Why are cortical GABA neurons relevant to internal focus in depression? A cross-level model linking cellular, biochemical and neural network findings

Georg Franz Josef Northoff, Etienne L. Sibille

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Major depression is a complex and severe psychiatric disorder whose symptomatology encompasses a critical shift in awareness, especially in the balance from external to internal mental focus. This is reflected by unspecific somatic symptoms and the predominance of the own cognitions manifested in increased self-focus and rumination. We posit here that sufficient empirical data has accumulated to build a coherent biologic model that links these psychologic concepts and symptom dimensions to observed biochemical, cellular, regional and neural network deficits. Specifically, deficits in inhibitory γ-aminobutyric acid regulating excitatory cell input/output and local cell circuit processing of information in key brain regions may underlie the shift that is observed in depressed subjects in resting-state activities between the perigenual anterior cingulate cortex and the dorsolateral prefrontal cortex. This regional dysbalance translates at the network level in a dysbalance between default-mode and executive networks, which psychopathologically surfaces as a shift in focus from external to internal mental content and associated symptoms. We focus here on primary evidence at each of those levels and on putative mechanistic links between those levels. Apart from its implications for neuropsychiatric disorders, our model provides for the first time a set of hypotheses for cross-level mechanisms of how internal and external mental contents may be constituted and balanced in healthy subjects, and thus also contributes to the neuroscientific debate on the neural correlates of consciousness. © 2014 Macmillan Publishers Limited All rights reserved.
Original languageEnglish
Pages (from-to)966-977
Number of pages12
JournalMolecular Psychiatry
Volume19
Issue number9
DOIs
Publication statusPublished - 2014

Fingerprint

GABAergic Neurons
Depression
Aminobutyrates
Biological Models
Gyrus Cinguli
Prefrontal Cortex
Consciousness
Automatic Data Processing
Cognition
Psychiatry
Healthy Volunteers
Brain
Medically Unexplained Symptoms

Keywords

  • 4 aminobutyric acid
  • 4 aminobutyric acid receptor
  • anterior cingulate
  • cognition
  • default mode network
  • depression
  • executive function
  • GABAergic system
  • human
  • interneuron
  • mental function
  • negative feedback
  • nerve cell
  • nerve cell network
  • neuropathology
  • prefrontal cortex
  • priority journal
  • pyramidal nerve cell
  • Review
  • biological model
  • brain cortex
  • major depression
  • metabolism
  • nerve tract
  • pathophysiology
  • physiology
  • psychology
  • self concept
  • Cerebral Cortex
  • Depressive Disorder, Major
  • GABAergic Neurons
  • gamma-Aminobutyric Acid
  • Humans
  • Models, Neurological
  • Neural Pathways
  • Self Concept

