ORIGINAL RESEARCH published: 24 March 2020 doi: 10.3389/fnhum.2020.00073 Developmental Dynamic Dysphasia: Are Bilateral Brain Abnormalities a Signature of Inefficient Neural Plasticity? Marcelo L. Berthier 1* † , Guadalupe Dávila 1,2† , María José Torres-Prioris 1,2 , Ignacio Moreno-Torres 3 , Jordi Clarimón 4,5 , Oriol Dols-Icardo 4,5 , María J. Postigo 6 , Victoria Fernández 6 , Lisa Edelkraut 1,2 , Lorena Moreno-Campos 1 , Edited by: Diana Molina-Sánchez 1 , Paloma Solo de Zaldivar 1 and Diana López-Barroso 1,2 Peter Sörös, 1 University of Oldenburg, Germany Cognitive Neurology and Aphasia Unit, Centro de Investigaciones Médico-Sanitarias, Instituto de Investigación Biomédica de Málaga (IBIMA), University of Malaga, Málaga, Spain, 2 Department of Psychobiology and Methodology of Behavioral Reviewed by: Sciences, Faculty of Psychology, University of Malaga, Málaga, Spain, 3 Department of Spanish Language I, University Sandrine Muller, of Malaga, Málaga, Spain, 4 Department of Neurology and Sant Pau Biomedical Research Institute, Hospital de la Santa Massachusetts General Hospital, Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain, 5 Center for Networked Biomedical Research into Harvard Medical School, Neurodegenerative Diseases, Madrid, Spain, 6 Neurophysiology Unit, Regional University Hospital Carlos Haya, Málaga, United States Spain Takenobu Murakami, Fukushima Medical University, Japan *Correspondence: The acquisition and evolution of speech production, discourse and communication Marcelo L. Berthier can be negatively impacted by brain malformations. We describe, for the first time, mbt@uma.es; marberthier@yahoo.es a case of developmental dynamic dysphasia (DDD) in a right-handed adolescent boy † These authors have contributed (subject D) with cortical malformations involving language-eloquent regions (inferior equally to this work frontal gyrus) in both the left and the right hemispheres. Language evaluation revealed a markedly reduced verbal output affecting phonemic and semantic fluency, Specialty section: This article was submitted to phrase and sentence generation and verbal communication in everyday life. Auditory Speech and Language, comprehension, repetition, naming, reading and spelling were relatively preserved, a section of the journal Frontiers in Human Neuroscience but executive function was impaired. Multimodal neuroimaging showed a malformed Received: 12 June 2019 cerebral cortex with atypical configuration and placement of white matter tracts Accepted: 19 February 2020 bilaterally and abnormal callosal fibers. Dichotic listening showed right hemisphere Published: 24 March 2020 dominance for language, and functional magnetic resonance imaging (fMRI) additionally Citation: revealed dissociated hemispheric language representation with right frontal activation Berthier ML, Dávila G, Torres-Prioris MJ, Moreno-Torres I, for phonology and bilateral dominance for semantic processing. Moreover, subject D Clarimón J, Dols-Icardo O, also had congenital mirror movements (CMM), defined as involuntary movements of Postigo MJ, Fernández V, Edelkraut L, Moreno-Campos L, one side of the body that mirror intentional movements of the other side. Transcranial Molina-Sánchez D, de Zaldivar PS magnetic stimulation and fMRI during voluntary unimanual (left and right) hand and López-Barroso D (2020) movements showed bilateral motor cortex recruitment and tractography revealed a Developmental Dynamic Dysphasia: Are Bilateral Brain Abnormalities lack of decussation of bilateral corticospinal tracts. Genetic testing aimed to detect a Signature of Inefficient Neural mutations that disrupt the development of commissural tracts correlating with CMM Plasticity? Front. Hum. Neurosci. 14:73. (e.g., Germline DCC mutations) was negative. Overall, our findings suggest that doi: 10.3389/fnhum.2020.00073 DDD in subject D resulted from the underdevelopment of the left inferior frontal Frontiers in Human Neuroscience | www.frontiersin.org 1 March 2020 | Volume 14 | Article 73 Berthier et al. Developmental Dynamic Dysphasia gyrus with limited capacity for plastic reorganization by its homologous counterpart in the right hemisphere. Corpus callosum anomalies probably contributed to hinder interhemispheric connectivity necessary to compensate language and communication deficits after left frontal involvement. Keywords: dynamic aphasia, congenital mirror movements, developmental cerebral anomalies, neuroimaging, brain stimulation INTRODUCTION its relationship with gross developmental brain anomalies has not been clearly defined. Children and adults with language and literacy impairments The syndrome of dynamic aphasia (DA) is a subtype of (specific language impairment, dyslexia, and autism spectrum transcortical motor aphasia (TCMA) (Goldstein, 1917; Kleist, disorders) tend to have weaker cerebral lateralization than 1934; Luria, 1977; Berthier, 1999; Alexander, 2006) usually neurotypically developing individuals (de Guibert et al., 2011; associated with acquired focal brain lesions (stroke, neoplasms) Bishop, 2013; Ogawa et al., 2019). In addition, there are (Robinson et al., 1998) or slowly progressive degenerative differences in the evolution of developmental and acquired disorders (e.g., primary progressive aphasia) (Esmonde et al., disorders in children (Temple, 1997; Luyster et al., 2011). 1996; Robinson et al., 2006) involving the left frontal lobe, basal Perinatal language impairments and acquired childhood aphasias ganglia, or both. In the original formulation of DA, Kleist (1934) due to unilateral lesions of the dominant hemisphere rarely described it as a syndrome characterized by reduced drive to lead to pervasive deficits because efficient (adaptive) neural generate propositional speech despite the relative preservation of plasticity promotes recovery (Rauschecker et al., 2009; Yeatman other language functions including spontaneous speech, object and Feldman, 2013). By contrast, the presence of long-lasting naming, word and sentence repetition, comprehension, and oral deficits is the rule in specific language impairments and this has reading (Luria, 1966, 1970). Luria segregated DA into different been related to bilateral brain abnormalities (Vargha-Khadem subtypes, but he did not delineate the differences from one et al., 1998; Guerreiro et al., 2002; Rapin et al., 2003; Soriano- another (Lebrun, 1995). It was Lebrun (1995) who separated DA Mas et al., 2009). In this respect, there is evidence of how into three subtypes; one subtype corresponded to typical TCMA, multiple brain systems may sustain the same function (e.g., another subtype resulted from what Luria called “spreading degeneracy – Noppeney et al., 2004; Stefaniak et al., 2019), which activation syndrome” (i.e., an impaired selection between may explain cases of resilience of language/cognitive functions competing verbal items that hampers verbal production), and the to brain lesions. The idea of degeneracy exists both within last type was described as a lack of drive to generate language. subject, aiding to compensate the damage to a given network, In the present case study, we focus on the last type of DA and over subjects as in normal neurodevelopmental variation referred to as “lack of drive to generate language.” While all that can result, for instance, in differences in hemispheric reported cases of DA were acquired (ADA) after brain injury lateralization (Biduła et al., 2017). However, the existence of or neurodegenerative disorders in adulthood (Alexander, 2006; multiple degenerate systems does not have to mean that such Magdalinou et al., 2018), the case described herein resulted systems can become efficient, a situation that may be particularly from developmental aberrations in both hemispheres mostly true in cases of developmental malformations (i.e., Oberman involving language-eloquent cortical regions and white matter et al., 2012; Zsoter et al., 2012; Mainberger et al., 2013). Specific tracts in a teenager male (subject D). Similar to other children and language impairments are associated with reduced or reversed adolescents with developmental language disorders associated functional lateralization of language networks (see references in to bilateral cortical anomalies (Guerreiro et al., 2000, 2002), Luyster et al., 2011), suggesting that both cerebral hemispheres subject D was brought to our Unit by his mother complaining are engaged to compensate language deficits through adaptive limited communicative ability. She claimed that “he does not neural plasticity. Thus, neural adaptation may be less efficient speak spontaneously and is not communicative.” This case can be in cases of bilateral brain abnormalities and might represent an endorsed to the category of Developmental Language Disorder earlier neural marker for developmental language disorders by (DLD) (American Psychiatric Association, 2013; Bishop et al., interfering with the continuous acquisition of skillful language 2017). It was noticeable, however, that the language disturbance functions (discourse, functional communication). in subject D did not fulfill the criteria for any type of DLD Many developmental language disorders are not associated reported up to now. Since it rather seems to be similar to one with gross structural brain changes, but speech-language delay of the three variants described in ADA (lack of drive to generate may also be associated to unilateral, bilateral or diffuse language) (Kleist, 1934; Alexander, 2006), after performing a developmental cortical anomalies (e.g., perisylvian cortical comprehensive testing, we classified the language disorder in dysplasia) (Graff-Radford et al., 1986; Guerreiro et al., 2000, subject D as developmental dynamic dysphasia (DDD). In this 2002; Barkovich, 2010). There is an association between language boy, DDD co-occurred with other neurodevelopmental disorders delay and developmental abnormalities of the cortical mantle and (mild left hemiparesis and congenital mirror movements - CMM) white matter tracts (Andrade et al., 2015; Paldino et al., 2015, (Méneret et al., 2014) which in our view does not invalidate 2016). Nevertheless, the characterization of language delay and the diagnosis of DDD (see Bishop, 2017). In fact, the primary Frontiers in Human Neuroscience | www.frontiersin.org 2 March 2020 | Volume 14 | Article 73 Berthier et al. Developmental Dynamic Dysphasia complain was language delay and subject D had normal hearing consent for