Dietary Liberalization in Tetrahydrobiopterin-Treated PKU Patients: Does It Improve Outcomes?

PURPOSE: this systematic review aimed to assess the effects of dietary liberalization following tetrahydrobiopterin (BH4) treatment on anthropometric measurements, nutritional biomarkers, quality of life, bone density, mental health and psychosocial functioning, and burden of care in PKU patients. METHODS: the PubMed, Cochrane, and Embase databases were searched on 7 April 2022. We included studies that reported on the aforementioned domains before and after dietary liberalization as a result of BH4 treatment in PKU patients. Exclusion criteria were: studies written in a language other than English; studies that only included data of a BH4 loading test; insufficient data for the parameters of interest; and wrong publication type. Both within-subject and between-subject analyses were assessed, and meta-analyses were performed if possible. RESULTS: twelve studies containing 14 cohorts and 228 patients were included. Single studies reported few significant differences. Two out of fifteen primary meta-analyses were significant; BMI was higher in BH4-treated patients versus controls (p = 0.02; standardized mean difference (SMD) (95% confidence interval (CI)) = -0.37 (-0.67, -0.06)), and blood cholesterol concentrations increased after starting BH4 treatment (p = 0.01; SMD (CI) = -0.70 (-1.26, -0.15)). CONCLUSION: there is no clear evidence that dietary liberalization after BH4 treatment has a positive effect on anthropometric measurements, nutritional biomarkers, or quality of life. No studies could be included for bone density, mental health and psychosocial functioning, and burden of care.

Management of early treated adolescents and young adults with phenylketonuria: Development of international consensus recommendations using a modified Delphi approach.

BACKGROUND: Early treated patients with phenylketonuria (PKU) often become lost to follow-up from adolescence onwards due to the historical focus of PKU care on the pediatric population and lack of programs facilitating the transition to adulthood. As a result, evidence on the management of adolescents and young adults with PKU is limited. METHODS: Two meetings were held with a multidisciplinary international panel of 25 experts in PKU and comorbidities frequently experienced by patients with PKU. Based on the outcomes of the first meeting, a set of statements were developed. During the second meeting, these statements were voted on for consensus generation (≥70% agreement), using a modified Delphi approach. RESULTS: A total of 37 consensus recommendations were developed across five areas that were deemed important in the management of adolescents and young adults with PKU: (1) general physical health, (2) mental health and neurocognitive functioning, (3) blood Phe target range, (4) PKU-specific challenges, and (5) transition to adult care. The consensus recommendations reflect the personal opinions and experiences from the participating experts supported with evidence when available. Overall, clinicians managing adolescents and young adults with PKU should be aware of the wide variety of PKU-associated comorbidities, initiating screening at an early age. In addition, management of adolescents/young adults should be a joint effort between the patient, clinical center, and parents/caregivers supporting adolescents with gradually gaining independent control of their disease during the transition to adulthood. CONCLUSIONS: A multidisciplinary international group of experts used a modified Delphi approach to develop a set of consensus recommendations with the aim of providing guidance and offering tools to clinics to aid with supporting adolescents and young adults with PKU.

Neurocognitive outcome and mental health in children with tyrosinemia type 1 and phenylketonuria: A comparison between two genetic disorders affecting the same metabolic pathway.

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine-tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal-Wallis tests with post-hoc Mann-Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions "working memory", "plan and organize" and "monitor", ASEBA dimensions "social problems" and "attention problems", and for the SSRS "assertiveness" scale (all p values <0.001). To conclude, TT1 patients showed cognitive impairments on all domains studied, and appeared to be significantly more affected than PKU patients. More attention should be paid to investigating and monitoring neurocognitive outcome in TT1 and research should focus on explaining the underlying pathophysiological mechanism.

Metabolic control during the neonatal period in phenylketonuria: associations with childhood IQ.

