Faculty Bibliography

Voltage-gated CaV1.2 channels (L-type calcium channel alpha1C subunits) are critical mediators of transcription-dependent neural plasticity. Whether these channels signal via the influx of calcium ion (Ca(2+)), voltage-dependent conformational change (VDeltaC), or a combination of the two has thus far been equivocal. We fused CaV1.2 to a ligand-gated Ca(2+)-permeable channel, enabling independent control of localized Ca(2+) and VDeltaC signals. This revealed an unexpected dual requirement: Ca(2+) must first mobilize actin-bound Ca(2+)/calmodulin-dependent protein kinase II, freeing it for subsequent VDeltaC-mediated accumulation. Neither signal alone sufficed to activate transcription. Signal order was crucial: Efficiency peaked when Ca(2+) preceded VDeltaC by 10 to 20 seconds. CaV1.2 VDeltaC synergistically augmented signaling by N-methyl-d-aspartate receptors. Furthermore, VDeltaC mistuning correlated with autistic symptoms in Timothy syndrome. Thus, nonionic VDeltaC signaling is vital to the function of CaV1.2 in synaptic and neuropsychiatric processes.

The accuracy of neural circuit assembly relies on the precise spatial and temporal control of synaptic specificity determinants during development. Hox transcription factors govern key aspects of motor neuron (MN) differentiation; however, the terminal effectors of their actions are largely unknown. We show that Hox/Hox cofactor interactions coordinate MN subtype diversification and connectivity through Ret/Gfralpha receptor genes. Hox and Meis proteins determine the levels of Ret in MNs and define the intrasegmental profiles of Gfralpha1 and Gfralpha3 expression. Loss of Ret or Gfralpha3 leads to MN specification and innervation defects similar to those observed in Hox mutants, while expression of Ret and Gfralpha1 can bypass the requirement for Hox genes during MN pool differentiation. These studies indicate that Hox proteins contribute to neuronal fate and muscle connectivity through controlling the levels and pattern of cell surface receptor expression, consequently gating the ability of MNs to respond to limb-derived instructive cues.

It is well known that hormones affect both brain and behavior, but less is known about the extent to which hormones affect economic decision-making. Numerous studies demonstrate gender differences in attitudes to risk and loss in financial decision-making, often finding that women are more loss and risk averse than men. It is unclear what drives these effects and whether cyclically varying hormonal differences between men and women contribute to differences in economic preferences. We focus here on how economic rationality and preferences change as a function of menstrual cycle phase in women. We tested adherence to the Generalized Axiom of Revealed Preference (GARP), the standard test of economic rationality. If choices satisfy GARP then there exists a well-behaved utility function that the subject's decisions maximize. We also examined whether risk attitudes and loss aversion change as a function of cycle phase. We found that, despite large fluctuations in hormone levels, women are as technically rational in their choice behavior as their male counterparts at all phases of the menstrual cycle. However, women are more likely to choose risky options that can lead to potential losses while ovulating; during ovulation women are less loss averse than men and therefore more economically rational than men in this regard. These findings may have market-level implications: ovulating women more effectively maximize expected value than do other groups.

OBJECTIVE: Diffusion tensor imaging (DTI) can identify structural connectivity alterations in attention-deficit/hyperactivity disorder (ADHD). Most ADHD DTI studies have concentrated on regional differences in fractional anisotropy (FA) despite its limited sensitivity to complex white matter architecture and increasing evidence of global brain differences in ADHD. Here, we examine multiple DTI metrics in separate samples of children and adults with and without ADHD with a principal focus on global between-group differences. METHOD: Two samples: adults with ADHD (n = 42) and without (n = 65) and children with ADHD (n = 82) and without (n = 80) were separately group matched for age, sex, and head motion. Five DTI metrics (FA, axial diffusivity, radial diffusivity, mean diffusivity, and mode of anisotropy) were analyzed via tract-based spatial statistics. Group analyses tested for diagnostic differences at the global (averaged across the entire white matter skeleton) and regional level for each metric. RESULTS: Robust global group differences in diffusion indices were found in adults, with the largest effect size for mode of anisotropy (MA; Cohen's d = 1.45). Global MA also differed significantly between groups in the pediatric sample (d = 0.68). In both samples, global MA increased classification accuracy compared to the model with clinical Conners' ADHD ratings alone. Regional diagnostic differences did not survive familywise correction for multiple comparisons. CONCLUSION: Global DTI metrics, particularly the mode of anisotropy, which is sensitive to crossing fibers, capture connectivity abnormalities in ADHD across both pediatric and adult samples. These findings highlight potential diffuse white matter microarchitecture differences in ADHD.

