Restoration of Kv7 Channel-Mediated Inhibition Reduces Cued-Reinstatement of Cocaine Seeking.

Cocaine addicts display increased sensitivity to drug-associated cues, due in part to changes in the prelimbic prefrontal cortex (PL-PFC). The cellular mechanisms underlying cue-induced reinstatement of cocaine seeking remain unknown. Reinforcement learning for addictive drugs may produce persistent maladaptations in intrinsic excitability within sparse subsets of PFC pyramidal neurons. Using a model of relapse in male rats, we sampled >600 neurons to examine spike frequency adaptation (SFA) and afterhyperpolarizations (AHPs), two systems that attenuate low-frequency inputs to regulate neuronal synchronization. We observed that training to self-administer cocaine or nondrug (sucrose) reinforcers decreased SFA and AHPs in a subpopulation of PL-PFC neurons. Only with cocaine did the resulting hyperexcitability persist through extinction training and increase during reinstatement. In neurons with intact SFA, dopamine enhanced excitability by inhibiting Kv7 potassium channels that mediate SFA. However, dopamine effects were occluded in neurons from cocaine-experienced rats, where SFA and AHPs were reduced. Pharmacological stabilization of Kv7 channels with retigabine restored SFA and Kv7 channel function in neuroadapted cells. When microinjected bilaterally into the PL-PFC 10 min before reinstatement testing, retigabine reduced cue-induced reinstatement of cocaine seeking. Last, using cFos-GFP transgenic rats, we found that the loss of SFA correlated with the expression of cFos-GFP following both extinction and re-exposure to drug-associated cues. Together, these data suggest that cocaine self-administration desensitizes inhibitory Kv7 channels in a subpopulation of PL-PFC neurons. This subpopulation of neurons may represent a persistent neural ensemble responsible for driving drug seeking in response to cues.SIGNIFICANCE STATEMENT Long after the cessation of drug use, cues associated with cocaine still elicit drug-seeking behavior, in part by activation of the prelimbic prefrontal cortex (PL-PFC). The underlying cellular mechanisms governing these activated neurons remain unclear. Using a rat model of relapse to cocaine seeking, we identified a population of PL-PFC neurons that become hyperexcitable following chronic cocaine self-administration. These neurons show persistent loss of spike frequency adaptation, reduced afterhyperpolarizations, decreased sensitivity to dopamine, and reduced Kv7 channel-mediated inhibition. Stabilization of Kv7 channel function with retigabine normalized neuronal excitability, restored Kv7 channel currents, and reduced drug-seeking behavior when administered into the PL-PFC before reinstatement. These data highlight a persistent adaptation in a subset of PL-PFC neurons that may contribute to relapse vulnerability.

Use of imperceptible wrist vibration to modulate sensorimotor cortical activity.

Peripheral sensory stimulation has been used as a method to stimulate the sensorimotor cortex, with applications in neurorehabilitation. To improve delivery modality and usability, a new stimulation method has been developed in which imperceptible random-frequency vibration is applied to the wrist concurrently during hand activity. The objective of this study was to investigate effects of this new sensory stimulation on the sensorimotor cortex. Healthy adults were studied. In a transcranial magnetic stimulation (TMS) study, resting motor threshold, short-interval intracortical inhibition, and intracortical facilitation for the abductor pollicis brevis muscle were compared between vibration on vs. off, while subjects were at rest. In an electroencephalogram (EEG) study, alpha and beta power during rest and event-related desynchronization (ERD) for hand grip were compared between vibration on vs. off. Results showed that vibration decreased EEG power and decreased TMS short-interval intracortical inhibition (i.e., disinhibition) compared with no vibration at rest. Grip-related ERD was also greater during vibration, compared to no vibration. In conclusion, subthreshold random-frequency wrist vibration affected the release of intracortical inhibition and both resting and grip-related sensorimotor cortical activity. Such effects may have implications in rehabilitation.

Evaluation of the effect scan pattern has on the trueness and precision of six intraoral digital impression systems.

