Gating of attentional effort through the central thalamus.

The central thalamus plays an important role in the regulation of arousal and allocation of attentional resources in the performance of even simple tasks. To assess the contribution of central thalamic neurons to short-term adjustments of attentional effort, we analyzed 166 microelectrode recordings obtained from two rhesus monkeys performing a visuomotor simple reaction time task with a variable foreperiod. Multiunit responses showed maintained firing rate elevations during the variable delay period of the task in ∼24% of recording sites. Simultaneously recorded local field potentials demonstrated significant decreases in power at ∼10-20 Hz and increases in power at 30-100 Hz during the delay period when compared against precue baselines. Comparison of the spectral power of local field potentials during the delay period of correct and incorrect trials showed that, during incorrect trials, similar, but reduced, shifts of spectral power occurred within the same frequency bands. Sustained performance of even simple tasks requires regulation of arousal and attention that combine in the concept of "attentional effort". Our findings suggest that central thalamic neurons regulate task performance through brief changes in firing rates and spectral power changes during task-relevant short-term shifts of attentional effort. Increases in attentional effort may be reflected in changes within the central thalamic local populations, where correct task performance associates with more robust maintenance of firing rates during the delay period. Such ongoing fluctuations of central thalamic activity likely reflect a mix of influences, including variations in moment-to-moment levels of motivation, arousal, and availability of cognitive resources.

Behavioural improvements with thalamic stimulation after severe traumatic brain injury.

Widespread loss of cerebral connectivity is assumed to underlie the failure of brain mechanisms that support communication and goal-directed behaviour following severe traumatic brain injury. Disorders of consciousness that persist for longer than 12 months after severe traumatic brain injury are generally considered to be immutable; no treatment has been shown to accelerate recovery or improve functional outcome in such cases. Recent studies have shown unexpected preservation of large-scale cerebral networks in patients in the minimally conscious state (MCS), a condition that is characterized by intermittent evidence of awareness of self or the environment. These findings indicate that there might be residual functional capacity in some patients that could be supported by therapeutic interventions. We hypothesize that further recovery in some patients in the MCS is limited by chronic underactivation of potentially recruitable large-scale networks. Here, in a 6-month double-blind alternating crossover study, we show that bilateral deep brain electrical stimulation (DBS) of the central thalamus modulates behavioural responsiveness in a patient who remained in MCS for 6 yr following traumatic brain injury before the intervention. The frequency of specific cognitively mediated behaviours (primary outcome measures) and functional limb control and oral feeding (secondary outcome measures) increased during periods in which DBS was on as compared with periods in which it was off. Logistic regression modelling shows a statistical linkage between the observed functional improvements and recent stimulation history. We interpret the DBS effects as compensating for a loss of arousal regulation that is normally controlled by the frontal lobe in the intact brain. These findings provide evidence that DBS can promote significant late functional recovery from severe traumatic brain injury. Our observations, years after the injury occurred, challenge the existing practice of early treatment discontinuation for patients with only inconsistent interactive behaviours and motivate further research to develop therapeutic interventions.

Longitudinal alterations in gamma-aminobutyric acid (GABAA) receptor availability over ∼ 1 year following traumatic brain injury.

