ItemVagus Nerve Stimulation Promotes Generalization of Conditioned Fear Extinction and Reduces Anxiety in Rats(Elsevier Science Inc, 2018-09-21) Noble, Lindsey J.; Meruva, Venkat B.; Hays, Seth A.; Rennaker, Robert L.; Kilgard, Michael P.; McIntyre, Christa K.; 0000-0003-4225-241X (Hays, SA); 13146094343400332984 (Hays, SA); Noble, Lindsey J.; Meruva, Venkat B.; Hays, Seth A.; Rennaker, Robert L.; Kilgard, Michael P.; McIntyre, Christa K.Background: Exposure-based therapies are used to treat a variety of trauma- and anxiety-related disorders by generating successful extinction following cue exposure during treatment. The development of adjuvant strategies that accelerate extinction learning, improve tolerability, and increase efficiency of treatment could increase the efficacy of exposure-based therapies. Vagus nerve stimulation (VNS) paired with exposure can enhance fear extinction, in rat models of psychiatric disorders, and chronic administration of VNS reduces anxiety in rats and humans. Objective: We tested whether VNS, like other cognitive enhancers, could produce generalization of extinction for stimuli that are not presented during the extinction sessions, but are associated with the fear event. Methods: Male Sprague Dawley rats underwent auditory fear conditioning with two easily discriminable auditory stimuli. Following fear conditioning, extinction training consisted of exposure to only one of the conditioned sounds. Half of the rats received VNS and half received sham stimulation during with sound presentations. VNS effects on anxiety were examined in a separate study where VNS was administered prior to testing on the elevated plus maze. Results: Sham stimulated rats given 20 presentations of a conditioned stimulus (CS) during the extinction session showed performance that was matched to VNS-treated rats given only 4 presentations of the CS. Despite comparable levels of freezing to the presented CS, only the VNS-treated rats showed a significant decrease in freezing to the CS that was not presented. VNS-induced generalization of extinction was observed only when the two sounds were paired with footshock within the same fear conditioning session; VNS did not promote generalization of extinction when the two sounds were conditioned on different days or in different contexts. On the anxiety test, VNS administration significantly increased time spent in the open arms of the elevated plus maze. Conclusion: These results provide evidence that VNS can promote generalization of extinction to other stimuli associated with a specific fear experience. Furthermore, non-contingent VNS appears to reduce anxiety. The ability to generalize extinction and reduce anxiety makes VNS a potential candidate for use as an adjunctive strategy to improve the efficacy and tolerability of exposure-based therapies. ItemNorepinephrine and Serotonin are Required for Vagus Nerve Stimulation Directed Cortical Plasticity(Academic Press Inc., 2019-06-07) Hulsey, Daniel R.; Shedd, Cristine M.; Sarker, Sadmaan F.; Kilgard, Michael P.; Hays, Seth A.; 0000-0003-4225-241X (Hays, SA); 13146094343400332984 (Hays, SA); Hulsey, Daniel R.; Shedd, Cristine M.; Sarker, Sadmaan F.; Kilgard, Michael P.; Hays, Seth A.Vagus nerve stimulation (VNS) paired with forelimb training drives robust, specific reorganization of movement representations in the motor cortex. This effect is hypothesized to be mediated by VNS-dependent engagement of neuromodulatory networks. VNS influences activity in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), but the involvement of these neuromodulatory networks in VNS-directed plasticity is unknown. We tested the hypothesis that cortical norepinephrine and serotonin are required for VNS-dependent enhancement of motor cortex plasticity. Rats were trained on a lever pressing task emphasizing proximal forelimb use. Once proficient, all rats received a surgically implanted vagus nerve cuff and cortical injections of either immunotoxins to deplete serotonin or norepinephrine, or