01/08/2026 | José Tadeu Arantes | FAPESP Agency

https://agencia.fapesp.br/estudo-combina-neuromodulacao-e-fisioterapia-para-reabilitar-pacientes-apos-avc/56847 

The multicenter Titan Trial project investigates a method to treat unilateral spatial neglect, a sequela of stroke that affects the perception of the opposite side of the affected cerebral hemisphere.

A clinical study involving several centers will test an innovative method to treat a disabling sequela of stroke: unilateral spatial neglect (USN), a condition that affects the perception of one side of space and hinders functional rehabilitation. Called the Titan Trial, the project investigates the combination of two non-invasive neuromodulation techniques – transcranial direct current stimulation (tDCS) and theta burst (TB) transcranial magnetic stimulation – with task-based physiotherapy sessions.

NEU causes a person to forget or not perceive one side of their body or environment. For example, they may only eat what is on the right side of the plate; collide with objects or people on the left side; comb, shave, or apply makeup only to the right side of their head; not hear when someone calls from the left side, etc. It is not a motor or visual deficit, but a perceptual deficit, which can continue even if the affected individual recovers strength and movement.

“This new initiative is a derivation of our research line in post-stroke neurorehabilitation, supported through Regular Grants from FAPESP,” says neurologist Rodrigo Bazan, professor at the Botucatu Faculty of Medicine of the São Paulo State University (FMB-Unesp) and coordinator of the study. This initiative continues a research trajectory that had already yielded promising results in a previous study conducted by the same group. Supported by FAPESP, the researchers tested the effectiveness of anodal tDCS (stimulatory) in patients with lesions in the right cerebral hemisphere, especially in the parietal region, responsible for the perception of space on the left.

“In that study, which we called the Electron Trial, we showed that anodal electrical stimulation applied to the right parietal region favors brain plasticity and reduces spatial neglect,” recalls Bazan. “Six articles were published, including one in the Annals of Neurology, one of the most respected journals in neuroscience.”

Based on these results, the group decided to move towards a more comprehensive and potentially more effective approach. In the Titan Trial, in addition to electrical stimulation of the affected (right) hemisphere, patients receive continuous theta burst (inhibitory) transcranial magnetic stimulation in the contralateral (left) hemisphere. “The logic is this: stimulate the side that suffered the injury and inhibit the other side, which, due to poor compensation, may be hindering recovery,” explains Bazan.

This is because, when a stroke occurs, the hemisphere that suffered the injury may become hypoactive and the side contralateral to the injury may become hyperactive, causing an interhemispheric imbalance. The combination of the two techniques helps to rebalance brain activity and enhance the effects of physiotherapy.

The procedures are considered completely safe and have been used in other treatments for depression, anxiety, chronic pain, and motor impairments resulting from stroke. Electrical and magnetic stimulation do not hurt, causing, at most, a slight tingling or a small pressure in the head, which passes quickly.

“We are using the best of both techniques: anodal tDCS [stimulatory], which has already shown good results in our previous study, and TB [inhibitory], which allows for faster and more concentrated sessions, with great potential for impact on cortical reorganization,” says physiotherapist Luana Aparecida Miranda Bonome, a doctoral candidate in the postgraduate program in Physiopathology in Clinical Medicine at FMB-Unesp. The study is part of her research project.

According to her, the differentiating factor of the Titan Trial lies precisely in the combination of the two techniques, stimulatory and inhibitory, coupled with specific physiotherapy. “All patients undergo physiotherapy focused on specific tasks, which enhances the effects of neuromodulation. There's no point in opening the window of brain plasticity and not taking advantage of it with a functional intervention,” comments Bonome.

The study is multicenter, with participation from institutions in various regions of Brazil, including the Federal University of Triângulo Mineiro (UFTM), with Gustavo Luvizutto, a physiotherapist and active member of the team with significant involvement in the previous study (Eletron Trial); the University of São Paulo (USP); the State University of Campinas (Unicamp); and specialized centers in Salvador (BA), Campo Grande (MS), and Joinville (SC), among others. There is also international collaboration with the University of Toronto, Canada, which will participate in the analysis of clinical outcomes, and physiotherapists Brenton Hordacre and Emily Ramage, researchers from Australia with experience in conducting clinical trials and neuromodulation. At least 51 patients will be recruited, divided into three groups: combined active stimulation, isolated electrical stimulation, and a placebo group, all groups receiving physiotherapy with task-oriented therapy.

“The selection of participants is rigorous. We only included patients with ischemic stroke of the right hemisphere and a confirmed diagnosis of spatial neglect. We excluded cases of bilateral lesions, severe cognitive deficits, or comorbidities that compromise adherence to treatment,” informs Bonome.

The interventions will be carried out during 15 sessions, with intermediate and follow-up evaluations after three, six, and 12 months. The interventions and evaluations will be conducted at the Clinical Research Unit (Upeclin), a major supporter of the project. Among the monitored outcomes, the main one is the reduction of NEU (neuroneurogenic stress), in addition to the analysis of improvements in functionality, autonomy, quality of life, and self-efficacy. The researchers hope that the results can consolidate the clinical application of combined neuromodulation as an effective and feasible strategy in the context of the Brazilian Unified Health System (SUS). “This will be an important step in transforming advanced technology into everyday healthcare practice,” concludes Bazan.