Cognitive reserve involves decision making and is associated with left parietal and hippocampal hypertrophy in neurodegeneration.

Cognitive reserve is the ability to actively cope with brain deterioration and delay cognitive decline in neurodegenerative diseases. It operates by optimizing performance through differential recruitment of brain networks or alternative cognitive strategies. We investigated cognitive reserve using Huntington's disease (HD) as a genetic model of neurodegeneration to compare premanifest HD, manifest HD, and controls. Contrary to manifest HD, premanifest HD behave as controls despite neurodegeneration. By decomposing the cognitive processes underlying decision making, drift diffusion models revealed a response profile that differs progressively from controls to premanifest and manifest HD. Here, we show that cognitive reserve in premanifest HD is supported by an increased rate of evidence accumulation compensating for the abnormal increase in the amount of evidence needed to make a decision. This higher rate is associated with left superior parietal and hippocampal hypertrophy, and exhibits a bell shape over the course of disease progression, characteristic of compensation.

Language disorders in patients with striatal lesions: Deciphering the role of the striatum in language performance.

The classical neural model of language refers to a cortical network involving frontal, parietal and temporal regions. However, patients with subcortical lesions of the striatum have language difficulties. We investigated whether the striatum is directly involved in language or whether its role in decision-making has an indirect effect on language performance, by testing carriers of Huntington's disease (HD) mutations and controls. HD is a genetic neurodegenerative disease primarily affecting the striatum and causing language disorders. We asked carriers of the HD mutation in the premanifest (before clinical diagnosis) and early disease stages, and controls to perform two discrimination tasks, one involving linguistic and the other non-linguistic stimuli. We used the hierarchical drift diffusion model (HDDM) to analyze the participants' responses and to assess the decision and non-decision parameters separately. We hypothesized that any language deficits related to decision-making impairments would be reflected in the decision parameters of linguistic and non-linguistic tasks. We also assessed the relative contributions of both HDDM decision and non-decision parameters to the participants' behavioral data (response time and discriminability). Finally, we investigated whether the decision and non-decision parameters of the HDDM were correlated with brain atrophy. The HDDM analysis showed that patients with early HD have impaired decision parameters relative to controls, regardless of the task. In both tasks, decision parameters better explained the variance of response time and discriminability performance than non-decision parameters. In the linguistic task, decision parameters were positively correlated with gray matter volume in the ventral striatum and putamen, whereas non-decision parameters were not. Language impairment in patients with striatal atrophy is better explained by a deficit of decision-making than by a deficit of core linguistic processing. These results suggest that the striatum is involved in language through the modulation of decision-making, presumably by regulating the process of choice between linguistic alternatives.

A case-study of language-specific executive disorder.

Executive control is recruited for language processing, particularly in complex linguistic tasks. Although the issue of the existence of an executive control specific to language is still an open issue, there is much evidence that executively-demanding language tasks rely on domain-general rather than language-specific executive resources. Here, we addressed this issue by assessing verbal and non-verbal executive capacities in LG, an aphasic patient after a stroke. First, we showed that LG's performance was spared in all non-verbal tasks regardless of the executive demands. Second, by contrasting conditions of high and low executive demand in verbal tasks, we showed that LG was only impaired in verbal task with high executive demand. The performance dissociation between low and high executive demand conditions in the verbal domain, not observed in the non-verbal domain, shows that verbal executive control partly dissociates from non-verbal executive control. This language-specific executive disorder suggests that some executive processes might be language-specific.

Striatum and language processing: Where do we stand?

