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.

Visual, delay, and oculomotor timing and tuning in macaque dorsal pulvinar during instructed and free choice memory saccades.

Causal perturbations suggest that primate dorsal pulvinar plays a crucial role in target selection and saccade planning, though its basic neuronal properties remain unclear. Some functional aspects of dorsal pulvinar and interconnected frontoparietal areas-e.g. ipsilesional choice bias after inactivation-are similar. But it is unknown if dorsal pulvinar shares oculomotor properties of cortical circuitry, in particular delay and choice-related activity. We investigated such properties in macaque dorsal pulvinar during instructed and free-choice memory saccades. Most recorded units showed visual (12%), saccade-related (30%), or both types of responses (22%). Visual responses were primarily contralateral; diverse saccade-related responses were predominantly post-saccadic with a weak contralateral bias. Memory delay and pre-saccadic enhancement was infrequent (11-9%)-instead, activity was often suppressed during saccade planning (25%) and further during execution (15%). Surprisingly, only few units exhibited classical visuomotor patterns combining cue and continuous delay activity or pre-saccadic ramping; moreover, most spatially-selective neurons did not encode the upcoming decision during free-choice delay. Thus, in absence of a visible goal, the dorsal pulvinar has a limited role in prospective saccade planning, with patterns partially complementing its frontoparietal partners. Conversely, prevalent visual and post-saccadic responses imply its participation in integrating spatial goals with processing across saccades.

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.

Predicting Individual Treatment Response to rTMS for Motor Recovery After Stroke: A Review and the CanStim Perspective.

Background: Rehabilitation is critical for reducing stroke-related disability and improving quality-of-life post-stroke. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique used as stand-alone or adjunct treatment to physiotherapy, may be of benefit for motor recovery in subgroups of stroke patients. The Canadian Platform for Trials in Non-Invasive Brain Stimulation (CanStim) seeks to advance the use of these techniques to improve post-stroke recovery through clinical trials and pre-clinical studies using standardized research protocols. Here, we review existing clinical trials for demographic, clinical, and neurobiological factors which may predict treatment response to identify knowledge gaps which need to be addressed before implementing these parameters for patient stratification in clinical trial protocols. Objective: To provide a review of clinical rTMS trials of stroke recovery identifying factors associated with rTMS response in stroke patients with motor deficits and develop research perspectives for pre-clinical and clinical studies. Methods: A literature search was performed in PubMed, using the Boolean search terms stroke AND repetitive transcranial magnetic stimulation OR rTMS AND motor for studies investigating the use of rTMS for motor recovery in stroke patients at any recovery phase. A total of 1,676 articles were screened by two blinded raters, with 26 papers identified for inclusion in this review. Results: Multiple possible factors associated with rTMS response were identified, including stroke location, cortical thickness, brain-derived neurotrophic factor (BDNF) genotype, initial stroke severity, and several imaging and clinical factors associated with a relatively preserved functional motor network of the ipsilesional hemisphere. Age, sex, and time post-stroke were generally not related to rTMS response. Factors associated with greater response were identified in studies of both excitatory ipsilesional and inhibitory contralesional rTMS. Heterogeneous study designs and contradictory data exemplify the need for greater protocol standardization and high-quality controlled trials. Conclusion: Clinical, brain structural and neurobiological factors have been identified as potential predictors for rTMS response in stroke patients with motor impairment. These factors can inform the design of future clinical trials, before being considered for optimization of individual rehabilitation therapy for stroke patients. Pre-clinical models for stroke recovery, specifically developed in a clinical context, may accelerate this process.

Eye position signals in the dorsal pulvinar during fixation and goal-directed saccades.

