Todd Constable

Nanosystems for Simultaneous Imaging and Drug Delivery to T Cells

The T-cell response defines the pathogenesis of many common chronic disease states, including diabetes, rheumatoid arthritis, and transplant rejection. Therefore, a diagnostic strategy that visualizes this response can potentially lead to early therapeutic intervention, avoiding catastrophic organ failure or prolonged sickness. In addition, the means to deliver a drug dose to those cells in situ with the same specificity used to image those cells would provide for a powerful therapeutic alternative for many disease states involving T cells. In this report, we review emerging nanosystems that can be used for simultaneous tracking and drug delivery to those cells. Because of their versatility, these systems—which combine specific receptor targeting with an imaging agent and drug delivery—are suited to both basic science and applications, from developing therapeutic strategies for autoimmune and alloimmune diseases, to noninvasive tracking of pathogenic T-cell migration.

Altered Age-Related Trajectories of Amygdala-Prefrontal Circuitry in Adolescents at Clinical High Risk for Psychosis: A Preliminary Study

Emotion processing deficits are prominent in schizophrenia and exist prior to the onset of overt psychosis. However, developmental trajectories of neural circuitry subserving emotion regulation and the role that they may play in illness onset have not yet been examined in patients at risk for psychosis. The present study employed a cross-sectional analysis to examine age-related functional activation in amygdala and prefrontal cortex, as well as functional connectivity between these regions, in adolescents at clinical high risk (CHR) for psychosis relative to typically developing adolescents. Participants (n=34) performed an emotion processing fMRI task, including emotion labeling, emotion matching, and non-emotional control conditions. Regression analyses were used to predict activation in the amygdala and ventrolateral prefrontal cortex (vlPFC) based on age, group, sex, and the interaction of age by group. CHR adolescents exhibited altered age-related variation in amygdala and vlPFC activation, relative to controls. Controls displayed decreased amygdala and increased vlPFC activation with age, while patients exhibited the opposite pattern (increased amygdala and decreased vlPFC activation), suggesting a failure of prefrontal cortex to regulate amygdala reactivity. Moreover, a psychophysiological interaction analysis revealed decreased amygdala-prefrontal functional connectivity among CHR adolescents, consistent with disrupted brain connectivity as a vulnerability factor in schizophrenia. These results suggest that the at-risk syndrome is marked by abnormal development and functional connectivity of neural systems subserving emotion regulation. Longitudinal data are needed to confirm aberrant developmental trajectories intra-individually and to examine whether these abnormalities are predictive of conversion to psychosis, and of later deficits in socioemotional functioning.

Reliability of an fMRI paradigm for emotional processing in a multisite longitudinal study

Multisite neuroimaging studies can facilitate the investigation of brain‐related changes in many contexts, including patient groups that are relatively rare in the general population. Though multisite studies have characterized the reliability of brain activation during working memory and motor functional magnetic resonance imaging tasks, emotion processing tasks, pertinent to many clinical populations, remain less explored. A traveling participants study was conducted with eight healthy volunteers scanned twice on consecutive days at each of the eight North American Longitudinal Prodrome Study sites. Tests derived from generalizability theory showed excellent reliability in the amygdala ( Eρ2  = 0.82), inferior frontal gyrus (IFG; Eρ2  = 0.83), anterior cingulate cortex (ACC; Eρ2  = 0.76), insula ( Eρ2  = 0.85), and fusiform gyrus ( Eρ2  = 0.91) for maximum activation and fair to excellent reliability in the amygdala ( Eρ2  = 0.44), IFG ( Eρ2  = 0.48), ACC ( Eρ2  = 0.55), insula ( Eρ2  = 0.42), and fusiform gyrus ( Eρ2  = 0.83) for mean activation across sites and test days. For the amygdala, habituation ( Eρ2  = 0.71) was more stable than mean activation. In a second investigation, data from 111 healthy individuals across sites were aggregated in a voxelwise, quantitative meta‐analysis. When compared with a mixed effects model controlling for site, both approaches identified robust activation in regions consistent with expected results based on prior single‐site research. Overall, regions central to emotion processing showed strong reliability in the traveling participants study and robust activation in the aggregation study. These results support the reliability of blood oxygen level‐dependent signal in emotion processing areas across different sites and scanners and may inform future efforts to increase efficiency and enhance knowledge of rare conditions in the population through multisite neuroimaging paradigms. Hum Brain Mapp 36:2558–2579, 2015.