participation in the study and for the publication of by audiometry and an intellectual quotient (IQ) > 70 (see the results. The protocol of this study was approved by the Ethical Guerreiro et al., 2002). Research Committee Provincial of Malaga, Spain. We performed a multimodal evaluation to identify the brain- cognitive profile of subject D including testing of cognitive, Cognitive and Intelligence Testing language, and motor functions. Multimodal neuroimaging Although subjects with pure cases of ADA with deficits included structural magnetic resonance imaging (MRI; high- confined to speech production have been described (Costello and resolution T1 -weighted image), functional MRI (fMRI) during Warrington, 1989; Gold et al., 1997; Robinson et al., 1998), others four different tasks (phonemic fluency, semantic decision and have more widespread speech and language deficits involving left and right finger tapping) that allowed to evaluate functional phonological, lexical and syntactical functions (mixed ADA) cerebral dominance for language and motor functions, and (Esmonde et al., 1996; Snowden et al., 1996; Raymer et al., 2002; diffusion tensor imaging (DTI)-Tractography of white matter Warren et al., 2003) and still others present with additional tracts, that enabled the visualization of the language and non-language cognitive deficits (Robinson et al., 2006; Caine motor pathways. In addition, transcranial magnetic stimulation et al., 2018; Magdalinou et al., 2018). Thus, the cognitive profile (TMS) and genetic testing were performed to detect mutations of DDD in subject D was also explored with tests tapping that disrupt the development of commissural tracts (e.g., intelligence, concept formation and reasoning, memory, and Germline DCC mutations). executive functions. Methods MATERIALS AND METHODS Subject D was evaluated with the Wechsler Intelligence Scale for Children (WISC) (Wechsler, 1974) and the Raven Colored Case Description Progressive Matrices (RCPM) (Raven et al., 1975). Memory was Subject D was a 12-year-old right-handed boy with concurrent examined with the Test of Memory and Learning (TOMAL) DDD and CCM who was brought by his mother to our Unit (Reynolds and Bigler, 1994) and executive functions were tested for language testing. She reported that subject D had “problems with the Trail-Making Test (TMT) (Reitan, 1958; Arango- to verbally explain things. . . showing poor communication Lasprilla et al., 2017), the Hayling Sentence Completion Test and sometimes making nonsense comments.” She provided (HSCT) (Burgess and Shallice, 1997; Abusamra et al., 2007; information about family history and her son’s developmental Cartoceti et al., 2008), the Wisconsin Card Sorting Test (WCST) milestones. The father of subject D was described as “shy and (Grant and Berg, 1948; Heaton et al., 2009) and the Stroop Test non-communicative.” The parents and the brother of subject (Stroop, 1935). D were also right handed. Subject D was the second born of non-consanguineous parents. He was the product of a full-term Results pregnancy of 38 weeks. Maternal age at delivery was 30 years Table 1 shows the results of the cognitive evaluation. On the old. Delivery was normal and subject D’s Apgar scores at 1 and WISC, subject D performed in the inferior range in all three IQ 5 minutes after birth were 9 and 10, respectively. His birth weight scores and his performance was also impaired on the RCPM. was 3.500 g. Shortly after birth subject D developed a short-lived Subject D’s learning and memory functions were also impaired bilateral arm tremor that disappeared before hospital discharge with slightly lower scores in the verbal memory index than in 24 h later. Developmental milestones were slightly delayed for the non-verbal memory index. On all tests tapping executive language, communication and motor functions. function, subject D had impaired performance. Analysis of the During infancy, subject D was discovered to have pattern of performance of subject D on the HSCT provided several medical, neurological, ophthalmological and skeletal information on the mechanism underlying DDD. He was abnormalities. At 9 months of age he was operated on for impaired in the two sections of the sentence completion task bilateral inguinal hernia, and at 3 years-old he was operated (HSCT) exclusively due to omissions and prolonged response of bilateral strabismus. CMM were discovered at age 4 in times (>20 s). While he could successfully complete many kindergarten. Skeletal and neurological exams at the ages of 8 open-ended sentences (0.73) in the sensible completion Section and 12 years disclosed mild dorsal scoliosis, pectum carinatum 1, he was totally unable to choose a word unrelated to both and turricephaly. He also had mild developmental delay, mild the syntactic and semantic context of the frame sentence in left-sided hemiparesis, increased blinking and CMM of the the unrelated completion Section 2, producing no responses opposite hand and foot during voluntary movements. Cognitive to any sentence. testing at school when subject D was 8.10 years, showed a verbal IQ of 73, below average performance in the Colored Raven Progressive Matrices (Raven et al., 1975) and limited vocabulary Orientation, Perception and Motor Tests with impaired ability to define words. Subject D was right handed Methods (+100) as assessed by the Edinburgh Inventory of Handedness Several tests were administered to evaluate these skills. These (Oldfield, 1971). included the Right-Left Orientation (RLO), Tactile Form The study was performed in compliance with the Declaration Perception (TFP), Finger Localization (FL), and Judgment of Line of Helsinki. The parents of subject D signed a written informed Orientation (JLO) (Benton et al., 1983). Frontiers in Human Neuroscience | www.frontiersin.org 3 March 2020 | Volume 14 | Article 73 Berthier et al. Developmental Dynamic Dysphasia TABLE 1 | Cognitive testing. Language Testing Tests Subject Performance Normative Auditory Processing, Word Semantics, Receptive D’s scores descriptor data Vocabulary, Reading and Spelling Intelligence Methods Verbal IQ 77 Inferior Auditory processing and word semantics were assessed Performance IQ 76 Inferior with several subtests of the Spanish version (EPLA) of Full Scale IQ 78 Inferior >5th%ile the Psycholinguistic Assessments of Language Processing Raven Colored Progressive 26 BA 25th%ile for Aphasia (PALPA) (Kay et al., 1992; Valle and Cuetos, Matrices (max: 36) 1995). These included Non-word Minimal Pairs (PALPA 1), Memory Word Minimal Pairs (PALPA 2), Repetition: Syllable Length Test of Memory and (PALPA 7), Repetition: Non-words (PALPA 8), Repetition: Learning (TOMAL) Imageability × Frequency (PALPA 9), Sentence Repetition Verbal memory index 73 BA 100 ± 15 (PALPA 12), Digit Production/Matching span (PALPA 13) and Non-verbal memory index 81 BA 100 ± 15 Spoken Word-Picture Matching (PALPA 47). The receptive Composite memory index 74 BA 100 ± 15 vocabulary ability was examined with the Peabody Picture Executive function Vocabulary-III (Dunn et al., 2010). Oral reading and spelling to Trail-Making Test dictation were tested also using PALPA subtests. Oral reading was Part A (sec/errors) 58/1 BA <5th%ile tested for Letter Length (PALPA 29), Imageability × Frequency Part B (sec/errors) 109/1 BA <5th%ile (PALPA 31), Grammatical Class (PALPA 32), and Grammatical Hayling Sentence Class × Imageability (PALPA 33), Morphological Endings Completion Test α (PALPA 34), Regularity (PALPA 35), and Non-words (PALPA Section 1 – sensible completion 11/4* A – 36). Spelling to dictation was tested for Letter Length (PALPA (max: 39), Imageability × Frequency (PALPA 40), Morphological 15)/errors 0/15 BA – Endings (PALPA 43), Regularity (PALPA 44) and Non-words Section 2 – unrelated completion/errors (PALPA 45). The PALPA has been originally designed for use Wisconsin Card Sorting Test with people with acquired disorders and hence it does not (64 cards) include developmental norms (Kay and Terry, 2004). One Categories 3 BA >16th%ile requisite for the diagnosis of ADA is that comprehension, Correct responses 46 – naming and transcoding (repetition and oral reading) should be Perseverations 18 SBA 45th%ile relatively spared or remarkably less impaired than spontaneous Stroop Test speech (Luria, 1966, 1977). Therefore, to be confident that Word reading (score/errors) 46/0 BA <25th%ile performance on language domains in subject D was not so Naming colors (score/errors) 38/1 BA 25th%ile affected as spontaneous speech, subtests of the PALPA were Word-Color 18 BA compared with adult norms for Spanish speaking subjects (Valle Interference −2.81 BA and Cuetos, 1995). Results on these subtests were classified as α The “average” when scores were within 2 standard deviations or less Argentinian version by Abusamra et al. (2007) was used. *All errors were omissions in both Sections. Data from healthy children show that errors from the mean (scores between 0.96 and 1.0 relative to normative in Section 1 are around 1.9% and responses in Section 2 are 58% correct data); “slightly below average” (scores between 0.90 and 0.95 (Cartoceti et al., 2008). relative to normative data), and “below average” (scores < 0.90).1 Scores on the Peabody Picture Vocabulary-III were compared with age-matched normative data (Dunn et al., 2010). Results On the RLO, he showed a flawless performance when he was Results asked to orient in his own body (12/12) but showed a severe Table 2 shows the results on tasks tapping auditory processing, confronting person defect (1/8). In the TFP, he had normal word semantics and receptive vocabulary. Most scores on PALPA performance with the preferred right hand (9/10) and mildly subtests (18 out of 21) ranged from average (12/21) to slightly impaired tactile perception with the non-preferred left hand below average (6/21) and only a few scores were below average (7/10) (Spreen and Gaddes, 1969). On the FL, he demonstrated (3/21). Subject D performance on Non-word Minimal Pairs no deficit in the identification of single fingers both with (PALPA 1) and Word Minimal Pairs were preserved obtaining hidden hands (20/20) and with visible hands (19/20), but a better scores in the latter. Scores in Repetition: Syllable Length mildly impaired performance on identifying two simultaneously (PALPA 7) and Repetition: Non-words (PALPA 8) were flawless touched fingers when the hand was hidden (11/20), particularly and almost intact in the Repetition: Imageability × Frequency for the left hand (4/10). Overall, the total score is mildly (PALPA 9) subtest where subject D only performed 4 errors impaired in this task (total: 50/60; age-matched controls from 1 In the validation of the Spanish version of the PALPA, healthy subjects performed Wake, 1957: mean = 54.4; n = 70). Subject D had average almost at ceiling. Thus, standard deviations were low indicating that the data performance on the JLO test (21/30; age-matched controls: points tended to be close to the mean and that failing only one item in a given 24.7 ± 3.8, Benton et al., 1983). test placed the scores of subject D two standard deviations below the mean. Frontiers in Human Neuroscience | www.frontiersin.org 4 March 2020 | Volume 14 | Article 73 Berthier et al. Developmental Dynamic Dysphasia TABLE 2 | Language testing. TABLE 3 | Oral reading and spelling. Tests Subject Performance Normative Tests Subject Performance Normative D’s scores descriptor data1 D’s scores descriptor data1 (proportion) (proportion) Auditory Processing: Comprehension Tests Oral Reading Non-word minimal Oral Reading: Letter Length 24 (1.0) A 23.95 ± 0.21 pairs (PALPA 1) (PALPA 29) Same (n = 28) 24 (0.86) BA 27.45 ± 0.99 Oral Reading: Imag x Freq Different (n = 28) 25 (0.89) A 27.09 ± 1.24 (PALPA 31) Word minimal pairs High imageability-High 20 (1.0) A 19.95 ± 0.21 (PALPA 2) frequency (n = 20) High imageability-Low 19 (0.95) SBA 19.95 ± 0.21 Same (n = 28) 25 (0.89) A 27.54 ± 1.27 frequency (n = 20) Different (n = 28) 26 (0.93) SBA 27.68 ± 0.76 Low imageability-High 20 (1.0) A 19.95 ± 0.29 Auditory Lexical frequency (n = 20) Decision: Imag x Freq Low imageability-Low 20 (1.0) A 19.68 ± 0.55 (PALPA 5) frequency (n = 20) High imageability-High 20 (1.0) A 20.00 ± 0.00 Oral Reading: Grammatical frequency (n = 20) Class (n = 40) (PALPA 32) High imageability-Low 19 (0.95) SBA 20.00 ± 0.00 Nouns (n = 20) 19 (0.95) SBA 19.95 ± 0.21 frequency (n = 20) Adjectives (n = 20) 20 (1.0) A 19.86 ± 0.34 Low imageability-High 19 (0.95) SBA 19.95 ± 0.21 Verbs (n = 20) 20 (1.0) A 19.95 ± 0.21 frequency (n = 20) Functional Words (n = 20) 19 (0.95) A 19.77 ± 0.42 Low imageability-Low 13 (0.65) BA 19.41 ± 1.15 Oral Reading: Grammatical frequency (n = 20) Class x Imag (n = 40) (PALPA Non-words (n = 80) 73 (0.91) SBA 78.18 ± 1.95 33) Spoken Word-Picture 39 (0.97) A 39.45 ± 1.67 Nouns (n = 20) 19 (0.95) SBA 19.91 ± 0.29 Matching (n = 40) (PALPA Functional Words (n = 20) 19 (0.95) SBA 20.00 ± 0.00 47) Oral Reading: Morphological Peabody Picture 135 BA 30th%ile Endings (PALPA 34) Vocabulary Test Regular Words (n = 30) 27 (0.90) A 29.54 ± 1.30 Auditory Processing: Repetition Tests Irregular Words (n = 30) 14 (0.53) SBA 26.36 ± 5.84 Repetition: Syllable 24 (1.0) A 23.8 ± 0.23 Oral Reading: Non-words 22 (0.92) A 23.22 ± 0,69 Length (PALPA 7) (n = 24) (PALPA 36) (n = 24) Repetition: Non-words 24 (1.0) A 22.9 ± 0.64 Spelling (PALPA 8) (n = 24) Spelling to Dictation: Letter 24 (1.0) A 23.8 ± 0.23 Words, Imag x Freq Length (PALPA 39) (n = 24) (PALPA 9) Spelling to Dictation: High imageability-High 20 (1.0) A 20.00 ± 0.001 Grammatical Class (PALPA 41) frequency (n = 20) Nouns (n = 5) 5 A 4.68 ± 0.55 High imageability-Low 20 (1.0) A 19.82 ± 0.65 Adjectives (n = 5) 5 A 4.91 ± 0.29 frequency (n = 20) Verbs (n = 5) 5 A 4.91 ± 0.29 Low imageability-High 20 (1.0) A 19.68 ± 1.02 Functional Words (n = 5) 4 A 4.77 ± 0.52 frequency (n = 20) Spelling to Dictation: 9 (0.90) A 9.73 ± 0.67 Low imageability-Low 19 (0.95) SBA 19.27 ± 1.93 Grammatical Class x Imag frequency (n = 20) (PALPA 42) Non-words (n = 80) 76 (0.96) A 77.68 ± 3.35 Nouns (n = 10) 8 (0.80) SBA 9.82 ± 0.49 Repetition: Sentences 34 (0.94) A – Functional Words (n = 10) (PALPA 12) (n = 36) Spelling to Dictation: 24 (1.0) A 22.54 ± 0.76 Digit Production (PALPA 4 SBA 5.91 ± 0.67 Non-words (PALPA 45) 13) (n = 24) Matching Span (PALPA 5 A 6.18 ± 1.34 13) All test are from PALPA unless specified; 1 Normative data from Valle and Cuetos (1995). The “performance descriptors” have been obtained by comparison with All test are from PALPA unless specified; 1 Normative data from Valle and Cuetos normative data as follows: A indicates average, SBA slightly below average, and (1995). The “performance descriptors” have been obtained by comparison with BA below average (see further details in text). normative data as follows: A indicates average, SBA slightly below average, and BA below average (see further details in text). Performance on the Spoken Word-Picture Matching (PALPA and all of them were lexicalizations (e.g., “cuabro”→ cuadro 47) and the Peabody Picture Vocabulary-III were preserved. [painting]). Sentence Repetition was also preserved, but Digit Oral reading and spelling to dictation were preserved in most Production/Matching Span (PALPA 13) was mildly reduced. tasks (Table 3). Frontiers in Human Neuroscience | www.frontiersin.org 5 March 2020 | Volume 14 | Article 73 Berthier et al. Developmental Dynamic Dysphasia Speech Production words should not only be intelligible in context, but also be Naming for Nouns and Verbs accurate, relevant and informative with respect to the stimulus. Methods Meaningless utterances, perseverations, paraphasias and other Oral naming was assessed by using black and white pictures inappropriate information (exclamations) were counted as from standardized naming batteries. In particular, noun naming words, but not classified as CIUs. The duration of the was assessed with the standardized set of 260 pictures of the narrative, the total number of words, the number of words Snodgrass and Vanderwart (1980) battery, whereas verb naming per minute and the pauses were counted. Pauses ≥ 3 s were was tested with 100 items from the Action Naming Battery considered abnormal. (Druks and Masterson, 2000). Results Results The description of the picture was extremely poor. It contained 31 The performance of subject D in noun naming was mildly words produced in 53 s. Although the examiner requested subject impaired (214/260 [0.82]) in part due to the inclusion of D to be more explicative in two occasions, he was unable to add items not known by subject D (i.e., footballhelmet, sled, further information. Since there were no linguistic errors in the spinningwheel). Error analysis mostly disclosed semantic errors narrative, the number of words and CIUs were the same (31). (e.g., “envelope”→ message) (28 [0.61]) and omissions (14[0.30]), There were 4 pauses, two of which were long (6.47. and 8.28 s). whereas other errors were rarely seen. There were 2 phonological Subject D produced the following description of the Picnic Scene: (0.04), 1 formal (0.2) and 1 visual (0.02) errors. His performance “They are having a snack. . . (2.51 s), a man is speaking, a comet in verb naming was preserved (91/100 [0.91]). Error analysis with a dog. . . (6.47 s) there is a man fishing. . . (8.28 s), there are disclosed the production of a noun instead of a verb (e.g., two men on a boat. . . (1.51 s) and there is a child collecting water.” 2 “surf ”→ boat) (5), and omissions which were always benefited To examine communication in daily life, the mother of with phonemic cueing (4). subject D was interviewed using questions of a communication scale developed for adults with aphasia (Communicative Activity Verbal Fluency Log; Pulvermüller and Berthier, 2008). The mother reported Methods that her son had marked impairment in frequency and quality Phonemic verbal fluency was assessed with the Controlled Oral of communication in questions evaluating making statements Word Association Task (F.A.S.) (Borkowski et al., 1967), and or reports about facts, write down short notes, communicate semantic fluency was assessed with two categories of living when relaxed or under stressful situations and communicating things (animals and fruits) and two categories of artifacts with foreigners. (clothes and transport). Results Dynamic Dysphasia Testing To elicit the typical language features of DA, an adaptation of The performance of subject D in phonemic fluency was very a series of experimental tests developed by Robinson and co- poor since he was only able to produce three words in 3 min. In workers to assess ADA (Robinson et al., 1998) was used. The semantic fluency, his performance was also impaired in the four original English version of these experimental tests was slightly categories (animals: 9; fruits: 7; clothes: 5; transport: 5). modified and adapted to be administered to Spanish speaking Narrative Production and Communication in Activities individuals (Berthier et al., in preparation). Since these tests are experimental, they were also administered to a group of 10 of Daily Living healthy control adolescent boys matched by age (age range: 10– Methods 14; mean age ± SD: 11.87 ± 1.12; Crawford t-test, two tailed: A sample of picture-generated narrative was used. Subject D t = 0.111; p = 0.914), handedness (all right handers), and years was asked to generate a story that corresponds to a novel of schooling (although subject D needed additional classes and scene depicting a picnic day with many people along the training, he did not repeat any academic course). The scores riverside, enjoying a picnic and performing different activities. obtained by Subject D in each of these tasks were compared to The Picnic Scene from the Western Aphasia Battery (Kertesz, those obtained by the control group using a two-tailed Crawford’s 1982) was used. Subject D was encouraged to describe the modified t-tests. This test allows comparing outcomes from one elements depicted in the card (nouns) as well as indicate or more individuals with results derived from small control the actions that the persons were doing (action verbs) during samples (Crawford and Howell, 1998; Crawford and Garthwaite, a time limit of 5 minutes. He was also encouraged to 2002; Crawford et al., 2010). Performance on these tests in subject describe the scenes using sentences. The description was audio- D and healthy controls was analyzed in terms of number of taped and transcribed. The speech sample was analyzed for correct responses. The methodology and results of these tests are percentage of correct information units (%CIU) defined as described below. non-redundant content words that convey correct information about the stimulus (Nicholas and Brookshire, 1993; Marchina et al., 2011; Zipse et al., 2012), using the following formula: 2 This excerpt has been translated from Spanish. Note that the number of words