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Combining TMS-EEG with transcranial direct current stimulation language treatment in aphasia a

a

a

ab

Susanna Cipollari , Domenica Veniero , Carmela Razzano , Carlo Caltagirone , Giacomo ab

Koch

& Paola Marangolo

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a 1

IRCCS Fondazione Santa Lucia, Roma, Italy

b 2

Università di Tor Vergata, Roma, Italy

c 3

Dipartimento di Studi Umanistici, Università Federico II, Napoli, Italy Published online: 29 Jun 2015.

Click for updates To cite this article: Susanna Cipollari, Domenica Veniero, Carmela Razzano, Carlo Caltagirone, Giacomo Koch & Paola Marangolo (2015) Combining TMS-EEG with transcranial direct current stimulation language treatment in aphasia, Expert Review of Neurotherapeutics, 15:7, 833-845 To link to this article: http://dx.doi.org/10.1586/14737175.2015.1049998

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Original Research

Combining TMS-EEG with transcranial direct current stimulation language treatment in aphasia Downloaded by [Emory University] at 09:01 23 August 2015

Expert Rev. Neurother. 15(7), 833–845 (2015)

Susanna Cipollari1, Domenica Veniero1, Carmela Razzano1, Carlo Caltagirone1,2, Giacomo Koch*1,2 and Paola Marangolo*1,3 1 IRCCS Fondazione Santa Lucia, Roma, Italy 2 Universita` di Tor Vergata, Roma, Italy 3 Dipartimento di Studi Umanistici, Universita` Federico II, Napoli, Italy *Author for correspondence: [email protected]; [email protected]

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Despite the fact that different studies have been performed using transcranial direct current stimulation (tDCS) in aphasia, so far, to what extent the stimulation of a cerebral region may affect the activity of anatomically connected regions remains unclear. The authors used a combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to explore brain areas’ excitability modulation before and after active and sham tDCS. Six chronic aphasics underwent 3 weeks of language training coupled with tDCS over the right inferior frontal gyrus. To measure the changes induced by tDCS, TMS-EEG closed to the area stimulated with tDCS were calculated. A significant improvement after tDCS stimulation was found which was accompained by a modification of the EEG over the stimulated region. KEYWORDS: aphasia . brain stimulation . language rehabilitation . tDCS . TMS-EEG

Several studies have emphasized the use of transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique, to modulate cortical excitability [1] and promote cerebral plasticity which is associated with cognitive and behavioral changes [2–6]. As directly shown in animal studies, anodal tDCS increases cortical excitability, inducing a depolarization of the resting membrane potential and increasing neuronal firing rates. In contrast, cathodal tDCS decreases cortical excitability, shifting the resting membrane potential toward hyperpolarization and reducing the firing rate of neurons [7–9]. A small but growing body of evidence has already indicated that tDCS may provide a supplementary treatment approach for different language deficits in patients with chronic stroke-induced aphasia, such as word-finding difficulties [10–13], non-fluent speech [12,14] and articulatory disorders [15–19]. In fact, in a preliminary study on a small sample of chronic patients, Marangolo et al. [15] showed that repetitive anodal tDCS over the left inferior frontal gyrus (IFG), coupled with language training helped patients to recover from their articulatory disturbances. Also, follow-up testing

10.1586/14737175.2015.1049998

revealed that the improvement in response accuracy persisted up to 2 months after treatment and generalized in different oral and writing tasks (i.e., repetition, reading and writing under dictation). More recently, the authors wondered if similar results would be achieved using bihemispheric tDCS delivered over the left and right IFG [16]. Eight aphasic persons with apraxia of speech (AOS) underwent intensive language treatment in two different conditions: real anodic ipsilesional stimulation over the left Broca’s area and cathodic contralesional stimulation over the right homolog of Broca’s area, and a sham condition. In both conditions, all patients underwent 10 days of concurrent language therapy for their AOS. Results showed a significant recovery not only in terms of better accuracy and speed in articulating the treated stimuli but also in other language tasks (i.e., picture description, noun and verb naming, word repetition, word reading), which persisted in the follow-up session. Using a different language treatment method, an intonation-based intervention named the melodic intonation therapy (MIT), Vines et al. wondered if tDCS coupled with


