Electrophysiological correlates of thalamocortical function in acute severe traumatic brain injury

Few reliable biomarkers of consciousness exist for patients with acute severe brain injury. Tools assaying the neural networks that modulate consciousness may allow for tracking of recovery. The mesocircuit model, and its instantiation as the ABCD framework, classifies resting-state EEG power spectral densities into categories reflecting widely separated levels of thalamocortical network function and correlates with outcome in post-cardiac arrest coma. We applied the ABCD framework to acute severe traumatic brain injury and tested four hypotheses: 1) EEG channel-level ABCD classifications are spatially heterogeneous and temporally variable; 2) ABCD classifications improve longitudinally, commensurate with the degree of behavioural recovery; 3) ABCD classifications correlate with behavioural level of consciousness; and 4) the Coma Recovery Scale-Revised arousal facilitation protocol improves EEG dynamics along the ABCD scale. In this longitudinal cohort study, we enrolled 20 patients with acute severe traumatic brain injury requiring intensive care and 16 healthy controls. Through visual inspection, channel-level spectra from resting-state EEG were classified based on spectral peaks within frequency bands defined by the ABCD framework: A = no peaks above delta (<4 Hz) range (complete thalamocortical disruption); B = theta (4-8 Hz) peak (severe thalamocortical disruption); C = theta and beta (13-24 Hz) peaks (moderate thalamocortical disruption); or D = alpha (8-13 Hz) and beta peaks (normal thalamocortical function). We assessed behavioural level of consciousness with the Coma Recovery Scale-Revised or neurological examination and, in 12 patients, performed repeat EEG and behavioural assessments at ≥6-months post-injury. Acutely, 95% of patients demonstrated D signals in at least one channel but exhibited heterogeneity in the proportion of different channel-level ABCD classifications (mean percent D signals: 37%, range: 0-90%). By contrast, healthy participants and patients at follow-up predominantly demonstrated signals corresponding to intact thalamocortical network function (mean percent D signals: 94%). In patients studied acutely, ABCD classifications improved after the Coma Recovery Scale-Revised arousal facilitation protocol (P<0.05), providing electrophysiological evidence for the effectiveness of this commonly performed technique. ABCD classification did not correspond with behavioural level of consciousness acutely, where patients demonstrated substantial within-session temporal variability in ABCD classifications. However, ABCD classification distinguished patients with and without command-following in the subacute-to-chronic phase of recovery (P<0.01). Patients also demonstrated significant longitudinal improvement in EEG dynamics along the ABCD scale (median change in D signals: 37%, P<0.05). These findings support the use of the ABCD framework to characterize channel-level EEG dynamics and track fluctuations in functional thalamocortical network integrity in spatial detail.

The impact of a closed-loop thalamocortical model on the spatiotemporal dynamics of cortical and thalamic traveling waves

Propagation of activity in spatially structured neuronal networks has been observed in awake, anesthetized, and sleeping brains. How these wave patterns emerge and organize across brain structures, and how network connectivity affects spatiotemporal neural activity remains unclear. Here, we develop a computational model of a two-dimensional thalamocortical network, which gives rise to emergent traveling waves similar to those observed experimentally. We illustrate how spontaneous and evoked oscillatory activity in space and time emerge using a closed-loop thalamocortical architecture, sustaining smooth waves in the cortex and staggered waves in the thalamus. We further show that intracortical and thalamocortical network connectivity, cortical excitation/inhibition balance, and thalamocortical or corticothalamic delay can independently or jointly change the spatiotemporal patterns (radial, planar and rotating waves) and characteristics (speed, direction, and frequency) of cortical and thalamic traveling waves. Computer simulations predict that increased thalamic inhibition induces slower cortical frequencies and that enhanced cortical excitation increases traveling wave speed and frequency. Overall, our results provide insight into the genesis and sustainability of thalamocortical spatiotemporal patterns, showing how simple synaptic alterations cause varied spontaneous and evoked wave patterns. Our model and simulations highlight the need for spatially spread neural recordings to uncover critical circuit mechanisms for brain functions.