Sensorimotor cortical areas contain eye position information thought to ensure perceptual stability across saccades and underlie spatial transformations supporting goal-directed actions. One pathway by which eye position signals could be relayed to and across cortical areas is via the dorsal pulvinar. Several studies have demonstrated saccade-related activity in the dorsal pulvinar, and we have recently shown that many neurons exhibit postsaccadic spatial preference. In addition, dorsal pulvinar lesions lead to gaze-holding deficits expressed as nystagmus or ipsilesional gaze bias, prompting us to investigate the effects of eye position. We tested three starting eye positions (-15°, 0°, 15°) in monkeys performing a visually cued memory saccade task. We found two main types of gaze dependence. First, ~50% of neurons showed dependence on static gaze direction during initial and postsaccadic fixation, and might be signaling the position of the eyes in the orbit or coding foveal targets in a head/body/world-centered reference frame. The population-derived eye position signal lagged behind the saccade. Second, many neurons showed a combination of eye-centered and gaze-dependent modulation of visual, memory, and saccadic responses to a peripheral target. A small subset showed effects consistent with eye position-dependent gain modulation. Analysis of reference frames across task epochs from visual cue to postsaccadic fixation indicated a transition from predominantly eye-centered encoding to representation of final gaze or foveated locations in nonretinocentric coordinates. These results show that dorsal pulvinar neurons carry information about eye position, which could contribute to steady gaze during postural changes and to reference frame transformations for visually guided eye and limb movements.NEW & NOTEWORTHY Work on the pulvinar focused on eye-centered visuospatial representations, but position of the eyes in the orbit is also an important factor that needs to be taken into account during spatial orienting and goal-directed reaching. We show that dorsal pulvinar neurons are influenced by eye position. Gaze direction modulated ongoing firing during stable fixation, as well as visual and saccade responses to peripheral targets, suggesting involvement of the dorsal pulvinar in spatial coordinate transformations.

Reach and grasp deficits following damage to the dorsal pulvinar.

Expansion of the dorsal pulvinar in humans and its anatomical connectivity suggests its involvement in higher-order cognitive and visuomotor functions. We investigated visuomotor performance in a 31 year old patient (M.B.) with a lesion centered on the medial portion of the dorsal pulvinar (left > right) due to an atypical Sarcoidosis manifestation. Unlike lesions with a vascular etiology, the lesion of M.B. did not include primary sensory or motor thalamic nuclei. Thus, this patient gave us the exceedingly rare opportunity to study the contribution of the dorsal pulvinar to visuomotor behavior in a human without confounding losses in primary sensory or motor domains. We investigated reaching, saccade and visual decision making performance. Patient data in each task was compared to at least seven age matched healthy controls. While saccades were hypometric towards both hemifields, the patient did not show any spatial choice bias or perceptual deficits. At the same time, he exhibited reach and grasp difficulties, which shared features with both, parietal and cerebellar damage. In particular, he had problems to form a precision grip and exhibited reach deficits expressed in decreased accuracy, delayed initiation and prolonged movement durations. Reach deficits were similar in foveal and extrafoveal viewing conditions and in both visual hemifields but were stronger with the right hand. These results suggest that dorsal pulvinar function in humans goes beyond its subscribed role in visual cognition and is critical for the programming of voluntary actions with the hands.

Electrical Microstimulation of the Pulvinar Biases Saccade Choices and Reaction Times in a Time-Dependent Manner.

The pulvinar complex is interconnected extensively with brain regions involved in spatial processing and eye movement control. Recent inactivation studies have shown that the dorsal pulvinar (dPul) plays a role in saccade target selection; however, it remains unknown whether it exerts effects on visual processing or at planning/execution stages. We used electrical microstimulation of the dPul while monkeys performed saccade tasks toward instructed and freely chosen targets. Timing of stimulation was varied, starting before, at, or after onset of target(s). Stimulation affected saccade properties and target selection in a time-dependent manner. Stimulation starting before but overlapping with target onset shortened saccadic reaction times (RTs) for ipsiversive (to the stimulation site) target locations, whereas stimulation starting at and after target onset caused systematic delays for both ipsiversive and contraversive locations. Similarly, stimulation starting before the onset of bilateral targets increased ipsiversive target choices, whereas stimulation after target onset increased contraversive choices. Properties of dPul neurons and stimulation effects were consistent with an overall contraversive drive, with varying outcomes contingent upon behavioral demands. RT and choice effects were largely congruent in the visually-guided task, but stimulation during memory-guided saccades, while influencing RTs and errors, did not affect choice behavior. Together, these results show that the dPul plays a primary role in action planning as opposed to visual processing, that it exerts its strongest influence on spatial choices when decision and action are temporally close, and that this choice effect can be dissociated from motor effects on saccade initiation and execution.SIGNIFICANCE STATEMENT Despite a recent surge of interest, the core function of the pulvinar, the largest thalamic complex in primates, remains elusive. This understanding is crucial given the central role of the pulvinar in current theories of integrative brain functions supporting cognition and goal-directed behaviors, but electrophysiological and causal interference studies of dorsal pulvinar (dPul) are rare. Building on our previous studies that pharmacologically suppressed dPul activity for several hours, here we used transient electrical microstimulation at different periods while monkeys performed instructed and choice eye movement tasks, to determine time-specific contributions of pulvinar to saccade generation and decision making. We show that stimulation effects depend on timing and behavioral state and that effects on choices can be dissociated from motor effects.