OBJECTIVE: Clinicians have been slow to adopt digital impression technologies due possibly to perceived technique sensitivities involved in data acquisition. This research has two aims: determine whether scan pattern and sequence affects the accuracy of the three-dimensional (3D) model created from this digital impression and to compare the 5 imaging systems with regards to their scanning accuracy for sextant impressions. MATERIALS AND METHODS: Six digital intraoral impression systems were used to scan a typodont sextant with optical properties similar to natural teeth. The impressions were taken using five different scan patterns and the resulting digital models were overlayed on a master digital model to determine the accuracy of each scanner performing each scan pattern. Furthermore, regardless of scan pattern, each digital impression system was evaluated for accuracy to the other systems in this same manner. RESULTS: No differences of significance were noted in the accuracy of 3D models created using six distinct scan patterns with one exception involving the CEREC Omnicam. Planmeca Planscan was determined to be the truest scanner while 3Shape Trios was determined to be the most precise for sextant impression making. CONCLUSIONS: Scan pattern does not significantly affect the accuracy of the resulting digital model for sextant scanning. CLINICAL SIGNIFICANCE: Companies who make digital impression systems often recommend a scan pattern specific for their system. However, every clinical scanning scenario is different and may require a different approach. Knowing how important scan pattern is with regards to accuracy would be helpful for guiding a growing number of practitioners who are utilizing this technology.

Sensitivity of diffusion MRI to perilesional reactive astrogliosis in focal ischemia.

Reactive astrogliosis is a response to injury in the central nervous system that plays an essential role in inflammation and tissue repair. It is characterized by hypertrophy of astrocytes, alterations in astrocyte gene expression and astrocyte proliferation. Reactive astrogliosis occurs in multiple neuropathologies, including stroke, traumatic brain injury and Alzheimer's disease, and it has been proposed as a possible source of the changes in diffusion magnetic resonance imaging (dMRI) metrics observed with these diseases. In this study, the sensitivity of dMRI to reactive astrogliosis was tested in an animal model of focal acute and subacute ischemia induced by the vasoconstricting peptide, endothelin-1. Reactive astrogliosis in perilesional cortex was quantified by calculating the astrocyte surface density as determined with a glial fibrillary acidic protein (GFAP) antibody, whereas perilesional diffusion changes were measured in vivo with diffusional kurtosis imaging. We found substantial changes in the surface density of GFAP-positive astrocyte processes and modest changes in dMRI metrics in the perilesional motor cortex following stroke. Although there are time point-specific correlations between dMRI and histological measures, there is no definitive evidence for a causal relationship.

Evaluation of the accuracy of 7 digital scanners: An in vitro analysis based on 3-dimensional comparisons.

STATEMENT OF PROBLEM: As digital impressions become more common and more digital impression systems are released onto the market, it is essential to systematically and objectively evaluate their accuracy. PURPOSE: The purpose of this in vitro study was to evaluate and compare the trueness and precision of 6 intraoral scanners and 1 laboratory scanner in both sextant and complete-arch scenarios. Furthermore, time of scanning was evaluated and correlated with trueness and precision. MATERIAL AND METHODS: A custom complete-arch model was fabricated with a refractive index similar to that of tooth structure. Seven digital impression systems were used to scan the custom model for both posterior sextant and complete arch scenarios. Analysis was performed using 3-dimensional metrology software to measure discrepancies between the master model and experimental casts. RESULTS: Of the intraoral scanners, the Planscan was found to have the best trueness and precision while the 3Shape Trios was found to have the poorest for sextant scanning (P<.001). The order of trueness for complete arch scanning was as follows: 3Shape D800 >iTero >3Shape TRIOS 3 >Carestream 3500 >Planscan >CEREC Omnicam >CEREC Bluecam. The order of precision for complete-arch scanning was as follows: CS3500 >iTero >3Shape D800 >3Shape TRIOS 3 >CEREC Omnicam >Planscan >CEREC Bluecam. For the secondary outcome evaluating the effect time has on trueness and precision, the complete- arch scan time was highly correlated with both trueness (r=0.771) and precision (r=0.771). CONCLUSIONS: For sextant scanning, the Planscan was found to be the most precise and true scanner. For complete-arch scanning, the 3Shape Trios was found to have the best balance of speed and accuracy.

