Investigation of non-invasive focused ultrasound efficacy on depressive-like behavior in hemiparkinsonian rats.

Depression is a common non-motor symptom in Parkinson's disease (PD) that includes anhedonia and impacts quality of life but is not effectively treated with conventional antidepressants clinically. Vagus nerve stimulation improves treatment-resistant depression in the general population, but research about its antidepressant efficacy in PD is limited. Here, we administered peripheral non-invasive focused ultrasound to hemiparkinsonian ('PD') and non-parkinsonian (sham) rats to mimic vagus nerve stimulation and assessed its antidepressant-like efficacy. Following 6-hydroxydopamine (6-OHDA) lesion, akinesia-like immobility was assessed in the limb-use asymmetry test, and despair- and anhedonic-like behaviors were evaluated in the forced swim test and sucrose preference test, respectively. After, tyrosine hydroxylase immuno-staining was employed to visualize and quantify dopaminergic degeneration in the substantia nigra pars compacta, ventral tegmental area, and striatum. We found that PD rats exhibited akinesia-like immobility and > 90% reduction in tyrosine hydroxylase immuno-staining ipsilateral to the lesioned side. PD rats also demonstrated anhedonic-like behavior in the sucrose preference test compared to sham rats. No 6-OHDA lesion effect on immobility in the forced swim test limited conclusions about the efficacy of ultrasound on despair-like behavior. However, ultrasound improved anhedonic-like behavior in PD rats and this efficacy was sustained through the end of the 1-week recovery period. The greatest number of animals demonstrating increased sucrose preference was in the PD group receiving ultrasound. Our findings here are the first to posit that peripheral non-invasive focused ultrasound to the celiac plexus may improve anhedonia in PD with further investigation needed to reveal its potential for clinical applicability.

Widespread alternative splicing dysregulation occurs presymptomatically in CAG expansion spinocerebellar ataxias.

The spinocerebellar ataxias (SCAs) are a group of dominantly inherited neurodegenerative diseases, several of which are caused by CAG expansion mutations (SCAs 1, 2, 3, 6, 7 and 12) and more broadly belong to the large family of over 40 microsatellite expansion diseases. While dysregulation of alternative splicing is a well defined driver of disease pathogenesis across several microsatellite diseases, the contribution of alternative splicing in CAG expansion SCAs is poorly understood. Furthermore, despite extensive studies on differential gene expression, there remains a gap in our understanding of presymptomatic transcriptomic drivers of disease. We sought to address these knowledge gaps through a comprehensive study of 29 publicly available RNA-sequencing datasets. We identified that dysregulation of alternative splicing is widespread across CAG expansion mouse models of SCAs 1, 3 and 7. These changes were detected presymptomatically, persisted throughout disease progression, were repeat length-dependent, and were present in brain regions implicated in SCA pathogenesis including the cerebellum, pons and medulla. Across disease progression, changes in alternative splicing occurred in genes that function in pathways and processes known to be impaired in SCAs, such as ion channels, synaptic signalling, transcriptional regulation and the cytoskeleton. We validated several key alternative splicing events with known functional consequences, including Trpc3 exon 9 and Kcnma1 exon 23b, in the Atxn1154Q/2Q mouse model. Finally, we demonstrated that alternative splicing dysregulation is responsive to therapeutic intervention in CAG expansion SCAs with Atxn1 targeting antisense oligonucleotide rescuing key splicing events. Taken together, these data demonstrate that widespread presymptomatic dysregulation of alternative splicing in CAG expansion SCAs may contribute to disease onset, early neuronal dysfunction and may represent novel biomarkers across this devastating group of neurodegenerative disorders.

Assessing the Location, Relative Expression and Subclass of Dopamine Receptors in the Cerebellum of Hemi-Parkinsonian Rats.