vehicle control. Following surgical recovery, rats received half second bursts of 0.8 mA or sham VNS after successful trials. After five days of pairing intracortical microstimulation (ICMS) was performed in the motor cortex contralateral to the trained limb. VNS paired with training more than doubled cortical representations of proximal forelimb movements. Depletion of either cortical norepinephrine or serotonin prevented this effect. The requirement of multiple neuromodulators is consistent with earlier studies showing that these neuromodulators regulate synaptic plasticity in a complimentary fashion. ©2019 Elsevier Inc. ItemVagus Nerve Stimulation Reverses the Extinction Impairments in a Model of PTSD with Prolonged and Repeated Trauma(Taylor and Francis Ltd, 2019-04-23) Souza, Rimenez R.; Robertson, Nicole M.; Pruitt, David T.; Gonzales, Phillip A.; Hays, Seth A.; Rennaker, Robert L.; Kilgard, Michael P.; McIntyre, Crista K.; 0000-0003-4225-241X (Hays, SA); 13146094343400332984 (Hays, SA); Souza, Rimenez R.; Robertson, Nicole M.; Pruitt, David T.; Gonzales, Phillip A.; Hays, Seth A.; Rennaker, Robert L.; Kilgard, Michael P.; McIntyre, Crista K.We have shown that vagus nerve stimulation (VNS) enhances extinction of conditioned fear and reduces anxiety in rat models of PTSD using moderate stress. However, it is still unclear if VNS can be effective in enhancing extinction of severe fear after prolonged and repeated trauma. Severe fear was induced in adult male rats by combining single prolonged stress (SPS) and protracted aversive conditioning (PAC). After SPS and PAC procedures, rats were implanted with stimulating cuff electrodes, exposed to five days of extinction training with or without VNS, and then tested for extinction retention, return of fear in a new context and reinstatement. The elevated plus maze, open field and startle were used to test anxiety. Sham rats showed no reduction of fear during extensive extinction training. VNS-paired with extinction training reduced freezing at the last extinction session by 70% compared to sham rats. VNS rats exhibited half as much fear as shams, as well as less fear renewal. Sham rats exhibited significantly more anxiety than naive controls, whereas VNS rats did not. These results demonstrate that VNS enhances extinction and reduces anxiety in a severe model of PTSD that combined SPS and a conditioning procedure that is 30 times more intense than the conditioning procedures in previous VNS studies. The broad utility of VNS in enhancing extinction learning in rats and the strong clinical safety record of VNS suggest that VNS holds promise as an adjuvant to exposure-based therapy in people with PTSD and other complex forms of this condition. ©2019 Informa UK Limited, trading as Taylor & Francis Group. ItemEnhancing Plasticity in Central Networks Improves Motor and Sensory Recovery after Nerve Damage(Springer Nature, 2019-12-19) Meyers, Eric C.; Kasliwal, Nimit; Solorzano, Bleyda R.; Lai, Elaine; Bendale, Geetanjali; Berry, Abigail; Ganzer, Patrick D.; Romero-Ortega, Mario; Rennaker, Robert L.; Kilgard, Michael P.; Hays, Seth A.; 0000-0002-2013-5450 (Meyers, EC); 0000-0001-6314-9062 (Kasliwal, N); 0000-0003-2576-2629 (Romero-Ortega, M); 0000-0003-4225-241X (Hays, SA); Meyers, Eric C.; Kasliwal, Nimit; Solorzano, Bleyda R.; Lai, Elaine; Bendale, Geetanjali; Berry, Abigail; Ganzer, Patrick D.; Romero-Ortega, Mario; Rennaker, Robert L.; Kilgard, Michael P.; Hays, Seth A.Nerve damage can cause chronic, debilitating problems including loss of motor control and paresthesia, and generates maladaptive neuroplasticity as central networks attempt to compensate for the loss of peripheral connectivity. However, it remains unclear if this is a critical feature responsible for the expression of symptoms. Here, we use brief bursts of closed-loop vagus nerve stimulation (CL-VNS) delivered during rehabilitation to reverse the aberrant central plasticity resulting from forelimb nerve transection. CL-VNS therapy drives extensive