More than a century ago, Broca (1861), Wernicke (1874) and Lichteim (1885) laid the foundations for the first anatomo-functional model of language, secondarily enriched by Geschwind (1967), leading to the Broca-Wernicke-Lichteim-Geschwind model. This model included the frontal, parietal, and temporal cortices as well as a subcortical structure, which could be the striatum, whose nature and role have remained unclear. Although the emergence of language deficits in patients with striatal injury has challenged the cortical language models developed over the past 30 years, the integration of the striatum into language processing models remains rare. The main argument for not including the striatum in language processing is that the disorders observed in patients with striatal dysfunction may result from the striatal role in cognitive functions beyond language, and not from the impairment of language itself. Indeed, unraveling the role of the striatum and the frontal cortex, linked by the fronto-striatal pathway, is a challenge. Here, we first reviewed the studies that explored the link between striatal functions and the different levels of language (phonetics, phonology, morphology, syntax, and lexico-semantics). We then looked at the language models, which included the striatum, and found that none of them captured the diversity of experimental data in this area. Finally, we propose an integrative anatomo-functional model of language processing combining traditional language processing levels and some "executive" functions, known to improve the efficiency and fluidity of language: control, working memory, and attention. We argue that within this integrative model, the striatum is a central node of a verbal executive network that regulates, monitors, and controls the allocations of limited cognitive resources (verbal working memory and verbal attention), whatever the language level. This model combines data from neurology, psycholinguistics, and cognitive science.

Aberrant brain network connectivity in presymptomatic and manifest Huntington's disease: A systematic review.

Resting-state functional magnetic resonance imaging (rs-fMRI) has the potential to shed light on the pathophysiological mechanisms of Huntington's disease (HD), paving the way to new therapeutic interventions. A systematic literature review was conducted in three online databases according to PRISMA guidelines, using keywords for HD, functional connectivity, and rs-fMRI. We included studies investigating connectivity in presymptomatic (pre-HD) and manifest HD gene carriers compared to healthy controls, implementing seed-based connectivity, independent component analysis, regional property, and graph analysis approaches. Visual network showed reduced connectivity in manifest HD, while network/areas underpinning motor functions were consistently altered in both manifest HD and pre-HD, showing disease stage-dependent changes. Cognitive networks underlying executive and attentional functions showed divergent anterior-posterior alterations, possibly reflecting compensatory mechanisms. The involvement of these networks in pre-HD is still unclear. In conclusion, aberrant connectivity of the sensory-motor network is observed in the early stage of HD while, as pathology spreads, other networks might be affected, such as the visual and executive/attentional networks. Moreover, sensory-motor and executive networks exhibit hyper- and hypo-connectivity patterns following different spatiotemporal trajectories. These findings could potentially help to implement future huntingtin-lowering interventions.

Improving language evaluation in neurological disorders: The French Core Assessment of Language Processing (CALAP).

Aphasia is a devastating brain disorder, detrimental for medical care and social interaction. The early diagnosis of language disorders and accurate identification of patient-specific deficits are crucial for patients' care, as aphasia rehabilitation is more effective when focused on patient-specific language deficits. We developed the Core Assessment of Language Processing (CALAP), a new scale combining screening and detailed evaluation to rapidly diagnose and identify patient-specific language deficits. This scale is based on a model of language processing distinguishing between the comprehension, production, and repetition modalities, and their different components: phonology (set of speech-sounds), morphology (how the sounds combine to form words), lexicon (words), syntax (how words combine to form sentences), and concept (semantic knowledge). This scale was validated by 189 participants who underwent the CALAP, and patients not unequivocally classified as without aphasia by a speech-language pathologist underwent the Boston Diagnosis Aphasia Evaluation as the gold standard. CALAP-screening classified patients with and without aphasia with a sensitivity of 1 and a specificity of 0.72, in 3.14 ± 1.23 min. CALAP-detailed evaluation specifically assessed the language components in 8.25 ± 5.1 min. Psychometric properties including concurrent validity, internal validity, internal consistency and interrater reliability showed that the CALAP is a valid and reliable scale. The CALAP provides an aphasia diagnosis along with the identification of patient-specific impairment making it possible to improve clinical follow up and deficit-based rehabilitation. It is a short and easy-to-use scale that can be scored and interpreted by clinicians nonexpert in language, in patients with fatigue and concentration deficits. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The role of the striatum in linguistic selection: Evidence from Huntington's disease and computational modeling.

