IS 45. Brain stimulation-enhanced therapy for visual neglect

Abstract

‘Neglect’ is a common disabling neurological syndrome after right hemisphere stroke. It is a multifaceted disorder in which patients lose the capacity to voluntarily attend to the left half of space, objects or the body. While spontaneous remission can occur over time, one third of patients suffer chronic neglect and life-long disability. Prism adaptation (PA) is a behavioural intervention in which patients learn to adapt to a rightward optical (prismatic) shift, by re-calibrating their pointing behaviour from the right (intact) into the left (neglected) hemi-space. Following PA, patients exhibit a leftward shift in pointing behaviour, known as a prism after-effect. While this after-effect is present, neglect symptoms are improved (Rossetti et al., 1998 Nature; 395). A few minutes of PA can induce transient gains across a remarkable range of deficits (e.g.: visual search, drawing, postural control, wheelchair driving and reading; Pisella et al., 1996 Restor Neurol Neurosci; 24). However, not all patients respond, and in those who do, repeated interventions are required to produce lasting benefit. Our goal was to devise a brain stimulation protocol that would enhance the efficacy of prism therapy for neglect. Specifically, we aimed to test the hypothesis that a plasticity-promoting protocol would enhance consolidation of prism after-effects, and thus cause lasting improvements in visual neglect. We used a bench-to-bedside translational strategy, devising protocols and testing hypotheses first in healthy controls ( N = 52), and then transferring the most promising intervention to patients. In a series of six experiments, we tested the effect of transcranial direct current stimulation (TDCS) to a variety of cortical regions on learning and retention rates for PA. Next, in a series of longitudinal studies in three patients, we tested the impact of the most promising stimulation protocol on performance of a battery of neglect tests. The experiments in healthy volunteers enabled us to identify a protocol that enhanced consolidation of prism after-effects over a time-scale of several days, in a manner that was functionally, anatomically and neurochemically specific, as well as cognitive state dependent. When we translated this protocol to patients, we found that a single 20-min intervention significantly improved neglect [relative gain: 66% (patient 1 session 1), 45% (session 2), 53% (patient 2), 25% (patient 3)]. These effects lasted weeks to months and did not return to baseline [duration of benefit: 80 days (patient 1 session 1), 46 days (session 2), 46 days (patient 2), 21 days (patient 3)]. Notably, this occurred in patients with chronic, severe, neglect who showed no response to prism therapy alone. In a single-case double crossover design (patient 1) comparing real versus sham TDCS, the patient exhibited a large positive response to each real TDCS, and the effects accumulated, suggesting that repeated treatments might induce gradual recovery. This is the first proof-of-principle demonstration that a single-shot, simple behavioural procedure combined with TDCS can remediate treatment-unresponsive chronic visual neglect. TDCS provoked a positive therapeutic response in patients who did not otherwise respond to the behavioural therapy. By enhancing the consolidation of prism therapy, TDCS increased both the gain and longevity of therapeutic response, yielding large, long-lasting improvements in visual neglect.