has number of CIUs/number of words × 100. According to been counted in Spanish (n = 31), so that the number (n = 33) does not coincide Nicholas and Brookshire (1993) to be classified as CIUs, with the English translation. Frontiers in Human Neuroscience | www.frontiersin.org 6 March 2020 | Volume 14 | Article 73 Berthier et al. Developmental Dynamic Dysphasia Test A Test D Generation of a single word to complete a sentence Generation of a sentence from a single picture Methods. Two sets of sentences were used. The first included Methods. Subject D and the control group were presented with 20 high-constraint sentences with not many usable referent 10 pictures of common objects (e.g., an iron or an umbrella) words (e.g., “bicycles have two . . .”) and the second set and asked to produce a whole sentence incorporating the was composed of 20 low-constraint sentences with numerous noun of the picture. One point per item was given if the usable referent words (e.g., “It is good to be . . .”). One point generated sentence was complete (not to simply name the item), per item was given if the generated word was appropriate. grammatically correct and related to the presented picture. Sentences were presented in a random order. Results: Subject Results: Subject D had a moderately impaired performance D completed 17 out of 20 high-constraint sentences correctly in this task as he failed to generate a sentence in 3 out of (0.85). By contrast, his performance in the low-constraint 10 examples (bicycle, eyeglasses, and rabbit) (0.30). In the sentences was poor, completing 5 out of 20 sentences (0.25). remaining items, although the generation of the sentences Even though there was no time limit for completion of open- were correct, responses were very simple (e.g., example: ended sentences, all errors were omissions. When asked for the iron; generated sentence: “The iron is used for ironing”). high number of omissions, subject D replied, “I cannot find In addition, it was noticeable that the generation of correct words” or “no words come to my head.” The total score of sentences was preceded by prolonged latencies (ranging from subject D was low (44/80), whereas the control group scores 3.73 to 24.58 s) in four sentences. The performance in the (78.1 ± 1.91) were significantly better (Crawford t-test, two- control group was 10 ± 0.0 (Crawford t-test, two-tailed: tailed: t = −17.02, p < 0.001). t = −57.20, p < 0.001). Test B Test E Generation of a sentence from a single word Sentence given a pictorial scene Methods. In this task, subject D and controls were asked to Methods. Subject D and the control group were asked to produce a whole sentence containing the word spoken by the produce a sentence to describe simple pictorial scenes selected examiner. Ten common nouns (e.g., “apple”) and 10 verbs from the Object and Action Naming Battery (Druks and (e.g., “sleep”) were randomly presented. Proper names were Masterson, 2000). Twenty pictorial scenes (e.g., a boy playing not used. Two points per item were given if the generated basketball, a dancing couple) were used. Two points per sentence was complete and grammatically correct and one point item was given if the sentence generated was complete, if the sentence was correct but not very informative. Results: grammatically correct and related to the presented scene. Results: Subject D produced 18 out of 20 phrases correctly (0.90) and Subject D obtained a score of 28/40 (0.70), whereas controls’ his score was 36/40, whereas the performance of the control performance was flawless (40 ± 0.0) (Crawford t-test, two-tailed: group was flawless (40 ± 0.0) (Crawford t-test, two tailed: t = −114.41, p < 0.001). t = −38.13, p < 0.001). Test C Test F Generation of a sentence from a given sentence context Generation of sentences from a pictorial scene. what might Methods. In this task, subject D was asked to generate a second happen next? sentence around the theme of the first. For example, the sentence Methods. Subject D and controls were presented with simple “Carmen is always smiling” could be followed by the sentence pictures selected from the Object and Action Naming Battery “because she is always very happy.” Twenty sentences were (Druks and Masterson, 2000) and asked to generate a presented and one point per item was given if the generated sentence describing what might happen next. For instance, sentence was complete, grammatically correct and thematically a picture showing a man bleeding after being bitten by related to the first stimulus sentence. Results: The performance of a dog would be followed by the sentence “he went to subject D in this task was impaired. He did not generate a novel the hospital.” Twenty pictorial scenes (e.g., a boat sinking, sentence in 11/20 occasions (0.55). In the remaining sentences, a person tying the laces of his trainers) were presented. he used some words of the target sentence in the response, Two points per item were given if the generated sentence usually repeating the verb verbatim or changing the verb tense, was complete, grammatically correct and it was not a mere indicating echo-answer3 . The performance in the control group description of the scene, but a prediction of what would was better than in subject D (25.6 ± 9.2) but the difference follow the corresponding situation. One point was given did not reach statistical significance (Crawford t-test, two-tailed: for an incomplete description. Results: The performance of t = −0.78, p = 0.45). subject D was significantly worse (5/40, [0.12]) than the one achieved by the control group (39.8 ± 0.42) (Crawford t-test, 3 Echo-answer refers to the inadvertent repetition of words or sentence fragments two-tailed: t = −79, p < 0.001). The qualitative analysis of the target stimulus into the response, in general, with the purpose of improving showed that subject D was unable to generate a description auditory comprehension (Berthier et al., 2017). This was not the case in subject in 11 frame pictures (0.55). In the remaining 9 frame D because he had preserved auditory comprehension. It is possible that in this subject, echo-answer resulted from limited linguistic resources to generate novel pictures there were 2 correct descriptions, 2 incomplete and 5 sentences. descriptions of the picture. Frontiers in Human Neuroscience | www.frontiersin.org 7 March 2020 | Volume 14 | Article 73 Berthier et al. Developmental Dynamic Dysphasia Test G saw an animal that was a farm animal. Half of the animals were Story generation from a pictorial context farm animals and the other half were not. (2b) In addition, a Methods. Subject D and the control group were presented with finger tapping paradigm was used to evaluate the CMM. Two simple pictures and asked to generate a brief story describing fMRI runs, one for the left hand and another for the right what might happen. Ten pictorial contexts (e.g., a man watering hand, were carried out. The four functional runs were presented the plants, a woman petting a cat) were presented. One point following identical fMRI block designs which consisted of five per item was given if the generated speech consisted of two or task blocks interspersed with five blocks of rest in which the more related or connected complete and grammatically correct participant was just required to stop doing the task and simply sentences. Results: As expected from the results obtained by wait with the eyes open looking to a fixation point. The fMRI subject D in Test F, he was totally unable to generate any story. experiment followed a block design in order to measure the Therefore, the test was interrupted after five consecutive failures. sustained brain responses related to the studied language and The performance of the control group was normal (20 ± 0.0), all motor processes. Each block (task and rest blocks) lasted 30 s, of them generated brief meaningful and very illustrative stories. therefore the total duration of each run was of 5 min. During the active block, the participant was required to perform a self- paced unimanual finger-tapping task. One run required finger Neuroimaging tapping of the right hand (Right finger Tapping Task), and the Functional Activations Related to Language and other required the movement of the left-hand finger (Left Finger Motor Functions Tapping Task). (3) fMRI pre-processing and analysis. Functional Methods imaging data were pre-processed using standard procedures (1) MRI data acquisition. MRI data was acquired on a on a 3-T implemented in the Statistical Parametric Mapping software MRI whole-body scanner (Philips 3T Intera, Release 3.2.3.1, with (SPM12)4 . The same processing steps were performed for each an eight-channel platform) equipped with a six-channel Philips functional run corresponding with each task. Both the high- SENSE head coil. Head movements were minimized using head resolution structural T1 image, and the fMRI runs were AC-PC pads and a forehead strap. First, high-resolution T1-weighted oriented. Functional images of each run were realigned to the structural images of the whole brain were acquired with the first scan of each series. The functional scans were co-registered following parameters: TR = 10.03 ms, TE = 4.606 ms, slice to the T1 image. T1 image was segmented into different tissues, thickness 0.8 mm, 200 slices, voxel size: 0.75 × 0.75 × 0.8, flip and the parameters derived from the segmentation were used for angle = 8◦ , matrix size 320 × 320 × 200. Then, Diffusion Tensor the normalization of the T1-weighted and the functional images. Imaging (DTI) acquisition was performed using multi-slice Finally, all functional images were spatially smoothed with an single-shot spin-echo echo-planar imaging (EPI) with specific 8-mm FWHM kernel. Then, two conditions were specified for parameters as follows: matrix size 128 × 128 × 65, an acquisition each task/run: Task and Rest. The mean timelines of BOLD voxel of 1.67 mm × 1.67 mm × 2.00 mm, TE = 91 ms, TR = 11621 signal in white matter and cerebrospinal fluid were included in ms, b factor = 800, flip angle 90◦ . After the acquisition of the the model as covariates together with realignment parameters, structural data, four different fMRI were carried out following to remove signal from non-neural sources. The general linear a block design. Each task involved a functional run consisting model was applied to find activations of interest using the on 100 functional images (FFE/EPI sequence with epi factor contrast: Task > Rest. Unless otherwise stated, all statistical 35, TR = 3000 ms and TE = 35 ms and flip angle 90◦ . The results are reported at p < 0.001 uncorrected for multiple image matrix was 64/64 r. 30 axial slices were acquired for each comparisons at the whole-brain level, with a minimal cluster volume, with a 4 mm slice-thickness and no gap. Voxel size extent of 20 voxels. was 1.8 mm x 1.8 mm x 4 mm). (2) fMRI experimental design. (2a) To evaluate the brain functional correlates of the language Results function in subject D, two different fMRI paradigms were used, Morphological description of the brain. A visual inspection of one to study the functional correlates of phonological fluency the T1-weighted anatomical image of subject D showed several and another one of semantic decision. Language production and developmental brain anomalies (Figure 1). The brain of subject comprehension may follow a different lateralization pattern (e.g., D showed dilated right lateral ventricles, with hypertrophy of left hemisphere for production and comprehension, and right bilateral thalamus, caudate head and putamen. In addition, in hemisphere for comprehension), as it has been shown in healthy the left hemisphere, he showed an open frontal operculum, subjects (Bernal and Ardila, 2009; Lidzba et al., 2011) and in the sylvian fissure was short and it ended in a marked individuals with developmental brain anomalies (see Berthier ascending direction compared to a normal brain. Consequently, et al., 2011). For the Phonological fluency Task, subject D was the left perisylvian area was reduced and the frontal gyri, required to mentally evoke as many words as possible beginning the posterior temporal gyrus and the inferior parietal cortex with a specific letter. At the beginning of each active block, the were displaced. The right hemisphere seems to be larger than participant heard a letter, and then he was instructed to start the left one and there was a right occipital petalia, findings producing the words. The letter was different for each block (F, already reported in children with specific language impairments A, S. . .). In the Semantic Decision Task, thirty draws of animals (Soriano-Mas et al., 2009). were presented (6 in each block) via MRI compatible goggles and the participant was required to move the right finger if he 4 http://www.fil.ion.ucl.ac.uk/spm/ Frontiers in Human Neuroscience | www.frontiersin.org 8 March 2020 | Volume 14 | Article 73 Berthier et al. Developmental Dynamic Dysphasia FIGURE 1 | Depiction of subject D’s structural T1-weighted images. Axial slices of the brain in native space show the asymmetry of the volume of the lateral ventricles (right > left) with right occipital colpocephaly. There is an “open operculum sign” in the left hemisphere due to arrested development of the inferior frontal gyrus and superior temporal gyrus with exposure of the insular cortex (red circle). L, left; R, right. Brain activation during phonological fluency task. The activation Functional Lateralization Indexes for Language and pattern associated to phonological fluency mainly involved areas Motor Tasks of the right frontal lobe, such us the inferior and middle frontal Methods gyri, and the left cerebellum (Figure 2A and Table 4). Two A lateralization index (LI) was calculated considering the clusters of increased activation in left hemisphere appeared only activation difference between the left and right sides throughout with an uncorrected p < 0.01 threshold (Figure 2A). An overlap different regions of interest (ROIs). ROIs were defined using of the activation found in subject D in the phonological fluency WFU-Pickatlas toolbox5 ; Maldjian et al., 2003). For the four task vs. rest contrast with a map resulting from a meta-analysis contrasts (Phonological fluency vs. rest, Semantic Decision vs. of fMRI studies focused on verbal fluency is reported in the rest, Left Tapping vs. rest, and Right Tapping vs. rest), a LI Supplementary Figure S1A. was calculated using different ROIs: Hemisphere ROI (the whole Brain activation during semantic decision task. Semantic decision right and left hemispheres) was used to calculate the LI in the activated a network comprising the typical ventral language four contrasts, IFG ROI (i.e., corresponding to Broca’s area) stream bilaterally (see for instance Saur et al., 2008; López- was used to explore the LI in the two language contrasts, Barroso et al., 2015) (Figure 2B and Table 4). These areas and the precentral gyrus ROI (i.e., corresponding to primary include bilateral IFG, both pars triangularis and pars opercularis, motor cortex) was used to calculate the LI on the two motor the anterior temporal lobe, the anterior and posterior superior contrasts. The formula used to calculate the LI was: (Right – temporal gyrus and the inferior parietal cortex. An overlap Left)/(Right + Left)∗ 100, where Left and Right indicated the between the activation found in subject D in the semantic number of activated voxels in the corresponding left and right decision task vs. rest contrast and a map resulting from a meta- ROIs, respectively. The threshold used for the LI was identical analysis of fMRI studies focused on semantics is reported in the as the one used for the contrasts (p < 0.001, uncorrected). Supplementary Figure S1B. The lateralization index ranges between -100 (extreme left lateralization) and 100 (extreme right lateralization). Values Brain activation during right motor finger tapping task. Subject between −20 and 20 represent bilateral activation, and positive D showed a bilateral pattern of activation involving the pre- above 20 indicates left lateralization. This cut off to classify the and post- central gyri in both hemispheres as well as bilateral patterns of lateralization was based on previous studies (Binder SMA, IFG and cerebellum. Results are reported in Table 4 et al., 1996; Springer et al., 1999). and Figure 2C. Results Brain activation during left motor finger tapping task. Subject D In subject D, the LI comparing Phonological Fluency vs. rest showed a robust activation in the right precentral and postcentral contrast disclosed that the LI was 100 for both analyses, gyri, and small clusters of activation in the right insula and using the Hemisphere and the IFG ROIs, thus showing an bilateral cerebellum. All significant results are reported in Table 4 and Figure 2D. 5 http://www.nitrc.org/projects/wfu_pickatlas/ Frontiers in Human Neuroscience | www.frontiersin.org 9 March 2020 | Volume 14 | Article 73 Berthier et al. Developmental Dynamic Dysphasia FIGURE 2 | Brain activation during language and motor tasks in subject D. (A) Phonological fluency vs. Rest contrast showed a restricted pattern of activation, mainly in the right frontal lobe. Notice that subject D had a marked deficit in fluency tasks, which correspond with the weak activation pattern during the task. (B) Enhanced fMRI activity for the Semantic decision vs. Rest contrast was found in a bilateral network involving frontal, temporal and parietal areas. (C) Activation in the bilateral pre- and post- central gyri and Supplementary Motor Area (SMA) on the Right motor tapping vs. Rest contrast. (D) Left motor tapping vs. Rest contrast revealed increased activity in the right pre-and post-central gyri as well as in the SMA. Results are shown at three different thresholds: p < 0.05 corrected; p < 0.001 uncorrected; and p < 0.01 uncorrected threshold, with 20 voxels cluster extent. Results are shown in standard space over subject D’s normalized T1-weighted image. L, left; R, right. extreme right lateralization in both cases (Figure 3). The showed a bilateral pattern of activation during semantic decision LI for the activation related to semantic decision revealed (Figure 3). The LI for the activation related to right motor that for the hemisphere ROI, the LI was of −13%, and tapping was −14% when analyses were restricted to the whole of −10% when using the IFG ROI. Therefore, subject D hemispheres, and −7% when they were restricted to the Frontiers in Human Neuroscience | www.frontiersin.org 10 March 2020 | Volume 14 | Article 73 Berthier et al. Developmental Dynamic Dysphasia TABLE 4 | Brain activations during the semantic decision, phonological fluency, left motor tapping and right motor tapping tasks. Contrast Cluster Brain areas Coordinates (Cluster peak) Cluster size FWE p-value Unc. p-value (no. of voxels) (cluster level) (peak level) x y z Phon. fluency vs. 1 R IFG pars triangularis 46 32 30 51 0.646 0.000 Rest 2 L cerebellum Crus 1 −46 −60 −36 49 0.669 0.000 3 R precental gyrus 28 41 20 48 0.681 0.000 4 R IFG orbitalis 46 18 −14 37 0.808 0.000 5 R middle frontal gyrus 30 44 22 45 0.716 0.000 1 R IFG orbitalis, R superior 46 24 −14 2994 0.000 0.000 temporal pole, R superior temporal gyrus 2 L superior temporal gyrus, L −58 −32 20 2553 0.000 0.000 inferior parietal cortex, L middle temporal gyrus 3 L superior frontal gyrus −22 62 20 366 0.000 0.000 4 L cerebellum (Crus 2 and 1), R −8 −88 −24 2943 0.000 0.000 cerebellum 5 L IFG triangularis, L superior −54 24 −2 2131 0.000 0.000 temporal gyrus 6 R SMA, L SMA 10 8 66 463 0.000 0.000 7 L medial superior frontal gyrus 2 26 42 648 0.000 0.000 8 R precentral gyrus 137 42 8 36 0.09 0.000 9 Midbrain −6 −30 −20 743 0.000 0.000 10 R middle frontal gyrus, 34 42 24 162 0.054 0.000 Semantic 11 R inferior temporal gyrus 50 −46 −20 27 0.97 0.000 decision vs. Rest (occipito-temporal) 12 R posterior cingulate gyrus, 18 −44 32 398 0.001 0.000 precuneus 13 Cerebellum (vermis) 6 −52 −8 35 0.82 0.000 14 Midbrain 10 −28 −16 73 0.40 0.000 R superior frontal gyrus 20 62 28 20 0.95 0.000 15 R inferior temporal gyrus −56 −52 −16 21 0.95 0.000 (occipito-temporal) 16 R anterior parahippocampal 20 −10 −32 20 0.95 0.000 gyrus 17 R medial superior frontal gyrus 12 42 44 30 0.87 0.000 18 R postcentral gyrus 56 −22 50 53 0.6 0.000 L middle frontal gyrus −54 18 40 27 0.9 0.000 19 L anterior cingulum 0 38 22 23 0.93 0.000 Right tapping vs. 1 R cerebellum, L cerebellum 14 −72 −44 338 0.002 0.000 Rest 2 R superior frontal gyrus, R 20 −10 72 5477 0.000 0.000 postcentral gyrus, R precentral gyrus 3 L superior parietal cortex, L −32 −52 64 6322 0.000 0.000 precentral gyrus, 4 R cerebellum, vermis, L 22 −56 −26 2805 0.000 0.000 cerebellum 5 L superior frontal gyrus −26 62 22 192 0.025 0.000 6 R posterior middle temporal 44 −66 12 87 0.278 0.000 gyrus 7 R insula, R rolandic operculum 48 10 0 122 0.121 0.000 8 L lingual gyrus −8 −92 −14 