synaptic reorganization in central networks paralleled by improved sensorimotor recovery without any observable changes in the nerve or muscle. Depleting cortical acetylcholine blocks the plasticity-enhancing effects of CL-VNS and consequently eliminates recovery, indicating a critical role for brain circuits in recovery. These findings demonstrate that manipulations to enhance central plasticity can improve sensorimotor recovery and define CL-VNS as a readily translatable therapy to restore function after nerve damage. ItemA Suite of Automated Tools to Quantify Hand and Wrist Motor Function after Cervical Spinal Cord Injury(BioMed Central Ltd.) Grasse, Katelyn M.; Hays, Seth A.; Rahebi, Kimiya C.; Warren, Victoria S.; Garcia, Elizabeth A.; Wigginton, Jane G.; Kilgardi Mchael P.; Rennaker, Robert L.; 0000-0003-4225-241X (Hays, SA); 13146094343400332984 (Hays, SA); Grasse, Katelyn M.; Hays, Seth A.; Rahebi, Kimiya C.; Warren, Victoria S.; Garcia, Elizabeth A.; Wigginton, Jane G.; Kilgard, Michael P.; Rennaker, Robert L.Background: Cervical spinal cord injury (cSCI) often causes chronic upper extremity disability. Reliable measurement of arm function is critical for development of therapies to improve recovery after cSCI. In this study, we report a suite of automated rehabilitative tools to allow simple, quantitative assessment of hand and wrist motor function. Methods: We measured range of motion and force production using these devices in cSCI participants with a range of upper limb disability and in neurologically intact participants at two time points separated by approximately 4 months. Additionally, we determined whether measures collected with the rehabilitative tools correlated with standard upper limb assessments, including the Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP) and the Jebsen Hand Function Test (JHFT). Results: We find that the rehabilitative devices are useful to provide assessment of upper limb function in physical units over time in SCI participants and are well-correlated with standard assessments. Conclusions: These results indicate that these tools represent a reliable system for longitudinal evaluation of upper extremity function after cSCI and may provide a framework to assess the efficacy of strategies aimed at improving recovery of upper limb function. ©2019 The Author(s). ItemVagus Nerve Stimulation Rate and Duration Determine Whether Sensory Pairing Produces Neural Plasticity(Elsevier Ltd) Buell, Elizabeth P.; Borland, Michael S.; Loerwald, Kristopher W.; Chandler, Collin; Hays, Seth A.; Engineer, Crystal T.; Kilgard, Michael P.; 0000-0003-4225-241X (Hays, SA); 13146094343400332984 (Hays, SA); Buell, Elizabeth P.; Borland, Michael S.; Loerwald, Kristopher W.; Chandler, Collin; Hays, Seth A.; Engineer, Crystal T.; Kilgard, Michael P.Repeatedly pairing a brief train of vagus nerve stimulation (VNS) with an auditory stimulus drives reorganization of primary auditory cortex (A1), and the magnitude of this VNS-dependent plasticity is dependent on the stimulation parameters, including intensity and pulse rate. However, there is currently little data to guide the selection of VNS train durations, an easily adjusted parameter that could influence the effect of VNS-based therapies. Here, we tested the effect of varying the duration of the VNS train on the extent of VNS-dependent cortical plasticity. Rats were exposed to a 9 kHz tone 300 times per day for 20 days. Coincident with tone presentation, groups received trains of 4, 16, or 64 pulses of VNS delivered at 30 Hz, corresponding to train durations of 0.125 s, 0.5 s, and 2.0 s, respectively. High-density microelectrode mapping of A1 revealed that 0.5 s duration VNS trains significantly increased the number of neurons in A1 that responded to tones near the paired tone frequency. Trains lasting 0.125 or 2.0 s failed to alter A1 responses, indicating that both shorter and longer stimulation durations are less effective at enhancing plasticity. A second set of experiments evaluating