Differential Modulation of Local Field Potentials in the Primary and Premotor Cortices during Ipsilateral and Contralateral Reach to Grasp in Macaque Monkeys.

Hand movements are associated with modulations of neuronal activity across several interconnected cortical areas, including the primary motor cortex (M1) and the dorsal and ventral premotor cortices (PMd and PMv). Local field potentials (LFPs) provide a link between neuronal discharges and synaptic inputs. Our current understanding of how LFPs vary in M1, PMd, and PMv during contralateral and ipsilateral movements is incomplete. To help reveal unique features in the pattern of modulations, we simultaneously recorded LFPs in these areas in two macaque monkeys performing reach and grasp movements with either the right or left hand. The greatest effector-dependent differences were seen in M1, at low (≤13 Hz) and γ frequencies. In premotor areas, differences related to hand use were only present in low frequencies. PMv exhibited the greatest increase in low frequencies during instruction cues and the smallest effector-dependent modulation during movement execution. In PMd, δ oscillations were greater during contralateral reach and grasp, and ß activity increased during contralateral grasp. In contrast, ß oscillations decreased in M1 and PMv. These results suggest that while M1 primarily exhibits effector-specific LFP activity, premotor areas compute more effector-independent aspects of the task requirements, particularly during movement preparation for PMv and production for PMd. The generation of precise hand movements likely relies on the combination of complementary information contained in the unique pattern of neural modulations contained in each cortical area. Accordingly, integrating LFPs from premotor areas and M1 could enhance the performance and robustness of brain-machine interfaces.

Spared Premotor Areas Undergo Rapid Nonlinear Changes in Functional Organization Following a Focal Ischemic Infarct in Primary Motor Cortex of Squirrel Monkeys.

Recovery of motor function after stroke is accompanied by reorganization of movement representations in spared cortical motor regions. It is widely assumed that map reorganization parallels recovery, suggesting a causal relationship. We examined this assumption by measuring changes in motor representations in eight male and six female squirrel monkeys in the first few weeks after injury, a time when motor recovery is most rapid. Maps of movement representations were derived using intracortical microstimulation techniques in primary motor cortex (M1), ventral premotor cortex (PMv), and dorsal premotor cortex (PMd) in 14 adult squirrel monkeys before and after a focal infarct in the M1 distal forelimb area. Maps were derived at baseline and at either 2 (n = 7) or 3 weeks (n = 7) postinfarct. In PMv the forelimb maps remained unchanged at 2 weeks but contracted significantly (-42.4%) at 3 weeks. In PMd the forelimb maps expanded significantly (+110.6%) at 2 weeks but contracted significantly (-57.4%) at 3 weeks. Motor deficits were equivalent at both time points. These results highlight two features of plasticity after M1 lesions. First, significant contraction of distal forelimb motor maps in both PMv and PMd is evident by 3 weeks. Second, an unpredictable nonlinear pattern of reorganization occurs in the distal forelimb representation in PMd, first expanding at 2 weeks, and then contracting at 3 weeks postinjury. Together with previous results demonstrating reliable map expansions in PMv several weeks to months after M1 injury, the subacute time period may represent a critical window for the timing of therapeutic interventions.SIGNIFICANCE STATEMENT The relationship between motor recovery and motor map reorganization after cortical injury has rarely been examined in acute/subacute periods. In nonhuman primates, premotor maps were examined at 2 and 3 weeks after injury to primary motor cortex. Although maps are known to expand late after injury, the present study demonstrates early map expansion at 2 weeks (dorsal premotor cortex) followed by contraction at 3 weeks (dorsal and ventral premotor cortex). This nonlinear map reorganization during a time of gradual behavioral recovery suggests that the relationship between map plasticity and motor recovery is much more complex than previously thought. It also suggests that rehabilitative motor training may have its most potent effects during this early dynamic phase of map reorganization.

Porcine Model of Cerebral Ischemic Stroke Utilizing Intracortical Recordings for the Continuous Monitoring of the Ischemic Area.

