Imaging: Pain Imaging and Neuroimaging

Long-term Imaging of Neuronal and Non-neuronal Spinal Cord Cells in the Awake, Behaving Mouse

Despite decades of study of the properties of spinal cord neurons that process nociceptive information (1) with very few exceptions studies were performed in anesthetized animals, (2) cannot follow the activity of the same genetically-defined population of neurons over time; and (3) cannot provide a correlate of activity changes over time with behavioral endpoints of chronic pain development or in response to existing and novel pain-relieving analgesics. This presentation will describe a spinal cord calcium imaging preparation in which it is possible to record from spinal cord neurons over time, in the awake, behaving mouse. This preparation will greatly facilitate our understanding of the spinal cord circuit activity changes that occur in the setting of tissue or nerve injury and that contribute to inflammatory and neuropathic chronic pain, respectively. This new approach also permits study of microglial cell responsiveness over time before and after injury.

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Decoding Cortical Ensembles of Acute Pain and their Reorganisation in Chronic Pain

Decoding distinct sensory stimuli in a complex multisensory milieu is fundamental property of organisms that is pivotal for survival. However, the neural basis of how distinct sensory modalities are encoded and delineated in the cortex is not well understood. It is postulated that modality-specificity could come about via distinct hard-wired cortical circuits or via distinct spatiotemporal patterns of activity generated within a common set of cortical neurons. By employing multiphoton imaging of neuronal activity in the somatosensory cortex of mice in vivo coupled with mathematical decoding algorithms, we identified specific cortical neuronal ensembles encoding distinct modalities of nociception in the mouse S1 cortex.
The medial prefrontal cortex is a key hub in limbic pathways that are of key significance in the emotional dimension of pain. Large scale alterations in prefrontal recruitment and connectivity have been reported over pain chronicity in macroscopic MRI studies on chronic pain patients. Using GRIN-lens-assisted deep imaging, we addressed alterations in prefrontal activity at a single cellular resolution across columnar networks in neuropathic mice. The data reveal a dysbalance between excitatory and inhibitory circuits in prefrontal networks over distinct stages of establishment and maintenance of neuropathic pain, and uncover the cellular origins thereof.

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Encoding and Transmission of Information by Primary Sensory Afferents

The lecture will highlight how optical techniques, enabling multiscale imaging can uncover previously inaccessible principles of sensory coding. First, we know that sensory afferents transduce environmental stimuli into activity that is transmitted centrally to be decoded into corresponding sensations. Despite years of work on molecular mechanisms of transduction, culminating in this year’s Nobel prize in medicine, how natural stimuli are represented remains debated. This can only be properly addressed by monitoring the activity of large ensembles of individually identified afferents. I will describe how multiphoton imaging from hundreds of neurons in dorsal root ganglia revealed that different sensory modalities use separate coding strategies; different stimuli activate distinct combinations of diversely tuned neurons, enabling rich, yet distinct population-level information transfer. Another challenge has been understanding communication between primary afferents and spinal neurons. Recording from afferent terminals has remained extremely challenging with most mechanisms inferred from indirect or distant measurements. I will show how high resolution, random access multiphoton imaging from afferent boutons reveals a rich and diverse regulation of presynaptic activity by action potentials, excitatory and inhibitory signaling, respectively. These approaches pave the way to understanding miscoding and abnormal transmission in pathological pain conditions.

