Faculty Bibliography

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.

Introduction: Achalasia is an esophageal dysmotility disorder. Rarely, untreated achalasia can lead to massive dilatation of the esophagus causing tracheal compression and respiratory compromise. We report a case of achalasia causing acute life-threatening ventilatory failure requiring emergent bronchoscopic management. Case report: A forty-seven year old female with presumptive achalasia was admitted to an outside hospital with shortness of breath, six months of weight loss and progressive inability to tolerate oral intake. Chest CT showed a massively dilated esophagus with anterior displacement and compression of the trachea and mainstem bronchi. Two days after admission, she was allowed to eat and developed respiratory distress requiring intubation. Soon after transfer to our institution she was extubated and was without stridor. Esophagogastroduodenoscopy demonstrated an esophagus full of food and inability to pass the endoscope into the stomach. A liquid diet was recommended but the patient continued to eat solids. Several days later the patient vomited, aspirated and developed respiratory distress. She was found to have a pH of 6.86, pCO₂ of 193mmHg and pO₂ of 87mmHg. Airway examination demonstrated diffuse neck enlargement and during direct laryngoscopy only the epiglottis could be visualized. An endotracheal (ET) tube was placed and secured at 20cm at the incisors. However ventilation was nearly impossible with high inspiratory pressures, minimal tidal volume and extremely prolonged exhalation. Bronchoscopy revealed severe extrinsic compression of the trachea and mainstem bronchi (figure 1) causing occlusion of the trachea below the level of the ET tube. The ET tube was advanced to 1cm above the carina with normalization of airway pressures. Several hours later desaturation occurred and clinical exam as well as chest radiograph revealed right mainstem intubation. Bronchoscopy was again performed and the ET tube was placed with the tip immediately above the carina when the neck was in full flexion. Chest CT confirmed previous findings (figure 2). Discussion: There are approximately 30 reported cases of achalasia causing respiratory compromise due to tracheal compression and only a handful of these required intubation for respiratory failure. This case is unique in that the dilated esophagus caused anterior displacement of the larynx, complicating laryngoscopy, and compression of almost the entire trachea, requiring bronchoscopy to precisely place the ET tube to stent open the airway to permit ventilation. This case highlights that achalasia is a possible cause of extrinsic laryngeal, tracheal and bronchial compression whose management may be optimized using fiberoptic bronchoscopy. (Figure Presented)

Background: Anti-amyloid immunotherapy reduces Ab plaques and prevents cognitive decline in transgenic mouse models of Alzheimer's disease (AD) (Asuni et al, 2006). Nevertheless, in humans, a strategy based on Ab1- 42 peptide induced encephalomyelitis and possibly microhemorrhages (Orgogozo et al, 2003; Ferrer et al, 2004). These outcomes were not expected from studies in rodents. Mouse lemur, as a primate model may be more predictive of human side effects. A small proportion of old animals develop spontaneously Ab plaques (Mestre-Franc-es et al, 2000). Thus this primate models prodromal AD stages, and we used it to evaluate side effects of immunotherapies. Methods: Animals were treated with K6Ab1-30 (n = 4; 5.860.2 years) or Ab1-42 (n = 4; 5.960.2 years) immunogens in alum adjuvant. They were followed-up for 9 months with biochemistry (anti-Ab40 antibodies and Ab40 levels in the plasma), as well as T2-weighted (T2w) and T2-weighted (T2w) MRI (7T PharmaScan-Bruker; resolutions =(234x234x234)mm3. Histological analyses was performed to evaluate amyloidosis, neuroinflammation, and iron deposits/microhemorrhages. Age-associated occurrences of hypointense signals were evaluated in twenty other naive animals (1.5 to 4.9 years). Results: In this particular study, the animals responded mainly to the Ab1-42 immunogen, which differs from our prior study with this Ab derivative (Trouche et al, 2009). This treatment induced an immune response and increased Ab levels in plasma. No severe neuroinflammation were observed (either on MRI or histology). Compared to K6Ab1-30 vaccine, Ab1-42 immunogen increased microhemorrhages (Mann Whitney test U=1, P<0.05) and the size of hypointense signal corresponding to iron deposits in the choroid plexus (CP) (F(2,5)= 4.627; P<0.05). The study in naive lemurs showed that iron accumulates in the CP with normal aging (r=0.60; P<0.001). Hence, immunotherapy with Ab1-42 immunogen accelerated this age-associated phenomenon. Conclusions: Ab-immunization can lead to side effects such as microhemorrhages in a primate model of normal aging or prodromal stage of AD with minimal extracellular Ab deposition. Also, iron accumulation in the CP is a potential side effect of Ab-immunization. This should be taken into account in future evaluations of clinical trials with AD patients

Integrated within neural circuits, astrocytes have recently been shown to modulate brain rhythms thought to mediate sleep function. Experimental evidence suggests that local impact of astrocytes on single synapses translates into global modulation of neuronal networks and behavior. We discuss these findings in the context of current conceptual models of sleep generation and function, each of which have historically focused on neural mechanisms. We highlight the implications and the challenges introduced by these results from a conceptual and computational perspective. We further provide modeling directions on how these data might extend our knowledge of astrocytic properties and sleep function. Given our evolving understanding of how local cellular activities during sleep lead to functional outcomes for the brain, further mechanistic and theoretical understanding of astrocytic contribution to these dynamics will undoubtedly be of great basic and translational benefit.