PURPOSE: Our aim was to use intracortical recording to enable the tracking of ischemic infarct development over the first few critical hours of ischemia with a high time resolution in pigs. We employed electrophysiological measurements to obtain quick feedback on neural function, which might be useful for screening, e.g., for the optimal dosage and timing of agents prior to further pre-clinical evaluation. METHODS: Micro-electrode arrays containing 16 (animal 1) or 32 electrodes (animal 2-7) were implanted in the primary somatosensory cortex of seven female pigs, and continuous electrical stimulation was applied at 0.2 Hz to a cuff electrode implanted on the ulnar nerve. Ischemic stroke was induced after 30 min of baseline recording by injection of endothelin-1 onto the cortex adjacent to the micro-electrode array. Evoked responses were extracted over a moving window of 180 s and averaged across channels as a measure of cortical excitability. RESULTS: Across the animals, the cortical excitability was significantly reduced in all seven 30 min segments following endothelin-1 injection, as compared to the 30 min preceding this intervention. This difference was not explained by changes in the anesthesia, ventilation, end-tidal CO2, mean blood pressure, heart rate, blood oxygenation, or core temperature, which all remained stable throughout the experiment. CONCLUSIONS: The animal model may assist in maturing neuroprotective approaches by testing them in an accessible model of resemblance to human neural and cardiovascular physiology and body size. This would constitute an intermediate step for translating positive results from rodent studies into human application, by more efficiently enabling effective optimization prior to chronic pre-clinical studies in large animals.

Enriched Rehabilitation Reduces Abnormal Motor Synergies and Enhances Motor Plasticity Following Severe Stroke in Rats.

BACKGROUND: Stroke results in loss of upper motor neuron control over voluntary movements and emergence of abnormal synergies. Presently, it is unclear to what extent poststroke recovery reflects true recovery (restitution), compensation, or some combination of these processes. Here, we investigated this question using behavioral and kinematic analyses of skilled reaching in rats subjected to severe stroke that affected both the forelimb motor cortex and dorsolateral striatum. METHODS: After stroke, male rats either spontaneously recovered or received enriched rehabilitation. We assessed forelimb motor recovery using behavioral and kinematic outcome measures. To provide insights into the mechanisms underlying the effects of rehabilitation on behavior, we used intracortical microstimulation and FosB (protein fosB) immunostaining techniques. RESULTS: Enriched rehabilitation significantly improved food pellet retrieval in the staircase-reaching task. Rehabilitation resulted in several poststroke flexion synergies returning to prestroke patterns, and across subjects, these changes correlated with the intensity of rehabilitation. Enriched rehabilitation increased the proportion of distal movement representation in the perilesional cortex and increased use-dependent activation in the ipsilesional red nucleus. CONCLUSIONS: These results provide evidence that enriched rehabilitation enhances recovery, at least in part, by restitution of forelimb function following severe stroke. Furthermore, the restitution of function is associated with changes in multiple motor-related structures at different levels of the central nervous system. A better understanding of the processes that underlie improved motor performance, along with the identification of midbrain circuits activated by rehabilitation, represent new insights and potential targets for optimizing poststroke recovery.

Rapid and Bihemispheric Reorganization of Neuronal Activity in Premotor Cortex after Brain Injury.

Brain injuries cause hemodynamic changes in several distant, spared areas from the lesion. Our objective was to better understand the neuronal correlates of this reorganization in awake, behaving female monkeys. We used reversible inactivation techniques to "injure" the primary motor cortex, while continuously recording neuronal activity of the ventral premotor cortex in the two hemispheres, before and after the onset of behavioral impairments. Inactivation rapidly induced profound alterations of neuronal discharges that were heterogeneous within each and across the two hemispheres, occurred during movements of either the affected or nonaffected arm, and varied during different phases of grasping. Our results support that extensive, and much more complex than expected, neuronal reorganization takes place in spared areas of the bihemispheric cortical network involved in the control of hand movements. This broad pattern of reorganization offers potential targets that should be considered for the development of neuromodulation protocols applied early after brain injury.SIGNIFICANCE STATEMENT It is well known that brain injuries cause changes in several distant, spared areas of the network, often in the premotor cortex. This reorganization is greater early after the injury and the magnitude of early changes correlates with impairments. However, studies to date have used noninvasive brain imaging approaches or have been conducted in sedated animals. Therefore, we do not know how brain injuries specifically affect the activity of neurons during the generation of movements. Our study clearly shows how a lesion rapidly impacts neurons in the premotor cortex of both hemispheres. A better understanding of these complex changes can help formulate hypotheses for the development of new treatments that specifically target neuronal reorganization induced by lesions in the brain.