Though accumulating evidence indicates that the striatum is recruited during language processing, the specific function of this subcortical structure in language remains to be elucidated. To answer this question, we used Huntington's disease as a model of striatal lesion. We investigated the morphological deficit of 30 early Huntington's disease patients with a novel linguistic task that can be modeled within an explicit theory of linguistic computation. Behavioral results reflected an impairment in HD patients on the linguistic task. Computational model-based analysis compared the behavioral data to simulated data from two distinct lesion models, a selection deficit model and a grammatical deficit model. This analysis revealed that the impairment derives from an increased randomness in the process of selecting between grammatical alternatives, rather than from a disruption of grammatical knowledge per se. Voxel-based morphometry permitted to correlate this impairment to dorsal striatal degeneration. We thus show that the striatum holds a role in the selection of linguistic alternatives, just as in the selection of motor and cognitive programs.

Structural priming in sentence comprehension: A single prime is enough.

Experiencing a syntactic structure affects how we process subsequent instances of that structure. This phenomenon, called structural priming, is observed both in language production and in language comprehension. However, while abstract syntactic structures can be primed independent of lexical overlap in sentence production, evidence for structural priming in comprehension is more elusive. In addition, when structural priming in comprehension is found, it can often be accounted for in terms of participants' explicit expectations. Participants may use the structural repetition over several sentences and build expectations, which create a priming effect. Here, we use a new experimental paradigm to investigate structural priming in sentence comprehension independent of lexical overlap and of participants' expectations. We use an outcome dependent variable instead of commonly used online measures, which allows us to more directly compare these effects with those found in sentence production studies. We test priming effects in syntactically homogeneous and heterogeneous conditions on a sentence-picture matching task that forces participants to fully parse the sentences. We observe that, while participants learn the structural regularity in the homogeneous condition, structural priming is also found in the heterogeneous condition, in which participants do not expect any particular structure. In fact, we find that a single prime is enough to trigger priming. Our results indicate that-like in sentence production-structural priming can be observed in sentence comprehension without lexical repetition and independent of participants' expectation.

COMT Val158Met Polymorphism Modulates Huntington's Disease Progression.

Little is known about the genetic factors modulating the progression of Huntington's disease (HD). Dopamine levels are affected in HD and modulate executive functions, the main cognitive disorder of HD. We investigated whether the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, which influences dopamine (DA) degradation, affects clinical progression in HD. We carried out a prospective longitudinal multicenter study from 1994 to 2011, on 438 HD gene carriers at different stages of the disease (34 pre-manifest; 172 stage 1; 130 stage 2; 80 stage 3; 17 stage 4; and 5 stage 5), according to Total Functional Capacity (TFC) score. We used the Unified Huntington's Disease Rating Scale to evaluate motor, cognitive, behavioral and functional decline. We genotyped participants for COMT polymorphism (107 Met-homozygous, 114 Val-homozygous and 217 heterozygous). 367 controls of similar ancestry were also genotyped. We compared clinical progression, on each domain, between groups of COMT polymorphisms, using latent-class mixed models accounting for disease duration and number of CAG (cytosine adenine guanine) repeats. We show that HD gene carriers with fewer CAG repeats and with the Val allele in COMT polymorphism displayed slower cognitive decline. The rate of cognitive decline was greater for Met/Met homozygotes, which displayed a better maintenance of cognitive capacity in earlier stages of the disease, but had a worse performance than Val allele carriers later on. COMT polymorphism did not significantly impact functional and behavioral performance. Since COMT polymorphism influences progression in HD, it could be used for stratification in future clinical trials. Moreover, DA treatments based on the specific COMT polymorphism and adapted according to disease duration could potentially slow HD progression.

Pointing to others: How the target gender influences pointing performance.

