Effects of transcranial direct current stimulation and transcranial random noise stimulation on working memory and task-related EEG in major depressive disorder.

OBJECTIVE: To compare effects of transcranial direct current stimulation (tDCS) and transcranial random noise stimulation with a direct-current offset (tRNS + DC-offset) on working memory (WM) performance and task-related electroencephalography (EEG) in individuals with Major Depressive Disorder (MDD). METHODS: Using a sham-controlled, parallel-groups design, 49 participants with MDD received either anodal tDCS (N = 16), high-frequency tRNS + DC-offset (N = 16), or sham stimulation (N = 17) to the left dorsolateral prefrontal cortex (DLPFC) for 20-minutes. The Sternberg WM task was completed with concurrent EEG recording before and at 5- and 25-minutes post-stimulation. Event-related synchronisation/desynchronisation (ERS/ERD) was calculated for theta, upper alpha, and gamma oscillations during WM encoding and maintenance. RESULTS: tDCS significantly increased parieto-occipital upper alpha ERS/ERD during WM maintenance, observed on EEG recorded 5- and 25-minutes post-stimulation. tRNS + DC-offset did not significantly alter WM-related oscillatory activity when compared to sham stimulation. Neither tDCS nor tRNS + DC-offset improved WM performance to a significantly greater degree than sham stimulation. CONCLUSIONS: Although tDCS induced persistent effects on WM-related oscillatory activity, neither tDCS nor tRNS + DC-offset enhanced WM performance in MDD. SIGNIFICANCE: This reflects the first sham-controlled comparison of tDCS and tRNS + DC-offset in MDD. These findings directly contrast with evidence of tRNS-induced enhancements in WM in healthy individuals.

Transforaminal lumbar interbody fusion vs. posterolateral instrumented fusion: cost-utility evaluation along side an RCT with a 2-year follow-up.

PURPOSE: Long-lasting low back pain is an increasing problem, and for some patients surgery is the final option for improvement. Several techniques for spinal fusion are available and the optimal technique remains uncertain. The objective of this study was to assess the cost-effectiveness and cost-utility of transforaminal lumbar interbody fusion (TLIF) compared to posterolateral instrumented fusion (PLF) from the societal perspective. METHODS: 100 Patients were randomized to TLIF or PLF (51/49) and followed for 2 years. Cost data were acquired from national registers, and outcomes were measured using the Oswestry Disability Index and SF-6D questionnaires. Conventional cost-effectiveness methodology was employed to estimate net benefit and to illustrate cost-effectiveness acceptability curves. The statistical analysis was based on means and bootstrapped confidence intervals. RESULTS: Results showed no statistically significant difference in either cost or effects although a tendency for the TLIF regimen being more costly on bed days (2,554) and production loss (1,915) was observed. The probability that TLIF would be cost-effective did not exceed 30 % for any threshold of willingness to pay per quality-adjusted life year. Sensitivity analysis was conducted and supported the statistical model for handling of missing data. CONCLUSION: TLIF does not seem to be a relevant alternative to PLF from a socioeconomic, societal point of view.

Characterization of the myotonic dystrophy region predicts multiple protein isoform-encoding mRNAs.

The mutation underlying myotonic dystrophy (DM) has been identified as an expansion of a polymorphic CTG-repeat in a gene encoding protein kinase activity. Brain and heart transcripts of the DM-kinase (DMR-B15) gene are subject to alternative RNA splicing in both human and mouse. The unstable [CTG]5-30 motif is found uniquely in humans, although the flanking nucleotides are also present in mouse. Characterization of the DM region of both species reveals another active gene (DMR-N9) in close proximity to the kinase gene. DMR-N9 transcripts, mainly expressed in brain and testis, possess a single, large open reading frame, but the function of its protein product is unknown. Clinical manifestation of DM may be caused by the expanded CTG-repeat compromising the (alternative) expression of DM-kinase or DMR-N9 proteins.

A randomized trial of unilateral and bilateral prefrontal cortex transcranial magnetic stimulation in treatment-resistant major depression.