68 0.433 0.000 9 L middle occipital gyrus −42 −76 18 27 0.9 0.000 10 L inferior temporal gyrus −54 −54 −16 51 0.62 0.000 11 L middle temporal gyrus −42 −56 18 40 0.76 0.000 (Continued) Frontiers in Human Neuroscience | www.frontiersin.org 11 March 2020 | Volume 14 | Article 73 Berthier et al. Developmental Dynamic Dysphasia TABLE 4 | Continued Contrast Cluster Brain areas Coordinates (Cluster peak) Cluster size FWE p-value Unc. p-value (no. of voxels) (cluster level) (peak level) x y z 12 R calcarine 8 −74 18 189 0.027 0.000 13 L putamen −18 −4 −10 36 0.8 0.000 14 Midbrain −4 −20 −22 162 0.049 0.000 15 R lingual gyrus 20 −64 −27 74 0.37 0.000 16 L cerebellum (Crus 1) −48 −68 −26 22 0.94 0.000 17 R insula 42 6 −18 41 0.74 0.000 Left tapping vs. 1 R superior frontal gyrus, R SMA 18 −8 74 432 0.000 0.000 Rest 2 R postcentral gyrus, R 28 −32 52 2216 0.000 0.000 precentral gyrus 3 L cerebellum −12 −68 −44 27 0.9 0.000 4 L cerebellum −6 −48 −14 534 0.000 0.000 5 R insula, R rolandic operculum 38 −8 12 145 0.06 0.000 6 R cerebellum 20 −60 −24 104 0.16 0.000 7 L postcentral gyrus −40 −20 28 46 0.66 0.000 All results are reported p < 0.001, uncorrected for multiple comparisons at the voxel level, with a minimum cluster extent of 20 voxels. Likewise, the results that are also corrected for multiple comparisons (FWE, p < 0.05) are also reported. Peak coordinates are reported in MNI coordinates. precentral gyrus ROIs. Both LIs suggest a symmetrical activation color maps and used to isolate single tracts following previously pattern (Figure 3) for the right motor tapping task. Finally, the reported procedures (Catani and Thiebaut de Schotten, 2008; LI for the activation related to left motor tapping was of 100% López-Barroso et al., 2013). When required, spurious fibers were using both the hemisphere ROIs and the precentral gyrus ROIs, removed from the main fiber tracts by using an additional suggesting an extreme right lateralization (Figure 3). avoidance ROI. All tracts were dissected in native space and in both cerebral hemispheres. Diffusion Tensor Imaging (DTI) Pre-processing Diffusion data pre-processing started with motion and eddy Results. All the tracts were intact (Figure 4) and could be virtually current correction as using FMRIB’s Diffusion Toolbox (FDT) reconstructed contrary to what happens when there is a brain (Smith et al., 2004; Woolrich et al., 2009), and the Brain injury, however, the morphology of some of these tracts was extraction was performed with the Brain Extraction Tool (BET), atypical. In the left hemisphere, among the dorsal tracts the both parts of the FMRIB Software Library (FLS)6 . Diffusion FAT was reconstructed and it showed a normal morphology; the tensor estimation was carried out using Diffusion Toolkit’s long, the anterior and the posterior segments of the AF were least-square estimation algorithm for each voxel (Ruopeng voluminous, especially the long AF segment, but accordingly Wang and Van J. Wedeen, TrackVis.org, Martinos Center for to the shape of the sylvian fissure in the left hemisphere, both Biomedical Imaging, Massachusetts General Hospital). Whole- the frontal and the temporal branches were shorter than in brain tractography used an angular threshold of 35◦ and an FA a normal brain, while the dorsal terminations of the frontal threshold of 0.15. A fractional anisotropy (FA) map was generated branches of the anterior and the long segments reached the using Diffusion Toolkit. superior frontal gyrus. The posterior and anterior segments terminated in the inferior parietal cortex, but their atypical shape Deterministic tractography was a consequence of the displacement of these cortical areas Methods. Different white matter tracts were selected as tracts of (Figure 4). In the right hemisphere, the FAT showed a typical interest due to their implication in language or motor functions, shape, whereas again the three segments of the AF showed an and consequently they were reconstructed and examined. atypical pattern, associated to the atypical morphology of the Specifically, as tracts related to language, we selected the three perysilvian cortex. The ventral tracts were reconstructed in both segments of the arcuate fasciculus (AF) (long, anterior, and hemispheres (Figure 4). The UF and IFOF of the left hemisphere posterior) and the frontal aslant tract (FAT) as dorsal language showed greater volume than in the right hemisphere, following pathways; while the inferior fronto-occipital fasciculus (IFOF) the pattern found for the AF. and the uncinate fasciculus (UF) were selected as ventral language The studied motor tracts were also successfully reconstructed pathways. Referred to the motor function, we examined the (Figure 4). With the current methodological resolution, we corpus callosum and the corticospinal tracts. Virtual dissections were not able to find evidence for pyramid decussation at the of the tracts were performed using the software TrackVis7 . level of the medulla oblongata. The right corticospinal tract Spheres a hand-drawn ROIs were defined over the FA or FA (CST) showed greater volume than the left CST. The corpus callosum that connect the motor areas from both hemispheres 6 www.fmrib.ox.ac.uk/fsl/ was displaced, thus we could not reconstruct direct connections 7 www.trackvis.org between contralateral frontal motor areas. Frontiers in Human Neuroscience | www.frontiersin.org 12 March 2020 | Volume 14 | Article 73 Berthier et al. Developmental Dynamic Dysphasia with a monopulse stimulator (Magstim 100) with a round coil (12 cm). The coil was placed tangentially to the scalp with its center over the vertex for cortical stimulation, and spinal roots were stimulated at C6–C7 and L4–L5 spaces while recording at the same positions bilaterally over the target muscles (1st dorsal interosseous and tibialis anterior muscles) with surface electrodes. Central conduction time (CCT in milliseconds) was measured as the difference between total and peripheral motor conduction time. The amplitude (µv) of the cortical response was measured as the average at least 3 supramaximal responses and as an amplitude ratio with the compound motor action potential (CMAP) electrically elicited (ZAMPR). For identification of cortical silent periods (CSP) the same protocol as for eliciting the MEP (while subject D performed a maximal voluntary contraction) was used. The CSP was quantified as the time elapsed between the onset of the MEP and the time at which the post-stimulus background EMG returned to the pre-stimulus mean amplitude (Poston et al., 2012). FIGURE 3 | Lateralization indexes (LI) for the four fMRI contrasts and the Results region of interest (ROI) used. LI values greater than 20% mean right The TMS disclosed cortical bilateral responses with the lateralization and are marked with an asterisk; LI values greater than –20% mean left lateralization and no LI was found with this pattern. Values between same latency and amplitude for both 1st dorsal interosseous –20 and 20% (gray color) mean a symmetrical pattern of activation. muscles with unilateral stimulation of hand motor cortical area, with a normal threshold (greater when stimulating the right hemisphere). Stimulation of both hemispheres showed Dichotic listening a markedly diminished cortical silent periods (CSP) for both Methods. Dichotic listening was evaluated with a Spanish version muscles. Values of different parameters (e.g., motor threshold, of the three-pair dichotic listening task (DLT) (Strouse and central conduction time, MEP latency, MEP cortical amplitude) Wilson, 1999; Zenker et al., 2007). Before performing this task, obtained for hands and feet of subject D are presented in subject D underwent a tonal audiometry which revealed normal Supplementary Tables S1–S4. hearing bilaterally. Subject D was presented with a series of one to three pairs of numbers. Each pair consists of one number (from Genetic Testing one to ten) presented on the left ear and a different number Methods (from one to ten) presented on the right ear. After each number Genetic testing was performed to detect mutations that disrupt was presented, subject D was required to orally repeat which the development of commissural tracts (i.e., Germline DCC digits he has heard in each ear. Based on the DLT, Zenker et al. mutations) and are associated with CMM (Méneret et al., (2007) obtained the LI, which is computed as: LI = [(Right- 2014). The coding and flanking intronic regions of DCC Left)/(Right + Left)]∗ 100, where Right and Left are computed (deleted in colorectal carcinoma [OMIM ∗ 120470]), RAD51 as the total number of individual digits recognized presented (RAD51 recombinase [OMIM ∗ 179617]), and DNAL4 (Dynein respectively to the right and left ears. In Zenker et al.’s (2007) Axonemal Light Chain 4 [OMIM ∗ 610565]), were amplified by study, the LI was 17% for the 6–12 age group and 5% for the polymerase chain reaction (PCR) and Sanger sequenced on an 13–19 age group. ABI 3100 automatic sequencer (Applied Biosystems, Foster City, CA, United States). Resulting electropherograms were visually Results. In the DLT, subject D recognized 30% of the digits analyzed using Sequencher software (Gene Codes Corp. Ann presented to the left ear, and only 19% of the digits presented Arbor, MI, United States). Primer pair sequences and PCR to the right ear. The LI was -55% (i.e., strongly right brain conditions are available under request. lateralized), clearly below the scores of his age group (i.e., 17%). This means that subject D was less able to detect stimuli Results processed in the left hemisphere than in the right hemisphere, The genetic study did not disclose any pathogenic variant in the thus suggesting that his right hemisphere was dominant for three analyzed genes (DCC, RAD51, and DNAL4). auditory processing. These results complemented the findings from fMRI, which showed right hemisphere lateralization for speech production. DISCUSSION Transcranial Magnetic Stimulation We described, for the first time, the case of an adolescent boy Methods who met diagnostic criteria for DLD (DSM-V, code: 315.32 Motor evoked potentials (MEP) to the four limbs were obtained [F80.2]; American Psychiatric Association, 2013) showing a simultaneously using a transcranial magnetic stimulation (TMS) profile of language impairment resembling DA. In all previous Frontiers in Human Neuroscience | www.frontiersin.org 13 March 2020 | Volume 14 | Article 73 Berthier et al. Developmental Dynamic Dysphasia