Transdermal Electrical Neuromodulation for Anxiety and Sleep Problems in High-Functioning Autism Spectrum Disorder: Feasibility and Preliminary Findings.

BACKGROUND: Autism spectrum disorder (ASD) is associated with anxiety and sleep problems. We investigated transdermal electrical neuromodulation (TEN) of the cervical nerves in the neck as a safe, effective, comfortable and non-pharmacological therapy for decreasing anxiety and enhancing sleep quality in ASD. METHODS: In this blinded, sham-controlled study, seven adolescents and young adults with high-functioning ASD underwent five consecutive treatment days, one day of the sham followed by four days of subthreshold TEN for 20 min. Anxiety-provoking cognitive tasks were performed after the sham/TEN. Measures of autonomic nervous system activity, including saliva α-amylase and cortisol, electrodermal activity, and heart rate variability, were collected from six participants. RESULTS: Self-rated and caretaker-rated measures of anxiety were significantly improved with TEN treatment as compared to the sham, with effect sizes ranging from medium to large depending on the rating scale. Sleep scores from caretaker questionnaires also improved, but not significantly. Performance on two of the three anxiety-provoking cognitive tasks and heart rate variability significantly improved with TEN stimulation as compared to the sham. Four of the seven (57%) participants were responders, defined as a ≥ 30% improvement in self-reported anxiety. Salivary α-amylase decreased with more TEN sessions and decreased from the beginning to the end of the session on TEN days for responders. TEN was well-tolerated without significant adverse events. CONCLUSIONS: This study provides preliminary evidence that TEN is well-tolerated in individuals with ASD and can improve anxiety.

The neural correlates of mindfulness-induced depression reduction in adults with autism spectrum disorder: A pilot study.

Adults with autism spectrum disorder (ASD) experience high rates of depression and anxiety, and some evidence suggests mindfulness-based stress reduction (MBSR) is effective in reducing these symptoms. However, the neural mechanisms of symptom alleviation, and benefit of MBSR beyond education/support groups are unknown. Maladaptive forms of self-reflection are linked to ASD, depression, and anxiety. In this pilot study, we hypothesized (a) MBSR would reduce depression and anxiety in adults with ASD and (b) a mechanism of symptom alleviation would be increased blood oxygen level-dependent signal in neural self-reflection hubs. Twenty-eight adults were randomly assigned to an 8-week MBSR group (n = 15) or a support group (n = 13) that met for the same amount of time with relaxation education materials. Based on previous self-reflection literature in ASD, regions of interest (ROIs) were middle cingulate cortex (MCC) and ventromedial prefrontal cortex (vmPFC). Only the MBSR group demonstrated significant reductions in depression, and neither group significantly changed in anxiety. Only the MBSR group increased activity of right MCC during self-reflection, and the increase correlated with depression alleviation. There were no changes in vmPFC for the MBSR group or either ROI for the support/education group. Seed-to-voxel connectivity analysis revealed that only the MBSR group increased functional connectivity between right MCC and pre/postcentral gyrus, suggesting MBSR may increase primary sensorimotor input to higher order cognitive brain regions. Taken together, MBSR may be effective for reducing depression in adults with ASD, and the neural mechanism may be increasing frontal circuit involvement during self-directed thought.

Temporary persistence of conduction block after prolonged kilohertz frequency alternating current on rat sciatic nerve.

OBJECTIVE: Application of kilohertz frequency alternating current (KHFAC) waveforms can result in nerve conduction block that is induced in less than a second. Conduction recovers within seconds when KHFAC is applied for about 5-10 min. This study investigated the effect of repeated and prolonged application of KHFAC on rat sciatic nerve with bipolar platinum electrodes. APPROACH: Varying durations of KHFAC at signal amplitudes for conduction block with intervals of no stimulus were studied. Nerve conduction was monitored by recording peak Gastrocnemius muscle force utilizing stimulation electrodes proximal (PS) and distal (DS) to a blocking electrode. The PS signal traveled through the block zone on the nerve, while the DS went directly to the motor end-plate junction. The PS/DS force ratio provided a measure of conduction patency of the nerve in the block zone. MAIN RESULTS: Conduction recovery times were found to be significantly affected by the cumulative duration of KHFAC application. Peak stimulated muscle force returned to pre-block levels immediately after cessation of KHFAC delivery when it was applied for less than about 15 min. They fell significantly but recovered to near pre-block levels for cumulative stimulus of 50 ± 20 min, for the tested On/Off times and frequencies. Conduction recovered in two phases, an initial fast one (60-80% recovery), followed by a slower phase. No permanent conduction block was seen at the end of the observation period during any experiment. SIGNIFICANCE: This carry-over block effect may be exploited to provide continuous conduction block in peripheral nerves without continuous application of KHFAC.