A machine learning approach to characterize sequential movement-related states in premotor and motor cortices.

Nonhuman primate (NHP) movement kinematics have been decoded from spikes and local field potentials (LFPs) recorded during motor tasks. However, the potential of LFPs to provide network-like characterizations of neural dynamics during planning and execution of sequential movements requires further exploration. Is the aggregate nature of LFPs suitable to construct informative brain state descriptors of movement preparation and execution? To investigate this, we developed a framework to process LFPs based on machine-learning classifiers and analyzed LFP from a primate, implanted with several microelectrode arrays covering the premotor cortex in both hemispheres and the primary motor cortex on one side. The monkey performed a reach-to-grasp task, consisting of five consecutive states, starting from rest until a rewarding target (food) was attained. We use this five-state task to characterize neural activity within eight frequency bands, using spectral amplitude and pairwise correlations across electrodes as features. Our results show that we could best distinguish all five movement-related states using the highest frequency band (200-500 Hz), yielding an 87% accuracy with spectral amplitude, and 60% with pairwise electrode correlation. Further analyses characterized each movement-related state, showing differential neuronal population activity at above-γ frequencies during the various stages of movement. Furthermore, the topological distribution for the high-frequency LFPs allowed for a highly significant set of pairwise correlations, strongly suggesting a concerted distribution of movement planning and execution function is distributed across premotor and primary motor cortices in a specific fashion, and is most significant in the low ripple (100-150 Hz), high ripple (150-200 Hz), and multiunit frequency bands. In summary, our results show that the concerted use of novel machine-learning techniques with coarse grained queue broad signals such as LFPs may be successfully used to track and decode fine movement aspects involving preparation, reach, grasp, and reward retrieval across several brain regions.NEW & NOTEWORTHY Local field potentials (LFPs), despite lower spatial resolution compared to single-neuron recordings, can be used with machine learning classifiers to decode sequential movements involving motor preparation, execution, and reward retrieval. Our results revealed heterogeneity of neural activity on small spatial scales, further evidencing the utility of micro-electrode array recordings for complex movement decoding. With further advancement, high-dimensional LFPs may become the gold standard for brain-computer interfaces such as neural prostheses in the near future.

Poststroke Impairment and Recovery Are Predicted by Task-Specific Regionalization of Injury.

Lesion size and location affect the magnitude of impairment and recovery following stroke, but the precise relationship between these variables and functional outcome is unknown. Herein, we systematically varied the size of strokes in motor cortex and surrounding regions to assess effects on impairment and recovery of function. Female Sprague Dawley rats (N = 64) were evaluated for skilled reaching, spontaneous limb use, and limb placement over a 7 week period after stroke. Exploration and reaching were also tested in a free ranging, more naturalistic, environment. MRI voxel-based analysis of injury volume and its likelihood of including the caudal forelimb area (CFA), rostral forelimb area (RFA), hindlimb (HL) cortex (based on intracranial microstimulation), or their bordering regions were related to both impairment and recovery. Severity of impairment on each task was best predicted by injury in unique regions: impaired reaching, by damage in voxels encompassing CFA/RFA; hindlimb placement, by damage in HL; and spontaneous forelimb use, by damage in CFA. An entirely different set of voxels predicted recovery of function: damage lateral to RFA reduced recovery of reaching, damage medial to HL reduced recovery of hindlimb placing, and damage lateral to CFA reduced recovery of spontaneous limb use. Precise lesion location is an important, but heretofore relatively neglected, prognostic factor in both preclinical and clinical stroke studies, especially those using region-specific therapies, such as transcranial magnetic stimulation.SIGNIFICANCE STATEMENT By estimating lesion location relative to cortical motor representations, we established the relationship between individualized lesion location, and functional impairment and recovery in reaching/grasping, spontaneous limb use, and hindlimb placement during walking. We confirmed that stroke results in impairments to specific motor domains linked to the damaged cortical subregion and that damage encroaching on adjacent regions reduces the ability to recover from initial lesion-induced impairments. Each motor domain encompasses unique brain regions that are most associated with recovery and likely represent targets where beneficial reorganization is taking place. Future clinical trials should use individualized therapies (e.g., transcranial magnetic stimulation, intracerebral stem/progenitor cells) that consider precise lesion location and the specific functional impairments of each subject since these variables can markedly affect therapeutic efficacy.