Background: Conventional cine MRI provides data on the variation of cardiac dimensions across the cardiac cycle; cardiac function analysis primarily focuses on the difference between end-diastolic (ED) and endsystolic (ES) dimensions of the left and right ventricles (LV and RV). With cardiorespiratory-synchronized (CRS) CMR, there is an additional effective dimension of information available, related to the effect of the respiratory cycle phase on cardiac dimensions. However, there are currently no established ways to analyze this potentially useful additional physiological data. We have developed a set of tools for the functional analysis of CRS CMR, particularly for the study of the respiratory effects on LV-RV interaction, and derived some initial normative values for the results. Methods: We have developed a set of interactive CMR function analysis programs. Images from CRS CMR are organized in a two-dimensional matrix, sorted by cardiac and respiratory cycle phases. The user can interactively position an analysis line across the ventricles in a representative image; this line can then be automatically tracked across the other cardiac and respiratory phases. The intensity profile along the line is then used to automatically track the corresponding positions of the edges of the LV and RV free walls and the interventricular septum (IVS). A variety of absolute and normalized variables can be derived from these varying positions, including ED and ES dimensions, and displayed as functional images over the cardiac and respiratory cycle dimensions. CRS CMR was performed with a sparsity-based method (XD-GRASP), using continuous acquisition of radial k-space samples with golden-angle increments and retrospective cardiac and respiratory phase sorting in reconstruction. An initial set of CRS CMR data from 9 normal subjects (age 28.33 +/- 5.85) was analyzed, as well as from 3 patients (age 40 +/- 9.66, one with HCM). Results: On visual inspection of the images, it is apparent that there is a clear shift in the relative position of the IVS over the respiratory cycle, to the left in inspiration and to the right in expiration, reflecting the LV-RV interaction; this is much more prominent near ED than ES. For the normal subjects, in midlevel short-axis views, the respiratory-related absolute shift in IVS position was 1.07-3.23 mm at ED and 0.69-2.14 mm at ES; corresponding values normalized to ED dimension were 2.65-7.08 pp and 1.99-5.18 pp. The ED-ES difference for the normalized shift ranges was -1.9-4.35 pp (median 1.35, first quartile 0.68). For the HCM patient, the difference between the shift ranges was 0.79 pp. Linear regression when plotting NCD against NEDD (reflecting the Frank-Starling relationship and giving an estimate of contractility) was 0.68 +/- 0.11 in the normal subjects. Conclusions: Novel physiologic data on LV-RV interaction can be derived from CRS CMR; this seems to show consistent ranges in normal subjects, and may provide useful information on disease-related changes in cardiac function. (Figure Presented)

Background: Three-dimensional (3D) virtual models are valuable tools that may help to better understand complex cardiovascular anatomy and facilitate surgical planning in patients with congenital heart disease (CHD). Although computed tomography (CT) images are used most commonly to create these models [1,2], Magnetic Resonance Imaging (MRI) may be an attractive alternative, since it offers superior soft-tissue characterization and flexible image contrast mechanisms, and avoids the use of ionizing radiation. However, segmentation on MRI images is inherently challenging due to noise/artifacts, magnetic field inhomogeneity, and relatively lower spatial resolution compared to CT. The purpose of this study was to evaluate the image quality and assess the feasibility of creating virtual 3D heart models using a novel prototype 3D whole heart self-navigated radial MRI technique. Methods: Free-breathing self-navigated whole heart MRI was performed on three pediatric patients: two with complex CHD (average age=17 months) and one with normal cardiac anatomy (age=17years), using a 3D radial, non-slice-selective, T2-prepared, fat-saturated bSSFP sequence on a 1.5T MRI scanner (MAGNETOM Aera, Siemens, Germany). The acquisition window (~50-55 ms) was placed in mid-diastole and was adapted for different heart rates. Imaging parameters were as follows: TR/TE=3.1/1.56 ms, FOV=200 mm3, voxel size=1 mm3, FA=115degree, and acquisition time=5-6 minutes (~12000 radial lines). Respiratory motion correction and image reconstruction was performed on the scanner as described in [3]. For comparison, conventional non-gated 3D FLASH or navigator-gated 3D bSSFP sequences were also performed. All results were blinded and randomized for image quality assessment by one pediatric cardiologist and one cardiac radiologist using a five-point scale (1=non-diagnostic, 2=poor, 3=adequate, 4=good, 5=excellent). Statistical analysis was performed to compare mean scores. DICOM images were imported to a 3D workstation (Mimics, Materialise, Leuven, Belgium) for 3D postprocessing. The cardiovascular anatomy was first segmented using a combination of automated and manual techniques; and volume rendering was performed to depict the anatomy of interest. Results: The free-breathing self-navigated 3D radial acquisition provided significantly improved image quality and myocardial wall-blood contrast (Figure 1). Mean scores were 4.58 and 2.67 for the 3D radial and FLASH/ bSSFP sequences respectively (p = 0.003). The cardiovascular anatomy was well depicted on all virtual 3D models (Figure 2). Conclusions: 3D virtual models are frequently being created to understand complex anatomy, influence surgical planning, and provide intra-operative guidance for patients with CHD. This novel free-breathing, self-navigated whole heart 3D radial sequence provided excellent image quality as compared to existing routine MR sequences. Furthermore, the (Figure Presented) superb image quality provided using this novel sequence makes it an excellent choice for the creation of 3D models

