Publications by authors named "Ioan Opris"

53 Publications

Deep brain stimulation of midbrain locomotor circuits in the freely moving pig.

Brain Stimul 2021 Feb 27;14(3):467-476. Epub 2021 Feb 27.

Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL, USA; The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address:

Background: Deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR) has been studied as a therapeutic target in rodent models of stroke, parkinsonism, and spinal cord injury. Clinical DBS trials have targeted the closely related pedunculopontine nucleus in patients with Parkinson's disease as a therapy for gait dysfunction, with mixed reported outcomes. Recent studies suggest that optimizing the MLR target could improve its effectiveness.

Objective: We sought to determine if stereotaxic targeting and DBS in the midbrain of the pig, in a region anatomically similar to that previously identified as the MLR in other species, could initiate and modulate ongoing locomotion, as a step towards generating a large animal neuromodulation model of gait.

Methods: We implanted Medtronic 3389 electrodes into putative MLR structures in Yucatan micropigs to characterize the locomotor effects of acute DBS in this region, using EMG recordings, joint kinematics, and speed measurements on a manual treadmill.

Results: MLR DBS initiated and augmented locomotion in freely moving micropigs. Effective locomotor sites centered around the cuneiform nucleus and stimulation frequency controlled locomotor speed and stepping frequency. Off-target stimulation evoked defensive and aversive behaviors that precluded locomotion in the animals.

Conclusion: Pigs appear to have an MLR and can be used to model neuromodulation of this gait-promoting center. These results indicate that the pig is a useful model to guide future clinical studies for optimizing MLR DBS in cases of gait deficiencies associated with such conditions as Parkinson's disease, spinal cord injury, or stroke.
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http://dx.doi.org/10.1016/j.brs.2021.02.017DOI Listing
February 2021

Population Averaged Stereotaxic T2w MRI Brain Template for the Adult Yucatan Micropig.

Front Neuroanat 2020 13;14:599701. Epub 2020 Nov 13.

Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL, United States.

Population averaged brain templates are an essential tool for imaging-based neuroscience research, providing investigators with information about the expected size and morphology of brain structures and the spatial relationships between them, within a demographic cross-section. This allows for a standardized comparison of neuroimaging data between subjects and provides neuroimaging software with a probabilistic framework upon which further processing and analysis can be based. Many different templates have been created to represent specific study populations and made publicly available for human and animal research. An increasingly studied animal model in the neurosciences that still lacks appropriate brain templates is the adult Yucatan micropig. In particular, T2-weighted templates are absent in this species as a whole. To address this need and provide a tool for neuroscientists wishing to pursue neuroimaging research in the adult micropig, we present the construction of population averaged ( = 16) T2-weighted MRI brain template for the adult Yucatan micropig. Additionally, we present initial analysis of T1-weighted ( = 3), and diffusion-weighted ( = 3) images through multimodal registration of these contrasts to our T2 template. The strategies used here may also be generalized to create similar templates for other study populations or species in need of template construction.
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http://dx.doi.org/10.3389/fnana.2020.599701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691581PMC
November 2020

Dissecting Brainstem Locomotor Circuits: Converging Evidence for Cuneiform Nucleus Stimulation.

Front Syst Neurosci 2020 21;14:64. Epub 2020 Aug 21.

Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL, United States.

There are a pressing and unmet need for effective therapies for freezing of gait (FOG) and other neurological gait disorders. Deep brain stimulation (DBS) of a midbrain target known as the pedunculopontine nucleus (PPN) was proposed as a potential treatment based on its postulated involvement in locomotor control as part of the mesencephalic locomotor region (MLR). However, DBS trials fell short of expectations, leading many clinicians to abandon this strategy. Here, we discuss the potential reasons for this failure and review recent clinical data along with preclinical optogenetics evidence to argue that another nearby nucleus, the cuneiform nucleus (CnF), may be a superior target.
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http://dx.doi.org/10.3389/fnsys.2020.00064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473103PMC
August 2020

Effects of Transcranial Magnetic Stimulation Therapy on Evoked and Induced Gamma Oscillations in Children with Autism Spectrum Disorder.

Brain Sci 2020 Jul 3;10(7). Epub 2020 Jul 3.

Department of Biomedical Sciences, University of South Carolina School of Medicine-Greenville, 701 Grove Rd., Greenville, SC 29605, USA.

Autism spectrum disorder (ASD) is a behaviorally diagnosed neurodevelopmental condition of unknown pathology. Research suggests that abnormalities of elecltroencephalogram (EEG) gamma oscillations may provide a biomarker of the condition. In this study, envelope analysis of demodulated waveforms for evoked and induced gamma oscillations in response to Kanizsa figures in an oddball task were analyzed and compared in 19 ASD and 19 age/gender-matched neurotypical children. The ASD group was treated with low frequency transcranial magnetic stimulation (TMS), (1.0 Hz, 90% motor threshold, 18 weekly sessions) targeting the dorsolateral prefrontal cortex. In ASD subjects, as compared to neurotypicals, significant differences in evoked and induced gamma oscillations were evident in higher magnitude of gamma oscillations pre-TMS, especially in response to non-target cues. Recordings post-TMS treatment in ASD revealed a significant reduction of gamma responses to task-irrelevant stimuli. Participants committed fewer errors post-TMS. Behavioral questionnaires showed a decrease in irritability, hyperactivity, and repetitive behavior scores. The use of a novel metric for gamma oscillations. i.e., envelope analysis using wavelet transformation allowed for characterization of the impedance of the originating neuronal circuit. The results suggest that gamma oscillations may provide a biomarker reflective of the excitatory/inhibitory balance of the cortex and a putative outcome measure for interventions in autism.
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http://dx.doi.org/10.3390/brainsci10070423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408068PMC
July 2020

Translational Neuroscience in Autism: From Neuropathology to Transcranial Magnetic Stimulation Therapies.

