evidence and perspectives supporting the central role of thalamic circuits in schizophrenia neuropathology. This body of evidence unequivocally implicates thalamic disruptions in schizophrenia. However, important outstanding questions remain, which this Special Issue hopes to shape. While thalamic abnormalities may be replicable, which constitutes a major success for the field,
understanding of molecular mechanisms and clinical specificity of these findings remain large knowledge gaps. In particular, it remains unknown if the thalamo-cortical disruptions characterized in schizophrenia persist cross-diagnostically as a generic feature of altered neurodevelopment (Nair et al., 2013; Woodward et al., 2016) or appear more exclusively in relation specific symptom dimensions (e.g. severity of cognitive deficits or psychosis). A likely possibility is that every neuropsychiatric condition exhibits some abnormalities in thalamic function. The key challenge will be to tease apart the precise nature and upstream causal pathways driving such alterations (Schmitt and Halassa, 2016). Furthermore, it is unknown if key patterns of alterations can be more readily captured in certain thalamic nuclei (e.g. the TRN or the medio-dorsal associative thalamic nuclei (Delevich et al., 2015)). In turn, it is unknown if such disruptions persist across the rest of the CSTC loop or are confined more preferentially within the thalamus itself. Also, studies in humans have yet to explicitly leverage the multiple imaging modalities considered in this review – namely the combination of high-resolution T1-weighted magnetic resonance scans capturing thalamic geometry, electrophysiological studies capturing oscillatory disruptions, as well as functional resting-state and probabilistic diffusion tractography work designed to assay functional and structural integrity of large scale networks. In other words, we may obtain rich new information by explicitly moving towards ‘multimodality’ in neuroimaging of thalamic alterations in schizophrenia. While a number of outstanding questions remain, it is evident from this special issue that the field has made major progress in better understanding the role of thalamic circuits in schizophrenia neuropathology. We argue that such continued efforts will be vital to develop disease-specific neural markers that can help map risk factors for schizophrenia onset, its long-term progression and ultimately rational development of treatments. Role of the funding source Financial support was provided by National Institutes of Health Grants DP50D01210904 [to A.A., PI (principal investigator)], R01 MH108590 [to A.A., PI (principal investigator)], and the NARSAD Young Investigator Grant [A.A., PI]. The funding source had no further role in the current study with regard to data collection, data analysis and interpretation of findings or in manuscript preparation and the submission decision. Contributors AA conceptualized and wrote the paper.
Financial disclosures Dr. Alan Anticevic serves on the Scientific Advisory Board and consults for BlackThorn Therapeutics. Acknowledgements I would like to thank all the contributors to the special issue and all the reviewers who have helped improve the submissions with constructive feedback.
References Abi-Dargham, A., 2014. Schizophrenia: overview and dopamine dysfunction. J. Clin. Psychiatry 75 (11), e31. Andreasen, N.C., 1997. The role of the thalamus in schizophrenia. Can. J. Psychiatr. 42 (1), 27–33. Anticevic, A., Cole, M.W., Repovs, G., Savic, A., Driesen, N.R., Yang, G., Cho, Y.T., Murray, J.D., Glahn, D.C., Wang, X.-J., Krystal, J.H., 2013. Connectivity, pharmacology, and computation: toward a mechanistic understanding of neural system dysfunction in schizophrenia. Front. Psychiatry 4 (169). Anticevic, A., Cole, M.W., Repovs, G., Murray, J.D., Brumbaugh, M.S., Winkler, A.M., Savic, A., Krystal, J.H., Pearlson, G.D., Glahn, D.C., 2014. Characterizing thalamo-cortical disturbances in schizophrenia and bipolar illness. Cereb. Cortex 24, 3116–3130. Anticevic, A., Haut, K., Murray, J.D., Repovs, G., Yang, G.J., Diehl, C., McEwen, S.C., Bearden, C.E., Addington, J., Goodyear, B., Cadenhead, K.S., Mirzakhanian, H., Cornblatt, B.A., Olvet, D., Mathalon, D.H., McGlashan, T.H., Perkins, D.O., Belger, A., Seidman, L.J., Tsuang, M.T., van Erp, T.G., Walker, E.F., Hamann, S., Woods, S.W., Qiu, M., Cannon, T.D., 2015. Association of thalamic dysconnectivity and conversion to psychosis in youth and young adults at elevated clinical risk. JAMA Psychiatry 72 (9), 882–891. Baker, J.T., Holmes, A.J., Masters, G.A., Yeo, B.T., Krienen, F., Buckner, R.L., Ongür, D., 2014. Disruption of cortical association networks in schizophrenia and psychotic bipolar disorder. JAMA Psychiatry 72 (2), 109–118.
