Impaired prefrontal synaptic gain in people with psychosis and their relatives during the mismatch negativity.
The mismatch negativity (MMN) evoked potential, a preattentive brain response to a discriminable change in auditory stimulation, is significantly reduced in psychosis. Glutamatergic theories of psychosis propose that hypofunction of NMDA receptors (on pyramidal cells and inhibitory interneurons) causes a loss of synaptic gain control. We measured changes in neuronal effective connectivity underlying the MMN using dynamic causal modeling (DCM), where the gain (excitability) of superficial pyramidal cells is explicitly parameterised. EEG data were obtained during a MMN task--for 24 patients with psychosis, 25 of their first-degree unaffected relatives, and 35 controls--and DCM was used to estimate the excitability (modeled as self-inhibition) of (source-specific) superficial pyramidal populations. The MMN sources, based on previous research, included primary and secondary auditory cortices, and the right inferior frontal gyrus. Both patients with psychosis and unaffected relatives (to a lesser degree) showed increased excitability in right inferior frontal gyrus across task conditions, compared to controls. Furthermore, in the same region, both patients and their relatives showed a reversal of the normal response to deviant stimuli; that is, a decrease in excitability in comparison to standard conditions. Our results suggest that psychosis and genetic risk for the illness are associated with both context-dependent (condition-specific) and context-independent abnormalities of the excitability of superficial pyramidal cell populations in the MMN paradigm. These abnormalities could relate to NMDA receptor hypofunction on both pyramidal cells and inhibitory interneurons, and appear to be linked to the genetic aetiology of the illness, thereby constituting potential endophenotypes for psychosis.
Division of Psychiatry, University College London, London, United Kingdom.
Siri
S
Ranlund
Division of Psychiatry, University College London, London, United Kingdom.|Institute of Cognitive Neuroscience, University College London, London, United Kingdom.
Rick A
RA
Adams
Division of Psychiatry, University College London, London, United Kingdom.
Álvaro
Á
Díez
Department of Psychiatry, Hospital Beatriz Angelo, Lisbon, Portugal.
Miguel
M
Constante
The South London and Maudsley NHS Foundation Trust, NIHR Biomedical Research Centre for Mental Health at the Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Anirban
A
Dutt
Psychology Research Laboratory, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, USA.
Mei-Hua
MH
Hall
The South London and Maudsley NHS Foundation Trust, NIHR Biomedical Research Centre for Mental Health at the Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Amparo
A
Maestro Carbayo
Department of Psychiatry, Clinical Science Institute, National University of Ireland, Galway, Ireland.
Colm
C
McDonald
The South London and Maudsley NHS Foundation Trust, NIHR Biomedical Research Centre for Mental Health at the Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.|Department of Psychiatry, Clinical and Experimental Science Institute, University of Foggia, Italy.
Sabrina
S
Petrella
The South London and Maudsley NHS Foundation Trust, University Hospital Lewisham, London, United Kingdom.
Katja
K
Schulze
The South London and Maudsley NHS Foundation Trust, NIHR Biomedical Research Centre for Mental Health at the Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.|Neuroepidemiology and Ageing Research Unit, Imperial College, London, United Kingdom.
Madiha
M
Shaikh
Division of Psychiatry, University College London, London, United Kingdom.|The South London and Maudsley NHS Foundation Trust, NIHR Biomedical Research Centre for Mental Health at the Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Muriel
M
Walshe
The Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, United Kingdom.
Karl
K
Friston
The Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, United Kingdom.
Dimitris
D
Pinotsis
Division of Psychiatry, University College London, London, United Kingdom.|Institute of Cognitive Neuroscience, University College London, London, United Kingdom.|The South London and Maudsley NHS Foundation Trust, NIHR Biomedical Research Centre for Mental Health at the Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Elvira
E
Bramon
D000161:Acoustic Stimulation; D000293:Adolescent; D000328:Adult; D001930:Brain Injuries / Q000150:complications* / Q000473:pathology*; D003265:Contingent Negative Variation / Q000502:physiology*; D004569:Electroencephalography; D005072:Evoked Potentials, Auditory / Q000502:physiology*; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D017711:Nonlinear Dynamics; D017397:Prefrontal Cortex / Q000473:pathology / Q000503:physiopathology*; D011618:Psychotic Disorders / Q000150:complications*; D055815:Young Adult
DCM; NMDA receptor; cortical excitability; cortical gain; dynamic causal modeling; effective connectivity; genetic risk; psychosis; schizophrenia; unaffected relatives