Phonological impairments in Hindi aphasics: Error analyses and cross-linguistic comparisons.

We assessed phonological and apraxic impairments in Hindi persons with aphasia (PwA) and compared them to Italian PwA reported in previous studies. Overall, we found strong similarities. Phonological errors were present across production tasks (repetition, reading and naming), most errors were non-lexical and, among those, a majority involved individual phonemes. There were significant effects of length, but not frequency. Hindi PwA, like the Italian PwA, showed strong effects of syllabic structure, with most errors occurring on consonants and weak syllabic positions, preserving syllable structure and simplifying phonemes or syllabic templates. These similarities were modulated by some language-specific patterns. Vowel insertions were more common in Hindi, possibly due to the presence of a central vowel, and segmental simplifications concentrated on marked aspiration and retroflection features. We hope our study will encourage further research in Hindi and other Indian languages. This will improve clinical diagnosis and our understanding of cross-linguistic differences.

The impact of metabolic control on cognition, neurophysiology, and well-being in PKU: A systematic review and meta-analysis of the within-participant literature.

Phenylketonuria (PKU) is a metabolic disease where Phenylalanine (Phe) rises much above normal levels. Cross-sectional and correlational studies provide valuable information on the importance of maintaining low blood-Phe to achieve good outcomes, but they may be confounded, at least partially, by differences in participant demographics. Moreover, the effect of Phe at older ages is difficult to ascertain because of strong associations between Phe levels across ages. Within-participant studies avoid confounding issues. We have reviewed these studies. We followed PRISMA guidelines to search the literature for studies reporting the impact of Phe changes within participants. Phe was either increased or decreased through diet relaxation/resumption or through pharmacological interventions. Forty-six separate articles reported, singly or in combination, results on cognition (N = 37), well-being (N = 22) and neurophysiological health (N = 14). For all studies, we established, in a binary way, whether a benefit of lower Phe was or was not demonstrated and compared numbers showing benefit versus a null or negative outcome. We then analyzed whether critical parameters (e.g., length of the study/condition for the change, size of Phe change achieved) influenced presence or absence of benefit. For a subset of studies that reported quantitative cognitive outcomes, we carried out a meta-analysis to estimate the size of change in cognitive performance associated with a change in Phe and its significance. There were significantly more studies with benefits than no benefits, both for cognitive and well-being outcomes, and a trend in this direction for neurophysiological outcomes. The meta-analysis showed a highly significant effect size both overall (0.55) and when studies with adults/adolescents were considered separately (0.57). There was some indication that benefits were easier to demonstrate when differences in Phe were larger and achieved across a longer period, but these effects were not always consistent. These results reinforce results from the literature by demonstrating the importance of lower Phe in children as well as in adolescents and adults, even when confounding factors in group composition are eliminated. The field would benefit from further studies where Phe levels are contrasted within-participants to ascertain how much Phe needs to be changed and for how long to see a difference and which measures demonstrate a difference (e.g., which cognitive tasks).

Metabolic control and clinical outcome in adolescents with phenylketonuria.

The main neurological, cognitive, and behavioural consequences of phenylketonuria have been eradicated thanks to new-born screening and Phe-restricted diet therapy. However, the effects of high phenylalanine levels during adolescence and adulthood on neurocognitive functions remain a concern. This systematic review aimed at collecting clinical data suggesting the safest metabolic target for early treated PKU during the second decade of life. Twenty studies met the inclusion criteria for full-text review. Relevant studies included papers that (a) examined the relationship between metabolic control and neurocognitive functions during adolescence or (b) investigated the impact of metabolic control in adolescence on adult outcomes. Most studies showed a positive correlation between metabolic control during adolescence and neurocognitive outcomes across ages. This was true both for IQ and executive functions, although data on executive functions were less clear, and it remains to be established whether they are more vulnerable to Phe than IQ. Taken together present evidence confirm brain vulnerability to Phe during adolescence and suggests that low average Phe levels and low Phe fluctuations should be maintained throughout life. While results are fully compatible with current European recommendations, clinical and methodological limitations coupled with remarkable interindividual variability prevented a clear identification of a safe threshold for Phe blood levels during adolescence.