BACKGROUND: In phenylketonuria, treatment and subsequent lowering of phenylalanine levels usually occur within the first month of life. This study investigated whether different indicators of metabolic control during the neonatal period were associated with IQ during late childhood/early adolescence. METHODS: Overall phenylalanine concentration during the first month of life (total "area under the curve"), proportion of phenylalanine concentrations above upper target level (360 µmol/L) and proportion below lower target level (120 µmol/L) during this period, diagnostic phenylalanine levels, number of days until phenylalanine levels were <360 µmol/L, and lifetime and concurrent phenylalanine levels were correlated with IQ scores of 64 PKU patients (mean age 10.8 years, SD 2.9). RESULTS: Overall phenylalanine concentration and proportion of phenylalanine concentrations >360 µmol/L during the first month of life negatively correlated with IQ in late childhood/early adolescence. Separately, phenylalanine concentrations during different periods within the first month of life (0-10 days, 11-20 days, 21-30 days) were negatively correlated with later IQ as well, but correlation strengths did not differ significantly. No further significant associations were found. CONCLUSIONS: In phenylketonuria, achievement of target-range phenylalanine levels during the neonatal period is important for cognition later in life, also when compared to other indicators of metabolic control. IMPACT: In phenylketonuria, it remains unclear during which age periods or developmental stages metabolic control is most important for later cognitive outcomes. Phenylalanine levels during the neonatal period were clearly and negatively related to later IQ, whereas no significant associations were observed for other indices of metabolic control. This emphasizes the relative importance of this period for cognitive development in phenylketonuria. No further distinctions were observed in strength of associations with later IQ between different indicators of metabolic control during the neonatal period. Thus, achievement of good metabolic control within 1 month after birth appears "safe" with respect to later cognitive outcomes.

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.

The Role of Inhibitory Control, Attention and Vocabulary in Physical Aggression Trajectories From Infancy to Toddlerhood.

Physical aggression has its origin very early in development, but no studies to date have examined physical aggression trajectories starting before the age of 1.5 years. This study examined whether cognition plays a role in the development of physical aggression from infancy onward. In a sample of 182 mother-child dyads (94 boys; 88 girls), child physical aggression was assessed by maternal report using the Physical Aggression Scale for Early Childhood at 12, 20, and 30 months. Children performed cognitive tasks measuring inhibitory control and attention, and mothers rated children's vocabulary at 12 and 30 months. Results showed that differential development of physical aggression already starts at 12 months of age: low-stable, low-increasing, moderate-decreasing and high-stable trajectory groups were identified. Inhibitory control, attention and vocabulary at 12 months and development of these abilities from 12 to 30 months were selectively related to the likelihood of following the low-increasing and moderate-decreasing trajectories compared to the low-stable physical aggression trajectory. This study is the first to show that specific aspects of cognition and cognitive development are related to differential physical aggression development from infancy onward.

Aggressive behavior during toddlerhood: Interrelated effects of prenatal risk factors, negative affect, and cognition.

Prenatal risk, temperamental negative affect, and specific cognitive abilities have all individually been identified as predictors of behavior problems during early childhood, but less is known about their interplay in relation to aggression during toddlerhood. This study examined the main and interaction effects of prenatal risk, negative affect, inhibitory control, attention, and vocabulary in the prediction of aggression in 150 children (75 boys). During pregnancy, a cumulative risk index was calculated based on the presence of 10 well-established maternal risk factors, such as prenatal substance use, maternal psychiatric disorder, and financial problems. Negative affect was measured at 6 and 20 months using maternal report. Child cognition was examined at 30 months using laboratory tasks for inhibitory control and attention, and a questionnaire was administered to assess vocabulary. In addition, mothers reported on their children's aggressive behavior at 30 months. Higher prenatal risk and negative affect at 20 months and, to a lesser extent, at 6 months were related to more aggression at 30 months. Poorer inhibitory control and, to a lesser extent, vocabulary at 30 months also predicted higher levels of aggressive behavior. Two-way interaction effects were found for cumulative risk and inhibitory control, negative affect (at 20 months) and inhibitory control, and negative affect (at 6 months) and vocabulary: aggressive behavior was most pronounced when combinations of high prenatal risk, high negative affect, and poor cognition were present. These results suggest that the impact of prenatal risk and child temperament depends in part on child's cognitive development during toddlerhood.

