A fundamental issue in cognitive neuroscience is the nature of developmental changes in human cerebral functional organization for higher cognitive functions. Event-related functional magnetic resonance imaging was used to measure developmental changes in the functional neuroanatomy subserving controlled lexical association. First, brain regions showing significant differences in activity between school-age children and young adults, despite equivalent task performance, were identified. Then, activity in these regions was more fully characterized in individuals spanning the ages of 7-32 years old. Cross-sectional and regression analyses showed systematic increases and decreases in levels of activity over age, by region. Age-related increases in activity were primarily newly recruited, later-stage processing regions, such as in left frontal and left parietal cortex. Decreases, on the other hand, were all positive activations that attenuated with age and were found across a wider neuroanatomical range, including earlier processing regions such as bilateral extrastriate cortex. The hemodynamic magnitude, neuroanatomical location and maturational timecourse of these progressive and regressive changes have implications for models of the developing specialization in human cerebral functional organization.

A critical issue in developmental cognitive neuroscience is the extent to which the functional neuroanatomy underlying task performance differs in adults and children. Direct comparisons of brain activation in the left frontal and extrastriate cortex were made in adults and children (aged 7 to 10 years) performing single-word processing tasks with visual presentation; differences were found in circumscribed frontal and extrastriate regions. Conceivably, these differences could be attributable exclusively to performance discrepancies; alternatively, maturational differences in functional neuroanatomy could exist despite similar performance. Some of the brain regions examined showed differences attributable to age independent of performance, suggesting that maturation of the pattern of regional activations for these tasks is incomplete at age 10.

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In this study of reading development, children (ages 7-10) and adults (ages 18-32) performed overt single-word reading and aural repetition tasks on high-frequency word stimuli during functional magnetic resonance imaging. Most regions showed similar activity across age groups. These widespread regions of similarity indicate that children and adults use largely overlapping mechanisms when processing high-frequency words. Significant task-related differences included greater activity in occipital cortex for the read task, and greater activity in temporal cortex for the repeat task; activity levels in these regions were similar for adults and children. However, age group differences were found in several posterior regions, including a set of regions implicated in adult reading: the left supramarginal gyrus, the left angular gyrus, and bilateral anterior extrastriate cortex. The angular and supramarginal gyrus regions, hypothesized to play a role in phonology, showed decreased activity in adults relative to children for high-frequency words. The extrastriate regions had significant activity for both the visual read task and auditory repeat task in children, but just for the read task in adults, showing significant task and age interactions. These results are consistent with decreasing reliance on phonological processing, and increasing tuning of visual mechanisms, with age.

Objective We developed a novel method to map behavioral effects of deep brain stimulation (DBS) across a 3D brain region and to assign statistical significance after stringent Type I error correction. This method was applied to behavioral changes in Parkinson disease (PD) induced by subthalamic nucleus (STN) DBS to determine whether these responses depended on anatomical location of DBS. Method Fifty-one PD participants with STN DBS were evaluated off medication, with DBS off and during unilateral STN DBS with clinically optimized settings. Dependent variables included DBS-induced changes in Unified Parkinson Disease Rating Scale (UPDRS) subscores, kinematic measures of bradykinesia and rigidity, working memory, response inhibition, mood, anxiety, and akathisia. Weighted t-tests at each voxel produced p images showing where DBS most significantly affected each dependent variable based on outcomes of participants with nearby DBS. Finally, a permutation test computed the probability that this p image indicated significantly different responses based on stimulation site. Results Most motor variables improved with DBS anywhere in the STN region, but several motor, cognitive and affective responses significantly depended on precise location stimulated, with peak p values in superior STN/zona incerta (quantified bradykinesia), dorsal STN (mood, anxiety), and inferior STN/substantia nigra (UPDRS tremor, working memory). Interpretation Our method identified DBS-induced behavioral changes that depended significantly on DBS site. These results do not support complete functional segregation within STN, since movement improved with DBS throughout, and mood improved with dorsal STN DBS. Rather, findings support functional convergence of motor, cognitive and limbic information in STN.