BACKGROUND: Although several studies have reported that repetitive transcranial magnetic stimulation (rTMS) treatment has demonstrable efficacy in patients with depression, the parameters needed to optimize therapeutic efficacy remain unclear. To this end we determined the efficacy of low-frequency right rTMS to the dorsolateral prefrontal cortex (DLPFC) compared to two forms of bilateral rTMS to the DLPFC: (1) sequential low-frequency right-sided followed by high-frequency left-sided rTMS and (2) sequential low-frequency rTMS to both hemispheres. METHOD: A total of 219 patients with treatment-resistant depression (TRD) were randomized to a 4-week course of rTMS applied with one of the three treatment conditions. Outcomes were assessed with standard rating scales. RESULTS: Overall, slightly more than 50% of the patients achieved clinical response criteria. There was no substantial difference in response between the unilateral and bilateral treatment groups. Successful response to rTMS was predicted by a greater degree of baseline depression severity. CONCLUSIONS: There is no substantial difference in efficacy between unilateral right-sided rTMS and the two forms of bilateral rTMS assessed in the study. Furthermore, our results call into question the specificity between frequency and laterality and rTMS response.

Transcranial random noise stimulation is more effective than transcranial direct current stimulation for enhancing working memory in healthy individuals: Behavioural and electrophysiological evidence.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been shown to improve working memory (WM) performance in healthy individuals, however effects tend to be modest and variable. Transcranial random noise stimulation (tRNS) can be delivered with a direct-current offset (DC-offset) to induce equal or even greater effects on cortical excitability than tDCS. To-date, no research has directly compared the effects of these techniques on WM performance or underlying neurophysiological activity. OBJECTIVE: To compare the effects of anodal tDCS, tRNS + DC-offset, or sham stimulation over the left dorsolateral prefrontal cortex (DLPFC) on WM performance and task-related EEG oscillatory activity in healthy adults. METHODS: Using a between-subjects design, 49 participants were allocated to receive either anodal tDCS (N = 16), high-frequency tRNS + DC-offset (N = 16), or sham stimulation (N = 17) to the left DLPFC. Changes in WM performance were assessed using the Sternberg WM task completed before and 5- and 25-min post-stimulation. Event-related synchronisation/desynchronisation (ERS/ERD) of oscillatory activity was analysed from EEG recorded during WM encoding and maintenance. RESULTS: tRNS induced more pronounced and consistent enhancements in WM accuracy when compared to both tDCS and sham stimulation. Improvements in WM performance following tRNS were accompanied by increased theta ERS and diminished gamma ERD during WM encoding, which were significantly greater than those observed following anodal tDCS or sham stimulation. CONCLUSIONS: These findings demonstrate the potential of tRNS + DC-offset to modulate cognitive and electrophysiological measures of WM and raise the possibility that tRNS + DC-offset may be more effective and reliable than tDCS for enhancing WM performance in healthy individuals.

Reduction in size of the myotonic dystrophy trinucleotide repeat mutation during transmission.

Myotonic dystrophy (DM) is an autosomal-dominant disorder that affects 1 in 8000 individuals. Amplification of an unstable trinucleotide CTG repeat, located within the 3' untranslated region of a gene, correlates with a more severe DM phenotype. In three cases, the number of CTG repeats was reduced during the transmission of the DM allele; in one of these cases, the number was reduced to within the normal range and correlated at least with a delay in the onset of clinical signs of DM. Haplotype data of six polymorphic markers in the DM gene region indicate that, in this latter case, two stretches of the affected chromosome had been exchanged with that region of the wild-type chromosome.

Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene.

Myotonic dystrophy (DM) is the most common inherited neuromuscular disease in adults, with a global incidence of 1 in 8000 individuals. DM is an autosomal dominant, multisystemic disorder characterized primarily by myotonia and progressive muscle weakness. Genomic and complementary DNA probes that map to a 10-kilobase Eco RI genomic fragment from human chromosome 19q13.3 have been used to detect a variable length polymorphism in individuals with DM. Increases in the size of the allele in patients with DM are now shown to be due to an increased number of trinucleotide CTG repeats in the 3' untranslated region of a DM candidate gene. An increase in the severity of the disease in successive generations (genetic anticipation) is accompanied by an increase in the number of trinucleotide repeats. Nearly all cases of DM (98 percent or 253 of 258 individuals) displayed expansion of the CTG repeat region. These results suggest that DM is primarily caused by mutations that generate an amplification of a specific CTG repeat.