Cite this

@article{94238b2972cd4fc0ab56d1454c63bbce,
title = "Why are cortical GABA neurons relevant to internal focus in depression? A cross-level model linking cellular, biochemical and neural network findings",
abstract = "Major depression is a complex and severe psychiatric disorder whose symptomatology encompasses a critical shift in awareness, especially in the balance from external to internal mental focus. This is reflected by unspecific somatic symptoms and the predominance of the own cognitions manifested in increased self-focus and rumination. We posit here that sufficient empirical data has accumulated to build a coherent biologic model that links these psychologic concepts and symptom dimensions to observed biochemical, cellular, regional and neural network deficits. Specifically, deficits in inhibitory γ-aminobutyric acid regulating excitatory cell input/output and local cell circuit processing of information in key brain regions may underlie the shift that is observed in depressed subjects in resting-state activities between the perigenual anterior cingulate cortex and the dorsolateral prefrontal cortex. This regional dysbalance translates at the network level in a dysbalance between default-mode and executive networks, which psychopathologically surfaces as a shift in focus from external to internal mental content and associated symptoms. We focus here on primary evidence at each of those levels and on putative mechanistic links between those levels. Apart from its implications for neuropsychiatric disorders, our model provides for the first time a set of hypotheses for cross-level mechanisms of how internal and external mental contents may be constituted and balanced in healthy subjects, and thus also contributes to the neuroscientific debate on the neural correlates of consciousness. {\circledC} 2014 Macmillan Publishers Limited All rights reserved.",
keywords = "4 aminobutyric acid, 4 aminobutyric acid receptor, anterior cingulate, cognition, default mode network, depression, executive function, GABAergic system, human, interneuron, mental function, negative feedback, nerve cell, nerve cell network, neuropathology, prefrontal cortex, priority journal, pyramidal nerve cell, Review, biological model, brain cortex, major depression, metabolism, nerve tract, pathophysiology, physiology, psychology, self concept, Cerebral Cortex, Depressive Disorder, Major, GABAergic Neurons, gamma-Aminobutyric Acid, Humans, Models, Neurological, Neural Pathways, Self Concept",
author = "Northoff, {Georg Franz Josef} and Sibille, {Etienne L.}",
note = "Cited By :6 Export Date: 11 May 2016 CODEN: MOPSF Correspondence Address: Northoff, G.; Department of Psychiatry, University of Ottawa Institute of Mental Health Research, Royal Ottawa Hospital, 1145 Carling Avenue, Canada Chemicals/CAS: 4 aminobutyric acid, 28805-76-7, 56-12-2; gamma-Aminobutyric Acid Funding Details: CIHR, Canadian Institutes of Health Research Funding Details: HDRF, Canadian Institutes of Health Research Funding Details: MH077159, NIMH, Canadian Institutes of Health Research Funding Details: MH084060, NIMH, Canadian Institutes of Health Research References: WHO, (2008) World Health Organization - The Global Burden of Disease - 2004 Update, , WHO Library: Geneva, Switzerland; Mayberg, H.S., Modulating limbic-cortical circuits in depression: Targets of antidepressant treatments (2002) Semin Clin Neuropsychiatry, 7, pp. 255-268; Belmaker, R.H., Agam, G., Major depressive disorder (2008) N Engl J Med, 358, pp. 55-68; Kupfer, D.J., Frank, E., Phillips, M.L., Major depressive disorder: New clinical, neurobiological, and treatment perspectives (2012) Lancet, 379, pp. 1045-1055; Mayberg, H.S., Positron emission tomography imaging in depression: A neural systems perspective (2003) Neuroimag Clin N Am, 13, pp. 805-815; Holtzheimer, P.E., Mayberg, H.S., Stuck in a rut: Rethinking depression and its treatment (2011) Trends Neurosci, 34, pp. 1-9; Northoff, G., Walter, M., Schulte, R.F., Beck, J., Dydak, U., Henning, A., GABA concentrations in the human anterior cingulate cortex predict negative BOLD responses in fMRI (2007) Nat Neurosci, 10, pp. 1515-1517; Price, J.L., Drevets, W.C., Neural circuits underlying the pathophysiology of mood disorders (2012) Trends Cogn Sci, 16, pp. 61-71; Northoff, G., Wiebking, C., Feinberg, T., Panksepp, J., The 'resting-state hypothesis' of major depressive disorder - A translational subcortical-cortical framework for a system disorder (2011) Neurosci Biobehav Rev, 35, pp. 1929-1945; Alcaro, A., Panksepp, J., Witczak, J., Hayes, D.J., Northoff, G., Is subcortical-cortical midline activity in depression mediated by glutamate and GABA? 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year = "2014",
doi = "10.1038/mp.2014.68",
language = "English",
volume = "19",
pages = "966--977",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - Why are cortical GABA neurons relevant to internal focus in depression? A cross-level model linking cellular, biochemical and neural network findings

AU - Northoff, Georg Franz Josef

AU - Sibille, Etienne L.

N1 - Cited By :6 Export Date: 11 May 2016 CODEN: MOPSF Correspondence Address: Northoff, G.; Department of Psychiatry, University of Ottawa Institute of Mental Health Research, Royal Ottawa Hospital, 1145 Carling Avenue, Canada Chemicals/CAS: 4 aminobutyric acid, 28805-76-7, 56-12-2; gamma-Aminobutyric Acid Funding Details: CIHR, Canadian Institutes of Health Research Funding Details: HDRF, Canadian Institutes of Health Research Funding Details: MH077159, NIMH, Canadian Institutes of Health Research Funding Details: MH084060, NIMH, Canadian Institutes of Health Research References: WHO, (2008) World Health Organization - The Global Burden of Disease - 2004 Update, , WHO Library: Geneva, Switzerland; Mayberg, H.S., Modulating limbic-cortical circuits in depression: Targets of antidepressant treatments (2002) Semin Clin Neuropsychiatry, 7, pp. 255-268; Belmaker, R.H., Agam, G., Major depressive disorder (2008) N Engl J Med, 358, pp. 55-68; Kupfer, D.J., Frank, E., Phillips, M.L., Major depressive disorder: New clinical, neurobiological, and treatment perspectives (2012) Lancet, 379, pp. 1045-1055; Mayberg, H.S., Positron emission tomography imaging in depression: A neural systems perspective (2003) Neuroimag Clin N Am, 13, pp. 805-815; Holtzheimer, P.E., Mayberg, H.S., Stuck in a rut: Rethinking depression and its treatment (2011) Trends Neurosci, 34, pp. 1-9; Northoff, G., Walter, M., Schulte, R.F., Beck, J., Dydak, U., Henning, A., GABA concentrations in the human anterior cingulate cortex predict negative BOLD responses in fMRI (2007) Nat Neurosci, 10, pp. 1515-1517; Price, J.L., Drevets, W.C., Neural circuits underlying the pathophysiology of mood disorders (2012) Trends Cogn Sci, 16, pp. 61-71; Northoff, G., Wiebking, C., Feinberg, T., Panksepp, J., The 'resting-state hypothesis' of major depressive disorder - A translational subcortical-cortical framework for a system disorder (2011) Neurosci Biobehav Rev, 35, pp. 1929-1945; Alcaro, A., Panksepp, J., Witczak, J., Hayes, D.J., Northoff, G., Is subcortical-cortical midline activity in depression mediated by glutamate and GABA? 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PY - 2014