Longitudinal alterations of gamma-aminobutyric acid (GABAA) receptor availability following traumatic brain injury have remained uncharacterized and may reflect changes in neuronal structure and function linked to cognitive recovery. We measured GABAA receptor availability using the tracer [11C]flumazenil in nine adults with traumatic brain injury (3-6 months after injury, subacute scan) and in 20 non-brain-injured individuals. A subset of subjects with traumatic brain injury (n = 7) were scanned at a second chronic time-point, 7-13 months after their first scan; controls (n = 9) were scanned for a second time, 5-11 months after the first scan. After accounting for atrophy in subjects with traumatic brain injury, we find broad decreases in GABAA receptor availability predominantly within the frontal lobes, striatum, and posterior-medial thalami; focal reductions were most pronounced in the right insula and anterior cingulate cortex (p < 0.05). Greater relative increase, compared to controls, in global GABAA receptor availability appeared between subacute and chronic scans. At chronic scan (>1 year post-injury), we find increased pallidal receptor availability compared to controls. Conversely, receptor availability remained depressed across the frontal cortices. Longitudinal improvement in executive attention correlated with increases in receptor availability across bilateral fronto-parietal cortical regions and the anterior-lateral aspects of the thalami. The specific observations of persistent bi-frontal lobe reductions and bilateral pallidal elevation are consistent with the anterior forebrain mesocircuit hypothesis for recovery of consciousness following a wide range of brain injuries; our results provide novel correlative data in support of specific cellular mechanisms underlying persistent cognitive deficits. Collectively, these measurements support the use of [11C]flumazenil to track recovery of large-scale network function following brain injuries and measure response to therapeutics.

Selective activation of central thalamic fiber pathway facilitates behavioral performance in healthy non-human primates.

Central thalamic deep brain stimulation (CT-DBS) is an investigational therapy to treat enduring cognitive dysfunctions in structurally brain injured (SBI) patients. However, the mechanisms of CT-DBS that promote restoration of cognitive functions are unknown, and the heterogeneous etiology and recovery profiles of SBI patients contribute to variable outcomes when using conventional DBS strategies,which may result in off-target effects due to activation of multiple pathways. To disambiguate the effects of stimulation of two adjacent thalamic pathways, we modeled and experimentally compared conventional and novel 'field-shaping' methods of CT-DBS within the central thalamus of healthy non-human primates (NHP) as they performed visuomotor tasks. We show that selective activation of the medial dorsal thalamic tegmental tract (DTTm), but not of the adjacent centromedian-parafascicularis (CM-Pf) pathway, results in robust behavioral facilitation. Our predictive modeling approach in healthy NHPs directly informs ongoing and future clinical investigations of conventional and novel methods of CT-DBS for treating cognitive dysfunctions in SBI patients, for whom no therapy currently exists.

Clinical and advanced neurophysiology in the prognostic and diagnostic evaluation of disorders of consciousness: review of an IFCN-endorsed expert group.

The analysis of spontaneous EEG activity and evoked potentialsis a cornerstone of the instrumental evaluation of patients with disorders of consciousness (DoC). Thepast few years have witnessed an unprecedented surge in EEG-related research applied to the prediction and detection of recovery of consciousness after severe brain injury,opening up the prospect that new concepts and tools may be available at the bedside. This paper provides a comprehensive, critical overview of bothconsolidated and investigational electrophysiological techniquesfor the prognostic and diagnostic assessment of DoC.We describe conventional clinical EEG approaches, then focus on evoked and event-related potentials, and finally we analyze the potential of novel research findings. In doing so, we (i) draw a distinction between acute, prolonged and chronic phases of DoC, (ii) attempt to relate both clinical and research findings to the underlying neuronal processes and (iii) discuss technical and conceptual caveats.The primary aim of this narrative review is to bridge the gap between standard and emerging electrophysiological measures for the detection and prediction of recovery of consciousness. The ultimate scope is to provide a reference and common ground for academic researchers active in the field of neurophysiology and clinicians engaged in intensive care unit and rehabilitation.

Human consciousness is supported by dynamic complex patterns of brain signal coordination.

Adopting the framework of brain dynamics as a cornerstone of human consciousness, we determined whether dynamic signal coordination provides specific and generalizable patterns pertaining to conscious and unconscious states after brain damage. A dynamic pattern of coordinated and anticoordinated functional magnetic resonance imaging signals characterized healthy individuals and minimally conscious patients. The brains of unresponsive patients showed primarily a pattern of low interareal phase coherence mainly mediated by structural connectivity, and had smaller chances to transition between patterns. The complex pattern was further corroborated in patients with covert cognition, who could perform neuroimaging mental imagery tasks, validating this pattern's implication in consciousness. Anesthesia increased the probability of the less complex pattern to equal levels, validating its implication in unconsciousness. Our results establish that consciousness rests on the brain's ability to sustain rich brain dynamics and pave the way for determining specific and generalizable fingerprints of conscious and unconscious states.