Parkinson's Disease (PD) is a neurodegenerative disease with loss of dopaminergic neurons in the nigrostriatal pathway resulting in basal ganglia (BG) dysfunction. This is largely why much of the preclinical and clinical research has focused on pathophysiological changes in these brain areas in PD. The cerebellum is another motor area of the brain. Yet, if and how this brain area responds to PD therapy and contributes to maintaining motor function fidelity in the face of diminished BG function remains largely unanswered. Limited research suggests that dopaminergic signaling exists in the cerebellum with functional dopamine receptors, tyrosine hydroxylase (TH) and dopamine transporters (DATs); however, much of this information is largely derived from healthy animals and humans. Here, we identified the location and relative expression of dopamine 1 receptors (D1R) and dopamine 2 receptors (D2R) in the cerebellum of a hemi-parkinsonian male rat model of PD. D1R expression was higher in PD animals compared to sham animals in both hemispheres in the purkinje cell layer (PCL) and granule cell layer (GCL) of the cerebellar cortex. Interestingly, D2R expression was higher in PD animals than sham animals mostly in the posterior lobe of the PCL, but no discernible pattern of D2R expression was seen in the GCL between PD and sham animals. To our knowledge, we are the first to report these findings, which may lay the foundation for further interrogation of the role of the cerebellum in PD therapy and/or pathophysiology.

The effects of low intensity focused ultrasound on neuronal activity in pain processing regions in a rodent model of common peroneal nerve injury.

BACKGROUND: Non-invasive, external low intensity focused ultrasound (liFUS) offers promise for treating neuropathic pain when applied to the dorsal root ganglion (DRG). OBJECTIVE: We examine how external liFUS treatment applied to the L5 DRG affects neuronal changes in single-unit activity from the primary somatosensory cortex (SI) and anterior cingulate cortex (ACC) in a common peroneal nerve injury (CPNI) rodent model. METHODS: Male Sprague Dawley rats were divided into two cohorts: CPNI liFUS and CPNI sham liFUS. Baseline single-unit activity (SUA) recordings were taken 20 min prior to treatment and for 4 h post treatment in 20 min intervals, then analyzed for frequency and compared to baseline. Recordings from the SI and ACC were separated into pyramidal and interneurons based on waveform and principal component analysis. RESULTS: Following CPNI surgery, all rats (n = 30) displayed a significant increase in mechanical sensitivity. In CPNI liFUS rats, there was a significant increase in pyramidal neuron spike frequency in the SI region compared to the CPNI sham liFUS animals beginning at 120 min following liFUS treatment (p < 0.05). In the ACC, liFUS significantly attenuated interneuron firing beginning at 80 min after liFUS treatment (p < 0.05). CONCLUSION: We demonstrate that liFUS changed neuronal spiking in the SI and ACC regions 80 and 120 min after treatment, respectively, which may in part correlate with improved sensory thresholds. This may represent a mechanism of action how liFUS attenuates neuropathic pain. Understanding the impact of liFUS on pain circuits will help advance the use of liFUS as a non-invasive neuromodulation option.

Group 2 innate lymphoid cells are numerically and functionally deficient in the triple transgenic mouse model of Alzheimer's disease.

BACKGROUND: The immune pathways in Alzheimer's disease (AD) remain incompletely understood. Our recent study indicates that tissue-resident group 2 innate lymphoid cells (ILC2) accumulate in the brain barriers of aged mice and that their activation alleviates aging-associated cognitive decline. The regulation and function of ILC2 in AD, however, remain unknown. METHODS: In this study, we examined the numbers and functional capability of ILC2 from the triple transgenic AD mice (3xTg-AD) and control wild-type mice. We investigated the effects of treatment with IL-5, a cytokine produced by ILC2, on the cognitive function of 3xTg-AD mice. RESULTS: We demonstrate that brain-associated ILC2 are numerically and functionally defective in the triple transgenic AD mouse model (3xTg-AD). The numbers of brain-associated ILC2 were greatly reduced in 7-month-old 3xTg-AD mice of both sexes, compared to those in age- and sex-matched control wild-type mice. The remaining ILC2 in 3xTg-AD mice failed to efficiently produce the type 2 cytokine IL-5 but gained the capability to express a number of proinflammatory genes. Administration of IL-5, a cytokine produced by ILC2, transiently improved spatial recognition and learning in 3xTg-AD mice. CONCLUSION: Our results collectively indicate that numerical and functional deficiency of ILC2 might contribute to the cognitive impairment of 3xTg-AD mice.