FIGURE 4 | Language-related and motor-related white matter pathways of subject D were tracked using deterministic Tractography. Notice that all studied language related pathways (dorsal and ventral) could be reconstructed, however the three segments of the AF showed an atypical distribution. Although they connect frontal, parietal and temporal regions, since these areas were displaced in Subject D due to the morphological abnormality in his brain, the shape of these tracts is abnormal. The motor tracts were also reconstructed, but we could not find the pyramid decussation normally found in the caudal part of the medulla oblongata. reports of ADA it was associated with focal brain lesions selection between competing verbal responses (Robinson et al., (tumors, stroke) and cortical-subcortical atrophy secondary 1998, 2005), inadequate semantic strategy formation (Gold et al., to progressive degenerative disorders mostly involving fronto- 1997) and reduced spontaneous and intentional activation of subcortical regions. However, in subject D the occurrence of lexical-semantic representations (Raymer et al., 2002; Cox and such syndrome coexisted with a malformed brain. Therefore, Heilman, 2011; Satoer et al., 2014). These disrupted mechanisms the neurobiological underpinnings of DDD in this adolescent may explain the language-specific form of the syndrome boy could be considered of developmental origin. In the next (Robinson et al., 1998, 2015). Nevertheless, complementary section we examine what could be the causal mechanisms that proposals suggest that reduced speech production may also be might underlie DDD. related to domain-general deficits resulting from impairment in novel thought generation and deficits in fluent sequencing of novel thoughts (Robinson et al., 2006, 2015a,b; Bormann Mechanisms Underpinning et al., 2008; Robinson, 2013). Interpretation of ADA within Developmental Dynamic Dysphasia this broader framework coincide with the original formulation Several competing theoretical interpretations have been advanced by Luria and Tsvetkova (1967), who viewed this syndrome to account for ADA (see Robinson et al., 2006). Indeed, cases as a condition derived from general executive and attentional of ADA have variously linked to impaired verbal planning impairments related to lesions in the frontal lobes. Therefore, (Costello and Warrington, 1989; Bormann et al., 2008), impaired it seems that some cases ADA may result from a hybrid Frontiers in Human Neuroscience | www.frontiersin.org 14 March 2020 | Volume 14 | Article 73 Berthier et al. Developmental Dynamic Dysphasia mechanism that combines failures in domain-general and semantic comprehension, repetition of words, non-words and language-specific functions. sentences, noun and verb naming, oral reading and spelling) were Another candidate mechanism to account for ADA is the slightly below average or average. This dissociation, characteristic impairment of automatic spreading activation of lexical items of ADA (Robinson et al., 1998, 2006; Berthier, 1999), may also during production tasks. Luria introduced the term “spreading characterize DDD. Defective semantic strategy formation has activation syndrome” for explaining a subtype of ADA (see been considered implicated in some case of ADA (Gold et al., Lebrun, 1995). In this context, the word “spreading” means that 1997), but subject D was fully capable of activating semantic during speech production tasks (e.g., naming) many words are knowledge when given an external stimulus as demonstrated by activated simultaneously interfering one each other while the his preserved ability to name nouns and verbs. This pattern of subject is selecting which one should be produced (Dell, 1986; performance (failure in initiating and sustaining a response in Thompson-Schill et al., 1997; Levelt et al., 1999; Moss et al., the absence of external cues) in subject D may be indicative of 2005; Silkes and Rogers, 2012; Anders et al., 2017; Schnur, 2017). failure to spontaneously active lexical semantic representations In this connection, we recently studied an adult person with (Cox and Heilman, 2011) perhaps due to impaired attentional ADA due to a left opercular-insular infarction, who commented processes (energization) (Stuss and Alexander, 2007; Stuss, 2011; on that during language tasks “many words come to my mind, Barker et al., 2018). but I cannot decide which one to choose. . .” (Berthier et al., in preparation). However, this mechanism seems not to be the one that explain DDD in subject D, who instead reported that Pitfalls of Establishing Brain-Behavior no words come to him during speech production tasks. Subject Relationships in a Malformed Brain D was capable of carrying out most language tasks dependent The syndrome of ADA is uncommon (Robinson et al., 1998; upon external stimuli (naming, repetition), but creating and Berthier, 1999; Alexander, 2006) and we envisage that a DDD, as organizing a narrative was challenging for him. It seems that the one found in subject D, may be even rarer because it coexisted in the case of subject D a marked reduced activation of lexical with bilateral brain malformations that distorted the architecture items prevails as a possible explanation for the impaired ability and connectivity of networks mediating expressive language and to generate words and sentences in both real life and testing communication. Nevertheless, piecemeal analysis of the different situations (see Alexander, 2006; Stuss and Alexander, 2007; malformations may illuminate the mechanisms underlying DDD Cox and Heilman, 2011; Silkes and Rogers, 2012). Moreover, in the present case. In first place, we analyze the role of cognitive testing in subject D revealed impaired performance gyral abnormalities in the left operculum on speech production in all tasks tapping executive functions (TMT, HSCT, WCST, deficits. The structural MRI showed a short sylvian fissure with ST) unveiling that dysfunctional domain-general mechanisms are arrested development of the left fronto-temporal operculum also contributing to dDD. and exposure of a hypoplastic insular cortex (open operculum) The pattern of performance exhibited by subject D on the indicative of a cortical dysplasia (Tatum et al., 1989; Piven et al., two-part sentence completion task (HSCT) and on experimental 1990; Van Bogaert et al., 1998). Detailed visual analysis of thin tasks for DA would further illuminate the putative mechanism slices in high-resolution MRI also revealed that the configuration of reduced activation of lexical items underlying DDD. The of the right Sylvian fissure was also atypical. Functional imaging HSCT is thought to assess both initiation speed and response also showed atypical results. While healthy subjects activate suppression (Burgess and Shallice, 1997); therefore, delays in the left IFG in fluency tasks, as revealed by the Neurosynth completing the missing word (Section 1) and failures to inhibit a meta-analysis for the term “verbal fluency” (Supplementary strongly activated response before generating a new unconnected Figure S1A), the fMRI acquired during a phonological fluency one (Section 2) are the expected outcomes in persons with task in subject D revealed that increased activation in the left frontal lobe involvement (Robinson et al., 2015a, 2016). Analysis inferior frontal gyrus resulted only when using an uncorrected of this task in subject D revealed impaired performance in p < 0.01 statistical threshold during this language task compared the two sections and errors were omissions. No automatic to rest. Small foci of activation were found in the homologous completions were produced in Section 2 and, instead, subject D contralateral gyrus at a lower statistical threshold p < 0.001 produced no responses. Failure to generate a completion word uncorrected). Although the fMRI experiment and the structure has been associated with left frontal lesions (Robinson et al., of the fluency task applied in this study did not allow to separate 2015b, 2016) and represents a typical pattern of performance right from bad trials (i.e., sustained brain response was measured in individuals with ADA (Robinson et al., 2005). In the same during the whole block in which the subject was instructed to vein, he performed significantly worse than healthy controls in mentally evoke as many words as possible), the atypical pattern of experimental tests of DA (Robinson et al., 1998), particularly in functional activation together with the fact that subject D showed the more demanding ones. One constant characteristic of subject a poor performance in fluency task, suggest that contralateral D while performing these tasks was that he frequently remained functional plasticity in this case has been maladaptive. These silent when asked to produce a sentence or to generate a brief results suggest that in the presence of a dysfunctional left story. When he was asked why he did not produce the requested frontal cortex, the right anterior perisylvian area was not information, he said “I have no words. . .. Words don’t come fully competent to subserve efficient communication. Thus, it to me.” Moreover, his performance on the picture-generated seems that this cross-hemispheric plasticity (left → right) could narrative and phonological and semantic fluency tasks were compensate basic language operations (i.e., object and verb also extremely poor. Nevertheless, other language functions (i.e., naming, repetition), but was not sufficient to guarantee more Frontiers in Human Neuroscience | www.frontiersin.org 15 March 2020 | Volume 14 | Article 73 Berthier et al. Developmental Dynamic Dysphasia elaborated language and communication skills required for the In second place, we examine the putative role of the generation of fluent discourse. dysmorphic white matter tracts in DDD. Previous studies Early left hemisphere injury may result in functional have shown a strong relationship between the failure to reorganization that, although permits sparing of language and identify the left AF and language dysfunction in cases with motor skills, may distort the development of right hemisphere developmental cortical gyral abnormalities (Andrade et al., functions (Sandson et al., 1994; Satz et al., 1994). Moreover, 2015; Paldino et al., 2015, 2016). Poor development of the individuals with unilateral, bilateral or diffuse gyral abnormalities left FAT has been related to profound expressive language in the frontotemporal