Faculty Bibliography

Machine learning is becoming an increasingly common component of routine data analyses in clinical research. The past decade in pain research has witnessed great advances in human neuroimaging and machine learning. With each finding, the pain research community takes one step closer to uncovering fundamental mechanisms underlying chronic pain and at the same time proposing neurophysiological biomarkers. However, it remains challenging to fully understand chronic pain due to its multidimensional representations within the brain. By utilizing cost-effective and non-invasive imaging techniques such as electroencephalography (EEG) and analyzing the resulting data with advanced analytic methods, we have the opportunity to better understand and identify specific neural mechanisms associated with the processing and perception of chronic pain. This narrative literature review summarizes studies from the last decade describing the utility of EEG as a potential biomarker for chronic pain by synergizing clinical and computational perspectives.

INTRODUCTION/UNASSIGNED:Chronic pain negatively impacts a range of sensory and affective behaviors. Previous studies have shown that the presence of chronic pain not only causes hypersensitivity at the site of injury but may also be associated with pain-aversive experiences at anatomically unrelated sites. While animal studies have indicated that the cingulate and prefrontal cortices are involved in this generalized hyperalgesia, the mechanisms distinguishing increased sensitivity at the site of injury from a generalized site-nonspecific enhancement in the aversive response to nociceptive inputs are not well known. METHODS/UNASSIGNED: = 15) by analyzing behavioral and electroencephalographic (EEG) data. RESULTS/UNASSIGNED:As expected, participants with chronic pain endorsed enhanced pain with mechanical stimuli in both back and hand. We further analyzed electroencephalographic (EEG) recordings during these evoked pain episodes. Brain oscillations in theta and alpha bands in the medial orbitofrontal cortex (mOFC) were associated with localized hypersensitivity, while increased gamma oscillations in the anterior cingulate cortex (ACC) and increased theta oscillations in the dorsolateral prefrontal cortex (dlPFC) were associated with generalized hyperalgesia. DISCUSSION/UNASSIGNED:These findings indicate that chronic pain may disrupt multiple cortical circuits to impact nociceptive processing.

Pain associated with breast cancer is a prevalent problem that negatively affects quality of life. Breast cancer pain is not limited to the disease course itself but is also induced by current therapeutic strategies. This, combined with the increasing number of patients living with breast cancer, make pain management for breast cancer patients an increasingly important area of research. This narrative review presents a summary of pain associated with breast cancer, including pain related to the cancer disease process itself and pain associated with current therapeutic modalities including radiation, chemotherapy, immunotherapy, and surgery. Current pain management techniques, their limitations, and novel analgesic strategies are also discussed.

PURPOSE/UNASSIGNED:The COVID-19 pandemic led to a drastic expansion in utilizing telemedicine, circumventing some of the geographical barriers to accessing pain care. However, uncertainties around the impact of telemedicine across various sociodemographic groups still exist, prompting further exploration. Therefore, this study aimed to evaluate the impact of sociodemographic factors in telemedicine utilization during and after the COVID-19 pandemic. PATIENTS AND METHODS/UNASSIGNED:All outpatient non-procedural visits at the pain medicine division of a large academic institution in the epicenter of the pandemic (New York, USA), between March 2019 and October 2021, were retrospectively included. Sociodemographic data including gender, age, ethnicity/race, postal code, and type of health insurance, across three time periods associated with the COVID-19 pandemic - pre-lockdown (in-office visits only), lockdown (telemedicine visits only) and post-lockdown (offering both in-office and telemedicine visits) - were analyzed and compared. RESULTS/UNASSIGNED:In total, 12,615 unique patients - The majority being women (58%) - were seen during the whole study period. In the post-lockdown period, telemedicine was utilized by 42% of all patients. Follow-up visits, younger patients, white patients, patients residing further away from the hospital, and privately insured patients were more likely to utilize telemedicine post-lockdown (p <0.05). Older patients, minorities, Manhattan residents, and Medicare/Medicaid recipients, were more likely to use in-office visits post-lockdown (p <0.05). CONCLUSION/UNASSIGNED:We identified disparities in the utilization of telemedicine in Pain Medicine, which may be due to socioeconomic factors such as lack of access to reliable internet access, cost of devices, and technological know-how. This emphasizes the need for further studies to better understand the reasons for and barriers to telemedicine use. This could help inform policymaking to safeguard equitable access to telemedicine use for pain care.

