Computational Synaptic Modeling of Pitch and Duration Mismatch Negativity in First-Episode Psychosis Reveals Selective Dysfunction of the N-Methyl-D-Aspartate Receptor.

Mismatch negativity (MMN) to pitch (pMMN) and to duration (dMMN) deviant stimuli is significantly more attenuated in long-term psychotic illness compared to first-episode psychosis (FEP). It was recently shown that source-modeling of magnetically recorded MMN increases the detection of left auditory cortex MMN deficits in FEP, and that computational circuit modeling of electrically recorded MMN also reveals left-hemisphere auditory cortex abnormalities. Computational modeling using dynamic causal modeling (DCM) can also be used to infer synaptic activity from EEG-based scalp recordings. We measured pMMN and dMMN with EEG from 26 FEP and 26 matched healthy controls (HCs) and used a DCM conductance-based neural mass model including α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, N-methyl-D-Aspartate (NMDA), and Gamma-aminobutyric acid receptors to identify any changes in effective connectivity and receptor rate constants in FEP. We modeled MMN sources in bilateral A1, superior temporal gyrus, and inferior frontal gyrus (IFG). No model parameters distinguished groups for pMMN. For dMMN, reduced NMDA receptor activity in right IFG in FEP was detected. This finding is in line with literature of prefrontal NMDA receptor hypofunction in chronic schizophrenia and suggests impaired NMDA-induced synaptic plasticity may be present at psychosis onset where scalp dMMN is only moderately reduced. To the best of our knowledge, this is the first report of impaired NMDA receptor activity in FEP found through computational modeling of dMMN and shows the potential of DCM to non-invasively reveal synaptic-level abnormalities that underly subtle functional auditory processing deficits in early psychosis.

Nociceptive activation in spinal cord and brain persists during deep general anaesthesia.

BACKGROUND: In clinical practice, analgesic drug doses applied during general anaesthesia are considered sufficient when clinical responses (e.g. movement, blood pressure and heart rate elevations) are suppressed during noxious stimulation. We investigated whether absent clinical responses are indicative of suppressed spinal and brain responsiveness to noxious stimulation in anaesthetised subjects. METHODS: Ten healthy volunteers were investigated during deep propofol anaesthesia supplemented with increasing doses of remifentanil in a stepwise manner. Noxious electrical stimuli at an intensity comparable with surgical stimulation were repeatedly administered at each targeted remifentanil concentration. During stimulation, we monitored both clinical responses (blood pressure, heart rate, and movement) and neuronal responses. Neuronal responses were assessed using functional magnetic resonance imaging, spinal reflex responses, and somatosensory evoked potentials. RESULTS: This monitoring combination was able to faithfully detect brain and spinal neuronal responses to the noxious stimulation. Although clinical responses were no longer detected at analgesic dosages similar to those used for general anaesthesia in clinical practice, spinal and brain neuronal responses were consistently observed. Opioid doses that are significantly larger than is usually used in clinical practice only reduced neuronal responses to 41% of their maximal response. CONCLUSIONS: Nociceptive activation persists during deep general anaesthesia despite abolished clinical responses. Absent clinical responses are therefore not indicative of absent nociception-specific activation. Thus, commonly accepted clinical responses might be inadequate surrogate markers to assess anti-nociception during general anaesthesia. Further research is required to investigate whether persistent nociception causes adverse effects on patient outcome.

Linking canonical microcircuits and neuronal activity: Dynamic causal modelling of laminar recordings.

Neural models describe brain activity at different scales, ranging from single cells to whole brain networks. Here, we attempt to reconcile models operating at the microscopic (compartmental) and mesoscopic (neural mass) scales to analyse data from microelectrode recordings of intralaminar neural activity. Although these two classes of models operate at different scales, it is relatively straightforward to create neural mass models of ensemble activity that are equipped with priors obtained after fitting data generated by detailed microscopic models. This provides generative (forward) models of measured neuronal responses that retain construct validity in relation to compartmental models. We illustrate our approach using cross spectral responses obtained from V1 during a visual perception paradigm that involved optogenetic manipulation of the basal forebrain. We find that the resulting neural mass model can distinguish between activity in distinct cortical layers - both with and without optogenetic activation - and that cholinergic input appears to enhance (disinhibit) superficial layer activity relative to deep layers. This is particularly interesting from the perspective of predictive coding, where neuromodulators are thought to boost prediction errors that ascend the cortical hierarchy.