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.

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.

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).

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.

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 Outcomes and Relationships with Phenylalanine in Phenylketonuria: A Comparison between Italian and English Adult Samples.

We aimed to assess if the same cognitive batteries can be used cross-nationally to monitor the effect of Phenylketonuria (PKU). We assessed whether a battery, previously used with English adults with PKU (AwPKU), was also sensitive to impairments in Italian AwPKU. From our original battery, we selected a number of tasks that comprehensively assessed visual attention, visuo-motor coordination, executive functions (particularly, reasoning, planning, and monitoring), sustained attention, and verbal and visual memory and learning. When verbal stimuli/or responses were involved, stimuli were closely matched between the two languages for psycholinguistic variables. We administered the tasks to 19 Italian AwPKU and 19 Italian matched controls and compared results from with 19 English AwPKU and 19 English matched controls selected from a previously tested cohort. Participant election was blind to cognitive performance and metabolic control, but participants were closely matched for age and education. The Italian AwPKU group had slightly worse metabolic control but showed levels of performance and patterns of impairment similar to the English AwPKU group. The Italian results also showed extensive correlations between adult cognitive measures and metabolic measures across the life span, both in terms of Phenylalanine (Phe) levels and Phe fluctuations, replicating previous results in English. These results suggest that batteries with the same and/or matched tasks can be used to assess cognitive outcomes across countries allowing results to be compared and accrued. Future studies should explore potential differences in metabolic control across countries to understand what variables make metabolic control easier to achieve.

The ability to learn new written words is modulated by language orthographic consistency.

INTRODUCTION: It is well known that a difficulty in forming lexical representations is a strong predictor of reading and spelling difficulties even after controlling for the effects of other cognitive skills. Our study had two main interrelated aims. First, we wanted to examine whether the ability to learn new written words (lexical learning) varies as a function of the orthographic consistency of the language of the learner. Second, we wanted to evaluate the cognitive abilities involved in orthographic lexical learning and whether they differed as a function of language consistency. METHOD: 163 Italian children and 128 English children performed a lexical learning task as well as tasks assessing several cognitive skills potentially related to the ability to establish orthographic representations. RESULTS: We found that children learning an orthographic inconsistent orthography (English) were better able to learn novel written words presented in association with pictures than children learning a consistent orthography (Italian). This was true for both younger and older primary school children and also when children were matched for school grade. Lexical learning may be better in English children because the many irregularities of this language promote storing in memory whole-word representations and processing larger orthographic units. In Italian, instead, reading can be accomplished successfully on the basis of grapheme-phoneme conversion rules and on processing smaller orthographic units. This interpretation was supported by the pattern of cognitive skills associated with lexical learning skills in the two languages. Variations in lexical learning were explained by spatial visual memory and phonological awareness tasks in both languages, but phonological STM explained further variance in Italian, while a task tapping visuo-attentional capacity explained further variance in English. CONCLUSION: Learning a language with inconsistent orthography is associated with better lexical learning skills in children at different stages of primary school; the pattern of cognitive skills associated with lexical learning skills is also partially modulated by orthographic consistency.

Emotional health in early-treated adults with phenylketonuria (PKU): Relationship with cognitive abilities and blood phenylalanine.

Introduction: Mental health, physical health, and cognitive skills have been scarcely investigated in the same sample of adults with PKU (AwPKU). This is striking since emotional difficulties may potentially contribute to cognitive impairments and vice-versa. Here we aim to fill this gap.Method: Thirty-six early-treated AwPKU and 40 controls were given an extensive battery of cognitive tasks assessing complex executive functions, inhibitory control, short-term memory, sustained attention, visuospatial attention, language production (reading and naming), visuomotor coordination, spoken language and orthographic processing. In addition, participants were given tasks tapping emotion recognition and completed questionnaires to assess depression (BDI-II), empathy (IRI) and mental/physical health-related quality of life (SF-36).Results: As a group, AwPKU performed significantly worse than controls especially in tasks tapping complex executive functions and across tasks when speed was measured but did not differ for emotional-health and physical health. In the PKU group, cognitive measures and measures of physical health-related quality of life were inter-correlated (differently than in the control group), and both measures were associated with metabolic control: better metabolic control, better cognition, and better physical health. Instead, cognitive measures and measures of emotional-health/mental-health-related quality of life did not correlate with one another and better metabolic control was not associated with better emotional health. Instead, some negative correlations were found. Better metabolic control was associated with worse perspective taking and more distress in socially stressful situations. Furthermore, difficulties in keeping the diet were associated with less emotional well-being.Conclusions: Taken together, these results indicate the advantages, but also possible emotional difficulties related to maintain a PKU diet, suggesting the importance of developing alternative therapy options.

