Faculty Bibliography

TBX3 is critical for human development: mutations in TBX3 cause congenital anomalies in patients with ulnar-mammary syndrome. Data from mice and humans suggest multiple roles for Tbx3 in development and function of the cardiac conduction system. The mechanisms underlying the functional development, maturation, and maintenance of the conduction system are not well understood. We tested the requirements for Tbx3 in these processes. We generated a unique series of Tbx3 hypomorphic and conditional mouse mutants with varying levels and locations of Tbx3 activity within the heart, and developed techniques for evaluating in vivo embryonic conduction system function. Disruption of Tbx3 function in different regions of the developing heart causes discrete phenotypes and lethal arrhythmias: sinus pauses and bradycardia indicate sinoatrial node dysfunction, whereas preexcitation and atrioventricular block reveal abnormalities in the atrioventricular junction. Surviving Tbx3 mutants are at increased risk for sudden death. Arrhythmias induced by knockdown of Tbx3 in adults reveal its requirement for conduction system homeostasis. Arrhythmias in Tbx3-deficient embryos are accompanied by disrupted expression of multiple ion channels despite preserved expression of previously described conduction system markers. These findings indicate that Tbx3 is required for the conduction system to establish and maintain its correct molecular identity and functional properties. In conclusion, Tbx3 is required for the functional development, maturation, and homeostasis of the conduction system in a highly dosage-sensitive manner. TBX3 and its regulatory targets merit investigation as candidates for human arrhythmias.

Abstract Objective. Brain iron deficiency has been supposed to be involved in the pathophysiology of ADHD. Available studies assessing iron in ADHD are based on serum ferritin, a peripheral marker of iron status. To what extent serum ferritin correlates with brain iron (BI) is unclear. The main aim of this study was to compare BI, estimated with magnetic resonance imaging (MRI) in the putamen, pallidum, caudate, and thalamus, between children with and without ADHD. The secondary aim was to assess the correlation between serum ferritin and BI levels. Methods. Thirty-six children (18 with and 18 without ADHD, the latter including nine healthy controls and nine psychiatric controls) completed MRI and blood sampling. Brain iron levels were estimated by imaging T2*. Results. Children with ADHD showed significantly lower estimated BI in right and left thalamus compared to healthy controls. Estimated BI did not differ significantly between children with ADHD and psychiatric controls. Children with ADHD had significantly lower levels of serum ferritin than healthy as well as psychiatric controls. Serum ferritin and T2* values did not correlate significantly in most regions. Conclusions. Low iron in the thalamus may contribute to ADHD pathophysiology.

Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRI-induced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF(Val/Val)) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF(Met/Met)). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF(Met/Met) mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF(Met/Met) mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.

OBJECTIVES: Several recent studies report the presence of a specific EEG pattern named Thalamocortical Dysrhythmia (TCD) in patients with severe chronic neurogenic pain. This is of major interest since so far no neuroscientific indicator of chronic pain could be identified. We investigated whether a TCD-like pattern could be found in patients with moderate chronic back pain, and we compared patients with neuropathic and non-neuropathic pain components. We furthermore assessed the presence of psychopathology and the degree of psychological functioning and examined whether the strength of the TCD-related EEG markers is correlated with psychological symptoms and pain ratings. DESIGN: Controlled clinical trial with age and sex matched healthy controls. METHODS: Spontaneous EEG was recorded in 37 back pain patients and 37 healthy controls. RESULTS: We were not able to observe a statistically significant TCD effect in the EEG data of the whole patient group, but a subsample of patients with evidence for root damage showed a trend in this direction. Pain patients showed markedly increased psychopathology. In addition, patients' ratings of pain intensity within the last 1 to 12 months showed strong correlations with EEG power, while psychopathology was correlated to the peak frequency. CONCLUSION: Out of several possible interpretations the most likely conclusion is that only patients with severe pain as well as root lesions with consecutive thalamic deafferentation develop the typical TCD pattern. Our primary method of defining 'neuropathic pain' could not reliably determine if such a deafferentation was present. Nevertheless the analysis of a specific subsample as well as correlations between pain ratings, psychopathology and EEG power and peak frequency give some support to the TCD concept. TRIAL REGISTRATION: ClinicalTrials.gov NCT00744575.

