Effects of Tdcs on Sound Duration in Patients with Apraxia of Speech in Primary Progressive Aphasia

brain sciences

Article Effects of tDCS on Sound Duration in Patients with Apraxia of Speech in Primary Progressive Aphasia

Charalambos Themistocleous 1 , Kimberly Webster 2 and Kyrana Tsapkini 1,*

1 Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21210, USA; [email protected] 2 Department of Otolaryngology, Johns Hopkins Medicine, Baltimore, MD 21210, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-410-7362940

Abstract: Transcranial direct current stimulation (tDCS) over the left inferior frontal gyrus (IFG) was found to improve oral and written naming in post-stroke and primary progressive aphasia (PPA), speech fluency in stuttering, a developmental speech-motor disorder, and apraxia of speech (AOS) symptoms in post-stroke aphasia. This paper addressed the question of whether tDCS over the left IFG coupled with speech therapy may improve sound duration in patients with apraxia of speech (AOS) symptoms in non-fluent PPA (nfvPPA/AOS) more than sham. Eight patients with non-fluent PPA/AOS received either active or sham tDCS, along with speech therapy for 15 sessions. Speech therapy involved repeating words of increasing syllable-length. Evaluations took place before, immediately after, and two months post-intervention. Words were segmented into vowels and consonants and the duration of each vowel and consonant was measured. Segmental duration was significantly shorter after tDCS compared to sham and tDCS gains generalized to untrained words. The effects of tDCS sustained over two months post-treatment in trained and untrained sounds. Taken together, these results demonstrate that tDCS over the left IFG may facilitate speech production by reducing segmental duration. The results provide preliminary evidence that tDCS Citation: Themistocleous, C.; may maximize efficacy of speech therapy in patients with nfvPPA/AOS. Webster, K.; Tsapkini, K. Effects of tDCS on Sound Duration in Patients Keywords: apraxia of speech (AOS); transcranial direct current stimulation (tDCS); primary progres- with Apraxia of Speech in Primary sive aphasia (PPA); inferior frontal gyrus (IFG); sound duration; brain stimulation Progressive Aphasia. Brain Sci. 2021, 11, 335. https://doi.org/10.3390/ brainsci11030335

Academic Editor: Paola Marangolo 1. Introduction Apraxia of speech (AOS) is a condition that affects oral motor speech planning and Received: 31 December 2020 production. It results in impaired speech fluency due to inhibition of the neural pro- Accepted: 3 March 2021 gramming of articulation [1]. It can occur in the absence of dysarthria (i.e., a language Published: 6 March 2021 impairment characterized by paralysis or paresis and muscular control problems) [2] and aphasia (a multimodal language impairment affecting language comprehension and pro- Publisher’s Note: MDPI stays neutral duction) [3,4]. Usually, AOS results from stroke, but neurodegeneration, traumatic brain with regard to jurisdictional claims in injury, genetic disorders, or syndromes (e.g., childhood apraxia of speech) may also trigger published maps and institutional affil- AOS [1,5–9]. In this study, we will refer to AOS in the context of primary progressive iations. aphasia (PPA), a neurodegenerative condition with speech and language deficits as its primary symptoms [10–12]. According to the consensus criteria for subtyping of PPA [13], AOS and agrammatism are key symptoms for identifying patients with the non-fluent PPA (nfvPPA) variant from patients with other PPA variants. However, since agrammatism Copyright: © 2021 by the authors. occurs without AOS in some patients [14] and AOS is the only symptom in others [15], a Licensee MDPI, Basel, Switzerland. number of studies suggested a clinicopathological presentation of AOS as a distinct PPA This article is an open access article variant, primary progressive apraxia of speech (PPAOS) [16–18]. distributed under the terms and The primary characteristics of AOS are articulatory and prosodic deficits with different conditions of the Creative Commons degrees of severity (mild to severe) [19,20], resulting in effortful, slow speech, manifested Attribution (CC BY) license (https:// by longer consonants and vowels [21–24]. For example, Duffy and colleagues (2017) [21] creativecommons.org/licenses/by/ argued that slow speech rate and abnormal lexical stress are primary characteristics of 4.0/).

Brain Sci. 2021, 11, 335. https://doi.org/10.3390/brainsci11030335 https://www.mdpi.com/journal/brainsci Brain Sci. 2021, 11, 335 2 of 18

progressive AOS that make speech in patients with progressive AOS effortful, slow, la- bored. Thus, longer segmental duration (vowels and consonants) [25,26] constitute a primary deficit of patients with AOS that distinguishes them from patients with other PPA symptoms [21–24]. These measures may also serve as an objective and ecologically valid measure of AOS and an excellent outcome measure to estimate the effects of treatment(s) and symptom progression. Patients with AOS exhibit inconsistent and non-systematic speech articulatory errors and irregular insertions, distortions, deletions, substitutions, and transpositions of sounds [27–30]. They often produce consonants with irregular voicing [31], stop consonants (e.g., /p/ and /t/) with irregular plosive distortions and increased voice onset time (VOT) [24,26,32] or fricative consonants (e.g., /f/ and /θ/) with misplacing and/or misshaping the active articulator (tongue) relative to the passive articulator (a place along the palate) [33]. AOS results in reduced coarticulation of adjacent sounds, a slowing down of syllable transitions, and non-canonical syllable segmentation [26]. Further, irregular prosody and rhythm have been reported as characteristics of speech in patients with AOS [34], affecting lexical (e.g., stress) and post-lexical prominence patterns and tonalities. AOS symptoms have been associated with the left inferior frontal gyrus (IFG), an area involved in kinematic and sound representations of speech production [6,16,17,35,36]. Patients with AOS show subtle structural and functional irregularities in the IFG, including other areas of the frontal operculum: the posterior frontal gyrus (i.e., pars opercularis [BA44]), which enables the cognitive selection of vocal and orofacial actions [35,37], the pre-supplementary motor area (pre-SMA), which controls vocalization [17], and the insula under the left IFG, which facilitates articulatory planning [20,38]. BA 44 (pars opercularis) is proximal to the premotor cortex, an area involved in articulation and is bi-directionally connected with BA 40 via the ventral component of the superior longitudinal fasciculus (SLF III). This interaction with BA 40 provides BA 44 (which organizes speech production by selecting the phonemes, the words, and their order to form the sentence to be spoken) with critical phonological information. Thus, this cortico-cortical circuit appears to be the phonological loop in the left hemisphere. This parieto-frontal circuit formed by the SLF III (and perhaps the arcuate fasciculus) is involved in phonological processing [39]. The anterior insula is found to be involved in motor speech planning [40]. Other proximal and distal brain regions have also been associated with AOS, such as the parietal lobe [4], the basal ganglia, and the cerebellum [41]. Additionally, there are few behavioral studies with encouraging results targeting AOS symptoms in nfvPPA/AOS [42]. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation that modulates neuronal excitability by modifying neural cells’ resting membrane potential either by hyperpolarizing or depolarizing. The placement of the anode (positive electrode) and cathode (negative electrode), intensity, and the duration of stimulation are known to affect the efficacy of tDCS. Recent studies by our group [43] and others [44,45] provided novel insights into the mechanisms of tDCS, showing that changes in functional connectivity (FC) and gamma aminobutyric acid (GABA) concentrations and may be important tDCS mechanisms. We found that tDCS modulated (decreased) functional connectivity (FC) between the stimulated area and the functionally, or structurally, connected temporal areas of the language network, as well as the homologous area in the right hemisphere (but not the default mode network (DMN)); these FC changes were maintained up to 2 months. These results, which are in line with similar decreases in connectivity observed after tDCS over the left IFG in aging [46] and other neurodegenerative conditions, may be interpreted as an indication that fewer resources are needed after tDCS than before for related language tasks. We also tested the hypothesis that tDCS reduces GABA in the stimulated tissue in PPA. We applied GABA-edited magnetic resonance spectroscopy (MRS) to quantify GABA levels before and after a sham-controlled tDCS intervention with language therapy in PPA. Participants receiving tDCS had significantly greater language improvements than those receiving sham immediately after the intervention and at 2 months follow-up. GABA levels in the targeted tissue decreased after the intervention and remained so for 2 months [43]. Brain Sci. 2021, 11, 335 3 of 18

The association of motor planning and speech articulatory deficits to the left IFG has motivated neuromodulatory studies with tDCS that targeted this area. Specifically, in Marangolo, Marinelli, Bonifazi, Fiori, Ceravolo, Provinciali and Tomaiuolo [19], three subjects with post-stroke aphasia with AOS participated in a randomized double-blinded experiment involving articulatory training in tDCS and sham conditions. Each subject participated in five consecutive daily sessions of anodal tDCS (20 min, 1 mA) and sham stimulation over left IFG. tDCS resulted in more improvement than sham condition. Chesters, et al. [47] tested the effect of tDCS in adults who stuttered and found that anodal tDCS did not improve sentence reading, although, they observed a trend towards a reduction in stuttering when tDCS was coupled with a fluency intervention. In a follow up study, Chesters, et al. [48] tested 30 individuals who stuttered, in which 15 had tDCS and 15 had sham and speech fluency intervention using choral and metronome-timed speech. The authors showed a significant fluency improvement in individuals with tDCS measured one week after the intervention compared to intervention without tDCS. The effects of tDCS were maintained six weeks after therapy during reading but not during conversation. Chester and colleagues concluded that tDCS may be effective for improving speech articulation in other patient populations. Furthermore, the positive effects of tDCS in speech production are supported by studies showing that tDCS improves speech production in typical speakers [49]. Although previous tDCS studies in PPA, including our group’s largest–to our knowledge—double-blind, sham-controlled, cross-over trial of tDCS efficacy in PPA have shown positive effects of tDCS on spoken and written naming and spelling [50–55], there is no tDCS study demonstrating the potential of tDCS in reducing AOS symptoms despite the fact that AOS is a prominent feature in patients with nfvPPA or PPAOS (here referred to as nfvPPA/AOS to avoid classification debates). To our knowledge, this is the first study to provide preliminary, proof-of-concept evidence of tDCS efficacy as an adjuvant to speech therapy in PPA patients with AOS symptoms. The present study does not intend to suggest any criterion about AOS diagnosis or test the reliability of perceptual judgments for PPAOS diagnosis (e.g., Dabul et al.’s, questionnaire), or provide evidence for the presence or absence of AOS derived from perceptual judgments. The present study tests a simple hypothesis: if temporal acoustic measures, such as longer sound durations, are a characteristic of AOS [19–27], and the left IFG is a critical area for motor planning in speech production [6,16,17,36–40], then tDCS over the left IFG may normalize these sound durations significantly better than speech therapy alone in nfvPPA/AOS. In the present study, we hypothesized that tDCS over the left IFG coupled with speech production therapy will reduce AOS symptoms in patients with nfvPPA/AOS more than sham, i.e., speech production treatment alone. We used sound duration as a measure of AOS symptoms and reduced sound duration as an improvement of speech production in these patients. As slow speech production is a distinguishing characteristic of speech for patients with nfvPPA/AOS, a decrease in sound duration was considered as a therapeutic improvement corresponding to faster speech articulation. We asked three questions: (1) is tDCS more effective than sham in reducing sound duration in patients with nfvPPA/AOS? (2) Are tDCS effects sustainable over a two-months period? (3) Do tDCS effects generalize to untrained items? To answer these questions, we designed an experimental study where patients with nfvPPA/AOS received anodal tDCS over the left IFG or sham stimulation for the same duration paired with a word repetition task. Patients were evaluated three times: before treatment, immediately after treatment, and two months post-treatment. All words produced were segmented into vowels and consonants and we measured their temporal properties. Changes in syllable length do not affect equally their constituents, namely the vowels and consonants that make up these syllables [26,56,57], as changes in length primarily involve vowels. Therefore, the effects of tDCS on vowel and consonant duration may be different, which motivated us to study the two sound categories separately. Brain Sci. 2021, 11, 335 4 of 18

2. Materials and Methods 2.1. Study Design and Participants The study had a double-blind, cross-over design with two periods. In the present study, we analyzed only the ﬁrst period to avoid potential carryover effects. Eight patients with nfvPPA/AOS participated and were recruited from Johns Hopkins clinics or referrals from diagnostic centers. Inclusion criteria were as follows: native English speakers, minimum of high-school education, progressive speech/language disorder diagnosis, and absence of developmental or other neurogenic disorders (e.g., stroke). All participants provided informed consent. We included only those patients with nfvPPA and AOS symptoms (i.e., nfvPPA/AOS). Patients received tDCS or sham for three weeks (15 sessions) and were evaluated three times: before therapy, immediately after therapy, and two months post- therapy. Five participants received anodal tDCS over the left IFG and three participants received sham stimulation, both paired with speech therapy. Patients in the tDCS and sham groups were matched for baseline demographic characteristics and language severity. They were also matched for the segmental duration, which was the dependent variable of the study.

2.2. Clinical Assessment The subtyping of individuals with nfvPPA/AOS followed formal consensus criteria of PPA and was based on cognitive, speech and language testing, neurological examination, and neuroimaging [13]. Table1 shows the demographic (e.g., age at the beginning of therapy, sex, education) and neuropsychological evaluations for each participant. We report on patients’ performance on the digit span forward and backward, a test measuring short-term and working memory, the Pyramids and Palm Trees [58], a test measuring semantic knowledge, the Boston Naming Test (BNT) [59], a test measuring confrontational naming, and the Subject-relative, Object-relative, Active, and Passive (SOAP), a test for syntactic comprehension [60], and letter and semantic ﬂuency [61]. We also report on disease progression using Fronto-temporal Dementia Clinical Dementia Rating (FTD-CDR) Scale scores for language and total severity (sum of domains) [62]. Severity scores for each domain range from normal (0) to questionable/very mild (0.5), mild (1.0), moderate (2.0), and severe (3.0). Domains included are memory, orientation, judgment and problem- solving, community affairs, home and hobbies, personal care, behavior/comportment, personality, and language [62].

