Raghavan Gopalakrishnan

Foot forces during exercise on the International Space Station

Long-duration exposure to microgravity has been shown to have detrimental effects on the human musculoskeletal system. To date, exercise countermeasures have been the primary approach to maintain bone and muscle mass and they have not been successful. Up until 2008, the three exercise countermeasure devices available on the International Space Station (ISS) were the treadmill with vibration isolation and stabilization (TVIS), the cycle ergometer with vibration isolation and stabilization (CEVIS), and the interim resistance exercise device (iRED). This article examines the available envelope of mechanical loads to the lower extremity that these exercise devices can generate based on direct in-shoe force measurements performed on the ISS. Four male crewmembers who flew on long-duration ISS missions participated in this study. In-shoe forces were recorded during activities designed to elicit maximum loads from the various exercise devices. Data from typical exercise sessions on Earth and on-orbit were also available for comparison. Maximum on-orbit single-leg loads from TVIS were 1.77 body weight (BW) while running at 8mph. The largest single-leg forces during resistance exercise were 0.72 BW during single-leg heel raises and 0.68 BW during double-leg squats. Forces during CEVIS exercise were small, approaching only 0.19 BW at 210W and 95RPM. We conclude that the three exercise devices studied were not able to elicit loads comparable to exercise on Earth, with the exception of CEVIS at its maximal setting. The decrements were, on average, 77% for walking, 75% for running, and 65% for squats when each device was at its maximum setting. Future developments must include an improved harness to apply higher gravity replacement loads during locomotor exercise and the provision of greater resistance exercise capability. The present data set provides a benchmark that will enable future researchers to judge whether or not the new generation of exercise countermeasures recently added to the ISS will address the need for greater loading.

A magnetoencephalography study of visual processing of pain anticipation.

Anticipating pain is important for avoiding injury; however, in chronic pain patients, anticipatory behavior can become maladaptive, leading to sensitization and limiting function. Knowledge of networks involved in pain anticipation and conditioning over time could help devise novel, better-targeted therapies. With the use of magnetoencephalography, we evaluated in 10 healthy subjects the neural processing of pain anticipation. Anticipatory cortical activity elicited by consecutive visual cues that signified imminent painful stimulus was compared with cues signifying nonpainful and no stimulus. We found that the neural processing of visually evoked pain anticipation involves the primary visual cortex along with cingulate and frontal regions. Visual cortex could quickly and independently encode and discriminate between visual cues associated with pain anticipation and no pain during preconscious phases following object presentation. When evaluating the effect of task repetition on participating cortical areas, we found that activity of prefrontal and cingulate regions was mostly prominent early on when subjects were still naive to a cues contextual meaning. Visual cortical activity was significant throughout later phases. Although visual cortex may precisely and time efficiently decode cues anticipating pain or no pain, prefrontal areas establish the context associated with each cue. These findings have important implications toward processes involved in pain anticipation and maladaptive pain conditioning.

The use of contact heat evoked potential stimulator (CHEPS) in magnetoencephalography for pain research.

BACKGROUND Contact heat evoked potentials (CHEP) is a thermal stimulus modality used in pain research. We examine a commercial CHEP stimulator (CHEPS) that is designed to work in an fMRI environment, but poorly understood in the MEG environment. The CHEPS attains target temperatures rapidly using sophisticated control signals that unfortunately induce artifacts in the MEG. In this paper, we summarize our experiences using the CHEPS in MEG to study pain using an experimental paradigm, and propose a novel method for managing its artifact. NEW METHOD We introduce a novel damped sinusoid modeling (DSM) technique to remove the CHEPS artifact based on estimates of the underlying sinusoids and damping factors. We show comparisons to signal space projection (SSP) and temporal signal space separation (tSSS) methods. RESULTS The CHEPS artifact is highly dynamic, yet deterministic, switching rapidly from one frequency to another, with different spatial components. The galvanic connection between the subject and the CHEPS probe alters its performance, making pre-characterization difficult. COMPARISON WITH EXISTING METHODS SSP methods failed to remove the artifact completely. TSSS performed better than SSP; however, tSSS requires the use of a multipolar head model that decreases the dimensionality and possibly the information content of the data. In contrast, DSM offers a strictly temporal modeling approach in which the artifact is estimated as a sum of damped sinusoids which is subtracted from the data. CONCLUSION Though the CHEPS increases the noise floor and introduces artifacts to the data, we believe the device can be successfully used in MEG if appropriate artifact removal techniques are followed.

Early event related fields during visually evoked pain anticipation.

OBJECTIVE Pain experience is not only a function of somatosensory inputs. Rather, it is strongly influenced by cognitive and affective pathways. Pain anticipatory phenomena, an important limitation to rehabilitative efforts in the chronic state, are processed by associative and limbic networks, along with primary sensory cortices. Characterization of neurophysiological correlates of pain anticipation, particularly during very early stages of neural processing is critical for development of therapeutic interventions. METHODS Here, we utilized magnetoencephalography to study early event-related fields (ERFs) in healthy subjects exposed to a 3 s visual countdown task that preceded a painful stimulus, a non-painful stimulus or no stimulus. RESULTS We found that the first countdown cue, but not the last cue, evoked critical ERFs signaling anticipation, attention and alertness to the noxious stimuli. Further, we found that P2 and N2 components were significantly different in response to first-cues that signaled incoming painful stimuli when compared to non-painful or no stimuli. CONCLUSIONS The findings indicate that early ERFs are relevant neural substrates of pain anticipatory phenomena and could be potentially serve as biomarkers. SIGNIFICANCE These measures could assist in the development of neurostimulation approaches aimed at curbing the negative effects of pain anticipation during rehabilitation.

