Cumulative Blood Pressure Exposure, Basal Ganglia, and Thalamic Morphology in Midlife.

High blood pressure (BP) negatively affects brain structure and function. Hypertension is associated with white matter hyperintensities, cognitive and mobility impairment in late-life. However, the impact of BP exposure from young adulthood on brain structure and function in mid-life is unclear. Identifying early brain structural changes associated with BP exposure, before clinical onset of cognitive dysfunction and mobility impairment, is essential for understanding mechanisms and developing interventions. We examined the effect of cumulative BP exposure from young adulthood on brain structure in a substudy of 144 (61 female) individuals from the CARDIA (Coronary Artery Risk Development in Young Adults) study. At year 30 (Y30, ninth visit), participants (56±4 years old) completed brain magnetic resonance imaging and gait measures (pace, rhythm, and postural control). Cumulative systolic and diastolic BP (cumulative systolic blood pressure, cDBP) over 9 visits were calculated, multiplying mean values between 2 consecutive visits by years between visits. Surface-based analysis of basal ganglia and thalamus was achieved using FreeSurfer-initiated Large Deformation Diffeomorphic Metric Mapping. Morphometric changes were regressed onto cumulative BP to localize regions of shape variation. Y30 white matter hyperintensity volumes were small and positively correlated with cumulative BP but not gait. Negative morphometric associations with cumulative systolic blood pressure were seen in the caudate, putamen, nucleus accumbens, pallidum, and thalamus. A concave right medial putamen shape mediated the relationship between cumulative systolic blood pressure and stride width. Basal ganglia and thalamic morphometric changes, rather than volumes, may be earlier manifestation of gray matter structural signatures of BP exposure that impact midlife gait.

Outward subcortical curvature associated with sub-clinical depression symptoms in adolescents.

OBJECTIVE: Subclinical or subthreshold depressive symptoms (StD) are frequent in adolescence and are related to suicidality and onset of depression in adulthood, however, their neurobiology is poorly understood. We examined the relationship between StD and subcortical grey matter structures in unmedicated adolescents with no history of axis I diagnosis. METHODS: 277 youths from Chicago aged 14 years participated, undergoing a structural MRI scan and completing the Revised Children's Anxiety and Depression Scale (RCADS). Blood samples provided a composite of five pro-inflammatory cytokines. Regions of interest (ROI) for vertex-based surface analysis were the left and right amygdala, hippocampus, thalamus, caudate, nucleus accumbens, pallidum and putamen. Covariates were age, pubertal status, socioeconomic disadvantage and intracranial volume. Males and females were analysed separately. RESULTS: StD had positive associations (outward shape) with subcortical morphology in the right amygdala and left hippocampus in females, and the bilateral putamen and the left caudate, hippocampus and thalamus in males. However, we also found negative associations with StD (inward contractions) in the hippocampus in females and the caudate in males. Pro-inflammatory cytokines did not mediate the relationship between StD and outward morphology or volume. CONCLUSION: This is one of the first studies to examine subcortical morphology of basal ganglia and thalamic regions related to StD in adolescents, and the first study to report mostly positive associations between StD, volume and outward morphology in youths. These findings could reflect intact neurogenesis or resilience to depression, however longitudinal research is needed to further understand the neurobiology of StD in adolescents.

Subcortical structural variations associated with low socioeconomic status in adolescents.

Low socioeconomic status (SES) is associated with a higher probability of multiple exposures (e.g., neighborhood violence, poor nutrition, housing instability, air pollution, and insensitive caregiving) known to affect structural development of subcortical brain regions that subserve threat and reward processing, however, few studies have examined the relationship between SES and such subcortical structures in adolescents. We examined SES variations in volume and surface morphometry of subcortical regions. The sample comprised 256 youth in eighth grade (mean age = 13.9 years), in whom high dimensional deformation mapping of structural 3T magnetic resonance imaging scans was performed. Vertex-wise linear regression analyses examined associations between income to poverty ratio and surfaces of the hippocampus, amygdala, thalamus, caudate, putamen, nucleus accumbens and pallidum, with the covariates age, pubertal status, and intracranial volume. Given sex differences in pubertal development and subcortical maturation at this age, the analyses were stratified by sex. Among males, who at this age average an earlier pubertal stage than females, the relationship between SES and local shape variation in subcortical regions was almost entirely positive. For females, the relationship between SES and local shape variation was negative. Racial identity was associated with SES in our sample, however supplementary analyses indicated that most of the associations between SES and subcortical structure were independent of it. Although these cross-sectional results are not definitive, they are consistent with a scenario where low SES delays structural maturation of subcortical regions involved with threat and reward processing. Future longitudinal studies are needed to test this hypothesis.

Epidural Electrical Stimulation for Stroke Rehabilitation: Results of the Prospective, Multicenter, Randomized, Single-Blinded Everest Trial.

