Faculty Bibliography

BACKGROUND: The formation of an odor percept in humans is strongly associated with visual information. However, much less is known about the roles of learning and memory in shaping the multisensory nature of odor representations in the brain. METHOD: The dynamics of odor and visual association in olfaction was investigated using three functional magnetic resonance imaging (fMRI) paradigms. In two paradigms, a visual cue was paired with an odor. In the third, the same visual cue was never paired with an odor. In this experimental design, if the visual cue was not influenced by odor-visual pairing, then the blood-oxygen-level-dependent (BOLD) signal elicited by subsequent visual cues should be similar across all three paradigms. Additionally, intensity, a major dimension of odor perception, was used as a modulator of associative learning which was characterized in terms of the spatiotemporal behavior of the BOLD signal in olfactory structures. RESULTS: A single odor-visual pairing cue could subsequently induce primary olfactory cortex activity when only the visual cue was presented. This activity was intensity dependent and was also detected in secondary olfactory structures and hippocampus. CONCLUSION: This study provides evidence for a rapid learning response in the olfactory system by a visual cue following odor and visual cue pairing. The novel data and paradigms suggest new avenues to explore the dynamics of odor learning and multisensory representations that contribute to the construction of a unified odor percept in the human brain.

Familial dysautonomia (FD) is a rare genetic disease with extremely labile blood pressure due to baroreflex deafferentation. Patients have marked surges in sympathetic activity, frequently surrounding meals. We conducted an observational study to document the autonomic responses to eating in patients with FD, and to determine whether sympathetic activation was caused by chewing, swallowing or stomach distension. Blood pressure and RR intervals were measured continuously while chewing gum (n = 15), eating (n = 20) and distending the stomach with a percutaneous endoscopic gastrostomy (PEG) tube feeding (n = 9). Responses were compared to those of normal controls (n = 10) and of patients with autonomic failure (n = 10) who have chronically impaired sympathetic outflow. In patients with FD, eating was associated with a marked, but transient pressor response (p<0.0001) and additional signs of sympathetic activation including tachycardia, diaphoresis and flushing of the skin. Chewing gum evoked a similar increase in blood pressure that was higher in patients with FD than in controls (p = 0.0001), but was absent in patients with autonomic failure. In patients with FD distending the stomach with a PEG tube feeding failed to elicit a pressor response. The results provide indirect evidence that chewing triggers sympathetic activation. The increase in blood pressure that is exaggerated in patients with FD due to blunted afferent baroreceptor signalling. The chewing pressor response may be useful as a counter-manoeuvre to raise blood pressure and prevent symptomatic orthostatic hypotension in patients with FD

RATIONALE: The NEWMEDS initiative (Novel Methods leading to New Medications in Depression and Schizophrenia, http://www.newmeds-europe.com ) is a large industrial-academic collaborative project aimed at developing new methods for drug discovery for schizophrenia. As part of this project, Work package 2 (WP02) has developed and validated a comprehensive battery of novel touchscreen tasks for rats and mice for assessing cognitive domains relevant to schizophrenia. OBJECTIVES: This article provides a review of the touchscreen battery of tasks for rats and mice for assessing cognitive domains relevant to schizophrenia and highlights validation data presented in several primary articles in this issue and elsewhere. METHODS: The battery consists of the five-choice serial reaction time task and a novel rodent continuous performance task for measuring attention, a three-stimulus visual reversal and the serial visual reversal task for measuring cognitive flexibility, novel non-matching to sample-based tasks for measuring spatial working memory and paired-associates learning for measuring long-term memory. RESULTS: The rodent (i.e. both rats and mice) touchscreen operant chamber and battery has high translational value across species due to its emphasis on construct as well as face validity. In addition, it offers cognitive profiling of models of diseases with cognitive symptoms (not limited to schizophrenia) through a battery approach, whereby multiple cognitive constructs can be measured using the same apparatus, enabling comparisons of performance across tasks. CONCLUSION: This battery of tests constitutes an extensive tool package for both model characterisation and pre-clinical drug discovery.