Psychiatr Clin North Am 2020 06 8;43(2):229-248. Epub 2020 Apr 8.

State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China.

The presence of heterotopias, increased regional density of neurons at the gray-white matter junction, and focal cortical dysplasias all suggest an abnormality of neuronal migration in autism spectrum disorder (ASD). The abnormality is borne from a dissonance in timing between radial and tangentially migrating neuroblasts to the developing cortical plate. The uncoupling of excitatory and inhibitory cortical cells disturbs the coordinated interactions of neurons within local networks, thus providing abnormal patterns of brainwave activity in the gamma bandwidth. In ASD, gamma oscillation abnormalities and autonomic markers offer measures of therapeutic progress and help in the identification of subgroups.
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http://dx.doi.org/10.1016/j.psc.2020.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245584PMC
June 2020

Editorial: Neuromodulatory Control of Brainstem Function in Health and Disease.

Front Neurosci 2020 11;14:86. Epub 2020 Feb 11.

Center for Respiratory Research and Rehabilitation, Department of Physical Therapy, University of Florida, Gainesville, FL, United States.

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http://dx.doi.org/10.3389/fnins.2020.00086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027270PMC
February 2020

Editorial: Application of Neural Technology to Neuro-Management and Neuro-Marketing.

Front Neurosci 2020 14;14:53. Epub 2020 Feb 14.

Neuroscience Area, International School for Advanced Studies (SISSA), Trieste, Italy.

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http://dx.doi.org/10.3389/fnins.2020.00053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034133PMC
February 2020

Editorial: Nanotechnologies in Neuroscience and Neuroengineering.

Front Neurosci 2020 12;14:33. Epub 2020 Feb 12.

Department of Biomedical Sciences, University of South Carolina School of Medicine at Greenville, Greenville, SC, United States.

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http://dx.doi.org/10.3389/fnins.2020.00033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028747PMC
February 2020

Activation of Brainstem Neurons During Mesencephalic Locomotor Region-Evoked Locomotion in the Cat.

Front Syst Neurosci 2019 14;13:69. Epub 2019 Nov 14.

The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, United States.

The distribution of locomotor-activated neurons in the brainstem of the cat was studied by c- immunohistochemistry in combination with antibody-based cellular phenotyping following electrical stimulation of the mesencephalic locomotor region (MLR) - the anatomical constituents of which remain debated today, primarily between the cuneiform (CnF) and the pedunculopontine tegmental nuclei (PPT). Effective MLR sites were co-extensive with the CnF nucleus. Animals subject to the locomotor task showed abundant labeling in the CnF, parabrachial nuclei of the subcuneiform region, periaqueductal gray, locus ceruleus (LC)/subceruleus (SubC), Kölliker-Fuse, magnocellular and lateral tegmental fields, raphe, and the parapyramidal region. Labeled neurons were more abundant on the side of stimulation. In some animals, -labeled cells were also observed in the ventral tegmental area, medial and intermediate vestibular nuclei, dorsal motor nucleus of the vagus, n. tractus solitarii, and retrofacial nucleus in the ventrolateral medulla. Many neurons in the reticular formation were innervated by serotonergic fibers. Numerous locomotor-activated neurons in the parabrachial nuclei and LC/SubC/Kölliker-Fuse were noradrenergic. Few cholinergic neurons within the PPT stained for . In the medulla, serotonergic neurons within the parapyramidal region and the nucleus raphe magnus were positive for . Control animals, not subject to locomotion, showed few -labeled neurons in these areas. The current study provides positive evidence for a role for the CnF in the initiation of locomotion while providing little evidence for the participation of the PPT. The results also show that MLR-evoked locomotion involves the parallel activation of reticular and monoaminergic neurons in the pons/medulla, and provides the anatomical and functional basis for spinal monoamine release during evoked locomotion. Lastly, the results indicate that vestibular, cardiovascular, and respiratory centers are centrally activated during MLR-evoked locomotion. Altogether, the results show a complex pattern of neuromodulatory influences of brainstem neurons by electrical activation of the MLR.
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http://dx.doi.org/10.3389/fnsys.2019.00069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868058PMC
November 2019

Human Brain/Cloud Interface.

Front Neurosci 2019 29;13:112. Epub 2019 Mar 29.

Institute for Molecular Manufacturing, Palo Alto, CA, United States.