Psychosocial adjustment to multiple sclerosis: exploration of identity redefinition.

PURPOSE: As multiple sclerosis (MS) often occurs in the prime of life and is unpredictable in nature, there is likely to be a strong psychological effect, with changes in values and beliefs and how the individual sees him or her self. This article presents the findings of a focus group study which aimed to explore the subjective experiences of living with, and adjusting to, MS. METHOD: Seven individuals who had been diagnosed with MS for at least 5 years reflected on their reactions to being diagnosed, how they cope with the day to day challenges of the disease, and the changes that they have experienced. Data were transcribed verbatim and analysed using interpretative phenomenological analysis. RESULTS: Diagnosis was met with negative reactions: denial, concealment and diminished confidence. However, the majority reported that, over time, there were positive changes in terms of their values and outlook. It would appear that the functional difficulties and psychological challenges, such as uncertainty and depression, are ameliorated to some extent by an increased appreciation for life and spirituality. CONCLUSIONS: The findings provide insight into the psychological process of identity redefinition associated with adjusting to MS. Given this, interventions should target role/identity re-examination to assist individuals with MS in better managing the disease and enjoying life.

Neurobiological effects of transcranial direct current stimulation in younger adults, older adults and mild cognitive impairment.

Transcranial direct current stimulation (tDCS) has been investigated as a way to improve motor and cognitive functioning, with largely variable results. Currently, relatively little is known about the neurobiological effects, and possible drivers of variability, in either healthy or clinical populations. Therefore, this study aimed to characterise the neurobiological effects to tDCS in younger adults, older adults and adults with mild cognitive impairment (MCI), and their relationship to cognitive performance. 20 healthy younger adults, 20 healthy older adults and 9 individuals with MCI participated in the study. All completed neuropsychological tasks and TMS-EEG, prior to and following delivery of 20 min of anodal tDCS to the left dorsolateral prefrontal cortex (DLPFC). EEG was also recorded during the 2-Back working memory task. Following tDCS, younger adults demonstrated alterations in early TMS-Evoked Potentials (TEPs), namely P30 and P60. Both younger and older adults exhibited a larger task-related N250 amplitude after stimulation, with contrasting relationships to cognitive performance. The MCI group showed no change in TEPs or ERPs over time. Comparisons between the groups revealed differences in the change in amplitude of early TEP (P60) and ERP (N100) peaks between younger and older adults. Our findings indicate that tDCS was able to modulate cortical activity in younger and older healthy adults, but in varying ways. These findings suggest that varied response to tDCS may be related to factors such as age and the presence/absence of cognitive impairment, and these factors should be considered when assessing the effectiveness of tDCS in healthy and pathological aging.

Individuals with depression display abnormal modulation of neural oscillatory activity during working memory encoding and maintenance.

PURPOSE: To investigate neural oscillatory activity supporting working memory (WM) processing in depressed individuals and healthy controls. METHODS: Forty-six participants with Major Depressive Disorder (MDD) and 41 healthy controls balanced on age, gender, and WM ability completed a Sternberg verbal WM task with concurrent electroencephalography recording. Oscillatory activity was calculated for upper alpha, theta, and gamma frequency bands during WM encoding and maintenance. RESULTS: WM performance did not differ between groups. When compared to healthy controls, depressed individuals displayed reduced frontal-midline theta power and increased occipital upper alpha power during WM encoding, and reductions in frontal-midline theta power and occipital gamma and upper alpha power during WM maintenance. Higher depression severity was associated with greater reductions upper alpha and gamma power during WM maintenance. CONCLUSIONS: Depressed individuals displayed prominent alterations in oscillatory activity during WM encoding and maintenance, indicating that the neural processes which support WM processing are altered in MDD even when no cognitive impairments are observed.

Differentiating responders and non-responders to rTMS treatment for depression after one week using resting EEG connectivity measures.