Background: Complex ventricular-arterial (VA) relationships in patients with double outlet right ventricle (DORV) make preoperative assessment of potential repair pathways challenging. The relationship of the ventricular septal defect (VSD) to one or both great arteries must be understood and this influences the choice of surgical procedure [1] In neonates and infants with DORV, Computed Tomography (CT) is often performed due to the ability to get high spatial resolution and ECG gated images [2], however it is possible to get the necessary information from Magnetic Resonance (MR) imaging with an added advantage of avoiding exposure to ionizing radiation. Both CT and MR allow image acquisition in three dimensions (3D) but traditional viewing of the anatomy using the multiplanar reformatting is actually done in two dimensions (2D). Volume rendering from either modality may also be performed, but typically only the external vascular anatomy is depicted. We hypothesized that it is possible to accurately define the intracardiac anatomy in infants with DORV using virtual and physical 3D printed (rapid prototyped) models created from either MR or CT and this can both aid in better defining potential VA pathways and may assist in surgical decision making. Methods: Virtual and physical 3D models were generated for three patients with DORV. Non-ECG-gated 3D spoiled fast gradient echo sequence MR angiography was used for two patients. Retrospective ECG gated CT angiography images acquired in diastole were used in the third patient (to better define the coronary arteries given the suspicion of a single coronary artery by echocardiography). Blood pool segmentation (Figure 1a) was performed in all the three patients (Mimics, Materialise, Leuven, Belgium). A 2 mm shell was added to the blood pool and it was hollowed to create a patient specific heart replica (3-matic, Materialise, Leuven, Belgium). All virtual models were cut to best demonstrate the VA relationships and the models were printed. Results: The VSD and VA relationships were well visualized in all three patients using both the virtual and physical models (Figure 1b,c). The models helped the surgeons better understand the anatomy in all patients: in two patients the surgical plan was altered while the plan was confirmed in the third patient (Table 1). Conclusions: Construction of 3D models in patients with DORV is feasible and allows for extensive examination and surgical planning. This may facilitate a focused and informed surgical procedure and improve the potential for successful outcome. For purposes of DORV, non-gated MRA is sufficient to delineate the VA relationships adequately for 3D printing and enhanced clinical decision-making. CT imaging should be reserved for only those patients where additional information like coronary artery anatomy is desired

Motor impairments in Parkinson's disease are thought to result from hypoactivation of striatal projection neurons in the direct pathway. In this issue of Neuron, Parker et al. (2016) report that dopamine depletion selectively weakens thalamic but not cortical afferents onto these neurons, implicating the thalamus as playing a key role in Parkinsonian motor symptoms.

Aggression is a prevalent behavior in the animal kingdom that is used to settle competition for limited resources. Given the high risk associated with fighting, the central nervous system has evolved an active mechanism to modulate its expression. Lesioning the lateral septum (LS) is known to cause "septal rage," a phenotype characterized by a dramatic increase in the frequency of attacks. To understand the circuit mechanism of LS-mediated modulation of aggression, we examined the influence of LS input on the cells in and around the ventrolateral part of the ventromedial hypothalamus (VMHvl)-a region required for male mouse aggression. We found that the inputs from the LS inhibited the attack-excited cells but surprisingly increased the overall activity of attack-inhibited cells. Furthermore, optogenetic activation of the projection from LS cells to the VMHvl terminated ongoing attacks immediately but had little effect on mounting. Thus, LS projection to the ventromedial hypothalamic area represents an effective pathway for suppressing male aggression.

OBJECTIVES: Clinical neuroscience is increasingly turning to imaging the human brain for answers to a range of questions and challenges. To date, the majority of studies have focused on the neural basis of current psychiatric symptoms, which can facilitate the identification of neurobiological markers for diagnosis. However, the increasing availability and feasibility of using imaging modalities, such as diffusion imaging and resting-state fMRI, enable longitudinal mapping of brain development. This shift in the field is opening the possibility of identifying predictive markers of risk or prognosis, and also represents a critical missing element for efforts to promote personalized or individualized medicine in psychiatry (i.e., stratified psychiatry). METHODS: The present work provides a selective review of potentially high-yield populations for longitudinal examination with MRI, based upon our understanding of risk from epidemiologic studies and initial MRI findings. RESULTS: Our discussion is organized into three topic areas: (1) practical considerations for establishing temporal precedence in psychiatric research; (2) readiness of the field for conducting longitudinal MRI, particularly for neurodevelopmental questions; and (3) illustrations of high-yield populations and time windows for examination that can be used to rapidly generate meaningful and useful data. Particular emphasis is placed on the implementation of time-appropriate, developmentally informed longitudinal designs, capable of facilitating the identification of biomarkers predictive of risk and prognosis. CONCLUSIONS: Strategic longitudinal examination of the brain at-risk has the potential to bring the concepts of early intervention and prevention to psychiatry. (JINS, 2016, 22, 164-179).