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Original Research

Cipollari, Veniero, Razzano, Caltagirone, Koch & Marangolo

the language treatment would lead to significant improvements in six patients with articulatory difficulties [20]. The MIT technique, inspired by the common observation that severe aphasic patients are better at singing than speaking, uses a simplified exaggerated prosody to train patients to intone and articulate words and phrases syllable by syllable, in order to facilitate language production [21–27]. The underlying assumption is that MIT engages language regions in both hemispheres [21,28], particularly in the right hemisphere. Indeed, although impairments in melodic and temporal music information processing have been associated with acquired lesions in both right and left hemispheres, right hemisphere-lesioned patients have revealed more of an impairment in melodic contour and meter, suggesting that interventions emphasizing these aspects of an intonation-based therapy might particularly engage right hemisphere structures [25,26,29,30]. In accordance with this assumption, in Schlaug et al. studies [25,26], the comparison of the performance before and after the MIT treatment in two single cases through functional magnetic resonance imaging (fMRI) showed that the improvement in AOS significantly engaged a right hemisphere network involving the premotor, the inferior frontal and the temporal lobes. Using diffusion tensor imaging, the same authors found an improvement in verbal fluency in six aphasic patients, which was correlated with an increase of the right arcuate fasciculus volume [29]. Similarly, Zipse et al., using an adapted version of MIT, treated an adolescent girl with a very large left hemisphere lesion and severe nonfluent aphasia secondary to an ischemic stroke [30]. Following an intensive course of MIT treatment, her performance improved on both trained and untrained phrases, as well as on speech and language tasks. These behavioral improvements were accompanied by fMRI changes in the right frontal lobe, as well as by an increased volume of white matter pathways in the right hemisphere. No increase in white matter volume was seen in her healthy twin sister, who was scanned twice over the same time period. Based on the evidence that MIT-induced improvements in speech output correlate with increased activity in the right IFG, Vines et al. contrasted the effects of two tDCS conditions (anodal and sham) over the right IFG during MIT sessions [20]. Six patients with moderate to severe nonfluent aphasia underwent three consecutive days of anodal tDCS and an equivalent series of sham tDCS, both conditions coupled with the MIT treatment. Compared to the effects of sham, anodal tDCS led to a significant improvement in speech fluency. However, although much evidence exists in favor of tDCS benefits in language recovery [31,32], to date, the neurophysiological changes induced by tDCS over the stimulated area and its spatial resolution have not yet been clarified. In the motor domain, some studies have combined tDCS with neuroimaging methods, such as fMRI and electroencephalography (EEG), in order to obtain more detailed information on the functional modulation exerted by the stimulation over the motor cortex [33–37]. In a group of healthy participants, Pellicciari et al. 834

investigated the modulation induced by tDCS on the motor system by recording the transcranial magnetic evoked potentials (TEPs) using EEG [38]. Anodal tDCS over the left primary motor cortex (M1) induced an enhancement of corticospinal excitability, whereas cathodal stimulation produced a reduction. These changes in excitability were indexed by changes in the amplitude of motor evoked potentials. More interestingly, tDCS modulated the cortical reactivity, which is the neuronal activity evoked by transcranial magnetic stimulation (TMS), in a polaritydependent and site-specific manner. Cortical reactivity increased after anodal stimulation over the left motor cortex, whereas it decreased with cathodal stimulation. These effects were partially present also at long-term evaluation. With regard to the language domain, only two studies, both on healthy subjects, have investigated the modulation induced by tDCS over the language areas, specifically over the left IFG, through the use of fMRI [39,40]. In Holland et al. study, anodic tDCS delivered over the left IFG during a picture naming task led to significant behavioral and regionally specific neural facilitation effects [39]. Faster naming responses significantly correlated with decreased blood oxygen level dependent signal over the targeted area. Similarly, Meinzer et al. [40] found that anodic tDCS over the left IFG significantly increased verbal fluency, which, as in Holland et al’s study [39], correlated with a decrease in the blood oxygen level dependent signal in the stimulated area. However, as far as we know, no one, to date, has directly evaluated the neurophysiological changes induced by tDCS during a language treatment in the aphasic population. Starting from this scenario, in the present study, the authors wanted to investigate polarity-dependent tDCS-induced effects using a multimodal experimental procedure. They wondered if the application of anodic tDCS over the right IFG with simultaneous MIT training in six aphasic participants would lead to a greater improvement in their articulatory disturbances, compared to the sham condition. Before and after the training, neural changes in excitability over the right targeted area were indexed by the following measures: TEPs and EEG frequency. Combining EEG during TMS allowed the authors to assess the impact of MIT training alone and in combination with tDCS through the evaluation of TEPs, which represent a marker of cortical reactivity and reflect direct activation of the cortical neurons at the site of the stimulation and the spreading of this activation toward connected sites [38]. The choice to stimulate the right IFG was based on the results of previous research which demonstrate that this area contributes to singing through the mapping of sounds to articulatory actions [20,25,26,41,42] and serves as a key region in the process of recovery from aphasia, particularly in patients with large left hemisphere lesions [43]. Moreover, since the modulation of the phrasal intonation during the treatment was accompanied by movement of the left hand, the authors reasoned that the excitement of the right IFG, adjacent to the motor area, would favor the synchronization of the hand movements with the melody. Expert Rev. Neurother. 15(7), (2015)

Combining TMS-EEG with tDCS language treatment in aphasia

Original Research

Materials & methods

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Participants

Six left brain–injured participants (three male and three female) were included in the study (FIGURE 1). Inclusion criteria were: being proficient in Italian, having premorbid right-handedness (based on the Edinburgh Handedness Questionnaire) [44] and having had a single left hemispheric stroke at least 6 months prior to the investigation. None of the participants were taking any other medication associated with other neurological disorders apart from aphasia. The data analyzed in the current study conformed with the Code of Ethics of the World Medical Association (Declaration of Helsinky) printed in the British Journal (18 July 1964), and were collected in accordance with the Institutional Review Board of the IRCCS Fondazione Santa Lucia, Rome, Italy. The Institutional Review Board specifically approved this study with the understanding and written consent of each subject. Clinical data