Y1 - 2014

N2 - Major depression is a complex and severe psychiatric disorder whose symptomatology encompasses a critical shift in awareness, especially in the balance from external to internal mental focus. This is reflected by unspecific somatic symptoms and the predominance of the own cognitions manifested in increased self-focus and rumination. We posit here that sufficient empirical data has accumulated to build a coherent biologic model that links these psychologic concepts and symptom dimensions to observed biochemical, cellular, regional and neural network deficits. Specifically, deficits in inhibitory γ-aminobutyric acid regulating excitatory cell input/output and local cell circuit processing of information in key brain regions may underlie the shift that is observed in depressed subjects in resting-state activities between the perigenual anterior cingulate cortex and the dorsolateral prefrontal cortex. This regional dysbalance translates at the network level in a dysbalance between default-mode and executive networks, which psychopathologically surfaces as a shift in focus from external to internal mental content and associated symptoms. We focus here on primary evidence at each of those levels and on putative mechanistic links between those levels. Apart from its implications for neuropsychiatric disorders, our model provides for the first time a set of hypotheses for cross-level mechanisms of how internal and external mental contents may be constituted and balanced in healthy subjects, and thus also contributes to the neuroscientific debate on the neural correlates of consciousness. © 2014 Macmillan Publishers Limited All rights reserved.

AB - Major depression is a complex and severe psychiatric disorder whose symptomatology encompasses a critical shift in awareness, especially in the balance from external to internal mental focus. This is reflected by unspecific somatic symptoms and the predominance of the own cognitions manifested in increased self-focus and rumination. We posit here that sufficient empirical data has accumulated to build a coherent biologic model that links these psychologic concepts and symptom dimensions to observed biochemical, cellular, regional and neural network deficits. Specifically, deficits in inhibitory γ-aminobutyric acid regulating excitatory cell input/output and local cell circuit processing of information in key brain regions may underlie the shift that is observed in depressed subjects in resting-state activities between the perigenual anterior cingulate cortex and the dorsolateral prefrontal cortex. This regional dysbalance translates at the network level in a dysbalance between default-mode and executive networks, which psychopathologically surfaces as a shift in focus from external to internal mental content and associated symptoms. We focus here on primary evidence at each of those levels and on putative mechanistic links between those levels. Apart from its implications for neuropsychiatric disorders, our model provides for the first time a set of hypotheses for cross-level mechanisms of how internal and external mental contents may be constituted and balanced in healthy subjects, and thus also contributes to the neuroscientific debate on the neural correlates of consciousness. © 2014 Macmillan Publishers Limited All rights reserved.

KW - 4 aminobutyric acid

KW - 4 aminobutyric acid receptor

KW - anterior cingulate

KW - cognition

KW - default mode network

KW - depression

KW - executive function

KW - GABAergic system

KW - human

KW - interneuron

KW - mental function

KW - negative feedback

KW - nerve cell

KW - nerve cell network

KW - neuropathology

KW - prefrontal cortex

KW - priority journal

KW - pyramidal nerve cell

KW - Review

KW - biological model

KW - brain cortex

KW - major depression

KW - metabolism

KW - nerve tract

KW - pathophysiology

KW - physiology

KW - psychology

KW - self concept

KW - Cerebral Cortex

KW - Depressive Disorder, Major

KW - GABAergic Neurons

KW - gamma-Aminobutyric Acid

KW - Humans

KW - Models, Neurological

KW - Neural Pathways

KW - Self Concept

U2 - 10.1038/mp.2014.68

DO - 10.1038/mp.2014.68

M3 - Article

VL - 19

SP - 966

EP - 977

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 9

ER -