Desirée A. White

Neural correlates of recovery from aphasia after damage to left inferior frontal cortex

Objective: To determine neural correlates of recovery from aphasia after left frontal injury. Methods: The authors studied the verbal performance of patients with infarcts centered in the left inferior frontal gyrus (IFG), using a battery of attention-demanding lexical tasks that normally activate the left IFG and a simpler reading task that does not normally recruit the left IFG. The authors used positron emission tomography (PET) and functional MRI (fMRI) to record neural activity in the same group of patients during word-stem completion, one of the attention-demanding lexical tasks. To identify potential neural correlates of compensation/recovery, they analyzed the resulting data for the group as a whole (PET, fMRI) and also for each participant (fMRI). Results: Patients with damage to the left IFG were impaired on all attention-demanding lexical tasks, but they completed the word-reading tasks normally. The imaging studies demonstrated a stronger-than-normal response in the right IFG, a region homologous to the damaged left IFG. The level of activation in the right IFG did not correlate with verbal performance, however. In addition, a perilesional response within the damaged left IFG was localized in the two patients who gave the best performance in the word-stem completion task and showed the most complete recovery from aphasia. Conclusions: Right-IFG activity may represent either the recruitment of a preexisting neural pathway through alternative behavioral strategies or an anomalous response caused by removal of the left IFG. Perilesional activity in the left IFG may represent sparing or restoration of normal function in peri-infarctual tissue that was inactive early on after injury. This activity may be of greater functional significance than right IFG activity because it was associated with more normal verbal performance.

Controlled Trial of Transfusions for Silent Cerebral Infarcts in Sickle Cell Anemia

BACKGROUND Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care. METHODS In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct. RESULTS A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04). CONCLUSIONS Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).

Neuropsychological studies of asymptomatic human immunodeficiency virus-type-1 infected individuals. The HNRC Group. HIV Neurobehavioral Research Center.

The current review was conducted to address the ongoing debate regarding the presence or absence of neuropsychological impairment in asymptomatic HIV-Type 1 (HIV-1) seropositive individuals. Results were summarized from 57 studies that compared the performances of seropositive asymptomatic and seronegative individuals. Overall, the differences observed between median rates of impairment for asymptomatic (35%) and seronegative (12%) groups provided the clearest indication of deficits in asymptomatics. In addition, five variables were examined as possible contributors to inconsistencies found in the literature: mode of infection, test battery type, test battery size, sample size, and method of data analysis. Of these variables, only mode of infection and test battery size appeared to substantially influence the outcome of the studies reviewed with regard to identifying neuropsychological impairment in asymptomatics.

Executive function in early-treated phenylketonuria: Profile and underlying mechanisms

Despite early and continuous dietary intervention, individuals with early-treated phenylketonuria (PKU) experience significant neurocognitive sequelae. An area of cognitive ability that is believed to be particularly affected is executive function (EF). This paper provides a critical review of the evidence for EF impairment in early-treated PKU within the context of recent advances in neuropsychological theory and research. The most consistent findings of PKU-related EF impairment were in executive working memory and prepotent response inhibition. Surprisingly, findings on shifting ability and other more complex aspects of EF were largely equivocal. Cohort (e.g., age, phenylalanine (Phe) levels) and task (e.g., standard clinical versus experimental tasks) related differences likely contributed to the variability in findings reported by these studies. Day-to-day EF also appears to be impaired although the precise pattern of impairment remains unclear, as does the relationship between laboratory measures of EF and questionnaires assessing day-to-day EF. Similarly, whereas several studies have found a relationship between Phe levels and EF, the best predictor variable (e.g., concurrent Phe level, lifetime Phe level, Phe level variability) of current EF performance varied from study to study. Neurologic compromise related to dopamine deficiency, white matter abnormalities, and disruptions in functional connectivity likely underlies the EF impairments described in this review. In closing, this review identifies remaining unanswered questions and future avenues for research.

