Analgesic efficacy of theta-burst stimulation for postoperative pain.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) may be a relevant method to assist postoperative pain. However, studies to date have only used conventional 10 Hz rTMS and targeted the DLPFC for postoperative pain. A more recent form of rTMS, termed intermittent Theta Burst Stimulation (iTBS), enables to increase cortical excitability in a short period of time. This preliminary double-blind, randomised, sham controlled study was designed to evaluate the efficacy of iTBS in postoperative care across two distinct stimulation targets. METHODS: A group of 45 patients post laparoscopic surgery were randomised to receive a single session of iTBS over either the dorsolateral prefrontal cortex (DLPFC), primary motor cortex (M1), or Sham stimulation (1:1:1 ratio). Outcome measurements were number of pump attempts, total anaesthetic volume used, and self-rated pain experience, assessed at 1 hour, 6 hours, 24 hours, and 48 hours post stimulation. All randomised patients were analysed (n = 15 in each group). RESULTS: Compared to Sham stimulation, DLPFC-iTBS reduced pump attempts at 6 (DLPFC = 0.73 ± 0.88, Sham = 2.36 ± 1.65, P = 0.031), 24 (DLPFC = 1.40 ± 1.24, Sham = 5.03 ± 3.87, P = 0.008), and 48 (DLPFC = 1.47 ± 1.41, Sham = 5.87 ± 4.34, P = 0.014) hours post-surgery, whereby M1 stimulation had no effect. No group effect was observed on total anaesthetics, which was mainly provided through the continuous administration of opioids at a set speed for each group. There was also no group or interaction effect on pain ratings. Pump attempts were positively associated with pain ratings in the DLPFC (r = 0.59, P = 0.02) and M1 (r = 0.56, P = 0.03) stimulation. CONCLUSIONS: Our findings show that iTBS to the DLPFC reduces pump attempts for additional anaesthetics following a laparoscopic surgery. However, reduced pump attempts by DLPFC stimulation did not translate into a significantly smaller volume of total anaesthetic, due to the continuous administration of opioids at a set speed for each group. SIGNIFICANCE: Our findings therefore provide preliminary evidence for iTBS targeting the DLPFC to be used to improve postoperative pain management.

The influence of endogenous estrogen on high-frequency prefrontal transcranial magnetic stimulation.

BACKGROUND: The use of repetitive transcranial magnetic stimulation (rTMS) as both therapeutic and experimental tools has grown enormously over the past decade. However, variability in response to rTMS is one challenge that remains to be solved. Estrogen can impact neural plasticity and may also affect plastic changes following rTMS. The present study investigated whether estrogen levels influence the neurophysiological effects of high-frequency (HF) rTMS in the left dorsolateral prefrontal cortex (DLPFC). HYPOTHESIS: It was hypothesised that individuals with higher endogenous estrogen would demonstrate greater rTMS-induced changes in cortical reactivity. METHODS: 29 healthy adults (15M/14F) received HF-rTMS over left DLPFC. Females attended two sessions, one during a high-estrogen (HE) phase of the menstrual cycle, another during a low-estrogen (LE) phase. Males attended one session. Estrogen level was verified via blood assay. TMS-EEG was used to probe changes in cortical plasticity and comparisons were made using cluster-based permutation statistics and Bayesian analysis. RESULTS: In females, a significant increase in TMS-evoked P60 amplitude, and decrease in N45, N100 and P180 amplitudes was observed during HE. A less pervasive pattern of change was observed during LE. No significant changes in TEPs were seen in males. Between-condition comparisons revealed higher likelihood of the change in N100 and/or P180 being larger in females during HE compared to both females during LE and males. CONCLUSIONS: These preliminary findings indicate that a greater neuroplastic response to prefrontal HF-rTMS is seen in women when estrogen is at its highest compared to men, suggesting that endogenous estrogen levels contribute to variability in response to HF-rTMS.

