Successful use of closed-loop allostatic neurotechnology for post-traumatic stress symptoms in military personnel： self-reported and autonomic improvements

Background:Military-related post-traumatic stress(PTS)is associated with numerous symptom clusters and diminished autonomic cardiovascular regulation.Highresolution,relational,resonance-based,electroencephalic mirroringis a noninvasive,closed-loop,allostatic,acoustic stimulation neurotechnology that produces realtime translation of dominant brain frequencies into audible tones of variable pitch and timing to support the autocalibration of neural oscillations.We report clinical,autonomic,and functional effects after the use offor symptoms of military-related PTS.Methods:Eighteen service members or recent veterans(15 active-duty,3 veterans,most from special operations,1 female),with a mean age of 40.9(SD=6.9)years and symptoms of PTS lasting from 1 to 25 years,undertook19.5(SD=1.1)sessions over 12 days.Inventories for symptoms of PTS(Posttraumatic Stress Disorder Checklist–Military version,PCL-M),insomnia(Insomnia Severity Index,ISI),depression(Center for Epidemiologic Studies Depression Scale,CES-D),and anxiety(Generalized Anxiety Disorder 7-item scale,GAD-7)were collected before(Visit1,V1),immediately after(Visit2,V2),and at 1 month(Visit3,V3),3(Visit4,V4),and 6(Visit5,V5)months after intervention completion.Other measures only taken at V1 and V2 included blood pressure and heart rate recordings to analyze heart rate variability(HRV)and baroreflex sensitivity(BRS),functional performance(reaction and grip strength)testing,blood and saliva for biomarkers of stress and inflammation,and blood for epigenetic testing.Paired t-tests,Wilcoxon signed-rank tests,and a repeated-measures ANOVA were performed.Results:Clinically relevant,significant reductions in all symptom scores were observed at V2,with durability through V5.There were significant improvements in multiple measures of HRV and BRS[Standard deviation of the normal beat to normal beat interval(SDNN),root mean square of the successive differences(rMSSD),high frequency(HF),low frequency(LF),and total power,HF alpha,sequence all,and systolic,diastolic and mean arterial pressure]as well as reaction testing.Trends were seen for improved grip strength and a reduction in C-Reactive Protein(CRP),Angiotensin II to Angiotensin 1–7 ratio and Interleukin-10,with no change in DNA n-methylation.There were no dropouts or adverse events reported. Conclusion:Service members or veterans showed reductions in symptomatology of PTS,insomnia,depressive mood,and anxiety that were durable through 6 months after the use of a closed-loop allostatic neurotechnology for the autocalibration of neural oscillations.This study is the first to report increased HRV or BRS after the use of an intervention for service members or veterans with PTS.Ongoing investigations are strongly warranted.Trial registration:NCT03230890,retrospectively registered July 25,2017.

Systems Neuroengineering: Understanding and Interacting with the Brain

In this paper, we review the current state- of-the-art techniques used for understanding the inner workings of the brain at a systems level. The neural activity that governs our everyday lives involves an intricate coordination of many processes that can be attributed to a variety of brain regions. On the surface, many of these functions can appear to be controlled by specific anatomical structures; however, in reality, numerous dynamic networks within the brain contribute to its function through an interconnected web of neuronal and synaptic pathways. The brain, in its healthy or pathological state, can therefore be best understood by taking a systems-level approach. While numerous neuroengineering technologies exist, we focus here on three major thrusts in the field of systems neuroengineering： neuroimaging, neural interfacing, and neuromodulation. Neuroimaging enables us to delineate the structural and functional organization of the brain, which is key in understanding how the neural system functions in both normal and disease states. Based on such knowledge, devices can be used either to communicate with the neural system, as in neural interface systems, or to modulate brain activity, as in neuromodulation systems. The consideration of these three fields is key to the development and application of neuro-devices. Feedback-based neuro-devices require the ability to sense neural activity （via a neuroimaging modality） through a neural interface （invasive or noninvasive） and ultimately to select a set of stimulation parameters in order to alter neural function via a neuromodulation modality. Systems neuroengineering refers to the use of engineering tools and technologies to image, decode, and modulate the brain in order to comprehend its functions and to repair its dysfunction. Interactions between these fields will help to shape the future of systems neuroengineering--to develop neurotechniques for enhancing the understanding of whole- brain function and dysfunction, and the management of neurological and mental disorders.

Introduction and recent progress of BRAIN Initiative in the United States

The presidential research program Brain Research through Advancing Innovative Neurotechnologies(BRAIN)Initiative was established5years ago in the United States;it has been a driving force of the United States government and private factors to promote technology development in basic and translational neuroscience research.We here summarize the research plan and recent progress in cellular neuroscience,electrical and optical engineering,chemical and systems neurobiology,and brain mapping technologies.The research plan recognizes the importance of identifying different cell populations and unknown cell types in the human brain and diseased models.Technological advances in multielectrode arrays and chemical flow measurement probes not only demonstrate the capacity of detecting neural activities in large areas,but also enable a new era of studying the neural coding information.Large-scale coordination of neuronal activity and brain mapping information will allow for the identification of therapeutic targets in neurological disorders,which is benefited by big data acquisition and analysis.Specifically,increased brain databases will expedite the dissection of thoughts,emotions,cognition,and will thereby help the development of better understanding and treatments of brain disorders.Since cell therapy demonstrates potential for regenerative medicine,the utilization of the newly advanced technologies may further improve the translational potentials and precision controls of transplanted grafts.The development of new diagnostic and therapeutic tools also requires international collaborations on science,technology,advocating,healthcare and medical ethics to advance the innovation and clinical practices.

Nano functional neural interfaces

Engineered functional neural interfaces （fNIs） serve as essential abiotic-biotic transducers between an engineered system and the nervous system. They convert external physical stimuli to cellular signals in stimulation mode or read out biological processes in recording mode. Information can be exchanged using electricity, light, magnetic fields, mechanical forces, heat, or chemical signals. fNIs have found applications for studying processes in neural circuits from cell cultures to organs to whole organisms, fNI-facilitated signal transduction schemes, coupled with easily manipulable and observable external physical signals, have attracted considerable attention in recent years. This enticing field is rapidly evolving toward miniaturization and biomimicry to achieve long-term interface stability with great signal transduction efficiency. Not only has a new generation of neuroelectrodes been invented, but the use of advanced fNIs that explore other physical modalities of neuromodulation and recording has begun to increase. This review covers these exciting developments and applications of fNIs that rely on nanoelectrodes, nanotransducers, or bionanotransducers to establish an interface with the nervous system. These nano fNIs are promising in offering a high spatial resolution, high target specificity, and high communication bandwidth by allowing for a high density and count of signal channels with minimum material volume and area to dramatically improve the chronic integration of the fNI to the target neural tissue. Such demanding advances in nano fNIs will greatly facilitate new opportunities not only for studying basic neuroscience but also for diagnosing and treating various neurological diseases.