Towards precision medicine for phenylketonuria: The effect of restoring a strict metabolic control in adult patients with early-treated phenylketonuria.

BACKGROUND AND OBJECTIVE: Neonatal screening and early treatment have changed the natural history of PKU, preventing severe neurological and intellectual disability. Nevertheless, the outcome of the disease in early-treated adult patients (ETPKU) is less than optimal, the predictive value of metabolic biomarkers is feeble, and the recommended levels of blood phenylalanine (Phe) for adulthood are controversial. A crucial question whose answer will improve our understanding and treatment of PKU is whether cognitive outcomes can be modulated by levels of Phe even in early-treated adults. To address this question, we carried out an interventional study in seven ETPKU women planning a pregnancy. METHODS: They underwent an extensive neurocognitive assessment at baseline, and 3 and 6 months after having attained the blood Phe concentration recommended to prevent PKU fetopathy, but before pregnancy. RESULTS: After 3 and 6 months with a stable blood Phe level of about 240 µmol/L, all participants experienced significant improvements in almost all neurocognitive domains and tasks. IQ also increased of 11 to 21 points from the last assessment before enrolment. This pattern remained strong and consistent after correction for multiple comparisons. CONCLUSION: Our results indicate that a) strong cognitive improvement is possible even in adulthood and may be demonstrated by lowering Phe near normal levels; b) testing cognition under different metabolic conditions may unveil an individual vulnerability to Phe. These results pave the way for personalised treatment of the disease in adults with ETPKU.

Effects of delay, length, and frequency on onset RTs and word durations: Articulatory planning uses flexible units but cannot be prepared.

There is debate regarding whether most articulatory planning occurs offline (rather than online) and whether the products of off-line processing are stored in a separate articulatory buffer until a large enough chunk is ready for production. This hypothesis predicts that delayed naming conditions should reduce not only onset RTs but also word durations because articulatory plans will be buffered and kept ready. We have tested this hypothesis with young control speakers, an aphasic speaker , and an age and education-matched speaker, using repetition, reading and picture-naming tasks. Contrary to the off-line hypothesis, delayed conditions strongly reduced onset RTs, but had no benefit for word durations. In fact, we found small effects in the opposite direction. Moreover, frequency and imageability affected word durations even in delayed conditions, consistent with articulatory processing continuing on-line. The same pattern of results was found in CS and in control participants, strengthening confidence in our results. There is debate regarding whether most articulatory planning occurs offline (rather than online) and whether the results of off-line processing are stored in a separate articulatory buffer until a large enough chunk is ready for production. This hypothesis predicts that delayed naming conditions should reduce not only onset RTs but also word durations because articulatory plans will be buffered and kept ready. We have tested young control speakers, an aphasic speaker, and an age and education matched speaker, using repetition, reading and picture naming tasks. Contrary to the off-line hypothesis, delayed conditions strongly reduced onset RTs, but had no benefit for word durations. In fact, we found small effects in the opposite direction. Moreover, frequency and imageability affected word durations even in delayed conditions, consistent with articulatory processing continuing on-line. The same pattern of results was found in CS and in control participants, strengthening confidence in our results.

Semantic interference and facilitation in picture naming: The effects of type of impairment and compensatory strategies.

We assessed effects of semantic interference in people with aphasia (PWA). Two naming tasks (continuous naming and cyclic blocking) were contrasted with tasks which required suppression of competitors but minimized lexical access (probe task) or required extra-lexical mechanisms of control (Stroop task). In continuous naming, some PWA showed increased interference compared to control participants, with slower RTs and increased omissions. Others showed normal or weaker interference effects in terms of RTs but increased semantic errors. Patterns were consistent only between naming tasks. We explain results by assuming that some PWA are slow at implementing mechanisms of control/selection which weed-out competitors. Others, instead, will have activation difficulties which will induce them to lower the threshold needed for selection. Results highlight how different kinds of brain damage may induce different compensatory strategies and how semantic relatedness may induce both interference and facilitation. Implications for models of lexical selection are discussed.