The influence of endogenous estrogen on transcranial direct current stimulation: A preliminary study.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulatory technique. Responses to tDCS differ substantially between individuals. Sex hormones that modulate cortical excitability, such as estrogen, may contribute to this inter-individual variability. The influence of estrogen on tDCS after-effects has not yet been researched. This study aimed to investigate whether endogenous estrogen levels influence cortical response to tDCS. Data from 15 male and 14 female healthy adults were analyzed. Males completed one experimental session. Females completed two, one during the early follicular phase of the menstrual cycle when estrogen was low, one during the mid-luteal phase when estrogen was high. Each session comprised 15-min of anodal tDCS delivered to the left dorsolateral prefrontal cortex (DLPFC). Response to stimulation was assessed using electroencephalography with DLPFC transcranial magnetic stimulation (TMS) administered before, immediately after, and 20-min after tDCS. Changes in amplitudes of N120 and P200 components of TMS-evoked potentials over time were compared between males, women with low estrogen and women with high estrogen. Blood assays verified estrogen levels. Women with high estrogen demonstrated a significant increase in P200 amplitude at both time points and change over time was greater for the high estrogen group compared with males. No significant differences were observed between males and women with low estrogen, or between women with low and high estrogen. These preliminary results indicate that greater neuroplastic response to DLPFC tDCS is seen in highest compared with lowest estrogen states, suggesting that endogenous estrogen levels contribute to inter-individual variability of tDCS outcomes.

Electroconvulsive therapy (ECT) during pregnancy: quantifying and assessing the electric field strength inside the foetal brain.

Electroconvulsive therapy (ECT) is an effective treatment option for severe mental illness during pregnancy. However, there is little knowledge about the amount of electric field produced inside the foetus, which is important to understand the effects of ECT on the foetal excitable tissues. Thus, in this paper, the electric field strength inside the foetus was computed and compared to the basic restriction of the International Commission for Non-Ionizing Radiation Protection (ICNIRP). A computational human phantom representing a 30-weeks pregnant female, four types of electrode placements and a range of stimulus pulse width (0.25 ms-2 ms) and frequency (10 Hz-140 Hz) were used to compute the electric field inside the foetus. A linear relationship between the maximum electric field inside the foetal brain and the electrode current was derived. The results suggest that, considering the maximum current output, pulse width, and frequency range of constant-current ECT devices, the electric field produced inside the foetal brain is most likely below the ICNIRP basic restriction. This is based on the practical scenario of a 30-weeks foetus with a bottom-up and head-down foetal position and the mother taller than 1.62 m.

Impact of Cannabis Use on Long-Term Remission in Bipolar I and Schizoaffective Disorder.

OBJECTIVE: To investigate the impact of regular cannabis use on long-term remission of mood symptoms in bipolar spectrum disorders. METHODS: The 24-month prospective observational study included patients (n=239) with bipolar I disorder and schizoaffective disorder, bipolar type. Participants were classified as regular cannabis users (three times or more per week) or non-users. The primary outcome measure was the achievement of remission on the evaluations during the 24 months. RESULTS: Of the 234 participants for whom data was available, 25 (10.7%) were regular cannabis users, and the group comprised significantly more males than females. In the total population, cannabis use was significantly associated with decreased likelihood of remission during the 24-month follow-up period. Subgroup analyses showed that cannabis use was significantly associated with lower remission rates on the Hamilton Depression Rating Scale in females (n=139) and patients prescribed mood stabilizers alone (n=151), whereas in males (n=95) and patients prescribed olanzapine and/or a mood stabilizer (n=83), cannabis use was significantly associated with lower remission rates on the Young Mania Rating Scale. Remission rates were lowest in the concurrent cannabis and tobacco smoking group (n=22) followed by the tobacco smoking only group (n=97), and the non-smoker group (n=116). The post-hoc analysis revealed that all remission rates were significantly lower in the concurrent cannabis and the tobacco smoking group compared to the non-smoker group. CONCLUSION: Cannabis use negatively affects the long-term clinical outcome in patients with bipolar spectrum disorders. A comprehensive assessment and integrated management of cannabis use are required to achieve better treatment outcomes for bipolar spectrum disorders.

Treatment and outcomes of an Australian cohort of outpatients with bipolar I or schizoaffective disorder over twenty-four months: implications for clinical practice.