Delayed grip relaxation and altered modulation of intracortical inhibition with aging.

Grip relaxation is a voluntary action that requires an increase in short-interval intracortical inhibition (SICI) in healthy young adults, rather than a simple termination of excitatory drive. The way aging affects this voluntary inhibitory action and timing of grip relaxation is currently unknown. The objective of this study was to examine aging-related delays in grip relaxation and SICI modulation for the flexor digitorum superficialis muscle during grip relaxation. The main finding was that young adults increased SICI to relax their grips, whereas older adults did not increase SICI with a prolonged grip relaxation time (p < 0.05 for both SICI modulation and grip relaxation time). A secondary experiment showed that both young and older adults did not change H reflex excitability during grip relaxation. Our data suggest that grip relaxation is mediated by increased cortical inhibitory output in young adults, and aging-related impairment in increasing cortical inhibitory output may hamper timely cessation of muscle activity. Our data also suggest a lesser role of the spinal circuits in grip muscle relaxation. This knowledge may contribute to understanding of aging-related movement deterioration and development of interventions for improving modulation of SICI to improve muscle relaxation and movement coordination.

Adiponectin and arterial stiffness in youth with type 1 diabetes: the SEARCH for diabetes in youth study.

Persons with type 1 diabetes are at increased risk of developing vascular disease. Adiponectin concentrations may play an intermediate role in this process. We sought to determine whether adiponectin is correlated with vascular stiffness in adolescents with type 1 diabetes. Plasma adiponectin, pulse wave velocity (PWV), augmentation index (AIx-75), and brachial distensibility (BrachD) were collected in 225 adolescents. Outcomes were evaluated by sex, and regression models were used to determine whether adiponectin was an independent determinant of arterial stiffness. Males had lower adiponectin levels and stiffer vessels (lower BrachD, p < 0.01) than females. Unadjusted correlations revealed that adiponectin was correlated with BrachD (p < 0.01) but not PWV and AIx-75. After adjustment, adiponectin was not a significant predictor of BrachD. The most consistent predictors of increased stiffness were age, male sex, blood pressure, obesity, and total cholesterol (p < 0.05). Adiponectin's contributions to arterial stiffness appear to be masked by other cardiovascular risk factors in persons with type 1 diabetes.

TheraBracelet Stimulation During Task-Practice Therapy to Improve Upper Extremity Function After Stroke: A Pilot Randomized Controlled Study.

BACKGROUND: Peripheral sensory stimulation has been used in conjunction with upper extremity movement therapy to increase therapy-induced motor gains in patients with stroke. The limitation is that existing sensory stimulation methods typically interfere with natural hand tasks and thus are administered prior to therapy, requiring patients' time commitment. To address this limitation, we developed TheraBracelet. This novel stimulation method provides subthreshold (ie, imperceptible) vibratory stimulation to the wrist and can be used during hand tasks/therapy without interfering with natural hand tasks. OBJECTIVE: The objective was to determine the feasibility of using TheraBracelet during therapy to augment motor recovery after stroke. DESIGN: The design was a triple-blinded pilot randomized controlled trial. METHODS: Twelve chronic stroke survivors were assigned to the treatment or control group. All participants completed 2-hour task practice therapy sessions thrice weekly for 2 weeks. Both groups wore a small vibrator on the paretic wrist, which was turned on to provide TheraBracelet stimulation for the treatment group and turned off for the control group to provide sham stimulation. Outcome measures (Box and Block Test [BBT] and Wolf Motor Function Test [WMFT]) were obtained at baseline, 6 days after therapy, and at follow-up 19 days after therapy. RESULTS: The intervention was feasible with no adverse events. The treatment group significantly improved their BBT scores after therapy and at follow-up compared with baseline, whereas the control group did not. For WMFT, the group × time interaction was short of achieving significance. Large effect sizes were obtained (BBT d = 1.43, WMFT d = 0.87). No indication of desensitization to TheraBracelet stimulation was observed. LIMITATIONS: The limitation was a small sample size. CONCLUSIONS: TheraBracelet could be a promising therapy adjuvant for upper extremity recovery after stroke.