The Internet comprises a decentralized global system that serves humanity's collective effort to generate, process, and store data, most of which is handled by the rapidly expanding cloud. A stable, secure, real-time system may allow for interfacing the cloud with the human brain. One promising strategy for enabling such a system, denoted here as a "human brain/cloud interface" ("B/CI"), would be based on technologies referred to here as "neuralnanorobotics." Future neuralnanorobotics technologies are anticipated to facilitate accurate diagnoses and eventual cures for the ∼400 conditions that affect the human brain. Neuralnanorobotics may also enable a B/CI with controlled connectivity between neural activity and external data storage and processing, via the direct monitoring of the brain's ∼86 × 10 neurons and ∼2 × 10 synapses. Subsequent to navigating the human vasculature, three species of neuralnanorobots (endoneurobots, gliabots, and synaptobots) could traverse the blood-brain barrier (BBB), enter the brain parenchyma, ingress into individual human brain cells, and autoposition themselves at the axon initial segments of neurons (endoneurobots), within glial cells (gliabots), and in intimate proximity to synapses (synaptobots). They would then wirelessly transmit up to ∼6 × 10 bits per second of synaptically processed and encoded human-brain electrical information via auxiliary nanorobotic fiber optics (30 cm) with the capacity to handle up to 10 bits/sec and provide rapid data transfer to a cloud based supercomputer for real-time brain-state monitoring and data extraction. A neuralnanorobotically enabled human B/CI might serve as a personalized conduit, allowing persons to obtain direct, instantaneous access to virtually any facet of cumulative human knowledge. Other anticipated applications include myriad opportunities to improve education, intelligence, entertainment, traveling, and other interactive experiences. A specialized application might be the capacity to engage in fully immersive experiential/sensory experiences, including what is referred to here as "transparent shadowing" (TS). Through TS, individuals might experience episodic segments of the lives of other willing participants (locally or remote) to, hopefully, encourage and inspire improved understanding and tolerance among all members of the human family.
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http://dx.doi.org/10.3389/fnins.2019.00112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450227PMC
March 2019

Multicellular Crosstalk Between Exosomes and the Neurovascular Unit After Cerebral Ischemia. Therapeutic Implications.

Front Neurosci 2018 6;12:811. Epub 2018 Nov 6.

Department of Neurology, Chair of Vascular Neurology, Dementia and Ageing Research, University Hospital Essen, Essen, Germany.

Restorative strategies after stroke are focused on the remodeling of cerebral endothelial cells and brain parenchymal cells. The latter, i.e., neurons, neural precursor cells and glial cells, synergistically interact with endothelial cells in the ischemic brain, providing a neurovascular unit (NVU) remodeling that can be used as target for stroke therapies. Intercellular communication and signaling within the NVU, the multicellular brain-vessel-blood interface, including its highly selective blood-brain barrier, are fundamental to the central nervous system homeostasis and function. Emerging research designates cell-derived extracellular vesicles and especially the nano-sized exosomes, as a complex mean of cell-to-cell communication, with potential use for clinical applications. Through their richness in active molecules and biological information (e.g., proteins, lipids, genetic material), exosomes contribute to intercellular signaling, a condition particularly required in the central nervous system. Cerebral endothelial cells, perivascular astrocytes, pericytes, microglia and neurons, all part of the NVU, have been shown to release and uptake exosomes. Also, exosomes cross the blood-brain and blood-cerebrospinal fluid barriers, allowing communication between periphery and brain, in normal and disease conditions. As such exosomes might be a powerful diagnostic tool and a promising therapeutic shuttle of natural nanoparticles, but also a means of disease spreading (e.g., immune system modulation, pro-inflammatory action, propagation of neurodegenerative factors). This review highlights the importance of exosomes in mediating the intercellular crosstalk within the NVU and reveals the restorative therapeutic potential of exosomes harvested from multipotent mesenchymal stem cells in ischemic stroke, a frequent neurologic condition lacking an efficient therapy.
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http://dx.doi.org/10.3389/fnins.2018.00811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232510PMC
November 2018

Editorial: Augmentation of Brain Function: Facts, Fiction and Controversy.

Front Syst Neurosci 2018 12;12:45. Epub 2018 Sep 12.

School of Medicine Greenville, University of South Carolina, Greenville, SC, United States.

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http://dx.doi.org/10.3389/fnsys.2018.00045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143785PMC
September 2018

Exploratory Study of rTMS Neuromodulation Effects on Electrocortical Functional Measures of Performance in an Oddball Test and Behavioral Symptoms in Autism.

Front Syst Neurosci 2018 28;12:20. Epub 2018 May 28.

Department of Biomedical Sciences, School of Medicine Greenville, University of South Carolina, Greenville, SC, United States.

There is no accepted pathology to autism spectrum disorders (ASD) but research suggests the presence of an altered excitatory/inhibitory (E/I) bias in the cerebral cortex. Repetitive transcranial magnetic stimulation (rTMS) offers a non-invasive means of modulating the E/I cortical bias with little in terms of side effects. In this study, 124 high functioning ASD children (IQ > 80, <18 years of age) were recruited and assigned using randomization to either a waitlist group or one of three different number of weekly rTMS sessions (i.e., 6, 12, and 18). TMS consisted of trains of 1.0 Hz frequency pulses applied over the dorsolateral prefrontal cortex (DLPFC). The experimental task was a visual oddball with illusory Kanizsa figures. Behavioral response variables included reaction time and error rate along with such neurophysiological indices such as stimulus and response-locked event-related potentials (ERP). One hundred and twelve patients completed the assigned number of TMS sessions. Results showed significant changes from baseline to posttest period in the following measures: motor responses accuracy [lower percentage of committed errors, slower latency of commission errors and restored normative post-error reaction time slowing in both early and later-stage ERP indices, enhanced magnitude of error-related negativity (ERN), improved error monitoring and post-error correction functions]. In addition, screening surveys showed significant reductions in aberrant behavior ratings and in both repetitive and stereotypic behaviors. These differences increased with the total number of treatment sessions. Our results suggest that rTMS, particularly after 18 sessions, facilitates cognitive control, attention and target stimuli recognition by improving discrimination between task-relevant and task-irrelevant illusory figures in an oddball test. The noted improvement in executive functions of behavioral performance monitoring further suggests that TMS has the potential to target core features of ASD.
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http://dx.doi.org/10.3389/fnsys.2018.00020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985329PMC
May 2018

George Marinesco in the Constellation of Modern Neuroscience.