BACKGROUND: The Bipolar Comprehensive Outcomes Study (BCOS) is a 2-year, prospective, non-interventional, observational study designed to explore the clinical and functional outcomes associated with 'real-world' treatment of participants with bipolar I or schizoaffective disorder. All participants received treatment as usual. There was no study medication. METHODS: Participants prescribed either conventional mood stabilizers (CMS; n = 155) alone, or olanzapine with, or without, CMS (olanzapine ± CMS; n = 84) were assessed every 3 months using several measures, including the Young Mania Rating Scale, 21-item Hamilton Depression Rating Scale, Clinical Global Impressions Scale - Bipolar Version, and the EuroQol Instrument. This paper reports 24-month longitudinal clinical, pharmacological, functional, and socioeconomic data. RESULTS: On average, participants were 42 (range 18 to 79) years of age, 58%; were female, and 73%; had a diagnosis of bipolar I. Polypharmacy was the usual approach to pharmacological treatment; participants took a median of 5 different psychotropic medications over the course of the study, and spent a median proportion of time of 100%; of the study on mood stabilizers, 90%; on antipsychotics, 9%; on antidepressants, and 5%; on benzodiazepines/hypnotics. By 24 months, the majority of participants had achieved both symptomatic and syndromal remission of both mania and depression. Symptomatic relapse rates were similar for both the CMS alone (65%;) and the olanzapine ± CMS (61%;) cohorts. CONCLUSIONS: Participants with bipolar I or schizoaffective disorder in this study were receiving complex medication treatments that were often discordant with recommendations made in contemporary major treatment guidelines. The majority of study participants demonstrated some clinical and functional improvements, but not all achieved remission of symptoms or syndrome.

Repetitive transcranial magnetic stimulation and drug addiction.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that is now being tested for its ability to treat addiction. This review discusses current research approaches and results of studies which measured the therapeutic use of rTMS to treat tobacco, alcohol and illicit drug addiction. The research in this area is limited and therefore all studies evaluating the therapeutic use of rTMS in tobacco, alcohol or illicit drug addiction were retained including case studies through NCBI PubMed ( http://www.ncbi.nlm.nih.gov ) and manual searches. A total of eight studies were identified that examined the ability of rTMS to treat tobacco, alcohol and cocaine addiction. The results of this review indicate that rTMS is effective in reducing the level of cravings for smoking, alcohol, and cocaine when applied at high frequencies to the dorsolateral prefrontal cortex (DLPFC). Furthermore, these studies suggest that repeated sessions of high frequency rTMS over the DLPFC may be most effective in reducing the level of smoking and alcohol consumption. Although work in this area is limited, this review indicates that rTMS is a promising modality for treating drug addiction.

Clinical course and analysis of ten fatal cases of clozapine-induced myocarditis and comparison with 66 surviving cases.

BACKGROUND: Fatal clozapine-induced myocarditis has not been investigated systematically. We describe the clinical course of 10 fatal cases of myocarditis with clozapine and identify factors associated with fatality. METHODS: Cases of myocarditis were documented from the patient's medical records and fatal cases also from autopsy reports. RESULTS: The fatal cases of myocarditis occurred 1996-2009 and were diagnosed at autopsy. Before death, three had no symptoms of illness and only three had cardiac-specific diagnostic results. None was investigated by cardiac imaging techniques, and in none was myocarditis suspected before death. Duration of clozapine for the fatal cases was 14-33 days with an outlier at 4.5 months. Only 3 cases had significant coronary artery disease at autopsy. Comparison of these ten cases with 66 non-fatal cases indicated no significant difference in gender, age, smoking status, dose at onset or concomitant sodium valproate. However, obesity (BMI > 30 kg/m2) was significantly more frequent among fatal than non-fatal cases (60% vs. 26%; p < 0.03) and duration of clozapine was significantly longer for fatal cases (20.8 vs. 17.0 days; p < 0.006), after exclusion of one outlier. Creatine kinase (CK) > 1000 U/L was also associated with death (p = 0.0004). CONCLUSIONS: Routine monitoring for myocarditis for the first 4 weeks of clozapine, and discontinuation of clozapine in the presence of evidence consistent with myocarditis may assist to prevent fatalities occurring from early-onset myocarditis. Investigation by cardiac imaging will give a measure of severity and need for intervention. Obesity may increase the risk of mortality and CK > 1000 U/L may indicate life-threatening illness.