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Each patient had nonfluent speech. Four out of six subjects were not able to produce any words in spontaneous speech, while in the remaining two patients, lanN.R. guage production was limited to a few phrases produced in a slow and labored way. All patients were administered a standardized test for the evaluation of articulation [45], which comprised 20 simple syllables (e.g., PA, MO, FU) and Figure 1. Lesion descriptions for six aphasic patients. The figure shows the MRI words (e.g., luna [moon], pipa [pipe]) to acquisitions of all patients. All patients underwent a 3.0-T scanner exam (Phillips Achieva Magnetom MR system) with acquisition of a T1 3D sequence. Individual volume lesions be repeated and read and a naming task were transformed into a standardized stereotaxic coordinate system using a computain which the pictures corresponding to tional semi-automatic procedure REGISTER; software provided by Brain Imaging Center, the same 20 words were presented to the Montreal Neurological Institute, McGill University, Canada. patient, one at a time, and he/she was A. M.’s lesion is localized in the left fronto-temporo-parietal cortex. asked to name them. Severe articulatory B. G.’s lesion is localized in the left fronto-temporo-parieto-occipital cortex. B. A.’s lesion is localized in the left temporal cortex. groping and distortions of phonemes B. N.’s lesion is localized in the left fronto-parietal cortex. were present in all the tasks. To deeply C. M.’s lesion is localized in the left fronto-temporo-parietal cortex. investigate the aphasics’ language perforN. R.’s lesion is localized in the left fronto-temporo-parietal cortices. mance, each subject was also administered a standardized language test [46]. The test included a picture description task (i.e., of the picture tasks, which were severely compromised due to the articulatory of an everyday life situation), an oral and written noun and disorders, the written tasks were included. The test also comverb naming tasks (n = 20 for noun naming, i.e., topo prised an auditory picture–word matching task (n = 20) and a [mouse]; n = 10 for verb naming, i.e., correre [to run], dormire simple command comprehension task (n = 20, i.e., alzi la [to sleep]), word repetition, reading and writing under dicta- mano sinistra [raise your left hand], apra il libro [open the tion (n = 20, i.e., letto [bed], tavolo [table]). In order to assess book]). In the picture description and oral naming tasks, four whether the language deficit was limited to the oral production out of six patients did not produce any response due to their informahealthcare.com

835

For each language task, the percentage of correct responses is reported (Esame del Linguaggio II, cut-off 100%, Ciurli et al., 1996; token test, cut-off 29/36, De Renzi and Faglioni, 1978). Compr: Comprehension; Ed: Educational; Picture descrip: Picture description; Repet: Repetition.

16/36 0 100 54 N. R.

M

13

1 year and 5 months/ ischemic stroke

0

15

0

100

75

30

0

25/36 25 100 51 C. M.

F

13

10 months/ischemic stroke

60

60

45

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60

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19/36 0 100 75 B. N.

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7

1 year and 4 months/ ischemic stroke

20

25

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17

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3 years/ischemic stroke

0

0

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100

20

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9/36 0 100 69 B. A.

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13

6 years and 7 months/ ischemic stroke

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0

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100

32

10

0

15/36 0 5 100 46 A. M.

M

16

6 years and 3 months/ ischemic stroke

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0

0

100

45

15

Written naming verb Word reading Word repet Sentence compr Word compr Oral naming verb Oral naming noun Picture descrip Time post-onset/ etiology Ed. level Age Sex Subjects

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Table 1. Sociodemographic and clinical data of the six nonfluent aphasic subjects. 836

Cipollari, Veniero, Razzano, Caltagirone, Koch & Marangolo

Written naming noun

Token test

Original Research

AOS disorder (TABLE 1). Word reading and repetition were better preserved, although with phoneme substitutions and distorsions. In five out of six patients, noun and verb written naming were severely impaired. Errors were mostly omissions of the entire word. Auditory comprehension abilities were adequate for words and simple commands in the language test [46], while patients still had difficulties in a more complex auditory comprehension task (token test cut-off 29/36, [47]) (TABLE 1). To evaluate nonverbal oral motor skills, the Oral Apraxia test [48] was administered. None of the patients showed apraxic disturbances. Materials

Two lists of 14 familiar sentences (4 interrogative [eg. come stai? {how are you?}], 4 affirmative [es. mi faccio la doccia {I’ll take a shower}], 3 negative [es. non mi piace {I don’t like it}], 3 social [es. buona domenica {enjoy your Sunday}], and 12 trisyllabic words [es. padella {pan}]) were used. The two lists of words were matched for the frequency of use and length, while the sentences were matched for social valence. All stimuli were presented in written form, each stimulus on a different card. Words were also presented with their correspondent picture. Procedure Transcranial direct current stimulation

tDCS was applied using a battery-driven Eldith (neuroConn GmbH, llmenau, Germany) Programmable Direct Current Stimulator with a pair of surface-soaked sponge electrodes (5  7 cm). Anodic stimulation consisted of passing 2 mA direct current for 20 min with the anode placed over the right IFG (F8 of the Extended International 10–20 System for EEG electrode placement, which has been found to correspond best to the homolog of the left Broca’s area, see Vines et al., 2011 [20]). If applied according to safety guidelines, tDCS is considered to be a safe brain stimulation technique with minor adverse effects [49]. The reference electrode was placed over the contralateral frontopolar cortex [50,51]. For sham stimulation, the same electrode position was used. The current was ramped up to 2 mA and slowly decreased over 30 s to ensure the typical initial tingling sensation [52]. In both conditions, patients underwent concurrent MIT therapy for their AOS disorder. The language treatment was performed in 15 daily sessions over 3 weeks (Monday–Friday, weekends off, Monday–Friday). There was a 14-day intersession interval between the anodic and sham conditions. The order of conditions was randomized across subjects (FIGURE 2). Both the patient and the clinician were blinded with respect to the administration of tDCS. At the end of each condition, subjects were asked if they were aware of which condition (anodic or sham) they were in. None of the subjects was able to ascertain differences in intensity of sensation between the two conditions. Transcranial magnetic stimulation-electroencephalography