Front Neurosci 2017 25;11:726. Epub 2017 Dec 25.

Bagdasar Arseni Hospital, Bucharest, Romania.

George Marinesco is the founder of Romanian School of Neurology and one of the most remarkable neuroscientists of the last century. He was the pupil of Jean-Martin Charcot in Salpêtrière Hospital in Paris, France, but visited many other neurological centers where he met the entire constellation of neurologists of his time, including Camillo Golgi and Santiago Ramón y Cajal. The last made the preface of Nervous Cell, written in French by Marinesco. The original title was "La Cellule Nerveuse" and is considered even now a basic reference book for specialists in the field. He was a refined clinical observer with an integrative approach, as could be seen from the multitude of his discoveries. The descriptions of the succulent hand in syringomyelia, senile plaque in old subjects, palmar jaw reflex known as Marinesco-Radovici sign, or the application of cinematography in medicine are some of his important contributions. He was the first who described changes of locus niger in a patient affected by tuberculosis, as a possible cause in Parkinson disease. Before modern genetics, Marinesco and Sjögren described a rare and complex syndrome bearing their names. He was a hardworking man, focused on his scientific research, did not accepted flattering of others and was a great fighter against the injustice of the time.
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http://dx.doi.org/10.3389/fnins.2017.00726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748083PMC
December 2017

What Is the Evidence for Inter-laminar Integration in a Prefrontal Cortical Minicolumn?

Front Neuroanat 2017 14;11:116. Epub 2017 Dec 14.

The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, United States.

The objective of this perspective article is to examine columnar inter-laminar integration during the executive control of behavior. The integration hypothesis posits that perceptual and behavioral signals are integrated within the prefrontal cortical inter-laminar microcircuits. Inter-laminar minicolumnar activity previously recorded from the dorsolateral prefrontal cortex (dlPFC) of nonhuman primates, trained in a visual delay match-to-sample (DMS) task, was re-assessed from an integrative perspective. Biomorphic multielectrode arrays (MEAs) played a unique role in the recording of columnar cell firing in the dlPFC layers 2/3 and 5/6. Several integrative aspects stem from these experiments: 1. Functional integration of perceptual and behavioral signals across cortical layers during executive control. The integrative effect of dlPFC minicolumns was shown by: (i) increased correlated firing on correct vs. error trials; (ii) decreased correlated firing when the number of non-matching images increased; and (iii) similar spatial firing preference across cortical-striatal cells during spatial-trials, and less on object-trials. 2. Causal relations to integration of cognitive signals by the minicolumnar turbo-engines. The inter-laminar integration between the perceptual and executive circuits was facilitated by stimulating the infra-granular layers with firing patterns obtained from supra-granular layers that enhanced spatial preference of percent correct performance on spatial trials. 3. Integration across hierarchical levels of the brain. The integration of intention signals (visual spatial, direction) with movement preparation (timing, velocity) in striatum and with the motor command and posture in midbrain is also discussed. These findings provide evidence for inter-laminar integration of executive control signals within brain's prefrontal cortical microcircuits.
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http://dx.doi.org/10.3389/fnana.2017.00116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735117PMC
December 2017

Atypical Processing of Novel Distracters in a Visual Oddball Task in Autism Spectrum Disorder.

Behav Sci (Basel) 2017 Nov 16;7(4). Epub 2017 Nov 16.

Department of Biomedical Sciences, University of South Carolina School of Medicine-Greenville, 200 Patewood Dr., Ste A200, Greenville, SC 29615, USA.

Several studies have shown that children with autism spectrum disorder (ASD) show abnormalities in P3b to targets in standard oddball tasks. The present study employed a three-stimulus visual oddball task with novel distracters that analyzed event-related potentials (ERP) to both target and non-target items at frontal and parietal sites. The task tested the hypothesis that children with autism are abnormally orienting attention to distracters probably due to impaired habituation to novelty. We predicted a lower selectivity in early ERPs to target, frequent non-target, and rare distracters. We also expected delayed late ERPs in autism. The study enrolled 32 ASD and 24 typically developing (TD) children. Reaction time (RT) and accuracy were analyzed as behavioral measures, while ERPs were recorded with a dense-array EEG system. Children with ASD showed higher error rate without normative post-error RT slowing and had lower error-related negativity. Parietal P1, frontal N1, as well as P3a and P3b components were higher to novels in ASD. Augmented exogenous ERPs suggest low selectivity in pre-processing of stimuli resulting in their excessive processing at later stages. The results suggest an impaired habituation to unattended stimuli that incurs a high load at the later stages of perceptual and cognitive processing and response selection when novel distracter stimuli are differentiated from targets.
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http://dx.doi.org/10.3390/bs7040079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746688PMC
November 2017

Mechatronic Wearable Exoskeletons for Bionic Bipedal Standing and Walking: A New Synthetic Approach.