Question: Verbal proficiency in 6 year-olds with Autistic Disorder (AD) is a prognostic factor of long-term functioning. As a first step toward identifying biomarkers as early as the first identification of AD, we characterize the neuronal underpinnings of verbal proficiency in children with AD. By means of resting-state fMRI (R-fMRI), we first examined intrinsic functional connectivity (iFC) of language-based circuits in a sample of school-age children. Then, to explore the stability of the identified marker(s), we examined its relationship with verbal proficiency in an independent group of preschoolers with AD. Methods: Two samples of children with AD included: 34 schoolage kids (age 11 +/- 2yrs) completing an awake R-fMRI scan; and 20 preschoolers (age 60 +/- 10months) completing a R-fMRI scan during natural sleep. To examine iFC of language circuits we focused on the left inferior frontal gyrus (IFG): the pars triangularis (pt), pars opercularis and ventral premotor cortex. We indexed verbal proficiency with the Vineland Expressive Language (VEL) standard scores of expressive language skills. In the 34 school-age children with AD, we examined the relationship between VEL scores and inter-individual differences in iFC patterns associated with each of the IFG seeds, at the voxel-wise, wholebrain level (Z > 2.3, p < 0.05, Gaussian random field theory corrected). Then, we examined the relationship between iFC of circuit( s) identified in the first step with the individual VEL score in the preschoolers with AD. We plan to apply one-class support vector machine to examine whether pattern of iFC can classify verbal proficient children with AD from those with poor verbal proficiency. Results: Voxel-wise analyses showed a significant positive relationship between VEL scores and the iFC between left IFGpt and a cluster in the posterior aspects of the right superior temporal sulcus (STS) in the school-age kids.Guided by this finding, we correlated the iFC within this circuit with VEL scores of 20 preschoolers with AD.The iFC of this circuit explained 16% of the variance in verbal proficiency (r = 0.40). Conclusions: R-fMRI during natural sleep provides a feasible means for identifying loci of disconnection in autism that may serve to identify prognostic markers of verbal proficiency at the individual level at the time of first diagnosis

Brain derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression as well as neuropsychiatric and neurodegenerative disorders. Recent studies show a role of BDNF in energy metabolism and body weight regulation. We examined BDNF levels in plasma and cerebrospinal fluid (CSF) samples from age matched elderly depressed and control subjects. Also, the association of BDNF levels with age, gender, body weight, body mass index (BMI), and cognitive performance was evaluated. We did not find any significant differences in plasma and CSF BDNF levels between depressed and control subjects. Plasma BDNF levels were negatively correlated with age (but not with BMI and body weight), when analyses were performed including both depressed and control subjects. A significant reduction in plasma BDNF levels was observed in females as compared to male subjects, and the change in BDNF levels were significantly and positively related to body weight in females. Furthermore, significant increases in Total Recall and Delayed Recall values were found in females as compared to males. In conclusion, the lower BDNF levels observed in females suggest that changes in peripheral BDNF levels are likely secondary to an altered energy balance. However, further studies using larger sample size are warranted.

Transgenic mice are used increasingly to model brain amyloidosis, mimicking the pathogenic processes involved in Alzheimer's disease (AD). In this chapter, an in vivo strategy is described that has been successfully used to map amyloid-beta deposits in transgenic mouse models of AD with magnetic resonance imaging (MRI), utilizing both the endogenous contrast induced by the plaques attributed to their iron content and by selectively enhancing the signal from amyloid-beta plaques using molecular-targeting vectors labeled with MRI contrast agents. To obtain sufficient spatial resolution for effective and sensitive mouse brain imaging, magnetic fields of 7-Tesla (T) or more are required. These are higher than the 1.5-T field strength routinely used for human brain imaging. The higher magnetic fields affect contrast agent efficiency and dictate the choice of pulse sequence parameters for in vivo MRI, all addressed in this chapter. Two-dimensional (2D) multi-slice and three-dimensional (3D) MRI acquisitions are described and their advantages and limitations are discussed. The experimental setup required for mouse brain imaging is explained in detail, including anesthesia, immobilization of the mouse's head to reduce motion artifacts, and anatomical landmarks to use for the slice alignment procedure to improve image co-registration during longitudinal studies and for subsequent matching of MRI with histology.