Each patient underwent three experimental sessions: one before MIT/tDCS treatment (baseline) and one after the end of each MIT/tDCS condition (post-anodic vs post-sham). Expert Rev. Neurother. 15(7), (2015)

Combining TMS-EEG with tDCS language treatment in aphasia

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Figure 2. Overview of the study design. Subjects underwent two intensive language treatments during two different conditions: anodic transcranial direct current stimulation over the right inferior frontal gyrus and a sham condition. Each condition was performed for 15 days over 3 weeks, with 2 weeks of intersession interval. F/U: Follow-up.

Single-pulse TMS were delivered using a SuperRapid transcranial magnetic stimulator connected to four booster modules and a double 70 mm standard figure-eight coil (Magstim, Whitland, UK). Motor evoked potentials were recorded from the first dorsal interosseus using Ag–AgCl surface cup electrodes of 9 mm diameter. The active electrode was placed over the belly muscle, while the reference electrode was placed over the metacarpophalangeal joint of the index finger. Responses were amplified using a Digitimer D360 amplifier (Digitimer Ltd, Welwyn Garden City, Hertfordshire, UK) through filters set at 20 Hz and 2 kHz with a sampling rate of 5 kHz, and then recorded by a computer using SIGNAL software (Cambridge Electronic Devices, Cambridge, UK). The coil was placed tangentially to the scalp with the handle pointing backward and laterally at about 45 angle away from the midline, approximately perpendicular to the central sulcus. Each experimental session started with the coil positioned over the right hemisphere. The hot spot was defined as the point where TMS induced the maximum motor evoked potential from the relaxed left first dorsal interosseus. The resting motor threshold (RMT) was then determined and defined as the lowest intensity that evoked five small responses (about 50 mV) in the contralateral first dorsal interosseus muscle in a series of 10 stimuli [53]. TMS intensity was then set to 90% of RMT. To precisely position the coil over the IFG sites, a neuronavigation system (Softaxic, E.M.S., Bologna, Italy) was employed using individual T1-weighted magnetic resonance imaging volumes as anatomical reference. In order to target the right IFG, the coil was positioned over the caudal portion of the pars opercularis. The coordinates were stored and used for neuronavigation to ensure comparable stimulation conditions across sessions. The closest electrode to this point was F8. TMS-compatible EEG equipment (BrainAmp 32MRplus; BrainProducts GmbH, Munich, Germany) was used for recording EEG activity from the scalp. The EEG was continuously acquired from 20 scalp sites positioned according to the 10– 20 International System, using electrodes mounted on an elastic cap. Additional electrodes were used as ground and reference. The ground electrode was positioned in AFz, while an active reference was positioned on the tip of the nose. The signal was bandpass filtered at 0.1–1000 Hz and digitized at a sampling rate of 5 kHz. In order to minimize overheating of the informahealthcare.com

electrodes proximal to the stimulating coil, TMS-compatible Ag/AgCl-sintered ring electrodes were used. Skin/electrode impedance was maintained below 5 kW. Horizontal electrooculogram (EOG) was recorded from the electrodes positioned on the outer canthi of both eyes, and vertical eye movements and blinks were recorded from the electrodes located beneath the right eye. To evaluate cortical excitability, 70 single-pulse TMS were delivered during each session at a rate of about 0.5 Hz (stimuli were randomly jittered by 20% of the total interval). Language treatment

Patients were administered all the standardized language tests at the beginning (baseline, T0), at the end of each treatment condition (T15) and 1 week after the end of treatment (follow-up, F/U). Since the main goal of the therapy was to train the patient to transpose what he had learned with the help of singing into spoken language, before and after the end of each treatment condition (anodic vs sham) and in the follow-up session, each patient was asked to repeat the entire corresponding list of stimuli using a normal intonation. One point was assigned for each correct answer. The examiner manually recorded the answers. Each list of stimuli was randomly assigned to one of the two stimulation conditions (anodic vs sham). In each condition, the order of presentation of stimuli was randomized across the treatment sessions. The therapy method was similar for all patients. For each condition, the whole list of stimuli was presented during each session. The clinician and the patient were seated face to face, so that the patient could watch the articulatory movements of the clinician as she spoke. The clinician presented one stimulus at a time and for each stimulus, treatment involved the use of five different steps which would progressively induce the patient to correctly reproduce it (based on the descriptions of Helm-Estabrooks et al. [54,55]). Before beginging the treatment, patients were presented with 10 sentences (social phrases) and were trained to use different melodic intonations which would help them during the therapy. Patients were also taught to rhythm the production of each syllable through the movement of the left hand. Data analysis Language treatment

Data were analyzed with SPSS 17.0 software. Two different repeated measures analyses of variance (ANOVAs) 2  3 were 837

Original Research

Cipollari, Veniero, Razzano, Caltagirone, Koch & Marangolo

run on the mean percentage of response accuracy for words and sentences. The authors excluded response time as a potential measure because they found a large variability among patients. Two within-subject factors were included: Time (baseline [T0] vs end of treatment [T15] vs F/UP) and Condition (anodic vs sham). Interactions were explored using the Scheffe`’s post-hoc test. For each subject, before and after the treatment, the percentage of correct responses in the language test was also calculated (c2 tests).