2.3. Speech Therapy Methods Speech therapy was conducted for 45 min total, with tDCS or sham stimulation occurring concurrently for the ﬁrst 20 min. The therapy task involved oral word repetition of increasingly complex words (e.g., method, methodology, methodological) modeled after Dabul et al.’s standardized assessment [63]. We used ten triplets of increasing morpho- logical complexity for trained words and ten triplets for untrained words matched for frequency, complexity, and length. The trained words were practiced during each therapy session whereas the untrained words were never practiced but were evaluated at all time- points for both tDCS and sham groups. Patients were initially trained on shorter words and when criterion was met (80% phonetic correctness) they proceeded to the list with increased syllables. The goal was to improve volitional control of participants’ articulators in order to produce co-articulated, intelligible speech, as well as to improve precision of articulation, speech rate, and speech ﬂuency. Brain Sci. 2021, 11, 335 5 of 18

Table 1. Demographic and neuropsychological data of the participants (numbers out of parenthesis in column mean, indicate the mean and in parenthesis the standard deviation). Total Severity = total severity scale from the Fronto-temporal Dementia Clinical Dementia Rating Scale [62]; Language Severity is the part of the Total Severity FTD-CDR that scores language skills; FAS = The F-A-S Test, a subtest of the Neurosensory Center Comprehensive Examination for Aphasia (NCCEA) [61]; BNT (30) = Boston Naming Test [59]; SOAP Total = Subject-relative, Object-relative, Active, and Passive total score [60]; p values are reported from a Kruskal–Wallis rank sum test; * = signiﬁcant.

Sham tDCS Participant ABN DAN JJI Mean BIN DRY GSH JBN CDY Mean p Education 16 16 16 16 (0) 16 16 20 20 16 18 (2.30) 0.2 Gender F F M - M F M M F - Condition onset 4 2.5 1.5 2.7 (1.3) 3 3.5 6 2 4 3.7 (1.48) 0.2 (years) Age at start of Therapy 54 71 78 67.67 (5.27) 65 53 68 65 74 65 (7.64) 0.5 FTD-CDR Language 2 1 2 1.67(0.58) 1 0.5 2 0.5 1 1(0.6) 0.2 Severity FTD-CDR Total 4 4.5 5.5 4.67 (0.54) 2 0.5 2.5 1 1.5 1.5 (0.79) 0.03 * Severity F.A.S. 6 11 4 7 (3.51) 21 34 21 31 15 24.4 (7.86) 0.02 * Fruits, Animals, 38 11 10 19.67 (5.32) 33 54 33 42 28 38 (10.27) 0.2 Vegetables Digit Span Forward 3.5 4 3.5 3.67 (0.25) 4.5 5.5 3.5 6 7 5.3 (1.35) 0.09 Digit Span Backward 2 3.5 2.5 2.67 (0.54) 4.5 5 3.5 3 5.5 4.3 (1.04) 0.07 Pyramids and 15 15 15 15 (0) 15 15 15 15 15 15 (0) 1 Palm Trees BNT (30) 28 28 15 23.67 (6.62) 29 30 24 30 23 27 (3.4) 0.3 SOAP Total (40) 30 33 27 30 (4.24) 35 37 35 33 37 35 (1.7) 0.03 *

2.4. tDCS Methods To estimate current distribution and guide experimental design, we conducted a current flow analysis for some of our patients of the main trial (see Figure1), for whom we could obtain those specific scans [64,65]. Stimulation was delivered using the Soterix Transcranial Direct Current Stimulator Clinical Trials Model 1500 at 2 mA intensity for 20 min for a total of 40 mA per session (estimated current density 0.08 mA/cm2)[66]. Current was transferred via nonmetallic, conductive rubber electrodes covering 5 × 5 cm (2.54 cm/inch) saline-soaked sponges. The anode was placed over the entire left IFG (see Figure1) which corresponds to the F7 electrode [53,67,68] based on the electroencephalogram (EEG) 10– 20 electrode position system [69]. The left IFG was co-registered to pretreatment magnetic resonance imaging (MRI) scans using a ﬁducial marker. The cathode was placed on the right cheek. Extracephalic cathodal placement has been shown to better target the area in question (Russell, 2006). Both the participant and the speech-language pathologist were blind to the stimulation condition by means of pre-registered codes on the tDCS device [66]. To mask the condition from participants, sham stimulation involved a short period of electrical current at stimulation onset, ramping up for 30 s and then ramping down, triggering a tingling sensation, which has been shown to blind the participant by creating the same initial sensation as in the tDCS condition [70]. To better simulate the actual tDCS condition during sham condition, we had our device modiﬁed to induce a second ramp up and down of the current for 30 s in the middle of the stimulation (about 10 min post-onset) creating an additional short-term tingling sensation to facilitate masking during sham. Patients were debriefed after treatment on whether they received sham or real tDCS and their responses were at chance (53% correct). Participants were asked to report their overall pain level using the Wong–Baker FACES Pain Rating Scale (www.WongBakerFACES.org, accessed on 10 June 2020). Brain Sci. 2021, 11, x FOR PEER REVIEW 6 of 19

Brain Sci. 2021, 11, 335 6 of 18

Figure 1. Model of current distribution for used stimulation montage (image courtesy of Dr. Marom Bikson). Figure 1. Model of current distribution for used stimulation montage (image courtesy of Dr. Marom Bikson). 2.5. Acoustic Analysis All evaluations (before, immediately after, and 2 months post-therapy) were recorded 2.5. Acoustic Analysis using an audio recorder that was placed approximately 1 ft in front of the patient. Audio recordings were converted into a 16,000 Hz mono wav file. All word productions were All evaluations manually(before, splitimmediately to distinguish afte ther, clinician and and2 months patient. Figurepost-therapy)2 shows the waveformwere rec- in orded using an audiothe recorder upper tier that for thewas word placed “methodology”, approximately which served 1 ft in as front part of of the the triplet patient.method , methodology, methodological (see AppendixA for the whole set of words evaluated); the Audio recordings werespectrogram converted is shown into undera 16,000 the waveform.Hz mono The wav thin file. vertical All lines word that productions extend from the were manually split tospectrogram distinguish to the the penultimate clinician tier and (measured patient. from Figure top to bottom) 2 shows indicate the thewaveform boundaries in the upper tier for theof vowels word and “methodology”, consonants. Each individual which served sound is as denoted partin of the the penultimate triplet method tier using, the international phonetic alphabet. The whole word is shown in the last tier. methodology, methodologicalWe (see segmented Appendix all individual A for vowels the andwhole consonants set of uttered words by clinicians evaluated); and patients the spectrogram is shownthat under made upthe each waveform. keyword as shownThe thin in Figure vertical2 (see also lines Appendix that Bextend, for word from character- the spectrogram to the penultimateistics). The segmentation tier (measure and labelingd from of vowelstop to and bottom) consonants indicate was conducted the bounda- manually by simultaneous inspection of waveforms and wide-band spectrograms and following ries of vowels and consonants.standard criteria Each of segmentation individual [71 sound]. The onset is denoted and offset ofin the the first penultimate two vowel formants tier using the international(F1 phonetic and F2) and alphabet. the fundamental The whole frequency word (F0) wereis shown employed in the for the last identification tier. of vowels [72,73]. The onset and offset of frication (i.e., the noisy portion) was employed for the identification of fricatives [74,75]. Stop consonants were measured at the onset of the closure phase, including the burst [76]. Segmentation was primarily conducted by the first author and a research assistant. To check for reliability of the segmentation procedures, the first author re-measured 3.5% of the data measured by the research assistant. The dupli- cate durational measurements of sounds were evaluated using Cohen’s cappa (κ = 0.97, p < 0.0001) and show significant agreement. All acoustic analyses were conducted in Praat [71], an acoustic analysis software [77]. From the segmented keywords, we measured the duration of each individual consonant and vowel. To compare consonant and vowel duration between patients and healthy controls, we acoustically analyzed clinicians’ productions, which were provided as prompts in the repetition task during evaluations.

Figure 2. Waveform and spectrogram of the word methodology/ˌmɛθəˈdɑləʤi/uttered by a female patient with nfvPPA/AOS. The middle tier shows with thick vertical lines the boundaries of vowels and consonants and the lower shows the target word. Brain Sci. 2021, 11, x FOR PEER REVIEW 6 of 19

Brain Sci. 2021, 11, x FOR PEER REVIEW 6 of 18

Figure 1. Model of current distribution for used stimulation montage (image courtesy of Dr. Marom Bikson).

2.5. Acoustic Analysis

All evaluations (before, immediately after, and 2 months post-therapy) were rec- Figureorded 1. Model using of current an audio distribution recorder for used that stimulation was placed montage approximately (image courtesy of 1 Dr. ft in front of the patient. MaromAudio Bikson). recordings were converted into a 16,000 Hz mono wav file. All word productions were manually split to distinguish the clinician and patient. Figure 2 shows the waveform 2.5. Acoustic Analysis in the upper tier for the word “methodology”, which served as part of the triplet method, All evaluations (before, immediately after, and 2 months post-therapy) were rec- ordedmethodology using an audio, methodological recorder that was(see placed Appendix approximately A for the 1 ft inwhole front ofset the of patient. words evaluated); the Audiospectrogram recordings wereis shown converted under into thea 16,000 waveform. Hz mono Thewav file.thin All vertical word productions lines that extend from the werespectrogram manually split to to the distinguish penultimate the clinic tierian (measureand patient.d Figurefrom 2top shows to bottom)the waveform indicate the bounda- in theries upper of vowels tier for theand word consonants. “methodology”, Each whichindividu servedal soundas part of is the denoted triplet method in the, penultimate tier Brain Sci. 2021, 11, 335 7 of 18 methodologyusing the, methodological international (see phonetic Appendix alphabet.A for the whole The whole set of words word evaluated); is shown thein the last tier. spectrogram is shown under the waveform. The thin vertical lines that extend from the spectrogram to the penultimate tier (measured from top to bottom) indicate the boundaries of vowels and consonants. Each individual sound is denoted in the penultimate tier using the international phonetic alphabet. The whole word is shown in the last tier.

FigureFigureFigure 2. 2.WaveformWaveform 2. Waveform and and spectrogram spectrogram and spectrogram of of the the word word of methodologymethodology the word/ˌ mmethodologyɛθəˈdɑləʤi/uttereduttered/ˌmɛθə by ˈd a ɑ female ləʤi/uttered patient with by nfvPPA/AOS.a female patientThe middle with nfvPPA/AOS. tier shows with The thick middle vertical tier lines shows the wi boundariesth thick vertical of vowels lines and the consonants boundaries and of the vow- lower shows the target word. els andpatient consonants with nfvPPA/AOS.and the lower shows The themiddle target tierword. shows with thick vertical lines the boundaries of vowels and consonants and the lower shows the target word. 2.6. Statistical Analysis Patients that received tDCS and sham were matched for segmental duration, the dependent variables of the study, thus they were not different at baseline. To remediate potential confounds due to unequal group sizes, we additionally used a linear mixed effect model that addresses unbalanced designs. We included the participant as a random slope to control for the individual differences between patients, even though the differences in FTD-CDR Total Severity, F.A.S., and SOAP do not reflect on the sound duration at baseline (see Figure3). Unlike the regression analysis and the analysis of variance (ANOVA), these models incorporate fixed and random effects [78]. The fixed effects are the parameters that we controlled experimentally (stimulation condition and timepoint). The random slope controls for individual differences in the error and increases the robustness of the fixed factors [78,79]. We conducted six linear mixed effects models in R (three for trained and three for untrained items) with the duration of vowels, consonants, and the total sound duration, which pools the duration of vowels and consonants, as dependent variables, and the condition (tDCS vs. sham) and timepoint (before, after, and two months post-therapy) as predictors. To model individual differences of participants, the participant was modelled as a random slope. The linear mixed effects models for trained and untrained items are shown in (1) to (3):

Sound duration ∼ condition ∗ timepoint + (1|participant) (1)

Vowel duration ∼ condition ∗ timepoint + (1|participant) (2) Consonant duration ∼ condition ∗ timepoint + (1|participant) (3) Linear mixed effects models were designed in R [80] using the “lme4: Linear Mixed- Effects Models using ‘Eigen’ and S4” package [81], and p values were calculated using the LmerTest package [82]. To compute post hoc contrasts, we employed the R package emmeans (EMMs, also known as least-squares means), which provides estimated marginal means [83]. A t test was performed to compare the duration of vowels and consonants produced by patients and clinicians. Brain Sci. 2021, 11, x FOR PEER REVIEW 8 of 19

BrainBrain Sci. Sci.2021 2021, ,11 11,, 335 x FOR PEER REVIEW 88 of 1819

Figure 3. Trained items (A) and untrained items (B) evaluated before (before), immediately after Figure 3.FigureTrained 3. itemsTrained (A) (after),items and untrained (andA) and 2 months itemsuntrained post-treatment (B) evaluated items (B before)(2 evaluated mp) (before),for ea beforech immediatelystimulation (before), condition. afterimmediately (after), The and ordinate after 2 months shows the post-treatment(after), (2 and mp) 2 for months eachsegmental stimulation post-treatment (vowels condition. and (2 consonants)mp) The for ordinate each duration showsstimulation the(log segmental transformed), condition. (vowels The error andordinate bars consonants) show shows 95% duration CI;the lower (log transformed),segmental error (vowels barsvalues: showand consonants) 95% shorter CI; lowersegments/faster duration values: shorter (log production. transformed), segments/faster Turquoise error production. lines bars show show TurquoisetDCS 95% effects; CI; lines lower red show lines tDCS show effects; redvalues: lines showshorter sham segments/fastersham effects. effects. production. Turquoise lines show tDCS effects; red lines show sham effects. 3.3. ResultsResults 3. Results AtAt baselinebaseline (Figure(Figure4 4A),A), the the sound sound duration duration for for trained trained items items did did not not differ differ between between patientspatients whowho received tDCS and and sham sham (t ((3009)t(3009) = =0.4, 0.4, p=p =0.7). 0.7). Both Both tDCS tDCS and and sham sham patient pa- At baseline (Figure 4A), the sound duration for trained items did not differ between tientgroups groups produced produced significantly signiﬁcantly longer longer sounds sounds (trained (trained and anduntrained) untrained) than thanhealthy healthy con- patients who receivedcontrolstrols (i.e., tDCS (i.e., the theclinicians).and clinicians). sham However,(t(3009) However, = immediat 0.4, immediately p= 0.7).ely afterBoth after treatment tDCS treatment and (Figure sham (Figure 4B), patient4 patientsB), patients who groups producedwhoreceived significantly received tDCS tDCS produced longer produced sounds significantly signiﬁcantly (trained shor shorterandter untrained)sounds sounds than than than those those healthy who who received con- shamsham trols (i.e., the clinicians).((tt(2508)(2508) == However,15, 15, pp << 0.0001), 0.0001), immediat and and their theirely sound after sound treatmentduration durationss approximated (Figure approximated 4B), patientsthose those produced producedwho by bycli- received tDCS cliniciansproducednicians (see (see significantlyFigure Figure 4B).4B). Importantly, Importantly, shorter sounds pati patientsents than who those received who tDCStDCS received maintainedmaintained sham thethe tDCS-tDCS- (t(2508) = 15, p