Visual Attention Affects the Amplitude of the Transcranial Magnetic Stimulation-associated Motor-evoked Potential: A Preliminary Study With Clinical Utility.

BACKGROUND: The transcranial magnetic stimulation (TMS)-elicited motor-evoked potential (MEP) is a valuable measure for clinical evaluations of various neurological disorders and is used to determine resting motor threshold for repetitive TMS dosing. Although MEP amplitude is primarily associated with motor system function, there is evidence that nonmotor factors may also influence amplitude. This experiment tested the hypotheses that manipulation of 2 factors (visual attention, cognitive regulation) in human participants would significantly affect MEP amplitude. METHODS: Blocks of MEPs were recorded from the dominant right hand as participants (N=20) were instructed to shift their visual attention (toward and away from the hand) and cognitively regulate the MEPs (rest, attenuate MEP amplitude, potentiate MEP amplitude) using their thoughts (6 blocks, 20 pulses/block, randomized, 110% resting motor threshold). RESULTS: MEP amplitude was significantly affected by the direction of visual attention; looking away from the hand led to higher amplitudes (P=0.003). The relationship with cognitive regulation was nonsignificant. CONCLUSIONS: The significant effect of visual attention on MEP suggests that this should be a standardized parameter in clinical and research studies. These data underscore the importance of rigorous reporting of methods and use of standardized practices for MEP acquisition and TMS dosing to ensure consistent clinical measurement and treatment.

An Assessment of Participant-Described Interprofessional Oral Health Referral Systems Across Rurality.

PURPOSE: As a means to identify and quantify oral health interprofessional collaborative practice (IPP), we examined participant-described medical-to-dental (M2D) referral networks and how they function across rurality. METHODS: We conducted a cross-sectional survey on the appraisal of IPP referral systems in 2016. Secondarily, we examined if rural health clinics (RHCs) have different experiences with M2D referrals compared to other practice types. Independent variables included geographic and organizational indicators, referral system attributes, and respondent characteristics. Data were coded by Census region and state Medicaid expansion status. Bivariable and multivariable analyses were conducted using SAS. FINDINGS: A convenience cohort (n = 559) from 44 states was examined. Nearly, half (48.7%) reported dependable M2D referral systems. In bivariate analysis, all independent variables were significant except for state Medicaid expansion status. In multivariable analysis, Census region retained significance (P = .0093). Organization type and practice issues with no shows/missed appointments continued to have significance (P < .001 and .002, respectively). Accountable care organizations were over 5 times (5.72, P = .001) more likely than RHCs to report dependable M2D referral systems. Federally qualified health clinics were slightly over 3 times more likely than RHCs to report dependable M2D referral (3.04, P < .001). No differences between RHCs and other private practices were observed. CONCLUSIONS: The importance of IPP continues to be promoted in the current health care environment. Our study demonstrates that, in this motivated study population, M2D referrals can work well, even in rural areas. Organization type, directionality of referral, broken appointment rates, and electronic health information management were all found to significantly impact the respondents' rating on the dependability of an M2D referral process.

Differences in Right Ventricular Functional Changes during Treatment between Systemic Sclerosis-associated Pulmonary Arterial Hypertension and Idiopathic Pulmonary Arterial Hypertension.

