| 1. |
- Andersen, Michael Aagaard, et al.
(författare)
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Polydimethylsiloxane as a more biocompatible alternative to glass in optogenetics
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Optogenetics is highly useful to stimulate or inhibit defined neuronal populations and is often used together with electrophysiological recordings. Due to poor penetration of light in tissue, there is a need for biocompatible wave guides. Glass wave guides are relatively stiff and known to cause glia reaction that likely influence the activity in the remaining neurons. We developed highly flexible micro wave guides for optogenetics that can be used in combination with long-lasting electrophysiological recordings. We designed and evaluated polydimethylsiloxane (PDMS) mono-fibers, which use the tissue as cladding, with a diameter of 71 ± 10 µm and 126 ± 5 µm. We showed that micro PDMS fibers transmitted 9–33 mW/mm2 light energy enough to activate channelrhodopsin. This was confirmed in acute extracellular recordings in vivo in which optogenetic stimulation through the PDMS fibers generated action potentials in rat hippocampus with a short onset latency. PDMS fibers had significantly less microglia and astrocytic activation in the zone nearest to the implant as compared to glass. There was no obvious difference in number of adjacent neurons between size matched wave guides. Micro PDMS wave guide demonstrates in vivo functionality and improved biocompatibility as compared to glass. This enables the delivery of light with less tissue damage.
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| 2. |
- Bakalkin, Georgy, et al.
(författare)
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Unilateral traumatic brain injury of the left and right hemisphere produces the left hindlimb response in rats
- 2021
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Ingår i: Experimental Brain Research. - : Springer Science and Business Media LLC. - 0014-4819 .- 1432-1106. ; 239:7, s. 2221-2232
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Tidskriftsartikel (refereegranskat)abstract
- Traumatic brain injury and stroke result in hemiplegia, hemiparesis, and asymmetry in posture. The effects are mostly contralateral; however, ipsilesional deficits may also develop. We here examined whether ablation brain injury and controlled cortical impact (CCI), a rat model of clinical focal traumatic brain injury, both centered over the left or right sensorimotor cortex, induced hindlimb postural asymmetry (HL-PA) with contralesional or ipsilesional limb flexion. The contralesional hindlimb was flexed after left or right side ablation injury. In contrast, both the left and right CCI unexpectedly produced HL-PA with flexion on left side. The flexion persisted after complete spinal cord transection suggesting that CCI triggered neuroplastic processes in lumbar neural circuits enabling asymmetric muscle contraction. Left limb flexion was exhibited under pentobarbital anesthesia. However, under ketamine anesthesia, the body of the left and right CCI rats bent laterally in the coronal plane to the ipsilesional side suggesting that the left and right injury engaged mirror-symmetrical motor pathways. Thus, the effects of the left and right CCI on HL-PA were not mirror-symmetrical in contrast to those of the ablation brain injury, and to the left and right CCI produced body bending. Ipsilateral effects of the left CCI on HL-PA may be mediated by a lateralized motor pathway that is not affected by the left ablation injury. Alternatively, the left-side-specific neurohormonal mechanism that signals from injured brain to spinal cord may be activated by both the left and right CCI but not by ablation injury.
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| 3. |
- Forni, Matilde, et al.
(författare)
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3D microelectrode cluster and stimulation paradigm yield powerful analgesia without noticeable adverse effects
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:41
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Tidskriftsartikel (refereegranskat)abstract
- The lack of satisfactory treatment for persistent pain profoundly impairs the quality of life for many patients. Stimulation of brainstem pain control systems can trigger powerful analgesia, but their complex network organization frequently prevents separation of analgesia from side effects. To overcome this long-standing challenge, we developed a biocompatible gelatin-embedded cluster of ultrathin microelectrodes that enables fine-tuned, high-definition three-dimensional stimulation in periaqueductal gray/dorsal raphe nucleus in awake rats. Analgesia was assessed from both motor reactions and intracortical signals, corresponding to pain-related signals in humans. We could select an individual-specific subset of microelectrodes in each animal that reliably provided strong pain inhibition during normal and hyperalgesia conditions, without noticeable behavioral side effects. Gait, spontaneous cortical activity at rest, and cortical tactile responses were minimally affected, indicating a highly selective action. In conclusion, our developed biocompatible microelectrode cluster and stimulation paradigm reliably enabled powerful, fine-tuned, and selective analgesia without noticeable side effects.