FigureFigure 4.4. SoundSound (vowels(vowels and and consonant) consonant) duration duration (trained (trained and and untrained) untrained) (log (log transformed) transformed) produced pro- byduced clinicians by clinicians and patients and patients that received that re tDCSceived and tDCS sham and evaluated sham evaluated before (A before), after (A (B),), after and 2(B months), and post-treatment2 months post-treatment (C). Error bars(C). showError 95%bars CI;show lower 95% values: CI; lower shorter values: segments/faster shorter segments/faster production. production. Figure 4. Sound (vowels and consonant) duration (trained and untrained) (log transformed) produced by clinicians and patients that received tDCS and sham evaluated before (A), after (B), and 2 months post-treatment (C). Error bars show 95% CI; lower values: shorter segments/faster production. Brain Sci. 2021, 11, 335 9 of 18

3.1. tDCS Effectiveness on Sound Duration in Trained Items The results for sound duration in the trained items are shown in Figure3A and Table2A. Immediately after therapy, sounds in trained items were 26% shorter in the tDCS condition compared to sham. This reduction in sound duration was significant as shown by the post hoc analysis using EMMs (β = −0.32, SE = 0.04, df = 4900.5, t = −64.48, p = 0.0001). At 2 months post-therapy, sounds in trained words were 29% shorter in tDCS condition compared to sham and the reduction was significant as well (β = −0.26, SE = 0.05, df = 4899.01, t = −5.47, p = 0.0001). Compared to baseline, sounds in trained words were 19% shorter immediately after therapy (β = 0.234, SE = 0.035, z(6.800), p < 0.0001) and 14% shorter at 2 months post-therapy which is a significant reduction (β = 0.234, SE = 0.035, z(6.800), p < 0.0001).

Table 2. Linear Mixed effects models on the effects of condition (tDCS vs. sham) and period (Before, Immediately After, 2 months post treatment (2 mp)) on trained (top) and untrained sound duration (bottom). The intercept of the model is the value of sham at baseline (Before).

Estimate SE df t p A. Trained Items Intercept 4.7955 0.1657 6.1702 28.95 <0.0001 tDCS vs. sham After −0.3194 0.0493 4900.5593 −6.48 <0.0001 tDCS vs. sham at 2 m post −0.2559 0.0468 4899.0188 −5.47 <0.0001 B. Untrained Items Intercept 4.7427 0.1838 6.12 25.81 0009 tDCS vs. sham After −0.59 0.0539 4118.06 −11.02 <0.0001 tDCS vs. sham at 2 m post −0.26 0.0495 4113.87 −5.19 <0.0001

3.2. tDCS Effectiveness on Sound Duration in Untrained Items Figure3B and Table2B show the results for sound duration in untrained items. Immediately after therapy, sounds in untrained words were 47% shorter in tDCS condition compared to sham and 22% shorter 2 months post-therapy. Compared to baseline, sounds in untrained words in the tDCS condition were 14% shorter immediately after therapy (β= 24, SE = 5, z(5.100), p < 0.0001). However, only a 2% difference in sound duration was observed at 2 months post-therapy for tDCS condition (β = 0, SE = 5, z(0.000), p = 1). Compared to baseline, sounds in untrained words in the sham condition were 26% longer immediately after therapy period (β = −47, SE = 6, z(−7.600), p < 0.0001) and 19% longer at 2 months post-therapy (β = −29, SE = 5, z(−5.600), p < 0.0001).

3.3. tDCS Effectiveness on Vowel Duration in Trained Items Figure5A and Table3A show the results for vowel duration in the trained items. Immediately after therapy, vowels in trained words in the tDCS condition were 27% shorter compared to sham (β = −0.2434, SE = 0.069, df = 2043.05, t = −3.54, p = 0.001). At 2 months post-therapy, vowels in trained words in the tDCS condition were 33% shorter compared to sham (β = −0.2820, SE = 0.07, df = 2041.63, t = −4.29, p = 0.001). With respect to baseline, vowels in trained words in the tDCS condition were 19% shorter immediately after therapy (β = 0.27, SE= 0.047, t = 5.900, p < 0.0001) and 15% shorter 2 months post-therapy (β = 0.17, SE = 0.041, t = 4.200, p < 0.0001). No signiﬁcant change was observed with respect to baseline in sham condition as vowels in trained words were 5.3% longer immediately after therapy (β = 0.33, SE= 0.219, t = 1.500, p = 0.68) and 11% longer 2 months post-therapy (β = −0.11, SE = 0.052, t = −2.100, p = 0.27).

3.4. tDCS Effectiveness on Vowel Duration in Untrained Items Figure5B and Table3B show the results for vowel duration in the untrained items. Immediately after therapy, vowels in untrained words in the tDCS condition were 55% shorter compared sham. They were 30% shorter at 2 months post-therapy compared to sham. With respect to baseline in the tDCS condition, vowels in untrained words were 18% shorter immediately after therapy (β = 0.24, SE = 0.043, t = 5.500, p < 0.0001) and 5% shorter at 2 months post-therapy (β = −0.02, SE= 0.043, t = −0.4, p = 1). With respect to Brain Sci. 2021, 11, x FOR PEER REVIEW 10 of 19

Brain Sci. 2021, 11, 335 10 of 18 shorter at 2 months post-therapy (β = −0.02, SE= 0.043, t = −0.4, p = 1). With respect to baseline in the sham condition, vowels in untrained words were 20% longer immediately baseline in the sham condition, vowels in untrained words were 20% longer immediately after therapy (β =after −0.37, therapy SE= 0.060, (β = −0.37, t = −SE6.100,= 0.060, p

FigureFigure 5. Trained 5. Trained items (A items) and untrained (A) and itemsuntrained (B) evaluated items ( beforeB) evaluated (before), immediatelybefore (before), after (after),immediately and 2 months after post-treatment(after), and (2 mp) 2 months for each condition.post-treatment The ordinate (2 mp) shows for voweleach condition. duration (log The transformed), ordinate errorshows bars vowel show 95%dura- CI; lower values: shorter segments/faster production. Turquoise lines show tDCS effects; red lines show sham effects. tion (log transformed), error bars show 95% CI; lower values: shorter segments/faster production. Turquoise lines show tDCS effects; red lines show sham effects. Table 3. Linear Mixed effects models on the effects of condition (sham vs. tDCS) and period (Before, After, 2 months post therapy (2 mp)) on trained (top) and untrained vowel duration (bottom). The Table 3. Linear Mixedintercept effects of the models model ison the the value effects of sham of condition in the before (sham phase. vs. tDCS) and period (Be- fore, After, 2 months post therapy (2 mp)) on trained (top) and untrained vowel duration (bottom). The intercept of the model is the value of sham in the beforeEstimate phase. SE df t p A. Trained Items Intercept 5.0919 0.1728 6.3419 29.47 <0.0001 tDCS in the After Estimate−0.2434 SE 0.0687 2043.0476df t− 3.54p 0004 timepoint A. Trained Items IntercepttDCS in the 2 mp timepoint 5.0919−0.2820 0.1728 0.0657 6.3419 2041.6251 29.47−4.29 <0.0001 <0.0001 B. Untrained Items Intercept 5.0122 0.1740 6.3172 28.81 <0.0001 tDCS in the After tDCStimepoint in the After −0.2434 0.0687 2043.0476 −3.54 0004 −0.6013 0.0738 1802.2565 −8.15 <0.0001 tDCS in the 2 mp timepointtimepoint −0.2820 0.0657 2041.6251 −4.29 <0.0001 tDCS in the 2 mp timepoint −0.2455 0.0670 1797.7502 −3.66 0002 B. Untrained Items Intercept 5.0122 0.1740 6.3172 28.81 <0.0001

3.5. tDCStDCS Effectiveness in the After on timepoint Consonant Duration−0.6013 in Trained 0.0738 Items 1802.2565 −8.15 <0.0001 FiguretDCS6 inA the and 2 Table mp 4timepointA show the results−0.2455 for consonant0.0670 1797.7502 duration in − the3.66 trained 0002 items. Consonants in the tDCS condition were 20% shorter than in the sham condition in the 3.5. tDCS Effectivenessafter period, on Consonant and 17% shorterDuration than in sham Trained in the Items 2 months post speech therapy. With respect to baseline consonants in trained items with tDCS were 15% shorter in the after period Figure 6A and(β = Table 0.176, SE4(A)= 0.046,showt =the 3.8, resultsp < 0.0001) for consonant 10% shorter induration the 2 months in the post trained therapy items. Consonantsperiod, in the an tDCS effect thatcondition was not were signiﬁcant 20% (shorterβ = 0.108, thanSE = in 0.041, the shamt = 2.60 conditionp = 0.09). Within the after period, respectand 17% to baseline, shorter consonants than sham in sham in the condition 2 months were onlypost 3.6% speech longer therapy. in the after With period − − respect to baseline(β =consonants0.16, SE = 0.045,in trainedt = 3.400, itemsp < with 0.01) andtDCS 4.3% were longer 15% in the shorter 2 months in postthe therapyafter period (β = −0.116, SE = 0.045, t = −2.6, p = 0.1100. period (β = 0.176, SE = 0.046, t = 3.8, p < 0.0001) 10% shorter in the 2 months post therapy period, an effect that was not significant (β = 0.108, SE = 0.041, t = 2.60 p = 0.09). With respect to baseline, consonants in sham condition were only 3.6% longer in the after period (β = −0.16, SE = 0.045, t = −3.400, p < 0.01) and 4.3% longer in the 2 months post therapy period (β = −0.116, SE = 0.045, t = −2.6, p = 0.1100.

3.6 tDCS Effectiveness on Consonant Duration in Untrained Items Figure 6B and Table 4(B) show the results for consonant duration in the untrained items. Immediately after therapy, consonants in untrained items in the tDCS condition were 36% shorter compared to sham. At 2 months post-therapy, consonants in untrained Brain Sci. 2021, 11, x FOR PEER REVIEW 11 of 19

items in the tDCS condition were 14% shorter compared to sham. With respect to baseline, consonants in untrained items in the tDCS condition were 10% shorter immediately after therapy, (β = 0.13, SE = 0.046, t = 2.9, p < 0.05) and there was a 0% difference at 2 months post-therapy (β = −0.03, SE = 0.05, t = −0.700, p = 0.9800). For consonants in untrained items in the sham condition, duration was 30% longer immediately after (β = −0.41, SE = 0.06, t Brain Sci. 2021, 11, 335= −7.2, p = 0.0001) and 18% longer 2 months post-therapy (β = −0.27, SE = 0.241, t = −1.100, 11 of 18 p = 0.85) compared to baseline.

Figure 6. TrainedFigure items6. Trained (A) and items untrained (A) and itemsuntrained (B) evaluateditems (B) evaluated before (before), before immediately(before), immediately after (after), after and 2 months post-treatment(after), (2 mp) and for 2 months each condition. post-treatment The ordinate (2 mp) showsfor each consonant condition. duration The ordinate (log transformed), shows consonant error bars show 95% CI; lower values:duration shorter (log segments/fastertransformed), error production. bars show Turquoise 95% CI; lower lines showvalues: tDCS shorter effects; segments/faster red lines show produc- sham effects. tion. Turquoise lines show tDCS effects; red lines show sham effects. Table 4. Linear mixed effects models on the effects of condition (sham vs. tDCS) and period Table 4. Linear mixed effects models on the effects of condition (sham vs. tDCS) and period (Be- (BeFigure2. months post therapy (2 mp)) on trained (top) and untrained consonant duration Figure 2. months post therapy (2 mp)) on trained (top) and untrained consonant duration (bot- (bottom). The intercept of the model is the value of sham in the before phase. tom). The intercept of the model is the value of sham in the before phase.