Learning, Memory, and Executive Control in Individuals With Obstructive Sleep Apnea Syndrome

A range of neuropsychological deficits have been identified in individuals with obstructive sleep apnea syndrome (OSAS) and have been related to disruptions in function of the frontal cortex of the brain. We hypothesized that impairments in the use of strategic, frontally-mediated processes that facilitate learning and memory would be associated with deficits in the long-term episodic memory of verbal material (i.e., word lists). We evaluated 28 adults with OSAS and 24 controls (ranging from 28 to 60 years of age) using the California Verbal Learning Test. General executive abilities were assessed using the Wisconsin Card Sorting Test, Letter fluency, and Category fluency. Individuals with OSAS exhibited poorer recall across learning trials, less efficient use of semantic clustering, and poorer use of semantic cues. Retention of previously encoded information and recognition, however, were intact. With the exception of letter fluency, deficits were not observed in general executive control. Results are discussed within the context of disruptions in the interactions between long-term memory and executive abilities that are subserved by frontal and distal brain regions.

Inhibitory control across the life span

Findings from previous research suggest that inhibitory control improves during early childhood and declines during late adulthood. Very few researchers, however, have examined life-span changes in this ability in single studies. Within this life-span context, we investigated 1 type of inhibitory control--the ability to inhibit aprepotent response and generate an incompatible response--in individuals ranging from 6 to 82 years of age. Examination of raw reaction time data revealed a significantly larger inhibitory control effect for children and older adults than for young adults. Using proportional and z score transformations, we demonstrated that a processing speed explanation is sufficient to account for the differences in performance between children and young adults; this explanation, however, did not adequately explain the discrepancy between young and older adults. Taken together, these findings suggest that, above and beyond differences in processing speed, inhibitory control was less efficient in older adults. Our findings are consistent with the assertion that inhibitory control develops quite early and declines at the later end of the developmental spectrum.

Phenylketonuria Scientific Review Conference: State of the science and future research needs

New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.

Effects of age, domain, and processing demands on memory span: Evidence for differential decline.

Analysis of cross-sectional data from the normative sample of the Wechsler Memory Scale - Third Edition (WMS-III) revealed different patterns of age-related differences in memory span measures depending on the type of memory item, processing demands, and the age of the older adult group. Regression of memory span on age revealed that the slope for Spatial Span raw scores was significantly more negative than the slope for Digit Span raw scores. There was no significant difference, however, either between the slopes for forward and backward Digit Span or between the slopes for forward and backward Spatial Span. Regression of Letter-Number Sequencing raw scores on age showed a distinctive, curvilinear pattern. Taken together, the present findings suggest that at least two mechanisms are involved in age-related differences in memory span. One mechanism, associated with a relatively linear decrease in memory span as a function of age, may differentially affect the storage of different types of information (e.g., sequences of digits vs. spatial locations). The other mechanism, evidenced by the curvilinear trend in Letter-Number Sequencing scores, may be tentatively attributed to a decline in executive aspects of working memory that becomes increasingly pronounced with age.

Exploring the relationship between age, executive abilities, and psychomotor speed

Age-related declines in executive abilities have been widely reported and are thought to result from neuropathological changes in the prefrontal cortex. Some investigators have suggested that age-related changes in cognition may be the result of slowed information processing speed rather than declines in specific cognitive abilities. We examined the relationships among age, executive abilities, and psychomotor speed in 40 older adults and 46 young adults. Both verbal and nonverbal tasks were administered that measured 2 aspects of executive ability: set formation and set shifting. Executive and psychomotor speed tasks were paired based on similarities in basic task demands. Our results revealed that poorer executive performance was associated with increasing age. Further, although psychomotor speed attenuated the relationship, age accounted for a unique and significant proportion of variance in executive performance after controlling for psychomotor speed. These results suggest that age has an effect on prefrontally mediated executive abilities that cannot be explained solely in terms of psychomotor slowing.

A latent variables examination of processing speed, response inhibition, and working memory during typical development.

This study addressed three related aims: (a) to replicate and extend previous work regarding the nonunitary nature of processing speed, response inhibition, and working memory during development; (b) to quantify the rate at which processing speed, response inhibition, and working memory develop and the extent to which the development of these latter abilities reflect general changes in processing speed; and (c) to evaluate whether commonly used tasks of processing speed, response inhibition, and working memory are valid and reliable when used with a developmentally diverse group. To address these aims, a latent variables approach was used to analyze data from 147 participants 6-24years of age. Results showed that processing speed, response inhibition, and working memory were separable abilities and that the extent of this separability was stable across the age range of participants. All three constructs improved as a function of age; however, only the effect of age on working memory remained significant after processing speed was controlled. The psychometric properties of tasks used to assess the constructs were age invariant, thereby validating their use in studies of executive development.