BACKGROUND: This prospective, single-blinded, multicenter study assessed the safety and efficacy of electrical epidural motor cortex stimulation (EECS) in improving upper limb motor function of ischemic stroke patients with moderate to moderately severe hemiparesis. METHODS: Patients ≥ 4 months poststroke were randomized 2:1 to an investigational (n = 104) or control (n = 60) group, respectively. Investigational patients were implanted (n = 94) with an epidural 6-contact lead perpendicular to the primary motor cortex and a pulse generator. Both groups underwent 6 weeks of rehabilitation, but EECS was delivered to investigational patients during rehabilitation. The primary efficacy endpoint (PE) was defined as attaining a minimum improvement of 4.5 points in the upper extremity Fugl-Meyer (UEFM) scale as well as 0.21 points in the Arm Motor Ability Test (AMAT) 4 weeks postrehabilitation. Follow-up assessments were performed 1, 4, 12, and 24 weeks postrehabilitation. Safety was evaluated by monitoring adverse events (AEs) that occurred between enrollment and the end of rehabilitation. RESULTS: Primary intent-to-treat analysis showed no group differences at 4 weeks, with PE being met by 32% and 29% of investigational and control patients, respectively (P = .36). Repeated-measures secondary analyses revealed no significant treatment group differences in mean UEFM or AMAT scores. However, post hoc comparisons showed that a greater proportion of investigational (39%) than control (15%) patients maintained or achieved PE (P = .003) at 24 weeks postrehabilitation. Investigational group mean AMAT scores also improved significantly (P < .05) when compared to the control group at 24 weeks postrehabilitation. Post hoc analyses also showed that 69% (n = 9/13) of the investigational patients who elicited movement thresholds during stimulation testing met PE at 4 weeks, and mean UEFM and AMAT scores was also significantly higher (P < .05) in this subgroup at the 4-, 12-, and 24-week assessments when compared to the control group. Headache (19%), pain (13%), swelling (7%), and infection (7%) were the most commonly observed implant procedure-related AEs. Overall, there were 11 serious AEs in 9 investigational group patients (7 procedure related, 4 anesthesia related). CONCLUSIONS: The primary analysis pertaining to efficacy of EECS during upper limb motor rehabilitation in chronic stroke patients was negative at 4 weeks postrehabilitation. A better treatment response was observed in a subset of patients eliciting stimulation induced upper limb movements during motor threshold assessments performed prior to each rehabilitation session. Post hoc comparisons indicated treatment effect differences at 24 weeks, with the control group showing significant decline in the combined primary outcome measure relative to the investigational group. These results have the potential to inform future chronic stroke rehabilitation trial design.

Selective neurophysiologic responses to music in instrumentalists with different listening biographies.

To appropriately adapt to constant sensory stimulation, neurons in the auditory system are tuned to various acoustic characteristics, such as center frequencies, frequency modulations, and their combinations, particularly those combinations that carry species-specific communicative functions. The present study asks whether such tunings extend beyond acoustic and communicative functions to auditory self-relevance and expertise. More specifically, we examined the role of the listening biography--an individual's long term experience with a particular type of auditory input--on perceptual-neural plasticity. Two groups of expert instrumentalists (violinists and flutists) listened to matched musical excerpts played on the two instruments (J.S. Bach Partitas for solo violin and flute) while their cerebral hemodynamic responses were measured using fMRI. Our experimental design allowed for a comprehensive investigation of the neurophysiology (cerebral hemodynamic responses as measured by fMRI) of auditory expertise (i.e., when violinists listened to violin music and when flutists listened to flute music) and nonexpertise (i.e., when subjects listened to music played on the other instrument). We found an extensive cerebral network of expertise, which implicates increased sensitivity to musical syntax (BA 44), timbre (auditory association cortex), and sound-motor interactions (precentral gyrus) when listening to music played on the instrument of expertise (the instrument for which subjects had a unique listening biography). These findings highlight auditory self-relevance and expertise as a mechanism of perceptual-neural plasticity, and implicate neural tuning that includes and extends beyond acoustic and communication-relevant structures.

Volume of left Heschl's Gyrus and linguistic pitch learning.

Research on the contributions of the human nervous system to language processing and learning has generally been focused on the association regions of the brain without considering the possible contribution of primary and adjacent sensory areas. We report a study examining the relationship between the anatomy of Heschl's Gyrus (HG), which includes predominately primary auditory areas and is often found to be associated with nonlinguistic pitch processing and language learning. Unlike English, most languages of the world use pitch patterns to signal word meaning. In the present study, native English-speaking adult subjects learned to incorporate foreign pitch patterns in word identification. Subjects who were less successful in learning showed a smaller HG volume on the left (especially gray matter volume), but not on the right, relative to learners who were successful. These results suggest that HG, typically shown to be associated with the processing of acoustic cues in nonspeech processing, is also involved in speech learning. These results also suggest that primary auditory regions may be important for encoding basic acoustic cues during the course of spoken language learning.