Associations between empathy, inhibitory control, and physical aggression in toddlerhood.

Impaired empathy has been associated with aggression in children, adolescents and adults, but results have been contradictory for the preschool period. Impaired inhibitory control also increases the risk of aggression, and possibly moderates empathy-aggression associations. The current study investigated whether empathy and inhibitory control are associated with aggression in toddlerhood. Furthermore, we aimed to clarify the role of inhibitory control in empathy and aggression, specifically, whether inhibitory control moderates the association between empathy and aggression. During a laboratory visit at age 30 months (N = 103), maternal reports of physical aggression were obtained and child inhibitory control was examined using a gift delay task. Empathy was examined by obtaining behavioral observations and recording physiological responses (heart rate response and respiratory sinus arrhythmia response) to an empathy-eliciting event (i.e., simulated distress). Reduced inhibitory control was associated with more aggression. Behavioral and physiological indicators of empathy were not associated with aggression. Hierarchical regression analyses revealed an interaction effect of heart rate response to distress simulation with inhibitory control in the prediction of aggression. Post hoc analyses indicated a negative association between heart rate response and aggression when inhibitory control was high, but a positive association was found in toddlers who demonstrated low inhibitory control. These results suggest that children are less aggressive when they have both high levels of empathy and inhibitory control. Therefore, both empathy and inhibition are important targets for interventions aiming to reduce or prevent aggression at a young age.

Infant emotional responses to challenge predict empathic behavior in toddlerhood.

Although emotional responses are theorized to be important in the development of empathy, findings regarding the prediction of early empathic behavior by infant behavioral and physiological responses are mixed. This study examined whether behavioral and physiological responses to mild emotional challenge (still face paradigm and car seat task) in 118 infants at age 6 months predicted empathic distress and empathic concern in response to an empathy-evoking task (i.e, experimenter's distress simulation) at age 20 months. Correlation analyses, corrected for sex and baseline levels of physiological arousal, showed that stronger physiological and behavioral responses to emotional challenge at age 6 months were positively related to observed empathic distress, but not empathic concern, at age 20 months. Linear regression analyses indicated that physiological and behavioral responses to challenge at 6 months independently predicted empathic distress at 20 months, which suggests an important role for both physiological and behavioral emotional responses in empathy development. In addition, curvilinear regression analyses showed quadratic associations between behavioral responses at 6 months, and empathic distress and empathic concern at 20 months, which indicates that moderate levels of behavioral responsivity predict the highest levels of empathic distress and empathic concern.

Emotional and behavioral problems, quality of life and metabolic control in NTBC-treated Tyrosinemia type 1 patients.

BACKGROUND: Treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) and dietary phenylalanine and tyrosine restriction improves physical health and life expectancy in Tyrosinemia type 1 (TT1). However, neurocognitive outcome is suboptimal. This study aimed to investigate behavior problems and health-related quality of life (HR-QoL) in NTBC-dietary-treated TT1 and to relate this to phenylalanine and tyrosine concentrations. RESULTS: Thirty-one TT1 patients (19 males; mean age 13.9 ± 5.3 years) were included in this study. Emotional and behavioral problems, as measured by the Achenbach System of Empirically Based Assessment, were present in almost all domains. Attention and thought problems were particularly evident. HR-QoL was assessed by the TNO AZL Children's and Adults QoL questionnaires. Poorer HR-QoL as compared to reference populations was observed for the domains: independent daily functioning, cognitive functioning and school performance, social contacts, motor functioning, and vitality. Both internalizing and externalizing behavior problems were associated with low phenylalanine (and associated lower tyrosine) concentrations during the first year of life. In contrast, high tyrosine (and associated higher phenylalanine) concentrations during life and specifically the last year before testing were associated with more internalizing behavior and/or HR-QoL problems. CONCLUSIONS: TT1 patients showed several behavior problems and a lower HR-QoL. Associations with metabolic control differed for different age periods. This suggests the need for continuous fine-tuning and monitoring of dietary treatment to keep phenylalanine and tyrosine concentrations within target ranges in NTBC-treated TT1 patients.

