Thalamocortical Disconnection in the Orbitofrontal Region Associated With Cortical Thinning in Schizophrenia

Kubota, Manabu; Miyata, Jun; Sasamoto, Akihiko; Sugihara, Genichi; Yoshida, Hiroo; Kawada, Ryosaku; Fujimoto, Sanji; Tanaka, Yusuke; Sawamoto, Nobukatsu; Fukuyama, Hidenao; Takahashi, Hidehiko; Murai, Toshiya

doi:10.1001/archgenpsychiatry.2012.1023

Cited by 72 publications

(71 citation statements)

References 61 publications

(82 reference statements)

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“…19,20 Our results indicate that this anomaly may be detected early, even in those with subthreshold clinical symptoms for the diagnosis of schizophrenia. Small neurodevelopmental alterations from early life are speculated to cause this, because the development of the thalamocortical connection begins early in the embryonic stage.…”

Section: Discussionmentioning

confidence: 59%

“…Of note here, a number of recent studies in schizophrenia have focused on connectivity between the thalamus and the prefrontal cortex rather than on the thalamus alone. Using diffusion weighted imaging (DWI), these studies report reduced white matter connectivity between the thalamus and the prefrontal cortex, 19,20 which are consistent with the disconnection theory of schizophrenia. 21,22 These findings are further supported by the fact that some of the symptoms in schizophrenia, such as dysfunction in execution, attention and sensory gating, are related to the thalamoprefrontal circuit.…”

Section: Introductionmentioning

confidence: 66%

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Altered Thalamo-Cortical White Matter Connectivity: Probabilistic Tractography Study in Clinical-High Risk for Psychosis and First-Episode Psychosis

Cho

Shenton

Kubicki

et al. 2015

SCHBUL

106

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Disrupted thalamo-cortical connectivity is regarded as a core psychopathology in patients diagnosed with schizophrenia. However, whether the thalamo-cortical white matter connectivity is disrupted before the onset of psychosis is still unknown. To determine this gap in knowledge, the strength of thalamo-cortical white matter anatomical connectivity in subjects at clinical-high risk for psychosis (CHR) was compared to that of first-episode psychosis (FEP) and healthy controls. A total of 37 CHR, 21 FEP, and 37 matched healthy controls underwent diffusion-weighted magnetic resonance imaging to examine the number of probabilistic tractography "counts" representing thalamo-cortical white matter connectivity. We also investigated the relationship with psychopathology. For FEP, the connectivity between the thalamus and parietal cortex was significantly increased (F = 5.65, P < .05) compared to that of healthy controls. However, the connectivity between thalamus and orbitofrontal cortex was significantly reduced compared to both healthy controls (F = 11.86, P < .005) and CHR (F = 6.63, P < .05). Interestingly, CHR exhibited a similar pattern as FEP, albeit with slightly reduced magnitude. Compared to healthy controls, there was a significant decrease (F = 4.16, P < .05) in CHR thalamo-orbitofrontal connectivity. Also, the strength of the thalamo-orbitofrontal connectivity was correlated with the Global Assessment of Functioning score in CHR (r = .35, P < .05). This observed pattern of white matter connectivity disruptions in FEP and in CHR suggests that this pattern of disconnectivity not only highlights the involvement of thalamus but also might be useful as an early biomarker for psychosis.

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Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 66%

Altered Thalamo-Cortical White Matter Connectivity: Probabilistic Tractography Study in Clinical-High Risk for Psychosis and First-Episode Psychosis