Advancing Stroke Recovery Through Improved Articulation of Nonpharmacological Intervention Dose.

Dose articulation is a universal issue of intervention development and testing. In stroke recovery, dose of a nonpharmaceutical intervention appears to influence outcome but is often poorly reported. The challenges of articulating dose in nonpharmacological stroke recovery research include: (1) the absence of specific internationally agreed dose reporting guidelines; (2) inadequate conceptualization of dose, which is multidimensional; and (3) unclear and inconsistent terminology that incorporates the multiple dose dimensions. To address these challenges, we need a well-conceptualized and consistent approach to dose articulation that can be applied across stroke recovery domains to stimulate critical thinking about dose during intervention development, as well as promote reporting of planned intervention dose versus actually delivered dose. We followed the Design Research Paradigm to develop a framework that guides how to articulate dose, conceptualizes the multidimensional nature and systemic linkages between dose dimensions, and provides reference terminology for the field. Our framework recognizes that dose is multidimensional and comprised of a duration of days that contain individual sessions and episodes that can be active (time on task) or inactive (time off task), and each individual episode can be made up of information about length, intensity, and difficulty. Clinical utility of this framework was demonstrated via hypothetical application to preclinical and clinical domains of stroke recovery. The suitability of the framework to address dose articulation challenges was confirmed with an international expert advisory group. This novel framework provides a pathway for better articulation of nonpharmacological dose that will enable transparent and accurate description, implementation, monitoring, and reporting, in stroke recovery research.

Interhemispheric modulations of motor outputs by the rostral and caudal forelimb areas in rats.

In rats, forelimb movements are evoked from two cortical regions, the caudal and rostral forelimb areas (CFA and RFA, respectively). These areas are densely interconnected and RFA induces complex and powerful modulations of CFA outputs. CFA and RFA also have interhemispheric connections, and these areas from both hemispheres send projections to common targets along the motor axis, providing multiple potential sites of interactions for movement production. Our objective was to characterize how CFA and RFA in one hemisphere can modulate motor outputs of the opposite hemisphere. To do so, we used paired-pulse protocols with intracortical microstimulation techniques (ICMS), while recording electromyographic (EMG) activity of forelimb muscles in sedated rats. A subthreshold conditioning stimulation was applied in either CFA or RFA in one hemisphere simultaneously or before a suprathreshold test stimulation in either CFA or RFA in the opposite hemisphere. Both CFA and RFA tended to facilitate motor outputs with short (0-2.5 ms) or long (20-35 ms) delays between the conditioning and test stimuli. In contrast, they tended to inhibit motor outputs with intermediate delays, in particular 10 ms. When comparing the two areas, we found that facilitatory effects from RFA were more frequent and powerful than the ones from CFA. In contrast, inhibitory effects from CFA on its homolog were more frequent and powerful than the ones from RFA. Our results demonstrate that interhemispheric modulations from CFA and RFA share some similarities but also have clear differences that could sustain specific functions these cortical areas carry for the generation of forelimb movements.NEW & NOTEWORTHY We show that caudal and rostral forelimb areas (CFA and RFA) have distinct effects on motor outputs from the opposite hemisphere, supporting that they are distinct nodes in the motor network of rats. However, the pattern of interhemispheric modulations from RFA has no clear equivalent among premotor areas in nonhuman primates, suggesting they contribute differently to the generation of ipsilateral hand movements. Understanding these interspecies differences is important given the common use of rodent models in motor control and recovery studies.