The application of a mathematical model linking structural and functional connectomes in severe brain injury.

Following severe injuries that result in disorders of consciousness, recovery can occur over many months or years post-injury. While post-injury synaptogenesis, axonal sprouting and functional reorganization are known to occur, the network-level processes underlying recovery are poorly understood. Here, we test a network-level functional rerouting hypothesis in recovery of patients with disorders of consciousness following severe brain injury. This hypothesis states that the brain recovers from injury by restoring normal functional connections via alternate structural pathways that circumvent impaired white matter connections. The so-called network diffusion model, which relates an individual's structural and functional connectomes by assuming that functional activation diffuses along structural pathways, is used here to capture this functional rerouting. We jointly examined functional and structural connectomes extracted from MRIs of 12 healthy and 16 brain-injured subjects. Connectome properties were quantified via graph theoretic measures and network diffusion model parameters. While a few graph metrics showed groupwise differences, they did not correlate with patients' level of consciousness as measured by the Coma Recovery Scale - Revised. There was, however, a strong and significant partial Pearson's correlation (accounting for age and years post-injury) between level of consciousness and network diffusion model propagation time (r = 0.76, p < 0.05, corrected), i.e. the time functional activation spends traversing the structural network. We concluded that functional rerouting via alternate (and less efficient) pathways leads to increases in network diffusion model propagation time. Simulations of injury and recovery in healthy connectomes confirmed these results. This work establishes the feasibility for using the network diffusion model to capture network-level mechanisms in recovery of consciousness after severe brain injury.

Common dynamics in temporal lobe seizures and absence seizures.

Similarities among the clinical features of complex partial temporal lobe seizures and absence (petit mal) seizures suggest shared underlying mechanisms, but dissimilar electrographic features of the two seizure types have cast doubt on common neuronal substrates. However, visual inspection and traditional approaches to quantitative analysis of the electroencephalogram and electrocorticogram, such as Fourier analysis, may not be appropriate to identify and characterize the highly non-linear mechanisms likely to underlie ictal events. We previously introduced a technique, non-linear autoregressive analysis, that is designed to identify non-linear dynamics in the electroencephalogram [Schiff N. D. et al. (1991) Society of Neuroscience 21st Annual Meeting, 638.6; Schiff N. D. et al. (1995) Biol. Cybern. 72, 519-526, 527-533]. The non-linear autoregressive analysis technique is aimed at describing seizure discharges as a disturbance of synchrony at the level of neuronal circuits. In absence seizures, we showed that non-linear autoregressive analysis revealed a consistent "fingerprint" of these non-linearities in 3/s discharges within and across patients. Here, we investigate the possibility that non-linear autoregressive modeling of seizure records from patients with temporal lobe epilepsy might reveal common circuit mechanisms when compared with the non-linear autoregressive analysis fingerprint of absence seizures. Electrocorticographic records of seizure activity were obtained in four patients who had received subdural grids or strips implanted in preparation for epilepsy surgery. Decomposition of the multichannel data recorded from these patients by principal component analysis revealed that at least three to five independent "generators" were required to model the data from each patient. Non-linear autoregressive analysis of these extracted generators revealed non-linear dynamics in two patients. In both patients, the temporal aspects of these non-linearities were similar to the characteristic non-linearities identified in the non-linear autoregressive analysis fingerprint of absence seizures. In particular, both patients showed a non-linear interaction of signals 90 ms in the past with signals 150 ms in the past. This was the most prominent interaction seen in all patients with absence seizures (typical and atypical). These results suggest that seizures from some patients with temporal lobe epilepsy may share common underlying circuit mechanisms with those of absence seizures. Physiological interpretations of these results are considered and proposed mechanisms are placed into the context of the alterations of consciousness seen in both epilepsies.

Does vestibular stimulation activate thalamocortical mechanisms that reintegrate impaired cortical regions?