Neural characteristics of successful and less successful speech and word learning in adults.

A remarkable characteristic of the human nervous system is its ability to learn to integrate novel (foreign) complex sounds into words. However, the neural changes involved in how adults learn to integrate novel sounds into words and the associated individual differences are largely unknown. Unlike English, most languages of the world use pitch patterns to mark individual word meaning. We report a study assessing the neural correlates of learning to use these pitch patterns in words by English-speaking adults who had no previous exposure to such usage. Before and after training, subjects discriminated pitch patterns of the words they learned while blood oxygenation levels were measured using fMRI. Subjects who mastered the learning program showed increased activation in the left posterior superior temporal region after training, while subjects who plateaued at lower levels showed increased activation in the right superior temporal region and right inferior frontal gyrus, which are associated with nonlinguistic pitch processing, and prefrontal and medial frontal areas, which are associated with increased working memory and attentional efforts. Furthermore, we found brain activation differences even before training between the two subject groups, including the superior temporal region. These results demonstrate an association between range of neural changes and degrees of language learning, specifically implicating the physiologic contribution of the left dorsal auditory cortex in learning success.

Chronic back pain is associated with decreased prefrontal and thalamic gray matter density.

The role of the brain in chronic pain conditions remains speculative. We compared brain morphology of 26 chronic back pain (CBP) patients to matched control subjects, using magnetic resonance imaging brain scan data and automated analysis techniques. CBP patients were divided into neuropathic, exhibiting pain because of sciatic nerve damage, and non-neuropathic groups. Pain-related characteristics were correlated to morphometric measures. Neocortical gray matter volume was compared after skull normalization. Patients with CBP showed 5-11% less neocortical gray matter volume than control subjects. The magnitude of this decrease is equivalent to the gray matter volume lost in 10-20 years of normal aging. The decreased volume was related to pain duration, indicating a 1.3 cm3 loss of gray matter for every year of chronic pain. Regional gray matter density in 17 CBP patients was compared with matched controls using voxel-based morphometry and nonparametric statistics. Gray matter density was reduced in bilateral dorsolateral prefrontal cortex and right thalamus and was strongly related to pain characteristics in a pattern distinct for neuropathic and non-neuropathic CBP. Our results imply that CBP is accompanied by brain atrophy and suggest that the pathophysiology of chronic pain includes thalamocortical processes.

Development of brain mechanisms for processing orthographic and phonologic representations.

Developmental differences in the neurocognitive networks for lexical processing were examined in 15 adults and 15 children (9- to 12-year-olds) using functional magnetic resonance imaging (fMRI). The lexical tasks involved spelling and rhyming judgments in either the visual or auditory modality. These lexical tasks were compared with nonlinguistic control tasks involving judgments of line patterns or tone sequences. The first main finding was that adults showed greater activation than children during the cross-modal lexical tasks in a region proposed to be involved in mapping between orthographic and phonologic representations. The visual rhyming task, which required conversion from orthography to phonology, produced greater activation for adults in the angular gyrus. The auditory spelling task, which required the conversion from phonology to orthography, also produced greater activation for adults in the angular gyrus. The greater activation for adults suggests they may have a more elaborated posterior heteromodal system for mapping between representational systems. The second main finding was that adults showed greater activation than children during the intra-modal lexical tasks in the angular gyrus. The visual spelling and auditory rhyming did not require conversion between orthography and phonology for correct performance but the adults showed greater activation in a system implicated for this mapping. The greater activation for adults suggests that they have more interactive convergence between representational systems during lexical processing.

Relation between brain activation and lexical performance.

Functional magnetic resonance imaging (fMRI) was used to determine whether performance on lexical tasks was correlated with cerebral activation patterns. We found that such relationships did exist and that their anatomical distribution reflected the neurocognitive processing routes required by the task. Better performance on intramodal tasks (determining if visual words were spelled the same or if auditory words rhymed) was correlated with more activation in unimodal regions corresponding to the modality of sensory input, namely the fusiform gyrus (BA 37) for written words and the superior temporal gyrus (BA 22) for spoken words. Better performance in tasks requiring cross-modal conversions (determining if auditory words were spelled the same or if visual words rhymed), on the other hand, was correlated with more activation in posterior heteromodal regions, including the supramarginal gyrus (BA 40) and the angular gyrus (BA 39). Better performance in these cross-modal tasks was also correlated with greater activation in unimodal regions corresponding to the target modality of the conversion process (i.e., fusiform gyrus for auditory spelling and superior temporal gyrus for visual rhyming). In contrast, performance on the auditory spelling task was inversely correlated with activation in the superior temporal gyrus possibly reflecting a greater emphasis on the properties of the perceptual input rather than on the relevant transmodal conversions.