Estimate EstimateSE dfSE t dfp t p A. Trained Items A. Trained Items Intercept Intercept 4.5697 0.1647 4.5697 6.2897 0.1647 27.75 6.2897 <0.0001 27.75 <0.0001 tDCS in the After tDCS in the After timepoint −0.3307 0.0647−0.3307 2804.4270 0.0647 −5.11 2804.4270 <0.0001− 5.11 <0.0001 timepoint tDCS in the 2 mptDCS timepoint in the 2 mp timepoint−0.2239 0.0613−0.2239 2803.4093 0.0613 −3.65 2803.4093 0.00027− 3.65 0.00027 B. Untrained ItemsB. Untrained Items Intercept Intercept 4.5255 0.1897 4.5255 6.1737 0.1897 23.85 6.1737 <0.0001 23.85 <0.0001 tDCS in the After timepointtDCS in the After−0.5427 0.0726 2259.5804 −7.48 <0.0001 −0.5427 0.0726 2259.5804 −7.48 <0.0001 tDCS in the 2 mp timepointtimepoint −0.2540 0.0668 2255.8899 −3.80 0.00015 tDCS in the 2 mp timepoint −0.2540 0.0668 2255.8899 −3.80 0.00015 4. Discussion 3.6. tDCS Effectiveness on Consonant Duration in Untrained Items In this study, we investigated whether tDCS over the left IFG coupled with speech therapy improves soundFigure 6durationB and Table in 4patientsB show thewith results nfvPPA/AOS for consonant more duration than sham, in the i.e., untrained items. speech therapyImmediately alone. First, after we evaluated therapy, consonants whether tDCS in untrained is more itemseffective in the than tDCS sham condition in were 36% improving soundshorter duration compared in patients to sham. with At 2nfvPPA/AOS months post-therapy, and whether consonants effects insustained untrained items in the for 2 months post-treatment.tDCS condition Second, were 14% we shorter evaluated compared whether to sham.the effects With of respect tDCS togeneral- baseline, consonants ized to untrainedin untraineditems. Third, items we evaluat in the tDCSed whether condition effects were differed 10% shorterbetween immediately vowels and after therapy, consonants. Our(β findings= 0.13, SE show= 0.046, that (1)t = tDCS 2.9, p in< conjunction 0.05) and there with was speech a 0% therapy difference reduces at 2 months post- − SE t − p sound durationtherapy significantly (β = more0.03, than= 0.05,speech= therapy0.700, alone= 0.9800). (sham). For Furthermore, consonants tDCS in untrained items in the sham condition, duration was 30% longer immediately after (β = −0.41, SE = 0.06, effects sustained over time, i.e., the tDCS advantage was maintained for up to 2 months t = −7.2, p = 0.0001) and 18% longer 2 months post-therapy (β = −0.27, SE = 0.241, post-treatment. (2) The effects of tDCS generalized to untrained items immediately after t = −1.100, p = 0.85) compared to baseline.

4. Discussion In this study, we investigated whether tDCS over the left IFG coupled with speech therapy improves sound duration in patients with nfvPPA/AOS more than sham, i.e., speech therapy alone. First, we evaluated whether tDCS is more effective than sham in improving sound duration in patients with nfvPPA/AOS and whether effects sustained for 2 months post-treatment. Second, we evaluated whether the effects of tDCS generalized to untrained items. Third, we evaluated whether effects differed between vowels and consonants. Our Brain Sci. 2021, 11, 335 12 of 18

findings show that (1) tDCS in conjunction with speech therapy reduces sound duration significantly more than speech therapy alone (sham). Furthermore, tDCS effects sustained over time, i.e., the tDCS advantage was maintained for up to 2 months post-treatment. (2) The effects of tDCS generalized to untrained items immediately after treatment but this improvement was not maintained at 2 months post-treatment. (3) Patients who received tDCS coupled with speech therapy produced shorter vowels and consonants than patients who received speech therapy alone (sham). Below, we discuss the findings in detail, the contribution and limitations of this study, and future directions. The most important finding of this study is that tDCS reduced sound duration immediately after and up to 2 months post-treatment with respect to baseline for trained and untrained items. Furthermore, in trained items, sound duration approached the sound duration of healthy controls, although sounds produced by patients with nfvPPA/AOS were still significantly longer than those produced by healthy controls. In sham condition, sound duration slightly increased (1.2%) immediately after treatment with respect to baseline and remained the same at 2 months post treatment. This study shows that com- bining speech training with tDCS induces more sustaining effects. Such sustaining effects of tDCS were observed in other studies related to speech fluency and articulation. For example, Marangolo, Marinelli, Bonifazi, Fiori, Ceravolo, Provinciali and Tomaiuolo [19] also found improvement in response accuracy 2 months post-treatment in three patients with stroke-induced speech apraxia. Chesters, Mottonen and Watkins [48] showed that the tDCS effect on stuttering severity sustained for six weeks post-treatment in reading (but not in conversation). Furthermore, tDCS showed significant generalization of improvement in sound duration relative to sham. Taken together our findings suggest that tDCS has the potential to improve AOS symptoms. This is particularly important for nfvPPA/AOS since some patients may only present with AOS symptomatology at least in initial stages [13,21]. The tDCS montage in the present study targeted the left IFG. As discussed in the Introduction, the left IFG, and in particular the left IFG opercularis, is associated with articulatory motor planning and is adjacent to the primary motor areas of the mouth and tongue [84,85]. Given the size of our electrodes (2 × 2 inches), we cannot claim that we targeted only the left IFG or the IFG opercularis, although this area would be functionally related to AOS symptoms. Recent evidence of the principle of ‘functional targeting’ in the tDCS literature, concurs with the opinion that the current flows only on active cells, those related to the function that is trained [86]. Our previous study has shown that a possible mechanism for tDCS effects is through changes in functional connectivity of the stimulated area, the left IFG, in particular [19]. Although stimulation over the left IFG improved speech production, our findings do not exclude a speech improvement due to stimulation over homologue areas in the right hemisphere or other adjacent areas of the premotor cortex or the insula [87]. A subsequent functional connectivity study would need to provide evidence that this particular stimulation montage caused the present effects of segmental duration of vowels and consonants. TDCS resulted in shorter vowels and consonants, yet the effects were greater on vowels than consonants. This is not surprising, since vowels and especially stressed vowels, are intrinsically longer than most consonants [22,57], and this is the case even for geminate consonants in languages that have geminates, such as Finnish and Estonian. Therefore, this effect may not reflect a selective effect on vowels but rather opportunities for shortening. There are several underlying causes for these intrinsic differences between vowels and consonants, such as stress, post-lexical prominence (nuclear or pronuclear pitch accents), or phonetic distribution of lengthening over the syllable onset nucleus and coda, which are language specific effects and further discussion would be beyond the scope of this paper. Sound duration is affected by both articulatory and linguistic parameters. Articulatory factors that affect sound duration may be related to articulatory planning, coordination, and timing of neural commands, execution of articulatory movements, control of the airflow from the lungs towards the oral cavity and the vocal fold vibration in the larynx [56,88–91]. Additionally, phonemic factors that affect sound duration may be related to lexical stress, accentual Brain Sci. 2021, 11, 335 13 of 18

prominence, lengthening effects demarcating the boundaries of words and phrases, speech fluency, and other communicative effects, such as emphasis [92]. In other words, sound duration is better seen as an integral measure of different processes affecting speech production. The fact that sound duration is improved means that it could be the effect of a multidomain improvement either articulatory or linguistic (lung air pressure, vocal fold vibration, articulatory target approximation, etc.). The additional effects of articulatory deficits in nfvPPA/AOS, may explain why temporal properties of speech have been shown to distinguish patients with AOS from other patients with PPA [8,20,21]. One remaining question is whether tDCS effects transfer to post-lexical coarticulation level phenomena and prosodic phenomena, such as phrasing, intonation, speech fluency, and speech rate that involve post-lexical processes. Word repetition provides very limited information on phrasing, partly because phrasing here would be defined as a measure between clinician-patient-clinician productions (which is partly determined by the clinician). With respect to intonation, it is difficult to study pitch accents (a nuclear pitch accent, a phrase accent, and a boundary tone) at the word level [93]. By studying only F0, it would be very difficult to explain what constitutes an amelioration of the deficit vs. normalization. Furthermore, speech fluency and speech rate require sentence level productions. Nevertheless, segmental duration should be highly correlated with these sentence-level measures, as reduced segmental duration would indicate faster sentence production. Future studies should also incorporate connected speech productions. The main limitation of this study is the small number of participants, and therefore it can only be considered as a preliminary, proof-of-concept study. A related possible limitation is the matching of participants between the two stimulation groups. We matched the patients with respect to the language component of the FTD-CDR. The participants in the sham group seemed to have a little higher overall severity score, although the difference was not very large (4.67 out of possible 27 in the sham group and 1.5 out of 27 in the tDCS group). The overall severity of the FTD-CDR includes the language component but also provides additional scores for memory, orientation, judgement, community affairs, home and hobbies, personal care, and behavior. Although it is possible to entertain that overall severity differences in other than language sections of the FTD-CDR may impact AOS treatment and tDCS effects, the two stimulation groups were matched at baseline on the AOS outcome measure (sound duration). This, in conjunction with their matched language severity, suggests that the overall severity differences did not affect the outcome measures. Similarly, patient differences in letter fluency (FAS), and syntactic comprehension (SOAP) were not reflected on sound duration at baseline (the dependent variable of this study) as both groups exhibited approximately the same mean sound duration as shown in Figure3. If differences in performance on letter fluency or syntactic comprehension tasks influence the neuromodulatory effect of tDCS on sound duration as a primary AOS symptom, it remains an empirical question. Such a finding would rather speak against the consensus classification, i.e., against the fact that nfvPPA is a unitary variant. Rather, it should be split in two as Duffy et al., 2017 have argued: one with AOS symptoms (PPAOS) but without initial fluency or syntactic deficits and another with initial fluency and syntactic deficits and no AOS symptoms. Nevertheless, we acknowledge these differences in the statistics we run, by considering the participant as a random slope. Another possible limitation is the inherent diffusivity in tDCS methodology, including the lack of specific current flow estimation for each of the present participants. Nevertheless, previous current modeling in Figure1 showed that the current distribution was centered in the left IFG. The choice for the 5 × 5 cm2 electrode patches in our tDCS montage in the present study as well as in most previous clinical studies is driven by the premise and ease of transferring this methodology to clinic, if shown to be efficacious. Although not as precise as other tDCS methodologies, such as high-definition tDCS, the inherent large spread of electrical current in the present and other clinical studies, may actually be the very reason of their efficacy as the current affects larger brain regions. Future studies comparing these methods are needed to determine their clinical efficacy. Brain Sci. 2021, 11, 335 14 of 18

5. Conclusions To our knowledge, despite the high prevalence of AOS in PPA, namely nfvPPA, there is no evidence as to whether tDCS may be a useful adjunct to speech therapy in nfvPPA patients with AOS symptomatology. The findings of the present proof-of-concept study, i.e., the remarkable improvement in sound duration immediately after and even up to 2 months post-treatment, shows that tDCS has the potential to enhance speech production in patients with nfvPPA/AOS and warrants a larger study of tDCS over the left IFG as a therapeutic approach to improve AOS symptoms in nfvPPA/AOS. Furthermore, the sustainability of the tDCS’s effects provides the premise that tDCS combined with AOS treatment may inhibit the progression of AOS symptoms in patients with nfvPPA/AOS whose language deteriorates over time due to the nature of neurodegenerative disease. Therefore, a larger behavioral and neuroimaging study is warranted to specifically test the clinical efficacy of tDCS in AOS and the neural structures involved.

Author Contributions: Conceptualization, K.T. and C.T.; methodology, C.T.; software, C.T.; vali- dation, C.T. and K.T.; formal analysis, C.T.; investigation, C.T.; resources, K.T.; data curation, K.T.; writing—original draft preparation, C.T.; writing—review and editing, C.T., K.W. and K.T.; visual- ization, C.T.; supervision, K.T. and CT; project administration, K.W.; funding acquisition, K.T. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Science of Learning Institute at Johns Hopkins University and by the National Institutes of Health (National Institute of Deafness and Communication Disorders), grant number NIH/NIDCD R01 DC014475. Institutional Review Board Statement: Ethics approval for the study was provided by the Johns Hopkins Hospital Institutional Review Board (IRB NA00071337). Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Data Availability Statement: Data are available after request; sound recordings are not available as they can identify the speaker. Acknowledgments: We want to thank Olivia Herman for proofreading the final manuscript and providing useful editorial comments. Conflicts of Interest: The authors declare no conflict of interest.

Appendix A

Set Lists Word Triplets SET 1 intervene intervention interventional progress progression progressive reflect reflection reflective stimulate stimulation stimulating stable stabilize stabilization success successful successfully excite excitable excitability improve improvement improving behave behavioral behaviorally perform performance performing SET 2 enhance enhancement enhancing suspend suspension suspending suppress suppression suppressive construct construction constructive accurate accuracy inaccurate therapy therapeutic therapeutically provide provision provisional hypothesis hypothesize hypothetical define definition definitive determine determination determining BrainBrainBrainBrainBrain Sci. BrainSci. Sci. Sci.Sci. 2021 2021 2021 Sci. 20212021, ,,11 , 202111 11,, ,1111 ,,x , x x x,,FOR FORFORx11xFOR FORFOR, x PEER PEER PEERFORPEER PEERPEER PEERREVIEW REVIEW REVIEWREVIEW REVIEWREVIEW REVIEW 151515 1515of of of of18 of1815 18 1818 of 18 BrainBrain Sci.Sci. 20212021,,, 1111,,, xxx FORFORFOR PEERPEERPEER REVIEWREVIEWREVIEW 1515 ofof 1818