Correlations of blood and brain biochemistry in phenylketonuria: Results from the Pah-enu2 PKU mouse.

BACKGROUND: In phenylketonuria (PKU), treatment monitoring is based on frequent blood phenylalanine (Phe) measurements, as this is the predictor of neurocognitive and behavioural outcome by reflecting brain Phe concentrations and brain biochemical changes. Despite clinical studies describing the relevance of blood Phe to outcome in PKU patients, blood Phe does not explain the variance in neurocognitive and behavioural outcome completely. METHODS: In a PKU mouse model we investigated 1) the relationship between plasma Phe and brain biochemistry (Brain Phe and monoaminergic neurotransmitter concentrations), and 2) whether blood non-Phe Large Neutral Amino Acids (LNAA) would be of additional value to blood Phe concentrations to explain brain biochemistry. To this purpose, we assessed blood amino acid concentrations and brain Phe as well as monoaminergic neurotransmitter levels in in 114 Pah-Enu2 mice on both B6 and BTBR backgrounds using (multiple) linear regression analyses. RESULTS: Plasma Phe concentrations were strongly correlated to brain Phe concentrations, significantly negatively correlated to brain serotonin and norepinephrine concentrations and only weakly correlated to brain dopamine concentrations. From all blood markers, Phe showed the strongest correlation to brain biochemistry in PKU mice. Including non-Phe LNAA concentrations to the multiple regression model, in addition to plasma Phe, did not help explain brain biochemistry. CONCLUSION: This study showed that blood Phe is still the best amino acid predictor of brain biochemistry in PKU. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters. TAKE-HOME MESSAGE: Blood Phe is still the best amino acid predictor of brain biochemistry in PKU. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters.

Psycholinguistic effects, types of impairments and processing levels in word production: Can we reduce confusions?

This commentary highlights three common difficulties faced by the literature that aims to specify models of speech production based on the performance of aphasic speakers, taking as a springboard a recent study by Mailend et al. These include: (1) difficulties with theoretical assumptions which linki psycholinguistic effects unequivocally to one processing level; (2) difficulties using clinical classifications to localize experimental effects; (3) difficulties making theoretical inferences given the controversial nature of the representations that characterize different processing levels. We argue that these three types of difficulties could be ameliorated by studies in which: (1) the level of psycholinguistic effects is demonstrated with converging analyses; (2) clinical classification is not taken as a starting point in studies investigating the nature of an impairment, but, instead, associations between clusters of symptoms are carefully analysed; (3) The nature of processing levels associated with deficits is made clear and results are not over-interpreted as supporting models whose characteristics go beyond an explanation of the results.

Cognitive style modulates semantic interference effects: evidence from field dependency.

The so-called semantic interference effect is a delay in selecting an appropriate target word in a context where semantic neighbours are strongly activated. Semantic interference effect has been described to vary from one individual to another. These differences in the susceptibility to semantic interference may be due to either differences in the ability to engage in lexical-specific selection mechanisms or to differences in the ability to engage more general, top-down inhibition mechanisms which suppress unwanted responses based on task-demands. However, semantic interference may also be modulated by an individual's disposition to separate relevant perceptual signals from noise, such as a field-independent (FI) or a field-dependent (FD) cognitive style. We investigated the relationship between semantic interference in picture naming and in an STM probe task and both the ability to inhibit responses top-down (measured through a Stroop task) and a FI/FD cognitive style measured through the embedded figures test (EFT). We found a significant relationship between semantic interference in picture naming and cognitive style-with semantic interference increasing as a function of the degree of field dependence-but no associations with the semantic probe and the Stroop task. Our results suggest that semantic interference can be modulated by cognitive style, but not by differences in the ability to engage top-down control mechanisms, at least as measured by the Stroop task.