Significance of oliguria in critically ill patients with chronic liver disease.

Clinical guidelines recommend using Kidney Disease Improving Global Outcomes (KDIGO) criteria for the diagnosis and classification of acute kidney injury (AKI) in patients with chronic liver disease (CLD). Concerns have been raised about the use of urine output (UO) criteria in CLD. We examined the significance of oliguria meeting the urine output criteria for AKI (AKI-UO) and examined its association with clinical outcomes in CLD patients. Using an 8-year clinical database from a large university medical center, 3458 patients with CLD were identified. AKI occurred in 2854 (82.5%) patients when they fulfilled any KDIGO criteria. When serum creatinine (SC) and UO criteria were used, 604 patients (17.5%) had no evidence of AKI and had the lowest hospital mortality rate (5%). Using AKI-UO criteria alone, 2103 patients (60.8%) were classified as stage 2-3 AKI. When only SC criteria were applied, 1281 (61%) of those patients with stage 2-3 AKI-UO were misclassified as either no AKI or AKI stage 1. Patients reclassified with AKI according to UO criteria (AKI-UO) had nearly a 3-fold increased rate of hospital mortality compared with patients without any AKI (14.6% versus 5%; P < 0.001) and more than a 50% increased mortality compared with stage 1 AKI-SC (14.6% versus 9%; P < 0.001). Patients with transient oliguria (AKI-UO stage 1) had increased mortality rates compared with patients without oliguria (14.9% versus 6.9%; P < 0.001). CONCLUSION: CLD patients have a high incidence of AKI. Compared with creatinine criteria alone, incorporating UO into the diagnostic criteria increased the measured incidence of AKI. Stage 2-3 AKI-UO has a high negative impact on hospital mortality. (Hepatology 2017;66:1592-1600).

Intensive Monitoring of Urine Output Is Associated With Increased Detection of Acute Kidney Injury and Improved Outcomes.

BACKGROUND: Urine output (UO) is a vital sign for critically ill patients, but standards for monitoring and reporting vary widely between ICUs. Careful monitoring of UO could lead to earlier recognition of acute kidney injury (AKI) and better fluid management. We sought to determine if the intensity of UO monitoring is associated with outcomes in patients with and those without AKI. METHODS: This was a retrospective cohort study including 15,724 adults admitted to ICUs from 2000 to 2008. Intensive UO monitoring was defined as hourly recordings and no gaps > 3 hours for the first 48 hours after ICU admission. RESULTS: Intensive monitoring for UO was conducted in 4,049 patients (26%), and we found significantly higher rates of AKI (OR, 1.22; P < .001) in these patients. After adjustment for age and severity of illness, intensive UO monitoring was associated with improved survival but only among patients experiencing AKI. With or without AKI, patients with intensive monitoring also had less cumulative fluid volume (2.98 L vs 3.78 L; P < .001) and less fluid overload (2.49% vs 5.68%; P < .001) over the first 72 hours of ICU stay. CONCLUSIONS: In this large ICU population, intensive monitoring of UO was associated with improved detection of AKI and reduced 30-day mortality in patients experiencing AKI, as well as less fluid overload for all patients. Our results should help inform clinical decisions and ICU policy about frequency of monitoring of UO, especially for patients at high risk of AKI or fluid overload, or both.

Chloride Content of Fluids Used for Large-Volume Resuscitation Is Associated With Reduced Survival.