RATIONALE: Patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) continue to have an unacceptably high mortality rate despite the progress achieved with pulmonary arterial vasodilator therapies. OBJECTIVES: We sought to determine whether SSc-PAH is a clinically distinct pulmonary vascular disease phenotype when compared with idiopathic pulmonary arterial hypertension (IPAH) on the basis of progression of echocardiographic right ventricular (RV) dysfunction. METHODS: Retrospective analysis of echocardiographic data in 13 patients with SSc-PAH and 11 patients with IPAH was used to delineate the progression of RV dysfunction during single or combination pulmonary arterial vasodilator therapy. All patients had right heart catheterization-confirmed pulmonary arterial hypertension as well as complete baseline (at the time of diagnosis) and follow-up (most recent) echocardiograms. We excluded patients with significant scleroderma-associated interstitial lung disease. Adjusting for time of follow-up and disease duration, we performed mixed model regression analyses comparing the changes between the two groups for different echocardiographic variables: tricuspid annular plane systolic excursion, tricuspid regurgitation jet velocity, right atrial area, and RV diameter. RESULTS: The mean ages for the SSc-PAH and IPAH groups were 60.8 and 48.2 years, respectively. The mean follow-up periods for the two groups were 3.8 and 1.95 years, respectively. Tricuspid annular plane systolic excursion did not improve in patients with SSc-PAH, whereas it increased in the patients with IPAH (-0.38 mm, P = 0.87; vs. +5.6 mm, P = 0.02). The other echocardiographic variables showed a trend toward worsening in the SSc-PAH group and improvement in the IPAH group. CONCLUSIONS: Our results indicate that, in patients with SSc-PAH, echocardiographic RV function does not improve over time compared with that of patients with IPAH, despite institution of pulmonary artery vasodilator therapies.

Effect of imperceptible vibratory noise applied to wrist skin on fingertip touch evoked potentials - an EEG study.

Random vibration applied to skin can change the sense of touch. Specifically, low amplitude white-noise vibration can improve fingertip touch perception. In fact, fingertip touch sensation can improve even when imperceptible random vibration is applied to other remote upper extremity areas such as wrist, dorsum of the hand, or forearm. As such, vibration can be used to manipulate sensory feedback and improve dexterity, particularly during neurological rehabilitation. Nonetheless, the neurological bases for remote vibration enhanced sensory feedback are yet poorly understood. This study examined how imperceptible random vibration applied to the wrist changes cortical activity for fingertip sensation. We measured somatosensory evoked potentials to assess peak-to-peak response to light touch of the index fingertip with applied wrist vibration versus without. We observed increased peak-to-peak somatosensory evoked potentials with wrist vibration, especially with increased amplitude of the later component for the somatosensory, motor, and premotor cortex with wrist vibration. These findings corroborate an enhanced cortical-level sensory response motivated by vibration. It is possible that the cortical modulation observed here is the result of the establishment of transient networks for improved perception.

Application of vibration to wrist and hand skin affects fingertip tactile sensation.

A recent study showed that fingertip pads' tactile sensation can improve by applying imperceptible white-noise vibration to the skin at the wrist or dorsum of the hand in stroke patients. This study further examined this behavior by investigating the effect of both imperceptible and perceptible white-noise vibration applied to different locations within the distal upper extremity on the fingertip pads' tactile sensation in healthy adults. In 12 healthy adults, white-noise vibration was applied to one of four locations (dorsum hand by the second knuckle, thenar and hypothenar areas, and volar wrist) at one of four intensities (zero, 60%, 80%, and 120% of the sensory threshold for each vibration location), while the fingertip sensation, the smallest vibratory signal that could be perceived on the thumb and index fingertip pads, was assessed. Vibration intensities significantly affected the fingertip sensation (P < 0.01) in a similar manner for all four vibration locations. Specifically, vibration at 60% of the sensory threshold improved the thumb and index fingertip tactile sensation (P < 0.01), while vibration at 120% of the sensory threshold degraded the thumb and index fingertip tactile sensation (P < 0.01) and the 80% vibration did not significantly change the fingertip sensation (P > 0.01), all compared with the zero vibration condition. This effect with vibration intensity conforms to the stochastic resonance behavior. Nonspecificity to the vibration location suggests the white-noise vibration affects higher level neuronal processing for fingertip sensing. Further studies are needed to elucidate the neural pathways for distal upper extremity vibration to impact fingertip pad tactile sensation.