The basal ganglia are thought to be important in the selection of wanted and the suppression of unwanted motor patterns according to explicit rules (i.e. response inhibition). The subthalamic nucleus has been hypothesized to play a particularly critical role in this function. Deep brain stimulation of the subthalamic nucleus in individuals with Parkinson's disease has been used to test this hypothesis, but results have been variable. Based on current knowledge of the anatomical organization of the subthalamic nucleus, we propose that the location of the contacts used in deep brain stimulation could explain variability in the effects of deep brain stimulation of the subthalamic nucleus on response inhibition tasks. We hypothesized that stimulation affecting the dorsal subthalamic nucleus (connected to the motor cortex) would be more likely to affect motor symptoms of Parkinson's disease, and stimulation affecting the ventral subthalamic nucleus (connected to higher order cortical regions) would be more likely to affect performance on a response inhibition task. We recruited 10 individuals with Parkinson's disease and bilateral deep brain stimulation of the subthalamic nucleus with one contact in the dorsal and another in the ventral subthalamic region on one side of the brain. Patients were tested with a Go-No-Go task and a motor rating scale in three conditions: stimulation off, unilateral dorsal stimulation and unilateral ventral stimulation. Both dorsal and ventral stimulation improved motor symptoms, but only ventral subthalamic stimulation affected Go-No-Go performance, decreasing hits and increasing false alarms, but not altering reaction times. These results suggest that the ventral subthalamic nucleus is involved in the balance between appropriate selection and inhibition of prepotent responses in cognitive paradigms, but that a wide area of the subthalamic nucleus region is involved in the motor symptoms of Parkinson's disease. This finding has implications for resolving inconsistencies in previous research, highlights the role of the ventral subthalamic nucleus region in response inhibition and suggests an approach for the clinical optimization of deep brain stimulation of the subthalamic nucleus for both motor and cognitive functions.

Wolfram Syndrome (WFS) is a rare autosomal recessive disease characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, deafness, and neurological dysfunction leading to death in mid-adulthood. WFS is caused by mutations in the WFS1 gene, which lead to endoplasmic reticulum (ER) stress-mediated cell death. Case studies have found widespread brain atrophy in late stage WFS. However, it is not known when in the disease course these brain abnormalities arise, and whether there is differential vulnerability across brain regions and tissue classes. To address this limitation, we quantified regional brain abnormalities across multiple imaging modalities in a cohort of young patients in relatively early stages of WFS. Children and young adults with WFS were evaluated with neurological, cognitive and structural magnetic resonance imaging measures. Compared to normative data, the WFS group had intact cognition, significant anxiety and depression, and gait abnormalities. Compared to healthy and type 1 diabetic control groups, the WFS group had smaller intracranial volume and preferentially affected gray matter volume and white matter microstructural integrity in the brainstem, cerebellum and optic radiations. Abnormalities were detected in even the youngest patients with mildest symptoms, and some measures did not follow the typical age-dependent developmental trajectory. These results establish that WFS is associated with smaller intracranial volume with specific abnormalities in the brainstem and cerebellum, even at the earliest stage of clinical symptoms. This pattern of abnormalities suggests that WFS has a pronounced impact on early brain development in addition to later neurodegenerative effects, representing a significant new insight into the WFS disease process. Longitudinal studies will be critical for confirming and expanding our understanding of the impact of ER stress dysregulation on brain development.

OBJECTIVEThe impact of type 1 diabetes mellitus (T1DM) on the developing central nervous system is not well understood. Cross-sectional, retrospective studies suggest that exposure to glycemic extremes during development is harmful to brain structure in youth with T1DM. However, these studies cannot identify brain regions that change differentially over time depending on the degree of exposure to glycemic extremes.RESEARCH DESIGN AND METHODSWe performed a longitudinal, prospective structural neuroimaging study of youth with T1DM (n = 75; mean age = 12.5 years) and their nondiabetic siblings (n = 25; mean age = 12.5 years). Each participant was scanned twice, separated by 2 years. Blood glucose control measurements (HbA1c, glucose meter results, and reports of severe hypoglycemia) were acquired during the 2-year follow-up. Sophisticated image registration algorithms were performed, followed by whole brain and voxel-wise statistical analyses of the change in gray and white matter volume, controlling for age, sex, and age of diabetes onset.RESULTSThe T1DM and nondiabetic control (NDC) sibling groups did not differ in whole brain or voxel-wise change over the 2-year follow-up. However, within the T1DM group, participants with more hyperglycemia had a greater decrease in whole brain gray matter compared with those with less hyperglycemia (P < 0.05). Participants who experienced severe hypoglycemia had greater decreases in occipital/parietal white matter volume compared with those with no severe hypoglycemia (P < 0.05) and compared with the NDC sibling group (P < 0.05).CONCLUSIONSThese results demonstrate that within diabetes, exposure to hyperglycemia and severe hypoglycemia may result in subtle deviation from normal developmental trajectories of the brain.