The Huynh–Feldt " correction factor was applied where appropriate to compensate for possible effects of nonsphericity in the compared measurements. In all conditions, the normal distribution was tested applying the Kolmogorov–Smirnov test (for all p > 0.2). The significance level was set at 5%. Post-hoc tests were performed to investigate significant effects, applying the Bonferroni correction as appropriate in the case of multiple comparisons. Results

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EEG analysis

EEG data were compared off-line to recordings using BrainVision Analyzer2 (BrainProducts GmbH, Munich, Germany). EEG signals were first re-referenced to the average of all electrodes and high-pass filtered at 0.1 Hz (Butterworth zero phase filter). For each patient and condition (baseline, post-anodic, post-sham), the epoching of EEG responses started 200 ms before and ended 500 ms after the TMS pulse. All epochs were baseline-corrected to a time period of 100 ms ( 100 to 0 ms) recorded before TMS delivery. The artifact induced by pulse delivery, typically lasting about 5–6 ms after the authors’ equipment [56], was removed using cubic interpolation for a conservative 10 ms interval following the TMS pulse. Independent component analysis was then used to identify and remove components reflecting muscle activity, eye movements, blinkrelated activity and residual TMS-related artifacts. Finally, epochs with excessively noisy EEG, residual eye movement artifacts (blinks or saccades) or muscle artifacts were excluded from further analysis by visual inspection [57]. Overall, the numer of rejected epochs was 9.6%, ranging from 6 to 20% of the trials. To assess the effect induced by the MIT treatment and tDCS, for each patient and experimental session, TEPs were calculated as the average signal of four electrodes corresponding to the area covered by the tDCS electrode (F4, F8, FC2, FC6). To detect the significant TEPs in the averaged signal, the peaks were visually identified and validated through a statistical analysis as local maxima or minima; that is, peaks were identified when the positive or negative responses measured with respect to the 100 ms preceding the TMS pulse for a minimum of 50 consecutive sampling points (equivalent to 10 ms) exceeded three-times the standard deviation of the baseline, which is in line with previous studies (for similar data analysis, see [58]). A separate one-way ANOVA with repeated measures was performed to evaluate the amplitude and latency of each component with Session (baseline, post-sham, post-anodic) as the within-subject factor. To exclude that any cortical modulation across sessions could be due to a different stimulation intensity, an additional repeated measures ANOVA was conducted on RMT values with Session (baseline, post-sham, post-anodic) as the withinsubject factor. To investigate the correlation between the stimulation intensity and the modulation of TEPs’ amplitude, the Pearson coefficient was calculated at the individual and group levels. 838

Language treatment Words

The analysis showed a significant effect of Time (baseline [T0] vs end of treatment [T15] vs F/U: F(2,10) = 378,58; p = 0.001) and Condition (anodic vs sham F(1,5) = 9,04; p = 0.03). The interaction Time  Condition was significant (F(2,10) = 4,31; p = 0.04). The Scheffe`’s post-hoc test revealed a significant increase in the percentage of correct words produced between T0 and T15 both for the anodic (difference T15 T0 = 73%, p = 0.001) and the sham condition (difference T15 T0 = 52%, p = 0.001) which persisted in the follow-up session (difference F/U T15 anodic = 3%, p = not significant (NS); difference F/U T15 sham = 1%, p = NS). However, at the end of treatment (T15), the percentage of correct words in the anodic condition was significantly higher than in the sham condition (difference anodic vs sham T15 = 24%, p = 0.03) (FIGURE 3). Sentences

The analysis showed a significant effect of Time (baseline [T0] vs end of treatment [T15] vs F/U: F(2,10) = 48,94; p = 0.001) and Condition (anodic vs sham F(1,5) = 13,21; p = 0.01). The interaction Time  Condition was significant (F(2,10) = 28,95; p = 0.001). The Scheffe`’s post-hoc test revealed a significant increase in the percentage of correct sentences produced between T0 and T15 both for the anodic (difference T15 T0 = 70%, p = 0.001) and the sham condition (difference T15 T0 = 36%, p = 0.001) which persisted in the follow-up session (difference T15 F/U, anodic = 7%, p = NS; difference T15 F/U sham = 7%, p = NS). However, at the end of treatment (T15), the percentage of correct sentences in the anodic condition was significantly higher than in the sham condition (difference anodic vs sham T15 = 30%, p = 0.001) (FIGURE 4). Generalization of the treatment

Comparison between the results achieved in the language test after treatment with the data collected before treatment revealed a generalization of the effects of the treatment on each language task, which in most patients was greater after performing the anodic stimulation condition (TABLE 2). TMS-electroencephalography

TMS did not cause any of the patients to experience adverse effects. The mean RMT values were 68 ± 11%, 67 ± 12% and Expert Rev. Neurother. 15(7), (2015)

Combining TMS-EEG with tDCS language treatment in aphasia

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Figure 3. Mean percentage of correct words at baseline (T0), at the end of treatment (T15) and in the F/U sesssion (after 1 week) for the anodic and the sham condition, respectively. Error bars represent standard error of the mean. F/U: Follow-up.

