Prefrontal-Thalamic Anatomical Connectivity and Executive Cognitive Function in Schizophrenia

doi:10.1016/j.biopsych.2017.09.022

Biological Psychiatry

Volume 83, Issue 6, 15 March 2018, Pages 509-517

https://doi.org/10.1016/j.biopsych.2017.09.022 Get rights and content

Abstract

Background

Executive cognitive functions, including working memory, cognitive flexibility, and inhibition, are impaired in schizophrenia. Executive functions rely on coordinated information processing between the prefrontal cortex (PFC) and thalamus, particularly the mediodorsal nucleus. This raises the possibility that anatomical connectivity between the PFC and mediodorsal thalamus may be 1) reduced in schizophrenia and 2) related to deficits in executive function. The current investigation tested these hypotheses.

Methods

Forty-five healthy subjects and 62 patients with a schizophrenia spectrum disorder completed a battery of tests of executive function and underwent diffusion-weighted imaging. Probabilistic tractography was used to quantify anatomical connectivity between six cortical regions, including PFC, and the thalamus. Thalamocortical anatomical connectivity was compared between healthy subjects and patients with schizophrenia using region-of-interest and voxelwise approaches, and the association between PFC-thalamic anatomical connectivity and severity of executive function impairment was examined in patients.

Results

Anatomical connectivity between the thalamus and PFC was reduced in schizophrenia. Voxelwise analysis localized the reduction to areas of the mediodorsal thalamus connected to lateral PFC. Reduced PFC-thalamic connectivity in schizophrenia correlated with impaired working memory but not cognitive flexibility and inhibition. In contrast to reduced PFC-thalamic connectivity, thalamic connectivity with somatosensory and occipital cortices was increased in schizophrenia.

Conclusions

The results are consistent with models implicating disrupted PFC-thalamic connectivity in the pathophysiology of schizophrenia and mechanisms of cognitive impairment. PFC-thalamic anatomical connectivity may be an important target for procognitive interventions. Further work is needed to determine the implications of increased thalamic connectivity with sensory cortex.

Section snippets

Study Participants

Forty-seven healthy subjects and 67 patients with a schizophrenia spectrum disorder (i.e., schizophreniform disorder, schizophrenia, schizoaffective disorder) who participated in an ongoing study of thalamocortical networks in psychotic disorders were screened for inclusion in this study. All patients with a schizophrenia spectrum diagnosis, hereafter referred to as schizophrenia, were recruited through the Psychotic Disorders Program at the Vanderbilt Psychiatric Hospital. Healthy subjects

Results

Seven subjects (2 healthy individuals and 5 patients) were excluded owing to presence of neuroimaging data artifacts based on visual inspection. Thus, the final sample included 45 healthy subjects and 62 patients with schizophrenia (Table 1). With the exception of education, the groups did not differ in demographic variables. No significant differences in HARDI QA metrics were detected between groups, including mean head translation and rotation in X, Y, and Z directions and percentage of

Discussion

Motivated by evidence implicating PFC-thalamic circuitry in the pathophysiology of schizophrenia and mechanisms of cognitive impairment, we tested the hypothesis that anatomical connectivity between the PFC and thalamus is 1) reduced in schizophrenia and 2) related to impaired executive function. Our first hypothesis was supported; total connectivity of the PFC with the thalamus was significantly reduced in schizophrenia. Voxelwise analyses confirmed the reduction in connectivity localized to

Acknowledgments and Disclosures

This work was supported by the National Institute of Mental Health (Grant No. R01-MH102266 to NDW) and Vanderbilt Clinical and Translational Science Award (Grant No. UL1-RR024975) from the National Center for Research Resources, National Institute of Health.

We thank the individuals who participated in the study and Kristan Armstrong, Erin Brosey, Molly Boyce, and Yasmeen Iqbal for their assistance recruiting and screening subjects for participation in the study.

The authors report no biomedical

References (68)

A. Miyake et al.
The unity and diversity of executive functions and their contributions to complex “Frontal Lobe” tasks: A latent variable analysis
Cogn Psychol
(2000)
D. Dickinson et al.
General and specific cognitive deficits in schizophrenia: Goliath defeats David?
Biol Psychiatry
(2008)
N.D. Woodward et al.
A meta-analysis of cognitive change with haloperidol in clinical trials of atypical antipsychotics: Dose effects and comparison to practice effects
Schizophr Res
(2007)
L. de Witte et al.
Cognitive, affective and behavioural disturbances following vascular thalamic lesions: A review
Cortex
(2011)
Y.D. Van der Werf et al.
Deficits of memory, executive functioning and attention following infarction in the thalamus; a study of 22 cases with localised lesions
Neuropsychologia
(2003)
S. Parnaudeau et al.
Inhibition of mediodorsal thalamus disrupts thalamofrontal connectivity and cognition
Neuron
(2013)
S. Parnaudeau et al.
Mediodorsal thalamus hypofunction impairs flexible goal-directed behavior
Biol Psychiatry
(2015)
D.C. Glahn et al.
Meta-analysis of gray matter anomalies in schizophrenia: Application of anatomic likelihood estimation and network analysis
Biol Psychiatry
(2008)
M. Giraldo-Chica et al.
Review of thalamocortical resting-state fMRI studies in schizophrenia
Schizophr Res
(2017)
A.J. Asman et al.
Hierarchical performance estimation in the statistical label fusion framework
Med Image Anal
(2014)

J. Ashburner

A fast diffeomorphic image registration algorithm

Neuroimage

(2007)

T.E. Behrens et al.