hypothesishypothesishypothesishypothesishypothesishypothesishypothesishypothesis hypothesizehypothesizehypothesizehypothesizehypothesizehypothesizehypothesizehypothesize hypothetical hypothetical hypothetical hypothetical hypothetical hypothetical hypothetical hypothetical Brain Sci. 2021, 11, 335 15 of 18 definedefinedefinedefinedefinedefinedefinedefine definition definition definition definition definition definition definition definition definitive definitive definitive definitive definitive definitive definitive definitive determinedeterminedeterminedeterminedeterminedeterminedeterminedetermine determinationdeterminationdeterminationdeterminationdeterminationdeterminationdeterminationdetermination determiningdeterminingdeterminingdeterminingdeterminingdeterminingdeterminingdetermining SETSETSETSETSET 3 3SET3 33 3 inform inform inform inform inform inform information information information information information information informative informative informative informative informative informative Set Lists Word Triplets supposesupposesupposesupposesupposesupposesupposesuppose suppositionsuppositionsuppositionsuppositionsuppositionsuppositionsuppositionsupposition supposedlysupposedlysupposedlysupposedlysupposedlysupposedlysupposedlysupposedly SET 3 inform information informative restrictrestrictrestrictrestrictrestrictrestrictrestrictrestrict restrictionrestrictionrestrictionrestrictionrestrictionrestrictionrestrictionrestriction restrictive restrictive restrictive restrictive restrictive restrictive restrictive restrictive suppose supposition supposedly concentrateconcentrateconcentrateconcentrateconcentrateconcentrateconcentrate concentrationconcentrationconcentrationconcentrationconcentrationconcentrationconcentration concentrated concentrated concentrated concentrated concentrated concentrated concentrated concentrateconcentraterestrict concentrationconcentration restriction concentrated concentrated restrictive inhibit inhibition inhibiting inhibitinhibitinhibitinhibitinhibitinhibitinhibitconcentrate inhibiti inhibiti inhibiti inhibiti inhibiti inhibiti inhibiti concentrationonononon inhibitinginhibitinginhibiting concentratedinhibiting investigateinvestigateinvestigateinvestigateinvestigateinvestigateinvestigateinvestigateinhibit investigationinvestigationinvestigationinvestigationinvestigationinvestigationinvestigationinvestigation inhibition investigator investigator investigator investigator investigator investigator investigator inhibiting investigator combinecombinecombinecombinecombinecombinecombinecombineinvestigate combinationcombinationcombinationcombinationcombinationcombinationcombinationcombination investigation combinatorycombinatorycombinatorycombinatorycombinatorycombinatorycombinatory investigatorcombinatory combine combination combinatory cognitioncognitioncognitioncognitioncognitioncognitioncognitioncognition cognitive cognitive cognitive cognitive cognitive cognitive cognitive cognitive cognitively cognitively cognitively cognitively cognitively cognitively cognitively cognitively cognitioncognition cognitive cognitive cognitively cognitively methodmethodmethodmethodmethod methodologymethodologymethodologymethodologymethodology methodologicalmethodologicalmethodologicalmethodologicalmethodological methodmethodmethodmethodmethod method methodologymethodologymethodologymethodologymethodology methodology methodologicalmethodologicalmethodologicalmethodologicalmethodological methodological couragecouragecouragecouragecouragecouragecouragecourage courage courageouscourageouscourageouscourageouscourageouscourageouscourageouscourageous courageous encouragingencouragingencouragingencouragingencouragingencouragingencouraging encouragingencouraging