Caloric stimulation induced a transient reversal of multimodal hemispatial cognitive deficits in an 81-year-old woman with an acute left cerebral hemisphere stroke. The patient had unawareness of her right hand (asomatognosia), right-sided visual unawareness (hemineglect), aphasia and right-sided weakness (hemiplegia) prior to the stimulation. Transient improvements in impaired sensory, motor, linguistic and cognitive function developed within 30 s following application of the caloric stimulus and onset of horizontal nystagmus. The effect persisted for 3 min and ceased completely after 5 min. While several recent reports have described the capacity of caloric stimulation to transiently improve or reverse a wide range of attentional, cognitive and motor impairments, most examples are in right-hemisphere-damaged patients with long-standing brain injury. Typically, patients have been tested several months or years after the onset of the deficit. A possible mechanism for the temporary reintegration of multiple cognitive functions in this patient is discussed.

Power spectra and coherence in the EEG of a vegetative patient with severe asymmetric brain damage.

OBJECTIVES: To examine differences in power spectra and intra-hemispheric coherence between the left and right hemispheres in the presence of severe asymmetric brain damage. METHODS: Power spectra and coherence functions were computed for a patient with severe damage to subcortical gray matter structures on the right side but relative preservation on the left. RESULTS: Power spectra differed modestly over the hemispheres, with greater low frequency power and less high frequency power over the more damaged right hemisphere. Coherence differed dramatically, with marked reduced coherence over the right hemisphere, particularly frontally where the damage was most extensive. CONCLUSIONS: Damage to subcortical structures of one hemisphere may result in a marked reduction in coherence in the ipsilateral EEG with only a modest change in the power spectrum. We speculate that the physiologic basis of this selective change is damage to structures mediating communication between cortical areas.

The role of arousal and "gating" systems in the neurology of impaired consciousness.

A brief taxonomy of neurologic disorders resulting in global impairments of consciousness is presented. Particular emphasis is placed on focal injuries of subcortical structures that may produce disorders that are otherwise associated to large bilateral cortical injuries. A distinction between subcortical arousal and "gating" systems is developed. Both clinical and experimental studies are reviewed in the context of these disorders and their possible underlying mechanisms.

A neuromodulation strategy for rational therapy of complex brain injury states.

We review initial efforts at neuromodulation in the vegetative state and organize several aspects of recent studies of the underlying neurobiology of catastrophic brain injuries. An innovative strategy for patient and target selection for neuromodulation of impaired cognitive function is outlined. Scientific and ethical issues that will attend future efforts to appropriately risk-stratify patients and initiate interventions with therapeutic intent are considered.

Arterial spin labeling and altered cerebral blood flow patterns in the minimally conscious state.

OBJECTIVE: To use arterial spin labeling (ASL) to compare cerebral blood flow (CBF) patterns in minimally conscious state (MCS) patients with those in normal controls in an observational study design. METHODS: Subjects meeting MCS criteria and normal controls were identified. A pseudocontinuous ASL sequence was performed with subjects and controls in the resting awake state. Multiple CBF values for 10 predetermined regions of interest were sampled and average CBF was calculated and compared between controls and subjects. RESULTS: Ten normal controls were identified, with ages ranging from 26 to 54 years. Four subjects met the MCS criteria and received an ASL study, with one patient receiving a second study at a later date. Subjects ranged in age from 19 to 58 years and had traumatic brain injury, stroke, or hypoxic-ischemic encephalopathy. Regional CBF for controls ranged from 21.6 to 57.2 mL/100 g/min, with a pattern of relatively increased blood flow posteriorly including the posterior cingulate, parietal, and occipital cortices. CBF patterns for MCS subjects showed greater variability (from 7.7 to 33.1 mL/100 g/min), demonstrating globally decreased CBF in gray matter compared with that in normal controls, especially in the medial prefrontal and midfrontal regions. In the one subject studied longitudinally, global CBF values increased over time, which correlated with clinical improvement. CONCLUSIONS: We identified globally decreased CBF and a selective reduction of CBF within the medial prefrontal and midfrontal cortical regions as well as gray matter in MCS patients. ASL may serve as an adjunctive method to assess functional reserve in patients recovering from severe brain injuries.

