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•Combined brain perturbation and neuroimaging can reveal causal brain mechanisms.•Overview of perturbation methods used with non-human primate neuroimaging.•Methodological considerations of the different techniques are discussed.•Translational potential and future directions are laid out and critically assessed. Brain perturbation studies allow detailed causal inferences of behavioral and neural processes. Because the combination of brain perturbation methods and neural measurement techniques is inherently challenging, research in humans has predominantly focused on non-invasive, indirect brain perturbations, or neurological lesion studies. Non-human primates have been indispensable as a neurobiological system that is highly similar to humans while simultaneously being more experimentally tractable, allowing visualization of the functional and structural impact of systematic brain perturbation. This review considers the state of the art in non-human primate brain perturbation with a focus on approaches that can be combined with neuroimaging. We consider both non-reversible (lesions) and reversible or temporary perturbations such as electrical, pharmacological, optical, optogenetic, chemogenetic, pathway-selective, and ultrasound based interference methods. Method-specific considerations from the research and development community are offered to facilitate research in this field and support further innovations. We conclude by identifying novel avenues for further research and innovation and by highlighting the clinical translational potential of the methods.

A central challenge of neuroscience is to elucidate how brain function supports consciousness. Here, we combine the specificity of focal deep brain stimulation with fMRI coverage of the entire cortex, in awake and anaesthetised non-human primates. During propofol, sevoflurane, or ketamine anaesthesia, and subsequent restoration of responsiveness by electrical stimulation of the central thalamus, we investigate how loss of consciousness impacts distributed patterns of structure-function organisation across scales. We report that distributed brain activity under anaesthesia is increasingly constrained by brain structure across scales, coinciding with anaesthetic-induced collapse of multiple dimensions of hierarchical cortical organisation. These distributed signatures are observed across different anaesthetics, and they are reversed by electrical stimulation of the central thalamus, coinciding with recovery of behavioural markers of arousal. No such effects were observed upon stimulating the ventral lateral thalamus, demonstrating specificity. Overall, we identify consistent distributed signatures of consciousness that are orchestrated by specific thalamic nuclei. The brain’s role in supporting consciousness is unclear. Here, authors show that global markers of consciousness in macaque cortex are suppressed by many anaesthetics, and restored by local stimulation of a thalamic nucleus that also induces awakening.

Studies assessing personality dimensions by the \"Temperament and Character Inventory\" (TCI) have previously found an association between Parkinson's disease (PD) and lower Novelty Seeking and higher Harm Avoidance scores. Here, we aimed to describe personality dimensions of PD patients with motor fluctuations and compare them to a normative population and other PD populations. All PD patients awaiting Deep Brain Stimulation (DBS) answered the TCI before neurosurgery. Their results were compared to those of historical cohorts (a French normative population, a de novo PD population, and a PD population with motor fluctuations). Most personality dimensions of our 333 included PD patients with motor fluctuations who are candidates for DBS were different from those of the normative population and some were also different from those of the De Novo PD population, whereas they were similar to those of another population of PD patients with motor fluctuations. During the course of PD, personality dimensions can change in parallel with the development of motor fluctuations, either due to the evolution of the disease and/or dopaminergic treatments.

Abstract The role of the primate prefrontal cortex (PFC) in conscious perception is debated. The global neuronal workspace theory of consciousness predicts that PFC neurons should contain a detailed code of the current conscious contents. Previous research showed that PFC is indeed activated in paradigms of conscious visual perception, including no-report paradigms where no voluntary behavioral report of the percept is given, thus avoiding a conflation of signals related to visual consciousness with signals related to the report. Still, it has been argued that prefrontal modulation could reflect post-perceptual processes that may be present even in the absence of report, such as thinking about the perceived stimulus, therefore reflecting a consequence rather than a direct correlate of conscious experience. Here, we investigate these issues by recording neuronal ensemble activity from the macaque ventrolateral PFC during briefly presented visual stimuli, either in isolated trials in which stimuli were clearly perceived or in sequences of rapid serial visual presentation (RSVP) in which perception and post-perceptual processing were challenged. We report that the identity of each stimulus could be decoded from PFC population activity even in the RSVP condition. The first visual signals could be detected at 60 ms after stimulus onset and information was maximal at 150 ms. However, in the RSVP condition, 200 ms after the onset of a stimulus, the decoding accuracy quickly dropped to chance level and the next stimulus started to be decodable. Interestingly, decoding in the ventrolateral PFC was stronger compared to posterior parietal cortex for both isolated and RSVP stimuli. These results indicate that neuronal populations in the macaque PFC reliably encode visual stimuli even under conditions that have been shown to challenge conscious perception and/or substantially reduce the probability of post-perceptual processing in humans. We discuss whether the observed activation reflects conscious access, phenomenal consciousness, or merely a preconscious bottom-up wave.