Modulatory effects of the supplementary motor area on primary motor cortex outputs.

Premotor areas of primates are specialized cortical regions that can contribute to hand movements by modulating the outputs of the primary motor cortex (M1). The goal of the present work was to study how the supplementary motor area (SMA) located within the same hemisphere [i.e., ipsilateral SMA (iSMA)] or the opposite hemisphere [i.e., contralateral (cSMA)] modulate the outputs of M1. We used paired-pulse protocols with intracortical stimulations in sedated capuchin monkeys. A conditioning stimulus in iSMA or cSMA was delivered simultaneously or before a test stimulus in M1 with different interstimulus intervals (ISIs) while electromyographic activity was recorded in hand and forearm muscles. The pattern of modulation from iSMA and cSMA shared some clear similarities. In particular, both areas predominantly induced facilitatory effects on M1 outputs with shorter ISIs and inhibitory effects with longer ISIs. However, the incidence and strength of facilitatory effects were greater for iSMA than cSMA. We then compared the pattern of modulatory effects from SMA to the ones from the dorsal and ventral premotor cortexes (PMd and PMv) collected in the same series of experiments. Among premotor areas, the impact of SMA on M1 outputs was always weaker than the one of either PMd or PMv, and this was regardless of the hemisphere, or the ISI, tested. These results show that SMA exerts a unique set of modulations on M1 outputs, which could support its specific function for the production of hand movements.NEW & NOTEWORTHY We unequivocally isolated stimulation to either the ipsilateral or contralateral supplementary motor area (SMA) using invasive techniques and compared their modulatory effects on the outputs of primary motor cortex (M1). Modulations from both SMAs shared many similarities. However, facilitatory effects evoked from ipsilateral SMA were more common and more powerful. This pattern differs from the ones of other premotor areas, which suggests that each premotor area makes unique contributions to the production of motor outputs.

Contrasting Modulatory Effects from the Dorsal and Ventral Premotor Cortex on Primary Motor Cortex Outputs.

The dorsal and ventral premotor cortices (PMd and PMv, respectively) each take part in unique aspects for the planning and execution of hand movements. These premotor areas are components of complex anatomical networks that include the primary motor cortex (M1) of both hemispheres. One way that PMd and PMv could play distinct roles in hand movements is by modulating the outputs of M1 differently. However, patterns of effects from PMd and PMv on the outputs of M1 have not been compared systematically. Our goals were to study how PMd within the same (i.e., ipsilateral or iPMd) and in the opposite hemisphere (i.e., contralateral or cPMd) can shape M1 outputs and then compare these effects with those induced by PMv. We used paired-pulse protocols with intracortical microstimulation techniques in sedated female cebus monkeys while recording EMG signals from intrinsic hand and forearm muscles. A conditioning stimulus was delivered in iPMd or cPMd concurrently or before a test stimulus in M1. The patterns of modulatory effects from PMd were compared with those from PMv collected in the same animals. Striking differences were revealed. Conditioning stimulation in iPMd induced more frequent and powerful inhibitory effects on M1 outputs compared with iPMv. In the opposite hemisphere, cPMd conditioning induced more frequent and powerful facilitatory effects than cPMv. These contrasting patterns of modulatory effects could allow PMd and PMv to play distinct functions for the control of hand movements and predispose them to undertake different, perhaps somewhat opposite, roles in motor recovery after brain injury.SIGNIFICANCE STATEMENT The dorsal and ventral premotor cortices (PMd and PMv, respectively) are two specialized areas involved in the control of hand movements in primates. One way that PMd and PMv could participate in hand movements is by modulating or shaping the primary motor cortex (M1) outputs to hand muscles. Here, we studied the patterns of modulation from PMd within the same and in the opposite hemisphere on the outputs of M1 and compared them with those from PMv. We found that PMd and PMv have strikingly different effects on M1 outputs. These contrasting patterns of modulation provide a substrate that may allow PMd and PMv to carry distinct functions for the preparation and execution of hand movements and for recovery after brain injury.