Please cite this article as: Anticevic, A., , Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.11.044
A. Anticevic / Schizophrenia Research xxx (2016) xxx–xxx Barch, D.M., Ceaser, A., 2012. Cognition in schizophrenia: core psychological and neural mechanisms. Trends Cogn. Sci. 16 (1), 27–34. Behrens, T.E., Johansen-Berg, H., Woolrich, M.W., Smith, S.M., Wheeler-Kingshott, C.A., Boulby, P.A., Barker, G.J., Sillery, E.L., Sheehan, K., Ciccarelli, O., Thompson, A.J., Brady, J.M., Matthews, P.M., 2003. Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging. Nat. Neurosci. 6 (7), 750–757. Cobia, D.J., Smith, M.J., Salinas, I., Ng, C., Gado, M., Csernansky, J.G., Wang, L., 2016. Progressive deterioration of thalamic nuclei relates to cortical network decline in schizophrenia. Schizophr. Res. Coyle, J.T., 2006. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell. Mol. Neurobiol. 26 (4–6), 365–384. Dandash, O., Pantelis, C., Fornito, A., 2016. Dopamine, fronto-striato-thalamic circuits and risk for psychosis. Schizophr. Res. Delevich, K., Tucciarone, J., Huang, Z.J., Li, B., 2015. The mediodorsal thalamus drives feedforward inhibition in the anterior cingulate cortex via parvalbumin interneurons. J. Neurosci. 35 (14), 5743–5753. Dorph-Petersen, K.A., Lewis, D.A., 2016. Postmortem structural studies of the thalamus in schizophrenia. Schizophr. Res. Ferrarelli, F., Tononi, G., 2016. Reduced sleep spindle activity point to a TRN-MD thalamus-PFC circuit dysfunction in schizophrenia. Schizophr. Res. Fischl, B., Salat, D.H., Busa, E., Albert, M., Dieterich, M., 2002. Whole brain segmentation automated labeling of neuroanatomical structures in the human brain. Neuron 33 (3), 341–355. Giraldo-Chica, M., Woodward, N.D., 2016. Review of thalamocortical resting-state fMRI studies in schizophrenia. Schizophr. Res. Glahn, D.C., Bearden, C.E., Barguil, M., Barrett, J., Reichenberg, A., Bowden, C.L., Soares, J.C., Velligan, D.I., 2007. The neurocognitive signature of psychotic bipolar disorder. Biol. Psychiatry 62 (8), 910–916. Howes, O., McCutcheon, R., Stone, J., 2015. Glutamate and dopamine in schizophrenia: an update for the 21st century. J. Psychopharmacol. 29 (2), 97–115. Klingner, C.M., Langbein, K., Dietzek, M., Smesny, S., Witte, O.W., Sauer, H., Nenadic, I., 2014. Thalamocortical connectivity during resting state in schizophrenia. Eur. Arch. Psychiatry Clin. Neurosci. 264 (2), 111–119. Krystal, J.H., D'Souza, D.C., Mathalon, D., Perry, E., Belger, A., Hoffman, R., 2003. NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology 169 (3–4), 215–233. Lisman, J., 2012. Excitation, inhibition, local oscillations, or large-scale loops: what causes the symptoms of schizophrenia? Curr. Opin. Neurobiol. 22 (3), 537–544. Michalopoulou, P.G., Lewis, S.W., Wykes, T., Jaeger, J., Kapur, S., 2013. Treating impaired cognition in schizophrenia: the case for combining cognitive-enhancing drugs with cognitive remediation. European neuropsychopharmacology. J. Eur. Coll. Neuropsychopharmacol. Murray, J.D., Anticevic, A., 2016. Toward understanding thalamocortical dysfunction in schizophrenia through computational models of neural circuit dynamics. Schizophr. Res.