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| 4. |
- Forni, Matilde, et al.
(författare)
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Sustained and potent analgesia with negligible side effects enabled by adaptive individualized granular stimulation in rat brainstem
- 2023
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Ingår i: Journal of Neural Engineering. - 1741-2560. ; 20:3
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. To clarify if an adaptive current stimulation protocol, in which current amplitude is modulated during continuous stimulation, provides better efficacy than constant current stimulation protocol with respect to analgesia caused by individualized stimulation in rat periaqueductal gray matter (PAG) /dorsal raphe nuclei (DRN). Approach. Ultrathin microelectrodes adapted for recording (n = 6) and stimulation (n = 16) were implanted in rat primary somatosensory cortex and PAG/DRN, respectively. In each animal included (n = 12), a subset of PAG/DRN microelectrodes (n = 1-3 per animal) was selected that on simultaneous stimulation blocked nociceptive withdrawal reflexes in awake unrestrained animals without noticeable side effects. Analgesic effects were subsequently assessed from both nociceptive withdrawal reflexes and intracortical pain-related responses on CO2 laser hind paw stimulation. The analgesic effects of adaptive current PAG/DRN stimulation comprising incremental increases of 5 μA/microelectrode (initial median current 30 μA/microelectrode) when effects declined were compared to the effects of constant current stimulation. Behavioral effects and brain state related changes were analyzed using quantitative movement analysis and electrocorticography (recorded on top of the dura mater), respectively. Tissue reactions and probe placement in PAG/DRN were assessed with immunohistochemistry. Main results. Powerful and sustained (4 h) analgesia was achieved with the adaptive current protocol within a rather wide area of PAG/DRN. Analgesic after-effects were seen for up to 30 min. Behavioral and brain state related side effects were minimal. Moreover, 6 weeks after implantation, there were no traces of bleedings, only small glial reactions and small but not statistically significant loss of neurons nearby indicating that the microelectrode stimulation employed is biocompatible. Significance. The results indicate that sustained and powerful analgesia with minimal side effects can be achieved by granular and individualized stimulation in PAG/DRN using an adaptive current stimulation protocol. This microelectrode technology and stimulation paradigm thus has the potential of providing a highly efficient and safe pain therapy.
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| 5. |
- Holmkvist, Alexander Dontsios, et al.