Interhemispheric interactions between trunk muscle representations of the primary motor cortex.

Unilateral arm movements require trunk stabilization through bilateral contraction of axial muscles. Interhemispheric interactions between primary motor cortices (M1) could enable such coordinated contractions, but these mechanisms are largely unknown. Using transcranial magnetic stimulation (TMS), we characterized interhemispheric interactions between M1 representations of the trunk-stabilizing muscles erector spinae at the first lumbar vertebra (ES L1) during a right isometric shoulder flexion. These interactions were compared with those of the anterior deltoid (AD), the main agonist in this task, and the first dorsal interosseous (FDI). TMS over the right M1 elicited ipsilateral silent periods (iSP) in all three muscles on the right side. In ES L1, but not in AD or FDI, ipsilateral motor evoked potential (iMEP) could precede the iSP or replace it. iMEP amplitude was not significantly different whether ES L1 was used to stabilize the trunk or was voluntarily contracted. TMS at the cervicomedullary junction showed that the size of cervicomedullary evoked potential was unchanged during the iSP but increased during iMEP, suggesting that the iSP, but not the iMEP, is due to intracortical mechanisms. Using a dual-coil paradigm with two coils over the left and right M1, interhemispheric inhibition could be evoked at interstimulus intervals of 6 ms in ES L1 and 8 ms in AD and FDI. Together, these results suggest that interhemispheric inhibition is dominant when axial muscles are involved in a stabilizing task. The ipsilateral facilitation could be evoked by ipsilateral or subcortical pathways and could be used depending on the role axial muscles play in the task.NEW & NOTEWORTHY The mechanisms involved in the bilateral coordination of axial muscles during unilateral arm movement are poorly understood. We thus investigated the nature of interhemispheric interactions in axial muscles during arm motor tasks in healthy subjects. By combining different methodologies, we showed that trunk muscles receive both inhibitory and facilitatory cortical outputs during activation of arm muscles. We propose that inhibition may be conveyed mainly through interhemispheric mechanisms and facilitation by subcortical mechanisms or ipsilateral pathways.

Different Patterns of Cortical Inputs to Subregions of the Primary Motor Cortex Hand Representation in Cebus apella.

The primary motor cortex (M1) plays an essential role in the control of hand movements in primates and is part of a complex cortical sensorimotor network involving multiple premotor and parietal areas. In a previous study in squirrel monkeys, we found that the ventral premotor cortex (PMv) projected mainly to 3 regions within the M1 forearm representation [rostro-medial (RM), rostro-lateral (RL), and caudo-lateral (CL)] with very few caudo-medial (CM) projections. These results suggest that projections from premotor areas to M1 are not uniform, but rather segregated into subregions. The goal of the present work was to study how inputs from diverse areas of the ipsilateral cortical network are organized within the M1 hand representation. In Cebus apella, different retrograde neuroanatomical tracers were injected in 4 subregions of the hand area of M1 (RM, RL, CM, and CL). We found a different pattern of input to each subregion of M1. RM receives inputs predominantly from dorsal premotor cortex, RL from PMv, CM from area 5, and CL from area 2. These results support that the M1 hand representation is composed of several subregions, each part of a unique cortical network.

Modulatory Effects of the Ipsi and Contralateral Ventral Premotor Cortex (PMv) on the Primary Motor Cortex (M1) Outputs to Intrinsic Hand and Forearm Muscles in Cebus apella.