Estrogens and men with schizophrenia: is there a case for adjunctive therapy?

Adjunctive use of estrogen therapy has been shown to be effective in enhancing the treatment of schizophrenia in women. In men, consideration of estrogen therapy has been impacted by concerns of feminising side effects, however, clinical trials of the use of estrogen in treating prostate cancer, bone density loss and even aggression and psychosis in dementia or traumatic brain injury, show this to be a safe and effective therapy. The current 14-day randomised placebo-controlled trial in 53 men with schizophrenia was conducted to evaluate the efficacy of 2 mg oral estradiol valerate as an adjunct to atypical antipsychotic treatment. Results demonstrated for estradiol participants a more rapid reduction in general psychopathology that occurred in the context of greater increases in serum estrogen levels and reductions in FSH and testosterone levels. Approximately 28% of estradiol participants did not achieve an increase (at least a 50% from baseline) in serum estrogen suggesting that further research is needed to refine the type, dose and administration route for estrogen therapy in men. Findings do, however, suggest further exploration of a therapeutic role for adjunctive estradiol treatment in men with schizophrenia is warranted.

A prospective study of the impact of smoking on outcomes in bipolar and schizoaffective disorder.

BACKGROUND: Tobacco smoking is more prevalent among people with mental illnesses, including bipolar disorder, than in the general community. Most data are cross-sectional, and there are no prospective trials examining the relationship of smoking to outcome in bipolar disorder. The impact of tobacco smoking on mental health outcomes was investigated in a 24-month, naturalistic, longitudinal study of 240 people with bipolar disorder or schizoaffective disorder. METHOD: Participants were interviewed and data recorded by trained study clinicians at 9 interviews during the study period. RESULTS: Comparisons were made between participants who smoked daily (n = 122) and the remaining study participants (n = 117). During the 24-month study period, the daily smokers had poorer scores on the Clinical Global Impressions-Depression (P = .034) and Clinical Global Impressions-Overall Bipolar (P = .026) scales and had lengthier stays in hospital (P = .012), compared with nonsmokers. LIMITATIONS: Smoking status was determined by self-report. Nicotine dependence was not measured. CONCLUSION: These findings suggest that smoking is associated with poorer mental health outcomes in bipolar and schizoaffective disorder.

Piloting the effective therapeutic dose of adjunctive selective estrogen receptor modulator treatment in postmenopausal women with schizophrenia.

Estrogen treatment may enhance the recovery of schizophrenia in women. However, adverse effects on uterine and breast tissue and other physical side effects may limit the long-term therapeutic use of estrogen. Raloxifene hydrochloride is a selective estrogen receptor modulator that acts as an estrogen antagonist in breast tissue and may have agonistic actions in the brain, potentially offering mental health benefits with few estrogenic side effects. To provide an indication of the potential therapeutic dose for raloxifene hydrochloride in postmenopausal women with schizophrenia, this study pools data from an ongoing randomized controlled trial of adjunctive 120 mg/day oral raloxifene hydrochloride (n=13) versus oral placebo (n=13), with data from a previous pilot study administering 60 mg/day raloxifene hydrochloride (n=9). Analysis of variance found significant interaction effects for total (p=.01) and general (p=.02) Positive and Negative Syndrome Scale (PANSS) symptomatology. Participants randomized to receive 120 mg/day raloxifene hydrochloride experienced a significantly more rapid recovery of total and general psychotic symptoms compared to both 60 mg/day raloxifene hydrochloride and placebo. The demonstrated benefit of adjunctive treatment with 120 mg/day raloxifene hydrochloride offers support for the potential role of this selective estrogen receptor modulator in treating postmenopausal women with schizophrenia.

Estrogen in severe mental illness: a potential new treatment approach.