Prenatal risk and physical aggression during the first years of life: The gender-specific role of inhibitory control.

Prenatal risk and a lack of inhibitory control have consistently been related to the development of physical aggression in older children. This study examined whether inhibitory control mediated the relation between prenatal risk and aggression in infants and toddlers. The role of gender in this mediation model was also examined. The sample consisted of 161 mother-child dyads (83 boys). A prenatal cumulative risk score was created from a number of well-established risk factors including maternal psychopathology, substance use, and social and socioeconomic disadvantages. At 12 months, children performed an inhibitory control task. Physical aggression was assessed through maternal reports at 12 and 20 months of age. Results showed that higher prenatal risk was associated with more physical aggression. Inhibitory control mediated this association at both 12 and 20 months: higher prenatal risk was related to lower inhibitory control, which in turn led to higher aggression. At 20 months, gender moderated the mediation effect: the mediating role of inhibitory control was only found for girls. These results suggest that even before 2 years of age, inhibitory control is an important construct involved in the relation between prenatal risk and physical aggression.

The impact of metabolic control and tetrahydrobiopterin treatment on health related quality of life of patients with early-treated phenylketonuria: A PKU-COBESO study.

The aim of this study was to examine Health-Related Quality of Life (HRQoL) of patients with Phenylketonuria (PKU) in three different age groups and to investigate the impact of metabolic control and tetrahydrobiopterin (BH4) treatment on HRQoL of these patients. Participants were 90 early-treated patients aged 7 to 40 years (M = 21.0, SD = 10.1) and 109 controls aged 7 to 40.8 years (M = 19.4, SD = 8.6). HRQoL was assessed with the (generic) TNO-AZL questionnaires. Overall, good HRQoL was reported for children below 12 years of age, although they were judged to be less autonomic than their healthy counterparts. Adolescents aged 12-15 years showed poorer HRQoL in the domain "cognitive functioning" compared to controls. For adults ≥16 years, poorer age-controlled HRQoL was found for the domains cognition, depressive moods, and anger, with a further trend for the domain "pain". With respect to metabolic control, only for adult PKU-patients robust associations were observed, indicating poorer functioning, most notably in the domains cognition, sleep, pain, sexuality and anger, with higher historical and concurrent Phe-levels. With respect to BH4-use, effects on HRQoL were again only observed for adult PKU-patients. After controlling for age and historical Phe-levels, small but significant differences in favor of adult BH4-users compared to non-users were observed for HRQoL-categories happiness, anger, and social functioning. Together, these results show that, particularly for adult PKU-patients, HRQoL-problems are evident and that many of these problems are related to (history of) metabolic control. Beneficial effects of BH4-use appear to be limited to those associated with relief from the practical burdens related to the strict dietary treatment regimen, i.e. general mood and sociability, whereas metabolic control is more strongly related to basic physical and cognitive functioning.

Executive Functioning, Reward/Punishment Sensitivity, and Conduct Problems in Boys With Callous-Unemotional Traits.

Callous-unemotional (CU) traits are thought to characterize children exhibiting persistent and severe conduct problems (CPs). Reward and punishment sensitivity have often been investigated, yet executive function problems have mostly been studied in adults. Moreover, the level of co-occurring CPs is important to take into account. Therefore, the current study investigated differences in reward responsivity, punishment sensitivity, and executive functioning (EF) between four subgroups of general community boys ( N = 346, Mage = 14.01 years, SD = 1.19): high CU/high CP, low CU/high CP, high CU/low CP, and low CU/low CP. Boys with high CU/high CP showed significantly more EF problems, but similar reward and punishment sensitivity as low CU/high CP boys. Boys with high CU/low CP did not differ from low CU/low CP boys. Severity of executive function problems appears to distinguish boys who show a combination of CU-traits and CPs from boys with CPs alone.