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Nair, A., Treiber, J.M., Shukla, D.K., Shih, P., Muller, R.A., 2013. Impaired thalamocortical connectivity in autism spectrum disorder: a study of functional and anatomical connectivity. Brain 136 (Pt 6), 1942–1955. Pergola, G., Trizio, S., Di Carlo, P., Taurisano, P., Mancini, M., Amoroso, N., Nettis, M.A., Andriola, I., Caforio, G., Popolizio, T., Rampino, A., Di Giorgio, A., Bertolino, A., Blasi, G., 2016. Grey matter volume patterns in thalamic nuclei are associated with familial risk for schizophrenia. Schizophr. Res. Platt, J.R., 1964. Strong inference. Science 146 (3642), 347–353. Pratt, J., Dawson, N., Morris, B.J., Grent-'t-Jong, T., Roux, F., Uhlhaas, P.J., 2016. Thalamocortical communication, glutamatergic neurotransmission and neural oscillations: a unique window into the origins of ScZ? Schizophr. Res. Reichenberg, A., Harvey, P.D., 2007. Neuropsychological impairments in schizophrenia: integration of performance-based and brain imaging findings. Psychol. Bull. 133 (5), 833–858. Reichenberg, A., Harvey, P.D., Bowie, C.R., Mojtabai, R., Rabinowitz, J., Heaton, R.K., Bromet, E., 2009. Neuropsychological function and dysfunction in schizophrenia and psychotic affective disorders. Schizophr. Bull. 35 (5), 1022–1029. Richard, E.A., Khlestova, E., Nanu, R., Lisman, J.E., 2016. Potential synergistic action of 19 schizophrenia risk genes in the thalamus. Schizophr. Res. Schmitt, L.I., Halassa, M.M., 2016. Interrogating the mouse thalamus to correct human neurodevelopmental disorders. Mol. Psychiatry. Stephan, K.E., Friston, K.J., Frith, C.D., 2009. Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring. Schizophr. Bull. 35 (3), 509–527. Uhlhaas, P.J., 2013. Dysconnectivity, large-scale networks and neuronal dynamics in schizophrenia. Curr. Opin. Neurobiol. 23 (2), 283–290. Uhlhaas, P.J., Roux, F., Singer, W., 2013. Thalamocortical synchronization and cognition: implications for schizophrenia? Neuron 77 (6), 997–999. Wells, M.F., Wimmer, R.D., Schmitt, L.I., Feng, G., Halassa, M.M., 2016. Thalamic reticular impairment underlies attention deficit in Ptchd1(Y/−) mice. Nature 532 (7597), 58–63. Welsh, R.C., Chen, A.C., Taylor, S.F., 2010. Low-frequency BOLD fluctuations demonstrate altered thalamocortical connectivity in schizophrenia. Schizophr. Bull. 36 (4), 713–722. Woodward, N.D., Karbasforoushan, H., Heckers, S., 2012. Thalamocortical dysconnectivity in schizophrenia. Am. J. Psychiatry 169 (10), 1092–1099. Woodward, N.D., Giraldo-Chica, M., Rogers, B., Cascio, C.J., 2016. Thalamocortical Dysconnectivity in Autism Spectrum Disorder: An Analysis of the Autism Brain Imaging Data Exchange Biological Psychiatry [Epub]. Young, A., Wimmer, R.D., 2016. Implications for the thalamic reticular nucleus in impaired attention and sleep in schizophrenia. Schizophr. Res. Zhang, D., Snyder, A.Z., Shimony, J.S., Fox, M.D., Raichle, M.E., 2010. Noninvasive functional and structural connectivity mapping of the human thalamocortical system. Cereb. Cortex 20 (5), 1187–1194.