Appendix B AppendixAppendixAppendixAppendix B B B B In addition to the quantified measurements, we observed several co-articulatory and InInInInIn In addition additionadditionaddition additionaddition to tototo to toto the thethethe thethethe quantified quantifiedquantifiedquantified quantified quantifiedquantified measurements measurementsmeasurementsmeasurements measurementsmeasurements measurements,,, ,,, we wewewe,we, wewe we observed observedobservedobservedobserved observedobserved observed several severalseveralseveralseveral severalseveral several co-articulatory co-articulatoryco-articulatoryco-articulatoryco-articulatory co-articulatoryco-articulatory co-articulatory and andandandand andand phonemic processes that were characteristic of the productions in individuals with phonemicphonemicandphonemicphonemic phonemic processesprocessesprocesses processes processes thatthatthat that that werewerewere were were characteristiccharacteristiccharacteristic characteristic characteristic ofofofof of ofof of thethethethe the thethe productionsproductionsproductionsproductions productions productionsproductionsproductions inininin in in inin individualsindividualsindividualsindividuals individuals individualsindividuals with withwith with withwith nfvPPA/AOS,nfvPPA/AOS,nfvPPA/AOS,nfvPPA/AOS,nfvPPA/AOS, such suchsuch such such such as asas as as several severalseveral asseveral several phenomena phenomenaphenomena phenomena phenomena that thatthat that were that werewerewere were werewere were observed observedobserved observedobserved observedobserved observed in inin inin inin re-occurring re-occurring re-occurringre-occurringre-occurring re-occurringinre-occurring re-occurring speech speech speechspeechspeech speechspeech speech of ofofof ofof of thesethesethesethesethesethesethese individuals. individuals. individuals. individuals. individuals.individuals. individuals. Specifically, Specifically, Specifically, Specifically,Specifically, Specifically,Specifically, Specifically, voiceless voiceless voicelessvoiceless voicelessvoiceless voiceless conson conson consonantsconsonconson consonconson consonantsantsantsants were antswere were were were oftenoften often often often produced produced produced produced produced as as as as voiced voiced voiced voicedas voiced before before before before before voicedvoicedvoicedvoicedvoiced nasals nasals nasals nasals nasals (e.g., (e.g., (e.g., (e.g., (e.g., encouraging encouraging encouraging encouraging encouraging / /ɪ/ɪ ɪnɪɪn/nˈɪɪˈˈnkˈk kʰɜˈ/ˈʰɜʰɜkɪʰɜnrʰɜrʰɜrərˈəəkʤɪrrʤɪʤɪəʰɜəʤɪn/rn/n/ən/ ʤɪ > >> [>n/ [ɛ[ɛ ɛnɛ[n nɛ>ˈɡɜːɛˈɡɜːˈɡɜːnˈɡɜː [ˈɡɜːˈɡɜːɛrnrrɪʤɪrˈɡɜːɪʤɪɪʤɪɪʤɪɪʤɪrrɪʤɪɪʤɪn],n],rn],ɪʤɪn], , where where where n],where where the the the the vibration vibrationvibrationthe vibration vibration of of of of the thethe theof the vocalvocalvocalvocalvocal folds folds folds folds folds during duringduring during during the thethethe the production productionproductionthe production production of ofof of the thethe theof nasal/n/does nasal/n/doesnasal/n/doesthe nasal/n/does nasal/n/does not notnot not not cease ceaseceasenot cease cease before beforebefore before before the the thethe the production production productionthe production production of ofof of of thethethethethethe adjacent adjacentadjacent adjacentthe adjacentadjacent adjacent voiceless voicelessvoicelessvoiceless voicelessvoiceless voiceless consonant/k/). consonant/k/).consonant/k/).consonant/k/).consonant/k/). consonant/k/).consonant/k/). consonant/k/). Voiced VoicedVoicedVoiced Voiced VoicedVoiced Voiced consonants consonantsconsonantsconsonants consonants consonantsconsonants consonants were werewerewere werewere were often oftenoften often oftenoften often produced producedproduced produced producedproduced produced as asas as as as devoiced devoiceddevoiced devoiced devoicedasdevoiced devoiced (definitive(definitive(definitive(definitive(definitive(definitive(definitive(definitive /d /d/d/d /dɪˈ/dɪˈɪˈɪˈɪˈfffɪˈɪ ɪˈfɪ/dɪnɪɪnfnfɪɪɪɪtnɪˈɪɪttɪtɪɪv/fɪɪv/tv/ɪtɪnɪ v/ > ɪ>>t ɪ[ > [v/ˌ[ˌˌ tˌt[tʰɪt ʰɪˌʰɪˌ>ʰɪtvtv ʰɪvʰɪ[ɪɪɪnˌɪvɪnntɪˈɪʰɪɪɪˈɪˈnɪˈɪˈtvttɪˈʰɪɪˈtʰɪʰɪɪʰɪtv];ntv];ʰɪv];ʰɪɪˈv];; t aspiration ʰɪ aspirationaspiration v];aspiration aspiration results resultsresults results results from fromfrom from from the thethethe the phonemic phonemicphonemicthe phonemic phonemic rule rulerulerule rule in rule ininin in English EnglishEnglish Englishin English thatthatthatthatthatthat aspiratesthat aspirates aspiratesaspirates aspiratesaspirates aspirates onset onset onsetonset onsetonset onset stop stop stopstop stopstop stop consonants consonants consonantsconsonants consonantsconsonants consonants [94]. [94]. [[94].[94].94 [94].[94].]. [94]. Ov Ov OvershootingOvOv OvOvershootingershootingershooting Overshootingershootingershooting or or or or or undershoot undershootingundershootundershoot orundershootundershoot undershootinginginginginginging of of ofofingof ofof articulatory articulatoryarticulatoryarticulatoryarticulatory articulatoryofarticulatory articulatory targetstargetstargetstargetstargetstargetstargets related related relatedrelated relatedrelated related to to toto toto the the thethe thetothe place place placeplacethe placeplace place of ofofof ofof articulation articulationarticulationarticulation articulationofarticulation articulation (e.g., (e.g.,(e.g.,(e.g.,(e.g., (e.g.,(e.g., (e.g., simulation simulationsimulationsimulationsimulation simulationsimulation simulation / //ˌ/ˌˌ s ˌs/s/sɪˌɪˌɪmjɪɪsmjsmj ɪɪ/mjˌəəsəˈˈɪˈleəˈəmjleleleleˈˈɪʃleɪʃleɪʃɪʃɪʃənnɪʃnɪʃˈ/̩ le/̩̩̩/̩n ̩̩/̩ > >>/̩ɪʃ/̩> / > n/>/ˌʃɪ/ˌʃɪˌʃɪ ˌʃɪ/̩// ˌʃɪmjˌʃɪ>mjmj /mjəˌʃɪəəˈˈˈleəˈəmjleleleleˈˈɪʃleɪʃleɪʃɪʃɪʃənnɪʃnɪʃˈ/̩ le/̩̩̩/̩ n̩̩/̩ an an/̩anɪʃ/̩an annan /̩ an alveolaralveolaralveolaralveolaralveolar fricative fricative fricative fricative fricative sound soundsoundsound sound sound becomes becomesbecomes becomes becomes postalveolar postalveolarpostalveolar postalveolar postalveolar fricative fricative fricativefricativefricative fricativefricative fricative when when whenwhenwhen whenwhen when it it itititapproaches approaches itit approachesapproachesapproaches approaches approachesit approaches an an ananan alveopalatalanan alveopala- alveopala-alveopala-alveopala- analveopala-alveopala- alveopala- taltaltalconsonant).taltaltal consonant). consonant).consonant).consonant). talconsonant).consonant). consonant). Spirantization Spirantization SpirantizationSpirantizationSpirantization SpirantizationSpirantization Spirantization phenomena phenomena phenomenaphenomenaphenomena phenomenaphenomena phenomena were were werewerewere werewere especiallywere especially especiallyespeciallyespecially especiallyespecially especially common common commoncommoncommon commoncommon common at at atatat atat word wordwordword wordwordat word codas codascodascodas codascodas codas (d (d(d(d (d (d > >>> ð): > ð):(d>ð):ð): ):ð):ð): > ð): methodmethodmethodmethodmethod / /ˈ/ˈˈ mˈm/mˈˈɛːmɛː ɛːɛː/θəɛːθəˈɛːθəmθəd/d/ɛːd/d/ θə > >> [ > d/[ˈ[ˈˈ mˈm[m ˈˈ>ɛːmɛː ɛːɛː[θəɛːθəˈɛːθəmθəððɛːðəəəðθə].].].ə].ə . Affrication ].]. AffricationðAffricationAffrication Affrication əAffricationAffrication]. Affrication of ofofof of ofof a aaa astop a stopofastopstop stopstopstop a stopthat thatthatthat thatthat is that isisis isproduced producedproducedproduced producedproduced is produced as asasas as as asfricative fricativefricativefricative fricativeasfricative fricative fricative or ororor or or affri- or affri-affri-affri- affri-oraffri- af- affri- catecatefricatecatecatecatecate (interventional cate (interventional(interventional(interventional (interventional(interventional (interventional (interventional / /ˌɪ//ˌɪˌɪ ˌɪ/nt/ntˌɪntˌɪntə ə/ərˌɪrrˈərəˈˈvntˈrvrvˈɛˈɛɛvənɛnnrɛɛʧʧˈnʧəvəəʧnʧɛnnəənənəl/ʧl/l/l/əl/ə >l/ l/ n>>>> ə [i > [i>[i[i[il/ʰ ʰʰ[int[iʰ ntnt>ʰʰntʃʰ ʃʰ[iʃʰʃʰ..ʰʃʰɪ..ʃʰ.ɪɪntɪɪntnt..ɪɪntʃʰɝʃʰʃʰɝʃʰɝʃʰɝ.ʃʰɝɪʃʰɝnt..ˈ...ˈˈ ˈ væ.stʃʰɝ. . væ.stvæ.stˈvæ.stˈvæ.st væ.stvæ.st.ˈ væ.stɔɔɔɔ.n.n.n.n.nɔɔə.n.nəəl]).l]).l]).l]).ɔəl]).ə.nl]).l]). ). Lastly, əLastly,Lastly,Lastly,Lastly, l]). Lastly,Lastly,Lastly, Lastly, other otherotherotherother other otherother other coarticula- coarticula-coarticula-coarticula-coarticula- coarticula-coarticula- coarticula- torytorytorytorytorytory phenomena toryphenomena phenomenaphenomena phenomenaphenomena phenomena were werewere werewere werewere were also alsoalso alsoalso alsoalso observed, alsoobserved, observed,observed, observed,observed, observed, such such suchsuch suchsuch such as as as asas as as cluster cluster cluster clusterclustercluster clusterclusteras cluster simplification: simplification: simplification: simplification:simplification:simplification: simplification:simplification: simplification:(the/st/): (the/st/): (the/st/): (the/st/):(the/st/):(the/st/): (the/st/):(the/st/): (the/st/): stable/ stable/ stable/ stablestable/stable/ stable/stable/ stable/ˈˈˈsteˈstestesteˈˈstesteɪɪɪblɪɪblˈblsteɪɪ/̩bl/̩̩̩/̩ ̩̩/̩ /̩/̩ɪ bl /̩ >>> / >/ˈ/ˈˈ seˈse/seseˈˈ>seɪseɪɪ bɪɪb/bəˈɪɪəəbse/;/;/;;ə/;ə ɪ omission:/; /;omission:bomission:omission: əomission:omission:/; omission: (the (the(the(the (the(the aspiration/h/): aspira (the aspiraaspiraaspira aspiraaspira aspiration/h/):tion/h/):tion/h/):tion/h/):tion/h/):tion/h/):tion/h/): enhancement enhancementenhancement enhancement enhancementenhancement enhancement / //ɛ/ɛ ɛ nɛ/n/nɛɛˈˈˈnhænsmˈ hænsmhænsm/ˈˈɛhænsmnˈhænsməəənt/nt/nt/əənt/ > ə>> nt/ / >/ɛ/ɛ ɛnɛ/n nɛɛˈ>ˈˈnæsmˈ æsmæsm/ˈˈɛæsmnˈəæsməəns/ns/ns/əəns/ hereə hereherens/ here here thethethethethethe articulatory articulatoryarticulatory articulatorythe articulatoryarticulatory articulatory command command commandcommand commandcommand command for for forfor forfor its its its itsfor itsits production production productionproduction itsproductionproduction production fa fafailsfafa ilsfafailsilsilsilsilsils to fa totototo ilstoto activate). activate).activate).activate).activate). activate).activate).to activate). Compensatory Compensatory CompensatoryCompensatoryCompensatory CompensatoryCompensatory Compensatory measures measuresmeasuresmeasuresmeasures measuresmeasures measures to totototo toto to produceproduceproduceproduceproduce lexical lexicallexical lexical lexical stress: stress:stress: stress: stress: stress: i. i.i. i. longer i.longer longer longerlonger i. longer syllable syllablesyllable syllable syllable dura duradura dura duration; tion;duration;tion;tion;tion;tion; tion; ii. ii. ii.ii. ii.ii. splitting ii.splitting splittingsplitting splittingsplittingii. splitting splitting the the thethe thethe the stressed stressed stressed stressedthe stressedstressed stressed stressed syllable syllable syllablesyllable syllablesyllable syllable syllable from from fromfrom fromfrom from from the the thethe thethe the precedingprecedingtheprecedingpreceding precedingpreceding part: part:part: part: part:part: excitability excitabilityexcitability excitability excitability / /ɪ/ɪɪk ɪɪk/kˌɪɪˌˌsakˌsasa saˌ/ˌsaɪsaɪɪtkɪɪttətəˌɪəɪˈtsatˈˈbəˈəbbɪˈˈɪɪɪlɪbɪtllɪlləɪɪti/ɪɪti/ti/lˈti/lɪɪbti/ ti/ >ɪ >>l> ɪ [ ti/> >[[ɪ[ɪ ɪkɪ ɪk[k[ ˌɪ>ɪˌˌsakˌsa sasaˌ[ˌsaɪsaɪɪtkɪɪttətəˌɪəɪ.tsat.ˈ..ə.ˈəˈbˈb.b.ɪɪˈˈtɪɪlɪbɪləlɪllɪɪti].ɪ.ɪti].ti].lˈti].lɪɪbti].ti]. ɪ Slowl SlowSlowɪSlow ti]. SlowSlow. Slow speech speechspeechspeech speechspeech speech production productionproductionproduction productionproduction production and andandand andand and effortfuleffortfulandeffortfuleffortfuleffortfuleffortful effortful speech. speech.speech. speech.speech. speech. speech. To ToTo ToTo explain explainexplain To explainexplain To explain explain the thethe thethe complex complex complexthe complexcomplex the complex complex inte inteinte inteinteractionsractions ractionsractionsinteractionsractions interactionsractions between between betweenbetween betweenbetween between between brain brain brainbrain brainbrain brain areas areas areasareas areasareas brain areas and and andand andand areas impairment impairment andimpairmentimpairment impairmentimpairment andimpairment im- ininpairmentininin inin patients patientspatientspatientspatients patientspatientsin patientsin with withwithwithwith patientswithwith with nfvPPA/AOS, nfvPPA/AOS,nfvPPA/AOS,nfvPPA/AOS,nfvPPA/AOS, nfvPPA/AOS,nfvPPA/AOS, nfvPPA/AOS, with nfvPPA/AOS, cognitive cognitivecognitivecognitivecognitive cognitivecognitive cognitive models modelsmodelsmodelsmodels cognitive modelsmodels models were werewerewerewere werewere models were developed developeddevelopeddevelopeddeveloped developeddeveloped developed were developedfor forforforfor forfor apraxia apraxiaapraxiaapraxia apraxiafor apraxiaapraxia apraxia for of ofofofof ofof speech speechapraxiaspeechspeechspeech speechspeechof speech ofof-of-of-ofof of-ofof- tententenspeechtententen based basedbasedbasedten basedbased oftenbased on ononon onon language basedlanguagelanguagelanguage onlanguagelanguage language on models, language models,models,models, models,models, models, su sususumodels, susuchchchch chch su as asasas chas as those thosethosethose suchthoseasthose those proposed proposedproposedproposed as proposedproposed those proposed proposed by bybyby byby Leve LeveLeveLeve byLeveLeve Leveltltltltlt by [95] lt lt [95][95][95][95] [95][95] Leveltlt and and[95]andandand andand aim andaimaim [aimaim95 aimaim] to aimtoto andtoto toto describe describedescribedescribedescribe describedescribeto aim describe to thethethedescribethethethe processes processesprocessestheprocesses processesprocesses processes the processes involved involvedinvolvedinvolved involvedinvolved involved involved in ininin inin apraxia apraxiaapraxiaapraxia apraxiainapraxia apraxia in modeling modelingmodeling apraxiamodeling modelingmodeling modeling modeling the thethethe thethe invariant invariantinvarianttheinvariant invariantinvariant invariant the invariant and andandand andand variant andvariantvariantvariant variantvariantand variant aspects variantaspectsaspectsaspects aspectsaspects aspects of aspectsofofof ofof speech speechspeechspeech speechofspeech speech of productionproductionspeechproductionproductionproduction production [96,97]. [96,97].[96,97]. [96,97]. [96,97]. [96 ,97 ]. References ReferencesReferencesReferencesReferencesReferences 1. Ogar, J.; Willock, S.; Baldo, J.; Wilkins, D.; Ludy, C.; Dronkers, N. Clinical and anatomical correlates of apraxia of speech. Brain 1.1.1. 1. 1. Ogar,1.Ogar,Ogar, Ogar,Ogar, J.; J.;J.;J.;J.; J.; Willock,J.; Willock,Willock, Willock, J.; Willock, S.; S.;S.; S.; S.; Baldo, Baldo,Baldo, Baldo,S.; Baldo, J.; J.;J.;J.;J.; J.; Wilkins,J.; Wilkins,Wilkins, Wilkins, J.; Wilkins, D.; D.;D.; D.; Ludy, Ludy,Ludy, D.; Ludy, Ludy, C.; C.;C.; C.; Dronkers, Dronkers,Dronkers, C.;Dronkers, Dronkers, N. N.N. N. Clinical ClinicalClinical ClinicalN. Clinical and andand andand anatomical anatomicalanatomicaland anatomicalanatomical anatomical correlates correlatescorrelatescorrelates correlatescorrelates correlates of ofof of apraxia apraxiaapraxia apraxiaapraxiaof apraxia of ofof of speech. speech.speech.speech. speech.speech.of speech. Brain BrainBrainBrainBrain BrainBrain Brain 1. Lang.Ogar,2006 J.; Willock,, 97, 343–350. S.; Baldo, [CrossRef J.; Wilkins,][PubMed D.; Ludy,] C.; Dronkers, N. Clinical and anatomical correlates of apraxia of speech. Brain Lang.Lang.Lang.Lang. Lang. 2006 20062006 20062006, , ,2006,, 97 97979797,, 97,97, ,,, 343–350, 343–350,,343–350,,, 97343–350,343–350,, 343–350, doi:10.1016/j.ba doi:10.1016/j.badoi:10.1016/j.ba doi:10.1016/j.ba doi:10.1016/j.bandl.2006.01.008.ndl.2006.01.008.ndl.2006.01.008.ndl.2006.01.008.ndl.2006.01.008. 2. Jordan,Lang. 2006 L.C.;, 97 Hillis,, 343–350, A.E. doi:10.1016/j.ba Disorders of speechndl.2006.01.008. and language: Aphasia, apraxia and dysarthria. Curr Opin Neurol 2006, 19, 580–585. 2.2.2. 2. 2. Jordan,2.Jordan,Jordan,Jordan,Jordan, Jordan,Jordan,Jordan, L.C.; L.C.;L.C.; L.C.; L.C.; Hillis, Hillis,Hillis, Hillis, Hillis, A.E. A.E.A.E. A.E. Disorders A.E. DisordersDisorders Disorders Disorders of ofof of speech speechspeechspeech speechspeechof speech and andand andand language: language:language:andlanguage:language: language:language: language: Aphasia, Aphasia,Aphasia,Aphasia,Aphasia, Aphasia,Aphasia, Aphasia, apraxia apraxiaapraxia apraxiaapraxia apraxia and andand andand dysarthria. dysarthria.anddysarthria. dysarthria. dysarthria. Curr CurrCurrCurrCurr CurrCurr OpinCurr OpinOpinOpinOpin OpinOpin Opin Neurol NeurolNeurolNeurolNeurol NeurolNeurol Neurol 2006 20062006 20062006, , ,2006,, 19 191919,19, ,1919, ,,, 580– 580–,580–, , 19580–580–, 580– 2. [Jordan,CrossRef L.C.;] Hillis, A.E. Disorders of speech and language: Aphasia, apraxia and dysarthria. Curr Opin Neurol 2006, 19, 580– 585,585,585,585,585, doi:10.1097/WCO.0b013e3280109260. doi:10.1097/WCO.0b013e3280109260.585,doi:10.1097/WCO.0b013e3280109260. doi:10.1097/WCO.0b013e3280109260. doi:10.1097/WCO.0b013e3280109260. 3. Graff-Radford,585, doi:10.1097/WCO.0b013e3280109260. J.; Jones, D.T.; Strand, E.A.; Rabinstein, A.A.; Duffy, J.R.; Josephs, K.A. The neuroanatomy of pure apraxia of 3.3.3. 3. 3. Graff-Radford,3.Graff-Radford,Graff-Radford, Graff-Radford,Graff-Radford, J.; J.;J.;J.;J.; J.; J.; Jones, Jones,Jones,Jones,Jones, Jones,Jones,J.; Jones, D.T.; D.T.;D.T.; D.T.; D.T.; Strand, Strand,Strand, Strand,Strand, Strand, E.A.; E.A.;E.A.; E.A.; E.A.; Rabinstein, Rabinstein,Rabinstein, Rabinstein, Rabinstein, A.A.; A.A.;A.A.; A.A.; A.A.; Duffy, Duffy,Duffy, Duffy, Duffy, J.R.; J.R.;J.R.;J.R.;J.R.; J.R.;J.R.; Josephs, Josephs,J.R.;Josephs,Josephs,Josephs, Josephs,Josephs, Josephs, K.A. K.A.K.A. K.A. TheK.A. TheThe The neuroanatomy neuroanatomyTheneuroanatomy neuroanatomy neuroanatomy of ofof of pure purepure pureof pure apraxia apraxiaapraxia apraxiaapraxia apraxia of ofof of of 3. speechGraff-Radford, in stroke. J.;Brain Jones, Lang. D.T.;2014 Strand,, 129, E.A.; 43–46. Rabinstein, [CrossRef ]A.A.; Duffy, J.R.; Josephs, K.A. The neuroanatomy of pure apraxia of speechspeechspeechspeechspeechspeechspeech in inininin in instroke. stroke.stroke.stroke. stroke.stroke.in stroke. Brain BrainBrainBrainBrain BrainBrain Brain Lang. Lang.Lang.Lang.Lang. Lang.Lang. Lang. 2014 20142014 20142014, , ,2014,, 129 129129129129,, 129129,, ,,, 43–46, 43–46,12943–46,,, 43–46,43–46,, 43–46, doi:10.1016/j.bandl.2014.01.004. doi:10.1016/j.bandl.2014.01.004.doi:10.1016/j.bandl.2014.01.004. doi:10.1016/j.bandl.2014.01.004. doi:10.1016/j.bandl.2014.01.004. 4. Moser,speech D.;in stroke. Basilakos, Brain A.; Lang. Fillmore, 2014, P.; 129 Fridriksson,, 43–46, doi:10.1016/j.bandl.2014.01.004. J. Brain damage associated with apraxia of speech: Evidence from case studies. 4.4.4. 4. 4. Moser,4.Moser,Moser, Moser,Moser, D.; D.; D.; D.; Basilakos, Basilakos, Basilakos, D.; Basilakos, Basilakos, A.; A.; A.; A.; Fillmore, Fillmore, Fillmore, A.; Fillmore, Fillmore, P.; P.; P.; P.; Fridriksson, Fridriksson, Fridriksson, Fridriksson,P.; Fridriksson, J. J. J.J.J. Brain J.Brain J.Brain Brain J. Brain damage damage damage damage damage associated associated associated associatedassociated associated with with with with apraxia with apraxia apraxia apraxiaapraxia apraxia of of of ofspeech: speech: speech:speech: speech: speech:of speech: Evidence Evidence EvidenceEvidence EvidenceEvidence Evidence from from fromfromfrom fromfrom casefrom case casecase casecase studies. studies. casestudies.studies. studies.studies. studies. 4. NeurocaseMoser, D.;2016 Basilakos,, 22, 346–356. A.; Fillmore, [CrossRef P.; Fridriksson,] J. Brain damage associated with apraxia of speech: Evidence from case studies. NeurocaseNeurocaseNeurocaseNeurocaseNeurocase 2016 20162016 20162016, , ,2016,, 22 22222222,, 22,22, ,,, 346–356, 346–356,,346–356,,, 22346–356,346–356,, 346–356, doi:10.1080/13554794.2016.1172645. doi:10.1080/13554794.2016.1172645.doi:10.1080/13554794.2016.1172645. doi:10.1080/13554794.2016.1172645. doi:10.1080/13554794.2016.1172645. 5. Rosenbek,Neurocase 2016 J.C.;, Lemme,22, 346–356, M.L.; doi:10.1080/13554794.2016.1172645. Ahern, M.B.; Harris, E.H.; Wertz, R.T. A treatment for apraxia of speech in adults. J. Speech Hear. 5.5.5. 5. 5. Rosenbek,5.Rosenbek,Rosenbek, Rosenbek,Rosenbek, J.C.; J.C.;J.C.;J.C.; J.C.;J.C.; Lemme, Lemme,J.C.;Lemme, Lemme, Lemme, M.L.; M.L.;M.L.; M.L.; M.L.; Ahern, Ahern,Ahern, Ahern, Ahern, M.B.; M.B.;M.B.; M.B.; M.B.; Harris, Harris,Harris, Harris, Harris, E.H.; E.H.;E.H.; E.H.; E.H.; Wertz, Wertz,Wertz, Wertz, Wertz, R.T. R.T.R.T. R.T. A AR.T.A A treatment treatmenttreatmenttreatment treatment treatmentA treatment for forforfor forfor apraxia apraxiaapraxia for apraxiaapraxia apraxia of ofof of speech speechspeechspeech speechspeechof speech in inininin in inadults. adults.adults. adults.adults.in adults. J. J.J.J.J. Speech J. SpeechJ.SpeechSpeechSpeech SpeechSpeech J. Speech Hear. Hear.Hear.Hear.Hear. Hear.Hear. Hear. 5. Disord.Rosenbek,1973 J.C.;J.C.;, 38 ,Lemme, 462–472. M.L.; [CrossRef Ahern,][ PubMedM.B.; Harris,] E.H.; Wertz, R.T. A treatmenttreatment forfor apraxia of speech inin adults. J.J. SpeechSpeech Hear.Hear. Disord.Disord.Disord.Disord.Disord. 1973 19731973 19731973, , ,1973,, 38 38383838,, ,3838, ,,, 462–472, 462–472,,462–472,,, 38462–472,462–472,, 462–472, doi:10.1044/jshd.3804.462. doi:10.1044/jshd.3804.462.doi:10.1044/jshd.3804.462. doi:10.1044/jshd.3804.462. doi:10.1044/jshd.3804.462. 6. Ogar,Disord. J.; 1973 Slama,,, 3838,,H.; 462–472, Dronkers, doi:10.1044/jshd.3804.462. N.; Amici, S.; Gorno-Tempini, M.L. Apraxia of speech: An overview. Neurocase 2005, 11, 427–432. 6.6.6. 6. 6. Ogar,6.Ogar,Ogar, Ogar,Ogar, J.; J.;J.;J.; J.; Slama,J.; Slama, Slama, Slama, Slama,J.; Slama, H.; H.;H.; H.; Dronkers, Dronkers,Dronkers, H.; Dronkers, Dronkers, N.; N.; N.; N.; Amici, Amici,Amici, N.; Amici, Amici, S.; S.;S.; S.; S.; Gorno-Tempini, Gorno-Tempini,Gorno-Tempini, Gorno-Tempini,S.; Gorno-Tempini, M.L. M.L. M.L. M.L. ApraxiaM.L. Apraxia Apraxia Apraxia Apraxia of ofof of speech: speech:speech:speech: speech:speech:of speech: An AnAnAn AnAn overview. overview.overview. An overview. overview. Neurocase NeurocaseNeurocaseNeurocaseNeurocase NeurocaseNeurocase Neurocase 2005 20052005 20052005, , ,2005,, 11 11111111,, 11,11, ,,, 427–432, 427–432,427–432,,,, 11427–432,427–432,, 427–432, 6. [Ogar,CrossRef J.;J.; Slama,][PubMed H.; Dronkers,] N.; Amici, S.; Gorno-Tempini, M.L. Apraxia of speech: An overview. NeurocaseNeurocase 2005,, 1111,, 427–432, doi:10.1080/13554790500263529.doi:10.1080/13554790500263529.doi:10.1080/13554790500263529.doi:10.1080/13554790500263529.doi:10.1080/13554790500263529. 7. Josephs,doi:10.1080/13554790500263529. K.A.; Duffy, J.R. Apraxia of speech and nonfluent aphasia: A new clinical marker for corticobasal degeneration and 7.7.7. 7. 7. Josephs,7.Josephs,Josephs,Josephs, Josephs,Josephs,Josephs, K.A.; K.A.;K.A.; K.A.; K.A.; Duffy, Duffy,Duffy, Duffy, Duffy, J.R. J.R.J.R.J.R. J.R.J.R. Apraxia ApraxiaApraxiaJ.R. Apraxia Apraxia of ofof of speech speechspeech speechspeechof speech and andand andand nonfluent nonfluentandnonfluent nonfluent nonfluent aphasia: aphasia:aphasia: aphasia:aphasia: aphasia: A AA A newA newnew newA clinical newclinicalclinical clinicalclinical clinical marker markermarker marker marker for forforfor forfor corticobasal corticobasal corticobasal for corticobasalcorticobasal corticobasal degeneration degenerationdegeneration degeneration degeneration and andand andand and 7. progressiveJosephs,Josephs, K.A.; supranuclear Duffy, J.R.J.R. palsy.ApraxiaCurr. of speech Opin. Neurol. and nonfluent2008, 21, aphasia: 688–692. A [CrossRef new clinical][PubMed marker] forfor corticobasal degeneration and progressiveprogressiveprogressiveprogressiveprogressive supranuclear supranuclearsupranuclearsupranuclear supranuclearsupranuclear supranuclear palsy. palsy.palsy. palsy. palsy. Curr. Curr.Curr.Curr.Curr. Curr.Curr. Curr. Opin. Opin.Opin.Opin.Opin. Opin.Opin. Opin. Neurol. Neurol.Neurol.Neurol.Neurol. Neurol.Neurol. Neurol. 2008 20082008 20082008, , ,2008,, 21 21212121,, ,2121, ,,, 688–692, 688–692,,688–692,,, 21688–692,688–692,, 688–692, doi:10.1097/WCO.0b013e3283168ddd. doi:10.1097/WCO.0b013e3283168ddd.doi:10.1097/WCO.0b013e3283168ddd. doi:10.1097/WCO.0b013e3283168ddd. doi:10.1097/WCO.0b013e3283168ddd. 8. Laganaro,progressive M.; supranuclear Croisier, M.; palsy. Bagou, Curr.Curr. O.; Opin.Opin. Assal, Neurol.Neurol. F. Progressive 2008,, 2121,, apraxia 688–692, of doi:10.1097/WCO.0b013e3283168ddd. speech as a window into the study of speech planning processes. Cortex 2012, 48, 963–971. [CrossRef] 9. Trupe, L.A.; Varma, D.D.; Gomez, Y.; Race, D.; Leigh, R.; Hillis, A.E.; Gottesman, R.F. Chronic apraxia of speech and Broca’s area. Stroke 2013, 44, 740–744. [CrossRef] Brain Sci. 2021, 11, 335 16 of 18