Front Neurosci 2016 29;10:343. Epub 2016 Sep 29.

Holistic Dental Medicine Institute - ROPOSTURO Bucharest, Romania.

During the last few years, interest has been growing to mechatronic and robotic technologies utilized in wearable powered exoskeletons that assist standing and walking. The available literature includes single-case reports, clinical studies conducted in small groups of subjects, and several recent systematic reviews. These publications have fulfilled promotional and marketing objectives but have not yet resulted in a fully optimized, practical wearable exoskeleton. Here we evaluate the progress and future directions in this field from a joint perspective of health professionals, manufacturers, and consumers. We describe the taxonomy of existing technologies and highlight the main improvements needed for the development and functional optimization of the practical exoskeletons.
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http://dx.doi.org/10.3389/fnins.2016.00343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5040717PMC
September 2016

Neostriatal Neuronal Activity Correlates Better with Movement Kinematics under Certain Rewards.

Front Neurosci 2016 5;10:336. Epub 2016 Aug 5.

Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center Memphis, TN, USA.

This study investigated how the activity of neostriatal neurons is related to the kinematics of movement when monkeys performed visually and vibratory cued wrist extensions and flexions. Single-unit recordings of 142/236 neostriatal neurons showed pre-movement activity (PMA) in a reaction time task with unpredictable reward. Monkeys were pseudo-randomly (75%) rewarded for correct performance. A regression model was used to determine whether the correlation between neostriatal neuronal activity and the kinematic variables (position, velocity, and acceleration) of wrist movement changes as a function of reward contingency, sensory cues, and movement direction. The coefficients of determination (CoD) representing the proportion of the variance in neuronal activity explained by the regression model on a trial by trial basis, together with their temporal occurrences (time of best regression/correlation, ToC) were compared across sensory modality, movement direction, and reward contingency. The best relationship (correlation) between neuronal activity and movement kinematic variables, given by the average coefficient of determination (CoD), was: (a) greater during trials in which rewards were certain, called "A" trials, as compared with those in which reward was uncertain called ("R") trials, (b) greater during flexion (Flex) trials as compared with extension (Ext) trials, and (c) greater during visual (VIS) cued trials than during vibratory (VIB) cued trials, for the same type of trial and the same movement direction. These results are consistent with the hypothesis that predictability of reward for correct performance is accompanied by faster linkage between neostriatal PMA and the vigor of wrist movement kinematics. Furthermore, the results provide valuable insights for building an upper-limb neuroprosthesis.
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http://dx.doi.org/10.3389/fnins.2016.00336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986930PMC
August 2016

Intrusive Thoughts Elicited by Direct Electrical Stimulation during Stereo-Electroencephalography.

Front Neurol 2016 18;7:114. Epub 2016 Jul 18.

Department of Neurology, University Emergency Hospital, Bucharest, Romania; Department of Neurology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.

Cortical direct electrical stimulation (DES) is a method of brain mapping used during invasive presurgical evaluation of patients with intractable epilepsy. Intellectual auras like intrusive thoughts, also known as forced thinking (FT), have been reported during frontal seizures. However, there are few reports on FT obtained during DES in frontal cortex. We report three cases in which we obtained intrusive thoughts while stimulating the dorsolateral prefrontal cortex and the white matter in the prefrontal region. In order to highlight the effective connectivity that might explain this clinical response, we have analyzed cortico-cortical potentials evoked by single pulse electrical stimulation.
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http://dx.doi.org/10.3389/fneur.2016.00114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947963PMC
August 2016

A cognitive prosthesis for memory facilitation by closed-loop functional ensemble stimulation of hippocampal neurons in primate brain.

Exp Neurol 2017 01 24;287(Pt 4):452-460. Epub 2016 May 24.

USC, United States.

Very productive collaborative investigations characterized how multineuron hippocampal ensembles recorded in nonhuman primates (NHPs) encode short-term memory necessary for successful performance in a delayed match to sample (DMS) task and utilized that information to devise a unique nonlinear multi-input multi-output (MIMO) memory prosthesis device to enhance short-term memory in real-time during task performance. Investigations have characterized how the hippocampus in primate brain encodes information in a multi-item, rule-controlled, delayed match to sample (DMS) task. The MIMO model was applied via closed loop feedback micro-current stimulation during the task via conformal electrode arrays and enhanced performance of the complex memory requirements. These findings clearly indicate detection of a means by which the hippocampus encodes information and transmits this information to other brain regions involved in memory processing. By employing the nonlinear dynamic multi-input/multi-output (MIMO) model, developed and adapted to hippocampal neural ensemble firing patterns derived from simultaneous recorded multi-neuron CA1 and CA3 activity, it was possible to extract information encoded in the Sample phase of DMS trials that was necessary for successful performance in the subsequent Match phase of the task. The extension of this MIMO model to online delivery of electrical stimulation patterns to the same recording loci that exhibited successful CA1 firing in the DMS Sample Phase provided the means to increase task performance on a trial-by-trial basis. Increased utility of the MIMO model as a memory prosthesis was exhibited by the demonstration of cumulative increases in DMS task performance with repeated MIMO stimulation over many sessions. These results, reported below in this article, provide the necessary demonstrations to further the feasibility of the MIMO model as a memory prosthesis to recover and/or enhance encoding of cognitive information in humans with memory disruptions resulting from brain injury, disease or aging.
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http://dx.doi.org/10.1016/j.expneurol.2016.05.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633045PMC
January 2017

Successful epilepsy surgery in frontal lobe epilepsy with startle seizures: a SEEG study.