67 ± 11% of the maximum stimulator output for the baseline, post-sham and post-anodic sessions, respectively. The statistical analysis performed on these values revealed no differences across sessions (F(2,10) = 0.2; p = 0.81). When TMS was applied over the right IFG, six components were evoked, showing a similar temporal profile in all sessions (FIGURE 4). The earliest pattern, peaking at 18 ± 2 ms after the pulse delivery, was characterized by a positivity involving the stimulated area (right IFG) and a contralateral negativity involving central and parietal sites. This dipolar pattern reached its maximal amplitude at 32 ± 3 ms. The topographical distribution of these components could suggest the activation of the right IFG by the TMS pulse. This pattern evolved into a widespread negativity centered over the left central areas 100

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Figure 4. Mean percentage of correct sentences at baseline (T0), at the end of treatment (T15) and in the F/U sesssion (after 1 week) for the anodic and the sham condition, respectively. Error bars represent standard error of the mean. F/U: Follow-up.

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Original Research

~70 ms after the TMS pulse (68 ± 5 ms). The following TEP (87 ± 8 ms) showed a topographical distribution comparable to the earliest components, with a dipole characterized by a positivity peaking over the stimulated area and a negativity peaking over the left centro-frontal electrodes. This pattern evolved at 115 ± 6 ms into a more posterior positivity peaking over the left parietal areas. Finally, the component recorded after 200 ± 5 ms was clearly characterized by a strong positivity centered over the stimulated area. As clearly shown in FIGURE 4, the TEP latencies did not differ across conditions (all with p > 0.05), but the ANOVA performed on the amplitude values showed a significant effect of the Session for two components. When comparing the three sessions, the amplitude of the TEPs peaking at 87 ms was found to be significantly different (F(2,10) = 5.14; p = 0.03). Post-hoc comparisons, indeed, revealed that after anodic tDCS, there was a significant increase in the amplitude when compared to the baseline (p = 0.01) and the post-sham sessions (p = 0.04) (FIGURE 5). Interestingly, the amplitude of this component was significantly modulated even when the patients underwent the language treatment without any effective stimulation. Indeed, the amplitude of this component recorded during the post-sham sessions was significantly larger when compared to the baseline session (p = 0.05), thus indicating that the MIT treatment alone was able to induce a change in cortical excitability. Finally, the language treatment and the anodic tDCS modulated the amplitude of the TEPs evoked after 115 ms (F(2,10) = 4.21; p = 0.05). Post-hoc tests revealed a significant difference between the post-anodic and the post-sham sessions (p = 0.05) and a trend toward significance when comparing the post-anodic and the baseline sessions (p = 0.06). Since the stimulation intensity varied across sessions according to the patients’ motor threshold, during each session, the Pearson coefficient was calculated between the intensity used to evoke TEPs (% maximum stimulator output) and the corresponding amplitude of the two significantly modulated TEPs. A significant correlation (r = 0.55; p < 0.05) emerged when testing the component peaking at 115 ms. To exclude that this correlation was due to an increase in the amplitude component with increasing the intensity across participants, the authors calculated the Pearson coefficient for each patient. As clearly shown in FIGURE 6, the intensity used in the three sessions was comparable for most of the patients (from no changes to 4 points), except for patient number 3 and 5. Moreover, the intensity variations were not related to the amplitude and no significant correlation was found, except for patient 2 (r = 0.9, p < 0.05). Thus, the modulation on this component cannot be explained by a change in the stimulation intensity. Discussion

The aim of the present study was to investigate whether anodic tDCS applied over the right IFG with concomitant language training would enhance language recovery and, in particular, the ability to articulate speech in a group of left chronic 839

840

0 0 0 0 60 65

0 0 0 0 65 30

60 70 62 77 82

§

87 100 20 25 32 55 30 10 Sham

The order of conditions was randomized across subjects. † p < 0.05. ‡ p < 0.01. § p < 0.001 (c2 tests). Cond: Condition; S: Subjects.

100

72 70

75 25 0 55 15 0 N. R.

Anodic

10

‡

§

80 85 75

§ §

80 90 Sham

60

70 45 85 45 80 60 90 60 Anodic C. M.

42 52

§ §

45 55 42

‡ §

55 40 Sham

50

52§ 25 55§ 15 25 40‡

0 Anodic

20 B. N.

0 Sham B. G.

Anodic

15 10§

55§

57§ 30 10§ 0

0 0 15§ 0 0

35 0

0 Anodic

20

§

5

25

§

28†

30 20

52

67

† §

32 0 0 5 0 0 0 Sham B. A.

45 40§ 10 30 0 Anodic

40§

67§

45 30 0 0 Sham A. M.

0

T0

45 0

10

§

T15 T0 T15 T0 T15 Cond S

T0

§

T15

§

80

70§ 25 77 52 80 60

10 10 20 20

§ ‡

45 47

10§ 0 20§ 2 47§

0 0

0 0

17

0 0 0 0

0 0 0 0

0 47 20

0 0

0 0

7

†

0

Cipollari, Veniero, Razzano, Caltagirone, Koch & Marangolo

§

0 10 52‡

20

25‡ 10 50† 35 70§ 42 82§

10§ 0 35 5 42 15

T15 T0 T15 T0

§ §

T15 T0

Written naming verb Written naming noun Word reading Word repetition Oral naming verb Oral naming noun Picture description

Table 2. Percentage of correct responses in the pre-anodic, post-anodic, pre-sham and post-sham administration of the language test (cut-off score 100%, Esame del Linguaggio II; Ciurli et al., 1996).