(författare)
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Local delivery of minocycline-loaded PLGA nanoparticles from gelatin-coated neural implants attenuates acute brain tissue responses in mice
- 2020
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Ingår i: Journal of Nanobiotechnology. - : Springer Science and Business Media LLC. - 1477-3155. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neural interfaces often elicit inflammatory responses and neuronal loss in the surrounding tissue which adversely affect the function and longevity of the implanted device. Minocycline, an anti-inflammatory pharmaceutics with neuroprotective properties, may be used for reducing the acute brain tissue responses after implantation. However, conventional administration routes require high doses which can cause adverse systemic side effects. Therefore, the aim of this study was to develop and evaluate a new drug-delivery-system for local and sustained administration of minocycline in the brain. Methods: Stainless steel needles insulated with Parylene-C were dip-coated with non-crosslinked gelatin and minocycline-loaded PLGA nanoparticles (MC-NPs) were incorporated into the gelatin-coatings by an absorption method and subsequently trapped by drying the gelatin. Parylene-C insulated needles coated only with gelatin were used as controls. The expression of markers for activated microglia (CD68), all microglia (CX3CR1-GFP), reactive astrocytes (GFAP), neurons (NeuN) and all cell nuclei (DAPI) surrounding the implantation sites were quantified at 3 and 7 days after implantation in mice. Results: MC-NPs were successfully incorporated into gelatin-coatings of neural implants by an absorption method suitable for thermosensitive drug-loads. Immunohistochemical analysis of the in vivo brain tissue responses, showed that MC-NPs significantly attenuate the activation of microglial cells without effecting the overall population of microglial cells around the implantation sites. A delayed but significant reduction of the astrocytic response was also found in comparison to control implants. No effect on neurons or total cell count was found which may suggest that the MC-NPs are non-toxic to the central nervous system. Conclusions: A novel drug-nanoparticle-delivery-system was developed for neural interfaces and thermosensitive drug-loads. The local delivery of MC-NPs was shown to attenuate the acute brain tissue responses nearby an implant and therefore may be useful for improving biocompatibility of implanted neuro-electronic interfaces. The developed drug-delivery-system may potentially also be used for other pharmaceutics to provide highly localized and therefore more specific effects as compared to systemic administration.
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| 6. |
- Kumosa, Lucas, et al.
(författare)
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Profound alterations in brain tissue linked to hypoxic episode after device implantation
- 2021
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Ingår i: Biomaterials. - : Elsevier BV. - 0142-9612. ; 278, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- To enable authentic interfacing with neuronal structures in the brain, preventing alterations of tissue during implantation of devices is critical. By transiently implanting oxygen microsensors into rat cortex cerebri for 2 h, substantial and long lasting (>1 h) hypoxia is routinely generated in surrounding tissues; this hypoxia is linked to implantation generated compressive forces. Preferential loss of larger neurons and reduced metabolic components in surviving neurons indicates decreased viability one week after such hypoxic, compressive implantations. By devising an implantation method that relaxes compressive forces; magnitude and duration of hypoxia generated following such an implantation are ameliorated and neurons appear similar to naïve tissues. In line with these observations, astrocyte proliferation was significantly more pronounced for more hypoxic, compressive implantations. Surprisingly, astrocyte processes were frequently found to traverse cellular boundaries into nearby neuronal nuclei, indicating injury induction of a previously not described astrocyte-neuron interaction. Found more frequently in less hypoxic, force-relaxed insertions and thus correlating to a more beneficial outcome, this finding may suggest a novel protective mechanism. In conclusion, substantial and long lasting insertion induced hypoxia around brain implants, a previously overlooked factor, is linked to significant adverse alterations in nervous tissue.
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| 7. |
- Lukoyanov, Nikolay, et al.
(författare)
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Endocrine signaling mediates asymmetric motor deficits after unilateral brain injury
- 2020
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- A paradigm in neurology is that brain injury-induced motor deficits (e.g. hemiparesis and hemiplegia) arise due to aberrant activity of descending neural pathways. We discovered that a unilateral injury of the hindlimb sensorimotor cortex of rats with completely transected thoracic spinal cord produces hindlimb postural asymmetry with contralateral flexion, and asymmetric changes in nociceptive hindlimb withdrawal reflexes and gene expression patterns in lumbar spinal cord. The injury-induced postural effects were abolished by prior hypophysectomy and were mimicked by transfusion of serum from animals with unilateral brain injury. Antagonists of the opioid and vasopressin receptors blocked formation of hindlimb postural asymmetry suggesting that these neurohormones mediate effects of brain injury on lateralized motor responses. Our data indicate that descending neural control of spinal circuits is complemented by a previously unknown humoral signaling from injured brain to the contra- and ipsilesional hindlimbs, and suggest the existence of a body side-specific neuroendocrine regulation in bilaterally symmetric animals.
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| 8. |
- Lukoyanov, Nikolay, et al.
