Publications

Experimental and clinical studies of consciousness identify brain states (i.e. quasi-stable functional cerebral organization) in a non-systematic manner and largely independent of the research into brain state modulation. In this narrative review, we synthesize advances in the identification of brain states associated with consciousness in animal models and physiological (sleep), pharmacological (anaesthesia) and pathological (disorders of consciousness) states of altered consciousness in humans. We show that in reduced consciousness the frequencies in which the brain operates are slowed down and that the pattern of functional communication is sparser, less efficient, and less complex. The results also highlight damaged resting-state networks, in particular the default mode network, decreased connectivity in long-range connections and especially in the thalamocortical loops. Next, we show that therapeutic approaches to treat disorders of consciousness, through pharmacology (e.g. amantadine, zolpidem), and (non-) invasive brain stimulation (e.g. transcranial direct current stimulation, deep brain stimulation) have shown partial effectiveness in promoting consciousness recovery. Although some features of conscious brain states may improve in response to neuromodulation, targeting often remains non-specific and does not always lead to (behavioural) improvements. The fields of brain state identification and neuromodulation of brain states in relation to consciousness are showing fascinating developments that, when integrated, might propel the development of new and better-targeted techniques for disorders of consciousness. We here propose a therapeutic framework for the identification and modulation of brain states to facilitate the interaction between the two fields. We propose that brain states should be identified in a predictive setting, followed by theoretical and empirical testing (i.e. in animal models, under anaesthesia and in patients with a disorder of consciousness) of neuromodulation techniques to promote consciousness in line with such predictions. This framework further helps to identify where challenges and opportunities lay for the maturation of brain state research in the context of states of consciousness. It will become apparent that one angle of opportunity is provided through the addition of computational modelling. Finally, it aids in recognizing possibilities and obstacles for the clinical translation of these diagnostic techniques and neuromodulation treatment options across both the multimodal and multi-species approaches outlined throughout the review.

JTD Keywords: (disorders of) consciousness, Anaesthesia, Animal model, Animal models, Area induces reanimation, Brain states, Direct-current stimulation, Disorder, Electrical-stimulation, Functional connectivity, General-anesthesia, Neuromodulation, Propofol-induced loss, Thalamic-stimulation, Transcranial magnetic stimulation, Vegetative state

(1) Background: Restoring arm and hand function is a priority for individuals with cervical spinal cord injury (cSCI) for independence and quality of life. Transcutaneous spinal cord stimulation (tSCS) promotes the upper extremity (UE) motor function when applied at the cervical region. The aim of the study was to determine the effects of cervical tSCS, combined with an exoskeleton, on motor strength and functionality of UE in subjects with cSCI. (2) Methods: twenty-two subjects participated in the randomized mix of parallel-group and crossover clinical trial, consisting of an intervention group (n = 15; tSCS exoskeleton) and a control group (n = 14; exoskeleton). The assessment was carried out at baseline, after the last session, and two weeks after the last session. We assessed graded redefined assessment of strength, sensibility, and prehension (GRASSP), box and block test (BBT), spinal cord independence measure III (SCIM-III), maximal voluntary contraction (MVC), ASIA impairment scale (AIS), and WhoQol-Bref; (3) Results: GRASSP, BBT, SCIM III, cylindrical grip force and AIS motor score showed significant improvement in both groups (p ≤ 0.05), however, it was significantly higher in the intervention group than the control group for GRASSP strength, and GRASSP prehension ability (p ≤ 0.05); (4) Conclusion: our findings show potential advantages of the combination of cervical tSCS with an exoskeleton to optimize the outcome for UE.

JTD Keywords: arm function, cervical spinal cord injury, electrical-stimulation, functional walking, functionality, grip force, hand function, individuals, injury, motor function, reliability, robotics, spasticity, transcutaneous electrical spinal cord stimulation, upper extremity, Epidural stimulation, Transcutaneous electrical spinal cord stimulation, Upper extremity

Peripheral inputs continuously shape brain function and can influence memory acquisition, but the underlying mechanisms have not been fully understood. Cannabinoid type-1 receptor (CB1R) is a well-recognized player in memory performance, and its systemic modulation significantly influences memory function. By assessing low arousal/non-emotional recognition memory in mice, we found a relevant role of peripheral CB1R in memory persistence. Indeed, the peripherally-restricted CB1R specific antagonist AM6545 showed significant mnemonic effects that were occluded in adrenalectomized mice, and after peripheral adrenergic blockade. AM6545 also transiently impaired contextual fear memory extinction. Vagus nerve chemogenetic inhibition reduced AM6545-induced mnemonic effect. Genetic CB1R deletion in dopamine β-hydroxylase-expressing cells enhanced recognition memory persistence. These observations support a role of peripheral CB1R modulating adrenergic tone relevant for cognition. Furthermore, AM6545 acutely improved brain connectivity and enhanced extracellular hippocampal norepinephrine. In agreement, intra-hippocampal β-adrenergic blockade prevented AM6545 mnemonic effects. Altogether, we disclose a novel CB1R-dependent peripheral mechanism with implications relevant for lengthening the duration of non-emotional memory.© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.

JTD Keywords: antagonist, consolidation, contextual fear memory, electrical-stimulation, hippocampal function, improves memory, locus-coeruleus, reconsolidation, stress, Vagus nerve-stimulation

Abstract Background Neural tissue has limited regenerative ability. To cope with that, in recent years a diverse set of novel tools has been used to tailor neurostimulation therapies and promote functional regeneration after axonal injuries. Method In this report, we explore cell-specific methods to modulate neuronal activity, including opto- and chemogenetics to assess the effect of specific neuronal stimulation in the promotion of axonal regeneration after injury. Results Opto- and chemogenetic stimulations of neuronal activity elicited increased in vitro neurite outgrowth in both sensory and cortical neurons, as well as in vivo regeneration in the sciatic nerve, but not after spinal cord injury. Mechanistically, inhibitory substrates such as chondroitin sulfate proteoglycans block the activity induced increase in axonal growth. Conclusions We found that genetic modulations of neuronal activity on both dorsal root ganglia and corticospinal motor neurons increase their axonal growth capacity but only on permissive environments.

JTD Keywords: activation, chemogenetics, electrical-stimulation, expression, functional recovery, increases, injury, motor cortex, neuronal activity, optogenetics, permissive substrate, promotes recovery, regeneration, Optogenetics, Regeneration, Spinal-cord