Motor Thalamic Deep Brain Stimulation Alters Cortical Activity and Shows Therapeutic Utility for Treatment of Parkinson's Disease Symptoms in a Rat Model.

Deep brain stimulation (DBS) in Parkinson's disease (PD) alters neuronal function and network communication to improve motor symptoms. The subthalamic nucleus (STN) is the most common DBS target for PD, but some patients experience adverse effects on memory and cognition. Previously, we reported that DBS of the ventral anterior (VA) and ventrolateral (VL) nuclei of the thalamus and at the interface between the two (VA|VL), collectively VA-VL, relieved forelimb akinesia in the hemiparkinsonian 6-hydroxydopamine (6-OHDA) rat model. To determine the mechanism(s) underlying VA-VL DBS efficacy, we examined how motor cortical neurons respond to VA-VL DBS using single-unit recording electrodes in anesthetized 6-OHDA lesioned rats. VA-VL DBS increased spike frequencies of primary (M1) and secondary (M2) motor cortical pyramidal cells and M2, but not M1, interneurons. To explore the translational merits of VA-VL DBS, we compared the therapeutic window, rate of stimulation-induced dyskinesia onset, and effects on memory between VA-VL and STN DBS. VA-VL and STN DBS had comparable therapeutic windows, induced dyskinesia at similar rates in hemiparkinsonian rats, and adversely affected performance in the novel object recognition (NOR) test in cognitively normal and mildly impaired sham animals. Interestingly, a subset of sham rats with VA-VL implants showed severe cognitive deficits with DBS off. VA-VL DBS improved NOR test performance in these animals. We conclude that VA-VL DBS may exert its therapeutic effects by increasing pyramidal cell activity in the motor cortex and interneuron activity in the M2, with plausible potential to improve memory in PD.

Non-invasive peripheral focused ultrasound neuromodulation of the celiac plexus ameliorates symptoms in a rat model of inflammatory bowel disease.

NEW FINDINGS: What is the central question of this study? Does peripheral non-invasive focused ultrasound targeted to the celiac plexus improve inflammatory bowel disease? What is the main finding and its importance? Peripheral non-invasive focused ultrasound targeted to the celiac plexus in a rat model of ulcerative colitis improved stool consistency and reduced stool bloodiness, which coincided with a longer and healthier colon than in animals without focused ultrasound treatment. The findings suggest that this novel neuromodulatory technology could serve as a plausible therapeutic approach for improving symptoms of inflammatory bowel disease. ABSTRACT: Individuals suffering from inflammatory bowel disease (IBD) experience significantly diminished quality of life. Here, we aim to stimulate the celiac plexus with non-invasive peripheral focused ultrasound (FUS) to modulate the enteric cholinergic anti-inflammatory pathway. This approach may have clinical utility as an efficacious IBD treatment given the non-invasive and targeted nature of this therapy. We employed the dextran sodium sulfate (DSS) model of colitis, administering lower (5%) and higher (7%) doses to rats in drinking water. FUS on the celiac plexus administered twice a day for 12 consecutive days to rats with severe IBD improved stool consistency scores from 2.2 ± 1 to 1.0 ± 0.0 with peak efficacy on day 5 and maximum reduction in gross bleeding scores from 1.8 ± 0.8 to 0.8 ± 0.8 on day 6. Similar improvements were seen in animals in the low dose DSS group, who received FUS only once daily for 12 days. Moreover, animals in the high dose DSS group receiving FUS twice daily maintained colon length (17.7 ± 2.5 cm), while rats drinking DSS without FUS exhibited marked damage and shortening of the colon (13.8 ± 0.6 cm) as expected. Inflammatory cytokines such as interleukin (IL)-1ß, IL-6, IL-17, tumour necrosis factor-α and interferon-γ were reduced with DSS but coincided with control levels after FUS, which is plausibly due to a loss of colon crypts in the former and healthier crypts in the latter. Lastly, overall, these results suggest non-invasive FUS of peripheral ganglion can deliver precision therapy to improve IBD symptomology.