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Original Research

aphasic persons. The choice to stimulate the right IFG was based on the results of previous research which demonstrated that this area contributes to melodic information processing [20,25,26,41,42]. Moreover, since all the patients of this study had large left hemisphere lesions, the authors reasoned that excitatory stimulation over this region would have enhanced the process of recovery from aphasia [43]. In all subjects, the analysis showed that there was a significant improvement in response accuracy both for the anodic and the sham conditions. This was because all the six subjects underwent intensive language training in both conditions. However, the beneficial effect of anodic stimulation was evident because response accuracy was greater after stimulation. Moreover, the follow-up testing revealed retention of the achieved performance, which did not show any decrement after 1 week suggesting a persistency of the beneficial effect found. This result allows us to affirm that the effects of combined tDCS and MIT lasted beyond the treatment period. As previously reported, similar results were obtained by Vines et al. [20]. Contrasting the effects of two tDCS conditions (anodic vs sham) applied over the right IFG during MIT sesssions, the authors found that anodal tDCS led to significant improvement in speech fluency. However, unlike this study, Vines et al. [20] did not collect data to measure the longevity of the effects found. More importantly, results from transfer of treatment effects revealed that the language treatment resulted in a positive effect on the production of stimuli not only treated but also belonging to other tasks. Indeed, after the anodic tDCS condition, all patients showed a reduction in phonological errors in different oral production tasks, the reduction being due to improvement in speech praxis. The fact that in our patients the improvement was not limited to the treated items but generalized to different oral production tasks allows us to state that the MIT therapy and its standardized protocol was, indeed, appropriate. Moreover, since the assessment battery was administered at the end of each experimental condition (anodic vs sham) and the two conditions were counterbalanced across subjects, the authors believe that any result due to practice effects was equally distributed across sections. Consistent with the behavioral data, the TMS-EEG analysis performed before and after the language treatment showed a modulation of Expert Rev. Neurother. 15(7), (2015)

Combining TMS-EEG with tDCS language treatment in aphasia

Original Research

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mV

TMS cortical reactivity recorded from the electrodes close to the IFG, regardless of the tDCS condition. In particular, the MIT 2 treatment alone (tDCS sham) was associated with changes in cortical excitability as confirmed by the modulation of the brain activity evoked after 87 ms. How1 ever, the authors’ TMS-EEG data also showed that the cortical excitability changes were maximized when the MIT 0 treatment was associated with an effective anodal stimulation of the IFG as conBaseline firmed by the modulation of the same Post-anodic component, reaching its maximal ampli–1 tude during the post-anodal condition. Post-sham Thus, the TMS-EEG data suggest that the anodal stimulation could further –2 increase the beneficial effects of the MIT 150 200 250 50 0 50 100 ms treatment. However, it has to be noted that although the behavioral data were associated with different modulations in the cortical excitability after the two tDCS conditions (sham vs anodic), because of the limited number of Figure 5. Grand average of TMS-evoked potentials evoked by the stimulation of patients, no correlation analysis was perthe right inferior frontal gyrus recorded during the baseline session (black line), formed to directly link the electrophysioafter the melodic intonation therapy/anodic transcranial direct current stimulalogical and behavioral data. To test the tion treatment (post-anodic, red line) and after the melodic intonation therapy/ changes in cortical excitability, the authors sham transcranial direct current stimulation treatment (post-sham, green line). used single-pulse TMS delivered at about Each waveform represents the average activity of four electrodes (F4, F8, FC2, FC6) close 0.5 Hz, which is usually described as to the stimulation site. The bottom horizontal black lines indicate significant differences across conditions, whereas the maps indicate the topographical distribution of each inhibitory stimulation; but in order to evoked response calculated for the post-anodic session. avoid any effect of participants’ expectation, the inter-stimulus interval varied from 2 to 2.4 s. Moreover, the total stimulation time was as EEG signals from other brain areas (e.g., the contralateral left short as about 3 min, excluding any long-lasting TMS-related IFG), it cannot be excluded that given the low spatial resolueffect. However, although the stimulation pattern is unlikely to tion of tDCS, the stimulation has also influenced cortical excitaccount for the result of this study, the possibility that this may ability in areas others than the targeted one. Indeed, evidence have interacted with the cortical excitability in a different way from modeling has already suggested that the supraorbital referafter the two tDCS conditions cannot be ruled out. ence electrode is not inert with respect to brain activity, but it Another component which was modulated in this study is influences cortical excitability as well as the active electrode [61]. the TEP peaking at 115 ms. This response could reflect a Therefore, it might be possible that the electrodes montage tDCS-specific modulation, as it was significantly modulated used has acted as bilateral stimulation. after the anodic stimulation but did not change after the sham In summary, these results confirm that in patients with condition. However, its amplitude after the anodic tDCS was severe articulatory disturbances, it is useful to plan a treatment not clearly different from the baseline session, possibly because focused on the recovery of AOS combined with anodic tDCS of the variability across patients. All these data fit well with the over the right IFG, since an improvement of this component results of previous studies which have emphasized that melody would determine beneficial effects in different oral production information exerts more right hemispheric than left hemi- tasks. These data seem to contradict previous results by spheric activation [30,41,42]. Accordingly, patients with right Marangolo et al. [15,16] where the improvement in articulation hemisphere lesions have greater difficulty with melody and con- resulted from excitatory stimulation over the left IFG. Howtour processing than those with left hemisphere damage [59,60]. ever, while in those studies tDCS stimulation was combined Indeed, in this study, it might be the case that the involvement with a traditional treatment for articulatory disorders [15,16], in of the right IFG was due to the language treatment chosen the present study, the MIT approach involved both melodic which took advantage of the superiority of the right hemisphere and rhythmic aspects of music which, as previously stated, are in melody. However, since the authors did not measure TMS- likely subserved by right hemispheric structures [30,41,42]. In informahealthcare.com