Cognitive impairments in inherited metabolic diseases: Promises and challenges.

This is an introduction to the special issue on cognitive impairments in inherited metabolic diseases (IMD). It provides an overview of the studies included, focusing on the possibility of selective impairments which could provide unique evidence on the specificity of neural circuitries mediating cognitive functions. It will suggest that these circuitries have different metabolic properties which make them especially apt to carry out certain functions, but also particularly susceptible to certain forms of metabolic disruption. Knowledge of selective impairments is also crucial to properly evaluate the difficulties engendered by individual diseases and track treatment outcomes. IMR research holds the promise of a more complete understanding of cognition, from cellular functioning to behaviour and of further improvements in treatment. Advances, however, will require detailed assessments, comparisons across diseases, and the integration of different levels of explanation. This will be possible only through close collaborations between centres and types of professionals.

Language processing and executive functions in early treated adults with phenylketonuria (PKU).

We provide an in-depth analysis of language functions in early-treated adults with phenylketonuria (AwPKUs, N = 15-33), as compared to age- and education-matched controls (N = 24-32; N varying across tasks), through: a. narrative production (the Cinderella story), b. language pragmatics comprehension (humour, metaphors, inferred meaning), c. prosody discrimination d. lexical inhibitory control and planning (Blocked Cyclic Naming; Hayling Sentence Completion Test, Burgess & Shallice, 1997). AwPKUs exhibited intact basic language processing (lexical retrieval, phonology/articulation, sentence construction). Instead, deficits emerged in planning and reasoning abilities. Compared to controls, AwPKUs were: less informative in narrative production (lower rate of Correct Information Units); slower in metaphorical understanding and inferred meaning; less accurate in focused lexical-search (Hayling test). These results suggest that i) executive deficits in PKU cannot be explained by an accumulation of lower-order deficits and/or general speed impairments, ii) executive functions engage dedicated neurophysiological resources, rather than simply being an emergent property of lower-level systems.

Speed of processing and executive functions in adults with phenylketonuria: Quick in finding the word, but not the ladybird.

A reduction in processing speed is widely reported in phenylketonuria (PKU), possibly due to white matter pathology. We investigated possible deficits and their relationships with executive functions in a sample of 37 early-treated adults with PKU (AwPKUs). AwPKUs were not characterized by a generalized speed deficit, but instead their performance could be explained by two more specific impairments: (a) a deficit in the allocation of visuo-spatial attention that reduced speed in visual search tasks, in some reading conditions and visuo-motor coordination tasks; and (b) a more conservative decision mechanism that slowed down returning an answer across domains. These results suggest that the impairments in executive functions seen in AwPKUs are not the consequence of a generalized speed deficit. They also suggest that processing speed is linked to the efficiency of a particular cognitive component and cannot be considered a general function spanning domains. Similarities with patterns in ageing are discussed.

Comparing phoneme frequency, age of acquisition, and loss in aphasia: Implications for phonological universals.

Phonological complexity may be central to the nature of human language. It may shape the distribution of phonemes and phoneme sequences within languages, but also determine age of acquisition and susceptibility to loss in aphasia. We evaluated this claim using frequency statistics derived from a corpus of phonologically transcribed Italian words (phonitalia, available at phonitalia,org), rankings of phoneme age of acquisition (AoA) and rate of phoneme errors in patients with apraxia of speech (AoS) as an indication of articulatory complexity. These measures were related to cross-linguistically derived markedness rankings. We found strong correspondences. AoA, however, was predicted by both apraxic errors and frequency, suggesting independent contributions of these variables. Our results support the reality of universal principles of complexity. In addition they suggest that these complexity principles have articulatory underpinnings since they modulate the production of patients with AoS, but not the production of patients with more central phonological difficulties.

Morphological-compound dysgraphia in an aphasic patient: "A wild write through the lexicon".