Peripheral neuropathy in adolescents and young adults with type 1 and type 2 diabetes from the SEARCH for Diabetes in Youth follow-up cohort: a pilot study.

OBJECTIVE: To estimate the prevalence of and risk factors for diabetic peripheral neuropathy (DPN) in a pilot study among youth participating in the SEARCH for Diabetes in Youth study. RESEARCH DESIGN AND METHODS: DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI) (examination for foot abnormalities, distal vibration perception, and ankle reflexes). An MNSI exam (MNSIE) score >2 is diagnostic for DPN. RESULTS: The MNSIE was completed in 399 subjects, including 329 youth with type 1 diabetes (mean age 15.7 ± 4.3 years, duration 6.2 ± 0.9 years) and 70 with type 2 diabetes (mean age 21.6 ± 4.1 years, duration 7.6 ± 1.8 years). Glycated hemoglobin (A1C) was similar in both groups (8.8 ± 1.8% for type 1 vs. 8.5 ± 2.9% for type 2). The prevalence of DPN was significantly higher in youth with type 2 compared with those with type 1 diabetes (25.7 vs. 8.2%; P < 0.0001). In unadjusted analyses, diabetes type, older age, longer duration of diabetes, increased waist circumference, elevated blood pressure, lower HDL cholesterol, and presence of microalbuminuria (urinary albumin-to-creatinine ratio >30 mg/g) were associated with DPN. The association between diabetes type and DPN remained significant after adjustment for age and sex (odds ratio 2.29 [95% CI 1.05-5.02], P = 0.03). CONCLUSIONS: DPN prevalence among youth with type 2 diabetes approached rates reported in adult populations with diabetes. Our findings suggest not only that youth with diabetes are at risk for DPN but also that many already show measurable signs of DPN.

Albuminuria according to status of autoimmunity and insulin sensitivity among youth with type 1 and type 2 diabetes.

OBJECTIVE: To evaluate whether etiologic diabetes type is associated with the degree of albuminuria in children with diabetes. RESEARCH DESIGN AND METHODS SEARCH: is an observational, longitudinal study of children with diabetes. Youth with newly diagnosed diabetes were classified according to diabetes autoantibody (DAA) status and presence of insulin resistance. We defined insulin resistance as an insulin sensitivity score <25th percentile for the United States general youth population. DAA status was based on positivity for the 65-kD isoform of glutamate decarboxylase and insulinoma-associated protein 2 antigens. The four etiologic diabetes type groups were as follows: DAA(+)/insulin-sensitive (IS) (n = 1,351); DAA(+)/insulin-resistant (IR) (n = 438); DAA(-)/IR (n = 379); and DAA(-)/IS (n = 233). Urinary albumin:creatinine ratio (UACR) was measured from a random urine specimen. Multivariable regression analyses assessed the independent relationship between the four diabetes type groups and magnitude of UACR. RESULTS: Adjusted UACR means across the four groups were as follows: DAA(+)/IS = 154 µg/mg; DAA(+)/IR = 137 µg/mg; DAA(-)/IR = 257 µg/mg; and DAA(-)/IS = 131 µg/mg (P < 0.005). Only DAA(-)/IR was significantly different. We performed post hoc multivariable regression analysis restricted to the two IR groups to explore the contribution of DAA status and insulin sensitivity (continuous) to the difference in UACR between the IR groups. Only insulin sensitivity was significantly associated with UACR (ß = -0.54; P < 0.0001). CONCLUSIONS: In youth with diabetes, the DAA(-)/IR group had a greater UACR than all other groups, possibly because of the greater magnitude of insulin resistance. Further exploration of the relationships between severity of insulin resistance, autoimmunity, and albuminuria in youth with diabetes is warranted.