RATIONALE: The touchscreen continuous trial-unique non-matching-to-location task (cTUNL) has been developed to optimise a battery of tasks under NEWMEDS (Novel Methods leading to New Medication in Depression and Schizophrenia, http://www.newmeds-europe.com ). It offers novel task features of both a practical and a theoretical nature compared to existing touchscreen tasks for spatial working memory. OBJECTIVES: The objective of this study was to determine whether the cTUNL task is sufficiently sensitive to differentiate between dentate gyrus (DG) and CA3 hippocampal subregion contributions to performance. METHODS: The effect of DG and CA3 dysfunction on memory for locations in the cTUNL task was tested. Rats were assessed on versions of the task-two-choice and three-choice-that differed in memory load. Performance was challenged using manipulations of delay and the spatial separation between target and sample locations. RESULTS: Dysfunction of the DG disrupts performance across both delay and spatial separations in two-choice cTUNL when the delay is variable and unpredictable. Increasing the working memory load (three stimuli) increases sensitivity to DG dysfunction, with deficits apparent at fixed, short delays. In contrast, CA3 dysfunction did not disrupt performance. CONCLUSION: Acquisition of cTUNL was rapid, and the task was sensitive to manipulations of delays and separations. A three-choice version of the task was found to be viable. Finally, both the two- and three-choice versions of the task were able to differentiate between limited dysfunction to different areas within the hippocampus. DG dysfunction affected performance when using unpredictable task parameters. CA3 dysfunction did not result in impairment, even at the longest delays tested.

Background: Sudden death during sleep is the leading causes of death in patients with familial dysautonomia (FD). Patients with FD have impaired ventilatory responses to hypoxia and hypercapnia and sleep disordered breathing, but it is unclear whether these are associated with sudden death. Aim: To identify features that are associated with sudden death during sleep in FD. Methods: We retrospectively selected patients who died suddenly during sleep and compared their sleep studies, arterial blood gases and ECG, performed within 1-year prior to death with those of FD subjects that were alive. Results: Of 108 patients that died suddenly during sleep, 32 had a sleep study, arterial blood gases and ECG performed within 1-year prior to death. Similar information was available in 23 patients with FD that were alive. There were no significant differences in the apnea hypopnea index (p= 0.10), average heart rate (p=0.30) or other ECG parameters. The average lowest oxygen saturation during sleep was not different either (p =0.17), although in 7 deceased patients oxygen saturation fell below 60% while in none of the alive group fell as low. The arterial HCO3 levels were significantly higher in the deceased group (p= 0.005) although there were no differences in average pCO2 levels (p=0.10). Conclusions: FD patients that died suddenly during sleep had a propensity toward more pronounced nocturnal oxygen desaturations and had significantly higher levels of plasma HCO3 suggesting compensatory metabolic alkalosis

OBJECTIVE: This study aimed to demonstrate feasibility of free-breathing radial acquisition with respiratory motion-resolved compressed sensing reconstruction [extra-dimensional golden-angle radial sparse parallel imaging (XD-GRASP)] for multiphase dynamic gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced liver imaging, and to compare image quality to compressed sensing reconstruction with respiratory motion-averaging (GRASP) and prior conventional breath-held Cartesian-sampled data sets [BH volume interpolated breath-hold examination (VIBE)] in same patients. SUBJECTS AND METHODS: In this Health Insurance Portability and Accountability Act-compliant prospective study, 16 subjects underwent free-breathing continuous radial acquisition during Gd-EOB-DTPA injection and had prior BH-VIBE available. Acquired data were reconstructed using motion-averaging GRASP approach in which consecutive 84 spokes were grouped in each contrast-enhanced phase for a temporal resolution of approximately 14 seconds. Additionally, respiratory motion-resolved reconstruction was performed from the same k-space data by sorting each contrast-enhanced phase into multiple respiratory motion states using compressed sensing algorithm named XD-GRASP, which exploits sparsity along both the contrast-enhancement and respiratory-state dimensions.Contrast-enhanced dynamic multiphase XD-GRASP, GRASP, and BH-VIBE images were anonymized, pooled together in a random order, and presented to 2 board-certified radiologists for independent evaluation of image quality, with higher score indicating more optimal examination. RESULTS: The XD-GRASP reconstructions had significantly (all P < 0.05) higher overall image quality scores compared to GRASP for early arterial (reader 1: 4.3 +/- 0.6 vs 3.31 +/- 0.6; reader 2: 3.81 +/- 0.8 vs 3.38 +/- 0.9) and late arterial (reader 1: 4.5 +/- 0.6 vs 3.63 +/- 0.6; reader 2: 3.56 +/- 0.5 vs 2.88 +/- 0.7) phases of enhancement for both readers. The XD-GRASP also had higher overall image quality score in portal venous phase, which was significant for reader 1 (4.44 +/- 0.5 vs 3.75 +/- 0.8; P = 0.002). In addition, the XD-GRASP had higher overall image quality score compared to BH-VIBE for early (reader 1: 4.3 +/- 0.6 vs 3.88 +/- 0.6; reader 2: 3.81 +/- 0.8 vs 3.50 +/- 1.0) and late (reader 1: 4.5 +/- 0.6 vs 3.44 +/- 0.6; reader 2: 3.56 +/- 0.5 vs 2.94 +/- 0.9) arterial phases. CONCLUSION: Free-breathing motion-resolved XD-GRASP reconstructions provide diagnostic high-quality multiphase images in patients undergoing Gd-EOB-DTPA-enhanced liver examination.

BACKGROUND: Although cognitive deficits in patients with schizophrenia are rooted early in development, the impact of psychosis on the course of cognitive functioning remains unclear. In this study a nested case-control design was used to examine the relationship between emerging psychosis and the course of cognition in individuals ascertained as clinical high-risk (CHR) who developed psychosis during the study (CHR + T). METHOD: Fifteen CHR + T subjects were administered a neurocognitive battery at baseline and post-psychosis onset (8.04 months, s.d. = 10.26). CHR + T subjects were matched on a case-by-case basis on age, gender, and time to retest with a group of healthy comparison subjects (CNTL, n = 15) and two groups of CHR subjects that did not transition: (1) subjects matched on medication treatment (i.e. antipsychotics and antidepressants) at both baseline and retesting (Meds-matched CHR + NT, n = 15); (2) subjects unmedicated at both assessments (Meds-free CHR + NT, n = 15). RESULTS: At baseline, CHR + T subjects showed large global neurocognitive and intellectual impairments, along with specific impairments in processing speed, verbal memory, sustained attention, and executive function. These impairments persisted after psychosis onset and did not further deteriorate. In contrast, CHR + NT subjects demonstrated stable mild to no impairments in neurocognitive and intellectual performance, independent of medication treatment. CONCLUSIONS: Cognition appears to be impaired prior to the emergence of psychotic symptoms, with no further deterioration associated with the onset of psychosis. Cognitive deficits represent trait risk markers, as opposed to state markers of disease status and may therefore serve as possible predictors of schizophrenia prior to the onset of the full illness.

Background: Multiple system atrophy (MSA) is a fatal and poorly understood rare neurodegenerative disorder. Here we describe the baseline characteristics of patients with MSA enrolled in a prospective multicenter natural history study of the NIH-sponsored U.S. Autonomic Disorders Consortium. Methods: Patients with a clinical diagnosis of MSA were prospectively enrolled at 5 participating centers. Demographic data, clinical variables, and autonomic testing results were included. Results: One hundred and nine patients with MSA (45 women) have been enrolled. MSA-C was predominant (60 patients, 55%). Mean age at symptom onset was 56.5 +/- 8.8 and at enrollment was 61.2+/-8.04 years old. Mini Mental score was 28.9 +/-1.4 indicating normal cognition. Both the E:I ratio (1.09+/-0.08) and the Valsalva ratio (1.24+/-0.28) were low, indicating cardiovagal impairment. In the supine position, blood pressure (SBP/

Patients with familial dysautonomia (FD) have afferent baroreflex failure and often experience extremely low blood pressure when upright, but rarely complain of symptoms of hypoperfusion. This suggests that patients either fail to recognize cerebral ischemia or have a better than normal cerebrovascular auto-regulatory capacity. Our aim was to examine the relationship between blood pressure, cerebral blood flow, and orthostatic symptoms in FD patients. We measured continuous blood pressure, RR intervals, end-tidal carbon dioxide and middle cerebral artery blood flow velocity (transcranial Doppler) supine, sitting, and standing in eleven patients with FD (age 27+/-2 years, 5males) and seven age-matched controls. Subjects were asked to report the presence or absence of symptoms at one-minute intervals. In patients with FD, systolic blood pressure fell significantly from 137+/-8 mmHg to 105 +/- 9 mmHg after 3 minutes of standing (p < 0.006, range 55 to 149 mmHg). Despite the fall in blood pressure none of the patients reported symptoms of orthostatic hypotension. Changes in cerebral blood flow were minimal (mean DELTA-6+/-3%), and not statistically different to controls (DELTA-3+/- 2%, p=0.39), which maintained their blood pressure well on standing. The results show that patients with FDhave an excellent auto-regulatory capacity and maintain cerebral blood flow within the normal range despite severe hypotension. This study highlights the usefulness of cerebral blood flow recordings to understand the relationship between symptoms and blood pressure in patients with abnormal baroreflex function