Effective treatments for chronic pain remain limited. Conceptually, a closed-loop neural interface combining sensory signal detection with therapeutic delivery could produce timely and effective pain relief. Such systems are challenging to develop because of difficulties in accurate pain detection and ultrafast analgesic delivery. Pain has sensory and affective components, encoded in large part by neural activities in the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC), respectively. Meanwhile, studies show that stimulation of the prefrontal cortex (PFC) produces descending pain control. Here, we designed and tested a brain-machine interface (BMI) combining an automated pain detection arm, based on simultaneously recorded local field potential (LFP) signals from the S1 and ACC, with a treatment arm, based on optogenetic activation or electrical deep brain stimulation (DBS) of the PFC in freely behaving rats. Our multiregion neural interface accurately detected and treated acute evoked pain and chronic pain. This neural interface is activated rapidly, and its efficacy remained stable over time. Given the clinical feasibility of LFP recordings and DBS, our findings suggest that BMI is a promising approach for pain treatment.

Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or α-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 Å from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.

The prefrontal cortex (PFC) regulates a wide range of sensory experiences. Chronic pain is known to impair normal neural response, leading to enhanced aversion. However, it remains unknown how nociceptive responses in the cortex are processed at the population level and whether such processes are disrupted by chronic pain. Using in vivo endoscopic calcium imaging, we identify increased population activity in response to noxious stimuli and stable patterns of functional connectivity among neurons in the prelimbic (PL) PFC from freely behaving rats. Inflammatory pain disrupts functional connectivity of PFC neurons and reduces the overall nociceptive response. Interestingly, ketamine, a well-known neuromodulator, restores the functional connectivity among PL-PFC neurons in the inflammatory pain model to produce anti-aversive effects. These results suggest a dynamic resource allocation mechanism in the prefrontal representations of pain and indicate that population activity in the PFC critically regulates pain and serves as an important therapeutic target.

Peripheral nerve injury-induced mechanical allodynia is often accompanied by abnormalities in the higher cortical regions, yet the mechanisms underlying such maladaptive cortical plasticity remain unclear. Here, we show that in male mice, structural and functional changes in the primary somatosensory cortex (S1) caused by peripheral nerve injury require neuron-microglial signaling within the local circuit. Following peripheral nerve injury, microglia in the S1 maintain ramified morphology and normal density but up-regulate the mRNA expression of brain-derived neurotrophic factor (BDNF). Using in vivo two-photon imaging and Cx3cr1CreER;Bdnfflox mice, we show that conditional knockout of BDNF from microglia prevents nerve injury-induced synaptic remodeling and pyramidal neuron hyperactivity in the S1, as well as pain hypersensitivity in mice. Importantly, S1-targeted removal of microglial BDNF largely recapitulates the beneficial effects of systemic BDNF depletion on cortical plasticity and allodynia. Together, these findings reveal a pivotal role of cerebral microglial BDNF in somatosensory cortical plasticity and pain hypersensitivity.

To examine the association of preoperative opioids and/or benzodiazepines on postoperative outcomes in total knee and hip arthroplasty, we retrospectively compared postoperative outcomes in those prescribed preoperative opioids and/or benzodiazepines versus those who were not who underwent elective total knee and hip arthroplasty at a single urban academic institution. Multivariable logistic regression was performed for readmission rate, respiratory failure, infection, and adverse cardiac events. Multivariable zero-truncated negative binomial regression was used for length of stay. After exclusions, there were 4307 adult patients in the study population, 2009 of whom underwent total knee arthroplasty and 2298 of whom underwent total hip arthroplasty. After adjusting for potential confounders, preoperative benzodiazepine use was associated with increased odds of readmission (p < 0.01). Preoperative benzodiazepines were not associated with increased odds of respiratory failure nor increased length of stay. Preoperative opioids were not associated with increased odds of the examined outcomes. There were insufficient numbers of infection and cardiac events for analysis. In this study population, preoperative benzodiazepines were associated with increased odds of readmission. Preoperative opioids were not associated with increased odds of the examined outcomes. Studies are needed to further examine risks associated with preoperative benzodiazepine use.

Pain is a complex, multidimensional experience that involves dynamic interactions between sensory-discriminative and affective-emotional processes. Pain experiences have a high degree of variability depending on their context and prior anticipation. Viewing pain perception as a perceptual inference problem, we propose a predictive coding paradigm to characterize evoked and non-evoked pain. We record the local field potentials (LFPs) from the primary somatosensory cortex (S1) and the anterior cingulate cortex (ACC) of freely behaving rats-two regions known to encode the sensory-discriminative and affective-emotional aspects of pain, respectively. We further use predictive coding to investigate the temporal coordination of oscillatory activity between the S1 and ACC. Specifically, we develop a phenomenological predictive coding model to describe the macroscopic dynamics of bottom-up and top-down activity. Supported by recent experimental data, we also develop a biophysical neural mass model to describe the mesoscopic neural dynamics in the S1 and ACC populations, in both naive and chronic pain-treated animals. Our proposed predictive coding models not only replicate important experimental findings, but also provide new prediction about the impact of the model parameters on the physiological or behavioral read-out-thereby yielding mechanistic insight into the uncertainty of expectation, placebo or nocebo effect, and chronic pain.