OBJECTIVE: We sought to investigate if the chloride content of fluids used in resuscitation was associated with short- and long-term outcomes. DESIGN: We identified patients who received large-volume fluid resuscitation, defined as greater than 60 mL/kg over a 24-hour period. Chloride load was determined for each patient based on the chloride ion concentration of the fluids they received during large-volume fluid resuscitation multiplied by the volume of fluids. We compared the development of hyperchloremic acidosis, acute kidney injury, and survival among those with higher and lower chloride loads. SETTING: University Medical Center. PATIENTS: Patients admitted to ICUs from 2000 to 2008. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 4,710 patients receiving large-volume fluid resuscitation, hyperchloremic acidosis was documented in 523 (11%). Crude rates of hyperchloremic acidosis, acute kidney injury, and hospital mortality all increased significantly as chloride load increased (p < 0.001). However, chloride load was no longer associated with hyperchloremic acidosis or acute kidney injury after controlling for total fluids, age, and baseline severity. Conversely, each 100 mEq increase in chloride load was associated with a 5.5% increase in the hazard of death even after controlling for total fluid volume, age, and severity (p = 0.0015) over 1 year. CONCLUSIONS: Chloride load is associated with significant adverse effects on survival out to 1 year even after controlling for total fluid load, age, and baseline severity of illness. However, the relationship between chloride load and development of hyperchloremic acidosis or acute kidney injury is less clear, and further research is needed to elucidate the mechanisms underlying the adverse effects of chloride load on survival.

Psychometric properties of the children's sleep habits questionnaire in children with autism spectrum disorder.

BACKGROUND AND PURPOSE: Sleep disturbances in autism spectrum disorder (ASD) are very common. Psychometrically sound instruments are essential to assess these disturbances. Children's Sleep Habit Questionnaire (CSHQ) is a widely used measure in ASD. The purpose of this study was to explore the psychometric properties of the CSHQ in a sample of children with ASD. PARTICIPANTS AND METHODS: Parents/caregivers of 310 children (mean age: 4.7) with ASD completed the CSHQ at study enrollment. Correlations between intelligence quotient (IQ) scores and the original CSHQ scales were calculated. Item endorsement frequencies and percentages were also calculated. A principal component analysis (PCA) was performed, and internal consistency was assessed for the newly extracted components. RESULTS: Correlations between IQ scores and CSHQ subscales and total scores ranged from .015 to .001 suggesting a weak, if any, association. Item endorsement frequencies were high for bedtime resistance items, but lower for parasomnia and sleep-disordered breathing items. A PCA suggested that a five-component solution best fits the data. Internal consistency of the newly extracted five components ranged α = .87-.50. CONCLUSIONS: Item endorsement frequencies were highest for bedtime resistance items. A PCA suggested a five-component solution. Three of the five components (Sleep Routine Problems, Insufficient Sleep, and Sleep-onset Association Problems) were types of sleep disturbances commonly reported in ASD, but the other two components (Parasomnia/Sleep-disordered Breathing and Sleep Anxiety) were less clear. Internal consistencies ranged from mediocre to good. Further development of this measure for use in children with ASD is encouraged.

Psychometric Properties of the Brief Autism Mealtime Behaviors Inventory.

The purpose of this study was to explore the psychometric properties of the Brief Autism Mealtime Behaviors Inventory (BAMBI). In a sample of 273 well-characterized children with ASD, we explored the factor structure of the BAMBI, determined the internal consistency of a newly derived factor structure and provide an empirically derived cut-off for the BAMBI total score. The new psychometrically identified structure consists of 4 factors: (1) Food Selectivity, (2) Disruptive Mealtime Behaviors, (3) Food Refusal and (4) Mealtime Rigidity. Internal consistency was acceptable. A cut off score of 34 is suggested based on our results. The new 15-item BAMB with an alternative 4-factor structure with clinical utility is promising in assessing feeding and mealtime problems in children with ASD.

Behavioral parent training to address sleep disturbances in young children with autism spectrum disorder: a pilot trial.