OBJECT: Recent technological developments open the field of therapeutic application of focused ultrasound to the brain through the intact cranium. The goal of this study was to apply the new transcranial magnetic resonance imaging-guided focused ultrasound (tcMRgFUS) technology to perform noninvasive central lateral thalamotomies (CLTs) as a treatment for chronic neuropathic pain. METHODS: In 12 patients suffering from chronic therapy-resistant neuropathic pain, tcMRgFUS CLT was proposed. In 11 patients, precisely localized thermal ablations of 3-4 mm in diameter were produced in the posterior part of the central lateral thalamic nucleus at peak temperatures between 51 degrees C and 64 degrees C with the aid of real-time patient monitoring and MR imaging and MR thermometry guidance. The treated neuropathic pain syndromes had peripheral (5 patients) or central (6 patients) origins and covered all body parts (face, arm, leg, trunk, and hemibody). RESULTS: Patients experienced mean pain relief of 49% at the 3-month follow-up (9 patients) and 57% at the 1-year follow-up (8 patients). Mean improvement according to the visual analog scale amounted to 42% at 3 months and 41% at 1 year. Six patients experienced immediate and persisting somatosensory improvements. Somatosensory and vestibular clinical manifestations were always observed during sonication time because of ultrasound-based neuronal activation and/or initial therapeutic effects. Quantitative electroencephalography (EEG) showed a significant reduction in EEG spectral overactivities. Thermal ablation sites showed sharply delineated ellipsoidal thermolesions surrounded by short-lived vasogenic edema. Lesion reconstructions (18 lesions in 9 patients) demonstrated targeting precision within a millimeter for all 3 coordinates. There was 1 complication, a bleed in the target with ischemia in the motor thalamus, which led to the introduction of 2 safety measures, that is, the detection of a potential cavitation by a cavitation detector and the maintenance of sonication temperatures below 60 degrees C. CONCLUSIONS: The authors assert that tcMRgFUS represents a noninvasive, precise, and radiation-free neurosurgical technique for the treatment of neuropathic pain. The procedure avoids mechanical brain tissue shift and eliminates the risk of infection. The possibility of applying sonication thermal spots free from trajectory restrictions should allow one to optimize target coverage. The real-time continuous MR imaging and MR thermometry monitoring of targeting accuracy and thermal effects are major factors in optimizing precision, safety, and efficacy in an outpatient context.

The object of this study was to describe a method of measuring targeting accuracy in functional neurosurgery using MR imaging and the Stereotactic Atlas of the Human Thalamus and Basal Ganglia. This method should be useful for any functional procedure using these tools or similar ones, and is described here in the specific context of focused ultrasound surgery. The authors describe the atlas coordinate system used, the different relevant targeting and accuracy definitions, the tools used, the intraoperative target determination, the postoperative target reconstructions, and the calculation of the therapeutic lesion volume. The proposed method has been applied to the specific situation of measuring targeting accuracy in focused ultrasound functional neurosurgery. The authors found mean absolute global targeting accuracies between 0.54 and 0.72 mm (SDs between 0.34 and 0.42 mm), with 85% of measured coordinates within 1 mm. The proposed method may be particularly useful in the context of functional neurosurgical procedures implying therapeutic ablations, be they through radiofrequency, focused ultrasound, or any other technique. This method allows an ongoing control of the targeting precision, a basic requirement in any functional neurosurgical procedure.

Studies have shown that certain beverages decrease urinary lithogenicity by increasing urine citrate excretion. Diet Sunkist Orange soda had the highest concentration of citrate and total alkali content among 12 diet sodas previously assayed. We studied the effect of Diet Sunkist Orange soda consumption on urinary chemistry. Nine healthy men and women ages 26-54 years completed the study. During the control period, subjects drank 36 oz of water for 3 days in addition to their own, self-selected diet and recorded a food diary. During the study period, the subjects drank three 12-oz cans of Diet Sunkist Orange soda a day instead of water, and replicated their diets from the control period. In each period, the subjects performed 24-h urine collections on days 2 and 3. Urine chemical analysis was performed, including urinary citrate levels and pH. Diet Sunkist Orange soda increased urinary citrate excretion by 60 mg/day, which was not statistically significant (95% CI -75 to 195, P value 0.34). There was no significant change in pH from the control period to the study period (pH: 6.29-6.21; 95% CI: -0.09 to 0.25, P = 0.30). Urine volumes and creatinine excretions were not significantly different between the control and study periods. Despite the relatively high citrate and total alkali content of Diet Sunkist Orange soda, the volume consumed in this study (36 oz per day) did not provide sufficient potential base to significantly alter urine composition in healthy subjects with normocitraturia. The effect of Diet Sunkist Orange soda on urinary chemistry in patients with hypocitraturia and nephrolithiasis is not likely to have a clinically significant effect to prevent calcium or uric acid stones.