The ventral premotor cortex (PMv) is a key node in the neural network involved in grasping. One way PMv can carry out this function is by modulating the outputs of the primary motor cortex (M1) to intrinsic hand and forearm muscles. As many PMv neurons discharge when grasping with either arm, both PMv within the same hemisphere (ipsilateral; iPMv) and in the opposite hemisphere (contralateral; cPMv) could modulate M1 outputs. Our objective was to compare modulatory effects of iPMv and cPMv on M1 outputs to intrinsic hand and forearm muscles. We used paired-pulse protocols with intracortical microstimulations in capuchin monkeys. A conditioning stimulus was applied in either iPMv or cPMv simultaneously or prior to a test stimulus in M1 and the effects quantified in electromyographic signals. Modulatory effects from iPMv were predominantly facilitatory, and facilitation was much more common and powerful on intrinsic hand than forearm muscles. In contrast, while the conditioning of cPMv could elicit facilitatory effects, in particular to intrinsic hand muscles, it was much more likely to inhibit M1 outputs. These data show that iPMv and cPMv have very different modulatory effects on the outputs of M1 to intrinsic hand and forearm muscles.

Which Aspects of Stroke Do Animal Models Capture? A Multitracer Micro-PET Study of Focal Ischemia with Endothelin-1.

BACKGROUND: Cortical injections of the vasoconstrictor endothelin-1 (ET1) have widely been used to induce focal circumscribed ischemic lesions in the motor cortex of rodents in the context of stroke recovery studies. In order to apply this model correctly, it is essential to understand the time course of regional flow changes and of the development of penumbra and infarction. METHODS: Multitracer micro-PET of ET1 focal ischemia in rats was performed using [11C]-flumazenil ([11C]FMZ) as a flow- and viability tracer and [18F]-fluoromisonidazole ([18F]FMISO) as hypoxia marker in order to characterize the physiological time-course of this model. Nine adult Sprague-Dawley rats received stereotaxic injections of ET1 into the right primary motor cortex, 3 served as controls. PET imaging was started 2, 3 and 20 h after the last ET1 injection. Histology was obtained at the end of the scans. Standardized uptake value ratios reflecting cerebral blood flow (CBF), [11C]FMZ-binding and [18F]FMISO-retention were calculated for the region of hypoperfusion and the normoperfused cortex. RESULTS: CBF in the hypoperfused cortex was significantly reduced (p < 0.01) at 5 h (0.58 ± 0.025), 6 h (0.54 ± 0.043) and 23 h (0.66 ± 0.024) compared to controls (1.00 ± 0.011) and moderately reduced (p < 0.05) in the remainder of the affected hemisphere at 5 h (0.93 ± 0.036). [11C]FMZ-binding was within the control range at all time points. Significant [18F]FMISO-retention (1.16 ± 0.091, p < 0.05) was observed only after 6 h in the ischemic core that later turned into infarct. CONCLUSION: ET1 injections yield reproducible, slowly developing ischemic lesions with constant levels of hypoperfusion. This multitracer micro-PET study suggests that the ET1 model is appropriate for inducing chronic circumscribed ischemic lesions but seems to be less suited for studying acute stroke pathophysiology.

Gaussian-process-based Bayesian optimization for neurostimulation interventions in rats.

Effective neural stimulation requires adequate parametrization. Gaussian-process (GP)-based Bayesian optimization (BO) offers a framework to discover optimal stimulation parameters in real time. Here, we first provide a general protocol to deploy this framework in neurostimulation interventions and follow by exemplifying its use in detail. Specifically, we describe the steps to implant rats with multi-channel electrode arrays in the hindlimb motor cortex. We then detail how to utilize the GP-BO algorithm to maximize evoked target movements, measured as electromyographic responses. For complete details on the use and execution of this protocol, please refer to Bonizzato and colleagues (2023).1.

A translational roadmap for transcranial magnetic and direct current stimulation in stroke rehabilitation: Consensus-based core recommendations from the third stroke recovery and rehabilitation roundtable.