Epileptic Disord 2015 Dec;17(4):363-71

Neurology Department, University Emergency Hospital, Bucharest, Romania, Neurology Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.

Pre-surgical assessment and surgical management of frontal epilepsy with normal MRI is often challenging. We present a case of a 33-year-old, right-handed, educated male. During childhood, his seizures presented with mandibular myoclonus and no particular trigger. As a young adult, he developed seizures with a startle component, triggered by unexpected noises. During his ictal episodes, he felt fear and grimaced with sudden head flexion and tonic axial posturing. Similar seizures also occurred without startle. Neuropsychological assessment showed executive dysfunction and verbal memory deficit. The cerebral MRI was normal. Electro-clinical reasoning, investigations performed, the results obtained and follow-up are discussed in detail. [Published with video sequence].
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http://dx.doi.org/10.1684/epd.2015.0790DOI Listing
December 2015

Distributed encoding of spatial and object categories in primate hippocampal microcircuits.

Front Neurosci 2015 6;9:317. Epub 2015 Oct 6.

Department of Physiology and Pharmacology, Wake Forest University School of Medicine Winston-Salem, NC, USA.

The primate hippocampus plays critical roles in the encoding, representation, categorization and retrieval of cognitive information. Such cognitive abilities may use the transformational input-output properties of hippocampal laminar microcircuitry to generate spatial representations and to categorize features of objects, images, and their numeric characteristics. Four nonhuman primates were trained in a delayed-match-to-sample (DMS) task while multi-neuron activity was simultaneously recorded from the CA1 and CA3 hippocampal cell fields. The results show differential encoding of spatial location and categorization of images presented as relevant stimuli in the task. Individual hippocampal cells encoded visual stimuli only on specific types of trials in which retention of either, the Sample image, or the spatial position of the Sample image indicated at the beginning of the trial, was required. Consistent with such encoding, it was shown that patterned microstimulation applied during Sample image presentation facilitated selection of either Sample image spatial locations or types of images, during the Match phase of the task. These findings support the existence of specific codes for spatial and numeric object representations in primate hippocampus which can be applied on differentially signaled trials. Moreover, the transformational properties of hippocampal microcircuitry, together with the patterned microstimulation are supporting the practical importance of this approach for cognitive enhancement and rehabilitation, needed for memory neuroprosthetics.
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http://dx.doi.org/10.3389/fnins.2015.00317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594006PMC
October 2015

Distinguishing cognitive state with multifractal complexity of hippocampal interspike interval sequences.

Front Syst Neurosci 2015 17;9:130. Epub 2015 Sep 17.

Department of Physiology and Pharmacology, Wake Forest School of Medicine Winston-Salem, NC, USA.

Fractality, represented as self-similar repeating patterns, is ubiquitous in nature and the brain. Dynamic patterns of hippocampal spike trains are known to exhibit multifractal properties during working memory processing; however, it is unclear whether the multifractal properties inherent to hippocampal spike trains reflect active cognitive processing. To examine this possibility, hippocampal neuronal ensembles were recorded from rats before, during and after a spatial working memory task following administration of tetrahydrocannabinol (THC), a memory-impairing component of cannabis. Multifractal detrended fluctuation analysis was performed on hippocampal interspike interval sequences to determine characteristics of monofractal long-range temporal correlations (LRTCs), quantified by the Hurst exponent, and the degree/magnitude of multifractal complexity, quantified by the width of the singularity spectrum. Our results demonstrate that multifractal firing patterns of hippocampal spike trains are a marker of functional memory processing, as they are more complex during the working memory task and significantly reduced following administration of memory impairing THC doses. Conversely, LRTCs are largest during resting state recordings, therefore reflecting different information compared to multifractality. In order to deepen conceptual understanding of multifractal complexity and LRTCs, these measures were compared to classical methods using hippocampal frequency content and firing variability measures. These results showed that LRTCs, multifractality, and theta rhythm represent independent processes, while delta rhythm correlated with multifractality. Taken together, these results provide a novel perspective on memory function by demonstrating that the multifractal nature of spike trains reflects hippocampal microcircuit activity that can be used to detect and quantify cognitive, physiological, and pathological states.
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http://dx.doi.org/10.3389/fnsys.2015.00130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585000PMC
October 2015

Disruption of columnar and laminar cognitive processing in primate prefrontal cortex following cocaine exposure.

Front Syst Neurosci 2015 29;9:79. Epub 2015 May 29.

Department of Physiology and Pharmacology, Wake Forest University School of Medicine Winston-Salem, NC, USA.