Isovaline efficacy in a rat pup model of infantile spasms.

Infantile spasms, also known as epileptic spasms during infancy, is an epileptic disorder of infancy and early childhood that is associated with developmental delay or regression, high mortality rate and is difficult to treat with conventional antiseizure medication. Previously, we reported that a unique amino acid called isovaline had potent anticonvulsive efficacy in the 4-aminopyridine and pilocarpine rat models of seizures. In this study, we examined whether isovaline possess therapeutic utility in a well-established rat model of infantile spasms which involves the pretreatment of a pregnant dam with betamethasone and subsequent induction of spasms with N-methyl-D-asparate (NMDA), a glutamate receptor agonist, in 15-day old pups. We treated seven of these pups with saline prior to administering NMDA and eight of these pups with isovaline (300 mg/kg) intraperitoneal (i.p.) prior to NMDA. Isovaline significantly reduced the number of full-body jumps from 18.1 ± 5.0 to 6.3 ± 1.8 and leg/arm/tail strains from 4.4 ± 1.6 to 1.1 ± 0.5. A trend in a reduction of body twitch was noted in rat pups administered isovaline (P = 0.05), but no significant difference was seen in NMDA-induced head nods (P = 0.221). In conclusion, our data demonstrate a potential for isovaline to attenuate an aggressive form of epilepsy that typically requires highly toxic medications to treat in children.

Effects of subthalamic nucleus deep brain stimulation on neuronal spiking activity in the substantia nigra pars compacta in a rat model of Parkinson's disease.

Parkinson's Disease (PD) patients undergoing subthalamic nucleus deep brain stimulation (STN-DBS) therapy can reduce levodopa equivalent daily dose (LEDD) by approximately 50 %, leading to less symptoms of dyskinesia. The underlying mechanisms contributing to this reduction remain unclear, but studies posit that STN-DBS may increase striatal dopamine levels by exciting remaining dopaminergic cells in the substantia nigra pars compacta (SNc). Yet, no direct evidence has shown how SNc neuronal activity responds during STN-DBS in PD. Here, we use a hemiparkinsonian rat model of PD and employ in vivo electrophysiology to examine the effects of STN-DBS on SNc neuronal spiking activity. We found that 43 % of SNc neurons in naïve rats reduced their spiking frequency to 29.8 ± 18.5 % of baseline (p = 0.010). In hemiparkinsonian rats, a higher number of SNc neurons (88 % of recorded cells) decreased spiking frequency to 61.6 ± 4.4 % of baseline (p = 0.030). We also noted that 43 % of SNc neurons in naïve rats increased spiking frequency from 0.2 ± 0.0 Hz at baseline to 1.8 ± 0.3 Hz during stimulation, but only 1 SNc neuron from 1 hemiparkinsonian rat increased its spiking frequency by 12 % during STN-DBS. Overall, STN-DBS decreased spike frequency in the majority of recorded SNc neurons in a rat model of PD. Less homogenous responsiveness in directionality in SNc neurons during STN-DBS was seen in naive rats. Plausibly, poly-synaptic network signaling from STN-DBS may underlie these changes in SNc spike frequencies.

Use of Functional Magnetic Resonance Imaging to Assess How Motor Phenotypes of Parkinson's Disease Respond to Deep Brain Stimulation.