the effect of delivering 4 or 64 pulses in a fixed 0.5 s VNS train duration paired with tone presentation reveal that both slower and faster stimulation rates are less effective at enhancing plasticity. We incorporated these results with previous findings describing the effect of stimulation parameters on VNS-dependent plasticity and activation of neuromodulatory networks to generate a model of synaptic activation by VNS. ©2019 Elsevier Ltd ItemCortical Map Plasticity as a Function of Vagus Nerve Stimulation Rate(Elsevier Inc.) Buell, Elizabeth P.; Loerwald, Kristofer W.; Engineer, Crystal T.; Borland, Michael S .; Buell, John M.; Kelly, C. A.; Khan, I. I.; Hays, Seth A.; Kilgard, Michael P.; Buell, Elizabeth P.; Loerwald, Kristofer W.; Engineer, Crystal T.; Borland, Michael S .; Buell, John M.; Kelly, C. A.; Khan, I. I.; Hays, Seth A.; Kilgard, Michael P.Background: Repeatedly pairing a brief train of vagus nerve stimulation (VNS) with an external event can reorganize the sensory or motor cortex. A 30 Hz train of sixteen VNS pulses paired with a tone significantly increases the number of neurons in primary auditory cortex (A1) that respond to tones near the paired tone frequency. The effective range of VNS pulse rates for driving cortical map plasticity has not been defined. Objective/Hypothesis: This project investigated the effects of VNS rate on cortical plasticity. We expected that VNS pulse rate would affect the degree of plasticity caused by VNS-tone pairing. Methods: Rats received sixteen pulses of VNS delivered at a low (7.5 Hz), moderate (30 Hz), or high (120 Hz) rate paired with 9 kHz tones 300 times per day over a 20 day period. Results: More A1 neurons responded to the paired tone frequency in rats from the moderate rate VNS group compared to naïve controls. The response strength was also increased in these rats. In contrast, rats that received high or low rate VNS failed to exhibit a significant increase in the number of neurons tuned to sounds near 9 kHz. Conclusion: Our results demonstrate that the degree of cortical plasticity caused by VNS-tone pairing is an inverted-U function of VNS pulse rate. The apparent high temporal precision of VNS-tone pairing helps identify optimal VNS parameters to achieve the beneficial effects from restoration of sensory or motor function. ItemClosed-Loop Neuromodulation Restores Network Connectivity and Motor Control After Spinal Cord Injury(eLife Sciences Publications Ltd) Ganzer, Patrick D.; Darrow, Michael J.; Meyers, Eric C.; Solorzano, Bleyda R.; Ruiz, Andrea D.; Robertson, Nicole M.; Adcock, Katherine S.; James, Justin T.; Jeong, Han S.; Becker, April M.; Goldberg, Mark P.; Pruitt, David T.; Hays, Seth A.; Kilgard, Michael P.; Rennaker, Robert L. II; Ganzer, Patrick D.; Darrow, Michael J.; Meyers, Eric C.; Solorzano, Bleyda R.; Ruiz, Andrea D.; Robertson, Nicole M.; Adcock, Katherine S.; James, Justin T.; Jeong, Han S.; Pruitt, David T.; Hays, Seth A.; Kilgard, Michael P.; Rennaker, Robert L. IIRecovery from serious neurological injury requires substantial rewiring of neural circuits. Precisely-timed electrical stimulation could be used to restore corrective feedback mechanisms and promote adaptive plasticity after neurological insult, such as spinal cord injury (SCI) or stroke. This study provides the first evidence that closed-loop vagus nerve stimulation (CLV) based on the synaptic eligibility trace leads to dramatic recovery from the most common forms of SCI. The addition of CLV to rehabilitation promoted substantially more recovery of forelimb function compared to rehabilitation alone following chronic unilateral or bilateral cervical SCI in a rat model. Triggering stimulation on the most successful movements is critical to maximize recovery. CLV enhances recovery by strengthening synaptic connectivity from remaining motor networks to the grasping muscles in the forelimb. The benefits of CLV persist long after the end of stimulation because connectivity in critical neural circuits has been restored.