Faculty Bibliography

Among the many neuromodulators used by the mammalian brain to regulate circuit function and plasticity, dopamine (DA) stands out as one of the most behaviorally powerful. Perturbations of DA signaling are implicated in the pathogenesis or exploited in the treatment of many neuropsychiatric diseases, including Parkinson's disease (PD), addiction, schizophrenia, obsessive compulsive disorder, and Tourette's syndrome. Although the precise mechanisms employed by DA to exert its control over behavior are not fully understood, DA is known to regulate many electrical and biochemical aspects of neuronal function including excitability, synaptic transmission, integration and plasticity, protein trafficking, and gene transcription. In this Review, we discuss the actions of DA on ionic and synaptic signaling in neurons of the prefrontal cortex and striatum, brain areas in which dopaminergic dysfunction is thought to be central to disease.

The substantia nigra pars compacta and ventral tegmental area contain the two largest populations of dopamine-releasing neurons in the mammalian brain. These neurons extend elaborate projections in the striatum, a large subcortical structure implicated in motor planning and reward-based learning. Phasic activation of dopaminergic neurons in response to salient or reward-predicting stimuli is thought to modulate striatal output through the release of dopamine to promote and reinforce motor action. Here we show that activation of dopamine neurons in striatal slices rapidly inhibits action potential firing in both direct- and indirect-pathway striatal projection neurons through vesicular release of the inhibitory transmitter GABA (gamma-aminobutyric acid). GABA is released directly from dopaminergic axons but in a manner that is independent of the vesicular GABA transporter VGAT. Instead, GABA release requires activity of the vesicular monoamine transporter VMAT2, which is the vesicular transporter for dopamine. Furthermore, VMAT2 expression in GABAergic neurons lacking VGAT is sufficient to sustain GABA release. Thus, these findings expand the repertoire of synaptic mechanisms used by dopamine neurons to influence basal ganglia circuits, show a new substrate whose transport is dependent on VMAT2 and demonstrate that GABA can function as a bona fide co-transmitter in monoaminergic neurons.

INTRODUCTION: The incidence of asthma may be increased in patients with obesity. However, recognition of airway disease is confounded by abnormal lung physiology seen in obesity per se. Healthy obese patients with normal spirometry have elevated resistance (oscillometry) similar to non-obese patients with obstructive spirometry. However, in obese patients elevated resistance is associated with decreased FRC (mass loading), whereas FRC is normal-high in non-obese patients with airway obstruction. We hypothesize that obese patients with obstructive dysfunction can be distinguished from obese patients without airway disease by relating oscillometry findings to resting lung volume (FRC). METHODS: 183 obese subjects (BMI 30-73 kg/m²) were divided into 3 groups. Group 1: healthy obese (non-smoker, no history of lung disease, normal FEV₁/FVC; n= 62) Group 2: obstructive airway disease (reduced FEV₁/FVC; n= 40) Group 3: reported diagnosis of asthma with normal airflow (normal FEV₁/FVC; n= 81). All subjects underwent spirometry and plethysmography. Oscillometry was performed at baseline and repeated during voluntary inflation to predicted FRC to minimize the confounding effect of reduced lung volume on airway resistance. Oscillometry parameters included resistance at 5 and 20Hx (R₅, R₂₀). RESULTS: VC, IC, and ERV were similar in Groups 1 and 2 (Table 1). FRC was reduced in all subjects of Group 1; in Group 2 higher values were seen extending into normal range despite obesity. R₅ and R₂₀ were elevated in all subjects to a similar degree in Groups 1 and 2; calculation of specific conductance for R₅ and R₂₀ (SGrs5, SGrs20) distinguished Group 1 from Group 2. Based on these observations, Group 3 was divided into normal vs. reduced FRC (Table 2). To minimize the effect of lung volume on resistance in Group 3, oscillometry data were analyzed at similar lung volumes (i.e. during voluntary inflation in subjects with reduced FRC vs. at baseline in remaining subjects with normal FRC). Subjects with normal FRC demonstrated higher values for R₅ and R₂₀ compared to subjects with reduced FRC. Response to bronchodilator was only noted in those subjects with normal FRC. CONCLUSIONS: Preservation of FRC occurred in obese patients with known airway disease and reduced FEV₁/FVC. In patients with normal airflow despite self reported asthma, increased airway resistance was associated with normal FRC. Therefore, whereas a reduction in FRC is expected in healthy obese subjects, a normal FRC may reflect pseudo-normalization as a manifestation of airway disease even when FEV₁/FVC is normal. (Table Presented)