BACKGROUND: Deep brain stimulation (DBS) is a well-accepted treatment of Parkinson's disease (PD). Motor phenotypes include tremor-dominant (TD), akinesia-rigidity (AR), and postural instability gait disorder (PIGD). The mechanism of action in how DBS modulates motor symptom relief remains unknown. OBJECTIVE: Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to determine whether the functional activity varies in response to DBS depending on PD phenotypes. MATERIALS AND METHODS: Subjects underwent an fMRI scan with DBS cycling ON and OFF. The effects of DBS cycling on BOLD activation in each phenotype were documented through voxel-wise analysis. For each region of interest, ANOVAs were performed using T-values and covariate analyses were conducted. Further, a correlation analysis was performed comparing stimulation settings to T-values. Lastly, T-values of subjects with motor improvement were compared to those who worsened. RESULTS: As a group, BOLD activation with DBS-ON resulted in activation in the motor thalamus (p < 0.01) and globus pallidus externa (p < 0.01). AR patients had more activation in the supplementary motor area (SMA) compared to PIGD (p < 0.01) and TD cohorts (p < 0.01). Further, the AR cohort had more activation in primary motor cortex (MI) compared to the TD cohort (p = 0.02). Implanted nuclei (p = 0.01) and phenotype (p = <0.01) affected activity in MI and phenotype alone affected SMA activity (p = <0.01). A positive correlation was seen between thalamic activation and pulse-width (p = 0.03) and between caudate and total electrical energy delivered (p = 0.04). CONCLUSIONS: These data suggest that DBS modulates network activity differently based on patient motor phenotype. Improved understanding of these differences may further our knowledge about the mechanisms of DBS action on PD motor symptoms and to optimize treatment.

Effects of external low intensity focused ultrasound on electrophysiological changes in vivo in a rodent model of common peroneal nerve injury.

Non-invasive treatment methods for neuropathic pain are lacking. We assess how modulatory low intensity focused ultrasound (liFUS) at the L5 dorsal root ganglion (DRG) affects behavioral responses and sensory nerve action potentials (SNAPs) in a common peroneal nerve injury (CPNI) model. Rats were assessed for mechanical and thermal responses using Von Frey filaments (VFF) and the hot plate test (HPT) following CPNI surgery. Testing was repeated 24 h after liFUS treatment. Significant increases in mechanical and thermal sensory thresholds were seen post-liFUS treatment, indicating a reduction in sensitivity to pain (p < 0.0001, p = 0.02, respectively). Animals who received CPNI surgery had significant increases in SNAP latencies compared to sham CPNI surgery animals (p = 0.0003) before liFUS treatment. LiFUS induced significant reductions in SNAP latency in both CPNI liFUS and sham CPNI liFUS cohorts, for up to 35 min post treatment. No changes were seen in SNAP amplitude and there was no evidence of neuronal degeneration 24 h after liFUS treatment, showing that liFUS did not damage the tissue being modulated. This is the first in vivo study of the impact of liFUS on peripheral nerve electrophysiology in a model of chronic pain. This study demonstrates the effects of liFUS on peripheral nerve electrophysiology in vivo. We found that external liFUS treatment results in transient decreased latency in common peroneal nerve (CPN) sensory nerve action potentials (SNAPs) with no change in signal amplitude.

Deep brain stimulation of the ventroanterior and ventrolateral thalamus improves motor function in a rat model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease with affected individuals exhibiting motor symptoms of bradykinesia, muscle rigidity, tremor, postural instability and gait dysfunction. The current gold standard treatment is pharmacotherapy with levodopa, but long-term use is associated with motor response fluctuations and can cause abnormal movements called dyskinesias. An alternative treatment option is deep brain stimulation (DBS) with the two FDA-approved brain targets for PD situated in the basal ganglia; specifically, in the subthalamic nucleus (STN) and globus pallidus pars interna (GPi). Both improve quality of life and motor scores by ~50-70% in well-selected patients but can also elicit adverse effects on cognition and other non-motor symptoms. Therefore, identifying a novel DBS target that is efficacious for patients not optimally responsive to current DBS targets with fewer side-effects has clear clinical merit. Here, we investigate whether the ventroanterior (VA) and ventrolateral (VL) motor nuclei of the thalamus can serve as novel and effective DBS targets for PD. In the limb-use asymmetry test (LAT), hemiparkinsonian rats showcased left forelimb akinesia and touched only 6.5 ±â€¯1.3% with that paw. However, these animals touched equally with both forepaws with DBS at 10 Hz, 100 µsec pulse width and 100 uA cathodic stimulation in the VA (n = 7), VL (n = 8) or at the interface between the two thalamic nuclei which we refer to as the VA|VL (n = 12). With whole-cell patch-clamp recordings, we noted that VA|VL stimulation in vitro increased the number of induced action potentials in proximal neurons in both areas albeit VL neurons transitioned from bursting to non-bursting action potentials (APs) with large excitatory postsynaptic potentials time-locked to stimulation. In contrast, VA neurons were excited with VA|VL electrical stimulation but with little change in spiking phenotype. Overall, our findings show that DBS in the VA, VL or VA|VL improved motor function in a rat model of PD; plausibly via increased excitation of residing neurons.