Long-Term Follow-Up of Cognition and Mental Health in Adult Phenylketonuria: A PKU-COBESO Study.

Cognitive and mental health problems in individuals with the inherited metabolic disorder phenylketonuria (PKU) have often been associated with metabolic control and its history. For the present study executive functioning (EF) was assessed in 21 PKU patients during childhood (T1, mean age 10.4 years, SD = 2.0) and again in adulthood (T2, mean age 25.8 years, SD = 2.3). At T2 additional assessments of EF in daily life and mental health were performed. Childhood (i.e. 0-12 years) blood phenylalanine was significantly related to cognitive flexibility, executive motor control, EF in daily life and mental health in adulthood (i.e. at T2). Patients with a greater increase in phenylalanine levels after the age of 12 performed more poorly on EF-tasks at T2. Group-based analyses showed that patients with phenylalanine <360 µmol/L in childhood and phenylalanine ≥360 µmol/L from age 13 onwards (n = 11) had better cognitive flexibility and executive motor control than those who had phenylalanine ≥360 µmol/L throughout life (n = 7), supporting the notion that phenylalanine should be below the recommended upper treatment target of 360 µmol/L during childhood for better outcome in adulthood. Despite some results indicating additional influence of phenylalanine levels between 13 and 17 years of age, evidence for a continued influence of phenylalanine levels after childhood on adult outcomes was largely lacking. This may be explained by the fact that the patients in the present study had relatively low phenylalanine levels during childhood (mean: 330 µmol/L, range: 219-581 µmol/L) and thereafter (mean Index of Dietary Control at T2: 464 µmol/L, range: 276-743 µmol/L), which may have buffered against transitory periods of poor metabolic control during adolescence and early adulthood.

Neurological and Neuropsychological Problems in Tyrosinemia Type I Patients.

Clinically, Hereditary Tyrosinemia type I (HTI) is especially characterized by severe liver dysfunction in early life. However, recurrent neurological crises are another main finding in these patients when they are treated with a tyrosine and phenylalanine restricted diet only. This is caused by the accumulation of δ-aminolevulinic acid due to the inhibitory effect of succinylacetone on the enzyme that metabolizes δ-aminolevulinic acid. Due to the biochemical and clinical resemblance of these neurological crises and acute intermittent porphyria, this group of symptoms in HTI patients is mostly called porphyria-like-syndrome. The neurological crises in HTI patients disappeared after the introduction of treatment with 2-(2 nitro-4-3 trifluoro-methylbenzoyl)-1, 3-cyclohexanedione (NTBC). However, if NTBC treatment is stopped for a while, severe neurological dysfunction will reappear.If NTBC treatment is started early and given continuously, all clinical problems seem to be solved. However, recent research findings indicate that HTI patients have a non-optimal neurocognitive outcome, showing (among others) a lower IQ and impaired executive functioning and social cognition. Unfortunately the exact neuropsychological profile of these HTI patients is not known yet, neither are the exact pathophysiological mechanisms underlying these impairments. It may be hypothesized that the biochemical changes such as high blood tyrosine or low blood phenylalanine concentrations are important in this respect, but an direct toxic effect of NTBC or production of toxic metabolites (that previously characterized the disease before introduction of NTBC) cannot be excluded either. This chapter discusses the neurological and neuropsychological symptoms associated with HTI in detail. An extended section on possible underlying pathophysiological mechanisms of such symptoms is also included.

Cognitive profile and mental health in adult phenylketonuria: A PKU-COBESO study.