10. Mesulam, M.M. Primary progressive aphasia—A language-based dementia. N. Engl. J. Med. 2003, 349, 1535–1542. [CrossRef] 11. Grossman, M. Progressive aphasic syndromes: Clinical and theoretical advances. Curr. Opin. Neurol. 2002, 15, 409–413. [CrossRef] [PubMed] 12. Grossman, M. Primary progressive aphasia: Clinicopathological correlations. Nat. Rev. Neurol. 2010, 6, 88–97. [CrossRef] 13. Gorno-Tempini, M.L.; Hillis, A.E.; Weintraub, S.; Kertesz, A.; Mendez, M.; Cappa, S.F.; Ogar, J.M.; Rohrer, J.D.; Black, S.; Boeve, B.F.; et al. Classification of primary progressive aphasia and its variants. Neurology 2011, 76, 1006–1014. [CrossRef][PubMed] 14. Thompson, C.K.; Cho, S.; Hsu, C.J.; Wieneke, C.; Rademaker, A.; Weitner, B.B.; Mesulam, M.M.; Weintraub, S. Dissociations Between Fluency And Agrammatism In Primary Progressive Aphasia. Aphasiology 2012, 26, 20–43. [CrossRef][PubMed] 15. Duffy, J.R. Apraxia of speech in degenerative neurologic disease. Aphasiology 2006, 20, 511–527. [CrossRef] 16. Duffy, J.R.; Strand, E.A.; Clark, H.; Machulda, M.; Whitwell, J.L.; Josephs, K.A. Primary progressive apraxia of speech: Clinical features and acoustic and neurologic correlates. Am. J. Speech Lang. Pathol. 2015, 24, 88–100. [CrossRef] 17. Josephs, K.A.; Duffy, J.R.; Strand, E.A.; Whitwell, J.L.; Layton, K.F.; Parisi, J.E.; Hauser, M.F.; Witte, R.J.; Boeve, B.F.; Knopman, D.S.; et al. Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain 2006, 129, 1385–1398. [CrossRef] 18. Josephs, K.A.; Whitwell, J.L.; Duffy, J.R.; Vanvoorst, W.A.; Strand, E.A.; Hu, W.T.; Boeve, B.F.; Graff-Radford, N.R.; Parisi, J.E.; Knopman, D.S.; et al. Progressive aphasia secondary to Alzheimer disease vs FTLD pathology. Neurology 2008, 70, 25–34. [CrossRef] 19. Marangolo, P.; Marinelli, C.V.; Bonifazi, S.; Fiori, V.; Ceravolo, M.G.; Provinciali, L.; Tomaiuolo, F. Electrical stimulation over the left inferior frontal gyrus (IFG) determines long-term effects in the recovery of speech apraxia in three chronic aphasics. Behav. Brain Res. 2011, 225, 498–504. [CrossRef] 20. Utianski, R.L.; Duffy, J.R.; Clark, H.M.; Strand, E.A.; Botha, H.; Schwarz, C.G.; Machulda, M.M.; Senjem, M.L.; Spychalla, A.J.; Jack, C.R., Jr.; et al. Prosodic and phonetic subtypes of primary progressive apraxia of speech. Brain Lan.g 2018, 184, 54–65. [CrossRef] 21. Duffy, J.R.; Hanley, H.; Utianski, R.; Clark, H.; Strand, E.; Josephs, K.A.; Whitwell, J.L. Temporal acoustic measures distinguish primary progressive apraxia of speech from primary progressive aphasia. Brain Lang. 2017, 168, 84–94. [CrossRef] 22. Themistocleous, C.; Ficek, B.; Webster, K.; den Ouden, D.-B.; Hillis, A.E.; Tsapkini, K. Automatic Subtyping of Individuals with Primary Progressive Aphasia. J. Alzheimer’s Dis. 2021, 79, 1185–1194. [CrossRef] 23. Ballard, K.J.; Azizi, L.; Duffy, J.R.; McNeil, M.R.; Halaki, M.; O’Dwyer, N.; Layfield, C.; Scholl, D.I.; Vogel, A.P.; Robin, D.A. A predictive model for diagnosing stroke-related apraxia of speech. Neuropsychologia 2016, 81, 129–139. [CrossRef][PubMed] 24. Basilakos, A. Towards Improving the Evaluation of Speech Production Deficits in Chronic Stroke; University of South Carolina: Los Angeles, CA, USA, 2016. 25. Collins, M.; Rosenbek, J.C.; Wertz, R.T. Spectrographic analysis of vowel and word duration in apraxia of speech. J. Speech Hear. Res. 1983, 26, 224–230. [CrossRef] 26. Kent, R.D.; Rosenbek, J.C. Acoustic patterns of apraxia of speech. J. Speech Hear. Res. 1983, 26, 231–249. [CrossRef] 27. Hardcastle, W.J. Electropalatographic study of articulation disorders in verbal dyspraxia. In Phonetic Approaches to Speech Production in Aphasia and Related Disorders; Ryalls, J.H., Ed.; College-Hill Press: Boston, MA, USA, 1987; pp. 113–136. 28. Itoh, M. Articulatory movements in apraxia of speech. In Apraxia of Speech: Physiology, Acoustics, Linguistics, Management; Ryalls, J.H., Ed.; College Hill: Boston, MA, USA, 1984; pp. 135–165. 29. Itoh, M.; Sasanuma, S.; Tatsumi, I.F.; Murakami, S.; Fukusako, Y.; Suzuki, T. Voice onset time characteristics in apraxia of speech. Brain Lang. 1982, 17, 193–210. [CrossRef] 30. Cunningham, K.T.; Haley, K.L.; Jacks, A. Speech sound distortions in aphasia and apraxia of speech: Reliability and diagnostic significance. Aphasiology 2016, 30, 396–413. [CrossRef] 31. Varley, R.A.; Whiteside, S.P. Voicing in severe apraxia of speech: Perceptual and acoustic analysis of a single case. J. Neurolinguistics 1998, 11, 259–273. [CrossRef] 32. Mauszycki, S.C.; Dromey, C.; Wambaugh, J.L. Variability in apraxia of speech: A perceptual, acoustic, and kinematic analysis of stop consonants. J. Med. Speech-Lang. Pathol. 2007, 15, 223–242. 33. Haley, K.L. Temporal and spectral properties of voiceless fricatives in aphasia and apraxia of speech. Aphasiology 2002, 16, 595–607. [CrossRef] 34. Haley, K.L.; Jacks, A. Word-level prosodic measures and the differential diagnosis of apraxia of speech. Clin. Linguist. Phon. 2019, 33, 479–495. [CrossRef] 35. Hillis, A.E.; Work, M.; Barker, P.B.; Jacobs, M.A.; Breese, E.L.; Maurer, K. Re-examining the brain regions crucial for orchestrating speech articulation. Brain 2004, 127, 1479–1487. [CrossRef][PubMed] 36. Ogar, J.M.; Dronkers, N.F.; Brambati, S.M.; Miller, B.L.; Gorno-Tempini, M.L. Progressive nonfluent aphasia and its characteristic motor speech deficits. Alzheimer Dis. Assoc. Disord. 2007, 21, S23–S30. [CrossRef][PubMed] 37. Alexander, M.P.; Benson, D.F.; Stuss, D.T. Frontal lobes and language. Brain Lang. 1989, 37, 656–691. [CrossRef] 38. Dronkers, N.F. A new brain region for coordinating speech articulation. Nature 1996, 384, 159–161. [CrossRef][PubMed] 39. Saur, D.; Kreher, B.W.; Schnell, S.; Kummerer, D.; Kellmeyer, P.; Vry, M.S.; Weiller, C. Ventral and dorsal pathways for language. Proc. Natl. Acad. Sci.USA 2008, 105, 18035. [CrossRef] 40. Hickok, G.; Poeppel, D. The cortical organization of speech processing. Nat. Rev. Neurosci. 2007, 8, 393–402. [CrossRef][PubMed] Brain Sci. 2021, 11, 335 17 of 18