OBJECTIVES: A large percentage of children with autism spectrum disorders (ASD) have bedtime and sleep disturbances. However, the treatment of these disturbances has been understudied. The purpose of our study was to develop a manualized behavioral parent training (BPT) program for parents of young children with ASD and sleep disturbances and to test the feasibility, fidelity, and initial efficacy of the treatment in a small randomized controlled trial (RCT). PARTICIPANTS AND METHODS: Parents of a sample of 40 young children diagnosed with ASD with an average age of 3.5years were enrolled in our study. Participants were randomized to either the BPT program group or a comparison group who were given nonsleep-related parent education. Each participant was individually administered a 5-session program delivered over the 8-week study. Outcome measures of feasibility, fidelity, and efficacy were collected at weeks 4 and 8 after the baseline time point. Children's sleep was assessed by parent report and objectively by actigraphy. RESULTS: Of the 20 participants in each group, data were available for 15 participants randomized to BPT and 18 participants randomized to the comparison condition. Results supported the feasibility of the manualized parent training program and the comparison program. Treatment fidelity was high for both groups. The BPT program group significantly improved more than the comparison group based on the primary sleep outcome of parent report. There were no objective changes in sleep detected by actigraphy. CONCLUSIONS: Our study is one of few RCTs of a BPT program to specifically target sleep disturbances in a well-characterized sample of young children with ASD and to demonstrate the feasibility of the approach. Initial efficacy favored the BPT program over the comparison group and suggested that this manualized parent training approach is worthy of further examination of the efficacy within a larger RCT.

Comparison of sleep questionnaires in the assessment of sleep disturbances in children with autism spectrum disorders.

BACKGROUND AND PURPOSE: The purpose of this study was to compare two parent completed questionnaires, the Modified Simonds & Parraga Sleep Questionnaire (MSPSQ) and the Children's Sleep Habits Questionnaire (CSHQ), used to characterize sleep disturbances in young children with autism spectrum disorders (ASD). Both questionnaires have been used in previous work in the assessment and treatment of children with ASD and sleep disturbance. PARTICIPANTS AND METHODS: Parents/caregivers of a sample of 124 children diagnosed with ASD with an average age of six years completed both sleep questionnaires regarding children's sleep behaviors. Internal consistency of the items for both measures was evaluated as well as the correlation between the two sleep measures. A Receiver Operating Characteristics (ROC) curve analysis was also conducted to examine the predictive power of the MSPSQ. RESULTS: More than three quarters of the sample (78%) were identified as poor sleepers on the CSHQ. Cronbach's alpha for the items on the CSHQ was 0.68 and Cronbach's alpha for items on the MSPSQ was 0.67. The total scores for MSPSQ and CSHQ were significantly correlated (r=.70, p<.01). After first identifying the poor sleepers based on the CSHQ, an area under the curve was 0.89 for the MSPSQ. Using a cut off score of 56 on the MSPSQ, sensitivity was .86 and specificity was .70. CONCLUSIONS: In this sample of children with ASD, sleep disturbances were common across all cognitive levels. Preliminary findings suggest that, similar to the CSHQ, the MSPSQ has adequate internal consistency. The two measures were also highly correlated. A preliminary cut off of 56 on the MSPSQ offers high sensitivity and specificity commensurate with the widely used CSHQ.

Electrical conduction block in large nerves: high-frequency current delivery in the nonhuman primate.

Recent studies have made significant progress toward the clinical implementation of high-frequency conduction block (HFB) of peripheral nerves. However, these studies were performed in small nerves, and questions remain regarding the nature of HFB in large-diameter nerves. This study in nonhuman primates shows reliable conduction block in large-diameter nerves (up to 4.1 mm) with relatively low-threshold current amplitude and only moderate nerve discharge prior to the onset of block.

Separated interface nerve electrode prevents direct current induced nerve damage.

Direct current, DC, can be used to quickly and reversibly block activity in excitable tissue, or to quickly and reversibly increase or decrease the natural excitability of a neuronal population. However, the practical use of DC to control neuronal activity has been extremely limited due to the rapid tissue damage caused by its use. We show that a separated interface nerve electrode, SINE, is a much safer method to deliver DC to excitable tissue and may be valuable as a laboratory research tool or potentially for clinical treatment of disease.

Conduction block of whole nerve without onset firing using combined high frequency and direct current.