Prefrontal cortical activity in primate brain plays a critical role in cognitive processes involving working memory and the executive control of behavior. Groups of prefrontal cortical neurons within specified cortical layers along cortical minicolumns differentially generate inter- and intra-laminar firing to process relevant information for goal oriented behavior. However, it is not yet understood how cocaine modulates such differential firing in prefrontal cortical layers. Rhesus macaque nonhuman primates (NHPs) were trained in a visual delayed match-to-sample (DMS) task while the activity of prefrontal cortical neurons (areas 46, 8 and 6) was recorded simultaneously with a custom multielectrode array in cell layers 2/3 and 5. Animals were reinforced with juice for correct responses. The first half of the recording session (control) was conducted following saline injection and in the second half of the same session cocaine was administered. Prefrontal neuron activity with respect to inter- and intra-laminar firing in layers 2/3 and 5 was assessed in the DMS task before and after the injection of cocaine. Results showed that firing rates of both pyramidal cells and interneurons increased on Match phase presentation and the Match Response (MR) in both control and cocaine halves of the session. Differential firing under cocaine vs. control in the Match phase was increased for interneurons but decreased for pyramidal cells. In addition, functional' interactions between prefrontal pyramidal cells in layer 2/3 and 5 decreased while intra-laminar cross-correlations in both layers increased. These neural recordings demonstrate that prefrontal neurons differentially encode and process information within and between cortical cell layers via cortical columns which is disrupted in a differential manner by cocaine: administration.
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http://dx.doi.org/10.3389/fnsys.2015.00079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448003PMC
June 2015

Autism spectrum disorders: linking neuropathological findings to treatment with transcranial magnetic stimulation.

Acta Paediatr 2015 Apr;104(4):346-55

Department of Psychiatry, University of Louisville, Louisville, KA, USA.

Unlabelled: Postmortem studies in autism spectrum disorder (ASD) individuals indicate the presence of abnormalities within the peripheral neuropil space (PNS) of cortical minicolumns. The geometrical orientation of inhibitory elements within the PNS suggests using repetitive transcranial magnetic stimulation (rTMS) to up-regulate their activity. Several rTMS trials in ASD have shown marked improvements in motor symptomatology, attention and perceptual binding.

Conclusion: rTMS is the first therapeutic attempt at ASD aimed at correcting some of its core pathology.
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http://dx.doi.org/10.1111/apa.12943DOI Listing
April 2015

Neurons and networks organizing and sequencing memories.

Brain Res 2015 Sep 29;1621:335-44. Epub 2014 Dec 29.

Department of Physiology & Pharmacology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1083, USA.

Hippocampal CA1 and CA3 neurons sampled randomly in large numbers in primate brain show conclusive examples of hierarchical encoding of task specific information. Hierarchical encoding allows multi-task utilization of the same hippocampal neural networks via distributed firing between neurons that respond to subsets, attributes or "categories" of stimulus features which can be applied in events in different contexts. In addition, such networks are uniquely adaptable to neural systems unrestricted by rigid synaptic architecture (i.e. columns, layers or "patches") which physically limits the number of possible task-specific interactions between neurons. Also hierarchical encoding is not random; it requires multiple exposures to the same types of relevant events to elevate synaptic connectivity between neurons for different stimulus features that occur in different task-dependent contexts. The large number of cells within associated hierarchical circuits in structures such as hippocampus provides efficient processing of information relevant to common memory-dependent behavioral decisions within different contextual circumstances. This article is part of a Special Issue entitled SI: Brain and Memory.
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http://dx.doi.org/10.1016/j.brainres.2014.12.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485978PMC
September 2015

Identification of functional synaptic plasticity from spiking activities using nonlinear dynamical modeling.

J Neurosci Methods 2015 Apr 2;244:123-35. Epub 2014 Oct 2.

Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA. Electronic address:

This paper presents a systems identification approach for studying the long-term synaptic plasticity using natural spiking activities. This approach consists of three modeling steps. First, a multi-input, single-output (MISO), nonlinear dynamical spiking neuron model is formulated to estimate and represent the synaptic strength in means of functional connectivity between input and output neurons. Second, this MISO model is extended to a nonstationary form to track the time-varying properties of the synaptic strength. Finally, a Volterra modeling method is used to extract the synaptic learning rule, e.g., spike-timing-dependent plasticity, for the explanation of the input-output nonstationarity as the consequence of the past input-output spiking patterns. This framework is developed to study the underlying mechanisms of learning and memory formation in behaving animals, and may serve as the computational basis for building the next-generation adaptive cortical prostheses.
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http://dx.doi.org/10.1016/j.jneumeth.2014.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383743PMC
April 2015

Modifying cognition and behavior with electrical microstimulation: implications for cognitive prostheses.

Neurosci Biobehav Rev 2014 Nov 19;47:321-35. Epub 2014 Sep 19.

Departments of Neuroscience and Psychiatry, Columbia University, New York, NY 10032, USA.

A fundamental goal of cognitive neuroscience is to understand how brain activity generates complex mental states and behaviors. While neuronal activity may predict or correlate with behavioral responses in a cognitive task, the use of electrical microstimulation presents the possibility to augment such correlational findings with direct evidence for causal relationships. Although microstimulation has been used for many years as a tool for mapping sensory and motor function, its role in learning, memory and decision-making has emerged only recently. Focal microstimulation of higher cortical areas can produce complex mental states and sequences of action. However, the relationship between the locus of stimulation and the percepts or actions evoked is often stereotyped and inflexible. The challenge is to develop stimulation systems that do not have fixed output but can flexibly contribute to complex cognitive and behavioral tasks. We discuss how microstimulation has been instrumental in manipulating a wide spectrum of cognitive functions including working memory, perceptual decisions and executive control by enhancing attention, re-ordering temporal sequence of saccades, improving associative learning or cognitive performance. For example, stimulation in prefrontal, parietal and sensory cortices may establish causal effects on decision-making, while microstimulation of inferotemporal cortex or caudate nucleus enhances associative learning. Building cognitive prosthetics based on the insights gleaned from such studies may depend on the development of multiple-input, multiple-output (MIMO) devices that allow subjects to control stimulation with their own thoughts in a closed-loop system.
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http://dx.doi.org/10.1016/j.neubiorev.2014.09.003DOI Listing
November 2014

rTMS neuromodulation improves electrocortical functional measures of information processing and behavioral responses in autism.