Physical and geometrical modeling for image-based recovery of left ventricular deformation

Information about left ventricular (LV) mechanical performance is of critical importance in understanding the etiology of ischemic heart disease. Regional measurements derived from non-invasive imaging to assist in assessing this performance have been in use for decades, and certain parameters derived from these measurements often are useful clinically, as they correlate to some extent with gross physiological hypotheses. However, relatively little work has been done to date to carefully understand the relationship of regional myocardial injury to the local mechanical performance of the heart as derived from image data acquired non-invasively for a particular patient in 3 spatial dimensions over time. This paper describes efforts to take advantage of recent developments in 3D non-invasive imaging and biomechanical modeling to design an integrated computational platform capable of assembling a variety of displacement and velocity data derived from each image frame to deform a volumetric model representation of a portion of the myocardium. A brief description of the reasoning behind this strategy an overview of the approach and some initial results are described.

Modulation of functional connectivity with the syntactic and semantic demands of a Noun Phrase Formation Task: a possible role for the Default Network.

Neuroimaging studies of language processing have shown that different circuits within the language network are isolated by syntactic and semantic tasks. We examined differential activation in an fMRI study of language when a single task with two minimally distinct conditions is employed. 16 subjects participated in a Noun Phrase Formation Task that encompassed a minimal difference between syntactic and semantic conditions. In-magnet accuracy and response times were compared, imaging data were evaluated for effects of task conditions, and the functional connectivity between areas of differential response to conditions were evaluated using cross-subject, interregional correlations between measures of BOLD activity. Although no difference in performance was observed between conditions, random effects analysis pinpointed pivotal components of the syntactic and semantic circuits (p<0.01 corrected for multiple comparisons) usually isolated with more complex, sentence-level stimuli. These included bilateral Brocas area and left inferior parietal lobe in the syntactic condition and left BA47 and left middle temporal gyrus in the semantic. Correlations among these regions did not pattern straightforwardly with the two task conditions, contrary to our expectations. Two significantly correlated circuits were identified (p<0.01): the well-documented connection between the left inferior parietal lobe and Brocas area and a connection between the medial frontal lobe and BA 47. An intriguing pattern was revealed in how the two sets of regions correlated with three areas of significantly differential deactivation to task, areas that are co-extensive with the Default Network. The deactivating regions, plus those areas that inversely correlated with them, formed one coordinated sub-circuit, encompassing the regions identified with syntax. Areas that positively correlated with the deactivating regions encompassed the semantic circuit. We suggest that by leveraging the Default Network, a partial bifurcation in connectivity was obtained that appeared to be conditioned externally. These regions could be viewed as an interface, balancing activation between the two overlapping, condition-dependent sub-circuits to enhance differential brain response within a complex cognitive network.

Diffusion Tensor Imaging in Patients with Glioblastoma Multiforme Using the Supertoroidal Model