Pointing is a communicative gesture that allows individuals to share information about surrounding objects with other humans. Patients with heterotopagnosia are specifically impaired in pointing to other humans' body parts but not in pointing to themselves or to objects. Here, we describe a female patient with heterotopagnosia who was more accurate in pointing to men's body parts than to women's body parts. We replicated this gender effect in healthy participants with faster reaction times for pointing to men's body parts than to women's body parts. We discuss the role of gender stereotypes in explaining why it is more difficult to point to women than to men.

Complex linguistic rules modulate early auditory brain responses.

During speech perception, listeners compensate for phonological rules of their language. For instance, English place assimilation causes green boat to be typically pronounced as greem boat; English listeners, however, perceptually compensate for this rule and retrieve the intended sound (n). Previous research using EEG has focused on rules with clear phonetic underpinnings, showing that perceptual compensation occurs at an early stage of speech perception. We tested whether this early mechanism also accounts for the compensation for more complex rules. We examined compensation for French voicing assimilation, a rule with abstract phonological restrictions on the contexts in which it applies. Our results reveal that perceptual compensation for this rule by French listeners modulates an early ERP component. This is evidence that early stages of speech sound categorization are sensitive to complex phonological rules of the native language.

The second person in "I"-"you"-"it" triadic interactions.

Second person social cognition cannot be restricted to dyadic interactions between two persons (the "I" and the "you"). Many instances of social communication are triadic, and involve a third person (the "him/her/it"), which is the object of the interaction. We discuss neuropsychological and brain imaging data showing that triadic interactions involve dedicated brain networks distinct from those of dyadic interactions.

Awareness of memory deficits in early stage Huntington's disease.

Patients with Huntington's disease (HD) are often described as unaware of their motor symptoms, their behavioral disorders or their cognitive deficits, including memory. Nevertheless, because patients with Parkinson's disease (PD) remain aware of their memory deficits despite striatal dysfunction, we hypothesize that early stage HD patients in whom degeneration predominates in the striatum can accurately judge their own memory disorders whereas more advanced patients cannot. In order to test our hypothesis, we compared subjective questionnaires of memory deficits (in HD patients and in their proxies) and objective measures of memory dysfunction in patients. Forty-six patients with manifest HD attending the out-patient department of the French National Reference Center for HD and thirty-three proxies were enrolled. We found that HD patients at an early stage of the disease (Stage 1) were more accurate than their proxies at evaluating their own memory deficits, independently from their depression level. The proxies were more influenced by patients' functional decline rather than by patients' memory deficits. Patients with moderate disease (Stage 2) misestimated their memory deficits compared to their proxies, whose judgment was nonetheless influenced by the severity of both functional decline and depression. Contrasting subjective memory ratings from the patients and their objective memory performance, we demonstrate that although HD patients are often reported to be unaware of their neurological, cognitive and behavioral symptoms, it is not the case for memory deficits at an early stage. Loss of awareness of memory deficits in HD is associated with the severity of the disease in terms of CAG repeats, functional decline, motor dysfunction and cognitive impairment, including memory deficits and executive dysfunction.

Specificity in rehabilitation of word production: a meta-analysis and a case study.

Speech production impairment is a frequent deficit observed in aphasic patients and rehabilitation programs have been extensively developed. Nevertheless, there is still no agreement on the type of rehabilitation that yields the most successful outcomes. Here, we ran a detailed meta-analysis of 39 studies of word production rehabilitation involving 124 patients. We used a model-driven approach for analyzing each rehabilitation task by identifying which levels of our model each task tapped into. We found that (1) all rehabilitation tasks are not equally efficient and the most efficient ones involved the activation of the two levels of the word production system: the phonological output lexicon and the phonological output, and (2) the activation of the speech perception system as it occurs in many tasks used in rehabilitation is not successful in rehabilitating word production. In this meta-analysis, the effect of the activation of the phonological output lexicon and the phonological output cannot be assessed separately. We further conducted a rehabilitation study with DPI, a patient who suffers from a damage of the phonological output lexicon. Our results confirm that rehabilitation is more efficient, in terms of time and performance, when specifically addressing the impaired level of word production.