Optogenetic activation of striatal D1/D2 medium spiny neurons differentially engages downstream connected areas beyond the basal ganglia

The basal ganglia (BG) are a group of subcortical nuclei responsible for motor control, motor learning and executive function. Central to BG function are striatal medium spiny neurons (MSNs) expressing D1 and D2 dopamine receptors. D1 and D2 MSNs are typically considered functional antagonists that facilitate voluntary movements and inhibit competing motor patterns, respectively. While their opposite role is well documented for certain sensorimotor loops of the BG-thalamocortical network, it is unclear whether MSNs maintain a uniform functional role across the striatum and which influence they exert on brain areas outside the BG. Here, we addressed these questions by combining optogenetic activation of D1 and D2 MSNs in the mouse ventrolateral caudoputamen (vl CPu) with whole-brain functional MRI (fMRI) recordings. Neuronal excitation of either cell population in the vl CPu evoked distinct activity patterns in key regions of the BG-thalamocortical network including the pallidum, thalamus and motor cortex. Importantly, we report that striatal D1 and D2 MSN stimulation differentially engaged cerebellar and prefrontal regions. We characterised these long-range interactions by computational modelling of effective connectivity and confirmed that changes in D1 / D2 output drive functional relationships between regions within and beyond the BG. These results suggest a more complex functional organization of MSNs across the striatum than previously anticipated and provide evidence for the existence of an interconnected fronto - BG - cerebellar network modulated by striatal D1 and D2 MSNs.Graphical Abstract

0158 Loss of Connexin 36 Elicits Abnormalities in Thalamocortical Network Activity Relevant to Neuropsychiatric Disorders

Introduction Neuronal gap-junctions are extensively expressed in mammalian forebrain and suggested to contribute to state-regulation and thalamocortical network activity. However, the physiological role of gap-junctions on these processes remains poorly understood. Connexin-36 (Cxn36) is highly expressed in the brain, representing a mechanism for electrical coupling of inhibitory neurons. We examined the effects of global Cnx36 deletion on sleep/wake and spontaneous and evoked EEG activity. Methods We recorded in vivo EEG/EMG in Cxn36KO mice and littermate controls. Electrodes were stereotaxically implanted above frontal cortices. We analyzed sleep/wake states and algorithmically detected sleep spindles over 24 hours. Mice underwent auditory stimulation paradigms including the auditory steady state response (ASSR; 1 second train 20-50Hz clicks, 100 reps., 85dB) and mismatch negativity (MMN; 2.5kHz standard 90%, 10kHz deviant 10%, 300ms ISI, 90dB). Social behavior and investigation-evoked EEG activity were also assessed via the social habituation task (repeated 5 min exposures to novel mouse). Results Cnx36KO mice exhibited limited sleep/wake abnormalities (n=7/group). Power spectra of EEG revealed significant impairments in spontaneous gamma-band activity (30-80Hz; All States, Light & Dark Phases), and beta activity (15-25Hz; All States, Light Phase). Sigma activity (10-15Hz) was significantly decreased (NREM and REM, Light phase). This was particularly pronounced during NREM-REM transitions. Despite no changes in spindle density, both spindle amplitude and duration were significantly decreased in Cnx36KOs. Cxn36KOs exhibited a blunted gamma-band response to acute ketamine (15mg/kg; IP), impaired 30 & 40Hz ASSR, and an abnormal response in the MMN task (decrease ERP peak amplitude & gamma). Finally, Cxn36KO mice exhibit impaired social habituation and significantly decreased investigation evoked slow gamma-band activity (30 - 55Hz). Conclusion Our data suggest Cxn36 plays a critical role in regulating thalamocortical network activity. Further, impairments in Cnx36KO mice reflect abnormalities in neuropsychiatric disorders, including schizophrenia, implicating Cnx36 containing gap junctions as a novel therapeutic target. Support Research supported by VA CDA Award BX002130 (JMM), VA Merit Awards BX004500 (JMM), BX001404 (RB), and NIMH RO1 MH39683 (Ritchie E. Brown).