Adult cognitive outcomes in phenylketonuria: explaining causes of variability beyond average Phe levels.

OBJECTIVE: The objective was to deepen the understanding of the causes of individual variability in phenylketonuria (PKU) by investigating which metabolic variables are most important for predicting cognitive outcomes (Phe average vs Phe variation) and by assessing the risk of cognitive impairment associated with adopting a more relaxed approach to the diet than is currently recommended. METHOD: We analysed associations between metabolic and cognitive measures in a mixed sample of English and Italian early-treated adults with PKU (N = 56). Metabolic measures were collected through childhood, adolescence and adulthood; cognitive measures were collected in adulthood. Metabolic measures included average Phe levels (average of median values for each year in a given period) and average Phe variations (average yearly standard deviations). Cognition was measured with IQ and a battery of cognitive tasks. RESULTS: Phe variation was as important, if not more important, than Phe average in predicting adult outcomes and contributed independently. Phe variation was particularly detrimental in childhood. Together, childhood Phe variation and adult Phe average predicted around 40% of the variation in cognitive scores. Poor cognitive scores (> 1 SD from controls) occurred almost exclusively in individuals with poor metabolic control and the risk of poor scores was about 30% higher in individuals with Phe values exceeding recommended thresholds. CONCLUSIONS: Our results provide support for current European guidelines (average Phe value = < 360 µmol/l in childhood; = < 600 µmo/l from 12 years onwards), but they suggest an additional recommendation to maintain stable levels (possibly Phe SD = < 180 µmol/l throughout life). PUBLIC SIGNIFICANCE STATEMENTS: We investigated the relationship between how well people with phenylketonuria control blood Phe throughout their life and their ability to carry out cognitive tasks in adulthood. We found that avoiding blood Phe peaks was as important if not more important that maintaining average low Phe levels. This was particularly essential in childhood. We also found that blood Phe levels above recommended European guidelines was associated with around 30% increase in the risk of poor cognitive outcomes.

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.

Null Effects on Working Memory and Verbal Fluency Tasks When Applying Anodal tDCS to the Inferior Frontal Gyrus of Healthy Participants.

Transcranial direct current stimulation (tDCS) is a technique used to modify cognition by modulating underlying cortical excitability via weak electric current applied through the scalp. Although many studies have reported positive effects with tDCS, a number of recent studies highlight that tDCS effects can be small and difficult to reproduce. This is especially the case when attempting to modulate performance using single applications of tDCS in healthy participants. Possible reasons may be that optimal stimulation parameters have yet to be identified, and that individual variation in cortical activity and/or level of ability confound outcomes. To address these points, we carried out a series of experiments in which we attempted to modulate performance in fluency and working memory probe tasks using stimulation parameters which have been associated with positive outcomes: we targeted the left inferior frontal gyrus (LIFG) and compared performance when applying a 1.5 mA anodal current for 25 min and with sham stimulation. There is evidence that LIFG plays a role in these tasks and previous studies have found positive effects of stimulation. We also compared our experimental group (N = 19-20) with a control group receiving no stimulation (n = 24). More importantly, we also considered effects on subgroups subdivided according to memory span as well as to more direct measures of executive function abilities and motivational levels. We found no systematic effect of stimulation. Our findings are in line with a growing body of evidence that tDCS produces unreliable effects. We acknowledge that our findings speak to the conditions we investigated, and that alternative protocols (e.g., multiple sessions, clinical samples, and different stimulation polarities) may be more effective. We encourage further research to explore optimal conditions for tDCS efficacy, given the potential benefits that this technique poses for understanding and enhancing cognition.

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.