A Magnetoencephalography study of multi-modal processing of pain anticipation in primary sensory cortices

Pain anticipation plays a critical role in pain chronification and results in disability due to pain avoidance. It is important to understand how different sensory modalities (auditory, visual or tactile) may influence pain anticipation as different strategies could be applied to mitigate anticipatory phenomena and chronification. In this study, using a countdown paradigm, we evaluated with magnetoencephalography the neural networks associated with pain anticipation elicited by different sensory modalities in normal volunteers. When encountered with well-established cues that signaled pain, visual and somatosensory cortices engaged the pain neuromatrix areas early during the countdown process, whereas the auditory cortex displayed delayed processing. In addition, during pain anticipation, the visual cortex displayed independent processing capabilities after learning the contextual meaning of cues from associative and limbic areas. Interestingly, cross-modal activation was also evident and strong when visual and tactile cues signaled upcoming pain. Dorsolateral prefrontal cortex and mid-cingulate cortex showed significant activity during pain anticipation regardless of modality. Our results show pain anticipation is processed with great time efficiency by a highly specialized and hierarchical network. The highest degree of higher-order processing is modulated by context (pain) rather than content (modality) and rests within the associative limbic regions, corroborating their intrinsic role in chronification.

Pain anticipatory phenomena in patients with central poststroke pain: a magnetoencephalography study

Central poststroke pain (CPSP) is characterized by hemianesthesia associated with unrelenting chronic pain. The final pain experience stems from interactions between sensory, affective, and cognitive components of chronic pain. Hence, managing CPSP will require integrated approaches aimed not only at the sensory but also the affective-cognitive spheres. A better understanding of the brains processing of pain anticipation is critical for the development of novel therapeutic approaches that target affective-cognitive networks and alleviate pain-related disability. We used magnetoencephalography (MEG) to characterize the neural substrates of pain anticipation in patients suffering from intractable CPSP. Simple visual cues evoked anticipation while patients awaited impending painful (PS), nonpainful (NPS), or no stimulus (NOS) to their nonaffected and affected extremities. MEG responses were studied at gradiometer level using event-related fields analysis and time-frequency oscillatory analysis upon source localization. On the nonaffected side, significantly greater responses were recorded during PS. PS (vs. NPS and NOS) exhibited significant parietal and frontal cortical activations in the beta and gamma bands, respectively, whereas NPS (vs. NOS) displayed greater activation in the orbitofrontal cortex. On the affected extremity, PS (vs. NPS) did not show significantly greater responses. These data suggest that anticipatory phenomena can modulate neural activity when painful stimuli are applied to the nonaffected extremity but not the affected extremity in CPSP patients. This dichotomy may stem from the chronic effects of pain on neural networks leading to habituation or saturation. Future clinically effective therapies will likely be associated with partial normalization of the neurophysiological correlates of pain anticipation.

Differential frequency modulation of neural activity in the lateral cerebellar nucleus in failed and successful grasps

The olivo-cerebellar system has an essential role in the detection and adaptive correction of movement errors. While there is evidence of an error signal in the cerebellar cortex and inferior olivary nucleus, the deep cerebellar nuclei have been less thoroughly investigated. Here, we recorded local field potential activity in the rodent lateral cerebellar nucleus during a skilled reaching task and compared event-related changes in neural activity between unsuccessful and successful attempts. Increased low gamma (40-50 Hz) band power was present throughout the reach and grasp behavior, with no difference between successful and unsuccessful trials. Beta band (12-30 Hz) power, however, was significantly increased in unsuccessful reaches, compared to successful, throughout the trial, including during the epoch preceding knowledge of the trials outcome. This beta band activity was greater in unsuccessful trials of high-performing days, compared to unsuccessful trials of low-performing days, indicating that this activity may reflect an error prediction signal, developed over the course of motor learning. These findings suggest an error-related discriminatory oscillatory hallmark of movement in the deep cerebellar nuclei.

Deep brain stimulation of the ventral striatal area for poststroke pain syndrome: a magnetoencephalography study

Poststroke pain syndrome (PSPS) is an often intractable disorder characterized by hemiparesis associated with unrelenting chronic pain. Although traditional analgesics have largely failed, integrative approaches targeting affective-cognitive spheres have started to show promise. Recently, we demonstrated that deep brain stimulation (DBS) of the ventral striatal area significantly improved the affective sphere of pain in patients with PSPS. In the present study, we examined whether electrophysiological correlates of pain anticipation were modulated by DBS that could serve as signatures of treatment effects. We recorded event-related fields (ERFs) of pain anticipation using magnetoencephalography (MEG) in 10 patients with PSPS preoperatively and postoperatively in DBS OFF and ON states. Simple visual cues evoked anticipation as patients awaited a painful (PS) or nonpainful stimulus (NPS) to the nonaffected or affected extremity. Preoperatively, ERFs showed no difference between PS and NPS anticipation to the affected extremity, possibly due to loss of salience in a network saturated by pain experience. DBS significantly modulated the early N1, consistent with improvements in affective networks involving restoration of salience and discrimination capacity. Additionally, DBS suppressed the posterior P2 (aberrant anticipatory anxiety) while enhancing the anterior N1 (cognitive and emotional regulation) in responders. DBS-induced changes in ERFs could potentially serve as signatures for clinical outcomes. NEW & NOTEWORTHY We examined the electrophysiological correlates of pain affect in poststroke pain patients who underwent deep brain stimulation (DBS) targeting the ventral striatal area under a randomized, controlled trial. DBS significantly modulated early event-related components, particularly N1 and P2, measured with magnetoencephalography during a pain anticipatory task, compared with baseline and the DBS-OFF condition, pointing to possible mechanisms of action. DBS-induced changes in event-related fields could potentially serve as biomarkers for clinical outcomes.