Please cite this article as: Anticevic, A., , Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.11.044
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Invited commentary
Understanding the role of thalamic circuits in schizophrenia neuropathology☆ Alan Anticevic Department of Psychiatry, Yale University, United States Department of Psychology, Yale University, United States
a r t i c l e
i n f o
Article history: Received 24 November 2016 Received in revised form 28 November 2016 Accepted 28 November 2016 Available online xxxx
© 2016 Published by Elsevier B.V.
Guest editorial, The complexity of schizophrenia symptoms has presented a major challenge for delineating neural circuits that may map onto underlying pathophysiological mechanism and in turn developed into viable biomarkers that can track illness risk, disease progression, and ultimately treatment response. It is now generally appreciated that schizophrenia is a ‘dysconnection’ syndrome (Stephan et al., 2009) whereby distributed large-scale neural circuits exhibit altered patterns of information flow (Woodward et al., 2012). Yet, it remains challenging to define any particular set of regions or networks as specifically associated with schizophrenia onset, progression and treatment response. The thalamus has offered a unique translational opportunity to map neural alterations in patients with schizophrenia. Examining functional and structural features of thalamic circuits capitalizes on key properties of this area. First, thalamic nuclei are topographically connected to the entire cortex and striatum (Behrens et al., 2003; Zhang et al., 2010), forming a major element of parallel cortico-thalamic-striatal-cortical (CTSC) loops. Therefore, thalamic circuits may be particularly sensitive to brain-wide disturbances that occur in schizophrenia (Andreasen, 1997). Second, the thalamus contains segregated nuclei, providing a method for probing parallel yet distributed large-scale alterations that may occur along distinct neural systems. Third, thalamic nuclei can be reliably identified using modern neuroimaging technology, allowing detailed functional and structural studies of this structure (Fischl et al.,
☆ DISCLOSURES: Dr. Anticevic is a consultant and a member of the SAB for BlackThorn Therapeutics E-mail address: [email protected].
2002). Finally, thalamic circuits have featured prominently in theoretical models of schizophrenia, given its critical role in both sensory and higher-order cognitive functions (Barch and Ceaser, 2012), as well as their focal interaction with a variety of neurotransmitter systems, such as dopamine, glutamate and γ-Aminobutyric acid (GABA) (Abi-Dargham, 2014; Coyle, 2006; Howes et al., 2015; Krystal et al., 2003). These reasons notwithstanding, neural disturbances in schizophrenia are likely not exclusively confined to thalamic circuits. In fact, there is good evidence that distributed cortical areas and networks are profoundly altered in patients suffering from schizophrenia (Baker et al., 2014). Instead, an alternative perspective could consider the thalamus as a central nexus point of distributed information flow and therefore a preferentially ‘fragile’ brain region that communicates with distributed neural systems, which may consequently be particularly affected in schizophrenia. In line with this hypothesis, several investigations have reported altered thalamo-cortical information flow in chronic SCZ (Anticevic et al., 2014; Klingner et al., 2014; Welsh et al., 2010; Woodward et al., 2012). Similar patterns were replicated in individuals who are at clinically elevated risk for developing psychosis (i.e. the schizophrenia prodrome (Anticevic et al., 2015)), ruling out the possibility that this effect is driven by illness chronicity or long-term medication effects. Similarly, animal models have repeatedly implicated thalamic dysfunction as one central mechanism for occurrence of cognitive deficits (Wells et al., 2016), which are a hallmark feature of schizophrenia spectrum disorders that is closely tied to functional outcome (Glahn et al., 2007; Michalopoulou et al., 2013; Reichenberg and Harvey, 2007; Reichenberg et al., 2009). Collectively, these lines of evidence suggest the importance of understanding the role of thalamic circuits in schizophrenia neuropathology as it may present a sensitive
http://dx.doi.org/10.1016/j.schres.2016.11.044 0920-9964/© 2016 Published by Elsevier B.V.