(författare)
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Left-right side-specific endocrine signaling complements neural pathways to mediate acute asymmetric effects of brain injury
- 2021
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Brain injuries can interrupt descending neural pathways that convey motor commands from the cortex to spinal motoneurons. Here, we demonstrate that a unilateral injury of the hindlimb sensorimotor cortex of rats with completely transected thoracic spinal cord produces hindlimb postural asymmetry with contralateral flexion and asymmetric hindlimb withdrawal reflexes within 3 hr, as well as asymmetry in gene expression patterns in the lumbar spinal cord. The injury-induced postural effects were abolished by hypophysectomy and were mimicked by transfusion of serum from animals with brain injury. Administration of the pituitary neurohormones beta-endorphin or Arg-vasopressin-induced side-specific hindlimb responses in naive animals, while antagonists of the opioid and vasopressin receptors blocked hindlimb postural asymmetry in rats with brain injury. Thus, in addition to the well-established involvement of motor pathways descending from the brain to spinal circuits, the side-specific humoral signaling may also add to postural and reflex asymmetries seen after brain injury.
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| 9. |
- Lukoyanov, Nikolay, et al.
(författare)
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Left-right side-specific endocrine signaling complements neural pathways to mediate acute asymmetric effects of brain injury
- 2021
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Ingår i: eLife. - 2050-084X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Brain injuries can interrupt descending neural pathways that convey motor commands from the cortex to spinal motoneurons. Here, we demonstrate that a unilateral injury of the hindlimb sensorimotor cortex of rats with completely transected thoracic spinal cord produces hindlimb postural asymmetry with contralateral flexion and asymmetric hindlimb withdrawal reflexes within 3 hr, as well as asymmetry in gene expression patterns in the lumbar spinal cord. The injury-induced postural effects were abolished by hypophysectomy and were mimicked by transfusion of serum from animals with brain injury. Administration of the pituitary neurohormones b-endorphin or Arg-vasopressin-induced side-specific hindlimb responses in naive animals, while antagonists of the opioid and vasopressin receptors blocked hindlimb postural asymmetry in rats with brain injury. Thus, in addition to the well-established involvement of motor pathways descending from the brain to spinal circuits, the side-specific humoral signaling may also add to postural and reflex asymmetries seen after brain injury.
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| 10. |
- Mohammed, Mohsin, et al.
(författare)
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Ice coating –A new method of brain device insertion to mitigate acute injuries
- 2020
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Ingår i: Journal of Neuroscience Methods. - : Elsevier BV. - 0165-0270. ; 343
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Tidskriftsartikel (refereegranskat)abstract
- Background: Reduction of insertion injury is likely important to approach physiological conditions in the vicinity of implanted devices intended to interface with the surrounding brain. New methods: We have developed a novel, low-friction coating around frozen, gelatin embedded needles. By introducing a layer of thawing ice onto the gelatin, decreasing surface friction, we mitigate damage caused by the implantation. Results and comparison with existing methods: The acute effects of a transient stab on neuronal density and glial reactions were assessed 1 and 7 days post stab in rat cortex and striatum both within and outside the insertion track using immunohistochemical staining. The addition of a coat of melting ice to the frozen gelatin embedded needles reduced the insertion force with around 50 %, substantially reduced the loss neurons (i.e. reduced neuronal void), and yielded near normal levels of astrocytes within the insertion track 1 day after insertion, as compared to gelatin coated probes of the same temperature without ice coating. There were negligible effects on glial reactions and neuronal density immediately outside the insertion track of both ice coated and cold gelatin embedded needles. This new method of implantation presents a considerable improvement compared to existing modes of device insertion. Conclusions: Acute brain injuries following insertion of e.g. ultra-flexible electrodes, can be reduced by providing an outer coat of ultra-slippery thawing ice. No adverse effect of lowered implant temperature was found, opening the possibility of locking fragile electrode construct configurations in frozen gelatin, prior to implantation into the brain.
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