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Introducing Optical Imaging Advances to Unravel Chronic Pain Mechanisms

Despite important advances in identifying molecular mechanisms in nociceptive sensitization, we are still far from treating pain disorders adequately. A major hindrance has been that the nature of neural circuits that mediate pain is not well understood and decoding how pain is generated and maintained remains a challenge. Although seminal insights have emerged from human imaging analyses at a macroscopic level, reaching an understanding of how structure generates function and specificity in pain has been challenging to achieve so far due to deficits in technologies that allow for observation and manipulation activity in specific cell types in an in vivo context during behavioural tasks in a temporally precise and functionally meaningful manner. Recent innovations in optical imaging technology now enable mapping activity and recruitment patterns with a high level of spatiotemporal precision. The goal of this workshop is to discuss key insights emerging from optical imaging studies on the encoding of sensory and affective dimensions of pain at multiple anatomical entities from peripheral sensory neurons to key brain regions. By decoding activity in microscopic and mesoscopic circuits, important principles governing specificity and causality are unveiled, principles that can be harnessed to improve efficacy of pharmacological and neuromodulation-based chronic pain therapies.

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Alpha Oscillations as a Potential Biomarker of Acute and Chronic Pain

The temporal code of neuronal activity underlying acute and chronic pain is not fully understood but is thought to involve neural oscillations at characteristic frequencies. In particular, alpha frequency oscillations have been recently linked to acute pain sensitivity and aspects of chronic pain and thus represent a potential pain biomarker. This workshop will provide an overview of approaches to measure (EEG, MEG) and modulate alpha oscillations. Dr Garcia-Larrea will provide an overview of the brain functions associated with human alpha rhythms, and how the modulation of these activities can help in the research, diagnosis and therapy of pain conditions. Dr. Seminowicz will present his findings that link peak alpha frequency activity with acute pain sensitivity. Dr. Davis will present her findings of abnormalities in regional peak alpha frequency and cross-regional coupling associated with neuropathic and non-neuropathic chronic pains. The panel will then lead a discussion on the specificity of alpha oscillations to specific types of pain and sex differences, and whether this represents a potentially clinically useful biomarker.

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The Alpha Activity in the Human Brain: A Conundrum with High Potentialities for Pain Research

Presentation Description
Human alpha rhythm was described almost one Century ago (1929) and despite such a long history its precise composition, sources and function remain incompletely understood. The EEG alpha consists of multiple phenomena, including globally coherent rhythms and more localized activity, and its sources combine long-range connective waves and thalamo-cortical networks. Participation of a brain region in internal (“self-referential”) mental processes, as opposed to the processing of external stimuli, is considered one primary function of alpha oscillations, and explains the paradox that alpha activity is suppressed when a brain region processes sensory stimuli, but increases during a number of cognitive tasks, notably working memory and problem solving. In this presentation we will discuss the alpha conundrum and how the recording and manipulation of this activity may be of use in studies of normal and pathological pain, both for diagnosis and for treatment.

Key Insight
Understanding the significance of alpha suppression / enhancement allows using this activity as a potential marker of pain-related brain functions, including pain encoding in memory buffers, and can also help determining the optimal stimulation frequency of cortical neurostimulation for pain relief.

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Peak Alpha Frequency is a Simple and Reliable Metric of Pain Sensitivity

We have shown that peak alpha frequency (PAF) is a simple and reliable metric of pain sensitivity across multiple pain models and time-scales. The speaker will describe ongoing studies of the mechanisms of PAF, including further analysis of the alpha spectrum data, and the use of simultaneous EEG-fMRI. The talk will conclude with new data from a large-scale validation study as well as several findings demonstrating the clinical utility of PAF.

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Peak Alpha Frequency as a Potential Biomarker of Chronic Neuropathic Pain with Some Sex Specificity

The Davis lab has identified abnormalities in alpha oscillations within the dynamic pain connectome across multiple chronic pain conditions, including multiple sclerosis, ankylosing spondylitis, and neuropathic pains. The speaker will describe the findings that point to deficits in  alpha activity that include the speed (i.e., alpha slowing) and power of the peak alpha frequency (PAF) as well as abnormal synchrony (i.e., functional coupling or functional connectivity) at alpha frequencies that normally occur between regions of the dynamic pain connectome. The speaker will also highlight the data that support the proposition that PAF is a biomarker of chronic neuropathic pain as well as data that point to sex-specificity of certain findings.

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