A network approach to assessing cognition in disorders of consciousness.

OBJECTIVE: Conventional assessments of consciousness rely on motor responses to indicate awareness. However, overt behaviors may be absent or ambiguous in patients with disorders of consciousness (DOC) resulting in underrating capacity for cognition. fMRI during a silent picture-naming task was evaluated as an indicator of command following when conventional methods are not sufficient. METHODS: A total of 10 patients with and without conventional evidence of awareness, who met diagnostic criteria for the minimally conscious state (MCS) (n = 5), vegetative state (VS) (n = 3), emerged from MCS (EMCS) (n = 1), and locked-in syndrome (LIS) (n = 1), participated in this observational fMRI study. RESULTS: The LIS and EMCS patients engaged a complete network of essential language-related regions during the object-naming task. The MCS and 2 of the VS patients demonstrated both complete and partial preservation of the object-naming system. Patients who engaged a complete network scored highest on the Coma Recovery Scale-Revised. CONCLUSIONS: This study supports the view that fMRI during object naming can elicit brain activations in patients with DOC similar to those observed in healthy subjects during command following, and patients can be stratified by completeness of the engaged neural system. These results suggest that activity of the language network may serve as an indicator of high-level cognition and possibly volitional processes that cannot be discerned through conventional behavioral assessment alone.

fMRI reveals large-scale network activation in minimally conscious patients.

BACKGROUND: The minimally conscious state (MCS) resulting from severe brain damage refers to a subset of patients who demonstrate unequivocal, but intermittent, behavioral evidence of awareness of self or their environment. Although clinical examination may suggest residual cognitive function, neurobiological correlates of putative cognition in MCS have not been demonstrated. OBJECTIVE: To test the hypothesis that MCS patients retain active cerebral networks that underlie cognitive function even though command following and communication abilities are inconsistent. METHODS: fMRI was employed to investigate cortical responses to passive language and tactile stimulation in two male adults with severe brain injuries leading to MCS and in seven healthy volunteers. RESULTS: In the case of the patient language-related tasks, auditory stimulation with personalized narratives elicited cortical activity in the superior and middle temporal gyrus. The healthy volunteers imaged during comparable passive language stimulation demonstrated responses similar to the patients' responses. However, when the narratives were presented as a time-reversed signal, and therefore without linguistic content, the MCS patients demonstrated markedly reduced responses as compared with volunteer subjects, suggesting reduced engagement for "linguistically" meaningless stimuli. CONCLUSIONS: The first fMRI maps of cortical activity associated with language processing and tactile stimulation of patients in the minimally conscious state (MCS) are presented. These findings of active cortical networks that serve language functions suggest that some MCS patients may retain widely distributed cortical systems with potential for cognitive and sensory function despite their inability to follow simple instructions or communicate reliably.

General strategy for hierarchical decomposition of multivariate time series: implications for temporal lobe seizures.

We describe a novel method for the analysis of multivariate time series that exploits the dynamic relationships among the multiple signals. The approach resolves the multivariate time series into hierarchically dependent underlying sources, each driven by noise input and influencing subordinate sources in the hierarchy. Implementation of this hierarchical decomposition (HD) combines principal components analysis (PCA), autoregressive modeling, and a novel search strategy among orthogonal rotations. For model systems conforming to this hierarchical structure, HD accurately extracts the underlying sources, whereas PCA or independent components analysis does not. The interdependencies of cortical, subcortical, and brainstem networks suggest application of HD to multivariate measures of brain activity. We show first that HD indeed resolves temporal lobe ictal electrocorticographic data into nearly hierarchical form. A previous analysis of these data identified characteristic nonlinearities in the PCA-derived temporal components that resembled those seen in absence (petit mal) seizure electroencephalographic traces. However, the components containing these characteristic nonlinearities accounted for only a small fraction of the power. Analysis of these data with HD reveals furthermore that components containing characteristic nonlinearities, though small, can be at the origin of the hierarchy. This finding supports the link between temporal lobe and absence epilepsy.