OBJECTIVE: The objective of this study was to review a single-institution contemporary experience with extracranial aneurysms of the carotid artery. METHODS: A retrospective review was conducted of patients evaluated for an aneurysm of the extracranial carotid artery from 2005 to 2010. Demographics, presentation, and operative management were reviewed. The mean follow-up was 22 months (range, 1-58 months). RESULTS: Over the study period, 16 aneurysms and pseudoaneurysms were identified in 15 patients. Of these, 14 aneurysms (in six men and eight women with mean age of 63 years) underwent surgical repair. The mean aneurysm size was 2.45 cm (range, 0.8-5 cm). One aneurysm (7.1%) was associated with neurologic symptoms, and 13 were asymptomatic. The underlying etiology was trauma in five (35.7%), prior carotid endarterectomy in five (35.7%), and degenerative atherosclerosis in four (28.6%). Aneurysms were isolated to the common carotid artery in six (42.9%), internal carotid artery in five (35.7%), and carotid bifurcation in three (21.4%). Five patients underwent aneurysmectomy with primary repair; seven underwent repair with an interposition graft, one required an innominate to common carotid artery bypass, and one patient had a plication and patch angioplasty. No mortalities or neurologic events were documented within 30 days. One patient had transient cranial nerve palsy. One patient required reintervention at 4 months for stenosis of the bypass graft, and one patient died at 10 months from an unrelated condition. There were no neurologic events on follow-up. CONCLUSIONS: Carotid artery aneurysms and pseudoaneurysms are uncommon and usually asymptomatic. Prior trauma and carotid surgery were common etiologies. The location of the aneurysms was equally distributed between the internal and common carotid arteries. Surgical repair was safe and effective with no significant morbidity or mortality and good midterm stroke prevention.

Idiopathic generalized epilepsy (IGE) is associated with widespread cortical network abnormalities on electroencephalography. Resting state functional connectivity (RSFC), based on fMRI, can assess the brain's global functional organization and its disruption in clinical conditions. We compared RSFC associated with the 'default mode network' (DMN) between people with IGE and healthy controls. Strength of functional connectivity within the DMN associated with seeds in the posterior cingulate cortex (PCC) and medial prefrontal cortices (MPFC) was compared between people with IGE and healthy controls and was correlated with seizure duration, age of seizure onset and age at scan. Those with IGE showed markedly reduced functional network connectivity between anterior and posterior cortical seed regions. Seizure duration positively correlates with RSFC between parahippocampal gyri and the PCC but negatively correlates with connectivity between the PCC and frontal lobe. The observed pattern of disruption provides evidence for integration- and segregation-type network abnormalities and supports aberrant network organization among people with IGE.

Phase-contrast (PC) cine MRI is a promising method for assessment of pathologic hemodynamics, including cardiovascular and hepatoportal vascular dynamics, but its low data acquisition efficiency limits the achievable spatial and temporal resolutions within clinically acceptable breath-hold durations. We propose to accelerate PC cine MRI using an approach which combines compressed sensing and parallel imaging (k-t SPARSE-SENSE). We validated the proposed 6-fold accelerated PC cine MRI against 3-fold accelerated PC cine MRI with parallel imaging (generalized autocalibrating partially parallel acquisitions). With the programmable flow pump, we simulated a time varying waveform emulating hepatic blood flow. Normalized root mean square error between two sets of velocity measurements was 2.59%. In multiple blood vessels of 12 control subjects, two sets of mean velocity measurements were in good agreement (mean difference = -0.29 cm/s; lower and upper 95% limits of agreement = -5.26 and 4.67 cm/s, respectively). The mean phase noise, defined as the standard deviation of the phase in a homogeneous stationary region, was significantly lower for k-t SPARSE-SENSE than for generalized autocalibrating partially parallel acquisitions (0.05 +/- 0.01 vs. 0.19 +/- 0.06 radians, respectively; P < 0.01). The proposed 6-fold accelerated PC cine MRI pulse sequence with k-t SPARSE-SENSE is a promising investigational method for rapid velocity measurement with relatively high spatial (1.7 mm x 1.7 mm) and temporal ( approximately 35 ms) resolutions. Magn Reson Med, 2011. (c) 2011 Wiley Periodicals, Inc.