We describe the case of a dysgraphic aphasic individual--S.G.W.--who, in writing to dictation, produced high rates of formally related errors consisting of both lexical substitutions and what we call morphological-compound errors involving legal or illegal combinations of morphemes. These errors were produced in the context of a minimal number of semantic errors. We could exclude problems with phonological discrimination and phonological short-term memory. We also excluded rapid decay of lexical information and/or weak activation of word forms and letter representations since S.G.W.'s spelling showed no effect of delay and no consistent length effects, but, instead, paradoxical complexity effects with segmental, lexical, and morphological errors that were more complex than the target. The case of S.G.W. strongly resembles that of another dysgraphic individual reported in the literature--D.W.--suggesting that this pattern of errors can be replicated across patients. In particular, both patients show unusual errors resulting in the production of neologistic compounds (e.g., "bed button" in response to "bed"). These patterns can be explained if we accept two claims: (a) Brain damage can produce both a reduction and an increase in lexical activation; and (b) there are direct connections between phonological and orthographic lexical representations (a third spelling route). We suggest that both patients are suffering from a difficulty of lexical selection resulting from excessive activation of formally related lexical representations. This hypothesis is strongly supported by S.G.W.'s worse performance in spelling to dictation than in written naming, which shows that a phonological input, activating a cohort of formally related lexical representations, increases selection difficulties.

PhonItalia: a phonological lexicon for Italian.

In this article, we present the first open-access lexical database that provides phonological representations for 120,000 Italian word forms. Each of these also includes syllable boundaries and stress markings and a comprehensive range of lexical statistics. Using data derived from this lexicon, we have also generated a set of derived databases and provided estimates of positional frequency use for Italian phonemes, syllables, syllable onsets and codas, and character and phoneme bigrams. These databases are freely available from phonitalia.org. This article describes the methods, content, and summarizing statistics for these databases. In a first application of this database, we also demonstrate how the distribution of phonological substitution errors made by Italian aphasic patients is related to phoneme frequency.

Lachancea thermotolerans and Saccharomyces cerevisiae in simultaneous and sequential co-fermentation: a strategy to enhance acidity and improve the overall quality of wine.

In the last few years there is an increasing interest on the use of mixed fermentation of Saccharomyces and non-Saccharomyces wine yeasts for inoculation of wine fermentations to enhance the quality and improve complexity of wines. In the present work Lachancea (Kluyveromyces) thermotolerans and Saccharomyces cerevisiae were evaluated in simultaneous and sequential fermentation with the aim to enhance acidity and improve the quality of wine. In this specific pairing of yeast strains in mixed fermentations (S. cerevisiae EC1118 and L. thermotolerans 101), this non-Saccharomyces yeast showed a high level of competitiveness. Nevertheless the S. cerevisiae strain dominated the fermentation over the spontaneous S. cerevisiae strains also under the industrial fermentation conditions. The different condition tested (modalities of inoculum, temperature of fermentation, different grape juice) influenced the specific interactions and the fermentation behaviour of the co-culture of S. cerevisiae and L. thermotolerans. However, some metabolic behaviours such as pH reduction and enhancement of 2-phenylethanol and glycerol, were shown here under all of the conditions tested. The specific chemical profiles of these wines were confirmed by the sensory analysis test, which expressed these results at the tasting level as significant increases in the spicy notes and in terms of total acidity increases.

Meta-analyses of cognitive functions in early-treated adults with phenylketonuria.

Our study estimated size of impairment for different cognitive functions in early-treated adults with PKU (AwPKU) by combining literature results in a meta-analytic way. We analysed a large set of functions (N = 19), each probed by different measures (average = 12). Data were extracted from 26 PKU groups and matched controls, with 757 AwPKU contributing 220 measures. Effect sizes (ESs) were computed using Glass' ∆ where differences in performance between clinical/PKU and control groups are standardized using the mean and standard deviation of the control groups. Significance was assessed using measures nested within independent PKU groups as a random factor. The weighted Glass' ∆ was - 0.44 for all functions taken together, and - 0.60 for IQ, both highly significant. Separate, significant impairments were found for most functions, but with great variability (ESs from -1.02 to -0.18). The most severe impairments were in reasoning, visual-spatial attention speed, sustained attention, visuo-motor control, and flexibility. Effect sizes were larger with speed than accuracy measures, and with visuo-spatial than verbal stimuli. Results show a specific PKU profile that needs consideration when monitoring the disease.