Effects of subthalamic deep brain stimulation with gabapentin and morphine on mechanical and thermal thresholds in 6-hydroxydopamine lesioned rats.

Chronic pain is the most common non-motor symptom among Parkinson's disease (PD) patients, with 1.85 million estimated to be in debilitating pain by 2030. Subthalamic deep brain stimulation (STN DBS) programmed for treating PD motor symptoms has also been shown to significantly improve pain scores. However, even though most patients' pain symptoms improve or disappear, 74% of patients treated develop new pain symptoms within 8 years. Previously we have shown that duloxetine and STN high frequency stimulation (HFS) significantly increase mechanical thresholds more than either alone. The current project specifically investigates the effects of gabapentin and morphine alone and with high (150 Hz; HFS) and low (50 Hz; LFS) frequency stimulation in the 6-hydroxydopamine rat model for PD. We found that HFS, LFS, gabapentin 15 mg/kg and morphine 1 mg/kg all independently improve von Frey (VF) thresholds. Neither drug augments the HFS response significantly. Morphine at 1 mg/kg showed a trend to increasing thresholds compared to LFS alone (p = 0.062). Interestingly, gabapentin significantly reduced (p = 0.019) the improved VF thresholds and Randall Selitto thresholds seen with LFS. Thus, though neither drug augments DBS, we found effects of both compounds independently increase VF thresholds, informing use of our model of chronic pain in PD. Gabapentin's reversal of LFS effects warrants further exploration.

The use of focused ultrasound for the treatment of cutaneous allodynia associated with chronic migraine.

Chronic migraines (CM) are the third most common disease and are refractory to medical treatment in 15% of patients. Currently, temporary relief is achieved with steroid blocks or pulsed radiofrequency ablation, which have short-term benefits. Our project aims to develop a non-invasive treatment for medically refractory chronic migraine, which does not require a permanent implant. This project investigates the safety and effectiveness of pulsed focused ultrasound (FUS) in a validated rodent headache model of cutaneous allodynia associated with chronic migraine (CM) as compared to sumatriptan and ablative lesioning. We demonstrate a significant reduction in mechanical thresholds as measured through Von Frey filaments in CM in the forepaw and periorbital region (p < 0.001). Sumatriptan and pulsed FUS both significantly improve thresholds at day 3 after treatment in the periorbital region. Ablative lesioning has no effect. This study provides initial evidence that FUS may provide an important therapeutic option for patients suffering from CM.

Ventral pallidum deep brain stimulation attenuates acute partial, generalized and tonic-clonic seizures in two rat models.

