Impairment of autonomic emotional response for executive function in children with ADHD: A multi-modal fNIRS and pupillometric study during the Wisconsin Card Sorting Test.

OBJECTIVE: Children with attention deficit hyperactivity disorder (ADHD) often experience difficulties with emotional control and a consequent inability to perform tasks. To clarify the effects of emotional behavior on cognitive functions, we aimed to determine the association between emotional changes and executive functions in children with ADHD by measuring the pupil diameter changes associated with emotional changes. PARTICIPANTS AND METHODS: This study included 14 children with ADHD and 10 typically developing children (TDC) aged between 10 and 16 years. During the Wisconsin Card Sorting Test (WCST), which is related to context formation and task switching among executive functions, changes in pupil diameter and frontal oxygenated hemoglobin (oxy-Hb) using functional near-infrared spectroscopy (fNIRS) were recorded simultaneously. Pupil diameter changes during "cognitive shift" and "consecutive correction" were compared between both groups. RESULTS: During cognitive shift, the pupils of children with ADHD contracted, whereas those of the TDC were mydriatic. During consecutive correction, the pupils of children with ADHD were mydriatic, whereas those of the TDC tended to contract. These results correlated with WCST performance. Moreover, during cognitive shifts, changes in bilateral frontal blood flow were increased in TDC, but not in children with ADHD. CONCLUSION: The locus coeruleus-norepinephrine (LC-NE) system plays an important role in pupillary diameter response. These results suggest that the LC-NE system may be dysfunctional in children with ADHD, and the system's abnormality may lead to affective abnormalities in such patients, which results in poor performance on WCST (i.e., impaired executive functions).

Developmental changes in autonomic responses are associated with future reward/punishment expectations: A study of sympathetic skin responses in the Markov decision task.

OBJECTIVE: Autonomic nervous system activity is recognized as a major component of emotional responses. Future reward/punishment expectations depend upon the process of decision making in the frontal lobe, which is considered to play an important role in executive function. The aim of this study was to investigate the relationship between autonomic responses and decision making during reinforcement tasks using sympathetic skin responses (SSR). METHODS: Nine adult and 9 juvenile (mean age, 10.2years) volunteers were enrolled in this study. SSRs were measured during the Markov decision task (MDT), which is a reinforcement task. In this task, subjects must endure a small immediate loss to ultimately get a large reward. The subjects had to undergo three sets of tests and their scores in these tests were assessed and evaluated. RESULTS: All adults showed gradually increasing scores for the MDT from the first to third set. As the trial progressed from the first to second set in adults, SSR appearance ratios remarkably increased for both punishment and reward expectations. In comparison with adults, children showed decreasing scores from the first to second set. There were no significant inter-target differences in the SSR appearance ratio in the first and second set in children. In the third set, the SSR appearance ratio for reward expectations was higher than that in the neutral condition. CONCLUSIONS: In reinforcement tasks, such as MDT, autonomic responses play an important role in decision making. We assume that SSRs are elicited during efficient decision making tasks associated with future reward/punishment expectations, which demonstrates the importance of autonomic function. In contrast, in children around the age of 10years, the autonomic system does not react as an organized response specific to reward/punishment expectations. This suggests the immaturity of the future reward/punishment expectations process in children.

Disinhibition in children with attention-deficit/hyperactivity disorder: Changes in [oxy-Hb] on near-infrared spectroscopy during "rock, paper, scissors" task.

OBJECTIVE: Attention-deficit/hyperactivity disorder (AD/HD) is a common developmental disorder. Many reports have suggested that symptoms of AD/HD are related to frontal lobe dysfunctions, particularly disinhibition. However, measuring neurological findings with biomarkers during frontal functional tasks has sometimes been difficult in children with AD/HD. This study aimed to investigate frontal inhibitory function objectively in children with AD/HD during "rock, paper, scissors" (RPS) tasks, as a familiar game for Japanese children, using near-infrared spectroscopy (NIRS). SUBJECTS AND METHODS: Eighteen children with AD/HD were compared with 27 typically developing children (TDC). Children from each group were divided into two age groups: younger, 6-10years; and older, 11-16years. Changes in oxygenated hemoglobin [oxy-Hb] were measured in the prefrontal region using NIRS during a 'to lose' RPS task, in which subjects were asked to present the RPS signal that would lose in response to one of the three signals displayed randomly on a computer screen every 2.0s. RESULTS: The rate of correct performance with both TDC and AD/HD increased with age. Only in the older group, the rate of correct performance was significantly higher with TDC than with AD/HD. However, children with AD/HD in both age groups showed significantly lower [oxy-Hb] activity in the prefrontal region during the 'to lose' RPS task, particularly in the dorsolateral area. CONCLUSIONS: Our results suggest that prefrontal region activation during the 'to lose' RPS task could offer a biomarker for diagnosing AD/HD, and may help in the early treatment of AD/HD.