BACKGROUND: Non-response to repetitive transcranial magnetic stimulation (rTMS) treatment for depression is costly for both patients and clinics. Simple and cheap methods to predict response would reduce this burden. Resting EEG measures differentiate responders from non-responders, so may have utility for response prediction. METHODS: Fifty patients with treatment resistant depression and 21 controls had resting electroencephalography (EEG) recorded at baseline (BL). Patients underwent 5-8 weeks of rTMS treatment, with EEG recordings repeated at week 1 (W1). Forty-two participants had valid BL and W1 EEG data, and 12 were responders. Responders and non-responders were compared at BL and W1 in measures of theta (4-8 Hz) and alpha (8-13 Hz) power and connectivity, frontal theta cordance and alpha peak frequency. Control group comparisons were made for measures that differed between responders and non-responders. A machine learning algorithm assessed the potential to differentiate responders from non-responders using EEG measures in combination with change in depression scores from BL to W1. RESULTS: Responders showed elevated theta connectivity across BL and W1. No other EEG measures differed between groups. Responders could be distinguished from non-responders with a mean sensitivity of 0.84 (p = 0.001) and specificity of 0.89 (p = 0.002) using cross-validated machine learning classification on the combination of all EEG and mood measures. LIMITATIONS: The low response rate limited our sample size to only 12 responders. CONCLUSION: Resting theta connectivity at BL and W1 differ between responders and non-responders, and show potential for predicting response to rTMS treatment for depression.

Timing in the absence of supraspinal input I: variable, but not fixed, spaced stimulation of the sciatic nerve undermines spinally-mediated instrumental learning.

Rats with complete spinal transections are capable of acquiring a simple instrumentally trained response. If rats receive shock to one hind limb when the limb is extended (controllable shock), the spinal cord will learn to hold the leg in a flexed position that minimizes shock exposure. If shock is delivered irrespective of leg position, subjects do not exhibit an increase in flexion duration and subsequently fail to learn when tested with controllable shock (learning deficit). Just 6 min of variable intermittent shock produces a learning deficit that lasts 24 h. Evidence suggests that the neural mechanisms underlying the learning deficit may be related to those involved in other instances of spinal plasticity (e.g. windup, long-term potentiation). The present paper begins to explore these relations by demonstrating that direct stimulation of the sciatic nerve also impairs instrumental learning. Six minutes of electrical stimulation (mono- or biphasic direct current [DC]) of the sciatic nerve in spinally transected rats produced a voltage-dependent learning deficit that persisted for 24 h (experiments 1-2) and was dependent on C-fiber activation (experiment 7). Exposure to continuous stimulation did not produce a deficit, but intermittent burst or single pulse (as short as 0.1 ms) stimulation (delivered at a frequency of 0.5 Hz) did, irrespective of the pattern (fixed or variable) of stimulus delivery (experiments 3-6, 8). When the duration of stimulation was extended from 6 to 30 min, a surprising result emerged; shocks applied in a random (variable) fashion impaired subsequent learning whereas shocks given in a regular pattern (fixed spacing) did not (experiments 9-10). The results imply that spinal neurons are sensitive to temporal relations and that stimulation at regular intervals can have a restorative effect.

Responders to rTMS for depression show increased fronto-midline theta and theta connectivity compared to non-responders.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression, but only some individuals respond. Predicting response could reduce patient and clinical burden. Neural activity related to working memory (WM) has been related to mood improvements, so may represent a biomarker for response prediction. PRIMARY HYPOTHESES: We expected higher theta and alpha activity in responders compared to non-responders to rTMS. METHODS: Fifty patients with treatment resistant depression and twenty controls performed a WM task while electroencephalography (EEG) was recorded. Patients underwent 5-8 weeks of rTMS treatment, repeating the EEG at week 1 (W1). Of the 39 participants with valid WM-related EEG data from baseline and W1, 10 were responders. Comparisons between responders and non-responders were made at baseline and W1 for measures of theta (4-8 Hz), upper alpha (10-12.5 Hz), and gamma (30-45 Hz) power, connectivity, and theta-gamma coupling. The control group's measures were compared to the depression group's baseline measures separately. RESULTS: Responders showed higher levels of WM-related fronto-midline theta power and theta connectivity compared to non-responders at baseline and W1. Responder's fronto-midline theta power and connectivity was similar to controls. Responders also showed an increase in gamma connectivity from baseline to W1, with a concurrent improvement in mood and WM reaction times. An unbiased combination of all measures provided mean sensitivity of 0.90 at predicting responders and specificity of 0.92 in a predictive machine learning algorithm. CONCLUSION: Baseline and W1 fronto-midline theta power and theta connectivity show good potential for predicting response to rTMS treatment for depression.