Please cite this article as: Anticevic, A., , Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.11.044
2
A. Anticevic / Schizophrenia Research xxx (2016) xxx–xxx
point of disruption with rich translational opportunities for developing a family of biomarkers across the schizophrenia spectrum and perhaps other neuropsychiatric conditions (Schmitt and Halassa, 2016). In an attempt to help achieve this goal, the “Pathologies of the Thalamus in Schizophrenia” Special Issue features a combination of empirical and review manuscripts detailing what we consider state-of-the-art understanding of thalamic alterations in schizophrenia. The featured articles span review papers on thalamic neurobiology as well as evidence for its disruption in schizophrenia from a structural, functional and genetic perspective. First, Pratt and colleagues review the central role of the thalamus as a possible window into the origins of schizophrenia by considering its interplay with cortex, its reliance on glutamatergic neurotransmission, and its vital role in generating neural oscillations (Pratt et al., 2016), which are disrupted in schizophrenia (Lisman, 2012; Uhlhaas, 2013; Uhlhaas et al., 2013). Next, Pergola et al. present new evidence for gray matter thalamic volume alterations and associations of such disruptions with familial risk for schizophrenia (Pergola et al., 2016), suggesting a genetic basis for thalamic structural alterations. This is followed by related empirical work from Cobia and colleagues, which details longitudinal structural thalamic alterations that were most prominent for higher order associative thalamic nuclei (Cobia et al., 2016). Dorph-Petersen & Lewis in turn review post-mortem work detailing thalamic structural alterations in schizophrenia (DorphPetersen and Lewis, 2016). Next, Ferrarelli & Tononi consider a key functional property of the thalamus and its particular involvement in schizophrenia – namely the thalamic reticular nucleus (TRN) that forms a layer of GABA cells wrapped around the central thalamic nuclei. Their piece articulates the functional role of the TRN for generating thalamic inhibition and how altered TRN function points to alterations between higher-order thalamic nuclei and prefrontal cortex in schizophrenia (Ferrarelli and Tononi, 2016). Young & Wimmer expand on this topic by considering TRN impairment in schizophrenia in relation to cognitive disturbances and sleep alterations (Young and Wimmer, 2016). Dandash and colleagues discuss the broader role of the thalamus in CSTC circuits, particularly in relation to well-known dopamine disturbances in schizophrenia (Dandash et al., 2016). Giraldo-Chica & Woodward in turn review the recently emerging resting-state functional neuroimaging work that has revealed replicable patterns of widespread thalamo-cortical alterations in schizophrenia (Giraldo-Chica and Woodward, 2016). Richard and colleagues offer a review of recent genetic findings in schizophrenia and how such mounting yet complex genetic evidence could collectively impact thalamic circuits (Richard et al., 2016). Finally, Murray and Anticevic provide a perspective for how forthcoming thalamic neuroimaging studies of schizophrenia in humans could benefit from formal neuroscience theory and computational modeling (Murray and Anticevic, 2016). Here the case is presented that the rich and growing translational empirical base can be leveraged to develop biophysically-based computational models of thalamo-cortical circuits. Such models can in turn generate competing predictions with regard to specific features of thalamic physiology – for instance feed-forward versus feedback thalamo-cortical and cortico-thalamic projections as well as differences between associative versus sensory thalamic nuclei. Incorporating such detail will be vital to obtain a ‘strong inference’ framework (Platt, 1964) whereby future human neuroimaging and electrophysiological studies can rule out some hypotheses while confirming others. Such work can also be combined readily with pharmacological imaging studies that causally, safely and transiently manipulate thalamic circuits (Anticevic et al., 2013). Collectively, this Special Issue combines distinct lines of evidence and perspectives supporting the central role of thalamic circuits in schizophrenia neuropathology. This body of evidence unequivocally implicates thalamic disruptions in schizophrenia. However, important outstanding questions remain, which this Special Issue hopes to shape. While thalamic abnormalities may be replicable, which constitutes a major success for the field,