This study investigates a novel technique for blocking a nerve using a combination of direct and high frequency alternating currents (HFAC). HFAC can produce a fast acting and reversible conduction block, but cause intense firing at the onset of current delivery. We hypothesized that a direct current (DC) block could be used for a very brief period in combination with HFAC to block the onset firing, and thus establish a nerve conduction block which does not transmit onset response firing to an end organ. Experiments were performed in rats to evaluate (1) nerve response to anodic and cathodic DC of various amplitudes, (2) degree of nerve activation to ramped DC, (3) a method of blocking onset firing generated by high frequency block with DC, and (4) prolonged non-electrical conduction failure caused by DC delivery. The results showed that cathodic currents produced complete block of the sciatic nerve with a mean block threshold amplitude of 1.73 mA. Ramped DC waveforms allowed for conduction block without nerve activation; however, down ramps were more reliable than up ramps. The degree of nerve activity was found to have a non-monotonic relationship with up ramp time. Block of the onset response resulting from 40 kHz current using DC was achieved in each of the six animals in which it was attempted; however, DC was found to produce a prolonged conduction failure that likely resulted from nerve damage.

Design, fabrication and evaluation of a conforming circumpolar peripheral nerve cuff electrode for acute experimental use.

Nerve cuff electrodes are a principle tool of basic and applied electro-neurophysiology studies and are championed for their ability to achieve good nerve recruitment with low thresholds. We describe the design and method of fabrication for a novel circumpolar peripheral nerve electrode for acute experimental use. This cylindrical cuff-style electrode provides approximately 270° of radial electrode contact with a nerve for each of an arbitrary number of contacts, has a profile that allows for simple placement and removal in an acute nerve preparation, and is designed for adjustment of the cylindrical diameter to ensure a close fit on the nerve. For each electrode, the electrical contacts were cut from 25 µm platinum foil as an array so as to maintain their positions relative to each other within the cuff. Lead wires were welded to each intended contact. The structure was then molded in silicone elastomer, after which the individual contacts were electrically isolated. The final electrode was curved into a cylindrical shape with an inner diameter corresponding to that of the intended target nerve. The positions of these contacts were well maintained during the molding and shaping process and failure rates during fabrication due to contact displacements were very low. Established electrochemical measurements were made on one electrode to confirm expected behavior for a platinum electrode and to measure the electrode impedance to applied voltages at different frequencies. These electrodes have been successfully used for nerve stimulation, recording, and conduction block in a number of different acute animal experiments by several investigators.

Frequency- and amplitude-transitioned waveforms mitigate the onset response in high-frequency nerve block.

High-frequency alternating currents (HFAC) have proven to be a reversible and rapid method of blocking peripheral nerve conduction, holding promise for treatment of disorders associated with undesirable neuronal activity. The delivery of HFAC is characterized by a transient period of neural firing at its inception, termed the 'onset response'. The onset response is minimized for higher frequencies and higher amplitudes, but requires larger currents. However, the complete block can be maintained at lower frequencies and amplitudes, using lower currents. In this in vivo study on whole mammalian peripheral nerves, we demonstrate a method to minimize the onset response by initiating the block using a stimulation paradigm with a high frequency and large amplitude, and then transitioning to a low-frequency and low-amplitude waveform, reducing the currents required to maintain the conduction block. In five of six animals, it was possible to transition from a 30 kHz to a 10 kHz waveform without inducing any transient neural firing. The minimum transition time was 0.03 s. Transition activity was minimized or eliminated with longer transition times. The results of this study show that this method is feasible for achieving a nerve block with minimal onset responses and current amplitude requirements.

Effect of nerve cuff electrode geometry on onset response firing in high-frequency nerve conduction block.

The delivery of high-frequency alternating currents has been shown to produce a focal and reversible conduction block in whole nerve and is a potential therapeutic option for various diseases and disorders involving pathological or undesired neurological activity. However, delivery of high-frequency alternating current to a nerve produces a finite burst of neuronal firing, called the onset response, before the nerve is blocked. Reduction or elimination of the onset response is very important to moving this type of nerve block into clinical applications since the onset response is likely to result in undesired muscle contraction and pain. This paper describes a study of the effect of nerve cuff electrode geometry (specifically, bipolar contact separation distance), and waveform amplitude on the magnitude and duration of the onset response. Electrode geometry and waveform amplitude were both found to affect these measures. The magnitude and duration of the onset response showed a monotonic relationship with bipolar separation distance and amplitude. The duration of the onset response varied by as much as 820% on average for combinations of different electrode geometries and waveform amplitudes. Bipolar electrodes with a contact separation distance of 0.5 mm resulted in the briefest onset response on average. Furthermore, the data presented in this study provide some insight into a biophysical explanation for the onset response. These data suggest that the onset response consists of two different phases: one phase which is responsive to experimental variables such as electrode geometry and waveform amplitude, and one which is not and appears to be inherent to the transition to the blocked state. This study has implications for nerve block electrode and stimulation parameter selection for clinical therapy systems and basic neurophysiology studies.