Approximately 30% of individuals with epilepsy are refractory to antiepileptic drugs and currently approved neuromodulatory approaches fall short of providing seizure freedom for many individuals with limited utility for generalized seizures. Here, we expand on previous findings and investigate whether ventral pallidum deep brain stimulation (VP-DBS) can be efficacious for various acute seizure phenotypes. For rats administered pilocarpine, we found that VP-DBS (50 Hz) decreased generalized stage 4/5 seizure median frequency from 9 to 6 and total duration from 1667 to 264 s even after generalized seizures emerged. The transition to brainstem seizures was prevented in almost all animals. VP-DBS immediately after rats exhibited their first partial forebrain stage 3 seizure did not affect the frequency of partial seizures but reduced median partial seizure duration from 271 to 54 s. Stimulation after partial seizures also reduced the occurrence and duration of secondarily generalized stage 4/5 seizures. VP-DBS prior to pilocarpine administration prevented the appearance of partial seizures in almost all animals. Lastly, VP-DBS delayed the onset of generalized tonic-clonic seizures (GTCSs) from 111 to 823 s in rats administered another chemoconvulsant, pentylenetetrazol (PTZ, 90 mg/kg). In this particular rat seizure model, stimulating electrodes placed more laterally in both VP hemispheres and more posterior in the left VP hemisphere provided greatest efficacy for GTCSs. In conclusion, our findings posit that VP-DBS can serve as an effective novel neuromodulatory approach for a variety of acute seizure phenotypes.

Effect of Eye Opening on Single-Unit Activity and Local Field Potentials in the Subthalamic Nucleus.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN DBS) is an established treatment in Parkinson's disease (PD). We investigate the effect of eye opening on neuronal activity and local field potentials (LFPs) in the STN. METHODS: We prospectively enrolled 25 PD patients undergoing STN DBS in our institution. During DBS, single-unit activity (SUA) and LFPs were measured when eyes were open and closed. As movement is known to result in changes in LFPs, we tested response to eye opening in the presence and absence of movement. RESULTS: Neither eye state nor arm movement has a significant influence on SUA recordings. There is a statistically significant interaction between eye state and arm movement (p < 0.05). In the presence of movement, STN SUA increase when eyes open (p < 0.05). When eyes are closed, STN SUA decrease with movement (p < 0.05). STN theta LFP oscillations decrease when eyes are open compared to closed, irrespective of movement status (p < 0.05). DISCUSSION: STN activity is influenced by eye state and arm movement. It is unclear whether this is attributed to a change in the STN's role in oculomotor control or from a change in attentional state. Understanding how physiologic normal activity alters neural activity is critical for the optimization of DBS therapy, particularly in closed-loop neuromodulation.

Occipital Nerve Stimulation Attenuates Neuronal Firing Response to Mechanical Stimuli in the Ventral Posteromedial Thalamus of a Rodent Model of Chronic Migraine.

BACKGROUND: Chronic migraine (CM) is a highly debilitating disease, and many patients remain refractory to medicinal therapy. Given the convergent nature of neuronal networks in the ventral posteromedial nucleus (VPM) and the evidence of sensitization of pain circuitry in this disease, we hypothesize CM rats will have increased VPM neuronal firing, which can be attenuated using occipital nerve stimulation (ONS). OBJECTIVE: To determine whether VPM firing frequency differs between CM and sham rats, and whether ONS significantly alters firing rates during the application of mechanical stimuli. METHODS: Fourteen male Sprague-Dawley rats were infused with inflammatory media once daily through an epidural cannula for 2 wk to induce a CM state. Sham animals (n = 6) underwent cannula surgery but received no inflammatory media. ONS electrodes were implanted bilaterally and single-unit recordings were performed in the VPM of anesthetized rats during mechanical stimulation of the face and forepaw in the presence and absence of ONS. RESULTS: CM rats had significantly higher neuronal firing rates (P < .001) and bursting activity (P < .01) in response to mechanical stimuli when compared to shams. ONS significantly reduced neuronal firing in the VPM of CM rats during the application of 0.8 g (P = .04), 4.0 g (P = .04), and 15.0 g (P = .02) Von Frey filaments. ONS reduced bursting activity in CM rats during the 4.0 and 15 g filaments (P < .05). No significant changes in bursting activity or firing frequency were noted in sham animals during ONS. CONCLUSION: We demonstrate that neuronal spike frequencies and bursting activity in the VPM are increased in an animal model of CM compared to shams. Our results suggest that the mechanism of ONS may involve attenuation of neurons in the VPM of CM rats during the application of mechanical stimuli.