At rest, the brain is traversed by spontaneous functional connectivity patterns. Two hypotheses have been proposed for their origins: they may reflect a continuous stream of ongoing cognitive processes as well as random fluctuations shaped by a fixed anatomical connectivity matrix. Here we show that both sources contribute to the shaping of resting-state networks, yet with distinct contributions during consciousness and anesthesia. We measured dynamical functional connectivity with functional MRI during the resting state in awake and anesthetized monkeys. Under anesthesia, the more frequent functional connectivity patterns inherit the structure of anatomical connectivity, exhibit fewer small-world properties, and lack negative correlations. Conversely, wakefulness is characterized by the sequential exploration of a richer repertoire of functional configurations, often dissimilar to anatomical structure, and comprising positive and negative correlations among brain regions. These results reconcile theories of consciousness with observations of long-range correlation in the anesthetized brain and show that a rich functional dynamics might constitute a signature of consciousness, with potential clinical implications for the detection of awareness in anesthesia and brain-lesioned patients. Significance What are the origins of resting-state functional connectivity patterns? One dominating view is that they index ongoing cognitive processes. However, this conclusion is in conflict with studies showing that long-range functional connectivity persists after loss of consciousness, possibly reflecting structural connectivity maps. In this work we respond to this question showing that in fact both sources have a clear and separable contribution to resting-state patterns. We show that under anesthesia, the dominating functional configurations have low information capacity and lack negative correlations. Importantly, they are rigid, tied to the anatomical map. Conversely, wakefulness is characterized by the dynamical exploration of a rich, flexible repertoire of functional configurations. These dynamical properties constitute a signature of consciousness.

Background Effectiveness of Occipital Nerve Stimulation (ONS) in refractory chronic cluster headache (rCCH) is supported by series of cases and a unique controlled trial, and its risk/benefit ratio has been questioned. Our objective was to identify predictive factors of ONS effectiveness in rCCH patients, to optimize this risk/benefit ratio and better select eligible patients. Methods We analyzed 125 patients (43 women, mean age 46,4) included prospectively in the “French ONS registry”, suffering from rCCH, treated by ONS for more than one year, and with data concerning putative preoperative predictive factors of effectiveness, including demographic, CCH characteristics and severity, treatment use and co-morbidities. We studied factors associated with ONS response, defined as a ≥ 50% reduction of weekly attack frequency (WAF) between baseline and one year follow-up. Results Factors predictor of good response to ONS were high preoperative WAF ( p  = 0.0003), high number of days with attack treatment use ( p  = 0.0006) and absence of epilepsy ( p  = 0.019). The best cut-off to predict ONS effectiveness was a WAF of 14 attacks/w. ONS response’s rates were 77.0% and 37.3% in patients with WAF ≥ 14/w and WAF < 14/w, respectively. However, in both groups, quality of life was significantly improved after ONS ( p  < 0.001). Conclusion Preoperative WAF was the main predictive factors of ONS response in rCCH, with a cut-off of 14 attacks/w, which may help to select patients and increase the ONS risk/benefit ratio. However, this threshold should be used with caution, as patients with WAF < 14/w also benefited from ONS. Registration The study has been registered (clinicaltrials.gov identifier NCT01842763).