Model evaluation and case series data.

We discuss aggregation of data from neuropsychological patients and the process of evaluating models using data from a series of patients. We argue that aggregation can be misleading but not aggregating can also result in information loss. The basis for combining data needs to be theoretically defined, and the particular method of aggregation depends on the theoretical question and characteristics of the data. We present examples, often drawn from our own research, to illustrate these points. We also argue that statistical models and formal methods of model selection are a useful way to test theoretical accounts using data from several patients in multiple-case studies or case series. Statistical models can often measure fit in a way that explicitly captures what a theory allows; the parameter values that result from model fitting often measure theoretically important dimensions and can lead to more constrained theories or new predictions; and model selection allows the strength of evidence for models to be quantified without forcing this into the artificial binary choice that characterizes hypothesis testing methods. Methods that aggregate and then formally model patient data, however, are not automatically preferred to other methods. Which method is preferred depends on the question to be addressed, characteristics of the data, and practical issues like availability of suitable patients, but case series, multiple-case studies, single-case studies, statistical models, and process models should be complementary methods when guided by theory development.

Effects of syllable structure in aphasic errors: implications for a new model of speech production.

Current models of word production assume that words are stored as linear sequences of phonemes which are structured into syllables only at the moment of production. This is because syllable structure is always recoverable from the sequence of phonemes. In contrast, we present theoretical and empirical evidence that syllable structure is lexically represented. Storing syllable structure would have the advantage of making representations more stable and resistant to damage. On the other hand, re-syllabifications affect only a minimal part of phonological representations and occur only in some languages and depending on speech register. Evidence for these claims comes from analyses of aphasic errors which not only respect phonotactic constraints, but also avoid transformations which move the syllabic structure of the word further away from the original structure, even when equating for segmental complexity. This is true across tasks, types of errors, and, crucially, types of patients. The same syllabic effects are shown by apraxic patients and by phonological patients who have more central difficulties in retrieving phonological representations. If syllable structure was only computed after phoneme retrieval, it would have no way to influence the errors of phonological patients. Our results have implications for psycholinguistic and computational models of language as well as for clinical and educational practices.

Selected non-Saccharomyces wine yeasts in controlled multistarter fermentations with Saccharomyces cerevisiae.

Non-Saccharomyces yeasts are metabolically active during spontaneous and inoculated must fermentations, and by producing a plethora of by-products, they can contribute to the definition of the wine aroma. Thus, use of Saccharomyces and non-Saccharomyces yeasts as mixed starter cultures for inoculation of wine fermentations is of increasing interest for quality enhancement and improved complexity of wines. We initially characterized 34 non-Saccharomyces yeasts of the genera Candida, Lachancea (Kluyveromyces), Metschnikowia and Torulaspora, and evaluated their enological potential. This confirmed that non-Saccharomyces yeasts from wine-related environments represent a rich sink of unexplored biodiversity for the winemaking industry. From these, we selected four non-Saccharomyces yeasts to combine with starter cultures of Saccharomyces cerevisiae in mixed fermentation trials. The kinetics of growth and fermentation, and the analytical profiles of the wines produced indicate that these non-Saccharomyces strains can be used with S. cerevisiae starter cultures to increase polysaccharide, glycerol and volatile compound production, to reduce volatile acidity, and to increase or reduce the total acidity of the final wines, depending on yeast species and inoculum ratio used. The overall effects of the non-Saccharomyces yeasts on fermentation and wine quality were strictly dependent on the Saccharomyces/non-Saccharomyces inoculum ratio that mimicked the differences of fermentation conditions (natural or simultaneous inoculated fermentation).