Kamalini G. Ranasinghe

Dyspnea on Exertion in Obese Women Association with an Increased Oxygen Cost of Breathing

RATIONALE Although exertional dyspnea in obesity is an important and prolific clinical concern, the underlying mechanism remains unclear. OBJECTIVES To investigate whether dyspnea on exertion in otherwise healthy obese women was associated with an increase in the oxygen cost of breathing or cardiovascular deconditioning. METHODS Obese women with and without dyspnea on exertion participated in two independent experiments (n = 16 and n = 14). All participants underwent pulmonary function testing, hydrostatic weighing, ratings of perceived breathlessness during cycling at 60 W, and determination of the oxygen cost of breathing during eucapnic voluntary hyperpnea at 40 and 60 L/min. Cardiovascular exercise capacity, fat distribution, and respiratory mechanics were determined in 14 women in experiment 2. Data were analyzed between groups by independent t test, and the relationship between the variables was determined by regression analysis. MEASUREMENTS AND MAIN RESULTS In both experiments, breathlessness during 60 W cycling was markedly increased in over 37% of the obese women (P < 0.01). Age, height, weight, lung function, and %body fat were not different between the groups in either experiment. In contrast, the oxygen cost of breathing was significantly (P < 0.01) and markedly (38-70%) greater in the obese women with dyspnea on exertion. The oxygen cost of breathing was significantly (P < 0.001) correlated with the rating of perceived breathlessness obtained during the 60 W exercise in experiment 1 (r(2) = 0.57) and experiment 2 (r(2) = 0.72). Peak cardiovascular exercise capacity, fat distribution, and respiratory mechanics were not different between groups in experiment 2. CONCLUSIONS Dyspnea on exertion is prevalent in otherwise healthy obese women, which seems to be strongly associated with an increased oxygen cost of breathing. Exercise capacity is not reduced in obese women with dyspnea on exertion.

Incidence and impact of subclinical epileptiform activity in Alzheimer's disease

Seizures are more frequent in patients with Alzheimers disease (AD) and can hasten cognitive decline. However, the incidence of subclinical epileptiform activity in AD and its consequences are unknown. Motivated by results from animal studies, we hypothesized higher than expected rates of subclinical epileptiform activity in AD with deleterious effects on cognition.

Discrimination of brief speech sounds is impaired in rats with auditory cortex lesions

Auditory cortex (AC) lesions impair complex sound discrimination. However, a recent study demonstrated spared performance on an acoustic startle response test of speech discrimination following AC lesions (Floody et al., 2010). The current study reports the effects of AC lesions on two operant speech discrimination tasks. AC lesions caused a modest and quickly recovered impairment in the ability of rats to discriminate consonant-vowel-consonant speech sounds. This result seems to suggest that AC does not play a role in speech discrimination. However, the speech sounds used in both studies differed in many acoustic dimensions and an adaptive change in discrimination strategy could allow the rats to use an acoustic difference that does not require an intact AC to discriminate. Based on our earlier observation that the first 40 ms of the spatiotemporal activity patterns elicited by speech sounds best correlate with behavioral discriminations of these sounds (Engineer et al., 2008), we predicted that eliminating additional cues by truncating speech sounds to the first 40 ms would render the stimuli indistinguishable to a rat with AC lesions. Although the initial discrimination of truncated sounds took longer to learn, the final performance paralleled rats using full-length consonant-vowel-consonant sounds. After 20 days of testing, half of the rats using speech onsets received bilateral AC lesions. Lesions severely impaired speech onset discrimination for at least one-month post lesion. These results support the hypothesis that auditory cortex is required to accurately discriminate the subtle differences between similar consonant and vowel sounds.

Neural Mechanisms Supporting Robust Discrimination of Spectrally and Temporally Degraded Speech

Cochlear implants provide good speech discrimination ability despite highly limited amount of information they transmit compared with normal cochlea. Noise vocoded speech, simulating cochlear implants in normal hearing listeners, have demonstrated that spectrally and temporally degraded speech contains sufficient cues to provide accurate speech discrimination. We hypothesized that neural activity patterns generated in the primary auditory cortex by spectrally and temporally degraded speech sounds will account for the robust behavioral discrimination of speech. We examined the behavioral discrimination of noise vocoded consonants and vowels by rats and recorded neural activity patterns from rat primary auditory cortex (A1) for the same sounds. We report the first evidence of behavioral discrimination of degraded speech sounds by an animal model. Our results show that rats are able to accurately discriminate both consonant and vowel sounds even after significant spectral and temporal degradation. The degree of degradation that rats can tolerate is comparable to human listeners. We observed that neural discrimination based on spatiotemporal patterns (spike timing) of A1 neurons is highly correlated with behavioral discrimination of consonants and that neural discrimination based on spatial activity patterns (spike count) of A1 neurons is highly correlated with behavioral discrimination of vowels. The results of the current study indicate that speech discrimination is resistant to degradation as long as the degraded sounds generate distinct patterns of neural activity.