Probabilistic diffusion tractography with multiple fibre orientations: What can we gain?

Neuroimage

(2007)

N.D. Woodward et al.

Functional resting-state networks are differentially affected in schizophrenia

Schizophr Res

(2011)

J.E. Lisman et al.

A thalamo-hippocampal-ventral tegmental area loop may produce the positive feedback that underlies the psychotic break in schizophrenia

Biol Psychiatry

(2010)

I.S. Ramsay et al.

Increases in intrinsic thalamocortical connectivity and overall cognition following cognitive remediation in chronic schizophrenia

Biol Psychiatry Cogn Neurosci Neuroimaging

(2017)

N.D. Woodward et al.

Mapping thalamocortical functional connectivity in chronic and early stages of psychotic disorders

Biol Psychiatry

(2016)

D.B. Lerman-Sinkoff et al.

Network community structure alterations in adult schizophrenia: Identification and localization of alterations

Neuroimage Clin

(2016)

P.C. Tu et al.

Network-specific cortico-thalamic dysconnection in schizophrenia revealed by intrinsic functional connectivity analyses

Schizophr Res

(2015)

H.L. Wang et al.

Disrupted thalamic resting-state functional networks in schizophrenia

Front Behav Neurosci

(2015)

J. Mojsilovic et al.

Early development of the human thalamus: Golgi and Nissl study

Early Hum Dev

(1991)

R. Fama et al.

Thalamic structures and associated cognitive functions: Relations with age and aging

Neurosci Biobehav Rev

(2015)

T. Tourdias et al.

Visualization of intra-thalamic nuclei with optimized white-matter-nulled MPRAGE at 7T

Neuroimage

(2014)

R.W. Heinrichs et al.

Neurocognitive deficit in schizophrenia: A quantitative review of the evidence

Neuropsychology

(1998)

B.W. Palmer et al.

Is it possible to be schizophrenic yet neuropsychologically normal?

Neuropsychology

(1997)

C.M. Wilk et al.

No, it is not possible to be schizophrenic yet neuropsychologically normal

Neuropsychology

(2005)

T.W. Weickert et al.

Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect

Arch Gen Psychiatry

(2000)

M. Lepage et al.

Neurocognition: Clinical and functional outcomes in schizophrenia

Can J Psychiatry

(2014)

N.D. Woodward et al.

A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia

Int J Neuropsychopharmacol

(2005)

D.J. Simons et al.

Do “brain-training” programs work?

Psychol Sci Public Interest

(2016)

T.A. Niendam et al.

Meta-analytic evidence for a superordinate cognitive control network subserving diverse executive functions

Cogn Affect Behav Neurosci

(2012)

A.E. Block et al.

Thalamic-prefrontal cortical-ventral striatal circuitry mediates dissociable components of strategy set shifting

Cereb Cortex

(2007)

S.S. Bolkan et al.

Thalamic projections sustain prefrontal activity during working memory maintenance

Nat Neurosci

(2017)

L.I. Schmitt et al.

Thalamic amplification of cortical connectivity sustains attentional control

Nature

(2017)

M.J. Minzenberg et al.

Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia

Arch Gen Psychiatry

(2009)

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¹: MG-C and NDW contributed equally to this work.

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Archival ReportPrefrontal-Thalamic Anatomical Connectivity and Executive Cognitive Function in Schizophrenia

Abstract

Background

Methods

Results

Conclusions

Section snippets

Study Participants

Results

Discussion

Acknowledgments and Disclosures

Cogn Psychol

Biol Psychiatry

Schizophr Res

Cortex

Neuropsychologia

Neuron

Biol Psychiatry

Biol Psychiatry

Schizophr Res

Med Image Anal

Neuroimage

Neuroimage

Schizophr Res

Biol Psychiatry

Biol Psychiatry Cogn Neurosci Neuroimaging

Biol Psychiatry

Neuroimage Clin

Schizophr Res

Front Behav Neurosci

Early Hum Dev

Neurosci Biobehav Rev

Neuroimage

Neurocognitive deficit in schizophrenia: A quantitative review of the evidence

Neuropsychology

Is it possible to be schizophrenic yet neuropsychologically normal?

Neuropsychology

No, it is not possible to be schizophrenic yet neuropsychologically normal

Neuropsychology

Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect

Arch Gen Psychiatry

Neurocognition: Clinical and functional outcomes in schizophrenia

Can J Psychiatry

A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia

Int J Neuropsychopharmacol

Do “brain-training” programs work?

Psychol Sci Public Interest

Meta-analytic evidence for a superordinate cognitive control network subserving diverse executive functions

Cogn Affect Behav Neurosci

Thalamic-prefrontal cortical-ventral striatal circuitry mediates dissociable components of strategy set shifting

Cereb Cortex

Thalamic projections sustain prefrontal activity during working memory maintenance

Nat Neurosci

Thalamic amplification of cortical connectivity sustains attentional control

Nature

Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia

Arch Gen Psychiatry

Archival Report
Prefrontal-Thalamic Anatomical Connectivity and Executive Cognitive Function in Schizophrenia