Nonlinear autoregressive analysis of the 3/s ictal electroencephalogram: implications for underlying dynamics.

In a previous study, nonlinear autoregressive (NLAR) models applied to ictal electroencephalogram (EEG) recordings in six patients revealed nonlinear signal interactions that correlated with seizure type and clinical diagnosis. Here we interpret these models from a theoretical viewpoint. Extended models with multiple nonlinear terms are employed to demonstrate the independence of nonlinear dynamical interactions identified in the 'NLAR fingerprint' of patients with 3/s seizure discharges. Analysis of the role of periodicity in the EEG signal reveals that the fingerprints reflect the dynamics not only of the periodic discharge itself, but also of the fluctuations of each cycle about an average waveform. A stability analysis is used to make qualitative inferences concerning the network properties of the ictal generators. Finally, the NLAR fingerprint is analyzed in the context of Volterra-Weiner theory.

Gating of local network signals appears as stimulus-dependent activity envelopes in striate cortex.

Neuronal activity often is treated as a composition of a stimulus-driven component and a second component that corrupts the signal, adding or deleting spikes at random. Standard quantitative methods such as peristimulus histograms and Fourier analysis use stimulus-locked averaging to enhance detection of the driven component of neuronal responses and de-emphasize the "noise." However, neural activity also includes bursts, oscillations, and other episodic events that standard averaging methods overlook. If this activity is stimulus independent, it can be characterized by standard power spectral analysis (or autocorrelation). But activity that is excited by (but not temporally locked to) the visual stimulus cannot be characterized by averaging or standard spectral analysis. Phase-locked spectral analysis (PLSA) is a new method that examines this "residual" activity-the difference between the individual responses to each cycle of a periodic stimulus and their average. With PLSA, residual activity is characterized in terms of temporal envelopes and their carriers. Previously, PLSA demonstrated broadband interactions between periodic visual stimuli and fluctuations in the local field potential of macaque V1. In the present study, single-unit responses (SUA) from parafoveal V1 in anesthetized macaque monkey are examined with this technique. Recordings were made from 21 neurons, 6 of which were recorded in pairs along with multiunit activity (MUA) from separate electrodes and 8 of which were recorded along with MUA from the same electrode. PLSA was applied to responses to preferred (orientation, direction, and spatial frequency) and nonpreferred drifting gratings. For preferred stimuli, all cells demonstrated broadband (1-10 Hz and higher) residual activity that waxed and waned with the stimulus cycle, suggesting that changes in the residual activity are introduced routinely by visual stimulation. Moreover, some reconstructed envelopes indicate that the residual activity was sharply gated by the stimulus cycle. Oscillations occasionally were seen in the power spectrum of single units. Phase-locked cross-spectra were determined for 3 SUA/SUA pairs and 11 SUA/MUA pairs. Residual activity in the cross-spectra was generally much less than the residual activity determined separately from each neuron. The reduction in the residual activity in the cross-spectra suggests that nearby neurons may gate inputs from distinct and relatively independent neuronal subpopulations that together generate the background rhythms of striate cortex.

Characteristic nonlinearities of the 3/s ictal electroencephalogram identified by nonlinear autoregressive analysis.

We describe a method for the characterization of electroencephalographic (EEG) signals based on a model which features nonlinear feedback. The characteristic EEG 'fingerprints' obtained through this approach display the time-course of nonlinear interactions, rather than aspects susceptible to standard spectral analysis. Fingerprints of seizure discharges in six patients (five with typical absence seizures, one with complex partial seizures) revealed significant nonlinear interactions. The timing and pattern of these interactions correlated closely with the seizure type. Nonlinear autoregressive (NLAR) analysis is compared with other nonlinear dynamical measures that have been applied to the EEG.