BACKGROUND AND AIMS: The purpose of this Third Stroke Recovery and Rehabilitation Roundtable (SRRR3) was to develop consensus recommendations to address outstanding barriers for the translation of preclinical and clinical research using the non-invasive brain stimulation (NIBS) techniques Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) and provide a roadmap for the integration of these techniques into clinical practice. METHODS: International NIBS and stroke recovery experts (N = 18) contributed to the consensus process. Using a nominal group technique, recommendations were reached via a five-stage process, involving a thematic survey, two priority ranking surveys, a literature review and an in-person meeting. RESULTS AND CONCLUSIONS: Results of our consensus process yielded five key evidence-based and feasibility barriers for the translation of preclinical and clinical NIBS research, which were formulated into five core consensus recommendations. Recommendations highlight an urgent need for (1) increased understanding of NIBS mechanisms, (2) improved methodological rigor in both preclinical and clinical NIBS studies, (3) standardization of outcome measures, (4) increased clinical relevance in preclinical animal models, and (5) greater optimization and individualization of NIBS protocols. To facilitate the implementation of these recommendations, the expert panel developed a new SRRR3 Unified NIBS Research Checklist. These recommendations represent a translational pathway for the use of NIBS in stroke rehabilitation research and practice.

A translational roadmap for transcranial magnetic and direct current stimulation in stroke rehabilitation: Consensus-based core recommendations from the third stroke recovery and rehabilitation roundtable.

BACKGROUND AND AIMS: The purpose of this Third Stroke Recovery and Rehabilitation Roundtable (SRRR3) was to develop consensus recommendations to address outstanding barriers for the translation of preclinical and clinical research using the non-invasive brain stimulation (NIBS) techniques Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) and provide a roadmap for the integration of these techniques into clinical practice. METHODS: International NIBS and stroke recovery experts (N = 18) contributed to the consensus process. Using a nominal group technique, recommendations were reached via a five-stage process, involving a thematic survey, two priority ranking surveys, a literature review and an in-person meeting. RESULTS AND CONCLUSIONS: Results of our consensus process yielded five key evidence-based and feasibility barriers for the translation of preclinical and clinical NIBS research, which were formulated into five core consensus recommendations. Recommendations highlight an urgent need for (1) increased understanding of NIBS mechanisms, (2) improved methodological rigor in both preclinical and clinical NIBS studies, (3) standardization of outcome measures, (4) increased clinical relevance in preclinical animal models, and (5) greater optimization and individualization of NIBS protocols. To facilitate the implementation of these recommendations, the expert panel developed a new SRRR3 Unified NIBS Research Checklist. These recommendations represent a translational pathway for the use of NIBS in stroke rehabilitation research and practice.

Transcranial magnetic stimulation in non-human primates: A systematic review.

Transcranial magnetic stimulation (TMS) is widely employed as a tool to investigate and treat brain diseases. However, little is known about the direct effects of TMS on the brain. Non-human primates (NHPs) are a valuable translational model to investigate how TMS affects brain circuits given their neurophysiological similarity with humans and their capacity to perform complex tasks that approach human behavior. This systematic review aimed to identify studies using TMS in NHPs as well as to assess their methodological quality through a modified reference checklist. The results show high heterogeneity and superficiality in the studies regarding the report of the TMS parameters, which have not improved over the years. This checklist can be used for future TMS studies with NHPs to ensure transparency and critical appraisal. The use of the checklist would improve methodological soundness and interpretation of the studies, facilitating the translation of the findings to humans. The review also discusses how advancements in the field can elucidate the effects of TMS in the brain.

Autonomous optimization of neuroprosthetic stimulation parameters that drive the motor cortex and spinal cord outputs in rats and monkeys.

Neural stimulation can alleviate paralysis and sensory deficits. Novel high-density neural interfaces can enable refined and multipronged neurostimulation interventions. To achieve this, it is essential to develop algorithmic frameworks capable of handling optimization in large parameter spaces. Here, we leveraged an algorithmic class, Gaussian-process (GP)-based Bayesian optimization (BO), to solve this problem. We show that GP-BO efficiently explores the neurostimulation space, outperforming other search strategies after testing only a fraction of the possible combinations. Through a series of real-time multi-dimensional neurostimulation experiments, we demonstrate optimization across diverse biological targets (brain, spinal cord), animal models (rats, non-human primates), in healthy subjects, and in neuroprosthetic intervention after injury, for both immediate and continual learning over multiple sessions. GP-BO can embed and improve "prior" expert/clinical knowledge to dramatically enhance its performance. These results advocate for broader establishment of learning agents as structural elements of neuroprosthetic design, enabling personalization and maximization of therapeutic effectiveness.