Evidence for the improvement of fatigue in fibromyalgia: A 4-week left dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation randomized-controlled trial.

BACKGROUND: Fibromyalgia is a complex chronic disorder with few effective treatments currently available. One promising treatment option is repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique that has shown promise in disorders effecting the central nervous system. METHODS: We assessed the efficacy of a course of high-frequency (10 Hz) left-hemisphere dorsolateral prefrontal cortex (DLPFC) rTMS in 26 patients (14 active; 12 sham) with a diagnosis of fibromyalgia. Participants underwent a double-blind stimulation protocol of daily (Monday-Friday) rTMS sessions over four consecutive weeks (total of 20 sessions; 75 × 4-s 10 Hz trains at 120% resting motor threshold). Assessments were conducted at baseline, 4 weeks and at 1-month follow-up. RESULTS: Using mixed-model analysis we did not identify a group difference for our primary outcome measures. However, we found that patients in the active group compared to sham treatment group had significantly greater improvement in the Physical Fatigue (p = 0.045) and General Fatigue (p = 0.023) scales of the Multidimensional Fatigue Inventory-20 at the 1 month follow-up. In a responder analysis, we also found the active group was significantly more likely (2.84 times) to achieve a minimum 30% improvement in pain intensity ratings. (p = 0.024). CONCLUSIONS: High-frequency rTMS applied daily for 4 weeks to the left DLPFC induces significant relief from fatigue and a greater chance of clinically meaningful improvement in pain intensity in patients with fibromyalgia. These results suggest DLPFC rTMS may be a relevant therapy for fibromyalgia. SIGNIFICANCE: This study provides evidence that 4-weeks of daily rTMS to the left DLPFC is able to improve fatigue in fibromyalgia. This novel finding provides impetus for the further investigation of the utility of TMS approaches for the relief of fatigue, an otherwise difficult-to-treat symptom, in fibromyalgia and related disorders.

Metabolic studies in total parenteral nutrition with lipid in man. Comparison with glucose.

A study was undertaken of patients on a regimen of total parenteral nutrition comparing the nitrogen balance, energy substrates, blood amino acids, immunoreactive insulin, and immunoreactive glucagon levels during the sequential infusion of nonprotein calories as either glucose alone (glucose system) or 83% as Intralipid (Pharmacia Fine Chemicals, Montreal, Canada) and 17% glucose (lipid system). These nonprotein calories were administered with a constant background of amino acids (1 g/kg per day), vitamins, and minerals. Each system was infused for a week at a time and the order of infusion randomized. In some patients whole blood arteriovenous (A-V) levels of amino acids were measured across forearm muscle. During the glucose system there was a significantly higher level of pyruvate, lactate, alanine, and immunoreactive insulin, consistent with glucose being the principal source of energy. In contrast, during the lipid system there was a rise in free fatty acids and ketone bodies with a fall in insulin, suggesting that lipid was now the principal source of energy. Despite these two very diverse metabolic situations the nitrogen balance with both systems was positive to a comparable degree after the establishment of equilibrium. Correspondingly, A-V differences of whole blood amino acid nitrogen showed uptake by muscle to an equivalent degree with both systems. Clinical studies indicated that the lipid system as defined herein could be infused by peripheral vein for up to 43 days with resultant weight gain, elevation of serum proteins, and healing of fistulae. Our studies suggest that for both metabolic and clinical reasons exogenously infused lipid is a suitable source of nonprotein calories.

Psychotropic prescribing patterns among adolescents in Northern Ireland presenting with psychotic symptoms during a 5-year period.