CONTEXT: Accumulating evidence suggests that estrogens may have therapeutic effects in severe mental illnesses, including schizophrenia, via neuromodulatory and neuroprotective activity. OBJECTIVE: To compare the efficacy of adjunctive transdermal estradiol with that of adjunctive placebo in the treatment of acute psychotic symptoms. DESIGN: Randomized, double-blind study. SETTING: Patients were recruited from inpatient acute hospital wards and outpatient clinics of 2 metropolitan Melbourne general hospitals. PARTICIPANTS: One hundred two women of childbearing age with schizophrenia. All participants were in an acute or chronic phase of their illness; 73 participants were outpatients and the rest were inpatients. Intervention Patients were randomized to receive 100 microg of transdermal estradiol (n = 56) or transdermal placebo (n = 46) for 28 days. MAIN OUTCOME MEASURES: Psychopathological symptoms were assessed weekly with the Positive and Negative Syndrome Scale. RESULTS: The addition of 100 microg of transdermal estradiol significantly reduced positive (P < .05) and general psychopathological (P < .05) symptoms during the 28-day trial period compared with women receiving antipsychotic medication alone. CONCLUSION: Estradiol appears to be a useful treatment for women with schizophrenia and may provide a new adjunctive therapeutic option for severe mental illness. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00206570.

Transcranial magnetic stimulation to understand the pathophysiology and treatment of substance use disorders.

Recent studies support an association between substance use disorders (SUDs) and cortical excitability. Transcranial magnetic stimulation (TMS) is a non-invasive tool that can be used to assess cortical physiological processes (e.g., inhibition, excitation) and has proven to be a useful diagnostic tool in brain disorders associated with alterations in cortical excitability. In this manuscript, we review studies that employ TMS to evaluate cortical excitability in patients with SUDs. Furthermore, we discuss preliminary studies that examine repetitive TMS (rTMS) as a potential treatment for patients with SUDs. Although the use of TMS to evaluate and to treat those individuals with SUDs is in its early stages, these studies reveal significant alterations in both cortical inhibition and excitation. Specifically, elevated cortical inhibition was reported in both cocaine and nicotine dependent individuals, while one study demonstrated an increase in cortical excitability in those who use 3, 4-methylenedioxymethamphetamine (MDMA). Furthermore, three studies examining rTMS as a potential treatment in cocaine and nicotine addiction report decreases in the level of cravings and in the number of cigarettes smoked following rTMS administration to the dorsal lateral prefrontal cortex. Thus, TMS has provided early interesting findings vis à vis cortical excitability in SUDs. Moreover, preliminary evidence suggests that rTMS is efficacious in the treatment of cocaine and nicotine addiction. Further work is needed to enhance our understanding of the altered neurophysiology in SUDs as well as the ways in which rTMS treatment can be directed to optimize treatment.

The use of tDCS and CVS as methods of non-invasive brain stimulation.

Transcranial direct current stimulation (tDCS) and caloric vestibular stimulation (CVS) are safe methods for selectively modulating cortical excitability and activation, respectively, which have recently received increased interest regarding possible clinical applications. tDCS involves the application of low currents to the scalp via cathodal and anodal electrodes and has been shown to affect a range of motor, somatosensory, visual, affective and cognitive functions. Therapeutic effects have been demonstrated in clinical trials of tDCS for a variety of conditions including tinnitus, post-stroke motor deficits, fibromyalgia, depression, epilepsy and Parkinson's disease. Its effects can be modulated by combination with pharmacological treatment and it may influence the efficacy of other neurostimulatory techniques such as transcranial magnetic stimulation. CVS involves irrigating the auditory canal with cold water which induces a temperature gradient across the semicircular canals of the vestibular apparatus. This has been shown in functional brain-imaging studies to result in activation in several contralateral cortical and subcortical brain regions. CVS has also been shown to have effects on a wide range of visual and cognitive phenomena, as well as on post-stroke conditions, mania and chronic pain states. Both these techniques have been shown to modulate a range of brain functions, and display potential as clinical treatments. Importantly, they are both inexpensive relative to other brain stimulation techniques such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS).