Amanmeet Garg

Neonatal Pain-Related Stress Predicts Cortical Thickness at Age 7 Years in Children Born Very Preterm

Background Altered brain development is evident in children born very preterm (24–32 weeks gestational age), including reduction in gray and white matter volumes, and thinner cortex, from infancy to adolescence compared to term-born peers. However, many questions remain regarding the etiology. Infants born very preterm are exposed to repeated procedural pain-related stress during a period of very rapid brain development. In this vulnerable population, we have previously found that neonatal pain-related stress is associated with atypical brain development from birth to term-equivalent age. Our present aim was to evaluate whether neonatal pain-related stress (adjusted for clinical confounders of prematurity) is associated with altered cortical thickness in very preterm children at school age. Methods 42 right-handed children born very preterm (24–32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children with severe brain injury and major motor/sensory/cognitive impairment were excluded. Regional cortical thickness was calculated using custom developed software utilizing FreeSurfer segmentation data. The association between neonatal pain-related stress (defined as the number of skin-breaking procedures) accounting for clinical confounders (gestational age, illness severity, infection, mechanical ventilation, surgeries, and morphine exposure), was examined in relation to cortical thickness using constrained principal component analysis followed by generalized linear modeling. Results After correcting for multiple comparisons and adjusting for neonatal clinical factors, greater neonatal pain-related stress was associated with significantly thinner cortex in 21/66 cerebral regions (p-values ranged from 0.00001 to 0.014), predominately in the frontal and parietal lobes. Conclusions In very preterm children without major sensory, motor or cognitive impairments, neonatal pain-related stress appears to be associated with thinner cortex in multiple regions at school age, independent of other neonatal risk factors.

Morphological alterations in the caudate, putamen, pallidum, and thalamus in Parkinson's disease

Like many neurodegenerative diseases, the clinical symptoms of Parkinsons disease (PD) do not manifest until significant progression of the disease has already taken place, motivating the need for sensitive biomarkers of the disease. While structural imaging is a potentially attractive method due to its widespread availability and non-invasive nature, global morphometric measures (e.g., volume) have proven insensitive to subtle disease change. Here we use individual surface displacements from deformations of an average surface model to capture disease related changes in shape of the subcortical structures in PD. Data were obtained from both the University of British Columbia (UBC) [n = 54 healthy controls (HC) and n = 55 Parkinsons disease (PD) patients] and the publicly available Parkinsons Progression Markers Initiative (PPMI) [n = 137 (HC) and n = 189 (PD)] database. A high dimensional non-rigid registration algorithm was used to register target segmentation labels (caudate, putamen, pallidum, and thalamus) to a set of segmentation labels defined on the average-template. The vertex-wise surface displacements were significantly different between PD and HC in thalamic and caudate structures. However, overall displacements did not correlate with disease severity, as assessed by the Unified Parkinsons Disease Rating Scale (UPDRS). The results from this study suggest disease-relevant shape abnormalities can be robustly detected in subcortical structures in PD. Future studies will be required to determine if shape changes in subcortical structures are seen in the prodromal phases of the disease.

Physiological interdependence of the cardiovascular and postural control systems under orthostatic stress.

The cardiovascular system has been observed to respond to changes in human posture and the environment. On the same lines, frequent fallers have been observed to suffer from cardiovascular deficits. The present article aims to demonstrate the existence of interactions between the cardiovascular and postural control systems. The behavior of the two systems under orthostatic challenge was studied through novel adaptations of signal processing techniques. To this effect, the interactions between the two systems were assessed with two metrics, coherence and phase lock value, based on the wavelet transform. Measurements from the cardiovascular system (blood pressure), lower limb muscles (surface electromyography), and postural sway (center of pressure) were acquired from young healthy adults (n = 28, men = 12, age = 20-28 yr) during quiet stance. The continuous wavelet transform was applied to decompose the representative signals on a time-scale basis in a frequency region of 0.01 to 0.1 Hz. Their linear coupling was quantified through a coherence metric, and the synchrony was characterized via the phase information. The outcomes of this study present evidence that the cardiovascular and postural control systems work together to maintain homeostasis under orthostatic challenge. The inferences open a new direction of study for effects under abnormalities and extreme environmental conditions.

Skeletal Muscle Pump Drives Control of Cardiovascular and Postural Systems

The causal interaction between cardio-postural-musculoskeletal systems is critical in maintaining postural stability under orthostatic challenge. The absence or reduction of such interactions could lead to fainting and falls often experienced by elderly individuals. The causal relationship between systolic blood pressure (SBP), calf electromyography (EMG), and resultant center of pressure (COPr) can quantify the behavior of cardio-postural control loop. Convergent cross mapping (CCM) is a non-linear approach to establish causality, thus, expected to decipher nonlinear causal cardio-postural-musculoskeletal interactions. Data were acquired simultaneously from young participants (25 ± 2 years, n = 18) during a 10-minute sit-to-stand test. In the young population, skeletal muscle pump was found to drive blood pressure control (EMG → SBP) as well as control the postural sway (EMG → COPr) through the significantly higher causal drive in the direction towards SBP and COPr. Furthermore, the effect of aging on muscle pump activation associated with blood pressure regulation was explored. Simultaneous EMG and SBP were acquired from elderly group (69 ± 4 years, n = 14). A significant (p = 0.002) decline in EMG → SBP causality was observed in the elderly group, compared to the young group. The results highlight the potential of causality to detect alteration in blood pressure regulation with age, thus, a potential clinical utility towards detection of fall proneness.

Significant role of the cardiopostural interaction in blood pressure regulation during standing

Cardiovascular and postural control systems have been studied independently despite the increasing evidence showing the importance of cardiopostural interaction in blood pressure regulation. In this study, we aimed to assess the role of the cardiopostural interaction in relation to cardiac baroreflex in blood pressure regulation under orthostatic stress before and after mild exercise. Physiological variables representing cardiovascular control (heart rate and systolic blood pressure), lower limb muscle activation (electromyography), and postural sway (center of pressure derived from force and moment data during sway) were measured from 17 healthy participants (25 ± 2 yr, 9 men and 8 women) during a sit-to-stand test before and after submaximal exercise. The cardiopostural control (characterized by baroreflex-mediated muscle-pump effect in response to blood pressure changes, i.e., muscle-pump baroreflex) was assessed using wavelet transform coherence and causality analyses in relation to the baroreflex control of heart rate. Significant cardiopostural blood pressure control was evident counting for almost half of the interaction time with blood pressure changes that observed in the cardiac baroreflex (36.6-72.5% preexercise and 34.7-53.9% postexercise). Thus, cardiopostural input to blood pressure regulation should be considered when investigating orthostatic intolerance. A reduction of both cardiac and muscle-pump baroreflexes in blood pressure regulation was observed postexercise and was likely due to the absence of excessive venous pooling and a less stressed system after mild exercise. With further studies using more effective protocols evoking venous pooling and muscle-pump activity, the cardiopostural interaction could improve our understanding of the autonomic control system and ultimately lead to a more accurate diagnosis of cardiopostural dysfunctions.NEW & NOTEWORTHY We examined the interaction between cardiovascular and postural control systems during standing before and after mild exercise. Significant cardiopostural input to blood pressure regulation was shown, suggesting the importance of cardiopostural integration when investigating orthostatic hypotension. In addition, we observed a reduction of baroreflex-mediated blood pressure regulation after exercise.

Alteration in cardiovascular and postural control relationship in non-fainting elderly individuals

It is known that standing induces orthostatic stress on the cardiovascular system. Our previous works have presented that the postural control during standing and cardiovascular changes are related to each other in the health young individuals. However, it remains to be checked if such a relationship is present in the elderly individuals as well. The present study conducted experiments similar to our previous studies and collected data for the muscle activation in lower leg muscles along with blood pressure during a passive stand test. Application of wavelet transform coherence method provided time frequency distribution of the coherence between the two signals. High coherence (>threshold) was observed between the two signals suggesting a strong relationship. Additionally, a frequency dependent behavior was observed between the two signals. The results from this study present strong evidence that there is a change in the relationship between the two signals with aging.