41. Peach, R.K.; Tonkovich, J.D. Phonemic characteristics of apraxia of speech resulting from subcortical hemorrhage. J. Commun. Disord. 2004, 37, 77–90. [CrossRef] 42. Henry, M.L.; Meese, M.V.; Truong, S.; Babiak, M.C.; Miller, B.L.; Gorno-Tempini, M.L. Treatment for apraxia of speech in nonfluent variant primary progressive aphasia. Behav. Neurol. 2013, 26, 77–88. [CrossRef] 43. Harris, A.D.; Wang, Z.; Ficek, B.; Webster, K.; Edden, R.A.E.; Tsapkini, K. Reductions in GABA following a tDCS-language intervention for primary progressive aphasia. Neurobiol. Aging 2019, 79, 75–82. [CrossRef√] 44. Antonenko, D.; Schubert, F.; Bohm, F.; Ittermann, B.; Aydin, S.; Hayek, D.; Grittner, U.; Fl ∂el, A. tDCS-Induced Modulation of GABA Levels and Resting-State Functional Connectivity in Older Adults. J. Neurosci. Off. J. Soc. Neurosci. 2017, 37, 4065–4073. [CrossRef] 45. Stagg, C.J.; Nitsche, M.A. Physiological basis of transcranial direct current stimulation. Neurosci. Rev. J. Bringing Neurobiol. Neurol. Psychiatry 2011, 17, 37–53. [CrossRef] 46. Ficek, B.N.; Wang, Z.; Zhao, Y.; Webster, K.T.; Desmond, J.E.; Hillis, A.E.; Frangakis, C.; Faria, A.V.; Caffo, B.; Tsapkini, K. The effect of tDCS on functional connectivity in primary progressive aphasia. Neuroimage Clin. 2018.[CrossRef] 47. Chesters, J.; Watkins, K.E.; Möttönen, R. Investigating the feasibility of using transcranial direct current stimulation to enhance fluency in people who stutter. Brain Lang. 2017, 164, 68–76. [CrossRef][PubMed] 48. Chesters, J.; Mottonen, R.; Watkins, K.E. Transcranial direct current stimulation over left inferior frontal cortex improves speech fluency in adults who stutter. Brain 2018, 141, 1161–1171. [CrossRef] 49. Buchwald, A.; Calhoun, H.; Rimikis, S.; Lowe, M.S.; Wellner, R.; Edwards, D.J. Using tDCS to facilitate motor learning in speech production: The role of timing. Cortex 2019, 111, 274–285. [CrossRef] 50. Tsapkini, K.; Frangakis, C.; Davis, C.; Gomez, Y.; Chakravarty, T.; Hillis, A. Spelling rehabilitation using transcranial direct current (tDCS) in primary progressive aphasia (PPA). Front. Psychol. 2014, 5, 1. 51. Tsapkini, K.; Frangakis, C.; Gomez, Y.; Davis, C.; Hillis, A.E. Augmentation of spelling therapy with transcranial direct current stimulation in primary progressive aphasia: Preliminary results and challenges. Aphasiology 2014, 28, 1112–1130. [CrossRef] 52. de Aguiar, V.; Zhao, Y.; Ficek, B.N.; Webster, K.; Rofes, A.; Wendt, H.; Frangakis, C.; Caffo, B.; Hillis, A.E.; Rapp, B.; et al. Cognitive and language performance predicts effects of spelling intervention and tDCS in Primary Progressive Aphasia. Cortex 2020, 124, 66–84. [CrossRef] 53. Tsapkini, K.; Webster, K.T.; Ficek, B.N.; Desmond, J.E.; Onyike, C.U.; Rapp, B.; Frangakis, C.E.; Hillis, A.E. Electrical brain stimulation in different variants of primary progressive aphasia: A randomized clinical trial. Alzheimers Dement. 2018, 4, 461–472. [CrossRef] 54. Roncero, C.; Kniefel, H.; Service, E.; Thiel, A.; Probst, S.; Chertkow, H. Inferior parietal transcranial direct current stimulation with training improves cognition in anomic Alzheimer’s disease and frontotemporal dementia. Alzheimers Dement. 2017, 3, 247–253. [CrossRef][PubMed] 55. McConathey, E.M.; White, N.C.; Gervits, F.; Ash, S.; Coslett, H.B.; Grossman, M.; Hamilton, R.H. Baseline Performance Predicts tDCS-Mediated Improvements in Language Symptoms in Primary Progressive Aphasia. Front. Hum. Neurosci. 2017, 11, 347. [CrossRef] 56. Byrd, D.; Saltzman, E. The elastic phrase: Modeling the dynamics of boundary-adjacent lengthening. J. Phon. 2003, 31, 149–180. [CrossRef] 57. Themistocleous, C. Edge-Tone Effects and Prosodic Domain Effects on Final Lengthening. Linguist. Var. 2014, 14, 129–160. [CrossRef] 58. Howard, D.; Patterson, K. The Pyramid and Palm Trees Test: A Test of Semantic Access from Words and Pictures; Thames Valley Test Company: Bury St. Edmunds, UK, 1992. 59. Kaplan, E.; Goodglass, H.; Weintraub, S. Boston Naming Test; Pro-Ed: Austin, TX, USA, 2001. 60. Love, T.; Oster, E. On the categorization of aphasic typologies: The SOAP (a test of syntactic complexity). J. Psycholinguist Res. 2002, 31, 503–529. [CrossRef] 61. Spreen, O.; Benton, A.L. Neurosensory Center Comprehensive Examination for Aphasia: Manual of Directions, Revised Edition; Department of Psychology, University of Victoria: Vicotria, BC, Canada, 1977. 62. Knopman, D.S.; Kramer, J.H.; Boeve, B.F.; Caselli, R.J.; Graff-Radford, N.R.; Mendez, M.F.; Miller, B.L.; Mercaldo, N. Development of methodology for conducting clinical trials in frontotemporal lobar degeneration. Brain 2008, 131, 2957–2968. [CrossRef] 63. Dabul, B. ABA-2: Apraxia Battery for Adults: Examiner’s Manual; Pro-Ed: Austin, TX, USA, 2000. 64. Unal, G.; Ficek, B.; Webster, K.; Shahabuddin, S.; Truong, D.; Hampstead, B.; Bikson, M.; Tsapkini, K. Impact of brain atrophy on tDCS and HD-tDCS current flow: A modeling study in three variants of primary progressive aphasia. Neurol. Sci. Off. J. Ital. Neurol. Soc. Ital. Soc. Clin. Neurophysiol. 2020, 41, 1781–1789. [CrossRef] 65. de Aguiar, V.; Zhao, Y.; Faria, A.; Ficek, B.; Webster, K.T.; Wendt, H.; Wang, Z.; Hillis, A.E.; Onyike, C.U.; Frangakis, C.; et al. Brain volumes as predictors of tDCS effects in primary progressive aphasia. Brain Lang. 2020, 200, 104707. [CrossRef] 66. Senn, S. Cross-Over Trials in Clinical Research, 2nd ed.; John Wiley & Sons, Ltd.: New York, NY, USA, 2002. 67. Purcell, J.J.; Turkeltaub, P.E.; Eden, G.F.; Rapp, B. Examining the central and peripheral processes of written word production through meta-analysis. Front. Psychol. 2011, 2, 239. [CrossRef] 68. Price, C.J. A review and synthesis of the first 20years of PET and fMRI studies of heard speech, spoken language and reading. NeuroImage 2012, 62, 816–847. [CrossRef] Brain Sci. 2021, 11, 335 18 of 18

69. Homan, R.W.; Herman, J.; Purdy, P. Cerebral location of international 10-20 system electrode placement. Electroencephalogr. Clin. Neurophysiol. 1987, 66, 376–382. [CrossRef] 70. Gandiga, P.C.; Hummel, F.C.; Cohen, L.G. Transcranial DC stimulation (tDCS): A tool for double-blind sham-controlled clinical studies in brain stimulation. Clin. Neurophysiol 2006, 117, 845–850. [CrossRef] 71. Peterson, G.E.; Lehiste, I. Duration of Syllable Nuclei in English. J. Acoust. Soc. Am. 1960, 32, 693–703. [CrossRef] 72. Themistocleous, C. The Nature of Phonetic Gradience across a Dialect Continuum: Evidence from Modern Greek Vowels. Phonetica 2017, 74, 157–172. [CrossRef][PubMed] 73. Themistocleous, C. Dialect classiﬁcation using vowel acoustic parameters. Speech Commun. 2017, 92, 13–22. [CrossRef] 74. Themistocleous, C.; Savva, A.; Aristodemou, A. Effects of stress on fricatives: Evidence from Standard Modern Greek. In Proceedings of the Interspeech 2016, San Francisco, CA, USA, 8–12 September 2016; pp. 1–4. 75. Themistocleous, C. Dialect Classification From a Single Sonorant Sound Using Deep Neural Networks. Front. Commun. 2019, 4, 1–12. [CrossRef] 76. Themistocleous, C. The bursts of stops can convey dialectal information. J. Acoust. Soc. Am. 2016, 140, EL334–EL339. [CrossRef] [PubMed] 77. Boersma, P.; Weenink, D. Praat: Doing Phonetics by Computer (Version 6.0.37); University of Amsterdam: Amsterdam, The Netherlands, 2018. 78. Baayen, R.H. Analyzing Linguistic Data: A Practical Introduction to Statistics Using R; Cambridge University Press: Cambridge, UK, 2008. 79. Schielzeth, H.; Dingemanse, N.J.; Nakagawa, S.; Westneat, D.F.; Allegue, H.; Teplitsky, C.; Réale, D.; Dochtermann, N.A.; Garamszegi, L.Z.; Araya-Ajoy, Y.G. Robustness of linear mixed-effects models to violations of distributional assumptions. Methods Ecol. Evol. 2020, 11, 1141–1152. [CrossRef] 80. R Core Team. R: A Language and Environment for Statistical Computing; R Foundation for Statistical Computing: Vienna, Austria, 2020. 81. Bates, D.; Mächler, M.; Bolker, B.; Walker, S. Fitting Linear Mixed-Effects Models Using lme4. J. Stat. Softw. 2015, 67, 1–48. [CrossRef] 82. Kuznetsova, A.; Bruun Brockhoff, P.; Haubo Bojesen Christensen, R. lmerTest: Tests in Linear Mixed Effects Models; R Foundation for Statistical Computing: Vienna, Austria, 2016. 83. Russell, L. emmeans: Estimated Marginal Means, aka Least-Squares Means; R Foundation for Statistical Computing: Vienna, Austria, 2020. 84. Margulies, D.S.; Petrides, M. Distinct parietal and temporal connectivity proﬁles of ventrolateral frontal areas involved in language production. J. Neurosci 2013, 33, 16846–16852. [CrossRef][PubMed] 85. Wang, J.; Wu, D.; Cheng, Y.; Song, W.; Yuan, Y.; Zhang, X.; Zhang, D.; Zhang, T.; Wang, Z.; Tang, J.; et al. Effects of Transcranial Direct Current Stimulation on Apraxia of Speech and Cortical Activation in Patients With Stroke: A Randomized Sham-Controlled Study. Am. J. Speech-Lang. Pathol. 2019, 28, 1625–1637. [CrossRef] 86. Bikson, M.; Grossman, P.; Thomas, C.; Zannou, A.L.; Jiang, J.; Adnan, T.; Mourdoukoutas, A.P.; Kronberg, G.; Truong, D.; Boggio, P.; et al. Safety of Transcranial Direct Current Stimulation: Evidence Based Update 2016. Brain Stimul. 2016, 9, 641–661. [CrossRef] 87. Marangolo, P.; Fiori, V.; Cipollari, S.; Campana, S.; Razzano, C.; Paola, M.D.; Koch, G.; Caltagirone, C. Bihemispheric stimulation over left and right inferior frontal region enhances recovery from apraxia of speech in chronic aphasia. Eur. J. Neurosci. 2013, 38, 3370–3377. [CrossRef] 88. Lehiste, I. Suprasegmentals; MIT Press: Cambridge, MA, USA, 1970. 89. Ohala, J. The application of phonological universals in speech pathology. Speech Lang. 1980, 3, 75–97. 90. Stevens, K.N. Acoustic Phonetics; MIT Press: Cambridge, MA, USA, 1998. 91. Fant, G. Acoustic Theory of Speech Production. Slav. East. Eur. J. 1960, 5, 285. [CrossRef] 92. Themistocleous, C. Seeking an Anchorage. Stability and Variability in Tonal Alignment of Rising Prenuclear Pitch Accents in Cypriot Greek. Lang. Speech 2016, 59, 433–461. [CrossRef] 93. Pierrehumbert, J. Phonology and Phonetics of English Intonation; Massachusetts Institute of Technology: Boston, MA, USA, 1980. 94. Cruttenden, A. Gimson’s Pronunciation of English, 7th ed.; Hodder Education: London, UK, 2008. 95. Levelt, W.J.M. Speaking: From Intention to Articulation; MIT Press: Cambridge, MA, USA, 1993. 96. Kelso, J.A.; Tuller, B. Toward a theory of apractic syndromes. Brain Lang. 1981, 12, 224–245. [CrossRef] 97. Whiteside, S.P.; Varley, R.A. A reconceptualisation of apraxia of speech: A synthesis of evidence. Cortex 1998, 34, 221–231. [CrossRef]