Weight Loss via Diet and Exercise Improves Exercise Breathing Mechanics in Obese Men

BACKGROUND Obesity alters breathing mechanics during exercise. Weight loss improves lung function at rest, but the effect of weight loss, especially regional fat loss, on exercise breathing mechanics is unclear. We hypothesized that weight loss, especially a decrease in abdominal fat, would improve breathing mechanics during exercise because of an increase in end-expiratory lung volume (EELV). METHODS Nine obese men were studied before and after weight loss (13% ± 8% of total fat weight, mean ± SD). Subjects underwent pulmonary function testing, underwater weighing, fat distribution estimates (MRI), and graded cycle ergometry before and after a 12-week diet and exercise program. In seven men, esophageal and gastric pressures were measured. The effects of weight loss were analyzed at rest, at ventilatory threshold (VTh), and during peak exercise by dependent Student t test, and the relationship among variables was determined by correlation analysis. RESULTS Subjects lost 7.4 ± 4.2 kg of body weight (P < .001), but the distribution of fat remained unchanged. After weight loss, lung volume subdivisions at rest were increased (P < .05) and were moderately associated (P < .05) with changes in chest, waist, and hip circumferences. At VTh, EELV increased, and gastric pressure decreased significantly (P < .05). The changes in waist circumference, hip circumference, BMI, and sum of chest, waist, and hip circumferences were also consistently and significantly correlated (P < .05) with changes in gastric pressure during exercise at VTh. CONCLUSIONS Modest weight loss improves breathing mechanics during submaximal exercise in otherwise healthy obese men, which is clinically encouraging. Improvement appears to be related to the cumulative loss of chest wall fat.

Regional functional connectivity predicts distinct cognitive impairments in Alzheimer’s disease spectrum

Understanding neural network dysfunction in neurodegenerative disease is imperative to effectively develop network-modulating therapies. In Alzheimer’s disease (AD), cognitive decline associates with deficits in resting-state functional connectivity of diffuse brain networks. The goal of the current study was to test whether specific cognitive impairments in AD spectrum correlate with reduced functional connectivity of distinct brain regions. We recorded resting-state functional connectivity of alpha-band activity in 27 patients with AD spectrum − 22 patients with probable AD (5 logopenic variant primary progressive aphasia, 7 posterior cortical atrophy, and 10 early-onset amnestic/dysexecutive AD) and 5 patients with mild cognitive impairment due to AD. We used magnetoencephalographic imaging (MEGI) to perform an unbiased search for regions where patterns of functional connectivity correlated with disease severity and cognitive performance. Functional connectivity measured the strength of coherence between a given region and the rest of the brain. Decreased neural connectivity of multiple brain regions including the right posterior perisylvian region and left middle frontal cortex correlated with a higher degree of disease severity. Deficits in executive control and episodic memory correlated with reduced functional connectivity of the left frontal cortex, whereas visuospatial impairments correlated with reduced functional connectivity of the left inferior parietal cortex. Our findings indicate that reductions in region-specific alpha-band resting-state functional connectivity are strongly correlated with, and might contribute to, specific cognitive deficits in AD spectrum. In the future, MEGI functional connectivity could be an important biomarker to map and follow defective networks in the early stages of AD.

Speech discrimination after early exposure to pulsed-noise or speech

Early experience of structured inputs and complex sound features generate lasting changes in tonotopy and receptive field properties of primary auditory cortex (A1). In this study we tested whether these changes are severe enough to alter neural representations and behavioral discrimination of speech. We exposed two groups of rat pups during the critical period of auditory development to pulsed-noise or speech. Both groups of rats were trained to discriminate speech sounds when they were young adults, and anesthetized neural responses were recorded from A1. The representation of speech in A1 and behavioral discrimination of speech remained robust to altered spectral and temporal characteristics of A1 neurons after pulsed-noise exposure. Exposure to passive speech during early development provided no added advantage in speech sound processing. Speech training increased A1 neuronal firing rate for speech stimuli in naïve rats, but did not increase responses in rats that experienced early exposure to pulsed-noise or speech. Our results suggest that speech sound processing is resistant to changes in simple neural response properties caused by manipulating early acoustic environment.

Cognition and neuropsychiatry in behavioral variant frontotemporal dementia by disease stage

Objective: To characterize the cognitive and neuropsychiatric symptoms of patients with behavioral variant frontotemporal dementia (bvFTD) over the natural course of the disease. Methods: We examined the initial and subsequent neuropsychological test performance and neuropsychiatric symptoms in a large cohort of patients with bvFTD (n = 204) across progressive stages of disease as measured by the Clinical Dementia Rating (CDR). We also compared cognitive and neuropsychiatric impairments of patients with bvFTD to those of an age-matched cohort with Alzheimer disease (AD) dementia (n = 674). Results: At the earliest stage (CDR = 0.5), patients with bvFTD had profound neuropsychiatric disturbances, insensitivity to errors, slower response times, and poor naming, with intact attention span, memory, and facial affect naming. Tests continuing to show progressive, statistically significant stepwise declines after the CDR = 1 stage included free recall, visuoconstruction, set-shifting, error insensitivity, semantic fluency, design fluency, emotion naming, calculations, confrontation naming, syntax comprehension, and verbal agility. At CDR = 0.5, patients with bvFTD significantly outperformed patients with AD in episodic memory and were faster in set-shifting, while scoring quantitatively worse in lexical fluency, emotion naming, and error sensitivity. The overall rate of disease progression in bvFTD was more rapid than in AD. Conclusion: There are distinct patterns of cognitive deficits differentiating the earlier and later disease stages in bvFTD, with the pattern of cognitive decline revealing in greater detail the natural history of the disease. These cognitive symptoms are readily apparent clinical markers of dysfunction in the principal brain networks known to undergo molecular and anatomical changes in bvFTD, thus are important indicators of the evolving pathology in individual patients.

Deconstructing empathy: Neuroanatomical dissociations between affect sharing and prosocial motivation using a patient lesion model

ABSTRACT Affect sharing and prosocial motivation are integral parts of empathy that are conceptually and mechanistically distinct. We used a neurodegenerative disease (NDG) lesion model to examine the neural correlates of these two aspects of real‐world empathic responding. The study enrolled 275 participants, including 44 healthy older controls and 231 patients diagnosed with one of five neurodegenerative diseases (75 Alzheimers disease, 58 behavioral variant frontotemporal dementia (bvFTD), 42 semantic variant primary progressive aphasia (svPPA), 28 progressive supranuclear palsy, and 28 non‐fluent variant primary progressive aphasia (nfvPPA). Informants completed the Revised Self‐Monitoring Scales Sensitivity to the Expressive Behavior of Others (RSMS‐EX) subscale and the Interpersonal Reactivity Indexs Empathic Concern (IRI‐EC) subscale describing the typical empathic behavior of the participants in daily life. Using regression modeling of the voxel based morphometry of T1 brain scans prepared using SPM8 DARTEL‐based preprocessing, we isolated the variance independently contributed by the affect sharing and the prosocial motivation elements of empathy as differentially measured by the two scales. We found that the affect sharing component uniquely correlated with volume in right>left medial and lateral temporal lobe structures, including the amygdala and insula, that support emotion recognition, emotion generation, and emotional awareness. Prosocial motivation, in contrast, involved structures such as the nucleus accumbens (NaCC), caudate head, and inferior frontal gyrus (IFG), which suggests that an individual must maintain the capacity to experience reward, to resolve ambiguity, and to inhibit their own emotional experience in order to effectively engage in spontaneous altruism as a component of their empathic response to others. HIGHLIGHTSHuman lesion models can reveal the necessary and sufficient neuroanatomy of empathy.Affect sharing (AS) and prosocial motivation (PM) derive from distinct neural circuits.Temporal structures mediate emotion recognition/generation/awareness supporting AS.Frontal‐subcortical structures mediate reward/inhibition of emotion supporting PM.

Increasing diversity of neural responses to speech sounds across the central auditory pathway.

Neurons at higher stations of each sensory system are responsive to feature combinations not present at lower levels. As a result, the activity of these neurons becomes less redundant than lower levels. We recorded responses to speech sounds from the inferior colliculus and the primary auditory cortex neurons of rats, and tested the hypothesis that primary auditory cortex neurons are more sensitive to combinations of multiple acoustic parameters compared to inferior colliculus neurons. We independently eliminated periodicity information, spectral information and temporal information in each consonant and vowel sound using a noise vocoder. This technique made it possible to test several key hypotheses about speech sound processing. Our results demonstrate that inferior colliculus responses are spatially arranged and primarily determined by the spectral energy and the fundamental frequency of speech, whereas primary auditory cortex neurons generate widely distributed responses to multiple acoustic parameters, and are not strongly influenced by the fundamental frequency of speech. We found no evidence that inferior colliculus or primary auditory cortex was specialized for speech features such as voice onset time or formants. The greater diversity of responses in primary auditory cortex compared to inferior colliculus may help explain how the auditory system can identify a wide range of speech sounds across a wide range of conditions without relying on any single acoustic cue.