Differential Effects of Speech and Language Therapy and rTMS in Chronic Versus Subacute Post-stroke Aphasia: Results of the NORTHSTAR-CA Trial

Anna Zumbansen, Heike Kneifel, Latifa Lazzouni, Anja Ophey, Sandra E Black, Joyce L Chen, Dylan Edwards, Thomas Funck, Alexander Erich Hartmann, Wolf-Dieter Heiss, Franziska Hildesheim, Sylvain Lanthier, Paul Lespérance, George Mochizuki, Caroline Paquette, Elizabet Rochon, Ilona Rubi-Fessen, Jennie Valles, Susan Wortman-Jutt, Alexander Thiel, NORTHSTAR-study group, Anna Zumbansen, Heike Kneifel, Latifa Lazzouni, Anja Ophey, Sandra E Black, Joyce L Chen, Dylan Edwards, Thomas Funck, Alexander Erich Hartmann, Wolf-Dieter Heiss, Franziska Hildesheim, Sylvain Lanthier, Paul Lespérance, George Mochizuki, Caroline Paquette, Elizabet Rochon, Ilona Rubi-Fessen, Jennie Valles, Susan Wortman-Jutt, Alexander Thiel, NORTHSTAR-study group

Abstract

Background & objective: Contralesional 1-Hz repetitive transcranial magnetic stimulation (rTMS) over the right pars triangularis combined with speech-language therapy (SLT) has shown positive results on the recovery of naming in subacute (5-45 days) post-stroke aphasia. NORTHSTAR-CA is an extension of the previously reported NORTHSTAR trial to chronic aphasia (>6 months post-stroke) designed to compare the effectiveness of the same rTMS protocol in both phases.

Methods: Sixty-seven patients with left middle cerebral artery infarcts (28 chronic, 39 subacute) were recruited (01-2014 to 07-2019) and randomized to receive rTMS (N = 34) or sham stimulation (N = 33) with SLT for 10 days. Primary outcome variables were Z-score changes in naming, semantic fluency and comprehension tests and adverse event frequency. Intention-to-treat analyses tested between-group effects at days 1 and 30 post-treatment. Chronic and subacute results were compared.

Results: Adverse events were rare, mild, and did not differ between groups. Language outcomes improved significantly in all groups irrespective of treatment and recovery phase. At 30-day follow-up, there was a significant interaction of stimulation and recovery phase on naming recovery (P <.001). Naming recovery with rTMS was larger in subacute (Mdn = 1.91/IQR = .77) than chronic patients (Mdn = .15/IQR = 1.68/P = .015). There was no significant rTMS effect in the chronic aphasia group.

Conclusions: The addition of rTMS to SLT led to significant supplemental gains in naming recovery in the subacute phase only. While this needs confirmation in larger studies, our results clarify neuromodulatory vs training-induced effects and indicate a possible window of opportunity for contralesional inhibitory stimulation interventions in post-stroke aphasia.

Northstar trial registration: https://ichgcp.net/clinical-trials-registry/NCT02020421.

Keywords: aphasia; language therapy; randomized controlled trial; speech therapy; stroke; transcranial magnetic stimulation.

Conflict of interest statement

Declaration of Conflicting Interests: The authors declare that there is no conflict of interest.

Figures

Figure 1.
Figure 1.
NORTHSTAR-CA participant flow diagram.
Figure 2.
Figure 2.
Improvement in naming at follow-up (day 30) after speech-language therapy combined with rTMS or sham stimulation in patients in the subacute or chronic phase. Error bars represent Interquartile ranges (IQR); * indicates significant differences; n.s., non-significant; BNT, Boston Naming Test. There was a significant interaction between stimulation and phase (P < .001). In subacute patients, naming was significantly improved by rTMS (Mdn = 1.91, IQR = .77) compared to sham stimulation (Mdn = 1.02, IQR = 1.71, P = .046 φ = .39, medium–large effect). Chronic patients, however, did not differ between treatment groups. Naming recovery with rTMS was larger in subacute (Mdn=1.91/IQR=.77) than chronic patients (Mdn = .15, IQR = 1.68, P = .015, φ = .48, medium–large effect). There was similar improvement in chronic and subacute patients allocated to sham stimulation (i.e.,, speech-language therapy only).
Figure 3.
Figure 3.
Lesion overlap maps spatially normalized to MNI-stereotaxic space for subgroups of patients, and lesion volumes in mL (means and standard deviations). Lesion volumes were not significantly different in rTMS and sham groups (main effect: F [1, 54] < .01, P = .99, partial η2 = .00) and there was no statistically significant interaction between phases and treatment groups (F [1, 54] = .86, P = .36, partial η2 = .02). Patients in the chronic phase had significantly larger lesions than patients in the subacute phase (main effect: F [1, 54] = 11.97, P < .01, partial η2 = .18). (a) Subacute phase patients in the rTMS group (M = 39.2, SD = 37.1). (b) Subacute phase patients in the sham group (M = 51.3, SD = 39.9). (c) Chronic phase patients in the rTMS group (M = 98.8, SD = 65.3). (d) Chronic phase patients in the sham group (M = 85.8, SD = 60.1).

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