Effect of diazepam and yohimbine on neuronal activity in sham and hemiparkinsonian rats.

The prefrontal cortex and the amygdala are critical for the emotional guidance of behavior and are believed to be a site of action for many anxiolytics and anxiogenics. Despite extensive studies examining how these drugs affect behavior, there is little information regarding their effects on neuronal activity. Additionally, with recent recognition of anxiety as a non-motor symptom of Parkinson's disease, it is unknown if activity in the cortex and the amygdala is altered. Previously, we reported that hemiparkinsonian rats had higher baseline anxiety-like behavior and diminished responsiveness to the acute anxiolytic, diazepam. In contrast, sham-lesioned rats exhibited anxiolytic behavior to diazepam. In this study, we monitored in vivo single-unit spiking activity simultaneously from the anterior cingulate cortex (ACC) and the basolateral amygdala (BLA) in anesthetized sham-lesioned and hemiparkinsonian rats to unmask neuro-circuits underpinning the difference in diazepam responsiveness. We found that baseline spiking activity in the ACC was the same in both sham and hemiparkinsonian rats. We also noted a similar phenomenon for baseline activity in the BLA between sham and hemiparkinsonian rats. However, neuronal spiking activity after diazepam administration (1.5mg/kg, SubQ) was lower than in controls in the ACC of sham-lesioned rats whereas no difference was noted after diazepam treatment in hemiparkinsonian rats. BLA neuronal spiking activity was unaffected by diazepam administration in either animal group. On the other hand, yohimbine treatment (5mg/kg, SubQ) coincided with lower neuronal spiking activity compared to controls in the BLA of sham-lesioned rats, but was unchanged from controls in hemiparkinsonian rats. Yohimbine did not affect ACC neuronal spiking activity in either group. Overall, the lack of ACC responsiveness to diazepam in hemiparkinsonian, but not sham-lesioned rats underscores a plausible fundamental difference in anxiety-related neural signaling between animal groups.

Effects of subthalamic deep brain stimulation with duloxetine on mechanical and thermal thresholds in 6OHDA lesioned rats.

Chronic pain is the most common non-motor symptom of Parkinson's disease (PD) and is often overlooked. Unilateral 6-hydroxydopamine (6-OHDA) medial forebrain bundle lesioned rats used as models for PD exhibit decreased sensory thresholds in the left hindpaw. Subthalamic deep brain stimulation (STN DBS) increases mechanical thresholds and offers improvements with chronic pain in PD patients. However, individual responses to STN high frequency stimulation (HFS) in parkinsonian rats vary with 58% showing over 100% improvement, 25% showing 30-55% improvement, and 17% showing no improvement. Here we augment STN DBS by supplementing with a serotonin-norepinephrine reuptake inhibitor commonly prescribed for pain, duloxetine. Duloxetine was administered intraperitoneally (30mg/kg) in 15 parkinsonian rats unilaterally implanted with STN stimulating electrodes in the lesioned right hemisphere. Sensory thresholds were tested using von Frey, Randall-Selitto and hot-plate tests with or without duloxetine, and stimulation to the STN at HFS (150Hz), low frequency (LFS, 50Hz), or off stimulation. With HFS or LFS alone (left paw; p=0.016; p=0.024, respectively), animals exhibited a higher mechanical thresholds stable in the three days of testing, but not with duloxetine alone (left paw; p=0.183). Interestingly, the combination of duloxetine and HFS produced significantly higher mechanical thresholds than duloxetine alone (left paw, p=0.002), HFS alone (left paw, p=0.028), or baseline levels (left paw; p<0.001). These findings show that duloxetine paired with STN HFS increases mechanical thresholds in 6-OHDA-lesioned animals more than either treatment alone. It is possible that duloxetine augments STN DBS with a central and peripheral additive effect, though a synergistic mechanism has not been excluded.