Developmental changes in autonomic emotional response during an executive functional task: A pupillometric study during Wisconsin card sorting test.

OBJECTIVE: The autonomic nervous system has a deep relationship with the cognitive network when performing cognitive tasks. We hypothesize that autonomic emotional responses can affect cognitive function, especially executive function. The aim of this study was to clarify the involvement of the autonomic system during an executive functional task via developmental changes assessed using pupillometry. SUBJECTS AND METHODS: Subjects were 16 healthy children and 9 healthy adults. Children were divided into 3 groups (Group A, 7-9years; Group B, 10-14years; Group C, 15-17years). Pupil diameter was recorded using an eye mark recorder during cognitive shift (CS) during the Wisconsin card sorting test (WCST). The rate of pupil variations was integrated and compared within each group, focusing on performance during CS. RESULTS: Categories achieved (CA) in the behavioral results of WCST increased with age, with significant differences between Group A and other groups. The change of pupillary diameter was increased with CS and decreased at the correct answers after CS in adults. Changes of pupillary diameter with CS showed a linear increase with age, and the pattern of the pupillary response at the age of 10-14years was comparable to adults. The integrated rate of pupil diameter with CS increased with age, and there was a significant difference between Group A and adults. In addition, the degree of mydriasis correlated with the number of CA. CONCLUSION: These findings suggest that autonomic emotional response play an important role as a part of the process for executive function.

[Evaluation of quality of life in attention-deficit hyperactivity disorder children without comorbidity].

OBJECT: Improving quality of life (QOL) is one of the most important therapeutic goals for children with attention-deficit hyperactiv- ity disorder (AD/HD). The aim of this study was to measure QOL in AD/HD children without comorbidity and to examine associations between QOL and clinical symptoms of AD/HD for targeting early intervention. METHODS: Twenty-two enrolled patients and their parents completed the Questionnaire for Measuring Health-Related Quality of Life in Children (KINDL-R). Patients and teachers completed AD/HD rating scale-IV. Associations between QOL and clinical symptoms were assessed using t tests and correlations. RESULTS: Mean total score of the self-reported KINDL-R was 70.8. No difference in total QOL score was seen between AD/HD children and controls; however, the self-esteem subscale rated by AD/HD children was significantly higher than that of controls (p < 0.001). Total KINDL-R score correlated negatively with AD/HD rating scale-IV rated by teachers (p < 0.05). A difference was observed between AD/HD children in a lower QOL group and their parents in a subscale regarding QOL at school. CONCLUSIONS: These findings suggest that evaluation of QOL in AD/HD children without comorbidity is useful for identifying AD/HD children who might benefit from early intervention.

Sequential prefrontal lobe volume changes and cognitive dysfunctions in children with Panayiotopoulos syndrome presenting with status epilepticus.

Panayiotopoulos syndrome (PS) is usually not associated with neurodevelopmental problems. However, neuropsychological impairments may also be present in at least some of the patients with PS. On the other hand, several degrees of neuronal damage due to status epilepticus (SE) may occur in the cortex. We prospectively measured frontal and prefrontal lobe volumes using three-dimensional magnetic resonance imaging (3D-MRI)-based volumetry in patients with PS with and without SE. Moreover, the neuropsychological outcome in relation to the presence of SE in children with PS is also discussed. We studied six patients with a final diagnosis of PS, including three cases with SE and cognitive impairments/behavioral problems (SE group) and three cases without SE (non-SE group). Serial 3D-MRI studies were performed five times (at onset of clinical symptoms and 1-4 years after onset) in both the SE and non-SE patients. All patients were studied with a set of Wechsler Intelligence Scale for Children, version III (WISC-III) or Wechsler Preschool and Primary Scale of Intelligence tests and the Kaufman Assessment Battery for Children (K-ABC). Growth of the frontal and prefrontal lobes was slightly decreased for some time after SE episodes in the SE patients. Moreover, the prefrontal-to-frontal lobe volume ratio was stagnant for some time after SE in the SE patients. The scores on the neuropsychological tests were decreased in the SE patients. Moreover, the average WISC and K-ABC scores in the SE group remained low and did not reach the levels of the initial examinations. Occurrence of SE in patients with PS at least in some patients may be associated with retarded prefrontal lobe growth, which was related to neuropsychological problems and ultimately, neuropsychological outcomes. Treatment management may be required to prevent SE as much as possible to achieve optimal prognosis in PS at least in some patients.

Developmental changes in frontal lobe function during a verbal fluency task: a multi-channel near-infrared spectroscopy study.