understanding of molecular mechanisms and clinical specificity of these findings remain large knowledge gaps. In particular, it remains unknown if the thalamo-cortical disruptions characterized in schizophrenia persist cross-diagnostically as a generic feature of altered neurodevelopment (Nair et al., 2013; Woodward et al., 2016) or appear more exclusively in relation specific symptom dimensions (e.g. severity of cognitive deficits or psychosis). A likely possibility is that every neuropsychiatric condition exhibits some abnormalities in thalamic function. The key challenge will be to tease apart the precise nature and upstream causal pathways driving such alterations (Schmitt and Halassa, 2016). Furthermore, it is unknown if key patterns of alterations can be more readily captured in certain thalamic nuclei (e.g. the TRN or the medio-dorsal associative thalamic nuclei (Delevich et al., 2015)). In turn, it is unknown if such disruptions persist across the rest of the CSTC loop or are confined more preferentially within the thalamus itself. Also, studies in humans have yet to explicitly leverage the multiple imaging modalities considered in this review – namely the combination of high-resolution T1-weighted magnetic resonance scans capturing thalamic geometry, electrophysiological studies capturing oscillatory disruptions, as well as functional resting-state and probabilistic diffusion tractography work designed to assay functional and structural integrity of large scale networks. In other words, we may obtain rich new information by explicitly moving towards ‘multimodality’ in neuroimaging of thalamic alterations in schizophrenia. While a number of outstanding questions remain, it is evident from this special issue that the field has made major progress in better understanding the role of thalamic circuits in schizophrenia neuropathology. We argue that such continued efforts will be vital to develop disease-specific neural markers that can help map risk factors for schizophrenia onset, its long-term progression and ultimately rational development of treatments. Role of the funding source Financial support was provided by National Institutes of Health Grants DP50D01210904 [to A.A., PI (principal investigator)], R01 MH108590 [to A.A., PI (principal investigator)], and the NARSAD Young Investigator Grant [A.A., PI]. The funding source had no further role in the current study with regard to data collection, data analysis and interpretation of findings or in manuscript preparation and the submission decision. Contributors AA conceptualized and wrote the paper.
Financial disclosures Dr. Alan Anticevic serves on the Scientific Advisory Board and consults for BlackThorn Therapeutics. Acknowledgements I would like to thank all the contributors to the special issue and all the reviewers who have helped improve the submissions with constructive feedback.
References Abi-Dargham, A., 2014. Schizophrenia: overview and dopamine dysfunction. J. Clin. Psychiatry 75 (11), e31. Andreasen, N.C., 1997. The role of the thalamus in schizophrenia. Can. J. Psychiatr. 42 (1), 27–33. Anticevic, A., Cole, M.W., Repovs, G., Savic, A., Driesen, N.R., Yang, G., Cho, Y.T., Murray, J.D., Glahn, D.C., Wang, X.-J., Krystal, J.H., 2013. Connectivity, pharmacology, and computation: toward a mechanistic understanding of neural system dysfunction in schizophrenia. Front. Psychiatry 4 (169). Anticevic, A., Cole, M.W., Repovs, G., Murray, J.D., Brumbaugh, M.S., Winkler, A.M., Savic, A., Krystal, J.H., Pearlson, G.D., Glahn, D.C., 2014. Characterizing thalamo-cortical disturbances in schizophrenia and bipolar illness. Cereb. Cortex 24, 3116–3130. Anticevic, A., Haut, K., Murray, J.D., Repovs, G., Yang, G.J., Diehl, C., McEwen, S.C., Bearden, C.E., Addington, J., Goodyear, B., Cadenhead, K.S., Mirzakhanian, H., Cornblatt, B.A., Olvet, D., Mathalon, D.H., McGlashan, T.H., Perkins, D.O., Belger, A., Seidman, L.J., Tsuang, M.T., van Erp, T.G., Walker, E.F., Hamann, S., Woods, S.W., Qiu, M., Cannon, T.D., 2015. Association of thalamic dysconnectivity and conversion to psychosis in youth and young adults at elevated clinical risk. JAMA Psychiatry 72 (9), 882–891. Baker, J.T., Holmes, A.J., Masters, G.A., Yeo, B.T., Krienen, F., Buckner, R.L., Ongür, D., 2014. Disruption of cortical association networks in schizophrenia and psychotic bipolar disorder. JAMA Psychiatry 72 (2), 109–118.
Please cite this article as: Anticevic, A., , Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.11.044
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Please cite this article as: Anticevic, A., , Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.11.044