Front Syst Neurosci 2014 6;8:134. Epub 2014 Aug 6.

Department of Psychiatry and Behavioral Sciences, University of Louisville Louisville, KY, USA.

Objectives: Reports in autism spectrum disorders (ASD) of a minicolumnopathy with consequent deficits of lateral inhibition help explain observed behavioral and executive dysfunctions. We propose that neuromodulation based on low frequency repetitive Transcranial Magnetic Stimulation (rTMS) will enhance lateral inhibition through activation of inhibitory double bouquet interneurons and will be accompanied by improvements in the prefrontal executive functions. In addition we proposed that rTMS will improve cortical excitation/inhibition ratio and result in changes manifested in event-related potential (ERP) recorded during cognitive tests.

Materials And Methods: Along with traditional clinical behavioral evaluations the current study used ERPs in a visual oddball task with illusory figures. We compared clinical, behavioral and electrocortical outcomes in two groups of children with autism (TMS, wait-list group). We predicted that 18 session long course in autistic patients will have better behavioral and ERP outcomes as compared to age- and IQ-matched WTL group. We used 18 sessions of 1 Hz rTMS applied over the dorso-lateral prefrontal cortex in 27 individuals with ASD diagnosis. The WTL group was comprised of 27 age-matched subjects with ASD tested twice. Both TMS and WTL groups were assessed at the baseline and after completion of 18 weekly sessions of rTMS (or wait period) using clinical behavioral questionnaires and during performance on visual oddball task with Kanizsa illusory figures.

Results: Post-TMS evaluations showed decreased irritability and hyperactivity on the Aberrant Behavior Checklist (ABC), and decreased stereotypic behaviors on the Repetitive Behavior Scale (RBS-R). Following rTMS course we found decreased amplitude and prolonged latency in the frontal and fronto-central N100, N200 and P300 (P3a) ERPs to non-targets in active TMS treatment group. TMS resulted in increase of P2d (P2a to targets minus P2a to non-targets) amplitude. These ERP changes along with increased centro-parietal P100 and P300 (P3b) to targets are indicative of more efficient processing of information post-TMS treatment. Another important finding was decrease of the latency and increase of negativity of error-related negativity (ERN) during commission errors that may reflect improvement in error monitoring and correction function. Enhanced information processing was also manifested in lower error rate. In addition we calculated normative post-error treaction time (RT) slowing response in both groups and found that rTMS treatment was accompanied by post-error RT slowing and higher accuracy of responses, whereas the WTL group kept on showing typical for ASD post-error RT speeding and higher commission and omission error rates.

Conclusion: RESULTS from our study indicate that rTMS improves executive functioning in ASD as evidenced by normalization of ERP responses and behavioral reactions (RT, accuracy) during executive function test, and also by improvements in clinical evaluations.
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http://dx.doi.org/10.3389/fnsys.2014.00134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123734PMC
August 2014

Multifractal analysis of information processing in hippocampal neural ensembles during working memory under Δ⁹-tetrahydrocannabinol administration.

J Neurosci Methods 2015 Apr 30;244:136-53. Epub 2014 Jul 30.

Dept. of Biomedical Engineering, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Background: Multifractal analysis quantifies the time-scale-invariant properties in data by describing the structure of variability over time. By applying this analysis to hippocampal interspike interval sequences recorded during performance of a working memory task, a measure of long-range temporal correlations and multifractal dynamics can reveal single neuron correlates of information processing.

New Method: Wavelet leaders-based multifractal analysis (WLMA) was applied to hippocampal interspike intervals recorded during a working memory task. WLMA can be used to identify neurons likely to exhibit information processing relevant to operation of brain-computer interfaces and nonlinear neuronal models.

Results: Neurons involved in memory processing ("Functional Cell Types" or FCTs) showed a greater degree of multifractal firing properties than neurons without task-relevant firing characteristics. In addition, previously unidentified FCTs were revealed because multifractal analysis suggested further functional classification. The cannabinoid type-1 receptor (CB1R) partial agonist, tetrahydrocannabinol (THC), selectively reduced multifractal dynamics in FCT neurons compared to non-FCT neurons.

Comparison With Existing Methods: WLMA is an objective tool for quantifying the memory-correlated complexity represented by FCTs that reveals additional information compared to classification of FCTs using traditional z-scores to identify neuronal correlates of behavioral events.

Conclusion: z-Score-based FCT classification provides limited information about the dynamical range of neuronal activity characterized by WLMA. Increased complexity, as measured with multifractal analysis, may be a marker of functional involvement in memory processing. The level of multifractal attributes can be used to differentially emphasize neural signals to improve computational models and algorithms underlying brain-computer interfaces.
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http://dx.doi.org/10.1016/j.jneumeth.2014.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312266PMC
April 2015