operculum, like the ones found in subject impairmentin a child with a sex-linked chromosomopathy D, have language delay (Guerreiro et al., 2002) which may (karyotype 49, XXXXY) syndrome (Dhakar et al., 2016) and persist into adulthood (Graff-Radford et al., 1986; Guerreiro therapeutic interventions improving speech production and et al., 2000). In such cases, positron emission tomography shows everyday verbal communication in post-stroke aphasia correlated altered (decreased, increased or both) metabolic activity in both with structural plasticity of the FAT and direct segment of the cerebral hemispheres (Van Bogaert et al., 1998; Luat et al., 2006). AF (Berthier et al., 2017). While there is marked individual In the same line, children with specific language impairments variability in the configuration of left and right white matter (developmental dysphasia) show lack of fMRI activation during tracts in healthy subjects (Gharabaghi et al., 2009; Berthier category fluency, responsive naming and picture naming tasks et al., 2012), the spatial arrangement of most white matter in left perisylvian language areas with hyperactivation in the bundles in subject D was atypical. We could retrieve all long- right inferior frontal gyrus, insula and caudate nucleus (de distance white matter tracts in both cerebral hemispheres, but Guibert et al., 2011). Note that the compensation of language their configuration was distorted adopting an architecture that deficits by the right hemisphere in left brain-damaged children markedly deviated from the normal pattern. The cumbersome is variable and depends on the residual capacity of the left arrangements of most retrieved white matter tracts in both hemisphere to maintain some language function (see references cerebral hemispheres were probably the result of the non- in Reilly et al., 2013). Nevertheless, another influential factor canonical configuration of the cortical mantle. DTI-tractography for the expected bias of transferring language functions to also disclosed abnormal decussation of the CSTs, a finding that the right hemisphere in cases with left hemisphere damage correlated in subject D with the CMM. (developmental or acquired) would be the functional status of The study of neurophysiological correlates of CMM with the right hemisphere. We suggest that DDD in subject D may TMS study showed that unilateral stimulation of hand motor have resulted from the left perisylvian dysgenesis and also for cortical area disclosed cortical bilateral responses. There are the limited capacity of the unfit right hemisphere to ensure some limitations of our TMS study. First, TMS was not the development and evolution of more elaborated aspects of guided by a neuronavigation software module. Therefore, we oral expression (i.e., conversation, narrative discourse) (Berthier cannot confidently determine the position of the current with et al., 2012; Catani and Bambini, 2014; Lomlomdjian et al., respect to the brain sulcus and surface of subject D. Second, 2017). In other words, impaired language generation (verbal the use of a round coil in our TMS study cannot rule out adynamia) in subject D may have resulted from inefficient the simultaneous stimulation of the motor cortex in both neural plasticity in both hemispheres. By contrast, auditory hemispheres because of the coil structure. Third, we also comprehension in subject D ranged from preserved to mildly found that stimulation of both cerebral hemispheres showed impaired performance in most tasks and the fMRI showed that diminished cortical silent periods (CSP) for both muscles. CSP activation during a semantic decision task occurred in canonical are indexes of corticospinal inhibition during a tonic muscular areas mostly linked by the ventral stream (Saur et al., 2008; contraction probably representing a GABAb-mediated inhibitory López-Barroso et al., 2015). These areas include bilateral IFG, neurotransmission (Tergau et al., 1999). Therefore, shortened both pars triangularis and opercularis, the anterior temporal CSP after unilateral TMS in subject D may reflect the output lobe, the anterior and posterior superior temporal gyrus and from the non-stimulated M1 so that both the activity of motor the inferior parietal cortex. Supplementary Results revealed that cortices (M1) was released with intended uni-manual movements although there was a substantial overlap between the meta- (Cincotta et al., 2002). These bilateral responses were absent analysis fMRI results in healthy subjects for the term “semantic” when studying the cortical stimulations for leg muscles. Genetic and the results from the contrast Semantic Decision vs. rest in testing to identify mutations associated to altered development subject D (Supplementary Figure S1B), the pattern found in of commissural tracts (i.e., Germline DCC mutations) (Méneret subject D was more bilateral. This higher overlap compared to et al., 2014) were negative. the one observed for the fluency task is in line with the fact that subject D’s performance in comprehension and semantic tasks was acceptable, and in addition it would show some evidence Is the Diagnosis of Developmental that at least in some functions, the atypical brain configuration Dynamic Dysphasia Reliable? observed in this case can be functional. Nevertheless, since results There is a caveat about reliability of diagnosis when one describes from the supplementary Neurosynth fMRI meta-analysis come a well-known yet rare syndrome occurring for the first time from heterogeneous studies (e.g., different population, different in association with a new pathological condition (abnormal tasks), these results should be taken cautiously and interpreted brain development). Analysis of more cases is clearly needed as a whole with the rest of the image results and clinical to confirm or reject the accuracy of the diagnosis. Note, characteristics reported. however, that original cases of ADA were invariably associated Frontiers in Human Neuroscience | www.frontiersin.org 16 March 2020 | Volume 14 | Article 73 Berthier et al. Developmental Dynamic Dysphasia to focal lesions (tumors, stroke, trauma) (i.e., Costello and AUTHOR CONTRIBUTIONS Warrington, 1989; Robinson et al., 1998) but several years later similar cases have been related to different neurodegenerative All authors listed have made a substantial, direct and conditions (i.e., Parkinson’s dementia, progressive supranuclear intellectual contribution to the work, and approved it for palsy, corticobasal degeneration, prion diseases) (Kartsounis publication. MB, GD, MT-P, and DL-B were involved in et al., 1991; Esmonde et al., 1996; Warren et al., 2003; Caine conception and design, acquisition of data, or analysis et al., 2018; Magdalinou et al., 2018). The syndrome of ADA and interpretation of data. LE, LM-C, DM-S, and PZ is a variant of TCMA (Berthier, 1999) and cases of this were involved in cognitive and language testing. JC and syndrome of developmental origin have not been reported so OD-I performed genetic testing. IM-T, VF, and MP far. However, developmental conduction aphasia has recently performed the neurophysiological studies. MB and DL-B been reported in a group study showing that specific and long- interpreted the neuroimaging data. MB, GD, and DL-B lasting problems with speech repetition were similar to the drafted the manuscript and revised it critically for important syndrome reported in adults (Northam et al., 2018). Similarly, intellectual content. the foreign accent syndrome previously described associated to focal lesions (Moreno-Torres et al., 2016) and neurodegenerative disorders (Luzzi et al., 2008) has recently been reported as a FUNDING developmental disorder (Mariën et al., 2009; Berthier et al., 2016; Keulen et al., 2016). The second point is that subject D had non- MT-P and LE have been funded by Ph.D. scholarships from language cognitive and motor disorders that may cast doubts the Spanish Ministry of Education, Culture and Sport under on the reliability of the diagnosis of DDD. The contribution of the FPU program (MT-P: FPU14/04021 and LE: FPU17/04136). impaired performance on tasks tapping executive functions to DL-B has been supported the “Juan de la Cierva-Incorporación” DDD is in agreement with reports of ADA, which attributed program (IJCI-2017-34164) of the Spanish Ministry of Economy such deficits to impaired domain-general mechanisms (Robinson and Competitiveness. LM-C has been supported by funds et al., 2006). Nevertheless, we consider the presence of CMM from the European Social Fund (E-29-201-0705972). IM-T and low intellectual function unrelated to DDD. In support of has been supported by a grant from the Ministerio de this argument, most cases of CMM are discrete and not disabling Ciencia, Innovación y Universidades (RTI2018-094846-B-100). coursing without concomitant cognitive deficits (Méneret et al., This study has been supported in part by a Grant from 2014, 2015) and low IQ is a constant feature of patients with ADA the Ministerio de Economia, Industria y Competitividad of of different etiologies (Robinson et al., 1998, 2006, 2015). Spain (PI16/01514). DATA AVAILABILITY STATEMENT ACKNOWLEDGMENTS The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to The authors thank subject D and his mother for their willingness any qualified researcher. to participate in this study and for their patience during prolonged interviews and testing sessions. ETHICS STATEMENT SUPPLEMENTARY MATERIAL The studies involving human participants were reviewed and approved by the Ethical Research Committee Provincial of The Supplementary Material for this article can be found Malaga, Spain. The participants provided their written informed online at: https://www.frontiersin.org/articles/10.3389/fnhum. consent to participate in the study. 2020.00073/full#supplementary-material REFERENCES Andrade, C. S., Figueiredo, K. G., Valeriano, C., Mendoza, M., Valente, K. D., Otaduy, M. C., et al. (2015). DTI-based tractography of the arcuate fasciculus Abusamra, V., Miranda, M. A., and Ferreres, A. (2007). Evaluación de la iniciación in patients with polymicrogyria and language disorders. Eur. J. Radiol. 84, e inhibición verbal en español: adaptación y normas del test de hayling. Rev. 2280–2286. doi: 10.1016/j.ejrad.2015.07.014 Arg. Neuropsicol. 9, 19–32. Arango-Lasprilla, J. C., Rivera, D., Ramos-Usuga, D., Vergara-Moragues, Alexander, M. P. (2006). 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