Nerve conduction block using combined thermoelectric cooling and high frequency electrical stimulation.

Conduction block of peripheral nerves is an important technique for many basic and applied neurophysiology studies. To date, there has not been a technique which provides a quickly initiated and reversible "on-demand" conduction block which is both sustainable for long periods of time and does not generate activity in the nerve at the onset of the conduction block. In this study we evaluated the feasibility of a combined method of nerve block which utilizes two well established nerve blocking techniques in a rat and cat model: nerve cooling and electrical block using high frequency alternating currents (HFAC). This combined method effectively makes use of the contrasting features of both nerve cooling and electrical block using HFAC. The conduction block was initiated using nerve cooling, a technique which does not produce nerve "onset response" firing, a prohibitive drawback of HFAC electrical block. The conduction block was then readily transitioned into an electrical block. A long-term electrical block is likely preferential to a long-term nerve cooling block because nerve cooling block generates large amounts of exhaust heat, does not allow for fiber diameter selectivity and is known to be unsafe for prolonged delivery.

Conduction block of peripheral nerve using high-frequency alternating currents delivered through an intrafascicular electrode.

Many diseases are characterized by undesired or pathological neural activity. The local delivery of high-frequency currents has been shown to be an effective method for blocking neural conduction in peripheral nerves and may provide a therapy for these conditions. To date, all studies of high-frequency conduction block have utilized extraneural (cuff) electrodes to achieve conduction block. In this study we show that high-frequency conduction block is feasible using intrafascicular electrodes.

Reduction of the onset response in high frequency nerve block with amplitude ramps from non-zero amplitudes.

High frequency alternating current (HFAC) waveforms reversibly block conduction in mammalian peripheral nerves. The initiation of the HFAC produces an onset response in the nerve before complete block occurs. An amplitude ramp, starting from zero amplitude, is ineffective in eliminating this onset response. In fact, it makes the onset worse. We postulated that initiating the ramp from a non-zero amplitude would produce a different effect on the onset. This was tested in an in-vivo rat sciatic nerve model. HFAC was applied at supra block threshold amplitudes and then reduced to a lower amplitude (0%, 25% 50 %, 75% and 90% of the suprathreshold amplitude). The amplitude was then increased again to the original supra block threshold amplitude. This normally produces a second period of onset response if increased as a step. However, an amplitude ramp was successful in eliminating this onset. This was always possible for the ramps up from 50%, 75 % and 90% block threshold amplitude, but never from 0% or 25% of the block threshold amplitude. This maneuver can potentially be used to maintain complete nerve block, transition to partial block and then resume complete block without initiating another onset.

Electrode design for high frequency block: effect of bipolar separation on block thresholds and the onset response.

The delivery of high frequency alternating currents (HFAC) to peripheral nerves has been shown to produce a rapid and reversible nerve conduction block at the site of the electrode, and holds therapeutic promise for diseases associated with undesired or pathological neural activity. It has been known since 1939 that the configuration of an electrode used for nerve block can impact the quality of the block, but to date no formal study of the impact of electrode design on high frequency nerve block has been performed. Using a mammalian small animal model, it is demonstrated that the contact separation distance for a bipolar nerve cuff electrode can impact two important factors related to high frequency nerve block: the amplitude of HFAC required to block the nerve (block threshold), and the degree to which the transient "onset response" which always occurs when HFAC is first applied to peripheral nerves, is present. This study suggests that a bipolar electrode with a separation distance of 1.0 mm minimizes current delivery while producing high frequency block with a minimal onset response in the rat sciatic nerve.