Cho

Shenton

Kubicki

et al. 2015

SCHBUL

106

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“…But neurophysiological evidence of impaired temporal coordination of neural activity in the brains of patients has more recently given the theory a neurophysiological basis (Friston, 1999; Friston and Frith, 1995; Lawrie et al, 2002; Scariati et al, 2016; Stephan et al, 2009). Consistent with this hypothesis, functional imaging studies in patients have repeatedly shown that schizophrenia weakens functional coupling in prefrontal networks based on reduced temporal correlations in BOLD signal across brain areas (Kang et al, 2011; Kubota et al, 2013; Lawrie et al, 2002; Mitelman et al, 2005; Mukherjee et al, 2016; Scariati et al, 2016; Tu et al, 2012, 2013). Measurements of brain activity at higher temporal resolution using electroencephalograms (EEG) and magnetoencephalography (MEG) have shown reduced synchrony in gamma band during task performance (Dale et al, 2016; Uhlhaas and Singer, 2015).…”

Section: Discussionmentioning

confidence: 79%

Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia

Zick

Blackman

Crowe

et al. 2018

Neuron

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SUMMARY We employed multi-electrode array recording to evaluate the influence of NMDA receptors (NMDAR) on spike-timing dynamics in prefrontal networks of monkeys as they performed a cognitive control task measuring specific deficits in schizophrenia. Systemic, periodic administration of an NMDAR antagonist (phencyclidine) reduced the prevalence and strength of synchronous (0-lag) spike correlation in simultaneously recorded neuron pairs. We employed transfer entropy analysis to measure effective connectivity between prefrontal neurons at lags consistent with monosynaptic interactions and found that effective connectivity was persistently reduced following exposure to the NMDAR antagonist. These results suggest that a disruption of spike timing and effective connectivity might be interrelated factors in pathogenesis, supporting an activity-dependent disconnection theory of schizophrenia. In this theory, disruption of NMDAR synaptic function leads to dys-regulated timing of action potentials in prefrontal networks, accelerating synaptic disconnection through a spike-timing-dependent mechanism.

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“…Imaging data during this phase showed global changes in neural connectivity (Friedman et al, 2008). Furthermore, both white and gray matters, especially cortical thickness have been shown altered in these patients, whose degree of changes may be correlated with their functional status (Kubota et al, 2013; Sasamoto et al, 2014; Ubukata et al, 2013). These patients may show a lack of motivation as well as difficulty in activating task-relevant networks.…”

Section: Neurobiological Basis For Cognitive Impairments In Schizomentioning

confidence: 94%

Converging models of schizophrenia – Network alterations of prefrontal cortex underlying cognitive impairments

Sakurai

Gamo

Hikida

et al. 2015

Progress in Neurobiology

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The prefrontal cortex (PFC) and its connections with other brain areas are crucial for cognitive function. Cognitive impairments are one of the core symptoms associated with schizophrenia, and manifest even before the onset of the disorder. Altered neural networks involving PFC contribute to cognitive impairments in schizophrenia. Both genetic and environmental risk factors affect the development of the local circuitry within PFC as well as development of broader brain networks, and make the system vulnerable to further insults during adolescence, leading to the onset of the disorder in young adulthood. Since spared cognitive functions correlate with functional outcome and prognosis, a better understanding of the mechanisms underlying cognitive impairments will have important implications for novel therapeutics for schizophrenia focusing on cognitive functions. Multidisciplinary approaches, from basic neuroscience to clinical studies, are required to link molecules, circuitry, networks, and behavioral phenotypes. Close interactions among such fields by sharing a common language on connectomes, behavioral readouts, and other concepts are crucial for this goal.

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Thalamocortical Disconnection in the Orbitofrontal Region Associated With Cortical Thinning in Schizophrenia

Abstract: These results suggest that, in schizophrenia, regional thalamocortical white matter pathology is specifically associated with cortical pathology in regions where fibers connect.

Cited by 72 publications

References 61 publications

Altered Thalamo-Cortical White Matter Connectivity: Probabilistic Tractography Study in Clinical-High Risk for Psychosis and First-Episode Psychosis

Altered Thalamo-Cortical White Matter Connectivity: Probabilistic Tractography Study in Clinical-High Risk for Psychosis and First-Episode Psychosis

Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia

Converging models of schizophrenia – Network alterations of prefrontal cortex underlying cognitive impairments

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