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Cipollari, Veniero, Razzano, Caltagirone, Koch & Marangolo

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Baseline

Post sham

Post anodic

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% MSO

Figure 6. (A) Intensity used to evoke TMS-evoked potentials for each patient and each session (baseline, post-sham and post-anodic). (B) For each patient, the amplitude of the component peaking at 115 ms after the TMS pulse is plotted as a function of the stimulation intensity expressed as percentage of MSO. MSO: Maximum stimulator output.

accordance with this hypothesis, in an fMRI study, Ozdemir et al. [62] found that singing and speaking shared some bilateral frontotemporal neural correlates, but singing, or intoned speaking, led to additional activation of the right more than the left superior temporal and the right more than the left central operculum, compared to the speaking condition. Thus, singing could be a way to access language-capable regions in the right hemisphere for the purpose of facilitating language recovery [63]. It is most likely that the two unique elements of MIT, the melodic intonation with its inherent sustained vocalization and the rhythmic tapping of the left hand, made the strongest contribution to the therapy’s beneficial effect. Since concurrent speech and hand use occur in daily life and gestures are frequently used during speech, hand movements, possibly in synchrony with articulatory movements, may have a facilitating effect on speech production. The authors hypothesize that tapping the left hand might have engaged a right hemispheric sensorimotor network that coordinates not only hand movements but orofacial and articulatory movements as well [64–67]. 842

An additional explanation is that the left hand tapping served the same function as a metronome, and in so doing, facilitated speech production through rhythmic anticipation and entrainment [68]. The authors are aware that in this study, the absence of a nonlinguistic control task does not allow them to unequivocally state that the changes observed in EEG signal were specific to changes in the language network. However, taking into account the topography of the modulated cortical responses, they believe that their data at least suggest that the MIT treatment and the tDCS stimulation were able to improve the patients’ performance by acting on the cortical excitability of the targeted region. The authors are also aware that in their study, the inclusion of a small number of subjects does not allow them to offer any definite conclusion about their data, and that this limitation would be overcome by including a larger sample of subjects. However, in the aphasia research, it is very hard to find a larger sample of subjects with homogenous clinical symptoms, in order to plan the same treatment approach. Therefore, the Expert Rev. Neurother. 15(7), (2015)

Combining TMS-EEG with tDCS language treatment in aphasia

authors believe that their results, although preliminary, can offer some useful information for aphasia research. In conclusion, the authors believe that melodic intonation and left hand tapping are the critical elements of MIT that may likely be responsible for its therapeutic effect and may explain the predominant right hemispheric activation pattern seen in their patients. The results of this study fit well with previous data suggesting that potentially, adding tDCS to any behavioral therapy may augment the beneficial effects of the stimulation. Given the huge variability among aphasic patients at the clinical and neurological level, it is highly unlikely that a single procedure may be universally effective. Indeed, in the future, tailored

Original Research

interventions combining tDCS with other brain imaging and neurophysiologic mapping methods (e.g., fMRI and/or TMSEEG) in larger samples of subjects may be the most promising innovative approach to aphasia therapy. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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Key issues .

In the last few years, non-invasive brain stimulation methods have been provided useful as adjuvant techniques for language recovery.

.

The neurophysiological changes induced by transcranial direct current stimulation (tDCS) over the stimulated area and its spatial resolution have not yet been clarified.

.

In the present study, polarity-dependent tDCS-induced effects were investigated before and after anodic tDCS over the right inferior frontal gyrus (IFG) with simultaneous melodic intonation therapy (MIT) training for the recovery of articulatory disturbances in six aphasic participants.

.

Neural changes in excitability over the right targeted area were indexed by TMS-evoked potentials (TEPs) and EEG frequency.

.

Results showed that after the training, there was a greater improvement in response accuracy in speech articulation in the anodic compared to the sham condition, which generalized to untrained items.

.

Consistent with the behavioral data, the TMS-EEG analysis performed before and after the language treatment showed a modulation of cortical reactivity recorded from the electrodes close to the IFG, regardless of the tDCS condition.

.

However, the cortical excitability changes were maximized when the MIT treatment was associated with an effective anodal stimulation of the IFG.

.

Thus, the TMS-EEG data suggest that the anodal stimulation could further increase the beneficial effects of the MIT treatment.

.

The results fit well with previous data suggesting that potentially adding tDCS to any behavioral therapy may augment the beneficial effects of the stimulation.

.

Tailored interventions combining tDCS with other brain imaging and neurophysiologic mapping methods in larger samples of subjects may be the most promising innovative approach to aphasia therapy.

stimulation in cognitive neurorehabilitation. Brain Stimulat 2008;22:326-36

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