Purpose Diffusion Tensor Imaging (DTI) is a powerful imaging technique that has led to improvements in the diagnosis and prognosis of cerebral lesions and neurosurgical guidance for tumor resection. Traditional tensor modeling, however, has difficulties in differentiating tumor-infiltrated regions and peritumoral edema. Here, we describe the supertoroidal model, which incorporates an increase in surface genus and a continuum of toroidal shapes to improve upon the characterization of Glioblastoma multiforme (GBM). Materials and Methods DTI brain datasets of 18 individuals with GBM and 18 normal subjects were acquired using a 3T scanner. A supertoroidal model of the diffusion tensor and two new diffusion tensor invariants, one to evaluate diffusivity, the toroidal volume (TV), and one to evaluate anisotropy, the toroidal curvature (TC), were applied and evaluated in the characterization of GBM brain tumors. TV and TC were compared with the mean diffusivity (MD) and fractional anisotropy (FA) indices inside the tumor, surrounding edema, as well as contralateral to the lesions, in the white matter (WM) and gray matter (GM). Results The supertoroidal model enhanced the borders between tumors and surrounding structures, refined the boundaries between WM and GM, and revealed the heterogeneity inherent to tumor-infiltrated tissue. Both MD and TV demonstrated high intensities in the tumor, with lower values in the surrounding edema, which in turn were higher than those of unaffected brain parenchyma. Both TC and FA were effective in revealing the structural degradation of WM tracts. Conclusions Our findings indicate that the supertoroidal model enables effective tensor visualization as well as quantitative scalar maps that improve the understanding of the underlying tissue structure properties. Hence, this approach has the potential to enhance diagnosis, preoperative planning, and intraoperative image guidance during surgical management of brain lesions.

Humans with obesity have disordered brain responses to food images during physiological hyperglycemia

Blood glucose levels influence brain regulation of food intake. This study assessed the effect of mild physiological hyperglycemia on brain response to food cues in individuals with obesity (OB) versus normal weight individuals (NW). Brain responses in 10 OB and 10 NW nondiabetic healthy adults [body mass index: 34 (3) vs. 23 (2) kg/m2, means (SD), P < 0.0001] were measured with functional MRI (blood oxygen level-dependent contrast) in combination with a two-step normoglycemic-hyperglycemic clamp. Participants were shown food and nonfood images during normoglycemia (~95 mg/dl) and hyperglycemia (~130 mg/dl). Plasma glucose levels were comparable in both groups during the two-step clamp ( P = not significant). Insulin and leptin levels were higher in the OB group compared with NW, whereas ghrelin levels were lower (all P < 0.05). During hyperglycemia, insula activity showed a group-by-glucose level effect. When compared with normoglycemia, hyperglycemia resulted in decreased activity in the hypothalamus and putamen in response to food images ( P < 0.001) in the NW group, whereas the OB group exhibited increased activity in insula, putamen, and anterior and dorsolateral prefrontal cortex (aPFC/dlPFC; P < 0.001). These data suggest that OB, compared with NW, appears to have disruption of brain responses to food cues during hyperglycemia, with reduced insula response in NW but increased insula response in OB, an area involved in food perception and interoception. In a post hoc analysis, brain activity in obesity appears to be associated with dysregulated motivation (striatum) and inappropriate self-control (aPFC/dlPFC) to food cues during hyperglycemia. Hyperstimulation for food and insensitivity to internal homeostatic signals may favor food consumption to possibly play a role in the pathogenesis of obesity.

Ipsilateral synkinesia involves the supplementary motor area

The supplementary motor area coordinates movements. Synkinesia is a rare disorder in which an involuntary movement occurs coordinated with a voluntary movement. Here, we test the hypothesis that the supplementary motor area is involved in involuntary coordination of movement. We collected functional magnetic resonance imaging (fMRI) data from two patients with ipsilateral hand-foot synkinesia and two control participants while they performed rhythmic tasks. In synkinesia patients, both the supplementary motor area and the foot motor cortex were significantly activated during the hand motor task. This pattern was not seen in controls. Our findings suggest that the supplementary motor area plays a central role in involuntary coordination observed in synkinesia, and provides insight into how the supplementary motor area orchestrates movements.

S142. A Predictive Approach to Identify Clinical State, Emotional Valence and Pharmacologic Effect in Human Task-Based fMRI Data

Clinically approved antidepressants modulate the brain’s emotional valence circuits, suggesting that the response of these circuits could serve as a biomarker for screening candidate antidepressant drugs. Here, we apply a cross-validated predictive model to classify clinical state, emotional valence, and pharmacologic effect across eight task-based fMRI studies (n=306) of the effect of antidepressant administration on emotional face processing.