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)

Brain-machine interfaces (BMIs) rely on decoding neuronal activity from a large number of electrodes. The implantation procedures, however, do not guarantee that all recorded units encode task-relevant information: selection of task-relevant neurons is critical to performance but is typically performed based on heuristics. Here, we describe an algorithm for decoding/classification of volitional actions from multiple spike trains, which automatically selects the relevant neurons. The method is based on sparse decomposition of the high-dimensional neuronal feature space, projecting it onto a low-dimensional space of codes serving as unique class labels. The new method is tested against a range of existing methods using simulations and recordings of the activity of 1592 neurons in 23 neurosurgical patients who performed motor or speech tasks. The parameter estimation algorithm is orders of magnitude faster than existing methods and achieves significantly higher accuracies for both simulations and human data, rendering sparse decoding highly attractive for BMIs.

Human speech sounds are produced through a coordinated movement of structures along the vocal tract. Here we show highly structured neuronal encoding of vowel articulation. In medial-frontal neurons, we observe highly specific tuning to individual vowels, whereas superior temporal gyrus neurons have nonspecific, sinusoidally modulated tuning (analogous to motor cortical directional tuning). At the neuronal population level, a decoding analysis reveals that the underlying structure of vowel encoding reflects the anatomical basis of articulatory movements. This structured encoding enables accurate decoding of volitional speech segments and could be applied in the development of brain-machine interfaces for restoring speech in paralysed individuals.

Ultrasound waves, widely used as a non-invasive diagnostic modality, were recently shown to stimulate neuronal activity. Functionally meaningful stimulation, as is required in order to form a unified percept, requires the dynamic generation of simultaneous stimulation patterns. In this paper, we examine the general feasibility and properties of an acoustic retinal prosthesis, a new vision restoration strategy that will combine ultrasonic neuro-stimulation and ultrasonic field sculpting technology towards non-invasive artificial stimulation of surviving neurons in a degenerating retina. We explain the conceptual framework for such a device, study its feasibility in an in vivo ultrasonic retinal stimulation study and discuss the associated design considerations and tradeoffs. Finally, we simulate and experimentally validate a new holographic method--the angular spectrum-GSW--for efficient generation of uniform and accurate continuous ultrasound patterns. This method provides a powerful, flexible solution to the problem of projecting complex acoustic images onto structures like the retina.

The hybrid nature of optoacoustic imaging might impose limitations on concurrent placement of optical and ultrasonic detection components, especially in high resolution microscopic applications that require dense arrangements and miniaturization of components. This hinders optimal deployment of the optical excitation and ultrasonic detection paths, leading to reduction of imaging speed and spatial resolution performance. We suggest a compact coaxial design for optoacoustic microscopy that allows optimizing both the light illumination and ultrasonic detection parameters of the imaging system. System performance is showcased in phantoms and in vivo imaging of microvasculature, achieving real time operation in two dimensions and penetration of 6 mm into optically dense human tissues.

A simple technique for remote scanning of the focal plane in temporal focusing multiphoton microscopy is demonstrated both theoretically and experimentally. A new on-axis light propagation optical setup design enables this scanning, which was considered not feasible in previous studies. The focal plane is axially displaced by the movement of a remote optical device, consisting of a double prism grating, and optionally a cylindrical lens. The displacement is linear, and its slope is inversely proportional to the square of the optical system's magnification.