OBJECTIVE: To report new prescriptions of psychotropic medications among adolescents presenting with new onset psychotic symptoms during a 5-year period. METHODS: The Northern Ireland Early Onset Psychosis Study is a naturalistic longitudinal observational study of patients with an early onset first psychotic episode. All patients aged <18 years presenting to specialist mental health services across Northern Ireland with new onset psychotic symptoms between 2001 and 2006 were recruited (n=113). Clinical case notes were analysed retrospectively for details of subsequent treatment with psychotropic medications. RESULTS: A total of 100 patients (88.5%) were prescribed some form of psychotropic medication. Over three-quarters of patients received an antipsychotic as their first medication. Risperidone (45.8%), olanzapine (24.0%) and chlorpromazine (12.5%) were the most commonly prescribed first-line antipsychotic medications. Of a total of 160 antipsychotic prescriptions, 81 (50.6%) were off-label. Prescriptions were most likely to have been deemed off-label owing to medications not being licensed in under-18s (71.6% of off-label prescriptions) but other reasons were medications being used outside licensed age ranges (23.5%) and outside licensed indications (4.9%). CONCLUSIONS: This is the first study examining psychotropic prescribing patterns in a complete sample of all children and adolescents presenting with early onset psychotic episodes in a single geographical area. The observation of risperidone as the most commonly prescribed antipsychotic was in keeping with previous studies in child and adolescent populations. Rates of off-label prescribing were lower than previously observed although our study was the first to investigate off-label prescribing solely in children and adolescents presenting with psychotic symptoms.

Recalibration of the Pseudomonas aeruginosa strain PAO chromosome map in time units using high-frequency-of-recombination donors.

High-frequency-of-recombination donors of P. aeruginosa strain PAO were generated using a temperature-sensitive, replication mutant of the IncP-1 plasmid R68, loaded with the transposon Tn2521. Fourteen donors so isolated mobilized the chromosome in a polarized manner from a number of different transfer origins. The donors were used to construct a time of entry map of the entire chromosome and this was achieved by determining the time of entry of 32 randomly dispersed markers in crosses using nalidixic acid to interrupt chromosome transfer. Analysis of the time of entry data enabled the recalibration of the chromosome map to 75 min.

Neural evidence that conscious awareness of errors is reduced in depression following a traumatic brain injury.

Impaired error awareness is related to poorer outcome following traumatic brain injury (TBI). Error awareness deficits are also found in major depressive disorder (MDD), but have not been examined in the MDD that follows a TBI (TBI-MDD). This study assessed neural activity related to error awareness in TBI-MDD. Four groups completed a response inhibition task while EEG was recorded- healthy controls (N = 15), MDD-only (N = 15), TBI-only (N = 16), and TBI-MDD (N = 12). Error related EEG activity was compared using powerful randomisation statistics that included all electrodes and time points. Participants with TBI-MDD displayed less frontally distributed neural activity, suggesting reduced contribution from frontal generating sources. Neural activity during this time window is thought to reflect conscious awareness of errors. The TBI-only and MDD-only groups did not differ from controls, and early error processing was unaffected, suggesting early error detection is intact.

Perinatal salt intake alters blood pressure and salt balance in hypertensive rats.

Blood pressure and the rate of excretion of an oral salt load were examined in spontaneously hypertensive rats of the Okamoto strain after exposure in utero and during suckling to a high salt (3% NaCl, wt/wt), low salt (0.1%), control salt (0.8%), or high potassium (2.2% KCl, wt/wt) [corrected] maternal diet. After weaning, all offspring were given a diet containing 0.8% NaCl. There were small but significant differences in growth rate among offspring groups over the 60 weeks of observation, with rats exposed to perinatal low salt and high salt diet being lighter than those given control or high potassium diet. There were positive, significant correlations between body weight and blood pressure in all dietary groups at 8 weeks of age but not 16 or 24 weeks. Rats exposed to perinatal low salt diet had significantly lower blood pressures than the other three groups, which had similar blood pressures. Low salt rats also exhibited an exaggerated natriuresis after a single, oral salt load (0.15 M saline, 1% body weight) compared with the other three diet groups, which were not different from each other. High potassium rats had a reduced kaliuresis and diuresis after the salt load when compared with the other three groups. At 60 weeks of age, rats that received perinatal low salt diet had significantly heavier adrenal glands when compared with the other groups, and the high potassium group had significantly elevated plasma renin concentrations. Thus, maternal electrolyte intake during the perinatal phase may alter body fluid homeostasis in genetically susceptible individuals at maturity.