OBJECTIVE: Near-infrared spectroscopy (NIRS) is commonly used to investigate continuous changes of brain activation and has excellent time resolution. Verbal fluency task (VFT) is widely used as a neuropsychological test of frontal lobe function. The aim of this study was to investigate normal developmental change in frontal lobe function during VFT performance using multi-channel NIRS, specifically focusing on oxygenation hemoglobin (oxyHb) changes. METHODS: The subjects were 9 adults and 37 childrens who were all healthy right-handed volunteers. Children were divided into four age groups (group A, 6-8 years; group B, 9-11 years; group C, 12-14 years; group D, 15-18 years). The [oxyHb] changes were measured with 22 channels of NIRS during VFT. We defined the frontopolar region as the region of interest for analysis, and calculated the Z-score to compare the data between groups. RESULTS: The task performance changed with age. There were significant differences between group A and other groups. The Z-score of [oxyHb] also significantly increased with age, when comparing adults to groups A and B. The task performances decreased with time in all groups. In contrast, [oxyHb] only continued to increase in the adult group. CONCLUSION: The verbal retrieval functions begin to mature in early adolescence and continue to grow up to adulthood.

Do sequential EEG changes predict atypical clinical features in rolandic epilepsy?

AIM: Although the prognosis for rolandic epilepsy is regarded to be favourable, a small proportion of cases that initially present as rolandic epilepsy evolve into atypical benign partial epilepsy (ABPE) of childhood. The purpose of our study was to determine electroencephalogram (EEG) criteria in relation to atypical seizure manifestations, and cognitive and behavioural problems in rolandic epilepsy. METHODS: The rolandic epilepsy group consisted of 10 children (mean age 5y 6mo, SD 1y 1mo, median age 5y 5mo; six males, four females). The ABPE group comprised five children (mean age 5y, SD 1y 2mo, median age 4y 5mo; three males, two females). We recorded the number of spikes, the locations of spikes, and the duration of the spike activity. The Wechsler Intelligence Scale for Children-Third Edition or the Wechsler Preschool and Primary Scale of Intelligence, depending on age, was administered to all children at the onset of seizures and every year thereafter. The diagnosis of attention-deficit-hyperactivity disorder was made according to the DSM-IV. RESULTS: Significant correlations were found between atypical clinical features and extended periods of high-frequency paroxysmal EEG abnormalities (>24mo after onset; p<0.01) and frontal EEG focus (>10mo after onset; p<0.003). INTERPRETATION: A combination of spike rate and extended periods of high-frequency paroxysmal EEG abnormalities may predict the evolution of atypical rolandic epilepsy.

Duration of recognized fever in febrile seizure predicts later development of epilepsy.

BACKGROUND: The current report examines the risk of and predictors for developing epilepsy in children with febrile seizure (FS). The present study addresses two factors that were previously identified as predictors of recurrent FS in previous reports: maximum temperature and duration of fever prior to the initial FS. METHODS: Children aged 6 months-6 years with an initial simple FS were eligible for the study. The interview included questions about the child's illness, family history of seizures, and other exposure information. In particular, they were asked about the duration of recognized fever prior to the seizure. After the initial interview, parents were called every 3-4 months to ascertain whether any further seizures had occurred and the circumstances under which such seizures occurred. Follow up ≥ 3 years was attempted for all children. Statistical analysis was done with χ(2) test, Fisher's exact test, Mann-Whitney U-tests and logistic regression analysis. RESULTS: Five of 92 children (5.4%) experienced unprovoked seizures and were considered part of an epilepsy group. In four of these five patients, the duration of recognized fever prior to FS fell more than ± 2.5 SD outside the distribution for the non-epilepsy group. Either an unusually short or long recognized fever prior to the initial FS was associated with an increased risk of unprovoked seizures. CONCLUSIONS: The duration of recognized fever appears to provide useful information about the risk for the later development of epilepsy.

EEG characteristics predict subsequent epilepsy in children with febrile seizure.

The role of electroencephalography (EEG) in the work-up of febrile seizure (FS) remains controversial. We investigated the importance of EEG characteristics, especially the localizations of paroxysmal discharges, as predictors for subsequent epilepsy. Patients were referred from the outpatient department for EEG within 7-20 days after the seizure. EEGs were classified as paroxysmally abnormal based on the presence of spikes, sharp waves, or spike-wave complexes, whether focal or generalized, that were considered abnormal for age and state. Of 119 patients with FS, 26 (21.8%) revealed paroxysmal abnormality on EEG and 9 (7.6%) developed epilepsy. Of nine patients with later epilepsy, 6 (66.7%) revealed paroxysmal EEG abnormality. Of 26 patients with paroxysmal abnormality, 6 (23.1%) developed epilepsy. Of 10 patients with generalized paroxysmal spike and wave activity, one (10%) developed epilepsy. Of seven patients with rolandic discharge (RD), two (28.5%) developed epilepsy. Of four patients with paroxysms in the frontal region, three (75%) developed epilepsy. Of five patients with paroxysms in the occipital region, none developed epilepsy. Compared with generalized EEG foci, the relative risk (RR) for patients with frontal EEG foci was 27.0. Patients with frontal EEG paroxysms had a significantly higher risk of developing epilepsy than those with paroxysms in other regions of EEG foci (p=0.035). These findings suggest that patients with FS presenting with frontal paroxysmal EEG abnormalities may be at risk for epilepsy. In patients with frontal paroxysmal EEG abnormalities, serial EEG should be performed, even though it does not contribute to treatment.

