Chronic pain is characterized by discrete pain episodes of unpredictable frequency and duration. This hinders the study of pain mechanisms and contributes to the use of pharmacological treatments associated with side effects, addiction and drug tolerance. Here, we show that a closed-loop brain–machine interface (BMI) can modulate sensory-affective experiences in real time in freely behaving rats by coupling neural codes for nociception directly with therapeutic cortical stimulation. The BMI decodes the onset of nociception via a state-space model on the basis of the analysis of online-sorted spikes recorded from the anterior cingulate cortex (which is critical for pain processing) and couples real-time pain detection with optogenetic activation of the prelimbic prefrontal cortex (which exerts top–down nociceptive regulation). In rats, the BMI effectively inhibited sensory and affective behaviours caused by acute mechanical or thermal pain, and by chronic inflammatory or neuropathic pain. The approach provides a blueprint for demand-based neuromodulation to treat sensory-affective disorders, and could be further leveraged for nociceptive control and to study pain mechanisms.
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Closed-loop stimulation using a multiregion brain-machine interface has analgesic effects in rodents
Pain relief on-demand Chronic pain is a debilitating condition for which there are no effective treatments. The primary somatosensory cortex (S1) and the anterior cingulate cortex (ACC) are involved in decoding pain components, and electrical stimulation of the prefrontal cortex (PFC) has been shown to exert analgesic effects. Here, Sun et al. developed a multiregion brain-machine interface (BMI) able to detect pain from electrical signals in S1 and ACC and provide on-demand PFC stimulation. The BMI was able to accurately detect and treat acute and chronic pain in rats; the analgesic effects were stable over time. The results suggest that BMI approaches might be effective for treating chronic pain of different etiologies.
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- Award ID(s):
- 1835000
- NSF-PAR ID:
- 10394674
- Date Published:
- Journal Name:
- Science Translational Medicine
- Volume:
- 14
- Issue:
- 651
- ISSN:
- 1946-6234
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Objective . There has been growing interest in understanding multisensory integration in the cortex through activation of multiple sensory and motor pathways to treat brain disorders, such as tinnitus or essential tremors. For tinnitus, previous studies show that combined sound and body stimulation can modulate the auditory pathway and lead to significant improvements in tinnitus symptoms. Considering that tinnitus is a type of chronic auditory pain, bimodal stimulation could potentially alter activity in the somatosensory pathway relevant for treating chronic pain. As an initial step towards that goal, we mapped and characterized neuromodulation effects in the somatosensory cortex (SC) in response to sound and/or electrical stimulation of the body.Approach. We first mapped the topographic organization of activity across the SC of ketamine-anesthetized guinea pigs through electrical stimulation of different body locations using subcutaneous needle electrodes or with broadband acoustic stimulation. We then characterized how neural activity in different parts of the SC could be facilitated or suppressed with bimodal stimulation.Main results . The topography in the SC of guinea pigs in response to electrical stimulation of the body aligns consistently to that shown in previous rodent studies. Interestingly, auditory broadband noise stimulation primarily excited SC areas that typically respond to stimulation of lower body locations. Although there was only a small subset of SC locations that were excited by acoustic stimulation alone, all SC recording sites could be altered (facilitated or suppressed) with bimodal stimulation. Furthermore, specific regions of the SC could be modulated by stimulating an appropriate body region combined with broadband noise.Significance . These findings show that bimodal stimulation can excite or modulate firing across a widespread yet targeted population of SC neurons. This approach may provide a non-invasive method for altering or disrupting abnormal firing patterns within certain parts of the SC for chronic pain treatment. -
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The behavioral and neural effects of the endogenous release of acetylcholine following stimulation of the Nucleus Basalis of Meynert (NB) have been recently examined in two male monkeys (Qi et al. 2021). Counterintuitively, NB stimulation enhanced behavioral performance while broadening neural tuning in the prefrontal cortex (PFC). The mechanism by which a weaker mnemonic neural code could lead to better performance remains unclear. Here, we show that increased neural excitability in a simple continuous bump attractor model can induce broader neural tuning and decrease bump diffusion, provided neural rates are saturated. Increased memory precision in the model overrides memory accuracy, improving overall task performance. Moreover, we show that bump attractor dynamics can account for the nonuniform impact of neuromodulation on distractibility, depending on distractor distance from the target. Finally, we delve into the conditions under which bump attractor tuning and diffusion balance in biologically plausible heterogeneous network models. In these discrete bump attractor networks, we show that reducing spatial correlations or enhancing excitatory transmission can improve memory precision. Altogether, we provide a mechanistic understanding of how cholinergic neuromodulation controls spatial working memory through perturbed attractor dynamics in PFC.
Significance statement Acetylcholine has been thought to improve cognitive performance by sharpening neuronal tuning in prefrontal cortex. Recent work has shown that electrical stimulation of the cholinergic forebrain in awake-behaving monkeys induces a reduction in prefrontal neural tuning under stimulation conditions that improve performance. To reconcile these divergent observations, we provide network simulations showing that these derive consistently from specific conditions in prefrontal attractor dynamics: firing rate saturation leads to increased storage precision and reduced neural tuning upon cholinergic activation via an increase in neural excitability, a reduction in neural correlations, and an increase in excitatory transmission. Our study integrates previously reported data into a consistent mechanistic view of how acetylcholine controls spatial working memory via attractor network dynamics in prefrontal cortex.
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1126/scitranslmed.abm5868