Primate brains can detect a variety of unexpected deviations in auditory sequences. The local-global paradigm dissociates two hierarchical levels of auditory predictive coding by examining the brain responses to first-order (local) and second-order (global) sequence violations. Using the macaque model, we previously demonstrated that, in the awake state, local violations cause focal auditory responses while global violations activate a brain circuit comprising prefrontal, parietal and cingulate cortices. Here we used the same local-global auditory paradigm to clarify the encoding of the hierarchical auditory regularities in anesthetized monkeys and compared their brain responses to those obtained in the awake state as measured with fMRI. Both, propofol, a GABAA-agonist, and ketamine, an NMDA-antagonist, left intact or even enhanced the cortical response to auditory inputs. The local effect vanished during propofol anesthesia and shifted spatially during ketamine anesthesia compared with wakefulness. Under increasing levels of propofol, we observed a progressive disorganization of the global effect in prefrontal, parietal and cingulate cortices and its complete suppression under ketamine anesthesia. Anesthesia also suppressed thalamic activations to the global effect. These results suggest that anesthesia preserves initial auditory processing, but disturbs both short-term and long-term auditory predictive coding mechanisms. The disorganization of auditory novelty processing under anesthesia relates to a loss of thalamic responses to novelty and to a disruption of higher-order functional cortical networks in parietal, prefrontal and cingular cortices. [Display omitted] •Higher orders of auditory novelties activate a fronto-parietal network in awake macaques•Anesthesia disrupted the fronto-parietal network response to higher orders of auditory novelties•The suppression of parietal and thalamic responses to novelty paralleled the anesthesia phenomena

During the sleep-wake cycle, the brain undergoes profound dynamical changes, which manifest subjectively as transitions between conscious experience and unconsciousness. Yet, neurophysiological signatures that can objectively distinguish different consciousness states based are scarce. Here, we show that differences in the level of brain-wide signals can reliably distinguish different stages of sleep and anesthesia from the awake state in human and monkey fMRI resting state data. Moreover, a whole-brain computational model can faithfully reproduce changes in global synchronization and other metrics such as functional connectivity, structure-function relationship, integration and segregation across vigilance states. We demonstrate that the awake brain is close to a Hopf bifurcation, which naturally coincides with the emergence of globally correlated fMRI signals. Furthermore, simulating lesions of individual brain areas highlights the importance of connectivity hubs in the posterior brain and subcortical nuclei for maintaining the model in the awake state, as predicted by graph-theoretical analyses of structural data.

Functional connectivity (FC) of resting-state fMRI time series can be estimated using methods that differ in their temporal sensitivity (static vs. dynamic) and the number of regions included in the connectivity estimation (derived from a prior atlas). This paper presents a novel framework for identifying and quantifying resting-state networks using resting-state fMRI recordings. The study employs a linear latent variable model to generate spatially distinct brain networks and their associated activities. It specifically addresses the atlas selection problem, and the statistical inference and multivariate analysis of the obtained brain network activities. The approach is demonstrated on a dataset of resting-state fMRI recordings from monkeys under different anesthetics using static FC. Our results suggest that two networks, one fronto-parietal and cingular and another temporo-parieto-occipital (posterior brain) strongly influences shifts in consciousness, especially between anesthesia and wakefulness. Interestingly, this observation aligns with the two prominent theories of consciousness: the global neural workspace and integrated information theories of consciousness. The proposed method is also able to decipher the level of anesthesia from the brain network activities. Overall, we provide a framework that can be effectively applied to other datasets and may be particularly useful for the study of disorders of consciousness.

Anesthesia induces a reconfiguration of the repertoire of functional brain states leading to a high function-structure similarity. However, it is unclear how these functional changes lead to loss of consciousness. Here we suggest that the mechanism of conscious access is related to a general dynamical rearrangement of the intrinsic hierarchical organization of the cortex. To measure cortical hierarchy, we applied the Intrinsic Ignition analysis to resting-state fMRI data acquired in awake and anesthetized macaques. Our results reveal the existence of spatial and temporal hierarchical differences of neural activity within the macaque cortex, with a strong modulation by the depth of anesthesia and the employed anesthetic agent. Higher values of Intrinsic Ignition correspond to rich and flexible brain dynamics whereas lower values correspond to poor and rigid, structurally driven brain dynamics. Moreover, spatial and temporal hierarchical dimensions are disrupted in a different manner, involving different hierarchical brain networks. All together suggest that disruption of brain hierarchy is a new signature of consciousness loss.