Is the word-length effect linked to subvocal rehearsal?

Models of phonological short-term memory (pSTM) generally distinguish between two components: a phonological buffer and a subvocal rehearsal. Evidence for these two components comes, respectively, from the phonological similarity effect and the word-length effect which disappears under articulatory suppression. But alternative theories posit that subvocal rehearsal is only an optional component of the pSTM. According to them, the depletion of the length effect under articulatory suppression results from the interference of the self-produced speech rather than the disruption of subvocal rehearsal. In order to disentangle these two theories, we tested two patients with a short-term memory deficit. FA, who presents a pseudoword repetition deficit, and FL, who does not. FA's deficit allowed for the observance of an ecological case of subvocal rehearsal disruption without any articulatory suppression task. FA's performance in pSTM tasks reveals as controls a phonological similarity effect, and contrary to controls no word-length effect. In contrast, the second patient, FL, exhibits the same effects as control subjects. This result is in accordance with models of pSTM in which the word-length effect emerges from subvocal rehearsal and disappears when this latter is disrupted.

Breaking the mirror: Asymmetrical disconnection between the phonological input and output codes.

In this paper, we study the link between the processing systems that sustain speech perception and production in a patient (F.A.) with conduction aphasia. Her pattern of performance in repetition task - quantitative but also qualitative striking difference in errors with pseudowords versus words - cannot be properly accounted for either by a perception deficit or by a production deficit. We discuss this finding according to theoretical models of phonological processing and show that it is best explained by an impaired ability to transfer phonological information from the perception to the production system. We also probed for a phonological link in the opposite direction, from the production to the perception system. F.A.'s results show that this link was not impaired. Overall, our results suggest that (a) the phonological codes in perception and in production are separate but connected by two conversion mechanisms and that (b) these two mechanisms can be disrupted independently.

What is the relationship between phonological short-term memory and speech processing?

Traditionally, models of speech comprehension and production do not depend on concepts and processes from the phonological short-term memory (pSTM) literature. Likewise, in working memory research, pSTM is considered to be a language-independent system that facilitates language acquisition rather than speech processing per se. We discuss couplings between pSTM, speech perception and speech production, and we propose that pSTM arises from the cycling of information between two phonological buffers, one involved in speech perception and one in speech production. We discuss the specific role of these processes in speech processing, and argue that models of speech perception and production, and our understanding of their neural bases, will benefit from incorporating them.

Misperception in sentences but not in words: Speech perception and the phonological buffer.

We report two case studies of aphasic patients with a working-memory impairment due to reduced storage in the phonological buffer. The two patients display excellent performance in phonological discrimination tasks as long as the tasks do not involve a memory load. We then show that their performance drops when they have to maintain fine-grained phonological information for sentence comprehension: They are impaired at mispronunciation detection and at comprehending sentences involving minimal word pairs. We argue that the phonological buffer plays a role in sentence perception during the phonological analysis of the speech stream: It sustains the temporary storage of phonological input in order to check and resolve phonological ambiguities, and it also allows reexamination of the phonological input if necessary.

Phonological grammar shapes the auditory cortex: a functional magnetic resonance imaging study.

Languages differ depending on the set of basic sounds they use (the inventory of consonants and vowels) and on the way in which these sounds can be combined to make up words and phrases (phonological grammar). Previous research has shown that our inventory of consonants and vowels affects the way in which our brains decode foreign sounds (Goto, 1971; Näätänen et al., 1997; Kuhl, 2000). Here, we show that phonological grammar has an equally potent effect. We build on previous research, which shows that stimuli that are phonologically ungrammatical are assimilated to the closest grammatical form in the language (Dupoux et al., 1999). In a cross-linguistic design using French and Japanese participants and a fast event-related functional magnetic resonance imaging (fMRI) paradigm, we show that phonological grammar involves the left superior temporal and the left anterior supramarginal gyri, two regions previously associated with the processing of human vocal sounds.