Serial changes of prefrontal lobe growth in the patients with benign childhood epilepsy with centrotemporal spikes presenting with cognitive impairments/behavioral problems.

Several studies have reported a higher incidence of learning and behavioral difficulties in association with frontal lobe dysfunctions in children with benign childhood epilepsy with centrotemporal spikes (BCECTS). We studied serial changes in frontal and prefrontal lobe volumes using three-dimensional magnetic resonance imaging in BCECTS with or without cognitive impairments and behavioral problems and evaluated correlations between prefrontal lobe growth and active seizure period. Serial changes in regional cerebral volumes were measured in two patients with cognitive impairments and behavioral problems (BCECTS(+)) and five patients without neuropsychiatric deficits (BCECTS(-)). Eleven normal subjects (4-13years old) served as controls. Volumes of the frontal and prefrontal lobes were determined using a workstation, and the prefrontal-to-frontal lobe volume ratio was calculated. Frontal and prefrontal lobe volumes revealed growth disturbance in BCECTS(+) compared with BCECTS(-) and control subjects. In addition, prefrontal-to-frontal lobe volume ratio increased serially in BCECTS(-) similarly to controls, but was stagnant or decreased in BCECTS(+). Prefrontal growth also revealed more rapid recovery in a BCECTS(+) patient with shorter active seizure period. These findings suggest that longer active seizure period as frequent spike-waves coupled with the occurrence of frequent seizures may be associated with prefrontal lobe growth disturbance, which relates to neuropsychological problems.

[A case of recurrent paraneoplastic cerebellar ataxia with antibodies to GluR epsilon 2 causally related to ganglioneuroma].

Acute cerebellar ataxia (ACA) in childhood following viral infection is a self-limited disease. We present a boy with recurrent episodes of paraneoplastic cerebellar ataxia associated with a ganglioneuroma. A 20-month-old boy developed the first episode of cerebellar ataxia after nonspecific respiratory tract infections. During this episode he showed a wide gait and truncal ataxia with intention tremor and horizontal nystagmus. Our initial diagnosis was ACA, and gradual improvement of ataxia was observed thereafter. At 2 years and 6 months, similar cerebellar symptoms recurred after respiratory tract infections. Speech difficulty and cognitive problems developed thereafter. We suspected paraneoplastic syndrome. Computed tomography revealed a retroperitoneal tumor, and autoantibodies against GluR epsilon 2 were detected in the cerebrospinal fluid. After the tumor resection, the cerebellar symptoms did not recur and speech difficulty and cognitive problems improved gradually. Recent neuroimaging and neuropsychological studies have revealed that cerebellar function contributes to higher brain functions including cognition and learning. We will follow up this patient's long-term cognitive function and consider special educational support and programs.

Saccade eye movements as a quantitative measure of frontostriatal network in children with ADHD.

BACKGROUND: Evidence of poor inhibition in attention deficit hyperactivity disorder (ADHD) comes primarily from neuropsychological tasks and neuroimaging studies, many of which have revealed structural/functional abnormalities of the frontostriatal network with opposing functions of disinhibition and inhibition. Studies of saccades have therefore contributed to the understanding of the pathophysiological basis of ADHD. OBJECT: To investigate the development of reflexive/voluntary control of saccades in normal children, compare saccade parameters between ADHD and control groups, and clarify dysfunctional nervous systems in ADHD. METHODS: Subjects comprised 50 normal subjects (6-35 years), 19 ADHD patients (6-11 years) and four patients with frontal lesions (13-15 years). Saccade latency and accuracy were computed in all saccade tasks, while percentage of anticipatory errors (PAE) was determined in memory-guided saccade task, and percentage of direction errors (PDE) was determined in antisaccade task. RESULTS: In normal controls, significant correlations were observed between saccade latency, saccade accuracy, error rates and age. Significant differences existed between ADHD and 6- to 8-year-old controls in saccade latency and accuracy. The ADHD group showed significantly higher PAE and PDE rates than controls. Patients with frontal lesions showed significantly higher PAE and PDE. CONCLUSIONS: These results suggest that saccade eye movements do not fully mature until adolescence, and that ADHD patients show dysfunction in "response inhibition", which is modulated by the frontal lobe, particularly the prefrontal cortex, cingulate cortex and basal ganglia.