Wavelet transform coherence based investigation of existence of relationship between the cardiovascular and postural control systems during orthostatic challenge

Previous studies have established the effects of orthostatic challenge on the cardiovascular and postural control systems, but the interdependent behavior of the systems under such condition is unclear. In the present study we examined the simultaneous changes in posture muscle electromyography (EMG) and systolic blood pressure (SBP) during quiet standing in healthy young individuals. Photoplethysmography based SBP, surface EMG, electrocardiogram (Lead II ECG) and posturography data were acquired during the experiment. Wavelet transform coherence (WTC) analysis was applied to identify the zones of interdependent behavior of the systems. The WTC thresholds were identified for the specific data under investigation. The coherence was analyzed in three frequency bands namely, LF (0.05 - 0.1 Hz), VLF (0.01-0.05 Hz) and ULF (0.005 - 0.01 Hz). WTC estimates for the EMG - SBP comparison showed greater than threshold values in all three frequency bands (LF: 0.31 ± 0.02; VLF: 0.41 ± 0.01; ULF: 0.45 ± 0.01). In conclusion this study showed the existence of relationship between the posture muscle EMG and blood pressure during natural orthostatic stress, by validation based on wavelet transform coherence. Further validation is required to objectively characterize this relationship between the two systems during orthostatic stress.

Vertical ground reaction force marker for Parkinson’s disease

Parkinson’s disease (PD) patients regularly exhibit abnormal gait patterns. Automated differentiation of abnormal gait from normal gait can serve as a potential tool for early diagnosis as well as monitoring the effect of PD treatment. The aim of current study is to differentiate PD patients from healthy controls, on the basis of features derived from plantar vertical ground reaction force (VGRF) data during walking at normal pace. The current work presents a comprehensive study highlighting the efficacy of different machine learning classifiers towards devising an accurate prediction system. Selection of meaningful feature based on sequential forward feature selection, the swing time, stride time variability, and center of pressure features facilitated successful classification of control and PD gaits. Support Vector Machine (SVM), K-nearest neighbor (KNN), random forest, and decision trees classifiers were used to build the prediction model. We found that SVM with cubic kernel outperformed other classifiers with an accuracy of 93.6%, the sensitivity of 93.1%, and specificity of 94.1%. In comparison to other studies, utilizing same dataset, our designed prediction system improved the classification performance by approximately 10%. The results of the current study underscore the ability of the VGRF data obtained non-invasively from wearable devices, in combination with a SVM classifier trained on meticulously selected features, as a tool for diagnosis of PD and monitoring effectiveness of therapy post pathology.

Causality in the cardio-postural interactions during quiet stance

Cardiovascular and postural systems are understood to interact with each other to maintain equilibrium. Prolonged standing is known to induce postural sway, pre-syncope symptoms and muscle fatigue. Prior work has shown the presence of interactions between the cardiovascular and postural systems during quiet stance. The cause-and-effect relation between the representative signals of the two systems remains to be established. This preliminary work presents a study to identify the causal relationship between the blood pressure waveform (BP) and resultant center of pressure (COPr) as well as between systolic arterial pressure (SAP) and COPr signals during quiet stance. A 5 minute sit-to-stand experiment was conducted for 7 healthy young participants to acquire data for the SAP and COP signals. The statistical framework of Granger causality was applied to test for the bidirectional causal relation between the BP-COPr and SAP-COPr signal pairs. The algorithm computed the F-statistic and critical value from an F distribution for null hypothesis of no causality between the signals. Data were extracted for a window of 15 seconds length, translated with an overlap of 5 seconds over the last 4 minutes of the quiet stance phase to obtain 22 to 23 time windows. Data for subjects rejected the null hypothesis for both BPCOPr and SAP-COPr signal pairs. The results from this study suggest that during quiet stance bidirectional interaction exist between BP and COPr as well as between SAP and COPr.

Manually segmented template library for 8-year-old pediatric brain MRI data with 16 subcortical structures.

Abstract. Manual segmentation of anatomy in brain MRI data taken to be the closest to the “gold standard” in quality is often used in automated registration-based segmentation paradigms for transfer of template labels onto the unlabeled MRI images. This study presents a library of template data with 16 subcortical structures in the central brain area which were manually labeled for MRI data from 22 children (8 male, mean age=8±0.6  years). The lateral ventricle, thalamus, caudate, putamen, hippocampus, cerebellum, third vevntricle, fourth ventricle, brainstem, and corpuscallosum were segmented by two expert raters. Cross-validation experiments with randomized template subset selection were conducted to test for their ability to accurately segment MRI data under an automated segmentation pipeline. A high value of the dice similarity coefficient (0.86±0.06, min=0.74, max=0.96) and small Hausdorff distance (3.33±4.24, min=0.63, max=25.24) of the automated segmentation against the manual labels was obtained on this template library data. Additionally, comparison with segmentation obtained from adult templates showed significant improvement in accuracy with the use of an age-matched library in this cohort. A manually delineated pediatric template library such as the one described here could provide a useful benchmark for testing segmentation algorithms.