OBJECTIVE: Despite early dietary treatment phenylketonuria patients have lower IQ and poorer executive functions compared to healthy controls. Cognitive problems in phenylketonuria have often been associated with phenylalanine levels. The present study examined the cognitive profile and mental health in adult phenylketonuria, in relation to phenylalanine levels and tetrahydrobiopterin treatment. METHOD: Fifty-seven early treated adult patients with phenylketonuria and 57 healthy matched controls (18-40 years) performed IQ subtests and executive function tests from the Amsterdam Neuropsychological Tasks. They also completed the Adult Self-Report on mental health problems. Analyses of variance were performed to examine group differences. RESULTS: Patients with phenylketonuria had normal IQs although lower than controls. They performed poorer on working memory, inhibitory control, and sustained attention tasks. Patients reported Depressive and Avoidant Personality problems more frequently. Specifically, patients with childhood and lifetime phenylalanine ≥360 µmol/L had poorer cognitive and mental health outcomes than controls. In a subset of patients, comparisons between patients on and off tetrahydrobiopterin showed that nontetrahydrobiopterin users (matched for childhood, pretreatment phenylalanine) were slower (on number of tasks) and reported more mental health problems. CONCLUSIONS: Adult patients had lower IQ and poorer executive functions than controls, resembling problems observed in younger patients with phenylketonuria, as well as more internalizing problems. Group differences and phenylalanine-outcome associations were smaller than those observed in younger populations. A subset of nontetrahydrobiopterin users, matched for childhood phenylalanine level, had a poorer outcome on some tests than tetrahydrobiopterin users, which might indicate an impact of tetrahydrobiopterin treatment beyond lowering phenylalanine. However, clinical relevance needs further investigation. (PsycINFO Database Record

Key European guidelines for the diagnosis and management of patients with phenylketonuria.

We developed European guidelines to optimise phenylketonuria (PKU) care. To develop the guidelines, we did a literature search, critical appraisal, and evidence grading according to the Scottish Intercollegiate Guidelines Network method. We used the Delphi method when little or no evidence was available. From the 70 recommendations formulated, in this Review we describe ten that we deem as having the highest priority. Diet is the cornerstone of treatment, although some patients can benefit from tetrahydrobiopterin (BH4). Untreated blood phenylalanine concentrations determine management of people with PKU. No intervention is required if the blood phenylalanine concentration is less than 360 µmol/L. Treatment is recommended up to the age of 12 years if the phenylalanine blood concentration is between 360 µmol/L and 600 µmol/L, and lifelong treatment is recommended if the concentration is more than 600 µmol/L. For women trying to conceive and during pregnancy (maternal PKU), untreated phenylalanine blood concentrations of more than 360 µmol/L need to be reduced. Treatment target concentrations are as follows: 120-360 µmol/L for individuals aged 0-12 years and for maternal PKU, and 120-600 µmol/L for non-pregnant individuals older than 12 years. Minimum requirements for the management and follow-up of patients with PKU are scheduled according to age, adherence to treatment, and clinical status. Nutritional, clinical, and biochemical follow-up is necessary for all patients, regardless of therapy.

Infant autonomic nervous system response and recovery: Associations with maternal risk status and infant emotion regulation.

This study examined whether risk status and cumulative risk were associated with autonomic nervous system reactivity and recovery, and emotion regulation in infants. The sample included 121 6-month-old infants. Classification of risk status was based on World Health Organization criteria (e.g., presence of maternal psychopathology, substance use, and social adversity). Heart rate, parasympathetic respiratory sinus arrhythmia, and sympathetic preejection period were examined at baseline and across the still face paradigm. Infant emotion regulation was coded during the still face paradigm. Infants in the high-risk group showed increased heart rate, parasympathetic withdrawal, and sympathetic activation during recovery from the still face episode. Higher levels of cumulative risk were associated with increased sympathetic nervous system activation. Moreover, increased heart rate during recovery in the high-risk group was mediated by both parasympathetic and sympathetic activity, indicating mobilization of sympathetic resources when confronted with socioemotional challenge. Distinct indirect pathways were observed from maternal risk to infant emotion regulation during the still face paradigm through parasympathetic and sympathetic regulation. These findings underline the importance of specific measures of parasympathetic and sympathetic response and recovery, and indicate that maternal risk is associated with maladaptive regulation of stress early in life reflecting increased risk for later psychopathology.